1 00:00:05,680 --> 00:01:41,160 >>I'M JULIE, DIVISION DIRECTOR, NHLBI 2 00:01:41,160 --> 00:01:42,400 >>THANK YOU, JULIE. 3 00:01:42,400 --> 00:01:42,960 OKAY. 4 00:01:42,960 --> 00:01:44,560 SO AFTER ALL THE FIRE DRILLS, I 5 00:01:44,560 --> 00:01:46,640 THINK WE'RE ALL PUMPED UP SO 6 00:01:46,640 --> 00:01:48,440 WE'RE READY, WE HAVE A FULL 7 00:01:48,440 --> 00:01:52,680 AGENDA FOR THE NEXT THREE DAYS, 8 00:01:52,680 --> 00:01:55,640 AND I WOULD LIKE TO MAKE SURE 9 00:01:55,640 --> 00:01:57,520 THE CHAIRS OF EACH OF THESE 10 00:01:57,520 --> 00:01:58,600 SESSIONS KEEP TIME FOR THEIR 11 00:01:58,600 --> 00:02:00,240 SPEAKERS. 12 00:02:00,240 --> 00:02:02,760 WE HAVE TIME KEEPERS TO KEEP ALL 13 00:02:02,760 --> 00:02:07,360 OF US ON TIME, AND I DON'T THINK 14 00:02:07,360 --> 00:02:11,320 WE NEED ANY MEETING LOGISTICS AT 15 00:02:11,320 --> 00:02:14,920 THIS POINT, ADD ON THEM TO THE 16 00:02:14,920 --> 00:02:17,760 BREAK TIME. 17 00:02:17,760 --> 00:02:19,600 WE HAVE AN APHERESIS WORKING 18 00:02:19,600 --> 00:02:20,480 GROUP THAT'S WORKING IN THE 19 00:02:20,480 --> 00:02:21,800 AFTERNOON AND WE CAN FILL IN THE 20 00:02:21,800 --> 00:02:23,080 DETAILS DURING THE BREAK TIME. 21 00:02:23,080 --> 00:02:28,120 SO WITHOUT ANY FURTHER ADO, 22 00:02:28,120 --> 00:02:31,760 DELAYS, SO I WILL INTRODUCE OUR 23 00:02:31,760 --> 00:02:34,400 FIRST SYMPOSIUM, CURATIVE 24 00:02:34,400 --> 00:02:35,680 THERAPIES FOR SICKLE CELL 25 00:02:35,680 --> 00:02:41,480 DISEASE, PART 1. 26 00:02:41,480 --> 00:02:43,720 SHARED BY DR. LAKSHMANAN 27 00:02:43,720 --> 00:02:44,520 KRISHNAMURTI FROM YALE AND HE'S 28 00:02:44,520 --> 00:02:45,840 GOING TO INTRODUCE THE REST OF 29 00:02:45,840 --> 00:02:46,400 THE SPEAKER PANEL. 30 00:02:46,400 --> 00:02:52,640 THANK YOU. 31 00:02:52,640 --> 00:02:54,080 >>GOOD MORNING AND 32 00:02:54,080 --> 00:02:55,040 CONGRATULATION ON REACTING 33 00:02:55,040 --> 00:02:57,440 APPROPRIATELY TO THE FIRE DRILL. 34 00:02:57,440 --> 00:02:58,200 I'M LAKSHMANAN KRISHNAMURTI FROM 35 00:02:58,200 --> 00:03:00,000 YALE UNIVERSITY, AND IT'S MY 36 00:03:00,000 --> 00:03:04,040 PLEASURE TO INTRODUCE THE 37 00:03:04,040 --> 00:03:07,480 SYMPOSIUM ON CURATIVE THERAPIES, 38 00:03:07,480 --> 00:03:09,440 PART 1. 39 00:03:09,440 --> 00:03:14,840 >>HI, I'M CO-CHAIRING THE 40 00:03:14,840 --> 00:03:16,280 SESSION WITH KRISH. 41 00:03:16,280 --> 00:03:18,440 >>BY WAY OF INTRODUCTION, WE 42 00:03:18,440 --> 00:03:19,920 HAVE TRIED TO BRING TOGETHER ALL 43 00:03:19,920 --> 00:03:21,320 OF THE WORK THAT'S HAPPENED IN 44 00:03:21,320 --> 00:03:24,360 THE LAST 365 DAYS FROM OUR 45 00:03:24,360 --> 00:03:25,440 TRANSPLANT AND CURATIVE 46 00:03:25,440 --> 00:03:28,400 THERAPIES FOR SICKLE CELL 47 00:03:28,400 --> 00:03:30,040 DISEASE, AND WE HAVE TRIED TO 48 00:03:30,040 --> 00:03:33,760 REFLECT THE DIVERSITY IN TERMS 49 00:03:33,760 --> 00:03:34,960 OF YOUNG INVESTIGATORS AND 50 00:03:34,960 --> 00:03:36,160 SENIOR INVESTIGATORS IN 51 00:03:36,160 --> 00:03:37,600 DIFFERENT INSTITUTIONS TO BRING 52 00:03:37,600 --> 00:03:39,240 TOGETHER THIS SYMPOSIUM AND OVER 53 00:03:39,240 --> 00:03:42,120 TO YOU, BETH. 54 00:03:42,120 --> 00:03:44,800 >>THEY'RE PULLING UP SLIDES FOR 55 00:03:44,800 --> 00:03:46,560 US WITH REVIEW OF OUR AGENDA BUT 56 00:03:46,560 --> 00:03:48,120 IT'S IN THE HANDOUT, SO JUST A 57 00:03:48,120 --> 00:03:49,960 REMINDER FOR SPEAKERS, YOU HAVE 58 00:03:49,960 --> 00:03:51,720 8 MINUTES FOR YOUR PRESENTATIONS 59 00:03:51,720 --> 00:03:52,480 AND 2 MINUTE FOR QUESTIONS IF 60 00:03:52,480 --> 00:03:55,080 THERE'S TIME. 61 00:03:55,080 --> 00:03:58,320 AND SO WITH THAT, AS HE'S 62 00:03:58,320 --> 00:03:59,480 GETTING SLIDES UP I'LL GO AHEAD 63 00:03:59,480 --> 00:04:05,480 AND -- I'M SORRY? 64 00:04:05,480 --> 00:04:08,000 I'LL INTRODUCE OUR FIRST 65 00:04:08,000 --> 00:04:09,520 SPEAKER. 66 00:04:09,520 --> 00:04:11,280 DR. CYNTHIA SINHA IS FROM EMORY 67 00:04:11,280 --> 00:04:12,240 UNIVERSITY AND SHE'LL BE 68 00:04:12,240 --> 00:04:13,560 PRESENTING ON PARENTAL 69 00:04:13,560 --> 00:04:15,960 PERSPECTIVE ON THE RISK OF 70 00:04:15,960 --> 00:04:17,200 INFERTILITY AND FERTILITY 71 00:04:17,200 --> 00:04:18,120 PRESERVATION OPTIONS FOR 72 00:04:18,120 --> 00:04:20,000 CHILDREN AND ADOLESCENTS WITH 73 00:04:20,000 --> 00:04:21,480 SICKLE CELL DISEASE CONSIDERING 74 00:04:21,480 --> 00:04:24,120 TRANSPLANT. 75 00:04:24,120 --> 00:04:26,880 >>GOOD MORNING. 76 00:04:26,880 --> 00:04:28,680 AS DR. STENGER SAID, MY FREN 77 00:04:28,680 --> 00:04:30,680 PREN TAITION IS ENTITLED 78 00:04:30,680 --> 00:04:32,240 PARENTAL PERSPECTIVE ON THE RISK 79 00:04:32,240 --> 00:04:33,520 OF INFERTILITY AND FERTILITY 80 00:04:33,520 --> 00:04:34,560 PRESERVATION OPTIONS FOR 81 00:04:34,560 --> 00:04:35,920 CHILDREN AND ADOLESCENTS WITH 82 00:04:35,920 --> 00:04:40,840 SICKLE CELL DISEASE. 83 00:04:40,840 --> 00:04:42,200 SO YES, WE KNOW THEY'RE 84 00:04:42,200 --> 00:04:43,480 SUCCESSFUL AND THEY DO HAVE SOME 85 00:04:43,480 --> 00:04:44,080 RISK. 86 00:04:44,080 --> 00:04:45,360 JUMP AHEAD REALLY QUICKLY. 87 00:04:45,360 --> 00:04:47,680 WE ALSO KNOW AS A CONDITIONING 88 00:04:47,680 --> 00:04:50,920 REGIMEN, PATIENT ARE EXPOSED TO 89 00:04:50,920 --> 00:04:53,760 CHEMOTHERAPY WHICH RESULTS IN 90 00:04:53,760 --> 00:04:55,880 OVARIAN INSUFFICIENCY IN 89% OF 91 00:04:55,880 --> 00:04:57,400 PEDIATRIC AND ADOLESCENT AGED 92 00:04:57,400 --> 00:04:59,800 FEMALES AND LOW SPERM COUNT. 93 00:04:59,800 --> 00:05:00,680 IN OUR PREVIOUS RESEARCH WE 94 00:05:00,680 --> 00:05:02,200 WANTED TO UNDERSTAND WHAT 95 00:05:02,200 --> 00:05:03,440 MOTIVATED PARENTS AND FAMILIES 96 00:05:03,440 --> 00:05:04,720 TO ACTUALLY WALK THROUGH THE 97 00:05:04,720 --> 00:05:07,000 DOOR AND MEET WITH AN HCT 98 00:05:07,000 --> 00:05:08,240 PHYSICIAN AND WE REALLY FOCUSED 99 00:05:08,240 --> 00:05:10,080 ON SOME OF THEIR MOTIVATIONS AS 100 00:05:10,080 --> 00:05:11,840 DIMINISHED QUALITY OF LIFE, 101 00:05:11,840 --> 00:05:13,440 RECENT COMPLICATIONS, NEED TO 102 00:05:13,440 --> 00:05:15,400 MAKE A MAJOR MEDICAL DECISION 103 00:05:15,400 --> 00:05:17,960 LIKE A CHRONIC BLOOD 104 00:05:17,960 --> 00:05:19,600 TRANSFUSION, AND ALSO CONCERNS 105 00:05:19,600 --> 00:05:21,320 ABOUT FUTURE SEVERE 106 00:05:21,320 --> 00:05:21,880 COMPLICATIONS. 107 00:05:21,880 --> 00:05:23,960 WHILE WE DIDN'T REALLY SEE -- 108 00:05:23,960 --> 00:05:25,280 WHAT WE DIDN'T REALLY SEE WAS 109 00:05:25,280 --> 00:05:27,800 THEIR CONCERN ABOUT WHERE DID 110 00:05:27,800 --> 00:05:29,320 INFERTILITY FALL IN ALL OF THIS, 111 00:05:29,320 --> 00:05:31,080 AND SO AS A KNOWLEDGE GAP, WE 112 00:05:31,080 --> 00:05:33,960 WERE INTERESTED IN LEARNING, DO 113 00:05:33,960 --> 00:05:35,240 PARENTS AND FAMILYS HAVE A 114 00:05:35,240 --> 00:05:36,000 REALISTIC UNDERSTANDING ABOUT 115 00:05:36,000 --> 00:05:38,520 THE RISK OF INFERTILITY AFTER TO 116 00:05:38,520 --> 00:05:40,400 TRANSPLANT OR ARE THEY IN 117 00:05:40,400 --> 00:05:40,800 DENIAL. 118 00:05:40,800 --> 00:05:43,560 WHAT ARE THEIR CAREGIVERS' 119 00:05:43,560 --> 00:05:45,200 PERCEPTION ABOUT FERTILITY 120 00:05:45,200 --> 00:05:46,160 PRESERVATION OPTIONS, WHAT DO 121 00:05:46,160 --> 00:05:47,280 THEY UNDERSTAND, AND AFTER 122 00:05:47,280 --> 00:05:49,680 ATTENDING THE CONSULTATION, HOW 123 00:05:49,680 --> 00:05:51,760 DO THEY PERCEIVE THE RISK OF HCT 124 00:05:51,760 --> 00:05:54,160 AND HOW DOES THIS SPECIFICALLY 125 00:05:54,160 --> 00:05:55,680 FIGURE IN TO THEIR 126 00:05:55,680 --> 00:05:56,480 DECISION-MAKING PROCESS TO MOVE 127 00:05:56,480 --> 00:05:56,880 FORWARD. 128 00:05:56,880 --> 00:06:00,920 THAT'S OUR FO FORMAL RESEARCH 129 00:06:00,920 --> 00:06:02,280 QUESTION, HOW DO CAREGIVERS 130 00:06:02,280 --> 00:06:04,440 PERCEIVE THE RISK OF INFERTILITY 131 00:06:04,440 --> 00:06:07,720 FROM HCT AND HOW HAS THIS RISK 132 00:06:07,720 --> 00:06:08,800 IMPACT THEIR DECISION-MAKING. 133 00:06:08,800 --> 00:06:15,480 IT'S AN IRB-APPROVED STUDY WITH 134 00:06:15,480 --> 00:06:16,440 CONSENT OBTAINED AFTER THE 135 00:06:16,440 --> 00:06:18,760 PRIMARY CAREGIVER HAD ATTENDED A 136 00:06:18,760 --> 00:06:19,440 CONSULTATION, QUALITATIVE 137 00:06:19,440 --> 00:06:20,960 INTERVIEWS WERE CONDUCTED WITH 138 00:06:20,960 --> 00:06:22,440 THESE PRIMARY CAREGIVERS FROM 139 00:06:22,440 --> 00:06:24,320 ONE SINGLE HCT CH CLINIC IN 140 00:06:24,320 --> 00:06:25,520 ATLANTA, ALL INTERVIEWS WERE 141 00:06:25,520 --> 00:06:27,280 OVER THE PHONE USING A SEMI 142 00:06:27,280 --> 00:06:28,280 STRUCTURED INTERVIEW GUIDE AND 143 00:06:28,280 --> 00:06:29,920 ALL AUDIO RECORDINGS OF THE 144 00:06:29,920 --> 00:06:31,600 INTERVIEW WERE TRANSCRIBED VER 145 00:06:31,600 --> 00:06:35,960 BAY TI. WE HAD 19 FE FEMALE ADUS 146 00:06:35,960 --> 00:06:38,240 ALL IDENTIFIED AS AFRICAN 147 00:06:38,240 --> 00:06:41,520 AMERICAN, CAREGIVER RANGE FROM 148 00:06:41,520 --> 00:06:43,160 25 TO 506 YEARS OLD WITH A 149 00:06:43,160 --> 00:06:46,000 MEDIAN AGE OF 39 AND PATIENT 150 00:06:46,000 --> 00:06:48,200 FROM 2 TO 18 YEARS WITH MEDIAN 151 00:06:48,200 --> 00:06:50,920 AGE OF 10 YEARS AND LINE BY LINE 152 00:06:50,920 --> 00:06:52,440 ANALYSIS WAS CONDUCTED TO 153 00:06:52,440 --> 00:06:53,520 IDENTIFY THE PARTICIPANT 154 00:06:53,520 --> 00:06:57,160 RESPONSE GROUPED THEM TOGETHER S 155 00:06:57,160 --> 00:06:59,800 ALL WERE ACCEPTED REGARDLESS OF 156 00:06:59,800 --> 00:07:01,200 AVAILABILITY OF DONOR OR 157 00:07:01,200 --> 00:07:02,240 ELIGIBILITY FOR AN OPEN CLINICAL 158 00:07:02,240 --> 00:07:02,880 TRIAL. 159 00:07:02,880 --> 00:07:04,520 AFTER ATTENDING THE HCT 160 00:07:04,520 --> 00:07:05,800 CONSULTATION AT THIS PARTICULAR 161 00:07:05,800 --> 00:07:07,760 CLINIC, FAMILIES MAY SCHEDULE 162 00:07:07,760 --> 00:07:09,640 FERTILITY CONSULTATION 163 00:07:09,640 --> 00:07:11,800 REGARDLESS OF STATUS OR 164 00:07:11,800 --> 00:07:15,200 SCHEDULING OF THE HCT PROCEDURE. 165 00:07:15,200 --> 00:07:17,400 NOW, IDEALLY WE WANTED FAMILIES 166 00:07:17,400 --> 00:07:19,800 TO HAVE ATTENDED BOTH 167 00:07:19,800 --> 00:07:21,120 CONSULTATIONS, BUT JUST WITH THE 168 00:07:21,120 --> 00:07:25,040 SCHEDULING AND THE SAMPLE SIZE, 169 00:07:25,040 --> 00:07:28,440 IF THEY HAD ATTENDED THE HCT 170 00:07:28,440 --> 00:07:29,520 CONSULTATION, I REACHED OUT TO 171 00:07:29,520 --> 00:07:29,760 THEM. 172 00:07:29,760 --> 00:07:32,280 SO THIS IS A QUICK TABLE TO SAY 173 00:07:32,280 --> 00:07:34,560 THAT APPROXIMATELY HALF THE 174 00:07:34,560 --> 00:07:37,840 SAMPLE, ABOUT 10, HAD NOT 175 00:07:37,840 --> 00:07:40,360 ATTENDED THE CONSULTATION AT 176 00:07:40,360 --> 00:07:41,800 ALL, AND NINE HAD. 177 00:07:41,800 --> 00:07:45,520 AND OF THOSE, THAT WERE GOING TO 178 00:07:45,520 --> 00:07:48,560 MOVE FORWARD TRANSPLANT, FOUR 179 00:07:48,560 --> 00:07:51,400 SAID THEY WOULD SEEK FERTILITY 180 00:07:51,400 --> 00:07:52,720 PRESERVATION OPTIONS, TWO WERE 181 00:07:52,720 --> 00:07:53,800 CONSIDERING AND THREE HAD SAID 182 00:07:53,800 --> 00:07:56,000 NO. 183 00:07:56,000 --> 00:07:57,240 CAREGIVER DEMOGRAPHICS QUICKLY, 184 00:07:57,240 --> 00:08:02,040 THE MAJORITY REPORTED THEY WERE 185 00:08:02,040 --> 00:08:03,120 MARRIED AND HAD SOME COLLEGE 186 00:08:03,120 --> 00:08:05,520 WITH A RATHER HIGH 187 00:08:05,520 --> 00:08:06,760 POSTGRADUATE DEGREE IN THE 188 00:08:06,760 --> 00:08:07,280 SAMPLE. 189 00:08:07,280 --> 00:08:11,440 EMPLOYMENT STATUS , ABOUT HALF 190 00:08:11,440 --> 00:08:12,600 EMPLOYED FULL TIME AND HALF NOT 191 00:08:12,600 --> 00:08:12,960 EMPLOYED. 192 00:08:12,960 --> 00:08:15,920 LASTLY THE TYPE OF INSURANCE, 193 00:08:15,920 --> 00:08:18,160 THE MAJORITY HAD UTILIZED PUBLIC 194 00:08:18,160 --> 00:08:18,560 HEALTH INSURANCE. 195 00:08:18,560 --> 00:08:20,120 SO WHAT WE FOUND IS THAT MOTHERS 196 00:08:20,120 --> 00:08:24,000 WERE WORRIED ABOUT DEATH AND 197 00:08:24,000 --> 00:08:25,320 GVHD FROM THE TRANSPLANT MORE SO 198 00:08:25,320 --> 00:08:27,080 THAN THE RISK OF INFERTILITY AND 199 00:08:27,080 --> 00:08:28,600 THAT THEY DID HAVE A REALISTIC 200 00:08:28,600 --> 00:08:30,560 UNDERSTANDING OF THE RISK OF 201 00:08:30,560 --> 00:08:31,560 INFERTILITY AFTER TRANSPLANT AND 202 00:08:31,560 --> 00:08:33,440 THEY TOOK THAT INTO 203 00:08:33,440 --> 00:08:33,840 CONSIDERATION. 204 00:08:33,840 --> 00:08:35,280 THEY WEREN'T IN DENIAL BUT THEY 205 00:08:35,280 --> 00:08:37,560 WERE HOPEFUL. 206 00:08:37,560 --> 00:08:41,480 LASTLY, FOR CA CAREGIVERS WHO HA 207 00:08:41,480 --> 00:08:42,840 VERY YOUNG CHILD, IT WAS SORT OF 208 00:08:42,840 --> 00:08:44,920 A TRIFECTA BARRIER TO SEEKING 209 00:08:44,920 --> 00:08:45,600 FERTILITY PRESERVATIONS. 210 00:08:45,600 --> 00:08:47,960 THAT IS, WE FOUND THEY DIDN'T 211 00:08:47,960 --> 00:08:49,160 IMMEDIATELY EMBRACE THIS OPTION 212 00:08:49,160 --> 00:08:51,680 SO IT WAS PRESENTED TO THEM. 213 00:08:51,680 --> 00:08:53,560 FIRST IT WAS THE INCONVENIENCE 214 00:08:53,560 --> 00:08:54,480 AT THE TIME OF THE INTERVIEW, 215 00:08:54,480 --> 00:08:55,800 THE TIME OF INCONVENIENCE TO 216 00:08:55,800 --> 00:08:58,160 TRAVEL TO ANOTHER STATE FOR THE 217 00:08:58,160 --> 00:08:59,800 PROCEDURE AND IT WAS A PROCEDURE 218 00:08:59,800 --> 00:09:01,440 THEY CONSIDERED VERY INVASIVE 219 00:09:01,440 --> 00:09:06,320 PRIOR TO THE WHOLE TRAN FRAN TRT 220 00:09:06,320 --> 00:09:08,280 PROCEDURE AND LASTLY THE 221 00:09:08,280 --> 00:09:09,720 CAREGIVERS PERCEPTION WE FOUND 222 00:09:09,720 --> 00:09:11,480 IS THEY LACKED CONFIDENCE IN 223 00:09:11,480 --> 00:09:13,320 FERTILITY PRESERVATION IN THESE 224 00:09:13,320 --> 00:09:14,680 PATIENTS THAT THE TISSUE TAKEN 225 00:09:14,680 --> 00:09:16,280 TODAY WOULD PRODUCE A BIOLOGICAL 226 00:09:16,280 --> 00:09:17,280 CHILD IN THE FUTURE. 227 00:09:17,280 --> 00:09:18,360 AND SOME QUOTES I'LL JUST GO 228 00:09:18,360 --> 00:09:20,320 THROUGH VERY QUICKLY. 229 00:09:20,320 --> 00:09:22,080 IN REGARDS TO BEING WORRIED 230 00:09:22,080 --> 00:09:26,000 ABOUT GVHD FROM HCT. 231 00:09:26,000 --> 00:09:29,120 THE MAIN TWO WORRIES FOR ME IS 232 00:09:29,120 --> 00:09:30,160 INFERTILITY AND GVHD. 233 00:09:30,160 --> 00:09:32,920 IF I HAD TO PICK BETWEEN THE 234 00:09:32,920 --> 00:09:34,440 TWO, GVHD SCARES ME MORE THAN 235 00:09:34,440 --> 00:09:35,560 PROBABLY LIFE ITSELF. 236 00:09:35,560 --> 00:09:36,520 THAT'S RATHER STRONG. 237 00:09:36,520 --> 00:09:38,040 THEY HAVE A REALISTIC 238 00:09:38,040 --> 00:09:39,680 UNDERSTANDING OF THE RISK OF 239 00:09:39,680 --> 00:09:40,120 INFERTILITY. 240 00:09:40,120 --> 00:09:41,640 I BELIEVE IT IS ALMOST ABSOLUTE 241 00:09:41,640 --> 00:09:44,240 FOR BOYS, BASED OFF WHAT THE 242 00:09:44,240 --> 00:09:45,160 PHYSICIAN SAID BECAUSE WE ASKED 243 00:09:45,160 --> 00:09:46,680 A BUNCH OF QUESTIONS ABOUT THAT. 244 00:09:46,680 --> 00:09:48,480 I ASKED IF THEY HAD ANY STUDIES 245 00:09:48,480 --> 00:09:51,240 OR KNEW OF ANY STUDIES WHERE WAS 246 00:09:51,240 --> 00:09:52,360 SPONTANEOUS BIRTHS FROM THE 247 00:09:52,360 --> 00:09:52,920 MALES. 248 00:09:52,920 --> 00:09:53,920 THE PHYSICIAN TALKING ABOUT 249 00:09:53,920 --> 00:09:56,120 THERE WERE SPONTANEOUS BIRTHS 250 00:09:56,120 --> 00:09:57,200 WITH SOME OF THE FEMALE, YOU 251 00:09:57,200 --> 00:10:00,040 KNOW, SO I KIND OF HAD TO GRIEVE 252 00:10:00,040 --> 00:10:02,000 THE THOUGHT OF NOT HAVING 253 00:10:02,000 --> 00:10:03,000 GRANDCHILDREN, AT LEAST NOT FROM 254 00:10:03,000 --> 00:10:03,200 HIM. 255 00:10:03,200 --> 00:10:06,720 SO YOU CAN SEE SHE'S HOPEFUL BUT 256 00:10:06,720 --> 00:10:07,800 SHE'S ALSO REALISTIC. 257 00:10:07,800 --> 00:10:11,720 AGAIN WITH THE BARRIERS TO THE 258 00:10:11,720 --> 00:10:14,160 PREBPREPUBESCENT CHILDREN AND 259 00:10:14,160 --> 00:10:15,160 SEEKING FERTILITY PRESERVATION, 260 00:10:15,160 --> 00:10:16,320 IN TERMS OF THEM REMOVING SOME 261 00:10:16,320 --> 00:10:20,200 OF HIS CELLS IN THE FUTURE, THET 262 00:10:20,200 --> 00:10:21,160 YET SO THERE'S THE POSSIBILITY 263 00:10:21,160 --> 00:10:22,400 OF HIM NOT BEING ABLE TO HAVE 264 00:10:22,400 --> 00:10:23,200 CHILDREN. 265 00:10:23,200 --> 00:10:24,480 FOR ONE, WE DON'T WANT HER TO 266 00:10:24,480 --> 00:10:26,120 HAVE SURGERY TWO TIMES. 267 00:10:26,120 --> 00:10:27,600 ANOTHER REASON, THE PHYSICIAN 268 00:10:27,600 --> 00:10:29,760 WAS TELLING US THAT IT WASN'T -- 269 00:10:29,760 --> 00:10:31,920 IT WAS STILL LIKE A STUDY, SO IT 270 00:10:31,920 --> 00:10:33,240 WASN'T 100% SURE IT WAS GOING TO 271 00:10:33,240 --> 00:10:34,080 WORK. 272 00:10:34,080 --> 00:10:37,040 NOW WITH AD ADOLESCENT BOYS, ITS 273 00:10:37,040 --> 00:10:38,680 A RESISTANCE TO FERTILITY 274 00:10:38,680 --> 00:10:39,000 PRESERVATION. 275 00:10:39,000 --> 00:10:41,080 SO EVEN IF THE FAMILY HAD NOT 276 00:10:41,080 --> 00:10:44,080 MET WITH A FERTILITY TEAM, AS 277 00:10:44,080 --> 00:10:47,640 YOU KNOW, SPE SPERM BANKING, THT 278 00:10:47,640 --> 00:10:48,960 EXPLANATION WAS PRETTY FORWARD 279 00:10:48,960 --> 00:10:49,920 SO THOSE FAMILIES WOULD TAKE 280 00:10:49,920 --> 00:10:51,880 THAT AWAY FROM THE HCT CONSULT. 281 00:10:51,880 --> 00:10:53,480 HE IS LIKE, MOM, I DON'T WANT NO 282 00:10:53,480 --> 00:10:53,840 CHILDREN. 283 00:10:53,840 --> 00:10:55,000 I'M LIKE, YOU'RE GOING TO WANT 284 00:10:55,000 --> 00:10:56,480 KIDS AND HE'S LIKE, WELL, IF I 285 00:10:56,480 --> 00:10:57,800 DO, THEY SAID I WOULD BE ABLE TO 286 00:10:57,800 --> 00:10:59,040 DO THE SPERM BANK OR SOMETHING. 287 00:10:59,040 --> 00:11:00,440 HE JUST BUST OUT LAUGHING. 288 00:11:00,440 --> 00:11:01,720 HE IS REALLY GOOFY ABOUT IT 289 00:11:01,720 --> 00:11:03,040 RIGHT NOW, HE IS NOT THINKING 290 00:11:03,040 --> 00:11:04,200 ABOUT THAT TYPE OF STUFF. 291 00:11:04,200 --> 00:11:05,840 NOW UNFORTUNATELY, THE FOUR 292 00:11:05,840 --> 00:11:07,160 ADOLESCENT GIRLS IN THE STUDY, 293 00:11:07,160 --> 00:11:09,560 THEY HAD NOT BEEN TO THE 294 00:11:09,560 --> 00:11:10,800 FERTILITY CONSULTATION, SO IT 295 00:11:10,800 --> 00:11:12,640 WAS A LITTLE DIFFICULT TO 296 00:11:12,640 --> 00:11:15,680 DISCUSS THAT WITH THEM AS IT 297 00:11:15,680 --> 00:11:18,000 BEING A MORE COMPLEX PROCEDURE. 298 00:11:18,000 --> 00:11:19,840 AND ALSO PARENTS WERE CONCERNED 299 00:11:19,840 --> 00:11:21,320 ABOUT DECISIONAL REGRET LATER 300 00:11:21,320 --> 00:11:22,920 AND WHY THEY DID CONSIDER 301 00:11:22,920 --> 00:11:24,480 FERTILITY PRESERVATION OR 302 00:11:24,480 --> 00:11:25,680 WAITING UNTIL THE CHILD WAS OLD 303 00:11:25,680 --> 00:11:26,720 ENOUGH TO WEIGH IN ON WHETHER OR 304 00:11:26,720 --> 00:11:30,800 NOT THEY WANTED TO PURSUE 305 00:11:30,800 --> 00:11:31,120 TRANSPLANT. 306 00:11:31,120 --> 00:11:32,760 I DON'T WANT HIM TO GET 307 00:11:32,760 --> 00:11:33,200 HOSPITALIZED AGAIN. 308 00:11:33,200 --> 00:11:34,240 THAT HAS BEEN PLAYING THROUGH MY 309 00:11:34,240 --> 00:11:34,440 MIND. 310 00:11:34,440 --> 00:11:35,520 THERE ARE OTHER OPTIONS. 311 00:11:35,520 --> 00:11:38,440 HE STILL HAS OPTIONS TO ADOPT 312 00:11:38,440 --> 00:11:39,880 BUT IS THAT -- YOU KNOW, WHAT IF 313 00:11:39,880 --> 00:11:40,640 HE RESENTS YOU? 314 00:11:40,640 --> 00:11:42,160 SO IN SUMMARY, WE LEARNED THAT 315 00:11:42,160 --> 00:11:45,000 THE RISK OF DEATH AND/OR GVHD IS 316 00:11:45,000 --> 00:11:46,760 CONSIDERED GREATER THAN THE 317 00:11:46,760 --> 00:11:48,480 RISK -- CONSIDERING THE RISK OF 318 00:11:48,480 --> 00:11:49,400 INFERTILITY. 319 00:11:49,400 --> 00:11:51,440 CAREGIVERS OF PREPUBESCENT 320 00:11:51,440 --> 00:11:52,840 CHILDREN WERE NOT IMMEDIATELY 321 00:11:52,840 --> 00:11:54,520 EMBRACING OF FERTILITY 322 00:11:54,520 --> 00:11:55,920 PRESERVATION OPTIONS. 323 00:11:55,920 --> 00:11:57,480 ADOLESCENT MALES MAY NOT FEEL 324 00:11:57,480 --> 00:11:58,560 COMFORTABLE SPERM BANKING OR MAY 325 00:11:58,560 --> 00:12:00,000 NOT FEEL COMFORTABLE THINKING 326 00:12:00,000 --> 00:12:02,480 ABOUT FUTURE FATHERHOOD. 327 00:12:02,480 --> 00:12:03,360 LASTLY, PARENTS ARE CONCERNED 328 00:12:03,360 --> 00:12:06,000 ABOUT DECISIONAL REGRET LATER IN 329 00:12:06,000 --> 00:12:09,200 LIFE WHEN CHILDREN ARE INFERTILE 330 00:12:09,200 --> 00:12:12,680 AS A RESULT OF TRANSPLANT. 331 00:12:12,680 --> 00:12:14,080 FUTURE RESEARCH SHOULD INCLUDE 332 00:12:14,080 --> 00:12:15,320 PATIENTS TO ASCERTAIN THEIR 333 00:12:15,320 --> 00:12:17,480 UNDERSTANDING OF THE RISK OF 334 00:12:17,480 --> 00:12:18,240 INFERTILITY, FUTURE PARENTHOOD 335 00:12:18,240 --> 00:12:20,000 AND FERTILITY PRESERVATION 336 00:12:20,000 --> 00:12:21,760 OPTIONS AND THE INCONVENIENCE 337 00:12:21,760 --> 00:12:24,400 AND INVASIVENESS OF FERTILITY 338 00:12:24,400 --> 00:12:25,360 PRESERVATION PROCEDURES ARE 339 00:12:25,360 --> 00:12:27,000 MAJOR BARRIERS AND FUTURE 340 00:12:27,000 --> 00:12:28,840 RESEARCH MUST AIM AT ADDRESSING 341 00:12:28,840 --> 00:12:29,960 THESE BARRIERS. 342 00:12:29,960 --> 00:12:36,440 THANK YOU. 343 00:12:36,440 --> 00:12:40,000 >>THANK YOU, DR. SINHA, FOR 344 00:12:40,000 --> 00:12:42,960 GETTING YOUR PRESERVATION DONE 345 00:12:42,960 --> 00:12:45,280 IN TIME AFTER STARTING TROUBLES. 346 00:12:45,280 --> 00:12:47,360 ANY QUESTIONS FOR DR. SINHA, 347 00:12:47,360 --> 00:12:48,960 ANYBODY FROM THE AUDIENCE? 348 00:12:48,960 --> 00:12:50,240 LOOKS LIKE YOU DID A REALLY GOOD 349 00:12:50,240 --> 00:12:50,400 JOB. 350 00:12:50,400 --> 00:12:51,800 THANK YOU, CINDY. 351 00:12:51,800 --> 00:12:56,840 OH, THERE IS A QUESTION, SORRY. 352 00:12:56,840 --> 00:13:07,320 INTRODUCE YOURSELF, PLEASE. 353 00:13:18,440 --> 00:13:21,520 >>THAT WAS A RATHER INTERESTING 354 00:13:21,520 --> 00:13:25,000 POINT. 355 00:13:25,000 --> 00:13:25,920 IT WASN'T, REALLY. 356 00:13:25,920 --> 00:13:26,720 THEY DIDN'T UNDERSTAND THAT. 357 00:13:26,720 --> 00:13:28,320 IN FACT, I TRIED TO PROBE TO SEE 358 00:13:28,320 --> 00:13:31,680 IF THEY UNDERSTOOD HOW SICKLE 359 00:13:31,680 --> 00:13:35,000 CELL DISEASE IMPACTS FERTILITY, 360 00:13:35,000 --> 00:13:36,280 WITHOUT A TRANSPLANT, AND THERE 361 00:13:36,280 --> 00:13:39,080 SEEMED TO BE A HUGE KNOWLEDGE 362 00:13:39,080 --> 00:13:39,400 GAB. 363 00:13:39,400 --> 00:13:40,280 IN KEEPING WITH THE TIME, I 364 00:13:40,280 --> 00:13:41,200 DIDN'T HAVE AN OPPORTUNITY TO 365 00:13:41,200 --> 00:13:44,160 SORT OF ENCLOSE THAT, BUT I ONLY 366 00:13:44,160 --> 00:13:45,920 FOUND LIKE TWO PARENTS 367 00:13:45,920 --> 00:13:49,200 UNDERSTOOD THAT HYDROXYURIA MAY 368 00:13:49,200 --> 00:13:52,720 BE ASSOCIATED WITH INFERTILITY 369 00:13:52,720 --> 00:13:56,000 SPRELS PRIOPRISSMM AND OVERALL 370 00:13:56,000 --> 00:13:56,760 DECLINE IN HEALTH BUT THAT WAS 371 00:13:56,760 --> 00:13:58,600 AN INTERESTING POINT THAT MAY 372 00:13:58,600 --> 00:14:00,160 NEED TO BE ADDRESSED A LITTLE 373 00:14:00,160 --> 00:14:01,240 CLEARER IN THE FUTURE, IS THERE 374 00:14:01,240 --> 00:14:03,080 A RUSK OF INFERTILITY FROM 375 00:14:03,080 --> 00:14:04,200 TRANSPLANT, DO THEY UNDERSTAND 376 00:14:04,200 --> 00:14:05,840 THE RISK OF INFERTILITY FROM 377 00:14:05,840 --> 00:14:08,040 SICKLE CELL DISEASE. 378 00:14:08,040 --> 00:14:09,520 >>THANK YOU VERY MUCH, 379 00:14:09,520 --> 00:14:10,080 DR. SINHA. 380 00:14:10,080 --> 00:14:11,320 IT'S MY PLEASURE NOW TO 381 00:14:11,320 --> 00:14:12,840 INTRODUCE OUR NEXT SPEAKER, 382 00:14:12,840 --> 00:14:13,800 DR. MONICA HULBERT FROM 383 00:14:13,800 --> 00:14:15,280 WASHINGTON UNIVERSITY. 384 00:14:15,280 --> 00:14:18,840 AND SHE WILL BE SPEAKING ON THE 385 00:14:18,840 --> 00:14:24,120 NORMALIZATION OF CEREBRAL 386 00:14:24,120 --> 00:14:25,640 HEMODYNAMICS AFTER HSCT IN 387 00:14:25,640 --> 00:14:26,400 CHILDREN WITH SICKLE CELL 388 00:14:26,400 --> 00:14:27,280 DISEASE. 389 00:14:27,280 --> 00:14:27,560 DR. HULBERT. 390 00:14:27,560 --> 00:14:27,920 >>THANK YOU. 391 00:14:27,920 --> 00:14:30,120 THANK YOU FOR THE OPPORTUNITY TO 392 00:14:30,120 --> 00:14:34,600 DISCUSS OUR WORK IN THIS FORUM. 393 00:14:34,600 --> 00:14:35,800 SO WE ALL KNOW SICKLE CELL 394 00:14:35,800 --> 00:14:37,880 DISEASE CAUSES MORE THAN JUST 395 00:14:37,880 --> 00:14:39,280 STROKES. 396 00:14:39,280 --> 00:14:40,840 BESIDES OVERT STROKES AND 397 00:14:40,840 --> 00:14:42,600 ABNORMAL TCDs, THROUGHOUT THE 398 00:14:42,600 --> 00:14:43,640 LIFESPAN THERE'S INCREASING 399 00:14:43,640 --> 00:14:45,200 PREVALENCE OF SILENT STROKE AND 400 00:14:45,200 --> 00:14:46,520 MANY PATIENTS EXPERIENCE 401 00:14:46,520 --> 00:14:47,960 ACADEMIC AND COGNITIVE 402 00:14:47,960 --> 00:14:49,360 IMPAIRMENTS. 403 00:14:49,360 --> 00:14:51,880 SO I WORK WITH A GROUP OF 404 00:14:51,880 --> 00:14:53,640 NEUROLOGISTS AND 405 00:14:53,640 --> 00:14:55,720 NEURORADIOLOGISTS AND 406 00:14:55,720 --> 00:14:57,000 HEMATOLOGISTS TO INVESTIGATE THE 407 00:14:57,000 --> 00:14:58,640 ROLE OF CEREBRAL AUTO REGULATION 408 00:14:58,640 --> 00:15:02,800 IN SICKLE CELL DISEASE. 409 00:15:02,800 --> 00:15:04,600 SO BRIEFLY THIS IS A DYNAMIC 410 00:15:04,600 --> 00:15:06,400 PROCESS THAT MAINTAINS CEREBRAL 411 00:15:06,400 --> 00:15:07,840 OXYGEN DELIVERY AND ACCOMPLISHES 412 00:15:07,840 --> 00:15:09,240 THIS THROUGH DILATION AND 413 00:15:09,240 --> 00:15:10,440 CONSTRICTION OF BLOOD VESSELS TO 414 00:15:10,440 --> 00:15:11,680 CHANGE GLOBAL AND REGIONAL BLOOD 415 00:15:11,680 --> 00:15:13,640 FLOW AND OXYGEN DELIVERY 416 00:15:13,640 --> 00:15:16,160 DEPENDING ON THE BRAIN'S NEEDS. 417 00:15:16,160 --> 00:15:19,000 SO THIS IS AFFECTED BY MANY 418 00:15:19,000 --> 00:15:19,480 DIFFERENT PHYSIOLOGICAL 419 00:15:19,480 --> 00:15:20,880 CONDITIONS. 420 00:15:20,880 --> 00:15:23,360 AND CHIEFLY HEMOGLOBIN AND 421 00:15:23,360 --> 00:15:24,880 OXYGEN SATURATION ARE VERY 422 00:15:24,880 --> 00:15:27,120 IMPORTANT COMPONENTS OF THE 423 00:15:27,120 --> 00:15:28,840 ARTERIAL OXYGEN CONTENT, SO YOU 424 00:15:28,840 --> 00:15:31,040 CAN IMAGINE THAT IN SICKLE CELL 425 00:15:31,040 --> 00:15:32,240 DISEASE, THIS CAN BE 426 00:15:32,240 --> 00:15:33,960 SIGNIFICANTLY IMPAIRED. 427 00:15:33,960 --> 00:15:36,800 AND A STROKE OCCURS WHEN OXYGEN 428 00:15:36,800 --> 00:15:38,680 DELIVERY IS INADEQUATE AND THE 429 00:15:38,680 --> 00:15:40,640 BRAIN IS NOT ABLE TO COMPENSATE. 430 00:15:40,640 --> 00:15:43,280 SO WHAT DO WE KNOW ABOUT 431 00:15:43,280 --> 00:15:44,360 CEREBRAL HEMODYNAMICS IN SICKLE 432 00:15:44,360 --> 00:15:45,400 CELL DISEASE? 433 00:15:45,400 --> 00:15:47,640 CEREBRAL BLOOD FLOW AND OXYGEN 434 00:15:47,640 --> 00:15:49,040 EXTRACTION FRACTION ARE THE 435 00:15:49,040 --> 00:15:50,040 MEASURES MOST COMMONLY 436 00:15:50,040 --> 00:15:50,400 DISCUSSED. 437 00:15:50,400 --> 00:15:54,880 WE KNOW THE THEY ARE GLOBALLY AD 438 00:15:54,880 --> 00:15:55,480 REGIONALLY ELEVATED IN SICKLE 439 00:15:55,480 --> 00:15:56,640 CELL COMPARED WITH SIBLING 440 00:15:56,640 --> 00:15:58,120 CONTROLS, AND THEY CORRELATE IP 441 00:15:58,120 --> 00:16:00,360 VERSELY WITH ANEMIA. 442 00:16:00,360 --> 00:16:01,760 SO THE MORE ANEMIC THE PATIENT 443 00:16:01,760 --> 00:16:06,040 IS, THE HIGHER THEIR CBF AND OEF 444 00:16:06,040 --> 00:16:06,640 ELEVATIONS. 445 00:16:06,640 --> 00:16:07,760 BOTH MEASURES WE HAVE 446 00:16:07,760 --> 00:16:08,960 DEMONSTRATED IMPROVE WITHIN 24 447 00:16:08,960 --> 00:16:10,520 HOURS AFTER A TRANSFUSION, SO 448 00:16:10,520 --> 00:16:13,480 WHEN WE IMPROVE THEIR HEMOGLOBIN 449 00:16:13,480 --> 00:16:15,640 ACUTELY, THEN THE STRESS ON 450 00:16:15,640 --> 00:16:18,720 THEIR BRAIN IMPROVES A BIT. 451 00:16:18,720 --> 00:16:20,600 AND OUR GROUP HAS ALSO 452 00:16:20,600 --> 00:16:22,640 IDENTIFIED AN AREA OF EXTREME 453 00:16:22,640 --> 00:16:25,080 OXYGEN EXTRACTION ELEVATION IN 454 00:16:25,080 --> 00:16:26,600 THE PERIVENTRICULAR WHITE MATTER 455 00:16:26,600 --> 00:16:28,720 WITH COINCIDES WITH A LOW -- A 456 00:16:28,720 --> 00:16:30,280 REGION OF VERY LOW CEREBRAL 457 00:16:30,280 --> 00:16:31,720 BLOOD FLOW, THE WATERSHED 458 00:16:31,720 --> 00:16:32,720 REGION, AND ALSO COINCIDES WITH 459 00:16:32,720 --> 00:16:36,000 THE HIGHEST DENSITY OF SILENT 460 00:16:36,000 --> 00:16:36,880 STROKES. 461 00:16:36,880 --> 00:16:38,760 SO ONE OF MY COLLEAGUES, 462 00:16:38,760 --> 00:16:39,800 DR. MELANIE FIELDS, PUBLISHED 463 00:16:39,800 --> 00:16:42,560 THIS PAPER DEMONSTRATING THAT 464 00:16:42,560 --> 00:16:44,840 THE AMOUNT OF BRAIN TISSUE AT 465 00:16:44,840 --> 00:16:46,400 HIGHEST RISK WITH THE MOST 466 00:16:46,400 --> 00:16:49,200 ELEVATED OXYGEN EXTRACTION 467 00:16:49,200 --> 00:16:50,840 FRACTION DECREASES WITH 468 00:16:50,840 --> 00:16:52,960 INCREASING INTENSITY OF THERAPY. 469 00:16:52,960 --> 00:16:55,440 SO PATIENTS ON THE LEFT WITH NO 470 00:16:55,440 --> 00:16:56,880 THERAPY HAVE A VERY HIGH VOLUME 471 00:16:56,880 --> 00:17:00,160 OF BRAIN TISSUE IN THAT 472 00:17:00,160 --> 00:17:00,880 PERIVENTRICULAR WHITE MATTER 473 00:17:00,880 --> 00:17:02,120 REGION WHERE IS WHERE MOST 474 00:17:02,120 --> 00:17:02,880 SILENT STROKES OCCUR. 475 00:17:02,880 --> 00:17:05,000 THAT APPEARS TO BE AT HIGHEST 476 00:17:05,000 --> 00:17:05,520 RISK. 477 00:17:05,520 --> 00:17:08,600 THOSE ON HYDROXYUREA HAVE AN 478 00:17:08,600 --> 00:17:09,920 IMPROVED AREA BUT THERE'S STILL 479 00:17:09,920 --> 00:17:11,440 SOME THAT DOES APPEAR TO BE AT 480 00:17:11,440 --> 00:17:13,080 HIGH RISK AND THOSE ON 481 00:17:13,080 --> 00:17:14,360 TRANSFUSION THERAPY HAVE A MUCH 482 00:17:14,360 --> 00:17:15,800 IMPROVED AMOUNT OF BRAIN TISSUE 483 00:17:15,800 --> 00:17:18,400 WITH EXTREME OEF ELEVATION. 484 00:17:18,400 --> 00:17:21,920 SO NATURALLY WE WANTED TO 485 00:17:21,920 --> 00:17:25,440 INVESTIGATE THE CHANGES IN 486 00:17:25,440 --> 00:17:27,480 CEREBRAL BLOOD FLOW AND OXYGEN 487 00:17:27,480 --> 00:17:29,480 EXTRACTION FRACTION THAT HAPPEN 488 00:17:29,480 --> 00:17:30,440 AFTER A TRANSPLANT. 489 00:17:30,440 --> 00:17:34,280 SO WE ENROLLED 10 SUBJECTS WITH 490 00:17:34,280 --> 00:17:35,280 SICKLE CELL DISEASE WITH AN 491 00:17:35,280 --> 00:17:36,440 IMAGE BEFORE AND AFTER 492 00:17:36,440 --> 00:17:36,720 TRANSPLANT. 493 00:17:36,720 --> 00:17:41,160 SEVEN OF THEM HAD HEMOGLOBIN SS 494 00:17:41,160 --> 00:17:45,680 AND THREE HAD HEMOGLOBIN S BETA 495 00:17:45,680 --> 00:17:47,960 PLUS THALASSEMIA. 496 00:17:47,960 --> 00:17:49,280 THEY UNDERWENT MEASURES BEFORE 497 00:17:49,280 --> 00:17:50,720 AND ONE TO TWO YEARS AFTER 498 00:17:50,720 --> 00:17:52,480 TRANSPLANT AND WE COMPARED THEM 499 00:17:52,480 --> 00:17:54,000 WITH 20 CHRONIC TRANSFUSION 500 00:17:54,000 --> 00:17:55,080 RECIPIENTS AND 20 SIBLING 501 00:17:55,080 --> 00:17:58,040 CONTROLS. 502 00:17:58,040 --> 00:18:00,880 SO THE TRANSPLANT PREP REGIMEN 503 00:18:00,880 --> 00:18:10,200 FOR EIGHT OF THE SUBJECTS WAS 504 00:18:10,200 --> 00:18:11,680 ALEMTUZUMAN -- THERE WERE TWO 505 00:18:11,680 --> 00:18:13,520 SUBJECTS WHO WERE IMAGED BEFORE 506 00:18:13,520 --> 00:18:14,760 AND AFTER A SECOND TRANSPLANT 507 00:18:14,760 --> 00:18:15,880 HAVING REJECTED THEIR FIRST 508 00:18:15,880 --> 00:18:17,520 USING THE ABOVE REGIMEN, AND 509 00:18:17,520 --> 00:18:21,360 THEY WERE PREPPED WITH FLEW DARE 510 00:18:21,360 --> 00:18:23,200 BEAN, CYCLOPHOSPHAMIDE AND ATG. 511 00:18:23,200 --> 00:18:24,640 THE TRANSPLANT INDICATIONS, 512 00:18:24,640 --> 00:18:26,240 THREE HAD OVERT STROKES, FIVE 513 00:18:26,240 --> 00:18:28,560 HAD SILENT STROKES, THREE HAD 514 00:18:28,560 --> 00:18:31,240 ABNORMAL TCDs, AND SEVEN HAD 515 00:18:31,240 --> 00:18:33,920 FREQUENT PAIN OR OTHER RECURRENT 516 00:18:33,920 --> 00:18:34,400 VASOOCCLUSIVE EVENTS. 517 00:18:34,400 --> 00:18:36,240 SO YOU CAN SEE SOME PATIENTS HAD 518 00:18:36,240 --> 00:18:39,280 MULTIPLE INDICATIONS. 519 00:18:39,280 --> 00:18:42,120 FORTUNATELY, THERE WERE NO 520 00:18:42,120 --> 00:18:43,080 NEUROLOGICAL COMPLICATIONS 521 00:18:43,080 --> 00:18:44,200 DURING OR AFTER THE TRANSPLANT 522 00:18:44,200 --> 00:18:46,280 AND NO NEW INFARCTIONS 523 00:18:46,280 --> 00:18:48,120 IDENTIFIED ON THEIR MRI POST 524 00:18:48,120 --> 00:18:48,560 TRANSPLANT. 525 00:18:48,560 --> 00:18:52,360 THERE WAS NO HIGH GRADE ACUTE OR 526 00:18:52,360 --> 00:18:52,920 CHRONIC GRAFT-VERSUS-HOST 527 00:18:52,920 --> 00:18:53,160 DISEASE. 528 00:18:53,160 --> 00:18:55,360 SO THESE ARE THE SUBJECTS. 529 00:18:55,360 --> 00:18:57,560 YOU CAN SEE THEIR AGES RANGED 530 00:18:57,560 --> 00:19:01,920 FROM 6 1/2 TO 21.6 YEARS. 531 00:19:01,920 --> 00:19:03,880 SEVEN OF THEM HAD MATCHED 532 00:19:03,880 --> 00:19:07,520 SIBLING DONORS AND THREE HAD 533 00:19:07,520 --> 00:19:09,240 8 OF 8 MATCHED UNRELATED DONORS. 534 00:19:09,240 --> 00:19:11,000 THEY ALL NORMALIZED THEIR 535 00:19:11,000 --> 00:19:13,480 HEMOGLOBIN AND THEIR HEMOGLOBIN 536 00:19:13,480 --> 00:19:15,480 S WAS CONSISTENT WITH THEIR 537 00:19:15,480 --> 00:19:18,320 DONOR AFTER THE TRANSPLANT. 538 00:19:18,320 --> 00:19:20,320 SO OUR MOST IMPORTANT FINDING 539 00:19:20,320 --> 00:19:22,800 WAS THAT CEREBRAL BLOOD FLOW AND 540 00:19:22,800 --> 00:19:23,920 OXYGEN EXTRACTION FRACTION 541 00:19:23,920 --> 00:19:24,560 NORMALIZE AFTER TRANSPLANT. 542 00:19:24,560 --> 00:19:28,440 SO IN THIS GRAPH, YOU CAN SEE 543 00:19:28,440 --> 00:19:29,680 BEFORE THE TRANSPLANT, WHICH IS 544 00:19:29,680 --> 00:19:32,400 GREEN, AND COMPARED TO THE 545 00:19:32,400 --> 00:19:35,280 PATIENT'S THERAPY BEFORE 546 00:19:35,280 --> 00:19:36,480 TRANSFUSION IN RED, THERE WAS NO 547 00:19:36,480 --> 00:19:38,120 SIGNIFICANT DIFFERENCE IN THEIR 548 00:19:38,120 --> 00:19:38,440 CBF. 549 00:19:38,440 --> 00:19:41,160 AFTER THE TRANSPLANT, THE 550 00:19:41,160 --> 00:19:44,240 RECIPIENTS HAD A REDUCTION IN 551 00:19:44,240 --> 00:19:46,640 THEIR CEREBRAL BLOOD FLOW THAT 552 00:19:46,640 --> 00:19:50,360 WAS NOT DWICIALA DISTINGUISHABLM 553 00:19:50,360 --> 00:19:51,680 CONTROLS SO THEY ESSENTIALLY 554 00:19:51,680 --> 00:19:52,760 NORMALIZED TO THE LEVEL OF 555 00:19:52,760 --> 00:19:53,280 CONTROLS. 556 00:19:53,280 --> 00:19:56,040 THEN THIS GRAPH SHOWS THE WHOLE 557 00:19:56,040 --> 00:19:57,560 BRAIN OXYGEN EXTRACTION 558 00:19:57,560 --> 00:19:57,920 FRACTION. 559 00:19:57,920 --> 00:19:59,440 BEFORE THE TRANSPLANT THE 560 00:19:59,440 --> 00:20:00,320 TRANSPLANT RECIPIENTS WERE 561 00:20:00,320 --> 00:20:02,280 SIMILAR TO THE PRE-TRANSFUSION 562 00:20:02,280 --> 00:20:02,760 PATIENTS. 563 00:20:02,760 --> 00:20:04,720 AFTER THE TRANSPLANT, THE 564 00:20:04,720 --> 00:20:06,600 RECIPIENTS HAD NORMALIZED THEIR 565 00:20:06,600 --> 00:20:07,600 OXYGEN EXTRACTION FRACTION AND 566 00:20:07,600 --> 00:20:09,600 IT WAS, AGAIN, NOT DIFFERENT 567 00:20:09,600 --> 00:20:11,600 FROM CONTROLS. 568 00:20:11,600 --> 00:20:14,120 HOWEVER, WITH OEF, ADDITIONALLY 569 00:20:14,120 --> 00:20:15,280 WE WERE ABLE TO IDENTIFY THAT 570 00:20:15,280 --> 00:20:19,280 AFTER THE TRANSPLANT, THE OEF 571 00:20:19,280 --> 00:20:25,440 WAS EVEN LOWER COMPARED TO THE 572 00:20:25,440 --> 00:20:26,440 PATIENTS AFTER A CHRONIC 573 00:20:26,440 --> 00:20:27,200 TRANSFUSION. 574 00:20:27,200 --> 00:20:31,240 SO ESSENTIALLY THE OEF WAS MORE 575 00:20:31,240 --> 00:20:33,760 NORMAL AFTER TRANSPLANT. 576 00:20:33,760 --> 00:20:39,120 AND HERE IS A MAP REPRESENTATION 577 00:20:39,120 --> 00:20:40,320 OF OUR PATIENTS -- AT ONE 578 00:20:40,320 --> 00:20:41,600 PATIENT WHO UNDERWENT 579 00:20:41,600 --> 00:20:41,920 TRANSPLANT. 580 00:20:41,920 --> 00:20:43,400 ON THE LEFT IS A SIBLING CONTROL 581 00:20:43,400 --> 00:20:46,040 WITH NORMAL CBF AND OEF VALUES, 582 00:20:46,040 --> 00:20:48,320 AND THEN YOU CAN SEE THE 583 00:20:48,320 --> 00:20:50,840 PRE-TRANSPLANT STATE FOR THIS 584 00:20:50,840 --> 00:20:52,880 SUBJECT WITH A SIGNIFICANTLY 585 00:20:52,880 --> 00:20:54,880 ELEVATED CBF AND OEF, AND THEN 586 00:20:54,880 --> 00:20:56,080 AFTER TRANSPLANT, THESE VALUES 587 00:20:56,080 --> 00:20:57,600 HAVE NORMALIZED TO BE VERY 588 00:20:57,600 --> 00:21:01,080 SIMILAR TO THE CONTROLS. 589 00:21:01,080 --> 00:21:04,160 SO WE WERE ABLE TO ALSO IDENTIFY 590 00:21:04,160 --> 00:21:05,560 THAT THE PRIMARY DRIVER OF THIS 591 00:21:05,560 --> 00:21:07,360 AT LEAST IN OUR SAMPLE WAS 592 00:21:07,360 --> 00:21:10,160 CORRECTION OF ANEMIA, AND THE 593 00:21:10,160 --> 00:21:12,680 TRAJECTORY OF ANEMIA IMPROVEMENT 594 00:21:12,680 --> 00:21:14,200 STRONGLY WAS CORRELATED WITH THE 595 00:21:14,200 --> 00:21:17,160 CHANGE IN IMPROVEMENT IN OEF. 596 00:21:17,160 --> 00:21:19,040 SO WHEN A PATIENT IS RECEIVING 597 00:21:19,040 --> 00:21:21,040 CHRONIC TRANSFUSION THERAPY, WE 598 00:21:21,040 --> 00:21:22,440 THINK THAT THE REASON FOR THIS 599 00:21:22,440 --> 00:21:24,840 IS THAT THEIR HEMOGLOBIN 600 00:21:24,840 --> 00:21:26,800 FLUCTUATES BETWEEN 1 TO 3 GRAMS 601 00:21:26,800 --> 00:21:28,560 PER DECILITER ON AVERAGE BETWEEN 602 00:21:28,560 --> 00:21:29,960 THEIR TRANSFUSIONS AND THIS DOES 603 00:21:29,960 --> 00:21:31,520 LEAVE THEM AT RISK FOR ACUTE 604 00:21:31,520 --> 00:21:33,480 SICKLE CELL EVENTS THAT COULD 605 00:21:33,480 --> 00:21:36,200 ACUTELY REDUCE OXYGEN DELIVERY 606 00:21:36,200 --> 00:21:37,320 AND REQUIRE CEREBRAL 607 00:21:37,320 --> 00:21:38,280 COMPENSATION AND ALSO PUT THEM 608 00:21:38,280 --> 00:21:40,800 AT RISK FOR STROKES. 609 00:21:40,800 --> 00:21:42,680 HOWEVER, AFTER TRANSPLANT, THE 610 00:21:42,680 --> 00:21:44,320 HEMOGLOBIN STABILIZES AND 611 00:21:44,320 --> 00:21:45,720 NORMALIZES THEIR BLOOD OXYGEN 612 00:21:45,720 --> 00:21:47,480 CONTENT, THUS ALLOWING THE CBF 613 00:21:47,480 --> 00:21:49,440 AND OEF TO RETURN TO NORMAL 614 00:21:49,440 --> 00:21:50,320 RANGES. 615 00:21:50,320 --> 00:21:52,640 WE FOUND THAT OEF WHICH IS SHOWN 616 00:21:52,640 --> 00:21:54,600 HERE HAS A STRONGER CORRELATION 617 00:21:54,600 --> 00:21:56,320 THAN CBF. 618 00:21:56,320 --> 00:21:58,880 AND WE ALSO, INTERESTINGLY, 619 00:21:58,880 --> 00:22:03,880 FOUND THAT HEMATOCRIT CORRELATED 620 00:22:03,880 --> 00:22:09,560 A LITTLE MORE -- THAN HEMOGLOBIN 621 00:22:09,560 --> 00:22:13,360 DID. 622 00:22:13,360 --> 00:22:15,040 CORRELATE IMPROVEMENTS WITH 623 00:22:15,040 --> 00:22:15,920 COGNITION, HEALTH RELATED 624 00:22:15,920 --> 00:22:18,840 QUALITY OF LIFE, FUNCTIONAL 625 00:22:18,840 --> 00:22:20,040 CONNECTIVITY -- THE DIFFERENCES 626 00:22:20,040 --> 00:22:21,880 BETWEEN HEMOGLOBIN AND 627 00:22:21,880 --> 00:22:23,240 HEMATOCRIT I THINK ARE KIND OF 628 00:22:23,240 --> 00:22:24,360 INTRIGUING AND I'D LIKE TO BE 629 00:22:24,360 --> 00:22:25,560 ABLE TO INVESTIGATE THAT MORE. 630 00:22:25,560 --> 00:22:28,040 WE WERE NOT ABLE TO LOOK AT 631 00:22:28,040 --> 00:22:29,880 SPECIFIC TRANSPLANT-RELATED 632 00:22:29,880 --> 00:22:30,320 FACTORS. 633 00:22:30,320 --> 00:22:31,840 SINCE THE SAMPLE SIZE WAS PRETTY 634 00:22:31,840 --> 00:22:36,120 SMALL. 635 00:22:36,120 --> 00:22:38,000 THIS I THINK WOULD BE VERY 636 00:22:38,000 --> 00:22:39,440 INTERESTING TO STUDY INPATIENTS 637 00:22:39,440 --> 00:22:41,480 WHO RECEIVE GENE THERAPY AND 638 00:22:41,480 --> 00:22:43,560 ULTIMATELY AN A REALLY IMPORTANT 639 00:22:43,560 --> 00:22:45,000 QUESTION FOR OUR FIELD IS 640 00:22:45,000 --> 00:22:47,080 WHETHER EARLIER CURATIVE THERAPY 641 00:22:47,080 --> 00:22:48,720 CAN STABILIZE OR EVEN IMPROVE 642 00:22:48,720 --> 00:22:49,560 COGNITION IN KIDS WITH SICKLE 643 00:22:49,560 --> 00:22:50,760 CELL DISEASE. 644 00:22:50,760 --> 00:22:53,080 SO IN CONCLUSION, ANEMIA IS A 645 00:22:53,080 --> 00:22:55,800 MAJOR DRIVER OF NEUROLOGICAL 646 00:22:55,800 --> 00:22:57,680 DISEASE. 647 00:22:57,680 --> 00:22:59,000 HEMODYNAMICS IMPROVE 648 00:22:59,000 --> 00:23:01,080 PROGRESSIVELY WITH INCREASINGLY 649 00:23:01,080 --> 00:23:02,240 INTENSIVE DISEASE-MODIFYING 650 00:23:02,240 --> 00:23:03,480 THERAPY AND WE'VE DEMONSTRATED 651 00:23:03,480 --> 00:23:05,040 THAT WHOLE BRAIN CEREBRAL BLOOD 652 00:23:05,040 --> 00:23:07,960 FLOW AND OXYGEN EJECTION 653 00:23:07,960 --> 00:23:09,280 FRACTION NORMALIZE AFTER 654 00:23:09,280 --> 00:23:09,840 SUCCESSFUL TRANSPLANT. 655 00:23:09,840 --> 00:23:11,280 THESE ARE MY COLLEAGUES AND 656 00:23:11,280 --> 00:23:12,040 COLLABORATORS AND FUNDING 657 00:23:12,040 --> 00:23:13,880 SOURCES. 658 00:23:13,880 --> 00:23:16,520 AND OF COURSE THIS WOULDN'T BE 659 00:23:16,520 --> 00:23:17,720 POSSIBLE WITHOUT THE EAGER 660 00:23:17,720 --> 00:23:18,800 PARTICIPATION OF OUR PATIENTS. 661 00:23:18,800 --> 00:23:23,080 THANK YOU. 662 00:23:23,080 --> 00:23:24,920 >>WE'RE ACTUALLY GOING TO SAVE 663 00:23:24,920 --> 00:23:26,680 QUESTIONS TO THE VERY END NOW SO 664 00:23:26,680 --> 00:23:28,000 WE'LL HAVE THE SPEAKERS AT THE 665 00:23:28,000 --> 00:23:30,800 VERY END OF THE SESSION COME UP 666 00:23:30,800 --> 00:23:32,040 AND TAKE QUESTIONS IF THERE'S 667 00:23:32,040 --> 00:23:32,680 TIME. 668 00:23:32,680 --> 00:23:34,120 OUR NEXT SPEAKER IS DR. NITYA 669 00:23:34,120 --> 00:23:35,440 BAKSHI FROM EMORY UNIVERSITY AND 670 00:23:35,440 --> 00:23:37,200 SHE'LL BE PRESENTING ON 671 00:23:37,200 --> 00:23:38,040 MULTIMODAL PHENOTYPING AND 672 00:23:38,040 --> 00:23:40,760 CORRELATES OF PAIN FOLLOWING HCT 673 00:23:40,760 --> 00:23:42,000 IN CHILDREN WITH SICKLE CELL 674 00:23:42,000 --> 00:23:57,000 DISEASE. 675 00:23:57,000 --> 00:23:59,520 SO THIS WAS AN OBSERVATIONAL 676 00:23:59,520 --> 00:24:00,800 STUDY IN CHILDREN 8 YEARS AND 677 00:24:00,800 --> 00:24:03,200 OLDER WHO WERE ENGLISH-SPEAKING 678 00:24:03,200 --> 00:24:06,480 AND SCHEDULED FOR HEMATOPOIETIC 679 00:24:06,480 --> 00:24:07,920 CELL TRANSPLANT FOR SICKLE CELL 680 00:24:07,920 --> 00:24:08,440 DISEASE. 681 00:24:08,440 --> 00:24:10,120 IN THIS STUDY, WE SOUGHT TO 682 00:24:10,120 --> 00:24:11,400 STUDY THE FEASIBILITY OF 683 00:24:11,400 --> 00:24:13,400 COLLECTING PAIN, 684 00:24:13,400 --> 00:24:14,920 PATIENT-REPORTED OUTCOMES, 685 00:24:14,920 --> 00:24:16,880 HEALTH RELATED QUALITY OF LIFE, 686 00:24:16,880 --> 00:24:18,560 INTERVIEWS, AND EXPERIMENTAL 687 00:24:18,560 --> 00:24:20,160 PAIN SENSITIVITY DATA BEFORE AND 688 00:24:20,160 --> 00:24:21,280 AFTER TRANSPLANT. 689 00:24:21,280 --> 00:24:23,800 AND OUR SECONDARY GOAL WAS TO 690 00:24:23,800 --> 00:24:25,520 COMPARE THESE DATA BEFORE AND 691 00:24:25,520 --> 00:24:29,120 AFTER TRANSPLANT. 692 00:24:29,120 --> 00:24:30,280 SO THESE WERE THE BASELINE 693 00:24:30,280 --> 00:24:32,320 CHARACTERISTICS OF OUR PATIENTS. 694 00:24:32,320 --> 00:24:33,960 OUR AVERAGE AGE WAS 13.5. 695 00:24:33,960 --> 00:24:35,600 THE VAST MAJORITY OF PATIENTS IN 696 00:24:35,600 --> 00:24:38,760 THIS STUDY WERE MALE. 697 00:24:38,760 --> 00:24:41,960 AND THEY HAD FAIRLY HIGH RATES 698 00:24:41,960 --> 00:24:42,960 OF HEALTHCARE UTILIZATION BEFORE 699 00:24:42,960 --> 00:24:43,960 THE TIME THAT THEY WERE 700 00:24:43,960 --> 00:24:45,760 CONSIDERED FOR TRANSPLANT. 701 00:24:45,760 --> 00:24:47,760 ALMOST ALL OF THEM WERE ON SOME 702 00:24:47,760 --> 00:24:49,200 FORM OF DISEASE MODIFYING 703 00:24:49,200 --> 00:24:52,800 THERAPY AND THE VAST MAJORITY OF 704 00:24:52,800 --> 00:24:56,640 THEM HAD A -- DONOR TRANSPLANT. 705 00:24:56,640 --> 00:24:57,920 ALL OF THE PATIENTS IN THE 706 00:24:57,920 --> 00:25:01,080 TRANSPLANT HAD DONOR DERIVED 707 00:25:01,080 --> 00:25:03,080 ERYTHROPOIESIS POST TRANSPLANT 708 00:25:03,080 --> 00:25:05,560 AND TWO HAD CHRONIC GBHD. 709 00:25:05,560 --> 00:25:08,720 SO THIS IS A BRIEF SNAPSHOT OF 710 00:25:08,720 --> 00:25:10,600 HOW MANY PEOPLE WERE ACTUALLY 711 00:25:10,600 --> 00:25:13,160 ABLE TO COMPLETE PROCEDURES AT 712 00:25:13,160 --> 00:25:15,720 EVERY TIME POINT TO REMIND YOU 713 00:25:15,720 --> 00:25:18,600 THE TOTAL SAMPLE WAS 8 PEOPLE. 714 00:25:18,600 --> 00:25:25,200 AND AS YOU CAN SEE, YOU KNOW, 715 00:25:25,200 --> 00:25:26,000 PROCEDURES SUCH AS 716 00:25:26,000 --> 00:25:26,840 QUESTIONNAIRES WERE COMPLETED A 717 00:25:26,840 --> 00:25:28,160 LITTLE MORE FREQUENTLY THAN THE 718 00:25:28,160 --> 00:25:32,880 MORE TIME-INTENSIVE ONES SUCH 719 00:25:32,880 --> 00:25:33,720 AS -- INTERVIEWED. 720 00:25:33,720 --> 00:25:36,800 NOT EVERYBODY WHO SIGNED UP FOR 721 00:25:36,800 --> 00:25:39,440 THE STUDY ALSO SIGNED UP FOR THE 722 00:25:39,440 --> 00:25:40,720 OPTIONAL EXPERIMENTAL PAIN 723 00:25:40,720 --> 00:25:42,720 SENSITIVITY PROCEDURES, BUT YOU 724 00:25:42,720 --> 00:25:45,960 GENERALLY CAN SEE THAT THERE IS 725 00:25:45,960 --> 00:25:47,520 SOME DECLINE OVER TIME IN 726 00:25:47,520 --> 00:25:54,760 COMPLETION OF PROCEDURES. 727 00:25:54,760 --> 00:25:57,920 THIS IS A SNAPSHOT OF INDIVIDUAL 728 00:25:57,920 --> 00:25:59,880 LEVEL OF PAIN REPORTED OUTCOMES 729 00:25:59,880 --> 00:26:01,320 POST TRANSPLANT COMPARED TO 730 00:26:01,320 --> 00:26:01,720 PRETRANSPLANT. 731 00:26:01,720 --> 00:26:03,480 I WANTED TO SHOW THESE FIGURES 732 00:26:03,480 --> 00:26:06,760 TO SHOW YOU THAT THERE IS DOMAIN 733 00:26:06,760 --> 00:26:08,640 LEVEL HETEROGENEITY AND 734 00:26:08,640 --> 00:26:10,920 INDIVIDUAL LEVEL HETEROGENEITY 735 00:26:10,920 --> 00:26:13,120 AND CHANGE IN PATIENT-REPORTED 736 00:26:13,120 --> 00:26:13,880 OUTCOMES AFTER TRANSPLANT. 737 00:26:13,880 --> 00:26:15,960 SO WHILE THERE ARE OVERALL 738 00:26:15,960 --> 00:26:16,840 DECREASES ACROSS GROUPS, YOU 739 00:26:16,840 --> 00:26:18,240 KNOW, THE STORY MAY NOT BE THE 740 00:26:18,240 --> 00:26:21,480 SAME WHEN YOU LOOK AT DATA AT 741 00:26:21,480 --> 00:26:22,400 THE INDIVIDUAL LEVEL. 742 00:26:22,400 --> 00:26:24,480 OVERALL, THOUGH, YOU CAN SEE 743 00:26:24,480 --> 00:26:30,520 PAIN INTENSITY TEND TO 744 00:26:30,520 --> 00:26:31,800 DECREASE -- TENDS TO DECREASE AS 745 00:26:31,800 --> 00:26:36,640 WELL AND SO DOES -- AND A 746 00:26:36,640 --> 00:26:38,840 SIMILAR STORY IS SEEN HERE, THIS 747 00:26:38,840 --> 00:26:41,560 IMPROVEMENT IN PHYSICAL 748 00:26:41,560 --> 00:26:43,400 FUNCTION, REDUCTION IN ANXIETY 749 00:26:43,400 --> 00:26:44,920 AND DEPRESSIVE SYMPTOMS AND 750 00:26:44,920 --> 00:26:46,040 IMPROVEMENT IN PEER 751 00:26:46,040 --> 00:26:50,400 RELATIONSHIPS POST TRANSPLANT. 752 00:26:50,400 --> 00:26:53,040 WHEN MEASURED USING THE PAIN 753 00:26:53,040 --> 00:26:55,760 DIARY, YOU HAVE A MORE GRANULAR 754 00:26:55,760 --> 00:26:57,600 VIEW, AND WE HAD A FAIRLY GOOD 755 00:26:57,600 --> 00:27:01,120 RATE OF DIARY COMPLETION FOR OUR 756 00:27:01,120 --> 00:27:01,560 STUDY. 757 00:27:01,560 --> 00:27:04,240 YOU CAN SEE, THOUGH, AS SHOWN IN 758 00:27:04,240 --> 00:27:05,600 THE SECOND LINE, THE PROPORTION 759 00:27:05,600 --> 00:27:09,400 OF DAYS WITH PAIN REDUCES OVER 760 00:27:09,400 --> 00:27:11,920 TIME, PARTICULARLY AROUND 1 AND 761 00:27:11,920 --> 00:27:13,600 2 YEARS POST TRANSPLANT, AND THE 762 00:27:13,600 --> 00:27:16,080 MEAN DAILY PAIN INTENSITY, WHICH 763 00:27:16,080 --> 00:27:19,840 IS THE THIRD ROLE, YOU CAN ALSO 764 00:27:19,840 --> 00:27:20,800 SEE DECREASES OVER TIME. 765 00:27:20,800 --> 00:27:22,440 THIS IS A SMALL SAMPLE, BUT I 766 00:27:22,440 --> 00:27:24,960 THINK IT JUST SHOWS US THAT EVEN 767 00:27:24,960 --> 00:27:27,240 IF YOU MEASURE WITH A DIFFERENT 768 00:27:27,240 --> 00:27:28,520 INSTRUMENT, THAT IN GENERAL, 769 00:27:28,520 --> 00:27:30,640 WE'RE SHOWING IMPROVEMENT IN 770 00:27:30,640 --> 00:27:34,160 PAIN INTENSITY AND NUMBER OF 771 00:27:34,160 --> 00:27:35,680 DAYS WITH PAIN OVER TIME POST 772 00:27:35,680 --> 00:27:36,360 TRANSPLANT. 773 00:27:36,360 --> 00:27:38,080 I HAVE NOT SHOWN ALL THE DATA ON 774 00:27:38,080 --> 00:27:39,600 CHANGES IN EXPERIMENTAL PAIN 775 00:27:39,600 --> 00:27:40,960 SENSITIVITY, BUT THESE ARE ALL 776 00:27:40,960 --> 00:27:43,000 AVAILABLE AND PUBLISHED IN THE 777 00:27:43,000 --> 00:27:43,280 MANUSCRIPT. 778 00:27:43,280 --> 00:27:46,280 I WANTED TO HIGHLIGHT THE TWO 779 00:27:46,280 --> 00:27:48,680 DOMAINS THAT WE SAW A LITTLE BIT 780 00:27:48,680 --> 00:27:51,200 OF A SIGNAL IN, AS YOU CAN SEE, 781 00:27:51,200 --> 00:27:54,280 IT APPEARS THAT PRESSURE PAIN 782 00:27:54,280 --> 00:27:55,040 THRESHOLD TENDS TO INCREASE OVER 783 00:27:55,040 --> 00:27:55,720 TIME. 784 00:27:55,720 --> 00:27:58,520 THESE ARE, AGAIN, SMALL SAMPLES, 785 00:27:58,520 --> 00:28:00,160 BUT EVEN WITH THESE SMALLER 786 00:28:00,160 --> 00:28:01,720 SAMPLES, WE HAVE REASONABLE 787 00:28:01,720 --> 00:28:05,640 EFFECT SIZES, AND WE CAN SEE THE 788 00:28:05,640 --> 00:28:07,960 PRESSURE PAIN THRESHOLD TENDS TO 789 00:28:07,960 --> 00:28:09,920 INCREASE OVER TIME, WHICH MEANS 790 00:28:09,920 --> 00:28:12,840 PEOPLE ARE LESS SENSITIVE TO 791 00:28:12,840 --> 00:28:16,920 PRESSURE PAIN AND COLD PAIN 792 00:28:16,920 --> 00:28:18,320 THRESHOLD TENDS TO DECREASE 793 00:28:18,320 --> 00:28:21,840 WHERE COLD PAIN IS -- SO THIS 794 00:28:21,840 --> 00:28:25,560 ACTUALLY MEANS THAT PEOPLE ARE 795 00:28:25,560 --> 00:28:27,160 LESS SENSITIVE TO COLD PAIN OVER 796 00:28:27,160 --> 00:28:29,280 TIME. 797 00:28:29,280 --> 00:28:31,080 AND SO THESE WERE THE TWO 798 00:28:31,080 --> 00:28:34,600 DOMAINS THAT WE SAW SOME SIGNAL 799 00:28:34,600 --> 00:28:37,160 IN WHEN WE COMPARED CHILDREN PRE 800 00:28:37,160 --> 00:28:39,880 TO POST TRANSPLANT. 801 00:28:39,880 --> 00:28:41,960 WHEN WE LOOK AT QUALITATIVE 802 00:28:41,960 --> 00:28:43,240 INTERVIEWS, AGAIN, THIS IS JUST 803 00:28:43,240 --> 00:28:46,120 A VERY HIGH LEVEL SUMMARY. 804 00:28:46,120 --> 00:28:49,040 IN GENERAL, OUR TAKEAWAYS WERE 805 00:28:49,040 --> 00:28:50,240 THAT THERE WAS SIGNIFICANT 806 00:28:50,240 --> 00:28:51,360 IMPACT OF PAIN ON QUALITY OF 807 00:28:51,360 --> 00:28:53,880 LIFE PRIOR TO TRANSPLANT IN 808 00:28:53,880 --> 00:28:58,680 PRETTY MUCH EVERY DOMAIN, AND 809 00:28:58,680 --> 00:29:02,640 THAT -- CAN WE DI GO TO THE NEXT 810 00:29:02,640 --> 00:29:07,760 SLIDE, PLEASE? 811 00:29:07,760 --> 00:29:11,040 AND PAIN INFLUENCED -- THERE WAS 812 00:29:11,040 --> 00:29:12,280 SIGNIFICANT IMPACT OF PAIN ON 813 00:29:12,280 --> 00:29:14,200 EVERY ASPECT OF LIFE. 814 00:29:14,200 --> 00:29:16,080 POST TRANSPLANT, PAIN WAS REALLY 815 00:29:16,080 --> 00:29:17,520 INFLUENTIAL IN THE DECISION TO 816 00:29:17,520 --> 00:29:20,120 CONSIDER TRANSPLANT. 817 00:29:20,120 --> 00:29:21,880 PARTICIPANTS AND/OR THEIR PARENT 818 00:29:21,880 --> 00:29:24,160 REPORTED THAT THEY WANTED TO BE 819 00:29:24,160 --> 00:29:26,280 CURED OF OR HAVE NO MORE SICKLE 820 00:29:26,280 --> 00:29:28,240 CELL DISEASE OR RELATED PAIN. 821 00:29:28,240 --> 00:29:30,280 AND POST TRANSPLANT, EVEN THOUGH 822 00:29:30,280 --> 00:29:33,360 OUR SAMPLE WAS SMALL, WE SAW 823 00:29:33,360 --> 00:29:35,320 THAT MOST PARTICIPANTS DID NOT 824 00:29:35,320 --> 00:29:37,720 REPORT SICKLE CELL PAIN AND 825 00:29:37,720 --> 00:29:39,360 IMPORTANTLY, MANY OF THEM 826 00:29:39,360 --> 00:29:40,680 MENTIONED THAT THEY DID NOT HAVE 827 00:29:40,680 --> 00:29:42,760 THE SAME ACTIVITY LIMITATIONS 828 00:29:42,760 --> 00:29:45,200 THAT THEY HAD PRETRANSPLANT, 829 00:29:45,200 --> 00:29:48,120 THEY HAD LESS FATIGUE, MORE 830 00:29:48,120 --> 00:29:51,200 ENERGY, AND OVERALL, THEIR 831 00:29:51,200 --> 00:29:54,040 EXPERIENCE EVEN THOUGH WAS 832 00:29:54,040 --> 00:29:57,200 CAPTURED IN A MORE GRANULAR WAY 833 00:29:57,200 --> 00:29:58,440 USING THESE QUALITATIVE 834 00:29:58,440 --> 00:30:02,680 INTERVIEWS. 835 00:30:02,680 --> 00:30:05,160 SO OUR CONCLUSIONS ARE THAT IT 836 00:30:05,160 --> 00:30:07,600 APPEARS TO BE FEASIBLE TO 837 00:30:07,600 --> 00:30:09,480 CONDUCT MULTIMODAL PAIN 838 00:30:09,480 --> 00:30:10,880 ASSESSMENTS BEFORE AND AFTER 839 00:30:10,880 --> 00:30:12,400 TRANSPLANT, BUT THERE ARE SOME 840 00:30:12,400 --> 00:30:13,760 UNIQUE CHALLENGES. 841 00:30:13,760 --> 00:30:17,680 EVEN IN VERY LARGE CENTERS, IT 842 00:30:17,680 --> 00:30:20,760 IS CHALLENGING TO OFFER 843 00:30:20,760 --> 00:30:22,720 PARTICIPATION TO PARTICIPANTS, 844 00:30:22,720 --> 00:30:24,560 THERE'S A NARROW WINDOW 845 00:30:24,560 --> 00:30:27,840 PRETRANSPLANT IN WHICH TO OFFER 846 00:30:27,840 --> 00:30:28,840 PARTICIPATION. 847 00:30:28,840 --> 00:30:30,440 JUST GIVEN THE INTENSITY OF THE 848 00:30:30,440 --> 00:30:32,720 PROCEDURE OF TRANSPLANT, EVEN 849 00:30:32,720 --> 00:30:36,160 DOING THINGS LIKE SURVEYS MIGHT 850 00:30:36,160 --> 00:30:37,800 BE REALLY BURDENSOME FOR 851 00:30:37,800 --> 00:30:38,240 PARTICIPANTS. 852 00:30:38,240 --> 00:30:39,520 THERE'S A LONG DURATION OF 853 00:30:39,520 --> 00:30:41,960 FOLLOW-UP NEEDED TO STUDY 854 00:30:41,960 --> 00:30:42,520 CHANGES. 855 00:30:42,520 --> 00:30:45,120 THERE IS A RISK OF LOSS TO 856 00:30:45,120 --> 00:30:47,560 FOLLOW-UP, WHICH MAY BE DUE TO 857 00:30:47,560 --> 00:30:50,680 MEDICAL COMPLICATIONS OR JUST 858 00:30:50,680 --> 00:30:52,760 PARTICIPANT BURDEN. 859 00:30:52,760 --> 00:30:54,280 AND THEN OUR DATA SUGGESTS THAT 860 00:30:54,280 --> 00:30:56,600 THERE IS INDIVIDUAL AND 861 00:30:56,600 --> 00:30:58,000 DOMAIN-LEVEL HETEROGENEITY IN 862 00:30:58,000 --> 00:30:59,320 CHANGE IN PROs AFTER 863 00:30:59,320 --> 00:30:59,680 TRANSPLANT. 864 00:30:59,680 --> 00:31:03,280 I THINK STUDYING PROs 865 00:31:03,280 --> 00:31:07,000 SEPARATELY OR DIVIDED BY HCT 866 00:31:07,000 --> 00:31:08,320 PAIN PHENOTYPES COULD PROVIDE 867 00:31:08,320 --> 00:31:13,800 MORE INSIGHT. 868 00:31:13,800 --> 00:31:15,320 AND OUR SAMPLE SIZE WAS SMALL 869 00:31:15,320 --> 00:31:17,400 BUT STILL OUR RESULTS COULD SHED 870 00:31:17,400 --> 00:31:20,440 SOME INSIGHT INTO THE WHOLE 871 00:31:20,440 --> 00:31:23,080 QUESTION OF PAIN AFTER 872 00:31:23,080 --> 00:31:24,040 TRANSPLANT. 873 00:31:24,040 --> 00:31:26,240 I THINK BIGGER STUDIES SUCH AS 874 00:31:26,240 --> 00:31:36,760 THE EXREEN RECENTLY COMPLETED S, 875 00:31:36,760 --> 00:31:37,960 1503, 1505, WILL HELP ANSWER 876 00:31:37,960 --> 00:31:38,960 THIS QUESTION FURTHER. 877 00:31:38,960 --> 00:31:40,200 AND THANK YOU, I'D BE HAPPY TO 878 00:31:40,200 --> 00:31:41,360 TAKE ANY QUESTIONS. 879 00:31:41,360 --> 00:31:43,960 THE LINK TO THE PUBLICATION AND 880 00:31:43,960 --> 00:31:54,400 THE INDEX IS LISTED BELOW. 881 00:31:55,880 --> 00:31:58,520 >>THANK YOU, DR. BAKSHI, FOR 882 00:31:58,520 --> 00:32:01,040 THAT EXCELLENT PRESENTATION ON 883 00:32:01,040 --> 00:32:01,920 PAIN AND PROs. 884 00:32:01,920 --> 00:32:04,560 I WANT TO CONGRATULATE ALL THE 885 00:32:04,560 --> 00:32:06,600 SPEAKERS FOR STAYING ON TIME AND 886 00:32:06,600 --> 00:32:09,800 WE'LL HAVE ENOUGH TIME IN THE 887 00:32:09,800 --> 00:32:13,480 END I'M SURE, SO CONTINUE THE 888 00:32:13,480 --> 00:32:14,600 THEME ON PAIN AND 889 00:32:14,600 --> 00:32:15,480 PATIENT-REPORTED OUTCOMES, I'D 890 00:32:15,480 --> 00:32:17,240 LIKE TO INTRODUCE OUR NEXT 891 00:32:17,240 --> 00:32:20,160 SPEAKER, DR. ALEXIS LEONARD FROM 892 00:32:20,160 --> 00:32:20,840 ST. JUDE CHILDREN'S HOSPITAL. 893 00:32:20,840 --> 00:32:23,560 AND DR. LEONARD WILL BE SPEAKING 894 00:32:23,560 --> 00:32:26,200 ON REDUCTION IN VASOOCCLUSIVE 895 00:32:26,200 --> 00:32:29,040 EVENT FOLLOWING STEM CELL 896 00:32:29,040 --> 00:32:30,000 TRANSPLANTATION IN PATIENTS WITH 897 00:32:30,000 --> 00:32:32,400 SICKLE CELL DISEASE, AND 898 00:32:32,400 --> 00:32:35,160 DR. LEONARD WILL BE PRESENTING 899 00:32:35,160 --> 00:32:35,800 REMOTELY. 900 00:32:35,800 --> 00:32:39,440 WELCOME, DR. LEONARD. 901 00:32:39,440 --> 00:32:40,000 >>THANK YOU. 902 00:32:40,000 --> 00:32:42,480 THANK YOU ALL FOR INVITING ME TO 903 00:32:42,480 --> 00:32:43,360 SPEAK ON THIS PUBLICATION THAT 904 00:32:43,360 --> 00:32:46,880 WE HAD PUT OUT EARLIER THIS 905 00:32:46,880 --> 00:32:47,080 YEAR. 906 00:32:47,080 --> 00:32:49,400 AS YOU CAN SEE THE TITLE THERE, 907 00:32:49,400 --> 00:32:51,800 I'M ALEXIS LEONARD, A RATHER NEW 908 00:32:51,800 --> 00:32:53,560 MEMBER IN THE DEPARTMENT OF 909 00:32:53,560 --> 00:32:55,920 HEMATOLOGY AT ST. JUDE, HAVING 910 00:32:55,920 --> 00:32:57,280 RECENTLY BEEN AT THE NIH DOING 911 00:32:57,280 --> 00:32:58,240 CLINICAL WORK AT CHILDREN'S 912 00:32:58,240 --> 00:33:00,960 NATIONAL. 913 00:33:00,960 --> 00:33:03,600 IN D.C. . 914 00:33:03,600 --> 00:33:05,720 SO AS WE ALL KNOW, TRANSPLANT IS 915 00:33:05,720 --> 00:33:06,600 POTENTIALLY CURATIVE FOR THE 916 00:33:06,600 --> 00:33:08,520 LONG TERM DISEASE MANAGEMENT AND 917 00:33:08,520 --> 00:33:10,400 PREVENTION OF ORGAN DAMAGE SEEN 918 00:33:10,400 --> 00:33:11,800 IN SICKLE CELL DISEASE, AND THAT 919 00:33:11,800 --> 00:33:13,800 PATIENTS THAT DO EXPERIENCE 920 00:33:13,800 --> 00:33:16,200 STABLE DONOR ENGRAFTMENT DO NOT 921 00:33:16,200 --> 00:33:17,640 EXPERIENCE SICKLE-RELATED 922 00:33:17,640 --> 00:33:19,040 SYMPTOMS AND CAN HAVE EITHER 923 00:33:19,040 --> 00:33:20,560 STABILIZATION OR IMPROVEMENT IN 924 00:33:20,560 --> 00:33:22,280 THEIR END-ORGAN PATHOLOGY. 925 00:33:22,280 --> 00:33:23,640 HOWEVER, THESE LONG-TERM EFFECTS 926 00:33:23,640 --> 00:33:29,640 REMAIN TO BE FULLY ESTABLISHED. 927 00:33:29,640 --> 00:33:31,720 SO WHEN WE'RE TALKING ABOUT 928 00:33:31,720 --> 00:33:33,560 INDICATIONS FOR TRANSPLANT, 929 00:33:33,560 --> 00:33:34,880 EXCEPT FOR STROKE, THESE 930 00:33:34,880 --> 00:33:36,640 INDICATIONS ARE NOT UNIVERSALLY 931 00:33:36,640 --> 00:33:38,280 AGREED UPON AND VARY AMONG 932 00:33:38,280 --> 00:33:39,240 STUDY, BUT TYPICALLY ARE 933 00:33:39,240 --> 00:33:41,000 RESERVED FOR THOSE WITH THE MOST 934 00:33:41,000 --> 00:33:42,120 SEVERE DISEASE COMPLICATIONS OR 935 00:33:42,120 --> 00:33:44,200 AT RISK FOR THOSE LONG TERM 936 00:33:44,200 --> 00:33:45,280 DISEASE-RELATED COMPLICATIONS. 937 00:33:45,280 --> 00:33:48,240 THIS IS A TABLE A FEW YEARS OLD 938 00:33:48,240 --> 00:33:51,840 BUT IT'S SHOWING VARIOUS 939 00:33:51,840 --> 00:33:53,400 INDICATIONS, AS YOU CAN SEE, IT 940 00:33:53,400 --> 00:33:57,400 VARIES BASED ON DONOR STATUS BUT 941 00:33:57,400 --> 00:33:59,160 IN ALL OF THESE STUDIES, HAVING 942 00:33:59,160 --> 00:34:02,680 RECURRENT SEVERE PAIN DESPITE 943 00:34:02,680 --> 00:34:03,440 HYDROXYUREA THERAPY ARE 944 00:34:03,440 --> 00:34:04,440 INDICATIONS FOR TRANSPLANT. 945 00:34:04,440 --> 00:34:06,280 AND WHEN EAR TALKING ABOUT -- 946 00:34:06,280 --> 00:34:09,000 THESE ARE FOR ALLOGENEIC 947 00:34:09,000 --> 00:34:09,360 STUDIES. 948 00:34:09,360 --> 00:34:11,960 WHEN WE'RE TALKING ABOUT 949 00:34:11,960 --> 00:34:15,440 AUTOLOGOUS GENE THERAPY, HAVING 950 00:34:15,440 --> 00:34:17,600 SEVERE VASOOCCLUSIVE EVENTS ARE 951 00:34:17,600 --> 00:34:24,200 THE REQUIREMENT. 952 00:34:24,200 --> 00:34:25,280 SO WHEN YOU LOOK AT THE 953 00:34:25,280 --> 00:34:27,240 LITERATURE AT LONG TERM OUTCOME, 954 00:34:27,240 --> 00:34:31,080 EACH ORGAN SYSTEM HAS SOME 955 00:34:31,080 --> 00:34:32,160 DEDICATED LITERATURE TO IT. 956 00:34:32,160 --> 00:34:34,320 WE'VE ALREADY HEARD FROM OUR 957 00:34:34,320 --> 00:34:35,200 COLLEAGUES THIS MORNING ABOUT 958 00:34:35,200 --> 00:34:37,080 THE NEUROLOGIC CHANGES, THE 959 00:34:37,080 --> 00:34:40,040 NORMALIZATION OF WHOLE BRAIN 960 00:34:40,040 --> 00:34:41,160 HEMODYNAMICS FROM DR. HOLBERT, 961 00:34:41,160 --> 00:34:42,680 AND YOU CAN SEE EACH ORGAN 962 00:34:42,680 --> 00:34:44,080 SYSTEM HAS SOME DEDICATED 963 00:34:44,080 --> 00:34:47,040 LITERATURE TO IT. 964 00:34:47,040 --> 00:34:50,400 MORE RECENTLY, WE HAVE MORE 965 00:34:50,400 --> 00:34:51,760 LITERATURE ON THE ENDOCRINE 966 00:34:51,760 --> 00:34:54,760 FUNCTION. 967 00:34:54,760 --> 00:34:56,720 BUT REALLY IN ALL OF THESE 968 00:34:56,720 --> 00:34:58,600 STUDIES, WHETHER IT'S ON OUTCOME 969 00:34:58,600 --> 00:35:02,480 FROM A TRIAL OR THESE LONG-TERM 970 00:35:02,480 --> 00:35:05,240 OUTCOMES, WE REALLY ONLY GET 971 00:35:05,240 --> 00:35:06,520 REPORTS THAT SIMPLY COMMENT 972 00:35:06,520 --> 00:35:07,880 THERE'S A REDUCTION IN PAIN 973 00:35:07,880 --> 00:35:09,080 HOWEVER THE DATA SPECIFICALLY 974 00:35:09,080 --> 00:35:10,040 REPORTING PAIN AFTER TRANSPLANT 975 00:35:10,040 --> 00:35:10,480 IS LACKING. 976 00:35:10,480 --> 00:35:12,040 AT THE TIME WE DID THIS STUDY, 977 00:35:12,040 --> 00:35:15,160 WE DIDN'T HAVE DR. BAKSHI'S DATA 978 00:35:15,160 --> 00:35:20,440 THAT SHE JUST REPORTED. 979 00:35:20,440 --> 00:35:21,640 PRIOR TO WRITING THIS UP AND 980 00:35:21,640 --> 00:35:23,400 DOING THIS STUDY, THERE WAS 981 00:35:23,400 --> 00:35:25,360 REALLY ONLY ONE STUDY THAT 982 00:35:25,360 --> 00:35:26,840 SINGLE HANDEDLY LOOKED AT PAIN 983 00:35:26,840 --> 00:35:28,520 AND IT WAS ONLY UP TO ONE YEAR 984 00:35:28,520 --> 00:35:29,520 POST TRANSPLANT. 985 00:35:29,520 --> 00:35:31,920 AND THIS WAS IN AN ADULT 986 00:35:31,920 --> 00:35:35,280 POPULATION AT THE NIH OF 35 987 00:35:35,280 --> 00:35:37,080 PATIENTS THAT DOCUMENTED THAT 988 00:35:37,080 --> 00:35:38,480 THERE WAS A FRACTION OF PATIENTS 989 00:35:38,480 --> 00:35:41,120 IN THIS COHORT, 40% STILL HAD 990 00:35:41,120 --> 00:35:43,080 PERSISTENT PAIN REQUIRING 991 00:35:43,080 --> 00:35:43,840 OPIATES AT ONE YEAR POST 992 00:35:43,840 --> 00:35:48,120 TRANSPLANT. 993 00:35:48,120 --> 00:35:50,080 AND AS WE'RE GETTING MORE DATA 994 00:35:50,080 --> 00:35:52,040 ON THE AUTOLOGOUS GENE THERAPY 995 00:35:52,040 --> 00:35:54,120 TRIAL, WE'RE GETTING REPORT 996 00:35:54,120 --> 00:35:56,960 ABOUT REDUCTION OR RESOLUTION OF 997 00:35:56,960 --> 00:35:58,320 THESE SEVERE VASO-OCCLUSIVE 998 00:35:58,320 --> 00:35:58,600 EVENTS. 999 00:35:58,600 --> 00:36:01,040 THESE ARE DATA THAT WE SEE FROM 1000 00:36:01,040 --> 00:36:04,640 THE BLOOMBERG STUDY ON THE LEFT 1001 00:36:04,640 --> 00:36:06,840 AND THE CRISPR STUDY ON THE 1002 00:36:06,840 --> 00:36:07,920 RIGHT BOTH OF WHICH ARE 1003 00:36:07,920 --> 00:36:10,720 CURRENTLY UNDER REVIEW. 1004 00:36:10,720 --> 00:36:12,600 AND SO THE RATIONALE FOR DOING 1005 00:36:12,600 --> 00:36:13,880 THIS ARTICLE IN THIS STUDY WAS 1006 00:36:13,880 --> 00:36:16,000 THAT IN ORDER FOR US TO REALLY 1007 00:36:16,000 --> 00:36:17,720 ADEQUATELY INFORM AND ASSESS THE 1008 00:36:17,720 --> 00:36:19,920 RESULTS OF THESE NEWER 1009 00:36:19,920 --> 00:36:21,400 AUTOLOGOUS GENE STUDY THAIRPTS, 1010 00:36:21,400 --> 00:36:23,760 WE NEED BETTER PUBLISHED DATA 1011 00:36:23,760 --> 00:36:24,440 INCLUDING VASO-OCCLUSIVE EVENTS 1012 00:36:24,440 --> 00:36:27,600 BEFORE AND AFTER ALLOGENEIC 1013 00:36:27,600 --> 00:36:29,560 TRANSPLANT. 1014 00:36:29,560 --> 00:36:32,320 SO THAT LED TO THIS 1015 00:36:32,320 --> 00:36:33,960 RETROSPECTIVE STUDY WHERE WE 1016 00:36:33,960 --> 00:36:36,440 LOOKED AT 163 PATIENTS WITH 1017 00:36:36,440 --> 00:36:37,680 SICKLE CELL DISEASE, PEDIATRIC 1018 00:36:37,680 --> 00:36:40,320 AND ADULT, WHO UNDERWENT AN 1019 00:36:40,320 --> 00:36:40,680 ALLOTRANSPLANT. 1020 00:36:40,680 --> 00:36:42,480 WE LOOKED AT THE NUMBER OF 1021 00:36:42,480 --> 00:36:43,480 VASO-OCCLUSIVE EVENTS IN THE TWO 1022 00:36:43,480 --> 00:36:44,880 YEARS BEFORE TRANSPLANT, AND 1023 00:36:44,880 --> 00:36:46,640 COMPARED THEM WITH THE NUMBER OF 1024 00:36:46,640 --> 00:36:48,400 EVENTS IN THE ZERO TO 12 MONTHS 1025 00:36:48,400 --> 00:36:51,000 AND THEN 12 TO 24 MONTHS AFTER 1026 00:36:51,000 --> 00:36:52,240 TRANSPLANT, AND WHAT WE REPORT 1027 00:36:52,240 --> 00:36:53,440 IS THAT VASO-OCCLUSIVE EVENTS 1028 00:36:53,440 --> 00:36:54,520 ARE SIGNIFICANTLY REDUCED IN 1029 00:36:54,520 --> 00:36:59,600 THIS PATIENT POPULATION AFTER 1030 00:36:59,600 --> 00:37:00,800 ALLOTRANSPLANT. 1031 00:37:00,800 --> 00:37:02,840 SO HOW DO WE DEFINE VOE? 1032 00:37:02,840 --> 00:37:04,160 SO WE USED -- BECAUSE WE WANTED 1033 00:37:04,160 --> 00:37:05,680 THIS TO BE AN IMPORTANT ABILITY 1034 00:37:05,680 --> 00:37:07,880 TO COMPARE TO THESE YOU AUTOLOGS 1035 00:37:07,880 --> 00:37:11,680 STUDIES, WE USED THE BLOOMBERG 1036 00:37:11,680 --> 00:37:12,880 BIOSTUDY, ONE OF THE LARGEST AT 1037 00:37:12,880 --> 00:37:14,000 THE TIME, WHICH IS HIGHLIGHTED 1038 00:37:14,000 --> 00:37:16,840 AT THE BOTTOM. 1039 00:37:16,840 --> 00:37:19,840 SPECIFIC DEFINITIONS FOR 1040 00:37:19,840 --> 00:37:22,680 OBTAINING ACUTE -- FOR PAIN THAT 1041 00:37:22,680 --> 00:37:25,280 MEANS MORE THAN 24 HOURS OF 1042 00:37:25,280 --> 00:37:29,760 HOSPITALIZATION FOR PAIN OR ER 1043 00:37:29,760 --> 00:37:30,880 VISITS, TWO VISITS OVER A 1044 00:37:30,880 --> 00:37:31,680 CERTAIN PERIOD OF TIME. 1045 00:37:31,680 --> 00:37:34,880 YOU CAN SEE WE INCLUDED 11 1046 00:37:34,880 --> 00:37:37,600 DIFFERENT CLINICAL TRIALS FOR 1047 00:37:37,600 --> 00:37:39,880 ALLO TRANSPLANT BETWEEN NIH AND 1048 00:37:39,880 --> 00:37:42,720 CHILDREN'S NATIONAL, OF WHICH 1049 00:37:42,720 --> 00:37:44,200 THEY HAD VARYING DEFINITIONS OF 1050 00:37:44,200 --> 00:37:46,800 WHAT WAS INCLUDED FOR THE STUDY 1051 00:37:46,800 --> 00:37:54,480 FOR PAIN OR ACUTE CHEST. 1052 00:37:54,480 --> 00:37:56,640 SO THIS IS A BUSY SLIDE BUT THIS 1053 00:37:56,640 --> 00:37:58,280 IS PATIENT CHARACTERISTICS AND 1054 00:37:58,280 --> 00:37:58,800 OUTCOMES. 1055 00:37:58,800 --> 00:38:01,360 ON THE LEFT PATIENT 1056 00:38:01,360 --> 00:38:02,720 CHARACTERISTICS, WE HAD 153 1057 00:38:02,720 --> 00:38:05,800 PATIENTS OF WHICH A MAJORITY ARE 1058 00:38:05,800 --> 00:38:12,720 MALE, HEMOGLOBIN SS -- AVERAGE 1059 00:38:12,720 --> 00:38:16,640 AGE 20 FOR THE ENTIRE COHORT, 1060 00:38:16,640 --> 00:38:20,120 YOUNGEST BEING 7 MONTHS, OLDEST 1061 00:38:20,120 --> 00:38:20,680 BEING 64. 1062 00:38:20,680 --> 00:38:25,920 THE MAJORITY, 75% UNDERWENT A 1063 00:38:25,920 --> 00:38:26,920 NON-MYELOOWE BLAITIVE 1064 00:38:26,920 --> 00:38:27,360 CONDITIONING REGIMEN. 1065 00:38:27,360 --> 00:38:29,960 YOU CAN SEE VARYING DONOR TYPES, 1066 00:38:29,960 --> 00:38:34,480 MAJORITY BEING MATCHED SIBLING. 1067 00:38:34,480 --> 00:38:36,880 PAIN WAS THE MOST FREQUENT, 1068 00:38:36,880 --> 00:38:39,160 FOLLOWED BY RECURRENT ACUTE 1069 00:38:39,160 --> 00:38:39,360 CHEST. 1070 00:38:39,360 --> 00:38:41,920 IN TERMS OF THE OUTCOMES OF THIS 1071 00:38:41,920 --> 00:38:44,760 STUDY, ENGRAFTMENT OCCURRED IN 1072 00:38:44,760 --> 00:38:46,960 88% OF THE PATIENT POPULATION, 1073 00:38:46,960 --> 00:38:49,240 WITH AN AVERAGE MYELOID 1074 00:38:49,240 --> 00:38:50,320 CHIMERISM OF AROUND 80% AND YOU 1075 00:38:50,320 --> 00:38:53,600 CAN SEE THE RATES OF GBHD. 1076 00:38:53,600 --> 00:38:54,680 THIS TABLE IS IN THE ARTICLE AND 1077 00:38:54,680 --> 00:38:56,680 I'M GOING TO GO THROUGH THE 1078 00:38:56,680 --> 00:38:57,440 NUMBER OF EVENTS IN THE 1079 00:38:57,440 --> 00:39:03,920 FOLLOWING SLIDES. 1080 00:39:03,920 --> 00:39:07,280 SO THIS STUDY -- THE FIGURE THAT 1081 00:39:07,280 --> 00:39:09,360 YOU SEE THERE ON THE LEFT IN 1082 00:39:09,360 --> 00:39:11,560 BLUE ARE THE NUMBER OF 1083 00:39:11,560 --> 00:39:12,320 VASO-OCCLUSIVE EVENTS FOR THOSE 1084 00:39:12,320 --> 00:39:14,480 WHO ENGRAFTED IN THE TWO YEARS 1085 00:39:14,480 --> 00:39:15,080 BEFORE. 1086 00:39:15,080 --> 00:39:16,680 IN PINK ARE THE NUMBER OF 1087 00:39:16,680 --> 00:39:17,560 VASO-OCCLUSIVE EVENTS 1088 00:39:17,560 --> 00:39:19,080 PRETRANSPLANT AND THOSE WHO 1089 00:39:19,080 --> 00:39:20,840 ULTIMATELY HAD GBHD AND THEN IN 1090 00:39:20,840 --> 00:39:22,400 GREEN ARE THE ONES THAT 1091 00:39:22,400 --> 00:39:22,960 REJECTED. 1092 00:39:22,960 --> 00:39:24,040 IN YELLOW ARE THE NUMBER OF 1093 00:39:24,040 --> 00:39:25,760 EVENTS THAT OCCURRED IN THE ZERO 1094 00:39:25,760 --> 00:39:28,360 TO 12 MONTHS AND EMBED THE 12 TO 1095 00:39:28,360 --> 00:39:28,720 24 MONTHS. 1096 00:39:28,720 --> 00:39:31,040 YOU CAN SEE THE NUMBER OF EVENTS 1097 00:39:31,040 --> 00:39:32,120 LISTED HERE AVERAGE TWO YEARS 1098 00:39:32,120 --> 00:39:33,880 BEFORE WAS 5 1/2 EVENT BUT THAT 1099 00:39:33,880 --> 00:39:35,520 RANGED FROM ZERO IN SOME OF THE 1100 00:39:35,520 --> 00:39:42,200 PEDIATRIC PATIENTS TO 502. 1101 00:39:42,200 --> 00:39:44,160 TO 52. 1102 00:39:44,160 --> 00:39:45,680 OVERALL IN THE TWO-YEAR 1103 00:39:45,680 --> 00:39:46,720 PERIOD -- AS YOU CAN SEE, THE 1104 00:39:46,720 --> 00:39:48,000 MAJORITY OF THOSE EVENTS ARE 1105 00:39:48,000 --> 00:39:49,200 OCCURRING IN THE ZERO TO 12 1106 00:39:49,200 --> 00:39:53,160 MONTHS. 1107 00:39:53,160 --> 00:39:54,800 THIS IS ANOTHER WAY TO REPRESENT 1108 00:39:54,800 --> 00:39:56,520 THAT DATA BUT REALLY SEPARATED 1109 00:39:56,520 --> 00:39:58,840 OUT THE ENGRAFTED WITH AND 1110 00:39:58,840 --> 00:40:00,880 WITHOUT GBHD IN OUR REJECTED 1111 00:40:00,880 --> 00:40:01,280 PATIENTS. 1112 00:40:01,280 --> 00:40:02,680 THOSE WHO SUCCESSFULLY ENGRAFTED 1113 00:40:02,680 --> 00:40:05,080 HAD A RISK OF VASO-OCCLUSIVE 1114 00:40:05,080 --> 00:40:07,560 EVENT REDUCTION OF 75% IN THAT 1115 00:40:07,560 --> 00:40:10,240 FIRST YEAR, AND IT CLIMBED TO 1116 00:40:10,240 --> 00:40:11,200 99% IN THE SECOND YEAR AFTER 1117 00:40:11,200 --> 00:40:14,080 TRANSPLANT. 1118 00:40:14,080 --> 00:40:17,560 INTERESTINGLY, AS HAS 1119 00:40:17,560 --> 00:40:18,440 SUBJECTIVELY BEEN REPORTED EVEN 1120 00:40:18,440 --> 00:40:19,880 IN PATIENTS THAT REJECTED THEIR 1121 00:40:19,880 --> 00:40:21,280 GRAFT WE FOUND THERE WAS ALSO 1122 00:40:21,280 --> 00:40:22,480 SIGNIFICANT REDUCTION IN EVENT 1123 00:40:22,480 --> 00:40:25,440 IN THE ZERO TO 12 AND 12 TO 24 1124 00:40:25,440 --> 00:40:32,240 MONTHS AFTER REJECTION. 1125 00:40:32,240 --> 00:40:33,800 SO WE KNOW YOUNGER PATIENTS 1126 00:40:33,800 --> 00:40:35,280 GENERALLY HAVE LESS 1127 00:40:35,280 --> 00:40:36,600 VASO-OCCLUSIVE EVENTS PRE AND 1128 00:40:36,600 --> 00:40:37,280 POST TRANSPLANT AND THAT WAS 1129 00:40:37,280 --> 00:40:38,680 TRUE IN OUR POPULATION. 1130 00:40:38,680 --> 00:40:39,640 AS YOU CAN SEE IN THE GRAPH ON 1131 00:40:39,640 --> 00:40:42,200 THE LEFT, THIS IS SEPARATED BY 1132 00:40:42,200 --> 00:40:42,520 AGE. 1133 00:40:42,520 --> 00:40:46,480 THE YOUNGER PATIENT HAVING 1134 00:40:46,480 --> 00:40:48,560 SIGNIFICANTLY LESS EVENTS 1135 00:40:48,560 --> 00:40:49,360 PRETRANSPLANT, MORE COMMON 1136 00:40:49,360 --> 00:40:51,760 INDICATIONS WERE ACUTE CHEST -- 1137 00:40:51,760 --> 00:40:52,360 OR STROKE. 1138 00:40:52,360 --> 00:40:53,720 SO WHEN WE DID AGGRESSION 1139 00:40:53,720 --> 00:40:56,200 MODELING INCLUDING AGE, GENDER 1140 00:40:56,200 --> 00:40:58,520 AND NUMBER OF EVENTS 1141 00:40:58,520 --> 00:40:59,520 PRETRANSPLANT, WE FOUND THAT AGE 1142 00:40:59,520 --> 00:41:00,640 AND NUMBER OF VASO-OCCLUSIVE 1143 00:41:00,640 --> 00:41:02,040 EVENTS WERE PREDICTIVE OF THE 1144 00:41:02,040 --> 00:41:03,120 NUMBER OF EVENTS THAT WOULD 1145 00:41:03,120 --> 00:41:04,920 OCCUR IN THE ZERO TO 12 MONTHS 1146 00:41:04,920 --> 00:41:06,520 AFTER TRANSPLANT, BUT NOT THE 12 1147 00:41:06,520 --> 00:41:09,840 TO 24, GIVEN THERE WERE SO FEW 1148 00:41:09,840 --> 00:41:10,680 EVENTS. 1149 00:41:10,680 --> 00:41:12,280 WE ALSO DID ANOTHER ANALYSIS 1150 00:41:12,280 --> 00:41:18,720 LOOKING AT DONOR MY EMPLOYED MYD 1151 00:41:18,720 --> 00:41:23,200 CHIMERISM AT TWO YEARS. 1152 00:41:23,200 --> 00:41:25,200 -- AGAIN NOT SIGNIFICANT FOR 12 1153 00:41:25,200 --> 00:41:26,800 TO 24 MONTHS BECAUSE WE HAD SO 1154 00:41:26,800 --> 00:41:27,320 FEW EVENTS. 1155 00:41:27,320 --> 00:41:29,400 THIS FIGURE ON THE RIGHT SHOWS 1156 00:41:29,400 --> 00:41:32,800 THE TOP HALF OF IT IS 100% DONOR 1157 00:41:32,800 --> 00:41:34,240 MYELOID CHIMERISM AND AS YOU GET 1158 00:41:34,240 --> 00:41:39,400 LOWER IN YOUR CHIMERISM, YOU SEE 1159 00:41:39,400 --> 00:41:40,680 MORE EVENTS POST TRANSPLANT. 1160 00:41:40,680 --> 00:41:42,240 THE OTHER THING WE DID LOOK AT, 1161 00:41:42,240 --> 00:41:43,600 SPECIFICALLY THIS IS WHAT HAD 1162 00:41:43,600 --> 00:41:45,880 BEEN REPORTED, PATIENTS ON 1163 00:41:45,880 --> 00:41:47,520 EITHER LONG OR SHORT ACTING 1164 00:41:47,520 --> 00:41:49,040 OPIOIDS AT THE TIME OF 1165 00:41:49,040 --> 00:41:50,040 TRANSPLANT HAD SIGNIFICANTLY 1166 00:41:50,040 --> 00:41:53,120 MORE VOEs PRETRANSPLANT AND 1167 00:41:53,120 --> 00:41:55,120 WAS PREDICTIVE IN THAT ZERO TO 1168 00:41:55,120 --> 00:41:57,880 12 MONTH PERIOD BUT NOT THE 12 1169 00:41:57,880 --> 00:42:04,600 TO 24 MONTH PERIOD. 1170 00:42:04,600 --> 00:42:07,560 SO THIS STUDY HAS SIGNIFICANT 1171 00:42:07,560 --> 00:42:09,200 LIMITATIONS, NUMBER ONE BEING 1172 00:42:09,200 --> 00:42:10,160 RETROSPECTIVE, NUMBER TWO, THIS 1173 00:42:10,160 --> 00:42:13,160 WAS A TWO-CENTER STUDY AND WITH 1174 00:42:13,160 --> 00:42:14,240 VARYING POPULATIONS. 1175 00:42:14,240 --> 00:42:15,720 WE KNOW THE NIH POPULATION TENDS 1176 00:42:15,720 --> 00:42:18,720 TO BE OLDER, MORE SEVERE 1177 00:42:18,720 --> 00:42:20,040 DISEASE, SO HOW THAT TRANSLATES 1178 00:42:20,040 --> 00:42:21,800 TO THE REST OF THE SICKLE CELL 1179 00:42:21,800 --> 00:42:23,120 POPULATION IS UNKNOWN. 1180 00:42:23,120 --> 00:42:25,720 WE ALSO KNOW LOOKING AT PAIN IS 1181 00:42:25,720 --> 00:42:27,280 VERY COMPLEX, AND THAT ACUTE 1182 00:42:27,280 --> 00:42:31,760 PAIN IS A LOT MORE COMPLEX THAN 1183 00:42:31,760 --> 00:42:33,640 JUST VASOOCCLUSION SO THIS STUDY 1184 00:42:33,640 --> 00:42:35,200 LIKELY OVERESTIMATES THE PAIN 1185 00:42:35,200 --> 00:42:36,960 EXPERIENCE BOTH PRE AND POST 1186 00:42:36,960 --> 00:42:39,400 TRANSPLANT. 1187 00:42:39,400 --> 00:42:43,040 DESPITE ELIMINATION OF THE 1188 00:42:43,040 --> 00:42:44,040 SICKLE-RELATED VASOOCCLUSION 1189 00:42:44,040 --> 00:42:45,320 EVENTS, WE KNOW THAT PAIN AND 1190 00:42:45,320 --> 00:42:47,240 THE COMPLEXITY OF WHAT'S 1191 00:42:47,240 --> 00:42:49,160 REPORTED BY PATIENTS IS GOING TO 1192 00:42:49,160 --> 00:42:52,240 BE HARD TO UNTANGLE FROM A 1193 00:42:52,240 --> 00:42:53,320 LIFETIME OF THEIR SICKLE CELL 1194 00:42:53,320 --> 00:42:55,120 PAIN, WHETHER THAT'S THEIR PAIN 1195 00:42:55,120 --> 00:42:56,960 HISTORY, THEIR PAIN MEMORY, 1196 00:42:56,960 --> 00:42:58,600 PSYCHOLOGICAL STRESSORS OF BEING 1197 00:42:58,600 --> 00:42:59,720 RE-ADMITTED TO THE HOSPITAL 1198 00:42:59,720 --> 00:43:01,000 BECAUSE WE KNOW THAT HAPPENS 1199 00:43:01,000 --> 00:43:03,640 POST ALLOGENEIC TRANSPLANT, KNOW 1200 00:43:03,640 --> 00:43:05,600 THAT PATIENTS HAVE CHRONIC PAIN 1201 00:43:05,600 --> 00:43:14,040 DISORDERS, OPIATE HYPER AL JEEZ 1202 00:43:14,040 --> 00:43:14,280 ALGESIA -- 1203 00:43:14,280 --> 00:43:16,040 >>IF YOU CAN WRAP UP, PLEASE. 1204 00:43:16,040 --> 00:43:17,000 >>YEP. 1205 00:43:17,000 --> 00:43:18,200 WE PREVIOUSLY REPORTED THAT 40% 1206 00:43:18,200 --> 00:43:20,480 OF OUR ADULTS HAD PERSISTENT 1207 00:43:20,480 --> 00:43:21,920 PAIN AT 12 MONTHS, AND THIS 1208 00:43:21,920 --> 00:43:23,360 STUDY SHOWS THAT THE MAJORITY OF 1209 00:43:23,360 --> 00:43:24,920 THOSE PATIENTS WERE ABLE TO COME 1210 00:43:24,920 --> 00:43:27,960 OFF NARCOTICS BY 24 MONTHS. 1211 00:43:27,960 --> 00:43:31,360 AND THE MECHANISM FOR THOSE THAT 1212 00:43:31,360 --> 00:43:32,920 REJECTED IS NOT FULLY 1213 00:43:32,920 --> 00:43:36,240 UNDERSTOOD. 1214 00:43:36,240 --> 00:43:40,160 SO IN SUMMARY, WE KNOW THAT 1215 00:43:40,160 --> 00:43:41,360 VASO-OCCLUSIVE EVENTS ARE 1216 00:43:41,360 --> 00:43:43,800 REDUCED AFTER ALLOTRANSPLANT 1217 00:43:43,800 --> 00:43:45,280 SIGNIFICANTLY IN THAT 12 TO 24 1218 00:43:45,280 --> 00:43:47,640 MONTH PERIOD, AND IT OCCURS IN 1219 00:43:47,640 --> 00:43:48,920 EVEN THOSE WHO REJECT THEIR 1220 00:43:48,920 --> 00:43:51,360 GRAFT AND THIS SHOULD BE ABLE TO 1221 00:43:51,360 --> 00:43:54,200 INFLUENCE RESULTS OF YOU AUTOLOS 1222 00:43:54,200 --> 00:43:55,400 GENE STUDY THERAPIES. 1223 00:43:55,400 --> 00:43:57,680 QUICKLY JUST WANT TO THANK MY 1224 00:43:57,680 --> 00:43:59,800 CO-AUTHORS, CERTAINLY 1225 00:43:59,800 --> 00:44:00,560 DR. TISDALE FOR SPEARHEADING 1226 00:44:00,560 --> 00:44:04,320 THIS AND DR. ABRAHAM FOR BRI 1227 00:44:04,320 --> 00:44:06,480 BRINGING STUDIES TO THE 1228 00:44:06,480 --> 00:44:08,200 PEDIATRIC POPULATION AT 1229 00:44:08,200 --> 00:44:08,640 CHILDREN'S NATIONAL. 1230 00:44:08,640 --> 00:44:08,960 THANK YOU. 1231 00:44:08,960 --> 00:44:11,360 >>THANK YOU, DR. LEONARD. 1232 00:44:11,360 --> 00:44:13,200 I'LL INTRODUCE OUR NEXT SPEAKER 1233 00:44:13,200 --> 00:44:14,400 TO THE PODIUM TO PRESENT IN 1234 00:44:14,400 --> 00:44:15,920 PERSON. 1235 00:44:15,920 --> 00:44:18,360 THIS IS DR. HANNAH KINOSHITA, 1236 00:44:18,360 --> 00:44:20,080 SHE'LL BE PRESENTING ON OUTCOMES 1237 00:44:20,080 --> 00:44:22,960 FOLLOWING POST TRANSPLANT VIRUS 1238 00:44:22,960 --> 00:44:24,040 SPECIFIC T-CELL THERAPY IN 1239 00:44:24,040 --> 00:44:24,240 PATIENTS WITH SICKLE CELL 1240 00:44:24,240 --> 00:44:24,360 DISEASE. 1241 00:44:24,360 --> 00:44:32,280 >>THANK YOU SO MUCH FOR HAVING ME 1242 00:44:32,280 --> 00:44:33,400 AS EVERYONE HERE KNOWS INFECTION 1243 00:44:33,400 --> 00:44:34,880 IS A MAJOR CAUSE OF MORBIDITY 1244 00:44:34,880 --> 00:44:36,520 AND MORTALITY IN PATIENTS 1245 00:44:36,520 --> 00:44:38,760 FOLLOWING STEM CELL TRANSPLANT. 1246 00:44:38,760 --> 00:44:40,200 WITH CERTAIN VIRAL INFECTIONS 1247 00:44:40,200 --> 00:44:42,040 BEING IMPLICATED IN INDUCING 1248 00:44:42,040 --> 00:44:43,040 GRAFT FAILURE. 1249 00:44:43,040 --> 00:44:45,120 VIRAL INFECTIONS POST TRANSPLANT 1250 00:44:45,120 --> 00:44:46,440 IS OF PARTICULAR CONCERN IN 1251 00:44:46,440 --> 00:44:48,320 PATIENTS RECEIVING ALTERNATIVE 1252 00:44:48,320 --> 00:44:50,720 DONOR TRANSPLANTS AS IN THE CASE 1253 00:44:50,720 --> 00:44:53,560 OF SICKLE CELL DISEASE. 1254 00:44:53,560 --> 00:44:56,840 DR. PATEL AND COLLEAGUES LOOKED 1255 00:44:56,840 --> 00:45:01,040 AT POST HAPLOID IDENTICAL -- 1256 00:45:01,040 --> 00:45:02,760 SICKLE CELL DISEASE WHO RECEIVED 1257 00:45:02,760 --> 00:45:05,240 POST TRANSPLANT CYCLOPHOSPHAMIDE 1258 00:45:05,240 --> 00:45:07,120 AND SHOWED THERE WAS DELAYED 1259 00:45:07,120 --> 00:45:07,680 IMMUNOCONSTITUTION AND THAT 1260 00:45:07,680 --> 00:45:08,880 VIRAL INFECTIONS OCCURRED IN 1261 00:45:08,880 --> 00:45:10,480 ALMOST 70% OF THOSE PATIENTS 1262 00:45:10,480 --> 00:45:12,880 WITH CMV BEING THE MOST COMMON. 1263 00:45:12,880 --> 00:45:13,880 TREATMENT OF THESE VIRAL 1264 00:45:13,880 --> 00:45:16,160 INFECTIONS CAN BE CHALLENGING 1265 00:45:16,160 --> 00:45:17,360 PARTICULARLY IN PATIENTS WHO 1266 00:45:17,360 --> 00:45:19,480 HAVE RENAL OR HEPATIC 1267 00:45:19,480 --> 00:45:21,880 DYSFUNCTION AS THESE STANDARD 1268 00:45:21,880 --> 00:45:24,280 ANTIVIRAL MEDICATIONS CAN CAUSE 1269 00:45:24,280 --> 00:45:26,800 RENAL AND HEPATIC TOXICITY AS 1270 00:45:26,800 --> 00:45:28,440 WELL AS MYELOSUPPRESSION. 1271 00:45:28,440 --> 00:45:30,600 SO VIRUS SPECIFIC T-CELLS HAVE 1272 00:45:30,600 --> 00:45:32,000 BEEN SHOWN TO BE SAFE AND 1273 00:45:32,000 --> 00:45:33,040 EFFECTIVE POST TRANSPLANT IN THE 1274 00:45:33,040 --> 00:45:34,400 SETTING OF MANY DIFFERENT 1275 00:45:34,400 --> 00:45:36,440 UNDERLYING DISEASES. 1276 00:45:36,440 --> 00:45:38,560 FROM VARIOUS DONOR SOURCES 1277 00:45:38,560 --> 00:45:40,360 INCLUDING MATCHED, 1278 00:45:40,360 --> 00:45:41,480 HAPLOIDENTICAL AND UMBILICAL 1279 00:45:41,480 --> 00:45:43,480 CORD SOURCES AS WELL AS DONOR 1280 00:45:43,480 --> 00:45:44,720 DERIVED FROM THE STEM CELL 1281 00:45:44,720 --> 00:45:46,520 TRANSPLANT DONOR THEMSELVES AS 1282 00:45:46,520 --> 00:45:47,320 WELL AS THIRD PARTY DONORS. 1283 00:45:47,320 --> 00:45:49,000 SO THIS IS A SCHEMATIC JUST 1284 00:45:49,000 --> 00:45:50,640 BRIEFLY SHOWING THE RAPID 1285 00:45:50,640 --> 00:45:52,840 GENERATION PROTOCOL OF 1286 00:45:52,840 --> 00:45:53,920 VIRUS-SPECIFIC T-CELLS FOR 1287 00:45:53,920 --> 00:45:57,560 VARIOUS VIRUS TARGETS. 1288 00:45:57,560 --> 00:45:59,160 SO WE WANTED TO LOOK 1289 00:45:59,160 --> 00:46:00,160 SPECIFICALLY AT THE SICKLE CELL 1290 00:46:00,160 --> 00:46:03,360 POPULATION KNOWING THAT THEY ARE 1291 00:46:03,360 --> 00:46:04,400 DIFFERENT THAN OTHER PATIENTS 1292 00:46:04,400 --> 00:46:05,680 WHO ARE TRANSPLANTED FOR OTHER 1293 00:46:05,680 --> 00:46:07,520 DISEASES SUCH AS PRIMARY 1294 00:46:07,520 --> 00:46:08,280 IMMUNODEFICIENCIES OR 1295 00:46:08,280 --> 00:46:10,480 MALIGNANCIES. 1296 00:46:10,480 --> 00:46:13,680 AND SO THIS IS A SINGLE CENTER 1297 00:46:13,680 --> 00:46:14,520 RETROSPECTIVE REVIEW OF 1298 00:46:14,520 --> 00:46:20,720 PEDIATRIC PATIENTS WHO RECEIV 1299 00:46:20,720 --> 00:46:22,240 RECEIVED -- DO YOU WANT ME TO 1300 00:46:22,240 --> 00:46:22,440 STOP? 1301 00:46:22,440 --> 00:46:23,320 >>JUST TWO SECONDS. 1302 00:46:23,320 --> 00:46:26,280 >>SURE. 1303 00:46:26,280 --> 00:46:26,840 OKAY. 1304 00:46:26,840 --> 00:46:29,600 SO THIS IS A SINGLE CENTER 1305 00:46:29,600 --> 00:46:30,560 RETROSPECTIVE REVIEW OF 1306 00:46:30,560 --> 00:46:33,000 PEDIATRIC PATIENTS WHO RECEIVED 1307 00:46:33,000 --> 00:46:34,440 VIRUS SPECIFIC T-CELLS FOLLOWING 1308 00:46:34,440 --> 00:46:35,400 STEM CELL TRANSPLANT AT OUR 1309 00:46:35,400 --> 00:46:35,880 CENTER. 1310 00:46:35,880 --> 00:46:38,400 WE IDENTIFIED 13 PATIENTS ON SIX 1311 00:46:38,400 --> 00:46:39,440 CLINICAL TRIALS. 1312 00:46:39,440 --> 00:46:41,040 15VST PRODUCTS WERE INFUSED AND 1313 00:46:41,040 --> 00:46:42,240 THE DIFFERENCE IN THAT NUMBER IS 1314 00:46:42,240 --> 00:46:45,280 BECAUSE PATIENTS WERE ALLOWED TO 1315 00:46:45,280 --> 00:46:51,800 RECEIVE MULTIPLE PRO KU PRODUCTM 1316 00:46:51,800 --> 00:46:52,400 DIFFERENT CLINICAL TRIALS AS 1317 00:46:52,400 --> 00:46:57,920 LONG AS THEY WERE ELIGIBLE. 1318 00:46:57,920 --> 00:47:00,600 TWO OF THE TRIALS WERE VSTs 1319 00:47:00,600 --> 00:47:03,440 GENERATED FROM THE DONOR OF THE 1320 00:47:03,440 --> 00:47:04,760 TRANSPLANT THEMSELVES, TWO OF 1321 00:47:04,760 --> 00:47:07,320 THE TRIALS WERE FROM CORD BLOOD 1322 00:47:07,320 --> 00:47:08,640 DONORS AND TWO OF THE TRIALS 1323 00:47:08,640 --> 00:47:13,120 WERE FROM THIRD PARTY DONORS. 1324 00:47:13,120 --> 00:47:14,760 SO WHEN WE LOOK AT THE 1325 00:47:14,760 --> 00:47:16,080 SPECIFICITY OF THE PRODUCTS 1326 00:47:16,080 --> 00:47:18,200 AGAINST THE VIRAL TARGET 1327 00:47:18,200 --> 00:47:19,480 ANTIGENS, THERE'S QUITE A BIT OF 1328 00:47:19,480 --> 00:47:21,040 VARIABILITY AS YOU CAN SEE. 1329 00:47:21,040 --> 00:47:22,160 SO BETWEEN DIFFERENT VIRUSES 1330 00:47:22,160 --> 00:47:26,400 THAT WE TARGETED FROM CMV, EBV, 1331 00:47:26,400 --> 00:47:28,840 BKV VIRUS AS WELL AS WITHIN EACH 1332 00:47:28,840 --> 00:47:30,280 VIRUS FROM DONOR TO DONOR. 1333 00:47:30,280 --> 00:47:32,120 THIS IS LIKELY AT LEAST 1334 00:47:32,120 --> 00:47:34,480 PARTIALLY DUE TO THE DONOR'S OWN 1335 00:47:34,480 --> 00:47:36,640 EXPOSURE TO THESE DIFFERENT 1336 00:47:36,640 --> 00:47:37,720 VIRUSES. 1337 00:47:37,720 --> 00:47:40,160 WHEN WE LOOK AT THE CLINICAL 1338 00:47:40,160 --> 00:47:42,040 OUTCOMES OF VSTs IN THIS 1339 00:47:42,040 --> 00:47:44,160 COHORT, SO WE IDENTIFIED 13 1340 00:47:44,160 --> 00:47:45,640 PATIENTS, SIX OF WHOM RECEIVED 1341 00:47:45,640 --> 00:47:46,680 VSTs FOR TREATMENT. 1342 00:47:46,680 --> 00:47:48,520 FIVE OF THOSE PATIENTS ARE 1343 00:47:48,520 --> 00:47:50,720 ACTIVE VIREMIA AT THE TIME OF 1344 00:47:50,720 --> 00:47:52,600 FIRST VST INFUSION, OR IF THOSE 1345 00:47:52,600 --> 00:47:54,360 PATIENTS WERE IN REMISSION FOR 1346 00:47:54,360 --> 00:47:55,680 AT LEAST ONE OF THE TARGET 1347 00:47:55,680 --> 00:47:56,520 VIRUSES AFTER THAT FIRST 1348 00:47:56,520 --> 00:47:58,080 INFUSION WITH ONE PATIENT HAVING 1349 00:47:58,080 --> 00:48:00,000 PARTIAL REMISSION AFTER THE 1350 00:48:00,000 --> 00:48:01,720 FIRST VST INFUSION ULTIMATELY 1351 00:48:01,720 --> 00:48:03,320 GOING INTO SUSTAINED REMISSION 1352 00:48:03,320 --> 00:48:04,600 AFTER A SECOND INFUSION. 1353 00:48:04,600 --> 00:48:07,040 ONE PATIENT HAD ORGAN-SPECIFIC 1354 00:48:07,040 --> 00:48:08,200 VIRAL DISEASE, WHO UNFORTUNATELY 1355 00:48:08,200 --> 00:48:09,240 DID HAVE PROGRESSIVE DISEASE 1356 00:48:09,240 --> 00:48:11,640 AFTER THE FIRST VST INFUSION, 1357 00:48:11,640 --> 00:48:14,040 BUT ULTIMATELY WENT INTO 1358 00:48:14,040 --> 00:48:16,280 SUSTAINED REMISSION AFTER THE 1359 00:48:16,280 --> 00:48:17,560 SECOND VST INFUSION. 1360 00:48:17,560 --> 00:48:19,360 IT IS IMPORTANT TO NOTE ALL OF 1361 00:48:19,360 --> 00:48:20,640 THESE CLINICAL TRIALS WERE PHASE 1362 00:48:20,640 --> 00:48:22,040 1, PHASE 2 SO PATIENTS IN THE 1363 00:48:22,040 --> 00:48:23,240 TREATMENT GROUP WERE ALLOWED TO 1364 00:48:23,240 --> 00:48:26,480 BE RECEIVING CONCOMITANT 1365 00:48:26,480 --> 00:48:29,120 STANDARD ANTIVIRAL THERAPY. 1366 00:48:29,120 --> 00:48:34,480 IN THE -- WHEN WE WENT BACK AND 1367 00:48:34,480 --> 00:48:35,840 LOOKED AT THE VST PRODUCT FOR 1368 00:48:35,840 --> 00:48:37,600 THAT PATIENT, IT WAS IDENTIFIED 1369 00:48:37,600 --> 00:48:39,200 THAT IT LACKED SPECIFICITY FOR 1370 00:48:39,200 --> 00:48:43,840 THAT PARTICULAR VIRUS. 1371 00:48:43,840 --> 00:48:49,360 JUST IN TERMS OF SAFETY, NO 1372 00:48:49,360 --> 00:48:50,760 PATIENTS DIED FOLLOWING VST 1373 00:48:50,760 --> 00:48:53,000 INFUSION AND ALL REMAINED FREE 1374 00:48:53,000 --> 00:48:54,240 OF SICKLE CELL DISEASE. 1375 00:48:54,240 --> 00:48:57,600 TWO PATIENTS DID DEVELOP 1376 00:48:57,600 --> 00:48:58,240 GRAFT-VERSUS-HOST DISEASE GRADE 1377 00:48:58,240 --> 00:49:01,760 III OR HIGHER BUT -- WHEN WE 1378 00:49:01,760 --> 00:49:03,200 LOOKED AT THE T-CELL ANTIGEN 1379 00:49:03,200 --> 00:49:04,520 RESPONSE TO THE TARGET VIRUSES 1380 00:49:04,520 --> 00:49:05,880 IN THE PATIENTS, WE CAN SEE THAT 1381 00:49:05,880 --> 00:49:08,360 IN THOSE PATIENTS WHO RECEIVED 1382 00:49:08,360 --> 00:49:10,000 VSTs FOR TREATMENT, THE TIME 1383 00:49:10,000 --> 00:49:12,040 TO T-CELL ANTIGEN RESPONSE IN 1384 00:49:12,040 --> 00:49:14,560 VIVO, SO IN THE PATIENT'S 1385 00:49:14,560 --> 00:49:16,440 PERIPHERAL BLOOD POST-INFUSION, 1386 00:49:16,440 --> 00:49:17,360 IT WAS SHORTER THAN THOSE 1387 00:49:17,360 --> 00:49:19,520 PATIENTS WHO RECEIVED VSTs FOR 1388 00:49:19,520 --> 00:49:21,480 PROPHYLAXIS FOR CMV AND EBV. 1389 00:49:21,480 --> 00:49:23,400 AND SO THIS INDICATES TO US THAT 1390 00:49:23,400 --> 00:49:27,320 THERE'S LIKELY A ROLE FOR -- 1391 00:49:27,320 --> 00:49:28,520 ANTIGEN PRESENTATION IN THE POST 1392 00:49:28,520 --> 00:49:30,400 VST INFUSION THAT ENHANCES 1393 00:49:30,400 --> 00:49:34,000 T-CELL EXPANSION AND PERSIST 1394 00:49:34,000 --> 00:49:34,280 PERSISTENCE. 1395 00:49:34,280 --> 00:49:35,480 THIS IS FURTHER SHOWN IN THESE 1396 00:49:35,480 --> 00:49:38,760 PATIENTS WHO ONLY RECEIVED 1397 00:49:38,760 --> 00:49:41,240 HHV6 AND HUMAN PARAINFLUENZA 1398 00:49:41,240 --> 00:49:43,320 VIRUS, THREE SPECIFIC T-CELLS 1399 00:49:43,320 --> 00:49:44,840 FOR PROPHYLAXIS, SO NONE OF 1400 00:49:44,840 --> 00:49:46,400 THESE PATIENTS HAD ACTIVE 1401 00:49:46,400 --> 00:49:46,800 DISEASE. 1402 00:49:46,800 --> 00:49:48,800 YOU CAN SEE THE TIME TO T-CELL 1403 00:49:48,800 --> 00:49:51,640 ANTIGEN RESPONSE IS QUITE LATE, 1404 00:49:51,640 --> 00:49:53,000 AROUND 180 DAYS POST VST 1405 00:49:53,000 --> 00:49:57,680 INFUSION. 1406 00:49:57,680 --> 00:50:00,080 SO THIS REVIEW OUTLINED 1407 00:50:00,080 --> 00:50:01,720 LIMITATIONS AND FUTURE 1408 00:50:01,720 --> 00:50:02,360 DIRECTIONS WHERE WE CAN FURTHER 1409 00:50:02,360 --> 00:50:06,880 THE FIELD IN THIS AREA. 1410 00:50:06,880 --> 00:50:08,280 PARTICULARLY WITH RESPECT TO 1411 00:50:08,280 --> 00:50:10,240 ANTIGEN SPECIFICITY AND THE 1412 00:50:10,240 --> 00:50:11,600 VARIABILITY BETWEEN DR. VST SO 1413 00:50:11,600 --> 00:50:13,800 CAN IMPROVE THE SPECIFICITY. 1414 00:50:13,800 --> 00:50:14,080 OF 1415 00:50:14,080 --> 00:50:17,320 THOSE PRODUCTS AND CAUSE 1416 00:50:17,320 --> 00:50:19,240 INCREASE IN RESPONSE, CLINICAL 1417 00:50:19,240 --> 00:50:19,960 RESPONSE. 1418 00:50:19,960 --> 00:50:21,800 BUT ALSO TO LOOK AT THE THIRD 1419 00:50:21,800 --> 00:50:26,200 PARTY DONOR POPULATION IN TERMS 1420 00:50:26,200 --> 00:50:28,040 OF EXPANDING THAT BANK OF 1421 00:50:28,040 --> 00:50:30,720 PATIENTS WHO WE KNOW HAVE A GOOD 1422 00:50:30,720 --> 00:50:33,600 RESPONSE TO THE TARGET VIRUS 1423 00:50:33,600 --> 00:50:35,320 ANTIGENS. 1424 00:50:35,320 --> 00:50:36,440 THE CHALLENGE WITH OR SICKLE 1425 00:50:36,440 --> 00:50:37,640 CELL POPULATION OF COURSE IS YOU 1426 00:50:37,640 --> 00:50:40,640 STILL ARE GOING TO HAVE A 1427 00:50:40,640 --> 00:50:42,720 REASONABLE HLA-MATCHED DONOR 1428 00:50:42,720 --> 00:50:47,680 WITHIN THAT THIRD PARTY BANK. 1429 00:50:47,680 --> 00:50:48,520 AND THEN FURTHER TO LOOK AT THE 1430 00:50:48,520 --> 00:50:50,400 OPTIMAL TIMING OF VST INFUSION 1431 00:50:50,400 --> 00:50:52,680 FOR PROPHYLAXIS POST TRANSPLANT, 1432 00:50:52,680 --> 00:50:54,760 IT HAS YET TO BE ILL LEWIS DATED 1433 00:50:54,760 --> 00:51:00,800 ELUCIDATED BUTLIKELY CLOSER TO F 1434 00:51:00,800 --> 00:51:01,920 TRANSPLANT GIVEN -- THE 1435 00:51:01,920 --> 00:51:02,800 PROLONGED PERIOD OF TIME BEFORE 1436 00:51:02,800 --> 00:51:06,040 WE SEE A T-CELL IMMUNE RESPONSE 1437 00:51:06,040 --> 00:51:08,440 FOLLOWING VST INFUSION. 1438 00:51:08,440 --> 00:51:11,160 HOWEVER, ALL OF THIS DATA DOES 1439 00:51:11,160 --> 00:51:15,640 ADD TO THE BODY OF EVIDENCE 1440 00:51:15,640 --> 00:51:16,880 FURTHER SUPPORTING THE SAFETY OF 1441 00:51:16,880 --> 00:51:18,520 OUR SPECIFIC T-CELL INFUSION BUT 1442 00:51:18,520 --> 00:51:20,600 MORE SPECIFICALLY NOW WITHIN THE 1443 00:51:20,600 --> 00:51:23,000 SICKLE CELL DISEASE POPULATION. 1444 00:51:23,000 --> 00:51:25,480 AND SHOWS THAT THESE VSTs MAY 1445 00:51:25,480 --> 00:51:27,880 BE EFFECTIVE IN TREATMENT AND 1446 00:51:27,880 --> 00:51:32,160 PROPHYLAXIS IN OUR PATIENTS. 1447 00:51:32,160 --> 00:51:35,280 SO I'D LIKE TO THANK ALL OF OUR 1448 00:51:35,280 --> 00:51:36,600 COLLABORATORS AS WELL AS 1449 00:51:36,600 --> 00:51:39,520 EVERYONE IN THE STUDY LAB AT 1450 00:51:39,520 --> 00:51:42,520 CHILDREN'S NATIONAL HOSPITAL, 1451 00:51:42,520 --> 00:51:46,120 PARTICULARLY DR. ALLISTAIR 1452 00:51:46,120 --> 00:51:47,760 ABRAHAM WHO REALLY CHAMPIONED 1453 00:51:47,760 --> 00:51:49,840 THIS WORK. 1454 00:51:49,840 --> 00:51:51,360 >>THANK YOU. 1455 00:51:51,360 --> 00:51:53,080 I'M REALLY AMAZED AT HOW MUCH 1456 00:51:53,080 --> 00:51:56,880 WORK IS GOING ON IN THIS FIELD 1457 00:51:56,880 --> 00:51:58,120 COVERING SO MANY DIFFERENT 1458 00:51:58,120 --> 00:51:58,520 THEMES. 1459 00:51:58,520 --> 00:52:01,360 TO ADDRESS YET ANOTHER IMPORTANT 1460 00:52:01,360 --> 00:52:04,360 THEME, I'D LIKE TO INVITE 1461 00:52:04,360 --> 00:52:05,760 DR. ELIZABETH STENGER FROM EMORY 1462 00:52:05,760 --> 00:52:08,640 UNIVERSITY TO SPEAK ON LONG TERM 1463 00:52:08,640 --> 00:52:10,000 ORGAN FUNCTION AFTER TRANSPLANT 1464 00:52:10,000 --> 00:52:12,600 FOR SICKLE CELL DISEASE, A 1465 00:52:12,600 --> 00:52:14,240 REPORT FROM THE SICKLE CELL 1466 00:52:14,240 --> 00:52:16,240 TRANSPLANT ADVOCACY AND RESEARCH 1467 00:52:16,240 --> 00:52:17,000 ALLIANCE, STAR. 1468 00:52:17,000 --> 00:52:19,880 BETH? 1469 00:52:19,880 --> 00:52:23,640 >>THANK YOU, KRISH. 1470 00:52:23,640 --> 00:52:25,160 THIS IS A DISCLOSURE ABOUT STAR 1471 00:52:25,160 --> 00:52:26,560 BUT IS NOT RELEVANT TO THE DATA 1472 00:52:26,560 --> 00:52:27,760 I'M PRESENTING TODAY. 1473 00:52:27,760 --> 00:52:29,360 SO AS BACKGROUND, WE KNOW THAT 1474 00:52:29,360 --> 00:52:30,440 PERSONS WITH SICKLE CELL DISEASE 1475 00:52:30,440 --> 00:52:32,440 HAVE SIGNIFICANT MORBIDITY AS 1476 00:52:32,440 --> 00:52:34,000 WELL AS EARLY MORTALITY DESPITE 1477 00:52:34,000 --> 00:52:35,960 MODERN MEDICAL CARE, AND THAT 1478 00:52:35,960 --> 00:52:37,280 HCT IS THE ONLY CURATIVE 1479 00:52:37,280 --> 00:52:39,080 TREATMENT SUPPORTED BY LONG-TERM 1480 00:52:39,080 --> 00:52:40,520 DATA AT THIS POINT. 1481 00:52:40,520 --> 00:52:44,800 AND JUST BY INCREASING USE OF 1482 00:52:44,800 --> 00:52:45,440 TRANSPLANT PARTICULARLY IN THE 1483 00:52:45,440 --> 00:52:47,600 MOST RECENT DECADE, THERE'S 1484 00:52:47,600 --> 00:52:48,880 LIMITED SPECIFIC SICKLE CELL 1485 00:52:48,880 --> 00:52:52,480 SPECIFIC DATA ON LONG TERM ORGAN 1486 00:52:52,480 --> 00:52:54,080 FUNCTION AFTER TRANSPLANT, SO WE 1487 00:52:54,080 --> 00:52:55,480 SOUGHT TO ASSESS THE PREVALENCE 1488 00:52:55,480 --> 00:52:56,720 OF RISK IN THIS POPULATION 1489 00:52:56,720 --> 00:52:57,920 FOLLOWING TRANSPLANT. 1490 00:52:57,920 --> 00:52:59,120 WE HYPOTHESIZED THAT MOST 1491 00:52:59,120 --> 00:53:00,720 PATIENTS WILL HAVE STABLE TO 1492 00:53:00,720 --> 00:53:01,800 IMPROVED ORGAN FUNCTION 1493 00:53:01,800 --> 00:53:03,320 FOLLOWING TRANSPLANT AND SOME OF 1494 00:53:03,320 --> 00:53:05,520 THE PREDICTORS FOR ORGAN 1495 00:53:05,520 --> 00:53:08,440 DYSFUNCTION WOULD BE THOSE 1496 00:53:08,440 --> 00:53:08,880 LISTED. 1497 00:53:08,880 --> 00:53:11,480 FOR OUR METHODS, WE USED THE 1498 00:53:11,480 --> 00:53:13,000 STAR ALLIANCE RETROSPECTIVE 1499 00:53:13,000 --> 00:53:14,240 REGISTRY, WHICH INCLUDED 300 1500 00:53:14,240 --> 00:53:16,400 PATIENTS WHO HAD UNDERGONE 1501 00:53:16,400 --> 00:53:17,600 TRANSPLANT FOR SICKLE CELL 1502 00:53:17,600 --> 00:53:17,920 DISEASE. 1503 00:53:17,920 --> 00:53:19,840 PER THIS ANALYSIS, WE EXCLUDED 1504 00:53:19,840 --> 00:53:21,440 PATIENTS WHO HAD DIED OR WERE 1505 00:53:21,440 --> 00:53:23,640 LOST TO FOLLOW-UP PRIOR TO ONE 1506 00:53:23,640 --> 00:53:25,640 YEAR, SO THAT REMOVED 24 1507 00:53:25,640 --> 00:53:26,760 PATIENTS FROM THE ANALYSIS, AND 1508 00:53:26,760 --> 00:53:28,480 WE REMOVED PATIENTS WHO HAD 1509 00:53:28,480 --> 00:53:30,360 GRAFT FAILURE SECOND TRANSPLANT, 1510 00:53:30,360 --> 00:53:32,880 WHICH INCLUDED 29 PATIENTS. 1511 00:53:32,880 --> 00:53:35,280 WHICH LEFT US WITH 247 PATIENTS 1512 00:53:35,280 --> 00:53:37,120 FROM 13 STAR CENTERS IN THE U.S. 1513 00:53:37,120 --> 00:53:37,920 AND CANADA. 1514 00:53:37,920 --> 00:53:39,600 IN THIS ANALYSIS. 1515 00:53:39,600 --> 00:53:42,680 AND WITHIN THIS COHORT, WE 1516 00:53:42,680 --> 00:53:44,200 EVALUATED -- FOR THE PURPOSES OF 1517 00:53:44,200 --> 00:53:46,120 THIS PRESENTATION, I LIMIT TO 1518 00:53:46,120 --> 00:53:47,760 CARDIAC, PULMONARY AND 1519 00:53:47,760 --> 00:53:48,280 NEUROLOGIC DYSFUNCTION. 1520 00:53:48,280 --> 00:53:51,040 BUT THE PAPER DOES INCLUDE OTHER 1521 00:53:51,040 --> 00:53:53,160 ORGANS AS WELL. 1522 00:53:53,160 --> 00:53:55,880 AND FOR OUR MULTIVARIABLE COX 1523 00:53:55,880 --> 00:53:56,760 REGRESSION ANALYSIS, WE LIMITED 1524 00:53:56,760 --> 00:53:58,080 TO THESE THREE ORGANS. 1525 00:53:58,080 --> 00:54:00,200 THESE ARE OUR DEFINITIONS FOR 1526 00:54:00,200 --> 00:54:01,080 CARDIAC DYSFUNCTION. 1527 00:54:01,080 --> 00:54:05,480 LOWY JEX OR SHORTENING FRACTION, 1528 00:54:05,480 --> 00:54:07,280 PULMONARY DYSFUNCTION 1529 00:54:07,280 --> 00:54:08,880 RESTRICTIVE LUNG DISEASE OR ON 1530 00:54:08,880 --> 00:54:10,520 STRUCK TOUGH LUNG DISEASE. 1531 00:54:10,520 --> 00:54:14,440 NEUROLOGIC DYSFUNCTION, EVENTS 1532 00:54:14,440 --> 00:54:16,520 WERE INCLUDED AS NEW OR 1533 00:54:16,520 --> 00:54:17,600 PROGRESSIVE VASCULOPATHY OR 1534 00:54:17,600 --> 00:54:19,160 INFARCTS FOLLOWING TRANSPLANT. 1535 00:54:19,160 --> 00:54:21,360 THESE ARE OUR BASELINE SICKLE 1536 00:54:21,360 --> 00:54:22,440 CELL PATIENT CHARACTERISTICS FOR 1537 00:54:22,440 --> 00:54:24,520 THIS COHORT. 1538 00:54:24,520 --> 00:54:29,520 MEDIAN AGE IS 9.4 YEARS, PRETTY 1539 00:54:29,520 --> 00:54:33,560 EVENLY SPLIT MALE VERSUS THEE 1540 00:54:33,560 --> 00:54:35,520 MAIL, TWO THIRDS HAD SEVERE 1541 00:54:35,520 --> 00:54:37,040 CLINICAL DISEASE SEVERITY COMING 1542 00:54:37,040 --> 00:54:39,640 INTO TRANSPLANT WITH INDICATIONS 1543 00:54:39,640 --> 00:54:40,200 AS LISTED. 1544 00:54:40,200 --> 00:54:43,120 ABOUT A THIRD HAD RECEIVED 1545 00:54:43,120 --> 00:54:44,720 HYDROXYUREA TREATMENT COMING 1546 00:54:44,720 --> 00:54:45,920 INTO TRANSPLANT AND ABOUT HALF 1547 00:54:45,920 --> 00:54:47,920 HAD A HISTORY OF CHRONIC RED 1548 00:54:47,920 --> 00:54:52,440 BLOOD CELL TRANSFUSIONS SO OVER 1549 00:54:52,440 --> 00:54:54,520 A LIFETIME TRANSPLANTS RECEIVED 1550 00:54:54,520 --> 00:54:55,720 WERE HIGH AND IN THE 52 PATIENTS 1551 00:54:55,720 --> 00:54:58,040 WE HAD DATA WAS A MEDIAN OF 6. 1552 00:54:58,040 --> 00:55:00,720 OUR TRANSPLANT CHARACTERISTICS 1553 00:55:00,720 --> 00:55:02,280 MEDIAN YEAR OF TRANSPLANT WAS 1554 00:55:02,280 --> 00:55:03,000 2012. 1555 00:55:03,000 --> 00:55:03,640 ABOUT THREE QUARTERS OF THE 1556 00:55:03,640 --> 00:55:05,640 PATIENTS HAD A MATCH-RELATED 1557 00:55:05,640 --> 00:55:07,280 DONOR, WITH MOST OTHER PATIENT 1558 00:55:07,280 --> 00:55:09,480 HAVING A MATCHED OR MISMATCHED 1559 00:55:09,480 --> 00:55:10,560 UNRELATED DONOR. 1560 00:55:10,560 --> 00:55:11,880 MOST PATIENTS RECEIVED BONE 1561 00:55:11,880 --> 00:55:13,160 MARROW AS THEIR STEM CELL 1562 00:55:13,160 --> 00:55:14,840 SOURCE. 1563 00:55:14,840 --> 00:55:17,320 SLIGHTLY MORE THAN HALF RECEIVED 1564 00:55:17,320 --> 00:55:18,080 MYELOABLATIVE CONDITIONING SO WE 1565 00:55:18,080 --> 00:55:19,880 HAD A PRETTY DECENT PROPORTION 1566 00:55:19,880 --> 00:55:22,400 WHO RECEIVED REDUCED INTENSITY 1567 00:55:22,400 --> 00:55:23,000 CONDITIONING. 1568 00:55:23,000 --> 00:55:24,880 NEARLY ALL RECEIVED T-CELL 1569 00:55:24,880 --> 00:55:26,080 DEPLETION, WHICH IS STANDARD IN 1570 00:55:26,080 --> 00:55:28,800 THIS POPULATION, AND MOST 1571 00:55:28,800 --> 00:55:32,480 RECEIVED INHIBITOR FOR 1572 00:55:32,480 --> 00:55:32,800 PROPHYLAXIS. 1573 00:55:32,800 --> 00:55:35,880 AT A HIGH LEVEL OF TRANSPLANT 1574 00:55:35,880 --> 00:55:37,040 OUTCOME, AT TIME OF LAST 1575 00:55:37,040 --> 00:55:37,960 FOLLOW-UP WHICH IS MEDIAN OF 1576 00:55:37,960 --> 00:55:44,080 THREE YEARS, DONOR CHIMERISM RAS 1577 00:55:44,080 --> 00:55:44,520 99 TO 100%. 1578 00:55:44,520 --> 00:55:45,560 ABOUT A QUARTER OF PATIENTS 1579 00:55:45,560 --> 00:55:47,720 OVERALL HAD ACUTE OR CHRONIC 1580 00:55:47,720 --> 00:55:49,520 GVHD WITH THE SE VAIRTS LISTED 1581 00:55:49,520 --> 00:55:49,720 THERE. 1582 00:55:49,720 --> 00:55:52,880 AT THE TIME OF LAST FOLLOW-UP, 1583 00:55:52,880 --> 00:55:55,200 14 PATIENTS OR ABOUT 6% REQUIRED 1584 00:55:55,200 --> 00:55:56,760 CONTINUED IMMUNE SUPPRESSION, 1585 00:55:56,760 --> 00:55:58,440 WITH THE PRIMARY INDICATION 1586 00:55:58,440 --> 00:56:00,520 BEING GVHD, AND 13 PATIENTS DIED 1587 00:56:00,520 --> 00:56:02,400 IN THIS COHORT, MEANING THEY 1588 00:56:02,400 --> 00:56:04,000 DIED BEYOND ONE YEAR POST 1589 00:56:04,000 --> 00:56:05,040 TRANSPLANT. 1590 00:56:05,040 --> 00:56:07,160 MAJORITY FROM GVHD OR FROM 1591 00:56:07,160 --> 00:56:10,160 INFECTIONS WITHOUT GVHD. 1592 00:56:10,160 --> 00:56:12,560 SO MOVING TO OUR ORGAN 1593 00:56:12,560 --> 00:56:14,520 DYSFUNCTION, FIRST CARDIAC. 1594 00:56:14,520 --> 00:56:17,520 MOST RECENT ECHO PERFORMED AND A 1595 00:56:17,520 --> 00:56:21,480 MEDIAN OF 2.3 YEARS POST 1596 00:56:21,480 --> 00:56:22,680 TRANSPLANT. 1597 00:56:22,680 --> 00:56:24,840 EF DECREASED SIGNIFICANTLY FROM 1598 00:56:24,840 --> 00:56:28,520 THE PRETO THE POST ECHO. 1599 00:56:28,520 --> 00:56:30,960 ONLY A SUBSET OF 31 PATIENTS -- 1600 00:56:30,960 --> 00:56:32,560 AND THIS DID DECREASE SLIGHT 1601 00:56:32,560 --> 00:56:35,920 SLIETLY BUT NOT SIGNIFICANTLY. 1602 00:56:35,920 --> 00:56:38,120 THIS DATA IS ALSO SHOWN BY 1603 00:56:38,120 --> 00:56:39,720 CATEGORIZING AS LOW EF IN BLUE 1604 00:56:39,720 --> 00:56:43,760 OR LOW SF IN PINK PRE VERSUS 1605 00:56:43,760 --> 00:56:45,280 POST TRANSPLANT AND THERE WAS AN 1606 00:56:45,280 --> 00:56:46,560 INCREASED PROPORTION POST 1607 00:56:46,560 --> 00:56:48,640 TRANSPLANT OF THOSE WHO HAD LOW 1608 00:56:48,640 --> 00:56:55,720 EF ON THE LEFT AND LOW FF SF OE 1609 00:56:55,720 --> 00:56:58,120 RIGHT WHICH WAS SIGNIFICANTLY 1610 00:56:58,120 --> 00:56:58,680 SIGNIFICANT. 1611 00:56:58,680 --> 00:57:01,320 MOST RECENT PFTs PERFORMED AT 1612 00:57:01,320 --> 00:57:04,120 A MEDIAN OF 2.4 YEARS. 1613 00:57:04,120 --> 00:57:06,880 NO SIGNIFICANT CHANGE SEEN IN 1614 00:57:06,880 --> 00:57:09,000 FEV1, FVC OR DLCO. 1615 00:57:09,000 --> 00:57:11,440 WHEN WE CATEGORIZED PATIENT WE 1616 00:57:11,440 --> 00:57:13,960 DID NOT SEE A DIFFERENCE 1617 00:57:13,960 --> 00:57:14,640 PREVERSUS POST TRANSPLANT, 1618 00:57:14,640 --> 00:57:16,040 ALTHOUGH WE DID HAVE A SIZABLE 1619 00:57:16,040 --> 00:57:17,800 PROPORTION WITH RESTRICTIVE LUNG 1620 00:57:17,800 --> 00:57:20,360 DISEASE AT BOTH TIME POINTS. 1621 00:57:20,360 --> 00:57:22,000 IN TERMINGS OF NEUROLOGIC 1622 00:57:22,000 --> 00:57:22,960 OUTCOMES, THERE WERE NINE 1623 00:57:22,960 --> 00:57:24,240 STROKES THAT OCCURRED IN EIGHT 1624 00:57:24,240 --> 00:57:24,600 PATIENTS. 1625 00:57:24,600 --> 00:57:26,880 ONE HAD A HEMORRHAGIC AND AN 1626 00:57:26,880 --> 00:57:28,200 ISCHEMIC STROKE AND THESE 1627 00:57:28,200 --> 00:57:29,920 OCCURRED AT A MEDIAN OF 47 DAYS 1628 00:57:29,920 --> 00:57:32,720 RANGING FROM ZERO TRANSPLANT DAY 1629 00:57:32,720 --> 00:57:33,520 TO 243 DAYS POST. 1630 00:57:33,520 --> 00:57:36,240 WE HAD 159 PATIENTS THAT HAD 1631 00:57:36,240 --> 00:57:38,280 PREA AND POST TRANSPLANT BRAIN 1632 00:57:38,280 --> 00:57:40,240 MRI DATA REPORTED WITH THE POST 1633 00:57:40,240 --> 00:57:43,040 TRANSPLANT MRI PERFORMED AT A 1634 00:57:43,040 --> 00:57:44,720 MEDIAN OF 2.1 YEARS. 1635 00:57:44,720 --> 00:57:46,560 MAJORITY OF PATIENTS HAD NORMAL 1636 00:57:46,560 --> 00:57:48,280 OR STABLE FINDINGS MEANING 1637 00:57:48,280 --> 00:57:49,880 FINDINGS THEY HAD PRETRANSPLANT 1638 00:57:49,880 --> 00:57:51,760 WERE STABLE ON LAS FOLLOW-UP 1639 00:57:51,760 --> 00:57:52,080 MRI. 1640 00:57:52,080 --> 00:57:54,080 SEVEN PATIENTS HAD A NEW INFARCT 1641 00:57:54,080 --> 00:57:55,440 AND SIX PATIENTS EACH HAD A 1642 00:57:55,440 --> 00:57:58,400 PROGRESSIVE INFARCT, NEW 1643 00:57:58,400 --> 00:58:00,920 VASCULOPATHY OR PROGRESSIVE 1644 00:58:00,920 --> 00:58:01,240 VASCULOPATHY. 1645 00:58:01,240 --> 00:58:02,400 THESE ARE WHAT WERE COUNTED AS 1646 00:58:02,400 --> 00:58:03,520 EVENTS IN OUR MODELS. 1647 00:58:03,520 --> 00:58:05,800 SO NEXT MOVING TO OUR MODELS, I 1648 00:58:05,800 --> 00:58:07,600 DO NOT SHOW A FIGURE FOR 1649 00:58:07,600 --> 00:58:08,600 PULMONARY DYSFUNCTION BECAUSE 1650 00:58:08,600 --> 00:58:09,560 POST TRANSPLANT EENT WERE RARE, 1651 00:58:09,560 --> 00:58:11,600 SO WE DID NOT SEE ANY RISK 1652 00:58:11,600 --> 00:58:14,600 FACTORS THAT PREDICTED FOR 1653 00:58:14,600 --> 00:58:15,680 PULMONARY DYSFUNCTION POST 1654 00:58:15,680 --> 00:58:16,000 TRANSPLANT. 1655 00:58:16,000 --> 00:58:18,040 ON THE LEFT IS OUR CARDIAC 1656 00:58:18,040 --> 00:58:18,800 DYSFUNCTION MODEL. 1657 00:58:18,800 --> 00:58:21,640 THOSE WHO DEVELOPED SEVERE GRADE 1658 00:58:21,640 --> 00:58:23,760 3 TO 4 OR RECEIVED MYELOABLATIVE 1659 00:58:23,760 --> 00:58:26,000 CONDITIONING HAD A SIGNIFICANTLY 1660 00:58:26,000 --> 00:58:27,680 HIGHER RISK FOR DEVELOPMENT OF 1661 00:58:27,680 --> 00:58:28,280 CARDIAC DYSFUNCTION POST 1662 00:58:28,280 --> 00:58:28,800 TRANSPLANT. 1663 00:58:28,800 --> 00:58:31,280 ON THE RIGHT IS OUR MODEL FOR 1664 00:58:31,280 --> 00:58:32,880 NEW OR PROGRESSIVE CNS DISEASE 1665 00:58:32,880 --> 00:58:35,440 AND IN THIS MODEL WE ADJUSTED 1666 00:58:35,440 --> 00:58:37,320 FOR ACUTE GVHD, YEAR OF 1667 00:58:37,320 --> 00:58:38,400 TRANSPLANT AND CLINICAL 1668 00:58:38,400 --> 00:58:39,880 PHENOTYPE OR CLINICAL SEVERITY 1669 00:58:39,880 --> 00:58:40,640 COMING INTO TRANSPLANT, AND 1670 00:58:40,640 --> 00:58:44,560 THOSE WHO HAD A CNS INDICATION 1671 00:58:44,560 --> 00:58:46,200 FOR TRANSPLANT HAD SIGNIFICANTLY 1672 00:58:46,200 --> 00:58:49,400 HIGHER RISK TO DEVELOPING NEW OR 1673 00:58:49,400 --> 00:58:50,440 SIGNIFICANT -- POST TRANSPLANT. 1674 00:58:50,440 --> 00:58:52,480 WE ALSO LOOKED AT COMPOSITE 1675 00:58:52,480 --> 00:58:52,920 ORGAN DYSFUNCTION. 1676 00:58:52,920 --> 00:58:54,880 THIS SHOWS A SCORING MODEL WE 1677 00:58:54,880 --> 00:58:57,080 USED TO SCORE EACH SEPARATELY 1678 00:58:57,080 --> 00:58:58,360 FROM ZERO TO 2 SO TOTAL SCORE 1679 00:58:58,360 --> 00:59:01,680 RANGED FROM ZERO TO A MAXIMUM OF 1680 00:59:01,680 --> 00:59:02,200 6. 1681 00:59:02,200 --> 00:59:03,320 THAT MODEL IS SHOWN ON THE LEFT 1682 00:59:03,320 --> 00:59:05,320 WHERE AFTER WE ADJUSTED FOR CNS 1683 00:59:05,320 --> 00:59:07,400 INDICATION YEAR OF TRANSPLANT 1684 00:59:07,400 --> 00:59:11,200 AND ACCUSE GVHD THOSE WHO HAD A 1685 00:59:11,200 --> 00:59:12,200 SEVERE -- HAD SIGNIFICANTLY 1686 00:59:12,200 --> 00:59:14,360 HIGHER RISK FOR HAVING A HIGHER 1687 00:59:14,360 --> 00:59:16,000 COMPOSITE ORGAN DYSFUNCTION 1688 00:59:16,000 --> 00:59:16,200 SCORE. 1689 00:59:16,200 --> 00:59:17,800 ON THE RIGHT WE LOOKED AT AN END 1690 00:59:17,800 --> 00:59:21,200 POINT OF ONE OR MORE ORGAN 1691 00:59:21,200 --> 00:59:22,080 DYSFUNCTION AND AFTER ADJUSTING 1692 00:59:22,080 --> 00:59:24,240 FOR CNS INDICATION THOSE WHO 1693 00:59:24,240 --> 00:59:25,240 UNDERWENT TRANSPLANT AT GREATER 1694 00:59:25,240 --> 00:59:26,960 OR EQUAL TO 16 YEARS OF AGE HAD 1695 00:59:26,960 --> 00:59:28,920 A HIGHER RISK FOR HAVING ONE OR 1696 00:59:28,920 --> 00:59:30,440 MORE ORGAN WITH DYSFUNCTION POST 1697 00:59:30,440 --> 00:59:32,040 TRANSPLANT. 1698 00:59:32,040 --> 00:59:36,080 SO IN CONCLUSION, USING THIS 1699 00:59:36,080 --> 00:59:37,680 PEDIATRIC RETROSPECTIVE DATASET, 1700 00:59:37,680 --> 00:59:39,560 WE FOUND THE PREVALENCE OF ORGAN 1701 00:59:39,560 --> 00:59:41,000 DYSFUNCTION OVERALL TO BE LOW 1702 00:59:41,000 --> 00:59:42,200 FOLLOWING TRANSPLANT FOR SICKLE 1703 00:59:42,200 --> 00:59:43,400 CELL DISEASE, JUST NOTING A 1704 00:59:43,400 --> 00:59:44,800 SLIGHT INCREASE IN CARDIAC 1705 00:59:44,800 --> 00:59:45,880 DYSFUNCTION USING THE 1706 00:59:45,880 --> 00:59:48,360 DEFINITIONS WE USE IN STABLE 1707 00:59:48,360 --> 00:59:49,560 PROPORTION WITH RESTRICTIVE LUNG 1708 00:59:49,560 --> 00:59:50,240 DISEASE. 1709 00:59:50,240 --> 00:59:51,640 I'VE LISTED SOME OF THE RISK 1710 00:59:51,640 --> 00:59:53,160 FACTORS WE FOUND IN OUR MODELS 1711 00:59:53,160 --> 00:59:55,000 FOR ORGAN DYSFUNCTION AND 1712 00:59:55,000 --> 00:59:56,440 OVERALL, WE FELT THAT THESE 1713 00:59:56,440 --> 00:59:57,760 RESULTS SUPPORT CONSIDERATION OF 1714 00:59:57,760 --> 00:59:58,840 TRANSPLANT AT A YOUNGER AGE AND 1715 00:59:58,840 --> 01:00:01,240 USE OF LESS INTENSE REGIMENS TO 1716 01:00:01,240 --> 01:00:02,640 MINIMIZE TOXICITY. 1717 01:00:02,640 --> 01:00:05,040 OBVIOUSLY BALANCING RISK FOR 1718 01:00:05,040 --> 01:00:06,360 INCREASED RATES OF REJECTION 1719 01:00:06,360 --> 01:00:09,480 WITH LESS INTENSE CONDITIONING. 1720 01:00:09,480 --> 01:00:10,600 FOR FUTURE DIRECTIONS WE'RE 1721 01:00:10,600 --> 01:00:13,440 CONTINUING WORK THROUGH THIS 1722 01:00:13,440 --> 01:00:14,600 RETROSPECTIVE REGISTRY 1723 01:00:14,600 --> 01:00:17,560 HIGHLIGHTING OTHER PROSPECTIVE 1724 01:00:17,560 --> 01:00:21,600 REGISTRY BY OUR REJ 1725 01:00:21,600 --> 01:00:23,960 BIOREPOSITORY AND MRI BANK 1726 01:00:23,960 --> 01:00:26,040 PROJECT SICKLE CURE LED BY 1727 01:00:26,040 --> 01:00:28,680 DR. GREG GUILCHER. 1728 01:00:28,680 --> 01:00:32,040 OTHER ONGOING IMPORTANT LATE 1729 01:00:32,040 --> 01:00:33,920 EFFECTS STELLAR AND COALESCE. 1730 01:00:33,920 --> 01:00:37,000 I'D LIKE TO ACKNOWLEDGE THE 1731 01:00:37,000 --> 01:00:39,600 STUDY TEAM, PARTICULARLY MY 1732 01:00:39,600 --> 01:00:45,800 CO-PI, DR. ALISTAIR ABRAHAM, 1733 01:00:45,800 --> 01:00:47,760 CO-AUTHORS AND OUR FUNDING 1734 01:00:47,760 --> 01:00:48,000 SOURCES. 1735 01:00:48,000 --> 01:00:54,040 THANK YOU. 1736 01:00:54,040 --> 01:00:55,440 >>WE'LL INTRODUCE OUR 1737 01:00:55,440 --> 01:00:57,320 NEXT SPEAKER. 1738 01:00:57,320 --> 01:01:05,280 SO DR. LAWAL IS PRESENTING NEXT, 1739 01:01:05,280 --> 01:01:08,160 INCREASED INCIDENCE OF 1740 01:01:08,160 --> 01:01:09,120 HEMATOLOGIC MALIGNANCIES IN 1741 01:01:09,120 --> 01:01:10,760 SICKLE CELL DISEASE AFTER 1742 01:01:10,760 --> 01:01:11,560 TRANSPLANT IN ADULTS WITH GRAFT 1743 01:01:11,560 --> 01:01:12,240 FAILURE AND MIXED CHIMERISM. 1744 01:01:12,240 --> 01:01:13,320 >>GOOD MORNING, EVERYONE. 1745 01:01:13,320 --> 01:01:21,000 THANK YOU FOR THIS OPPORTUNITY. 1746 01:01:21,000 --> 01:01:22,120 IN SICKLE CELL DISEASE, WE KNOW 1747 01:01:22,120 --> 01:01:25,560 THAT RBCs HAVE SHORTENED LIFE 1748 01:01:25,560 --> 01:01:29,400 SURVIVAL, AND THIS -- INCREASED 1749 01:01:29,400 --> 01:01:30,600 INFLAMMATORY MEDIATORS AND 1750 01:01:30,600 --> 01:01:33,000 ULTIMATELY DAMAGE TO THE BONE 1751 01:01:33,000 --> 01:01:34,040 MARROW MICROENVIRONMENT. 1752 01:01:34,040 --> 01:01:36,800 FORTUNATELY WE DO HAVE 1753 01:01:36,800 --> 01:01:37,480 THERAPEUTIC OPTIONS. 1754 01:01:37,480 --> 01:01:38,880 AT THE NIH, WE HAVE PATIENTS 1755 01:01:38,880 --> 01:01:41,680 COME FOR HLA-MATCHED SIBLING 1756 01:01:41,680 --> 01:01:43,440 TRANSPLANTATION USING THIS 1757 01:01:43,440 --> 01:01:44,720 CONDITION REGIMEN SHOWN HERE 1758 01:01:44,720 --> 01:01:48,760 WHICH UTILIZED AL TEUZ MAN, 1759 01:01:48,760 --> 01:01:54,880 USING 300 CENTIGRADE, ALONG WI 1760 01:01:54,880 --> 01:01:57,520 WITH -- WE'VE SEEN GRAFT FAILURE 1761 01:01:57,520 --> 01:02:02,280 AT 13% IN A STUDY PUBLISHED IN 1762 01:02:02,280 --> 01:02:06,880 2021, WITH COLLABORATORS AT 1763 01:02:06,880 --> 01:02:08,000 CHICAGO, AND AT THE NIH. 1764 01:02:08,000 --> 01:02:11,360 WE ALSO UTILIZED HAPLOIDENTICAL 1765 01:02:11,360 --> 01:02:11,920 TRANSPLANTATION. 1766 01:02:11,920 --> 01:02:21,920 AGAIN USING AL EM -- WHICH YOU E 1767 01:02:21,920 --> 01:02:23,760 AND SIROLIMUS. 1768 01:02:23,760 --> 01:02:25,120 USING THIS CONDITION AND 1769 01:02:25,120 --> 01:02:26,520 REGIMEN, WE SEE GRAFT FAILURE AT 1770 01:02:26,520 --> 01:02:31,920 50% IN A STUDY PUBLISHED BY 1771 01:02:31,920 --> 01:02:32,400 DR. FITZHUGH IN 2017. 1772 01:02:32,400 --> 01:02:34,760 NOW WE HAVE NEWER STUDIES AND 1773 01:02:34,760 --> 01:02:38,040 NEWER CONDITIONS AND REGIMENS 1774 01:02:38,040 --> 01:02:45,120 WHICH UTILIZE INTRAVENOUS 1775 01:02:45,120 --> 01:02:47,720 PENTOSTATIN AND DAILY ORAL 1776 01:02:47,720 --> 01:02:48,920 CYCLOPHOSPHAMIDE FOR 14 DAYS. 1777 01:02:48,920 --> 01:02:50,680 TO DATE THE INCIDENT OF GRAFT 1778 01:02:50,680 --> 01:02:52,440 FAILURE IS MUCH LOWER. 1779 01:02:52,440 --> 01:02:56,240 AT THE NIH PATIENTS ALSO UNDERGO 1780 01:02:56,240 --> 01:02:58,960 GENE THERAPY WHERE THEY UNDERGO 1781 01:02:58,960 --> 01:03:00,800 MYELOABLATIVE CONDITIONING. 1782 01:03:00,800 --> 01:03:02,440 I'LL CALL ATTENTION TO GROUP A 1783 01:03:02,440 --> 01:03:03,640 WHERE PATIENTS RECEIVED LOWER 1784 01:03:03,640 --> 01:03:06,240 CELL DOSES AND THUS HAD 1785 01:03:06,240 --> 01:03:07,320 INADEQUATE THERAPEUTIC RESPONSE 1786 01:03:07,320 --> 01:03:12,040 AND HAD ONGOING ANEMIA. 1787 01:03:12,040 --> 01:03:14,240 IN OUR PAPER PUBLISHED IN 2022, 1788 01:03:14,240 --> 01:03:15,640 WE REVIEWED OUR PATIENTS THAT 1789 01:03:15,640 --> 01:03:16,840 HAD GRAFT FAILURE WITH SICKLE 1790 01:03:16,840 --> 01:03:17,800 CELL DISEASE AFTER TRANSPLANT 1791 01:03:17,800 --> 01:03:19,880 AND THEY ULTIMATELY DEVELOPED 1792 01:03:19,880 --> 01:03:20,840 MDS OR AML. 1793 01:03:20,840 --> 01:03:22,120 HERE I'M SHOWING YOU FIVE 1794 01:03:22,120 --> 01:03:22,400 PATIENTS. 1795 01:03:22,400 --> 01:03:24,520 THEY ALL HAD A PHENOTYPE OF 1796 01:03:24,520 --> 01:03:25,320 HEMOGLOBIN SS. 1797 01:03:25,320 --> 01:03:27,040 WE CAN SEE THAT THEIR AGES RANGE 1798 01:03:27,040 --> 01:03:28,520 FROM 20 TO 44. 1799 01:03:28,520 --> 01:03:30,920 WE HAVE THREE MALES, TWO 1800 01:03:30,920 --> 01:03:31,920 FEMALES, TWO MATCHED SIBLING 1801 01:03:31,920 --> 01:03:34,760 DONOR AND THREE HAPLOs. 1802 01:03:34,760 --> 01:03:36,920 THE DAY OF GRAFT FAILURE RANGED 1803 01:03:36,920 --> 01:03:38,800 ANYWHERE FROM 73 DAYS TO SEVEN 1804 01:03:38,800 --> 01:03:39,200 MONTHS. 1805 01:03:39,200 --> 01:03:41,400 AS YOU CAN SEE HERE, ALL THE 1806 01:03:41,400 --> 01:03:42,880 PATIENTS HAD AML EXCEPT FOR ONE 1807 01:03:42,880 --> 01:03:45,480 THAT HAD MDS. 1808 01:03:45,480 --> 01:03:47,400 WHEN WE LOOK AT THE TIME OF 1809 01:03:47,400 --> 01:03:48,440 MALIGNANCY POST TRANSPLANT, WE 1810 01:03:48,440 --> 01:03:52,240 SEE THAT IT RANGES FROM 0.33 TO 1811 01:03:52,240 --> 01:03:53,680 5.5 YEARS, AND ALL OF THESE 1812 01:03:53,680 --> 01:03:55,720 PATIENTS ARE CURRENTLY DECEASED. 1813 01:03:55,720 --> 01:03:57,600 NEXT WE'RE LOOKING AT MIXED 1814 01:03:57,600 --> 01:03:58,800 CHIMERISM IN OUR PATIENT 1815 01:03:58,800 --> 01:04:00,320 POPULATION, AND THESE PATIENTS 1816 01:04:00,320 --> 01:04:02,280 DEVELOPED OTHER HEMATOLOGIC 1817 01:04:02,280 --> 01:04:03,200 MALIGNANCIES AFTER TRANSPLANT, 1818 01:04:03,200 --> 01:04:04,680 WHICH WE'LL REVIEW. 1819 01:04:04,680 --> 01:04:07,840 WE HAVE THREE PATIENTS, ONE THAT 1820 01:04:07,840 --> 01:04:13,120 HAD HEMOGLOBIN S BETA --, THE 1821 01:04:13,120 --> 01:04:16,480 AGES RANGE FROM 19 TO 503. 1822 01:04:16,480 --> 01:04:18,040 WE HAVE TWO MALES AND ONE FEMALE 1823 01:04:18,040 --> 01:04:19,640 AND THEY WERE ALL PART OF THE 1824 01:04:19,640 --> 01:04:21,240 MATCHED SIBLING DONOR 1825 01:04:21,240 --> 01:04:21,640 TRANSPLANTATION. 1826 01:04:21,640 --> 01:04:22,520 AS YOU CAN SEE, THESE PATIENTS 1827 01:04:22,520 --> 01:04:24,680 DID NOT HAVE GRAFT FAILURE, AS 1828 01:04:24,680 --> 01:04:27,280 DEMONSTRATED BY THEIR CONTINUED 1829 01:04:27,280 --> 01:04:29,200 DONOR MYELOID AND -- CHIMERISM, 1830 01:04:29,200 --> 01:04:30,640 AND FOR THE FIRST PATIENT, THEY 1831 01:04:30,640 --> 01:04:35,680 HAD CML, THE SECOND -- AND THE 1832 01:04:35,680 --> 01:04:37,080 LAST, T-CELL ALL. 1833 01:04:37,080 --> 01:04:38,720 THE TIME OF MALIGNANCY POST 1834 01:04:38,720 --> 01:04:39,720 TRANSPLANT RANGED FROM THREE 1835 01:04:39,720 --> 01:04:41,760 YEARS TO NINE YEARS, AND ALL 1836 01:04:41,760 --> 01:04:43,200 THESE PATIENTS ARE CURRENTLY 1837 01:04:43,200 --> 01:04:43,720 ALIVE. 1838 01:04:43,720 --> 01:04:45,160 NOW WE'LL REVIEW THE INCIDENCE 1839 01:04:45,160 --> 01:04:47,840 OF MDS AND AML AT THE NIH AS 1840 01:04:47,840 --> 01:04:51,040 COMPARED TO OTHER INSTITUTIONS. 1841 01:04:51,040 --> 01:04:52,120 FIRST WE'RE LOOKING AT THE 1842 01:04:52,120 --> 01:04:53,040 MATCHED SIBLING CONDITION AND 1843 01:04:53,040 --> 01:04:54,280 REGIMEN THAT I REVIEWED FOR YOU. 1844 01:04:54,280 --> 01:04:57,080 YOU CAN SEE HERE IN THIS FIRST 1845 01:04:57,080 --> 01:04:59,000 ROW THIS, IS OUR ORIGINAL 1846 01:04:59,000 --> 01:04:59,840 CONDITION REGIMEN THAT I SHOWED 1847 01:04:59,840 --> 01:05:00,400 YOU. 1848 01:05:00,400 --> 01:05:02,720 IT'S ALSO USED BY COLLABORATORS 1849 01:05:02,720 --> 01:05:05,960 AT CHICAGO AND RIYADH AND IN 1850 01:05:05,960 --> 01:05:08,040 BETWEEN HERE IS THE NEW REGIMEN 1851 01:05:08,040 --> 01:05:09,040 I DEMONSTRATED EARLIER. 1852 01:05:09,040 --> 01:05:10,960 YOU CAN SEE THAT THE INCIDENCE 1853 01:05:10,960 --> 01:05:14,800 OF MDS TO AML RANGES FROM 1.6 TO 1854 01:05:14,800 --> 01:05:17,600 3.8 WITH A MEDIAN FOLLOW-UP FROM 1855 01:05:17,600 --> 01:05:18,160 4 TO 9.1 YEARS. 1856 01:05:18,160 --> 01:05:20,360 NEXT WE LOOK AT OUR 1857 01:05:20,360 --> 01:05:21,000 HAPLOIDENTICAL TRANSPLANT. 1858 01:05:21,000 --> 01:05:22,560 AGAIN STARTING WITH THE ORIGINAL 1859 01:05:22,560 --> 01:05:24,440 CONDITION AND REGIMEN AND THE 1860 01:05:24,440 --> 01:05:24,840 NEWER ONE. 1861 01:05:24,840 --> 01:05:26,480 WE SEE THAT WITH THE ORIGINAL 1862 01:05:26,480 --> 01:05:28,320 CONDITION AND REGIMEN, THE 1863 01:05:28,320 --> 01:05:30,040 INCIDENCE IS 14.3%, AND WITH THE 1864 01:05:30,040 --> 01:05:31,160 NEWER CONDITION AND REGIMEN, 1865 01:05:31,160 --> 01:05:32,840 THERE HAVE BEEN NO REPORTS OF 1866 01:05:32,840 --> 01:05:36,440 MDS OR AML TO DATE, AND THE 1867 01:05:36,440 --> 01:05:41,600 MEDIAN FOLLOW-UP RANGES FROM 8.. 1868 01:05:41,600 --> 01:05:42,720 OUR GROUP A IN OUR GROUP OF 1869 01:05:42,720 --> 01:05:44,560 PATIENTS THAT HAD GENE THERAPY 1870 01:05:44,560 --> 01:05:47,080 WITH THE INADEQUATE THERAPEUTIC 1871 01:05:47,080 --> 01:05:54,680 RESPONSE, ALSO WENT ON TO HAVE F 1872 01:05:54,680 --> 01:05:55,120 4.3%. 1873 01:05:55,120 --> 01:05:57,080 NOW WE'LL LOOK AT FRENCH GROUP 1874 01:05:57,080 --> 01:05:58,280 AND CIBMTR. 1875 01:05:58,280 --> 01:06:00,080 FOR THE FRENCH GROUP, NO REPORT 1876 01:06:00,080 --> 01:06:01,280 OUT OF 234 PATIENTS, AND I 1877 01:06:01,280 --> 01:06:02,920 SHOULD MENTION THAT FOR BOTH 1878 01:06:02,920 --> 01:06:04,240 THESE GROUPS, THEY HAD A LARGER 1879 01:06:04,240 --> 01:06:05,120 PROPORTION OF YOUNGER PATIENTS 1880 01:06:05,120 --> 01:06:06,640 THAN WE'VE SEEN AT THE NIH. 1881 01:06:06,640 --> 01:06:10,120 THE MEDIAN FOLLOW-UP FOR THE 1882 01:06:10,120 --> 01:06:13,520 FRENCH WAS 7.8 AND FOR THE 1883 01:06:13,520 --> 01:06:16,520 CIBMTR, YOU SEE THE INCIDENCE OF 1884 01:06:16,520 --> 01:06:18,760 0.22% WITH THE MEDIAN FOLLOW-UP 1885 01:06:18,760 --> 01:06:21,960 OF 2.1 TO 3.9. 1886 01:06:21,960 --> 01:06:26,360 AT THE NIH, OUR THERAPEUTIC GOAL 1887 01:06:26,360 --> 01:06:29,520 FOR THE NIH MIXED CHIMERISM. 1888 01:06:29,520 --> 01:06:31,160 WHEN WE LOOK AT BASELINE, AT THE 1889 01:06:31,160 --> 01:06:32,800 RISK OF LEUKEMIA IN PATIENTS 1890 01:06:32,800 --> 01:06:34,320 WITH SICKLE CELL DISEASE, WE 1891 01:06:34,320 --> 01:06:36,680 REVIEW HERE THIS PAPER BY BRUN 1892 01:06:36,680 --> 01:06:39,320 SON ET AL. WHERE THEY LOOKED AT 1893 01:06:39,320 --> 01:06:40,080 ABOUT 6,400 SICKLE CELL DISEASE 1894 01:06:40,080 --> 01:06:43,160 PATIENTS OBSERVED OVER 140,000 1895 01:06:43,160 --> 01:06:44,280 PERSON YEARS, AND THEY COMPARED 1896 01:06:44,280 --> 01:06:45,520 THEM WITH THE GENERAL CALIFORNIA 1897 01:06:45,520 --> 01:06:47,400 POPULATION. 1898 01:06:47,400 --> 01:06:49,160 WHAT THEY FOUND WAS AN INCREASED 1899 01:06:49,160 --> 01:06:50,960 RISK OF HEMATOLOGIC TUMORS. 1900 01:06:50,960 --> 01:06:52,520 WHEN WE LOOK SPECIFICALLY AT 1901 01:06:52,520 --> 01:06:53,920 LEUKEMIA, WE SEE THAT THIS RISK 1902 01:06:53,920 --> 01:06:55,400 IS ABOUT 2.3 AND IT'S 1903 01:06:55,400 --> 01:06:56,800 SIGNIFICANT. 1904 01:06:56,800 --> 01:06:58,160 THEY ALSO FOUND THE SIGNIFICANCE 1905 01:06:58,160 --> 01:07:00,000 WITH AML WITH AN INCREASED RISK 1906 01:07:00,000 --> 01:07:02,200 OF ABOUT 4. 1907 01:07:02,200 --> 01:07:05,160 SO WHEN WE LOOK AT OUR PATIENTS 1908 01:07:05,160 --> 01:07:07,000 WITH SICKLE CELL DISEASE THAT 1909 01:07:07,000 --> 01:07:08,280 DEVELOPED HEMATOLOGIC 1910 01:07:08,280 --> 01:07:11,680 MALIGNANCIES OVER 140,000 1911 01:07:11,680 --> 01:07:14,480 ROUNDED OFF PERSON YEARS, WE SEE 1912 01:07:14,480 --> 01:07:24,120 IT'S 0.021 PER 100 PERSON YEARS. 1913 01:07:24,120 --> 01:07:25,760 18 INDIVIDUALS WITHOUT SICKLE 1914 01:07:25,760 --> 01:07:27,480 CELL DISEASE WERE EXPECTED TO 1915 01:07:27,480 --> 01:07:29,440 DEVELOP HEMATOLOGIC PLG MAN SEES 1916 01:07:29,440 --> 01:07:30,760 WHEN CONTROLLED FOR AGE, SEX, 1917 01:07:30,760 --> 01:07:34,720 RACE AND ETHNICITY, YOU SEE IT'S 1918 01:07:34,720 --> 01:07:36,320 0.013 PER 100 PERSON YEARS. 1919 01:07:36,320 --> 01:07:38,600 THERE WAS THE RELATIVE RISK OF 1920 01:07:38,600 --> 01:07:39,600 HEMATOLOGIC MALIGNANCIES IS 1921 01:07:39,600 --> 01:07:41,480 HIGHER IN SICKLE CELL DISEASE 1922 01:07:41,480 --> 01:07:42,640 BUT THE ABSOLUTE RISK IS LOW. 1923 01:07:42,640 --> 01:07:45,280 THIS CORRELATES WITH THE RATE OF 1924 01:07:45,280 --> 01:07:46,440 HEMATOLOGIC MALIGNANCIES AFTER 1925 01:07:46,440 --> 01:07:48,080 MIXED CHIMERISM AND GRAFT 1926 01:07:48,080 --> 01:07:49,520 FAILURE WE SAW FOR SICKLE CELL 1927 01:07:49,520 --> 01:07:50,280 DISEASE. 1928 01:07:50,280 --> 01:07:52,680 8 OF OUR PATIENTS DEVELOPED 1929 01:07:52,680 --> 01:07:56,360 HEMATOLOGIC MALIGNANCIES OVER 1930 01:07:56,360 --> 01:07:59,120 844 PERSON YEARS, WHICH EQUATES 1931 01:07:59,120 --> 01:08:02,720 TO 0.94 PER 100 PERSON YEARS. 1932 01:08:02,720 --> 01:08:04,200 SO WHAT IS IT ABOUT OUR PATIENT 1933 01:08:04,200 --> 01:08:04,840 POPULATION? 1934 01:08:04,840 --> 01:08:06,280 WE HAVE ONGOING WORK TO TAKE A 1935 01:08:06,280 --> 01:08:08,240 CLOSER LOOK HE IT AGE, THE 1936 01:08:08,240 --> 01:08:13,200 SOURCE OF CELLS, OUR CONDITION 1937 01:08:13,200 --> 01:08:15,120 AND REGIMEN, OUR THERAPEUTIC 1938 01:08:15,120 --> 01:08:16,880 GOAL, THE USE OF PROLONGED 1939 01:08:16,880 --> 01:08:17,960 IMMUNOSUPPRESSION, AND OF COURSE 1940 01:08:17,960 --> 01:08:20,080 LOOKING AT REGENERATIVE 1941 01:08:20,080 --> 01:08:20,680 HEMATOPOIETIC STRESS, 1942 01:08:20,680 --> 01:08:21,320 SPECIFICALLY IN THE SETTING OF 1943 01:08:21,320 --> 01:08:23,440 GRAFT FAILURE AND INADEQUATE 1944 01:08:23,440 --> 01:08:24,640 THERAPEUTIC RESPONSE. 1945 01:08:24,640 --> 01:08:27,000 SO WE CONCLUDE THAT HEMATOLOGIC 1946 01:08:27,000 --> 01:08:29,360 MALIGNANCY IS A POTENTIAL 1947 01:08:29,360 --> 01:08:30,160 COMPLICATION OF SICKLE CELL 1948 01:08:30,160 --> 01:08:31,160 DISEASE CURATIVE THERAPY, AND 1949 01:08:31,160 --> 01:08:33,680 ALTHOUGH THE RELATIVE RISK OF 1950 01:08:33,680 --> 01:08:34,440 HEMATOLOGIC MALIGNANCY IS HIGH 1951 01:08:34,440 --> 01:08:35,400 IN PATIENTS WITH SICKLE CELL 1952 01:08:35,400 --> 01:08:36,520 DISEASE, THE ABSOLUTE RISK IS 1953 01:08:36,520 --> 01:08:38,680 LOW. 1954 01:08:38,680 --> 01:08:40,360 INCREASED MALIGNANCY AFTER GRAFT 1955 01:08:40,360 --> 01:08:41,760 REJECTION AND LOW CELL DOSE IS 1956 01:08:41,760 --> 01:08:42,960 SEEN. 1957 01:08:42,960 --> 01:08:46,040 AND THIS HIGHER INCIDENCE OF 1958 01:08:46,040 --> 01:08:47,000 MDS/AML POST TRANSPLANT IS 1959 01:08:47,000 --> 01:08:48,200 COMPARABLE TO THE RATE AFTER 1960 01:08:48,200 --> 01:08:51,240 GENE THERAPY WITH MYELOABLATIVE 1961 01:08:51,240 --> 01:08:53,080 BUSULFAN FOR THAT PARTICULAR 1962 01:08:53,080 --> 01:08:53,960 GROUP I SHOWED YOU. 1963 01:08:53,960 --> 01:08:55,720 THUS THE INCIDENCE OF 1964 01:08:55,720 --> 01:08:56,800 HEMATOLOGIC MALIGNANCY WAS MUCH 1965 01:08:56,800 --> 01:08:58,440 LOWER WITH CONDITIONING REGIMENS 1966 01:08:58,440 --> 01:09:00,080 WHERE THE THERAPEUTIC GOAL WAS 1967 01:09:00,080 --> 01:09:01,400 FULL DONOR CHIMERISM. 1968 01:09:01,400 --> 01:09:03,000 AND FOR THAT REASON, THE GOAL OF 1969 01:09:03,000 --> 01:09:05,440 THE NIH PROTOCOLS MOVING FORWARD 1970 01:09:05,440 --> 01:09:06,840 FOR SICKLE CELL DISEASE HAS 1971 01:09:06,840 --> 01:09:09,800 CHANGED TO FULL DONOR CHIMERISM. 1972 01:09:09,800 --> 01:09:10,320 AGAIN THANK YOU FOR THIS 1973 01:09:10,320 --> 01:09:20,000 OPPORTUNITY. 1974 01:09:20,000 --> 01:09:26,520 >>THANK YOU, DR. LAWAL. 1975 01:09:26,520 --> 01:09:28,680 TO CONTINUE THE THEME ON 1976 01:09:28,680 --> 01:09:29,960 SECONDARY NEOPLASMS AFTER 1977 01:09:29,960 --> 01:09:32,320 TRANSPLANT FOR SICKLE CELL 1978 01:09:32,320 --> 01:09:33,920 DISEASE, IT'S MY PLEASURE TO 1979 01:09:33,920 --> 01:09:37,680 INVITE DR. MARY EAPEN FROM THE 1980 01:09:37,680 --> 01:09:38,600 MEDICAL COLLEGE OF WISCONSIN TO 1981 01:09:38,600 --> 01:09:41,640 TALK ABOUT SECONDARY NEOPLASMS 1982 01:09:41,640 --> 01:09:43,040 AFTER HEMATOPOIETIC CELL 1983 01:09:43,040 --> 01:09:43,600 TRANSPLANT FOR SICKLE CELL 1984 01:09:43,600 --> 01:09:45,880 DISEASE. 1985 01:09:45,880 --> 01:09:50,960 DR. EAPEN. 1986 01:09:50,960 --> 01:09:51,760 >>GOOD MORNING, LADIES AND 1987 01:09:51,760 --> 01:09:52,040 GENTLEMEN. 1988 01:09:52,040 --> 01:09:53,760 I WILL TRY TO HURRY ALONG AND 1989 01:09:53,760 --> 01:09:56,600 STAY WITHIN MY 10 MINUTES. 1990 01:09:56,600 --> 01:09:58,160 SO THANK YOU FOR THE INVITATION. 1991 01:09:58,160 --> 01:10:01,640 I HAVE NOTHING TO DISCLOSE. 1992 01:10:01,640 --> 01:10:02,720 IT'S CLEAR TO THE AUDIENCE IN 1993 01:10:02,720 --> 01:10:04,600 THIS ROOM THAT TRANSPLANTATION 1994 01:10:04,600 --> 01:10:09,080 FOR SICKLE CELL DISEASE RESTORES 1995 01:10:09,080 --> 01:10:09,600 HEMATOPOIESIS. 1996 01:10:09,600 --> 01:10:13,760 SURVIVAL IS HIGHEST AFTER HLA 1997 01:10:13,760 --> 01:10:15,200 MATCHED SIBLING TRANSPLANT BUT 1998 01:10:15,200 --> 01:10:17,600 THERE'S ALL TERN TI DONOR 1999 01:10:17,600 --> 01:10:18,600 TRANSPLANT WHICH EXTENDS ACCESS 2000 01:10:18,600 --> 01:10:21,320 BUT THAT INCREASES RISK FOR 2001 01:10:21,320 --> 01:10:22,960 TRANSPLANT-RELATED COMPLICATION. 2002 01:10:22,960 --> 01:10:24,600 THE PREDOMINANT 2003 01:10:24,600 --> 01:10:25,360 CYTOREDUCTIONTIVE REGIMEN 2004 01:10:25,360 --> 01:10:28,920 INCLUDES FULL DOSES OF BUSULFAN 2005 01:10:28,920 --> 01:10:32,000 WITH CYCLOPHOSPHAMIDE OR 2006 01:10:32,000 --> 01:10:33,200 FLUDARABINE. 2007 01:10:33,200 --> 01:10:34,720 LESS INTENSIVE CYTOREDUCTIONTIVE 2008 01:10:34,720 --> 01:10:35,800 THERAPY IS USED FOR 2009 01:10:35,800 --> 01:10:36,480 TRANSPLANTATION WHICH IS 2010 01:10:36,480 --> 01:10:38,600 ASSOCIATED WITH FEWER EARLY 2011 01:10:38,600 --> 01:10:40,160 TOXICITY BUT LONGER FOLLOW-UP IS 2012 01:10:40,160 --> 01:10:44,200 REQUIRED TO ASCERTAIN LONG TERM 2013 01:10:44,200 --> 01:10:46,040 SEQUELAE. 2014 01:10:46,040 --> 01:10:54,480 GENERALLY SOLID NEOPLA NEOPLAS 2015 01:10:54,480 --> 01:10:55,600 HIGH. 2016 01:10:55,600 --> 01:10:57,200 SECONDARY SOLID NEOPLASMS DOUBLE 2017 01:10:57,200 --> 01:10:59,680 UP AT TWICE THE RATE EXPECTED ON 2018 01:10:59,680 --> 01:11:00,680 THE BASIS OF THE GENERAL 2019 01:11:00,680 --> 01:11:02,320 POPULATION. 2020 01:11:02,320 --> 01:11:03,640 THOSE STUDIES HAVE IDENTIFIED 2021 01:11:03,640 --> 01:11:05,920 THE USE OF RADIATION CONTAINING 2022 01:11:05,920 --> 01:11:07,480 REGIMENS AND CHRONIC 2023 01:11:07,480 --> 01:11:08,320 GRAFT-VERSUS-HOST DISEASE AS 2024 01:11:08,320 --> 01:11:09,720 RISK FACTORS. 2025 01:11:09,720 --> 01:11:11,360 SPECIFICALLY WHEN YOU LOOK AT 2026 01:11:11,360 --> 01:11:13,760 FULL DOSE BUSULFAN AND 2027 01:11:13,760 --> 01:11:14,560 CYCLOPHOSPHAMIDE, THE 2028 01:11:14,560 --> 01:11:16,200 PREDOMINANT REGIMEN THAT IS USED 2029 01:11:16,200 --> 01:11:17,840 FOR MATCHED SIBLING DONOR 2030 01:11:17,840 --> 01:11:19,160 TRANSPLANTATION IN SICKLE CELL 2031 01:11:19,160 --> 01:11:20,200 DISEASE, FOR THOSE WHO HAVE 2032 01:11:20,200 --> 01:11:23,520 RECEIVED THIS PARTICULAR REGIMEN 2033 01:11:23,520 --> 01:11:25,440 FOR HEMATOLOGIC MALIGNANCY 2034 01:11:25,440 --> 01:11:29,400 INCLUDING MYELOID LEUKEMIA AND 2035 01:11:29,400 --> 01:11:31,240 MYELODYSPLASTIC SYNDROME, THE 2036 01:11:31,240 --> 01:11:36,920 INCIDENCE RATE IS ON 1.4 TIMES 2037 01:11:36,920 --> 01:11:39,120 HIGHER THAN THE GENERAL 2038 01:11:39,120 --> 01:11:39,440 POPULATION. 2039 01:11:39,440 --> 01:11:40,520 THE RISK FACTORS IDENTIFIED 2040 01:11:40,520 --> 01:11:42,520 INCLUDE OLDER AGE, AGE GREATER 2041 01:11:42,520 --> 01:11:44,080 THAN 35 AT TRANSPLANTATION, AND 2042 01:11:44,080 --> 01:11:45,920 A HISTORY OF CHRONIC 2043 01:11:45,920 --> 01:11:49,960 GRAFT-VERSUS-HOST DISEASE. 2044 01:11:49,960 --> 01:11:51,920 IF YOU LOOK AT NON-MALIGNANT 2045 01:11:51,920 --> 01:11:52,680 DISEASE, LARGELY IN THE 2046 01:11:52,680 --> 01:11:55,840 PEDIATRIC POPULATION, WHICH 2047 01:11:55,840 --> 01:12:00,840 WOULD GIVE YOU A MEDIAN AGE OF K 2048 01:12:00,840 --> 01:12:03,920 COMPARED TO THE GENERAL 2049 01:12:03,920 --> 01:12:06,880 POPULATION, LARGELY DRIVEN BY 2050 01:12:06,880 --> 01:12:10,480 TRANSPLANTATION FOR FANCONI 2051 01:12:10,480 --> 01:12:12,240 ANEMIA, WHERE THE INCIDENT IS 2052 01:12:12,240 --> 01:12:12,880 ABOUT 6%. 2053 01:12:12,880 --> 01:12:15,600 HOWEVER, THE COMMON NEOPLASMS 2054 01:12:15,600 --> 01:12:18,000 ENCOUNTERED ARE LEUKEMIAS AND 2055 01:12:18,000 --> 01:12:19,560 CANCERS OF OROPHARYNGEAL AND 2056 01:12:19,560 --> 01:12:20,000 SKIN. 2057 01:12:20,000 --> 01:12:22,600 THE LEUKEMIAS TEND TO OCCUR 2058 01:12:22,600 --> 01:12:24,560 EARLY, TYPICALLY LESS THAN FIVE 2059 01:12:24,560 --> 01:12:26,200 YEARS, AND THE OROPHARYNGEAL AND 2060 01:12:26,200 --> 01:12:27,560 SKIN CANCERS AFTER A LONGER 2061 01:12:27,560 --> 01:12:31,360 PERIOD. 2062 01:12:31,360 --> 01:12:32,920 SO WHAT HAPPENS IN SICKLE CELL 2063 01:12:32,920 --> 01:12:33,440 DISEASE? 2064 01:12:33,440 --> 01:12:34,920 POPULATION BASED STUDY THE IN 2065 01:12:34,920 --> 01:12:36,160 UNITED KINGDOM AND THE UNITED 2066 01:12:36,160 --> 01:12:37,840 STATES REPORT INCREASED LIFETIME 2067 01:12:37,840 --> 01:12:39,440 RISK FOR MYELOID LEUKEMIA, AND 2068 01:12:39,440 --> 01:12:41,000 THERE ARE ALSO SEVERAL CASE 2069 01:12:41,000 --> 01:12:43,360 REPORTS OF MYELOID MALIGNANCY IN 2070 01:12:43,360 --> 01:12:45,680 SICKLE CELL DISEASE ASSOCIATED 2071 01:12:45,680 --> 01:12:48,520 WITH MIXED CHIMERISM OR GRAFT 2072 01:12:48,520 --> 01:12:49,880 FAILURE, AND THE SPEAKER JUST 2073 01:12:49,880 --> 01:12:52,240 PRIOR TO ME HAD PRESENTED THE 2074 01:12:52,240 --> 01:12:53,680 DATA FROM THE NIH CLINICAL 2075 01:12:53,680 --> 01:12:55,640 CENTER. 2076 01:12:55,640 --> 01:12:57,720 SO WITH INCREASING NUMBERS OF 2077 01:12:57,720 --> 01:12:59,040 TRANSPLANTS FOR SICKLE CELL 2078 01:12:59,040 --> 01:13:00,680 DISEASE, IT IS TIMELY TO STUDY 2079 01:13:00,680 --> 01:13:02,560 THE INCIDENCE AND RISK FACTORS 2080 01:13:02,560 --> 01:13:05,000 FOR SECONDARY NEOPLASM IN A 2081 01:13:05,000 --> 01:13:06,480 SUBSTANTIALLY LARGER POPULATION 2082 01:13:06,480 --> 01:13:08,920 THAN HAS BEEN REPORTED. 2083 01:13:08,920 --> 01:13:11,280 THE TRANSPLANT PERIOD CHOSEN WAS 2084 01:13:11,280 --> 01:13:13,520 1991 TO 2016. 2085 01:13:13,520 --> 01:13:16,480 THE DATASET DELIBERATELY ENDED 2086 01:13:16,480 --> 01:13:19,880 AT 2016, AND THAT WAS REALLY TO 2087 01:13:19,880 --> 01:13:20,880 LIMIT INCOMPLETE ASCERTAINMENT 2088 01:13:20,880 --> 01:13:23,560 OF CASES AND A POTENTIAL BIAS 2089 01:13:23,560 --> 01:13:25,440 FOR PREFERENTIAL FOLLOW-UP OF 2090 01:13:25,440 --> 01:13:26,880 PATIENTS CONSIDERED TO BE AT 2091 01:13:26,880 --> 01:13:30,240 HIGHER RISK FOR TRANSPLANTATION. 2092 01:13:30,240 --> 01:13:36,720 THE COHORT INCLUDED 1,096 2093 01:13:36,720 --> 01:13:37,920 ELIGIBLE PATIENTS. 2094 01:13:37,920 --> 01:13:38,600 THE PREDOMINANT CHARACTERISTICS 2095 01:13:38,600 --> 01:13:40,600 OF THE COHORT WAS THAT THE 2096 01:13:40,600 --> 01:13:43,040 MAJORITY WERE MATCHED SIBLING 2097 01:13:43,040 --> 01:13:43,400 RECIPIENTS. 2098 01:13:43,400 --> 01:13:45,640 THEY RECEIVED A MYELOABLATIVE 2099 01:13:45,640 --> 01:13:52,680 REGIMEN, A BONE MARROW GRAFT A 2100 01:13:52,680 --> 01:13:53,520 AND -- PROPHYLAXIS. 2101 01:13:53,520 --> 01:13:55,320 SO SHOWN HERE ARE THE 2102 01:13:55,320 --> 01:13:56,400 DIFFERENCES IN THE 2103 01:13:56,400 --> 01:13:58,040 CHARACTERISTICS BETWEEN CASES. 2104 01:13:58,040 --> 01:14:00,880 THERE WERE 22 CASES OF SECONDARY 2105 01:14:00,880 --> 01:14:03,600 NEOPLASM AND 174 CONTROLS. 2106 01:14:03,600 --> 01:14:06,880 THE CASES WERE OLDER. 2107 01:14:06,880 --> 01:14:08,560 THEY WERE MORE LIKELY TO RECEIVE 2108 01:14:08,560 --> 01:14:10,600 A LOW INTENSITY REGIMEN, WHICH 2109 01:14:10,600 --> 01:14:15,040 INCLUDED RADIATION. 2110 01:14:15,040 --> 01:14:18,520 AND PERIPHERAL BLOOD WAS THE 2111 01:14:18,520 --> 01:14:19,040 REDOMINANT GRAFT TYPE. 2112 01:14:19,040 --> 01:14:21,880 SO CONSIDERING THE 1,096 2113 01:14:21,880 --> 01:14:27,680 ELIGIBLE PATIENTS WITH 6,631 2114 01:14:27,680 --> 01:14:28,760 PERSON-YEARS, 22 SECONDARY 2115 01:14:28,760 --> 01:14:30,840 NEOPLASMS WERE IDENTIFIED. 2116 01:14:30,840 --> 01:14:32,280 THE 10-YEAR INCIDENCE OF ANY 2117 01:14:32,280 --> 01:14:36,440 SECONDARY NEOPLASM WAS 2.4%, FOR 2118 01:14:36,440 --> 01:14:40,680 AML OR MDS, 1.7%, AND FOR SOLID 2119 01:14:40,680 --> 01:14:43,520 NEOPLASMS, .7%. 2120 01:14:43,520 --> 01:14:45,120 THIS TABLE IS A DESCRIPTION OF 2121 01:14:45,120 --> 01:14:48,360 THE TYPE OF SECONDARY PLIG PLIG 2122 01:14:48,360 --> 01:14:49,760 NANCY AFTER THE LOW DOSE 2123 01:14:49,760 --> 01:14:51,840 RADIATION CONTAINING REGIMENS. 2124 01:14:51,840 --> 01:14:53,240 THE PREDOMINANT MALIGNANCY BEING 2125 01:14:53,240 --> 01:14:57,440 HERE A LEUKEMIA. 2126 01:14:57,440 --> 01:14:59,080 IN CONTRAST WITH THE USE OF 2127 01:14:59,080 --> 01:15:00,800 NON-RADIATION REGIMENS, IT WAS 2128 01:15:00,800 --> 01:15:02,120 EVENLY SPLIT BETWEEN LEUKEMIA 2129 01:15:02,120 --> 01:15:05,080 AND SOLID TUMOR. 2130 01:15:05,080 --> 01:15:07,560 OUT OF THE EIGHT PATIENTS, SIX 2131 01:15:07,560 --> 01:15:09,000 RECEIVED WHOLE DOSE BUSULFAN, 2132 01:15:09,000 --> 01:15:11,040 AND THERE WERE TWO THAT RECEIVED 2133 01:15:11,040 --> 01:15:15,040 A REDUCED INTENSITY CONDITIONING 2134 01:15:15,040 --> 01:15:19,800 WITH FLUDARABENE. 2135 01:15:19,800 --> 01:15:23,120 WE ALSO LOOKED AT SECONDARY 2136 01:15:23,120 --> 01:15:25,160 NEOPLASMS IN CHILDREN, SIMPLY TO 2137 01:15:25,160 --> 01:15:27,360 COMPARE WHAT HAPPENS IN THE 2138 01:15:27,360 --> 01:15:28,920 UNITED STATES TO WHAT HAPPENS IN 2139 01:15:28,920 --> 01:15:29,160 EUROPE. 2140 01:15:29,160 --> 01:15:32,560 THERE WAS A RECENT PUBLICATION, 2141 01:15:32,560 --> 01:15:33,560 PROBABLY ABOUT THREE OR FOUR 2142 01:15:33,560 --> 01:15:35,840 YEARS AGO, FROM THE FRENCH 2143 01:15:35,840 --> 01:15:37,920 REGISTRY, TRANSPLANT REGISTRY, 2144 01:15:37,920 --> 01:15:39,720 WITH FOLLOW-UP OF AT LEAST FIVE 2145 01:15:39,720 --> 01:15:43,520 YEARS ON ALL OF THEIR PATIENTS 2146 01:15:43,520 --> 01:15:44,600 AND THERE WERE NO REPORTED CASES 2147 01:15:44,600 --> 01:15:46,240 OF SECONDARY NEOPLASMS. 2148 01:15:46,240 --> 01:15:47,880 IN CONTRAST IN THE COHORT FROM 2149 01:15:47,880 --> 01:15:49,120 THE UNITED STATES, THERE WERE 2150 01:15:49,120 --> 01:15:51,400 EIGHT SECONDARY NEOPLASMS AND I 2151 01:15:51,400 --> 01:15:52,400 HAVE BROKEN THEM DOWN. 2152 01:15:52,400 --> 01:15:54,200 WHAT WAS STRIKING IS THE 2153 01:15:54,200 --> 01:15:56,560 RELATIVELY SHORT TIME TO 2154 01:15:56,560 --> 01:16:04,240 SECONDARY NEOPLA S NEOPLASM ALLH 2155 01:16:04,240 --> 01:16:06,400 OCCURRED LESS THAN FIVE YEARS 2156 01:16:06,400 --> 01:16:08,280 AFTER TRANSPLANTATION. 2157 01:16:08,280 --> 01:16:10,480 SO THERE ARE DIFFERENCES BETWEEN 2158 01:16:10,480 --> 01:16:13,120 THE PATTERN OF SECONDARY 2159 01:16:13,120 --> 01:16:14,080 NEOPLASMS IN SICKLE CELL DISEASE 2160 01:16:14,080 --> 01:16:17,040 AND OTHER DISEASES, LARGELY THE 2161 01:16:17,040 --> 01:16:20,840 RELATIVELY SHORT TIME TO 2162 01:16:20,840 --> 01:16:21,960 DEVELOPMENT, APPROXIMATELY THREE 2163 01:16:21,960 --> 01:16:22,280 YEARS. 2164 01:16:22,280 --> 01:16:24,360 LEUKEMIA IS THE PREDOMINANT, 2165 01:16:24,360 --> 01:16:26,160 UNLIKE OTHER TRANSPLANTATION 2166 01:16:26,160 --> 01:16:28,440 WHERE SOLID TUMORS IS THE 2167 01:16:28,440 --> 01:16:33,440 PREDOMINANT SECOND CANCER. 2168 01:16:33,440 --> 01:16:35,840 60% OF THE PRIMARY NEOPLASMS 2169 01:16:35,840 --> 01:16:37,320 OCCURRED AFTER LOW DOSE TBI 2170 01:16:37,320 --> 01:16:38,680 WHEREAS THE TRANSPLANT 2171 01:16:38,680 --> 01:16:40,080 LITERATURE LARGELY IN THE 2172 01:16:40,080 --> 01:16:41,600 SETTING OF HEMATOLOGIC 2173 01:16:41,600 --> 01:16:43,480 MALIGNANCY IN ALLOGENEIC 2174 01:16:43,480 --> 01:16:45,200 TRANSPLANTATION HAVE IDENTIFIED 2175 01:16:45,200 --> 01:16:50,920 SINGLE DOSE TBI600 TO 1,000 CGY 2176 01:16:50,920 --> 01:16:52,760 AND FRACK NATEED -- AS A RISK 2177 01:16:52,760 --> 01:16:53,000 FACTOR. 2178 01:16:53,000 --> 01:16:55,400 SO WHAT ARE THE RISK FACTORS FOR 2179 01:16:55,400 --> 01:16:56,480 SECONDARY NEOPLASM IN SICKLE 2180 01:16:56,480 --> 01:16:59,440 CELL DISEASE? 2181 01:16:59,440 --> 01:17:01,080 OUR ANALYSIS CONFIRMED THAT LOW 2182 01:17:01,080 --> 01:17:03,840 INTENSITY TBI REGIMEN INCREASES 2183 01:17:03,840 --> 01:17:07,320 THE RISK FOR ANY SECONDARY PLIG 2184 01:17:07,320 --> 01:17:10,720 MALIGNANCY AND FOR LEUKEMIA AND 2185 01:17:10,720 --> 01:17:11,280 MYELODYSPLASTIC SYNDROME. 2186 01:17:11,280 --> 01:17:12,880 A MATCHED PAIR ANALYSIS WAS 2187 01:17:12,880 --> 01:17:14,560 CONDUCTED MATCHING FOR AGE, 2188 01:17:14,560 --> 01:17:16,320 DONOR TYPE AND SURVIVAL TIME. 2189 01:17:16,320 --> 01:17:18,080 THE CONTROLS HAD TO BE ALIVE AT 2190 01:17:18,080 --> 01:17:20,160 LEAST AS LONG AS THE INTERVAL TO 2191 01:17:20,160 --> 01:17:22,920 DEVELOPING A NEOPLASM. 2192 01:17:22,920 --> 01:17:24,880 THE RESULTS OF THE MAIN ANALYSES 2193 01:17:24,880 --> 01:17:27,640 WERE CONFIRMED. 2194 01:17:27,640 --> 01:17:29,480 SO TO SUMMARIZE THE HIGHER 2195 01:17:29,480 --> 01:17:32,440 INCIDENCE OF SECONDARY NEOPLASM 2196 01:17:32,440 --> 01:17:34,320 LEUKEMIA AND MDS AFTER SICKLE 2197 01:17:34,320 --> 01:17:38,600 CELL DISEASE IS HIGHER COMPARED 2198 01:17:38,600 --> 01:17:41,320 TO OTHER NON-MALIGNANT DISEASES 2199 01:17:41,320 --> 01:17:43,440 WITH THE EXCEPTION OF FANCONI 2200 01:17:43,440 --> 01:17:44,840 ANEMIA. 2201 01:17:44,840 --> 01:17:49,000 LOW INTENSITY REGIMENS WERE 2202 01:17:49,000 --> 01:17:50,800 HIGHEST RISK BUT YOU DID HAVE 2203 01:17:50,800 --> 01:17:51,960 OTHER DEVELOPING AFTER OTHER 2204 01:17:51,960 --> 01:17:52,440 REGIMENS. 2205 01:17:52,440 --> 01:17:56,800 THE TYPE OF SECOND -- AS OPPOSED 2206 01:17:56,800 --> 01:17:59,320 TO SOLID NEOPLASMS. 2207 01:17:59,320 --> 01:18:04,440 IN 634 CHILDREN WITH 4,342 2208 01:18:04,440 --> 01:18:05,880 PERSON-YEARS AND EIGHT 2209 01:18:05,880 --> 01:18:08,520 NEOPLASMS, THAT TRANSLATES TO 2210 01:18:08,520 --> 01:18:09,720 1.8 CASES PER THOUSAND 2211 01:18:09,720 --> 01:18:15,720 PERSON-YEARS. 2212 01:18:15,720 --> 01:18:19,040 SO THE PREDOMINENCE OF LEUKEMIA 2213 01:18:19,040 --> 01:18:21,640 AND MYELODYSPLASTIC SYNDROME MAY 2214 01:18:21,640 --> 01:18:24,720 BE EXPLAINED BY LOW INTENSITY 2215 01:18:24,720 --> 01:18:27,120 REGIMENS THAT RELY ON TOLERANCE 2216 01:18:27,120 --> 01:18:28,440 INDUCTION THAT LEADS TO 2217 01:18:28,440 --> 01:18:30,080 PERSISTENCE OF RESIDUAL HOST 2218 01:18:30,080 --> 01:18:31,200 CELLS THAT WERE EXPOSED TO LOW 2219 01:18:31,200 --> 01:18:35,240 DOSE RADIATION. 2220 01:18:35,240 --> 01:18:36,880 -- POST TRANSPLANT 2221 01:18:36,880 --> 01:18:39,600 PROLIFERATIVE STRESS OR 2222 01:18:39,600 --> 01:18:42,600 UNDERLYING HEMATOPOIESIS. 2223 01:18:42,600 --> 01:18:44,040 SO THESE DATA SHOULD PROVIDE A 2224 01:18:44,040 --> 01:18:45,320 FOUNDATION TO DISCUSS THE RISK 2225 01:18:45,320 --> 01:18:46,760 FOF SECONDARY NEOPLASMS AND IT 2226 01:18:46,760 --> 01:18:50,160 WILL CERTAINLY IMPROVE CANCELS 2227 01:18:50,160 --> 01:18:52,120 AND DETERMINING THE RISK-BENEFIT 2228 01:18:52,120 --> 01:18:55,240 RATIO IN LIGHT OF THE EMERGING 2229 01:18:55,240 --> 01:18:57,920 SUCCESS OF TRANSPLANTATION 2230 01:18:57,920 --> 01:19:01,000 VERSUS -- CONTINUED SURVEILLANCE 2231 01:19:01,000 --> 01:19:02,240 IS ENCOURAGED. 2232 01:19:02,240 --> 01:19:03,760 HOWEVER, CONTINUED SURVEILLANCE 2233 01:19:03,760 --> 01:19:06,360 REQUIRES GUIDANCE FOR SYSTEMATIC 2234 01:19:06,360 --> 01:19:07,440 EVALUATION THAT IS CURRENTLY NOT 2235 01:19:07,440 --> 01:19:08,720 AVAILABLE. 2236 01:19:08,720 --> 01:19:11,440 SO I CALL ON THIS AUDIENCE TO 2237 01:19:11,440 --> 01:19:13,760 DEVELOP A GUIDANCE DOCUMENT FOR 2238 01:19:13,760 --> 01:19:15,080 SURVEILLANCE FOR SECONDARY 2239 01:19:15,080 --> 01:19:16,320 NEOPLASM WHEN ANY CURATIVE 2240 01:19:16,320 --> 01:19:18,200 TREATMENT IS CONSIDERED. 2241 01:19:18,200 --> 01:19:20,040 SOME TREATMENT PROTOCOLS MAY 2242 01:19:20,040 --> 01:19:21,960 HAVE THAT INCORPORATED. 2243 01:19:21,960 --> 01:19:25,560 ONE EXAMPLE IS THE NHLBI-FUNDED 2244 01:19:25,560 --> 01:19:26,880 GRASP TRIAL LED BY DR. DAVID 2245 01:19:26,880 --> 01:19:28,960 WILLIAMS AT BOSTON CHILDREN'S 2246 01:19:28,960 --> 01:19:32,560 HOSPITAL, WHERE HE'S SCREENING 2247 01:19:32,560 --> 01:19:35,760 SYSTEMATICALLY FOR PATHOGENIC 2248 01:19:35,760 --> 01:19:37,600 MUTATIONS IN GENES ASSOCIATED 2249 01:19:37,600 --> 01:19:40,240 WITH MYELOID MALIGNANCY, 2250 01:19:40,240 --> 01:19:42,440 BEGINNING PRETRANSPLANT, AND 2251 01:19:42,440 --> 01:19:44,080 SERIALLY USING A COMBINATION OF 2252 01:19:44,080 --> 01:19:47,600 BLOOD AND BONE MARROW THROUGH 12 2253 01:19:47,600 --> 01:19:48,800 MONTHS POST INFUSION. 2254 01:19:48,800 --> 01:19:52,960 IT'S REVIEWED IN A CENTRAL CLEAR 2255 01:19:52,960 --> 01:19:55,280 CERTIFIED LABORATORY AND 2256 01:19:55,280 --> 01:19:56,760 CENTRALLY ADJUDICATED. 2257 01:19:56,760 --> 01:19:57,920 WITH THAT, I'D LIKE TO 2258 01:19:57,920 --> 01:19:59,160 ACKNOWLEDGE THE FUNDING SUPPORT 2259 01:19:59,160 --> 01:20:00,560 FROM THE NATIONAL INSTITUTES OF 2260 01:20:00,560 --> 01:20:02,040 HEALTH, THE DEPARTMENT OF HEALTH 2261 01:20:02,040 --> 01:20:04,520 AND HUMAN SERVICES, MY 2262 01:20:04,520 --> 01:20:06,000 COLLABORATORS ON THE GRASP 2263 01:20:06,000 --> 01:20:08,520 PROTOCOL TEAM, AND MY 2264 01:20:08,520 --> 01:20:09,160 STATISTICAL COLLEAGUES. 2265 01:20:09,160 --> 01:20:13,200 THANK YOU. 2266 01:20:13,200 --> 01:20:14,560 >>THANK YOU, DR. EAPEN. 2267 01:20:14,560 --> 01:20:16,200 >>OUR LAST SPEAKER WILL BE 2268 01:20:16,200 --> 01:20:17,600 PRESENTING VIRTUALLY, 2269 01:20:17,600 --> 01:20:19,360 DR. LILLIAN MEACHAM IS FROM 2270 01:20:19,360 --> 01:20:20,600 EMORY UNIVERSITY, AND SHE'LL BE 2271 01:20:20,600 --> 01:20:22,000 PRESENTING FEMALE REPRODUCTIVE 2272 01:20:22,000 --> 01:20:23,760 HEALTH OUTCOMES AFTER TRANSPLANT 2273 01:20:23,760 --> 01:20:25,400 FOR SICKLE CELL DISEASE, IS 2274 01:20:25,400 --> 01:20:27,840 REDUCED INTENSITY BETTER THAN 2275 01:20:27,840 --> 01:20:29,640 MYELOABLATIVE CONDITIONING. 2276 01:20:29,640 --> 01:20:31,280 THANKS FOR INVITING ME TO TALK 2277 01:20:31,280 --> 01:20:33,880 ABOUT REPRODUCTIVE HEALTH 2278 01:20:33,880 --> 01:20:36,360 OUTCOMES. 2279 01:20:36,360 --> 01:20:37,160 AND -- WITH SICKLE CELL DISEASE 2280 01:20:37,160 --> 01:20:37,600 AFTER TRANSPLANT. 2281 01:20:37,600 --> 01:20:39,240 I THINK WHEN WE CONSIDER 2282 01:20:39,240 --> 01:20:40,280 REPRODUCTIVE HEALTH OUTCOMES, 2283 01:20:40,280 --> 01:20:42,760 WHAT WE WANT TO KNOW ARE RATES 2284 01:20:42,760 --> 01:20:44,480 OF INFERTILITY. 2285 01:20:44,480 --> 01:20:45,600 INFERTILITY IS A 2286 01:20:45,600 --> 01:20:46,760 PATIENT-REPORTED OUTCOME OF 12 2287 01:20:46,760 --> 01:20:48,240 MONTHS OF UNPROTECTED 2288 01:20:48,240 --> 01:20:50,080 INTERCOURSE WITHOUT PREGNANCY. 2289 01:20:50,080 --> 01:20:51,920 THIS IS A VERY DIFFICULT OUTCOME 2290 01:20:51,920 --> 01:20:53,920 TO CAPTURE, BECAUSE IT IS 2291 01:20:53,920 --> 01:20:55,320 SELF-REPORTED AND IT'S VERY HARD 2292 01:20:55,320 --> 01:20:58,280 TO GET A GOOD DENOMINATOR. 2293 01:20:58,280 --> 01:20:59,960 THEREFORE, WE HAVE TO RELY ON 2294 01:20:59,960 --> 01:21:03,200 OTHER THINGS TO INFORM OUTCOMES 2295 01:21:03,200 --> 01:21:04,760 IN FEMALES. 2296 01:21:04,760 --> 01:21:07,040 PRIMARILY PREMATURE OVARIAN 2297 01:21:07,040 --> 01:21:07,920 INSUFFICIENCY IS WHAT WE REPORT 2298 01:21:07,920 --> 01:21:08,560 OR POI. 2299 01:21:08,560 --> 01:21:10,760 THIS IS ALSO KNOWN AS OVARIAN 2300 01:21:10,760 --> 01:21:12,200 FAILURE OR MENOPAUSE AND IT'S 2301 01:21:12,200 --> 01:21:19,200 DEFINED BY MENOPAUSAL FSH TIMES 2302 01:21:19,200 --> 01:21:20,040 2 AND AMEN REYA. 2303 01:21:20,040 --> 01:21:21,680 WE ALSO TALK ABOUT DIMINISHED 2304 01:21:21,680 --> 01:21:22,680 OVARIAN RESERVE. 2305 01:21:22,680 --> 01:21:24,000 OVARIAN RESERVE REALLY LOOKS AT 2306 01:21:24,000 --> 01:21:26,080 THE PRIMORDIAL FOLLICLE POOL. 2307 01:21:26,080 --> 01:21:28,080 HERE IS A GRAPH THAT SHOWS THAT 2308 01:21:28,080 --> 01:21:31,280 AT BIRTH, EACH OVARY HAS 2309 01:21:31,280 --> 01:21:32,520 1 MILLION PRIMORDIAL FOLLICLES. 2310 01:21:32,520 --> 01:21:33,520 THESE ARE LOST OVER TIME AND 2311 01:21:33,520 --> 01:21:35,280 WHEN YOU HIT THE THRESHOLD OF 2312 01:21:35,280 --> 01:21:37,760 1,000, MENOPAUSE OCCURS, 2313 01:21:37,760 --> 01:21:38,640 TYPICALLY AT AGE 50. 2314 01:21:38,640 --> 01:21:40,000 WHEN A PATIENT IS EXPOSED TO 2315 01:21:40,000 --> 01:21:40,880 RADIATION OR CHEMOTHERAPY, 2316 01:21:40,880 --> 01:21:43,280 THERE'S A LOSS IN THE PRIMORDIAL 2317 01:21:43,280 --> 01:21:44,600 FOLLICLE POOL AND AFTER 2318 01:21:44,600 --> 01:21:46,880 TREATMENT, THEY HAVE GRADUAL 2319 01:21:46,880 --> 01:21:48,320 LOSS BUT THIS PATIENT AND THIS 2320 01:21:48,320 --> 01:21:49,840 EXAMPLE WILL HAVE MENOPAUSE AT 2321 01:21:49,840 --> 01:21:53,640 AGE 18. 2322 01:21:53,640 --> 01:21:56,440 THE PRIMORDIAL FOLLICLES LIVE IN 2323 01:21:56,440 --> 01:21:58,560 THE CORTEX, THE OUTER SURFACE OF 2324 01:21:58,560 --> 01:21:59,480 THE OVARY. 2325 01:21:59,480 --> 01:22:01,280 EVERY MONTH A CERTAIN NUMBER 2326 01:22:01,280 --> 01:22:01,880 WILL DEVELOP AND GROW. 2327 01:22:01,880 --> 01:22:04,160 THESE ARE THE PRIMARY 2328 01:22:04,160 --> 01:22:06,880 PREENTERAL, SMALL ENTERAL -- ONE 2329 01:22:06,880 --> 01:22:09,680 IS CHOSEN TO MATURE AND RELEASED 2330 01:22:09,680 --> 01:22:10,400 AS THE EGG. 2331 01:22:10,400 --> 01:22:13,480 THESE GROWING FOLLICLES PRODUCE 2332 01:22:13,480 --> 01:22:17,680 A HORMONE CALLED AMH. 2333 01:22:17,680 --> 01:22:19,320 AMH REFLECTS THE NUMBER OF 2334 01:22:19,320 --> 01:22:20,960 GROWING FOLLICLES, THE NUMBER OF 2335 01:22:20,960 --> 01:22:22,200 GROWING FOLLICLES REFLECTS THE 2336 01:22:22,200 --> 01:22:24,040 SIZE AND HOW ROBUST THE FOLLICLE 2337 01:22:24,040 --> 01:22:26,760 POOL IS. 2338 01:22:26,760 --> 01:22:28,600 SO WHEN WE WANT TO LOOK AT 2339 01:22:28,600 --> 01:22:29,640 OVARIAN RESERVE, WE CAN EITHER 2340 01:22:29,640 --> 01:22:32,280 DO THAT BY GETTING AN ANTRAL 2341 01:22:32,280 --> 01:22:33,160 FOLLICLE COUNT WHICH TYPICALLY 2342 01:22:33,160 --> 01:22:35,000 HAS TO BE OBTAINED BY TRANS 2343 01:22:35,000 --> 01:22:37,480 VAGINAL ULTRASOUND, OR LOOK AT 2344 01:22:37,480 --> 01:22:44,960 AN ANTIMA L ANTIM URKTS LLERIANE 2345 01:22:44,960 --> 01:22:45,840 COUNT. 2346 01:22:45,840 --> 01:22:46,800 DIMINISHED OVARIAN RESERVE IS 2347 01:22:46,800 --> 01:22:49,120 DIE FINED BY AML LESS THAN 1 OR 2348 01:22:49,120 --> 01:22:50,400 SOME USE A LITTLE LOWER 2349 01:22:50,400 --> 01:22:50,760 THRESHOLD. 2350 01:22:50,760 --> 01:22:53,600 IN PEDIATRICS, THE VALUE VARIES 2351 01:22:53,600 --> 01:22:54,720 THROUGHOUT CHILDHOOD AND 2352 01:22:54,720 --> 01:22:55,000 ADOLESCENCE. 2353 01:22:55,000 --> 01:22:57,000 SO WE HAVE TO LOOK AT AN AMH 2354 01:22:57,000 --> 01:22:58,760 THAT IS MORE THAN 2 STANDARD 2355 01:22:58,760 --> 01:23:01,040 DEVIATIONS BELOW THE MEAN, OR A 2356 01:23:01,040 --> 01:23:04,480 VALUE THAT IS BOW L BELOW THE NL 2357 01:23:04,480 --> 01:23:06,080 RANGE FOR AGE AND ASSAY, BECAUSE 2358 01:23:06,080 --> 01:23:07,680 ASSAYS ALSO VARY. 2359 01:23:07,680 --> 01:23:12,040 SO WE WANTED TO BEGIN TO LOOK AT 2360 01:23:12,040 --> 01:23:13,360 THIS AND BACK IN 2015 WE STARTED 2361 01:23:13,360 --> 01:23:15,200 AND WE WANTED TO LOOK AT OVARIAN 2362 01:23:15,200 --> 01:23:16,200 HEALTH IN TRANSPLANT PATIENTS 2363 01:23:16,200 --> 01:23:17,640 AND WE WONDERED WHO SHOULD WE 2364 01:23:17,640 --> 01:23:18,080 COMPARE TO. 2365 01:23:18,080 --> 01:23:21,920 SO WE LOOKED AT PATIENTS ON 2366 01:23:21,920 --> 01:23:22,680 HYDROXYUREA AND PATIENTS 2367 01:23:22,680 --> 01:23:23,760 RECEIVING STANDARD OF CARE OR 2368 01:23:23,760 --> 01:23:24,440 TRANSFUSIONS. 2369 01:23:24,440 --> 01:23:28,360 WE FOUND NOT SURPRISINGLY THAT 2370 01:23:28,360 --> 01:23:30,280 WITH STANDARD OF CARE ALL 2371 01:23:30,280 --> 01:23:31,680 PATIENTS HAD NORMAL OVARIAN 2372 01:23:31,680 --> 01:23:34,560 RESERVE AND NON-IT POI 2373 01:23:34,560 --> 01:23:35,960 OROVAIRIAN FAILURE. 2374 01:23:35,960 --> 01:23:38,400 FOR PATIENTS ON HYDROXYUREA, 2375 01:23:38,400 --> 01:23:40,120 ALMOST A QUARTER IT DIMINISHED 2376 01:23:40,120 --> 01:23:41,800 OVARIAN RESERVE, WHICH WAS A BIT 2377 01:23:41,800 --> 01:23:42,680 SURPRISING, BUT WHEN WE LOOKED 2378 01:23:42,680 --> 01:23:45,320 AT THE TRANSPLANTED PATIENTS, 2379 01:23:45,320 --> 01:23:47,080 100% HAD DIMINISHED OVARIAN 2380 01:23:47,080 --> 01:23:48,840 RESERVE, THEIR AMH VALUES WERE 2381 01:23:48,840 --> 01:23:51,240 NOT ONLY LOW, THEY WERE 2382 01:23:51,240 --> 01:23:52,560 UNDETECTABLE, AND NIEP TI% HAD 2383 01:23:52,560 --> 01:23:57,160 OVARIAN FAILURE. 2384 01:23:57,160 --> 01:23:58,560 SO THEN WE ASKED THE QUESTION, 2385 01:23:58,560 --> 01:24:01,000 HOW HEALTHY -- WELL, WE ASKED, 2386 01:24:01,000 --> 01:24:02,400 IS THE RECOVERY OVER TIME? 2387 01:24:02,400 --> 01:24:05,840 WE KNOW THAT IN HODGKIN'S 2388 01:24:05,840 --> 01:24:07,760 DISEASE, IN THE FIRST TWO YEARS 2389 01:24:07,760 --> 01:24:09,920 YOU CAN SEE RECOVERY OF A MH. 2390 01:24:09,920 --> 01:24:13,760 SO WE LOOKED AT AMH 2391 01:24:13,760 --> 01:24:14,560 LONGITUDINALLY UP TO 13 YEARS 2392 01:24:14,560 --> 01:24:18,560 AND THERE WAS NO RECOVERY. 2393 01:24:18,560 --> 01:24:21,200 OF AMH WITHIN THAT TIME FRA FRA 2394 01:24:21,200 --> 01:24:22,200 FRAME. 2395 01:24:22,200 --> 01:24:23,640 WE HAD THREE PATIENTS IN WHOM WE 2396 01:24:23,640 --> 01:24:24,960 HAD BASELINE AMH. 2397 01:24:24,960 --> 01:24:26,280 ALL OF THOSE WERE NORMAL. 2398 01:24:26,280 --> 01:24:27,360 THESE ARE SI UNITS. 2399 01:24:27,360 --> 01:24:29,240 SO WE KNEW THAT AT LEAST IN 2400 01:24:29,240 --> 01:24:30,880 THESE THREE PATIENTS, THEY WERE 2401 01:24:30,880 --> 01:24:33,280 NORMAL AT BASELINE, DEPLETED 2402 01:24:33,280 --> 01:24:34,400 POST TRANSPLANT AND DID NOT 2403 01:24:34,400 --> 01:24:38,320 RECOVER. 2404 01:24:38,320 --> 01:24:40,280 SO THEN WE WANTED TO LOOK MORE 2405 01:24:40,280 --> 01:24:42,160 BROADLY AT AMH BEFORE TRANSPLANT 2406 01:24:42,160 --> 01:24:43,240 AND AFTER TRANSPLANT. 2407 01:24:43,240 --> 01:24:45,600 AND THIS IS A GROUP OF 19 2408 01:24:45,600 --> 01:24:46,480 PATIENTS. 2409 01:24:46,480 --> 01:24:47,960 I HAVE THEIR BONE MARROW 2410 01:24:47,960 --> 01:24:49,440 TRANSPLANT REGIMENS AT A THROUGH 2411 01:24:49,440 --> 01:24:52,040 E AND I WILL DEFINE THESE IN A 2412 01:24:52,040 --> 01:24:53,240 FUTURE SLIDE. 2413 01:24:53,240 --> 01:24:54,120 SO I KNOW THIS ISN'T HELPFUL 2414 01:24:54,120 --> 01:24:55,760 RIGHT NOW, BUT WE'LL COME BACK 2415 01:24:55,760 --> 01:24:56,880 TO THAT. 2416 01:24:56,880 --> 01:24:59,600 AND YOU'LL SEE THAT AT AMH PRIOR 2417 01:24:59,600 --> 01:25:03,120 TO TRANSPLANT, 17 WERE NORMAL 2418 01:25:03,120 --> 01:25:05,000 AND TWO WERE LOW AND THOSE TWO 2419 01:25:05,000 --> 01:25:08,000 WERE ON HYDROXYUREA, AND POST 2420 01:25:08,000 --> 01:25:10,080 TRANSPLANT, THEY WERE ALL 2421 01:25:10,080 --> 01:25:11,000 UNDETECTABLE EXCEPT FOR TWO THAT 2422 01:25:11,000 --> 01:25:11,640 WERE LOW. 2423 01:25:11,640 --> 01:25:13,920 WE LOOKED AT POI, AND POI CAN 2424 01:25:13,920 --> 01:25:15,400 ONLY BE MEASURED IN PATIENTS WHO 2425 01:25:15,400 --> 01:25:18,880 ARE OLD ENOUGH TO ACTIVATE THEIR 2426 01:25:18,880 --> 01:25:21,840 HYPOTHATHALAMIC ACCESS, SO THERE 2427 01:25:21,840 --> 01:25:23,720 WERE ONLY SIX PATIENTS ELIGIBLE 2428 01:25:23,720 --> 01:25:25,760 AND HALF OF THOSE AT THE TIME OF 2429 01:25:25,760 --> 01:25:28,920 TESTING DEMONSTRATED POI. 2430 01:25:28,920 --> 01:25:30,400 SO THEN WE ASKED THE QUESTION, 2431 01:25:30,400 --> 01:25:32,400 ARE ALL CONDITIONING REGIMENS 2432 01:25:32,400 --> 01:25:33,880 HIGH RISK? 2433 01:25:33,880 --> 01:25:35,200 OR DO THEY ALL CONFER THE SAME 2434 01:25:35,200 --> 01:25:36,080 LEVEL OF RISK? 2435 01:25:36,080 --> 01:25:37,840 OR, ARE REDUCED INTENSITY 2436 01:25:37,840 --> 01:25:43,400 REGIMENS LESS O OWE VO TOXIC THN 2437 01:25:43,400 --> 01:25:46,840 MYELOABLATIVE REGIMENS? 2438 01:25:46,840 --> 01:25:48,600 SO IN ORDER TO CLASSIFY 2439 01:25:48,600 --> 01:25:53,760 REGIMENS, WE USED THIS PAPER 2440 01:25:53,760 --> 01:25:56,400 WHICH WAS PUBLISHED BY LIMERICK 2441 01:25:56,400 --> 01:25:58,720 AND ABRAHAM TO ASSIGN WHETHER A 2442 01:25:58,720 --> 01:26:01,120 PROTOCOL WAS MYELOABLATIVE OR 2443 01:26:01,120 --> 01:26:03,120 REDUCED INTENSITY. 2444 01:26:03,120 --> 01:26:04,560 WE THEN LOOKED AT EACH OF THE 2445 01:26:04,560 --> 01:26:11,440 REGIMENS AND WE CONVERTED THE 2446 01:26:11,440 --> 01:26:12,000 CYCLOPHOSPHAMIDE EQUIVALENT 2447 01:26:12,000 --> 01:26:12,200 DOSE. 2448 01:26:12,200 --> 01:26:13,840 THIS IS USED EXTENSIVELY IN 2449 01:26:13,840 --> 01:26:21,400 ONCOLOGY AND SURVIVORSHIP SO WE 2450 01:26:21,400 --> 01:26:25,680 CAN GET COMPARISONS. 2451 01:26:25,680 --> 01:26:27,000 SO THESE ARE THE REGIMENS THAT 2452 01:26:27,000 --> 01:26:28,600 WE LOOKED AT. 2453 01:26:28,600 --> 01:26:30,400 AND THEY'RE A THROUGH I. 2454 01:26:30,400 --> 01:26:33,240 I'VE LISTED THE DIFFERENT AGENTS 2455 01:26:33,240 --> 01:26:36,320 USED, AND THEN IN RED, YOU CAN 2456 01:26:36,320 --> 01:26:39,800 SEE WITH THE CYCLOPHOSPHAMIDE 2457 01:26:39,800 --> 01:26:41,040 EQUIVALENT DOSE IS FOR EACH 2458 01:26:41,040 --> 01:26:41,640 REGIMEN. 2459 01:26:41,640 --> 01:26:45,760 THEY GO FROM 3,300 UP TO 2460 01:26:45,760 --> 01:26:47,040 18,000 MILLIGRAMS PER METER 2461 01:26:47,040 --> 01:26:48,920 SQUARED OF CYCLOPHOSPHAMIDE. 2462 01:26:48,920 --> 01:26:51,240 THE LAST LINE SHOWS WHETHER THIS 2463 01:26:51,240 --> 01:26:53,000 REGIMEN WOULD HAVE BEEN 2464 01:26:53,000 --> 01:26:55,040 CLASSIFIED AS MYELOABLATIVE OR 2465 01:26:55,040 --> 01:26:55,720 REDUCED INTENSITY. 2466 01:26:55,720 --> 01:26:58,480 YOU CAN SEE THE LOWEST CED IS 2467 01:26:58,480 --> 01:26:59,880 ACTUALLY MYELOABLATIVE, AND THE 2468 01:26:59,880 --> 01:27:04,160 TWO TOP HIGHEST CEDs AT 2469 01:27:04,160 --> 01:27:05,480 17 GRAMS PER METER SQUARED AND 2470 01:27:05,480 --> 01:27:07,760 18 GRAMS PER METER SQUARED ARE 2471 01:27:07,760 --> 01:27:09,000 ACTUALLY REDUCED INTENSITY 2472 01:27:09,000 --> 01:27:13,160 REGIMENS. 2473 01:27:13,160 --> 01:27:14,680 WE THEN WENT AND -- THIS WAS A 2474 01:27:14,680 --> 01:27:15,680 LITTLE BIT CONFUSING. 2475 01:27:15,680 --> 01:27:17,080 WE'VE DONE THREE STUDIES WHERE 2476 01:27:17,080 --> 01:27:18,520 WE'VE REPORTED DIMINISHED 2477 01:27:18,520 --> 01:27:19,280 OVARIAN RESERVE. 2478 01:27:19,280 --> 01:27:20,640 SO I'VE HIGHLIGHTED THE FINDINGS 2479 01:27:20,640 --> 01:27:21,480 IN THOSE STUDIES. 2480 01:27:21,480 --> 01:27:22,520 IT IS IMPORTANT TO NOTE THAT 2481 01:27:22,520 --> 01:27:25,120 SOME OF THESE ARE -- THEY ARE 2482 01:27:25,120 --> 01:27:27,280 NOT MUTUALLY EXCLUSIVE STUDIES. 2483 01:27:27,280 --> 01:27:28,280 BUT THE FIRST STUDY YOU'VE 2484 01:27:28,280 --> 01:27:29,520 ALREADY SEEN, WHICH WAS A 2485 01:27:29,520 --> 01:27:32,200 LONGITUDINAL STUDY PUBLISHED IN 2486 01:27:32,200 --> 01:27:33,240 2020. 2487 01:27:33,240 --> 01:27:36,000 THE PRE AND POST AMH BY GEORGE 2488 01:27:36,000 --> 01:27:37,440 IN 2022, AND THEN DR. GEORGE HAS 2489 01:27:37,440 --> 01:27:38,920 GOT ANOTHER STUDY THAT'S IN 2490 01:27:38,920 --> 01:27:39,640 PROGRESS. 2491 01:27:39,640 --> 01:27:40,880 WHAT YOU'LL NOTICE FOR 2492 01:27:40,880 --> 01:27:43,000 DIMINISHED OVARIAN RESERVE, THAT 2493 01:27:43,000 --> 01:27:46,080 IN ALMOST ALL OF THESE PATIENTS, 2494 01:27:46,080 --> 01:27:47,760 100% OF PATIENTS HAD DIMINISHED 2495 01:27:47,760 --> 01:27:49,600 OVARIAN RESERVE, AND AGAIN NOT 2496 01:27:49,600 --> 01:27:53,320 JUST DIMINISHED BUT DEPLETED. 2497 01:27:53,320 --> 01:27:55,400 IT'S UNDETECTABLE AM EXCEPT 2498 01:27:55,400 --> 01:27:59,040 EXCEPT FOR TWO, WHICH IS B AND 2499 01:27:59,040 --> 01:27:59,440 H. 2500 01:27:59,440 --> 01:28:02,320 AGAIN, IN ONE PLACE, IT'S CED OF 2501 01:28:02,320 --> 01:28:05,320 5.6, AND THE OTHER, A CED OF 2502 01:28:05,320 --> 01:28:07,880 17.6. 2503 01:28:07,880 --> 01:28:11,160 WE THEN LOOKED AT PREMATURE 2504 01:28:11,160 --> 01:28:11,720 OVARIAN INSUFFICIENCY. 2505 01:28:11,720 --> 01:28:13,280 I THINK THIS IS MESSY DATA 2506 01:28:13,280 --> 01:28:14,720 BECAUSE NOT ALL PATIENTS CAN BE 2507 01:28:14,720 --> 01:28:15,600 STUDIED BECAUSE THEY'RE NOT OLD 2508 01:28:15,600 --> 01:28:16,240 ENOUGH. 2509 01:28:16,240 --> 01:28:19,440 AND IT'S NOT AS CLEAN OR CLEAR, 2510 01:28:19,440 --> 01:28:22,160 BUT I'VE LISTED THE RATES OF POI 2511 01:28:22,160 --> 01:28:23,280 IN THESE DIFFERENT STUDIES FOR 2512 01:28:23,280 --> 01:28:25,240 PATIENTS THAT WERE ELIGIBLE TO 2513 01:28:25,240 --> 01:28:27,360 BE EVALUATED, WHICH ARE 2514 01:28:27,360 --> 01:28:28,400 BASICALLY PATIENTS OLDER THAN 13 2515 01:28:28,400 --> 01:28:30,480 WHO SHOULD HAVE ENTERED PUBERTY. 2516 01:28:30,480 --> 01:28:32,520 AND YOU SEE THAT THE RANGES ARE 2517 01:28:32,520 --> 01:28:34,400 A LITTLE BIT SCATTERED, BUT I 2518 01:28:34,400 --> 01:28:36,240 HIGHLIGHTED IN YELLOW THOSE THAT 2519 01:28:36,240 --> 01:28:37,560 WERE LESS THAN 50%. 2520 01:28:37,560 --> 01:28:43,040 AND AGAIN, IT'S THE MELPHALAN 2521 01:28:43,040 --> 01:28:44,680 STUDY, BUT IT'S ALSO THIS STUDY, 2522 01:28:44,680 --> 01:28:52,960 A PROTOCOL G, SO WHEN YOU LOOK 2523 01:28:52,960 --> 01:28:57,160 AT CED, BY CED, MYELOABLATIVE IS 2524 01:28:57,160 --> 01:29:01,160 NOT MORE TOXIC REDUCED INTENSITY 2525 01:29:01,160 --> 01:29:03,000 IF WE JUST LOOK AT CED. 2526 01:29:03,000 --> 01:29:04,800 THE SECOND POINT WOULD BE 2527 01:29:04,800 --> 01:29:06,840 DIMINISHED OVARIAN RESERVE IS 2528 01:29:06,840 --> 01:29:11,000 ALMOST FOUND IN ALL PATIENTS. 2529 01:29:11,000 --> 01:29:13,160 AND THAT PREMATURE OVARIAN 2530 01:29:13,160 --> 01:29:14,160 INSUFFICIENCY IS LESS UNIFORM 2531 01:29:14,160 --> 01:29:17,120 AND PERHAPS A DEVELOPING PICT 2532 01:29:17,120 --> 01:29:18,680 PICTURE. 2533 01:29:18,680 --> 01:29:19,880 THOSE OF US IN THE FIELD THINK 2534 01:29:19,880 --> 01:29:23,480 OF DIMINISHED OVARIAN RESERVE AS 2535 01:29:23,480 --> 01:29:25,560 A WARNING THAT IT'S COMING. 2536 01:29:25,560 --> 01:29:27,320 SO RECOMMENDS PROVIDE FERTILITY 2537 01:29:27,320 --> 01:29:29,520 CONSULTS TO ALL PATIENTS, OFFER 2538 01:29:29,520 --> 01:29:32,440 FERTILITY PRESERVATION AS A 2539 01:29:32,440 --> 01:29:33,560 HARVEST OF OVARIAN TISSUE, 2540 01:29:33,560 --> 01:29:35,520 MONITOR FUNCTION AFTERWARDS, AND 2541 01:29:35,520 --> 01:29:36,640 THERE'S A CONSIDERATION THAT WE 2542 01:29:36,640 --> 01:29:39,480 COULD TALK ABOUT, ALTHOUGH 2543 01:29:39,480 --> 01:29:40,920 UNLIKELY TO WORK BECAUSE OF THE 2544 01:29:40,920 --> 01:29:43,520 LOW AMH AND THAT WOULD BE POST 2545 01:29:43,520 --> 01:29:46,080 TRANSPLANT EGG HARVEST. 2546 01:29:46,080 --> 01:29:47,840 NEXT SLIDE WHICH IS MY LAST 2547 01:29:47,840 --> 01:29:48,800 SLIDE. 2548 01:29:48,800 --> 01:29:50,080 I THINK REPRODUCTIVE HEALTH IS 2549 01:29:50,080 --> 01:29:51,080 COMPLICATED IN PATIENTS WITH 2550 01:29:51,080 --> 01:29:52,320 SICKLE CELL DISEASE BUT DESERVES 2551 01:29:52,320 --> 01:29:53,200 ATTENTION. 2552 01:29:53,200 --> 01:29:55,280 I'D LIKE TO THANK MY 2553 01:29:55,280 --> 01:29:56,600 COLLABORATORS. 2554 01:29:56,600 --> 01:29:57,440 AND OUR FUNDING. 2555 01:29:57,440 --> 01:30:02,200 THANK YOU. 2556 01:30:02,200 --> 01:30:05,160 >>BIG HAND TO THE SPEAKERS. 2557 01:30:05,160 --> 01:30:08,640 WE WILL PREFERENTIALLY READ OUT 2558 01:30:08,640 --> 01:30:09,480 QUESTIONS FROM THE CHAT, PLEASE? 2559 01:30:09,480 --> 01:30:11,080 >>WE HAVE A COUPLE OF QUESTIONS 2560 01:30:11,080 --> 01:30:15,240 ON CHAT AND ALANA IS GOING TO BE 2561 01:30:15,240 --> 01:30:17,840 TALKING -- 2562 01:30:17,840 --> 01:30:19,520 >>IF YOU HAVE A QUESTION FOR 2563 01:30:19,520 --> 01:30:20,920 THE SPEAKER, GO TO THE NEAREST 2564 01:30:20,920 --> 01:30:21,080 MIC. 2565 01:30:21,080 --> 01:30:23,360 >>SO THE FIRST QUESTION IS FOR 2566 01:30:23,360 --> 01:30:23,880 DR. STENGER. 2567 01:30:23,880 --> 01:30:27,080 WHILE THE REDUCTIONS IN LV 2568 01:30:27,080 --> 01:30:27,640 EJECTION FRACTION ARE 2569 01:30:27,640 --> 01:30:28,920 INTERESTING, THEY ARE BOTH 2570 01:30:28,920 --> 01:30:29,800 WITHIN NORMAL LIMITS. 2571 01:30:29,800 --> 01:30:31,120 IS IT POSSIBLE THAT WHAT IS 2572 01:30:31,120 --> 01:30:35,880 BEING OBSERVED IS A REDUCTION IN 2573 01:30:35,880 --> 01:30:37,160 THE CARDIAC OUTPUT WHICH WILL 2574 01:30:37,160 --> 01:30:38,920 OCCUR WITH THE CORRECTION OF 2575 01:30:38,920 --> 01:30:40,000 ANEMIA? 2576 01:30:40,000 --> 01:30:42,360 ARE THERE OTHER CARDIOPULMONARY 2577 01:30:42,360 --> 01:30:47,280 VARIABLES AVAILABLE? 2578 01:30:47,280 --> 01:30:48,000 >>SO THANK YOU FOR THE 2579 01:30:48,000 --> 01:30:48,360 QUESTION. 2580 01:30:48,360 --> 01:30:49,760 SO FOR THIS ANALYSIS, WE LIMITED 2581 01:30:49,760 --> 01:30:51,280 TO EJECTION FRACTION AND 2582 01:30:51,280 --> 01:30:52,120 SHORTENING FRACTION AND AGAIN 2583 01:30:52,120 --> 01:30:54,880 THE SUBSET THAT HAD -- BUT WE DO 2584 01:30:54,880 --> 01:30:56,680 HAVE SOURCE DOCUMENTS FOR THE 2585 01:30:56,680 --> 01:30:58,320 PULMONARY FUNCTION TESTS AND THE 2586 01:30:58,320 --> 01:31:00,240 ECHOES, SO WE'RE WORKING NOW ON 2587 01:31:00,240 --> 01:31:03,720 POOLING THAT DATA WITH MORE 2588 01:31:03,720 --> 01:31:05,160 DETAILED PARAMETERS FROM BOTH SO 2589 01:31:05,160 --> 01:31:07,200 THAT WE CAN DO SOME FUTURE 2590 01:31:07,200 --> 01:31:08,560 ANALYSES. 2591 01:31:08,560 --> 01:31:09,640 SO HOPE TO HAVE BETTER DATA. 2592 01:31:09,640 --> 01:31:12,280 THANK YOU FOR THE QUESTION. 2593 01:31:12,280 --> 01:31:12,960 >>OKAY. 2594 01:31:12,960 --> 01:31:17,360 I HAVE ONE MORE QUESTION FOR DR. 2595 01:31:17,360 --> 01:31:19,960 AND THE QUESTION IS WHETHER YOU 2596 01:31:19,960 --> 01:31:23,840 HAVE CONDUCTED MRA FOR 2597 01:31:23,840 --> 01:31:27,680 HEMODYNAMIC ANALYSIS ON CEREBRAL 2598 01:31:27,680 --> 01:31:29,520 VASOCULTURE. 2599 01:31:29,520 --> 01:31:32,360 >>I'M SORRY, CAN YOU REPEAT THE 2600 01:31:32,360 --> 01:31:32,640 QUESTION? 2601 01:31:32,640 --> 01:31:33,160 >>SURE. 2602 01:31:33,160 --> 01:31:35,520 THE QUESTION IS WHETHER THERE 2603 01:31:35,520 --> 01:31:41,840 HAS BEEN ANY CONDUCTED MRA FOR 2604 01:31:41,840 --> 01:31:44,760 HEMODYNAMIC ANALYSIS ON CEREBRAL 2605 01:31:44,760 --> 01:31:45,080 VASOCULTURE. 2606 01:31:45,080 --> 01:31:46,840 >>VASOOCCLUSION, I ASSUME THAT 2607 01:31:46,840 --> 01:31:47,160 MEANS. 2608 01:31:47,160 --> 01:31:47,960 THAT'S A GREAT QUESTION. 2609 01:31:47,960 --> 01:31:49,800 IN OUR COHORT OF TRANSPLANT 2610 01:31:49,800 --> 01:31:52,640 PATIENTS, ONE OF THE PATIENTS 2611 01:31:52,640 --> 01:31:55,320 HAD CEREBRAL VASCULOPATHY AND 2612 01:31:55,320 --> 01:31:59,600 HAD UNDERGONE A UNILATERAL -- 2613 01:31:59,600 --> 01:32:01,680 REVASCULARIZATION PROCEDURE. 2614 01:32:01,680 --> 01:32:04,440 IN OUR TRANSFUSION POPULATION, I 2615 01:32:04,440 --> 01:32:06,160 BELIEVE TWO OF THE PATIENTS, 2616 01:32:06,160 --> 01:32:09,240 MAYBE THREE, HAD 2617 01:32:09,240 --> 01:32:10,680 REVASCULARIZATION -- HAD 2618 01:32:10,680 --> 01:32:13,400 VASCULOPATHY, ONE HAD HAD 2619 01:32:13,400 --> 01:32:14,240 REVASCULARIZATION, THE OTHERS 2620 01:32:14,240 --> 01:32:14,960 HADN'T. 2621 01:32:14,960 --> 01:32:16,720 WE DIDN'T SEE ANY DIFFERENCES 2622 01:32:16,720 --> 01:32:18,240 IS, BUT AGAIN, IT WAS A REALLY 2623 01:32:18,240 --> 01:32:26,600 SMALL SAMPLE SIZE. 2624 01:32:26,600 --> 01:32:28,880 >>WITH THAT, WE'LL GO AHEAD AND 2625 01:32:28,880 --> 01:32:29,840 WRAP UP OUR SESSION. 2626 01:32:29,840 --> 01:32:31,440 IF IN-PERSON FOLKS HAVE 2627 01:32:31,440 --> 01:32:32,280 QUESTIONS FOR THE SPEAKERS, 2628 01:32:32,280 --> 01:32:33,720 PLEASE DON'T HESITATE TO GRAB 2629 01:32:33,720 --> 01:32:35,160 THEM OR REACH OUT VIA EMAIL. 2630 01:32:35,160 --> 01:32:38,120 THANK YOU, EVERYONE, TO OUR 2631 01:32:38,120 --> 01:32:38,560 SPEAKERS. 2632 01:32:38,560 --> 01:32:39,680 GREAT SESSION. 2633 01:32:39,680 --> 01:32:42,720 >>THANK YOU. 2634 01:32:42,720 --> 01:32:43,920 BIG HAND FOR THE SPEAKERS. 2635 01:32:43,920 --> 01:32:45,600 SO WE MOVE ON TO THE NEXT 2636 01:32:45,600 --> 01:32:47,120 SESSION, WHICH IS THE CURATIVE 2637 01:32:47,120 --> 01:32:51,040 THERAPIES FOR SICKLE CELL TWO, 2638 01:32:51,040 --> 01:32:57,560 GENE THERAPY/GENE EDITING. 2639 01:32:57,560 --> 01:32:59,200 >>SO MAYBE WE CAN JUST START 2640 01:32:59,200 --> 01:33:01,440 WITH THE INTRODUCTION WITHOUT 2641 01:33:01,440 --> 01:33:02,600 THE SLIDES. 2642 01:33:02,600 --> 01:33:07,320 SO BASICALLY THIS CURATIVE 2643 01:33:07,320 --> 01:33:10,080 THERAPY SESSION, WE WERE GOING 2644 01:33:10,080 --> 01:33:13,920 TO TALK ABOUT TWO DIFFERENT 2645 01:33:13,920 --> 01:33:16,680 APPROACHES OF GENETIC THERAPIES. 2646 01:33:16,680 --> 01:33:18,840 THE FIRST ONE BEING GENE 2647 01:33:18,840 --> 01:33:21,240 ADDITION WITH LENTIVIRAL VECTORS 2648 01:33:21,240 --> 01:33:23,160 AND THE SECOND BEING GENE ID 2649 01:33:23,160 --> 01:33:28,840 ITEDITING USING CRISPR/CAS. 2650 01:33:28,840 --> 01:33:30,200 THE GENE EDITING APPROACHES THAT 2651 01:33:30,200 --> 01:33:32,400 WE WERE GOING TO DISCUSS WOULD 2652 01:33:32,400 --> 01:33:35,000 BASICALLY INVOLVE LENTIVIRAL 2653 01:33:35,000 --> 01:33:38,440 VECTORS AND THEY CARRY AN 2654 01:33:38,440 --> 01:33:39,320 ANTICYCLING GENE THAT IS UNDER 2655 01:33:39,320 --> 01:33:42,040 THE CONTROL OF PROMOTERS AND 2656 01:33:42,040 --> 01:33:43,360 ENHANCERS. 2657 01:33:43,360 --> 01:33:46,120 THE LENTIVIRAL VECTOR INTEGRATES 2658 01:33:46,120 --> 01:33:48,400 RANDOMLY INTO THE GENOME, AND SO 2659 01:33:48,400 --> 01:33:52,680 THERE IS A SMALL POSSIBILITY OF 2660 01:33:52,680 --> 01:33:55,600 IT HAVING INSERTIONAL 2661 01:33:55,600 --> 01:33:57,880 GENOTOXICITY IF IT INTEGRATES 2662 01:33:57,880 --> 01:34:00,160 AND ACTIVATES AN ONCOGENE. 2663 01:34:00,160 --> 01:34:02,480 THAT SAID, THAT IS OVER 15 YEARS 2664 01:34:02,480 --> 01:34:06,320 OF EXPERIENCE WITH LENTIVIRAL 2665 01:34:06,320 --> 01:34:08,840 VECTORS, GLOBAL ANTIVIRAL 2666 01:34:08,840 --> 01:34:09,880 VECTORS -- SPECIFIC VECTORS AND 2667 01:34:09,880 --> 01:34:13,320 NO SUCH EVENT HAS BEEN REPORTED. 2668 01:34:13,320 --> 01:34:15,520 GENE EDITING ON THE OTHER HAND 2669 01:34:15,520 --> 01:34:19,240 IS USING SITE-SPECIFIC NUCLEASES 2670 01:34:19,240 --> 01:34:24,000 TO DIRECT A CAS NINE NUCLEASE TO 2671 01:34:24,000 --> 01:34:26,520 CREATE A CHANGE OR EDIT SEQUENCE 2672 01:34:26,520 --> 01:34:29,360 OF DNA. 2673 01:34:29,360 --> 01:34:32,880 AND WE HAVE AN ARRAY OF REALLY 2674 01:34:32,880 --> 01:34:37,720 GREAT SPEAKERS WHO ARE GOING TO 2675 01:34:37,720 --> 01:34:40,760 TALK, OUR FIRST SPEAKER IS JOHN 2676 01:34:40,760 --> 01:34:42,880 TISDALE WHO WILL BE SPEAKING ON 2677 01:34:42,880 --> 01:34:45,200 ANTIBODY CONDITIONING REGIMENS 2678 01:34:45,200 --> 01:34:48,800 AND APPROACHES OF DOING CURATIVE 2679 01:34:48,800 --> 01:34:50,920 THERAPIES WITH SICKLE CELL 2680 01:34:50,920 --> 01:34:51,920 DISEASE, AND BECAUSE WE'VE LOST 2681 01:34:51,920 --> 01:34:53,960 SOME TIME, I'M NOT GOING TO 2682 01:34:53,960 --> 01:34:55,600 SPEAK ABOUT THE TITLES OF ALL 2683 01:34:55,600 --> 01:34:56,760 THE OTHER SPEAKERS. 2684 01:34:56,760 --> 01:34:58,400 I'LL JUST LET JOHN TAKE IT AWAY. 2685 01:34:58,400 --> 01:35:01,200 THANK YOU FOR THE OPPORTUNITY TO 2686 01:35:01,200 --> 01:35:01,960 PRESENT OUR WORK. 2687 01:35:01,960 --> 01:35:04,160 BY NOW YOU'VE SEEN THIS SLIDE. 2688 01:35:04,160 --> 01:35:08,040 THIS IS HGB-206 STUDY, THE BLOOK 2689 01:35:08,040 --> 01:35:10,640 BERG STUDY OF HIV-BASED GENE 2690 01:35:10,640 --> 01:35:12,080 THERAPY FOR SICKLE CELL DISEASE. 2691 01:35:12,080 --> 01:35:13,160 THE IMPORTANT POINT BEING THAT 2692 01:35:13,160 --> 01:35:17,600 THERE WAS AN EVOLUTION OF THIS 2693 01:35:17,600 --> 01:35:21,760 PROTOCOL GOING FROM BONE 2694 01:35:21,760 --> 01:35:22,840 MARROWS, THE HSC SOURCE, SO 2695 01:35:22,840 --> 01:35:24,520 MANUFACTURING SUCH THAT WE GOT 2696 01:35:24,520 --> 01:35:25,960 MUCH HIGHER TRANSDUCTION EE FISH 2697 01:35:25,960 --> 01:35:28,440 SE TO CONDUCTING MOBILIZED 2698 01:35:28,440 --> 01:35:30,360 PERIPHERAL BLOOD AS THE SOURCE. 2699 01:35:30,360 --> 01:35:37,480 HERE WE ARE STUCK AGAIN. 2700 01:35:37,480 --> 01:35:38,840 CAN YOU ADVANCE? 2701 01:35:38,840 --> 01:35:48,880 >>PLEASE SAY "NEXT SLIDE." 2702 01:35:48,880 --> 01:35:51,200 SO THE ITERATIONS OF THIS 2703 01:35:51,200 --> 01:35:52,520 PROTOCOL HAVE BEEN PUBLISHED, 2704 01:35:52,520 --> 01:35:54,600 THERE ARE GROUPS A AND B HERE, 2705 01:35:54,600 --> 01:35:57,280 AND GROUP C IN THE SECOND 2706 01:35:57,280 --> 01:36:01,560 PUBLICATION. 2707 01:36:01,560 --> 01:36:04,040 THE TAKE-HOME POINT IS THAT 2708 01:36:04,040 --> 01:36:06,320 VECTOR COPY NUMBER IMPROVED FROM 2709 01:36:06,320 --> 01:36:10,880 .1 IN GROUP A TO 1.5 IN GROUP C, 2710 01:36:10,880 --> 01:36:13,400 AND AS YOU CAN SEE, THIS IS 2711 01:36:13,400 --> 01:36:14,400 STABLE OVER TIME. 2712 01:36:14,400 --> 01:36:16,320 JUST FOR REFERENCE .1 MEANS THAT 2713 01:36:16,320 --> 01:36:19,480 ON AVERAGE, ABOUT 10% OF THE 2714 01:36:19,480 --> 01:36:25,960 CELLS HAD ONE COPY. 2715 01:36:25,960 --> 01:36:29,000 THIS SHOWS THE TRANSLATION OF 2716 01:36:29,000 --> 01:36:30,560 THOSE CHANGES INTO AMOUNT OF 2717 01:36:30,560 --> 01:36:31,880 HEMOGLOBIN DERIVING FROM VECTOR 2718 01:36:31,880 --> 01:36:33,600 SO IT WAS ABOUT 10% AS YOU MIGHT 2719 01:36:33,600 --> 01:36:38,160 HAVE PREDICTED FROM THE ORIGINAL 2720 01:36:38,160 --> 01:36:40,560 COHORT, IT'S ALMOST HALF OF THE 2721 01:36:40,560 --> 01:36:45,160 HEMOGLOBIN IN GROUP C. 2722 01:36:45,160 --> 01:36:48,600 MODEST IMPROVEMENT OF TOTAL 2723 01:36:48,600 --> 01:36:50,920 HEMOGLOBIN AND GROUP C THE 2724 01:36:50,920 --> 01:36:55,720 HEMOGLOBIN NORMALIZED. 2725 01:36:55,720 --> 01:36:57,000 NOT ALL TOGETHER CERTAIN HOW 2726 01:36:57,000 --> 01:36:58,680 THESE SLIDES ARE GOING BUT I 2727 01:36:58,680 --> 01:36:59,360 KEEP HITTING NEXT -- 2728 01:36:59,360 --> 01:37:01,120 >>PLEASE SAY "NEXT SLIDE." 2729 01:37:01,120 --> 01:37:02,120 >>I'M SORRY? 2730 01:37:02,120 --> 01:37:04,560 >>PLEASE SAY "NEXT SLIDE" WHEN 2731 01:37:04,560 --> 01:37:05,320 YOU'RE READY. 2732 01:37:05,320 --> 01:37:05,960 >>NEXT. 2733 01:37:05,960 --> 01:37:06,600 OKAY. 2734 01:37:06,600 --> 01:37:08,600 SO THIS RESULTED IN A COMPLETE 2735 01:37:08,600 --> 01:37:11,360 RESOLUTION OF SEVERE 2736 01:37:11,360 --> 01:37:12,160 VASOOCCLUSIVE EVENT AS YOU SAW 2737 01:37:12,160 --> 01:37:17,480 EARLIER. 2738 01:37:17,480 --> 01:37:18,960 BUT UNFORTUNATELY THERE WAS A 2739 01:37:18,960 --> 01:37:20,720 SAFETY SIGNAL NOTED IN LONG-TERM 2740 01:37:20,720 --> 01:37:21,000 FOLLOW-UP. 2741 01:37:21,000 --> 01:37:24,000 SO YOU CAN SEE THE TREATMENT 2742 01:37:24,000 --> 01:37:25,120 EMERGING GRADE III AEs THAT 2743 01:37:25,120 --> 01:37:27,120 ARE TYPICAL FOR AN AUTO 2744 01:37:27,120 --> 01:37:32,160 TRANSPLANT, BUT WE HAD TWO CASES 2745 01:37:32,160 --> 01:37:38,200 OF ACS AML AS MENTIONED. 2746 01:37:38,200 --> 01:37:39,200 IN THE SECOND CASE, THERE WAS, 2747 01:37:39,200 --> 01:37:41,680 IN FACT, A VECTOR PRESENT IN THE 2748 01:37:41,680 --> 01:37:43,840 BLAST. 2749 01:37:43,840 --> 01:37:47,040 NOTABLY BOTH PATIENTS HAD 2750 01:37:47,040 --> 01:37:51,000 CLASSIC AML DRIVERS, AT 2751 01:37:51,000 --> 01:38:00,160 DIAGNOSIS, MONO SEW ME 7, 2752 01:38:00,160 --> 01:38:01,520 RUNX1 AND PTPN11. 2753 01:38:01,520 --> 01:38:03,400 WE DID AN EXHAUSTIVE EVALUATION 2754 01:38:03,400 --> 01:38:05,240 TO LOOK FOR WHETHER VECTOR WAS A 2755 01:38:05,240 --> 01:38:06,760 PASSENGER OR DRIVER IN THIS 2756 01:38:06,760 --> 01:38:08,320 MALIGNANT PROCESS. 2757 01:38:08,320 --> 01:38:10,120 AND TICKED OFF ALL OF THESE 2758 01:38:10,120 --> 01:38:11,960 BOXES AND FOUND THAT VECTOR 2759 01:38:11,960 --> 01:38:13,400 INTEGRATION, PER SE, WAS NOT 2760 01:38:13,400 --> 01:38:19,040 LIKELY CONTRIBUTING TO THE 2761 01:38:19,040 --> 01:38:24,840 LEUKEMOGENESIS. 2762 01:38:24,840 --> 01:38:26,240 SO WE HAD TO LOOK AT 2763 01:38:26,240 --> 01:38:28,720 CONDITIONING AS AT LEAST A 2764 01:38:28,720 --> 01:38:30,520 CONTRIBUTING FACTOR IN THE 2765 01:38:30,520 --> 01:38:33,200 MALIGNANCIES IN THESE PATIENTS, 2766 01:38:33,200 --> 01:38:35,160 AND AS YOU ARE ALL AWARE, WE'VE 2767 01:38:35,160 --> 01:38:36,760 MADE LOTS OF PROGRESS IN GENE 2768 01:38:36,760 --> 01:38:37,280 MODIFICATION. 2769 01:38:37,280 --> 01:38:38,040 YOU'RE GOING TO HEAR ABOUT A LOT 2770 01:38:38,040 --> 01:38:39,560 OF THAT, BUT WE'VE MADE VERY 2771 01:38:39,560 --> 01:38:43,360 LITTLE PROGRESS NE IN THE 2772 01:38:43,360 --> 01:38:44,200 CONDITIONING REGIMEN THAT WE 2773 01:38:44,200 --> 01:38:44,800 USE. 2774 01:38:44,800 --> 01:38:48,400 SO WE ALONG WITH HARVARD STEM 2775 01:38:48,400 --> 01:38:49,840 CELL INSTITUTE AND WHAT WAS MA 2776 01:38:49,840 --> 01:38:55,200 GENERAMAGENTA THERAPEUTICS LAUNA 2777 01:38:55,200 --> 01:39:00,200 BED TO BEDSIDE PROJECT TO LOOK 2778 01:39:00,200 --> 01:39:03,120 AT DRUG CONJUGATED CONDITIONING. 2779 01:39:03,120 --> 01:39:06,720 WE CHOSE ANTI-CD117, BY 2780 01:39:06,720 --> 01:39:08,640 ATTACHING A PAYLOAD THAT'S 2781 01:39:08,640 --> 01:39:09,960 KILLING BOTH QUIESCENT AND 2782 01:39:09,960 --> 01:39:11,720 DIVIDING CELLS AND THIS GIVES US 2783 01:39:11,720 --> 01:39:13,840 AN OPPORTUNITY FOR A LESS TOXIC 2784 01:39:13,840 --> 01:39:15,520 CONDITIONING WITH IMMUNE 2785 01:39:15,520 --> 01:39:16,920 PRESERVATION AND HOPEFULLY 2786 01:39:16,920 --> 01:39:18,360 AVOIDANCE OF SECONDARY 2787 01:39:18,360 --> 01:39:20,360 MALIGNANCY AND FERTILITY, BOTH 2788 01:39:20,360 --> 01:39:21,440 OF WHICH YOU'VE HEARD ABOUT THIS 2789 01:39:21,440 --> 01:39:24,880 MORNING. 2790 01:39:24,880 --> 01:39:27,720 SO CD117 OR C-KIT IS IDEAL 2791 01:39:27,720 --> 01:39:33,920 BECAUSE IT'S EXPRESSED ON -- AND 2792 01:39:33,920 --> 01:39:36,400 ONLY MAST CELLS BEYOND THAT, AND 2793 01:39:36,400 --> 01:39:38,920 A SINGLE DOSE CAN ENABLE ROBUST 2794 01:39:38,920 --> 01:39:40,880 ENGRAPHMENT IN MICE AS SHOWN 2795 01:39:40,880 --> 01:39:43,840 SOME YEARS BACK. 2796 01:39:43,840 --> 01:39:47,000 WE MADE AN ADC THAT'S POTENT FOR 2797 01:39:47,000 --> 01:39:49,600 KILLING BOTH HUMAN AND NON-HUMAN 2798 01:39:49,600 --> 01:39:55,480 PRIMATE CD34 CELLS AT LOW ICs. 2799 01:39:55,480 --> 01:40:00,040 THIS ALLOWS HSC DELIVERY OF THIS 2800 01:40:00,040 --> 01:40:01,360 ADC, AND YOU CAN SEE IN THE 2801 01:40:01,360 --> 01:40:11,480 BOTTOM PANEL HERE, AT BASELI 2802 01:40:11,480 --> 01:40:12,800 BASELINE -- EQUIVALENT TO WHAT 2803 01:40:12,800 --> 01:40:15,200 WE ACHIEVE WITH MYELOABLATIVE 2804 01:40:15,200 --> 01:40:17,320 BUSULFAN AT 6 MILLIGRAMS PER 2805 01:40:17,320 --> 01:40:20,560 COULD I GO KILOGRAM TIMES 4. 2806 01:40:20,560 --> 01:40:22,040 WE TESTED THIS APPROACH USING A 2807 01:40:22,040 --> 01:40:23,240 VECTOR THAT WE DEVELOPED 2808 01:40:23,240 --> 01:40:24,480 SPECIFICALLY FOR TREATMENT OF 2809 01:40:24,480 --> 01:40:29,800 SICKLE CELL DISEASE THAT HAS A 2810 01:40:29,800 --> 01:40:32,400 SMEAR FOR BC11A LIKE IN DAVID 2811 01:40:32,400 --> 01:40:34,000 WILLIAMS' TRIAL BUT WE ALSO 2812 01:40:34,000 --> 01:40:35,880 CO-EXPRESSED A TRUNCATED EE POE 2813 01:40:35,880 --> 01:40:36,880 RECEPTOR BECAUSE WE KNOW THAT 2814 01:40:36,880 --> 01:40:41,320 THIS TRUNCATED EE POE RECEPTOR 2815 01:40:41,320 --> 01:40:42,920 MAKES ERYTHROPROGENY MORE 2816 01:40:42,920 --> 01:40:45,680 SENSITIVE TO EPO AS EVIDENCED BY 2817 01:40:45,680 --> 01:40:47,720 THIS GUY WHO MEDALLED ACROSS 2818 01:40:47,720 --> 01:40:49,360 FOUR OLYMPICS WHO HAD A 2819 01:40:49,360 --> 01:40:50,960 TRUNCATED EPO RECEPTOR AND 2820 01:40:50,960 --> 01:40:51,880 HEMOGLOBIN OF ABOUT 21. 2821 01:40:51,880 --> 01:40:54,440 IT'S A BENIGN CONDITION WITH 2822 01:40:54,440 --> 01:40:55,080 ERYTHROCYTOSIS, SO WE THOUGHT 2823 01:40:55,080 --> 01:40:56,480 THAT WE MAY BE ABLE TO TAKE 2824 01:40:56,480 --> 01:40:58,000 ADVANTAGE OF THIS BY 2825 01:40:58,000 --> 01:40:59,320 CO-EXPRESSING THIS AND, 2826 01:40:59,320 --> 01:41:00,600 THEREFORE, SELECTING FOR CELLS 2827 01:41:00,600 --> 01:41:02,040 THAT ALSO HAD THE SMEARS. 2828 01:41:02,040 --> 01:41:05,520 WE MADE VECTORS WITH JUST THE 2829 01:41:05,520 --> 01:41:08,600 SMEAR OR THE SMEAR PLUS THE EPO 2830 01:41:08,600 --> 01:41:11,200 RECEPTOR, AND TRANSDUCED HUMAN 2831 01:41:11,200 --> 01:41:12,720 CELLS, PUT THOSE INTO 2832 01:41:12,720 --> 01:41:13,360 IMMUNODEFICIENT MICE AND HERE 2833 01:41:13,360 --> 01:41:16,760 YOU CAN SEE THE CONTROLS, THE 2834 01:41:16,760 --> 01:41:21,000 SMEAR ONLY WITH ABOUT 3 OR 4% 2835 01:41:21,000 --> 01:41:23,080 FETAL HEMOGLOBIN AT 6 MONTHS 2836 01:41:23,080 --> 01:41:25,240 WHEN WE TOOK THESE MICE DOWN. 2837 01:41:25,240 --> 01:41:32,880 WITH A GPA PROMOTOR OR THE 2838 01:41:32,880 --> 01:41:34,960 ANKERIN PROMOTER WE GOT REALLY 2839 01:41:34,960 --> 01:41:37,120 NICE FETAL HEMOGLOBIN LEVELS OF 2840 01:41:37,120 --> 01:41:37,880 ABOUT 40%. 2841 01:41:37,880 --> 01:41:39,240 WE THEN TRIED THIS VECTOR SYSTEM 2842 01:41:39,240 --> 01:41:41,040 IN THE NON-HUMAN PRIMATE WITH 2843 01:41:41,040 --> 01:41:42,960 JUST A SMEAR AND A PAIR OF 2844 01:41:42,960 --> 01:41:45,920 ANIMALS WHERE WE GOT PRETTY GOOD 2845 01:41:45,920 --> 01:41:47,040 FETAL HEMOGLOBIN INITIALLY BUT 2846 01:41:47,040 --> 01:41:48,320 IN ABSENCE OF DISEASE STATE, 2847 01:41:48,320 --> 01:41:50,720 THIS WENT DOWN TO PRE-TRANS 2848 01:41:50,720 --> 01:41:51,720 PLANT LEVELS. 2849 01:41:51,720 --> 01:41:58,760 BUT WITH THE SMEAR TO BCL11A 2850 01:41:58,760 --> 01:42:01,600 AND -- WE GOT NICE LEVELS OF 2851 01:42:01,600 --> 01:42:02,120 HEMOGLOBIN F. 2852 01:42:02,120 --> 01:42:04,200 SO THEN WE COMPARE THIS VECTOR 2853 01:42:04,200 --> 01:42:08,600 SYSTEM, THE SMEAR, WITH EPO, TOO 2854 01:42:08,600 --> 01:42:10,400 THESE MULTI-DOSE BUSULFAN 2855 01:42:10,400 --> 01:42:12,800 ANIMALS AS OPPOSED TO EITHER 2856 01:42:12,800 --> 01:42:16,080 .3 OR .4 MILLIGRAMS PER KILOGRAM 2857 01:42:16,080 --> 01:42:19,320 OF THE ANTIBODY. 2858 01:42:19,320 --> 01:42:20,960 HERE YOU SEE TRANSIENT 2859 01:42:20,960 --> 01:42:24,840 NEUTROPENIA AFTER THE ADC AT 2860 01:42:24,840 --> 01:42:27,440 .3 OR AT .4 MILLIGRAMS PER 2861 01:42:27,440 --> 01:42:31,400 KILOGRAM, AND COMPARE THAT TO 2862 01:42:31,400 --> 01:42:33,480 THE BUSULFAN CONDITIONING AS 2863 01:42:33,480 --> 01:42:40,680 SHOWN ON THE RIGHT. 2864 01:42:40,680 --> 01:42:44,240 HERE YOU SEE ENGRAFTMENT WITH 2865 01:42:44,240 --> 01:42:46,760 VECTOR COPY NUMBER, OR 2866 01:42:46,760 --> 01:42:47,640 HEMOGLOBIN F INDUCTION. 2867 01:42:47,640 --> 01:42:51,040 YOU CAN SEE IT'S EQUIVALENT 2868 01:42:51,040 --> 01:42:53,400 BETWEEN THE BUSULFAN ANIMALS AND 2869 01:42:53,400 --> 01:42:54,600 THE ANTIBODY ANIMALS WITH THE 2870 01:42:54,600 --> 01:42:57,320 EXCEPTION OF ONE ANIMAL DOSE, 2871 01:42:57,320 --> 01:43:05,280 THE LOWER DOSE. 2872 01:43:05,280 --> 01:43:08,120 WE SAW MINIMAL TOXICITIES WITH 2873 01:43:08,120 --> 01:43:11,280 THE DC117 ANTIBODY. 2874 01:43:11,280 --> 01:43:14,200 MOST NOTABLY WE DID NOT OBSERVE 2875 01:43:14,200 --> 01:43:14,640 AMENORRHEA. 2876 01:43:14,640 --> 01:43:16,920 SO THIS THE MENSTRUAL CYCLE PER 2877 01:43:16,920 --> 01:43:18,040 MONTH IN THESE ANIMALS TREATED 2878 01:43:18,040 --> 01:43:20,640 WITH THE ADC VERSUS CONTROL -- 2879 01:43:20,640 --> 01:43:22,680 HISTORICAL ANIMALS TREATED WITH 2880 01:43:22,680 --> 01:43:24,040 EITHER BUSULFAN OR TDI. 2881 01:43:24,040 --> 01:43:26,160 SO YOU CAN SEE THEY WERE HAVING 2882 01:43:26,160 --> 01:43:27,040 ONE CYCLE PER MONTH. 2883 01:43:27,040 --> 01:43:29,200 SO WE PUT THESE ANIMALS INTO A 2884 01:43:29,200 --> 01:43:31,560 BREEDING COLONY AND IN THE FIRST 2885 01:43:31,560 --> 01:43:32,560 BREEDING SEASON, WE'VE HAD TWO 2886 01:43:32,560 --> 01:43:35,960 OF THE FOUR FEMALES THAT HAVE 2887 01:43:35,960 --> 01:43:37,480 GIVEN BIRTH AND TWO OF THE MALES 2888 01:43:37,480 --> 01:43:39,640 HAVE SIRED. 2889 01:43:39,640 --> 01:43:43,600 AND ACTUALLY ONE OF THE PAIRS 2890 01:43:43,600 --> 01:43:45,760 WAS A FEMALE ANIMAL TREATED WITH 2891 01:43:45,760 --> 01:43:47,760 ADC PAIRED WITH A MALE ANIMAL 2892 01:43:47,760 --> 01:43:50,680 THAT WAS A DC-TREATED. 2893 01:43:50,680 --> 01:43:52,680 SO THAT'S FOUR SUCCESSFUL AMONG 2894 01:43:52,680 --> 01:44:03,240 SIX ANIMALS THAT WE TRANSFERRED. 2895 01:44:03,600 --> 01:44:05,160 I THINK WE CAN JUST MOVE TO THE 2896 01:44:05,160 --> 01:44:05,800 LAST SLIDE. 2897 01:44:05,800 --> 01:44:09,400 WE DID SIMILAR STUDIES WITH THE 2898 01:44:09,400 --> 01:44:12,560 CD45-TREATED COHORT. 2899 01:44:12,560 --> 01:44:16,800 AND FOR THAT, WE USED A BCL11A 2900 01:44:16,800 --> 01:44:17,480 ERYTHROENHANCER EDITING. 2901 01:44:17,480 --> 01:44:19,880 YOU CAN SEE HERE THE DROP IN 2902 01:44:19,880 --> 01:44:21,840 COUNTS. 2903 01:44:21,840 --> 01:44:24,800 THE COLORED LINES ARE ANIMALS 2904 01:44:24,800 --> 01:44:29,480 TREATED WITH THE CD45-ADC 2905 01:44:29,480 --> 01:44:30,480 COMPARED TO BUSULFAN CONTROLS IN 2906 01:44:30,480 --> 01:44:30,720 GREY. 2907 01:44:30,720 --> 01:44:32,480 YOU CAN SEE OVERALL PERCENT 2908 01:44:32,480 --> 01:44:33,880 EDITING IS SIMILAR TO THE BEU 2909 01:44:33,880 --> 01:44:37,720 SUL FEIGN-TREATED ANIMALS WHEN 2910 01:44:37,720 --> 01:44:40,040 ANIMALS WERE DOSED AT 2911 01:44:40,040 --> 01:44:45,720 .3 MILLIGRAMS PER KILOGRAM. 2912 01:44:45,720 --> 01:44:48,720 SO WE KNOW WE CAN CURE THIS 2913 01:44:48,720 --> 01:44:49,960 DISEASE, GENE THERAPY THROUGH 2914 01:44:49,960 --> 01:44:51,160 EDITING OR GENE ADDITION AS I'VE 2915 01:44:51,160 --> 01:44:53,720 SHOWN YOU CAN ALSO BE CURATIVE 2916 01:44:53,720 --> 01:44:56,240 AND HOPEFULLY THESE NOVEL 2917 01:44:56,240 --> 01:44:57,120 CONDITIONING REGIMENS WILL GET 2918 01:44:57,120 --> 01:44:59,160 US TO THE PLACE WHERE WE CAN 2919 01:44:59,160 --> 01:45:01,160 ALSO DO THIS WITHOUT MUCH 2920 01:45:01,160 --> 01:45:02,280 TOXICITY. 2921 01:45:02,280 --> 01:45:03,760 I'LL JUST SHOW THE CONTRIBUTORS 2922 01:45:03,760 --> 01:45:07,680 ON THE NEXT SLIDE. 2923 01:45:07,680 --> 01:45:17,800 THANKS. 2924 01:45:20,840 --> 01:45:22,600 >>WE CAN HAVE ONE QUESTION FOR 2925 01:45:22,600 --> 01:45:26,400 JOHN. 2926 01:45:26,400 --> 01:45:26,960 AT THE END? 2927 01:45:26,960 --> 01:45:37,120 ALL RIGHT. 2928 01:45:37,760 --> 01:45:39,760 SO THE NEXT TALK, I'M GOING TO 2929 01:45:39,760 --> 01:45:49,200 SPEAK ABO ABOUT RIC LENTIVIRAL E 2930 01:45:49,200 --> 01:45:51,960 THERAPY WITH MODIFIED HBF, 2931 01:45:51,960 --> 01:45:58,040 FUTURE DIRECTIONS OF OUR TRIAL. 2932 01:45:58,040 --> 01:46:01,440 SO AS THIS AUDIENCE WELL KNOWS, 2933 01:46:01,440 --> 01:46:04,400 FETAL HEMOGLOBIN IS A POTENT 2934 01:46:04,400 --> 01:46:12,960 ANTICYCLANTISICKLING HEMOGLOBINO 2935 01:46:12,960 --> 01:46:15,680 HAS A HIGHER AFFINITY FOR OXYGEN 2936 01:46:15,680 --> 01:46:18,840 THAN HEMOGLOBIN A OR HEMOGLOBIN 2937 01:46:18,840 --> 01:46:23,760 S, THEREBY RETAINING OXYGEN AND 2938 01:46:23,760 --> 01:46:25,760 PREVENTING POLYMERIZATION. 2939 01:46:25,760 --> 01:46:30,640 BEYOND THE WILD TYPE HBF, THE 2940 01:46:30,640 --> 01:46:32,000 HBFG16D MUTATION THAT WE MADE 2941 01:46:32,000 --> 01:46:33,200 ADDS A NEGATIVE CHARGE TO THE 2942 01:46:33,200 --> 01:46:34,840 GAMMA GLOBIN, INCREASING THE 2943 01:46:34,840 --> 01:46:35,840 COMPETITIVE ADVANTAGE TO BIND TO 2944 01:46:35,840 --> 01:46:38,160 THE POSITIVELY CHARGED ALPHA 2945 01:46:38,160 --> 01:46:40,560 GLOBIN SUBUNITS. 2946 01:46:40,560 --> 01:46:42,000 ADDITIONALLY, WE'VE ALSO IN 2947 01:46:42,000 --> 01:46:43,600 PRE-CLINICAL STUDIES OBSERVED 2948 01:46:43,600 --> 01:46:45,880 THAT IT IS MORE POTENT 2949 01:46:45,880 --> 01:46:48,160 ANTISICKLING GLOBIN THAN THE 2950 01:46:48,160 --> 01:46:54,560 ENDOGENOUS FETAL HEMOG HEMOGLOBD 2951 01:46:54,560 --> 01:46:55,040 T87Q. 2952 01:46:55,040 --> 01:46:57,560 SO WE DESIGNED THE VECTOR 2953 01:46:57,560 --> 01:47:00,960 INITIALLY NAMED GBGM AND THEN 2954 01:47:00,960 --> 01:47:03,720 LICENSED TO ARUVANT AND RENAMED 2955 01:47:03,720 --> 01:47:07,720 AS ARU-1801, WHICH ENCODES THIS 2956 01:47:07,720 --> 01:47:11,720 MUTANT GAMMA GLOBIN THAT HAS THE 2957 01:47:11,720 --> 01:47:20,880 POINT MUTATION G16D. 2958 01:47:20,880 --> 01:47:22,200 AND FOR THE CONDITIONING, JOHN 2959 01:47:22,200 --> 01:47:24,640 HAS ALREADY ALLUDED TO 2960 01:47:24,640 --> 01:47:26,560 CONDITIONING FOR AUTOLOGOUS GENE 2961 01:47:26,560 --> 01:47:28,760 THERAPY TRANSPLANTS, SO UNLIKE 2962 01:47:28,760 --> 01:47:30,560 IMMUNE DEFICIENCIES, CORRECTION 2963 01:47:30,560 --> 01:47:31,560 OF SICKLE CELL DISEASE REQUIRES 2964 01:47:31,560 --> 01:47:34,240 A MUCH HIGHER PERCENTAGE, ABOUT 2965 01:47:34,240 --> 01:47:38,640 15 TO 20% GENETICALLY MODIFIED 2966 01:47:38,640 --> 01:47:41,040 HEMATOPOIETIC STEM CELL 2967 01:47:41,040 --> 01:47:44,000 ENGRAFTMENT. 2968 01:47:44,000 --> 01:47:46,360 AND IN GENE THERAPY OR EDITING, 2969 01:47:46,360 --> 01:47:47,760 THE INFUSED DRUG PRODUCT 2970 01:47:47,760 --> 01:47:49,520 CONTAINS BOTH THE DESIRED 2971 01:47:49,520 --> 01:47:51,120 GENETICALLY MODIFIED AND THE 2972 01:47:51,120 --> 01:47:52,520 UNMODIFIED STEM CELLS. 2973 01:47:52,520 --> 01:47:54,480 HENCE, GENE ADDITION AND GENE 2974 01:47:54,480 --> 01:47:56,080 EDITING TRIALS FOR SICKLE CELL 2975 01:47:56,080 --> 01:47:58,520 DISEASE USE MYELOABLATIVE 2976 01:47:58,520 --> 01:48:00,800 CHEMOTHERAPY CONDITIONING, USING 2977 01:48:00,800 --> 01:48:04,360 BUSULFAN, TO ABLATE ALL THE 2978 01:48:04,360 --> 01:48:10,200 ENDOGENOUS RESIDUAL YOU'LL HSC, 2979 01:48:10,200 --> 01:48:14,840 GIVING THE HSC IN THE DRUG 2980 01:48:14,840 --> 01:48:20,040 PRODUCT ENGRAFTMENT ADVANTAGE. 2981 01:48:20,040 --> 01:48:20,840 HOWEVER MYELOABLATIVE 2982 01:48:20,840 --> 01:48:22,040 CHEMOTHERAPY RESULTS IN 2983 01:48:22,040 --> 01:48:25,280 PROLONGED NEUTROPENIA AND 2984 01:48:25,280 --> 01:48:26,160 THROMBOCYTOPENIA REQUIRING 2985 01:48:26,160 --> 01:48:27,320 SIGNIFICANT INFECTION, NUTRITION 2986 01:48:27,320 --> 01:48:31,680 AND TRANSFUSION SUPPORT. 2987 01:48:31,680 --> 01:48:33,000 REDUCED INTENSITY CONDITIONING 2988 01:48:33,000 --> 01:48:34,960 OFFERS ADVANTAGES. 2989 01:48:34,960 --> 01:48:37,240 ALTHOUGH IN REDUCED INTENSITY 2990 01:48:37,240 --> 01:48:40,160 CONDITIONING, THE INFUSED DRUG 2991 01:48:40,160 --> 01:48:41,680 PRODUCT HSC COMPETES WITH 2992 01:48:41,680 --> 01:48:44,560 RESIDUAL YOU'LL ENDOGENOUS HSC. 2993 01:48:44,560 --> 01:48:46,160 THE ADVANTAGES INCLUDE LESS 2994 01:48:46,160 --> 01:48:47,760 ACUTE SIDE EFFECTS, LESS DAYS IN 2995 01:48:47,760 --> 01:48:50,400 HOSPITAL FOLLOWING TRANSPLANT, 2996 01:48:50,400 --> 01:48:53,280 LESS CHEMOTHERAPY EXPOSURE, LESS 2997 01:48:53,280 --> 01:48:55,160 RISK OF INFERTILITY. 2998 01:48:55,160 --> 01:48:56,600 I WAS ACTUALLY VERY PLEASED TO 2999 01:48:56,600 --> 01:48:59,520 HEAR THE PREVIOUS SPEAKER TALK 3000 01:48:59,520 --> 01:49:03,080 ABOUT -- HAVING THE LOWEST RISK 3001 01:49:03,080 --> 01:49:03,960 OF INFERTILITY, AND LESS 3002 01:49:03,960 --> 01:49:06,360 TECHNICAL KNOW-HOW REQUIRED. 3003 01:49:06,360 --> 01:49:07,720 BESIDES THERE HAVE BEEN VERY 3004 01:49:07,720 --> 01:49:09,280 ELEGANT STUDIES IN TRANSPLANT 3005 01:49:09,280 --> 01:49:10,400 SHOWING PATIENTS WITH SICKLE 3006 01:49:10,400 --> 01:49:12,560 CELL ANEMIA WHO DEVELOP 3007 01:49:12,560 --> 01:49:16,880 PERSISTENT MIXED CHIMERISM HAVE 3008 01:49:16,880 --> 01:49:18,000 AMELIORATION OF ALL THEIR 3009 01:49:18,000 --> 01:49:18,760 DISEASE SYMPTOMS. 3010 01:49:18,760 --> 01:49:21,840 SO WE THEREFORE HYPOTHESIZE THAT 3011 01:49:21,840 --> 01:49:27,640 WITH RIC, A HIGH DOSE AND POTENT 3012 01:49:27,640 --> 01:49:29,440 VECTOR WE CAN PROVIDE A STRONG 3013 01:49:29,440 --> 01:49:30,880 SELECTIVE ADVANTAGE TO 3014 01:49:30,880 --> 01:49:32,440 GENETICALLY MODIFIED RED BLOOD 3015 01:49:32,440 --> 01:49:35,880 CELLS AND THIS MAY SUFFICE. 3016 01:49:35,880 --> 01:49:42,400 SO THE MOMENTUM STUDY IS A PHASE 3017 01:49:42,400 --> 01:49:46,120 I/II TRIAL OF ARU-1801 UTILIZING 3018 01:49:46,120 --> 01:49:46,960 REDUCED INTENSITY CONDITIONING 3019 01:49:46,960 --> 01:49:51,280 IN PATIENTS WITH SEVERE SICKLE 3020 01:49:51,280 --> 01:49:53,720 CELL DISEASE, FROM CINCINNATI 3021 01:49:53,720 --> 01:49:54,040 CHILDREN'S. 3022 01:49:54,040 --> 01:49:55,640 HERE WE HAVE THE STANDARD 3023 01:49:55,640 --> 01:49:56,760 INCLUSION CRITERIA OF PATIENTS 3024 01:49:56,760 --> 01:49:58,680 WITH VERY SEVERE DISEASE, AND 3025 01:49:58,680 --> 01:50:00,640 THE KEY EXCLUSION CRITERIA WERE 3026 01:50:00,640 --> 01:50:03,160 HISTORY OF STROKE OR PATIENTS 3027 01:50:03,160 --> 01:50:05,960 WITH ALPHA THALASSEMIA, TWO OR 3028 01:50:05,960 --> 01:50:07,160 MORE GENE DELETIONS. 3029 01:50:07,160 --> 01:50:08,520 PATIENTS WERE ENROLLED, THEY 3030 01:50:08,520 --> 01:50:11,120 WERE GIVEN TRANSFUSIONS, 3031 01:50:11,120 --> 01:50:12,080 PERIPHERAL STEM CELLS WERE 3032 01:50:12,080 --> 01:50:12,680 COLLECTED. 3033 01:50:12,680 --> 01:50:14,120 THE FIRST TWO PATIENTS, WE DID 3034 01:50:14,120 --> 01:50:16,880 BONE MARROW COLLECTION. 3035 01:50:16,880 --> 01:50:20,560 SUBSEQUENT PATIENTS WERE 3036 01:50:20,560 --> 01:50:25,720 APHERESED, TRANSDUCED FOR 36 3037 01:50:25,720 --> 01:50:26,920 HOURS AND PATIENTS WERE INFUSED 3038 01:50:26,920 --> 01:50:35,440 ON THE SECOND DAY AFTER GETTING 3039 01:50:35,440 --> 01:50:36,000 MELPHALAN. 3040 01:50:36,000 --> 01:50:37,800 SO WE'VE DONE SEVEN PATIENTS SO 3041 01:50:37,800 --> 01:50:43,840 FAR, AND THIS -- THE MEDIAN CD34 3042 01:50:43,840 --> 01:50:47,800 PLUS CELL DOSE AND MEDIAN DRUG 3043 01:50:47,800 --> 01:50:49,840 PRODUCT VECTOR COPY NUMBER OF 3044 01:50:49,840 --> 01:50:50,280 .47. 3045 01:50:50,280 --> 01:50:53,320 ONE PATIENT, PATIENT 2, HAD 3046 01:50:53,320 --> 01:50:56,600 INADEQUATE MELPHALAN EXPOSURE 3047 01:50:56,600 --> 01:51:02,240 BECAUSE HE A HIGH GFR RATE. 3048 01:51:02,240 --> 01:51:05,680 AND CLEARED HIS MELPHALAN. 3049 01:51:05,680 --> 01:51:07,240 SO THIS ILLUSTRATES THAT THIS 3050 01:51:07,240 --> 01:51:08,960 EXPOSURE I SHOWED YOU IS 3051 01:51:08,960 --> 01:51:10,880 ACTUALLY A REDUCED INTENSITY 3052 01:51:10,880 --> 01:51:15,160 CONDITIONING EXPOSURE. 3053 01:51:15,160 --> 01:51:17,480 AND IT RESULTS IN A MEDIAN 3054 01:51:17,480 --> 01:51:18,680 NEUTROPENIA OF EIGHT DAYS, SHOWN 3055 01:51:18,680 --> 01:51:20,920 ON YOUR RIGHT. 3056 01:51:20,920 --> 01:51:25,320 AND THROMBOCYTOPENIA OF -- 3057 01:51:25,320 --> 01:51:26,400 THROMBOCYTOPENIA OF FIVE DAYS. 3058 01:51:26,400 --> 01:51:32,360 WE ALSO DID -- WE HAD THE USUAL 3059 01:51:32,360 --> 01:51:35,440 REDUCED INTENSITY TRANSPLANT 3060 01:51:35,440 --> 01:51:37,720 RELATED MUCOSITIS AND THE 3061 01:51:37,720 --> 01:51:40,000 EXPECTED CHEMOTHERAPY-RELATED 3062 01:51:40,000 --> 01:51:41,480 ADVERSE EVENTS THAT WERE MILD 3063 01:51:41,480 --> 01:51:46,520 AND RESOLVED WITHIN A WEEK, JUST 3064 01:51:46,520 --> 01:51:48,160 IN PARALLEL WITH THE RESOLUTION 3065 01:51:48,160 --> 01:51:49,560 OF THE CYTOPENIA. 3066 01:51:49,560 --> 01:51:52,520 THESE PATIENTS, ALL OF THEM HAVE 3067 01:51:52,520 --> 01:51:59,080 HAD INTEGRATION SITE DEVELOPMENT 3068 01:51:59,080 --> 01:52:01,680 AND POLYCLONAL ENGRAFTMENT 3069 01:52:01,680 --> 01:52:09,240 AND -- LO LEUKEMIA/LYMPHOMA PAN, 3070 01:52:09,240 --> 01:52:13,640 FISH AND NGS FOR LEUKEMIA 3071 01:52:13,640 --> 01:52:14,440 ASSOCIATED -- AND THEY'RE 3072 01:52:14,440 --> 01:52:16,200 NEGATIVE. 3073 01:52:16,200 --> 01:52:18,920 SO FOR ALL SIX PATIENTS, PATIENT 3074 01:52:18,920 --> 01:52:24,760 2 AS I SAID HAS A DECREASING HBF 3075 01:52:24,760 --> 01:52:26,520 16D BECAUSE HAD INADEQUATE 3076 01:52:26,520 --> 01:52:30,440 EXPOSURE BUT THE REST HAD STABLE 3077 01:52:30,440 --> 01:52:33,360 EXPOSURE AND STABLE VCN LEVELS 3078 01:52:33,360 --> 01:52:35,360 AND THEY ARE ABOUT 77% OF THE 3079 01:52:35,360 --> 01:52:40,880 DRUG PRODUCT WE S VCN. 3080 01:52:40,880 --> 01:52:45,360 SO IN CONCLUSION, ARU-1801 GENE 3081 01:52:45,360 --> 01:52:47,200 THERAPY WITH REDUCED THERAPY 3082 01:52:47,200 --> 01:52:49,400 CONDITIONING HAS HIGH LEVELS OF 3083 01:52:49,400 --> 01:52:50,680 ANTISICKLING HEMOGLOBIN AT A 3084 01:52:50,680 --> 01:52:57,760 RELATIVELY MODDI MODEST GCN. 3085 01:52:57,760 --> 01:53:00,600 THE IN VIVO, VCN WAS ABOUT .4. 3086 01:53:00,600 --> 01:53:02,880 THE IMPROVEMENT IN ENGRAFTMENT, 3087 01:53:02,880 --> 01:53:05,720 IF WE IMPROVE THE ENGRAFTMENT OR 3088 01:53:05,720 --> 01:53:07,360 VCN FURTHER, IT WOULD RESULT IN 3089 01:53:07,360 --> 01:53:08,880 EVEN HIGHER ANTISICKLING 3090 01:53:08,880 --> 01:53:10,200 GLOBINS, AND IT MAY BE A 3091 01:53:10,200 --> 01:53:11,600 PROMISING ALTERNATIVE TO 3092 01:53:11,600 --> 01:53:13,640 THERAPIES REQUIRING 3093 01:53:13,640 --> 01:53:16,160 MYELOAPLAYTIVE CONDITIONING. 3094 01:53:16,160 --> 01:53:18,560 HOWEVER LATE LAST YEAR, ARUVANT 3095 01:53:18,560 --> 01:53:20,840 DECIDED TO STOP FURTHER 3096 01:53:20,840 --> 01:53:24,320 DEVELOPMENT OF ARU-1801. 3097 01:53:24,320 --> 01:53:28,000 AND SO THE IND IS BACK WITH 3098 01:53:28,000 --> 01:53:28,640 CINCINNATI CHILDREN'S AND WE'RE 3099 01:53:28,640 --> 01:53:29,520 GOING TO CONTINUE THIS TRIAL, 3100 01:53:29,520 --> 01:53:32,160 USE A NEW METHOD TO IMPROVE 3101 01:53:32,160 --> 01:53:39,160 HOMING AND AND ENGRAFTMENT OF 3102 01:53:39,160 --> 01:53:40,760 SPECIFICALLY GENETICALLY 3103 01:53:40,760 --> 01:53:41,880 MODIFIED HSCs. 3104 01:53:41,880 --> 01:53:43,240 WE'VE DEVELOPED A PACKETING 3105 01:53:43,240 --> 01:53:45,560 SYSTEM WHERE WE CAN DELIVER A 3106 01:53:45,560 --> 01:53:48,960 HOMING RECEPTOR CXCR4 AS A 3107 01:53:48,960 --> 01:53:51,240 PROTEIN DELIVERY IN THE LENT 3108 01:53:51,240 --> 01:53:51,520 VIRAL. 3109 01:53:51,520 --> 01:53:55,560 WE DID A PROOF OF CONCEPT IN 3110 01:53:55,560 --> 01:53:57,760 MICE WHERE THIS LENTIVIRAL 3111 01:53:57,760 --> 01:54:00,480 VECTOR, THE GENETIC -- IS THE 3112 01:54:00,480 --> 01:54:05,720 SAME, BUT THE VECTOR CARRIES THE 3113 01:54:05,720 --> 01:54:07,680 CXCR4 LATCHED ON TO THE -- 3114 01:54:07,680 --> 01:54:08,160 PROTEIN. 3115 01:54:08,160 --> 01:54:10,960 WHEN WE TRANSPLANTED NSG MICE 3116 01:54:10,960 --> 01:54:13,200 WITH THE CONTROL GFP LENTIVIRUS 3117 01:54:13,200 --> 01:54:20,000 OR THE CXCR4 CARRYING 3118 01:54:20,000 --> 01:54:23,240 LENTIVIRUS, IF YOU SEE ON THE 3119 01:54:23,240 --> 01:54:28,240 LEFT, THOSE WE GAVE CD34 CELL 3120 01:54:28,240 --> 01:54:29,560 DOAN'S INTRAVENOUSLY OR DIRECTLY 3121 01:54:29,560 --> 01:54:31,000 INTO THE BONE MARROW. 3122 01:54:31,000 --> 01:54:33,160 AND OF COURSE WITH THE BONE 3123 01:54:33,160 --> 01:54:34,280 MARROW, WE ALWAYS SEE A FOUR 3124 01:54:34,280 --> 01:54:35,920 FOLD HIGHER ENGRAFTMENT IN THE 3125 01:54:35,920 --> 01:54:42,240 LONG TERM, BUT IF WE GIVE THE 3126 01:54:42,240 --> 01:54:44,720 CXCR4 ANTIVIRAL VECTOR, WE SEE A 3127 01:54:44,720 --> 01:54:46,480 FOUR FOLD HIGHER ENGRAFTMENT IF 3128 01:54:46,480 --> 01:54:51,000 WE DELIVER THE CD34 CELLS IV, 3129 01:54:51,000 --> 01:54:55,440 AND A 14 -- HIGHER ENGRAFTMENT 3130 01:54:55,440 --> 01:54:57,040 IF WE DELIVER THEM INTRABONE 3131 01:54:57,040 --> 01:54:57,520 MARROW. 3132 01:54:57,520 --> 01:55:00,560 THIS IS SPECIFICALLY ONLY IN THE 3133 01:55:00,560 --> 01:55:02,320 GFP-POSITIVE CELLS, BECAUSE 3134 01:55:02,320 --> 01:55:03,600 THOSE ARE THE CELLS THAT GOT THE 3135 01:55:03,600 --> 01:55:03,960 VECTOR. 3136 01:55:03,960 --> 01:55:05,320 SO WE THINK THAT THIS METHOD 3137 01:55:05,320 --> 01:55:09,280 WILL REALLY IMPROVE GENE THERAPY 3138 01:55:09,280 --> 01:55:11,920 WITH REDUCED INTENSITY 3139 01:55:11,920 --> 01:55:15,560 CONDITIONING TO EVEN A HIGHER 3140 01:55:15,560 --> 01:55:16,960 ANTISICKLING LEVEL. 3141 01:55:16,960 --> 01:55:18,480 AND WITH THAT, I WOULD LIKE TO 3142 01:55:18,480 --> 01:55:19,880 THANK MY TEAM. 3143 01:55:19,880 --> 01:55:23,040 IT TAKES A VILLAGE TO DO THIS, 3144 01:55:23,040 --> 01:55:27,960 AND I'LL END HERE. 3145 01:55:27,960 --> 01:55:30,360 >>SO OUR NEXT SPEAKER -- SO NOW 3146 01:55:30,360 --> 01:55:32,440 WE ARE GOING TO SWITCH GEARS AND 3147 01:55:32,440 --> 01:55:34,240 DR. MITCH WEISS IS GOING TO 3148 01:55:34,240 --> 01:55:35,360 INTRODUCE GENE EDITING 3149 01:55:35,360 --> 01:55:39,040 STRATEGIES AND TALK ABOUT HIS 3150 01:55:39,040 --> 01:55:40,120 DATA, HEMOGLOBIN F INDUCTION 3151 01:55:40,120 --> 01:55:50,440 WITH GENE EDITING. 3152 01:56:00,240 --> 01:56:00,600 >>HI. 3153 01:56:00,600 --> 01:56:06,360 THANK YOU FOR INNOVATING ME. 3154 01:56:06,360 --> 01:56:06,920 I'M MITCH WEISS. 3155 01:56:06,920 --> 01:56:09,520 I'M A RESEARCH HEMATOLOGIST AT 3156 01:56:09,520 --> 01:56:11,080 ST. JUDE, AND THANK YOU GUYS FOR 3157 01:56:11,080 --> 01:56:12,800 INVITING ME. 3158 01:56:12,800 --> 01:56:14,320 I'M GOING TO TALK ABOUT GENOME 3159 01:56:14,320 --> 01:56:15,720 EDITING TO INDUCE FETAL 3160 01:56:15,720 --> 01:56:19,920 HEMOGLOBIN. 3161 01:56:19,920 --> 01:56:23,040 THIS IS THE PROTOCOL FOR 3162 01:56:23,040 --> 01:56:23,720 AUTOLOGOUS STEM CELL THERAPIES. 3163 01:56:23,720 --> 01:56:24,760 I THINK YOU ALL KNOW THAT. 3164 01:56:24,760 --> 01:56:26,120 AND THE REMARKABLE THING THAT 3165 01:56:26,120 --> 01:56:27,440 WE'RE HEARING ABOUT TODAY IS 3166 01:56:27,440 --> 01:56:29,600 THAT THERE IS A TREMENDOUS 3167 01:56:29,600 --> 01:56:32,280 NUMBER AND GROWING OF WAYS TO 3168 01:56:32,280 --> 01:56:33,480 MANIPULATE AUTOLOGOUS PATIENT 3169 01:56:33,480 --> 01:56:36,120 CELLS GENETICALLY TO TREAT AND 3170 01:56:36,120 --> 01:56:39,280 HOPEFULLY CURE FETAL HEMOGLOBIN. 3171 01:56:39,280 --> 01:56:41,880 I WAS ASKED TO TALK ABOUT J 3172 01:56:41,880 --> 01:56:43,280 GENETIC INDUCTION OF FETAL 3173 01:56:43,280 --> 01:56:45,680 HEMOGLOBIN USING CAS NINE 3174 01:56:45,680 --> 01:56:49,400 NUCLEASE OR BASE EDITING. 3175 01:56:49,400 --> 01:56:52,720 I WANT TO EMPHASIZE THAT THERE'S 3176 01:56:52,720 --> 01:56:54,800 A LOT OF APPROACHES AND THE BEST 3177 01:56:54,800 --> 01:56:55,760 ONES AREN'T KNOWN AND THE ONLY 3178 01:56:55,760 --> 01:56:57,600 WAY TO FIND THAT OUT IS IN 3179 01:56:57,600 --> 01:56:58,800 LONG-TERM STUDIES LIKE THE ONES 3180 01:56:58,800 --> 01:57:00,720 WE'VE HEARD THIS MORNING WHERE 3181 01:57:00,720 --> 01:57:04,000 WE TRACK ORGAN OUTCOME OVER TI 3182 01:57:04,000 --> 01:57:06,600 TIME. 3183 01:57:06,600 --> 01:57:08,160 WE ALL KNOW THAT SICKLE CELL 3184 01:57:08,160 --> 01:57:09,640 DISEASE BECOMES SYMPTOMATIC 3185 01:57:09,640 --> 01:57:12,400 AROUND BIRTH, AND THIS IS COENS 3186 01:57:12,400 --> 01:57:15,880 DENT WITH THE GAMMA TO BAY THAT 3187 01:57:15,880 --> 01:57:17,280 GLOBIN SWITCH SHOWN AT THE 3188 01:57:17,280 --> 01:57:17,720 BOTTOM. 3189 01:57:17,720 --> 01:57:19,680 GAMMA GLOBIN IS TURNED OFF AND 3190 01:57:19,680 --> 01:57:22,760 BETA GLOBIN IS TURNED ON, AND WE 3191 01:57:22,760 --> 01:57:28,960 GO FROM A OR S IF YOU'RE HBB -- 3192 01:57:28,960 --> 01:57:30,120 AND IT'S MUTATED IN SICKLE CELL 3193 01:57:30,120 --> 01:57:30,640 DISEASE. 3194 01:57:30,640 --> 01:57:32,960 WE ALSO KNOW THAT ELEVATED FETAL 3195 01:57:32,960 --> 01:57:33,880 HEMOGLOBIN AMELIORATES SICKLE 3196 01:57:33,880 --> 01:57:34,200 CELL DISEASE. 3197 01:57:34,200 --> 01:57:38,360 THIS IS AN OLD SLIDE FROM PLATT 3198 01:57:38,360 --> 01:57:42,240 SHOWING YOU LIVE HIGHER IF YOU 3199 01:57:42,240 --> 01:57:43,800 HAVE HIGHER HEMOTBLOA BINS IN 3200 01:57:43,800 --> 01:57:44,560 SICKLE CELL DISEASE. 3201 01:57:44,560 --> 01:57:47,840 WE ALSO KNOW THAT THERE IS A 3202 01:57:47,840 --> 01:57:51,400 BENIGN GENETIC CONDITION CALLED 3203 01:57:51,400 --> 01:57:53,040 HEREDITARY PERSISTENCE OF FETAL 3204 01:57:53,040 --> 01:57:54,880 HEMOGLOBIN AND IF YOU COINHERIT 3205 01:57:54,880 --> 01:57:55,960 IT WITH SICKLE CELL DISEASE, 3206 01:57:55,960 --> 01:57:59,320 YOU'RE WAY BETTER OFF AND MAYBE 3207 01:57:59,320 --> 01:58:01,520 CAN HAVE ALL OF THE PROBLEMS OF 3208 01:58:01,520 --> 01:58:04,800 SICKLE CELL DISEASE ELIMINATED. 3209 01:58:04,800 --> 01:58:08,960 WE KNOW THAT SOME FORMS OF HPFH, 3210 01:58:08,960 --> 01:58:10,920 THE KNOWN DELETIONAL FORMS ARE 3211 01:58:10,920 --> 01:58:12,760 CAUSED BY MUTATIONS IN GAMMA 3212 01:58:12,760 --> 01:58:14,400 GLOBIN GENE PROMOTERS. 3213 01:58:14,400 --> 01:58:17,840 POINT MUTATIONS OR SMALL 3214 01:58:17,840 --> 01:58:19,200 DELETION. 3215 01:58:19,200 --> 01:58:21,440 SO BECAUSE OF THIS, BEING ABLE 3216 01:58:21,440 --> 01:58:24,680 TO TURN ON FETAL HEMOGLOBIN IN 3217 01:58:24,680 --> 01:58:25,720 SICKLE CELL PATIENT RED BLOOD 3218 01:58:25,720 --> 01:58:28,920 CELLS OR RED CELL PRECURSORS HAS 3219 01:58:28,920 --> 01:58:29,640 BEEN A HOLY GRAIL, AND PEOPLE 3220 01:58:29,640 --> 01:58:31,080 HAVE BEEN WORKING AT IT FOR A 3221 01:58:31,080 --> 01:58:35,640 LONG TIME. 3222 01:58:35,640 --> 01:58:38,720 BUT NOW, TWO THINGS HAVE COME 3223 01:58:38,720 --> 01:58:40,240 TOGETHER TO REALLY REVOLUTIONIZE 3224 01:58:40,240 --> 01:58:40,960 THE FIELD. 3225 01:58:40,960 --> 01:58:42,840 GENETIC ENGINEERING TECHNOLOGIES 3226 01:58:42,840 --> 01:58:45,360 AND MECHANISTIC INSIGHTS INTO 3227 01:58:45,360 --> 01:58:46,200 GLOBIN GENE SWITCHING. 3228 01:58:46,200 --> 01:58:47,960 AND TOGETHER, THESE TWO THINGS 3229 01:58:47,960 --> 01:58:49,480 HAVE ACCELERATED PROGRESS 3230 01:58:49,480 --> 01:58:55,920 TREMENDOUSLY. 3231 01:58:55,920 --> 01:58:56,960 SO WHAT I'M GOING TO TELL YOU 3232 01:58:56,960 --> 01:58:58,320 ABOUT IS ONE OF THE MAJOR TOOLS, 3233 01:58:58,320 --> 01:59:01,880 WHICH IS CRISPR/CAS 9 RNA-GUIDED 3234 01:59:01,880 --> 01:59:02,160 NUCLEASES. 3235 01:59:02,160 --> 01:59:03,880 THIS WAS ADAPTED FROM A 3236 01:59:03,880 --> 01:59:05,200 BACTERIAL SYSTEM TO DEFEND 3237 01:59:05,200 --> 01:59:07,120 AGAINST VIRUSES. 3238 01:59:07,120 --> 01:59:13,240 AND WHAT WE MEAN, CAS9 IS A 3239 01:59:13,240 --> 01:59:14,360 PROMMABLE NUCLEASE AND WHAT WE 3240 01:59:14,360 --> 01:59:17,160 MEAN IS SHOWN ON THE RIGHT. 3241 01:59:17,160 --> 01:59:17,920 CAS9 COMBINES WITH SOMETHING 3242 01:59:17,920 --> 01:59:19,800 CALLED A GUIDE RNA THAT'S 3243 01:59:19,800 --> 01:59:20,560 COMPLEMENTARY TO SEQUENCES IN 3244 01:59:20,560 --> 01:59:22,040 THE GENOME THAT YOU WANT TO 3245 01:59:22,040 --> 01:59:25,680 MODIFY. 3246 01:59:25,680 --> 01:59:28,880 AND SO THAT'S SHOWN ON THE 3247 01:59:28,880 --> 01:59:29,520 RIGHT. 3248 01:59:29,520 --> 01:59:31,280 THE GUIDE RNA WILL TAKE CAS9 TO 3249 01:59:31,280 --> 01:59:34,200 A DESIRED SITE ANYWHERE IN THE 3250 01:59:34,200 --> 01:59:37,840 GENOME, AND ONCE THE CAS9 FINDS 3251 01:59:37,840 --> 01:59:39,800 ITS PLACE IN THE GENOME, IT WILL 3252 01:59:39,800 --> 01:59:41,040 CREATE A DOUBLE STRANDED DNA 3253 01:59:41,040 --> 01:59:41,240 BREAK. 3254 01:59:41,240 --> 01:59:42,760 I SHOULD ALSO POINT OUT, I THINK 3255 01:59:42,760 --> 01:59:46,880 YOU ALL KNOW THAT THE NOBEL 3256 01:59:46,880 --> 01:59:54,000 PRIZE IN CHEMISTRY WAS WON BY 3257 01:59:54,000 --> 01:59:55,480 JENNIFER -- IN 2020 FOR THIS 3258 01:59:55,480 --> 01:59:56,400 TECHNOLOGY. 3259 01:59:56,400 --> 01:59:58,440 SO CAS9 FIND ITS PLACE ON THE 3260 01:59:58,440 --> 02:00:00,040 DNA AND IT CREATES A DOUBLE 3261 02:00:00,040 --> 02:00:05,880 STRAND DNA BREAK. 3262 02:00:05,880 --> 02:00:07,280 CELLS DON'T LIKE DOUBLE STRAND 3263 02:00:07,280 --> 02:00:08,840 DNA BREAKS AND THEY TRY VERY 3264 02:00:08,840 --> 02:00:10,480 HARD TO CORRECT THEM QUICKLY, 3265 02:00:10,480 --> 02:00:12,360 AND THERE'S TWO WAYS TO CORRECT 3266 02:00:12,360 --> 02:00:14,480 A DOUBLE STRAND DNA BREAK. 3267 02:00:14,480 --> 02:00:16,760 THE FIRST ONE IS SHOWN ON YOUR 3268 02:00:16,760 --> 02:00:19,160 LEFT, NON-HOMOLOGOUS END 3269 02:00:19,160 --> 02:00:19,560 JOINING. 3270 02:00:19,560 --> 02:00:20,720 THIS IS A FAST WAY TO CORRECT 3271 02:00:20,720 --> 02:00:22,120 THINGS BUT IT'S IMPERFECT. 3272 02:00:22,120 --> 02:00:25,800 SO THE CELL WILL KR CREATE SMALL 3273 02:00:25,800 --> 02:00:29,200 INSERTIONS OR DELETIONS AT THE 3274 02:00:29,200 --> 02:00:30,280 SITE OF THE FUSION OF THE TWO 3275 02:00:30,280 --> 02:00:33,640 BROKEN ENDS. 3276 02:00:33,640 --> 02:00:34,640 ANOTHER MECHANISM THAT CELLS 3277 02:00:34,640 --> 02:00:36,920 HAVE IS CALLED HOMOLOGY DIRECTED 3278 02:00:36,920 --> 02:00:38,080 REPAIR OR HDR. 3279 02:00:38,080 --> 02:00:39,440 AND THAT OCCURS IN THE PRESENCE 3280 02:00:39,440 --> 02:00:42,920 OF A DONOR TEM PRAIT. 3281 02:00:42,920 --> 02:00:44,600 SO YOU PUT A TEMPLATE INTO THE 3282 02:00:44,600 --> 02:00:47,920 CELLS THAT LOOKS LIKE THE SITE 3283 02:00:47,920 --> 02:00:49,240 THAT NEEDS TO BE REPAIRED, BUT 3284 02:00:49,240 --> 02:00:52,000 IT COULD HAVE SMALL CHANGES IN 3285 02:00:52,000 --> 02:00:56,560 IT LIKE A NORMAL CODON AT 3286 02:00:56,560 --> 02:00:58,760 POSITION SIX INSTEAD OF THE 3287 02:00:58,760 --> 02:01:01,880 MUTATED VALENE. 3288 02:01:01,880 --> 02:01:03,080 THIS IS A VERY PRECISE WAY TO 3289 02:01:03,080 --> 02:01:05,280 CORRECT THINGS, AND YOU YOU CAN 3290 02:01:05,280 --> 02:01:09,440 CAN USETHIS TO CORRECT SICKLE CL 3291 02:01:09,440 --> 02:01:10,680 MUTATIONS. 3292 02:01:10,680 --> 02:01:12,840 SO NON-HOMOLOGOUS END JOINING IS 3293 02:01:12,840 --> 02:01:13,480 IMPRECISE. 3294 02:01:13,480 --> 02:01:15,960 IT OCCURS AT HIGH RATES IN 3295 02:01:15,960 --> 02:01:16,960 HEMATOPOIETIC STEM CELLS AND 3296 02:01:16,960 --> 02:01:18,800 IT'S EASY TO PERFORM. 3297 02:01:18,800 --> 02:01:21,320 ON THE OTHER HAND, HOMOLOGY 3298 02:01:21,320 --> 02:01:22,960 DIRECTED REPAIR IS VERY PRECISE, 3299 02:01:22,960 --> 02:01:25,560 BUT IT OCCURS AT LOW RATES IN 3300 02:01:25,560 --> 02:01:26,880 HEMATOPOIETIC STEM CELLS AND 3301 02:01:26,880 --> 02:01:28,160 IT'S TECHNICALLY DIFFICULT. 3302 02:01:28,160 --> 02:01:29,960 AND WE'LL HEAR MORE ABOUT THIS 3303 02:01:29,960 --> 02:01:35,200 LATER IN THE SESSION FROM MATT. 3304 02:01:35,200 --> 02:01:36,160 NON-HOMOLOGOUS END JOINING CAN 3305 02:01:36,160 --> 02:01:38,240 BE USED TO INDUCE FETAL 3306 02:01:38,240 --> 02:01:39,800 HEMOGLOBIN, AND HDR CAN BE USED 3307 02:01:39,800 --> 02:01:40,960 TO CORRECT THE SICKLE CELL 3308 02:01:40,960 --> 02:01:44,880 MUTATION. 3309 02:01:44,880 --> 02:01:46,920 SO NOW LET'S TALK ABOUT INSIGHTS 3310 02:01:46,920 --> 02:01:48,480 INTO GLOBIN SWITCHING. 3311 02:01:48,480 --> 02:01:51,320 WE KNOW THAT PERINATAL SILENCING 3312 02:01:51,320 --> 02:01:54,400 OF GAMMA GLOBIN OCCURS BY 3313 02:01:54,400 --> 02:01:58,000 TRANSCRIPTIONAL REPRESSION. 3314 02:01:58,000 --> 02:01:59,960 TWO REPRESSOR PROTEINS BIND THE 3315 02:01:59,960 --> 02:02:01,720 REGION OF THE GAMMA GLOBIN 3316 02:02:01,720 --> 02:02:05,840 PROMOTER AT BIRTH, ZBTB7A AND 3317 02:02:05,840 --> 02:02:06,080 BCL11A. 3318 02:02:06,080 --> 02:02:07,720 THEY CONTRIBUTE ABOUT 50/50 TO 3319 02:02:07,720 --> 02:02:12,240 REPRESSION. 3320 02:02:12,240 --> 02:02:13,960 WE ALSO KNOW THAT SOME NATURALLY 3321 02:02:13,960 --> 02:02:16,560 OCCURRING HPFH VARIANTS ARE 3322 02:02:16,560 --> 02:02:18,520 MUTATIONS THAT BLOCK THE ABILITY 3323 02:02:18,520 --> 02:02:20,720 OF THESE PROTEINS TO BIND DNA. 3324 02:02:20,720 --> 02:02:24,200 THESE HPFH MUTATIONS ARE SHOWN 3325 02:02:24,200 --> 02:02:24,520 HERE. 3326 02:02:24,520 --> 02:02:28,760 SO JUST LIKE THE HPFH MUTATIONS, 3327 02:02:28,760 --> 02:02:32,960 WE CAN USE CAS9 TO DIRECT 3328 02:02:32,960 --> 02:02:34,760 NON-HOMOLOGOUS END JOINING TO 3329 02:02:34,760 --> 02:02:36,680 DESTROY THESE REPRESSOR BINDING 3330 02:02:36,680 --> 02:02:39,600 SITES AND RE-CREATE THOSE HPFH 3331 02:02:39,600 --> 02:02:43,520 MUTATIONS. 3332 02:02:43,520 --> 02:02:44,880 THIS IS AN EXAMPLE FROM MY LAB 3333 02:02:44,880 --> 02:02:46,920 SHOWN HERE. 3334 02:02:46,920 --> 02:02:50,280 WE USED CAS9 AND A GUIDE RNA TO 3335 02:02:50,280 --> 02:02:53,120 DISRUPT THAT BCL11 BINDING SIDE 3336 02:02:53,120 --> 02:02:56,200 IN THE GAMMA GLOBIN -- TURN THEM 3337 02:02:56,200 --> 02:02:58,600 INTO RED CELLS BY IN VITRO 3338 02:02:58,600 --> 02:03:00,120 ERYTHROID DIFFERENTIATION AND 3339 02:03:00,120 --> 02:03:02,960 MEASURED FETAL HEMOGLOBIN. 3340 02:03:02,960 --> 02:03:05,920 WHAT YOU SEE IS THE RESULTS 3341 02:03:05,920 --> 02:03:09,200 HERE, THAT WHEN WE ARE EDIT CAN 3342 02:03:09,200 --> 02:03:11,680 CAS9 IN THE GUIDE RNA, FETAL 3343 02:03:11,680 --> 02:03:14,640 HEMOGLOBIN DWOAS GOES UP IN THOD 3344 02:03:14,640 --> 02:03:17,840 CELLS AS SHOWN BY THIS FLOW 3345 02:03:17,840 --> 02:03:20,080 CYTOMETRY PLOT. 3346 02:03:20,080 --> 02:03:22,400 SO THAT'S THE APPROACH THAT I 3347 02:03:22,400 --> 02:03:27,200 JUST SHOWED YOU IS ON THE LEFT. 3348 02:03:27,200 --> 02:03:28,720 AND THIS IS BEING TESTED IN A 3349 02:03:28,720 --> 02:03:31,560 CLINICAL TRIAL RIGHT NOW BY 3350 02:03:31,560 --> 02:03:32,760 EDITAS MEDICINE AND WE ARE 3351 02:03:32,760 --> 02:03:34,080 PLANNING TO DO SOMETHING SIMILAR 3352 02:03:34,080 --> 02:03:34,520 AT ST. JUDE. 3353 02:03:34,520 --> 02:03:37,240 THERE'S ALSO ANOTHER CAS9 3354 02:03:37,240 --> 02:03:40,400 NUCLEASE APPROACH. 3355 02:03:40,400 --> 02:03:42,520 AND THIS IS TO USE CAS9 TO 3356 02:03:42,520 --> 02:03:46,960 DISRUPT A CRITICAL SITE, A RED 3357 02:03:46,960 --> 02:03:48,640 CELL ERYTHROID-SPECIFIC ENHANCER 3358 02:03:48,640 --> 02:03:50,880 FOR THE BCL11A GENE ITSELF. 3359 02:03:50,880 --> 02:03:54,040 AND WHAT THIS DOES IS IT REDUCES 3360 02:03:54,040 --> 02:03:55,800 BCL11A EXPRESSION IN ERYTHROID 3361 02:03:55,800 --> 02:03:58,080 CELLS, AND THAT RAISES FETAL 3362 02:03:58,080 --> 02:03:59,080 HEMOGLOBIN. 3363 02:03:59,080 --> 02:04:01,560 AND THIS IS BEING EXAMINED IN A 3364 02:04:01,560 --> 02:04:03,640 CLINICAL TRIAL BY VERTEX. 3365 02:04:03,640 --> 02:04:05,120 I SHOULD SAY THAT THESE TWO 3366 02:04:05,120 --> 02:04:07,560 CLINICAL TRIALS FROM VERTEX AND 3367 02:04:07,560 --> 02:04:10,960 EDITAS ARE LOOKING PRETTY GOOD. 3368 02:04:10,960 --> 02:04:12,360 VERTEX IS FURTHER ALONG, BUT I 3369 02:04:12,360 --> 02:04:16,520 THINK THEY BOTH ARE PROMISING. 3370 02:04:16,520 --> 02:04:18,800 NOW THERE ARE THREE OTHER HPFH 3371 02:04:18,800 --> 02:04:21,120 VARIANTS THAT ARE DIFFERENT. 3372 02:04:21,120 --> 02:04:23,080 THESE INSTEAD OF BLOCKING 3373 02:04:23,080 --> 02:04:24,600 REPRESSOR BINDING SITES, THEY 3374 02:04:24,600 --> 02:04:26,240 CREATE NEW BINDING SITES FOR 3375 02:04:26,240 --> 02:04:28,440 TRANSCRIPTION FACTORS. 3376 02:04:28,440 --> 02:04:33,320 AND THESE ARE SHOWN HERE, A NEW 3377 02:04:33,320 --> 02:04:38,560 KLF1, TAL1 OR GATA1 MOTIF. 3378 02:04:38,560 --> 02:04:40,440 THEY CAN BE CREATED WITH BASE 3379 02:04:40,440 --> 02:04:40,800 EDITORS. 3380 02:04:40,800 --> 02:04:45,280 SO WHAT IS A BASE EDITOR? 3381 02:04:45,280 --> 02:04:48,200 A BASE EDITOR IS A CATALYTICALLY 3382 02:04:48,200 --> 02:04:49,200 IMPAIRED FORM OF CAS9. 3383 02:04:49,200 --> 02:04:50,960 IT DOESN'T CREATE DOUBLE STRAND 3384 02:04:50,960 --> 02:04:52,920 DNA BREAKS. 3385 02:04:52,920 --> 02:04:55,520 AND IT'S FUSED TO A DEAM NAIZ 3386 02:04:55,520 --> 02:04:58,240 THAT CAN CONVERT A TO G OR C TO 3387 02:04:58,240 --> 02:05:01,840 T. 3388 02:05:01,840 --> 02:05:04,160 SO WE USED THIS APPROACH TO 3389 02:05:04,160 --> 02:05:06,640 COMPARE -- WE COMPARED FIVE 3390 02:05:06,640 --> 02:05:08,520 DIFFERENT APPROACHES FOR FETAL 3391 02:05:08,520 --> 02:05:10,080 HEMOGLOBIN INDUCTION. 3392 02:05:10,080 --> 02:05:11,800 ALL OF THESE I'VE SHOWED YOU. 3393 02:05:11,800 --> 02:05:15,080 TWO CAS9 AND THREE WITH BASE 3394 02:05:15,080 --> 02:05:17,800 EDITORS TO CREATE NEW TRAN SCRIP 3395 02:05:17,800 --> 02:05:18,960 TORE BINDING SITES. 3396 02:05:18,960 --> 02:05:20,600 THIS IS A COLLABORATION BETWEEN 3397 02:05:20,600 --> 02:05:22,800 MY GROUP AND THE INDIVIDUALS 3398 02:05:22,800 --> 02:05:25,320 SHOWN HERE, INCLUDING DAVID LIU, 3399 02:05:25,320 --> 02:05:28,440 WHO INVENTED BASE EDITORS, AND 3400 02:05:28,440 --> 02:05:29,760 GREG NEWBY, WHO'S GOING TO TALK 3401 02:05:29,760 --> 02:05:33,440 IN THIS SESSION. 3402 02:05:33,440 --> 02:05:34,840 SO THESE ARE THE REQUIREMENTS, 3403 02:05:34,840 --> 02:05:37,120 WE THINK, FOR IDEAL THERAPEUTIC 3404 02:05:37,120 --> 02:05:38,320 INDUCTION OF FETAL HEMOGLOBIN. 3405 02:05:38,320 --> 02:05:39,840 MORE IS BETTER AND YOU NEED IT 3406 02:05:39,840 --> 02:05:44,840 IN ALL RED CELLS. 3407 02:05:44,840 --> 02:05:47,760 SO WE TREATED CD34 CELLS WITH 3408 02:05:47,760 --> 02:05:49,760 ABE, A BASE EDITORS OR CAS9 AND 3409 02:05:49,760 --> 02:05:54,960 WE MADE RED CELLS OUT OF THEM. 3410 02:05:54,960 --> 02:05:56,640 WE MEASURED FETAL HEMOGLOBIN. 3411 02:05:56,640 --> 02:05:57,960 YOU SEE ON THE LEFT HERE THAT 3412 02:05:57,960 --> 02:06:01,840 THE EDITING FREQUENCY IS HIGHER 3413 02:06:01,840 --> 02:06:04,400 FOR THE CAS9 APPROACHES, LOWER 3414 02:06:04,400 --> 02:06:10,400 FOR THE BASE EDITING APPROACHES. 3415 02:06:10,400 --> 02:06:12,560 BUT THE FETAL HEMOGLOBIN LEVELS 3416 02:06:12,560 --> 02:06:14,520 ARE ACTUALLY HIGHER COMPARED TO 3417 02:06:14,520 --> 02:06:16,160 BASE EDITING FORECAST 9. 3418 02:06:16,160 --> 02:06:18,040 IF YOU NORMALIZE FETAL 3419 02:06:18,040 --> 02:06:20,880 HEMOGLOBIN LEVELS PER PERCENT 3420 02:06:20,880 --> 02:06:23,480 EDITING YOU SEE WAY HIGHER 3421 02:06:23,480 --> 02:06:25,240 LEVELS FOR THESE BASE EDITING 3422 02:06:25,240 --> 02:06:26,840 APPROACHES. 3423 02:06:26,840 --> 02:06:29,240 AND WE FOUND THAT WE FOLLOWED UP 3424 02:06:29,240 --> 02:06:31,720 ON THE MINUS 175A TO G APPROACH 3425 02:06:31,720 --> 02:06:33,840 BECAUSE IT INDUCES FETAL 3426 02:06:33,840 --> 02:06:39,840 HEMOGLOBIN MOST POTENTLY. 3427 02:06:39,840 --> 02:06:42,040 WE THINK WE UNDERSTAND THE 3428 02:06:42,040 --> 02:06:43,480 MECHANISM OF THIS. 3429 02:06:43,480 --> 02:06:45,000 THIS MUTATION CREATES A NEW 3430 02:06:45,000 --> 02:06:47,400 BINDING SITE FOR TRANSCRIPTION 3431 02:06:47,400 --> 02:06:49,160 FACTOR TAL1 IN DNA THAT'S NEXT 3432 02:06:49,160 --> 02:06:53,080 TO A GATA1 SITE. 3433 02:06:53,080 --> 02:06:55,360 AND THIS CREATES A BINDING SITE 3434 02:06:55,360 --> 02:06:59,520 FOR A TRANSCRIPTIONAL COMPLEX 3435 02:06:59,520 --> 02:07:00,640 CONSISTING OF THESE MULTIPLE 3436 02:07:00,640 --> 02:07:01,160 PROTEINS. 3437 02:07:01,160 --> 02:07:03,240 THIS COMPLEX IS ALREADY PRESENT 3438 02:07:03,240 --> 02:07:06,320 AT THE LOCUS CONTROL REGION AND 3439 02:07:06,320 --> 02:07:08,360 UPSTREAM ENHANCER IN THE BETA 3440 02:07:08,360 --> 02:07:09,560 GLOBIN LOCUS. 3441 02:07:09,560 --> 02:07:12,520 AND WHEN YOU HAVE A NEW 3442 02:07:12,520 --> 02:07:14,040 TAL1 BINDING SITE CREATED BY 3443 02:07:14,040 --> 02:07:16,760 THIS MINUS 175A TO G, THIS 3444 02:07:16,760 --> 02:07:21,280 COMPLEX BINDS HE HERE, AND ONE F 3445 02:07:21,280 --> 02:07:24,800 THE COMPONENTS, LDV1, INTERACTS 3446 02:07:24,800 --> 02:07:25,200 WITH ITSELF. 3447 02:07:25,200 --> 02:07:27,080 WHAT IT DOES IS IT BRINGS THIS 3448 02:07:27,080 --> 02:07:28,160 STRONG ENHANCER NEXT TO THE 3449 02:07:28,160 --> 02:07:31,000 GAMMA GLOBIN GENES AND TURNS IT 3450 02:07:31,000 --> 02:07:32,560 ON. 3451 02:07:32,560 --> 02:07:36,360 SO WE PERFORM PROOF OF CONCEPT 3452 02:07:36,360 --> 02:07:38,240 STUDIES IN HEMATOPOIETIC -- TO 3453 02:07:38,240 --> 02:07:40,320 SEE IF WE CAN EDIT HEMATOPOIETIC 3454 02:07:40,320 --> 02:07:43,480 STEM CELLS. 3455 02:07:43,480 --> 02:07:48,720 WE ELECTROPORATEDCD34 HUSBAND 3456 02:07:48,720 --> 02:07:51,360 CELLS WITH -- WE PERFORMED BASE 3457 02:07:51,360 --> 02:07:53,080 EDITING, TRANSFERRED THESE CELLS 3458 02:07:53,080 --> 02:07:54,640 INTO IMMUNODEFICIENT MICE AND 3459 02:07:54,640 --> 02:07:56,200 ANALYZED THE DONOR CELLS AT 16 3460 02:07:56,200 --> 02:08:01,600 WEEKS. 3461 02:08:01,600 --> 02:08:04,000 WHAT WE SEE HERE AGAIN IS THE 3462 02:08:04,000 --> 02:08:05,080 EDITING EYE EFFICIENCIES ARE 3463 02:08:05,080 --> 02:08:06,320 LOWER WITH THE BASE EDITORS AND 3464 02:08:06,320 --> 02:08:07,520 WE'RE WORK ON THIS. 3465 02:08:07,520 --> 02:08:08,720 THESE HAVE TO BE IMPROVED. 3466 02:08:08,720 --> 02:08:14,280 BUT STILL THE FETAL HEMOGLOBIN 3467 02:08:14,280 --> 02:08:15,280 SELECTION IS HIGHER IN THESE 3468 02:08:15,280 --> 02:08:15,720 MICE. 3469 02:08:15,720 --> 02:08:17,880 IF WE PLOT PERCENT EDITING 3470 02:08:17,880 --> 02:08:19,840 VERSUS PERCENT FETAL HEMOGLOBIN, 3471 02:08:19,840 --> 02:08:20,960 THE BASE EDITORS DO MUCH BETTER 3472 02:08:20,960 --> 02:08:25,080 THAN THE CAS9 APPROACH. 3473 02:08:25,080 --> 02:08:27,680 WHEN WE DO CLONAL ANALYSIS OF 3474 02:08:27,680 --> 02:08:28,680 HEMATOPOIETIC COLONIES, WHAT WE 3475 02:08:28,680 --> 02:08:31,520 SEE IS THAT WITH THE CAS9 3476 02:08:31,520 --> 02:08:33,080 APPROACHES, ALMOST EVERY RED 3477 02:08:33,080 --> 02:08:35,640 CELL COLONY, EVERY PRECURSOR OR 3478 02:08:35,640 --> 02:08:39,200 STEM CELL GETS EDITED. 3479 02:08:39,200 --> 02:08:40,960 BUT WE'RE MISSING ABOUT 20% 3480 02:08:40,960 --> 02:08:42,720 EDITING WITH THE ABE APPROACHES 3481 02:08:42,720 --> 02:08:44,000 AND SO AGAIN, I THINK IN ORDER 3482 02:08:44,000 --> 02:08:46,000 TO REALLY MAKE THIS WORK WELL, 3483 02:08:46,000 --> 02:08:47,960 WE HAVE TO INCREASE THE EDITING 3484 02:08:47,960 --> 02:08:55,840 FREQUENCY OF THE BASE EDITOR. 3485 02:08:55,840 --> 02:08:57,120 I THINK THIS IS THE LAST DATA 3486 02:08:57,120 --> 02:08:57,880 SLIDE. 3487 02:08:57,880 --> 02:08:59,080 THIS IS A LITTLE COMPLICATED. 3488 02:08:59,080 --> 02:09:02,080 I'LL JUST GO FROM HERE. 3489 02:09:02,080 --> 02:09:05,320 I'LL JUST SHOW YOU THIS ONE. 3490 02:09:05,320 --> 02:09:07,320 THIS SHOWS PERCENT FETAL 3491 02:09:07,320 --> 02:09:08,920 HEMOGLOBIN IN CLONES, IN EDITED 3492 02:09:08,920 --> 02:09:10,240 COLONIES. 3493 02:09:10,240 --> 02:09:12,200 AND EVERY ONE OF THESE COLONIES 3494 02:09:12,200 --> 02:09:13,120 HAS FULL EDITING. 3495 02:09:13,120 --> 02:09:14,520 SO WE'RE JUST COMPARING THE 3496 02:09:14,520 --> 02:09:15,720 POTENCY OF THE EDITING. 3497 02:09:15,720 --> 02:09:18,240 AND WHAT WE SEE HERE IS THAT IN 3498 02:09:18,240 --> 02:09:20,960 THE CAS9 NUCLEASE APPROACHES, 3499 02:09:20,960 --> 02:09:22,720 THE PERCENT FETAL HEMOGLOBIN HAS 3500 02:09:22,720 --> 02:09:23,480 A BIG SPREAD. 3501 02:09:23,480 --> 02:09:24,800 THERE'S A LOT OF VARIABILITY. 3502 02:09:24,800 --> 02:09:27,640 BUT WITH THIS MINUS 175, THERE'S 3503 02:09:27,640 --> 02:09:30,480 A VERY TIGHT INDUCTION OF FETAL 3504 02:09:30,480 --> 02:09:34,960 HEMOGLOBIN THAT IS VERY HIGH. 3505 02:09:34,960 --> 02:09:39,960 ARE .AM I 3 MINUTES OVER? 3506 02:09:39,960 --> 02:09:43,320 SORRY, YOU'RE BEING VERY POLITE. 3507 02:09:43,320 --> 02:09:44,760 MAYBE I GOT A BREAK SINCE WE 3508 02:09:44,760 --> 02:09:47,440 HAVE TO SAY "NEXT SLIDE." 3509 02:09:47,440 --> 02:09:50,200 SO THIS IS THE CONCLUSION. 3510 02:09:50,200 --> 02:09:52,800 SO WHAT I SHOWED YOU IS THAT THE 3511 02:09:52,800 --> 02:09:54,120 BASE EDITOR APPROACHES THAT 3512 02:09:54,120 --> 02:09:57,080 CREATE NEW TRANSCRIPTION FACTOR 3513 02:09:57,080 --> 02:10:01,560 BINDING SITES ARE MORE POTENT 3514 02:10:01,560 --> 02:10:03,200 THAN THE CAS9 APPROACHES. 3515 02:10:03,200 --> 02:10:04,720 WHAT I'VE WRITTEN HERE IS THAT 3516 02:10:04,720 --> 02:10:07,360 THE TRANS ACTIVATION BY MINUS 3517 02:10:07,360 --> 02:10:09,000 175A TO G OVERRIDES DUAL 3518 02:10:09,000 --> 02:10:09,520 REPRESSION. 3519 02:10:09,520 --> 02:10:11,400 AND WHAT I MEAN IS I TOLD YOU 3520 02:10:11,400 --> 02:10:13,720 THAT THESE TWO REPRESSORS, EACH 3521 02:10:13,720 --> 02:10:15,120 REPRESS ABOUT 50/50. 3522 02:10:15,120 --> 02:10:18,400 HERE I HAVE 40/40. 3523 02:10:18,400 --> 02:10:20,600 BUT THIS GOES UP TO ABOUT 80% AT 3524 02:10:20,600 --> 02:10:23,000 ANY GIVEN GENE, SO IT OVERCOMES 3525 02:10:23,000 --> 02:10:24,400 THE ACTIVITIES OF TWO 3526 02:10:24,400 --> 02:10:26,200 REPRESSORS. 3527 02:10:26,200 --> 02:10:30,000 THIS EDIT PRODUCES MORE POTENT 3528 02:10:30,000 --> 02:10:31,440 FETAL HEMOGLOBIN INDUCTION WITH 3529 02:10:31,440 --> 02:10:32,640 MINIMAL DOUBLE STRAND DNA 3530 02:10:32,640 --> 02:10:34,040 BREAKS, AND WHAT I KIND OF 3531 02:10:34,040 --> 02:10:35,800 SHOWED YOU BUT I WENT THROUGH 3532 02:10:35,800 --> 02:10:41,800 QUICKLY IS NOT ALL CAS9 INDELS 3533 02:10:41,800 --> 02:10:43,320 RAISE FETAL HEMOGLOBIN EQUALLY. 3534 02:10:43,320 --> 02:10:48,040 WHAT THAT SAYS IS THE DIVERSE 3535 02:10:48,040 --> 02:10:49,160 INDELS, DIFFERENT SIZE DELETIONS 3536 02:10:49,160 --> 02:10:51,560 OR INSERTIONS GENERATED BY CAS9 3537 02:10:51,560 --> 02:10:52,960 NUCLEASE CAN CAUSE UNEXPECTED 3538 02:10:52,960 --> 02:10:54,280 VARIATIONS IN BIOLOGICAL 3539 02:10:54,280 --> 02:10:54,720 OUTCOMES. 3540 02:10:54,720 --> 02:10:56,240 AND THOSE CAN BE OVERCOME BY THE 3541 02:10:56,240 --> 02:10:57,880 PRECISION OF BASE EDITING. 3542 02:10:57,880 --> 02:11:01,920 AND FOR THAT REASON, 3543 02:11:01,920 --> 02:11:03,880 ADENOSINE-BASED EDITORS MAY BE A 3544 02:11:03,880 --> 02:11:05,520 SUPERIOR APPROACH FOR 3545 02:11:05,520 --> 02:11:06,840 THERAPEUTIC FETAL HEMOGLOAN 3546 02:11:06,840 --> 02:11:08,280 INDUCTION AN THAT'S BEING TESTED 3547 02:11:08,280 --> 02:11:10,840 IN A CLINICAL TRIAL RIGHT NOW BY 3548 02:11:10,840 --> 02:11:11,360 BEAM THERAPEUTICS. 3549 02:11:11,360 --> 02:11:13,520 I'M NOT SURE IF THEY'VE ENROLLED 3550 02:11:13,520 --> 02:11:14,280 THEIR FIRST PATIENT YET BUT 3551 02:11:14,280 --> 02:11:14,880 WE'LL FIND OUT. 3552 02:11:14,880 --> 02:11:16,360 SO AGAIN, THERE ARE A LOT OF 3553 02:11:16,360 --> 02:11:18,680 TECHNOLOGIES, AND WE HAVE TO 3554 02:11:18,680 --> 02:11:19,760 COMPARE THEM HEAD TO HEAD. 3555 02:11:19,760 --> 02:11:21,880 AND WHAT WE NEED TO DO THAT ARE 3556 02:11:21,880 --> 02:11:23,120 YOU INCLUDE NICHES OUT THERE WHO 3557 02:11:23,120 --> 02:11:24,160 ARE GOING TO FOLLOW THESE 3558 02:11:24,160 --> 02:11:28,400 PATIENTS FOR A LONG TIME. 3559 02:11:28,400 --> 02:11:29,520 OKAY. 3560 02:11:29,520 --> 02:11:31,360 I WANT TO THANK MY ORGANIZERS 3561 02:11:31,360 --> 02:11:35,560 FOR GIVING ME EXTRA TIME. 3562 02:11:35,560 --> 02:11:39,160 AND APOLOGIZE, AND THESE ARE MY 3563 02:11:39,160 --> 02:11:40,120 COLLABORATORS, THE MAIN ONES I 3564 02:11:40,120 --> 02:11:41,760 ALREADY MENTIONED, AND WE THANK 3565 02:11:41,760 --> 02:11:42,800 OUR FUNDING SOURCES, AND THANK 3566 02:11:42,800 --> 02:11:47,120 YOU GUYS. 3567 02:11:47,120 --> 02:11:50,840 >> THANK YOU, MITCH THE THE 3568 02:11:50,840 --> 02:11:52,360 NEXT SPEAKER IS PRESENTING 3569 02:11:52,360 --> 02:11:54,440 VIRTUALLY FROM PARIS ON 3570 02:11:54,440 --> 02:11:56,560 PRE-CLINICAL RESULTS ON BASE 3571 02:11:56,560 --> 02:11:59,840 EDITING TO REACTIVE FETAL 3572 02:11:59,840 --> 02:12:10,040 HEMOGLOBIN. 3573 02:12:14,000 --> 02:12:20,720 DR. ANNARITA MICCIO. 3574 02:12:20,720 --> 02:12:22,560 >>THIS IS A VIDEO TALK. 3575 02:12:22,560 --> 02:12:23,920 >>SO GOOD MORNING, EVERYBODY. 3576 02:12:23,920 --> 02:12:25,960 FIRST I WOULD LIKE TO THANK THE 3577 02:12:25,960 --> 02:12:27,240 ORGANIZERS FOR THE INVITATION, 3578 02:12:27,240 --> 02:12:30,240 AND TODAY I WILL DISCUSS EDITING 3579 02:12:30,240 --> 02:12:31,560 APPROACH TO SEQUENCE OF DISEASE, 3580 02:12:31,560 --> 02:12:34,640 IN PARTICULAR TO REACTIVATE 3581 02:12:34,640 --> 02:12:35,400 FETAL HEMOGLOBIN. 3582 02:12:35,400 --> 02:12:37,520 AS YOU HEARD, APPROACHES FOR 3583 02:12:37,520 --> 02:12:39,000 SICKLE CELL DISEASE HAVE BEEN 3584 02:12:39,000 --> 02:12:42,600 DEVELOPED USING CRISPR/CAS 3585 02:12:42,600 --> 02:12:44,040 9 SYSTEM BUT MORE RECENTLY ALSO 3586 02:12:44,040 --> 02:12:45,880 USING NOVEL EDITING PLATFORMS 3587 02:12:45,880 --> 02:12:48,240 SUCH AS BASE EDITORS. 3588 02:12:48,240 --> 02:12:50,320 SO THE CRISPR/CAS 9 NUCLEASE 3589 02:12:50,320 --> 02:12:51,880 SYSTEM HAS BEEN USED TO DEVELOP 3590 02:12:51,880 --> 02:12:53,200 THERAPEUTIC STRATEGY FOR SICKLE 3591 02:12:53,200 --> 02:12:55,360 CELL DISEASE AS IT GENERATES 3592 02:12:55,360 --> 02:12:56,920 DOUBLE STRAND BREAK IN THE 3593 02:12:56,920 --> 02:12:58,760 TARGET SITE THAT CAN BE REPAIRED 3594 02:12:58,760 --> 02:13:00,320 EITHER TO CORRECT THE GENES 3595 02:13:00,320 --> 02:13:06,960 THROUGH HDR OR BY GENERATING 3596 02:13:06,960 --> 02:13:10,480 THROUGH JOINING. 3597 02:13:10,480 --> 02:13:14,000 DOUBLE STRAND BREAK CAN INDUCE 3598 02:13:14,000 --> 02:13:19,560 RESPONSE, CAN ALSO CAUSE 3599 02:13:19,560 --> 02:13:21,080 REARRANGEMENTS. 3600 02:13:21,080 --> 02:13:22,520 STRATEGIES FOR SICKLE CELL 3601 02:13:22,520 --> 02:13:25,280 DISEASE, USING APPROACHES SUCH 3602 02:13:25,280 --> 02:13:28,120 AS BASE EDITORS THAT CAN MAKE C 3603 02:13:28,120 --> 02:13:31,160 TO T OR A TO G CONVERSION OR 3604 02:13:31,160 --> 02:13:37,400 PRIME EDITING TO CAN INDUCE 3605 02:13:37,400 --> 02:13:39,400 CONVERSION OR FINALLY EP GINO 3606 02:13:39,400 --> 02:13:49,080 EDEEPIGENOMEEDITOR FOR ACTIVE OE 3607 02:13:49,080 --> 02:13:49,800 TRANSCRIPTION. 3608 02:13:49,800 --> 02:13:51,040 IN PARTICULAR BASE EDITOR CAN 3609 02:13:51,040 --> 02:13:52,640 MAKE THESE PINPOINT CHANGES IN 3610 02:13:52,640 --> 02:13:56,320 THE DNA AS THEY CONTAIN -- THAT 3611 02:13:56,320 --> 02:13:58,720 MAKES ONLY SINGLE STRAND BREAKS 3612 02:13:58,720 --> 02:14:04,520 THAT FACILITATE CONVERSION IN C 3613 02:14:04,520 --> 02:14:10,680 TO G OR A TO G CONVERSION. 3614 02:14:10,680 --> 02:14:12,200 SO EDITING APPROACHES INCREASING 3615 02:14:12,200 --> 02:14:17,680 THE LEVEL OF FETAL HEMOIMLOA BI- 3616 02:14:17,680 --> 02:14:21,320 BY PERSISTENCE OF FETAL GAMMA 3617 02:14:21,320 --> 02:14:22,280 GLOBIN, TYPICALLY ASSOCIATED 3618 02:14:22,280 --> 02:14:28,720 WITH GENETIC VARIANCE. 3619 02:14:28,720 --> 02:14:31,720 SO OUR FIRST STRATEGY TO 3620 02:14:31,720 --> 02:14:38,320 REACTIVATE IS TO KNOCK OUT BC 3621 02:14:38,320 --> 02:14:42,760 BCL11, AND THIS CAN BE ACHIEVED 3622 02:14:42,760 --> 02:14:47,840 BY GATA1, BASICALLY BY 3623 02:14:47,840 --> 02:14:51,440 DELETING -- TO -- JOINING. 3624 02:14:51,440 --> 02:14:53,800 CURRENTLY BEING TESTED IN 3625 02:14:53,800 --> 02:14:56,960 CLINICAL TRIAL. 3626 02:14:56,960 --> 02:15:01,280 INTERESTINGLY, BASE EDITOR HAS 3627 02:15:01,280 --> 02:15:04,720 BEEN USED TO INACTIVATE 3628 02:15:04,720 --> 02:15:07,160 GATA1 ACHIEVING HIGH BASE 3629 02:15:07,160 --> 02:15:08,960 EDITING EFFICIENCY IN PROGENITOR 3630 02:15:08,960 --> 02:15:10,440 CELLS FROM SICKLE CELL DISEASE 3631 02:15:10,440 --> 02:15:10,960 PATIENT. 3632 02:15:10,960 --> 02:15:14,480 AND THIS LED TO FETAL HEMOGLOBIN 3633 02:15:14,480 --> 02:15:16,320 ACTIVATION IN THE PHENOTYPE. 3634 02:15:16,320 --> 02:15:18,960 SO TO FACTOR INCREASED FETAL 3635 02:15:18,960 --> 02:15:24,640 HEMOGLOBIN EXPRESSION, -- TO 3636 02:15:24,640 --> 02:15:26,760 ENHANCE THE BCL11 GENE USING 3637 02:15:26,760 --> 02:15:27,400 BASE EDITORS. 3638 02:15:27,400 --> 02:15:31,880 IN PARTICULAR, DUAL EDITING -- 3639 02:15:31,880 --> 02:15:35,840 PRIMARY HSPCs FROM SICKLE CELL 3640 02:15:35,840 --> 02:15:37,160 DISEASE PATIENTS LED TO HIGHER 3641 02:15:37,160 --> 02:15:38,800 EXPRESSION COMPARED TO THE 3642 02:15:38,800 --> 02:15:40,200 SINGLE EDITING. 3643 02:15:40,200 --> 02:15:42,280 WITHOUT ALTERING THE -- 3644 02:15:42,280 --> 02:15:44,240 POTENTIAL OF HSPCs. 3645 02:15:44,240 --> 02:15:46,960 AND THEN ANOTHER POTENTIAL 3646 02:15:46,960 --> 02:15:50,120 TARGET TO REACTIVATE FETAL 3647 02:15:50,120 --> 02:15:57,200 HEMOGLOBIN IS -- DISRUPT THE 3648 02:15:57,200 --> 02:15:58,760 BINDING SITE FOR TRANSCRIPTION 3649 02:15:58,760 --> 02:16:04,320 OF REPRESSOR OR GENETIC -- 3650 02:16:04,320 --> 02:16:05,080 TRANSCRIPTION ACTIVATORS. 3651 02:16:05,080 --> 02:16:09,440 SO WE HAVE INITIALLY USED THE 3652 02:16:09,440 --> 02:16:12,200 CRISPR/CAS 9 SYSTEM FROM THE 3653 02:16:12,200 --> 02:16:15,840 GAMMA GLOBIN PROMOTER -- 3654 02:16:15,840 --> 02:16:20,000 REPRESSOR BY -- INSIGHT 3655 02:16:20,000 --> 02:16:20,960 THROUGH -- CURRENTLY BEING 3656 02:16:20,960 --> 02:16:21,880 TESTED IN CLINICS. 3657 02:16:21,880 --> 02:16:24,280 ALSO IN THIS CASE WE DECIDED 3658 02:16:24,280 --> 02:16:26,760 TO -- TO TARGET THIS REGION AS 3659 02:16:26,760 --> 02:16:30,160 THEY CAN PRECISELY -- INHIBITING 3660 02:16:30,160 --> 02:16:34,440 THE BINDING OF REPRESSORS BUT -- 3661 02:16:34,440 --> 02:16:35,680 RECRUITING TRANSCRIPTIONAL 3662 02:16:35,680 --> 02:16:36,000 ACTIVATORS. 3663 02:16:36,000 --> 02:16:40,920 AND IN PARTICULAR, CBEs CAN BE 3664 02:16:40,920 --> 02:16:45,880 USED TO GENERATE -- OF THE GAMMA 3665 02:16:45,880 --> 02:16:47,640 GLOBIN PROMOTERS THAT DISRUPT 3666 02:16:47,640 --> 02:16:51,040 THE REPRESSOR BINDING SITE. 3667 02:16:51,040 --> 02:16:53,200 AND IN THE REGION, THIS EDITOR 3668 02:16:53,200 --> 02:16:55,440 CAN BE USED TO MAKE T TO C 3669 02:16:55,440 --> 02:17:01,240 CONVERSION AND GENERATE THE -- 3670 02:17:01,240 --> 02:17:05,400 ACTIVATOR BINDING SITE. 3671 02:17:05,400 --> 02:17:08,800 -- IN MY LAB -- GENERATED 3672 02:17:08,800 --> 02:17:11,040 THE -- IN HSPs FROM SICKLE 3673 02:17:11,040 --> 02:17:12,440 CELL DISEASE PATIENTS, ACHIEVING 3674 02:17:12,440 --> 02:17:14,600 BASE EDITING EFFICIENCY OF 3675 02:17:14,600 --> 02:17:17,240 BETWEEN 40 AND 50%, WITH LOW OR 3676 02:17:17,240 --> 02:17:19,520 ABSENT DOUBLE STRAND BREAK 3677 02:17:19,520 --> 02:17:21,600 INDUCED -- COMPARED TO THE 3678 02:17:21,600 --> 02:17:23,280 CAS9 -- WHERE WE USE THE 3679 02:17:23,280 --> 02:17:26,880 PREVIOUSLY DEVELOPED STRATEGY 3680 02:17:26,880 --> 02:17:30,480 DELETING THE -- BINDING INSIDE. 3681 02:17:30,480 --> 02:17:32,920 THE ANALYSIS SHOWED REACTIVATION 3682 02:17:32,920 --> 02:17:35,000 IN SAMPLES WHICH WAS EVEN HIGHER 3683 02:17:35,000 --> 02:17:41,240 THAN IN CRASS 9 TRE CAS9 TREATES 3684 02:17:41,240 --> 02:17:42,240 AND -- SAMPLES WAS LOWER 3685 02:17:42,240 --> 02:17:45,080 COMPARED TO THE CAS9 TREATED 3686 02:17:45,080 --> 02:17:47,280 SAMPLES. 3687 02:17:47,280 --> 02:17:49,920 -- SUFFICIENT TO CORRECT THE -- 3688 02:17:49,920 --> 02:17:51,680 PHENOTYPE. 3689 02:17:51,680 --> 02:17:55,720 IMPORTANTLY TYPICALLY OBSERVED 3690 02:17:55,720 --> 02:17:59,240 UPON DOUBLE STRAND BREAK -- WAS 3691 02:17:59,240 --> 02:18:02,640 NOT DETECTED IN BASE EDITED 3692 02:18:02,640 --> 02:18:05,600 CELLS AND MODEST -- SAMPLES. 3693 02:18:05,600 --> 02:18:10,080 SO TO IMPROVE THIS EDITING 3694 02:18:10,080 --> 02:18:11,600 EFFICIENCY WE TESTED SEVERAL 3695 02:18:11,600 --> 02:18:17,360 DRUGS THAT COULD IMPROVE IN H 3696 02:18:17,360 --> 02:18:21,680 SPCs, PROTOCOLS OR IN THE CASE 3697 02:18:21,680 --> 02:18:24,080 OF THIS EDITOR -- ABE WHICH 3698 02:18:24,080 --> 02:18:25,520 INCREASED BASE EDITING 3699 02:18:25,520 --> 02:18:26,040 EFFICIENCY. 3700 02:18:26,040 --> 02:18:27,160 AND WE HOPE TO BRING THIS 3701 02:18:27,160 --> 02:18:31,680 APPROACH SOON TO THE CLINICS. 3702 02:18:31,680 --> 02:18:36,720 WE ALSO -- ENRICHING FOR EDITS 3703 02:18:36,720 --> 02:18:42,520 CELLS, THE GAMMA GLOBIN PROMOTER 3704 02:18:42,520 --> 02:18:46,680 TO GENETICALLY -- OR DISRUPT 3705 02:18:46,680 --> 02:18:48,520 TORE -- AND FROM THE OTHER SIDE 3706 02:18:48,520 --> 02:18:50,320 OF THE GENE ENCODING FOR A 3707 02:18:50,320 --> 02:18:52,840 SURFACE MARKERS SUCH AS CD33. 3708 02:18:52,840 --> 02:18:54,480 SO THE IDEA WAS THAT THE 3709 02:18:54,480 --> 02:18:57,760 SELECTION OF CD33 NEGATIVE CELLS 3710 02:18:57,760 --> 02:19:01,160 WOULD DELETE TO HIGH BASE 3711 02:19:01,160 --> 02:19:02,720 EDITING EFFICIENCY -- POORLY 3712 02:19:02,720 --> 02:19:05,040 EDITED CELLS. 3713 02:19:05,040 --> 02:19:08,520 MULTIPLE -- STRONGLY IMPACTED 3714 02:19:08,520 --> 02:19:12,760 THE -- EXPRESSION IN SICKLE CELL 3715 02:19:12,760 --> 02:19:14,960 DISEASE PATIENTS -- CD34, A 3716 02:19:14,960 --> 02:19:18,000 MARKER OF PROGENITOR CELLS. 3717 02:19:18,000 --> 02:19:19,440 INTERESTINGLY WE OBSERVED HIGHER 3718 02:19:19,440 --> 02:19:23,280 BASE EDITING EFFICIENCY AT THE 3719 02:19:23,280 --> 02:19:27,760 GABA GLOBIN PROMOTER IN THE -- 3720 02:19:27,760 --> 02:19:28,880 POPULATION WHILE IMPORTANTLY -- 3721 02:19:28,880 --> 02:19:30,960 DID NOT AFFECT THE PROGENITOR 3722 02:19:30,960 --> 02:19:32,840 VARIABILITY. 3723 02:19:32,840 --> 02:19:35,560 AND THEN I BRIEFLY MENTIONED TO 3724 02:19:35,560 --> 02:19:37,120 YOU OTHER STRATEGIES SUCH AS 3725 02:19:37,120 --> 02:19:45,520 PRIME EDITING AND EP GINO EP EE 3726 02:19:45,520 --> 02:19:46,120 EDITING. 3727 02:19:46,120 --> 02:19:48,880 -- ALL THIS CONVERSION IT CAN 3728 02:19:48,880 --> 02:19:51,360 ALLOW TO -- AS IT WILL BE 3729 02:19:51,360 --> 02:19:54,400 DISCUSSED LATER IN THE SESSION. 3730 02:19:54,400 --> 02:19:56,640 AND AS PRIME EDITING CAN 3731 02:19:56,640 --> 02:19:58,120 GENERATE MULTIPLE MODIFICATION, 3732 02:19:58,120 --> 02:20:01,960 WE DECIDED TO INTRODUCE MULTIPLE 3733 02:20:01,960 --> 02:20:04,880 HBF -- THAT TOGETHER CAN BOOST 3734 02:20:04,880 --> 02:20:06,120 FETAL HEMOGLOBIN EXPRESSION. 3735 02:20:06,120 --> 02:20:09,280 IN PARTICULAR, WE'VE CHOSEN TO 3736 02:20:09,280 --> 02:20:12,800 INTRODUCE TWO MUTATIONS IN 3737 02:20:12,800 --> 02:20:14,720 EDITING SITES AS WE DEMONSTRATED 3738 02:20:14,720 --> 02:20:16,880 IN THE PRESENCE OF BOTH BINDING 3739 02:20:16,880 --> 02:20:19,400 SITES LEADS TO HIGHER FETAL 3740 02:20:19,400 --> 02:20:20,040 HEMOGLOBIN EXPRESSION COMPARED 3741 02:20:20,040 --> 02:20:21,600 TO THE INTRODUCTION OF 3742 02:20:21,600 --> 02:20:22,000 INDIVIDUAL SITES. 3743 02:20:22,000 --> 02:20:23,480 AND WE ARE CURRENTLY OPTIMIZING 3744 02:20:23,480 --> 02:20:26,120 THE FREQUENCY OF CONCOMITANT 3745 02:20:26,120 --> 02:20:30,000 INTRODUCTION OF BOTH AND THEN 3746 02:20:30,000 --> 02:20:30,840 MOVE TO PRIMARY CELLS. 3747 02:20:30,840 --> 02:20:36,760 AND FINALLY EP JOE K EPIGENOME G 3748 02:20:36,760 --> 02:20:38,720 APPROACHES TO SICKLE CELL 3749 02:20:38,720 --> 02:20:41,480 DISEASE TO ACTIVATE THE GAMMA 3750 02:20:41,480 --> 02:20:44,480 GLOBIN PROMOTERS, REMOVING 3751 02:20:44,480 --> 02:20:47,520 REPRESSIVE HISTONE MARKS, OR DNA 3752 02:20:47,520 --> 02:20:49,720 METHYLATION, AND WE CAN DO THE 3753 02:20:49,720 --> 02:20:55,080 OPPOSITE TO BCL11 -- GENERATING 3754 02:20:55,080 --> 02:20:56,400 ANY TYPE OF DNA DAMAGE 3755 02:20:56,400 --> 02:20:58,920 WHATSOEVER AS EPIGENOME 3756 02:20:58,920 --> 02:21:01,240 EDITOR -- CAS9 WITH NO DNA 3757 02:21:01,240 --> 02:21:02,040 CLEAVAGE ACTIVITY. 3758 02:21:02,040 --> 02:21:03,560 SO NOW OUR LAB WE FIRST COME 3759 02:21:03,560 --> 02:21:07,200 FROM THE GAMMA GLOBIN PROMOTER 3760 02:21:07,200 --> 02:21:09,080 HIGHLY METHYLATED WHEN SILENT 3761 02:21:09,080 --> 02:21:10,520 WHEN EXPRESSING HIGH LEVEL OF 3762 02:21:10,520 --> 02:21:13,280 FETAL HEMOGLOBIN, THEN 3763 02:21:13,280 --> 02:21:15,720 METHYLATION IS SUBSTANTIALLY -- 3764 02:21:15,720 --> 02:21:18,440 ALSO ACQUIRE THE HISTONE MARKS 3765 02:21:18,440 --> 02:21:20,120 OF THE -- TYPICALLY ASSOCIATED 3766 02:21:20,120 --> 02:21:23,000 WITH ACTIVE TRANSCRIPTION. 3767 02:21:23,000 --> 02:21:26,560 AND THEREFORE SIMONE IN MY LAB 3768 02:21:26,560 --> 02:21:30,680 USED THE EDITOR -- AND REMOVE 3769 02:21:30,680 --> 02:21:34,320 DNA METHYLATION AS ACTIVITY IN 3770 02:21:34,320 --> 02:21:36,320 FETAL HEMOGLOBIN EXPRESSION -- 3771 02:21:36,320 --> 02:21:39,600 ACTIVATION OVER TIME. 3772 02:21:39,600 --> 02:21:41,240 AND IN CONCLUSION, I SHOWED YOU 3773 02:21:41,240 --> 02:21:43,240 THAT THIS EDITING CAN BE USED 3774 02:21:43,240 --> 02:21:47,720 FOR ACTIVATING FETAL HEMOGLOBIN 3775 02:21:47,720 --> 02:21:51,440 BY -- GENERATED HB -- I'M PRETTY 3776 02:21:51,440 --> 02:21:52,920 SURE THAT MANY MORE TARGETS WILL 3777 02:21:52,920 --> 02:21:54,440 BE DISCOVERED IN THE FUTURE, AND 3778 02:21:54,440 --> 02:21:57,360 NOVEL AND POTENTIAL SAFER -- 3779 02:21:57,360 --> 02:21:58,600 POTENTIALLY SAFER EDITING TOOLS 3780 02:21:58,600 --> 02:22:01,240 COULD BE ALSO USED FOR THESE 3781 02:22:01,240 --> 02:22:01,560 PURPOSES. 3782 02:22:01,560 --> 02:22:03,880 HOWEVER I NEED TO MENTION THAT 3783 02:22:03,880 --> 02:22:08,800 CAS9 NUCLEASE STRATEGIES -- IN 3784 02:22:08,800 --> 02:22:11,240 CLINICS WITH PROMISING RESULT. 3785 02:22:11,240 --> 02:22:13,360 BASE EDITING STRATEGIES ARE ALSO 3786 02:22:13,360 --> 02:22:16,520 VERY PROMISING AND THE FIRST 3787 02:22:16,520 --> 02:22:17,600 CLINICAL TRIAL JUST STARTED WITH 3788 02:22:17,600 --> 02:22:18,160 THE FIRST PATIENT. 3789 02:22:18,160 --> 02:22:19,480 FINALLY I WOULD LIKE TO THANK 3790 02:22:19,480 --> 02:22:22,800 ALL THE MEMBERS OF MY LAB, 3791 02:22:22,800 --> 02:22:23,960 COLLABORATORS, FUNDING AGENCY 3792 02:22:23,960 --> 02:22:25,280 AND ESPECIALLY CLINICIANS AND 3793 02:22:25,280 --> 02:22:26,120 PATIENT AND YOU FOR YOUR 3794 02:22:26,120 --> 02:22:26,600 ATTENTION. 3795 02:22:26,600 --> 02:22:29,880 I. WILLI WILL BE HAPPY TO TAKE 3796 02:22:29,880 --> 02:22:31,160 QUESTIONS. 3797 02:22:31,160 --> 02:22:35,680 THANK YOU. 3798 02:22:35,680 --> 02:22:36,200 >>THANK YOU. 3799 02:22:36,200 --> 02:22:38,040 WITH THAT, I WOULD LIKE TO 3800 02:22:38,040 --> 02:22:41,080 INTRODUCE GREG NEWBY TO GIVE THE 3801 02:22:41,080 --> 02:22:43,560 NEXT TALK ON PRE-CLINICAL 3802 02:22:43,560 --> 02:22:45,760 RESULTS ON BASE EDITING AND 3803 02:22:45,760 --> 02:22:47,600 PRIME EDITING IN SICKLE CELL 3804 02:22:47,600 --> 02:22:57,720 DISEASE. 3805 02:22:57,720 --> 02:22:59,440 >>THANKS TO THE ORGANIZERS FOR 3806 02:22:59,440 --> 02:23:00,440 INVITING ME HERE TO TALK ABOUT 3807 02:23:00,440 --> 02:23:00,880 THIS WORK. 3808 02:23:00,880 --> 02:23:03,120 I JUST STARTED AS A PROFESSOR, A 3809 02:23:03,120 --> 02:23:04,600 NEW LAB AT JOHNS HOPKINS, BUT 3810 02:23:04,600 --> 02:23:05,520 THE WORK I'LL TELL YOU ABOUT 3811 02:23:05,520 --> 02:23:07,800 TODAY WAS DONE WHILE I WAS A 3812 02:23:07,800 --> 02:23:08,920 POSTDOCTORAL FELLOW IN THE LAB 3813 02:23:08,920 --> 02:23:11,160 OF DAVID LU AT THE BROAD 3814 02:23:11,160 --> 02:23:12,000 INSTITUTE IN COLLABORATION WITH 3815 02:23:12,000 --> 02:23:15,280 MITCH WEISS AND JONATHAN YEN AT 3816 02:23:15,280 --> 02:23:20,840 ST. JUDE. 3817 02:23:20,840 --> 02:23:22,240 SO TALKED TODAY ABOUT TWO 3818 02:23:22,240 --> 02:23:23,480 DIFFERENT STRATEGIES THAT WE'VE 3819 02:23:23,480 --> 02:23:25,360 BEEN DEVELOPING AND SHOWN IN 3820 02:23:25,360 --> 02:23:26,880 CELL AND ANIMAL MODELS THAT CAN 3821 02:23:26,880 --> 02:23:28,520 MODIFY THE SICKLE CELL MUTATION 3822 02:23:28,520 --> 02:23:29,960 ITSELF TO PREVENT SICKLE CELL 3823 02:23:29,960 --> 02:23:31,640 DISEASE OR TO TREAT -- HOPEFULLY 3824 02:23:31,640 --> 02:23:35,560 CURE THIS CONDITION. 3825 02:23:35,560 --> 02:23:39,400 WE REALLY NEED TO ENGINEER A PEE 3826 02:23:39,400 --> 02:23:40,560 SPOKE EDITING REAGENT. 3827 02:23:40,560 --> 02:23:41,880 IN THIS CASE HERE'S THE MOLECULE 3828 02:23:41,880 --> 02:23:45,640 THAT WE SETTLED ON FOR 3829 02:23:45,640 --> 02:23:47,520 MODIFICATION BY BASE EDITING OF 3830 02:23:47,520 --> 02:23:49,280 SICKLE CELL MUTATION. 3831 02:23:49,280 --> 02:23:50,840 HERE'S A SCHEMATIC SHOWING THE 3832 02:23:50,840 --> 02:23:54,320 SCWEENS AROUND THE SICKLE CELL 3833 02:23:54,320 --> 02:23:59,880 MUTATION WE CAN MAKE A TO G 3834 02:23:59,880 --> 02:24:01,360 POINT MUTATIONS WHICH CANNOT 3835 02:24:01,360 --> 02:24:02,800 PERFECTLY CORRECT THE T TO A 3836 02:24:02,800 --> 02:24:04,120 MUTATION THAT CAUSES SICKLE CELL 3837 02:24:04,120 --> 02:24:06,440 DISEASE BUT WE CAN CONVERT THE 3838 02:24:06,440 --> 02:24:07,960 CAUSATIVE NUCLEOTIDE INTO A G 3839 02:24:07,960 --> 02:24:10,760 WHICH PRODUCES A RARE FORM OF 3840 02:24:10,760 --> 02:24:14,440 HEMOGLOBIN CALLED HEMOGLOBIN 3841 02:24:14,440 --> 02:24:19,520 MAKASSAR WHICH IS DEBENI BENIGNS 3842 02:24:19,520 --> 02:24:21,360 NOT CAUSE DISEASE. 3843 02:24:21,360 --> 02:24:22,880 WE DELIVERED -- INTO CELLS FROM 3844 02:24:22,880 --> 02:24:23,800 SICKLE CELL PATIENTS. 3845 02:24:23,800 --> 02:24:27,960 THESE ARE CD34 HSPCs. 3846 02:24:27,960 --> 02:24:30,080 UP TO ABOUT 80% MODIFICATION OF 3847 02:24:30,080 --> 02:24:31,280 THE TARGET SICKLE CELL MUTATION 3848 02:24:31,280 --> 02:24:33,040 IN BLUE AND BYSTANDER MUTATIONS 3849 02:24:33,040 --> 02:24:34,560 WERE LARGELY ABSENT OR SILENT IN 3850 02:24:34,560 --> 02:24:36,640 GREEN AND OTHER COLORS THERE, SO 3851 02:24:36,640 --> 02:24:37,880 HIGH EFFICIENT EDITING OF OUR 3852 02:24:37,880 --> 02:24:39,840 TARGET SITE. 3853 02:24:39,840 --> 02:24:41,520 WE COMPARED THIS TO SOME OF THE 3854 02:24:41,520 --> 02:24:45,680 APPROACHES USING NUCLEASES TO 3855 02:24:45,680 --> 02:24:46,560 TREAT SICKLE CELL DISEASE, IN 3856 02:24:46,560 --> 02:24:52,200 THIS CASE, USING CAS9 -- 3857 02:24:52,200 --> 02:24:52,880 ENHANCER. 3858 02:24:52,880 --> 02:24:53,960 THIS IS SHOWN IN RED UP ABOVE 3859 02:24:53,960 --> 02:24:57,600 AND WHAT WE'RE LOOKING AT IS 3860 02:24:57,600 --> 02:24:59,800 P21, MARKER FOR THE DNA DAMAGE 3861 02:24:59,800 --> 02:25:00,040 RESPONSE. 3862 02:25:00,040 --> 02:25:01,520 ONE OF THE UNINTENDED OR 3863 02:25:01,520 --> 02:25:04,400 UNDESIRABLE OUT OUTCOMES THAT'N 3864 02:25:04,400 --> 02:25:12,960 REPORTED FOREC FOR CAS9 CAS9 NUE 3865 02:25:12,960 --> 02:25:13,920 TREATMENT. 3866 02:25:13,920 --> 02:25:15,040 WITH NO EDITOR AT ALL LEADS TO 3867 02:25:15,040 --> 02:25:17,440 THIS TRACE OF THE BLACK LINE, 3868 02:25:17,440 --> 02:25:18,920 AND OUR BASE EDITOR LEADS TO THE 3869 02:25:18,920 --> 02:25:20,120 BLUE TRACE THERE, SO NO 3870 02:25:20,120 --> 02:25:23,840 INDUCTION RE RELATIVE TO A ZERO 3871 02:25:23,840 --> 02:25:29,000 EDITOR CONTROL. 3872 02:25:29,000 --> 02:25:32,960 ELECTROPELECTROPORATION LEADS TE 3873 02:25:32,960 --> 02:25:34,840 DAMAGE ITSELF. 3874 02:25:34,840 --> 02:25:35,840 LARGER THAN DESIRED DELETIONS OF 3875 02:25:35,840 --> 02:25:36,920 THE TARGET SAY THE CAN BE CAUSED 3876 02:25:36,920 --> 02:25:41,240 BY TRANSLOCATIONS OR OTHER 3877 02:25:41,240 --> 02:25:46,920 DELETIONS OF 100 TO MANY 3878 02:25:46,920 --> 02:25:47,800 KILABASES. 3879 02:25:47,800 --> 02:25:50,960 -- THAT'S REMAINING EITHER 3880 02:25:50,960 --> 02:25:52,120 NUCLEASE OR BASE EDITOR 3881 02:25:52,120 --> 02:25:52,360 TREATMENT. 3882 02:25:52,360 --> 02:25:53,960 WE SEE THAT NUCLEASE TREATMENT 3883 02:25:53,960 --> 02:25:56,360 LEADS TO A LOSS OF ABOUT 13% OF 3884 02:25:56,360 --> 02:25:57,720 ALLELES IN THE RESULTING 3885 02:25:57,720 --> 02:25:58,480 SUBPOPULATION WHEREAS BASE 3886 02:25:58,480 --> 02:25:59,440 EDITOR TREATMENT LEADS TO NO 3887 02:25:59,440 --> 02:26:00,680 CHANGE, SO WE DON'T OBSERVE 3888 02:26:00,680 --> 02:26:02,440 THESE LARGER DELETIONS OR 3889 02:26:02,440 --> 02:26:04,320 REARRANGEMENTS. 3890 02:26:04,320 --> 02:26:05,520 ON THE OTHER HAND, WE DO OBSERVE 3891 02:26:05,520 --> 02:26:07,160 A DIFFERENT CLASS OF UNDESIRED 3892 02:26:07,160 --> 02:26:08,080 OUTCOMES THAT ARE ASSOCIATED 3893 02:26:08,080 --> 02:26:09,680 WITH BASE EDITORS RATHER THAN 3894 02:26:09,680 --> 02:26:11,560 CAS9 NUCLEASES WHICH IS OFF 3895 02:26:11,560 --> 02:26:16,200 TARGET BASE EDITING. 3896 02:26:16,200 --> 02:26:18,600 TO SHOW BOTH OF THESE TOGETHER, 3897 02:26:18,600 --> 02:26:22,720 SORRY, BACK ONE, SO WE ASSESSED 3898 02:26:22,720 --> 02:26:24,360 ABOUT 700 OFF-TARGET SITES THAT 3899 02:26:24,360 --> 02:26:28,600 WE IDENTIFIED VIA CIRCLE SEQ, 3900 02:26:28,600 --> 02:26:30,800 EXPERIMENTAL METHOD AND 3901 02:26:30,800 --> 02:26:31,600 COMPUTATIONAL SCAN. 3902 02:26:31,600 --> 02:26:35,080 OF THOSE 700, WE IDENTIFIED 54 3903 02:26:35,080 --> 02:26:38,040 SITES WITH OFF TARGET REAL BASE 3904 02:26:38,040 --> 02:26:40,240 EDITING, EACH OF THOSE SITE -- 3905 02:26:40,240 --> 02:26:41,320 THE MOST EFFICIENT OF THOSE 3906 02:26:41,320 --> 02:26:44,280 SITES IS SUMMARIZED AT LEFT WITH 3907 02:26:44,280 --> 02:26:45,880 OFF TARGET MOTIFS THEY BIND TO. 3908 02:26:45,880 --> 02:26:47,440 AT RIGHT I'M SHOWING THE PIE 3909 02:26:47,440 --> 02:26:49,160 CHART OF WHERE THOSE 54 OFF 3910 02:26:49,160 --> 02:26:52,360 TARGET SITES FALL. 3911 02:26:52,360 --> 02:26:53,360 LARGELY THEY'RE IN SPACE WHERE 3912 02:26:53,360 --> 02:26:57,160 WE DON'T EXPECT TO HAVE ANY 3913 02:26:57,160 --> 02:26:58,600 PHENOTYPIC IMPACT. 3914 02:26:58,600 --> 02:27:01,040 A FEW ARE UTRs BUT SEVERAL 3915 02:27:01,040 --> 02:27:03,680 HUNDRED BASE PAIRS AWAY FROM 3916 02:27:03,680 --> 02:27:06,600 WHERE WE EXPECT ANY IMPACT. 3917 02:27:06,600 --> 02:27:10,280 -- WE DIDN'T SEE ANY THAT SEEM 3918 02:27:10,280 --> 02:27:17,280 TO BE CLINICALLY PROBLEMATIC. 3919 02:27:17,280 --> 02:27:20,080 HERE I'M SHOWING SOME RESULTS 3920 02:27:20,080 --> 02:27:21,800 FOLLOWING A XENOGRAFT OF THESE 3921 02:27:21,800 --> 02:27:23,960 EDITED PATIENT HUMAN CELLS INTO 3922 02:27:23,960 --> 02:27:25,160 IMMUNOCOMPROMISED MICE TO TRACK 3923 02:27:25,160 --> 02:27:26,960 HOW DURABLY THESE CELLS CAN 3924 02:27:26,960 --> 02:27:27,920 REPOPULATE THE BONE MARROW. 3925 02:27:27,920 --> 02:27:30,680 WE SAW THAT AFTER FOUR MONTHS, 3926 02:27:30,680 --> 02:27:32,680 THE ANIMALS THAT RECEIVED OUR 3927 02:27:32,680 --> 02:27:37,160 EDITED CELLS MAINTAINED ABOUT 3928 02:27:37,160 --> 02:27:42,360 68% ALLELI, C -- THIS WAS 3929 02:27:42,360 --> 02:27:43,200 CONSISTENT AMONG ALL WE 3930 02:27:43,200 --> 02:27:43,640 ASSESSED. 3931 02:27:43,640 --> 02:27:46,280 USING A COLONY ASSAY, WE SAW 80 3932 02:27:46,280 --> 02:27:50,440 TO 90% OF CLONES HAD AT LEAST 3933 02:27:50,440 --> 02:27:52,080 ONE EDIT WHICH SHOULD BE 3934 02:27:52,080 --> 02:27:53,040 PHENOTYPICALLY NORMAL. 3935 02:27:53,040 --> 02:27:56,320 THE BOTTOM LEFT HERE, WE SEE 3936 02:27:56,320 --> 02:27:59,040 GREATLY REDUCED SICKLING 3937 02:27:59,040 --> 02:28:00,120 PROPENSITY QUANTIFIED HERE. 3938 02:28:00,120 --> 02:28:03,160 LOOKING AT THE LINEAGES OF CELLS 3939 02:28:03,160 --> 02:28:04,800 THAT'S GENERATED AFTER EDITING, 3940 02:28:04,800 --> 02:28:06,760 WE SEE NO DIFFERENCE TO THOSE 3941 02:28:06,760 --> 02:28:08,640 RECEIVING UNTREATED CELLS. 3942 02:28:08,640 --> 02:28:12,800 SO NO DEFECT IN THE CELL 3943 02:28:12,800 --> 02:28:14,240 LINEAGES FROM BASE EDITORS. 3944 02:28:14,240 --> 02:28:19,120 WE ALSO SIMULATED A AUTOLOGOUS 3945 02:28:19,120 --> 02:28:20,760 TRANSPLANT IN INBRED MICE. 3946 02:28:20,760 --> 02:28:25,280 WE EXTRACTED THEIR LIN MINUS 3947 02:28:25,280 --> 02:28:26,400 HSPCs AND RETRANSPLANTED INTO 3948 02:28:26,400 --> 02:28:27,040 MICE. 3949 02:28:27,040 --> 02:28:28,560 THESE MICE ARE GENETICALLY 3950 02:28:28,560 --> 02:28:29,960 MODIFIED SO THAT THEY CONTAIN 3951 02:28:29,960 --> 02:28:31,440 TWO COPIES OF THE SICKLE CELL 3952 02:28:31,440 --> 02:28:32,440 ALLELE. 3953 02:28:32,440 --> 02:28:33,840 WE ALSO DID THIS PROCEDURE 3954 02:28:33,840 --> 02:28:36,360 WITHOUT ANY EDITING AS A 3955 02:28:36,360 --> 02:28:37,320 NEGATIVE CONTROL AND USED A 3956 02:28:37,320 --> 02:28:39,240 SICKLE CELL TRAIT MOUSE LINE AS 3957 02:28:39,240 --> 02:28:41,200 A POSITIVE CONTROL FOR HEALTHY 3958 02:28:41,200 --> 02:28:41,960 CELLS. 3959 02:28:41,960 --> 02:28:46,920 HEALTHY MICE. 3960 02:28:46,920 --> 02:28:48,800 TRANSPLANTED THESE IN, 3961 02:28:48,800 --> 02:28:50,440 SACRIFICED THEM 16 WEEKS LATER. 3962 02:28:50,440 --> 02:28:51,320 SAW SUBSTANTIAL MAINTENANCE OF 3963 02:28:51,320 --> 02:28:53,360 THE EDITED GENOTYPE AND IN BLOOD 3964 02:28:53,360 --> 02:28:56,840 BY HPLC WE QUANTIFIED ABOUT 70 3965 02:28:56,840 --> 02:29:06,200 TO 80% MACOSARGLOBIN. 3966 02:29:06,200 --> 02:29:07,640 HERE WE'RE DOING A COMPLETE 3967 02:29:07,640 --> 02:29:11,760 BLOOD COUNT ON THE TRANSPLANTED 3968 02:29:11,760 --> 02:29:13,200 BLOOD, AND IN RED ARE THOSE 3969 02:29:13,200 --> 02:29:15,120 ANIMALS THAT WERE TRANSPLANTED 3970 02:29:15,120 --> 02:29:18,080 WITH UNMODIFIED SICKLE CELLS SO 3971 02:29:18,080 --> 02:29:20,040 THESE ARE DISEASE PHENOTYPES IN 3972 02:29:20,040 --> 02:29:21,600 TERMS OF THE TOTAL CONCENTRATION 3973 02:29:21,600 --> 02:29:27,640 OF HEMOGLOBIN, PERCENTAGE OF RE 3974 02:29:27,640 --> 02:29:31,080 RETICULOSITES, -- IN BLUE WE'RE 3975 02:29:31,080 --> 02:29:32,400 SHOWING OUTCOMES OF MICE WHO 3976 02:29:32,400 --> 02:29:33,480 RECEIVED EDITED CELLS AND THESE 3977 02:29:33,480 --> 02:29:35,680 ARE CORRECTED BACK TO THE LEVELS 3978 02:29:35,680 --> 02:29:37,720 OF HEALTHY CONTROL, SHOWN IN 3979 02:29:37,720 --> 02:29:40,320 PURPLE AND BROWN HERE. 3980 02:29:40,320 --> 02:29:42,920 SO THAT'S THE CONCLUSION OF WHAT 3981 02:29:42,920 --> 02:29:45,080 I WANTED TO TALK ABOUT BASE 3982 02:29:45,080 --> 02:29:45,800 EDITING. 3983 02:29:45,800 --> 02:29:47,760 THE SECOND APPROACH IS USING 3984 02:29:47,760 --> 02:29:48,720 PRIME EDITING TO CORRECT SICKLE 3985 02:29:48,720 --> 02:29:49,200 CELL DISEASE. 3986 02:29:49,200 --> 02:29:50,960 FOR MANY OF THESE EXPERIMENTS WE 3987 02:29:50,960 --> 02:29:52,120 DID THE VERY SAME ANALYSES WE 3988 02:29:52,120 --> 02:29:54,120 DID FOR BASE EDITING SO I'M NOT 3989 02:29:54,120 --> 02:29:55,800 GOING TO GO THROUGH ALL OF THEM 3990 02:29:55,800 --> 02:29:56,240 BUT I'LL SUMMARIZE. 3991 02:29:56,240 --> 02:29:58,560 SO PRIME EDITING ALSO DOES NOT 3992 02:29:58,560 --> 02:29:59,640 INVOLVE DOUBLE STRANDED BREAKS, 3993 02:29:59,640 --> 02:30:04,080 IT DOESN'T USE A DEAMINASE. 3994 02:30:04,080 --> 02:30:05,800 INSTEAD WE DIRECTLY WRITE IN 3995 02:30:05,800 --> 02:30:07,120 SEQUENCE INTO A TARGET REGION OF 3996 02:30:07,120 --> 02:30:07,560 THE GENOME. 3997 02:30:07,560 --> 02:30:09,480 SO WE TOOK CELLS FROM FOUR 3998 02:30:09,480 --> 02:30:13,520 SICKLE CELL DONORS HERE AND 3999 02:30:13,520 --> 02:30:16,240 ELECTROPROATED THESE WITH 4000 02:30:16,240 --> 02:30:18,240 ELECTROPRIME RNA AND 4001 02:30:18,240 --> 02:30:19,680 TRANSPLANTED THESE INTO 4002 02:30:19,680 --> 02:30:20,760 IMMUNODEFICIENT MICE AND LOOKED 4003 02:30:20,760 --> 02:30:22,320 FOUR MONTHS LATER AT HOW 4004 02:30:22,320 --> 02:30:24,200 EFFICIENTLY OUR EDITED CELLS 4005 02:30:24,200 --> 02:30:27,800 REPOPULATED THE BONE MARROW AND 4006 02:30:27,800 --> 02:30:28,480 HEMATOPOIETIC SYSTEM OF THESE 4007 02:30:28,480 --> 02:30:28,800 MICE. 4008 02:30:28,800 --> 02:30:30,480 IN THIS CASE WE'RE DOING BONE 4009 02:30:30,480 --> 02:30:32,120 MARROW ANALYSIS OF THE HUMAN 4010 02:30:32,120 --> 02:30:33,320 LINEAGES SO BETWEEN THE FOUR 4011 02:30:33,320 --> 02:30:34,680 DONORS, THERE IS SOME 4012 02:30:34,680 --> 02:30:35,440 VARIABILITY BUT IN EACH CASE, 4013 02:30:35,440 --> 02:30:37,040 WE'VE HAD CONSISTENT MAINTENANCE 4014 02:30:37,040 --> 02:30:38,960 OF THE EDITED CELLS OVER THIS 4015 02:30:38,960 --> 02:30:39,880 FOUR-MONTH PERIOD. 4016 02:30:39,880 --> 02:30:41,960 IN TOTAL, 15 TO 40% OF ALLELES 4017 02:30:41,960 --> 02:30:46,680 WERE DURABLY MODIFIED. 4018 02:30:46,680 --> 02:30:48,240 THERE'S A CLONAL ASSAY WHERE 4019 02:30:48,240 --> 02:30:49,800 WE'RE LOOKING AT WHETHER THIS 4020 02:30:49,800 --> 02:30:51,520 EDITING OCCURRED IN ZERO, ONE OR 4021 02:30:51,520 --> 02:30:54,120 TWO ALLELES, SO IN EACH CASE, 4022 02:30:54,120 --> 02:30:57,040 WE'VE GOT AT LEAST 20 AND UP TO 4023 02:30:57,040 --> 02:30:59,720 60% OF THE CELL POPULATION 4024 02:30:59,720 --> 02:31:01,360 RECEIVING AT LEAST ONE EDIT. 4025 02:31:01,360 --> 02:31:02,360 HERE WE'RE SHOWING THE 4026 02:31:02,360 --> 02:31:06,320 QUANTIFICATION OF SICKLING OF 4027 02:31:06,320 --> 02:31:07,560 HYPOXIA THIS THESE CELLS 4028 02:31:07,560 --> 02:31:09,480 DIFFERENTIATED TO ERYTHROID 4029 02:31:09,480 --> 02:31:12,800 CELLS IN VITRO AND RETREATED TO 4030 02:31:12,800 --> 02:31:16,360 HYPOXIA. 4031 02:31:16,360 --> 02:31:19,080 WE LOOKED AGAIN EXTENSIVELY AT 4032 02:31:19,080 --> 02:31:20,800 OFF-TARGET SITES AND WITH PRIME 4033 02:31:20,800 --> 02:31:24,080 EDITING WE DID NOT OBSERVE ANY 4034 02:31:24,080 --> 02:31:25,160 BEYOND THAT OF AN UNTREATED 4035 02:31:25,160 --> 02:31:26,440 CONTROL SO WE WERE DELIGHTED TO 4036 02:31:26,440 --> 02:31:27,640 SEE THIS. 4037 02:31:27,640 --> 02:31:29,240 AND THE REASON WHY WE EXPECT 4038 02:31:29,240 --> 02:31:31,280 THIS TO BE THE CASE IS DUE TO 4039 02:31:31,280 --> 02:31:32,720 THE UNIQUE MECHANISM OF PRIME 4040 02:31:32,720 --> 02:31:34,280 EDITING THAT HAS NOW THREE 4041 02:31:34,280 --> 02:31:35,600 QUALITY CONTROL STEPS WHERE IT 4042 02:31:35,600 --> 02:31:38,560 CAN REJECT OFF-TARGET EDITING 4043 02:31:38,560 --> 02:31:40,080 OUTCOMES OF FIRST OF THESE BEING 4044 02:31:40,080 --> 02:31:43,960 WITH ANY CAS9 KNEW CLEE AIZ O 4045 02:31:43,960 --> 02:31:46,080 OR -- MISMATCHES REDUCE THE 4046 02:31:46,080 --> 02:31:47,680 EFFICIENCY OF THIS INTERACTION. 4047 02:31:47,680 --> 02:31:48,920 THE SECOND IS THE PRIMER BINDING 4048 02:31:48,920 --> 02:31:52,760 SITE, SO WE NEED A COMPLEMENTARY 4049 02:31:52,760 --> 02:31:55,080 SEQUENCE ON THE GUIDE RNA TO 4050 02:31:55,080 --> 02:31:57,960 ANIL TO THE TARGET SITE TO -- 4051 02:31:57,960 --> 02:31:59,680 ANY MISMATCHES HERE REALLY 4052 02:31:59,680 --> 02:32:00,920 REDUCE THE EFFICIENCY OF THIS. 4053 02:32:00,920 --> 02:32:02,240 ONCE YOU GET SYNTHESIS OF THE 4054 02:32:02,240 --> 02:32:04,440 NEW STRAND OF DNA, THERE'S AN 4055 02:32:04,440 --> 02:32:06,080 EQUILIBRATION BETWEEN THE 4056 02:32:06,080 --> 02:32:07,280 ENDOGENOUS SEQUENCE AND THE NEW 4057 02:32:07,280 --> 02:32:08,640 SEQUENCE WE'VE SYNTHESIZED AND 4058 02:32:08,640 --> 02:32:10,280 ANY MISMATCHES IN THE 4059 02:32:10,280 --> 02:32:11,280 SURROUNDING REGION CAN REJECT 4060 02:32:11,280 --> 02:32:15,040 THE EDITING OUT COME AT THIS 4061 02:32:15,040 --> 02:32:15,720 STAGE AS WELL. 4062 02:32:15,720 --> 02:32:18,560 ONLY THOSE WITH GOOD HOMOLOGY TO 4063 02:32:18,560 --> 02:32:20,240 THE TARGET -- THIS IS WHY WE 4064 02:32:20,240 --> 02:32:21,560 THINK THE EDITING WITH PRIME 4065 02:32:21,560 --> 02:32:23,520 EDITORS ARE SO EXCLUSIVELY 4066 02:32:23,520 --> 02:32:25,080 PRECISE. 4067 02:32:25,080 --> 02:32:27,120 SO TO SUMMARIZE WHAT I TOLD YOU, 4068 02:32:27,120 --> 02:32:28,920 WE USE BASE EDITING TO CONVERT 4069 02:32:28,920 --> 02:32:31,040 THE SICKLE CELL MUTATION TO 4070 02:32:31,040 --> 02:32:33,040 BENIGN MAKASSAR AND THIS 4071 02:32:33,040 --> 02:32:33,920 CONVERTED THE DISEASE MUTATION 4072 02:32:33,920 --> 02:32:36,200 TO THE HEALTHY ONE IN 80 TO 90% 4073 02:32:36,200 --> 02:32:38,440 OF DURABLY ENGRAFTED 4074 02:32:38,440 --> 02:32:39,200 HEMATOPOIETIC STEM CELLS IN 4075 02:32:39,200 --> 02:32:39,960 MICE. 4076 02:32:39,960 --> 02:32:41,800 WE ALSO USED PRIME EDITING TO 4077 02:32:41,800 --> 02:32:43,000 CONVERT THE SICKLE CELL MUTATION 4078 02:32:43,000 --> 02:32:44,960 BACK TO THE WILD TYPE ALLELE, 4079 02:32:44,960 --> 02:32:47,360 AND THESE ALSO REPOPULATED MOUSE 4080 02:32:47,360 --> 02:32:49,200 BONE MARROW 20 TO 60% 4081 02:32:49,200 --> 02:32:49,680 EFFICIENCY. 4082 02:32:49,680 --> 02:32:52,440 I EXPECT THAT THERE'S FURTHER 4083 02:32:52,440 --> 02:32:53,520 DEVELOPMENT ON BOTH OF THESE 4084 02:32:53,520 --> 02:32:55,240 PROCESSES TO GET MORE EFFICIENT 4085 02:32:55,240 --> 02:32:56,720 EDITING AND ALSO TO REDUCE 4086 02:32:56,720 --> 02:32:58,080 OFF-TARGET ID ITING IN THE CASE 4087 02:32:58,080 --> 02:32:59,560 OF A BASE EDITORS. 4088 02:32:59,560 --> 02:33:00,960 WE EMPLOYED THE STRONGEST BY FAR 4089 02:33:00,960 --> 02:33:02,160 KNOWN DEAMINASE AND BY 4090 02:33:02,160 --> 02:33:03,280 FINE-TUNING THAT, I THINK 4091 02:33:03,280 --> 02:33:05,320 THERE'S MORE THAN 20 DIFFERENT 4092 02:33:05,320 --> 02:33:05,840 VARIANTS THAT HAVE BEEN 4093 02:33:05,840 --> 02:33:07,720 PUBLISHED NOW, SO I THINK FUTURE 4094 02:33:07,720 --> 02:33:09,360 RESEARCH CAN FIND EVEN MORE 4095 02:33:09,360 --> 02:33:11,200 PRECISE AND STILL VERY EFFICIENT 4096 02:33:11,200 --> 02:33:13,880 EEDITING STRATEGIES TO IMPROVE 4097 02:33:13,880 --> 02:33:17,600 THESE OUTCOMES. 4098 02:33:17,600 --> 02:33:18,840 JUST HIGHLIGHTING THAT BOTH OF 4099 02:33:18,840 --> 02:33:21,160 THESE STRATEGIES CAN SUPPORT 4100 02:33:21,160 --> 02:33:25,680 HEALTHY MULTIPOTENT 4101 02:33:25,680 --> 02:33:26,640 HEMATOPOIETIC STEM CELLS. 4102 02:33:26,640 --> 02:33:28,080 LONG TERM FOLLOW-UP IS GOING TO 4103 02:33:28,080 --> 02:33:29,200 BE NEEDED TO COMPARE THESE AND 4104 02:33:29,200 --> 02:33:30,400 ALL THE OTHER ALTERNATIVE 4105 02:33:30,400 --> 02:33:32,560 THERAPIES AND REALLY FIND THE 4106 02:33:32,560 --> 02:33:33,520 BEST ONE. 4107 02:33:33,520 --> 02:33:35,200 LAST SLIDE IS MY ACKNOWLEDGMENTS 4108 02:33:35,200 --> 02:33:36,360 OF ALL THE MANY PEOPLE THAT 4109 02:33:36,360 --> 02:33:37,320 CONTRIBUTED TO THESE STUDIES. 4110 02:33:37,320 --> 02:33:40,240 I WANT TO THANK MITCH WEISS OUR 4111 02:33:40,240 --> 02:33:42,400 COLLABORATOR AT ST. JUDE AND 4112 02:33:42,400 --> 02:33:45,720 JONATHAN YEN, OUR POSTDOCTORAL 4113 02:33:45,720 --> 02:33:48,080 MENTOR WHO LED OUR TIME TEEM AND 4114 02:33:48,080 --> 02:33:51,240 KELSEY EVERETT, AND OTHERS WHO 4115 02:33:51,240 --> 02:33:52,120 COLLABORATED ON THESE STUDIES. 4116 02:33:52,120 --> 02:33:53,520 THANK YOU VERY MUCH. 4117 02:33:53,520 --> 02:33:57,320 >>THANK YOU, GREG. 4118 02:33:57,320 --> 02:33:59,720 WE'LL PROCEED TO THE NEXT TALK 4119 02:33:59,720 --> 02:34:00,840 AND HAVE MAYBE QUESTIONS AT THE 4120 02:34:00,840 --> 02:34:01,160 END. 4121 02:34:01,160 --> 02:34:04,080 SO THE NEXT TALK IS VIRTUAL BY 4122 02:34:04,080 --> 02:34:05,360 HANS-PETER KIEM, AND HE'LL BE 4123 02:34:05,360 --> 02:34:07,680 TALKING ABOUT IN VIVO GENE 4124 02:34:07,680 --> 02:34:10,720 EDITING TH AND GENE THERAPY FOR 4125 02:34:10,720 --> 02:34:11,160 SICKLE CELL DISEASE. 4126 02:34:11,160 --> 02:34:15,600 >>I HOPE YOU CAN HEAR ME OKAY? 4127 02:34:15,600 --> 02:34:16,560 >>WE CAN HEAR YOU. 4128 02:34:16,560 --> 02:34:17,520 >>GOOD MORNING. 4129 02:34:17,520 --> 02:34:19,880 THANKS FOR ALLOWING ANDRE AND ME 4130 02:34:19,880 --> 02:34:21,720 TO PRESENT OUR VISION HERE FOR 4131 02:34:21,720 --> 02:34:23,200 IN VIVO HEMATOPOIETIC STEM CELL 4132 02:34:23,200 --> 02:34:24,400 GENE THERAPY FOR SICKLE CELL 4133 02:34:24,400 --> 02:34:27,120 DISEASE. 4134 02:34:27,120 --> 02:34:30,440 NEXT SLIDE. 4135 02:34:30,440 --> 02:34:31,120 NEXT SLIDE. 4136 02:34:31,120 --> 02:34:32,640 THERE ARE MANY DISEASES AND 4137 02:34:32,640 --> 02:34:34,480 CONDITIONS THAT COULD BE 4138 02:34:34,480 --> 02:34:36,640 TARGETED BY HEMATOPOIETIC STEM 4139 02:34:36,640 --> 02:34:37,440 CELL GENE THERAPY AND SOME OF 4140 02:34:37,440 --> 02:34:40,160 THOSE ARE LISTED HERE, BUT OF 4141 02:34:40,160 --> 02:34:41,320 COURSE THE LARGEST POPULATIONS 4142 02:34:41,320 --> 02:34:42,520 ARE PATIENTS WITH SICKLE CELL 4143 02:34:42,520 --> 02:34:43,840 DISEASE OR THALASSEMIA, OR 4144 02:34:43,840 --> 02:34:45,360 PEOPLE LIVING WITH HIV. 4145 02:34:45,360 --> 02:34:48,480 NOW USING EX VIVO GENE THERAPY 4146 02:34:48,480 --> 02:34:49,800 APPROACHES, THERE'S BEEN 4147 02:34:49,800 --> 02:34:50,960 TREMENDOUS SUCCESS AS YOU'VE NOW 4148 02:34:50,960 --> 02:34:53,040 HEARD FROM A NUMBER OF 4149 02:34:53,040 --> 02:34:54,480 PRESENTATIONS HERE AND PREVIOUS 4150 02:34:54,480 --> 02:34:56,440 SPEAKERS USING EX VIVO GENE 4151 02:34:56,440 --> 02:34:59,880 THERAPY APPROACHES AND EDITING 4152 02:34:59,880 --> 02:35:02,520 APPROACHES. 4153 02:35:02,520 --> 02:35:03,520 HOWEVER, ACCESS TO THOSE 4154 02:35:03,520 --> 02:35:06,520 THERAPIES IS HIGHLY LIMITED AS 4155 02:35:06,520 --> 02:35:09,120 WE KNOW AND OF THE ABOUT 4156 02:35:09,120 --> 02:35:09,880 20 MILLION PEOPLE LIVING WITH 4157 02:35:09,880 --> 02:35:11,360 SICKLE CELL DISEASE GLOBALLY, 4158 02:35:11,360 --> 02:35:13,480 ONLY ABOUT 25,000 OR SO PATIENTS 4159 02:35:13,480 --> 02:35:16,240 COULD BE TREATED WITH CURRENT EX 4160 02:35:16,240 --> 02:35:18,520 VIVO GENE THERAPY-BASED 4161 02:35:18,520 --> 02:35:19,040 APPROACHES. 4162 02:35:19,040 --> 02:35:22,120 THIS IS ALSO BASED ON ESTIMATES 4163 02:35:22,120 --> 02:35:24,600 BY CRISPR VERTEX AND -- PROBABLY 4164 02:35:24,600 --> 02:35:26,240 ONLY ABOUT 1% PATIENTS LIVING 4165 02:35:26,240 --> 02:35:27,000 WITH SICKLE CELL DISEASE WOULD 4166 02:35:27,000 --> 02:35:27,880 HAVE ACCESS. 4167 02:35:27,880 --> 02:35:30,600 SO MAIN REASON IS -- THE MAIN 4168 02:35:30,600 --> 02:35:31,640 REASON IS THE COMPLEX NATURE OF 4169 02:35:31,640 --> 02:35:33,240 THE KURN EX VIVO GENE THERAPY 4170 02:35:33,240 --> 02:35:37,160 APPROACHES AND PROTOCOLS. 4171 02:35:37,160 --> 02:35:39,280 SO THIS JUST OUTLINES A LITTLE 4172 02:35:39,280 --> 02:35:40,920 BIT OF THE CURRENT OF COURSE EX 4173 02:35:40,920 --> 02:35:43,560 VIVO GENE THERAPY STUDIES, 4174 02:35:43,560 --> 02:35:46,800 ACTUALLY -- FAIRLY INTENSIVE 4175 02:35:46,800 --> 02:35:50,840 CARE AND SIMILAR TO ALLOGENEIC 4176 02:35:50,840 --> 02:35:51,760 TRANSPLANTATION, LENGTHY -- 4177 02:35:51,760 --> 02:35:53,360 FAIRLY LENGTHY HOSPITALIZATIONS 4178 02:35:53,360 --> 02:35:55,320 AND CLEARLY A SPECIALIZED 4179 02:35:55,320 --> 02:35:56,600 FACILITIES AND CLINICS TO BE 4180 02:35:56,600 --> 02:35:59,200 ABLE TO DELIVER THIS APPROACH. 4181 02:35:59,200 --> 02:36:01,880 NOW WE PROPOSE REALLY A -- 4182 02:36:01,880 --> 02:36:05,400 HOPEFULLY A TRUE OFF THE 4183 02:36:05,400 --> 02:36:07,240 SHELF-TYPE ADMINISTRATION OF 4184 02:36:07,240 --> 02:36:09,840 THIS GENE THERAPY WITH A SINK EL 4185 02:36:09,840 --> 02:36:11,680 SHOT, HOPEFULLY AGAIN ULTIMATELY 4186 02:36:11,680 --> 02:36:15,160 AS AN OUTPATIENT TREATMENT 4187 02:36:15,160 --> 02:36:17,120 WITHOUT TOXIC PRECONDITIONING OR 4188 02:36:17,120 --> 02:36:23,640 PRE-TREATMENT. 4189 02:36:23,640 --> 02:36:29,000 SO TO ACCOMPLISH THIS, ANDRE AND 4190 02:36:29,000 --> 02:36:31,640 I HAVE BEEN COLLABORATING TO USE 4191 02:36:31,640 --> 02:36:35,760 A CAPSID-MODIFIED 4192 02:36:35,760 --> 02:36:37,160 HELPER-DEPENDENT ADENOVIRUS 4193 02:36:37,160 --> 02:36:38,840 VECTORS REALLY DEVELOPED BY AN 4194 02:36:38,840 --> 02:36:41,400 DREE LIEBER IN HIS LAB. 4195 02:36:41,400 --> 02:36:42,240 THE BASIC COMPONENTS OF THE 4196 02:36:42,240 --> 02:36:43,160 APPROACH ARE LISTED HERE. 4197 02:36:43,160 --> 02:36:44,960 THIS CAPSID IS LIKE A TROJAN 4198 02:36:44,960 --> 02:36:46,480 HORSE, ALL THE VIRAL GENES HAVE 4199 02:36:46,480 --> 02:36:48,120 BEEN REMOVED, WHICH ALLOWS US 4200 02:36:48,120 --> 02:36:51,360 NOW TO HAVE LIKE A 35KB CAPACITY 4201 02:36:51,360 --> 02:36:54,000 FOR TRANS GENES AND REGULATORS 4202 02:36:54,000 --> 02:36:55,880 OR ADDITIONAL COMPONENTS TO 4203 02:36:55,880 --> 02:36:57,720 INCORPORATE IN THIS TRANSFER 4204 02:36:57,720 --> 02:36:58,480 VECTOR. 4205 02:36:58,480 --> 02:37:01,640 THE FIBER KNOB CAN BE MODIFIED 4206 02:37:01,640 --> 02:37:04,680 OOR REPLACED AND CHANGED SO THE 4207 02:37:04,680 --> 02:37:07,720 CURRENT FIBER KNOB THAT WE HAVE 4208 02:37:07,720 --> 02:37:09,920 HAS HIGH AFFINITY TO CD46, WHICH 4209 02:37:09,920 --> 02:37:11,600 IS HIGHLY EXPRESSED IN 4210 02:37:11,600 --> 02:37:12,400 HEMATOPOIETIC STEM CELLS AND 4211 02:37:12,400 --> 02:37:13,800 OTHER BLOOD CELLS. 4212 02:37:13,800 --> 02:37:17,960 NOW, WITH THIS, WE CAN HAVE 4213 02:37:17,960 --> 02:37:19,400 EFFICIENT HEMATOPOIETIC STEM 4214 02:37:19,400 --> 02:37:20,560 CELL TRANSDUCTION, ESPECIALLY 4215 02:37:20,560 --> 02:37:23,080 THESE EARLY CD90 POSITIVE CELLS. 4216 02:37:23,080 --> 02:37:25,560 THERE'S MINIMAL HEPATOCYTE 4217 02:37:25,560 --> 02:37:26,480 TRANSDUCTION AS I WILL SHOW YOU 4218 02:37:26,480 --> 02:37:28,720 IN THE NEXT SLIDE AS WELL WITH 4219 02:37:28,720 --> 02:37:30,120 THIS FIBER MODIFICATION THAT 4220 02:37:30,120 --> 02:37:31,200 WE'VE INCORPORATED. 4221 02:37:31,200 --> 02:37:33,560 NOW OF COURSE THERE CAN BE 4222 02:37:33,560 --> 02:37:34,680 OTHER -- OTHER CAPSIDS CAN BE 4223 02:37:34,680 --> 02:37:39,400 USED AS WELL, AND ONE -- SEVERAL 4224 02:37:39,400 --> 02:37:40,320 ADDITIONAL ADVANTAGES ARE 4225 02:37:40,320 --> 02:37:42,000 THERE'S AN EP SOMOL VECTOR 4226 02:37:42,000 --> 02:37:44,400 SYSTEM SO WE CAN USE BASE AND 4227 02:37:44,400 --> 02:37:47,480 PRIME EDITORS, WE CAN USE AN 4228 02:37:47,480 --> 02:37:47,920 INTEGRATING SYSTEM. 4229 02:37:47,920 --> 02:37:49,880 I WILL SHOW YOU THIS USING A 4230 02:37:49,880 --> 02:37:52,880 SLEEPING BEAUTY TRANS POSASE SO 4231 02:37:52,880 --> 02:37:56,400 WE CAN INTEGRATE THE PAIR OR WE 4232 02:37:56,400 --> 02:37:58,720 CAN AGAIN SIMPLY USE ONE VECTOR 4233 02:37:58,720 --> 02:38:02,360 SYSTEM TO DELIVER BASE -- 4234 02:38:02,360 --> 02:38:03,680 IMPORTANTLY IT'S SIMPLE, 4235 02:38:03,680 --> 02:38:05,680 SCALABLE, IT ALLOW FOR SIMPLE 4236 02:38:05,680 --> 02:38:08,360 AND SCALABLE MANUFACTURING TO 4237 02:38:08,360 --> 02:38:14,200 HOPEFULLY ENABLE GLOBAL REACH. 4238 02:38:14,200 --> 02:38:15,600 SO HERE AGAIN YOU CAN SEE AN 4239 02:38:15,600 --> 02:38:18,920 EXAMPLE FROM MOUSE STUDIES AT 4240 02:38:18,920 --> 02:38:26,120 HOW THIS AD35 FIBER IS TARGETING 4241 02:38:26,120 --> 02:38:26,880 THE LIVER. 4242 02:38:26,880 --> 02:38:28,360 ON THE RIGHT-HAND SIDE YOU SEE 4243 02:38:28,360 --> 02:38:30,240 THERE'S NO LIVER ENZYME 4244 02:38:30,240 --> 02:38:32,720 ABNORMALITIES WHEN WE USE THIS 4245 02:38:32,720 --> 02:38:39,360 AT 35 FIBER. 4246 02:38:39,360 --> 02:38:42,360 SO HERE WE SEE THE DIFFERENT 4247 02:38:42,360 --> 02:38:43,880 PLATFORMS AS WE MENTIONED. 4248 02:38:43,880 --> 02:38:48,120 YOU SEE THE TWO VECTOR SYSTEM, 4249 02:38:48,120 --> 02:38:49,760 ADDITIONAL VECTOR TO FACILITATE 4250 02:38:49,760 --> 02:38:53,320 THE INTEGRATION OF THE PAYLOAD 4251 02:38:53,320 --> 02:38:59,520 OR HE WI WE CAN SIMPLY USE A 4252 02:38:59,520 --> 02:39:01,320 NON-INTEGRATING AND USE A PRIME 4253 02:39:01,320 --> 02:39:06,720 OR BASE EDITOR. 4254 02:39:06,720 --> 02:39:08,360 HERE'S A GENERAL OUTLINE HOW WE 4255 02:39:08,360 --> 02:39:11,280 DO THESE STUDIES IN OUR MOUSE 4256 02:39:11,280 --> 02:39:12,160 MODELS IN SICKLE CELL DISEASE 4257 02:39:12,160 --> 02:39:13,440 AND THALASSEMIA. 4258 02:39:13,440 --> 02:39:18,200 LIKE WE WOULD ENVISION IT IN 4259 02:39:18,200 --> 02:39:21,680 HUMANS, WE MODIFY THE BLOOD 4260 02:39:21,680 --> 02:39:27,120 YELLS IN THE BLOODSTREAM WITH D 4261 02:39:27,120 --> 02:39:30,000 CELLS IN THE BLOOD STWREEM. 4262 02:39:30,000 --> 02:39:32,600 FOR FURTHER ENRICHMENT IN VIVO, 4263 02:39:32,600 --> 02:39:33,920 AFTER THE INITIAL VECTORED A 4264 02:39:33,920 --> 02:39:35,480 STRAITION, AND THEN OF COURSE TO 4265 02:39:35,480 --> 02:39:40,000 CONFIRM THAT, WE REALLY -- TO 4266 02:39:40,000 --> 02:39:41,080 HEMATOPOIETIC STEM CELL, WE ALSO 4267 02:39:41,080 --> 02:39:45,360 LOOK AT SECONDARY TRANSPLANTS IN 4268 02:39:45,360 --> 02:39:47,880 MICE. 4269 02:39:47,880 --> 02:39:49,360 THIS HERE NOW SHOWS THE APPROACH 4270 02:39:49,360 --> 02:39:52,000 WITH AN INTEGRATING VECTOR 4271 02:39:52,000 --> 02:39:56,880 SYSTEM TO CURE A MOUSE MODEL OF 4272 02:39:56,880 --> 02:40:02,040 THALASSEMIA -- MEDIA. 4273 02:40:02,040 --> 02:40:04,080 ABOVE GAMMA GLOBIN DRIVEN BY A 4274 02:40:04,080 --> 02:40:06,280 LARGE PROMOTER AND THE SELECTION 4275 02:40:06,280 --> 02:40:08,560 CASSETTE THAT ALLOWS US TO 4276 02:40:08,560 --> 02:40:10,640 ENRICH IN VIVO AND THEN TO 4277 02:40:10,640 --> 02:40:13,040 INTEGRATE THIS CONSTRUCT, WE 4278 02:40:13,040 --> 02:40:16,040 CO-ADMINISTER THIS SLEEPING 4279 02:40:16,040 --> 02:40:21,840 BEAUTY TRANSPOSASE. 4280 02:40:21,840 --> 02:40:23,920 WE FURTHER ENRICH WITH THIS 4281 02:40:23,920 --> 02:40:25,520 ENRICH CH STRATEGY, WE CAN 4282 02:40:25,520 --> 02:40:26,800 TITRATE UCH THE MODIFICATION 4283 02:40:26,800 --> 02:40:28,800 LEVELS TO HOPEFULLY THEN, IF 4284 02:40:28,800 --> 02:40:30,520 NECESSARY, GET INTO A 4285 02:40:30,520 --> 02:40:31,920 THERAPEUTIC RANGE FOR PATIENTS. 4286 02:40:31,920 --> 02:40:34,320 THE GENE MODIFICATION IS STABLE. 4287 02:40:34,320 --> 02:40:35,840 ON THE RIGHT-HAND SIDE WE SHOW 4288 02:40:35,840 --> 02:40:38,560 THE SECONDARY TRANSPLANTS AND WE 4289 02:40:38,560 --> 02:40:40,520 SEE PHENOTYPIC CORRECTION IN 4290 02:40:40,520 --> 02:40:46,520 THESE MICE WITH MARKEDLY IMPR 4291 02:40:46,520 --> 02:40:49,480 IMPROVED SPLEEN SIZES, POINT OUT 4292 02:40:49,480 --> 02:40:51,880 THIS IS HIGHLY POLYCLONAL IN 4293 02:40:51,880 --> 02:40:52,560 THESE MICE. 4294 02:40:52,560 --> 02:40:55,120 NOW HERE'S AN EXAMPLE OF A 4295 02:40:55,120 --> 02:40:56,640 SINGLE VECTOR TO DELIVER A BASE 4296 02:40:56,640 --> 02:40:57,080 EDITOR. 4297 02:40:57,080 --> 02:41:00,560 SO I'M GLAD WE'VE HEARD FROM 4298 02:41:00,560 --> 02:41:02,440 MITCH AND GREG ABOUT BASE AND 4299 02:41:02,440 --> 02:41:03,400 PRIME EDITING. 4300 02:41:03,400 --> 02:41:07,160 WHERE WE CAN SIMPLY DELIVER A 4301 02:41:07,160 --> 02:41:09,520 BASE EDITOR AND THE BASE EDITOR 4302 02:41:09,520 --> 02:41:11,680 WE USED HERE IS VERY SIMPLE TO 4303 02:41:11,680 --> 02:41:14,400 DISRUPT THE BCLA11 BINDING SITE 4304 02:41:14,400 --> 02:41:17,760 AS YOU'VE HEARD AGAIN FROM MITCH 4305 02:41:17,760 --> 02:41:21,320 TO PRETTY MUCH RE-CREATE THE 4306 02:41:21,320 --> 02:41:22,760 HEREDITARY PERSISTENCE OF FETAL 4307 02:41:22,760 --> 02:41:24,520 HEMOGLOBIN STATUS IN THESE MICE. 4308 02:41:24,520 --> 02:41:26,560 AND THE VECTOR AGAIN THE SINGLE 4309 02:41:26,560 --> 02:41:28,400 VECTOR SHOWN AGAIN BELOW. 4310 02:41:28,400 --> 02:41:31,240 IT DOES INCLUDE AGAIN THIS 4311 02:41:31,240 --> 02:41:32,480 ENRICHMENT CASSETTE WHERE WE 4312 02:41:32,480 --> 02:41:34,720 COULD EARLY ON ENRICH FOR THESE 4313 02:41:34,720 --> 02:41:41,280 MODIFIED CELLS DIRECTLY IN VIVO. 4314 02:41:41,280 --> 02:41:44,640 NOW THIS HERE SHOWS WHERE WE CAN 4315 02:41:44,640 --> 02:41:46,600 SEE NOW IN THE EXAMPLE OF THIS 4316 02:41:46,600 --> 02:41:48,880 VECTOR, WE CAN SEE THE 4317 02:41:48,880 --> 02:41:50,960 EFFICIENCY ON THE RIGHT-HAND 4318 02:41:50,960 --> 02:41:51,280 SIDE. 4319 02:41:51,280 --> 02:41:54,400 WE SAW EDITING FAIRLY EFFICIENT 4320 02:41:54,400 --> 02:41:57,720 IN THE MINUS 113 SITE, WHICH 4321 02:41:57,720 --> 02:41:59,480 OFFICIALLY INCREASES THE GAMMA 4322 02:41:59,480 --> 02:42:02,520 GLOBIN POSITIVE -- CELLS AS 4323 02:42:02,520 --> 02:42:03,600 SHOWN HERE, AS YOU MOVE TO THE 4324 02:42:03,600 --> 02:42:05,400 RIGHT THERE, WITH AGAIN VERY LOW 4325 02:42:05,400 --> 02:42:09,400 LEVELS OF INDELS AND NO OFF 4326 02:42:09,400 --> 02:42:10,240 TARGET EDITING. 4327 02:42:10,240 --> 02:42:11,880 WE'VE ALSO SHOWN SIMILAR 4328 02:42:11,880 --> 02:42:15,360 EFFICACY NOW ALSO WITH EDITING 4329 02:42:15,360 --> 02:42:17,560 THE 1 MINUS 75 SITE WHICH YOU'VE 4330 02:42:17,560 --> 02:42:22,480 JUST HEARD ABOUT FROM MITCH. 4331 02:42:22,480 --> 02:42:23,560 NOW IN COLLABORATION WITH THE 4332 02:42:23,560 --> 02:42:26,080 DAVID LU LAB, WE'VE ALSO USED A 4333 02:42:26,080 --> 02:42:27,720 PRIME EDITOR TO DIRECTLY CORRECT 4334 02:42:27,720 --> 02:42:28,560 THE SICKLE CELL DISEASE 4335 02:42:28,560 --> 02:42:28,920 MUTATION. 4336 02:42:28,920 --> 02:42:31,800 NOW BECAUSE OF THE LARGE PACKAGE 4337 02:42:31,800 --> 02:42:34,560 CAPACITY OF OUR VECTOR, WE COULD 4338 02:42:34,560 --> 02:42:36,400 DELIVER A VERY HIGHLY OPTIMIZED 4339 02:42:36,400 --> 02:42:37,600 16KB PRIME EDITOR DEVELOPED BY 4340 02:42:37,600 --> 02:42:40,560 THE LU LAB TO FIX THE SICKLE 4341 02:42:40,560 --> 02:42:46,600 CELL DISEASE MUTATION IN THE C 4342 02:42:46,600 --> 02:42:47,760 CD46/TOWNES MICE AND I'LL SHOW 4343 02:42:47,760 --> 02:42:48,840 YOU RESULT IN ONE SLIDE. 4344 02:42:48,840 --> 02:42:49,920 THIS IS AGAIN THE RESULTS. 4345 02:42:49,920 --> 02:42:51,880 YOU CAN SEE THE EFFICIENCY OF 4346 02:42:51,880 --> 02:42:54,600 THE PRIME EDITING IN VIVO, SO 4347 02:42:54,600 --> 02:42:56,800 PRIME EDITING IN PERIPHERAL 4348 02:42:56,800 --> 02:42:59,920 BLOOD AFTER ININ VIVO GENE 4349 02:42:59,920 --> 02:43:03,120 MODIFICATION BY SEQUENCING AND T 4350 02:43:03,120 --> 02:43:07,480 TO A CONVERSION RATE WHICH -- 4351 02:43:07,480 --> 02:43:09,960 ABOUT 44% AT WEEK 16, WE ALSO 4352 02:43:09,960 --> 02:43:12,400 SAW EFFICIENT CORRECTION ON THE 4353 02:43:12,400 --> 02:43:14,960 PRONE LEVEL, ON THE RIGHT-HAND 4354 02:43:14,960 --> 02:43:17,200 SIDE, THEY'RE -- THE AVERAGE WE 4355 02:43:17,200 --> 02:43:19,800 SAW ABOUT 43% CORRECTION THERE. 4356 02:43:19,800 --> 02:43:21,240 WE ALSO SAW SIGNIFICANT 4357 02:43:21,240 --> 02:43:24,040 REDUCTION IN SICKLING IN THE 4358 02:43:24,040 --> 02:43:24,960 PERIPHERAL BLOOD SPLEENS AND 4359 02:43:24,960 --> 02:43:26,760 ALSO THE SPLEEN SIZES AS YOU CAN 4360 02:43:26,760 --> 02:43:32,120 SEE IN THE RIGHT LOWER SIDE. 4361 02:43:32,120 --> 02:43:35,000 NOW THIS IN VIVO ENRICHMENT HAS 4362 02:43:35,000 --> 02:43:37,240 BEEN DONE WITH A LOW DOSE OF 4363 02:43:37,240 --> 02:43:37,720 CHEMOTHERAPY. 4364 02:43:37,720 --> 02:43:39,440 OF COURSE YOU'VE HEARD A LOT OF 4365 02:43:39,440 --> 02:43:40,520 ANTIBODY-BASED CONDITIONING, AND 4366 02:43:40,520 --> 02:43:42,240 THIS IS EXACTLY ULTIMATELY WHAT 4367 02:43:42,240 --> 02:43:44,560 WE'D LIKE TO USE FOR IN VIVO 4368 02:43:44,560 --> 02:43:47,160 ENRICHMENT AS WELL, SO REPLEASE 4369 02:43:47,160 --> 02:43:52,720 ANY CHEMO -- THISIS JUST AN EXAN 4370 02:43:52,720 --> 02:43:55,240 MULTIPLEX WITH BASE EDITING TO 4371 02:43:55,240 --> 02:43:57,200 REALLY FACILITATE ANTIBODY-BASED 4372 02:43:57,200 --> 02:43:59,960 IN VIVO ENRICHMENT, SO WE MODIFY 4373 02:43:59,960 --> 02:44:03,080 THE STEM CELLS TO NOT BIND THE 4374 02:44:03,080 --> 02:44:04,080 PARTICULAR ANTIBODY THAT WE 4375 02:44:04,080 --> 02:44:06,280 WOULD USE FOR IN VIVO SELECTION 4376 02:44:06,280 --> 02:44:06,480 THEN. 4377 02:44:06,480 --> 02:44:09,640 HERE IS AN EXAMPLE SH, WE KNOCK 4378 02:44:09,640 --> 02:44:11,920 OUT CD33 AND AT THE SAME TIME 4379 02:44:11,920 --> 02:44:13,760 EDIT FOR FETAL HEMOGLOBIN 4380 02:44:13,760 --> 02:44:17,440 REACTIVATION AND SO WE CAN 4381 02:44:17,440 --> 02:44:19,000 MODIFY THESE CELLS IN VIVO 4382 02:44:19,000 --> 02:44:21,080 DIRECTLY AND THEN ENRICH FOR THE 4383 02:44:21,080 --> 02:44:22,520 MODIFIED CELLS USING ANTIBODY 4384 02:44:22,520 --> 02:44:23,200 BASED APPROACH. 4385 02:44:23,200 --> 02:44:25,320 AGAIN, THIS WAS DONE WITH 4386 02:44:25,320 --> 02:44:26,280 CD33 BUT OF COURSE WE'RE ALSO 4387 02:44:26,280 --> 02:44:33,280 LOOKING INTO CD117. 4388 02:44:33,280 --> 02:44:35,560 WE'VE TRANSLATED THIS INTO 4389 02:44:35,560 --> 02:44:37,440 NON-HUMAN PRIMATE STUDIES VERY 4390 02:44:37,440 --> 02:44:38,760 EFFICIENTLY. 4391 02:44:38,760 --> 02:44:40,520 WE'VE DONE PROBABLY ABOUT 20 4392 02:44:40,520 --> 02:44:44,640 MONKEYS WITH A SHORT TWO-DAY 4393 02:44:44,640 --> 02:44:45,600 IMMUNOSUPPRESSIVE REGIMEN. 4394 02:44:45,600 --> 02:44:47,360 WE'VE BEEN ABLE TO ADMINISTER 4395 02:44:47,360 --> 02:44:50,000 THIS SAFELY TO THESE PRIMATES 4396 02:44:50,000 --> 02:44:51,720 AND THIS IS JUST WHAT YOU SEE 4397 02:44:51,720 --> 02:44:54,080 DURING THE SLIDE IS THE 4398 02:44:54,080 --> 02:44:55,160 IL-6 LEVELS. 4399 02:44:55,160 --> 02:44:58,360 AGAIN, ALL THESE HAVE TOLERATED 4400 02:44:58,360 --> 02:45:03,200 THIS DELIVERY, VERY SAFELY WITH 4401 02:45:03,200 --> 02:45:05,040 ESSENTIALLY NO LIVER FUNCTION 4402 02:45:05,040 --> 02:45:06,760 ABNORMALITIES AND AGAIN NO 4403 02:45:06,760 --> 02:45:08,440 CYTOKINE REACTIVATION. 4404 02:45:08,440 --> 02:45:09,680 >>WE NEED TO WRAP IT UP. 4405 02:45:09,680 --> 02:45:12,720 >>THAT'S IT. 4406 02:45:12,720 --> 02:45:14,160 AND THESE ARE JUST OF COURSE THE 4407 02:45:14,160 --> 02:45:14,720 ACKNOWLEDGMENT HERE. 4408 02:45:14,720 --> 02:45:16,040 I'D LIKE TO THANK EVERYBODY 4409 02:45:16,040 --> 02:45:16,320 INVOLVED. 4410 02:45:16,320 --> 02:45:21,480 OF COURSE ESPECIALLY ANDRE 4411 02:45:21,480 --> 02:45:23,000 LIEBER AND HIS LAB WHOSE 4412 02:45:23,000 --> 02:45:24,520 PERFORMED MOST OF THESE STUDIES 4413 02:45:24,520 --> 02:45:26,240 AND SOME PEOPLE FROM MY LAB, 4414 02:45:26,240 --> 02:45:27,440 WE'VE COLLABORATED ON THIS FOR A 4415 02:45:27,440 --> 02:45:28,600 NUMBER OF YEARS, AND OF COURSE 4416 02:45:28,600 --> 02:45:30,400 THE OTHER COLLABORATORS, AND 4417 02:45:30,400 --> 02:45:31,400 ALSO THE FUNDING SOURCES AND I 4418 02:45:31,400 --> 02:45:34,800 SHOULD ALSO SAY ANDRE AND I ARE 4419 02:45:34,800 --> 02:45:37,680 CO-FOUNDERS OF ENSOMA, A COMPANY 4420 02:45:37,680 --> 02:45:38,480 THAT DEVELOPS THIS PARTICULAR 4421 02:45:38,480 --> 02:45:40,120 PLATFORM. 4422 02:45:40,120 --> 02:45:40,680 >>GREAT. 4423 02:45:40,680 --> 02:45:47,120 THANK YOU, HANS-PETER. 4424 02:45:47,120 --> 02:45:51,480 SO NOW WE HAVE THE LAST SPEAKER 4425 02:45:51,480 --> 02:46:01,040 WHO'S MATTHEW SPEAKING VIRTUA 4426 02:46:01,040 --> 02:46:01,520 VIRTUALLY. 4427 02:46:01,520 --> 02:46:04,080 IF WE HAVE TIME WE'LL HAVE A FEW 4428 02:46:04,080 --> 02:46:04,560 QUESTIONS AT THE END. 4429 02:46:04,560 --> 02:46:06,720 WE'LL GO AHEAD WITH MATT'S TALK. 4430 02:46:06,720 --> 02:46:07,800 ARE YOU THERE, MATT? 4431 02:46:07,800 --> 02:46:11,280 >>I AM. 4432 02:46:11,280 --> 02:46:12,920 THANKS FOR INVITING ME TO JOIN 4433 02:46:12,920 --> 02:46:14,480 THIS SESSION WHICH REALLY HAS 4434 02:46:14,480 --> 02:46:15,960 GIVEN A GREAT REVIEW OF THE 4435 02:46:15,960 --> 02:46:17,240 EXCITING NUMBER OF APPROACHES TO 4436 02:46:17,240 --> 02:46:18,360 SICKLE CELL DISEASE AND I'LL 4437 02:46:18,360 --> 02:46:19,800 CONCLUDE BY TALKING ABOUT 4438 02:46:19,800 --> 02:46:22,600 HOMOLOGY DIRECTOR REPAIR 4439 02:46:22,600 --> 02:46:23,200 EDITING. 4440 02:46:23,200 --> 02:46:25,480 MITCH GAVE A BRIEF SHOUT OUT 4441 02:46:25,480 --> 02:46:26,360 EARLIER. 4442 02:46:26,360 --> 02:46:27,840 I'LL JUST NOTE THAT PROBABLY 4443 02:46:27,840 --> 02:46:30,920 MAYBE MANY OF YOU DON'T REALIZE 4444 02:46:30,920 --> 02:46:35,160 THAT HDR EDITING WAS ACTUALLY 4445 02:46:35,160 --> 02:46:40,960 THE FIRST NOBEL PRIZE, I BECAUSE 4446 02:46:40,960 --> 02:46:42,200 OTHERS WON A NOBEL PRIZE FOR 4447 02:46:42,200 --> 02:46:44,840 WHAT WAS CALLED GENE TARGETING 4448 02:46:44,840 --> 02:46:49,000 WHICH IS HDR EDITING FOR -- STEM 4449 02:46:49,000 --> 02:46:52,320 CELLS. 4450 02:46:52,320 --> 02:46:53,760 HERE ARE MY POTENTIAL CONFLICTS 4451 02:46:53,760 --> 02:46:54,560 OF INTEREST. 4452 02:46:54,560 --> 02:46:56,320 THE MOST RELEVANT OF WHICH IS 4453 02:46:56,320 --> 02:46:58,520 GRAPHITE BIO, WHICH I'LL EXPLAIN 4454 02:46:58,520 --> 02:47:00,680 LATER. 4455 02:47:00,680 --> 02:47:04,280 SO WE'RE INTERESTED IN, AS HAS 4456 02:47:04,280 --> 02:47:06,360 BEEN MENTIONED BEFORE, DIRECTLY 4457 02:47:06,360 --> 02:47:11,840 REVERTING THE PATHOLOGIC -- OF 4458 02:47:11,840 --> 02:47:15,840 THE BETA GLOBIN GENE BACK TO THE 4459 02:47:15,840 --> 02:47:17,040 HEMOGLOBIN VERSION IN POSITION 4460 02:47:17,040 --> 02:47:19,800 TO CODON 6 OF THE BETA GLOBIN 4461 02:47:19,800 --> 02:47:20,280 GENE. 4462 02:47:20,280 --> 02:47:21,560 I'M NOT GOING TO GO THROUGH ALL 4463 02:47:21,560 --> 02:47:23,800 OF THE PATHOPHYSIOLOGY OF SICKLE 4464 02:47:23,800 --> 02:47:24,520 CELL DISEASE BECAUSE THIS 4465 02:47:24,520 --> 02:47:27,720 AUDIENCE KNOWS IT WELL. 4466 02:47:27,720 --> 02:47:30,240 AND SO THE SYSTEM WE USE IS A 4467 02:47:30,240 --> 02:47:31,640 SYSTEM THAT HAS TAKEN MANY YEARS 4468 02:47:31,640 --> 02:47:32,880 TO DEVELOP. 4469 02:47:32,880 --> 02:47:35,680 IT'S AN EX VIVO SYSTEM IN WHICH 4470 02:47:35,680 --> 02:47:37,200 CD34 CELLS ARE PURIFIED. 4471 02:47:37,200 --> 02:47:40,400 WE THEN PUT THEM INTO CELL 4472 02:47:40,400 --> 02:47:43,200 DIVISION BECAUSE HDR PROCESS IS 4473 02:47:43,200 --> 02:47:45,760 ACTIVE DURING SNG2 OF THE CELL 4474 02:47:45,760 --> 02:47:46,400 CYCLE. 4475 02:47:46,400 --> 02:47:49,040 WE DEVELOP OUR CRISPR/CAS 4476 02:47:49,040 --> 02:47:51,520 9 NUCLEASE AS A COLLECTION USING 4477 02:47:51,520 --> 02:47:55,040 A PURIFIED HIGH FIDELITY FORM OF 4478 02:47:55,040 --> 02:47:59,280 CAS9, COMPLEX TO A SI SYNTHETIC 4479 02:47:59,280 --> 02:47:59,920 GUIDE RNA. 4480 02:47:59,920 --> 02:48:01,960 WE THEN HAVE TO DELIVER OUR 4481 02:48:01,960 --> 02:48:03,320 DONOR TEMPLATE IN A WAY THAT 4482 02:48:03,320 --> 02:48:06,240 DOES NOT ACTIVATE THE TYPE 4483 02:48:06,240 --> 02:48:08,960 1 INTERFERON SYSTEM, AND WE HAVE 4484 02:48:08,960 --> 02:48:11,600 FOUND THAT AAV6, A 4485 02:48:11,600 --> 02:48:12,880 NON-INTEGRATING NATURALLY 4486 02:48:12,880 --> 02:48:17,400 OCCURRING VIRUS, CAN INFECT OR 4487 02:48:17,400 --> 02:48:19,560 TRANSDUCE CD34 CELLS WITHOUT 4488 02:48:19,560 --> 02:48:22,160 ACTIVATING THE TYPE 1 INTERFERON 4489 02:48:22,160 --> 02:48:23,680 SYSTEM. 4490 02:48:23,680 --> 02:48:27,080 USING -- SORRY. 4491 02:48:27,080 --> 02:48:30,040 THIS TRANSDUCTION OF AAV6 IS 4492 02:48:30,040 --> 02:48:32,880 ENHANCED BY ELECTROPORATING THE 4493 02:48:32,880 --> 02:48:34,840 CELLS WITHIN 15 TO 20 MINUTES OF 4494 02:48:34,840 --> 02:48:35,800 ADDING THE VIRUS. 4495 02:48:35,800 --> 02:48:37,640 AND USING THIS SYSTEM IN A WIDE 4496 02:48:37,640 --> 02:48:40,360 VARIETY OF CELL TYPES, WE CAN 4497 02:48:40,360 --> 02:48:43,520 ACHIEVE 40, 60 AND EVEN 80% 4498 02:48:43,520 --> 02:48:45,600 TARGETED INTEGRATION OR GENE 4499 02:48:45,600 --> 02:48:47,240 CORRECTION IN A WIDE VARIETY OF 4500 02:48:47,240 --> 02:48:53,680 CELL TYPES. 4501 02:48:53,680 --> 02:48:55,440 SO USING THIS SYSTEM AND A LARGE 4502 02:48:55,440 --> 02:48:58,200 TEAM OF PEOPLE PUBLISHED IN TWO 4503 02:48:58,200 --> 02:48:59,480 PAPERS, ONE IN 2016 AND THEN 4504 02:48:59,480 --> 02:49:01,720 MORE RECENTLY IN 2021, WE WERE 4505 02:49:01,720 --> 02:49:05,560 ABLE TO SHOW THAT IN CD34 CELLS 4506 02:49:05,560 --> 02:49:06,960 DERIVED FROM SICKLE CELL DISEASE 4507 02:49:06,960 --> 02:49:10,440 PATIENTS, WE COULD ACHIEVE 60 TO 4508 02:49:10,440 --> 02:49:12,560 70% ALLELE CORRECTION USING THE 4509 02:49:12,560 --> 02:49:14,600 SYSTEM I DESCRIBED BEFORE AND 4510 02:49:14,600 --> 02:49:18,720 USING A DOLE DONOR VECTOR THATD 4511 02:49:18,720 --> 02:49:20,080 OF COURSE CORRECT THE SICKLE 4512 02:49:20,080 --> 02:49:24,080 CELL CAUSING VARIANT, BUT ALSO 4513 02:49:24,080 --> 02:49:25,480 INTRODUCE SILENT SYNONYMOUS 4514 02:49:25,480 --> 02:49:27,160 CHANGES TO PREVENT RECUTTING OF 4515 02:49:27,160 --> 02:49:28,440 THE GENE AFTER CORRECTION 4516 02:49:28,440 --> 02:49:29,960 OCCURRED AND TO FACILITATE HIGH 4517 02:49:29,960 --> 02:49:33,880 FREQUENCIES OF HDR. 4518 02:49:33,880 --> 02:49:35,760 AND WHEN THESE CELLS ARE 4519 02:49:35,760 --> 02:49:37,280 DIFFERENTIATED INTO RED BLOOD 4520 02:49:37,280 --> 02:49:40,320 CELLS IN VITRO, WHAT YOU SEE IS 4521 02:49:40,320 --> 02:49:42,520 THAT INSTEAD OF COMPENSATING FOR 4522 02:49:42,520 --> 02:49:46,680 HEMOGLOBIN S, WE'RE DIRECTLY 4523 02:49:46,680 --> 02:49:48,200 REPLACING THE PATHOLOGIC 4524 02:49:48,200 --> 02:49:51,160 HEMOGLOBIN S WITH A 4525 02:49:51,160 --> 02:49:53,120 NON-PATHOLOGIC HEMOGLOBIN A AND 4526 02:49:53,120 --> 02:49:54,560 AFTER DIFFERENTIATION HAVE CLOSE 4527 02:49:54,560 --> 02:49:56,600 TO 60 TO 80% HEMOGLOBIN A, A 4528 02:49:56,600 --> 02:49:59,440 LITTLE BIT OF HEMOGLOBIN S, AND 4529 02:49:59,440 --> 02:50:02,400 ALMOST NO HEMOGLOBIN S, SO IT'S 4530 02:50:02,400 --> 02:50:07,560 REALLY A REPLACEMENT STRATEGY 4531 02:50:07,560 --> 02:50:08,880 IN -- TO A CORRECTION STRATEGY. 4532 02:50:08,880 --> 02:50:10,080 SO THE FIRST PATIENT WAS DOSED 4533 02:50:10,080 --> 02:50:13,680 JUST A LITTLE OVER A YEAR AGO. 4534 02:50:13,680 --> 02:50:17,480 WITH CELLS AUTOLOGOUS 4535 02:50:17,480 --> 02:50:18,120 4X4 MOBILIZED CELLS THAT HAVE 4536 02:50:18,120 --> 02:50:22,400 BEEN ENGINEERED USING AN 4537 02:50:22,400 --> 02:50:23,280 RMB86 SYSTEM AS I DESCRIBED. 4538 02:50:23,280 --> 02:50:27,160 IN JANUARY OF 2023, THAT IND AND 4539 02:50:27,160 --> 02:50:28,600 PROCESS WAS LICENSED TO GRAPHITE 4540 02:50:28,600 --> 02:50:29,040 BIO. 4541 02:50:29,040 --> 02:50:30,480 WE THEN TREATED THE FIRST 4542 02:50:30,480 --> 02:50:32,440 PATIENT AS I SAID ONE YEAR AGO. 4543 02:50:32,440 --> 02:50:35,280 IN JANUARY OF THIS YEAR -- 4544 02:50:35,280 --> 02:50:37,480 SORRY, NEXT SLIDE, PLEASE. 4545 02:50:37,480 --> 02:50:38,920 IN JANUARY OF THIS YEAR, 4546 02:50:38,920 --> 02:50:40,800 GRAPHITE BIO ANNOUNCED A 4547 02:50:40,800 --> 02:50:42,080 VOLUNTARY PAUSE ON THE TRIAL. 4548 02:50:42,080 --> 02:50:44,400 THE REASON FOR THIS VOLUNTARY 4549 02:50:44,400 --> 02:50:45,360 PAUSE IS THAT THE PATIENT FIVE 4550 02:50:45,360 --> 02:50:47,320 MONTHS POST INFUSION OF THE 4551 02:50:47,320 --> 02:50:49,400 CELLS WAS STILL REQUIRING RED 4552 02:50:49,400 --> 02:50:51,800 BLOOD CELL AND PLATELET 4553 02:50:51,800 --> 02:50:54,560 TRANSFUSIONS AND HAD BEEN 4554 02:50:54,560 --> 02:50:59,880 STARTED ON ALTRAMABAG AS A WAY 4555 02:50:59,880 --> 02:51:00,800 SUPPORTING HSC GROWTH IN THE 4556 02:51:00,800 --> 02:51:01,040 MARROW. 4557 02:51:01,040 --> 02:51:01,960 SINCE THAT TIME, HOWEVER, THE 4558 02:51:01,960 --> 02:51:03,160 PATIENT HAS CONTINUED TO IMPROVE 4559 02:51:03,160 --> 02:51:06,320 AND SHE'S NOW BEEN 4560 02:51:06,320 --> 02:51:06,920 TRANSFUSION-INDEPENDENT SINCE 4561 02:51:06,920 --> 02:51:07,600 APRIL OF THIS YEAR. 4562 02:51:07,600 --> 02:51:09,360 SHE'S NO LONGER ON ANY GROWTH 4563 02:51:09,360 --> 02:51:12,120 FACTORS, SHE HAS NO EVIDENCE OF 4564 02:51:12,120 --> 02:51:16,080 M DS OR ABNORMAL HEMATOPOIESIS 4565 02:51:16,080 --> 02:51:18,520 NOTING IT'S ONLY ONE YEAR OUT 4566 02:51:18,520 --> 02:51:22,600 AND HER MOST RECENT -- SHE HAS 4567 02:51:22,600 --> 02:51:24,920 LESS THAN 5% HEMOGLOBIN S AND 4568 02:51:24,920 --> 02:51:27,720 HAS A TOTAL HEMOGLOBIN GREATER 4569 02:51:27,720 --> 02:51:29,560 THAN 9. 4570 02:51:29,560 --> 02:51:33,200 THE FIRST DETAILS WILL BE REPORT 4571 02:51:33,200 --> 02:51:35,160 AT ASHE IN DECEMBER OF THIS 4572 02:51:35,160 --> 02:51:35,920 YEAR. 4573 02:51:35,920 --> 02:51:37,320 ONE COULD SAY SHOULDN'T WE HAVE 4574 02:51:37,320 --> 02:51:39,440 GONE ON AND TREATED A SECOND 4575 02:51:39,440 --> 02:51:40,080 PATIENT? 4576 02:51:40,080 --> 02:51:41,960 BUT I THINK THE FIRST PATIENT, 4577 02:51:41,960 --> 02:51:45,880 THERE WAS WERE VERY FEW THINGS 4578 02:51:45,880 --> 02:51:47,480 THAT THE SUBSEQUENT PATIENTS 4579 02:51:47,480 --> 02:51:52,080 COULD DO WOULD DO MUCH BETTER. 4580 02:51:52,080 --> 02:51:53,280 THE CELL DOSE WAS LOWER THAN WE 4581 02:51:53,280 --> 02:51:54,560 ANTICIPATED BUT NONETHELESS, 4582 02:51:54,560 --> 02:51:56,320 THINGS WENT RELATIVELY SMOOTHLY. 4583 02:51:56,320 --> 02:51:57,920 SO INSTEAD OF TREATING ANOTHER 4584 02:51:57,920 --> 02:51:59,480 PATIENT, WE WENT BACK TO THE 4585 02:51:59,480 --> 02:52:03,760 DRAWING BOARD AND SAID, CAN WE 4586 02:52:03,760 --> 02:52:06,920 DEVELOP AN IMPROVED 4587 02:52:06,920 --> 02:52:09,080 MANUFACTURING PROCESS SO THAT 4588 02:52:09,080 --> 02:52:11,200 THE SUBSEQUENT PATIENTS WOULD 4589 02:52:11,200 --> 02:52:13,640 HAVE BETTER OUTCOMES OR FASTER 4590 02:52:13,640 --> 02:52:14,080 OUTCOMES. 4591 02:52:14,080 --> 02:52:15,280 OF COURSE THIS HAS BEEN NOTED 4592 02:52:15,280 --> 02:52:20,880 BOTH BY PU PUNHAM AND JOHN THAT 4593 02:52:20,880 --> 02:52:22,080 GENETIC -- ENGINEERING IS MORE 4594 02:52:22,080 --> 02:52:27,440 COMMON THAN NOT. 4595 02:52:27,440 --> 02:52:28,400 SOMETHING HAPPENED HERE, BUT 4596 02:52:28,400 --> 02:52:30,760 WHAT'S SHOWN IN THE RED BOX, 4597 02:52:30,760 --> 02:52:32,360 IT'S A MAP TO P SEA CHANGE, 4598 02:52:32,360 --> 02:52:34,320 WHAT'S SHOWN HERE ON THE BOTH 4599 02:52:34,320 --> 02:52:37,920 LEFT AND RIGHT SIDE IS THAT THE 4600 02:52:37,920 --> 02:52:39,000 GREEN CELLS, WHICH ARE THE CELLS 4601 02:52:39,000 --> 02:52:41,200 THAT HAD UNDERGONE HDR EDITING 4602 02:52:41,200 --> 02:52:42,800 COMPARED TO THE BLUE CELLS THAT 4603 02:52:42,800 --> 02:52:46,040 HAD NOT UNDERGONE HDR EDITING, 4604 02:52:46,040 --> 02:52:51,320 THE LEVEL OF ENGRAFTMEN ENGRAFTR 4605 02:52:51,320 --> 02:52:52,440 PRE-CLINICAL TUMOR TALK STUDY 4606 02:52:52,440 --> 02:52:53,640 WAS LOWER OVERALL THAN THE BLUE 4607 02:52:53,640 --> 02:52:54,160 CELLS. 4608 02:52:54,160 --> 02:52:55,600 NOW THERE WAS SIGNIFICANT 4609 02:52:55,600 --> 02:52:55,880 OVERLAP. 4610 02:52:55,880 --> 02:52:59,720 YOU CAN SEE SOME OF THE MICE 4611 02:52:59,720 --> 02:53:00,880 RECEIVING BLUE CELLS ENGRAFTED 4612 02:53:00,880 --> 02:53:02,800 AT THE SAME FREQUENCY AS MANY OF 4613 02:53:02,800 --> 02:53:04,120 THE MICE RECEIVING THE GREEN 4614 02:53:04,120 --> 02:53:06,480 CELLS, WHICH IS WHY THE ADA 4615 02:53:06,480 --> 02:53:10,880 CLEAREFDACLEARED THE IND, BUT TW 4616 02:53:10,880 --> 02:53:12,080 BECAME A SIGNAL FOR US TO 4617 02:53:12,080 --> 02:53:12,600 IMPROVE ON. 4618 02:53:12,600 --> 02:53:15,120 CAN WE IMPROVE THE LEVEL OF 4619 02:53:15,120 --> 02:53:19,280 ENGRAFTMENT OF AGR EDITED CELLS. 4620 02:53:19,280 --> 02:53:23,280 AND SO WHAT HAS BEEN NOTED BY 4621 02:53:23,280 --> 02:53:24,640 ALBINI'S LAB AND OUR LAB AND 4622 02:53:24,640 --> 02:53:26,440 OTHERS AND HAS BEEN MENTIONED 4623 02:53:26,440 --> 02:53:28,680 PRIOR IS THAT THE HDR EDITING 4624 02:53:28,680 --> 02:53:32,560 PROCESS CAN INDUCE A P53 STRESS 4625 02:53:32,560 --> 02:53:34,440 RESPONSE THROUGH TWO MECHANISMS. 4626 02:53:34,440 --> 02:53:37,320 ONE IS THE CREATION OF A DOUBLE 4627 02:53:37,320 --> 02:53:38,720 STRANDED BREAK AT THE ON-TARGET 4628 02:53:38,720 --> 02:53:41,320 SITE, AND THE SECOND IS BY THE 4629 02:53:41,320 --> 02:53:46,640 DELIVERY OF AN A AAV GENOME INTO 4630 02:53:46,640 --> 02:53:48,840 THE NUCLEUS OF THE CELLS SO THIS 4631 02:53:48,840 --> 02:53:51,040 BECAME MINIMIZING THE STRESS 4632 02:53:51,040 --> 02:53:52,600 RESPONSE THUS BECOMES A REAL 4633 02:53:52,600 --> 02:53:54,240 TARGET FOR HOW WE IMPROVE THE 4634 02:53:54,240 --> 02:53:55,200 MANUFACTURING PROCESS. 4635 02:53:55,200 --> 02:53:58,800 AND WHAT WE FOUND, AS RECENTLY 4636 02:53:58,800 --> 02:54:00,440 PUBLISHED IN MOLECULAR THERAPY 4637 02:54:00,440 --> 02:54:01,640 METHODS IN CLINICAL DEVELOPMENT 4638 02:54:01,640 --> 02:54:04,280 IN THE LOWER LEFT CORNER IS THE 4639 02:54:04,280 --> 02:54:07,960 ACTIVATION OF P21, A DOWNSTREAM 4640 02:54:07,960 --> 02:54:10,160 TARGET OF P53, IS DIRECTLY 4641 02:54:10,160 --> 02:54:13,000 CORRELATED TO THE NUMBER OF 4642 02:54:13,000 --> 02:54:14,000 VECTORS IN THE CELLS. 4643 02:54:14,000 --> 02:54:18,160 SO BY LOWERING THE AMOUNT OF AAV 4644 02:54:18,160 --> 02:54:21,320 USED, ONE CAN REDUCE THE 4645 02:54:21,320 --> 02:54:22,800 P21 STRESS RESPONSE IN THE UPPER 4646 02:54:22,800 --> 02:54:25,000 LEFT IS SHOWN THAT IF WE COULD 4647 02:54:25,000 --> 02:54:28,240 REDUCE IT BY IT FOUR FOLD, WE 4648 02:54:28,240 --> 02:54:29,200 COULD REDUCE THAT STRESS 4649 02:54:29,200 --> 02:54:31,360 RESPONSE TO THE EQUIVALENT OF 4650 02:54:31,360 --> 02:54:33,320 JUST USING THE NUCLEASE ALONE 4651 02:54:33,320 --> 02:54:34,520 AND ON THE RIGHT-HAND SIDE SHOWS 4652 02:54:34,520 --> 02:54:37,280 SIMILAR RESCUE NOT JUST IN THE 4653 02:54:37,280 --> 02:54:39,440 P21 STRESS RESPONSE BUT IN THE 4654 02:54:39,440 --> 02:54:40,200 FUNCTIONALITY OF THE CELLS BY 4655 02:54:40,200 --> 02:54:41,560 RESCUING THE NUMBER OF COLONIES 4656 02:54:41,560 --> 02:54:47,120 THAT ARE FORMED PER 600 INPUT 4657 02:54:47,120 --> 02:54:53,880 CELLS. 4658 02:54:53,880 --> 02:54:58,600 SO USING THIS PROCESS, THE WE 4659 02:54:58,600 --> 02:55:00,440 HAVE NOW RE-DOSED THE 4660 02:55:00,440 --> 02:55:01,240 MANUFACTURING TIME FROM FIVE 4661 02:55:01,240 --> 02:55:02,480 DAYS TO THREE DAYS. 4662 02:55:02,480 --> 02:55:05,200 WE'VE INCLUDED A SMALL MOLECULE 4663 02:55:05,200 --> 02:55:06,800 BOOSTER OF HOMOLOGY DIRECT 4664 02:55:06,800 --> 02:55:07,280 REPAIR. 4665 02:55:07,280 --> 02:55:09,200 THIS HAS INCREASED THE FREQUENCY 4666 02:55:09,200 --> 02:55:11,320 OF GENE CORRECTION FROM 35 TO 4667 02:55:11,320 --> 02:55:13,520 50%, INCREASED OUR FREQUENCY OF 4668 02:55:13,520 --> 02:55:17,680 CELL CORRECTION FROM 40% TO 75%, 4669 02:55:17,680 --> 02:55:20,480 RESULTED IN A 40% INCREASE IN 4670 02:55:20,480 --> 02:55:23,240 THE TOTAL NUMBER OF COLONIES, 4671 02:55:23,240 --> 02:55:25,880 AND QUALITATIVELY, THE COLONIES 4672 02:55:25,880 --> 02:55:27,280 LOOK LARGER AND HEALTHIER. 4673 02:55:27,280 --> 02:55:32,960 IT HAS INDUCED THE P53 RESPONSE 4674 02:55:32,960 --> 02:55:36,800 DOWN TO RNP ALONE. 4675 02:55:36,800 --> 02:55:39,640 ALSO HAS REDUCED THE 4676 02:55:39,640 --> 02:55:41,800 MANUFACTURING COST BY ABOUT -- 4677 02:55:41,800 --> 02:55:43,800 CUT THE MANUFACTURING COST IN 4678 02:55:43,800 --> 02:55:44,240 HALF. 4679 02:55:44,240 --> 02:55:45,960 NOW THESE ARE STILL VERY HIGH 4680 02:55:45,960 --> 02:55:47,840 NUMBERS AND AS HAS BEEN 4681 02:55:47,840 --> 02:55:49,040 MENTIONED, IF WE'RE GOING TO GET 4682 02:55:49,040 --> 02:55:49,920 THESE SORT OF THERAPIES TO 4683 02:55:49,920 --> 02:55:51,240 PATIENTS AROUND THE WORLD, WE'LL 4684 02:55:51,240 --> 02:55:52,760 NEED TO FURTHER REDUCE THESE 4685 02:55:52,760 --> 02:55:54,520 COSTS, BUT I THINK MANY OF US 4686 02:55:54,520 --> 02:55:56,040 BELIEVE THAT THE 4687 02:55:56,040 --> 02:55:58,480 INDUSTRIALIZATION OF MANUFAC 4688 02:55:58,480 --> 02:55:59,400 MANUFACTURING AND REAGENTS FOR 4689 02:55:59,400 --> 02:56:01,400 ALL GENE THERAPIES HAS YET TO 4690 02:56:01,400 --> 02:56:02,480 OCCUR, AND WITH THAT, WE CAN 4691 02:56:02,480 --> 02:56:08,120 EXPECT FURTHER REDUCTIONS. 4692 02:56:08,120 --> 02:56:11,720 SO IN SUMMARY, WE'LL DESCRIBE AT 4693 02:56:11,720 --> 02:56:12,960 ASHE EVEN MORE OF THE DETAILS 4694 02:56:12,960 --> 02:56:15,880 ABOUT THE CLINICAL PROOF OF 4695 02:56:15,880 --> 02:56:18,920 CONCEPT THAT CAN -- CLEARLY ONE 4696 02:56:18,920 --> 02:56:23,120 YEAR IS NOT LONG-ENOUGH 4697 02:56:23,120 --> 02:56:26,600 FOLLOW-UP EFFICACY AND LONG TERM 4698 02:56:26,600 --> 02:56:28,560 SAFETY BUT REMIND YOU THE POINT 4699 02:56:28,560 --> 02:56:34,680 IS WE'RE NOT ONLY INCREASING 4700 02:56:34,680 --> 02:56:39,040 HEMOGLOBIN A BUT ALSO LOWERING 4701 02:56:39,040 --> 02:56:40,840 HEMOGLOBIN S. 4702 02:56:40,840 --> 02:56:42,840 CONVERSION OF ACADEMIC 4703 02:56:42,840 --> 02:56:46,200 MANUFACTURING PROCESS TO BIOTECH 4704 02:56:46,200 --> 02:56:48,800 PROCESS WITH IMPROVEMENTS IN ALL 4705 02:56:48,800 --> 02:56:51,320 METRICS, AND TAKE THIS IMPROVED 4706 02:56:51,320 --> 02:56:53,640 MANUFACTURING PROCESS, GET AN 4707 02:56:53,640 --> 02:56:55,360 IND AMENDMENT AND BEGIN TREATING 4708 02:56:55,360 --> 02:56:59,520 PATIENTS IN 2024. 4709 02:56:59,520 --> 02:57:00,800 SO WITH THAT, I WANT TO THANK 4710 02:57:00,800 --> 02:57:02,560 YOU, EVERYONE, FOR YOUR 4711 02:57:02,560 --> 02:57:03,200 ATTENTION AND OPPORTUNITY TO 4712 02:57:03,200 --> 02:57:04,960 PRESENT OUR WORK. 4713 02:57:04,960 --> 02:57:06,600 AS HAS BEEN MENTIONED PRIOR, IT 4714 02:57:06,600 --> 02:57:09,120 TAKES A VILLAGE, NOT ONLY WITH 4715 02:57:09,120 --> 02:57:13,960 TALENTED INVESTIGATORS IN MY L 4716 02:57:13,960 --> 02:57:18,840 LAB, MY GREAT COLLEAGUES, OUR 4717 02:57:18,840 --> 02:57:22,600 COLLEAGUES IN THE STANFORD 4718 02:57:22,600 --> 02:57:23,560 FACILITY, INDUSTRY COLLABORATORS 4719 02:57:23,560 --> 02:57:25,200 AROUND THE WORLD AND MONEY AND 4720 02:57:25,200 --> 02:57:27,320 SPONSORSHIP FROM A WIDE RANGE OF 4721 02:57:27,320 --> 02:57:28,600 INVESTIGATORS AND FOUNDATIONS. 4722 02:57:28,600 --> 02:57:31,320 SO WITH THAT, THANK YOU FOR 4723 02:57:31,320 --> 02:57:32,880 INCLUDING ME IN THIS SESSION, 4724 02:57:32,880 --> 02:57:34,400 AND I THINK I WILL END HERE AND 4725 02:57:34,400 --> 02:57:35,600 THAT SHOULD LEAVE TIME FOR A 4726 02:57:35,600 --> 02:57:36,280 COUPLE QUESTIONS. 4727 02:57:36,280 --> 02:57:43,800 THANK YOU VERY MUCH. 4728 02:57:43,800 --> 02:57:45,840 >>I THINK WE HAVE ONE OR TWO 4729 02:57:45,840 --> 02:57:46,240 ONLINE QUESTIONS. 4730 02:57:46,240 --> 02:57:48,600 >>I THINK WE'LL START WITH THE 4731 02:57:48,600 --> 02:57:50,640 ONLINE QUESTIONS IF THERE ARE 4732 02:57:50,640 --> 02:57:51,000 ANY. 4733 02:57:51,000 --> 02:57:52,440 CAN YOU PLEASE READ THOSE? 4734 02:57:52,440 --> 02:57:54,480 >>YEP. 4735 02:57:54,480 --> 02:57:58,880 WE HAVE ONE ONLINE QUESTION. 4736 02:57:58,880 --> 02:58:00,320 THE QUESTION IS FOR ANY OF THE 4737 02:58:00,320 --> 02:58:02,160 SPEAKERS WHO WOULD LIKE TO SHARE 4738 02:58:02,160 --> 02:58:03,760 THEIR OPINION ON WHETHER PATIENT 4739 02:58:03,760 --> 02:58:05,200 SHOULD WAIT UNTIL THERE IS 4740 02:58:05,200 --> 02:58:06,960 CONSENSUS ON THESE VARIOUS 4741 02:58:06,960 --> 02:58:10,120 APPROACHES BEFORE DECIDING ON A 4742 02:58:10,120 --> 02:58:10,720 SPECIFIC POTENTIALLY CURATIVE 4743 02:58:10,720 --> 02:58:13,280 THERAPY? 4744 02:58:13,280 --> 02:58:16,200 >>SINCE I'VE BEEN PINNED, I 4745 02:58:16,200 --> 02:58:20,640 THINK WE'VE HAD EIGHT SPEAKERS 4746 02:58:20,640 --> 02:58:22,240 IN THE SESSION. 4747 02:58:22,240 --> 02:58:23,960 I SUSPECT YOU'D GET EIGHT 4748 02:58:23,960 --> 02:58:25,200 DIFFERENT ANSWERS. 4749 02:58:25,200 --> 02:58:26,840 BUT MY ANSWER WOULD BE THAT IF 4750 02:58:26,840 --> 02:58:29,080 THE SEVERITY OF YOUR SICKLE CELL 4751 02:58:29,080 --> 02:58:31,280 DISEASE IS SUCH THAT IT IS 4752 02:58:31,280 --> 02:58:32,280 CAUSING SIGNIFICANT DISRUPTIONS 4753 02:58:32,280 --> 02:58:35,120 IN YOUR LIFE AND YOUR FUTURE 4754 02:58:35,120 --> 02:58:36,880 PROBABILITIES, IT IS NOT WORTH 4755 02:58:36,880 --> 02:58:37,120 WAITING. 4756 02:58:37,120 --> 02:58:40,920 IT ALSO IS CONSISTENT WITH -- 4757 02:58:40,920 --> 02:58:42,200 THAT RECOMMENDATION IS ALSO 4758 02:58:42,200 --> 02:58:43,600 CONSISTENT WITH THE DATA THAT 4759 02:58:43,600 --> 02:58:45,800 WAS PRESENTED IN THE FIRST 4760 02:58:45,800 --> 02:58:47,000 SESSION, THAT THIS IS A DISEASE 4761 02:58:47,000 --> 02:58:51,400 THAT CAN BE RESULT IN PERMANENT 4762 02:58:51,400 --> 02:58:53,360 END ORGAN DAMAGE THAT'S NOT 4763 02:58:53,360 --> 02:58:55,640 REVERSIBLE WHETHER BY AN ALLO 4764 02:58:55,640 --> 02:58:57,720 TRANSPLANT OR AUTOLOGOUS GENE 4765 02:58:57,720 --> 02:58:58,160 THERAPY TRANSPLANT. 4766 02:58:58,160 --> 02:59:00,880 SO I THINK IN CONSULTATION WITH 4767 02:59:00,880 --> 02:59:03,840 YOUR PHYSICIAN AND YOUR SUPPORT 4768 02:59:03,840 --> 02:59:04,720 NETWORK, IT IS SOMETIMES 4769 02:59:04,720 --> 02:59:06,920 APPROPRIATE TO INITIATE 4770 02:59:06,920 --> 02:59:10,160 THERAPIES WITH ONE OF THESE ON A 4771 02:59:10,160 --> 02:59:12,360 CLINICAL TRIAL EVEN IN 2023. 4772 02:59:12,360 --> 02:59:14,360 HOWEVER, I THINK IF YOUR DISEASE 4773 02:59:14,360 --> 02:59:16,760 IS MILDER AND IS NOT IMPACTING 4774 02:59:16,760 --> 02:59:19,040 ON YOUR LIFE, YOU PERHAPS MAY 4775 02:59:19,040 --> 02:59:20,240 CHOOSE TO WAIT LATER. 4776 02:59:20,240 --> 02:59:22,200 BUT I'LL STOP THERE AND LISTEN 4777 02:59:22,200 --> 02:59:25,000 TO THE DISAGREEMENTS. 4778 02:59:25,000 --> 02:59:28,240 >>SO I'LL TAKE THE CHAIR'S 4779 02:59:28,240 --> 02:59:33,160 PREROGATIVE AND GIVE MY OPINION. 4780 02:59:33,160 --> 02:59:35,440 I AGREE WITH MATT THAT I THINK 4781 02:59:35,440 --> 02:59:37,760 WE HAVE A LOT OF PATIENTS -- THE 4782 02:59:37,760 --> 02:59:40,520 ELIGIBILITY CRITERIA FOR GENE 4783 02:59:40,520 --> 02:59:42,640 THERAPY AND GENE EDITING IS ALSO 4784 02:59:42,640 --> 02:59:43,880 REALLY STRICT, AND IT REALLY IS 4785 02:59:43,880 --> 02:59:45,160 PATIENTS WHO ARE REALLY, REALLY 4786 02:59:45,160 --> 02:59:47,160 SICK AND ARE NOT RESPONDING TO 4787 02:59:47,160 --> 02:59:48,800 CURRENT DISEASE MODIFYING 4788 02:59:48,800 --> 02:59:52,560 THERAPIES. 4789 02:59:52,560 --> 02:59:54,040 I THINK THAT THEY SHOULD -- IT'S 4790 02:59:54,040 --> 02:59:57,200 GOOD THAT THEY HAVE SO MANY 4791 02:59:57,200 --> 03:00:01,720 DIFFERENT TYPES OF STRATEGIES 4792 03:00:01,720 --> 03:00:04,120 AVAILABLE, AND THAT DECISION OF 4793 03:00:04,120 --> 03:00:06,080 WHAT THEY SHOULD CHOOSE WILL 4794 03:00:06,080 --> 03:00:07,280 HAPPEN WITH A DISCUSSION WITH 4795 03:00:07,280 --> 03:00:08,400 THEIR PHYSICIAN. 4796 03:00:08,400 --> 03:00:11,160 BUT I DO THINK THAT PATIENTS WHO 4797 03:00:11,160 --> 03:00:13,680 DON'T HAVE ANY OTHER OPTIONS, 4798 03:00:13,680 --> 03:00:15,520 LIKE TRANSPLANT OR OTHER 4799 03:00:15,520 --> 03:00:16,600 DISEASE-MODIFYING THERAPIES, 4800 03:00:16,600 --> 03:00:22,400 HAVEN'T WORKED -- LIKE CHRON 4801 03:00:22,400 --> 03:00:23,280 CHRONIC -- PATIENTS ON OUR 4802 03:00:23,280 --> 03:00:25,880 TRIAL, HALF OF THEM RECEIVED 4803 03:00:25,880 --> 03:00:26,680 GENE THERAPY BECAUSE THEY 4804 03:00:26,680 --> 03:00:27,640 WEREN'T RESPONDING TO THE 4805 03:00:27,640 --> 03:00:28,760 STANDARD THERAPIES. 4806 03:00:28,760 --> 03:00:32,360 SO I THINK THEY SHOULD CONSIDER 4807 03:00:32,360 --> 03:00:34,640 IT NOW AND AT LEAST HAVE AN 4808 03:00:34,640 --> 03:00:37,040 INFORMED DISCUSSION WITH THEIR 4809 03:00:37,040 --> 03:00:39,160 PHYSICIAN, THERE SHOULD BE AN 4810 03:00:39,160 --> 03:00:40,880 INFORMED DECISION-MAKING. 4811 03:00:40,880 --> 03:00:45,840 BUT I DO THINK THAT -- I 4812 03:00:45,840 --> 03:00:47,040 COMPLETELY AGREE WITH MATT ON 4813 03:00:47,040 --> 03:00:48,520 THE MILDER PATIENTS. 4814 03:00:48,520 --> 03:00:51,800 >>I WAS JUST GOING TO SAY, IT'S 4815 03:00:51,800 --> 03:00:53,800 NOT ONLY ABOUT RESEARCH 4816 03:00:53,800 --> 03:00:54,080 ANYMORE -- 4817 03:00:54,080 --> 03:00:54,960 >>THAT'S NOT WORKING. 4818 03:00:54,960 --> 03:00:57,360 >>IT IS WORKING. 4819 03:00:57,360 --> 03:01:00,600 >>IT'S NOT JUST ABOUT RESEARCH 4820 03:01:00,600 --> 03:01:02,240 ANYMORE, THERE'S TWO GENE 4821 03:01:02,240 --> 03:01:03,640 THERAPIES THAT ARE PROBABLY 4822 03:01:03,640 --> 03:01:06,560 GOING TO BE APPROVED IN THE NEXT 4823 03:01:06,560 --> 03:01:08,840 YEAR. 4824 03:01:08,840 --> 03:01:12,040 AND I THINK THAT IT'S AN 4825 03:01:12,040 --> 03:01:12,520 INDIVIDUALIZED DECISION. 4826 03:01:12,520 --> 03:01:14,760 I THINK THAT IT'S AN 4827 03:01:14,760 --> 03:01:16,840 INDIVIDUALIZED DECISION, AND THE 4828 03:01:16,840 --> 03:01:20,240 MOST IMPORTANT THING IS 4829 03:01:20,240 --> 03:01:21,760 INFORMATION AND INFORMED 4830 03:01:21,760 --> 03:01:22,080 CONSENT. 4831 03:01:22,080 --> 03:01:26,000 AND THAT IS SO HARD TO DO, IT'S 4832 03:01:26,000 --> 03:01:28,080 SO HARD FOR ANYBODY TO 4833 03:01:28,080 --> 03:01:32,920 UNDERSTAND WHAT COULD HAPPEN, 4834 03:01:32,920 --> 03:01:34,120 LET ALONE PATIENTS. 4835 03:01:34,120 --> 03:01:37,520 SO THAT'S A HUGE ROLE OF THE 4836 03:01:37,520 --> 03:01:38,720 PEOPLE TAKING CARE OF THESE 4837 03:01:38,720 --> 03:01:40,240 PATIENTS TO REALLY EXPLAIN TO 4838 03:01:40,240 --> 03:01:40,440 THEM. 4839 03:01:40,440 --> 03:01:42,440 THAT WAS THE LAST THING THAT YOU 4840 03:01:42,440 --> 03:01:44,280 SAID, PUNHAM, AND I AGREE WITH 4841 03:01:44,280 --> 03:01:47,600 THAT. 4842 03:01:47,600 --> 03:01:49,200 >>ANY OTHER QUESTIONS FROM THE 4843 03:01:49,200 --> 03:01:59,360 AUDIENCE? 4844 03:02:01,120 --> 03:02:02,880 >>IS THIS ON? 4845 03:02:02,880 --> 03:02:03,400 YES. 4846 03:02:03,400 --> 03:02:06,600 THIS IS A QUESTION FORMAT 4847 03:02:06,600 --> 03:02:07,480 PORTEUS. 4848 03:02:07,480 --> 03:02:09,200 THANKS FOR GIVING THE UPDATE 4849 03:02:09,200 --> 03:02:10,400 ABOUT YOUR PATIENT INVOLVED IN 4850 03:02:10,400 --> 03:02:12,040 THE GRAPHITE BIO TRIAL. 4851 03:02:12,040 --> 03:02:13,320 I'M SURE YOU'LL GO INTO THIS AT 4852 03:02:13,320 --> 03:02:17,160 THE MEETING IN DECEMBER, BUT CAN 4853 03:02:17,160 --> 03:02:17,760 YOU TELL US ANY MORE ABOUT 4854 03:02:17,760 --> 03:02:18,800 WHETHER OR NOT THERE'S EVIDENCE 4855 03:02:18,800 --> 03:02:22,480 OF INEFFECTIVE ERYTHROPOIESIS 4856 03:02:22,480 --> 03:02:24,160 AND STRESS WITH POIESIS AND IF 4857 03:02:24,160 --> 03:02:25,880 THERE ARE ANY FEATURES OF 4858 03:02:25,880 --> 03:02:27,040 THALASSEMIA IN THAT PATIENT? 4859 03:02:27,040 --> 03:02:28,880 >>I CAN'T GIVE YOU A LOT -- 4860 03:02:28,880 --> 03:02:32,280 THOSE ARE ALL EXCELLENT QUEST 4861 03:02:32,280 --> 03:02:32,920 QUESTIONS, MARK. 4862 03:02:32,920 --> 03:02:35,760 HOPEFULLY WE'LL BE ABLE TO BRING 4863 03:02:35,760 --> 03:02:37,600 MORE INFORMATION TO THE 4864 03:02:37,600 --> 03:02:39,600 COMMUNITY IN DECEMBER. 4865 03:02:39,600 --> 03:02:41,440 NO EXCUSES, BUT OBVIOUSLY THE 4866 03:02:41,440 --> 03:02:43,760 TRANSITION OF THE PROGRAM OUT OF 4867 03:02:43,760 --> 03:02:46,360 GRAPHITE HAS SLOWED SOME OF OUR 4868 03:02:46,360 --> 03:02:47,120 STUDIES OF THOSE VERY IMPORTANT 4869 03:02:47,120 --> 03:02:48,560 QUESTIONS, BUT HOPEFULLY WE CAN 4870 03:02:48,560 --> 03:02:51,400 CATCH UP ON THEM BY THE TIME 4871 03:02:51,400 --> 03:02:56,880 DECEMBER ROLLS AROUND. 4872 03:02:56,880 --> 03:02:57,520 >>THANK YOU. 4873 03:02:57,520 --> 03:03:04,680 ANY OTHER QUESTIONS? 4874 03:03:04,680 --> 03:03:05,320 >>SORRY. 4875 03:03:05,320 --> 03:03:08,600 >>OH, SORRY. 4876 03:03:08,600 --> 03:03:09,000 GO AHEAD, PLEASE. 4877 03:03:09,000 --> 03:03:11,120 >>I HAVE A COMMENT, AND I THINK 4878 03:03:11,120 --> 03:03:12,680 IT ADDRESSES BOTH THE SESSIONS 4879 03:03:12,680 --> 03:03:14,200 THAT WE HAD THIS MORNING AND 4880 03:03:14,200 --> 03:03:15,400 TIES THEM TOGETHER. 4881 03:03:15,400 --> 03:03:19,200 AS A CLINICIAN WHO'S PRESENTING 4882 03:03:19,200 --> 03:03:22,720 THESE OPPORTUNITIES TO OUR 4883 03:03:22,720 --> 03:03:23,560 PATIENTS, EITHER ON CLINICAL 4884 03:03:23,560 --> 03:03:27,320 TRIALS OR SOON TO BE PERHAPS 4885 03:03:27,320 --> 03:03:28,960 AVAILABLE FDA-APPROVED 4886 03:03:28,960 --> 03:03:29,880 THERAPIES, IT'S SO IMPORTANT FOR 4887 03:03:29,880 --> 03:03:32,920 US TO HAVE THE INFORMATION THAT 4888 03:03:32,920 --> 03:03:34,880 COMPARES OUTCOMES, LONG-TERM 4889 03:03:34,880 --> 03:03:36,960 OUTCOMES THAT WERE PRESENTED IN 4890 03:03:36,960 --> 03:03:39,280 THE FIRST SESSION, IN COMPARISON 4891 03:03:39,280 --> 03:03:42,200 TO MODERN CONTEMPORANEOUS 4892 03:03:42,200 --> 03:03:43,440 CONTROLS, AND THAT'S WHAT I URGE 4893 03:03:43,440 --> 03:03:46,480 PEOPLE TO THINK ABOUT WHEN THEY 4894 03:03:46,480 --> 03:03:49,680 PRESENT THEIR DATA OR ARE 4895 03:03:49,680 --> 03:03:51,640 DESIGNING STUDIES, AND EVEN THE 4896 03:03:51,640 --> 03:03:53,720 NIH FOR FUNDING STUDIES THAT 4897 03:03:53,720 --> 03:03:54,920 HAVE THE APPROPRIATE CONTROLS, 4898 03:03:54,920 --> 03:04:00,520 WE DO HAVE THE OPPORTUNITY TO 4899 03:04:00,520 --> 03:04:02,040 USE REAL REAL WORLD DATA WHERE 4900 03:04:02,040 --> 03:04:03,800 YOU CAN USE MACHINE LEARNING TO 4901 03:04:03,800 --> 03:04:05,640 CREATE A COHORT THAT IS MATCHED 4902 03:04:05,640 --> 03:04:07,720 IN SEVERITY TO LOOK AT SOME 4903 03:04:07,720 --> 03:04:09,040 OUTCOMES. 4904 03:04:09,040 --> 03:04:11,120 THERE ARE, YOU KNOW, LARGE 4905 03:04:11,120 --> 03:04:12,200 DATABASES, AND IT'S SO 4906 03:04:12,200 --> 03:04:12,680 IMPORTANT. 4907 03:04:12,680 --> 03:04:14,720 SO IT HELPFUL FOR ME TO KNOW 4908 03:04:14,720 --> 03:04:18,320 JUST AS AN EXAMPLE, THAT THE 4909 03:04:18,320 --> 03:04:21,920 RARISK OF MALIGNANCY IS 45 FOLD 4910 03:04:21,920 --> 03:04:23,640 HIGHER WHEN THERE'S GRAFT 4911 03:04:23,640 --> 03:04:24,200 REJECTION, BUT WHAT'S THE 4912 03:04:24,200 --> 03:04:26,280 AVERAGE, AND WHAT'S THE AVERAGE 4913 03:04:26,280 --> 03:04:27,400 IN SICKLE CELL PATIENTS AND WHAT 4914 03:04:27,400 --> 03:04:31,080 ARE THE RISK FACTORS THAT CA SO 4915 03:04:31,080 --> 03:04:33,280 THAT CAN BE COMPARED IN A 4916 03:04:33,280 --> 03:04:34,800 MEANINGFUL MANNER WHEN YOU'RE 4917 03:04:34,800 --> 03:04:35,720 CONSENTING PATIENTS IN THE 4918 03:04:35,720 --> 03:04:35,960 CLINIC. 4919 03:04:35,960 --> 03:04:38,000 >>YES, I COULDN'T AGREE MORE. 4920 03:04:38,000 --> 03:04:44,520 I THINK THAT AS THESE THERAPIES 4921 03:04:44,520 --> 03:04:45,920 ARE MATURING AND COMING TO THE 4922 03:04:45,920 --> 03:04:48,360 CLINIC, WE REALLY NEED TO NOT 4923 03:04:48,360 --> 03:04:49,880 JUST LOOK AT THE SHORT TERM 4924 03:04:49,880 --> 03:04:51,400 EFFICACY BUT THE LONG TERM 4925 03:04:51,400 --> 03:04:51,640 RESULTS. 4926 03:04:51,640 --> 03:04:55,520 I THINK NIH AND ASHE, AND YOU 4927 03:04:55,520 --> 03:04:59,200 WERE PROBABLY PART OF THOSE 4928 03:04:59,200 --> 03:05:00,520 COMMITTEES, HAS IMPANELED 4929 03:05:00,520 --> 03:05:02,160 SEVERAL GROUPS TO MAKE 4930 03:05:02,160 --> 03:05:04,160 GUIDELINES AND RECOMMENDATIONS 4931 03:05:04,160 --> 03:05:06,000 FOR LONG TERM FOLLOW-UP AND WHAT 4932 03:05:06,000 --> 03:05:08,760 SHOULD BE DONE AND TESTED ON 4933 03:05:08,760 --> 03:05:09,440 THESE PATIENTS. 4934 03:05:09,440 --> 03:05:11,280 AND THE OTHER THING I DO FEEL IS 4935 03:05:11,280 --> 03:05:15,920 VERY IMPORTANT IS TRANSPARENCY, 4936 03:05:15,920 --> 03:05:17,840 ESPECIALLY FROM TRIALS THAT GO 4937 03:05:17,840 --> 03:05:22,240 TO PHARMA, WE HEAR JUST, YOU 4938 03:05:22,240 --> 03:05:24,160 KNOW, WHAT THEY WANT TO 4939 03:05:24,160 --> 03:05:25,200 DISCLOSE, AND I THINK 4940 03:05:25,200 --> 03:05:27,160 TRANSPARENCY IS SOMETHING THAT 4941 03:05:27,160 --> 03:05:30,280 WOULD REALLY HELP THE FIELD. 4942 03:05:30,280 --> 03:05:31,920 >>QUICK QUESTION FOR 4943 03:05:31,920 --> 03:05:32,560 HANS-PETER. 4944 03:05:32,560 --> 03:05:36,720 DOES YOUR APPROACH LEND ITSELF 4945 03:05:36,720 --> 03:05:39,440 TO IN UTERO? 4946 03:05:39,440 --> 03:05:41,000 OH, HANS IS ONLINE. 4947 03:05:41,000 --> 03:05:43,480 >>SORRY, I WAS LISTENING. 4948 03:05:43,480 --> 03:05:47,000 POTENTIALLY, YES. 4949 03:05:47,000 --> 03:05:51,040 >>THAT COULD POTENTIALLY 4950 03:05:51,040 --> 03:05:51,640 REDUCE -- AND MAKE THE TARGET 4951 03:05:51,640 --> 03:05:52,720 REALLY SMALLER. 4952 03:05:52,720 --> 03:05:58,360 >>YES. 4953 03:05:58,360 --> 03:06:00,360 >>THANK YOU, PUN H PUNHAM, AND 4954 03:06:00,360 --> 03:06:02,400 EVERYONE FOR GREAT SESSIONS. 4955 03:06:02,400 --> 03:06:06,880 >>LET'S GET STARTED WITH 4956 03:06:06,880 --> 03:06:14,320 OUR NEXT SESSION, UPDATES ON 4957 03:06:14,320 --> 03:06:16,360 CLINICAL TRIALS, SICKLE CELL 4958 03:06:16,360 --> 03:06:17,200 DISEASE. 4959 03:06:17,200 --> 03:06:20,760 THE FIRST ONE, WE HAVE -- NEXT 4960 03:06:20,760 --> 03:06:22,080 FOUR TALKS ARE ALL GOING TO BE 4961 03:06:22,080 --> 03:06:22,840 TALKING ABOUT THE CLINICAL 4962 03:06:22,840 --> 03:06:23,120 TRIALS. 4963 03:06:23,120 --> 03:06:26,120 SO THE NEXT TALK IS GOING TO BE 4964 03:06:26,120 --> 03:06:31,600 PROOF OF CONCEPT STUDY OF 4965 03:06:31,600 --> 03:06:35,880 NICOTINAMIDE AND ORAL 4966 03:06:35,880 --> 03:06:37,280 THU/DECITABINE TO TREAT HIGH 4967 03:06:37,280 --> 03:06:38,720 RISK SICKLE CELL DISEASE. 4968 03:06:38,720 --> 03:06:39,680 DR. YOGEN SAUNTHARARAJAH FROM 4969 03:06:39,680 --> 03:06:40,920 CLEVELAND CLINIC. 4970 03:06:40,920 --> 03:06:41,880 >>THANK YOU. 4971 03:06:41,880 --> 03:06:46,720 SO THANK YOU VERY MUCH, PUNKAJ 4972 03:06:46,720 --> 03:06:57,040 AND THE ORGANIZERS. 4973 03:07:02,320 --> 03:07:04,480 SO THESE ARE MY DISCLOSURES. 4974 03:07:04,480 --> 03:07:09,920 I HAVE PATENTS AROUND 4975 03:07:09,920 --> 03:07:10,800 DECITABINE, EQUITY AND BOARD 4976 03:07:10,800 --> 03:07:14,560 ROLES IN A COUPLE OF STARTUP 4977 03:07:14,560 --> 03:07:17,360 COMPANIES, NOVO NORDISK HAS 4978 03:07:17,360 --> 03:07:18,240 SUBLICENSED ONE OF THESE PATENTS 4979 03:07:18,240 --> 03:07:20,320 AND I HAVE ISSUED PATENTS IN 4980 03:07:20,320 --> 03:07:22,040 SOME OTHER SMALL MOLECULE 4981 03:07:22,040 --> 03:07:26,680 THERAPEUTICS AS WELL. 4982 03:07:26,680 --> 03:07:29,520 SO WE'VE HEARD A LOT ABOUT HE 4983 03:07:29,520 --> 03:07:32,800 RED DRI MISSENSE AND HOW IT DOWN 4984 03:07:32,800 --> 03:07:33,720 REGULATES SEVERITY OF SICKLE 4985 03:07:33,720 --> 03:07:35,000 CELL DISEASE AND WE ALL KNOW 4986 03:07:35,000 --> 03:07:38,920 THAT VARIATIONS IN THE BCL11A 4987 03:07:38,920 --> 03:07:41,000 GENE OR REGULATORY ELEMENTS CAN 4988 03:07:41,000 --> 03:07:43,520 CAUSE HEREDITARY PERSISTENCE OF 4989 03:07:43,520 --> 03:07:45,720 FETAL HEMOGLOBIN, A LITTLE WELL 4990 03:07:45,720 --> 03:07:47,560 LESS RECOGNIZED IS THERE'S A 4991 03:07:47,560 --> 03:07:49,200 MISSENSE MUTATION IN THE GENE 4992 03:07:49,200 --> 03:07:54,600 FOR THIS EPIGENETIC REGULATOR, 4993 03:07:54,600 --> 03:07:58,840 DNA TRANSFERASE 1, DNMT1. 4994 03:07:58,840 --> 03:08:03,760 THEIT IS ALSO A CALLS OF HPFH. 4995 03:08:03,760 --> 03:08:05,040 ACTUALLY IT'S ALL PART OF THAT 4996 03:08:05,040 --> 03:08:08,240 SAME HUB. 4997 03:08:08,240 --> 03:08:11,680 DNMT1 IS KNOWN TO BE RECRUITED 4998 03:08:11,680 --> 03:08:14,440 AT THE BETA GLOBIN LOCUS IN 4999 03:08:14,440 --> 03:08:17,000 ORDER TO EFFECT TRANSCRIPTION 5000 03:08:17,000 --> 03:08:20,280 REPRESSING FUNCTIONS. 5001 03:08:20,280 --> 03:08:21,800 AND SO BASICALLY THIS IS WHAT 5002 03:08:21,800 --> 03:08:23,440 THE POLYMORPHISM DOES, IS IT 5003 03:08:23,440 --> 03:08:27,280 DECREASES THE PROTEIN HALF-LIFE 5004 03:08:27,280 --> 03:08:29,800 TO CAUSE HPFH AND ACTUALLY WE DO 5005 03:08:29,800 --> 03:08:32,320 HAVE A SMALL MOLECULE 5006 03:08:32,320 --> 03:08:33,200 FDA-APPROVED IN THE CLINIC FOR 5007 03:08:33,200 --> 03:08:35,680 TREATING MYELOID MALIGNANCIES 5008 03:08:35,680 --> 03:08:36,880 THAT BASICALLY DOES THE SAME 5009 03:08:36,880 --> 03:08:37,440 THING. 5010 03:08:37,440 --> 03:08:40,920 IT DEGRADES DNMT1 PROTEIN. 5011 03:08:40,920 --> 03:08:42,280 SO WHAT IS THIS MOLECULE AND HOW 5012 03:08:42,280 --> 03:08:43,120 DOES DO IT? 5013 03:08:43,120 --> 03:08:52,120 THE NAME OF THE MOLECULE IS 5014 03:08:52,120 --> 03:08:52,840 DECITABINE. 5015 03:08:52,840 --> 03:08:55,160 AND IT BASICALLY HAS A SINGLE 5016 03:08:55,160 --> 03:09:01,600 ATOM CHANGE COMP. 5017 03:09:01,600 --> 03:09:02,960 SO IT'S SUBSTITUTED WITH A 5018 03:09:02,960 --> 03:09:06,560 NITROGEN, AND THAT HAPPENS TO BE 5019 03:09:06,560 --> 03:09:11,880 THE CARBON THAT IS METHYLATED BY 5020 03:09:11,880 --> 03:09:17,840 DNA METHYL TRA TRANSFERASE 1. 5021 03:09:17,840 --> 03:09:23,600 IT GETS DEGRADED SO YOU GET 5022 03:09:23,600 --> 03:09:24,600 DNMT1 PROTEIN DEPLETION FROM 5023 03:09:24,600 --> 03:09:24,920 CELLS. 5024 03:09:24,920 --> 03:09:27,560 AS MENTIONED, THERE'S ONLY A 5025 03:09:27,560 --> 03:09:30,480 SINGLE ATOM CHANGE COMPARED TO 5026 03:09:30,480 --> 03:09:36,200 THE OXYCYTABENE. 5027 03:09:36,200 --> 03:09:37,600 SO UNLIKE OTHERS WE USE IN THE 5028 03:09:37,600 --> 03:09:39,680 HEMATOLOGY AND ONCOLOGY CLINIC, 5029 03:09:39,680 --> 03:09:40,240 THAT'S UNUSUAL. 5030 03:09:40,240 --> 03:09:41,560 SO VERY OFTEN THE SUGAR IS 5031 03:09:41,560 --> 03:09:43,200 MODIFIED. 5032 03:09:43,200 --> 03:09:44,640 THE SUGAR IS PHYSIOLOGIC. 5033 03:09:44,640 --> 03:09:47,680 SO WHEN IT INCORPORATES INTO THE 5034 03:09:47,680 --> 03:09:49,520 NEWLY SYNTHESIZED DNA STRAND 5035 03:09:49,520 --> 03:09:52,120 DURING S-PHASE, IT DOESN'T 5036 03:09:52,120 --> 03:09:53,480 TERMINATE DNA CHAIN ELONGATION. 5037 03:09:53,480 --> 03:09:58,960 SO YOU CAN ACTUALLY ACHIEVE THE 5038 03:09:58,960 --> 03:09:59,720 DNMT1 DEPLETION AT 5039 03:09:59,720 --> 03:10:02,120 CONCENTRATIONS THAT DO NOT 5040 03:10:02,120 --> 03:10:05,160 CAUSE -- WHAT YOU'RE LOOKING AT 5041 03:10:05,160 --> 03:10:08,120 DNA DAMAGE MEASUREMENT IN CORD 5042 03:10:08,120 --> 03:10:13,040 BLOOD CD34 CELLS TREATED WITH 5043 03:10:13,040 --> 03:10:14,040 DECITABINE, ABOUT 10 TIMES MORE 5044 03:10:14,040 --> 03:10:17,320 THAN WHAT YOU NEED TO DEPLETE 5045 03:10:17,320 --> 03:10:22,240 DNMT1, AND HERE IS ECOMOLAR -- 5046 03:10:22,240 --> 03:10:26,160 CAUSING A LOT OF CYTOTOXICITY, 5047 03:10:26,160 --> 03:10:28,800 HYDROXYURIA CAUSES CYTOTOXICITY. 5048 03:10:28,800 --> 03:10:33,960 HIGHER CONCENTRATIONS DO PRODUCE 5049 03:10:33,960 --> 03:10:34,720 ANTIMETABOLITE EFFECTS, 5050 03:10:34,720 --> 03:10:36,760 TERMINATING OF DNA STRAND SINS 5051 03:10:36,760 --> 03:10:39,520 ZEST BUT A NUMBER OF OTHER 5052 03:10:39,520 --> 03:10:40,840 ANTIMETABOLITE EFFECTS THAT DO 5053 03:10:40,840 --> 03:10:41,800 CAUSE CYTOTOXICITY BUT THE 5054 03:10:41,800 --> 03:10:44,640 BOTTOM LINE IS THAT YOU CAN FIND 5055 03:10:44,640 --> 03:10:50,440 CONCENTRATIONS OR DOSES AGAINST 5056 03:10:50,440 --> 03:10:54,280 AN EPIGENETIC REGULATOR WITHOUT 5057 03:10:54,280 --> 03:10:55,920 EFFECTS OF CYTOTOXICITY. 5058 03:10:55,920 --> 03:10:58,000 SO YOU CAN ALSO IF YOU WANT TO 5059 03:10:58,000 --> 03:11:00,520 KILL STUFF, YOU CAN GIVE HIGHER 5060 03:11:00,520 --> 03:11:03,240 CONCENTRATIONS AND PRODUCE DNA 5061 03:11:03,240 --> 03:11:09,720 DAMAGE AND CYTOTOXICITY, YOU CAN 5062 03:11:09,720 --> 03:11:10,160 PRODUCE THIS EFFECT. 5063 03:11:10,160 --> 03:11:17,680 SO OBVIOUSLY THE GOAL WITH USING 5064 03:11:17,680 --> 03:11:18,440 DECITABINE, TALKING ABOUT 5065 03:11:18,440 --> 03:11:22,080 POTENTIALLY TRYING TO 5066 03:11:22,080 --> 03:11:24,040 RECAPITULATE THE MECHANISM, WE 5067 03:11:24,040 --> 03:11:27,200 ALREADY HAVE A DRUG HYDROXYUREA 5068 03:11:27,200 --> 03:11:28,200 TO INCREASE FETAL HEMOIMLOA BIN 5069 03:11:28,200 --> 03:11:30,880 IN OUR PATIENTS BUT OF COURSE 5070 03:11:30,880 --> 03:11:31,560 HYDROXYUREA DOES THAT 5071 03:11:31,560 --> 03:11:31,880 INDIRECTLY. 5072 03:11:31,880 --> 03:11:38,920 SO IT'S A RO RIBONUCLEOTIDE 5073 03:11:38,920 --> 03:11:42,560 REGULATOR, THAT PRODUCES 5074 03:11:42,560 --> 03:11:43,280 CYTOSTASIS, CYTOTOXICITY. 5075 03:11:43,280 --> 03:11:45,240 DURING THE RECOVERY PHASE FROM 5076 03:11:45,240 --> 03:11:50,400 THAT, SO STRESS ERYTHRO.EE CYST, 5077 03:11:50,400 --> 03:11:55,760 THE CHROMATIN CONFIGURATION IS 5078 03:11:55,760 --> 03:11:59,560 AFFECTED TO INCREASE FETAL 5079 03:11:59,560 --> 03:12:00,040 HEMOGLOBIN. 5080 03:12:00,040 --> 03:12:01,880 WHAT WE'RE TALKING ABOUT IS 5081 03:12:01,880 --> 03:12:03,440 CONCEPTUALLY DIFFERENT THAN 5082 03:12:03,440 --> 03:12:05,760 THAT, WE INTEND TO TARGET THIS 5083 03:12:05,760 --> 03:12:09,120 HUB DIRECTLY BY TARGETING 5084 03:12:09,120 --> 03:12:10,200 DNMT1 ABOUT WITH A SMALL MALL 5085 03:12:10,200 --> 03:12:10,400 KEUL. 5086 03:12:10,400 --> 03:12:13,040 A LOT OF THE GENE THERAPY WE'VE 5087 03:12:13,040 --> 03:12:14,000 HEARD ABOUT ARE ALSO TARGETING 5088 03:12:14,000 --> 03:12:15,760 THIS HUB BUT THEY'RE TARGETING 5089 03:12:15,760 --> 03:12:19,480 IT AT THE LEVEL OF THE BCA11 5090 03:12:19,480 --> 03:12:28,040 BINDING TO DNA OR TARGETING 5091 03:12:28,040 --> 03:12:29,040 BCLA11 LEVELS, ET CETERA, ET 5092 03:12:29,040 --> 03:12:29,240 CETERA. 5093 03:12:29,240 --> 03:12:30,640 SO WE'RE REALLY TRYING TO GO 5094 03:12:30,640 --> 03:12:34,480 AFTER THAT SAME HUB THAT CAUSES 5095 03:12:34,480 --> 03:12:35,800 DIRECTLY BUT USING A SMALL 5096 03:12:35,800 --> 03:12:36,760 MOLECULE INSTEAD OF GENE 5097 03:12:36,760 --> 03:12:37,320 THERAPY. 5098 03:12:37,320 --> 03:12:39,920 SO CONCEPTUAL DIFFERENCES WITH 5099 03:12:39,920 --> 03:12:41,240 HYDROXYUREA THAT WE USE TO TRY 5100 03:12:41,240 --> 03:12:45,520 TO INCREASE FETAL HEMOGLOBIN, IT 5101 03:12:45,520 --> 03:12:49,360 WORKS BY A STRESS 5102 03:12:49,360 --> 03:12:50,560 ERYTHROPOIESIS, THE 5103 03:12:50,560 --> 03:12:53,720 PHARMACODYNAMIC OBJECTIVES WITH 5104 03:12:53,720 --> 03:12:57,200 HYDROXYUREA IS RIBONUCLEOTIDE 5105 03:12:57,200 --> 03:12:58,200 REDUCTASE INHIBITION, WE'RE 5106 03:12:58,200 --> 03:13:04,320 TRYING TO DEPLETE DNMT1. 5107 03:13:04,320 --> 03:13:06,280 DERIVED FROM THE MAXIMUM 5108 03:13:06,280 --> 03:13:11,440 TOLERATED DOSE, WHEREAS WE'RE 5109 03:13:11,440 --> 03:13:12,520 HOPING TO OPERATE JUST BEFORE 5110 03:13:12,520 --> 03:13:16,640 THE THRESHOLD REQUIRED TO 5111 03:13:16,640 --> 03:13:17,760 DEPLETE DNMT1. 5112 03:13:17,760 --> 03:13:20,520 THAT'S WHY WE END UP WITH VERY 5113 03:13:20,520 --> 03:13:21,960 SMALL MOLAR EXPOSURES TO THE 5114 03:13:21,960 --> 03:13:24,880 AGENT IN THE CLINIC. 5115 03:13:24,880 --> 03:13:27,840 THERE ARE NEGATIVE PREDICTION 5116 03:13:27,840 --> 03:13:29,960 BIOMARKERS FOR RESPONSE TO 5117 03:13:29,960 --> 03:13:31,120 HYDROXYUREA MOST LIKELY RELATED 5118 03:13:31,120 --> 03:13:33,440 TO ITS MECHANISM OF ACTION AND 5119 03:13:33,440 --> 03:13:35,040 AS YOU WILL SEE, WE DON'T THINK 5120 03:13:35,040 --> 03:13:36,680 THOSE NEGATIVE PREDICTION 5121 03:13:36,680 --> 03:13:42,280 BIOMARKERS APPLY TO DESITE BEAN. 5122 03:13:42,280 --> 03:13:48,320 THERE IS SOME OVERLAP, APPLIED 5123 03:13:48,320 --> 03:13:52,240 IN THIS WAY YOU ALSO GET 5124 03:13:52,240 --> 03:13:52,640 THROMBOCYTOPENIA. 5125 03:13:52,640 --> 03:13:54,560 WE ACTUALLY GET HIGH PLATELET 5126 03:13:54,560 --> 03:13:55,520 COUNTS AS A SIDE EFFECT, BECAUSE 5127 03:13:55,520 --> 03:13:57,560 IT'S NOT CYTOTOXIC, AND THE WAY 5128 03:13:57,560 --> 03:14:00,640 THE DRUG WORKS IS BY 5129 03:14:00,640 --> 03:14:04,560 MANIPULATING MYELOID 5130 03:14:04,560 --> 03:14:06,440 DIFFERENTIATION. 5131 03:14:06,440 --> 03:14:08,240 IN ARE TWO OTHER IMPORTANT 5132 03:14:08,240 --> 03:14:09,160 PROPERTIES OF THIS MOLECULE. 5133 03:14:09,160 --> 03:14:10,680 ONE IS IT'S ACTUALLY A PRODRUG. 5134 03:14:10,680 --> 03:14:12,320 IT HAS TO BE PHOSPHORYLATED AND 5135 03:14:12,320 --> 03:14:15,680 THAT PHOSPHORYLATION DETERMINES 5136 03:14:15,680 --> 03:14:17,280 THE INTRACELLULAR HALF-LIFE AND 5137 03:14:17,280 --> 03:14:20,200 THE ENZYME THAT EXECUTES THAT 5138 03:14:20,200 --> 03:14:25,440 PHOSPHORYLATION IS DEOXYCITABINE 5139 03:14:25,440 --> 03:14:27,960 OR DCK, MUCH MORE HIGHLY 5140 03:14:27,960 --> 03:14:30,240 EXPRESSED IN THE HEMATOPOIETIC 5141 03:14:30,240 --> 03:14:33,200 COMPARTMENT AND WITHIN THE 5142 03:14:33,200 --> 03:14:35,280 MYELOID COMPARTMENT, IT'S MOST 5143 03:14:35,280 --> 03:14:37,920 HIGHLY EXPRESSED WITHIN 5144 03:14:37,920 --> 03:14:42,000 ERYTHROID PRECURSORS. 5145 03:14:42,000 --> 03:14:43,720 SO IN A WAY IT TARGETS THIS DRUG 5146 03:14:43,720 --> 03:14:48,080 TO MYELOID AND -- LINEAGE. 5147 03:14:48,080 --> 03:14:48,880 ANOTHER CLINICAL PROPERTY IS 5148 03:14:48,880 --> 03:14:51,200 IT'S RAPIDLY CATABOLIZED IN OUR 5149 03:14:51,200 --> 03:14:59,160 BODIES BY THIS ENZYME, CYTIDINE 5150 03:14:59,160 --> 03:14:59,800 DEAN MACE. 5151 03:14:59,800 --> 03:15:01,240 IF WE PUSH IT INTO THE VEIN OF A 5152 03:15:01,240 --> 03:15:02,960 HUMAN BEING, YOU CAN'T MEASURE 5153 03:15:02,960 --> 03:15:06,480 THE AGENT AFTER ABOUT FIVE, 5154 03:15:06,480 --> 03:15:07,120 MAXIMUM 10 MINUTES, AND THAT'S 5155 03:15:07,120 --> 03:15:15,040 BECAUSE OF THIS ENZYME CYTIDINE 5156 03:15:15,040 --> 03:15:16,440 DEANAMASE. 5157 03:15:16,440 --> 03:15:18,720 HISTORICALLY WE'VE NEVER 5158 03:15:18,720 --> 03:15:24,200 ADMINISTERED ANALOGS, WHETHER 5159 03:15:24,200 --> 03:15:25,520 DECITABINE, BY THE ORAL ROUTE, 5160 03:15:25,520 --> 03:15:27,720 BECAUSE THEY ALL RAPIDLY 5161 03:15:27,720 --> 03:15:30,000 CATABOLIZE THIS ENZYME, SO ORAL 5162 03:15:30,000 --> 03:15:31,320 BIOAVAILABILITY IS TRIVIAL. 5163 03:15:31,320 --> 03:15:33,840 NOW IT SO HAPPENS THAT THERE IS 5164 03:15:33,840 --> 03:15:38,320 ANOTHER AGENT CALLED 5165 03:15:38,320 --> 03:15:43,240 TETRAHYDROURADINE THAT INHIBITS, 5166 03:15:43,240 --> 03:15:46,080 WE CAN GIVE SMALL AMOUNTS OF 5167 03:15:46,080 --> 03:15:47,160 DECITABINE BY THE ORAL ROUTE AND 5168 03:15:47,160 --> 03:15:50,360 NOW WE GET BIOAVAILABILITY AND A 5169 03:15:50,360 --> 03:15:51,640 HALF-LIFE THAT CAN GO INTO THE 5170 03:15:51,640 --> 03:15:54,720 HOURS. 5171 03:15:54,720 --> 03:15:56,800 AND SO AS I MENTIONED IN THE -- 5172 03:15:56,800 --> 03:15:58,760 RIGHT IN THE BEGINNING, 5173 03:15:58,760 --> 03:16:00,200 DECITABINE IS AN FDA-APPROVED 5174 03:16:00,200 --> 03:16:03,120 DRUG FOR TREATING MYELOID 5175 03:16:03,120 --> 03:16:05,760 MALIGNANCIES, BUT THE DOSAGE 5176 03:16:05,760 --> 03:16:08,880 CONCEPTS THAT KIND OF DROVE HOW 5177 03:16:08,880 --> 03:16:10,360 IT WAS INTRODUCED INTO THE 5178 03:16:10,360 --> 03:16:13,400 CLINIC FOR TREATING MYELOID 5179 03:16:13,400 --> 03:16:15,960 MALIGNANCIES DERIVED FROM THE 5180 03:16:15,960 --> 03:16:16,920 CONVENTIONAL HISTORICAL 5181 03:16:16,920 --> 03:16:20,320 PRINCIPLES IN ONCOLOGY OF TRYING 5182 03:16:20,320 --> 03:16:23,600 TO PAUSE APOPTOSIS, SO THE 5183 03:16:23,600 --> 03:16:25,040 DOSAGE CONCEPTS WERE MAXIMUM 5184 03:16:25,040 --> 03:16:25,560 TOLERATED. 5185 03:16:25,560 --> 03:16:28,200 WHEREAS WE ARE USING MINIMUM BAY 5186 03:16:28,200 --> 03:16:29,480 LOGICALLY EFFECTIVE DOSE SO WE 5187 03:16:29,480 --> 03:16:31,360 GIVE TINY DOSES COMPARED TO THE 5188 03:16:31,360 --> 03:16:32,560 FDA-APPROVED DOSES AND THEN WE 5189 03:16:32,560 --> 03:16:33,640 CAN DISTRIBUTE THOSE FREQUENTLY, 5190 03:16:33,640 --> 03:16:35,840 SO WE CAN GIVE THEM ONCE TO 5191 03:16:35,840 --> 03:16:40,120 TWICE A WEEK. 5192 03:16:40,120 --> 03:16:41,520 SO WE'VE DONE SEVERAL CLINICAL 5193 03:16:41,520 --> 03:16:42,760 TRIALS TO SHOW THAT ACTUALLY YOU 5194 03:16:42,760 --> 03:16:45,920 CAN USE DECITABINE IN NON-HUMAN 5195 03:16:45,920 --> 03:16:47,640 PRIMATES AND IN HUMAN BEINGS IN 5196 03:16:47,640 --> 03:16:49,200 THIS WAY. 5197 03:16:49,200 --> 03:16:53,360 SO TO TARGET DNMT1 OR THE 5198 03:16:53,360 --> 03:16:54,640 MOLECULAR PHARMACODYNAMIC EFFECT 5199 03:16:54,640 --> 03:16:57,400 WITHOUT MEASURABLE CYTOTOXICITY. 5200 03:16:57,400 --> 03:17:00,120 AND WE ALSO DEFINED IN PHASE 5201 03:17:00,120 --> 03:17:04,080 1 TRIALS THE DOSES AND SCHEDULES 5202 03:17:04,080 --> 03:17:12,360 FOR HOW TO COMBINE THE 5203 03:17:12,360 --> 03:17:13,360 TETRAHYDROURIDINE AND DESITE 5204 03:17:13,360 --> 03:17:15,120 BEAN FOR THIS TARGETED MOLECULAR 5205 03:17:15,120 --> 03:17:19,360 THERAPY CONCEPT. 5206 03:17:19,360 --> 03:17:22,400 HERE IS SOME EVIDENCE OF THE 5207 03:17:22,400 --> 03:17:22,720 EFFECT. 5208 03:17:22,720 --> 03:17:26,400 HERE WE'RE TREATING HEALTHY 5209 03:17:26,400 --> 03:17:32,200 VOLUNTEERS SO A TOTAL OF 44 MALE 5210 03:17:32,200 --> 03:17:33,640 AND FEMALE, SMALL AMOUNTS THAT 5211 03:17:33,640 --> 03:17:35,480 WE'RE TALKING ABOUT, AND YOU CAN 5212 03:17:35,480 --> 03:17:37,000 SEE IN THE ENCIRCLE LATING 5213 03:17:37,000 --> 03:17:38,840 T-CELLS IN THE BLOOD, WE GET 5214 03:17:38,840 --> 03:17:42,280 VERY LARGE DECREASES IN 5215 03:17:42,280 --> 03:17:42,800 DNMT1 PROTEIN AMOUNTS. 5216 03:17:42,800 --> 03:17:45,520 SO THAT'S THE INTENDED MOLECULAR 5217 03:17:45,520 --> 03:17:49,360 PHARMACODYNAMIC EFFECT. 5218 03:17:49,360 --> 03:17:50,760 SO THE CLINICAL TRIAL I'M GOING 5219 03:17:50,760 --> 03:17:52,160 TO SHOW YOU IS ACTUALLY THE 5220 03:17:52,160 --> 03:17:54,720 FIRST CLINICAL TRIAL IN WHICH 5221 03:17:54,720 --> 03:17:56,040 WE'RE TREATING SICKLE CELL 5222 03:17:56,040 --> 03:18:02,960 DISEASE PATIENTS WITH THE ORAL 5223 03:18:02,960 --> 03:18:04,240 TETRAHYDRO -- THIS IS THE FIRST 5224 03:18:04,240 --> 03:18:05,240 TO DEFINE THESE DOSES THAT 5225 03:18:05,240 --> 03:18:07,720 YOU'RE GOING TO BE SEEING 5226 03:18:07,720 --> 03:18:09,000 APPLIED HERE, AND THIS IS THE 5227 03:18:09,000 --> 03:18:10,680 FIRST CLINICAL TRIAL TO ACTUALLY 5228 03:18:10,680 --> 03:18:11,560 APPLY THESE DOSES. 5229 03:18:11,560 --> 03:18:14,640 AND SO WE WANTED TO KNOW, CAN WE 5230 03:18:14,640 --> 03:18:16,880 ACTUALLY PRODUCE SUSTAINED FETAL 5231 03:18:16,880 --> 03:18:17,720 HEMOGLOBIN INCREASES OVER A 5232 03:18:17,720 --> 03:18:21,760 PERIOD OF 48 WEEKS, CAN WE 5233 03:18:21,760 --> 03:18:23,760 INCREASE HEMOGLOBIN FOR OVER 48 5234 03:18:23,760 --> 03:18:25,160 WEEKS WITHOUT THE EXPECTED SIDE 5235 03:18:25,160 --> 03:18:29,280 EFFECTS OF NEUTROPENIA OR 5236 03:18:29,280 --> 03:18:30,480 WORRISOME INCREASE IN PLATELET 5237 03:18:30,480 --> 03:18:34,840 COUNTS? 5238 03:18:34,840 --> 03:18:36,400 AND WE ALSO EXAMINED THE 5239 03:18:36,400 --> 03:18:38,800 POTENTIAL ROLE OF VITAL BIN B3. 5240 03:18:38,800 --> 03:21:42,560 OTHER NAMES ARE NICOTINAMIDE OR 5241 03:21:42,560 --> 03:21:43,880 SO WE DID SEE THE EXPD 5242 03:21:43,880 --> 03:21:47,120 TRENDS BUT THEY DID NOT CROSS 5243 03:21:47,120 --> 03:21:48,040 THRESHOLDS THAT REQUIRED HOLDING 5244 03:21:48,040 --> 03:21:49,440 OF ANY OF THE AGENTS. 5245 03:21:49,440 --> 03:21:54,040 I WILL SHOW YOU THE DATA ON THE 5246 03:21:54,040 --> 03:21:55,600 GRADE 3 AND 4 ADVERSE EVENTS. 5247 03:21:55,600 --> 03:21:58,840 AND SO THESE ARE THE DEMOGRAPHIC 5248 03:21:58,840 --> 03:22:00,200 CHARACTERISTICS OF THE SIX 5249 03:22:00,200 --> 03:22:02,560 PATIENTS. 5250 03:22:02,560 --> 03:22:06,400 UP HERE, SO EACH COLUMN IS A 5251 03:22:06,400 --> 03:22:06,640 PATIENT. 5252 03:22:06,640 --> 03:22:09,040 AS YOU CAN SEE, THEY ARE 5253 03:22:09,040 --> 03:22:10,040 SEVERELY ILL SICKLE CELL DISEASE 5254 03:22:10,040 --> 03:22:11,960 PATIENTS IN TERMS OF THEIR 5255 03:22:11,960 --> 03:22:15,200 COMPLICATION PROFILE. 5256 03:22:15,200 --> 03:22:20,720 THESE ARE THE VASO-OCCLUSIVE -- 5257 03:22:20,720 --> 03:22:22,440 THAT HAPPENED IN THE SIX WEEKS 5258 03:22:22,440 --> 03:22:24,120 PRIOR TO ENROLLMENT. 5259 03:22:24,120 --> 03:22:25,560 NONE OF THESE SIX PATIENTS HAD 5260 03:22:25,560 --> 03:22:27,600 DOSE LIMITING TOXICITY FOR THE 5261 03:22:27,600 --> 03:22:29,560 PROTOCOL, AND THREE OF THESE 5262 03:22:29,560 --> 03:22:31,880 PATIENTS HAD VASOOCCLUSIVE 5263 03:22:31,880 --> 03:22:33,520 CRISES ON STUDY. 5264 03:22:33,520 --> 03:22:35,480 ONE DURING THE FOLLOW-UP PHASE 5265 03:22:35,480 --> 03:22:37,480 AFTER THE STUDY DRUGS WERE 5266 03:22:37,480 --> 03:22:42,840 DISCONTINUED DURING THE 48-WEEK 5267 03:22:42,840 --> 03:22:43,800 TO 52-WEEK. 5268 03:22:43,800 --> 03:22:45,720 ONE WHILE THEY WERE RECEIVING 5269 03:22:45,720 --> 03:22:46,480 COMBINATION THERAPY AND ONE 5270 03:22:46,480 --> 03:22:47,520 WHILE THEY WERE RECEIVING 5271 03:22:47,520 --> 03:22:48,120 NICOTINAMIDE ALONE. 5272 03:22:48,120 --> 03:22:50,400 THERE WERE THREE OTHER GRADE 5273 03:22:50,400 --> 03:22:53,000 3 TO 4 ADVERSE EVENTS. 5274 03:22:53,000 --> 03:23:04,080 HYPOTHAT LEEHYPOKALEMIA -- AND E 5275 03:23:04,800 --> 03:23:05,920 OBJECTIVE LABORATORY PARAMETERS, 5276 03:23:05,920 --> 03:23:09,000 SO ON THE X AXIS, ON ALL THE 5277 03:23:09,000 --> 03:23:10,640 GRAPHS THAT I'M GOING TO SHOW IS 5278 03:23:10,640 --> 03:23:14,280 THE FULL STUDY PERIOD, SO 52 5279 03:23:14,280 --> 03:23:18,280 WEEKS IN TOTAL AND IN ORANGE IS 5280 03:23:18,280 --> 03:23:19,600 THE 12-WEEK PERIOD WHERE THEY 5281 03:23:19,600 --> 03:23:21,280 WERE RECEIVING NICOTINAMIDE 5282 03:23:21,280 --> 03:23:23,200 ALONE, IN BLUE IS WHERE THEY'RE 5283 03:23:23,200 --> 03:23:33,960 GETTING THU AND DESITE MEAN -- E 5284 03:23:38,160 --> 03:23:39,960 SIX PATIENTS ACTUALLY HAD A VERY 5285 03:23:39,960 --> 03:23:43,360 HIGH BODY WEIGHT WHICH WAS NOT 5286 03:23:43,360 --> 03:23:45,240 ANTICIPATED IN HOW WE WROTE THE 5287 03:23:45,240 --> 03:23:48,400 PROTOCOL SO THE DOSE SHE 5288 03:23:48,400 --> 03:23:51,680 RECEIVED OF THE THU WAS BELOW 5289 03:23:51,680 --> 03:23:55,440 THE MINL MEDIC MINIMALLY EFFECT. 5290 03:23:55,440 --> 03:23:57,280 THIS PATIENT HAD NO INCREASE IN 5291 03:23:57,280 --> 03:23:59,520 FETAL HEMOGLOBIN BUT EVERYBODY 5292 03:23:59,520 --> 03:24:01,120 ELSE, THERE WAS AN INCREASE IN 5293 03:24:01,120 --> 03:24:02,960 FETAL HEMOGLOBIN. 5294 03:24:02,960 --> 03:24:10,000 WITH THE THU DECITABINE ALONE -- 5295 03:24:10,000 --> 03:24:11,080 INTRODUCED INTO THE REGIMEN. 5296 03:24:11,080 --> 03:24:12,400 THOSE LEVELS WERE SUSTAINED. 5297 03:24:12,400 --> 03:24:13,920 ALTHOUGH IN TWO PATIENTS, WE 5298 03:24:13,920 --> 03:24:16,320 OBSERVED SOME DECLINE IN THE 5299 03:24:16,320 --> 03:24:17,760 FETAL HEMOGLOBIN AFTER 5300 03:24:17,760 --> 03:24:19,280 NICOTINAMIDE WAS INTRODUCED INTO 5301 03:24:19,280 --> 03:24:23,440 THE REGIMEN. 5302 03:24:23,440 --> 03:24:25,200 WE DID SOME SUBSEQUENT WORK AND 5303 03:24:25,200 --> 03:24:26,160 WE THINK WE KNOW WHY AND I'LL 5304 03:24:26,160 --> 03:24:27,280 TALK ABOUT THAT LATER. 5305 03:24:27,280 --> 03:24:28,920 AND HERE ARE THE TOTAL 5306 03:24:28,920 --> 03:24:30,760 HEMOGLOBIN LEVELS ON THERAPY. 5307 03:24:30,760 --> 03:24:34,800 AGAIN, WE SEE INCREASES IN TOTAL 5308 03:24:34,800 --> 03:24:36,560 HEMOGLOBIN, MOST OBVIOUSLY WITH 5309 03:24:36,560 --> 03:24:38,760 THE THU DECITABINE. 5310 03:24:38,760 --> 03:24:39,840 THERE WAS SOME SMALL INCREASE 5311 03:24:39,840 --> 03:24:41,720 WITH THE NICOTINAMIDE ALONE IN 5312 03:24:41,720 --> 03:24:43,480 THIS ONE PATIENT, AND IN THE TWO 5313 03:24:43,480 --> 03:24:45,840 PATIENTS IN WHOM FETAL 5314 03:24:45,840 --> 03:24:47,840 HEMOGLOBIN WENT DOWN AFTER THE 5315 03:24:47,840 --> 03:24:51,080 INITIATION OF NICOTINAMIDE, HEME 5316 03:24:51,080 --> 03:24:53,440 LEVELS ACTUALLY KIND OF STAYED 5317 03:24:53,440 --> 03:24:53,600 UP. 5318 03:24:53,600 --> 03:24:56,840 SO THE HEMOGLOBIN LEVELS DID NOT 5319 03:24:56,840 --> 03:24:58,600 DECLINE TO THE EXTENT THAT ONE 5320 03:24:58,600 --> 03:24:59,880 MIGHT HAVE EXPECTED FROM THE 5321 03:24:59,880 --> 03:25:01,520 DECLINE IN THE FETAL HEMOGLOBIN. 5322 03:25:01,520 --> 03:25:02,840 HERE THE NEUTROPHIL COUNTS AND 5323 03:25:02,840 --> 03:25:04,680 THE PLATELET COUNTS, SO AS 5324 03:25:04,680 --> 03:25:06,320 EXPECTED, THERE WAS A DOWNWARD 5325 03:25:06,320 --> 03:25:08,160 TREND IN NEUTROPHIL COUNTS ON 5326 03:25:08,160 --> 03:25:10,480 THERAPY, BUT IT DID NOT CROSS 5327 03:25:10,480 --> 03:25:13,880 THRESHOLDS FOR NEUTROPENIA. 5328 03:25:13,880 --> 03:25:15,520 EVEN HIGHLY CONSERVATIVE 5329 03:25:15,520 --> 03:25:16,400 THRESHOLDS FOR NEUTROPENIA. 5330 03:25:16,400 --> 03:25:18,720 HERE ARE THE PLATELET COUNTS AND 5331 03:25:18,720 --> 03:25:19,360 THERAPIES EXPECTED. 5332 03:25:19,360 --> 03:25:21,560 THERE WERE TRENDS FOR INCREASING 5333 03:25:21,560 --> 03:25:28,560 PLATELET COUNTS ON THE THU 5334 03:25:28,560 --> 03:25:29,640 DECITABINE BUT -- THAT WE 5335 03:25:29,640 --> 03:25:30,840 TYPICALLY SEE IN PATIENTS WITH 5336 03:25:30,840 --> 03:25:31,720 SICKLE CELL DISEASE ANYWAY. 5337 03:25:31,720 --> 03:25:34,840 HERE IS THE LDH DECLINE -- WE 5338 03:25:34,840 --> 03:25:36,000 SAUDI KLEINS ON NICOTINAMIDE 5339 03:25:36,000 --> 03:25:40,320 ALONE AS WELL AS ON THE 5340 03:25:40,320 --> 03:25:41,560 THU/DECITABINE. 5341 03:25:41,560 --> 03:25:44,640 WE SAUDI KLEINS IN TOTAL 5342 03:25:44,640 --> 03:25:45,480 BILIRUBIN ON NICOTINAMIDE ALONE 5343 03:25:45,480 --> 03:25:49,440 AS WELL AS ON THU/DECITABINE. 5344 03:25:49,440 --> 03:25:52,480 HERE'S D-DIMERSER AND CRP, 5345 03:25:52,480 --> 03:25:53,800 AGAIN, WE SAW SOME -- YOU CAN 5346 03:25:53,800 --> 03:25:58,400 SEE FOR YOURSELF. 5347 03:25:58,400 --> 03:26:00,160 THE CRPs KIND OF BOUNCE AROUND 5348 03:26:00,160 --> 03:26:02,360 A LITTLE BIT MORE. 5349 03:26:02,360 --> 03:26:03,240 OKAY. 5350 03:26:03,240 --> 03:26:06,480 SO THIS INTERIM ANALYSIS -- THE 5351 03:26:06,480 --> 03:26:15,240 ON VEST -- TTHERE'S OBVIOUS LIME 5352 03:26:15,240 --> 03:26:18,040 BUT THU/DECITABINE IS THE FIRST 5353 03:26:18,040 --> 03:26:20,280 AND THE LONGEST LONG-TERM 5354 03:26:20,280 --> 03:26:20,840 TREATMENT OF PATIENTS WITH 5355 03:26:20,840 --> 03:26:22,680 SICKLE CELL DISEASE, SO WE HAVE 5356 03:26:22,680 --> 03:26:26,720 ABOUT A YEAR OF DATA ON THESE 5357 03:26:26,720 --> 03:26:27,840 SIX PATIENTS. 5358 03:26:27,840 --> 03:26:29,040 AND CONSISTENT WITH THE DATA, 5359 03:26:29,040 --> 03:26:31,040 WITH THE SUBCUTANEOUS 5360 03:26:31,040 --> 03:26:32,320 DECITABINE, WE DON'T SEE 5361 03:26:32,320 --> 03:26:36,360 NEGATIVE PREDICTION BIOMARKERS 5362 03:26:36,360 --> 03:26:39,960 THAT OPERATE FOR HYDROXYUREA 5363 03:26:39,960 --> 03:26:41,200 APPLYING FOR THIS AGENT. 5364 03:26:41,200 --> 03:26:42,520 WE HAVE DISCOVERED AGAIN THERE 5365 03:26:42,520 --> 03:26:43,920 IS A MINIMUM BIOLOGICALLY 5366 03:26:43,920 --> 03:26:46,040 EFFECTIVE DOSE SO IF WE GO BELOW 5367 03:26:46,040 --> 03:26:47,120 THAT, WE'RE NOT GOING TO SEE THE 5368 03:26:47,120 --> 03:26:48,000 BENEFITS. 5369 03:26:48,000 --> 03:26:49,640 WE SEE SUSTAINED IMPROVEMENTS IN 5370 03:26:49,640 --> 03:26:54,040 BOTH OBJECTIVE AND SUBJECTIVE 5371 03:26:54,040 --> 03:26:54,360 BIOMARKERS. 5372 03:26:54,360 --> 03:26:58,200 WE DO THINK THERE'S ACTIVITY 5373 03:26:58,200 --> 03:27:00,800 WITH NICOTINAMIDE, BUT BASED 5374 03:27:00,800 --> 03:27:02,560 ALSO ON IN VITRO STUDIES, WE 5375 03:27:02,560 --> 03:27:05,840 THINK IT DIRECTLY ANTAGONIZES 5376 03:27:05,840 --> 03:27:10,320 THE UPTAKE OF DECITABINE BECAUSE 5377 03:27:10,320 --> 03:27:13,880 IT IS AN ENERGY -- FOR CELLS AND 5378 03:27:13,880 --> 03:27:17,880 THEY USE IT FOR DE NOVO PEER MI 5379 03:27:17,880 --> 03:27:18,320 DEAN SYNTHESIS. 5380 03:27:18,320 --> 03:27:20,800 SO WE'RE GOING TO MODIFY/AMEND 5381 03:27:20,800 --> 03:27:24,680 THE PROTOCOL SUCH THAT THE 5382 03:27:24,680 --> 03:27:26,880 PATIENTS DO NOT TAKE VITAMIN 5383 03:27:26,880 --> 03:27:33,200 B3 ON THE DAY THEY TAKE THE 5384 03:27:33,200 --> 03:27:33,600 THU/DECITABINE. 5385 03:27:33,600 --> 03:27:34,840 THAT'S THE LAST POINT. 5386 03:27:34,840 --> 03:27:36,680 SO I THINK I'LL END THERE AND 5387 03:27:36,680 --> 03:27:38,040 DOES ANYBODY HAVE ANY QUESTIONS? 5388 03:27:38,040 --> 03:27:43,840 THANK YOU VERY MUCH. 5389 03:27:43,840 --> 03:27:46,280 >>THANK YOU, YOGEN. 5390 03:27:46,280 --> 03:27:48,920 IS THERE AN ONLINE QUESTION FOR 5391 03:27:48,920 --> 03:27:49,120 YOGEN? 5392 03:27:49,120 --> 03:27:51,800 >>YES, WE DO HAVE AN ONLINE 5393 03:27:51,800 --> 03:27:52,880 QUESTION. 5394 03:27:52,880 --> 03:27:56,160 WHAT DOSE OF NICOTINAMIDE -- ANY 5395 03:27:56,160 --> 03:28:00,760 LIVER TOXICITY OR FLUSHING CAN 5396 03:28:00,760 --> 03:28:05,440 BE CONFUSING FOR CONSUMERS 5397 03:28:05,440 --> 03:28:07,720 LOOKING AT -- AS SO MANY 5398 03:28:07,720 --> 03:28:08,080 DIFFERENT FORMS. 5399 03:28:08,080 --> 03:28:09,640 I'M READING DIRECTLY. 5400 03:28:09,640 --> 03:28:09,840 SORRY. 5401 03:28:09,840 --> 03:28:12,440 >>THANK YOU FOR THAT QUESTION. 5402 03:28:12,440 --> 03:28:17,480 SO IT EASY FOR PATIENTS TO GET 5403 03:28:17,480 --> 03:28:18,240 CONFUSED BETWEEN NICOTINAMIDE 5404 03:28:18,240 --> 03:28:21,840 AND NIACIN. 5405 03:28:21,840 --> 03:28:23,040 SO FOR OBVIOUS REASONS, THE 5406 03:28:23,040 --> 03:28:24,080 NAME. 5407 03:28:24,080 --> 03:28:26,640 SO VITAMIN B3, ANOTHER NAME FOR 5408 03:28:26,640 --> 03:28:28,080 IT IS NIACINAMIDE, WHICH IS 5409 03:28:28,080 --> 03:28:29,160 ACTUALLY DIFFERENT FROM NIACIN, 5410 03:28:29,160 --> 03:28:30,840 BUT I HAVE SEEN THIS HAPPEN 5411 03:28:30,840 --> 03:28:32,760 WHERE PATIENTS WILL GO TO THE 5412 03:28:32,760 --> 03:28:38,000 VITAMIN SHOP OR THE CVS OR 5413 03:28:38,000 --> 03:28:43,920 WHATEVER, AND ASK FOR NI 5414 03:28:43,920 --> 03:28:45,240 NIACINAMIDE AND LEAVE WITH 5415 03:28:45,240 --> 03:28:46,560 NIACIN AND HAVE SIDE EFFECTS. 5416 03:28:46,560 --> 03:28:49,280 WE DON'T SEE SIDE EFFECTS WHEN 5417 03:28:49,280 --> 03:28:53,560 THEY ACTUALLY TAKE VITAMIN B3. 5418 03:28:53,560 --> 03:28:54,760 ONE SIDE EFFECT, I DON'T SHOW IT 5419 03:28:54,760 --> 03:28:59,880 IN THIS TRIAL DATA, BUT JUST 5420 03:28:59,880 --> 03:29:01,080 FROM CLINICAL EXPERIENCES, WE 5421 03:29:01,080 --> 03:29:02,720 CAN SEE A DECREASE IN PLATELET 5422 03:29:02,720 --> 03:29:04,960 COUNTS EVEN AS HEMOGLOBIN 5423 03:29:04,960 --> 03:29:05,440 INCREASES. 5424 03:29:05,440 --> 03:29:06,840 SO THAT IS A SIDE EFFECT, BUT IN 5425 03:29:06,840 --> 03:29:10,240 TERM OF HOW PATIENTS FEEL, 5426 03:29:10,240 --> 03:29:11,480 FLUSHING, GI, WE DON'T GET 5427 03:29:11,480 --> 03:29:13,200 ANYTHING LIKE THAT. 5428 03:29:13,200 --> 03:29:15,280 WITH NIACINAMIDE. 5429 03:29:15,280 --> 03:29:25,840 WHICH IS NOT THE SAME ACINI SIN. 5430 03:29:29,320 --> 03:29:39,400 THANK YOU. 5431 03:29:40,120 --> 03:29:43,440 DI 5432 03:29:43,440 --> 03:29:44,000 [INAUDIBLE QUESTION] 5433 03:29:44,000 --> 03:29:47,960 >>DID YOU SAY HEPATOTOXICITY? 5434 03:29:47,960 --> 03:29:49,240 >>I CAN REPEAT THE QUESTION. 5435 03:29:49,240 --> 03:29:50,000 HI. 5436 03:29:50,000 --> 03:29:51,360 LYDIA PACKARD, JOHNS HOPKINS. 5437 03:29:51,360 --> 03:29:52,760 THANK YOU FOR YOUR VERY HOPEFUL 5438 03:29:52,760 --> 03:29:54,480 TALK. 5439 03:29:54,480 --> 03:29:56,160 AND FOR REALLY INTERESTING DATA. 5440 03:29:56,160 --> 03:29:59,680 I WONDERED AS WE LOOK TO A 5441 03:29:59,680 --> 03:30:01,000 HOPEFUL TIME WHEN PEOPLE ARE 5442 03:30:01,000 --> 03:30:04,720 IMAIRING WHICH TRCOMPARING WHICY 5443 03:30:04,720 --> 03:30:06,120 WILL USE TO TREAT THEIR SICKLE 5444 03:30:06,120 --> 03:30:08,320 CELL DISEASE, I WAS WONDERING IF 5445 03:30:08,320 --> 03:30:10,760 YOU WOULD SPEAK TO THE 5446 03:30:10,760 --> 03:30:16,760 ESTABLISHED OR -- GONADOTOXICITY 5447 03:30:16,760 --> 03:30:17,480 OF THIS THERAPY? 5448 03:30:17,480 --> 03:30:18,200 >>THAT'S SOMETHING WE 5449 03:30:18,200 --> 03:30:20,360 DEFINITELY WILL HAVE TO LOOK 5450 03:30:20,360 --> 03:30:21,440 FORMALLY IN THE CLINICAL TRIAL 5451 03:30:21,440 --> 03:30:24,040 SETTING. 5452 03:30:24,040 --> 03:30:29,440 MY REASONS FOR BEING HOPEFUL, NO 5453 03:30:29,440 --> 03:30:31,720 DATA, BUT FOR BEING HOPEFUL ARE 5454 03:30:31,720 --> 03:30:33,680 KIND OF WHAT I SHOWED YOU IN THE 5455 03:30:33,680 --> 03:30:34,840 BEGINNING. 5456 03:30:34,840 --> 03:30:38,840 THESE DRUGS ARE PRO DRUGS, AND 5457 03:30:38,840 --> 03:30:42,560 THE TISSUE COMPARTMENT THAT IS 5458 03:30:42,560 --> 03:30:44,120 REALLY ENRICHED FOR THE ENZYMES 5459 03:30:44,120 --> 03:30:46,600 THAT ACTIVATE THE PRODRUG IS THE 5460 03:30:46,600 --> 03:30:49,000 MYELOID COMPARTMENT. 5461 03:30:49,000 --> 03:30:50,720 SO IT'S NO COINCIDENCE, FOR 5462 03:30:50,720 --> 03:30:51,920 EXAMPLE, THAT THESE DRUGS ARE 5463 03:30:51,920 --> 03:30:53,840 USED TO TREAT MYELOID 5464 03:30:53,840 --> 03:30:57,800 MALIGNANCIES, EVEN THOUGH DN MTR 5465 03:30:57,800 --> 03:30:58,880 TREATING ALL SORTS OF CANCERS, 5466 03:30:58,880 --> 03:31:01,840 BUT THERE ARE ONLY IN THE CLINIC 5467 03:31:01,840 --> 03:31:02,920 FDA-APPROVED FOR MYELOID. 5468 03:31:02,920 --> 03:31:06,240 IT'S RELATED TO THIS METABOLIC 5469 03:31:06,240 --> 03:31:07,680 ASPECT, AND NOW IF YOU GIVE A 5470 03:31:07,680 --> 03:31:09,200 LOT OF THE DRUG, OF COURSE 5471 03:31:09,200 --> 03:31:11,840 YOU'RE GOING TO GET ALL SORTS OF 5472 03:31:11,840 --> 03:31:15,400 PLACES, AND SO WE'RE GIVING SUCH 5473 03:31:15,400 --> 03:31:18,920 SMALL AMOUNTS AND GIVEN THIS 5474 03:31:18,920 --> 03:31:20,680 TARGETED CHARACTER, I THINK 5475 03:31:20,680 --> 03:31:23,000 THERE IS A REASON TO HOPE THAT 5476 03:31:23,000 --> 03:31:25,560 THERE MAY NOT BE GONADOTOXICITY. 5477 03:31:25,560 --> 03:31:27,840 BUT WE NEED TO LOOK FOR IT AND 5478 03:31:27,840 --> 03:31:35,920 EVALUATE FOR IT. 5479 03:31:35,920 --> 03:31:40,080 >>THANK YOU AGAIN, YOGEN. 5480 03:31:40,080 --> 03:31:41,280 SO OUR NEXT SPEAKER IS GOING TO 5481 03:31:41,280 --> 03:31:44,000 BE TALKING ABOUT CRISPR SICKLE 5482 03:31:44,000 --> 03:31:46,400 CELL DISEASE GENE EDITING TRIAL 5483 03:31:46,400 --> 03:31:46,840 UPDATE. 5484 03:31:46,840 --> 03:31:49,920 SO THE NEXT TWO TALKS ARE GOING 5485 03:31:49,920 --> 03:31:52,520 TO BE DR. MARK WALTERS FROM 5486 03:31:52,520 --> 03:31:53,560 UNIVERSITY OF CALIFORNIA, AND HE 5487 03:31:53,560 --> 03:31:55,160 WILL BE FOLLOWED BY DR. DAVID 5488 03:31:55,160 --> 03:32:05,320 WILLIAMS. 5489 03:32:05,560 --> 03:32:06,640 >>THANK YOU VERY MUCH. 5490 03:32:06,640 --> 03:32:08,720 GOOD AFTERNOON, EVERYONE. 5491 03:32:08,720 --> 03:32:09,720 I APPRECIATE THE OPPORTUNITY TO 5492 03:32:09,720 --> 03:32:10,920 GIVE AN UPDATE ABOUT OUR 5493 03:32:10,920 --> 03:32:12,440 CLINICAL TRIAL, WHICH IS STILL 5494 03:32:12,440 --> 03:32:13,480 IN THE PRE-CLINICAL PHASE OF 5495 03:32:13,480 --> 03:32:17,320 DEVELOPMENT. 5496 03:32:17,320 --> 03:32:19,360 SO I WANT TO HIGHLIGHT THE 5497 03:32:19,360 --> 03:32:20,240 PROJECT TEAM. 5498 03:32:20,240 --> 03:32:22,880 THE GENE EDITING REAGENTS, THE 5499 03:32:22,880 --> 03:32:25,080 EDITORS THAT WE'RE USING WERE 5500 03:32:25,080 --> 03:32:27,800 VELLED BY JACOB CORN AND MARK 5501 03:32:27,800 --> 03:32:28,600 DEWITT. 5502 03:32:28,600 --> 03:32:32,160 THOSE CONTINUE TO BE UTILIZED IN 5503 03:32:32,160 --> 03:32:36,320 THE MANUFACTURING PROTOCOL. 5504 03:32:36,320 --> 03:32:41,680 DAWN AND ZULEMA HAVE MADE SOME 5505 03:32:41,680 --> 03:32:42,920 IMPROVEMENTS TO THE PROTOCOL 5506 03:32:42,920 --> 03:32:44,000 WHICH HAS BEEN SUBMITTED IN 5507 03:32:44,000 --> 03:32:45,560 AMENDMENT TO THE IND, AND I'M 5508 03:32:45,560 --> 03:32:52,320 GOING TO SPEND A FAIR AMOUNT OF 5509 03:32:52,320 --> 03:32:54,600 TIME -- YES, I CAN. 5510 03:32:54,600 --> 03:33:00,200 LET ME SCRUNCH DOWN HERE. 5511 03:33:00,200 --> 03:33:01,520 THE BULK OF WHAT I'M GOING TO 5512 03:33:01,520 --> 03:33:05,680 PRESENT ARE ANALYSES BY DARIO 5513 03:33:05,680 --> 03:33:08,760 AND STACIA, WHO HEAD THE 5514 03:33:08,760 --> 03:33:09,360 BIOINFORMATICS TEAM ON THE 5515 03:33:09,360 --> 03:33:10,280 PROJECT. 5516 03:33:10,280 --> 03:33:15,720 AND THIS IS, OFTE OF COURSE, FUD 5517 03:33:15,720 --> 03:33:17,480 IN A PARTNERSHIP BETWEEN THE 5518 03:33:17,480 --> 03:33:18,280 CALIFORNIA INSTITUTE OF 5519 03:33:18,280 --> 03:33:21,960 REGENERATIVE MEDICINE AND NIH 5520 03:33:21,960 --> 03:33:22,720 NHLBI CURE SICKLE CELL 5521 03:33:22,720 --> 03:33:23,320 INITIATIVE. 5522 03:33:23,320 --> 03:33:25,960 I'M GOING TO START WITH THIS 5523 03:33:25,960 --> 03:33:28,240 SCHEMATIC OF THE TARGET SITE FOR 5524 03:33:28,240 --> 03:33:31,080 CRISPR/CAS 9 EDITING. 5525 03:33:31,080 --> 03:33:38,000 THE SEQUENCE ENCODES FOR 168 -- 5526 03:33:38,000 --> 03:33:40,200 IT ACTS AS THE DONOR FOR 5527 03:33:40,200 --> 03:33:42,240 HOMOLOGY DIRECTED REPAIR. 5528 03:33:42,240 --> 03:33:48,280 SO UNLIKE THE PRESENTATION THAT 5529 03:33:48,280 --> 03:33:50,240 MATT GAVE IN THE TRIAL LED BY 5530 03:33:50,240 --> 03:33:52,320 GRAPHITE BIO, THE DONOR IN THAT 5531 03:33:52,320 --> 03:33:53,920 PARTICULAR TRIAL IS A VIRAL 5532 03:33:53,920 --> 03:33:55,800 TEMPLATE, AV6. 5533 03:33:55,800 --> 03:33:57,240 OTHERWISE THE GUIDE RNA AND THE 5534 03:33:57,240 --> 03:34:00,720 KACAS9 ARE THE SAME IN BOTH. 5535 03:34:00,720 --> 03:34:04,080 WHAT I'VE UNDERLINED IN RED IS 5536 03:34:04,080 --> 03:34:05,960 WHERE THE COMPLEMENTARITY WITH 5537 03:34:05,960 --> 03:34:08,360 THE TEMPLATE OCCURS AND THEN THE 5538 03:34:08,360 --> 03:34:09,680 CLEAVAGE SITE IS THE RED 5539 03:34:09,680 --> 03:34:10,120 TRIANGLE. 5540 03:34:10,120 --> 03:34:14,400 SO THAT'S WHERE THE TEMPLATE 5541 03:34:14,400 --> 03:34:16,320 STRAND EXTENSION BEGINS TO 5542 03:34:16,320 --> 03:34:18,640 REPLACE THE SICKLE CODON WITH 5543 03:34:18,640 --> 03:34:20,480 THE WILD TYPE CODON, IT ADDS A 5544 03:34:20,480 --> 03:34:24,240 MUTATION TO THE PAM SITE SO THAT 5545 03:34:24,240 --> 03:34:26,080 REEDITING DOESN'T OCCUR ONCE HDR 5546 03:34:26,080 --> 03:34:29,240 HAS OCCURRED, AND THEN WE'VE 5547 03:34:29,240 --> 03:34:32,520 INCORPORATED ADDITIONAL SINGLE 5548 03:34:32,520 --> 03:34:34,520 BASE PAIR CHANGES TO KNOW THE 5549 03:34:34,520 --> 03:34:38,120 DIFFERENCE BETWEEN HGR AND 5550 03:34:38,120 --> 03:34:40,200 UNEDITED CELLS. 5551 03:34:40,200 --> 03:34:42,200 SO WHAT YOU MIGHT NOTICE IS THAT 5552 03:34:42,200 --> 03:34:45,760 THE SICKLE SNP IS DOWNSTREAM 5553 03:34:45,760 --> 03:34:46,880 FROM THE CLEAVAGE SITE, SO IT'S 5554 03:34:46,880 --> 03:34:49,160 POSSIBLE FOR THE TEMPLATE FORK 5555 03:34:49,160 --> 03:34:57,000 TO FALL OFF, EXTENDING -- THE 5556 03:34:57,000 --> 03:34:58,720 EXTENDING NATIVE STRAIN -- I'M 5557 03:34:58,720 --> 03:35:01,560 SORRY -- AS THAT EXTENSION 5558 03:35:01,560 --> 03:35:02,760 OCCURS BEFORE IT REACHES THE 5559 03:35:02,760 --> 03:35:03,320 SICKLE MUTATION. 5560 03:35:03,320 --> 03:35:05,640 SO THOSE WILL STILL SCORE AS HGR 5561 03:35:05,640 --> 03:35:07,080 EVENTS BECAUSE THE PAM HAS BEEN 5562 03:35:07,080 --> 03:35:10,120 MUTATED, BUT WON'T RESULT IN AN 5563 03:35:10,120 --> 03:35:11,880 ALTERED SICKLE SNP. 5564 03:35:11,880 --> 03:35:13,840 I'LL REFER TO THIS LATER IN A 5565 03:35:13,840 --> 03:35:14,840 SUBSEQUENT SLIDE BECAUSE IT 5566 03:35:14,840 --> 03:35:21,080 BECOMES IMPORTANT. 5567 03:35:21,080 --> 03:35:23,920 SO SEVERAL HUNDRED MICE WERE 5568 03:35:23,920 --> 03:35:31,800 XENOGRAFTED FOLLOWING ELECTRO 5569 03:35:31,800 --> 03:35:37,840 PORATION, HUMAN HEMATOPOIETIC 5570 03:35:37,840 --> 03:35:42,640 STEM CELLS AND RA HARVESTED 16 5571 03:35:42,640 --> 03:35:42,960 WEEKS LATER. 5572 03:35:42,960 --> 03:35:44,760 I'M GOING TO WALK FROM LEFT TO 5573 03:35:44,760 --> 03:35:46,280 RIGHT, SO BEGINNING WITH THE 5574 03:35:46,280 --> 03:35:48,680 PINK BARS, THOSE ARE THE 5575 03:35:48,680 --> 03:35:49,640 UNEDITED CONTROLS AND WHAT WE 5576 03:35:49,640 --> 03:35:54,680 DID IN THIS EXPERIMENT WAS TO 5577 03:35:54,680 --> 03:35:58,600 COMPARE UNFR UNFRACTION ATED BOE 5578 03:35:58,600 --> 03:36:01,840 MARROW, POSITIVE SELECTED HUMAN 5579 03:36:01,840 --> 03:36:11,240 CELLS AND -- GLYCOPORIN, SO IN 5580 03:36:11,240 --> 03:36:13,080 THAT INSTANCE WHERE THE 5581 03:36:13,080 --> 03:36:13,960 EXTENDING REPLICATION FORK FALLS 5582 03:36:13,960 --> 03:36:17,920 OFF BEFORE CORRECTING THE SNP 5583 03:36:17,920 --> 03:36:22,200 ALLELE, THE SICKLE ALLELE, 5584 03:36:22,200 --> 03:36:23,600 PAM-ONLY HDR LUCKILY ONLY 5585 03:36:23,600 --> 03:36:25,240 HAPPENS ABOUT 5% OF THE TIME, 5586 03:36:25,240 --> 03:36:27,000 AND THAT CONTRASTS WITH THOSE 5587 03:36:27,000 --> 03:36:29,240 MICE SCORED AS HAVING 5588 03:36:29,240 --> 03:36:30,640 SICKLE-CORRECTED HGRs. 5589 03:36:30,640 --> 03:36:32,600 SO THIS OCCURS ABOUT 20 TO 25% 5590 03:36:32,600 --> 03:36:36,560 OF THE TIME. 5591 03:36:36,560 --> 03:36:38,080 EACH MOUSE DEPICTED BY AN OPEN 5592 03:36:38,080 --> 03:36:40,600 GREY CIRCLE. 5593 03:36:40,600 --> 03:36:45,000 THE CORRECTION OCCURS AT EQUAL 5594 03:36:45,000 --> 03:36:46,120 FREQUENCY IN BOTH CELLS BUT 5595 03:36:46,120 --> 03:36:48,760 WHAT'S INTERESTING, THE 5596 03:36:48,760 --> 03:36:52,040 ERYTHROID LINEAGE, YOU SEE THIS 5597 03:36:52,040 --> 03:36:53,240 FOR CORRECTED ALLELES AND IT 5598 03:36:53,240 --> 03:36:54,800 ACCOUNTS FOR NEARLY 50% OF THE 5599 03:36:54,800 --> 03:36:56,000 MICE THAT WERE SCORED. 5600 03:36:56,000 --> 03:37:00,280 SO JUST AS OCCURS IN STABLE -- 5601 03:37:00,280 --> 03:37:01,360 ALLOGENIC TRANSPLANTATION, EVEN 5602 03:37:01,360 --> 03:37:03,720 AT THE LEVEL OF INEFFECTIVE 5603 03:37:03,720 --> 03:37:05,000 ERYTHROPOIESIS IN THE BONE 5604 03:37:05,000 --> 03:37:06,120 MARROWS OF THESE MICE, THERE'S 5605 03:37:06,120 --> 03:37:09,160 EXPANSION OF A CORRECTED 5606 03:37:09,160 --> 03:37:10,200 ERYTHROID COMPARTMENT. 5607 03:37:10,200 --> 03:37:14,240 THE NEXT TWO PANELS IN GREEN AND 5608 03:37:14,240 --> 03:37:17,440 YELLOW REPRESENT NON-HOMOLOGOUS 5609 03:37:17,440 --> 03:37:18,400 END JOINING. 5610 03:37:18,400 --> 03:37:19,760 THESE CREATE INSERTION DELETIONS 5611 03:37:19,760 --> 03:37:21,800 THAT TYPICALLY WILL CAUSE OUT OF 5612 03:37:21,800 --> 03:37:25,520 FRAME MUTATIONS THAT ELICIT A 5613 03:37:25,520 --> 03:37:27,160 THALASSEMIA GENOTYPE. 5614 03:37:27,160 --> 03:37:30,120 AND IN FACT, THESE HAPPEN MORE 5615 03:37:30,120 --> 03:37:32,080 COMMONLY THAN HGR, ABOUT 50 TO 5616 03:37:32,080 --> 03:37:37,920 60% OF THE TIME IN THE YELLOW 5617 03:37:37,920 --> 03:37:41,720 BARS, AND INTERESTING RILY, THEE 5618 03:37:41,720 --> 03:37:44,600 DON'T CONTRIBUTE TO 5619 03:37:44,600 --> 03:37:45,560 ERYTHROPOIESIS, SO THESE DROP 5620 03:37:45,560 --> 03:37:47,880 OUT BECAUSE OF INEFFECTIVE 5621 03:37:47,880 --> 03:37:48,880 ERYTHROPOIESIS AND DON'T 5622 03:37:48,880 --> 03:37:49,520 CONTRIBUTE. 5623 03:37:49,520 --> 03:37:52,360 THE NON-HOMOLOGOUS END FRAME, 5624 03:37:52,360 --> 03:37:54,000 NON-HOMOLOGOUS END JOINING 5625 03:37:54,000 --> 03:37:59,400 INFRAME, THESE ARE COLLEAGUES CS 5626 03:37:59,400 --> 03:38:01,800 THAT OCCUR IN MULTIPLES OF 5627 03:38:01,800 --> 03:38:02,240 THREE. 5628 03:38:02,240 --> 03:38:04,600 THE MOST COMMON ONE, THESE DO 5629 03:38:04,600 --> 03:38:06,760 CONTRIBUTE TO ERYTHROPOIESIS AND 5630 03:38:06,760 --> 03:38:07,640 REPRESENT THE REMAINING. 5631 03:38:07,640 --> 03:38:10,040 SO THIS IS THE PROOF OF 5632 03:38:10,040 --> 03:38:14,320 PRINCIPLE THAT CORRECTING BY 5633 03:38:14,320 --> 03:38:16,320 HGR, 20 TO 25% OF THE ALLELES IN 5634 03:38:16,320 --> 03:38:18,440 AT LEAST 20 TO 25% OF THE STEM 5635 03:38:18,440 --> 03:38:20,160 CELLS SHOULD ELICIT THERAPEUTIC 5636 03:38:20,160 --> 03:38:22,920 EFFECT. 5637 03:38:22,920 --> 03:38:27,840 WE HAVE DONE THIS EXPERIMENT IN 5638 03:38:27,840 --> 03:38:30,560 A GMP SCALE, A CLINICAL SCALE, 5639 03:38:30,560 --> 03:38:32,080 AND IN SICKLE CELL SMALL SCALE 5640 03:38:32,080 --> 03:38:36,120 DONOR RUNS, AND SELECTED -- 5641 03:38:36,120 --> 03:38:38,320 PICKED A NUMBER OF COLONIES, 5642 03:38:38,320 --> 03:38:39,440 812, AND THIS SHOWS THE 5643 03:38:39,440 --> 03:38:40,720 DISTRIBUTION BY GENOTYPE, SO 5644 03:38:40,720 --> 03:38:43,320 BLUE IS GOOD. 5645 03:38:43,320 --> 03:38:44,720 THESE ARE CLONES THAT HAVE AT 5646 03:38:44,720 --> 03:38:47,240 LEAST ONE CORRECTED ALLELE. 5647 03:38:47,240 --> 03:38:48,360 GREEN IS BAD. 5648 03:38:48,360 --> 03:38:51,960 THOSE HAVE NOT BEEN MODIFIED BY 5649 03:38:51,960 --> 03:38:54,160 THE CRISPR/CAS 9 REAGENT SO 5650 03:38:54,160 --> 03:38:56,000 THOSE ARE SICKLE CELL ANEMIA 5651 03:38:56,000 --> 03:38:58,720 CLONES STILL AND THEN THE INDELS 5652 03:38:58,720 --> 03:39:02,480 WHICH WOULD PREDICT A VA 5653 03:39:02,480 --> 03:39:03,680 THALASSEMIA GENOTYPE MOST OF THE 5654 03:39:03,680 --> 03:39:04,520 TIME ARE IN ORANGE. 5655 03:39:04,520 --> 03:39:07,440 WHAT WE OBSERVED, ON AVERAGE 40% 5656 03:39:07,440 --> 03:39:10,760 OF THE COLONY FORMING UNITS 5657 03:39:10,760 --> 03:39:12,200 DINED AT LEAST ONE CORRECTED 5658 03:39:12,200 --> 03:39:14,800 ALLELE FROM THE FIVE LOTS WE 5659 03:39:14,800 --> 03:39:16,560 ASSESSED, AND AN AVERAGE -- AN 5660 03:39:16,560 --> 03:39:19,760 EQUAL NUMBER, 40%, HAVE CFUs 5661 03:39:19,760 --> 03:39:24,800 THAT HAVE TWO INDEL ALLELES. 5662 03:39:24,800 --> 03:39:28,440 SO AGAIN WE'RE RELYING ON THIS 5663 03:39:28,440 --> 03:39:29,880 BALANCE OF THE CORRECTION OF THE 5664 03:39:29,880 --> 03:39:33,800 ALLELE COMPARED WITH INDELS THAT 5665 03:39:33,800 --> 03:39:35,240 WOULD BE DELETERIOUS. 5666 03:39:35,240 --> 03:39:36,240 THIS IS WHAT IT LOOKS LIKE. 5667 03:39:36,240 --> 03:39:38,200 THIS IS THE GMP MANUFACTURING 5668 03:39:38,200 --> 03:39:39,480 OUTCOMES THAT WE SUBMITTED IN 5669 03:39:39,480 --> 03:39:42,200 OUR IND THAT WAS ACCEPTED FOR 5670 03:39:42,200 --> 03:39:44,360 COMMENCING THE CLINICAL TRIAL. 5671 03:39:44,360 --> 03:39:47,000 THERE WAS EXCELLENT VIABILITY, 5672 03:39:47,000 --> 03:39:49,520 STERILITY AND ENDO TOXIC-FREE 5673 03:39:49,520 --> 03:39:53,560 MANUFACTURING PRODUCTS WERE 5674 03:39:53,560 --> 03:39:54,080 MADE. 5675 03:39:54,080 --> 03:39:56,720 AND THE CFE FORMATION WAS QUITE 5676 03:39:56,720 --> 03:39:57,280 ROBUST. 5677 03:39:57,280 --> 03:39:59,600 THE OVERALL CORRECTION WAS 26%, 5678 03:39:59,600 --> 03:40:04,440 AND THE INDE PELS AVERAGED 50%. 5679 03:40:04,440 --> 03:40:05,640 SO WHAT I'VE CIRCLED HERE IS 5680 03:40:05,640 --> 03:40:12,200 THAT RATIO COMPARING THE HGR -- 5681 03:40:12,200 --> 03:40:13,320 THALASSEMIA GENOTYPE. 5682 03:40:13,320 --> 03:40:14,840 THE CRITICAL QUESTION ASKED IN 5683 03:40:14,840 --> 03:40:18,600 THE KRIN CAL TRIAL, THE CRITICAL 5684 03:40:18,600 --> 03:40:19,880 SAFETY QUESTION, WHETHER OR NOT 5685 03:40:19,880 --> 03:40:21,440 THESE CELLS WILL ADAPT AFTER 5686 03:40:21,440 --> 03:40:24,400 THEY'VE BEEN MODIFIED BY THE 5687 03:40:24,400 --> 03:40:26,240 CRISPR/CAS 9, IS THE RATIO OF 5688 03:40:26,240 --> 03:40:28,920 CORRECTION TO THALASSEMIA 5689 03:40:28,920 --> 03:40:29,840 FAVORABLE. 5690 03:40:29,840 --> 03:40:30,680 SO TWO CRITICAL SAFETY ISSUES 5691 03:40:30,680 --> 03:40:32,080 THAT WILL BE ANSWERED IN THIS 5692 03:40:32,080 --> 03:40:35,640 CLINICAL TRIAL. 5693 03:40:35,640 --> 03:40:40,120 SO AS ZULEMA AND -- CONTINUE TO 5694 03:40:40,120 --> 03:40:42,320 WORK ON FAVORRIZATION BY 5695 03:40:42,320 --> 03:40:45,160 CHANGING THE MEDIA CONDITIONS BY 5696 03:40:45,160 --> 03:40:47,800 WHICH THE CELLS ARE EXPANDED 5697 03:40:47,800 --> 03:40:50,800 BEFORE THE ELECTROPORATION 5698 03:40:50,800 --> 03:40:51,200 OCCURS. 5699 03:40:51,200 --> 03:40:54,280 WHAT'S COMPARED IN THESE PANELS 5700 03:40:54,280 --> 03:40:58,760 ARE USING THE STANDARD EX VIVO 5701 03:40:58,760 --> 03:41:00,880 15 MEDIA WITH TWO NEW MEDIA, AOF 5702 03:41:00,880 --> 03:41:03,840 WHICH IS A GMP-READY MEDIA AND 5703 03:41:03,840 --> 03:41:06,360 AN FEM2, WHICH IS STILL 5704 03:41:06,360 --> 03:41:07,480 RESEARCH-USE ONLY OR 5705 03:41:07,480 --> 03:41:09,320 PRE-CLINICAL, AND THE 5706 03:41:09,320 --> 03:41:15,720 DIFFERENCES BETWEEN EX-VO VO AND 5707 03:41:15,720 --> 03:41:17,720 THE OTHER TWO, THE CELLS IN 5708 03:41:17,720 --> 03:41:19,440 G1 APPEAR TO BE EXPANDED. 5709 03:41:19,440 --> 03:41:21,320 IF I CAN SHIFT YOUR ATTENTION TO 5710 03:41:21,320 --> 03:41:22,600 THE LOWER LEFT-HAND PANEL, THE 5711 03:41:22,600 --> 03:41:24,280 MEDIA, SHIFTING FROM LIGHT BLUE 5712 03:41:24,280 --> 03:41:26,400 TO YELLOW AND ORANGE, SHOWS THE 5713 03:41:26,400 --> 03:41:30,080 CHANGES IN HGR AND THE CHANGES 5714 03:41:30,080 --> 03:41:31,840 IN NHEJ WITH CHANGES IN THE 5715 03:41:31,840 --> 03:41:32,400 MEDIA. 5716 03:41:32,400 --> 03:41:34,040 SO AS THE CELLS EXPAND, THEY'RE 5717 03:41:34,040 --> 03:41:36,400 MORE LIKELY TO UNDERGO HOMOLOGY 5718 03:41:36,400 --> 03:41:37,160 DIRECTED REPAIR. 5719 03:41:37,160 --> 03:41:39,240 THE NHEJ GOES DOWN AND THEN THE 5720 03:41:39,240 --> 03:41:40,200 RATIO IS IMPROVED. 5721 03:41:40,200 --> 03:41:41,800 AND THEN THOSE TWO PANELS ON THE 5722 03:41:41,800 --> 03:41:44,120 RIGHT, THE FIRST ONE JUST SHOWS 5723 03:41:44,120 --> 03:41:49,160 THE MIX OF CELLS RIGHT AFTER THE 5724 03:41:49,160 --> 03:41:50,160 ELECTROPORATION OCCURS AND THEY 5725 03:41:50,160 --> 03:41:51,240 DON'T APPEAR TO BE DIFFERENT. 5726 03:41:51,240 --> 03:41:52,320 IF YOU LOOK AT THE STEM CELLS 5727 03:41:52,320 --> 03:41:56,280 THAT ACTUALLY ENGRAFT IN THE 5728 03:41:56,280 --> 03:41:59,400 XENOGRAFTS, CONTRIBUTE TO 5729 03:41:59,400 --> 03:42:02,600 ERYTHROPOIESIS, THE NHEJ RATIO 5730 03:42:02,600 --> 03:42:04,240 MARKEDLY IMPROVES COMPARED WITH 5731 03:42:04,240 --> 03:42:04,760 EX VIVO 15. 5732 03:42:04,760 --> 03:42:06,840 SO WE THINK WE HAVE AN OPTIMIZED 5733 03:42:06,840 --> 03:42:08,280 MANUFACTURING PROTOCOL NOW THAT 5734 03:42:08,280 --> 03:42:13,000 WILL PUT THAT RATIO OF HGR TO 5735 03:42:13,000 --> 03:42:16,120 NH EJ IN A FAVORABLE POSITION. 5736 03:42:16,120 --> 03:42:18,320 AND ENHANCE SAFETY, PATIENTS WHO 5737 03:42:18,320 --> 03:42:18,960 PARTICIPATE IN THE TRIAL. 5738 03:42:18,960 --> 03:42:22,560 SO THIS IS HOW IT WILL WORK. 5739 03:42:22,560 --> 03:42:24,120 THIS IS NOT DIFFERENT FROM WHAT 5740 03:42:24,120 --> 03:42:25,360 WAS PRESENTED EARLIER TODAY. 5741 03:42:25,360 --> 03:42:27,400 PATIENTS ARE BROUGHT IN FOR 5742 03:42:27,400 --> 03:42:30,160 MOBILIZATION, SINGLE AGENT, 5743 03:42:30,160 --> 03:42:32,440 SHIFTED TO UCLA IN THEIR 5744 03:42:32,440 --> 03:42:36,240 MANUFACTURING FACILITY WHERE 5745 03:42:36,240 --> 03:42:38,640 ELECTROPORATION WILL BE 5746 03:42:38,640 --> 03:42:39,720 PERFORMED. 5747 03:42:39,720 --> 03:42:44,240 THE GENE EDITED CELLS 5748 03:42:44,240 --> 03:42:47,360 CRYOPRESERVED ARE SHIPPED AND 5749 03:42:47,360 --> 03:42:49,400 THE PATIENT WILL UNDERGO 5750 03:42:49,400 --> 03:42:51,800 ABLATION AND INFUSION OF THE 5751 03:42:51,800 --> 03:42:53,240 THAWED CELLS. 5752 03:42:53,240 --> 03:42:56,160 TIMELINE IS SHOWN HERE, SO OUR 5753 03:42:56,160 --> 03:42:58,560 GOAL IS TO ENROLL UP TO NINE 5754 03:42:58,560 --> 03:43:00,360 SUBJECTS, SIX ADULTS AND AS THE 5755 03:43:00,360 --> 03:43:02,200 TOXICITY AND EFFICACY PROFILES 5756 03:43:02,200 --> 03:43:05,840 ARE FAVORABLE, WE WOULD ENROLL 5757 03:43:05,840 --> 03:43:06,800 THREE ADOLESCENTS, BETWEEN 12 5758 03:43:06,800 --> 03:43:07,600 AND 17 YEARS OF AGE. 5759 03:43:07,600 --> 03:43:10,480 THE IND WAS FILED AS I 5760 03:43:10,480 --> 03:43:12,120 MENTIONED, COMING ON THREE YEARS 5761 03:43:12,120 --> 03:43:12,440 AGO. 5762 03:43:12,440 --> 03:43:14,000 IT TOOK A BIT OF TIME TO GET THE 5763 03:43:14,000 --> 03:43:15,880 FUNDING LINED UP, WHICH WE HAVE 5764 03:43:15,880 --> 03:43:19,400 NOW, AND OUR PRINCIPAL DELAY AT 5765 03:43:19,400 --> 03:43:23,360 THIS POINT IS MAKING GMP GRADE 5766 03:43:23,360 --> 03:43:23,720 OLIGONUCLEOTIDE. 5767 03:43:23,720 --> 03:43:25,480 THE RESEARCH USE ONLY SUPPLIER 5768 03:43:25,480 --> 03:43:27,640 DROPPED OUT OF THE GMP BUSINESS 5769 03:43:27,640 --> 03:43:29,760 BECAUSE OF MESSENGER RNA TAKING 5770 03:43:29,760 --> 03:43:32,960 OVER FOR VACCINES, AND SO WE HAD 5771 03:43:32,960 --> 03:43:34,360 TO SCRAMBLE TO FIND A NEW 5772 03:43:34,360 --> 03:43:34,960 VENDOR. 5773 03:43:34,960 --> 03:43:35,960 NONETHELESS, WE ANTICIPATE 5774 03:43:35,960 --> 03:43:37,200 HAVING THAT REAGENT RE CAN I BY 5775 03:43:37,200 --> 03:43:42,120 THREADY BY THEEND OF THIS CALEND 5776 03:43:42,120 --> 03:43:43,320 ENROLLING OUR FIRST PATIENT 5777 03:43:43,320 --> 03:43:43,880 EARLY NEXT YEAR. 5778 03:43:43,880 --> 03:43:45,320 SO WHAT ELSE COULD GO WRONG? 5779 03:43:45,320 --> 03:43:47,840 I'VE JUST SHARED WITH YOU THIS 5780 03:43:47,840 --> 03:43:55,680 IMPORTANT THALASSEMIA HDR RATIO. 5781 03:43:55,680 --> 03:43:57,960 CHROMOTHRIPSIS IS ANOTHER 5782 03:43:57,960 --> 03:44:01,120 PHENOMENON THAT'S BEEN 5783 03:44:01,120 --> 03:44:01,600 DESCRIBED. 5784 03:44:01,600 --> 03:44:10,280 IN THIS EXAMPLE, USING THE BC11A 5785 03:44:10,280 --> 03:44:12,240 ERYTHROSPECIFIC ENHANCER 5786 03:44:12,240 --> 03:44:15,000 KNOCKOUT RNP, THIS LAB SHOWED 5787 03:44:15,000 --> 03:44:17,640 THAT THE MICRO NUCLEI OCCUR 5788 03:44:17,640 --> 03:44:18,520 ABOUT 2.5% OF THE TIME, SO 5789 03:44:18,520 --> 03:44:20,600 THERE'S A PROBE ON EITHER SIDE 5790 03:44:20,600 --> 03:44:23,280 OF THE CUT SITE ON CHROMOSOME 5791 03:44:23,280 --> 03:44:25,000 2 WHERE BC11A IS LOCATED AND 5792 03:44:25,000 --> 03:44:26,640 IDEALLY YOU WOULD HAVE ONE COPY 5793 03:44:26,640 --> 03:44:29,320 OF EACH ON EITHER SIDE OF THE 5794 03:44:29,320 --> 03:44:32,160 CENTROMERE AND THE MICRO NUCLEI 5795 03:44:32,160 --> 03:44:34,400 HAS TWO COPIES OF THE BCL11A 5796 03:44:34,400 --> 03:44:38,560 GENE AS DEPICTED IN THIS 5797 03:44:38,560 --> 03:44:40,200 PARTICULAR PHOTOMICROGRAPH. 5798 03:44:40,200 --> 03:44:41,520 MOST OF THE TIME THEY DON'T 5799 03:44:41,520 --> 03:44:42,840 CONTRIBUTE, THEY UNDERGO 5800 03:44:42,840 --> 03:44:44,400 APOPTOSIS AND FALL OUT, BUT THEY 5801 03:44:44,400 --> 03:44:46,440 ARE ASSOCIATED WITH A HIGHER 5802 03:44:46,440 --> 03:44:48,160 RISK OF MALIGNANCY, SO WE ARE 5803 03:44:48,160 --> 03:44:52,520 SCRAMBLING TO WORK OUT A 5804 03:44:52,520 --> 03:44:54,320 CHROMOTHRI PSI S ASSAY FOR OUR 5805 03:44:54,320 --> 03:44:55,880 OWN GENE REEDITING AGENTS. 5806 03:44:55,880 --> 03:45:00,440 THE OTHER THING WE OBSERVED WAS 5807 03:45:00,440 --> 03:45:02,120 THIS DISPARITY BETWEEN THE 5808 03:45:02,120 --> 03:45:04,440 ASSORTMENT OF ALLELES POST 5809 03:45:04,440 --> 03:45:08,360 EDITING, BOTH HOMOZYGOUS AND 5810 03:45:08,360 --> 03:45:09,760 HETEROZYGOUS THAT SHOULD OCCUR 5811 03:45:09,760 --> 03:45:11,400 FOLLOWING THE HARVEY WEINBERG 5812 03:45:11,400 --> 03:45:12,520 PREDICTIONS AND WHAT WE ACTUALLY 5813 03:45:12,520 --> 03:45:13,360 OBSERVED. 5814 03:45:13,360 --> 03:45:15,360 IN PARTICULAR, THE HOME ZYGOTES, 5815 03:45:15,360 --> 03:45:25,080 WE OBSERVED MORE HOME S HO HOMO- 5816 03:45:25,080 --> 03:45:26,440 WE WONDERED IF ONE EXPLANATION 5817 03:45:26,440 --> 03:45:29,440 COULD BE THESE ARE ACTUALLY 5818 03:45:29,440 --> 03:45:30,560 HEMIZYGOUS, WITH ONE OF THE 5819 03:45:30,560 --> 03:45:33,480 ALLELES ACTUALLY REPRESENTING A 5820 03:45:33,480 --> 03:45:38,120 VERY LARGE DELETION THAWS 5821 03:45:38,120 --> 03:45:41,160 OUTSIDE OF THE SMALL 5822 03:45:41,160 --> 03:45:42,320 AMPLIFICATION DNA SEGMENT THAT 5823 03:45:42,320 --> 03:45:46,360 WE DETECT FOR HDR. 5824 03:45:46,360 --> 03:45:52,360 SO THIS WAS A RECENT PAPER AT 5825 03:45:52,360 --> 03:45:53,560 RICE UNIVERSITY, A GROUP WE'RE 5826 03:45:53,560 --> 03:45:54,760 COLLABORATING WITH, AND HE, IN 5827 03:45:54,760 --> 03:46:00,760 ADDITION TO LOOKING AT THE 5828 03:46:00,760 --> 03:46:02,360 SHORT -- RANGE, HE CREATED A 5829 03:46:02,360 --> 03:46:06,280 SYSTEM FOR PICKING UP UP TO 5KB 5830 03:46:06,280 --> 03:46:07,400 LONG-RANGE DELETIONS ON TARGET. 5831 03:46:07,400 --> 03:46:09,120 SO THE TWO AMPLICONS ARE SHOWN 5832 03:46:09,120 --> 03:46:10,520 IN THIS DEPICTION. 5833 03:46:10,520 --> 03:46:14,240 AND THEN HE USED A TECHNOLOGY 5834 03:46:14,240 --> 03:46:16,160 RELYING ON A SINGLE MOLECULE 5835 03:46:16,160 --> 03:46:18,760 REALTIME SEQUENCES SYSTEM 5836 03:46:18,760 --> 03:46:23,400 CREATED BY PACBIO USING THE 5837 03:46:23,400 --> 03:46:24,600 UNIVERSAL MOLECULAR IDENTIFIERS. 5838 03:46:24,600 --> 03:46:26,160 WHAT THIS DOES IS IT OVERCOMES 5839 03:46:26,160 --> 03:46:27,560 THE PROBLEM OF RECOMBINATION 5840 03:46:27,560 --> 03:46:31,240 THAT OCCUR BETWEEN THE TEMPLATES 5841 03:46:31,240 --> 03:46:33,320 DURING THE PCR AMPLIFICATION AND 5842 03:46:33,320 --> 03:46:35,280 ALSO REDUCES THE PCR ERROR RATE, 5843 03:46:35,280 --> 03:46:37,400 SO YOU AVOID SOME OF THE 5844 03:46:37,400 --> 03:46:38,920 ARTIFACTS THAT ARE INTRODUCED BY 5845 03:46:38,920 --> 03:46:39,280 PCR. 5846 03:46:39,280 --> 03:46:41,400 AND USING THIS SYSTEM, HE 5847 03:46:41,400 --> 03:46:44,000 CREATED A DATABASE THAT SHOWED A 5848 03:46:44,000 --> 03:46:45,120 QUITE STRIKING RESULT. 5849 03:46:45,120 --> 03:46:48,200 SO USING EXACTLY OUR TEMPLATE, 5850 03:46:48,200 --> 03:46:51,160 THE SAME OLIGONUCLEOTIDE AND 5851 03:46:51,160 --> 03:46:53,360 BOTH THE RNP, HE SHOWED THAT 5852 03:46:53,360 --> 03:46:55,360 FIRST OF ALL, USING RNP ALONE, 5853 03:46:55,360 --> 03:47:01,040 THE NUMBER OF LONG-RANGE 5854 03:47:01,040 --> 03:47:05,040 INSERTIONS WAS IMPRESSIVE, IN 5855 03:47:05,040 --> 03:47:10,200 FACT IT WAS NEARLY 40% BUT WHEN 5856 03:47:10,200 --> 03:47:11,720 THE OLIGONUCLEOTIDE TEMPLATE WAS 5857 03:47:11,720 --> 03:47:12,920 REDUCED, THE RATE WENT DOWN BUT 5858 03:47:12,920 --> 03:47:14,240 IT STILL ACCOUNTED FOR ABOUT 10 5859 03:47:14,240 --> 03:47:15,520 TO 12% OF THE TOTAL THAT WAS 5860 03:47:15,520 --> 03:47:15,920 OBSERVED. 5861 03:47:15,920 --> 03:47:22,360 SO AGAIN, THESE WILL BE -- WON'T 5862 03:47:22,360 --> 03:47:24,640 CONTRIBUTE TO ERYTHROPOIESIS SO 5863 03:47:24,640 --> 03:47:26,040 THESE ARE NEGATIVE RESULTS. 5864 03:47:26,040 --> 03:47:27,280 THE GOOD NEWS IS THAT THEY CAN 5865 03:47:27,280 --> 03:47:31,360 STILL BE OVERCOME BY A ROBUST 5866 03:47:31,360 --> 03:47:32,360 HDR FREQUENCY, AND THEY 5867 03:47:32,360 --> 03:47:34,840 SHOULDN'T BE ANY MORE DIFFICULT 5868 03:47:34,840 --> 03:47:36,800 TO OVERCOME THAN THE SMALL 5869 03:47:36,800 --> 03:47:39,400 INSERTION DELETIONS DEPICTED BY 5870 03:47:39,400 --> 03:47:43,440 THE GREEN SEGMENT OF THE PIE. 5871 03:47:43,440 --> 03:47:44,680 BUT STILL SOMETHING ELSE WE WANT 5872 03:47:44,680 --> 03:47:45,680 TO UNDERSTAND BETTER AND WE HAVE 5873 03:47:45,680 --> 03:47:48,280 SENT SOME OF OUR GENOMIC DNA TO 5874 03:47:48,280 --> 03:47:50,120 THE LAB FOR FURTHER ANALYSIS, SO 5875 03:47:50,120 --> 03:47:51,120 WE UNDERSTAND BETTER WHAT'S 5876 03:47:51,120 --> 03:47:57,320 HAPPENING IN OUR HANDS TOO. 5877 03:47:57,320 --> 03:47:58,680 THE LAST THING I WANTED TO SHOW 5878 03:47:58,680 --> 03:48:01,080 WAS SOMETHING WE DID FOR THE 5879 03:48:01,080 --> 03:48:02,960 RESEARCH USE ONLY SINGLE 5880 03:48:02,960 --> 03:48:04,360 STRANDED OLIGONUCLEOTIDE THAT 5881 03:48:04,360 --> 03:48:05,840 WAS UTILIZED IN THE PRE-CLINICAL 5882 03:48:05,840 --> 03:48:06,840 STUDY. 5883 03:48:06,840 --> 03:48:08,680 SO THIS IS DIRECT DNA SEQUENCING 5884 03:48:08,680 --> 03:48:10,880 OF THE OLIGONUCLEOTIDE, AND THE 5885 03:48:10,880 --> 03:48:12,680 LENGTH OF THOSE BARS HAS TO DO 5886 03:48:12,680 --> 03:48:14,760 WITH THE NUMBER OF 5887 03:48:14,760 --> 03:48:15,640 OLIGONUCLEOTIDES THAT WERE 5888 03:48:15,640 --> 03:48:16,720 SEQUENCED. 5889 03:48:16,720 --> 03:48:18,200 NOT SURPRISINGLY, THERE'S A LOT 5890 03:48:18,200 --> 03:48:20,640 OF -- LESS THAN FULL LENGTH 5891 03:48:20,640 --> 03:48:22,080 OLIGONUCLEOTIDES, WHICH IS OKAY. 5892 03:48:22,080 --> 03:48:29,440 BUT WHAT ISN'T OKAY 5893 03:48:29,440 --> 03:48:30,640 PARTICULARLY -- IS THERE ARE 5894 03:48:30,640 --> 03:48:31,840 SINGLE NUCLEOTIDE CHANGES, 5895 03:48:31,840 --> 03:48:33,040 ERRORS IN THE SEQUENCE, THAT 5896 03:48:33,040 --> 03:48:36,200 WERE NOT INTENDED, THAT OCCURRED 5897 03:48:36,200 --> 03:48:39,440 IN THE TEMPLATE REGION OF THE 5898 03:48:39,440 --> 03:48:39,880 OLIGONUCLEOTIDE. 5899 03:48:39,880 --> 03:48:42,920 SO THIS WAS ANALYSIS DONE BY 5900 03:48:42,920 --> 03:48:45,080 STACIA AND DARIO ON THE TEAM. 5901 03:48:45,080 --> 03:48:49,400 WHAT STACIA DID WAS THEN 5902 03:48:49,400 --> 03:48:50,600 CONVINCINGLY DID THIS ANALYSIS 5903 03:48:50,600 --> 03:48:52,800 WHICH IS FROM GENOMIC DNA THAT 5904 03:48:52,800 --> 03:48:54,760 WERE CREATED WITH THESE 5905 03:48:54,760 --> 03:48:55,680 REAGENTS. 5906 03:48:55,680 --> 03:48:57,760 AND AT REGULAR INTERVALS AND 5907 03:48:57,760 --> 03:48:59,000 PREDICTED BY THE 5908 03:48:59,000 --> 03:49:00,520 OLIGONUCLEOTIDE, THERE ARE 5909 03:49:00,520 --> 03:49:01,560 SNPs THAT HAVE BEEN INTRODUCED 5910 03:49:01,560 --> 03:49:03,480 INTO THE CLONES THAT WE WOULD 5911 03:49:03,480 --> 03:49:07,160 HAVE SCORED AS HOMOLOGY DIRECTED 5912 03:49:07,160 --> 03:49:09,200 CLONES AND THESE OCCUR AS 5913 03:49:09,200 --> 03:49:10,480 REGULAR INTERVALS. 5914 03:49:10,480 --> 03:49:13,560 IN THE HDR CLONES WHERE ONLY THE 5915 03:49:13,560 --> 03:49:15,160 PAM IS MUTATED, YOU CAN SEE 5916 03:49:15,160 --> 03:49:17,240 DOWNSTREAM FROM THAT, THE SNPs 5917 03:49:17,240 --> 03:49:17,560 DISAPPEAR. 5918 03:49:17,560 --> 03:49:19,280 SO THESE ARE ABSOLUTE -- THIS IS 5919 03:49:19,280 --> 03:49:21,840 CLEAR EVIDENCE THAT THE MISTAKES 5920 03:49:21,840 --> 03:49:23,880 MADE IN OLIGONUCLEOTIDE TEMPLATE 5921 03:49:23,880 --> 03:49:25,760 ARE BEING INCORPORATED IN THE 5922 03:49:25,760 --> 03:49:26,880 GENOMIC DNA, AND WOULD BE PART 5923 03:49:26,880 --> 03:49:30,120 OF AN HDR CLONE WE CAN USE IN 5924 03:49:30,120 --> 03:49:30,720 THE PATIENT. 5925 03:49:30,720 --> 03:49:37,640 SO THAT'S SOBERING. 5926 03:49:37,640 --> 03:49:39,640 BUT THE GOOD NEWS IS THERE'S 5927 03:49:39,640 --> 03:49:42,800 QUITE A VARIABILITY IN THE ERROR 5928 03:49:42,800 --> 03:49:43,600 RATE BY MANUFACTURER. 5929 03:49:43,600 --> 03:49:44,840 WHAT'S INTERESTING, THIS HAS 5930 03:49:44,840 --> 03:49:46,360 SOMETHING TO DO WITH THE 5931 03:49:46,360 --> 03:49:47,600 BIOSYNTHETIC, THE SYNTHESIS 5932 03:49:47,600 --> 03:49:48,400 CHEMISTRY THAT OCCURS WHEN YOU 5933 03:49:48,400 --> 03:49:50,600 MAKE AN OLIGONUCLEOTIDE OF THIS 5934 03:49:50,600 --> 03:49:51,600 LENGTH, THAT WHATEVER IS 5935 03:49:51,600 --> 03:49:52,840 HAPPENING, IT'S HAPPENING 5936 03:49:52,840 --> 03:49:54,640 SYSTEMATICALLY, AND THE 5937 03:49:54,640 --> 03:49:55,600 MANUFACTURERS DON'T UNDERSTAND 5938 03:49:55,600 --> 03:49:55,920 IT. 5939 03:49:55,920 --> 03:49:57,680 EXCEPT TO SAY THAT THEY TELL US 5940 03:49:57,680 --> 03:49:59,720 THAT THEY'RE AT THE LIMITS OF 5941 03:49:59,720 --> 03:50:00,600 THE TECHNOLOGY WITH THESE KIND 5942 03:50:00,600 --> 03:50:01,880 OF CHANGES, BUT WHAT WAS 5943 03:50:01,880 --> 03:50:05,400 INTERESTING IS THAT THE SNPs, 5944 03:50:05,400 --> 03:50:08,680 THE ERRORS IN OLIGONUCLEOTIDE 5945 03:50:08,680 --> 03:50:09,600 SEQUENCE OCCUR IN THE SAME 5946 03:50:09,600 --> 03:50:10,280 LOCATION REGARDLESS OF 5947 03:50:10,280 --> 03:50:10,960 MANUFACTURER. 5948 03:50:10,960 --> 03:50:12,400 SO THERE'S SOMETHING ABOUT THE 5949 03:50:12,400 --> 03:50:18,000 SYNTHESIS CHEMISTRY ITSELF 5950 03:50:18,000 --> 03:50:19,360 THAT'S CREATING THESE ERRORS. 5951 03:50:19,360 --> 03:50:21,200 THE GOOD NEWS IS THE ERROR RATE 5952 03:50:21,200 --> 03:50:23,000 IS MUCH LOWER IN THE CITY OF 5953 03:50:23,000 --> 03:50:31,000 HOPE NUCLEOTIDE CLINICAL TRIAL, 5954 03:50:31,000 --> 03:50:33,280 WHERE 5% OF THE TOTAL ALLELES IN 5955 03:50:33,280 --> 03:50:37,760 THE FIRST MANUFACTURER. 5956 03:50:37,760 --> 03:50:39,680 SO WE MAPPED OUT THE AMINO ACID 5957 03:50:39,680 --> 03:50:40,520 CHANGES THAT WILL OCCUR. 5958 03:50:40,520 --> 03:50:44,120 THESE ARE ALL NON-SYNONYMOUS 5959 03:50:44,120 --> 03:50:46,520 MUTATIONS THAT OCCUR. 5960 03:50:46,520 --> 03:50:48,880 I LOOKED UP ALL THESE VARIANTS 5961 03:50:48,880 --> 03:50:50,000 AND I'M HAPPY TO REPORT THAT 5962 03:50:50,000 --> 03:50:51,960 NONE OF THEM HAS ANY CLINICAL 5963 03:50:51,960 --> 03:50:52,400 PHENOTYPE. 5964 03:50:52,400 --> 03:50:54,960 SO WHILE THESE SNPs WILL BE 5965 03:50:54,960 --> 03:50:56,480 INTRODUCED AND ONE SHOULD 5966 03:50:56,480 --> 03:51:00,880 INTERTENTERTAIN THE POSSIBILITYT 5967 03:51:00,880 --> 03:51:02,480 THEY WILL CONTAIN SICKLE 5968 03:51:02,480 --> 03:51:04,040 PHENOTYPE, PERHAPS, THIS REVIEW 5969 03:51:04,040 --> 03:51:05,600 WAS, I THOUGHT, REASSURING. 5970 03:51:05,600 --> 03:51:08,440 AND THAT MOST OF THEM, FIVE OF 5971 03:51:08,440 --> 03:51:10,320 THE EIGHT WON'T CONTRIBUTE TO 5972 03:51:10,320 --> 03:51:19,080 ANEMIA OR OTHER SICKLING ERRORS. 5973 03:51:19,080 --> 03:51:20,360 SO I'D LIKE TO FINISH WITH WHERE 5974 03:51:20,360 --> 03:51:21,760 WE ARE FOR THE FUTURE OF THIS 5975 03:51:21,760 --> 03:51:26,360 PARTICULAR GENE EDITING PROJECT. 5976 03:51:26,360 --> 03:51:27,560 AGAIN I EMPHASIZE WILL THE 5977 03:51:27,560 --> 03:51:29,960 BALANCE OF ON-TARGET 5978 03:51:29,960 --> 03:51:30,720 INSERTION-DELETIONS SHORT TERM 5979 03:51:30,720 --> 03:51:33,000 AND LONG-RANGE AND 5980 03:51:33,000 --> 03:51:33,840 HOMOLOGY-DIRECTED REPAIR SUPPORT 5981 03:51:33,840 --> 03:51:35,240 A CLINICAL BENEFIT AND OVERCOME 5982 03:51:35,240 --> 03:51:36,800 A THALASSEMIA PHENOTYPE? 5983 03:51:36,800 --> 03:51:38,000 SO THAT'S SAFETY QUESTION NUMBER 5984 03:51:38,000 --> 03:51:39,160 ONE THAT WILL BE FOREMOST IN OUR 5985 03:51:39,160 --> 03:51:43,640 MINDS. 5986 03:51:43,640 --> 03:51:44,840 WE'VE HEARD THIS MORNING ABOUT 5987 03:51:44,840 --> 03:51:47,680 THIS RISK, IS THERE RISK OF 5988 03:51:47,680 --> 03:51:48,720 CLONAL HEMATOPOIESIS OR 5989 03:51:48,720 --> 03:51:50,160 SELECTION OF PROLIFERATIVE 5990 03:51:50,160 --> 03:51:52,360 CLONES AFTER EX VIVO EXPANSION 5991 03:51:52,360 --> 03:51:53,640 AND REPOPULATION OF A LIMITED 5992 03:51:53,640 --> 03:51:55,160 NUMBER OF STEM CELLS? 5993 03:51:55,160 --> 03:51:59,080 WE LACK LONG TERM OUTCOME AND 5994 03:51:59,080 --> 03:52:00,200 WE'LL NEED THAT LONG TERM DATA 5995 03:52:00,200 --> 03:52:01,800 TO BE ABLE TO ANSWER THIS 5996 03:52:01,800 --> 03:52:02,080 QUESTION. 5997 03:52:02,080 --> 03:52:03,560 CERTAINLY WE KNOW THIS CAN 5998 03:52:03,560 --> 03:52:04,880 OCCUR, AND THIS WILL BE GERMANE 5999 03:52:04,880 --> 03:52:08,480 TO ALL OF THE GENOMIC EDITING 6000 03:52:08,480 --> 03:52:09,760 GENE THERAPY TRIALS. 6001 03:52:09,760 --> 03:52:12,840 AND FINALLY, MAYBE MOST 6002 03:52:12,840 --> 03:52:13,480 IMPORTANTLY, IS THAT -- SO THIS 6003 03:52:13,480 --> 03:52:15,360 IS A PROJECT THAT'S COMPLETELY 6004 03:52:15,360 --> 03:52:16,320 PUBLIC FUNDED. 6005 03:52:16,320 --> 03:52:20,440 WE HAVEN'T LICENSED TO ANY 6006 03:52:20,440 --> 03:52:22,200 COMPANY. 6007 03:52:22,200 --> 03:52:23,160 BUT STILL AT THE END OF THE 6008 03:52:23,160 --> 03:52:25,080 PROJECT, IF IT'S SUCCESSFUL, 6009 03:52:25,080 --> 03:52:26,760 WILLITY COST AND COMPLEXITY 6010 03:52:26,760 --> 03:52:27,520 RESTRICT ACCESS TO CARE? 6011 03:52:27,520 --> 03:52:28,800 SO THIS IS A POLICY QUESTION 6012 03:52:28,800 --> 03:52:30,400 THAT HAS TO BE DIRECTED 6013 03:52:30,400 --> 03:52:30,920 IMMEDIATELY. 6014 03:52:30,920 --> 03:52:33,160 WILL THERE BE BROAD VERSUS 6015 03:52:33,160 --> 03:52:34,120 LIMITED AVAILABILITY OF THIS 6016 03:52:34,120 --> 03:52:35,240 APPROACH, AND IF IT'S LIMITED, 6017 03:52:35,240 --> 03:52:37,040 WE NEED TO MOVE ON TO THE NEXT 6018 03:52:37,040 --> 03:52:37,600 THING. 6019 03:52:37,600 --> 03:52:39,360 SOONER RATHER THAN LATER. 6020 03:52:39,360 --> 03:52:40,240 THANKS VERY MUCH FOR YOUR 6021 03:52:40,240 --> 03:52:44,640 ATTENTION. 6022 03:52:44,640 --> 03:52:48,480 >>THANK YOU, MARK. 6023 03:52:48,480 --> 03:52:53,840 TIME FOR ONE QUICK QUESTION. 6024 03:52:53,840 --> 03:52:54,840 IS THERE ANYTHING IN THE CHAT? 6025 03:52:54,840 --> 03:52:55,600 NO? 6026 03:52:55,600 --> 03:52:55,840 OKAY. 6027 03:52:55,840 --> 03:52:57,720 IT WAS VERY CLEAR. 6028 03:52:57,720 --> 03:53:01,480 SO NEXT TALK IS DR. WILLIAMS, 6029 03:53:01,480 --> 03:53:03,360 DR. DAVID WILLIAMS FROM BOSTON 6030 03:53:03,360 --> 03:53:08,440 CHILDREN'S HOSPITAL. 6031 03:53:08,440 --> 03:53:10,480 POST TRANSCRIPTIONAL SILENCING 6032 03:53:10,480 --> 03:53:17,080 OF B CL11A USING A LENTIVIRUS 6033 03:53:17,080 --> 03:53:18,760 SHMIR VECTOR, THE PHASE 2 GRASP 6034 03:53:18,760 --> 03:53:18,960 TRIAL. 6035 03:53:18,960 --> 03:53:19,480 >>THANK YOU VERY MUCH. 6036 03:53:19,480 --> 03:53:21,600 I HOPE YOU CAN HEAR ME? 6037 03:53:21,600 --> 03:53:22,760 >>YES, WE CAN. 6038 03:53:22,760 --> 03:53:24,200 >>I APOLOGIZE I'M NOT THERE, 6039 03:53:24,200 --> 03:53:25,520 I'M ACTUALLY IN CLINIC TODAY, SO 6040 03:53:25,520 --> 03:53:26,880 I'M GOING TO TALK TO YOU IN 6041 03:53:26,880 --> 03:53:27,640 BETWEEN PATIENTS. 6042 03:53:27,640 --> 03:53:30,040 BUT I'D LIKE TO SHARE SOME OF 6043 03:53:30,040 --> 03:53:35,440 OUR EXCITING DATA FROM THE TRIAL 6044 03:53:35,440 --> 03:53:36,680 WE HAVE ONGOING AS WELL AS THE 6045 03:53:36,680 --> 03:53:37,640 PHASE 1 TRIAL THAT HAS BEEN 6046 03:53:37,640 --> 03:53:43,120 COMPLETED. 6047 03:53:43,120 --> 03:53:44,880 I'M SEEING MARK'S LAST SLIDE 6048 03:53:44,880 --> 03:53:55,000 STILL. 6049 03:53:58,000 --> 03:53:59,480 I'LL JUST MAKE THE POINT WE CALL 6050 03:53:59,480 --> 03:54:07,400 THIS POST TRANS KRIPTIONAL 6051 03:54:07,400 --> 03:54:08,280 SILENCING BECAUSE AS OPPOSED TO 6052 03:54:08,280 --> 03:54:09,680 SOME OF THE METHODOLOGIES YOU 6053 03:54:09,680 --> 03:54:11,440 HEARD THIS MORNING, THE PROCESS 6054 03:54:11,440 --> 03:54:16,720 OF INDUCING FETAL HEMOGLOBIN BY 6055 03:54:16,720 --> 03:54:22,600 REDUCTION OF BC L11A OCCURS NOT 6056 03:54:22,600 --> 03:54:24,000 AT THE DNA LEVEL BUT AT THE RNA 6057 03:54:24,000 --> 03:54:26,720 LEVEL. 6058 03:54:26,720 --> 03:54:28,560 SO THESE ARE MY DISCLOSURES. 6059 03:54:28,560 --> 03:54:29,920 I'LL POINT OUT A COUPLE THAT ARE 6060 03:54:29,920 --> 03:54:31,280 RELEVANT. 6061 03:54:31,280 --> 03:54:34,200 SO BLUEBIRD BIO PROVIDED GMP 6062 03:54:34,200 --> 03:54:35,640 VECTOR FOR THE PHASE ONE TRIAL 6063 03:54:35,640 --> 03:54:38,760 AND FOR THE PHASE TWO TRIAL AS 6064 03:54:38,760 --> 03:54:41,360 PART OF A LICENSING AGREEMENT 6065 03:54:41,360 --> 03:54:45,360 WHICH HAS NOW BEEN ENDED. 6066 03:54:45,360 --> 03:54:46,440 ALSO WE'LL JUST MAKE THE POINT 6067 03:54:46,440 --> 03:54:49,680 THAT WE HAVE A SPONSORED 6068 03:54:49,680 --> 03:54:58,240 RESEARCH AGREEMENT WITH EXCEL 6069 03:54:58,240 --> 03:55:03,560 THERAPY LOOKING AT DNA DAMAGE IN 6070 03:55:03,560 --> 03:55:04,080 SICKLE CELL PATIENTS. 6071 03:55:04,080 --> 03:55:05,400 SO WE CALL THIS FLIPPING THE 6072 03:55:05,400 --> 03:55:06,360 FETAL TO ADULT SWITCH. 6073 03:55:06,360 --> 03:55:10,440 I DON'T THINK I HAVE TO RE -- 6074 03:55:10,440 --> 03:55:11,200 SPEND MUCH TIME ON THIS. 6075 03:55:11,200 --> 03:55:17,960 IF YOU CAN GO QUICKLY THROUGH 6076 03:55:17,960 --> 03:55:19,680 SOME ANIMATIONS, PLEASE. 6077 03:55:19,680 --> 03:55:20,920 SO QUICKLY AS YOU KNOW AFTER 6078 03:55:20,920 --> 03:55:22,880 BIRTH WE SHUT OFF FETAL 6079 03:55:22,880 --> 03:55:24,440 HEMOGLOBIN AND TURN ON BETA 6080 03:55:24,440 --> 03:55:27,160 ADULT HEMOGLOBIN, WHICH IN 6081 03:55:27,160 --> 03:55:27,720 PATIENTS WITH SICKLE CELL 6082 03:55:27,720 --> 03:55:29,600 DISEASE, OF COURSE, LEADS TO THE 6083 03:55:29,600 --> 03:55:30,480 CLINICAL SYMPTOMATOLOGY OF 6084 03:55:30,480 --> 03:55:31,040 SICKLE CELL. 6085 03:55:31,040 --> 03:55:41,480 AND SO OUR APPROACH IS TO 6086 03:55:43,560 --> 03:55:46,160 REVERSE THE SWITCH. 6087 03:55:46,160 --> 03:55:51,280 AS A THERAPEUTIC GOAL. 6088 03:55:51,280 --> 03:55:53,800 AND THE ADVANTAGE OF THIS IS 6089 03:55:53,800 --> 03:55:59,640 THAT WE SIMULTANEOUSLY INCREASE 6090 03:55:59,640 --> 03:56:01,440 HEMOGLOBIN F WHICH IS PROTECTIVE 6091 03:56:01,440 --> 03:56:04,600 AGAINST INTRACELLULAR 6092 03:56:04,600 --> 03:56:07,560 OXYGENATION OF -- AND REDUCE 6093 03:56:07,560 --> 03:56:10,200 HEMOGLOBIN IN THE CELL AND AS 6094 03:56:10,200 --> 03:56:11,880 YOU KNOW POLYMERIZATION OF 6095 03:56:11,880 --> 03:56:17,160 SICKLE IN DEOOXYGENATED STATE 6096 03:56:17,160 --> 03:56:18,800 IS -- OF THE CONCENTRATION OF 6097 03:56:18,800 --> 03:56:19,560 HEMOGLOBIN IN THE CELL. 6098 03:56:19,560 --> 03:56:23,000 SO WE'VE DONE THIS BY 6099 03:56:23,000 --> 03:56:27,480 ENGINEERING A SHMIR, AND THIS IS 6100 03:56:27,480 --> 03:56:30,640 A SH RNA TARGETING BCL11A THAT'S 6101 03:56:30,640 --> 03:56:38,440 EMBEDDED IN A MICRORNA SCAFFOLD. 6102 03:56:38,440 --> 03:56:40,120 AND THIS SHOWS YOU CONCEPTUALLY 6103 03:56:40,120 --> 03:56:42,080 WHAT THIS LOOKS LIKE. 6104 03:56:42,080 --> 03:56:46,280 WE'VE REMOVED PART OF THE 6105 03:56:46,280 --> 03:56:48,000 NATURALLY OCCURRING ENDOGENOUS 6106 03:56:48,000 --> 03:56:50,280 HAIRPIN OF THE MICRO RNA AND 6107 03:56:50,280 --> 03:56:53,320 REPLACED IT WITH THIS SH RNA 6108 03:56:53,320 --> 03:56:53,760 THAT TARGETS BCL11A. 6109 03:56:53,760 --> 03:56:55,640 THIS IS DESCRIBED IN THE 6110 03:56:55,640 --> 03:57:00,720 PUBLICATION SHOWN HERE. 6111 03:57:00,720 --> 03:57:02,480 THIS HAS ADVANTAGE BECAUSE IT 6112 03:57:02,480 --> 03:57:04,800 MIMICS INDIGENOUS MICRO RNA 6113 03:57:04,800 --> 03:57:06,120 LEVELS, LEADING TO MORE 6114 03:57:06,120 --> 03:57:09,200 PHYSIOLOGIC AND LOWER EXPRESSION 6115 03:57:09,200 --> 03:57:13,280 LEVELS THAT REDUCES NONSPECIFIC 6116 03:57:13,280 --> 03:57:15,080 TOXICITIES, AND BECAUSE OF THE 6117 03:57:15,080 --> 03:57:18,240 MICRORNA ARCHITECTURE, THIS 6118 03:57:18,240 --> 03:57:20,200 ALLOWS US TO EXPRESS THE SH RNA 6119 03:57:20,200 --> 03:57:22,880 IN A LIB YAJ-SPECIFIC FASHION. 6120 03:57:22,880 --> 03:57:26,040 TO ITS EXPRESSION IS ONLY IN 6121 03:57:26,040 --> 03:57:26,800 ERYTHROPRECURSORS, AND THAT 6122 03:57:26,800 --> 03:57:29,240 AVOIDS THE TOXICITIES OF BCL11A 6123 03:57:29,240 --> 03:57:33,560 KNOCKOUT OR KNOCK DOWN IN HSCs 6124 03:57:33,560 --> 03:57:40,000 AND THE LYMPHOCYTES. 6125 03:57:40,000 --> 03:57:43,240 SO THIS IS FROM OUR IND FOR THE 6126 03:57:43,240 --> 03:57:47,280 PHASE ONE TRIAL, AND YOU CAN SEE 6127 03:57:47,280 --> 03:57:48,760 ON THIS SLIDE THAT THREE 6128 03:57:48,760 --> 03:57:49,800 DIFFERENT PATIENTS WITH SICKLE 6129 03:57:49,800 --> 03:57:53,040 CELL WHO DONATED HEMATOPOIETIC 6130 03:57:53,040 --> 03:57:55,720 STEM CELLS FROM BONE MARROW DONE 6131 03:57:55,720 --> 03:57:57,960 IN TRIPLICATE. 6132 03:57:57,960 --> 03:57:59,000 THERE IS A VERY SIGNIFICANT 6133 03:57:59,000 --> 03:58:05,080 INDUCTION OF BOTH GAMMA 6134 03:58:05,080 --> 03:58:07,600 HEMOGLOBIN MRNA AND FETAL 6135 03:58:07,600 --> 03:58:13,000 HEMOGLOBIN PROTEIN BY HPLC. 6136 03:58:13,000 --> 03:58:15,440 AND AS WE WOULD THINK OF BY THE 6137 03:58:15,440 --> 03:58:17,400 FACT THAT WE'RE USING A 6138 03:58:17,400 --> 03:58:19,360 PHYSIOLOGIC SWITCH, THIS IS 6139 03:58:19,360 --> 03:58:21,800 ACCOMPANIED BY DRAMATIC DECREASE 6140 03:58:21,800 --> 03:58:23,120 IN THE CONCENTRATION OF 6141 03:58:23,120 --> 03:58:24,320 HEMOGLOBIN S IN EACH OF THOSE 6142 03:58:24,320 --> 03:58:27,080 PATIENTS. 6143 03:58:27,080 --> 03:58:28,920 SO YOU'RE BASICALLY GETTING A 6144 03:58:28,920 --> 03:58:30,760 TWO-FOR WITH THIS APPROACH: 6145 03:58:30,760 --> 03:58:32,920 REDUCTION IN S AND INCREASE IN 6146 03:58:32,920 --> 03:58:43,160 PROTECTIVE F. 6147 03:58:44,400 --> 03:58:45,680 SO THIS IS THE PROTOCOL WE USE 6148 03:58:45,680 --> 03:58:48,000 FOR THE PHASE 1 TRIAL WHICH HAS 6149 03:58:48,000 --> 03:58:49,480 COMPLETED ENROLLMENT WITH 10 6150 03:58:49,480 --> 03:58:49,880 PATIENTS. 6151 03:58:49,880 --> 03:59:00,080 WE USED PLERIXAFOR CELL 6152 03:59:00,080 --> 03:59:02,560 MOBILIZED STEM CELLS, CD34 6153 03:59:02,560 --> 03:59:04,560 SELECTION, AND THE TRANSDUCTION 6154 03:59:04,560 --> 03:59:07,000 THAT OCCURRED IN THE GMP 6155 03:59:07,000 --> 03:59:09,080 FACILITY, IN THIS CASE, THE C 6156 03:59:09,080 --> 03:59:11,400 MCF AT DANA FARBER CANCER 6157 03:59:11,400 --> 03:59:11,800 INSTITUTE. 6158 03:59:11,800 --> 03:59:18,040 AFTER RELEASE OF THE MEDICINAL 6159 03:59:18,040 --> 03:59:21,200 PRODUCT, THE PATIENTS WERE 6160 03:59:21,200 --> 03:59:24,280 ADMITTED FOR THE AGENT 6161 03:59:24,280 --> 03:59:25,560 CONDITIONING AND FOLLOWED FOR 6162 03:59:25,560 --> 03:59:27,560 TWO YEARS FOR HEMOGLOBIN F 6163 03:59:27,560 --> 03:59:31,960 LEVELS, THE PERCENT OF F CELLS, 6164 03:59:31,960 --> 03:59:35,480 BCL11A LEVELS AND SICKLE CELL 6165 03:59:35,480 --> 03:59:35,720 SYMPTOMS. 6166 03:59:35,720 --> 03:59:38,360 SO I WON'T BELABOR A LOT OF THE 6167 03:59:38,360 --> 03:59:40,120 DATA, BUT I'LL GIVE YOU SOME 6168 03:59:40,120 --> 03:59:41,640 SUMMARIES, AND PART OF THIS HAS 6169 03:59:41,640 --> 03:59:42,880 BEEN PUBLISHED IN THE NEW 6170 03:59:42,880 --> 03:59:46,360 ENGLAND JOURNAL OF MEDICINE IN 6171 03:59:46,360 --> 03:59:47,520 2020. 6172 03:59:47,520 --> 03:59:50,280 PREINFUSION, THE ONLY GRADE 3 6173 03:59:50,280 --> 03:59:52,160 AEs WERE CVL-RELATED. 6174 03:59:52,160 --> 03:59:54,440 WE HAD SEVERAL PATIENTS WHO 6175 03:59:54,440 --> 03:59:58,000 DEVELOPED CVL-ASSOCIATED 6176 03:59:58,000 --> 03:59:59,880 THROMBI, WE HAD ONE PATIENT THAT 6177 03:59:59,880 --> 04:00:01,680 DEVELOPED A PNEUMOTHORAX WITH 6178 04:00:01,680 --> 04:00:02,560 LINE PLACEMENT AND INFECTION. 6179 04:00:02,560 --> 04:00:05,600 THERE WERE NO GRADE III AEs 6180 04:00:05,600 --> 04:00:06,680 RELATED TO EITHER THE 6181 04:00:06,680 --> 04:00:08,960 MOBILIZATION OR COLLECTION 6182 04:00:08,960 --> 04:00:09,560 PROCEDURES. 6183 04:00:09,560 --> 04:00:11,440 THERE HAS BEEN NO ADVERSE EVENTS 6184 04:00:11,440 --> 04:00:13,080 ASSOCIATED WITH MEDICINAL 6185 04:00:13,080 --> 04:00:13,560 PRODUCT. 6186 04:00:13,560 --> 04:00:15,840 AND THERE'S BEEN NO CLONAL 6187 04:00:15,840 --> 04:00:17,400 DOMINANCE IN ANY SUBJECT. 6188 04:00:17,400 --> 04:00:21,560 ALL THE PATIENT HAS HAVE BEEN VY 6189 04:00:21,560 --> 04:00:23,240 POLYCLONAL, INCLUDING LOOKING AT 6190 04:00:23,240 --> 04:00:26,240 THESE PATIENTS USING SINGLE CELL 6191 04:00:26,240 --> 04:00:27,640 DNA IN A COLLABORATIVE EFFORT 6192 04:00:27,640 --> 04:00:29,720 WITH THE SANGER INSTITUTE IN THE 6193 04:00:29,720 --> 04:00:30,280 U.K. 6194 04:00:30,280 --> 04:00:31,960 THE LONGEST FOLLOW-UP IS NOW 6195 04:00:31,960 --> 04:00:38,080 APPROACHING FIVE YEARS. 6196 04:00:38,080 --> 04:00:41,720 SO THIS SHOWS YOU INDUCTION OF 6197 04:00:41,720 --> 04:00:43,920 BLOOD HEMOGLOBIN F AND THE 6198 04:00:43,920 --> 04:00:45,680 PATIENT IS INFUSED. 6199 04:00:45,680 --> 04:00:47,120 THERE'S ONE PATIENT, PATIENT 6200 04:00:47,120 --> 04:00:48,920 NUMBER 10 SHOWN WITH THE RED 6201 04:00:48,920 --> 04:00:50,800 ARROW, WHO WE CONSIDER A FAILURE 6202 04:00:50,800 --> 04:00:52,520 BECAUSE OF THE LACK OF 6203 04:00:52,520 --> 04:00:53,720 INDUCTION, AND THIS IS 6204 04:00:53,720 --> 04:00:56,200 ASSOCIATED WITH A LOW IN VIVO 6205 04:00:56,200 --> 04:00:58,040 VECTOR COPY NUMBER, THAT'S A 6206 04:00:58,040 --> 04:01:00,240 TERM THAT WE USE TO DESCRIBE THE 6207 04:01:00,240 --> 04:01:03,880 NUMBER OF STEM CELLS THAT HAVE 6208 04:01:03,880 --> 04:01:05,880 ENGRAFTED THAT CONTAIN THE SHMIR 6209 04:01:05,880 --> 04:01:07,480 THAT'S WITHIN THE LENTIVIRAL 6210 04:01:07,480 --> 04:01:11,800 VECTOR. 6211 04:01:11,800 --> 04:01:12,600 OTHERWISE THE PATIENTS HAVE HAD, 6212 04:01:12,600 --> 04:01:16,760 AS YOU CAN SEE, VERY LARGE 6213 04:01:16,760 --> 04:01:18,160 INCREASES IN THEIR BLOOD 6214 04:01:18,160 --> 04:01:19,480 HEMOGLOBIN F. 6215 04:01:19,480 --> 04:01:20,880 AND THIS IS ASSOCIATED WITH A 6216 04:01:20,880 --> 04:01:23,160 VERY BROADLY DISTRIBUTED 6217 04:01:23,160 --> 04:01:23,600 HEMOGLOBIN F. 6218 04:01:23,600 --> 04:01:26,120 YOU CAN SEE FOR MOST PATIENTS, 6219 04:01:26,120 --> 04:01:29,320 IT'S ABOVE 60%. 6220 04:01:29,320 --> 04:01:33,160 AGAIN, PATIENT 10, I MARK AS THE 6221 04:01:33,160 --> 04:01:35,360 PATIENT WHO FAILED BECAUSE OF A 6222 04:01:35,360 --> 04:01:42,920 LOW VCN IN VIVO. 6223 04:01:42,920 --> 04:01:43,600 NOW ONE OF THE INTERESTING 6224 04:01:43,600 --> 04:01:48,080 THINGS THAT WE HAVE STUDIED IS 6225 04:01:48,080 --> 04:01:50,720 TO COMPARE THE RELATIONSHIP OF 6226 04:01:50,720 --> 04:01:53,280 HEMOGLOBIN F INDUCTION WITH 6227 04:01:53,280 --> 04:01:54,160 HYDROXYUREA PATIENTS. 6228 04:01:54,160 --> 04:01:56,440 SO THIS IS A PAPER THAT'S IN 6229 04:01:56,440 --> 04:01:58,480 PRESS IN NATURE COMMUNICATION, 6230 04:01:58,480 --> 04:02:01,200 AND IT'S A LITTLE BIT 6231 04:02:01,200 --> 04:02:04,720 COMPLICATED BUT I'LL SHOW YOU ON 6232 04:02:04,720 --> 04:02:07,000 THE RIGHT-HAND SIDE WE COMPARED 6233 04:02:07,000 --> 04:02:10,880 THE NUMBER OF RED CELLS 6234 04:02:10,880 --> 04:02:13,720 CONTAINING MORE THAN 70% 6235 04:02:13,720 --> 04:02:15,680 HEMOGLOBIN S OF THE TOTAL 6236 04:02:15,680 --> 04:02:19,520 HEMOGLOBIN IN PATIENTS THAT HAD 6237 04:02:19,520 --> 04:02:21,480 HYDROXYUREA WITH LOW INDUCTION 6238 04:02:21,480 --> 04:02:22,320 OF HEMOGLOBIN F. 6239 04:02:22,320 --> 04:02:26,040 THOSE THAT HAD HIGH INDUCTION 6240 04:02:26,040 --> 04:02:27,680 WITH HYDROXYUREA AND THOSE IN 6241 04:02:27,680 --> 04:02:30,040 THE GENE THERAPY TRIALS. 6242 04:02:30,040 --> 04:02:30,360 TRIAL. 6243 04:02:30,360 --> 04:02:31,480 AND THE PATIENTS IN THE BLUE 6244 04:02:31,480 --> 04:02:33,920 PANEL ON THE RIGHT ARE PATIENTS 6245 04:02:33,920 --> 04:02:37,520 THAT HAD EQUIVALENT BLOOD 6246 04:02:37,520 --> 04:02:40,400 HEMOGLOBIN F WITH HYDROXYUREA AS 6247 04:02:40,400 --> 04:02:41,400 THE GENE THERAPY PATIENTS. 6248 04:02:41,400 --> 04:02:44,560 BUT YOU CAN SEE THAT THE 6249 04:02:44,560 --> 04:02:45,680 PATIENTS IN THE GENE THERAPY 6250 04:02:45,680 --> 04:02:47,560 TRIAL HAD SIGNIFICANTLY LOWER 6251 04:02:47,560 --> 04:02:51,360 NUMBER OF RED CELLS CONTAINING A 6252 04:02:51,360 --> 04:02:54,400 LOT OF HEMOGLOBIN S COMPARED TO 6253 04:02:54,400 --> 04:02:56,120 HOI DROOX EE UREA. 6254 04:02:56,120 --> 04:02:57,760 THIS SPEAKS TO THE MECHANISM BY 6255 04:02:57,760 --> 04:02:59,080 WHICH WE'RE ADDRESSING THE 6256 04:02:59,080 --> 04:03:02,160 INDUCTION OF HEMOGLOBIN F WHERE 6257 04:03:02,160 --> 04:03:03,600 WE'RE BASICALLY USING A 6258 04:03:03,600 --> 04:03:06,000 PHYSIOLOGIC SWITCH THAT'S 6259 04:03:06,000 --> 04:03:08,000 BINARY, SO THE AMOUNT OF S GOES 6260 04:03:08,000 --> 04:03:12,280 DOWN AS THE AMOUNT OF F GOES UP. 6261 04:03:12,280 --> 04:03:13,520 YOU CAN SEE AGAIN DOWN BELOW 6262 04:03:13,520 --> 04:03:17,680 THAT THE HYDROXYUREA F RANGE IN 6263 04:03:17,680 --> 04:03:25,280 BLUE WAS 27% COMPARED TO THE 6264 04:03:25,280 --> 04:03:28,760 BCL11A PATIENTS SHOWN ON THE 6265 04:03:28,760 --> 04:03:32,040 CHRONOLOGICAL AXIS ON THE LEFT. 6266 04:03:32,040 --> 04:03:34,840 THIS WAS ALSO SEEN HERE WHERE 6267 04:03:34,840 --> 04:03:39,840 WE'VE ASKED THE QUESTION UNDER 6268 04:03:39,840 --> 04:03:41,040 HYPOXIA CONDITIONS, WHAT HAPPENS 6269 04:03:41,040 --> 04:03:42,040 TO POLYMER FORMATION. 6270 04:03:42,040 --> 04:03:45,960 SO IN A, YOU CAN SEE A FLOW, 6271 04:03:45,960 --> 04:03:47,800 MICRO FLOW CHAMBER WITH RED 6272 04:03:47,800 --> 04:03:51,160 CELLS FLOWING AT 1.7% OXYGEN 6273 04:03:51,160 --> 04:03:53,080 TENSION, THAT'S THE OXYGEN 6274 04:03:53,080 --> 04:03:55,880 TENSION IN THE KIDNEY. 6275 04:03:55,880 --> 04:03:57,920 AND ON THE RIGHT, YOU CAN SEE 6276 04:03:57,920 --> 04:04:02,280 THE SAME FLOW AT 1.7% WITH 6277 04:04:02,280 --> 04:04:03,480 HEMOGLOBIN S POLYMER FORMATION 6278 04:04:03,480 --> 04:04:06,960 THAT YOU CAN SEE VISUALLY ON A 6279 04:04:06,960 --> 04:04:08,920 SINGLE CELL BASIS. 6280 04:04:08,920 --> 04:04:11,400 DOWN BELOW, AGAIN, IF YOU LOOK 6281 04:04:11,400 --> 04:04:14,720 AT THE GRAPHS, IT COMPARES THE 6282 04:04:14,720 --> 04:04:18,400 NUMBER OF RED CELLS WITH NO 6283 04:04:18,400 --> 04:04:19,160 DETECTABLE HEMOGLOBIN POLYMER 6284 04:04:19,160 --> 04:04:21,120 COULD BE TENT. 6285 04:04:21,120 --> 04:04:24,720 THAT'S IN C, AT 1.7%. 6286 04:04:24,720 --> 04:04:26,600 AGAIN, INSPITE OF THE FACT THAT 6287 04:04:26,600 --> 04:04:28,480 THE HEMOGLOBIN F LEVEL IN THE 6288 04:04:28,480 --> 04:04:30,160 PERIPHERAL BLOOD IS EQUIVALENT 6289 04:04:30,160 --> 04:04:31,400 IN THE HYDROXYUREA HIGH 6290 04:04:31,400 --> 04:04:34,400 RESPONDERS, THE NUMBER OF CELLS 6291 04:04:34,400 --> 04:04:39,000 CONTAINING POLYMER IS 6292 04:04:39,000 --> 04:04:40,000 SIGNIFICANTLY LESS IN THE GENE 6293 04:04:40,000 --> 04:04:46,560 THERAPY TREATED GROUP. 6294 04:04:46,560 --> 04:04:47,920 SO THIS AGAIN SUGGESTS THAT THE 6295 04:04:47,920 --> 04:04:49,680 NUMBER OF RED CELLS THAT HAVE 6296 04:04:49,680 --> 04:04:57,440 HIGH HEMOGLOBIN F ABOVE 8 OR 6297 04:04:57,440 --> 04:04:58,280 10PICOGRAMS IS HIGHER IN THE 6298 04:04:58,280 --> 04:04:59,680 GENE THERAPY TREATED PATIENTS 6299 04:04:59,680 --> 04:05:03,320 VERSUS THE HYDROXYUREA PATIENTS. 6300 04:05:03,320 --> 04:05:06,240 SO IN THIS INITIAL PILOT STUDY, 6301 04:05:06,240 --> 04:05:07,120 10 PATIENTS WERE TREATED. 6302 04:05:07,120 --> 04:05:10,520 WE WERE ABLE TO GENERATE A GMB 6303 04:05:10,520 --> 04:05:12,320 PRODUCT IN 11 PATIENTS, ONE 6304 04:05:12,320 --> 04:05:16,520 PATIENT WITHDREW FOR 6305 04:05:16,520 --> 04:05:17,680 CO-MORBIDITY REASONS BEFORE THE 6306 04:05:17,680 --> 04:05:18,200 INFUSION. 6307 04:05:18,200 --> 04:05:20,600 10 PATIENTS HAVE BEEN INFUSED. 6308 04:05:20,600 --> 04:05:24,840 THE SHMIR VECTOR IS SAFE WITH 6309 04:05:24,840 --> 04:05:26,040 FOLLOW-UP NOW ALMOST FIVE YEARS 6310 04:05:26,040 --> 04:05:27,160 IN THE LONGEST PATIENT. 6311 04:05:27,160 --> 04:05:28,520 THE VECTOR IS EXTREMELY 6312 04:05:28,520 --> 04:05:30,480 EFFICIENT IN TRANSDUCING HSCs. 6313 04:05:30,480 --> 04:05:35,200 THERE'S BEEN NO ADVERSE EVENTS 6314 04:05:35,200 --> 04:05:36,800 RELATED TO THE VECTOR. 6315 04:05:36,800 --> 04:05:39,480 EXPRESSION, I DIDN'T SHOW YOU 6316 04:05:39,480 --> 04:05:47,080 THE DATA, APPEARS 6317 04:05:47,080 --> 04:05:47,800 LINEAGE-SPECIFIC, AND GENE 6318 04:05:47,800 --> 04:05:54,160 MARKING IS STABLE. 6319 04:05:54,160 --> 04:05:55,880 HIGH HEMOGLOBIN F FOR F CELL 6320 04:05:55,880 --> 04:05:58,200 WITH REDUCED HEMOGLOBIN S PER 6321 04:05:58,200 --> 04:05:59,400 CELL AND THERE'S BEEN A 6322 04:05:59,400 --> 04:06:01,080 SIGNIFICANT ATTENUATION IN A 6323 04:06:01,080 --> 04:06:01,640 SICKLING PHENOTYPE IN THE 6324 04:06:01,640 --> 04:06:04,480 PATIENTS THAT WE'VE TREATED, 6325 04:06:04,480 --> 04:06:05,680 WITH THE EXCEPTION OF THE ONE 6326 04:06:05,680 --> 04:06:10,040 PATIENT WHO HAD A LOW VECTOR 6327 04:06:10,040 --> 04:06:20,360 COPY NUMBER IN VIVO. 6328 04:06:29,560 --> 04:06:30,720 OF THE 10 PATIENTS THAT WAVE 6329 04:06:30,720 --> 04:06:33,280 DONE THIS WITH, ONE OF THE 10 6330 04:06:33,280 --> 04:06:35,520 PATIENTS HAS A SOMATIC MUTATION 6331 04:06:35,520 --> 04:06:40,400 IN THE GENE ASSOCIATED WITH 6332 04:06:40,400 --> 04:06:43,320 CLONAL HEMATOPOE EE SES, DNMT3A. 6333 04:06:43,320 --> 04:06:44,320 IT'S INTERESTING THAT THIS 6334 04:06:44,320 --> 04:06:46,320 PATIENT HAD THIS DISCOVERED SIX 6335 04:06:46,320 --> 04:06:49,520 MONTHS POST INFUSION, AND THE 6336 04:06:49,520 --> 04:06:52,240 BASELINE ANALYSIS WAS NEGATIVE. 6337 04:06:52,240 --> 04:06:55,640 AND THAT WAS BECAUSE THE 6338 04:06:55,640 --> 04:06:57,360 MUTATION WAS PRESENT IN THE 6339 04:06:57,360 --> 04:07:03,440 BASELINE ANALYSIS, BUT THE 6340 04:07:03,440 --> 04:07:05,080 PRESAMPLE IN THE CLIA LAB WAS 6341 04:07:05,080 --> 04:07:07,520 BELOW THE LEVEL OF REPORT OUT AS 6342 04:07:07,520 --> 04:07:07,840 POSITIVE. 6343 04:07:07,840 --> 04:07:11,520 SO WE WERE QUITE INTERESTED IN 6344 04:07:11,520 --> 04:07:12,080 THIS PATIENT. 6345 04:07:12,080 --> 04:07:17,960 THE PATIENT WAS OFFERED GENETIC 6346 04:07:17,960 --> 04:07:19,200 COUNSELING AND HAS NOT TAKEN 6347 04:07:19,200 --> 04:07:21,520 THAT UP, BUT AS YOU CAN SEE, 6348 04:07:21,520 --> 04:07:23,960 WHAT'S INTERESTING IS THAT THIS 6349 04:07:23,960 --> 04:07:27,280 FRACTION OF THE DNMT3 ALLELE HAS 6350 04:07:27,280 --> 04:07:29,480 NOT INCREASED AFTER THE INITIAL 6351 04:07:29,480 --> 04:07:29,920 SIX MONTHS PERIOD. 6352 04:07:29,920 --> 04:07:35,160 YOU CAN SEE IT INCREASED 6353 04:07:35,160 --> 04:07:36,320 INITIALLY AFTER INFUSION AND 6354 04:07:36,320 --> 04:07:38,480 IT'S REMAINED RELATIVELY STABLE 6355 04:07:38,480 --> 04:07:39,840 OVER A LONG PERIOD OF TIME NOW, 6356 04:07:39,840 --> 04:07:46,240 2 1/2 YEARS IN PERIPHERAL BLOOD. 6357 04:07:46,240 --> 04:07:47,280 THE BONE MARROW OF THIS PATIENT 6358 04:07:47,280 --> 04:07:48,960 IS NORMAL EXCEPT FOR SOME EE RIT 6359 04:07:48,960 --> 04:07:56,120 RERYTHROID EXPANSION AND THE 6360 04:07:56,120 --> 04:07:57,040 PATIENT CONTINUES TO DO WELL. 6361 04:07:57,040 --> 04:08:00,000 I BRING THIS UP BECAUSE OF 6362 04:08:00,000 --> 04:08:01,360 COURSE IT IS AN ISSUE IN THE 6363 04:08:01,360 --> 04:08:02,680 FIELD AS TO WHETHER PATIENTS 6364 04:08:02,680 --> 04:08:04,080 WITH SICKLE CELL DISEASE HAVE AN 6365 04:08:04,080 --> 04:08:06,680 INCREASED RISK OF HEMATOLOGIC 6366 04:08:06,680 --> 04:08:07,240 MALIGNANCY. 6367 04:08:07,240 --> 04:08:10,520 WE ARE STUDYING THIS IN MORE 6368 04:08:10,520 --> 04:08:12,240 DETAIL, LOOKING AT THE 6369 04:08:12,240 --> 04:08:13,440 MANUFACTURING PROCESS, AS WELL 6370 04:08:13,440 --> 04:08:15,040 AS THE ENGRAFTMENT AT SINGLE 6371 04:08:15,040 --> 04:08:17,920 CELL DNA LEVELS, AND AS I 6372 04:08:17,920 --> 04:08:19,000 MENTIONED, THAT'S A 6373 04:08:19,000 --> 04:08:21,080 COLLABORATION WITH THE SANGER 6374 04:08:21,080 --> 04:08:21,600 INSTITUTE. 6375 04:08:21,600 --> 04:08:23,920 AND THOSE DATA FROM THE PILOT 6376 04:08:23,920 --> 04:08:26,240 STUDY ARE CURRENTLY UNDER REVIEW 6377 04:08:26,240 --> 04:08:27,680 AT NATURE MEDICINE AND HOPEFULLY 6378 04:08:27,680 --> 04:08:29,760 WILL BE ACCEPTED SHORTLY. 6379 04:08:29,760 --> 04:08:32,160 IN GENERAL, WE HAVEN'T SEEN ANY 6380 04:08:32,160 --> 04:08:34,160 SIGNATURE OF SICKLE CELL DISEASE 6381 04:08:34,160 --> 04:08:36,520 IN THOSE SINGLE CELL DNA 6382 04:08:36,520 --> 04:08:38,040 SEQUENCES THAT WE'VE DONE, AND 6383 04:08:38,040 --> 04:08:40,560 WE'RE CONTINUING THOSE STUDIES. 6384 04:08:40,560 --> 04:08:42,280 SO LET ME GO TO THE PHASE TWO 6385 04:08:42,280 --> 04:08:42,480 STUDY. 6386 04:08:42,480 --> 04:08:45,440 THIS IS CALLED THE GRASP STUDY, 6387 04:08:45,440 --> 04:08:48,360 GENE THERAPY TO REDUCE ALL 6388 04:08:48,360 --> 04:08:49,440 SICKLE PAIN. 6389 04:08:49,440 --> 04:08:50,880 IT'S CO-CHAIRED BY MARK AND 6390 04:08:50,880 --> 04:08:54,000 MYSELF AND IS FUNDED BY THE 6391 04:08:54,000 --> 04:09:00,360 NHLBI CURE SICKLE, AND BY CERM. 6392 04:09:00,360 --> 04:09:01,560 THE PRIMARY OBJECTIVE IS TO 6393 04:09:01,560 --> 04:09:03,960 DETERMINE IF A SINGLE INFUSION 6394 04:09:03,960 --> 04:09:06,560 OF AUTOLOGOUS HSCs TRANSDUCE 6395 04:09:06,560 --> 04:09:08,320 WITH THE SHMIR VECTOR CAN LEAD 6396 04:09:08,320 --> 04:09:11,280 TO THE COMPLETE ABSENCE OF 6397 04:09:11,280 --> 04:09:14,400 SEVERE VOEs DEFINED AS EITHER 6398 04:09:14,400 --> 04:09:18,320 ACS OR VOCs REQUIRING 6399 04:09:18,320 --> 04:09:19,720 PARENTERAL OPIOIDS IN THE PERIOD 6400 04:09:19,720 --> 04:09:21,160 OF 6 MONTHS TO 24 MONTHS AFTER 6401 04:09:21,160 --> 04:09:21,480 GENE THERAPY. 6402 04:09:21,480 --> 04:09:24,560 THIS TRIAL WAS HELD FOR A 6403 04:09:24,560 --> 04:09:25,200 SIGNIFICANT PERIOD OF TIME WHILE 6404 04:09:25,200 --> 04:09:30,320 WE WORKED OUT THE ISSUES OF THE 6405 04:09:30,320 --> 04:09:33,920 ANALYSIS OF CLONAL HEMATOPOIESIS 6406 04:09:33,920 --> 04:09:35,080 AND HOW THAT RELATED TO 6407 04:09:35,080 --> 04:09:37,720 INCLUSION IN THE TRIAL, BUT 6408 04:09:37,720 --> 04:09:43,960 OPENED IN JANUARY THIS YEAR. 6409 04:09:43,960 --> 04:09:45,560 AND SITES ARE SHOWN HERE, 6410 04:09:45,560 --> 04:09:46,400 MULTIPLE SITES IN CALIFORNIA AS 6411 04:09:46,400 --> 04:09:49,160 WELL AS THE REST OF THE COUNTRY. 6412 04:09:49,160 --> 04:09:51,560 ALL THESE SITES ARE NOW OPEN AND 6413 04:09:51,560 --> 04:09:53,840 ACCRUING, AND WE'VE NOW ACCRUED, 6414 04:09:53,840 --> 04:10:00,560 AS YOU CAN SEE, 13 PATIENTS 6415 04:10:00,560 --> 04:10:02,120 ALREADY INTO THE TRIAL, AND JUST 6416 04:10:02,120 --> 04:10:03,880 AS THE COMMENT FROM MY PREVIOUS 6417 04:10:03,880 --> 04:10:06,400 COMMENT ON CLONAL HEMATOPOIESIS, 6418 04:10:06,400 --> 04:10:11,400 12 OF THESE PATIENTS HAVE NOW 6419 04:10:11,400 --> 04:10:18,480 HAD THE ANALYSIS FOR CLONAL 6420 04:10:18,480 --> 04:10:19,680 HEMATOPOIESIS AND NONE OF THOSE 6421 04:10:19,680 --> 04:10:21,080 PATIENTS HAVE WE FOUND ANY 6422 04:10:21,080 --> 04:10:22,200 MUTATIONS IN GENES THAT WOULD 6423 04:10:22,200 --> 04:10:23,800 NOT ALLOW THEM TO CONTINUE INTO 6424 04:10:23,800 --> 04:10:32,040 THE TRIAL. 6425 04:10:32,040 --> 04:10:32,640 BECAUSE OF THE CHARACTERISTICS 6426 04:10:32,640 --> 04:10:34,320 OF THIS TRIAL AND THE RULES I'M 6427 04:10:34,320 --> 04:10:35,440 NOT ABLE TO PROVIDE MUCH IN THE 6428 04:10:35,440 --> 04:10:37,360 WAY OF CLINICAL OUTCOMES YET, 6429 04:10:37,360 --> 04:10:39,120 BUT I WOULD JUST SAY IN THE 6430 04:10:39,120 --> 04:10:43,120 PATIENTS THAT WE'VE ALREADY 6431 04:10:43,120 --> 04:10:44,320 COMPLETED COLLECTION ON, THOSE 6432 04:10:44,320 --> 04:10:49,240 HAVE ALL YIELDED EFFECTIVE 6433 04:10:49,240 --> 04:10:50,120 MEDICINAL PRODUCT AND THREE OF 6434 04:10:50,120 --> 04:10:51,200 THE PATIENTS HAVE ALREADY BEEN 6435 04:10:51,200 --> 04:11:00,240 INFUSED. 6436 04:11:00,240 --> 04:11:01,800 SO WE'VE GOT 15 PATIENTS 6437 04:11:01,800 --> 04:11:02,440 ENROLLED. 6438 04:11:02,440 --> 04:11:04,080 ONE WITHDREW FROM THE STUDY, AND 6439 04:11:04,080 --> 04:11:05,840 THE TARGET FOR THIS TRIAL IS 25 6440 04:11:05,840 --> 04:11:06,160 PATIENTS. 6441 04:11:06,160 --> 04:11:08,680 SO WE'RE OVER HALFWAY TO OUR 6442 04:11:08,680 --> 04:11:10,800 TARGET ACCRUAL IN THE FIRST AP 6443 04:11:10,800 --> 04:11:13,720 EIGHT MONTHS OF THE TRIAL. 6444 04:11:13,720 --> 04:11:17,040 SO FAR WE'VE HAD VERY EFFECTIVE 6445 04:11:17,040 --> 04:11:18,360 COLLECTION AND GMP PRODUCT 6446 04:11:18,360 --> 04:11:20,360 DEVELOPMENT FOR THE FIRST FOUR 6447 04:11:20,360 --> 04:11:23,720 PATIENTS AFTER THEIR TRANSFUSION 6448 04:11:23,720 --> 04:11:24,160 REQUIREMENT. 6449 04:11:24,160 --> 04:11:25,440 THREE OF THE FOUR ACTUALLY 6450 04:11:25,440 --> 04:11:28,360 ACQUIRED THEIR TARGET IN ONE 6451 04:11:28,360 --> 04:11:29,400 MOBILIZATION, THANKS A LOT TO 6452 04:11:29,400 --> 04:11:33,000 JOHN MANUS, WHO JUST HAD A 6453 04:11:33,000 --> 04:11:34,400 WORKSHOP ON THIS AT LUNCHTIME. 6454 04:11:34,400 --> 04:11:38,080 SO FAR THE HSCs HAVE BEEN 6455 04:11:38,080 --> 04:11:39,040 SUFFICIENTLY TRANSDUCED JUST AS 6456 04:11:39,040 --> 04:11:40,280 IN THE PILOT STUDY. 6457 04:11:40,280 --> 04:11:41,560 THREE PATIENTS HAVE BEEN 6458 04:11:41,560 --> 04:11:41,880 INFUSED. 6459 04:11:41,880 --> 04:11:44,080 THE LONGEST FOLLOW-UP IS THREE 6460 04:11:44,080 --> 04:11:45,760 MONTHS, AND THE INDUCTION OF THE 6461 04:11:45,760 --> 04:11:47,320 FIRST EVALUABLE PATIENT IS 6462 04:11:47,320 --> 04:11:48,680 COMPARABLE TO THE PILOT STUDY. 6463 04:11:48,680 --> 04:11:50,760 WE'RE OPENING A SECOND 6464 04:11:50,760 --> 04:11:53,000 MANUFACTURING SITE AT UCLA. 6465 04:11:53,000 --> 04:11:54,320 THE FIRST PRODUCT TO BE PRODUCED 6466 04:11:54,320 --> 04:11:56,520 THIS MONTH YET. 6467 04:11:56,520 --> 04:11:59,240 AND WE'RE TRANSITIONING OUR 6468 04:11:59,240 --> 04:12:02,280 VECTOR FROM A VECTOR THAT WAS 6469 04:12:02,280 --> 04:12:04,240 PRODUCED AS AN ADHERENT CULTURE 6470 04:12:04,240 --> 04:12:05,720 TO SUSPENSION CULTURE, WHICH IS 6471 04:12:05,720 --> 04:12:08,440 A MORE UP TO DATE MANUFACTURING 6472 04:12:08,440 --> 04:12:09,800 PROCESS, AND THE FIRST USAGE OF 6473 04:12:09,800 --> 04:12:11,440 THAT WILL BE IN AUGUST, WHICH IS 6474 04:12:11,440 --> 04:12:12,680 ACTUALLY WELL AHEAD OF THE 6475 04:12:12,680 --> 04:12:18,400 SCHEDULE THAT WE HAD PLANNED. 6476 04:12:18,400 --> 04:12:19,520 SO I'D JUST LIKE TO THANK 6477 04:12:19,520 --> 04:12:21,480 EVERYBODY THAT'S BEEN INVOLVED 6478 04:12:21,480 --> 04:12:23,160 FIRST AND FOREMOST, PATIENTS 6479 04:12:23,160 --> 04:12:24,960 WHO'VE BEEN WILLING TO ENROLL IN 6480 04:12:24,960 --> 04:12:27,440 A PHASE ONE AND NOW PHASE TWO 6481 04:12:27,440 --> 04:12:28,640 STUDY. 6482 04:12:28,640 --> 04:12:30,520 BOSTON CHILDREN'S SITE P.I. FOR 6483 04:12:30,520 --> 04:12:34,360 OUR STUDY, BOTH IN PHASE # AND D 6484 04:12:34,360 --> 04:12:37,520 THE PHASE 2 IS ERICA ESRICK. 6485 04:12:37,520 --> 04:12:39,400 WE'VE HAD GREAT SUPPORT FROM THE 6486 04:12:39,400 --> 04:12:41,120 TRANSLATIONAL LAB AT BOSTON 6487 04:12:41,120 --> 04:12:47,440 CHILDREN'S LED BY MYRI AM AMANT. 6488 04:12:47,440 --> 04:12:50,160 THE DANA FARBER, AND A NUMBER OF 6489 04:12:50,160 --> 04:12:51,040 OTHER COLLABORATIONS THAT HAVE 6490 04:12:51,040 --> 04:12:53,000 BEEN VERY FRUITFUL, INCLUDING 6491 04:12:53,000 --> 04:12:55,080 FOLKS AT BLUEBIRD BIO, WHO HAVE 6492 04:12:55,080 --> 04:12:56,800 BEEN GREAT COLLABORATORS, 6493 04:12:56,800 --> 04:12:59,000 ALTHOUGH THIS IS NOT THEIR TRIAL 6494 04:12:59,000 --> 04:12:59,680 OBVIOUSLY. 6495 04:12:59,680 --> 04:13:00,840 AND THEN I'VE MENTIONED ALREADY 6496 04:13:00,840 --> 04:13:05,200 THE FUNDING, WHICH IS BY NHLBI, 6497 04:13:05,200 --> 04:13:07,040 CURE SICKLE, AND WE HAVE 6498 04:13:07,040 --> 04:13:11,520 SEPARATE FUNDING FROM THE GATES 6499 04:13:11,520 --> 04:13:13,720 FOUNDATION TO TRANSITION OUR 6500 04:13:13,720 --> 04:13:16,040 TARGET INTO AN IN VIVO APPROACH, 6501 04:13:16,040 --> 04:13:17,240 WHICH WE'RE CARRYING OUT AT THIS 6502 04:13:17,240 --> 04:13:17,880 TIME. 6503 04:13:17,880 --> 04:13:19,280 I THINK THAT'S THE LAST SLIDE. 6504 04:13:19,280 --> 04:13:24,800 I'M HAPPY TO ANSWER QUESTIONS. 6505 04:13:24,800 --> 04:13:30,800 >>THANK YOU, DAVID. 6506 04:13:30,800 --> 04:13:31,280 QUESTIONS? 6507 04:13:31,280 --> 04:13:33,000 TIME FOR ONE QUICK QUESTION 6508 04:13:33,000 --> 04:13:36,280 MAYBE? 6509 04:13:36,280 --> 04:13:37,280 ANY QUESTIONS ONLINE? 6510 04:13:37,280 --> 04:13:38,400 NO QUESTIONS ONLINE. 6511 04:13:38,400 --> 04:13:40,200 THANK YOU, DAVID. 6512 04:13:40,200 --> 04:13:41,120 THANKS A LOT. 6513 04:13:41,120 --> 04:13:46,600 >>THANK YOU FOR INVITING ME. 6514 04:13:46,600 --> 04:13:50,880 >>SO OUR NEXT TALK IS GOING TO 6515 04:13:50,880 --> 04:13:54,520 BE A TAG TEAM BY MARK GLADWIN 6516 04:13:54,520 --> 04:13:55,480 AND KALEAB ABEBE FROM UNIVERSITY 6517 04:13:55,480 --> 04:13:57,240 OF PIT BURG AND UNIVERSITY OF 6518 04:13:57,240 --> 04:13:58,920 MARYLAND. 6519 04:13:58,920 --> 04:14:02,800 THIS IS GOING TO BE THE PRIMARY 6520 04:14:02,800 --> 04:14:04,920 RESULTS OF THE STEREO SICKLE 6521 04:14:04,920 --> 04:14:05,760 CELL DISEASE TRIAL. 6522 04:14:05,760 --> 04:14:07,720 MARK, CAN YOU HEAR ME? 6523 04:14:07,720 --> 04:14:08,840 >>I CAN HEAR YOU. 6524 04:14:08,840 --> 04:14:09,760 CAN YOU HEAR ME OKAY? 6525 04:14:09,760 --> 04:14:10,360 >>YES. 6526 04:14:10,360 --> 04:14:11,240 GO AHEAD. 6527 04:14:11,240 --> 04:14:13,520 >>DO YOU THINK I COULD SHARE MY 6528 04:14:13,520 --> 04:14:14,200 SLIDES? 6529 04:14:14,200 --> 04:14:15,200 THAT MAY HELP WITH THE 6530 04:14:15,200 --> 04:14:15,480 ANIMATION. 6531 04:14:15,480 --> 04:14:17,400 OR IS IT BETTER TO USE THEM 6532 04:14:17,400 --> 04:14:23,040 THROUGH YOU? 6533 04:14:23,040 --> 04:14:24,760 >>I THINK THEY ARE DOING ALL OF 6534 04:14:24,760 --> 04:14:25,440 THEM THROUGH HERE. 6535 04:14:25,440 --> 04:14:26,880 >>OKAY. 6536 04:14:26,880 --> 04:14:33,840 I'LL JUST GO THROUGH. 6537 04:14:33,840 --> 04:14:36,520 THIS WILL BE A PRESENTATION BY 6538 04:14:36,520 --> 04:14:38,760 BOTH ME AND KALEAB ABEBE, WHO IS 6539 04:14:38,760 --> 04:14:40,520 THE P.I. OF OUR DATA RECORDING 6540 04:14:40,520 --> 04:14:41,360 CENTER AT THE UNIVERSITY OF 6541 04:14:41,360 --> 04:14:41,640 PITTSBURGH. 6542 04:14:41,640 --> 04:14:43,240 AT THE END, I'LL RECOGNIZE ALL 6543 04:14:43,240 --> 04:14:45,760 THE SITES AND PIs THAT HAVE 6544 04:14:45,760 --> 04:14:46,120 PARTICIPATED. 6545 04:14:46,120 --> 04:14:50,480 BUT THIS IS A PHASE IIB 6546 04:14:50,480 --> 04:14:52,040 RANDOMIZED DOUBLE BLIND PLACEBO 6547 04:14:52,040 --> 04:14:54,200 CONTROLLED TRIAL TO STUDY THE 6548 04:14:54,200 --> 04:14:56,240 SAFETY, TOLERABILITY AND 6549 04:14:56,240 --> 04:14:57,120 EFFICACY OF RIOCIGUAT IN 6550 04:14:57,120 --> 04:15:04,400 PATIENTS WITH SICKLE CELL. 6551 04:15:04,400 --> 04:15:05,920 SO WE'LL JUST QUICKLY GO THROUGH 6552 04:15:05,920 --> 04:15:13,560 THESE BULLETS. 6553 04:15:13,560 --> 04:15:16,760 SO HEMOLYSIS THROUGH A VARIETY 6554 04:15:16,760 --> 04:15:22,880 OF MECHANISMS REDUCES ANO 6555 04:15:22,880 --> 04:15:24,040 BIOAVAILABILITY AND DAMAGES 6556 04:15:24,040 --> 04:15:26,040 BLOOD VESSELS LEADING TO A 6557 04:15:26,040 --> 04:15:30,320 NUMBER OF CLINICAL COMPLICATIONS 6558 04:15:30,320 --> 04:15:33,320 SHOWN HERE. 6559 04:15:33,320 --> 04:15:35,200 THESE COMPLICATIONS HAVE BEEN 6560 04:15:35,200 --> 04:15:36,640 ASSOCIATED WITH A NUMBER OF 6561 04:15:36,640 --> 04:15:40,320 OBJECTIVE FINDINGS LIKE SYSTEMIC 6562 04:15:40,320 --> 04:15:42,840 SYSTOLIC HYPERTENSION, PULMONARY 6563 04:15:42,840 --> 04:15:44,760 HYPERTENSION, AS ESTIMATED BY 6564 04:15:44,760 --> 04:15:48,160 THE HIGH TRICUSPID VELOCITY AND 6565 04:15:48,160 --> 04:15:49,560 PROTEINURIA WITH THE DEVELOPMENT 6566 04:15:49,560 --> 04:15:54,080 OF CHRONIC KIDNEY DISEASE. 6567 04:15:54,080 --> 04:15:55,240 IF YOU JUST WANT TO CLICK 6568 04:15:55,240 --> 04:15:57,680 THROUGH SOME OF THESE 6569 04:15:57,680 --> 04:15:58,480 ANIMATIONS. 6570 04:15:58,480 --> 04:16:01,280 SO THESE THREE THINGS ARE ALL 6571 04:16:01,280 --> 04:16:02,600 ASSOCIATED WITH INCREASED RISK 6572 04:16:02,600 --> 04:16:04,760 OF STROKE, CHRONIC KIDNEY 6573 04:16:04,760 --> 04:16:05,960 DISEASE, PULMONARY HYPERTENSION 6574 04:16:05,960 --> 04:16:11,400 AND DEATH. 6575 04:16:11,400 --> 04:16:13,160 A NUMBER OF STUDIES OVER THE 6576 04:16:13,160 --> 04:16:16,240 YEARS HAVE SHOWN THAT EVEN 6577 04:16:16,240 --> 04:16:18,560 RELATIVE SYSTOLIC HYPERTENSION 6578 04:16:18,560 --> 04:16:20,160 OR A HIGH PULSE PRESSURE IN 6579 04:16:20,160 --> 04:16:21,360 PATIENT WITH SICKLE CELL DISEASE 6580 04:16:21,360 --> 04:16:23,360 IS ASSOCIATED WITH RISK OF 6581 04:16:23,360 --> 04:16:25,200 STROKE, AS SHOWN HERE WITH 6582 04:16:25,200 --> 04:16:27,920 HAZARD RATIOS OF ABOUT 10 FOR 6583 04:16:27,920 --> 04:16:30,000 THE ASSOCIATION OF SYSTOLIC 6584 04:16:30,000 --> 04:16:35,440 HYPERTENSION WITH STROKE. 6585 04:16:35,440 --> 04:16:36,720 AND RELATIVE HYPERTENSION, AND 6586 04:16:36,720 --> 04:16:38,840 WHAT I MEAN BY RELATIVE IS 6587 04:16:38,840 --> 04:16:40,280 HYPERTENSION WITHIN POPULATIONS 6588 04:16:40,280 --> 04:16:42,320 OF SICKLE CELL PATIENTS AS 6589 04:16:42,320 --> 04:16:46,360 OPPOSED TO TRADITIONAL MEASURES 6590 04:16:46,360 --> 04:16:51,520 OF HYPERTENSION ARE ASSOCIATED 6591 04:16:51,520 --> 04:16:53,560 WITH A WORSE SURVIVAL. 6592 04:16:53,560 --> 04:16:58,400 AND IN THIS STUDY BY 6593 04:16:58,400 --> 04:16:59,160 DR. DORDEUK, HE SHOWED 6594 04:16:59,160 --> 04:17:00,160 INDIVIDUALS WITH SICKLE CELL 6595 04:17:00,160 --> 04:17:01,720 DISEASE, AS THE SYSTOLIC 6596 04:17:01,720 --> 04:17:03,960 PRESSURE RISES ABOVE 120 AND 6597 04:17:03,960 --> 04:17:05,160 PARTICULARLY ABOVE 140, THERE'S 6598 04:17:05,160 --> 04:17:09,120 AN INCREASED RISK OF HIGH -- 6599 04:17:09,120 --> 04:17:15,120 VELOCITY, SO AGAIN SYSTOLIC -- 6600 04:17:15,120 --> 04:17:17,960 AND INCREASED CREATININE VALUES 6601 04:17:17,960 --> 04:17:20,120 OVER TIME. 6602 04:17:20,120 --> 04:17:21,560 AND YOU CAN CLICK THROUGH THE 6603 04:17:21,560 --> 04:17:22,720 ANIMATION ON THIS SLIDE. 6604 04:17:22,720 --> 04:17:24,320 A NUMBER OF STUDIES THAT ALL OF 6605 04:17:24,320 --> 04:17:27,360 YOU ARE AWARE OF HAVE CLEARLY 6606 04:17:27,360 --> 04:17:30,320 ASSOCIATED THE NONINVASIVE 6607 04:17:30,320 --> 04:17:32,600 ESTIMATE OF PULMONARY ARTERY 6608 04:17:32,600 --> 04:17:35,120 SYSTOLIC PRESSURE WITH DEATH, 6609 04:17:35,120 --> 04:17:36,560 AND THIS AS YOU LOOK IN THE 6610 04:17:36,560 --> 04:17:42,120 LOWER LEFT, THERE IS A LINEAR OR 6611 04:17:42,120 --> 04:17:43,200 EXPONENTIAL INCREASE IN THE RISK 6612 04:17:43,200 --> 04:17:45,680 OF DEATH AS THE PRESSURE RISES 6613 04:17:45,680 --> 04:17:47,680 AND EVEN IF WE USE RIGHT HEART 6614 04:17:47,680 --> 04:17:50,880 CATH MEASURES, INVASIVE MEASURES 6615 04:17:50,880 --> 04:17:52,600 OF PULMONARY HYPERTENSION, 6616 04:17:52,600 --> 04:17:53,800 CLEARLY PREDICT INCREASED RISK 6617 04:17:53,800 --> 04:17:58,760 OF DEATH. 6618 04:17:58,760 --> 04:18:01,040 AND WE SEE THE SAME THING FOR 6619 04:18:01,040 --> 04:18:02,560 PROTEINURIA AND MEASURES OF 6620 04:18:02,560 --> 04:18:04,200 EARLY CHRONIC KIDNEY DISEASE. 6621 04:18:04,200 --> 04:18:08,240 AND THIS STUDY BY MARILYN 6622 04:18:08,240 --> 04:18:09,200 TELEN'S GROUP WAS ONE OF THE 6623 04:18:09,200 --> 04:18:12,080 FIRST TO SHOW A HIGH HAZARD 6624 04:18:12,080 --> 04:18:14,400 RATIO FOR PROTEINURIA BEING 6625 04:18:14,400 --> 04:18:20,720 ASSOCIATED WITH POOR SURVIVAL. 6626 04:18:20,720 --> 04:18:22,400 SO IN TERMS OF MECHANISM, AND 6627 04:18:22,400 --> 04:18:24,480 YOU CAN GO THROUGH THE 6628 04:18:24,480 --> 04:18:26,440 ANIMATION, CELL-FREE HEMOGLOBIN 6629 04:18:26,440 --> 04:18:28,920 AS WE KNOW CAN POTENTLY REACT 6630 04:18:28,920 --> 04:18:34,440 WITH AND SCAVENGE NITRIC OXIDE, 6631 04:18:34,440 --> 04:18:38,920 RECUSE DUESINREDUCING THE SIGNAT 6632 04:18:38,920 --> 04:18:43,200 NORMAL BINDING ACTIVATES THAT 6633 04:18:43,200 --> 04:18:44,480 ENZYME IN SMOOTH MUSCLE TO 6634 04:18:44,480 --> 04:18:48,640 INCREASE THE PRODUCTION OF 6635 04:18:48,640 --> 04:18:51,040 CYCLIC GMP WHICH INCREASES BLOOD 6636 04:18:51,040 --> 04:18:51,600 FLOW. 6637 04:18:51,600 --> 04:18:53,000 WE BECAME INTERESTED IN THE 6638 04:18:53,000 --> 04:18:55,480 DEVELOPMENT OF A SMALL MOLECULE 6639 04:18:55,480 --> 04:18:57,920 CALLED RIOCIGUAT, AND THIS IS A 6640 04:18:57,920 --> 04:18:58,840 SMALL MOLECULE THAT DIRECTLY 6641 04:18:58,840 --> 04:19:01,640 BINDS TO THE RECEPTOR FOR NITRIC 6642 04:19:01,640 --> 04:19:04,800 OXIDE, SOLUBLE CYCLASE, AND CAN 6643 04:19:04,800 --> 04:19:06,120 STIMULATE OR ACTIVATE THAT 6644 04:19:06,120 --> 04:19:06,360 ENZYME. 6645 04:19:06,360 --> 04:19:08,520 AND THIS MIGHT PROVIDE A 6646 04:19:08,520 --> 04:19:10,600 MECHANISM TO BYPASS THE 6647 04:19:10,600 --> 04:19:12,480 SCAVENGING REACTIONS OF NITRIC 6648 04:19:12,480 --> 04:19:13,360 OXIDE. 6649 04:19:13,360 --> 04:19:15,000 SO ONE OF THE FORMS OF COURSE IS 6650 04:19:15,000 --> 04:19:18,160 IF WE GIVE ARGININE OR -- 6651 04:19:18,160 --> 04:19:19,800 DONORS, THAT NITRIC OXIDE THAT'S 6652 04:19:19,800 --> 04:19:23,720 PRODUCED CAN BE SCAVENGED BY A 6653 04:19:23,720 --> 04:19:26,040 VARIETY OF THINGS, AND THE 6654 04:19:26,040 --> 04:19:29,440 RIOCIGUAT, WE HYPOTHESIZE, COULD 6655 04:19:29,440 --> 04:19:35,320 BYPASS THIS NO SCAVENGING. 6656 04:19:35,320 --> 04:19:37,080 SO THIS IS SORT OF LIKE NITRIC 6657 04:19:37,080 --> 04:19:38,520 OXIDE IN A PILL. 6658 04:19:38,520 --> 04:19:41,000 YOU CAN HIT THE ANIMATION. 6659 04:19:41,000 --> 04:19:42,560 AND THIS IS AN EXAMPLE OF 6660 04:19:42,560 --> 04:19:43,560 RIOCIGUAT, WHICH HAS BEEN FDA 6661 04:19:43,560 --> 04:19:48,640 HFDA-APPROVED FOR BOTH PULMONARY 6662 04:19:48,640 --> 04:19:54,480 ARTERIAL HYPERTENSION AND THROMT 6663 04:19:54,480 --> 04:19:56,440 NEVER TESTED IN THE SEGHT OF 6664 04:19:56,440 --> 04:19:59,280 SICKLE CELL. 6665 04:19:59,280 --> 04:19:59,720 SETTING OF 6666 04:19:59,720 --> 04:20:00,720 SICKLE CELL. 6667 04:20:00,720 --> 04:20:02,280 SO THIS IS A SMALL MOLECULE THAT 6668 04:20:02,280 --> 04:20:06,880 BINDS TO THE HEME SITE OF THE 6669 04:20:06,880 --> 04:20:07,920 ENZYME AND STIMULATES IT. 6670 04:20:07,920 --> 04:20:09,720 IT WILL ACTUALLY INCREASE THE 6671 04:20:09,720 --> 04:20:12,560 POTENCY OF NITRIC OXIDE AND ALSO 6672 04:20:12,560 --> 04:20:14,560 TURN THE ENZYME ON TO INCREASE 6673 04:20:14,560 --> 04:20:25,040 THE PRODUCTION OF CYCLIC GMP. 6674 04:20:26,160 --> 04:20:28,080 SO AGAIN OUR HYPOTHESIS IS WE 6675 04:20:28,080 --> 04:20:30,400 COULD DO AN ENRICHMENT PROCESS 6676 04:20:30,400 --> 04:20:31,880 IN THE STUDY WHERE WE COULD 6677 04:20:31,880 --> 04:20:33,680 SCREEN FOR PATIENTS THAT EITHER 6678 04:20:33,680 --> 04:20:35,480 HAD SYSTEMIC HYPERTENSION, 6679 04:20:35,480 --> 04:20:40,320 PROTEINURIA OR HIGH TRV. 6680 04:20:40,320 --> 04:20:44,040 AND THAT WOULD IDENTIFY AS A 6681 04:20:44,040 --> 04:20:45,000 SURROGATE PATIENTS AT HIGHER 6682 04:20:45,000 --> 04:20:48,600 RISK FOR STROKE, CONGRESS KIDNEY 6683 04:20:48,600 --> 04:20:51,560 DISEASE, HYPERTENSION AND RISK 6684 04:20:51,560 --> 04:20:52,200 OF DEATH. 6685 04:20:52,200 --> 04:20:55,040 AND THAT WE COULD TEST THIS 6686 04:20:55,040 --> 04:20:56,040 HYPOTHESIS, COULD RIOCIGUAT 6687 04:20:56,040 --> 04:20:57,880 SAFELY REDUCE THE HYPERTENSION, 6688 04:20:57,880 --> 04:21:00,080 THE TR JET PROTEINURIA WITHOUT 6689 04:21:00,080 --> 04:21:00,640 CAUSING PAIN. 6690 04:21:00,640 --> 04:21:02,040 SO THAT WAS OUR PRIMARY 6691 04:21:02,040 --> 04:21:03,240 HYPOTHESIS IN THIS VERY EARLY 6692 04:21:03,240 --> 04:21:09,080 STUDY. 6693 04:21:09,080 --> 04:21:10,400 SO ONE OF THE REASONS THIS WAS A 6694 04:21:10,400 --> 04:21:12,280 NECESSARY STUDY WAS BECAUSE IN 6695 04:21:12,280 --> 04:21:15,320 THE WALK-PHASST STUDY OF 6696 04:21:15,320 --> 04:21:17,520 PULMONARY HYPERTENSION, WE HAD 6697 04:21:17,520 --> 04:21:20,800 USED SILDENAFIL, ANOTHER WAY OF 6698 04:21:20,800 --> 04:21:23,840 INCREASING CYCLIC GLP. 6699 04:21:23,840 --> 04:21:25,600 SO IT ESSENTIALLY INHIBITS THE 6700 04:21:25,600 --> 04:21:28,400 ENZYME THAT BREAKS DOWN CYCLIC 6701 04:21:28,400 --> 04:21:29,400 GMP. 6702 04:21:29,400 --> 04:21:33,240 SO BOTH THIS DRUG, RIOCIGUAT, 6703 04:21:33,240 --> 04:21:34,360 AND SILDENAFIL, WOULD INCREASE 6704 04:21:34,360 --> 04:21:37,640 THE LEVELS OF CYCLIC GMP. 6705 04:21:37,640 --> 04:21:43,080 HOWEVER, IN THE WALK-PHA STST 6706 04:21:43,080 --> 04:21:46,000 STUDY, THAT STUDY WAS STOPPED 6707 04:21:46,000 --> 04:21:48,320 EARLY, RAISING CONCERNS THAT 6708 04:21:48,320 --> 04:21:52,360 THERAPIES THAT ENHANCE GMP 6709 04:21:52,360 --> 04:21:53,040 SIGNALING IN PATIENTS WITH 6710 04:21:53,040 --> 04:21:54,440 SICKLE CELL COULD HAVE A SIMILAR 6711 04:21:54,440 --> 04:21:55,840 EFFECT. 6712 04:21:55,840 --> 04:21:58,720 HOWEVER, OVER TIME, A HYPOTHESIS 6713 04:21:58,720 --> 04:22:00,440 HAS EMERGED THAT THIS 6714 04:22:00,440 --> 04:22:03,320 OBSERVATION FROM WALK-PHASST WAS 6715 04:22:03,320 --> 04:22:08,440 REALLY A CLASS EFFECT OF THE 6716 04:22:08,440 --> 04:22:09,640 PDE5 INHIBITORS. 6717 04:22:09,640 --> 04:22:16,240 IN MANY OF THE STUDIES -- THE 6718 04:22:16,240 --> 04:22:17,240 PDE5 INHIBITORS ALSO CAUSED 6719 04:22:17,240 --> 04:22:17,760 PAIN. 6720 04:22:17,760 --> 04:22:18,760 TYPICALLY THEY WOULD CAUSE LIMB 6721 04:22:18,760 --> 04:22:20,440 PAIN OR LOWER BACK PAIN OR 6722 04:22:20,440 --> 04:22:22,480 MUSCLE ACHES, AND IN FACT, OFTEN 6723 04:22:22,480 --> 04:22:24,760 IN PATIENTS WITH PULMONARY 6724 04:22:24,760 --> 04:22:25,960 ARTERIAL HYPERTENSION WHO DO NOT 6725 04:22:25,960 --> 04:22:27,160 HAVE SICKLE CELL WHEN THEY 6726 04:22:27,160 --> 04:22:30,120 RECEIVE PDE5 INHIBITORS, THEY'LL 6727 04:22:30,120 --> 04:22:30,760 DEVELOP SIGNIFICANT ACHES. 6728 04:22:30,760 --> 04:22:32,600 SO WE HAD HYPOTHESIZED THAT THIS 6729 04:22:32,600 --> 04:22:35,920 WASN'T A DIRECT EFFECT OF CYCLIC 6730 04:22:35,920 --> 04:22:37,440 GMP BUT MIGHT HAVE BEEN A CLASS 6731 04:22:37,440 --> 04:22:39,520 EFFECT OF THE PDE5 INHIBITORS, 6732 04:22:39,520 --> 04:22:41,280 AND PERHAPS WOULD NOT BE 6733 04:22:41,280 --> 04:22:42,720 OBSERVED WITH RIOCIGUAT, AND IN 6734 04:22:42,720 --> 04:22:46,240 FACT, IN THE PAH TRIALS AND CTEF 6735 04:22:46,240 --> 04:22:47,320 TRIALS WITH RIOCIGUAT, THERE WAS 6736 04:22:47,320 --> 04:22:50,160 NO OBSERVED LIMB PAIN OR BACK 6737 04:22:50,160 --> 04:22:51,480 PAIN IN PATIENTS THAT RECEIVED 6738 04:22:51,480 --> 04:22:56,280 THOSE DRUGS. 6739 04:22:56,280 --> 04:23:00,160 SO THIS PRIMARY DESIGN OF THIS 6740 04:23:00,160 --> 04:23:01,960 STUDY WAS TO TEST WHETHER 6741 04:23:01,960 --> 04:23:03,520 RIOCIGUAT WAS SAFE, AND WE 6742 04:23:03,520 --> 04:23:05,360 ACTUALLY POWERED TO 100 6743 04:23:05,360 --> 04:23:06,920 PATIENTS, WHICH WOULD HAVE 6744 04:23:06,920 --> 04:23:09,640 SUFFICIENT POWER WITH 50 PLACEBO 6745 04:23:09,640 --> 04:23:11,240 AND 50 RIOCIGUAT TO DETERMINE IF 6746 04:23:11,240 --> 04:23:13,720 THERE WAS A SIMILAR PAIN EFFECT 6747 04:23:13,720 --> 04:23:17,440 AS OBSERVED WITH SILDENAFIL. 6748 04:23:17,440 --> 04:23:20,520 WE WEREN'T EXPECTING RIOCIGUAT 6749 04:23:20,520 --> 04:23:22,040 TO HELP WITH PAIN BUT RATHER 6750 04:23:22,040 --> 04:23:23,760 THAT IT WOULD TARGET THE 6751 04:23:23,760 --> 04:23:24,520 CARDIOVASCULAR END POINTS THAT I 6752 04:23:24,520 --> 04:23:26,160 MENTIONED BUT THAT IT WOULD NOT 6753 04:23:26,160 --> 04:23:26,840 CAUSE PAIN. 6754 04:23:26,840 --> 04:23:32,080 SO IF WE GOT THROUGH THIS 6755 04:23:32,080 --> 04:23:34,720 100-PATIENT PHASE 12A TRIAL WE 6756 04:23:34,720 --> 04:23:35,680 WOULD KNOW WHETHER THIS DRUG 6757 04:23:35,680 --> 04:23:36,680 WOULD BE SAFE TO MOVE FORWARD 6758 04:23:36,680 --> 04:23:38,640 WITH. 6759 04:23:38,640 --> 04:23:41,200 SO THE STUDY HYPOTHESES ARE 6760 04:23:41,200 --> 04:23:44,440 SHOWN HERE. 6761 04:23:44,440 --> 04:23:45,640 SO WE ARE GOING TO TEST THE 6762 04:23:45,640 --> 04:23:47,920 SAFETY, THE TOLERABILITY, AND 6763 04:23:47,920 --> 04:23:50,360 PRELIMINARY EFFICACY IN PATIENTS 6764 04:23:50,360 --> 04:23:51,880 WITH SICKLE CELL DISEASE. 6765 04:23:51,880 --> 04:23:54,280 AND AGAIN, SAFETY THAT THIS 6766 04:23:54,280 --> 04:23:57,480 WOULD -- THAT THERE WOULD BE NO 6767 04:23:57,480 --> 04:23:59,000 INCREASE IN THE RATES OF 6768 04:23:59,000 --> 04:24:01,080 TREATMENT EMERGENT SAEs WITH 6769 04:24:01,080 --> 04:24:03,480 THIS DRUG, AND AGAIN, POWERED TO 6770 04:24:03,480 --> 04:24:05,440 HAVE THE SAME -- TO BE ABLE TO 6771 04:24:05,440 --> 04:24:09,280 SEE AN EFFECT THAT WOULD BE LAKE 6772 04:24:09,280 --> 04:24:12,440 THE WALK-PHASST TRIAL. 6773 04:24:12,440 --> 04:24:14,000 AND TOLERABILITY, AGAIN WE ALSO 6774 04:24:14,000 --> 04:24:16,280 LOOKED AT OTHER PAIN SIGNALS. 6775 04:24:16,280 --> 04:24:17,720 AND THEN WE LOOKED AT 6776 04:24:17,720 --> 04:24:20,840 PRELIMINARY EFFICACY. 6777 04:24:20,840 --> 04:24:22,200 NOW WE WERE POWERED TO SEE 6778 04:24:22,200 --> 04:24:23,840 CHANGES IN MEAN ARTERIAL 6779 04:24:23,840 --> 04:24:25,680 PRESSURE, AND WE WERE REALLY 6780 04:24:25,680 --> 04:24:28,960 UNDERPOWERED FOR TR JET, 6781 04:24:28,960 --> 04:24:30,600 6-MINUTE WALK, ET CETERA -- TO 6782 04:24:30,600 --> 04:24:32,360 LOOK AT EXPLORATORY END POINT 6783 04:24:32,360 --> 04:24:36,000 THERE. 6784 04:24:36,000 --> 04:24:46,520 I'LL TURN THIS OVER TO KALEAB 6785 04:24:47,640 --> 04:24:52,480 FOR THE NEXT PART OF THE 6786 04:24:52,480 --> 04:24:52,840 PRESENTATION. 6787 04:24:52,840 --> 04:24:55,760 NOT TO REPEAT TOO MUCH, THIS IS 6788 04:24:55,760 --> 04:24:57,280 REALLY AN EARLY PHASE 6789 04:24:57,280 --> 04:24:58,840 MULTICENTERRED RAN DOSMIZED 6790 04:24:58,840 --> 04:25:00,680 DOUBLE BLIND PLACEBO CONTROLLED 6791 04:25:00,680 --> 04:25:01,440 PARALLEL GROUP STUDY. 6792 04:25:01,440 --> 04:25:04,400 WE HAD RANDOMIZATION FROM THE 6793 04:25:04,400 --> 04:25:07,320 COORDINATING CENTER HERE AT THE 6794 04:25:07,320 --> 04:25:08,240 UNIVERSITY OF PITTSBURGH, THIS 6795 04:25:08,240 --> 04:25:11,200 WAS A DOUBLE-BLIND PLACEBO 6796 04:25:11,200 --> 04:25:12,400 CONTROLLED TRIAL SO THAT WE HAD 6797 04:25:12,400 --> 04:25:13,520 NECESSARY BLINDING ON THE 6798 04:25:13,520 --> 04:25:15,040 PARTICIPANT AND STUDY 6799 04:25:15,040 --> 04:25:16,040 INVESTIGATOR SIDE. 6800 04:25:16,040 --> 04:25:18,360 AND THEN WE OBVIOUSLY HAD 6801 04:25:18,360 --> 04:25:21,400 UNBLINDING PROCEDURES IN CASE 6802 04:25:21,400 --> 04:25:22,200 NEEDED. 6803 04:25:22,200 --> 04:25:24,120 THIS WAS A GROUP-SEQUENTIAL 6804 04:25:24,120 --> 04:25:25,800 DESIGN, SO THE WAY WE DID THIS 6805 04:25:25,800 --> 04:25:31,880 WAS UTILIZING THE 6806 04:25:31,880 --> 04:25:34,080 O'BRIEN-FLEMING ALPHA SPENDING 6807 04:25:34,080 --> 04:25:35,280 FUNCTION, TO SEE IF THERE WAS 6808 04:25:35,280 --> 04:25:38,240 ANY SORT OF SAFETY SIGNAL DURING 6809 04:25:38,240 --> 04:25:40,760 THE FIRST HALF OF THE RANDOMIZED 6810 04:25:40,760 --> 04:25:44,480 PARTICIPANTS. 6811 04:25:44,480 --> 04:25:46,000 AND AS MARK MENTIONED BEFORE, 6812 04:25:46,000 --> 04:25:49,360 PART OF THIS -- THE INCLUSION 6813 04:25:49,360 --> 04:25:50,720 CRITERIA YOU CAN SEE HERE BUT 6814 04:25:50,720 --> 04:25:53,920 REALLY HONING IN ON THE ORIGIN 6815 04:25:53,920 --> 04:25:54,440 PIECE OF THIS. 6816 04:25:54,440 --> 04:25:56,520 ONE OF THE KEY CRITERIA, THERE'S 6817 04:25:56,520 --> 04:25:58,480 REALLY FIVE THAT THEY COULD GET 6818 04:25:58,480 --> 04:26:01,440 THE STUDY BASED OFF OF, BLOOD 6819 04:26:01,440 --> 04:26:06,200 PRESSURE GREATER THAN 130, ALSO 6820 04:26:06,200 --> 04:26:08,920 MACROALBUMINU RI A, TRV VALUES 6821 04:26:08,920 --> 04:26:17,280 GREATER THAN 2.9 AND NT-PRO BNP 6822 04:26:17,280 --> 04:26:22,080 GREATER THAN 160 AND URINALYSIS 6823 04:26:22,080 --> 04:26:23,080 PROTEIN 1 PLUS OR HIGHER. 6824 04:26:23,080 --> 04:26:25,040 THESE ARE THE MAIN INCLUSION TIE 6825 04:26:25,040 --> 04:26:29,920 TIER YA FOR STERIO. 6826 04:26:29,920 --> 04:26:31,560 AND AS PART OF THIS BEING A 6827 04:26:31,560 --> 04:26:33,840 DOUBLE BLIND STUDY, WE RANDOMIZE 6828 04:26:33,840 --> 04:26:37,560 OBVIOUSLY TO THE RIOCIGUAT 6829 04:26:37,560 --> 04:26:38,880 PLACEBO, WE USED THE 6830 04:26:38,880 --> 04:26:42,560 INVESTIGATIONAL DRUG SERVICE 6831 04:26:42,560 --> 04:26:43,800 HERE, CENTRAL PHARMACY, NEARLY 6832 04:26:43,800 --> 04:26:44,920 ALL PARTICIPANTS WERE STARTED ON 6833 04:26:44,920 --> 04:26:46,800 A STARTING DOSE OF 1 MG THREE 6834 04:26:46,800 --> 04:26:48,320 TIMES A DAY AND THEY WERE 6835 04:26:48,320 --> 04:26:51,520 UPTITRATED ALL THE WAY TO 2.5 3 6836 04:26:51,520 --> 04:26:52,280 TIMES A DAY. 6837 04:26:52,280 --> 04:26:53,160 WE'LL SHOW A LITTLE LATER IN 6838 04:26:53,160 --> 04:26:54,680 TERMS OF HOW THAT LAID OUT 6839 04:26:54,680 --> 04:26:56,120 ACROSS THE 100 OR SO 6840 04:26:56,120 --> 04:26:56,640 PARTICIPANTS. 6841 04:26:56,640 --> 04:26:58,520 AND AGAIN, THE EXACT SAME 6842 04:26:58,520 --> 04:27:00,920 TITRATION PHASE WAS DONE ON THE 6843 04:27:00,920 --> 04:27:05,800 PLACEBO ARM. 6844 04:27:05,800 --> 04:27:08,640 SO THE PRIMARY OUT COME IS THAT 6845 04:27:08,640 --> 04:27:09,960 THE PRIMARY PROPORTION OF 6846 04:27:09,960 --> 04:27:11,160 PARTICIPANTS EXPERIENCING 6847 04:27:11,160 --> 04:27:17,280 GREATER THAN 1SAE. 6848 04:27:17,280 --> 04:27:18,320 SECONDARY, SPECIFICALLY RELATED 6849 04:27:18,320 --> 04:27:21,680 TO SICKLE CELLs, AS EVERYONE 6850 04:27:21,680 --> 04:27:23,000 KNOWS, VASOOCCLUSIVE CRISES WERE 6851 04:27:23,000 --> 04:27:24,760 THE KEY ONES. 6852 04:27:24,760 --> 04:27:27,720 IN GENERAL, TREATMENT EMERGENT 6853 04:27:27,720 --> 04:27:30,760 ADVERSE EVENTS, AND CHANGES IN 6854 04:27:30,760 --> 04:27:33,400 PAIN SEVERITY AND INTERFERENCE 6855 04:27:33,400 --> 04:27:35,720 FROM BASELINE OUT TO WEEK 12. 6856 04:27:35,720 --> 04:27:36,960 AND THEN I WON'T WALK THROUGH 6857 04:27:36,960 --> 04:27:39,640 THIS TOO MUCH, BUT JUST IN 6858 04:27:39,640 --> 04:27:41,760 GENERAL AS MARK WENT THROUGH 6859 04:27:41,760 --> 04:27:45,480 SOME OF THE PRELIM EFFICACY, 6860 04:27:45,480 --> 04:27:47,080 MAP, 6-MINUTE WALK BUT WE HAD A 6861 04:27:47,080 --> 04:27:49,080 FEW OTHER LAB MEASURES TO SEE IF 6862 04:27:49,080 --> 04:27:52,560 THERE WAS ANY PREHIM EFFICACY 6863 04:27:52,560 --> 04:27:52,920 SIGNAL. 6864 04:27:52,920 --> 04:27:55,160 WE WERE REALLY BASED ON OUR 6865 04:27:55,160 --> 04:27:56,960 NUMBERS POWERED FOR MAP AS A 6866 04:27:56,960 --> 04:28:03,080 PRELIMINARY EFFICACY OUTCOME. 6867 04:28:03,080 --> 04:28:05,600 OUR SAMPLE SIZE AND POWER, WE 6868 04:28:05,600 --> 04:28:07,400 NEEDED 100 COMPLETERS TO FINISH 6869 04:28:07,400 --> 04:28:09,440 THE 12-WEEK TO YIELD 6870 04:28:09,440 --> 04:28:11,440 APPROXIMATELY 82% POWER TO SEE 6871 04:28:11,440 --> 04:28:12,640 DIFFERENCES IN HOSPITALIZATIONS, 6872 04:28:12,640 --> 04:28:17,680 SIMILAR TO WHAT WE SAW IN 6873 04:28:17,680 --> 04:28:19,200 WALK-PHASST. 6874 04:28:19,200 --> 04:28:20,880 THEN FOR PRELIM EFFICACY, WE 6875 04:28:20,880 --> 04:28:23,280 WERE WELL POWERED AS I MENTIONED 6876 04:28:23,280 --> 04:28:24,520 BEFORE AND WE ALSO HAD A LITTLE 6877 04:28:24,520 --> 04:28:25,920 BIT LOWER POWER BUT THAT WASN'T 6878 04:28:25,920 --> 04:28:27,280 THE PRIMARY PURPOSE OF THAT FOR 6879 04:28:27,280 --> 04:28:30,480 THE 6-MINUTE WALK AND OTHER 6880 04:28:30,480 --> 04:28:32,760 PRELIM EFFICACY OUTCOMES. 6881 04:28:32,760 --> 04:28:35,600 OVERALL ANALYSIS, WE GUARDED 6882 04:28:35,600 --> 04:28:39,200 AGAINST A 10% ERROR RATE, 6883 04:28:39,200 --> 04:28:42,200 INCLUDED AN INTERIM ANALYSIS, WE 6884 04:28:42,200 --> 04:28:44,600 ALSO LOOK AT SAFETY AND 6885 04:28:44,600 --> 04:28:46,560 TOLERABILITY IN A PRETTY 6886 04:28:46,560 --> 04:28:49,960 STRAIGHTFORWARD WAY, UTILIZING 6887 04:28:49,960 --> 04:28:51,720 ANCOVA OR LINEAR MIXED MODELS 6888 04:28:51,720 --> 04:28:57,360 FOR LONGITUDINAL OUTCOMES. 6889 04:28:57,360 --> 04:29:01,840 THEN WE LOOKED AT A HANDFUL OF 6890 04:29:01,840 --> 04:29:03,520 EXPLORATORY ANALYSES. 6891 04:29:03,520 --> 04:29:04,440 EGFR, LOOKING TO SEE WHETHER OR 6892 04:29:04,440 --> 04:29:08,680 NOT THE CHANGES -- IN 12 WEEKS 6893 04:29:08,680 --> 04:29:09,800 ACROSS THESE LOOK DIFFERENT 6894 04:29:09,800 --> 04:29:14,040 ACROSS SOME OF THESE HIGH RISK 6895 04:29:14,040 --> 04:29:15,480 SUBGROUP CATEGORIES, AND WE ALSO 6896 04:29:15,480 --> 04:29:18,880 LOOKED AT MEDIAN AGE AND USE OF 6897 04:29:18,880 --> 04:29:26,520 HYDROXYUREA AT BASELINE. 6898 04:29:26,520 --> 04:29:27,680 SO AS WE GO THROUGH THE RESULTS 6899 04:29:27,680 --> 04:29:28,920 TO WALK THROUGH THE CONSORT, WE 6900 04:29:28,920 --> 04:29:30,400 HAVE AS MENTIONED BEFORE 6901 04:29:30,400 --> 04:29:33,920 SCREENED A NUMBER TO GET TO OUR 6902 04:29:33,920 --> 04:29:36,520 100 THAT COMPLETED THE PROTOCOL, 6903 04:29:36,520 --> 04:29:40,440 WE HAD 130 THAT WERE RANDOMIZED 6904 04:29:40,440 --> 04:29:41,960 AND THEY WERE EQUALLY BALANCED 6905 04:29:41,960 --> 04:29:46,760 INTO THE TWO ARMS IN RIO AND 6906 04:29:46,760 --> 04:29:48,600 PLACEBO ARM. 6907 04:29:48,600 --> 04:29:51,240 AND THEN IN TERMS OF REASONS FOR 6908 04:29:51,240 --> 04:29:53,840 DROPPING OUT, WE HAD ABOUT EQUAL 6909 04:29:53,840 --> 04:29:55,320 NUMBERS IN BOTH ARMS THAT 6910 04:29:55,320 --> 04:29:56,960 WITHDREW FROM THE STUDY PRIOR TO 6911 04:29:56,960 --> 04:30:01,680 THEIR LAST ON-PROTOCOL VISIT. 6912 04:30:01,680 --> 04:30:03,040 AND ONLY A HANDFUL OF THOSE 6913 04:30:03,040 --> 04:30:05,520 WITHDREW AFTER THAT. 6914 04:30:05,520 --> 04:30:08,080 BUT YOU CAN SEE THE REASONS, 6915 04:30:08,080 --> 04:30:10,160 PRIMARILY DUE TO SAFETY, ADVERSE 6916 04:30:10,160 --> 04:30:13,360 EVENTS, I SHOULD SAY, TREATMENT 6917 04:30:13,360 --> 04:30:14,560 INTERRUPTIONS BUT FAIRLY SIMILAR 6918 04:30:14,560 --> 04:30:15,880 BETWEEN ARMS WHICH WAS A GOOD 6919 04:30:15,880 --> 04:30:17,600 SIGN, AND OVERALL, WE HAD NEARLY 6920 04:30:17,600 --> 04:30:20,160 EVERYONE WAS INCLUDED IN THE 6921 04:30:20,160 --> 04:30:21,360 PRIMARY ANALYSES BASED ON WHAT 6922 04:30:21,360 --> 04:30:23,600 THEY WERE CONTRIBUTING OVER THE 6923 04:30:23,600 --> 04:30:25,200 12 WEEKS OF BEING ON PROTOCOL 6924 04:30:25,200 --> 04:30:30,880 AND SAFETY. 6925 04:30:30,880 --> 04:30:34,160 BASELINE CHARACTERISTICS, I JUST 6926 04:30:34,160 --> 04:30:35,600 WANT TO WALK THROUGH THIS JUST 6927 04:30:35,600 --> 04:30:36,120 BRIEFLY. 6928 04:30:36,120 --> 04:30:37,840 IN GENERAL, THE SHORT STORY IS 6929 04:30:37,840 --> 04:30:40,200 THAT IT WAS FAIRLY SIMILAR 6930 04:30:40,200 --> 04:30:41,680 ACROSS THE BOARD IN TERMS OF 6931 04:30:41,680 --> 04:30:44,520 BASELINE AND DEMOGRAPHIC 6932 04:30:44,520 --> 04:30:46,040 CHARACTERISTICS, SO AS YOU CAN 6933 04:30:46,040 --> 04:30:50,840 IMAGINE, MAJORITY BLACK, AFRICAN 6934 04:30:50,840 --> 04:30:52,000 AMERICAN, NON-HISPANIC, BUT YOU 6935 04:30:52,000 --> 04:30:53,720 CAN SEE IN TERMS OF SICKLE CELL 6936 04:30:53,720 --> 04:30:56,200 PHENOTYPE, THE MAJORITY, 75%, 6937 04:30:56,200 --> 04:31:00,200 THREE FOURTHS OF THE COHORT WAS 6938 04:31:00,200 --> 04:31:01,400 HBSS SICKLE CELL PHENOTYPE. 6939 04:31:01,400 --> 04:31:05,240 AND THEN IN TERMS OF THE BLOOD 6940 04:31:05,240 --> 04:31:08,520 PRESSURE, AROUND 125 TO 6941 04:31:08,520 --> 04:31:12,120 128/75 IN TERMS OF SYSTOLIC, AND 6942 04:31:12,120 --> 04:31:12,680 DIASTOLIC BLOOD PRESSURE. 6943 04:31:12,680 --> 04:31:14,800 THERE WAS A BIT MORE THAN 50% 6944 04:31:14,800 --> 04:31:17,880 HAD STAGE I HYPERTENSION BASED 6945 04:31:17,880 --> 04:31:20,600 ON THE BLOOD PRESSURE, AND HEART 6946 04:31:20,600 --> 04:31:21,960 RATE VALUES, YOU CAN SEE THERE 6947 04:31:21,960 --> 04:31:25,360 RIGHT AROUND IN THE LOW TO MID 6948 04:31:25,360 --> 04:31:29,280 80s. 6949 04:31:29,280 --> 04:31:30,920 AND THEN FOLLOWING THROUGH SOME 6950 04:31:30,920 --> 04:31:35,400 OF OUR CHARACTERISTICS FOR MAP, 6951 04:31:35,400 --> 04:31:37,840 91 TO 94 FOR MAP, AND THEN PAIN 6952 04:31:37,840 --> 04:31:40,600 SCORES WERE FAIRLY SIMILAR AFTER 6953 04:31:40,600 --> 04:31:42,480 BOTH THE SEVERITY INTERFERENCE 6954 04:31:42,480 --> 04:31:46,120 SCORES AND THE BPI, AND WALK 6955 04:31:46,120 --> 04:31:50,120 DISTANCE WAR ANYWHERE BETWEEN 6956 04:31:50,120 --> 04:31:51,680 375 TO 416 FOR THE 6-MINUTE WALK 6957 04:31:51,680 --> 04:31:57,960 TEST. 6958 04:31:57,960 --> 04:31:59,680 THEN JUST A FEW OTHER WITH THE 6959 04:31:59,680 --> 04:32:01,720 TR JET HOVERED AROUND JUST SHY 6960 04:32:01,720 --> 04:32:03,520 OF THE 2 1/2 MARK AUTOIMMUNE 6961 04:32:03,520 --> 04:32:07,160 ACROSS BOTHARMS AND THEN OTHER 6962 04:32:07,160 --> 04:32:08,040 CHARACTERISTICS WITH RESPECT TO 6963 04:32:08,040 --> 04:32:11,240 THE EJECTION FRACTION MACRO AND 6964 04:32:11,240 --> 04:32:13,080 THE ACR VALUES AS WELL. 6965 04:32:13,080 --> 04:32:17,480 BUT AGAIN, FAIRLY CONSISTENT 6966 04:32:17,480 --> 04:32:19,280 BETWEEN THE TWO COHORTS OR THE 6967 04:32:19,280 --> 04:32:20,560 TWO RANDOMIZED ARMS. 6968 04:32:20,560 --> 04:32:23,320 GO AHEAD. 6969 04:32:23,320 --> 04:32:24,840 >>I WOULD JUST POINT OUT IN 6970 04:32:24,840 --> 04:32:29,360 TERMS OF THE ENRICHMENT, ALMOST 6971 04:32:29,360 --> 04:32:30,560 44% OF THE PATIENTS IN THE TRIAL 6972 04:32:30,560 --> 04:32:36,480 HAD A TR JET OVER 2.5. 6973 04:32:36,480 --> 04:32:40,640 AND 40% HAD MACRO ALBUMINURIA. 6974 04:32:40,640 --> 04:32:42,960 SO WE DID ATTEMPT TO ENRICH FOR 6975 04:32:42,960 --> 04:32:46,960 THOSE GROUPS HOPING TO HAVE 6976 04:32:46,960 --> 04:32:48,160 ENOUGH GROUPS WITHIN THIS WHERE 6977 04:32:48,160 --> 04:32:53,640 WE COULD HAVE AT LEAST AN 6978 04:32:53,640 --> 04:32:56,160 EXPLORATORY LOOK AT EFFICACY. 6979 04:32:56,160 --> 04:33:00,560 >>NEXT SLIDE, PLEASE. 6980 04:33:00,560 --> 04:33:02,080 AND THEN JUST FINISHING OUT 6981 04:33:02,080 --> 04:33:05,040 BASELINE IN TERMS OF THE GFR, IN 6982 04:33:05,040 --> 04:33:07,040 TERMS OF RENAL FUNCTION AS WELL 6983 04:33:07,040 --> 04:33:09,360 AS SOME KEY CHARACTERISTICS 6984 04:33:09,360 --> 04:33:10,400 AROUND CIGARETTE SMOKING AND 6985 04:33:10,400 --> 04:33:11,320 BLOOD TRANSFUSION, AS YOU CAN 6986 04:33:11,320 --> 04:33:16,400 SEE THOSE VALUES THERE. 6987 04:33:16,400 --> 04:33:17,960 SO JUST WRAPPING THIS UP BEFORE 6988 04:33:17,960 --> 04:33:19,120 WE GET TO THE PRIMARY RESULTS 6989 04:33:19,120 --> 04:33:22,080 AND MARK WILL TAKE OVER, AROUND 6990 04:33:22,080 --> 04:33:25,360 AS I MENTIONED TH THE TITRATION, 6991 04:33:25,360 --> 04:33:30,280 THIS IS WHERE THE HIGHEST -- THE 6992 04:33:30,280 --> 04:33:32,360 MAJORITY, 60% ACROSS BOTH ARMS 6993 04:33:32,360 --> 04:33:37,840 AT LEAST REACHED OUR 2 1/2 HIGH 6994 04:33:37,840 --> 04:33:39,640 TITRATION, 2 1/2, 3 TIMES A DAY, 6995 04:33:39,640 --> 04:33:40,840 WHICH IS GREAT, BUT NOT ONLY 6996 04:33:40,840 --> 04:33:42,920 THAT, IT'S GREAT TO SEE THAT 6997 04:33:42,920 --> 04:33:43,720 CONSISTENCY BETWEEN ARMS. 6998 04:33:43,720 --> 04:33:45,720 AND THEN WE DID HAVE SOME 6999 04:33:45,720 --> 04:33:46,840 PREMATURE DISCONTINUATION, BUT 7000 04:33:46,840 --> 04:33:48,560 IT WAS ABOUT A QUARTER OF THE 7001 04:33:48,560 --> 04:33:51,960 COHORT, AND AGAIN, CONSISTENT -- 7002 04:33:51,960 --> 04:33:52,920 WAS NOT DIFFERENTIAL BETWEEN THE 7003 04:33:52,920 --> 04:33:58,760 TWO ARMS. 7004 04:33:58,760 --> 04:34:00,200 SO MARK WILL TAKE OVER HERE AND 7005 04:34:00,200 --> 04:34:02,520 WE'LL WALK THROUGH THE PRIMARY 7006 04:34:02,520 --> 04:34:03,720 END POINT, SAFETY, AS WELL AS 7007 04:34:03,720 --> 04:34:08,440 THE ADJUDICATED SAEs. 7008 04:34:08,440 --> 04:34:12,600 >>THANK YOU, KALEAB. 7009 04:34:12,600 --> 04:34:13,400 SO IN TERMS OF THE PRIMARY 7010 04:34:13,400 --> 04:34:14,720 SAFETY END POINT, AND REMEMBER 7011 04:34:14,720 --> 04:34:19,080 THE HYPOTHESIS WAS THAT WE WOULD 7012 04:34:19,080 --> 04:34:22,480 NOT SEE AN INCREASE IN PAIN WITH 7013 04:34:22,480 --> 04:34:23,120 TREATMENT CONSISTENT WITH WHAT 7014 04:34:23,120 --> 04:34:26,520 WAS OBSERVED WITH THE 7015 04:34:26,520 --> 04:34:27,320 PDE5 INHIBITORS, AND THAT WAS 7016 04:34:27,320 --> 04:34:30,280 THE TREATMENT EMERGENT 7017 04:34:30,280 --> 04:34:32,560 ADJUDICATED SAEs, WE SAW THAT 7018 04:34:32,560 --> 04:34:36,120 THERE'S 22% OF THESE EVENTS IN 7019 04:34:36,120 --> 04:34:37,720 THE RIOCIGUAT GROUP VERSUS 31% 7020 04:34:37,720 --> 04:34:38,760 IN THE PLACEBO. 7021 04:34:38,760 --> 04:34:40,920 THIS WAS NOT SIGNIFICANT IN 7022 04:34:40,920 --> 04:34:44,680 TERMS OF AN IMPROVEMENT WITH 7023 04:34:44,680 --> 04:34:46,760 RIO, BUT PRETTY REASSURING THAT 7024 04:34:46,760 --> 04:34:48,520 THIS DRUG WAS NOT CAUSING AN 7025 04:34:48,520 --> 04:34:50,200 INCREASE IN HOSPITALIZATION FOR 7026 04:34:50,200 --> 04:34:54,640 PAIN THAT WE DID SEE WITH 7027 04:34:54,640 --> 04:34:55,040 SILDENAFIL. 7028 04:34:55,040 --> 04:34:58,400 IN TERMS OF VOE EVENTS, IT WAS 7029 04:34:58,400 --> 04:35:05,120 16.7% WITH REY RIO VERSUS 29% WH 7030 04:35:05,120 --> 04:35:06,320 PLACEBO, AGAIN, NOT SIGNIFICANT. 7031 04:35:06,320 --> 04:35:15,520 WHEN WE LOOKED AT ALL TREATMENT 7032 04:35:15,520 --> 04:35:16,560 EMERGENT -- ADVERSE EVENT KNOWN 7033 04:35:16,560 --> 04:35:21,440 TO OCCUR WITH IT DRUG, LIKE SOME 7034 04:35:21,440 --> 04:35:24,320 REFLUX, SOME ESOPHAGEAL SPASM 7035 04:35:24,320 --> 04:35:28,840 PAIN, SOME HEADACHE, SOME 7036 04:35:28,840 --> 04:35:30,160 LIGHT-HEADEDNESS, THINGS KNOWN 7037 04:35:30,160 --> 04:35:31,880 TO HAVE BEEN OBSERVED BEFORE 7038 04:35:31,880 --> 04:35:33,600 WITH RIOCIGUAT, WHICH 7039 04:35:33,600 --> 04:35:38,080 INHIBITS -- OR ACTIVATES, EXCUSE 7040 04:35:38,080 --> 04:35:39,280 ME -- AND PRESSURE. 7041 04:35:39,280 --> 04:35:43,200 WE ALSO SO NO EFFECT OF PAIN 7042 04:35:43,200 --> 04:35:46,960 SEVERITY SCORES OR -- AND THIS 7043 04:35:46,960 --> 04:35:49,160 JUST SHOWS IN RED THE TREATMENT 7044 04:35:49,160 --> 04:35:51,800 EMERGENT SAEs AND BOTH 7045 04:35:51,800 --> 04:35:55,200 ADJUDICATED AND THE ADJUDICATED 7046 04:35:55,200 --> 04:35:56,600 VOE EVENTS WITH RIOCIGUAT IN RED 7047 04:35:56,600 --> 04:36:03,240 COMPARED TO THE PLACEBO IN BLUE. 7048 04:36:03,240 --> 04:36:07,720 THESE ARE SOME OF OUR EFFECTS. 7049 04:36:07,720 --> 04:36:11,080 WHILE AGAIN WE WERE 7050 04:36:11,080 --> 04:36:12,680 UNDERPOWERED, WE REALLY WOULD 7051 04:36:12,680 --> 04:36:15,320 HAVE NEED TO SEE AN IMPACT ON 7052 04:36:15,320 --> 04:36:18,520 #-MINUTE WALK, WE SAW NO 7053 04:36:18,520 --> 04:36:19,600 SIGNIFICANT IMPACT OF THE DRUG 7054 04:36:19,600 --> 04:36:21,560 ON 6-MINUTE WALK, AND FOR THE 7055 04:36:21,560 --> 04:36:23,160 SORT OF ADJUSTED RESPONSE, THERE 7056 04:36:23,160 --> 04:36:31,760 WAS ACTUALLY A DROP IN WALK WITH 7057 04:36:31,760 --> 04:36:35,280 REYRIO COMPARED TO PLACEBO. 7058 04:36:35,280 --> 04:36:37,680 IN TERMS OF BLOOD PRESSURE -- 7059 04:36:37,680 --> 04:36:39,280 LOWERING SYSTEMIC, DIASTOLIC AND 7060 04:36:39,280 --> 04:36:41,880 MEAN PRESSURE, HIGHLY 7061 04:36:41,880 --> 04:36:45,360 SIGNIFICANT WITH P VALUES LESS 7062 04:36:45,360 --> 04:36:45,920 THAN .001. 7063 04:36:45,920 --> 04:36:48,600 TR JET VELOCITY, THE ADJUSTED 7064 04:36:48,600 --> 04:36:50,600 CHANGE IN TR JET VELOCITY, THERE 7065 04:36:50,600 --> 04:36:54,080 WAS A TREND TOWARDS LOWER TR JET 7066 04:36:54,080 --> 04:36:55,160 VELOCITY IN THE RIOCIGUAT GROUP 7067 04:36:55,160 --> 04:36:58,600 WITH A P VALUE OF .12. 7068 04:36:58,600 --> 04:37:00,800 INTERESTINGLY, WE SAW 7069 04:37:00,800 --> 04:37:05,480 SIGNIFICANT REDUCTIONS IN LEFT 7070 04:37:05,480 --> 04:37:06,920 VENTRICULAR AND SYSTOLIC VOLUMES 7071 04:37:06,920 --> 04:37:09,160 WITH RIOCIGUAT, AND SIGNIFICANT 7072 04:37:09,160 --> 04:37:11,680 INCREASES IN EJECTION FRACTION 7073 04:37:11,680 --> 04:37:13,960 WITH RIOCIGUAT, AND VERY 7074 04:37:13,960 --> 04:37:16,360 SIGNIFICANT CHANGES THAT WERE 7075 04:37:16,360 --> 04:37:17,680 OBSERVED, THAT WAS A LITTLE BIT 7076 04:37:17,680 --> 04:37:19,480 UNEXPECTED, AND WE DIDN'T SEE 7077 04:37:19,480 --> 04:37:23,520 ANY CHANGE IN THE END TERMINAL 7078 04:37:23,520 --> 04:37:25,400 PRO BNP WITH RIOCIGUAT IN THIS 7079 04:37:25,400 --> 04:37:30,920 STUDY. 7080 04:37:30,920 --> 04:37:33,440 WE SAW NO CHANGE IN THE 7081 04:37:33,440 --> 04:37:40,680 BORROWBORGDYSPNEA SCALES. 7082 04:37:40,680 --> 04:37:44,200 WE DID SEE A REDUCTION -- WE 7083 04:37:44,200 --> 04:37:46,080 ALSO SAW CONSISTENT WITH THAT 7084 04:37:46,080 --> 04:37:54,440 REDUCTION IN THE DP. FR GFR, COT 7085 04:37:54,440 --> 04:37:55,440 WITH THE KNOWN EFFECTS OF 7086 04:37:55,440 --> 04:37:58,280 RIOCIGUAT IN LOWERING GFR, 7087 04:37:58,280 --> 04:37:59,360 LOWERING BLOOD PRESSURE AND 7088 04:37:59,360 --> 04:38:00,480 POTENTIALLY REDUCING 7089 04:38:00,480 --> 04:38:02,560 PROTEINURIA. 7090 04:38:02,560 --> 04:38:05,200 WE DIDN'T SEE ANY SIGNIFICANT 7091 04:38:05,200 --> 04:38:07,400 CHANGES IN HEMOGLOBIN OR LDH OR 7092 04:38:07,400 --> 04:38:11,440 ANY OTHER LAB PARAMETERS. 7093 04:38:11,440 --> 04:38:13,800 THIS JUST SHOWS THE MEAN 7094 04:38:13,800 --> 04:38:15,640 ARTERIAL PRESSURE, AND IN THE 7095 04:38:15,640 --> 04:38:18,080 STUDY, WHICH AGAIN REFLECTS THE 7096 04:38:18,080 --> 04:38:21,960 INCREASING DOSE BY DESIGN VERSUS 7097 04:38:21,960 --> 04:38:23,600 PLACEBO DOSE INCREASES. 7098 04:38:23,600 --> 04:38:26,000 AND SO THE MAP WAS VERY 7099 04:38:26,000 --> 04:38:30,120 SIGNIFICANT BY 12 WEEKS OF 7100 04:38:30,120 --> 04:38:32,960 STUDY. 7101 04:38:32,960 --> 04:38:34,800 AGAIN THIS SHOWS THE SAME THING 7102 04:38:34,800 --> 04:38:36,520 FOR BOTH SYSTOLIC AND DIASTOLIC 7103 04:38:36,520 --> 04:38:41,400 BLOOD PRESSURE. 7104 04:38:41,400 --> 04:38:43,320 THIS JUST SHOWS THE 6-MINUTE 7105 04:38:43,320 --> 04:38:43,720 WALK TEST. 7106 04:38:43,720 --> 04:38:47,080 THIS IS UNAJESTED PRE AND POST, 7107 04:38:47,080 --> 04:38:49,840 AND WITH RIOCIGUAT, WE SAW NO 7108 04:38:49,840 --> 04:38:51,080 CHANGE IN THE 6-MINUTE WALK 7109 04:38:51,080 --> 04:38:54,680 DISTANCE IN THIS GROUP. 7110 04:38:54,680 --> 04:38:56,760 ALTHOUGH AGAIN, ONLY ABOUT 40% 7111 04:38:56,760 --> 04:39:00,120 HAD ELEVATED TR JET IN THIS 7112 04:39:00,120 --> 04:39:01,440 PHASE 12A STUDY. 7113 04:39:01,440 --> 04:39:03,160 IF WE LOOKED AT THE SUBGROUP 7114 04:39:03,160 --> 04:39:07,040 THAT HAD A 6-MINUTE WALK LESS 7115 04:39:07,040 --> 04:39:08,360 THAN 450-METER, WHICH WOULD 7116 04:39:08,360 --> 04:39:10,880 TYPICALLY BE AN ENROLLMENT 7117 04:39:10,880 --> 04:39:12,280 CRITERIA, WE ALSO SAW NO CHANGE 7118 04:39:12,280 --> 04:39:12,680 IN WALK. 7119 04:39:12,680 --> 04:39:15,080 AND YOU CAN SEE OUR NUMBERS HERE 7120 04:39:15,080 --> 04:39:17,520 ABOUT BY THE END OF THE STUDY, 7121 04:39:17,520 --> 04:39:20,600 35 VERSUS 36 INDIVIDUALS. 7122 04:39:20,600 --> 04:39:21,480 AGAIN, VERY LOW PA WE ARED BUT 7123 04:39:21,480 --> 04:39:26,760 WE DID NOT SEE EFFECT IN THIS. 7124 04:39:26,760 --> 04:39:30,080 THIS IS THE N SYSTOLIC VOLUME, 7125 04:39:30,080 --> 04:39:31,080 AGAIN THIS WAS A HIGHLY 7126 04:39:31,080 --> 04:39:32,680 SIGNIFICANT DROP. 7127 04:39:32,680 --> 04:39:34,800 THESE ARE, BY THE WAY, 7128 04:39:34,800 --> 04:39:36,800 CONFIDENCE INTERVALS, THESE 7129 04:39:36,800 --> 04:39:38,000 AREN'T STANDARD ERRORS, THESE 7130 04:39:38,000 --> 04:39:41,120 ARE REALLY THE 90TH% CONFIDENCE 7131 04:39:41,120 --> 04:39:44,960 INTERVALS AROUND THE MEANS. 7132 04:39:44,960 --> 04:39:46,520 THIS IS THE EJECTION FRACTION 7133 04:39:46,520 --> 04:39:48,880 AGAIN SHOWING THE CONFIDENCE 7134 04:39:48,880 --> 04:39:50,600 INTERVALS WITH THE SIGNIFICANT 7135 04:39:50,600 --> 04:39:51,800 INCREASE IN EJECTION FRACTION 7136 04:39:51,800 --> 04:39:55,840 WITH RIOCIGUAT. 7137 04:39:55,840 --> 04:39:58,440 AND IN THE SUBGROUP, WE SAW A TR 7138 04:39:58,440 --> 04:40:01,480 JET GROUP LESS THAN 3 AND A 7139 04:40:01,480 --> 04:40:02,880 GROUP GREATER THAN 3. 7140 04:40:02,880 --> 04:40:04,280 THIS WAS JUST EXPLORATORY BUT WE 7141 04:40:04,280 --> 04:40:06,200 SAW AN INCREASE IN EJECTION 7142 04:40:06,200 --> 04:40:07,640 FRACTION WITHIN BOTH GROUPS THAT 7143 04:40:07,640 --> 04:40:10,760 WAS EVEN GREATER FOR THE GREATER 7144 04:40:10,760 --> 04:40:11,120 THAN 3. 7145 04:40:11,120 --> 04:40:13,080 YOU CAN SEE THE P VALUE WAS 7146 04:40:13,080 --> 04:40:14,040 HIGHLY SIGNIFICANT EVEN WITH 7147 04:40:14,040 --> 04:40:17,840 SMALL SAMPLE SIZES WITHIN THIS. 7148 04:40:17,840 --> 04:40:21,520 THIS IS THE GFR, AND AGAIN AS 7149 04:40:21,520 --> 04:40:23,480 I'VE TOLD YOU, THE GFR DID DROP 7150 04:40:23,480 --> 04:40:27,400 WITH THE P VALUE OF .06 AND 7151 04:40:27,400 --> 04:40:30,640 SHOWN FOR PLACEBO IN RED AND 7152 04:40:30,640 --> 04:40:36,480 RIOCIGUAT IN BLUE. 7153 04:40:36,480 --> 04:40:38,280 THIS IS JUST SOME OF THE SAEs, 7154 04:40:38,280 --> 04:40:40,800 JUST SHOWING YOU THE SAEs. 7155 04:40:40,800 --> 04:40:49,240 OUTSIDE OF THE OVERALL TREATMENT 7156 04:40:49,240 --> 04:40:51,560 EMERGENT ADJUDICATED -- AND THE 7157 04:40:51,560 --> 04:40:53,280 SPECIFIC VOEs, BUT WHEN WE 7158 04:40:53,280 --> 04:40:54,960 LOOK AT OTHER SIDE EFFECTS, WE 7159 04:40:54,960 --> 04:40:56,000 REALLY DIDN'T SEE SIGNIFICANT 7160 04:40:56,000 --> 04:40:56,320 DIFFERENCE. 7161 04:40:56,320 --> 04:40:57,320 THERE WAS SOME CONCERN DURING 7162 04:40:57,320 --> 04:40:58,840 THE STUDY, YOU KNOW, THERE WERE 7163 04:40:58,840 --> 04:41:01,720 A FEW PATIENTS WHERE 7164 04:41:01,720 --> 04:41:02,360 INVESTIGATORS TOOK PATIENTS OFF 7165 04:41:02,360 --> 04:41:03,240 THE TRIAL, CONCERNED ABOUT A 7166 04:41:03,240 --> 04:41:05,480 POTENTIAL FOR AN SAE, BUT WE 7167 04:41:05,480 --> 04:41:07,240 REALLY DIDN'T SEE A DIFFERENCE 7168 04:41:07,240 --> 04:41:10,160 WITHIN THESE SAEs BETWEEN 7169 04:41:10,160 --> 04:41:13,920 RICHARD CAPRIOLI AND PL PLACEBO. 7170 04:41:13,920 --> 04:41:15,920 THE ONLY ONE THAT WAS NOTABLE IS 7171 04:41:15,920 --> 04:41:24,520 WE DID HAVE 3EOPISM EVENTS, 7172 04:41:24,520 --> 04:41:26,600 WHICH IS INTERESTING -- COMPARED 7173 04:41:26,600 --> 04:41:31,440 TO ELEVATED CYCLIC GMP 7174 04:41:31,440 --> 04:41:31,720 SIGNALING. 7175 04:41:31,720 --> 04:41:34,280 SO I'LL LET KALEAB CONCLUDE THE 7176 04:41:34,280 --> 04:41:37,680 FINDINGS FROM THIS EARLY FIRST 7177 04:41:37,680 --> 04:41:46,720 IN SICKLE CELL TRIAL COLLAB. 7178 04:41:46,720 --> 04:41:48,640 >>SO WHAT SEEING HERE IS 7179 04:41:48,640 --> 04:41:50,480 POINTING TO THE FACT THAT RIO 7180 04:41:50,480 --> 04:41:55,760 DOES NOT SHOW ANYTHING TO 7181 04:41:55,760 --> 04:41:57,360 INCREASE WITH RESPECT TO THAT. 7182 04:41:57,360 --> 04:41:58,320 THERE'S POTENTIAL OF OPENING THE 7183 04:41:58,320 --> 04:42:01,160 DOOR TO SAFE USE OF RIO FOR 7184 04:42:01,160 --> 04:42:03,760 PULMONARY HYPERTENSION AND CTEPH 7185 04:42:03,760 --> 04:42:06,440 IN SICKLE CELL, AND THERE IS THE 7186 04:42:06,440 --> 04:42:07,760 SUGGESTION THAT MAYBE -- AND I 7187 04:42:07,760 --> 04:42:09,720 THINK THIS MAKES SENSE, BUT 7188 04:42:09,720 --> 04:42:14,680 HAVING A LARGER TRIAL IN THE 7189 04:42:14,680 --> 04:42:16,000 LARGER PATIENT POPULATION IS 7190 04:42:16,000 --> 04:42:21,360 KIND OF THE NEXT STEP. 7191 04:42:21,360 --> 04:42:22,920 WHAT WE SAW WAS TRENDS TOWARDS 7192 04:42:22,920 --> 04:42:25,280 REDUCED TREATMENT EMERGENT 7193 04:42:25,280 --> 04:42:27,120 SAEs BUT VOEs THAT WE SAW 7194 04:42:27,120 --> 04:42:28,960 WERE JUST FAR LESS THAN THE 7195 04:42:28,960 --> 04:42:32,720 REYOE ARM, WHAT WE'RE SEEING IS 7196 04:42:32,720 --> 04:42:34,280 THAT TOO MUCH IN TERMS OF DATA 7197 04:42:34,280 --> 04:42:37,360 THAT SUGGESTS THAT SGG SIGNALING 7198 04:42:37,360 --> 04:42:39,920 REDUCES PAIN BASED ON THE 7199 04:42:39,920 --> 04:42:45,480 RESULTS. 7200 04:42:45,480 --> 04:42:47,800 KIND OF GOING BACK TO THE 7201 04:42:47,800 --> 04:42:48,680 ENRICHMENT STRATEGY, KIND OF 7202 04:42:48,680 --> 04:42:49,720 WHAT MARK HAD POINTED OUT 7203 04:42:49,720 --> 04:42:51,160 BEFORE, WHAT WE'RE SEEING BASED 7204 04:42:51,160 --> 04:42:55,400 ON THESE FIVE KEY STRATEGY 7205 04:42:55,400 --> 04:42:57,520 POINTS HERE, THAT ROUGHLY ABOUT 7206 04:42:57,520 --> 04:42:59,880 45% THAT WE SAW SYSTOLIC BLOOD 7207 04:42:59,880 --> 04:43:03,240 PRESSURE GREATER THAN 130, 35% 7208 04:43:03,240 --> 04:43:05,600 WITH MACRO, ALMOST HALF HAD TRV 7209 04:43:05,600 --> 04:43:07,360 GREATER THAN 2 1/2 AND ABOUT 15% 7210 04:43:07,360 --> 04:43:10,600 HAD TRV GREATER THAN 2.9, AND 7211 04:43:10,600 --> 04:43:11,800 ABOUT 6%. 7212 04:43:11,800 --> 04:43:12,960 SO YOU'RE GETTING A SENSE OF 7213 04:43:12,960 --> 04:43:15,440 WHERE PEOPLE HIT IN TERMS OF THE 7214 04:43:15,440 --> 04:43:16,240 ENRICHMENT CRITERIA COMING INTO 7215 04:43:16,240 --> 04:43:18,040 THE STUDY, BUT IT'S FAIRLY 7216 04:43:18,040 --> 04:43:19,040 SUCCESSFUL IN TERMS OF 7217 04:43:19,040 --> 04:43:23,400 IDENTIFYING THIS COHORT. 7218 04:43:23,400 --> 04:43:25,560 SO IT'S WELL TOLERATED AND WE'RE 7219 04:43:25,560 --> 04:43:28,520 SEEING OBVIOUSLY A SIGNIFICANT 7220 04:43:28,520 --> 04:43:29,120 HEMODYNAMIC EFFECT ON BLOOD 7221 04:43:29,120 --> 04:43:31,120 PRESSURE, BUT OBVIOUSLY GIVEN 7222 04:43:31,120 --> 04:43:34,800 WHERE WE'RE AT AT THIS EARLY 7223 04:43:34,800 --> 04:43:38,560 STAGE, PHASE 1/2-ISH AREA, WE 7224 04:43:38,560 --> 04:43:40,600 SEE LARGER TRIALS TO SEE IF RIO 7225 04:43:40,600 --> 04:43:44,600 IMPROVES MEASURES OF END-ORGAN 7226 04:43:44,600 --> 04:43:45,640 FUNCTIONS. 7227 04:43:45,640 --> 04:43:48,200 AND THIS JUST COVERING THE -- 7228 04:43:48,200 --> 04:43:49,240 NOT ONLY THE STEERING COMMITTEE 7229 04:43:49,240 --> 04:43:51,640 AND SITES THAT MAKE UP THE STEER 7230 04:43:51,640 --> 04:43:54,040 YOE COMMITTEE AS WELL AS THE 7231 04:43:54,040 --> 04:43:55,400 MANY OTHER SITES AS MARK HAD 7232 04:43:55,400 --> 04:43:57,160 MENTIONED BEFORE, HE AND I ALONG 7233 04:43:57,160 --> 04:43:58,680 WITH OTHERS LED THE CLINICAL AND 7234 04:43:58,680 --> 04:44:03,440 DATA COORDINATING CENTERS, JUST 7235 04:44:03,440 --> 04:44:04,880 WANTED TO SHOW THE BREADTH OF 7236 04:44:04,880 --> 04:44:06,320 WORK THAT WENT INTO THIS AND THE 7237 04:44:06,320 --> 04:44:07,600 SITES THAT WERE INVOLVED AS 7238 04:44:07,600 --> 04:44:08,240 WELL. 7239 04:44:08,240 --> 04:44:09,200 MARK, DO YOU WANT TO SAY 7240 04:44:09,200 --> 04:44:09,640 ANYTHING ELSE? 7241 04:44:09,640 --> 04:44:15,160 >>NO, I JUST DO WANT TO 7242 04:44:15,160 --> 04:44:17,280 RECOGNIZE GREG KATO, WHO REALLY 7243 04:44:17,280 --> 04:44:18,960 HELPED DESIGN AND LEAD THIS 7244 04:44:18,960 --> 04:44:20,480 STUDY BEFORE MOVING FROM 7245 04:44:20,480 --> 04:44:21,920 PITTSBURGH INTO INDUSTRY, SO HE 7246 04:44:21,920 --> 04:44:22,840 WAS KEY TO THIS. 7247 04:44:22,840 --> 04:44:24,440 AND JUST RECOGNIZING THE 7248 04:44:24,440 --> 04:44:25,680 STEERING COMMITTEE MEMBERS WHO 7249 04:44:25,680 --> 04:44:27,480 PUT A LOT OF EFFORT INTO THIS 7250 04:44:27,480 --> 04:44:29,840 WORK, AND ALL THE SITE PIs WHO 7251 04:44:29,840 --> 04:44:31,840 HAVE CONTRIBUTED A LOT TO THIS 7252 04:44:31,840 --> 04:44:35,760 EFFORT. 7253 04:44:35,760 --> 04:44:37,520 >>I THINK THAT'S THE LAST SLIDE 7254 04:44:37,520 --> 04:44:39,920 WE HAVE. 7255 04:44:39,920 --> 04:44:40,520 >>GREAT. 7256 04:44:40,520 --> 04:44:41,760 THANK YOU SO MUCH. 7257 04:44:41,760 --> 04:44:47,760 GREAT TALK. 7258 04:44:47,760 --> 04:44:48,800 QUESTIONS? 7259 04:44:48,800 --> 04:44:49,880 >>THERE'S ONE IN THE CHAT. 7260 04:44:49,880 --> 04:44:51,040 >>WE HAVE A CHAT QUESTION? 7261 04:44:51,040 --> 04:44:51,840 >>YES. 7262 04:44:51,840 --> 04:44:55,960 ONE QUESTION IN THIS CHAT. 7263 04:44:55,960 --> 04:44:57,640 WERE P VALUES ADJUSTED FOR 7264 04:44:57,640 --> 04:45:00,520 MULTIPLE TESTING? 7265 04:45:00,520 --> 04:45:01,720 >>THAT'S A GREAT QUESTION. 7266 04:45:01,720 --> 04:45:04,200 SO OUR PRIMARY HYPOTHESIS HERE 7267 04:45:04,200 --> 04:45:05,720 WAS REALLY FOCUSED ON THE SAFETY 7268 04:45:05,720 --> 04:45:06,640 AND TOLERABILITY PIECE. 7269 04:45:06,640 --> 04:45:10,960 SO OUR OVERALL TYPE 1 WAS 7270 04:45:10,960 --> 04:45:12,160 STARTED AGAINST THAT 10% OF 7271 04:45:12,160 --> 04:45:12,600 THAT. 7272 04:45:12,600 --> 04:45:13,800 EVERYTHING ELSE WAS SECONDARY 7273 04:45:13,800 --> 04:45:14,560 AND EXPLORATORY. 7274 04:45:14,560 --> 04:45:15,760 SO FOR A CLINICAL TRIAL LIKE 7275 04:45:15,760 --> 04:45:17,280 THIS, WE DID NOT ADJUST FOR 7276 04:45:17,280 --> 04:45:18,760 MULTIPLE TESTING BECAUSE WE 7277 04:45:18,760 --> 04:45:21,200 NEVER ELEVATED THOSE TO ANY SORT 7278 04:45:21,200 --> 04:45:22,480 OF PRIMARY STATUS. 7279 04:45:22,480 --> 04:45:23,560 WE COULD HAVE LOOKED AT THAT, 7280 04:45:23,560 --> 04:45:27,640 BUT AGAIN, THAT WAS NOT THE GOAL 7281 04:45:27,640 --> 04:45:29,040 OF THOSE OTHER OUTCOMES. 7282 04:45:29,040 --> 04:45:31,400 THEY WERE REALLY FOCUSED ON 7283 04:45:31,400 --> 04:45:32,920 EXPLORATORY SECONDARY OUTCOMES. 7284 04:45:32,920 --> 04:45:38,280 THAT'S A GREAT QUESTION. 7285 04:45:38,280 --> 04:45:40,120 >>ONE MORE QUESTION HERE FROM 7286 04:45:40,120 --> 04:45:41,680 THE AUDIENCE. 7287 04:45:41,680 --> 04:45:44,120 >>REGINA CRAWFORD FROM THE OHIO 7288 04:45:44,120 --> 04:45:45,320 STATE UNIVERSITY. 7289 04:45:45,320 --> 04:45:46,320 REALLY NICE WORK. 7290 04:45:46,320 --> 04:45:49,360 HAD A QUESTION IN REGARDS TO THE 7291 04:45:49,360 --> 04:45:52,720 ENTRY CRITERIA IN TERMS OF THE 7292 04:45:52,720 --> 04:45:53,800 TR JET VELOCITY. 7293 04:45:53,800 --> 04:45:55,040 ARE YOU BASING IT ON WHEN 7294 04:45:55,040 --> 04:45:58,920 THEY'RE AT STEADY STATE OR JUST 7295 04:45:58,920 --> 04:46:00,360 ANY TR JET THAT MET THE 7296 04:46:00,360 --> 04:46:05,240 CRITERIA? 7297 04:46:05,240 --> 04:46:10,000 >>SO THE TR -- MARK, DID YOU 7298 04:46:10,000 --> 04:46:10,320 WANT TO -- 7299 04:46:10,320 --> 04:46:11,560 >>SORRY. 7300 04:46:11,560 --> 04:46:12,320 YES, GREAT QUESTION. 7301 04:46:12,320 --> 04:46:14,880 THE TR JET VELOCITY IS IN STEADY 7302 04:46:14,880 --> 04:46:15,200 STATE. 7303 04:46:15,200 --> 04:46:17,360 SO IT HAD TO BE WITHIN, YOU 7304 04:46:17,360 --> 04:46:19,880 KNOW, TWO WEEKS AWAY FROM A 7305 04:46:19,880 --> 04:46:22,560 HOSPITALIZATION FOR VOE. 7306 04:46:22,560 --> 04:46:26,400 SO THE IDEA OF THE TR JET, THE 7307 04:46:26,400 --> 04:46:27,920 PROTEINURIA, THE SYSTOLIC BLOOD 7308 04:46:27,920 --> 04:46:31,480 PRESSURE, THESE WERE REALLY 7309 04:46:31,480 --> 04:46:33,360 DESIGNED AS INCLUSION CRITERIA 7310 04:46:33,360 --> 04:46:39,200 TO ATTEMPT TO ENRICH THE STUDY 7311 04:46:39,200 --> 04:46:41,160 COHORT FOR CARDIOVASCULAR 7312 04:46:41,160 --> 04:46:42,160 COMPLICATIONS SO THAT WE MIGHT 7313 04:46:42,160 --> 04:46:44,680 HAVE MORE POWER FOR A 7314 04:46:44,680 --> 04:46:46,960 PRELIMINARY LOOK AT WHETHER 7315 04:46:46,960 --> 04:46:48,680 RIOCIGUAT HAD EFFICACY FOR SOME 7316 04:46:48,680 --> 04:46:50,400 OF THESE END POINTS, LIKE 7317 04:46:50,400 --> 04:46:52,480 PROTEINURIA, LIKE TR JET 7318 04:46:52,480 --> 04:46:52,760 VELOCITY. 7319 04:46:52,760 --> 04:46:54,080 THAT WAS THE REASON FOR THAT 7320 04:46:54,080 --> 04:46:54,760 DESIGN. 7321 04:46:54,760 --> 04:46:56,160 BUT IT WAS ALL STEADY STATE 7322 04:46:56,160 --> 04:46:57,360 MEASUREMENTS. 7323 04:46:57,360 --> 04:47:01,200 >>THANK YOU. 7324 04:47:01,200 --> 04:47:02,600 >>ONE MORE QUESTION. 7325 04:47:02,600 --> 04:47:05,800 >>HI. 7326 04:47:05,800 --> 04:47:06,520 ILA FROM EMORY. 7327 04:47:06,520 --> 04:47:08,440 DID YOU GUYS CHECK ORTHO 7328 04:47:08,440 --> 04:47:08,840 STATICS? 7329 04:47:08,840 --> 04:47:10,240 BECAUSE I FIND IT INTERESTING 7330 04:47:10,240 --> 04:47:14,160 THAT THE BLOOD PRESSURES WERE 7331 04:47:14,160 --> 04:47:17,800 RETUESDAYEDREDUCED, AND THAT COE 7332 04:47:17,800 --> 04:47:23,360 IMPACTED WHAT YOU SAW IN THE 7333 04:47:23,360 --> 04:47:25,360 WALK-PHASST EVALUATION. 7334 04:47:25,360 --> 04:47:28,680 >>SO WE DID NOT DO ORTHOSTATIC 7335 04:47:28,680 --> 04:47:30,680 BLOOD PRESSURE MEASUREMENTS. 7336 04:47:30,680 --> 04:47:36,440 WE WERE VERY CONCERNED THAT THIS 7337 04:47:36,440 --> 04:47:37,520 MEDICINE COULD LOWER BLOOD 7338 04:47:37,520 --> 04:47:39,320 PRESSURE TOO MUCH, AND WE IN 7339 04:47:39,320 --> 04:47:41,120 FACT, AS I SAID, WE HAD ABOUT 7340 04:47:41,120 --> 04:47:46,080 80% POWER TO DETECT A 7341 04:47:46,080 --> 04:47:47,280 6-MILLIMETER MERCURY DROP IN 7342 04:47:47,280 --> 04:47:49,080 MEAN ARTERIAL PRESSURE BASED ON 7343 04:47:49,080 --> 04:47:51,120 THE DATA FROM THE PULMONARY 7344 04:47:51,120 --> 04:47:52,520 HYPERTENSION TRIALS AND THE CTEF 7345 04:47:52,520 --> 04:47:53,440 TRIALS IN PATIENTS WITHOUT 7346 04:47:53,440 --> 04:47:53,840 SICKLE CELL. 7347 04:47:53,840 --> 04:47:58,520 THE OTHER THING IS SMOKING 7348 04:47:58,520 --> 04:48:02,560 CIGARETTES, FOR EXAMPLE, WILL 7349 04:48:02,560 --> 04:48:03,680 REDUCE -- LEAD TO A METABOLIC 7350 04:48:03,680 --> 04:48:05,960 EFFECT THAT REDUCES THE 7351 04:48:05,960 --> 04:48:06,800 METABOLISM OF RIOCIGUAT SO WE 7352 04:48:06,800 --> 04:48:10,520 WERE SOMEWHAT WORRIED ABOUT 7353 04:48:10,520 --> 04:48:12,160 SMOKERS AND SO WE WERE WATCHING 7354 04:48:12,160 --> 04:48:12,840 CAREFULLY BLOOD PRESSURE WITH 7355 04:48:12,840 --> 04:48:15,760 EVERY DOSE ESCALATION. 7356 04:48:15,760 --> 04:48:17,160 WE ALSO DID NOT KNOW, SINCE THIS 7357 04:48:17,160 --> 04:48:22,640 DRUG CAN SENSITIZE -- CYCLASE TO 7358 04:48:22,640 --> 04:48:26,480 NO AND HYDROXYUREA CAN BE 7359 04:48:26,480 --> 04:48:27,720 METABOLIZED TO NITRIC OXIDE, WE 7360 04:48:27,720 --> 04:48:28,800 DID NOT KNOW WHETHER THERE MIGHT 7361 04:48:28,800 --> 04:48:30,760 BE AN INTERACTION BETWEEN 7362 04:48:30,760 --> 04:48:31,920 HYDROXYUREA AND THIS DRUG ON 7363 04:48:31,920 --> 04:48:32,560 BLOOD PRESSURE. 7364 04:48:32,560 --> 04:48:36,760 WE DID NOT SEE A POTENTIATION OF 7365 04:48:36,760 --> 04:48:37,600 THE BLOOD PRESSURE EFFECT WITH 7366 04:48:37,600 --> 04:48:39,360 EITHER SMOKING OR HYDROXYUREA. 7367 04:48:39,360 --> 04:48:42,280 SO IT DOES APPEAR THAT THIS DRUG 7368 04:48:42,280 --> 04:48:44,360 IS SAFE AND TOLERABLE IN 7369 04:48:44,360 --> 04:48:46,640 PATIENTS WITH HYDROXYUREA AND 7370 04:48:46,640 --> 04:48:47,080 SMOKING. 7371 04:48:47,080 --> 04:48:50,400 WE DID HAVE PATIENTS THAT DID 7372 04:48:50,400 --> 04:48:53,280 GET LIGHT-HEADED OR COULD NOT 7373 04:48:53,280 --> 04:48:53,640 DOSE-ESCALATE. 7374 04:48:53,640 --> 04:48:55,080 SO AS YOU SEE BY THE END OF THE 7375 04:48:55,080 --> 04:48:58,160 STUDY, I THINK ABOUT 62% OF THE 7376 04:48:58,160 --> 04:49:02,480 PATIENTS TOLERATED THE FULL 7377 04:49:02,480 --> 04:49:03,520 2.5 MILLIGRAMS, AND THAT COULD 7378 04:49:03,520 --> 04:49:04,320 REFLECT THE FACT THAT SOME 7379 04:49:04,320 --> 04:49:08,200 PEOPLE JUST COULDN'T GO UP ON 7380 04:49:08,200 --> 04:49:09,720 DOSE, SO THERE WAS THIS DOSE 7381 04:49:09,720 --> 04:49:10,480 ESCALATION PART OF THE STUDY, 7382 04:49:10,480 --> 04:49:14,200 AND THE PLACEBO ALSO HAD A SHAM 7383 04:49:14,200 --> 04:49:16,440 DOSE ESCALATION WITH PLACEBO, 7384 04:49:16,440 --> 04:49:19,720 PILL DOSE ESCALATIONS. 7385 04:49:19,720 --> 04:49:21,040 BUT IT DOES APPEAR THAT IF YOU 7386 04:49:21,040 --> 04:49:22,840 FOLLOW THE FDA-APPROVED 7387 04:49:22,840 --> 04:49:26,480 ALGORITHM FOR DOSE ESCALATION 7388 04:49:26,480 --> 04:49:28,960 THAT'S APPROVED FOR PAH AND 7389 04:49:28,960 --> 04:49:30,360 CTEF, THAT THIS DRUG APPEARS TO 7390 04:49:30,360 --> 04:49:31,880 BE AS TOLERATED AS PLACEBO. 7391 04:49:31,880 --> 04:49:33,080 I HOPE THAT ANSWERS YOUR 7392 04:49:33,080 --> 04:49:33,520 QUESTION. 7393 04:49:33,520 --> 04:49:34,160 >>IT DOES. 7394 04:49:34,160 --> 04:49:36,520 THANK YOU. 7395 04:49:36,520 --> 04:49:38,000 >>SO YOU KNOW, A LOT OF PEOPLE 7396 04:49:38,000 --> 04:49:41,800 ARE USING THIS DRUG OFF LABEL 7397 04:49:41,800 --> 04:49:44,520 FOR PULMONARY HYPERTENSION AND 7398 04:49:44,520 --> 04:49:45,400 SICKLE CELL. 7399 04:49:45,400 --> 04:49:47,480 A LOT OF PEOPLE CONTACT ME, LIZ 7400 04:49:47,480 --> 04:49:49,720 AND OTHERS IN THE FIELD, WHAT'S 7401 04:49:49,720 --> 04:49:51,480 THE RIGHT DRUG TO USE IN A 7402 04:49:51,480 --> 04:49:53,680 PATIENT THAT HAS CTEF AND A 7403 04:49:53,680 --> 04:49:55,200 PATIENT THAT HAS SICKLE CELL 7404 04:49:55,200 --> 04:49:57,840 THAT HAS PULL KNOW NEAR O.A.R. 7405 04:49:57,840 --> 04:50:00,280 TIER YAL HYPERTENSION BY RIGHT 7406 04:50:00,280 --> 04:50:00,800 HEART CATH. 7407 04:50:00,800 --> 04:50:05,360 WE DON'T RECOMMEND USING SILL 15 7408 04:50:05,360 --> 04:50:07,760 FILL AND MANY PEOPLE USE AN ENDO 7409 04:50:07,760 --> 04:50:10,600 FI LIN RECEPTOR BLOCKER OR 7410 04:50:10,600 --> 04:50:12,120 INCREASINGLY PEOPLE ARE USING 7411 04:50:12,120 --> 04:50:13,520 RIOCIGUAT, AND LIZ PUBLISHED A 7412 04:50:13,520 --> 04:50:18,440 CASE SERIES OF THE SUCCESS WITH 7413 04:50:18,440 --> 04:50:19,840 RIOCIGUAT IN SMALL NUMBERS OF 7414 04:50:19,840 --> 04:50:20,960 PATIENTS, AND THIS STUDY AT 7415 04:50:20,960 --> 04:50:24,080 LEAST TELLS US THAT THE DOSE 7416 04:50:24,080 --> 04:50:25,720 ESCALATION PROTOCOL FOR RIO IS 7417 04:50:25,720 --> 04:50:26,480 SAFE IN PATIENTS WITH SICKLE 7418 04:50:26,480 --> 04:50:30,200 CELL DISEASE AND THAT THE DRUG 7419 04:50:30,200 --> 04:50:32,160 IS WELL TOLERATED. 7420 04:50:32,160 --> 04:50:33,800 THE OTHER THING -- THE ONLY 7421 04:50:33,800 --> 04:50:36,720 THING TO WATCH FOR IS PRIOPISM. 7422 04:50:36,720 --> 04:50:38,600 WE DID HAVE THREE CASE IS VERSUS 7423 04:50:38,600 --> 04:50:39,800 ZERO SO THERE IS A CONCERN AND 7424 04:50:39,800 --> 04:50:41,280 THAT'S GOING TO REQUIRE SOME 7425 04:50:41,280 --> 04:50:41,840 OBSERVATION IF PATIENTS ARE 7426 04:50:41,840 --> 04:50:44,840 STARTED ON THIS FOR PAH OR CTEF. 7427 04:50:44,840 --> 04:50:45,760 >>OKAY. 7428 04:50:45,760 --> 04:50:47,280 ONE LAST QUESTION FROM MARK HERE 7429 04:50:47,280 --> 04:50:48,640 IN THE AUDIENCE. 7430 04:50:48,640 --> 04:50:51,360 >>MARK WALTERS. 7431 04:50:51,360 --> 04:50:55,200 SHORT QUESTION. 7432 04:50:55,200 --> 04:50:58,720 DO YOU THINK WE GE THE EJECTION 7433 04:50:58,720 --> 04:51:00,360 FRACTION IMPROVEMENT WAS RELATED 7434 04:51:00,360 --> 04:51:04,840 TO AFTER LOAD OR -- 7435 04:51:04,840 --> 04:51:08,880 >>MARK, THAT'S A GREAT 7436 04:51:08,880 --> 04:51:11,680 QUESTION. 7437 04:51:11,680 --> 04:51:13,680 WE DON'T KNOW. 7438 04:51:13,680 --> 04:51:18,920 I WOULD PRESUME THAT IT IS AN 7439 04:51:18,920 --> 04:51:22,200 EFFECT AFTER LOAD. 7440 04:51:22,200 --> 04:51:24,440 IN FACT IN SOME DISCUSSIONS WITH 7441 04:51:24,440 --> 04:51:25,360 OUR COLLEAGUES IN FRANCE, THIS 7442 04:51:25,360 --> 04:51:27,360 STUDY REALLY ENROLLED ALL-COMERS 7443 04:51:27,360 --> 04:51:28,520 BECAUSE WE WANTED TO SEE IF THE 7444 04:51:28,520 --> 04:51:29,920 DRUG WAS SAFE, BUT THERE IS 7445 04:51:29,920 --> 04:51:33,240 CONCERN THAT THIS COULD ENHANCE 7446 04:51:33,240 --> 04:51:34,840 A HIGH CARDIAC OUTPUT STATE, 7447 04:51:34,840 --> 04:51:36,680 BECAUSE WE SAW THE TR JET DROP, 7448 04:51:36,680 --> 04:51:38,000 WE SAW THE BLOOD PRESSURE DROP, 7449 04:51:38,000 --> 04:51:41,360 WE SAW THE GFR DROP, BUT WE DID 7450 04:51:41,360 --> 04:51:43,080 NOT SEE AN IMPROVEMENT IN WALK 7451 04:51:43,080 --> 04:51:44,920 AND WE DID NOT SEE AN 7452 04:51:44,920 --> 04:51:49,360 IMPROVEMENT IN NT PRO BNP. 7453 04:51:49,360 --> 04:51:50,480 SO THIS IS POSSIBLE IF IT'S USED 7454 04:51:50,480 --> 04:51:53,000 IN PATIENTS WITHOUT PULMONARY 7455 04:51:53,000 --> 04:51:54,520 ARTERIAL HYPERTENSION WITHOUT RV 7456 04:51:54,520 --> 04:51:58,120 DYSFUNCTION, THAT WE COULD BE 7457 04:51:58,120 --> 04:52:01,720 DRIVING INCREASING EF AND 7458 04:52:01,720 --> 04:52:02,720 INCREASING STROKE VOLUME, AND 7459 04:52:02,720 --> 04:52:04,720 THAT THAT MAY BE MALADAPTIVE 7460 04:52:04,720 --> 04:52:05,000 OVER TIME. 7461 04:52:05,000 --> 04:52:09,040 SO I THINK THIS STUDY SORT OF 7462 04:52:09,040 --> 04:52:10,160 TELLS US THAT IT'S SAFE FOR 7463 04:52:10,160 --> 04:52:13,280 THREE MONTHS OF THERAPY AND IT 7464 04:52:13,280 --> 04:52:18,280 MAY HAVE EFFECTS ON LIMITING 7465 04:52:18,280 --> 04:52:19,160 PROTEINURIA, BUT IT DOESN'T 7466 04:52:19,160 --> 04:52:20,040 REALLY ANSWER THE QUESTION 7467 04:52:20,040 --> 04:52:21,960 WHETHER THIS WOULD BE EFFECTIVE 7468 04:52:21,960 --> 04:52:22,840 FOR A PATIENT WITH SICKLE CELL 7469 04:52:22,840 --> 04:52:24,160 THAT HAS PULMONARY HYPERTENSION 7470 04:52:24,160 --> 04:52:25,680 BECAUSE WE WERE JUST TOO 7471 04:52:25,680 --> 04:52:26,760 UNDERPOWERED TO REALLY STATE 7472 04:52:26,760 --> 04:52:28,640 THAT. 7473 04:52:28,640 --> 04:52:29,800 >>THANK YOU SO MUCH, MARK. 7474 04:52:29,800 --> 04:52:33,400 SO FOR US TO BE ON SCHEDULE, 7475 04:52:33,400 --> 04:52:35,160 WE'LL TAKE A QUICK BREAK. 7476 04:52:35,160 --> 04:52:37,240 WE CAN BE BACK HERE, A QUICK 7477 04:52:37,240 --> 04:52:41,840 BIOBREAK, WE CAN BE BACK HERE 7478 04:52:41,840 --> 04:52:42,240 5 AFTER 3:00. 7479 04:52:42,240 --> 04:52:43,440 PROMPTLY SO WE CAN START OUR 7480 04:52:43,440 --> 04:52:45,880 NEXT TALK. 7481 04:52:45,880 --> 04:52:47,760 THERE ARE SOME COMMENTS ON THE 7482 04:52:47,760 --> 04:52:48,840 CHAT. 7483 04:52:48,840 --> 04:52:51,560 AND I WOULD RECOMMEND THE 7484 04:52:51,560 --> 04:52:53,520 SPEAKERS TO PLEASE LOOK UP THE 7485 04:52:53,520 --> 04:52:54,720 CHATS AND TRY TO ANSWER THE 7486 04:52:54,720 --> 04:52:55,000 QUESTIONS. 7487 04:52:55,000 --> 04:52:55,520 THANK YOU. 7488 04:52:55,520 --> 04:53:02,600 THANK YOU, MARK, AND ABEBE, FOR 7489 04:53:02,600 --> 04:53:03,040 GREAT TALKS. 7490 04:53:03,040 --> 04:53:03,800 >>THANK YOU VERY MUCH. 7491 04:53:03,800 --> 04:53:27,920 APPRECIATE IT. 7492 04:53:27,920 --> 04:53:29,080 THANK YOU VERY MUCH. 7493 04:53:29,080 --> 04:53:31,120 MY NAME IS DAVID BROUSSEAU, 7494 04:53:31,120 --> 04:53:35,280 CHAIR OF THE PEDIATRICS IN 7495 04:53:35,280 --> 04:53:36,320 DELAWARE, PEDIATRIC EMERGENCY 7496 04:53:36,320 --> 04:53:37,920 MEDICINE BY TRAINING, SO I DON'T 7497 04:53:37,920 --> 04:53:38,920 KNOW HOW MANY PEDIATRIC 7498 04:53:38,920 --> 04:53:40,120 EMERGENCY MEDICINE PEOPLE ARE 7499 04:53:40,120 --> 04:53:41,200 SPEAKING HERE, BUT I'M GOING TO 7500 04:53:41,200 --> 04:53:42,640 TALK A LITTLE BIT ABOUT SICKLE 7501 04:53:42,640 --> 04:53:44,520 CELL CARE IN THE EMERGENCY 7502 04:53:44,520 --> 04:53:44,960 DEPARTMENT. 7503 04:53:44,960 --> 04:53:52,640 I AM CURRENTLY MPI WITH AMANDA 7504 04:53:52,640 --> 04:53:54,800 BRANDOW FUNDED BY NHLBI TO DO 7505 04:53:54,800 --> 04:53:55,240 THIS WORK. 7506 04:53:55,240 --> 04:53:56,680 WE'RE GOING TO TALK A LITTLE 7507 04:53:56,680 --> 04:53:58,080 ABOUT SICKLE CELL DISEASE AND 7508 04:53:58,080 --> 04:53:59,720 TIMELINESS OF EMERGENCY 7509 04:53:59,720 --> 04:54:02,680 DEPARTMENT CARE IN SICKLE CELL 7510 04:54:02,680 --> 04:54:06,200 DISEASE AND TYPE TWO 7511 04:54:06,200 --> 04:54:06,760 EFFECTIVENESS IMPLEMENTATION 7512 04:54:06,760 --> 04:54:06,960 TRIAL. 7513 04:54:06,960 --> 04:54:08,120 THERE'S ABOUT 100,000 PEOPLE 7514 04:54:08,120 --> 04:54:09,240 WITH SICKLE CELL DISEASE IN THE 7515 04:54:09,240 --> 04:54:10,960 UNITED STATES, ABOUT 36,000 OF 7516 04:54:10,960 --> 04:54:11,800 THOSE ARE CHILDREN. 7517 04:54:11,800 --> 04:54:14,240 THEY HAVE RECURRENT PAIN THAT'S 7518 04:54:14,240 --> 04:54:15,120 ALL THE BACKGROUND YOU GET. 7519 04:54:15,120 --> 04:54:17,320 I HOPE THAT'S PROBABLY MORE THAN 7520 04:54:17,320 --> 04:54:20,160 MOST OF YOU NEED. 7521 04:54:20,160 --> 04:54:21,920 SO, THE NHLBI DOES HAVE SICKLE 7522 04:54:21,920 --> 04:54:23,120 CELL ACUTE PAIN TREATMENT 7523 04:54:23,120 --> 04:54:24,560 GUIDELINES. 7524 04:54:24,560 --> 04:54:27,200 TO ADMINISTER OUR FIRST DOSE OF 7525 04:54:27,200 --> 04:54:29,600 OPIOIDS WITHIN 60 MINUTES OF 7526 04:54:29,600 --> 04:54:30,600 REGISTRATION OR 30 MINUTES OF 7527 04:54:30,600 --> 04:54:32,560 TRIAGE THAT IS TYPICALLY 7528 04:54:32,560 --> 04:54:33,680 OPERATIONALIZED AS WITHIN 60 7529 04:54:33,680 --> 04:54:36,080 MINUTES OF ARRIVAL FOR EMERGENCY 7530 04:54:36,080 --> 04:54:38,160 DEPARTMENT CARE WITH REPEAT 7531 04:54:38,160 --> 04:54:39,840 DOSES EVERY 15 TO 30 MINUTES 7532 04:54:39,840 --> 04:54:41,840 UNTIL THE PAIN IS MANAGED. 7533 04:54:41,840 --> 04:54:43,800 USUALLY AFTER THREE OR FOUR 7534 04:54:43,800 --> 04:54:45,120 DOSES, A PATIENT IS EITHER 7535 04:54:45,120 --> 04:54:46,360 DISCHARGED TO HOME OR ADMITTED 7536 04:54:46,360 --> 04:54:49,840 TO THE HOSPITAL. 7537 04:54:49,840 --> 04:54:51,400 SO IN ORDER TO STUDY THIS, WE 7538 04:54:51,400 --> 04:54:52,720 NEED TO DO A COUPLE OF THINGS. 7539 04:54:52,720 --> 04:54:55,040 WE NEED TO DEFINE AN 7540 04:54:55,040 --> 04:54:56,000 UNCOMPLICATED PAIN CRISIS THAT 7541 04:54:56,000 --> 04:54:58,120 WE COULD LOOK AT ACROSS MULTIPLE 7542 04:54:58,120 --> 04:54:59,320 INSTITUTIONS AND FOR A 7543 04:54:59,320 --> 04:54:59,680 REASONABLE COST. 7544 04:54:59,680 --> 04:55:01,080 LIKE I SAID, WE WANTED TO LOOK 7545 04:55:01,080 --> 04:55:02,200 AT MULTISITE DATA. 7546 04:55:02,200 --> 04:55:04,480 SO WE LEVERAGED DATA FROM THE 7547 04:55:04,480 --> 04:55:06,120 PEDIATRIC EMERGENCY CARE APLAYED 7548 04:55:06,120 --> 04:55:09,200 RESEARCH NETWORK, OR PECARN. 7549 04:55:09,200 --> 04:55:16,000 THE PECARN REGISTRY WAS 7550 04:55:16,000 --> 04:55:17,440 ESTABLISHED BY LAURIE 7551 04:55:17,440 --> 04:55:17,960 CHILDREN'S. 7552 04:55:17,960 --> 04:55:19,200 IT'S AN EMERGENCY CARE REGISTRY 7553 04:55:19,200 --> 04:55:20,840 THAT LITERALLY FOR THE SITES 7554 04:55:20,840 --> 04:55:22,960 LISTED DUMPS EVERY EMERGENCY 7555 04:55:22,960 --> 04:55:24,240 DEPARTMENT VISIT, EVERY 7556 04:55:24,240 --> 04:55:25,720 EMERGENCY DEPARTMENT VISIT, THAT 7557 04:55:25,720 --> 04:55:27,880 COMES TO THAT FACILITY TO A 7558 04:55:27,880 --> 04:55:29,600 CENTRAL DATA REPOSITORY. 7559 04:55:29,600 --> 04:55:35,560 IT WAS DEVELOPED TO DETERMINE 7560 04:55:35,560 --> 04:55:37,400 BENCHMARKS FOR ED PERFORMANCE 7561 04:55:37,400 --> 04:55:38,280 FOR SOME ALREADY ACCEPTED 7562 04:55:38,280 --> 04:55:38,840 STANDARDS OF CARE. 7563 04:55:38,840 --> 04:55:41,720 WE HAVE ELEVATED SICKLE CELL 7564 04:55:41,720 --> 04:55:42,360 TIMELINESS NOW TO BE ONE OF 7565 04:55:42,360 --> 04:55:43,480 THOSE QUALITY METRICS THAT IT 7566 04:55:43,480 --> 04:55:48,040 LOOKS AT WITHIN OUR DATABASE. 7567 04:55:48,040 --> 04:55:49,440 SO IN ORDER TO INITIALLY 7568 04:55:49,440 --> 04:55:50,800 CATEGORIZE VISITS AS 7569 04:55:50,800 --> 04:55:53,560 UNCOMPLICATED BASED ON 7570 04:55:53,560 --> 04:55:54,760 ICD-9/WHATEVER INFORMATION IS 7571 04:55:54,760 --> 04:55:56,840 AVAILABLE IN AN EMERGENCY 7572 04:55:56,840 --> 04:55:58,520 DEPARTMENT RECORD, WE DID A 7573 04:55:58,520 --> 04:55:59,960 ONE-SITE CHART REVIEW, WE LOOKED 7574 04:55:59,960 --> 04:56:02,200 AT ABOUT 1200 VISITS, WE 7575 04:56:02,200 --> 04:56:04,320 DETERMINED ABOUT 25% OF THEM 7576 04:56:04,320 --> 04:56:07,520 WERE COMPLICATED, THE OTHER 75% 7577 04:56:07,520 --> 04:56:08,960 OR 902 VISITS WERE 7578 04:56:08,960 --> 04:56:09,280 UNCOMPLICATED. 7579 04:56:09,280 --> 04:56:11,600 THESE ARE THE PATIENTS THAT WE 7580 04:56:11,600 --> 04:56:13,240 THINK THAT THE SICKLE CELL 7581 04:56:13,240 --> 04:56:15,080 GUIDELINE WAS MEANT TO APPLY TO, 7582 04:56:15,080 --> 04:56:19,400 ABOUT 40% OF THOSE ENDED UP 7583 04:56:19,400 --> 04:56:20,640 HOSPITALIZED. 7584 04:56:20,640 --> 04:56:21,920 WHEN TRYING TO IDENTIFY THESE BY 7585 04:56:21,920 --> 04:56:23,600 THINGS ALREADY ESTABLISHED IN AN 7586 04:56:23,600 --> 04:56:24,800 EHR, IF YOU LACK AT RECEIPT OF 7587 04:56:24,800 --> 04:56:27,440 AT LEAST ONE OPIOID, A CLINICAL 7588 04:56:27,440 --> 04:56:29,640 IMPRESSION OR ICD-9 CODE OF 7589 04:56:29,640 --> 04:56:31,480 CRISIS AND THEN EXCLUDE PATIENTS 7590 04:56:31,480 --> 04:56:36,320 WITH ACUTE CHEST, PRIAPISM, 7591 04:56:36,320 --> 04:56:37,640 CONSTIPATION OR SPLENIC 7592 04:56:37,640 --> 04:56:38,520 SEQUESTRATION AND EXCLUDE 7593 04:56:38,520 --> 04:56:40,560 ANYBODY WITH A FEVER GREATER 7594 04:56:40,560 --> 04:56:42,440 THAN 38.5 IN THE EMERGENCY 7595 04:56:42,440 --> 04:56:44,040 DEPARTMENT, THE RESULTING 7596 04:56:44,040 --> 04:56:45,800 POPULATION, 92% OF THOSE HAVE AN 7597 04:56:45,800 --> 04:56:47,200 UNCOMPLICATED PAIN CRISIS. 7598 04:56:47,200 --> 04:56:48,880 WE FIGURED FOR THE POINT OF THIS 7599 04:56:48,880 --> 04:56:50,880 STUDY, IF WE WERE 92% ACCURATE, 7600 04:56:50,880 --> 04:56:52,600 WE WERE PROBABLY GOOD ENOUGH TO 7601 04:56:52,600 --> 04:56:54,400 SHOW IF WE WERE MAKING 7602 04:56:54,400 --> 04:56:55,800 SIGNIFICANT CHANGE. 7603 04:56:55,800 --> 04:56:57,680 SO THESE ARE THE SITES CURRENTLY 7604 04:56:57,680 --> 04:57:01,000 CONTRIBUTED TO THE PECARN 7605 04:57:01,000 --> 04:57:01,280 REGISTRY. 7606 04:57:01,280 --> 04:57:03,280 OUR STUDY TAKES PLACE AFTER 7607 04:57:03,280 --> 04:57:05,040 2016, BUT JUST FOR HISTORICAL 7608 04:57:05,040 --> 04:57:06,600 PURPOSE, THE CHILDREN'S HOSPITAL 7609 04:57:06,600 --> 04:57:12,520 OF COLORADO, CHILDREN'S -- OR 7610 04:57:12,520 --> 04:57:18,400 CH -- LATER LURIE CHILDREN'S 7611 04:57:18,400 --> 04:57:19,800 HOSPITAL OF CHICAGO, CHILDREN'S 7612 04:57:19,800 --> 04:57:22,880 HOSPITAL OF WISCONSIN -- THEY 7613 04:57:22,880 --> 04:57:25,320 VARY IN SIZE CONSIDERABLY WITH 7614 04:57:25,320 --> 04:57:26,240 CHILDREN'S HOSPITAL OF COLORADO 7615 04:57:26,240 --> 04:57:28,680 HAVING THE SMALLEST SICKLE CELL 7616 04:57:28,680 --> 04:57:30,120 POPULATION IN CHILDREN'S 7617 04:57:30,120 --> 04:57:31,360 NATIONAL MEDICAL CENTER OF THESE 7618 04:57:31,360 --> 04:57:32,640 HAVING THE LARGEST. 7619 04:57:32,640 --> 04:57:35,840 SO WE LOOKED AT 2016 TO 2018 7620 04:57:35,840 --> 04:57:38,960 BASE LANE DATA AS PART OF A 7621 04:57:38,960 --> 04:57:40,240 PRELIMINARY GRANT, AND WHAT 7622 04:57:40,240 --> 04:57:42,440 WE'VE FOUND WAS ACROSS THESE 7623 04:57:42,440 --> 04:57:43,760 SEVEN MAJOR CHILDREN'S 7624 04:57:43,760 --> 04:57:45,400 HOSPITALS, THE TIME TO FIRST 7625 04:57:45,400 --> 04:57:47,040 OPIOID IN LESS THAN 60 MINUTES 7626 04:57:47,040 --> 04:57:48,880 WAS 48%. 7627 04:57:48,880 --> 04:57:50,040 IT'S ACTUALLY BETTER THAN WE 7628 04:57:50,040 --> 04:57:50,280 THOUGHT. 7629 04:57:50,280 --> 04:57:53,760 THAT'S BASED ON 4,578 VISITS, 7630 04:57:53,760 --> 04:57:55,280 NOW THERE WAS A SIGNIFICANT 7631 04:57:55,280 --> 04:57:57,960 RANGE IN THERE. 7632 04:57:57,960 --> 04:58:00,120 WITH SOME SITES AS LOW AS 22% 7633 04:58:00,120 --> 04:58:01,920 GETTING THE FIRST OPIOID WITHIN 7634 04:58:01,920 --> 04:58:03,760 60 MINUTES AND ONE SITE AS HIGH 7635 04:58:03,760 --> 04:58:04,160 AS 70. 7636 04:58:04,160 --> 04:58:05,560 I WILL SHOW YOU SOME DATA WHEN 7637 04:58:05,560 --> 04:58:07,280 WE PULL THAT 70 OUT AND WHY THAT 7638 04:58:07,280 --> 04:58:10,360 70 IS A BIT OF AN OUTLIER. 7639 04:58:10,360 --> 04:58:11,720 WE THEN LOOKED AT TIME BETWEEN 7640 04:58:11,720 --> 04:58:13,240 FIRST AND SECOND OPIOID LESS 7641 04:58:13,240 --> 04:58:14,600 THAN 30 MINUTES, AND THAT WAS 7642 04:58:14,600 --> 04:58:14,800 15%. 7643 04:58:14,800 --> 04:58:19,640 THAT WAS BASED ON 3,538 OF THOSE 7644 04:58:19,640 --> 04:58:21,200 INITIAL 4500 VISITS WITH A 7645 04:58:21,200 --> 04:58:28,880 RAPINGA RANGEOF 2% TO 36%, A LIN 7646 04:58:28,880 --> 04:58:30,640 OUTLIER BASED ON SOME PRELIM 7647 04:58:30,640 --> 04:58:31,120 DATA. 7648 04:58:31,120 --> 04:58:33,640 SO THIS WAS DATA FROM ONE SITE. 7649 04:58:33,640 --> 04:58:34,640 THIS WAS THE CHILDREN'S HOSPITAL 7650 04:58:34,640 --> 04:58:35,080 OF WISCONSIN. 7651 04:58:35,080 --> 04:58:36,480 IT WAS THE FIRST SITE TO GET 7652 04:58:36,480 --> 04:58:39,120 SOME PRELIMINARY DATA AND SOME 7653 04:58:39,120 --> 04:58:42,840 PILOT FUNDING TO TRY TO IMPROVE 7654 04:58:42,840 --> 04:58:44,600 TIME TO OPIOID ADMINISTRATION. 7655 04:58:44,600 --> 04:58:47,360 SO YOU CAN SEE ALONG THE BOTTOM, 7656 04:58:47,360 --> 04:58:48,760 THAT INITIAL STUDY THAT WE JUST 7657 04:58:48,760 --> 04:58:53,560 SHOWED WITH THE 48 AND 15% WAS 7658 04:58:53,560 --> 04:58:57,120 2,016 TO 2018, YOU CAN SEE 7659 04:58:57,120 --> 04:58:59,720 CHILDREN'S WISCONSIN MADE SOME 7660 04:58:59,720 --> 04:59:00,720 SIGNIFICANT PROGRESS BETWEEN 7661 04:59:00,720 --> 04:59:05,200 2016 AND 2018. 7662 04:59:05,200 --> 04:59:06,400 AND BOTH TIME TO FIRST WHICH IS 7663 04:59:06,400 --> 04:59:10,720 THE KIND OF LIGHTER BLUE UP TOP 7664 04:59:10,720 --> 04:59:12,360 WHERE OVER THE COURSE OF THE 7665 04:59:12,360 --> 04:59:13,880 FOUR YEARS OF PRELIM DATA, 7666 04:59:13,880 --> 04:59:14,800 CHILDREN'S HOSPITAL OF WISCONSIN 7667 04:59:14,800 --> 04:59:18,120 WENT FROM ABOUT 45 TO 50% TO 7668 04:59:18,120 --> 04:59:19,840 JUST UNDER 90% GUIDELINE 7669 04:59:19,840 --> 04:59:20,440 ADHERENT. 7670 04:59:20,440 --> 04:59:21,800 AND THEN FOR TIME BETWEEN FIRST 7671 04:59:21,800 --> 04:59:24,040 AND SECOND, THE BLACK LINE 7672 04:59:24,040 --> 04:59:27,480 WITHIN 30 MINUTE OF THE FIRST, 7673 04:59:27,480 --> 04:59:29,000 CHILDREN'S HOSPITAL OF WISCONSIN 7674 04:59:29,000 --> 04:59:31,080 IMPROVED FROM 20% TO 40%. 7675 04:59:31,080 --> 04:59:32,880 SO THIS WAS SOME NICE PRELIM 7676 04:59:32,880 --> 04:59:33,720 DATA. 7677 04:59:33,720 --> 04:59:34,880 REALLY IMPORTANT BECAUSE THERE 7678 04:59:34,880 --> 04:59:37,520 IS NOW MULTIPLE STUDIES THAT 7679 04:59:37,520 --> 04:59:40,320 SHOW TIME TO FIRST WITHIN 60 7680 04:59:40,320 --> 04:59:41,760 MINUTES SIGNIFICANTLY REDUCES 7681 04:59:41,760 --> 04:59:44,360 PAIN SCORES. 7682 04:59:44,360 --> 04:59:46,360 TIME TO SECOND LESS THAN 30 7683 04:59:46,360 --> 04:59:49,960 MINUTES IS MORE ASSOCIATED WITH 7684 04:59:49,960 --> 04:59:50,760 DISPOSITION HOME. 7685 04:59:50,760 --> 04:59:51,760 SO ENOUGH IMPROVEMENT IN PAIN 7686 04:59:51,760 --> 04:59:53,160 THAT YOU MIGHT BE ABLE TO 7687 04:59:53,160 --> 04:59:54,520 DISCHARGE PATIENTS TO HOME. 7688 04:59:54,520 --> 04:59:57,600 SO IT'S NOT JUST GETTING THERE 7689 04:59:57,600 --> 04:59:59,400 TIMELY IS GOOD, GETTING THE 7690 04:59:59,400 --> 05:00:00,520 FIRST DOSE IS GOOD, IT'S THE 7691 05:00:00,520 --> 05:00:01,400 RIGHT THING TO DO. 7692 05:00:01,400 --> 05:00:02,800 BUT THERE IS SOME MOUNTING 7693 05:00:02,800 --> 05:00:03,960 EVIDENCE THAT THAT TIME BETWEEN 7694 05:00:03,960 --> 05:00:05,720 FIRST AND SECOND MIGHT ACTUALLY 7695 05:00:05,720 --> 05:00:07,600 SIGNIFICANTLY ALTER THE 7696 05:00:07,600 --> 05:00:08,800 DISPOSITION, STOP HAVING SO MANY 7697 05:00:08,800 --> 05:00:09,880 PATIENTS HAVING TO SPEND THE 7698 05:00:09,880 --> 05:00:12,600 NIGHT IN THE HOSPITAL, MORE 7699 05:00:12,600 --> 05:00:13,040 GOING HOME. 7700 05:00:13,040 --> 05:00:14,680 SO WE WERE A LITTLE WORRIED, 7701 05:00:14,680 --> 05:00:15,960 RIGHT, THIS IS JUST TRENDS OVER 7702 05:00:15,960 --> 05:00:17,520 TIME. 7703 05:00:17,520 --> 05:00:19,160 SO CERTAINLY MAYBE EVERYBODY WAS 7704 05:00:19,160 --> 05:00:20,080 IMPROVING OVER TIME. 7705 05:00:20,080 --> 05:00:21,640 IT WASN'T JUST THAT CHILDREN'S 7706 05:00:21,640 --> 05:00:23,280 OF WISCONSIN WAS DOING SOME 7707 05:00:23,280 --> 05:00:24,480 THINGS -- PART OF THE PILOT 7708 05:00:24,480 --> 05:00:26,040 STUDY, SO WE REMOVED THAT DATA 7709 05:00:26,040 --> 05:00:28,360 AND JUST LOOKED AT THE OTHER SIX 7710 05:00:28,360 --> 05:00:29,360 SITES. 7711 05:00:29,360 --> 05:00:34,240 THIS IS THE OTHER SIX SITES. 7712 05:00:34,240 --> 05:00:35,440 SO IN THE LAST TWO YEARS OF THE 7713 05:00:35,440 --> 05:00:36,720 STUDY, YOU CAN SEE REALLY NO 7714 05:00:36,720 --> 05:00:38,040 IMPROVEMENT IN TIME TO FIRST 7715 05:00:38,040 --> 05:00:39,960 OPIOID WITHIN AN HOUR, WITH 7716 05:00:39,960 --> 05:00:41,800 BARELY GETTING OVER 40% BY THE 7717 05:00:41,800 --> 05:00:45,400 END OF THE STUDY. 7718 05:00:45,400 --> 05:00:46,720 AND THE TIME BETWEEN FIRST AND 7719 05:00:46,720 --> 05:00:47,840 SECOND ALSO SHOWING NO 7720 05:00:47,840 --> 05:00:49,280 IMPROVEMENT AND INABILITY TO GET 7721 05:00:49,280 --> 05:00:49,720 OVER 20%. 7722 05:00:49,720 --> 05:00:51,840 THIS IS DESPITE A LOT OF 7723 05:00:51,840 --> 05:00:57,520 INFORMATION, A LOT OF PRESS, 7724 05:00:57,520 --> 05:00:59,280 ABOUT RACIAL UNCONSCIOUS BIAS, 7725 05:00:59,280 --> 05:01:00,960 THE GEORGE FLOYD STUFF WAS 7726 05:01:00,960 --> 05:01:01,200 HAPPENING. 7727 05:01:01,200 --> 05:01:03,400 WE REALLY THOUGHT THERE MIGHT BE 7728 05:01:03,400 --> 05:01:04,720 SOME UNDERLYING IMPROVEMENT THAT 7729 05:01:04,720 --> 05:01:06,240 WE JUST DID NOT SEE. 7730 05:01:06,240 --> 05:01:09,240 SO AGAIN, LED A WHOLE BUNCH OF 7731 05:01:09,240 --> 05:01:10,240 CREDIBILITY TO THAT WE REALLY 7732 05:01:10,240 --> 05:01:12,640 NEED A DEDICATED EFFORT IN ORDER 7733 05:01:12,640 --> 05:01:14,960 TO IMPROVE TIMELINESS OF OPIOID 7734 05:01:14,960 --> 05:01:15,920 ADMINISTRATION AND REALLY SHOW 7735 05:01:15,920 --> 05:01:19,720 THAT THESE NHLBI GUIDELINES 7736 05:01:19,720 --> 05:01:20,720 WOULD AFFECT CARE IN A 7737 05:01:20,720 --> 05:01:21,200 DEMONSTRABLE WAY. 7738 05:01:21,200 --> 05:01:23,120 SO THE AIMS FOR OUR NOW-FUNDED 7739 05:01:23,120 --> 05:01:24,480 STUDY ARE FOR THE TREATMENT OF 7740 05:01:24,480 --> 05:01:26,840 CHILDREN WITH ACUTE PAINFUL 7741 05:01:26,840 --> 05:01:28,400 VASOOCCLUSIVE CRISES IN THE 7742 05:01:28,400 --> 05:01:29,920 EMERGENCY DEPARTED, AGAIN, 7743 05:01:29,920 --> 05:01:30,840 UNCOMPLICATED PAIN CRISES, TO 7744 05:01:30,840 --> 05:01:32,480 COMPARE THE PRIMARY 7745 05:01:32,480 --> 05:01:34,000 IMPLEMENTATION OUTCOMES OF 7746 05:01:34,000 --> 05:01:37,000 REACH, ADOPTION, AND 7747 05:01:37,000 --> 05:01:37,400 IMPLEMENTATION. 7748 05:01:37,400 --> 05:01:38,320 WE'LL GO OVER THESE IN A LITTLE 7749 05:01:38,320 --> 05:01:39,240 BIT, BETWEEN THE INTERVENTION 7750 05:01:39,240 --> 05:01:40,200 AND THE CONTROL GROUPS. 7751 05:01:40,200 --> 05:01:42,960 AND THEN TO COMPARE THE PRIMARY 7752 05:01:42,960 --> 05:01:45,800 CLINICAL OUTCOMES OF 7753 05:01:45,800 --> 05:01:46,880 GUIDELINE-ADHERENT TIMELINESS, 7754 05:01:46,880 --> 05:01:47,680 HOSPITALIZATION RATES, PAIN 7755 05:01:47,680 --> 05:01:48,720 SCORES BETWEEN THE INTERVENTION 7756 05:01:48,720 --> 05:01:52,440 AND CONTROL GROUPS. 7757 05:01:52,440 --> 05:01:54,160 SO IN OUR PRELIMINARY WORK, WE 7758 05:01:54,160 --> 05:01:55,160 DID SOME QUALITATIVE ANALYSES 7759 05:01:55,160 --> 05:01:56,640 LOOKING AT KIND OF THE 7760 05:01:56,640 --> 05:01:58,520 COMPONENTS OF ED TREATMENT AND 7761 05:01:58,520 --> 05:02:00,360 HOW WE COULD REALLY BREAK THOSE 7762 05:02:00,360 --> 05:02:02,600 DOWN TO HELP SITES IMPROVE IN 7763 05:02:02,600 --> 05:02:05,000 OUR IMPLEMENTATION EFFECTIVENESS 7764 05:02:05,000 --> 05:02:05,200 TRIAL. 7765 05:02:05,200 --> 05:02:06,800 IF YOU LOOK AT THE TARGET 7766 05:02:06,800 --> 05:02:08,600 BEHAVIORS, WE REALLY BROKE THE 7767 05:02:08,600 --> 05:02:09,960 STEPS IN EMERGENCY DEPARTMENT 7768 05:02:09,960 --> 05:02:12,960 CARE DOWN INTO FOUR STEPS. 7769 05:02:12,960 --> 05:02:14,040 RAPID ROOM PLACEMENT, INITIAL 7770 05:02:14,040 --> 05:02:15,680 TREAT M OF PAIN, PAIN 7771 05:02:15,680 --> 05:02:18,240 RE-ASSESSMENT AND THEN RE-DOSING 7772 05:02:18,240 --> 05:02:19,440 OF PAIN MEDICATION. 7773 05:02:19,440 --> 05:02:21,080 YOU BREAK DOWN EACH ONE OF THOSE 7774 05:02:21,080 --> 05:02:23,440 INTOITY STEPS. 7775 05:02:23,440 --> 05:02:23,800 INTO ITS STEPS. 7776 05:02:23,800 --> 05:02:25,400 HOW DO YOU GET INTO A ROOM 7777 05:02:25,400 --> 05:02:27,880 QUICKLY, YOU GET ESI LEVEL 2 OR 7778 05:02:27,880 --> 05:02:28,720 THE SECOND HIGHEST LEVEL OF 7779 05:02:28,720 --> 05:02:30,960 TRIAGE CATEGORY AND THEN YOU GET 7780 05:02:30,960 --> 05:02:33,360 DIRECT BEDDED OR PLACED INTO A 7781 05:02:33,360 --> 05:02:34,560 BED IMMEDIATELY ON ARRIVAL. 7782 05:02:34,560 --> 05:02:36,880 HOW DO YOU START PAIN TREATMENT 7783 05:02:36,880 --> 05:02:37,200 QUICKLY? 7784 05:02:37,200 --> 05:02:38,320 FIRST YOU DON'T LET THE MED 7785 05:02:38,320 --> 05:02:39,880 STUDENT GO IN AND THEN PRESENT 7786 05:02:39,880 --> 05:02:42,400 TO A RESIDENT AND THEN PRESENT 7787 05:02:42,400 --> 05:02:43,480 TO AN ATTENDING BEFORE YOU 7788 05:02:43,480 --> 05:02:45,280 FINALLY GET A PAIN MEDICATION 7789 05:02:45,280 --> 05:02:45,760 ORDERED. 7790 05:02:45,760 --> 05:02:47,600 YOU HAVE A TARGETED ASSESSMENT, 7791 05:02:47,600 --> 05:02:49,240 RULE OUT OTHER SEVERE 7792 05:02:49,240 --> 05:02:50,360 COMPLICATIONS AND IMMEDIATELY 7793 05:02:50,360 --> 05:02:52,240 GET PAIN MEDICATION ORDERED. 7794 05:02:52,240 --> 05:02:55,280 THEN THERE'S INTRANASAL 7795 05:02:55,280 --> 05:02:56,480 FENTANYL, IV OPIOIDS WITH THE 7796 05:02:56,480 --> 05:02:59,280 INITIAL ORDER, IV PLACEMENT 7797 05:02:59,280 --> 05:03:01,320 IMMEDIATELY AFTER NASAL FENTANYL 7798 05:03:01,320 --> 05:03:03,120 AND AS YOU MOVE DOWN, 7799 05:03:03,120 --> 05:03:04,480 RE-ASSESSING OF PAIN, REDOING OF 7800 05:03:04,480 --> 05:03:05,680 PAIN MEDICATIONS AND THEN KIND 7801 05:03:05,680 --> 05:03:06,880 OF THIS CONTINUOUS PATTERN. 7802 05:03:06,880 --> 05:03:08,360 HOW DO YOU DO THIS? 7803 05:03:08,360 --> 05:03:09,560 WELL, YOU NEED EVERYBODY'S 7804 05:03:09,560 --> 05:03:11,600 BUY-IN, BOTH IN THE DEPARTMENT 7805 05:03:11,600 --> 05:03:12,200 AND OUT OF THE EMERGENCY 7806 05:03:12,200 --> 05:03:13,240 DEPARTMENT. 7807 05:03:13,240 --> 05:03:15,000 THIS HEAVILY RELIES ON NURSES, 7808 05:03:15,000 --> 05:03:17,840 IT RELIES ON PATIENT' FAMILIES 7809 05:03:17,840 --> 05:03:19,400 ADVOCATING FOR THEMSELVES. 7810 05:03:19,400 --> 05:03:22,480 IT RELIES ON ED NURSE, ED 7811 05:03:22,480 --> 05:03:24,040 PROVIDERS, ED PHARMACIST, THE 7812 05:03:24,040 --> 05:03:27,080 SICKLE CELL PROVIDER IN THE 7813 05:03:27,080 --> 05:03:28,200 CLINIC REMINDING PATIENTS THAT 7814 05:03:28,200 --> 05:03:31,720 THIS IS WHAT HAPPENS IN THE 7815 05:03:31,720 --> 05:03:33,560 EMERGENCY DEPARTMENT, NOT TO 7816 05:03:33,560 --> 05:03:34,920 REFUSE INTRANASAL FENTANYL, THAT 7817 05:03:34,920 --> 05:03:35,920 THIS IS PART OF THE SAME CARE 7818 05:03:35,920 --> 05:03:37,120 CONTINUUM THAT WE WOULD DELIVER 7819 05:03:37,120 --> 05:03:39,320 IN AN OUTPATIENT HEME CLINIC NOW 7820 05:03:39,320 --> 05:03:40,920 BEING DELIVERED IN THE EMERGENCY 7821 05:03:40,920 --> 05:03:42,880 DEPARTMENT, AND THEN YOU CAN SEE 7822 05:03:42,880 --> 05:03:45,840 THAT THAT SORT OF COMBINED 7823 05:03:45,840 --> 05:03:48,320 STAKEHOLDER BUY-IN IS NECESSARY 7824 05:03:48,320 --> 05:03:49,000 THROUGHOUT THE PROCESS. 7825 05:03:49,000 --> 05:03:51,240 SO WE USE THE RE-AIM 7826 05:03:51,240 --> 05:03:52,200 IMPLEMENTATION FRAMEWORK LOOKING 7827 05:03:52,200 --> 05:03:53,840 AT REACH, THE PERCENT OF PEOPLE 7828 05:03:53,840 --> 05:03:56,760 WHO GET THE DESIRED TREATMENT. 7829 05:03:56,760 --> 05:03:58,240 EFFECTIVENESS IS REALLY THE 7830 05:03:58,240 --> 05:04:01,640 CLINICAL OUTCOMES, ADOPTION WAS 7831 05:04:01,640 --> 05:04:02,600 SOMEBODY ACTUALLY WILLING TO SAY 7832 05:04:02,600 --> 05:04:05,200 THEY WERE GOING TO DO THINGS, 7833 05:04:05,200 --> 05:04:05,880 IMPLEMENTATION, WHICH COMPONENTS 7834 05:04:05,880 --> 05:04:07,280 OF THIS PATHWAY DID THEY DO, AND 7835 05:04:07,280 --> 05:04:08,480 THEN MAINTENANCE, AFTER WE MADE 7836 05:04:08,480 --> 05:04:09,840 THE SWITCH, WERE WE ABLE TO 7837 05:04:09,840 --> 05:04:14,560 MAINTAIN THE IMPROVEMENT. 7838 05:04:14,560 --> 05:04:16,200 SO FOR OUR IMPLEMENTATIONS, WE 7839 05:04:16,200 --> 05:04:17,160 HAD LOCAL CHAMPIONS. 7840 05:04:17,160 --> 05:04:19,240 WE HAD AN ED AND HEMATOLOGY 7841 05:04:19,240 --> 05:04:20,880 PROVIDER AT EACH SITE FUNDED. 7842 05:04:20,880 --> 05:04:23,200 WE GAVE EACH SITE A REPORT CARD 7843 05:04:23,200 --> 05:04:24,640 ONCE THEY ENTERED THE TRANSITION 7844 05:04:24,640 --> 05:04:25,080 PHASE. 7845 05:04:25,080 --> 05:04:26,520 THEY THEN WERE ABLE TO USE ALL 7846 05:04:26,520 --> 05:04:31,040 OF THESE IMPLEMENTATION STEPS TO 7847 05:04:31,040 --> 05:04:32,360 TAILOR WHAT WOULD WORK AT THEIR 7848 05:04:32,360 --> 05:04:33,120 SITE. 7849 05:04:33,120 --> 05:04:35,440 THEY CONDUCTED MULTIDISCIPLINARY 7850 05:04:35,440 --> 05:04:39,120 WORKSHOPS, CHANGE, EPIC, 7851 05:04:39,120 --> 05:04:41,920 WHATEVER EHR THEY HAD TO 7852 05:04:41,920 --> 05:04:45,960 FACILITATE THESE THINGS, AND 7853 05:04:45,960 --> 05:04:47,120 REALLY FACILITATE PATIENT 7854 05:04:47,120 --> 05:04:48,120 CAREGIVERS AND HEMATOLOGISTS IN 7855 05:04:48,120 --> 05:04:48,560 THE PROCESS. 7856 05:04:48,560 --> 05:04:51,120 SO WE DID A FAIRLY STANDARD STEP 7857 05:04:51,120 --> 05:04:51,440 WEDGED DESIGN. 7858 05:04:51,440 --> 05:04:52,560 IF YOU'RE NOT FAMILIAR WITH A 7859 05:04:52,560 --> 05:04:54,400 STEP WEDGE DESIGN, YOU HAVE 7860 05:04:54,400 --> 05:04:57,280 SITES THAT TRANSITION SOCIETY 7861 05:04:57,280 --> 05:04:58,840 ONE TRANSITIONS IN QUARTER THREE 7862 05:04:58,840 --> 05:05:00,280 OF YEAR ONE. 7863 05:05:00,280 --> 05:05:02,120 THEY THEN STARTED THE CARE 7864 05:05:02,120 --> 05:05:03,480 PATHWAY OR IMPLEMENTATION PHASE 7865 05:05:03,480 --> 05:05:04,960 AND WHAT THAT ALLOWS IS ALL THE 7866 05:05:04,960 --> 05:05:08,120 OTHER SITES TO ACT AS STANDARD 7867 05:05:08,120 --> 05:05:10,080 SAN FRANCISCO CARE OR REALTIME 7868 05:05:10,080 --> 05:05:11,080 CONTROLS. 7869 05:05:11,080 --> 05:05:13,960 AS YOU STEP OTHER SITES, THE 7870 05:05:13,960 --> 05:05:16,240 OTHER SITES REMAIN AS REALTIME 7871 05:05:16,240 --> 05:05:18,200 CONTROL SO YOU GET AN EVALUATION 7872 05:05:18,200 --> 05:05:19,200 OF SITES PRE AND POST 7873 05:05:19,200 --> 05:05:25,000 TRANSITION, AND THEN TRANSITION 7874 05:05:25,000 --> 05:05:27,720 COMPARED TO NOT YET TRANSITION 7875 05:05:27,720 --> 05:05:28,920 AND -- ALREADY IMPROVED CARE. 7876 05:05:28,920 --> 05:05:30,520 SO THESE ARE THE STEPS IN OUR 7877 05:05:30,520 --> 05:05:31,720 IMPLEMENTATION OUTCOMES THAT WE 7878 05:05:31,720 --> 05:05:33,640 SHOW ALL THE SITES ONCE THEY 7879 05:05:33,640 --> 05:05:34,080 HAVE TRANSITIONED. 7880 05:05:34,080 --> 05:05:36,280 WE GIVE THEM REPORTS ON THEIR 7881 05:05:36,280 --> 05:05:39,400 DIRECT BEDDING, THE NUMBER THAT 7882 05:05:39,400 --> 05:05:40,760 ARE DIRECTORIAGE LEVEL 2, 7883 05:05:40,760 --> 05:05:42,680 WHETHER THEY HAVE A RAP PID 7884 05:05:42,680 --> 05:05:45,000 TARGETED ASSESSMENT BY PROVIDER 7885 05:05:45,000 --> 05:05:45,840 PRIOR TO INITIAL. 7886 05:05:45,840 --> 05:05:47,280 YOU CAN SEE UNDER THE REACH OUT 7887 05:05:47,280 --> 05:05:50,440 KS COUTCOME FOR THAT ONE, THAT'S 7888 05:05:50,440 --> 05:05:51,920 DEFINED FROM OUR ELECTRONIC 7889 05:05:51,920 --> 05:05:52,800 HEALTH RECORD FROM THE FIRST 7890 05:05:52,800 --> 05:05:54,200 TIME A PROVIDER SIGNS UP TO SEE 7891 05:05:54,200 --> 05:05:55,560 THE PATIENT TO THE FIRST OPIOID 7892 05:05:55,560 --> 05:05:55,960 ORDER. 7893 05:05:55,960 --> 05:05:57,000 IF THAT TAKES MORE THAN 15 7894 05:05:57,000 --> 05:05:59,000 MINUTES, THEY ARE NOT DOING A 7895 05:05:59,000 --> 05:06:00,840 RAPID ASSESSMENT FOLLOWING BY 7896 05:06:00,840 --> 05:06:02,200 ORDERING OF IV PAIN MEDICATION, 7897 05:06:02,200 --> 05:06:04,640 SO WE GIVE THEM FEEDBACK ON 7898 05:06:04,640 --> 05:06:05,080 THAT. 7899 05:06:05,080 --> 05:06:07,840 ORDER SETS FOR PAIN, WHETHER A 7900 05:06:07,840 --> 05:06:09,320 LAB ORDER AND AN OPIOID ORDER 7901 05:06:09,320 --> 05:06:11,000 ARE ORDERED WITHIN ONE MINUTE OF 7902 05:06:11,000 --> 05:06:12,360 EACH OTHER, USUALLY THAT MEANS 7903 05:06:12,360 --> 05:06:14,240 THEY'RE PART OF AN ORDER SET. 7904 05:06:14,240 --> 05:06:16,480 MOST PEOPLE DON'T GO IN AND 7905 05:06:16,480 --> 05:06:19,440 INDIVIDUALLY ORDER THINGS BUT 7906 05:06:19,440 --> 05:06:20,440 REPEATEDLY WITHIN ONE MINUTE, 7907 05:06:20,440 --> 05:06:24,480 AND THEN USE OF INTRANASAL 7908 05:06:24,480 --> 05:06:26,040 FENTANYL. 7909 05:06:26,040 --> 05:06:27,760 SO THE TIME BETWEEN SUBSEQUENT 7910 05:06:27,760 --> 05:06:29,080 OPIOID, AND THEN THE OUTCOMES 7911 05:06:29,080 --> 05:06:31,880 THAT MAY MATTER MORE TO PATIENT' 7912 05:06:31,880 --> 05:06:33,200 DISPOSITION, DID IT AFFECT THEIR 7913 05:06:33,200 --> 05:06:36,040 PAIN SCORES, MAYBE PROVIDERS, 7914 05:06:36,040 --> 05:06:37,840 DID IT AFFECT THE ED LENGTH OF 7915 05:06:37,840 --> 05:06:39,480 STAY, AND THEN SOME ADVERSE 7916 05:06:39,480 --> 05:06:40,840 OUTCOMES, IF WE SEND PEOPLE HOME 7917 05:06:40,840 --> 05:06:42,440 AND THEY ALL BOUNCE BACK, THAT'S 7918 05:06:42,440 --> 05:06:44,880 NOT NECESSARILY IDEAL, AND THEN 7919 05:06:44,880 --> 05:06:47,040 ADVERSE EVENT, WHAT PERCENT 7920 05:06:47,040 --> 05:06:48,680 NEEDED NALOXONE OR SUPPLEMENTAL 7921 05:06:48,680 --> 05:06:49,640 OXYGEN IF THERE'S A CONCERN THAT 7922 05:06:49,640 --> 05:06:52,360 YOU'RE ACTUALLY FIFING GIVING 7923 05:06:52,360 --> 05:06:53,440 MEDICATION SO FAST THAT MAYBE 7924 05:06:53,440 --> 05:06:54,640 YOU'RE SEDATING THEM AND THEY 7925 05:06:54,640 --> 05:06:56,920 HAVE SOME ADVERSE EVENT. 7926 05:06:56,920 --> 05:06:57,280 S. 7927 05:06:57,280 --> 05:06:59,520 SO THIS IS A SAMPLE REPORT CARD 7928 05:06:59,520 --> 05:06:59,960 FOR ONE SITE. 7929 05:06:59,960 --> 05:07:01,280 YOU CAN SEE WE JUST GIVE THEM 7930 05:07:01,280 --> 05:07:03,200 ALL OF THOSE NUMBERS, COMPARE TO 7931 05:07:03,200 --> 05:07:04,080 THE THREE MONTHS BEFORE, AND 7932 05:07:04,080 --> 05:07:06,520 THEN WE HAVE DATA FOR AS MANY 7933 05:07:06,520 --> 05:07:08,560 MONTHS AS THEY ARE IN THE STUDY. 7934 05:07:08,560 --> 05:07:09,960 SO HERE'S SOME DATA THAT YOU CAN 7935 05:07:09,960 --> 05:07:10,200 SEE. 7936 05:07:10,200 --> 05:07:12,240 SO THE FIRST SITE TO TRANSITION 7937 05:07:12,240 --> 05:07:15,320 IS THE FIRST, YOU CAN SEE THEIR 7938 05:07:15,320 --> 05:07:15,760 NUMBERS. 7939 05:07:15,760 --> 05:07:17,960 THE GREEN LINE WITH THE 7940 05:07:17,960 --> 05:07:19,000 TRIANGLES IS ALL THE SITES NOW 7941 05:07:19,000 --> 05:07:20,880 ON THE CARE PATHWAY, AND THE 7942 05:07:20,880 --> 05:07:23,840 GREEN LINE WITH THE CIRCLES ARE 7943 05:07:23,840 --> 05:07:25,240 ALL SITES THAT HAVE YET TO 7944 05:07:25,240 --> 05:07:25,680 TRANSITION. 7945 05:07:25,680 --> 05:07:27,920 SO THIS IS STILL ALL BLINDED, 7946 05:07:27,920 --> 05:07:30,360 THE DSMV IS AWARE -- BLINDED TO 7947 05:07:30,360 --> 05:07:31,120 THE SITES. 7948 05:07:31,120 --> 05:07:32,600 ONCE YOU TRANSITION, YOU GET TO 7949 05:07:32,600 --> 05:07:35,560 SEE ALL THIS. 7950 05:07:35,560 --> 05:07:37,560 SO THROUGH JUNE OF 2023, WE ARE 7951 05:07:37,560 --> 05:07:39,560 ONLY, AS I SHOWED YOU, YEAR TWO 7952 05:07:39,560 --> 05:07:41,320 OF THE STUDY. 7953 05:07:41,320 --> 05:07:42,760 USING OUR METHODS, WE HAVE 7954 05:07:42,760 --> 05:07:46,200 ALREADY ENROLLED 2,652 CHILDREN 7955 05:07:46,200 --> 05:07:46,520 IN THIS. 7956 05:07:46,520 --> 05:07:48,840 AND THIS IS THEIR TIMELINESS TO 7957 05:07:48,840 --> 05:07:49,360 DATE. 7958 05:07:49,360 --> 05:07:51,000 SOME EVIDENCE THAT MAYBE THINGS 7959 05:07:51,000 --> 05:07:52,320 ARE HELPFUL, BUT AGAIN, WE 7960 05:07:52,320 --> 05:07:54,600 HAVEN'T LOOKED AT MAINTENANCE, 7961 05:07:54,600 --> 05:07:56,000 WE HAVEN'T DONE ENOUGH ANALYSIS 7962 05:07:56,000 --> 05:07:58,960 OR HAD ENOUGH TIME. 7963 05:07:58,960 --> 05:08:01,120 OF TO LOOK AT ALL THE DATA TO 7964 05:08:01,120 --> 05:08:01,960 DEFINITIVELY SAY WHERE THESE 7965 05:08:01,960 --> 05:08:04,520 THINGS ARE GOING. 7966 05:08:04,520 --> 05:08:06,200 SO WE HAVE HAD A LOT OF SUCCESS 7967 05:08:06,200 --> 05:08:06,760 SO FAR TO DATE. 7968 05:08:06,760 --> 05:08:08,320 A LOT OF ENTHUSIASM FROM THE 7969 05:08:08,320 --> 05:08:10,160 LOCAL CHAMPIONS. 7970 05:08:10,160 --> 05:08:11,440 AGAIN, LET ME GO BACK AND SHOW 7971 05:08:11,440 --> 05:08:13,520 THAT DESPITE THE ENTHUSIASM, 7972 05:08:13,520 --> 05:08:15,280 DESPITE PEOPLE'S WILLINGNESS, 7973 05:08:15,280 --> 05:08:17,320 WE'RE STILL HAVING REALLY NO 7974 05:08:17,320 --> 05:08:18,440 IMPROVEMENT IN THE SITES THAT 7975 05:08:18,440 --> 05:08:19,400 HAVEN'T TRANSITIONED. 7976 05:08:19,400 --> 05:08:20,680 THERE'S A LOT OF THINGS GOING ON 7977 05:08:20,680 --> 05:08:22,120 IN THE WORLD AND WE ARE SEEING 7978 05:08:22,120 --> 05:08:25,400 ZERO CHANGE. 7979 05:08:25,400 --> 05:08:26,000 CHANGE IN THE EMERGENCY 7980 05:08:26,000 --> 05:08:27,480 DEPARTMENT IS HARD, ALL OF YOU 7981 05:08:27,480 --> 05:08:28,680 WHO TAKE CARE OF PATIENTS WITH 7982 05:08:28,680 --> 05:08:30,920 SICKLE CELL KNOW SOME OF THE 7983 05:08:30,920 --> 05:08:32,920 MOST FRUSTRATING TAIMS ARE WITH 7984 05:08:32,920 --> 05:08:33,880 THEY GO TO THE EMERGENCY 7985 05:08:33,880 --> 05:08:35,600 DEPARTMENT BUT WE ARE NOT SEEING 7986 05:08:35,600 --> 05:08:36,560 SIGNIFICANT IMPROVEMENT IN OUR 7987 05:08:36,560 --> 05:08:36,920 BASELINE GROUP. 7988 05:08:36,920 --> 05:08:38,160 BAD FOR THE PATIENTS, I GUESS, 7989 05:08:38,160 --> 05:08:40,600 GOOD FOR THE STUDY DESIGN. 7990 05:08:40,600 --> 05:08:42,360 SO OUR LOCAL CHAMPIONS HAVE BEEN 7991 05:08:42,360 --> 05:08:43,680 VERY ENGAGED. 7992 05:08:43,680 --> 05:08:45,200 OUR DSMV AND OTHER SICKLE CELL 7993 05:08:45,200 --> 05:08:47,680 EXPERTS HAVE BEEN EXTREMELY 7994 05:08:47,680 --> 05:08:48,440 HELPFUL. 7995 05:08:48,440 --> 05:08:53,160 WE DID FIND ONE SITE HAD A HIGH 7996 05:08:53,160 --> 05:08:54,600 NALOXONE RATE WHICH WHEN WE 7997 05:08:54,600 --> 05:08:56,000 FURTHER INVESTIGATED WAS ALL DUE 7998 05:08:56,000 --> 05:08:57,400 TO ITCHING, SO WE'VE BEEN ABLE 7999 05:08:57,400 --> 05:08:58,840 TO SEPARATE THAT OUT, HAD 8000 05:08:58,840 --> 05:09:03,160 NOTHING TO DO WITH UR OH OUR 8001 05:09:03,160 --> 05:09:03,800 TRANSITION PHASE. 8002 05:09:03,800 --> 05:09:04,800 THINGS WE'VE LEARNED ALREADY. 8003 05:09:04,800 --> 05:09:06,720 IF YOU GO BACK TO OUR STEP 8004 05:09:06,720 --> 05:09:09,800 WEDGE, WE ALLOWED A THREE-MONTH 8005 05:09:09,800 --> 05:09:11,240 TRAN CIRCLES WHICH WAS NICE 8006 05:09:11,240 --> 05:09:12,120 BECAUSE I THINK WE KIND OF 8007 05:09:12,120 --> 05:09:13,000 THOUGHT PEOPLE WOULD BE ALL 8008 05:09:13,000 --> 05:09:13,960 GEARED UP TO GO. 8009 05:09:13,960 --> 05:09:16,000 THAT IS CLEARLY TOO SHORT A 8010 05:09:16,000 --> 05:09:16,680 TRANSITION TIME TO IMPLEMENT ALL 8011 05:09:16,680 --> 05:09:17,800 THE THINGS WE NEED TO DO. 8012 05:09:17,800 --> 05:09:19,520 IT'S A MINIMUM OF SIX MONTHS, 8013 05:09:19,520 --> 05:09:20,680 PROBABLY NINE, AND WE'VE ALREADY 8014 05:09:20,680 --> 05:09:22,160 TALKED TO THE DATA COORDINATING 8015 05:09:22,160 --> 05:09:23,880 CENTER AT THE UNIVERSITY OF 8016 05:09:23,880 --> 05:09:26,520 UTAH. 8017 05:09:26,520 --> 05:09:27,800 THE PARTNERSHIP BETWEEN THE HEME 8018 05:09:27,800 --> 05:09:30,440 AND ED TEAMS ARE VITAL, AND THAT 8019 05:09:30,440 --> 05:09:32,480 MEANS THAT A LOT OF EDUCATION IN 8020 05:09:32,480 --> 05:09:34,320 THE HEMATOLOGY CLINIC BECAUSE 8021 05:09:34,320 --> 05:09:38,480 IT'S A LOT EASIER FOR PATIENTS 8022 05:09:38,480 --> 05:09:41,680 TO TAKE INTRANASAL FENTANYL IF 8023 05:09:41,680 --> 05:09:42,160 THEY'VE PREPPED THEM. 8024 05:09:42,160 --> 05:09:43,600 WE HAVE QR CODES AND PICTURES 8025 05:09:43,600 --> 05:09:44,800 THAT WE GIVE FAMILIES. 8026 05:09:44,800 --> 05:09:48,560 THE TRIPLEDEMIC, IF YOU REMEMBER 8027 05:09:48,560 --> 05:09:49,480 THAT THE NATIONAL PRESS WAS 8028 05:09:49,480 --> 05:09:54,800 COVERED WITH THE FACT THAT RSV, 8029 05:09:54,800 --> 05:09:56,240 FLU AND -- IS BAD FOR 8030 05:09:56,240 --> 05:09:57,360 EVERYBODY'S CARE ALTHOUGH I WILL 8031 05:09:57,360 --> 05:09:59,000 SAY THE TIMELINESS WAS 8032 05:09:59,000 --> 05:10:00,120 MAINTAINED IN THOSE SITES THAT 8033 05:10:00,120 --> 05:10:01,240 ALREADY TRANSITIONED, AND THEN 8034 05:10:01,240 --> 05:10:04,520 LOOKING AT REALLY IS ANY -- IS 8035 05:10:04,520 --> 05:10:06,720 THERE SOME SIGNAL HAVING A 8036 05:10:06,720 --> 05:10:08,280 DIVISION CHIEF OR SECTION LEADER 8037 05:10:08,280 --> 05:10:10,440 OR QUALITY CHAMPION ALREADY IN 8038 05:10:10,440 --> 05:10:13,160 THAT ROLE MIGHT BE MORE HELPFUL. 8039 05:10:13,160 --> 05:10:15,560 BUT THAT'S WHERE WE ARE IN THE 8040 05:10:15,560 --> 05:10:16,000 STUDY. 8041 05:10:16,000 --> 05:10:17,520 WE'RE ABOUT HALFWAY DONE. 8042 05:10:17,520 --> 05:10:18,640 WE'VE TRANSITIONED JUST OVER 8043 05:10:18,640 --> 05:10:20,760 HALF THE SITE WITH THE NEXT ONE 8044 05:10:20,760 --> 05:10:22,360 TRANSITION BUT WE ARE VERY 8045 05:10:22,360 --> 05:10:23,680 ENTHUSIASTIC ABOUT SOME OF THE 8046 05:10:23,680 --> 05:10:25,200 EARLY RESULTS AND HOPEFUL THAT 8047 05:10:25,200 --> 05:10:26,200 WE CAN MAKE A DIFFERENCE IN THE 8048 05:10:26,200 --> 05:10:27,760 LIVES OF CHILDREN WITH SICKLE 8049 05:10:27,760 --> 05:10:28,160 CELL DISEASE. 8050 05:10:28,160 --> 05:10:33,960 THANK YOU. 8051 05:10:33,960 --> 05:10:36,040 >>THANK YOU, DAVID. 8052 05:10:36,040 --> 05:10:36,280 QUESTIONS. 8053 05:10:36,280 --> 05:10:37,640 ARE THERE ANY QUESTIONS ONLINE? 8054 05:10:37,640 --> 05:10:37,960 >>YES. 8055 05:10:37,960 --> 05:10:41,240 >>OKAY. 8056 05:10:41,240 --> 05:10:41,680 >>HI. 8057 05:10:41,680 --> 05:10:44,200 SO THE QUESTION I HAVE IS, IN 8058 05:10:44,200 --> 05:10:51,000 TERMS OF TO THE -- GIVING PAIN 8059 05:10:51,000 --> 05:10:52,400 OPIOIDS WITHIN 60 MINUTES, I 8060 05:10:52,400 --> 05:10:54,280 THINK IT ALSO -- COMING FROM THE 8061 05:10:54,280 --> 05:10:57,640 ADULT POPULATION, IT ALSO 8062 05:10:57,640 --> 05:10:58,840 DEPENDS ON HOW MUCH THEY'RE 8063 05:10:58,840 --> 05:10:59,400 GIVING. 8064 05:10:59,400 --> 05:11:03,360 SO FOR THE ADULTS, THEIR 8065 05:11:03,360 --> 05:11:05,080 COMPLAINT IS THAT THEY KNOW WHAT 8066 05:11:05,080 --> 05:11:06,840 NORMALLY WORKS, BUT YET THEY'RE 8067 05:11:06,840 --> 05:11:09,640 GETTING ABOUT 25%, A QUARTER OF 8068 05:11:09,640 --> 05:11:11,960 WHAT NORMALLY WORKS. 8069 05:11:11,960 --> 05:11:15,320 SO IS THAT STILL PART OF YOUR 8070 05:11:15,320 --> 05:11:15,600 PROTOCOL? 8071 05:11:15,600 --> 05:11:17,640 IS THAT SOMETHING YOU STILL 8072 05:11:17,640 --> 05:11:21,040 ADVISE, OR YOU'RE WANTING THE 8073 05:11:21,040 --> 05:11:25,080 PATIENTS TO RECEIVE WHAT THEY 8074 05:11:25,080 --> 05:11:26,160 SHOULD RECEIVE, WHAT NORMALLY 8075 05:11:26,160 --> 05:11:27,880 WORKS FOR THEM, IN ORDER TO BE 8076 05:11:27,880 --> 05:11:28,160 EFFECTIVE? 8077 05:11:28,160 --> 05:11:31,480 >>YEAH, SO THE QUESTION IS A 8078 05:11:31,480 --> 05:11:34,400 LITTLE BIT INDIVIDUALIZED PAIN 8079 05:11:34,400 --> 05:11:35,080 PLANS. 8080 05:11:35,080 --> 05:11:37,160 WE ALLOW SITES TO USE INDIVIDUAL 8081 05:11:37,160 --> 05:11:38,840 PAIN PLANS, WHATEVER THEY ARE 8082 05:11:38,840 --> 05:11:41,000 ALREADY DOING AT THEIR SITE, WE 8083 05:11:41,000 --> 05:11:41,840 ARE NOT CHANGING. 8084 05:11:41,840 --> 05:11:43,240 WE WILL SAY IT WAS VERY CLEAR 8085 05:11:43,240 --> 05:11:44,520 FROM THE QUALITATIVE WORK AND 8086 05:11:44,520 --> 05:11:46,480 FROM THE WORK WE'RE DOING NOW 8087 05:11:46,480 --> 05:11:49,120 THAT SITES THAT USE 8088 05:11:49,120 --> 05:11:50,120 INDIVIDUALIZED PAIN PLANS, EVEN 8089 05:11:50,120 --> 05:11:52,600 IF IT'S THE RIGHT DOSE, GET 8090 05:11:52,600 --> 05:11:54,520 DRAMATICALLY SLOWER CARE IN THE 8091 05:11:54,520 --> 05:11:55,480 EMERGENCY DEPARTMENT BECAUSE YOU 8092 05:11:55,480 --> 05:11:56,760 CAN'T AUTO-POPULATE THAT. 8093 05:11:56,760 --> 05:11:58,520 IT TAKES TIME TO LOOK IT UP. 8094 05:11:58,520 --> 05:12:00,360 WHAT WE HAVE TALKED WITH THOSE 8095 05:12:00,360 --> 05:12:03,640 SITES IS, ARE THEY WILLING TO 8096 05:12:03,640 --> 05:12:05,520 LET AN INITIAL WEIGHT-BASED DOSE 8097 05:12:05,520 --> 05:12:07,360 GO, THEN WE GET THE INITIAL PAIN 8098 05:12:07,360 --> 05:12:08,640 MEDICATION IN, AND THEN YOU HAVE 8099 05:12:08,640 --> 05:12:11,680 TIME TO LOOK UP THE 8100 05:12:11,680 --> 05:12:12,680 INDIVIDUALIZED DOSE. 8101 05:12:12,680 --> 05:12:14,560 SO AGAIN, SOME OF THE 8102 05:12:14,560 --> 05:12:15,520 HEMATOLOGISTS ARE MORE 8103 05:12:15,520 --> 05:12:16,280 COMFORTABLE WITH THAT THAN 8104 05:12:16,280 --> 05:12:17,040 OTHERS. 8105 05:12:17,040 --> 05:12:17,920 WE'RE JUST TRYING TO GET THAT 8106 05:12:17,920 --> 05:12:18,960 FIRST DOSE IN AND THEN THE 8107 05:12:18,960 --> 05:12:19,560 SECOND. 8108 05:12:19,560 --> 05:12:21,680 BUT AGAIN, IF SITES WANT 8109 05:12:21,680 --> 05:12:24,520 INDIVIDUALIZED PAP PAIN PLANS OR 8110 05:12:24,520 --> 05:12:26,200 THAN WEIGHT BASED, EVERYTHING IN 8111 05:12:26,200 --> 05:12:28,320 PEDIATRIC IS WEIGHT-BASED, WE 8112 05:12:28,320 --> 05:12:29,920 ARE CERTAINLY WILLING TO LET 8113 05:12:29,920 --> 05:12:31,480 THEM USE INDIVIDUALIZED DOSING. 8114 05:12:31,480 --> 05:12:34,440 >>SO ON THE DOSES QUESTION, WE 8115 05:12:34,440 --> 05:12:35,960 HAVE A BUNCH OF QUESTIONS IN THE 8116 05:12:35,960 --> 05:12:37,360 CHAT. 8117 05:12:37,360 --> 05:12:40,080 THE FIRST ONE IS, WHAT IS THE 8118 05:12:40,080 --> 05:12:42,360 MORPHINE AND FENTANYL DOSAGE 8119 05:12:42,360 --> 05:12:46,960 THAT YOU USE IN YOUR PED AND MAX 8120 05:12:46,960 --> 05:12:47,200 DOSAGE? 8121 05:12:47,200 --> 05:12:53,200 >>SO AGAIN WE'RE NOT MANDATING 8122 05:12:53,200 --> 05:12:54,440 A CERTAIN DOSE. 8123 05:12:54,440 --> 05:12:56,680 WHAT MOST PEOPLE USE OF 8124 05:12:56,680 --> 05:12:59,480 INTRANASAL FENTANYL -- WHAT MOST 8125 05:12:59,480 --> 05:13:02,320 PEOPLE USE FOR MORPHINE IS 8126 05:13:02,320 --> 05:13:05,440 .1 PER KILO OF IV MORPHINE, MAX 8127 05:13:05,440 --> 05:13:06,360 OF 6 OR 8. 8128 05:13:06,360 --> 05:13:07,400 SOME PEOPLE KEEP THAT SECOND 8129 05:13:07,400 --> 05:13:08,840 DOSE THE SAME. 8130 05:13:08,840 --> 05:13:10,560 SOME SITES CUT IT IN HALF. 8131 05:13:10,560 --> 05:13:14,280 AGAIN, WE WERE NOT TRYING TO 8132 05:13:14,280 --> 05:13:15,280 NECESSARILY CHANGE THAT PROCESS. 8133 05:13:15,280 --> 05:13:16,960 WE HAVE SHARED WHAT ALL THE 8134 05:13:16,960 --> 05:13:18,400 SITES DO AMONG THE SITES BUT 8135 05:13:18,400 --> 05:13:21,920 HAVE NOT MANDATED THAT THEY 8136 05:13:21,920 --> 05:13:22,360 CHANGE. 8137 05:13:22,360 --> 05:13:25,320 THE NHLBI GUIDELINES DON'T 8138 05:13:25,320 --> 05:13:26,200 RECOMMEND THAT DECREASE IN DOSE 8139 05:13:26,200 --> 05:13:27,960 BUT IF A SITE IS COMFORTABLE 8140 05:13:27,960 --> 05:13:30,560 DOING THAT, THAT'S A BIGGER 8141 05:13:30,560 --> 05:13:32,000 HURDLE TO CLIMB THAN ACTUALLY 8142 05:13:32,000 --> 05:13:37,560 GIVE THEM TIMELY MEDICATION. 8143 05:13:37,560 --> 05:13:40,640 >>HI, DAVID. 8144 05:13:40,640 --> 05:13:44,320 MONICA HULBERT, ST. LOUIS. 8145 05:13:44,320 --> 05:13:47,040 THIS IS SUCH A PERSISTENT AND 8146 05:13:47,040 --> 05:13:48,160 COMMON PROBLEM AMONGST ALL OUR 8147 05:13:48,160 --> 05:13:48,600 CENTERS. 8148 05:13:48,600 --> 05:13:50,520 I THINK ONE OF THE THINGS THAT I 8149 05:13:50,520 --> 05:13:52,400 FIND MOST FRUSTRATING IS THAT 8150 05:13:52,400 --> 05:13:53,880 THESE INTERVENTIONS OFTENTIMES 8151 05:13:53,880 --> 05:13:55,320 LOOK REALLY GOOD WHEN THERE'S 8152 05:13:55,320 --> 05:13:57,200 FUNDING TO SUPPORT THE 8153 05:13:57,200 --> 05:13:58,400 INTERVENTION, BUT AS YOU KNOW, 8154 05:13:58,400 --> 05:13:59,920 LIKE OUR -- THE MEDICAL STAFF, 8155 05:13:59,920 --> 05:14:02,200 LIKE THE NURSING STAFF TURNS 8156 05:14:02,200 --> 05:14:04,080 OVER, YOU KNOW, ATTENDING 8157 05:14:04,080 --> 05:14:06,120 PHYSICIANS COME AND GO AND WE 8158 05:14:06,120 --> 05:14:08,880 HAVE LITERALLY NEW TRAINEES IN 8159 05:14:08,880 --> 05:14:09,520 THE EMERGENCY DEPARTMENT EVERY 8160 05:14:09,520 --> 05:14:10,120 SINGLE MONTH. 8161 05:14:10,120 --> 05:14:11,400 SO MAINTAINING THIS KIND OF 8162 05:14:11,400 --> 05:14:13,800 EFFORT OVER THE LONG TERM SEEMS 8163 05:14:13,800 --> 05:14:15,560 EVEN MORE DIFFICULT THAN 8164 05:14:15,560 --> 05:14:16,360 STARTING IT THE FIRST TIME, 8165 05:14:16,360 --> 05:14:17,640 BECAUSE WHEN YOU'RE JUST IN THE 8166 05:14:17,640 --> 05:14:19,040 MAINTENANCE PHASE, IT'S LIKE OH, 8167 05:14:19,040 --> 05:14:20,280 THIS IS BORING, WE'VE ALREADY 8168 05:14:20,280 --> 05:14:20,600 DONE THAT. 8169 05:14:20,600 --> 05:14:24,440 SO WHAT DO YOU THINK ARE WAYS 8170 05:14:24,440 --> 05:14:25,800 THAT IMPROVEMENTS CAN BE 8171 05:14:25,800 --> 05:14:27,840 SUSTAINED OVER TIME WHEN THERE'S 8172 05:14:27,840 --> 05:14:30,120 NO MORE GRAFNT FUNDING? 8173 05:14:30,120 --> 05:14:30,840 GRAND FUNDING? 8174 05:14:30,840 --> 05:14:33,080 >>THANK YOU, MONICA. 8175 05:14:33,080 --> 05:14:33,840 SO FIRST WE HAVE TO MAKE SURE 8176 05:14:33,840 --> 05:14:35,240 IT'S EVEN MAINTAINED DURING A 8177 05:14:35,240 --> 05:14:36,000 FUNDING PEER. 8178 05:14:36,000 --> 05:14:37,880 THAT'S WHY IT'S NICE IN THIS 8179 05:14:37,880 --> 05:14:39,160 STEP WEDGE DESIGN, WE WILL HAVE 8180 05:14:39,160 --> 05:14:40,400 THREE YEARS OF FUNDING AT SOME 8181 05:14:40,400 --> 05:14:40,720 SITES. 8182 05:14:40,720 --> 05:14:44,520 THE OTHER NICE THING ABOUT THE 8183 05:14:44,520 --> 05:14:46,360 WAY THIS STUDY IS DESIGNED, WE 8184 05:14:46,360 --> 05:14:48,200 HAVE NO REALTIME DATA COLLECTION 8185 05:14:48,200 --> 05:14:49,640 IN THE EMERGENCY DEPARTMENT, 8186 05:14:49,640 --> 05:14:49,840 RIGHT? 8187 05:14:49,840 --> 05:14:51,280 ALL OF THE DATA IS COLLECTED VIA 8188 05:14:51,280 --> 05:14:53,160 THE REGISTRY AS A DATA DUMP. 8189 05:14:53,160 --> 05:14:55,840 SO NOBODY IS THERE EVERY DAY 8190 05:14:55,840 --> 05:14:57,560 CONSENTING A FAMILY, REMINDING 8191 05:14:57,560 --> 05:14:59,800 PEOPLE THE STUDY IS ONGOING. 8192 05:14:59,800 --> 05:15:01,560 LIKE YOU SEE IN MANY 8193 05:15:01,560 --> 05:15:02,520 INTERVENTIONAL TRIALS WHERE THE 8194 05:15:02,520 --> 05:15:04,080 RESEARCH TEAM APPEARS AND 8195 05:15:04,080 --> 05:15:05,480 EVERYBODY SUDDENLY IS AWARE. 8196 05:15:05,480 --> 05:15:07,880 THIS IS REALLY ABOUT A CHANGE IN 8197 05:15:07,880 --> 05:15:08,360 CULTURE. 8198 05:15:08,360 --> 05:15:10,320 IT'S PRIORITIZING A PATIENT 8199 05:15:10,320 --> 05:15:12,080 POPULATION THAT WAS 8200 05:15:12,080 --> 05:15:13,520 UNFORTUNATELY NOT PRIORITIZED, 8201 05:15:13,520 --> 05:15:15,360 AND A LOT OF THE CHANGES WE'RE 8202 05:15:15,360 --> 05:15:18,360 DOING HAVE REALLY BECOME NEW 8203 05:15:18,360 --> 05:15:20,560 STANDARDS AT THOSE PLACES. 8204 05:15:20,560 --> 05:15:25,560 SOMETIMES PLACES ALREADY HAVE A 8205 05:15:25,560 --> 05:15:26,960 SPECIFIC -- WITH FEVER, SICKLE 8206 05:15:26,960 --> 05:15:28,760 CELL WITH FEVER THAT THEY DO 8207 05:15:28,760 --> 05:15:29,800 REALLY WELL WITH, THEY'RE JUST 8208 05:15:29,800 --> 05:15:31,240 THROWING PAIN INTO THAT METRIC 8209 05:15:31,240 --> 05:15:31,440 NOW. 8210 05:15:31,440 --> 05:15:32,840 SO I'M A LITTLE BIT MORE 8211 05:15:32,840 --> 05:15:34,160 OPTIMISTIC BECAUSE THIS STUDY 8212 05:15:34,160 --> 05:15:35,680 DOESN'T RELY ON BOOTS ON THE 8213 05:15:35,680 --> 05:15:39,840 GROUND FUNDING REALTIME TO 8214 05:15:39,840 --> 05:15:42,680 EFFECT CHANGE. 8215 05:15:42,680 --> 05:15:44,640 WHAT WE SEE OVER TIME IS ANY 8216 05:15:44,640 --> 05:15:45,760 IMPROVEMENT IS BETTER THAN WE 8217 05:15:45,760 --> 05:15:46,040 HAVE NOW. 8218 05:15:46,040 --> 05:15:46,400 >>THANK YOU. 8219 05:15:46,400 --> 05:15:48,120 I THINK WE NEED TO MOVE ON. 8220 05:15:48,120 --> 05:15:53,160 OUR NEXT TALK IS MAKING CASE OF 8221 05:15:53,160 --> 05:15:53,800 PALLIATIVE CARE IN SICKLE CELL 8222 05:15:53,800 --> 05:15:54,040 DISEASE. 8223 05:15:54,040 --> 05:15:56,120 WE HAVE A TAG TEAM OF THREE 8224 05:15:56,120 --> 05:16:00,600 DIFFERENT SPEAKERS. 8225 05:16:00,600 --> 05:16:02,240 DR. NKILE, DR. KISER AND 8226 05:16:02,240 --> 05:16:06,120 DR. ALLEN. 8227 05:16:06,120 --> 05:16:07,640 >>WE'RE GOING TO DO SOMETHING 8228 05:16:07,640 --> 05:16:08,480 DIFFERENT HERE. 8229 05:16:08,480 --> 05:16:12,760 WE HAVE TO SHARE OUR SCREEN. 8230 05:16:12,760 --> 05:16:16,160 >>KE WITH MO 8231 05:16:16,160 --> 05:16:19,640 >>WE'RE ACTUALLY USING OUR 8232 05:16:19,640 --> 05:16:19,960 SLIDES. 8233 05:16:19,960 --> 05:16:30,280 >>IS THAT YOURS? 8234 05:16:31,320 --> 05:16:35,080 >>CAN EVERYONE SEE OUR SLIDE? 8235 05:16:35,080 --> 05:16:37,960 HELLO, MY NAME IS ASHLEY ALLEN. 8236 05:16:37,960 --> 05:16:40,120 I'LL BE SPEAKING FIRST. 8237 05:16:40,120 --> 05:16:40,800 APPRECIATE EVERYONE HAVING US 8238 05:16:40,800 --> 05:16:41,440 HERE TODAY. 8239 05:16:41,440 --> 05:16:43,280 THIS IS A TOPIC WE'RE ALL 8240 05:16:43,280 --> 05:16:45,360 EXTREMELY PASSIONATE ABOUT, AND 8241 05:16:45,360 --> 05:16:49,280 HOPE YOU FIND INTERESTING. 8242 05:16:49,280 --> 05:16:53,960 SO THE TOPIC OF OUR PRESENTATION 8243 05:16:53,960 --> 05:16:55,720 TODAY IS MAKING THE CASE FOR 8244 05:16:55,720 --> 05:16:56,560 PALLIATIVE CARE IN SICKLE CELL 8245 05:16:56,560 --> 05:16:57,720 DISEASE. 8246 05:16:57,720 --> 05:17:00,240 A LITTLE INTERACTIVE, IF YOU 8247 05:17:00,240 --> 05:17:02,400 GUYS COULD USE -- BRING YOUR 8248 05:17:02,400 --> 05:17:04,800 SMARTPHONES OUT AND GO TO THIS 8249 05:17:04,800 --> 05:17:06,560 WEBSITE OR USE THE QR CODE AND 8250 05:17:06,560 --> 05:17:10,600 TYPE IN THIS SURVEY CODE. 8251 05:17:10,600 --> 05:17:12,040 THAT WOULD BE EXCELLENT. 8252 05:17:12,040 --> 05:17:13,640 WE HAVE A FEW QUESTIONS FOR YOU 8253 05:17:13,640 --> 05:17:16,160 AND I'LL GIVE EVERYONE A 8254 05:17:16,160 --> 05:17:26,680 FEW SECONDS TO SORT THAT OUT. 8255 05:17:38,840 --> 05:17:40,240 THOSE OF YOU WHO ARE VIRTUAL, 8256 05:17:40,240 --> 05:17:41,360 PLEASE DO THIS AS WELL. 8257 05:17:41,360 --> 05:17:45,000 SO HOPEFULLY THIS WORKS. 8258 05:17:45,000 --> 05:17:46,160 WE'RE GOING TO GO TO THE NEXT 8259 05:17:46,160 --> 05:17:47,640 SLIDE, AND IF YOU'RE HAVING A 8260 05:17:47,640 --> 05:17:51,920 HARD TIME GETTING TO THIS, THERE 8261 05:17:51,920 --> 05:17:53,200 WILL BE -- THE NUMBERS WILL BE 8262 05:17:53,200 --> 05:17:57,800 ON THE NEXT SLIDES AS WELL. 8263 05:17:57,800 --> 05:17:59,120 SO HERE WE GO. 8264 05:17:59,120 --> 05:18:00,520 THE FIRST QUESTION FOR THE POLL 8265 05:18:00,520 --> 05:18:02,440 IS, WHAT WORDS COME TO MIND WHEN 8266 05:18:02,440 --> 05:18:08,480 YOU HEAR "PALLIATIVE CARE"? 8267 05:18:08,480 --> 05:18:09,880 AND THEY SHOULD BE POPPING UP AS 8268 05:18:09,880 --> 05:18:12,960 YOU ALL ARE PUTTING THEM IN. 8269 05:18:12,960 --> 05:18:14,040 SO THE BIGGER WORDS ARE ONES 8270 05:18:14,040 --> 05:18:17,320 THAT MORE PEOPLE HAVE BEEN 8271 05:18:17,320 --> 05:18:18,840 PUTTING IN THE SURVEY. 8272 05:18:18,840 --> 05:18:24,440 SO END OF LIFE, TO COMFORT, 8273 05:18:24,440 --> 05:18:26,320 DEATH AND DYING, PAIN 8274 05:18:26,320 --> 05:18:27,640 MANAGEMENT. 8275 05:18:27,640 --> 05:18:29,680 SO A LOT OF PAIN AND SYMPTOM 8276 05:18:29,680 --> 05:18:32,120 MANAGEMENT I'M SEEING, COMFORT, 8277 05:18:32,120 --> 05:18:33,280 END OF LIFE. 8278 05:18:33,280 --> 05:18:35,120 VERY INTERESTING. 8279 05:18:35,120 --> 05:18:38,000 LAST RESORT, I'M SEEING 8280 05:18:38,000 --> 05:18:38,720 SOMEONE -- OH. 8281 05:18:38,720 --> 05:18:39,760 WE'LL TALK A LITTLE BIT MORE 8282 05:18:39,760 --> 05:18:42,240 ABOUT SOME OF THESE THINGS AS WE 8283 05:18:42,240 --> 05:18:43,560 GO, BUT THIS IS REALLY 8284 05:18:43,560 --> 05:18:44,760 INTERESTING. 8285 05:18:44,760 --> 05:18:45,480 NEXT QUESTION. 8286 05:18:45,480 --> 05:18:47,160 DO YOU THINK THERE IS A ROLE FOR 8287 05:18:47,160 --> 05:18:48,360 PALLIATIVE CARE IN THE CARE OF 8288 05:18:48,360 --> 05:18:49,200 PATIENTS WITH SICKLE CELL 8289 05:18:49,200 --> 05:18:50,240 DISEASE? 8290 05:18:50,240 --> 05:18:53,040 SO YES, NO, OR NOT SURE. 8291 05:18:53,040 --> 05:19:02,400 PLEASE CONVINCE ME. 8292 05:19:02,400 --> 05:19:04,240 WE'LL GIVE EVERYONE A FEW 8293 05:19:04,240 --> 05:19:09,320 MORE SECONDS. 8294 05:19:09,320 --> 05:19:11,640 SO THIS IS GOOD. 8295 05:19:11,640 --> 05:19:13,280 MORE THAN 80% OF YOU THINK THAT 8296 05:19:13,280 --> 05:19:14,160 THERE IS A ROLE. 8297 05:19:14,160 --> 05:19:15,600 AND WE HAVE A SOLID PERCENTAGE 8298 05:19:15,600 --> 05:19:17,160 OF PEOPLE WHO I THINK HOPEFULLY 8299 05:19:17,160 --> 05:19:18,880 WE CAN CONVINCE TODAY OR MAKE 8300 05:19:18,880 --> 05:19:20,680 YOU A LITTLE BIT MORE TOWARDS 8301 05:19:20,680 --> 05:19:21,560 YES. 8302 05:19:21,560 --> 05:19:24,560 AND THEN THE FINAL QUESTION IS, 8303 05:19:24,560 --> 05:19:26,640 WHAT ROLE OR ROLES DO YOU SEE 8304 05:19:26,640 --> 05:19:28,280 FOR PALLIATIVE CARE IN SICKLE 8305 05:19:28,280 --> 05:19:38,520 CELL DISEASE? 8306 05:19:40,040 --> 05:19:41,920 SO PAIN MANAGEMENT, A BIG ONE. 8307 05:19:41,920 --> 05:19:43,480 ONE THAT WE SEE OFTEN WHEN WE 8308 05:19:43,480 --> 05:19:46,920 ASK THESE QUESTIONS. 8309 05:19:46,920 --> 05:19:48,000 COMFORT. 8310 05:19:48,000 --> 05:19:49,200 SYMPTOM MANAGEMENT, QUALITY OF 8311 05:19:49,200 --> 05:19:58,000 LIFE. 8312 05:19:58,000 --> 05:19:59,040 AND WE'LL TALK ABOUT SEVERAL OF 8313 05:19:59,040 --> 05:20:00,320 THESE THINGS OVER THE COURSE OF 8314 05:20:00,320 --> 05:20:00,920 THE PRESENTATION, BUT I THINK 8315 05:20:00,920 --> 05:20:01,440 THIS IS GREAT. 8316 05:20:01,440 --> 05:20:06,480 I'M GLAD TO SEE QUALITY OF LIFE 8317 05:20:06,480 --> 05:20:06,880 GETTING BIGGER. 8318 05:20:06,880 --> 05:20:09,720 THAT'S GREAT. 8319 05:20:09,720 --> 05:20:10,920 SO A LITTLE BIT ABOUT WHAT WE'RE 8320 05:20:10,920 --> 05:20:11,920 GOING TO TALK ABOUT TODAY. 8321 05:20:11,920 --> 05:20:13,720 I'M GOING TO LEAD US OFF IN JUST 8322 05:20:13,720 --> 05:20:14,360 REVIEWING THE LITERATURE IN 8323 05:20:14,360 --> 05:20:15,240 SICKLE CELL DISEASE AND 8324 05:20:15,240 --> 05:20:17,760 PALLIATIVE CARE. 8325 05:20:17,760 --> 05:20:19,400 WE'LL THEN KIND OF TRANSITION TO 8326 05:20:19,400 --> 05:20:21,200 ASPECTS OF QUALITY OF LIFE AND 8327 05:20:21,200 --> 05:20:22,240 PSYCHOSOCIAL ASPECTS OF SICKLE 8328 05:20:22,240 --> 05:20:23,600 CELL DISEASE, WHICH I'M SURE 8329 05:20:23,600 --> 05:20:26,240 MANY OF YOU ARE ALREADY AWARE. 8330 05:20:26,240 --> 05:20:28,160 THEN WE'LL GO INTO THE RULES FOR 8331 05:20:28,160 --> 05:20:36,240 PALLIATIVE CARE AS WE SEE THEM, 8332 05:20:36,240 --> 05:20:37,640 EBERECHI WILL TALK ABOUT A STUDY 8333 05:20:37,640 --> 05:20:42,880 SHE RECENTLY COMPLETED, AND OUR 8334 05:20:42,880 --> 05:20:44,080 FIELDS IN PALLIATIVE CARE. 8335 05:20:44,080 --> 05:20:45,480 SO I CAN TELL YOU PRETTY 8336 05:20:45,480 --> 05:20:46,520 CONFIDENTLY THAT THE LITERATURE 8337 05:20:46,520 --> 05:20:48,720 IS EXTREMELY LIMITED WHEN IT 8338 05:20:48,720 --> 05:20:50,360 COMES TO SICKLE CELL DISEASE AND 8339 05:20:50,360 --> 05:20:51,200 PALLIATIVE CARE. 8340 05:20:51,200 --> 05:20:53,520 I INITIALLY DID THIS TALK FOR MY 8341 05:20:53,520 --> 05:20:57,800 PALLIATIVE CARE TBRAND RO GRANDN 8342 05:20:57,800 --> 05:20:59,360 2020 AND JUST SEARCHED -- THIS 8343 05:20:59,360 --> 05:21:00,680 WASN'T AN EXTENSIVE LITERATURE 8344 05:21:00,680 --> 05:21:03,280 REVIEW BUT I SEARCHED THE TERMS 8345 05:21:03,280 --> 05:21:04,320 PALLIATIVE CARE AND SICKLE CELL 8346 05:21:04,320 --> 05:21:05,720 DISEASE AND I CAME UP WITH SIX 8347 05:21:05,720 --> 05:21:06,840 ARTICLES, MOST OF WHICH WERE 8348 05:21:06,840 --> 05:21:08,920 OPINION PIECES, A CASE REPORT, 8349 05:21:08,920 --> 05:21:10,320 VERY MINIMAL LITERATURE ON THE 8350 05:21:10,320 --> 05:21:12,160 SUBJECT, AND THEN DID IT AGAIN 8351 05:21:12,160 --> 05:21:14,080 PRIOR TO THIS PRESENTATION, GOT 8352 05:21:14,080 --> 05:21:15,280 SEVEN ARTICLES. 8353 05:21:15,280 --> 05:21:17,720 NOW, AGAIN, THOSE ARE USING 8354 05:21:17,720 --> 05:21:20,120 THOSE SPECIFIC TERMS, SO THERE 8355 05:21:20,120 --> 05:21:21,800 IS RELATED LITERATURE THAT ISN'T 8356 05:21:21,800 --> 05:21:23,480 NECESSARILY THOSE TWO TERMS, BUT 8357 05:21:23,480 --> 05:21:26,200 I THINK IN GENERAL, KIND OF AN 8358 05:21:26,200 --> 05:21:26,760 INTERESTING FINDING. 8359 05:21:26,760 --> 05:21:28,560 SO VERY LIMITED. 8360 05:21:28,560 --> 05:21:32,800 BY COMPARISON, YOU DO THE SAME 8361 05:21:32,800 --> 05:21:34,560 SEARCH DO BE CF AND PALLIATIVE 8362 05:21:34,560 --> 05:21:43,360 CARE AND YOU GET 17 17 175 ARTI, 8363 05:21:43,360 --> 05:21:46,000 SO THIS IS ONE STUDY THAT'S 8364 05:21:46,000 --> 05:21:47,320 LOOKED AT ACUTE CARE UTILIZATION 8365 05:21:47,320 --> 05:21:49,240 AT THE END OF LIFE IN SICKLE 8366 05:21:49,240 --> 05:21:50,280 CELL DISEASE. 8367 05:21:50,280 --> 05:21:53,400 THEY LOOKED AT ALMOST A TOTAL OF 8368 05:21:53,400 --> 05:21:55,400 500 DEATHS WHERE THE MEDIAN AGE 8369 05:21:55,400 --> 05:21:58,120 WAS 45 YEARS, AND THE REALLY BIG 8370 05:21:58,120 --> 05:22:00,560 TAKEAWAY FROM THIS STUDY WAS 8371 05:22:00,560 --> 05:22:02,600 THAT 78% OF PATIENTS WERE DYING 8372 05:22:02,600 --> 05:22:05,200 EITHER IN THE HOSPITAL OR IN THE 8373 05:22:05,200 --> 05:22:07,000 EMERGENCY DEPARTMENT. 8374 05:22:07,000 --> 05:22:09,280 AND THAT WE SEE AN OPPORTUNITY 8375 05:22:09,280 --> 05:22:11,520 IN THIS STUDY THAT CAME ABOUT AS 8376 05:22:11,520 --> 05:22:13,040 WELL, IS THAT PATIENTS WERE 8377 05:22:13,040 --> 05:22:15,560 HOSPITALIZED FOR A TOTAL OF 42 8378 05:22:15,560 --> 05:22:16,960 DAYS IN THE LAST YEAR OF THEIR 8379 05:22:16,960 --> 05:22:19,040 LIFE, AND THIS WAS SPREAD OUT 8380 05:22:19,040 --> 05:22:20,360 OVER FIVE ADMISSIONS, AND SO WE 8381 05:22:20,360 --> 05:22:21,680 SEE THIS VERY MUCH AS AN 8382 05:22:21,680 --> 05:22:23,920 OPPORTUNITY FOR ADVANCED CARE 8383 05:22:23,920 --> 05:22:25,760 PLANNING, AND THEN AGAIN KIND OF 8384 05:22:25,760 --> 05:22:28,920 THAT LAST MONTH OF LIFE, THE 8385 05:22:28,920 --> 05:22:30,880 ACUTE CARE UTILIZATION REALLY 8386 05:22:30,880 --> 05:22:31,400 SPIKED. 8387 05:22:31,400 --> 05:22:33,720 SO VERY, VERY INTERESTING 8388 05:22:33,720 --> 05:22:35,240 COMPARED TO THE GENERAL 8389 05:22:35,240 --> 05:22:36,720 POPULATION IN TERMS OF LOCATION 8390 05:22:36,720 --> 05:22:40,560 OF DEATH. 8391 05:22:40,560 --> 05:22:43,280 THIS IS A STUDY EBERECHI DID 8392 05:22:43,280 --> 05:22:44,920 THAT LOOKED AT INPATIENT 8393 05:22:44,920 --> 05:22:49,120 PALLIATIVE CARE UTILIZATION IN 8394 05:22:49,120 --> 05:22:49,760 PATIENTS WITH SICKLE CELL 8395 05:22:49,760 --> 05:22:50,000 DISEASE. 8396 05:22:50,000 --> 05:22:52,960 SO THE ORANGE LINE IS THE KIND 8397 05:22:52,960 --> 05:22:54,720 OF RAY OF INPATIENT PALLIATIVE 8398 05:22:54,720 --> 05:22:58,720 CARE UTILIZATION IN TERMINAL 8399 05:22:58,720 --> 05:23:00,240 HOSPITALIZATION, SO YOU CAN SEE 8400 05:23:00,240 --> 05:23:01,880 INCREASED USE BUT ALSO AN 8401 05:23:01,880 --> 05:23:03,120 INCREASED RATE OF RISE OVER THE 8402 05:23:03,120 --> 05:23:05,880 COURSE OF THE STUDY. 8403 05:23:05,880 --> 05:23:08,280 HOWEVER, THE TOTAL NUMBER OF 8404 05:23:08,280 --> 05:23:09,080 HOSPITALIZATIONS WHERE PATIENTS 8405 05:23:09,080 --> 05:23:10,840 WERE RECEIVING PALLIATIVE CARE 8406 05:23:10,840 --> 05:23:13,240 SERVICE WAS ONLY .45%, SO VERY, 8407 05:23:13,240 --> 05:23:16,840 VERY LOW UTILIZATION. 8408 05:23:16,840 --> 05:23:17,840 BUT DID INCREASE OVER THE COURSE 8409 05:23:17,840 --> 05:23:18,760 OF THE STUDY. 8410 05:23:18,760 --> 05:23:20,000 AND THE USE OF PALLIATIVE CARE 8411 05:23:20,000 --> 05:23:24,160 WAS HIGHER IN PATIENTS WHO WERE 8412 05:23:24,160 --> 05:23:25,880 OLDER, MALE, HIGHER INCOME, 8413 05:23:25,880 --> 05:23:27,880 SICKER PATIENTS, WHICH MAKES 8414 05:23:27,880 --> 05:23:28,920 SENSE, AND THOSE IN URBAN 8415 05:23:28,920 --> 05:23:29,680 HOSPITALS. 8416 05:23:29,680 --> 05:23:33,120 THERE IS SOME DATA, AGAIN 8417 05:23:33,120 --> 05:23:34,040 LIMITED IN ADVANCED CARE 8418 05:23:34,040 --> 05:23:35,480 PLANNING IN SICKLE CELL DISEASE. 8419 05:23:35,480 --> 05:23:38,320 IT HAS SHOWN THAT ADVANCED CARE 8420 05:23:38,320 --> 05:23:39,920 PLANNING AND THESE CONVERSATIONS 8421 05:23:39,920 --> 05:23:43,560 ARE LIMITED BY MISTRUST, BOTH BY 8422 05:23:43,560 --> 05:23:45,160 KIND OF THE SYSTEM IN GENERAL AS 8423 05:23:45,160 --> 05:23:48,000 WELL AS HEALTHCARE PROVIDERS. 8424 05:23:48,000 --> 05:23:50,600 DESIRE NOT TO HAVE THESE 8425 05:23:50,600 --> 05:23:52,040 CONVERSATIONS DOCUMENTED AND A 8426 05:23:52,040 --> 05:23:53,040 RELUCTANCE GENERALLY TO TALK 8427 05:23:53,040 --> 05:23:55,280 ABOUT DYING. 8428 05:23:55,280 --> 05:23:56,520 THERE'S ALSO SOME DATA THAT 8429 05:23:56,520 --> 05:23:57,800 SUGGESTS IT'S NOT REALLY 8430 05:23:57,800 --> 05:23:58,800 HAPPENING, SO THEY LOOKED -- 8431 05:23:58,800 --> 05:24:02,440 THERE WAS A STUDY THAT LOOKED AT 8432 05:24:02,440 --> 05:24:03,880 ABOUT 70 PATIENT THAT MOST OF 8433 05:24:03,880 --> 05:24:06,480 WHICH DID NOT HAVE ANY KIND OF 8434 05:24:06,480 --> 05:24:08,000 WRITTEN DECISIONS FOR KIND OF IN 8435 05:24:08,000 --> 05:24:10,040 TERMS OF ADVANCED CARE PLANNING 8436 05:24:10,040 --> 05:24:11,680 IN TERMS OF THEIR DESIRES FOR 8437 05:24:11,680 --> 05:24:14,280 END OF LIFE MEDICAL TREATMENT. 8438 05:24:14,280 --> 05:24:15,800 IF THEY DID HAVE DOCUMENTATION, 8439 05:24:15,800 --> 05:24:17,400 THEY TENDED TO BE OLDER, SO 8440 05:24:17,400 --> 05:24:19,160 GREATER THAN 50. 8441 05:24:19,160 --> 05:24:21,960 AT THE SAME TIME, 90% WANTED TO 8442 05:24:21,960 --> 05:24:25,480 HAVE THESE CONVERSATIONS. 8443 05:24:25,480 --> 05:24:27,000 LOOKING A LITTLE BIT MORE INTO 8444 05:24:27,000 --> 05:24:28,680 THAT, THIS IS ACTUALLY A STUDY 8445 05:24:28,680 --> 05:24:29,720 OUT OF MY INSTITUTION, DUKE. 8446 05:24:29,720 --> 05:24:31,880 THIS IS A QUALITATIVE STUDY THAT 8447 05:24:31,880 --> 05:24:34,160 LOOKED AT KIND OF ATTITUDES AND 8448 05:24:34,160 --> 05:24:35,560 EXPERIENCES OF PREPARING FOR 8449 05:24:35,560 --> 05:24:36,960 DEATH IN OLDER ADULTS WITH 8450 05:24:36,960 --> 05:24:38,520 SICKLE CELL DISEASE, AND THEY 8451 05:24:38,520 --> 05:24:40,960 LOOKED AT -- THEY IDENTIFIED 8452 05:24:40,960 --> 05:24:43,920 FOUR DIFFERENT MAJOR THEMES. 8453 05:24:43,920 --> 05:24:45,360 THE FIRST BEING KIND OF 8454 05:24:45,360 --> 05:24:48,640 ANTICIPATION OF AN EARLY DEATH. 8455 05:24:48,640 --> 05:24:50,280 BEING ABLE TO KIND OF MAKE PLANS 8456 05:24:50,280 --> 05:24:54,400 FOR THIS AND BEING INFORMED OF 8457 05:24:54,400 --> 05:24:55,600 THAT. 8458 05:24:55,600 --> 05:24:58,640 MANY OF THE PATIENTS HAD ALREADY 8459 05:24:58,640 --> 05:24:59,880 EXPERIENCED NEAR-DEATH 8460 05:24:59,880 --> 05:25:00,200 EXPERIENCES. 8461 05:25:00,200 --> 05:25:01,640 AND REALLY THE THIRD THEME AS 8462 05:25:01,640 --> 05:25:02,800 BEING KIND OF DIFFERENCES IN 8463 05:25:02,800 --> 05:25:04,280 COMFORT LEVEL TALKING ABOUT 8464 05:25:04,280 --> 05:25:04,840 THIS. 8465 05:25:04,840 --> 05:25:06,280 FOR SOME PATIENTS THIS WAS DEATH 8466 05:25:06,280 --> 05:25:08,880 AS BEING KIND OF A PART OF LIFE. 8467 05:25:08,880 --> 05:25:10,840 AND FOR OTHERS, THIS WAS NOT 8468 05:25:10,840 --> 05:25:12,320 SOMETHING THAT THEY FELT 8469 05:25:12,320 --> 05:25:15,720 COMFORTABLE TALKING ABOUT. 8470 05:25:15,720 --> 05:25:21,120 AND THEN THE INFLAWNS OF INFLUEF 8471 05:25:21,120 --> 05:25:21,920 SPIRITUALITY. 8472 05:25:21,920 --> 05:25:23,880 GOD CONTROLS THE TIMING OF OUR 8473 05:25:23,880 --> 05:25:26,840 DEATH AND BELIEF IN AFTERLIFE 8474 05:25:26,840 --> 05:25:28,160 BEING A SUBTHEME IN THAT GROUP. 8475 05:25:28,160 --> 05:25:29,600 THIS IS ANOTHER STUDY BY THE 8476 05:25:29,600 --> 05:25:31,600 SAME GROUP THAT LOOKED AT 8477 05:25:31,600 --> 05:25:32,600 FACILITATORS AND BARRIERS OF 8478 05:25:32,600 --> 05:25:33,560 HAVING THESE CONVERSATIONS. 8479 05:25:33,560 --> 05:25:34,640 I WON'T GO OVER THIS, BUT I 8480 05:25:34,640 --> 05:25:35,720 THINK IT'S REALLY, REALLY 8481 05:25:35,720 --> 05:25:37,560 IMPORTANT TO UNDERSTAND 8482 05:25:37,560 --> 05:25:43,760 GENERALLY WHAT THESE ARE. 8483 05:25:43,760 --> 05:25:46,280 SO IN TERMS OF FACILITATORS, THE 8484 05:25:46,280 --> 05:25:47,680 BIG KEY POINT IS TO UNDERSTAND 8485 05:25:47,680 --> 05:25:48,960 THIS NEEDS TO BE IN THE RIGHT 8486 05:25:48,960 --> 05:25:49,960 PLACE, NOT IN THE HOSPITAL, NOT 8487 05:25:49,960 --> 05:25:50,920 HAD SOMEONE IS SICK. 8488 05:25:50,920 --> 05:25:52,720 IT NEEDS TO BE WITH A RESPECTED 8489 05:25:52,720 --> 05:25:54,960 AND TRUSTED PROVIDER, OFTENTIMES 8490 05:25:54,960 --> 05:25:57,360 AT THEIR PRIMARY HEMATOLOGIST. 8491 05:25:57,360 --> 05:25:59,160 HAVING FAMILY PRESENT IS A HUGE 8492 05:25:59,160 --> 05:26:02,800 FACILITATOR FOR THESE PATIENTS. 8493 05:26:02,800 --> 05:26:06,760 AND I THINK OPEN AND HONEST 8494 05:26:06,760 --> 05:26:08,400 COMMUNICATION IS A BIG 8495 05:26:08,400 --> 05:26:08,680 FACILITATOR. 8496 05:26:08,680 --> 05:26:10,560 IN TERMS OF BARRIERS, IT SORT OF 8497 05:26:10,560 --> 05:26:11,800 THE OPPOSITE OF THAT, BEING IN 8498 05:26:11,800 --> 05:26:13,280 THE HOSPITAL, BEING ACUTELY ILL, 8499 05:26:13,280 --> 05:26:16,400 NOT WITH A TRUSTED PROVIDER. 8500 05:26:16,400 --> 05:26:17,720 SPIRITUALITY DID SEEM TO BE A 8501 05:26:17,720 --> 05:26:20,320 BARRIER TO THESE CONVERSATIONS, 8502 05:26:20,320 --> 05:26:22,880 SO THINKING ABOUT PLANNING FOR 8503 05:26:22,880 --> 05:26:25,360 DEATH AS NOT BEING CONSISTENT 8504 05:26:25,360 --> 05:26:26,360 WITH ONE'S RELIGIOUS BELIEFS OR 8505 05:26:26,360 --> 05:26:28,080 THAT UNDERPINNING OF GOD 8506 05:26:28,080 --> 05:26:29,360 CONTROLS THE TIMING OF THIS, SO 8507 05:26:29,360 --> 05:26:31,880 I'M NOT GOING TO TALK ABOUT IT. 8508 05:26:31,880 --> 05:26:33,400 AND THEN PATIENTS' OWN NEGATIVE 8509 05:26:33,400 --> 05:26:35,120 EXPERIENCES OF END OF LIFE, 8510 05:26:35,120 --> 05:26:36,280 WHETHER IT'S WITH THEIR FAMILY 8511 05:26:36,280 --> 05:26:37,920 MEMBERS AND WHATNOT, AND PART OF 8512 05:26:37,920 --> 05:26:40,200 THAT IS THE MISTRUST OF MAYBE 8513 05:26:40,200 --> 05:26:41,320 THE PROVIDER THAT'S BRINGING 8514 05:26:41,320 --> 05:26:43,480 THIS UP BUT ALSO MISTRUST OF THE 8515 05:26:43,480 --> 05:26:45,800 SYSTEM. 8516 05:26:45,800 --> 05:26:48,080 SO NOW A TRANSITION TO SOME OF 8517 05:26:48,080 --> 05:26:49,800 THE BIG QUALITY OF LIFE AND 8518 05:26:49,800 --> 05:26:50,720 PSYCHOSOCIAL ASPECTS OF SICKLE 8519 05:26:50,720 --> 05:26:54,520 CELL DISEASE THAT UNDERPIN WHY 8520 05:26:54,520 --> 05:26:56,440 WE FEEL LIKE PALLIATIVE CARE HAS 8521 05:26:56,440 --> 05:26:58,960 A BIG ROLE. 8522 05:26:58,960 --> 05:27:00,360 AND ALL OF YOU KNOW THIS, BUT 8523 05:27:00,360 --> 05:27:03,680 ALWAYS GOOD TO REMEMBER SICKLE 8524 05:27:03,680 --> 05:27:06,160 CELL DISEASE IS MULTIORGAN, 8525 05:27:06,160 --> 05:27:07,880 AFFECTS EVERY BODY SYSTEM AND 8526 05:27:07,880 --> 05:27:08,840 ORGAN SYSTEM. 8527 05:27:08,840 --> 05:27:10,960 THERE'S BOTH ACUTE AND CHRONIC 8528 05:27:10,960 --> 05:27:12,800 COMPLICATIONS. 8529 05:27:12,800 --> 05:27:13,960 WHEN WE LOOK AT QUALITY OF LIFE 8530 05:27:13,960 --> 05:27:15,880 IN SICKLE CELL DISEASE, CHILDREN 8531 05:27:15,880 --> 05:27:18,840 ARE KIND OF IN THE GREEN AND 8532 05:27:18,840 --> 05:27:20,360 ADULTS IN YELLOW, THAT SICKLE 8533 05:27:20,360 --> 05:27:21,760 CELL DISEASE, THE HEALTH-RELATED 8534 05:27:21,760 --> 05:27:25,040 QUALITY OF LIFE IS EQUIVALENT IN 8535 05:27:25,040 --> 05:27:27,080 CHILDREN TO CHILDREN ON ACTIVE 8536 05:27:27,080 --> 05:27:28,160 CANCER TREATMENT. 8537 05:27:28,160 --> 05:27:29,920 AND FOR ADULTS WITH SICKLE CELL 8538 05:27:29,920 --> 05:27:31,160 DISEASE, THEIR HEALTH-RELATED 8539 05:27:31,160 --> 05:27:34,160 QUALITY OF LIFE IS ACTUALLY 8540 05:27:34,160 --> 05:27:37,040 WORSE THAN PATIENTS ON ACTIVE 8541 05:27:37,040 --> 05:27:38,360 CANCER TREATMENT, AS WELL AS 8542 05:27:38,360 --> 05:27:39,800 CYSTIC FIBROSIS AND MORE ON PAR 8543 05:27:39,800 --> 05:27:42,800 WITH ADULT ASTHMA. 8544 05:27:42,800 --> 05:27:45,640 SO PRETTY POWERFUL IMAGE IS THIS 8545 05:27:45,640 --> 05:27:46,840 ONE I GO TO A LOT WHEN I'M 8546 05:27:46,840 --> 05:27:48,040 TALKING TO PEOPLE WHO DON'T HAVE 8547 05:27:48,040 --> 05:27:49,800 A LOT OF KNOWLEDGE ABOUT SICKLE 8548 05:27:49,800 --> 05:27:50,520 CELL DISEASE AND PALLIATIVE 8549 05:27:50,520 --> 05:27:51,000 CARE. 8550 05:27:51,000 --> 05:27:52,920 THIS IS A SIMILAR KIND OF LOOK 8551 05:27:52,920 --> 05:27:56,880 AT QUALITY OF LIFE SO THE SICKLE 8552 05:27:56,880 --> 05:27:58,720 CELL DISEASE COHORT, THERE'S 8553 05:27:58,720 --> 05:28:03,320 BOTH THE UNAGISTED LIVE 8554 05:28:03,320 --> 05:28:04,960 EXPECTANCY AND -- YOU CAN SEE 8555 05:28:04,960 --> 05:28:07,360 UNADJUSTED IS AROUND 54, SO MUCH 8556 05:28:07,360 --> 05:28:10,880 LOWER THAN THE LIFE EXPECTANCY 8557 05:28:10,880 --> 05:28:12,280 OF THE U.S. GENERAL POPULATION 8558 05:28:12,280 --> 05:28:15,200 BUT THEN THE NON-SCD POPULATION 8559 05:28:15,200 --> 05:28:16,120 AS WELL. 8560 05:28:16,120 --> 05:28:23,240 THEN WHEN YOU ADJUST FOR 8561 05:28:23,240 --> 05:28:24,400 QUALITY -- QUALITY OF LIFE IS 8562 05:28:24,400 --> 05:28:26,800 DEEPLY AFFECTED BY THIS DISEASE. 8563 05:28:26,800 --> 05:28:31,720 THE PISCES STUDY IS ONE OF THE 8564 05:28:31,720 --> 05:28:33,560 KIND OF -- IS ONE OF THE BIG 8565 05:28:33,560 --> 05:28:35,000 STUDIES LOOKING AT 8566 05:28:35,000 --> 05:28:37,120 HEALTH-RELATED QUALITY OF LIFE. 8567 05:28:37,120 --> 05:28:39,480 THEY LOOKED AT EIGHT DIFFERENT 8568 05:28:39,480 --> 05:28:42,760 DOMAINS INCLUDING PHYSICAL 8569 05:28:42,760 --> 05:28:44,160 FUNCTION, EMOTIONAL BODILY PAIN, 8570 05:28:44,160 --> 05:28:46,000 VITALITY, ET CETERA, AND WAS A 8571 05:28:46,000 --> 05:28:47,320 LONGITUDINAL STUDY WHERE THEY 8572 05:28:47,320 --> 05:28:49,480 HAD PATIENTS DO DAILY PAIN 8573 05:28:49,480 --> 05:28:51,240 DIARIES THAT ALLOWED THEM TO 8574 05:28:51,240 --> 05:28:54,360 CALCULATE VARIOUS VARIABLES. 8575 05:28:54,360 --> 05:28:57,760 FOR PAIN, ABOUT 55% OF TOTAL 8576 05:28:57,760 --> 05:29:01,160 PAIN DAYS -- TOTAL DAYS WERE 8577 05:29:01,160 --> 05:29:04,080 SPENT WITH PATIENTS IN PAIN. 8578 05:29:04,080 --> 05:29:05,480 29% OF PATIENTS REPORTED DAILY 8579 05:29:05,480 --> 05:29:06,920 PAIN. 8580 05:29:06,920 --> 05:29:08,720 AND FOR MAJORITY OF THOSE 8581 05:29:08,720 --> 05:29:10,080 PATIENTS, THEY WERE MANAGING 8582 05:29:10,080 --> 05:29:10,840 THIS AT HOME. 8583 05:29:10,840 --> 05:29:12,760 TYPICALLY WITH THE USE OF 8584 05:29:12,760 --> 05:29:18,480 OPIOIDS, AND ONLY 3.5% OF DAYS 8585 05:29:18,480 --> 05:29:20,120 WAS PAIN REQUIRING SOME SORT OF 8586 05:29:20,120 --> 05:29:20,640 MEDICAL ATTENTION. 8587 05:29:20,640 --> 05:29:22,600 SO REALLY THE KEY HERE IS THAT 8588 05:29:22,600 --> 05:29:24,400 PAIN IS THE RULE AND NOT THE 8589 05:29:24,400 --> 05:29:25,880 EXCEPTION. 8590 05:29:25,880 --> 05:29:27,640 THIS WAS JUST HIGHLIGHTED IN THE 8591 05:29:27,640 --> 05:29:29,920 LAST PRESENTATION, BUT PAIN 8592 05:29:29,920 --> 05:29:31,120 MANAGEMENT ESPECIALLY IN THE 8593 05:29:31,120 --> 05:29:32,080 EMERGENCY DEPARTMENT IS 8594 05:29:32,080 --> 05:29:35,000 FREQUENTLY DELAYED, THOUGH LOTS 8595 05:29:35,000 --> 05:29:36,360 OF EFFORTS HAVE BEEN ONGOING. 8596 05:29:36,360 --> 05:29:38,000 THIS CAN OFTEN LEAD TO 8597 05:29:38,000 --> 05:29:39,320 UNDERTREATED AND INAPPROPRIATELY 8598 05:29:39,320 --> 05:29:40,640 MANAGED PAIN, AND CAN LEAD TO 8599 05:29:40,640 --> 05:29:42,800 THIS IDEA OF PSEUDOADDICTION 8600 05:29:42,800 --> 05:29:46,880 WHERE SOMEONE IS SHOWING RED 8601 05:29:46,880 --> 05:29:49,560 FLAG BEHAVIOR BUT ACTUALLY THEIR 8602 05:29:49,560 --> 05:29:52,160 BEHAVIOR IS A RESULT OF 8603 05:29:52,160 --> 05:29:53,800 UNDERTREATED INAPPROPRIATELY 8604 05:29:53,800 --> 05:29:54,360 MANAGED PAIN. 8605 05:29:54,360 --> 05:29:55,360 FOR ABOUT A THIRD OF THE 8606 05:29:55,360 --> 05:29:57,080 PATIENTS, THEY DON'T HAVE A 8607 05:29:57,080 --> 05:29:57,800 VASOOCCLUSIVE CRISIS OVER THE 8608 05:29:57,800 --> 05:29:59,840 COURSE OF THE YEAR, BUT ALMOST 8609 05:29:59,840 --> 05:30:08,160 20% HAVE GREATER THAN THREE 8610 05:30:08,160 --> 05:30:09,040 HOSPITALIZATION RATES. 8611 05:30:09,040 --> 05:30:11,400 SO ABOUT HALF THE TIME FOR PEDS 8612 05:30:11,400 --> 05:30:12,160 COMPARED TO ADULTS. 8613 05:30:12,160 --> 05:30:14,680 AND AGAIN, PHYSICAL EXAM 8614 05:30:14,680 --> 05:30:18,760 FINDINGS ARE OFTEN ABSENT. 8615 05:30:18,760 --> 05:30:19,680 SO A PATIENT-REPORTED PAIN IS 8616 05:30:19,680 --> 05:30:20,880 THE GOLD STANDARD. 8617 05:30:20,880 --> 05:30:23,360 IN ADDITION TO KIND OF THE 8618 05:30:23,360 --> 05:30:24,920 DETAILS ABOUT THE PAIN ITSELF, 8619 05:30:24,920 --> 05:30:26,880 THERE'S A LOT OF MISPERCEPTIONS 8620 05:30:26,880 --> 05:30:27,760 ABOUT SICKLE CELL DISEASE 8621 05:30:27,760 --> 05:30:31,360 PATIENTS AND THE PAIN THAT THEY 8622 05:30:31,360 --> 05:30:32,360 EXPERIENCE. 8623 05:30:32,360 --> 05:30:34,520 SO A LOT OF MISPERCEPTIONS FROM 8624 05:30:34,520 --> 05:30:37,160 ED PHYSICIANS, HEMATOLOGISTS, 8625 05:30:37,160 --> 05:30:38,040 FEELING LIKE PATIENTS ARE 8626 05:30:38,040 --> 05:30:40,400 ADDICTED TO OPIOIDS DESPITE THE 8627 05:30:40,400 --> 05:30:41,400 FACT THAT THE LITERATURE HAS 8628 05:30:41,400 --> 05:30:42,840 SHOWN THAT THEY ARE NOT, AND 8629 05:30:42,840 --> 05:30:45,440 THAT THEY HAVE EITHER EQUIVALENT 8630 05:30:45,440 --> 05:30:47,680 OR LESS OPIOID ADDICTION 8631 05:30:47,680 --> 05:30:49,240 COMPARED TO THE GENERAL 8632 05:30:49,240 --> 05:30:52,520 POPULATION. 8633 05:30:52,520 --> 05:30:55,040 AND THAT A 2005 SURVEY SHOWED 8634 05:30:55,040 --> 05:30:56,800 THAT HOSPITAL PHYSICIANS DID NOT 8635 05:30:56,800 --> 05:30:58,760 BELIEVE THAT A PATIENT'S OWN 8636 05:30:58,760 --> 05:31:00,040 SELF-REPORT WAS THE BEST 8637 05:31:00,040 --> 05:31:03,120 INDICATOR OF THEIR ACTUAL PAIN. 8638 05:31:03,120 --> 05:31:04,760 AND US IN PALLIATIVE CARE, WE 8639 05:31:04,760 --> 05:31:06,840 BELIEVE VERY STRONGLY THAT WORDS 8640 05:31:06,840 --> 05:31:08,360 MATTER, AND SO THE UNDERPINNINGS 8641 05:31:08,360 --> 05:31:10,720 OF SOME OF THESE WORD THAT WE 8642 05:31:10,720 --> 05:31:15,880 HEAR ALL THE TIME IN PRACTICE 8643 05:31:15,880 --> 05:31:20,520 REALLY VL RAC HAVE RACIAL UNDERS 8644 05:31:20,520 --> 05:31:23,120 THAT AFFECT THE CARE ULTIMATELY 8645 05:31:23,120 --> 05:31:24,040 THAT PATIENTS RECEIVE. 8646 05:31:24,040 --> 05:31:25,600 THE PSYCHOSOCIAL BURDEN IS ALSO 8647 05:31:25,600 --> 05:31:26,640 HUGE, AND WE'LL TALK A LITTLE 8648 05:31:26,640 --> 05:31:30,240 BIT MORE ABOUT THE PISCES STUDY 8649 05:31:30,240 --> 05:31:32,120 RESULTS OF MENTAL HEALTH BUT 8650 05:31:32,120 --> 05:31:34,200 HIGH LEVELS OF CO-MORBID 8651 05:31:34,200 --> 05:31:36,160 DEPRESSION AND ANXIETY, WHICH WE 8652 05:31:36,160 --> 05:31:37,800 KNOW IS IN SICKLE CELL DISEASE 8653 05:31:37,800 --> 05:31:40,240 BUT ALSO IN OTHER PAIN SI SYNDRS 8654 05:31:40,240 --> 05:31:41,520 THAT THIS LEADS TO HIGHER 8655 05:31:41,520 --> 05:31:43,720 SENSITIVITY TO PAIN, HIGHER 8656 05:31:43,720 --> 05:31:45,120 UTILIZATION, OTHER SOMATIC 8657 05:31:45,120 --> 05:31:47,080 SYMPTOMS, SLEEP DISTURBANCE, AND 8658 05:31:47,080 --> 05:31:49,280 ALSO IS ASSOCIATED WITH 8659 05:31:49,280 --> 05:31:52,200 DECREASED PRODUCTIVITY, SCHOOL 8660 05:31:52,200 --> 05:31:53,400 WORK PERFORMANCE, HIGHER LEVELS 8661 05:31:53,400 --> 05:31:53,960 OF STIGMA. 8662 05:31:53,960 --> 05:31:56,120 SO GOING INTO THE KIND OF 8663 05:31:56,120 --> 05:31:58,960 RESULTS OF THE PISCES STUDY, 8664 05:31:58,960 --> 05:32:02,800 ABOUT 28% OF PATIENTS WERE -- 8665 05:32:02,800 --> 05:32:04,000 HAD CO-MORBID DEPRESSION AND 8666 05:32:04,000 --> 05:32:07,520 THEN ABOUT 6.5% HAD CO-MORBID 8667 05:32:07,520 --> 05:32:08,160 ANXIETY. 8668 05:32:08,160 --> 05:32:10,320 THE DEPRESSED PATIENTS TENDED TO 8669 05:32:10,320 --> 05:32:14,240 HAVE PAIN ON MORE DAYS AND HAD 8670 05:32:14,240 --> 05:32:18,600 HIGHER MEAN PAIN, AND 8671 05:32:18,600 --> 05:32:20,360 INTERFERENCE ON PAIN ON 8672 05:32:20,360 --> 05:32:21,800 NON-CRISIS DAYS. 8673 05:32:21,800 --> 05:32:23,200 SIMILAR RESULTS WITH ANXIOUS 8674 05:32:23,200 --> 05:32:24,400 PATIENTS, IN ADDITION, THEY 8675 05:32:24,400 --> 05:32:26,920 TENDED TO HAVE MORE OPIOID USE. 8676 05:32:26,920 --> 05:32:31,080 AND WE WOULD BE REMISS WITHOUT 8677 05:32:31,080 --> 05:32:33,240 TALKING ABOUT THE EFFECT OF 8678 05:32:33,240 --> 05:32:35,760 INEQUITY AND RACISM ON THE 8679 05:32:35,760 --> 05:32:37,080 QUALITY OF LIFE THAT THESE 8680 05:32:37,080 --> 05:32:42,560 PATIENTS EXPERIENCE, SO THIS IS 8681 05:32:42,560 --> 05:32:44,200 OLD INFORMATION, A FEW YEARS 8682 05:32:44,200 --> 05:32:45,320 OLD, BUT I THINK IT'S REALLY 8683 05:32:45,320 --> 05:32:47,960 INTERESTING TO SEE THAT DESPITE 8684 05:32:47,960 --> 05:32:49,440 THE FACT THAT THE PREVALENCE OF 8685 05:32:49,440 --> 05:32:50,800 SICKLE CELL DISEASE IS HIGHER IN 8686 05:32:50,800 --> 05:32:52,640 THE U.S. POPULATION, THESE 8687 05:32:52,640 --> 05:32:54,600 PATIENTS RECEIVE LESS NIH 8688 05:32:54,600 --> 05:32:57,760 FUNDING PER PERSON, LESS 8689 05:32:57,760 --> 05:33:00,040 PHILANTHROPIC SUPPORT, FEWER 8690 05:33:00,040 --> 05:33:02,320 PUBLICATIONS, FEWER TRIALS, 8691 05:33:02,320 --> 05:33:04,840 FEWER DISEASE-SPECIFIC DRUGS. 8692 05:33:04,840 --> 05:33:12,920 SO VERY KIND OF HARD TO IGNORE 8693 05:33:12,920 --> 05:33:14,440 THE SCIEBD R KIND OF EFFECT OF 8694 05:33:14,440 --> 05:33:16,760 RACISM IN SICKLE CELL DISEASE. 8695 05:33:16,760 --> 05:33:20,440 THIS IS A BOOK IN MEDICAL SCHOOL 8696 05:33:20,440 --> 05:33:22,440 THAT I'M EXTREMELY PASSIONATE 8697 05:33:22,440 --> 05:33:23,760 ABOUT THIS SUBJECT. 8698 05:33:23,760 --> 05:33:27,040 THIS PERSPECTIVE PIECE ON THE 8699 05:33:27,040 --> 05:33:28,480 BOTTOM, I'M SURE 19 OF YOU HAVE 8700 05:33:28,480 --> 05:33:31,280 READ IT BUT IF YOU'RE NOT, IT'S 8701 05:33:31,280 --> 05:33:31,880 A NEW ENGLAND JOURNAL PIECE 8702 05:33:31,880 --> 05:33:34,040 ABOUT SORT OF THE UNDERPINNINGS 8703 05:33:34,040 --> 05:33:35,480 OF RACE IN SICKLE CELL DISEASE 8704 05:33:35,480 --> 05:33:38,520 AND HOW THAT'S AFFECTED THE 8705 05:33:38,520 --> 05:33:39,960 HISTORY, AND THEN IT MAKES VERY 8706 05:33:39,960 --> 05:33:40,920 SPECIFIC RECOMMENDATIONS FOR 8707 05:33:40,920 --> 05:33:41,920 PROPOSED CHANGES OF HOW WE CAN 8708 05:33:41,920 --> 05:33:46,000 CHANGE THE TRAJECTORY OF THEIR 8709 05:33:46,000 --> 05:33:46,280 CARE. 8710 05:33:46,280 --> 05:33:48,600 AND SO I ALSO WANTED TO POINT 8711 05:33:48,600 --> 05:33:52,640 OUT THAT WORDS LIKE SICKLIERS, 8712 05:33:52,640 --> 05:33:54,720 WHAT THEY DO IS THEY 8713 05:33:54,720 --> 05:33:55,560 DEPERSONALIZE THE PERSON AT THE 8714 05:33:55,560 --> 05:33:56,440 CENTER OF ALL OF THIS. 8715 05:33:56,440 --> 05:33:59,720 SO I THINK TO IGNORE THAT 8716 05:33:59,720 --> 05:34:01,880 EXPERIENCE IS ONE THAT IS HARD 8717 05:34:01,880 --> 05:34:09,520 TO DO. 8718 05:34:09,520 --> 05:34:10,840 SO NOW I'M GOING TO TRANSITION 8719 05:34:10,840 --> 05:34:12,040 TO STEPHANIE, WHO'S GOING TO 8720 05:34:12,040 --> 05:34:13,240 TALK ABOUT THE ROLE FOR 8721 05:34:13,240 --> 05:34:16,040 PALLIATIVE CARE. 8722 05:34:16,040 --> 05:34:17,240 >>THANK YOU, ASHLEY. 8723 05:34:17,240 --> 05:34:19,120 SO AS ASHLEY SAID, I'M GOING TO 8724 05:34:19,120 --> 05:34:21,120 SPEND A FEW MINUTES SORT OF 8725 05:34:21,120 --> 05:34:22,320 ZOOMING OUT WITH ALL OF THAT 8726 05:34:22,320 --> 05:34:24,480 BACKGROUND TO TALK ABOUT THE 8727 05:34:24,480 --> 05:34:25,840 PHILOSOPHY OF PALLIATIVE CARE 8728 05:34:25,840 --> 05:34:27,640 AND ALSO WHAT WE SEE AS THE 8729 05:34:27,640 --> 05:34:28,640 OPPORTUNITIES FOR RESEARCH AND 8730 05:34:28,640 --> 05:34:30,040 CLINICAL CARE IN THE FUTURE. 8731 05:34:30,040 --> 05:34:32,680 SO PALLIATIVE CARE IS REALLY A 8732 05:34:32,680 --> 05:34:33,720 PHILOSOPHY OF CARE FOR ANYONE 8733 05:34:33,720 --> 05:34:37,680 WITH A SERIOUS ILLNESS THAT 8734 05:34:37,680 --> 05:34:39,000 AIMED AS AN EXTRA LAYER OF 8735 05:34:39,000 --> 05:34:40,080 SUPPORT AND ALL OF THE OTHER 8736 05:34:40,080 --> 05:34:40,880 MEDICAL CARE THAT THEY'RE 8737 05:34:40,880 --> 05:34:42,120 ALREADY GETTING. 8738 05:34:42,120 --> 05:34:43,880 AND AS PALLIATIVE CARE 8739 05:34:43,880 --> 05:34:45,400 PHYSICIANS, WE FOCUS A LOT ON 8740 05:34:45,400 --> 05:34:46,600 QUALITY OF LIFE AND NOT ONLY 8741 05:34:46,600 --> 05:34:48,760 QUALITY OF LIFE FOR THE 8742 05:34:48,760 --> 05:34:51,160 INDIVIDUAL PATIENT BUT ALSO FOR 8743 05:34:51,160 --> 05:34:51,960 THE FAMILY AND OTHER SUPPORT 8744 05:34:51,960 --> 05:34:55,560 SYSTEMS AROUND THE PATIENT. 8745 05:34:55,560 --> 05:34:57,120 PALLIATIVE CARE REALLY FOCUSES 8746 05:34:57,120 --> 05:34:58,600 ON NOT ONLY WHAT WE CAN PROVIDE 8747 05:34:58,600 --> 05:35:00,600 ON PHYSICIANS, ALL THREE OF US 8748 05:35:00,600 --> 05:35:02,240 ARE PHYSICIAN, BUT WE ALSO WORK 8749 05:35:02,240 --> 05:35:04,000 IN INTERDISCIPLINARY TEAMS AND 8750 05:35:04,000 --> 05:35:05,000 RECOGNIZE THAT PROVIDERS FROM A 8751 05:35:05,000 --> 05:35:06,760 VARIETY OF TRAINING BACKGROUNDS 8752 05:35:06,760 --> 05:35:08,480 REALLY ENHANCE THE CARE OF THESE 8753 05:35:08,480 --> 05:35:10,440 PATIENTS SO THAT CAN INCLUDE 8754 05:35:10,440 --> 05:35:13,600 NURSES, SOCIAL WORKERS, AND 8755 05:35:13,600 --> 05:35:14,920 OTHER SUPPORT PEOPLE ON OUR 8756 05:35:14,920 --> 05:35:15,720 HEALTHCARE TEAMS. 8757 05:35:15,720 --> 05:35:17,360 AND THEN PALLIATIVE CARE IS 8758 05:35:17,360 --> 05:35:19,440 REALLY BASED ON THE NEEDS OF THE 8759 05:35:19,440 --> 05:35:21,000 PATIENT, NOT ON THE PATIENT'S 8760 05:35:21,000 --> 05:35:21,840 PROGNOSIS, SO IT'S APPROPRIATE 8761 05:35:21,840 --> 05:35:24,360 AT ANY AGE AND I STAGE IN A 8762 05:35:24,360 --> 05:35:27,320 SERIOUS ILLNESS, AND IT CAN -- 8763 05:35:27,320 --> 05:35:28,640 AND THIS IS REALLY IMPORTANT TO 8764 05:35:28,640 --> 05:35:32,640 US TO EMPHASIZE, IT CAN BE 8765 05:35:32,640 --> 05:35:34,400 REPORTED ALONG WITH CURATIVE 8766 05:35:34,400 --> 05:35:34,640 TREATMENT. 8767 05:35:34,640 --> 05:35:35,440 I THINK THAT'S TO SAY THAT'S ONE 8768 05:35:35,440 --> 05:35:36,840 OF THE BIGGEST MISCONCEPTIONS 8769 05:35:36,840 --> 05:35:40,720 THAT WE STILL IS HEAR A LOT WHE 8770 05:35:40,720 --> 05:35:42,160 BRING UP PALLIATIVE CARE NOT 8771 05:35:42,160 --> 05:35:43,480 ONLY IN THIS SPACE BUT OTHER 8772 05:35:43,480 --> 05:35:44,800 PATIENT POPULATIONS. 8773 05:35:44,800 --> 05:35:46,680 OFTENTIMES WHAT WE HEAR THE MAIN 8774 05:35:46,680 --> 05:35:47,960 FOCUS BEING ON IS END OF LIFE 8775 05:35:47,960 --> 05:35:49,280 AND SORT OF HOSPICE CARE AT THE 8776 05:35:49,280 --> 05:35:50,560 END OF SOMEONE'S CLINICAL 8777 05:35:50,560 --> 05:35:51,320 DISEASE COURSE. 8778 05:35:51,320 --> 05:35:52,240 AND WHILE THAT'S CERTAINLY AN 8779 05:35:52,240 --> 05:35:53,360 IMPORTANT PART OF PALLIATIVE 8780 05:35:53,360 --> 05:35:54,880 CARE, WHAT WE WANT TO EMPHASIZE 8781 05:35:54,880 --> 05:35:56,360 IS THAT PALLIATIVE CARE IS 8782 05:35:56,360 --> 05:35:57,600 REALLY APPROPRIATE FROM THE TIME 8783 05:35:57,600 --> 05:36:00,000 OF DIAGNOSIS. 8784 05:36:00,000 --> 05:36:01,440 SO IT IS REALLY IMPORTANT FOR US 8785 05:36:01,440 --> 05:36:02,960 TO FOCUS ON SYMPTOM MANAGEMENT 8786 05:36:02,960 --> 05:36:04,040 AND QUALITY OF LIFE FROM THE 8787 05:36:04,040 --> 05:36:05,440 TIME OF DIAGNOSIS ACROSS 8788 05:36:05,440 --> 05:36:09,280 SOMEONE'S DISEASE AND ILLNESS 8789 05:36:09,280 --> 05:36:12,440 COURSE. 8790 05:36:12,440 --> 05:36:16,280 WHEN WHICH THINK WE THINK ABOUE 8791 05:36:16,280 --> 05:36:17,600 APPROACH THINGS AS PALLIATIVE 8792 05:36:17,600 --> 05:36:19,840 CARE PROVIDERS, WE SEE THIS 8793 05:36:19,840 --> 05:36:21,360 WEDGE THAT REPRESENTS THIS TOTAL 8794 05:36:21,360 --> 05:36:22,440 OR HOLISTIC APPROACH. 8795 05:36:22,440 --> 05:36:24,400 STARTING AT THE TOP RIGHT, THE 8796 05:36:24,400 --> 05:36:26,360 PHYSICAL SYMPTOMS ARE SOME OF MT 8797 05:36:26,360 --> 05:36:27,480 COMMON THINGS PEOPLE THINK OF US 8798 05:36:27,480 --> 05:36:28,680 IN PALLIATIVE CARE AS BEING 8799 05:36:28,680 --> 05:36:30,560 HELPFUL WITH, AND FOR WHICH WE 8800 05:36:30,560 --> 05:36:31,960 OFTEN GET REFERRALS. 8801 05:36:31,960 --> 05:36:35,240 SO TREATING THINGS LIKE PAIN, 8802 05:36:35,240 --> 05:36:36,400 FATIGUE, DYSPNEA, WHICH ARE ALL 8803 05:36:36,400 --> 05:36:37,320 CERTAINLY IMPORTANT, BUT I JUST 8804 05:36:37,320 --> 05:36:38,600 WANT TO ALSO EMPHASIZE THAT WE 8805 05:36:38,600 --> 05:36:40,680 TRY TO TAKE A WHOLE APPROACH, 8806 05:36:40,680 --> 05:36:42,440 AGAIN, IN OUR INTERDISCIPLINARY 8807 05:36:42,440 --> 05:36:43,440 TEAMS TO ALSO THINK ABOUT ALL 8808 05:36:43,440 --> 05:36:46,520 THE OTHER WAYS IN WHICH SOMEONE 8809 05:36:46,520 --> 05:36:47,280 WITH A SERIOUS ILLNESS LIKE 8810 05:36:47,280 --> 05:36:48,240 SICKLE CELL DISEASE IS IMPACTED 8811 05:36:48,240 --> 05:36:49,160 BY THEIR ILLNESS. 8812 05:36:49,160 --> 05:36:51,560 SO THAT INCLUDES THINGS LIKE 8813 05:36:51,560 --> 05:36:53,640 EMOTIONAL ASPECTS, ASHLEY 8814 05:36:53,640 --> 05:36:55,040 POINTED OUT THAT THERE ARE HIGH 8815 05:36:55,040 --> 05:36:56,280 RATES OF ANXIETY AND DEPRESSION 8816 05:36:56,280 --> 05:36:57,400 AND THINKING ABOUT HOW YOU'RE 8817 05:36:57,400 --> 05:36:59,440 COPING WITH A SERIOUS ILLNESS. 8818 05:36:59,440 --> 05:37:00,600 SOCIAL SUPPORT, AND WE ALL KNOW 8819 05:37:00,600 --> 05:37:01,960 THAT MANY OF THE PATIENTS WITH 8820 05:37:01,960 --> 05:37:03,960 SICKLE CELL DISEASE HAVE 8821 05:37:03,960 --> 05:37:05,240 CHALLENGES WITH THEIR 8822 05:37:05,240 --> 05:37:06,000 RELATIONSHIP, THEIR LIVING 8823 05:37:06,000 --> 05:37:07,120 SITUATION AND FINANCIAL ISSUES 8824 05:37:07,120 --> 05:37:10,120 THAT IMPACT THEIR DISEASE. 8825 05:37:10,120 --> 05:37:10,600 SPIRITUALITY IF THAT IS 8826 05:37:10,600 --> 05:37:11,760 IMPORTANT TO THE PATIENT, WHERE 8827 05:37:11,760 --> 05:37:13,280 THEY FIND HOPE AND MEANING, AND 8828 05:37:13,280 --> 05:37:15,920 THEN AN OVERALL VIEW OF WHERE 8829 05:37:15,920 --> 05:37:17,560 THEY ARE IN THEIR ILLNESS, 8830 05:37:17,560 --> 05:37:19,720 THINKING ABOUT PROGNOSIS, THEIR 8831 05:37:19,720 --> 05:37:21,480 ILLNESS UNDERSTANDING, ADVANCED 8832 05:37:21,480 --> 05:37:24,480 CARE PLANNING, AND HOW TO REALLY 8833 05:37:24,480 --> 05:37:25,520 TAYLOR THEIR TREATMENT TO THEIR 8834 05:37:25,520 --> 05:37:28,160 OWN GOALS. 8835 05:37:28,160 --> 05:37:29,640 WHEN WE THINK ABOUT THE BENEFITS 8836 05:37:29,640 --> 05:37:31,360 OF PALLIATIVE CARE, I WILL SAY 8837 05:37:31,360 --> 05:37:33,360 AND AS ASHLEY POINTED OUT, 8838 05:37:33,360 --> 05:37:34,840 THERE'S VERY LIMITED DATA AND 8839 05:37:34,840 --> 05:37:36,360 EVIDENCE IN TERMS OF THE 8840 05:37:36,360 --> 05:37:39,480 INTEGRATION OF PALLIATIVE CARE 8841 05:37:39,480 --> 05:37:40,440 IN PATIENTS WITH SICKLE CELL 8842 05:37:40,440 --> 05:37:42,280 DISEASE. IN FACT, MUCH OF THE 8843 05:37:42,280 --> 05:37:43,480 EVIDENCE FOR PALLIATIVE CARE TO 8844 05:37:43,480 --> 05:37:44,480 DATE HAS BEEN INITIALLY STARTED 8845 05:37:44,480 --> 05:37:48,480 IN THE CANCER POPULATION, SO ONE 8846 05:37:48,480 --> 05:37:50,040 OF THE HALLMARK STUDIES WITHIN 8847 05:37:50,040 --> 05:37:52,080 OUR FIELD WAS ACTUALLY DONE WITH 8848 05:37:52,080 --> 05:37:53,080 THE GROUP AT THE HOSPITAL THAT I 8849 05:37:53,080 --> 05:37:54,640 WORK AT LOOKING AT PALLIATIVE 8850 05:37:54,640 --> 05:37:56,120 CARE INTEGRATION EARLY IN THE 8851 05:37:56,120 --> 05:37:58,240 DISEASE COURSE FOR THOSE WITH 8852 05:37:58,240 --> 05:37:59,880 METASTATIC NON-SMALL SELL LUNG 8853 05:37:59,880 --> 05:38:01,080 CANCER, AND WHAT THEY ACTUALLY 8854 05:38:01,080 --> 05:38:02,640 FOUND IN THAT STUDY WAS THAT 8855 05:38:02,640 --> 05:38:03,720 PATIENTS WHO HAD EARLY 8856 05:38:03,720 --> 05:38:05,320 PALLIATIVE CARE AS PART OF THEIR 8857 05:38:05,320 --> 05:38:06,760 DISEASE COURSE HAD NOT ONLY A 8858 05:38:06,760 --> 05:38:08,120 BETTER QUALITY OF LIFE BUT LOWER 8859 05:38:08,120 --> 05:38:10,040 RATES OF DEPRESSION AND ALSO A 8860 05:38:10,040 --> 05:38:11,680 LONGER SURVIVAL PERIOD WITH 8861 05:38:11,680 --> 05:38:12,360 THEIR DISEASE. 8862 05:38:12,360 --> 05:38:14,320 THIS HAS ALSO EXPANDED INTO 8863 05:38:14,320 --> 05:38:15,400 OTHER DISEASE STATES BEYOND 8864 05:38:15,400 --> 05:38:16,600 CANCER, SO THERE'S BEEN A LOT OF 8865 05:38:16,600 --> 05:38:19,560 EVIDENCE IN THE LAST FIVE TO 10 8866 05:38:19,560 --> 05:38:20,800 YEARS IN DISEASE STATES LIKE 8867 05:38:20,800 --> 05:38:23,200 HEART FAILURE, RECENTLY IN 8868 05:38:23,200 --> 05:38:24,440 CIRRHOSIS, AND AGAIN, NOT A LOT 8869 05:38:24,440 --> 05:38:26,080 OF EVIDENCE IN THE SICKLE CELL 8870 05:38:26,080 --> 05:38:26,880 POPULATION, BUT WE THINK THAT 8871 05:38:26,880 --> 05:38:28,120 THERE'S INCREDIBLE OPPORTUNITY 8872 05:38:28,120 --> 05:38:29,480 HERE. 8873 05:38:29,480 --> 05:38:31,040 A LOT OF THE INTEGRATION OF 8874 05:38:31,040 --> 05:38:32,120 PALLIATIVE CARE STUDIES HAVE 8875 05:38:32,120 --> 05:38:35,840 ALSO SHOWN IMPROVED CA CAREGIVER 8876 05:38:35,840 --> 05:38:37,720 AND FAMILY OUTCOMES AND THINGS 8877 05:38:37,720 --> 05:38:39,000 WHEN WE THINK THE HEALTHCARE 8878 05:38:39,000 --> 05:38:41,120 SYSTEM ARE ALSO BENEFICIAL, LIKE 8879 05:38:41,120 --> 05:38:43,320 COST SAVINGS, SHORTENED HOSPITAL 8880 05:38:43,320 --> 05:38:44,960 STAYS AND IMPROVED END OF LIFE 8881 05:38:44,960 --> 05:38:46,720 OUTCOMES AT THE END OF LIFE FOR 8882 05:38:46,720 --> 05:38:47,440 PATIENTS. 8883 05:38:47,440 --> 05:38:49,000 NOW TO SORT OF PUT THAT CONTEXT 8884 05:38:49,000 --> 05:38:50,800 AND HOW WE THINK ABOUT 8885 05:38:50,800 --> 05:38:52,160 PALLIATIVE CARE AND ITS EVIDENCE 8886 05:38:52,160 --> 05:38:53,240 BASE BACK INTO THE SICKLE CELL 8887 05:38:53,240 --> 05:38:55,080 DISEASE POPULATION. 8888 05:38:55,080 --> 05:38:56,600 AS ASHLEY POINTED OUT, YOU KNOW, 8889 05:38:56,600 --> 05:38:57,920 ONE OF THE FIRST THINGS WE WANT 8890 05:38:57,920 --> 05:38:59,400 TO MAKE A CASE FOR WHICH I DON'T 8891 05:38:59,400 --> 05:39:01,040 THINK WE HAVE TO CONVINCE ANY OF 8892 05:39:01,040 --> 05:39:03,760 YOU GUYS OF, IS THAT THIS 8893 05:39:03,760 --> 05:39:04,760 PATIENT POPULATION HAS SOME OF 8894 05:39:04,760 --> 05:39:06,840 THE HIGHEST NEED IN TERMS OF 8895 05:39:06,840 --> 05:39:08,560 PALLIATIVE CARE SUPPORT. 8896 05:39:08,560 --> 05:39:09,880 PARTICULARLY FROM A PROGNOSTIC 8897 05:39:09,880 --> 05:39:10,840 SENSE. 8898 05:39:10,840 --> 05:39:14,480 SO ASHLEY POINTED OUT THAT 8899 05:39:14,480 --> 05:39:15,760 RECENTLY THE AVERAGE LIFE 8900 05:39:15,760 --> 05:39:17,160 EXPECTANCY FOR SOMEONE WITH 8901 05:39:17,160 --> 05:39:18,360 SICKLE CELL DISEASE IS AROUND 50 8902 05:39:18,360 --> 05:39:19,400 YEARS OLD. 8903 05:39:19,400 --> 05:39:20,400 IT'S ALWAYS INCREDIBLE FOR ME TO 8904 05:39:20,400 --> 05:39:22,320 NOTE THAT AS RECENTLY AS 1970, 8905 05:39:22,320 --> 05:39:25,640 THAT WAS AS YOUNG AS 20 YEARS, 8906 05:39:25,640 --> 05:39:27,160 WE'VE MADE INCREDIBLE 8907 05:39:27,160 --> 05:39:28,240 IMPROVEMENT IN HOW LONG PEOPLE 8908 05:39:28,240 --> 05:39:32,640 ARE LIVING WITH THIS DISEASE, 8909 05:39:32,640 --> 05:39:34,880 BUT AS ASH LEA STATED, 50 YEARS 8910 05:39:34,880 --> 05:39:37,680 IS SO MUCH LOWER THAN THE 8911 05:39:37,680 --> 05:39:42,440 GENERATHAN THE LIFEEXPECTANCY OL 8912 05:39:42,440 --> 05:39:42,840 POPULATION. 8913 05:39:42,840 --> 05:39:44,080 THE MAIN CAUSES OF DEATH FOR 8914 05:39:44,080 --> 05:39:45,280 PATIENTS WITH SICKLE CELL 8915 05:39:45,280 --> 05:39:48,240 DISEASE, AS YOU GUYS WELL KNOW, 8916 05:39:48,240 --> 05:39:50,560 CVA, ACUTE CHEST, INFECTION, 8917 05:39:50,560 --> 05:39:51,840 MULTIORGAN FAILURE AND SUDDEN 8918 05:39:51,840 --> 05:39:52,280 CARDIAC DEATH. 8919 05:39:52,280 --> 05:39:54,040 AND WE ALSO KNOW THAT THERE IS 8920 05:39:54,040 --> 05:39:54,920 INEQUITY ACROSS THE SICKLE CELL 8921 05:39:54,920 --> 05:39:57,120 DISEASE POPULATION, AND THAT 8922 05:39:57,120 --> 05:40:00,720 SOME PATIENTS HAVE MORE SEVERE 8923 05:40:00,720 --> 05:40:01,840 DISEASE SUBTYPE AND THEY OFTEN 8924 05:40:01,840 --> 05:40:03,280 HAVE MORE CO-MORBIDITY WHEN WE 8925 05:40:03,280 --> 05:40:04,640 LOOK AT THINGS ACROSS THE 8926 05:40:04,640 --> 05:40:08,000 SPECTRUM. 8927 05:40:08,000 --> 05:40:09,520 SO THERE'S CERTAINLY INCREDIBLE 8928 05:40:09,520 --> 05:40:11,080 NEED FROM A PROGNOSTIC SENSE, 8929 05:40:11,080 --> 05:40:12,160 AND WE WOULD ALSO ARGUE THAT 8930 05:40:12,160 --> 05:40:14,800 WITH THIS INCREASING LIFE 8931 05:40:14,800 --> 05:40:16,360 EXPECTANCY COMES INCREASING RATE 8932 05:40:16,360 --> 05:40:17,920 OF MORBIDITY, SO ONE 8933 05:40:17,920 --> 05:40:20,360 OBSERVATIONAL STUDY SAW THAT 73% 8934 05:40:20,360 --> 05:40:23,120 OF SICKLE CELL DISEASE HAD 8935 05:40:23,120 --> 05:40:25,280 GREATER THAN ONE FORM OF 8936 05:40:25,280 --> 05:40:26,240 IRREVERSIBLE ORGAN DAMAGE, WHICH 8937 05:40:26,240 --> 05:40:28,120 WILL OFTEN COME WITH A VARIETY 8938 05:40:28,120 --> 05:40:29,200 OF SYMPTOMS. 8939 05:40:29,200 --> 05:40:32,080 SO THERE'S HIGHER SYMPTOM NEEDS, 8940 05:40:32,080 --> 05:40:33,600 AND THESE PATIENTS' 8941 05:40:33,600 --> 05:40:34,680 PSYCHOLOGICAL AND SOCIAL 8942 05:40:34,680 --> 05:40:36,560 STRESSORS, AND THEN AGAIN 8943 05:40:36,560 --> 05:40:38,240 THERE'S A PAUCITY OF ADVANCED 8944 05:40:38,240 --> 05:40:39,880 CARE PLANNING THAT'S OFTEN 8945 05:40:39,880 --> 05:40:40,480 HAPPENING. 8946 05:40:40,480 --> 05:40:42,240 SO WE SEE A REAL OPPORTUNITY 8947 05:40:42,240 --> 05:40:44,880 THERE TO THINK ABOUT MID CAL 8948 05:40:44,880 --> 05:40:52,080 MEDICALCARE PLANS, DECISION-MAKD 8949 05:40:52,080 --> 05:40:53,160 PLANNING FOR END OF LIFE WHICH 8950 05:40:53,160 --> 05:40:54,840 IS NOT REALLY HAPPENING RIGHT 8951 05:40:54,840 --> 05:40:55,160 NOW. 8952 05:40:55,160 --> 05:40:57,360 THERE'S A TON OF OPPORTUNITY, 8953 05:40:57,360 --> 05:40:58,680 AND I'LL JUST NAME SOME OF THE 8954 05:40:58,680 --> 05:41:00,000 WAYS IN WHICH WE FEEL LIKE WE 8955 05:41:00,000 --> 05:41:04,200 COULD MAKE A BETTER EVIDENCE 8956 05:41:04,200 --> 05:41:06,520 BASE AND HAVE A STRONGER 8957 05:41:06,520 --> 05:41:09,280 INTERVENTION FROM A PA PALLIATIE 8958 05:41:09,280 --> 05:41:10,120 CARE STANDPOINT. 8959 05:41:10,120 --> 05:41:11,600 SO I THINK ONE OF THE BIGGEST 8960 05:41:11,600 --> 05:41:13,000 NEEDS THAT YOU GUYS IDENTIFIED 8961 05:41:13,000 --> 05:41:14,560 WHEN WE STARTED OUT WITH THE 8962 05:41:14,560 --> 05:41:15,760 WORD CLOUD WAS IN PAIN AND 8963 05:41:15,760 --> 05:41:16,960 SYMPTOM MANAGEMENT. 8964 05:41:16,960 --> 05:41:18,200 ALSO ADVANCED CARE PLANNING, 8965 05:41:18,200 --> 05:41:19,080 THINKING ABOUT TRANSITIONS OF 8966 05:41:19,080 --> 05:41:19,480 CARE. 8967 05:41:19,480 --> 05:41:20,920 I KNOW THERE'S A VARIETY OF 8968 05:41:20,920 --> 05:41:22,520 PEOPLE HERE INTERESTED IN THAT 8969 05:41:22,520 --> 05:41:23,520 SPACE SPECIFICALLY, AND WE KNOW 8970 05:41:23,520 --> 05:41:25,640 THAT SOME OF THE OUTCOMES 8971 05:41:25,640 --> 05:41:27,160 WORSENED DURING THAT TIME IN 8972 05:41:27,160 --> 05:41:28,440 PARTICULAR. 8973 05:41:28,440 --> 05:41:29,920 THINKING ABOUT COMMUNICATION AND 8974 05:41:29,920 --> 05:41:33,440 CARE COORDINATION, IMPROVING 8975 05:41:33,440 --> 05:41:36,240 CAQUALITY OF LIFE AND FUNCTIONI, 8976 05:41:36,240 --> 05:41:37,920 A FOCUS ON TOTAL PAIN WHICH I'LL 8977 05:41:37,920 --> 05:41:39,640 TALK ABOUT IN A COUPLE OF 8978 05:41:39,640 --> 05:41:40,520 SLIDES, COMPLEX MEDICAL 8979 05:41:40,520 --> 05:41:40,880 DECISION-MAKING. 8980 05:41:40,880 --> 05:41:42,760 WE SEE AN INCREDIBLE ROLE FOR 8981 05:41:42,760 --> 05:41:44,680 SOCIAL JUSTICE AND ADVOCACY, AND 8982 05:41:44,680 --> 05:41:46,360 THEN THINKING ABOUT AGAIN 8983 05:41:46,360 --> 05:41:47,920 INTEGRATED AND MULTIDISCIPLINARY 8984 05:41:47,920 --> 05:41:49,000 CARE MODELS. 8985 05:41:49,000 --> 05:41:50,960 SO THIS IS JUST A SLIDE TO 8986 05:41:50,960 --> 05:41:52,920 HIGHLIGHT SORT OF THE 8987 05:41:52,920 --> 05:41:53,800 INTERDISCIPLINARY PALLIATIVE 8988 05:41:53,800 --> 05:41:57,200 CARE APPROACH THAT WE THINK HAS 8989 05:41:57,200 --> 05:41:59,080 INNATE VALUE AND REALLY ENHANCES 8990 05:41:59,080 --> 05:42:01,280 THE CARE OF THIS PATIENT 8991 05:42:01,280 --> 05:42:01,560 POPULATION. 8992 05:42:01,560 --> 05:42:03,520 THIS WAS A FIVE-YEAR STUDY AT 8993 05:42:03,520 --> 05:42:04,480 YALE CHILDREN'S THAT 8994 05:42:04,480 --> 05:42:07,360 DEMONSTRATED THE POWER OF JUST A 8995 05:42:07,360 --> 05:42:08,000 MULTIDISCIPLINARY APPROACH, SO 8996 05:42:08,000 --> 05:42:10,000 THEY WERE LOOKING AT PAIN AS AN 8997 05:42:10,000 --> 05:42:11,400 OUTCOME, AND THEY SAW THAT WHEN 8998 05:42:11,400 --> 05:42:14,240 THEY APPROACH IT FROM A 8999 05:42:14,240 --> 05:42:15,040 MULTIDISCIPLINARY STANDPOINT, 9000 05:42:15,040 --> 05:42:19,320 THEY ACTUALLY HAD A 61% OF 9001 05:42:19,320 --> 05:42:20,480 HOSPITALIZATIONS, DECREASED 9002 05:42:20,480 --> 05:42:22,080 LENGTH OF STAY AND REDUCED 9003 05:42:22,080 --> 05:42:22,920 READMISSION RATES BY ALMOST 9004 05:42:22,920 --> 05:42:23,280 HALF. 9005 05:42:23,280 --> 05:42:25,480 WHEN WE THINK ABOUT THE 9006 05:42:25,480 --> 05:42:26,480 OPPORTUNITY AGAIN JUST TO SORT 9007 05:42:26,480 --> 05:42:27,440 OF HIGHLIGHT SOME OF THE THINGS 9008 05:42:27,440 --> 05:42:28,760 THAT WE'VE NOTED IN THE DATA 9009 05:42:28,760 --> 05:42:30,600 THAT WE HAVE, PATIENTS WITH 9010 05:42:30,600 --> 05:42:31,600 SICKLE CELL DISEASE HAVE HIGHER 9011 05:42:31,600 --> 05:42:33,840 RATES OF DEPRESSION AND ANXIETY, 9012 05:42:33,840 --> 05:42:35,560 AND A LOT OF THIS IS WRAPPED 9013 05:42:35,560 --> 05:42:37,200 INTO THE COPING WITH THEIR 9014 05:42:37,200 --> 05:42:38,200 ILLNESS AND SPECIFICALLY HOW 9015 05:42:38,200 --> 05:42:39,400 THEY LEARN TO COPE OVER TIME 9016 05:42:39,400 --> 05:42:40,640 FROM BEING DIAGNOSED AND DEALING 9017 05:42:40,640 --> 05:42:42,560 WITH THIS THROUGHOUT THEIR LIFE. 9018 05:42:42,560 --> 05:42:44,320 AND SO PALLIATIVE CARE, I THINK 9019 05:42:44,320 --> 05:42:46,280 HAS A UNIQUE PERSPECTIVE IN THAT 9020 05:42:46,280 --> 05:42:47,720 SENSE AND CAN HELP WITH THAT IN 9021 05:42:47,720 --> 05:42:49,160 A WAY THAT MAYBE SOME OTHER 9022 05:42:49,160 --> 05:42:51,240 PROVIDERS WHO JUST APPROACH 9023 05:42:51,240 --> 05:42:54,280 DEPRESSION AND ANXIETY CAN'T. 9024 05:42:54,280 --> 05:42:56,760 AND THEN WHEN WE THINK ABOUT ARE 9025 05:42:56,760 --> 05:43:00,040 THERE SORT OF OPPORTUNITIES, 9026 05:43:00,040 --> 05:43:01,240 PATIENTS WITH -- OFTEN WILL HAVE 9027 05:43:01,240 --> 05:43:02,640 SOCIAL AND EMOTIONAL ISOLATION. 9028 05:43:02,640 --> 05:43:05,440 I CAN TELL YOU THAT I WORK IN A 9029 05:43:05,440 --> 05:43:06,320 COMPREHENSIVE ADULT SICKLE CELL 9030 05:43:06,320 --> 05:43:07,520 CLINIC AND IT'S MORE TIMES THAN 9031 05:43:07,520 --> 05:43:09,160 NOT THAT WHEN I ASK A PATIENT DO 9032 05:43:09,160 --> 05:43:10,880 YOU KNOW ANYONE ELSE IN YOUR 9033 05:43:10,880 --> 05:43:12,320 LIFE OR YOUR FAMILY WITH THIS 9034 05:43:12,320 --> 05:43:13,600 DISORDER, AND DESPITE IT BEING 9035 05:43:13,600 --> 05:43:14,960 VERY PREVALENT, THE ANSWER IS 9036 05:43:14,960 --> 05:43:17,160 OFTEN NO, AND THEY'VE OFTEN 9037 05:43:17,160 --> 05:43:21,960 SPENT THEIR WHOLE LIFE BEING THE 9038 05:43:21,960 --> 05:43:22,480 ONLY PERSON. 9039 05:43:22,480 --> 05:43:24,480 MANY OF MY ADULT PATIENTS ARE 9040 05:43:24,480 --> 05:43:25,720 FREQUENTLY NEEDING TO BE OUT OF 9041 05:43:25,720 --> 05:43:27,000 WORK OR GO OUT ON DISABILITY 9042 05:43:27,000 --> 05:43:29,480 BECAUSE OF THEIR PAIN CRISES AND 9043 05:43:29,480 --> 05:43:30,560 THEN HAVE GENERAL FRUSTRATION 9044 05:43:30,560 --> 05:43:31,800 WITH THE HEALTHCARE SYSTEM AND 9045 05:43:31,800 --> 05:43:33,640 HOW TO NAVIGATE THAT, AND 9046 05:43:33,640 --> 05:43:35,960 SUPPORT THEIR NEEDS WITH ALL OF 9047 05:43:35,960 --> 05:43:36,600 THE STABILITY. 9048 05:43:36,600 --> 05:43:38,120 AND THEN AS YOU GUYS KNOW, 9049 05:43:38,120 --> 05:43:40,880 THERE'S BEEN A TON OF RESEARCH 9050 05:43:40,880 --> 05:43:43,120 PRESENTED TODAY ON ADVANCED 9051 05:43:43,120 --> 05:43:45,520 THERAPIES, AND THINGS LIKE BONE 9052 05:43:45,520 --> 05:43:48,160 MARROW TRANSPLANTS, STEM CELL 9053 05:43:48,160 --> 05:43:48,760 TRANSPLANT, AND PATIENTS WITH 9054 05:43:48,760 --> 05:43:50,560 SICKLE CELL DISEASE ARE OFTEN 9055 05:43:50,560 --> 05:43:51,800 FACING THESE TREATMENT DECISIONS 9056 05:43:51,800 --> 05:43:54,000 AND I THINK THERE'S A NEED 9057 05:43:54,000 --> 05:43:55,080 OPPORTUNITY FOR US TO ASSIST 9058 05:43:55,080 --> 05:43:56,480 THEM IN THE DECISION-MAKING 9059 05:43:56,480 --> 05:43:57,200 THERE. 9060 05:43:57,200 --> 05:44:00,240 AND THEN FINALLY, AS WE THINK 9061 05:44:00,240 --> 05:44:02,440 ABOUT THEIR RISK FOR RECURRENT 9062 05:44:02,440 --> 05:44:04,400 HOSPITALIZATIONS AND ED VISITS 9063 05:44:04,400 --> 05:44:06,080 FROM COMPLICATIONS OF THE 9064 05:44:06,080 --> 05:44:08,880 DISEASE OVER TIME, ASH LEGAL 9065 05:44:08,880 --> 05:44:09,720 HIGHLIGHTED THAT MOST PEOPLE 9066 05:44:09,720 --> 05:44:11,160 WITH SICKLE CELL DISEASE DIE IN 9067 05:44:11,160 --> 05:44:12,040 THE HOSPITAL OR THE EMERGENCY 9068 05:44:12,040 --> 05:44:13,760 DEPARTMENT AND ALSO THEY OFTEN 9069 05:44:13,760 --> 05:44:17,200 SPEND THE LAST YEAR OF THEIR 9070 05:44:17,200 --> 05:44:18,560 LIFE MORE IN THE HOSPITAL THAN 9071 05:44:18,560 --> 05:44:19,120 NOT. 9072 05:44:19,120 --> 05:44:20,280 I THINK WHAT WE DON'T KNOW HERE 9073 05:44:20,280 --> 05:44:22,240 IS WE DON'T WANT TO PLACE ANY 9074 05:44:22,240 --> 05:44:22,920 VALUE ON WHERE WE THINK PATIENTS 9075 05:44:22,920 --> 05:44:23,600 WOULD WANT TO DIE. 9076 05:44:23,600 --> 05:44:27,200 WE CERTAINLY DON'T HAVE THAT 9077 05:44:27,200 --> 05:44:27,640 DATA. 9078 05:44:27,640 --> 05:44:29,360 BUT I THINK THIS SAYS A LOT 9079 05:44:29,360 --> 05:44:30,400 ABOUT WHAT'S HAPPENING AND HOW 9080 05:44:30,400 --> 05:44:31,400 LITTLE CONVERSATION IS HAPPENING 9081 05:44:31,400 --> 05:44:32,400 OVER TIME AND THE REAL 9082 05:44:32,400 --> 05:44:35,080 OPPORTUNITY THERE. 9083 05:44:35,080 --> 05:44:38,280 SO WHEN WE THINK ABOUT TOTAL 9084 05:44:38,280 --> 05:44:39,960 PAIN, THE THING THAT WE WANTED 9085 05:44:39,960 --> 05:44:41,720 TO EMPHASIZE FROM A PALLIATIVE 9086 05:44:41,720 --> 05:44:48,560 CARE LENS IS THAT -- IS PRIDE OF 9087 05:44:48,560 --> 05:44:49,800 CARE -- PAIN AS A TOTAL PAIN 9088 05:44:49,800 --> 05:44:50,680 EXPERIENCE. 9089 05:44:50,680 --> 05:44:51,760 WHAT WE KNOW IS THERE ARE 9090 05:44:51,760 --> 05:44:53,800 CERTAINLY BIOLOGICAL FACTORS. 9091 05:44:53,800 --> 05:44:55,640 THE BIOLOGY WE KNOW THAT'S 9092 05:44:55,640 --> 05:44:57,840 BEHIND SICKLE CELL DISEASE 9093 05:44:57,840 --> 05:44:59,840 THAT'S CAUSING PAIN EPISODES. 9094 05:44:59,840 --> 05:45:01,440 IN ADDITION TO THAT, ALL THE 9095 05:45:01,440 --> 05:45:03,040 OTHER THINGS WE MENTIONED, THE 9096 05:45:03,040 --> 05:45:04,360 PSYCHOLOGICAL DISTRESS THAT 9097 05:45:04,360 --> 05:45:05,240 THESE PATIENTS EXPERIENCE OVER 9098 05:45:05,240 --> 05:45:07,760 TIME AND ALSO THE SOCIAL FACTORS 9099 05:45:07,760 --> 05:45:09,400 REALLY CONTRIBUTE TO THIS TOTAL 9100 05:45:09,400 --> 05:45:10,920 PAIN EXPERIENCE, AND I KNOW THAT 9101 05:45:10,920 --> 05:45:16,520 MANY OF YOU WHO TAKE CARE OF 9102 05:45:16,520 --> 05:45:17,800 PATIENTS -- SOMETIMES PATIENTS 9103 05:45:17,800 --> 05:45:18,920 COME IN WITH WORSENING PAIN WHEN 9104 05:45:18,920 --> 05:45:20,560 THEY'RE HAVING PSYCHOLOGICAL 9105 05:45:20,560 --> 05:45:21,960 DISTRESS AND SOCIAL FACTORS THAT 9106 05:45:21,960 --> 05:45:23,680 ARE REALLY EXACERBATED IN THEIR 9107 05:45:23,680 --> 05:45:24,520 LIFE. 9108 05:45:24,520 --> 05:45:26,440 SO AS PALLIATIVE CARE DOCTORS, 9109 05:45:26,440 --> 05:45:29,360 WE REALLY ARE THINKING ABOUT 9110 05:45:29,360 --> 05:45:30,640 THAT, HOW TO TREAT TOTAL PAIN 9111 05:45:30,640 --> 05:45:33,040 AND ALSO HOW TO NOT ONLY TREAT 9112 05:45:33,040 --> 05:45:37,120 WITH OPIOIDS BUT ALSO THINK 9113 05:45:37,120 --> 05:45:38,720 ABOUT OTHER PAIN MANAGEMENT 9114 05:45:38,720 --> 05:45:39,280 INTERVENTIONS. 9115 05:45:39,280 --> 05:45:41,360 AND THEN AS WE THINK ABOUT, YOU 9116 05:45:41,360 --> 05:45:42,040 KNOW, SORT OF THE OPPORTUNITY 9117 05:45:42,040 --> 05:45:43,720 FOR ADVANCED CARE PLANNING AND 9118 05:45:43,720 --> 05:45:45,880 GOALS OF CARE DISCUSSIONS, THESE 9119 05:45:45,880 --> 05:45:47,320 PATIENTS REALLY HAVE TO NAVIGATE 9120 05:45:47,320 --> 05:45:49,320 THE MEDICAL SYSTEM THAT'S 9121 05:45:49,320 --> 05:45:50,640 BECOMING MORE AND MORE COMPLEX 9122 05:45:50,640 --> 05:45:50,960 OVER TIME. 9123 05:45:50,960 --> 05:45:52,600 WE'VE TALKED ABOUT THE INEQUITY 9124 05:45:52,600 --> 05:45:54,800 THAT THEY'VE ALL EXPERIENCED, 9125 05:45:54,800 --> 05:45:56,480 NOT ONLY IN INDIVIDUAL 9126 05:45:56,480 --> 05:45:57,120 ENCOUNTERS BUT SORT OF OVER THE 9127 05:45:57,120 --> 05:46:00,000 COURSE OF THEIR DISEASE OVER 9128 05:46:00,000 --> 05:46:01,600 TIME, AND THERE'S REALLY AN 9129 05:46:01,600 --> 05:46:04,680 OPPORTUNITY THERE TO FIF THEM GM 9130 05:46:04,680 --> 05:46:05,680 MORE SUPPORT AND 9131 05:46:05,680 --> 05:46:06,240 DECISION-MAKING. 9132 05:46:06,240 --> 05:46:07,840 AND THEN FINALLY, THEIR 9133 05:46:07,840 --> 05:46:08,840 PSYCHOLOGICAL AND SPIRITUAL 9134 05:46:08,840 --> 05:46:10,040 SUPPORT, A NEED FOR MENTAL 9135 05:46:10,040 --> 05:46:13,360 HEALTH SUPPORT AND ALSO SOCIAL 9136 05:46:13,360 --> 05:46:15,600 WORK CONGLOMERATE WHICH IS OFTEN 9137 05:46:15,600 --> 05:46:16,760 A PART OF OUR PALLIATIVE CARE 9138 05:46:16,760 --> 05:46:17,040 TEAMS. 9139 05:46:17,040 --> 05:46:19,960 SO JUST IN SUMMARY, I THINK WE 9140 05:46:19,960 --> 05:46:22,520 ALL AGREE THERE'S -- WE 9141 05:46:22,520 --> 05:46:25,280 DEFINITELY NEED TO DEVELOP MORE 9142 05:46:25,280 --> 05:46:26,560 EVIDENCE FOR THAT. 9143 05:46:26,560 --> 05:46:27,880 PATIENTS WITH SICKLE CELL 9144 05:46:27,880 --> 05:46:30,720 DISEASE OFTEN HAVE INCREDIBLE 9145 05:46:30,720 --> 05:46:32,320 MORBIDITY AND CONTINUE TO HAVE 9146 05:46:32,320 --> 05:46:32,960 HIGHER MORTALITY AT A YOUNGER 9147 05:46:32,960 --> 05:46:34,600 AGE THAT REALLY IS AN 9148 05:46:34,600 --> 05:46:35,600 OPPORTUNITY FOR PALLIATIVE CARE 9149 05:46:35,600 --> 05:46:35,800 SUPPORT. 9150 05:46:35,800 --> 05:46:38,800 I'M GOING TO TRANSITION TO 9151 05:46:38,800 --> 05:46:39,960 EBERECHI, WHO'S GOING TO TALK A 9152 05:46:39,960 --> 05:46:40,840 LITTLE BIT ABOUT THE DATA SHE 9153 05:46:40,840 --> 05:46:42,240 HAS COLLECTED FROM HER 9154 05:46:42,240 --> 05:46:45,920 CROSS-SECTIONAL STUDY. 9155 05:46:45,920 --> 05:46:54,640 >>THANK YOU SO MUCH, STEPH. 9156 05:46:54,640 --> 05:46:56,640 SO I HOPE OVER THE PAST FEW 9157 05:46:56,640 --> 05:46:58,120 MINUTES WE'VE BEEN HERE THAT 9158 05:46:58,120 --> 05:47:01,360 STEPH AND ASHLEY HAVE GIVEN YOU 9159 05:47:01,360 --> 05:47:04,440 A STRONG CASE FOR PALLIATIVE 9160 05:47:04,440 --> 05:47:09,160 CARE IN SICKLE CELL DISEASE. 9161 05:47:09,160 --> 05:47:10,920 SO THE BIG QUESTION THAT I ASK 9162 05:47:10,920 --> 05:47:13,080 IS YES, I KNOW HOW I FEEL ABOUT 9163 05:47:13,080 --> 05:47:14,200 PALLIATIVE CARE AND SICKLE CELL 9164 05:47:14,200 --> 05:47:15,640 DISEASE, BUT WHAT DO SICKLE CELL 9165 05:47:15,640 --> 05:47:18,040 DISEASE PROVIDERS THINK ABOUT 9166 05:47:18,040 --> 05:47:20,040 PALLIATIVE CARE? 9167 05:47:20,040 --> 05:47:21,600 SO TO ANSWER THIS QUESTION, WE 9168 05:47:21,600 --> 05:47:23,080 CONDUCTED A CROSS-SECTIONAL 9169 05:47:23,080 --> 05:47:25,480 STUDY OF SICKLE CELL PROVIDERS. 9170 05:47:25,480 --> 05:47:30,240 WHAT WE DID WAS WE CREATED A 9171 05:47:30,240 --> 05:47:32,320 47-ITEM CONFIDENTIAL LINE-BASED 9172 05:47:32,320 --> 05:47:35,760 STUDY THAT ADDRESSED FIVE NAMES 9173 05:47:35,760 --> 05:47:37,040 THAT LOOKED AT PALLIATIVE CARE 9174 05:47:37,040 --> 05:47:38,120 AND SICKLE CELL DISEASE. 9175 05:47:38,120 --> 05:47:39,760 THIS SURVEY WAS REVIEWED BY 9176 05:47:39,760 --> 05:47:41,400 THREE HEMATOLOGISTS AND ONE 9177 05:47:41,400 --> 05:47:42,640 PALLIATIVE CARE PHYSICIAN, AND 9178 05:47:42,640 --> 05:47:45,280 THEY WENT THROUGH MULTIPLE 9179 05:47:45,280 --> 05:47:47,240 ITERATIONS PRIOR TO LAUNCH. 9180 05:47:47,240 --> 05:47:51,960 WE TARGETED SICKLE CELL PROVIDER 9181 05:47:51,960 --> 05:47:54,360 GROUPS AND ALSO SENT INDIVIDUAL 9182 05:47:54,360 --> 05:47:57,880 EMAILS TO PROVIDERS, USING THE 9183 05:47:57,880 --> 05:47:59,440 SCAPN METHOD TO GET AS MANY 9184 05:47:59,440 --> 05:48:00,640 PARTICIPANTS AS POSSIBLE. 9185 05:48:00,640 --> 05:48:02,840 SO IN TERMS OF THIS STUDY, I 9186 05:48:02,840 --> 05:48:09,600 WOULD SAY OUR EXCLUSION CRITERIA 9187 05:48:09,600 --> 05:48:10,960 WAS ESSENTIALLY ANY PROVIDER WHO 9188 05:48:10,960 --> 05:48:13,600 DID NOT HAVE PROVIDER PRACTICE 9189 05:48:13,600 --> 05:48:14,520 WITH PATIENTS WITH SICKLE CELL 9190 05:48:14,520 --> 05:48:15,520 DISEASE. 9191 05:48:15,520 --> 05:48:18,960 THE SURVEY WAS COMPLETED OVER A 9192 05:48:18,960 --> 05:48:23,440 FOUR-MONTH PERIOD, SO I WILL 9193 05:48:23,440 --> 05:48:27,000 SPENT SOME -- WHAT WE DID WAS WE 9194 05:48:27,000 --> 05:48:31,280 PERFORMED EXPLORATORY FACTOR AND 9195 05:48:31,280 --> 05:48:32,560 THIS ANALYSIS YIELDED SEVEN 9196 05:48:32,560 --> 05:48:33,240 INDIVIDUAL FACTORS. 9197 05:48:33,240 --> 05:48:35,200 WE USED THESE SEVEN FACTORS TO 9198 05:48:35,200 --> 05:48:36,560 BE THE NEW DOMAINS FOR THE 9199 05:48:36,560 --> 05:48:39,040 SURVEY. 9200 05:48:39,040 --> 05:48:42,840 THIS WAS A NEW SURVEY FOR US. 9201 05:48:42,840 --> 05:48:46,480 WE ALSO DID INTERNAL CONSISTENCY 9202 05:48:46,480 --> 05:48:50,160 RELIABILITY OF EACH DOMAIN MAIN 9203 05:48:50,160 --> 05:48:53,480 USING CRONBACH'S ALPHA. 9204 05:48:53,480 --> 05:48:55,680 WE DID COMPOSITE SCORES THAT 9205 05:48:55,680 --> 05:49:01,640 WERE CALCULATED FOR THE DOMAINS. 9206 05:49:01,640 --> 05:49:07,680 WE DID A ZERO ORDER CORRELATION 9207 05:49:07,680 --> 05:49:11,920 SO I WILL GO OVER THE MAZE THAT 9208 05:49:11,920 --> 05:49:12,840 WE IDENTIFIED. 9209 05:49:12,840 --> 05:49:14,360 FIRST LET'S TALK ABOUT THE 9210 05:49:14,360 --> 05:49:14,720 PARTICIPANTS. 9211 05:49:14,720 --> 05:49:20,720 SO THE M MAJORITY OF PHYSICIANS 9212 05:49:20,720 --> 05:49:22,800 WERE FAIL MAIL, THERE WAS A NICE 9213 05:49:22,800 --> 05:49:25,000 MIX OF EARLY, YEAR AND MID 9214 05:49:25,000 --> 05:49:25,640 PROVIDERS. 9215 05:49:25,640 --> 05:49:31,520 THE MAJORITY WITH -- PEDIATRIC 9216 05:49:31,520 --> 05:49:32,360 HEMATOLOGIST? 9217 05:49:32,360 --> 05:49:34,320 IN TERMS OF PRACTICE TYPE, MOTH 9218 05:49:34,320 --> 05:49:36,880 WORK FROM TEACHING HOSPITALS AND 9219 05:49:36,880 --> 05:49:37,640 COMPREHENSIVE SICKLE CELL 9220 05:49:37,640 --> 05:49:38,080 CENTERS. 9221 05:49:38,080 --> 05:49:44,520 MOST HAD A MIXED -- IN 9222 05:49:44,520 --> 05:49:46,760 OUTPATIENT PRACTICE. 9223 05:49:46,760 --> 05:49:49,200 63% SAID THEY HAD A PRACTICE 9224 05:49:49,200 --> 05:49:50,320 THAT INCLUDED GREATER THAN 50% 9225 05:49:50,320 --> 05:49:51,440 OF CARE FOR PATIENTS WITH SICKLE 9226 05:49:51,440 --> 05:49:52,240 CELL DISEASE. 9227 05:49:52,240 --> 05:49:55,800 AND THEN THE MAJORITY OF OUR 9228 05:49:55,800 --> 05:49:57,120 PARTICIPANTS DID NOT HAVE PRIOR 9229 05:49:57,120 --> 05:50:03,440 PALLIATIVE CARE TRAINING. 9230 05:50:03,440 --> 05:50:04,680 ONLY 27% REPORTED TAKING COURSES 9231 05:50:04,680 --> 05:50:06,320 IN PALLIATIVE CARE OR ATTENDED A 9232 05:50:06,320 --> 05:50:08,000 LECTURE IN PALLIATIVE CARE, AND 9233 05:50:08,000 --> 05:50:10,080 THEN 13% SAID THEY HAD SOME SORT 9234 05:50:10,080 --> 05:50:11,800 OF FORMAL PALLIATIVE CARE 9235 05:50:11,800 --> 05:50:12,480 ROTATION DURING TRAINING, 9236 05:50:12,480 --> 05:50:14,840 WHETHER IT WAS A RESIDENCY OR IN 9237 05:50:14,840 --> 05:50:15,320 FELLOWSHIP. 9238 05:50:15,320 --> 05:50:17,320 AND THEN OF THE PROVIDERS, 40% 9239 05:50:17,320 --> 05:50:19,520 REPORTED THAT THEY HAVE NEVER 9240 05:50:19,520 --> 05:50:20,480 REFERRED A PATIENT TO PALLIATIVE 9241 05:50:20,480 --> 05:50:27,600 CARE. 9242 05:50:27,600 --> 05:50:29,600 THE FIRST DOMAIN WE LOOKED AT 9243 05:50:29,600 --> 05:50:32,120 LOOKED AT PROVIDERS' FREQUENCY 9244 05:50:32,120 --> 05:50:33,200 WITH PALLIATIVE CARE 9245 05:50:33,200 --> 05:50:33,760 COLLABORATION. 9246 05:50:33,760 --> 05:50:36,320 SO TO ADDRESS THIS, WE ASKED IN 9247 05:50:36,320 --> 05:50:38,040 YOUR DEALINGS WITH PATIENTS WITH 9248 05:50:38,040 --> 05:50:39,480 SICKLE CELL DISEASE, HOW OFTEN 9249 05:50:39,480 --> 05:50:40,800 DO YOU COLLABORATE WITH. 9250 05:50:40,800 --> 05:50:43,080 AND TO ORIENT YOU GUYS HERE, THE 9251 05:50:43,080 --> 05:50:44,680 OPTIONS FOR RESPONSE IS OFTEN, 9252 05:50:44,680 --> 05:50:48,920 WHICH IS GREEN, OCCASIONAL WHICH 9253 05:50:48,920 --> 05:50:49,800 IS BLUE, AND NEVER. 9254 05:50:49,800 --> 05:50:55,480 WHAT WE SEE HERE IS THAT 60% OF 9255 05:50:55,480 --> 05:50:57,120 THE PARTICIPANTS REPORT THAT 9256 05:50:57,120 --> 05:50:59,120 THEY OFTEN OR OCCASIONALLY 9257 05:50:59,120 --> 05:51:01,000 COLLABORATE WITH INPATIENT 9258 05:51:01,000 --> 05:51:02,960 PALLIATIVE CARE TEAMS. 9259 05:51:02,960 --> 05:51:04,800 37% REPORTS THAT THEY 9260 05:51:04,800 --> 05:51:06,840 COLLABORATE WITH OUTPATIENT 9261 05:51:06,840 --> 05:51:08,440 PALLIATIVE CARE TEAMS, BUT WHEN 9262 05:51:08,440 --> 05:51:10,000 IT CAME TO HOSPICE, WHETHER 9263 05:51:10,000 --> 05:51:11,520 INPATIENT OR OUTPATIENT, THAT 9264 05:51:11,520 --> 05:51:15,200 NUMBER DROPPED TO 20%. 9265 05:51:15,200 --> 05:51:20,720 THE NEXT DOUGH MAYBE DOMAIN WE S 9266 05:51:20,720 --> 05:51:21,360 PROVIDERS' DIRECT INVOLVEMENT IN 9267 05:51:21,360 --> 05:51:22,920 SYMPTOM MANAGEMENT. 9268 05:51:22,920 --> 05:51:24,800 AGAIN TO ORIENT YOU GUYS TO THIS 9269 05:51:24,800 --> 05:51:26,200 GRAPH, IT'S A LITTLE BUSY, SO WE 9270 05:51:26,200 --> 05:51:27,440 ASKED THEM, IN YOUR DEALINGS 9271 05:51:27,440 --> 05:51:29,040 WITH PATIENTS WITH SICKLE CELL 9272 05:51:29,040 --> 05:51:31,080 DISEASE, HOW OFTEN ARE YOU 9273 05:51:31,080 --> 05:51:32,720 INVOLVED WITH: AND WE HAVE 9274 05:51:32,720 --> 05:51:33,680 THOSE ITEMS THERE. 9275 05:51:33,680 --> 05:51:36,080 AND THE RESPONSE, THEY COULD 9276 05:51:36,080 --> 05:51:38,320 RESPOND TO US OFTEN, WHICH IS 9277 05:51:38,320 --> 05:51:39,760 GREEN, OCCASIONAL, WHICH IS 9278 05:51:39,760 --> 05:51:41,680 YELL, AND RARELY, WHICH IS 9279 05:51:41,680 --> 05:51:41,920 YELLOW. 9280 05:51:41,920 --> 05:51:42,760 TO KIND OF WRAP THIS UP NICELY 9281 05:51:42,760 --> 05:51:44,240 FOR YOU, WHAT I WOULD SUMMARIZE 9282 05:51:44,240 --> 05:51:48,480 FROM THIS IS THAT PROVIDERS 9283 05:51:48,480 --> 05:51:54,120 SPENT A GREAT DEAL MANAGING 9284 05:51:54,120 --> 05:51:54,720 SICKLE CELL SYMPTOMS AND 9285 05:51:54,720 --> 05:51:55,280 DISEASE. 9286 05:51:55,280 --> 05:51:59,720 SO FOR INSTANCE, WE HAVE -- 9287 05:51:59,720 --> 05:52:02,360 PERCENT REPORT THEY ARE OCCASION 9288 05:52:02,360 --> 05:52:04,160 OCCASIONALLY OR OFTEN INVOLVED 9289 05:52:04,160 --> 05:52:10,880 IN MANAGING CHRONIC PAIN. 9290 05:52:10,880 --> 05:52:17,840 80%, GNAW YA AND VOMITING, A 9291 05:52:17,840 --> 05:52:20,160 GOOD -- THEY ARE OCCASIONALLY 9292 05:52:20,160 --> 05:52:23,240 INVOLVED IN THIS SYMPTOM. 9293 05:52:23,240 --> 05:52:28,600 THE NEXT DOMAIN LOOKED AT DIRECT 9294 05:52:28,600 --> 05:52:33,120 INVOLVEMENT IN END OF LIFE CARE. 9295 05:52:33,120 --> 05:52:36,920 OFTEN, OCCASIONAL OR RARELY. 9296 05:52:36,920 --> 05:52:39,280 I THINK THE KEY POINT HERE TO 9297 05:52:39,280 --> 05:52:42,920 NOTE IS THAT UNLIKE THE LAST 9298 05:52:42,920 --> 05:52:43,920 DOMAIN, PROVIDERS REPORT THAT 9299 05:52:43,920 --> 05:52:46,520 THEY ARE RARELY INVOLVED IN 9300 05:52:46,520 --> 05:52:47,680 DISCUSSING END OF LIFE 9301 05:52:47,680 --> 05:52:48,600 PREFERENCES WITH THEIR PATIENTS. 9302 05:52:48,600 --> 05:52:52,640 SO WE HAVE 64%. 9303 05:52:52,640 --> 05:52:54,680 AND 77% SAID THEY ARE RARELY 9304 05:52:54,680 --> 05:52:56,200 INVOLVED IN RECOMMENDING HOSPICE 9305 05:52:56,200 --> 05:52:57,480 FOR PATIENTS. 9306 05:52:57,480 --> 05:53:02,320 SO I WOULD SAY FROM THE LAST TWO 9307 05:53:02,320 --> 05:53:04,960 DOMAINS TWO AND -- THIS IS 9308 05:53:04,960 --> 05:53:08,560 REALLY I THINK POTENTIAL FEUNTS 9309 05:53:08,560 --> 05:53:11,440 FOR US AS CHILD CARE PROVIDERS 9310 05:53:11,440 --> 05:53:13,680 TO WORK AND COLLABORATE AND WORK 9311 05:53:13,680 --> 05:53:16,720 HAND IN HAND WITH SICKLE CELL 9312 05:53:16,720 --> 05:53:18,800 PROVIDERS, AND THAT WE'RE ALSO 9313 05:53:18,800 --> 05:53:21,200 HAVING THESE CONVERSATIONS 9314 05:53:21,200 --> 05:53:23,360 REGARDING PREFERENCES, AND AS WE 9315 05:53:23,360 --> 05:53:25,640 TALK ABOUT IN ADVANCED CARE 9316 05:53:25,640 --> 05:53:26,280 PLANNING AS WELL. 9317 05:53:26,280 --> 05:53:30,480 SO THE NEXT DOMAIN WAS THAT 9318 05:53:30,480 --> 05:53:30,960 PROVIDERS ATTITUDE ABOUT 9319 05:53:30,960 --> 05:53:31,320 PALLIATIVE CARE. 9320 05:53:31,320 --> 05:53:33,120 AND THE QUESTION SAID DO YOU 9321 05:53:33,120 --> 05:53:34,200 AGREE WITH THE FOLLOWING 9322 05:53:34,200 --> 05:53:35,640 STATEMENTS ABOUT THE MANAGEMENT 9323 05:53:35,640 --> 05:53:39,080 OF PATIENTS WITH SICKLE CELL 9324 05:53:39,080 --> 05:53:42,440 DISEASE? 9325 05:53:42,440 --> 05:53:43,680 TO ORIENT YOU, THE RESPONSES 9326 05:53:43,680 --> 05:53:52,800 THEY GIVE STRONGLY AGREE, WHICH 9327 05:53:52,800 --> 05:53:54,000 GREEN, STRONGLY DISAGREE IS THE 9328 05:53:54,000 --> 05:53:54,640 DARK GREEN. 9329 05:53:54,640 --> 05:54:00,040 WHAT WE SEE HERE IS THAT 88% OF 9330 05:54:00,040 --> 05:54:01,280 PROVIDERS AGREED THAT PATIENTS 9331 05:54:01,280 --> 05:54:02,400 WITH SICKLE CELL WOULD BENEFIT 9332 05:54:02,400 --> 05:54:08,520 FROM PALLIATIVE CARE. 9333 05:54:08,520 --> 05:54:10,920 WHAT I FOUND EVEN MORE 9334 05:54:10,920 --> 05:54:12,280 INTERESTING WAS THAT 79% AGREED 9335 05:54:12,280 --> 05:54:13,480 THAT PATIENTS WITH SICKLE CELL 9336 05:54:13,480 --> 05:54:15,360 DISEASE WOULD BENEFIT FROM EARLY 9337 05:54:15,360 --> 05:54:18,600 INITIATION OF PALLIATIVE CARE, 9338 05:54:18,600 --> 05:54:21,200 AND THEN 99% DISAGREED THAT 9339 05:54:21,200 --> 05:54:22,520 PALLIATIVE CARE IS ONLY FOR 9340 05:54:22,520 --> 05:54:29,760 DYING PATIENTS. 9341 05:54:29,760 --> 05:54:31,720 THEN WE LOOKED AT ATTITUDES 9342 05:54:31,720 --> 05:54:33,200 ABOUT PALLIATIVE CARE PROVIDER, 9343 05:54:33,200 --> 05:54:34,720 AND I WOULD JUST SUMMARIZE AND 9344 05:54:34,720 --> 05:54:36,440 SAY WHICH IS THAT 40% OF 9345 05:54:36,440 --> 05:54:37,960 PROVIDERS FELT THAT OR AGREED 9346 05:54:37,960 --> 05:54:39,680 THAT PALLIATIVE CARE PROVIDERS, 9347 05:54:39,680 --> 05:54:41,240 WE, DO NOT HAVE ENOUGH 9348 05:54:41,240 --> 05:54:42,920 UNDERSTANDING OF SICKLE CELL TO 9349 05:54:42,920 --> 05:54:47,840 MANAGE THE PSYCHOLOGICAL 9350 05:54:47,840 --> 05:54:49,360 SYMPTOMS OF SICKLE CELL. 9351 05:54:49,360 --> 05:54:53,640 OVER 5 50% AGREED PALLIATIVE CAE 9352 05:54:53,640 --> 05:54:55,360 PROVIDERS DO NOT HAVE ENOUGH 9353 05:54:55,360 --> 05:54:56,400 KNOWLEDGE OF SICKLE CELL TO 9354 05:54:56,400 --> 05:54:57,240 MANAGE PHYSICAL SYMPTOMS OF 9355 05:54:57,240 --> 05:54:57,840 SICKLE CELL DISEASE. 9356 05:54:57,840 --> 05:55:00,360 THE NEXT DOMAIN LOOKED AT 9357 05:55:00,360 --> 05:55:01,520 PROVIDER SENSE OF OWNERSHIP OF 9358 05:55:01,520 --> 05:55:05,800 PALLIATIVE CARE INTERVENTIONS. 9359 05:55:05,800 --> 05:55:07,280 I WILL SAY AGAIN TO SUMMARIZE 9360 05:55:07,280 --> 05:55:10,440 THIS QUITE BUSY RESULTS HERE, 9361 05:55:10,440 --> 05:55:13,280 OVER 90% OF THE PROVIDERS AGREED 9362 05:55:13,280 --> 05:55:15,920 THAT THE SICKLE CELL PROVIDER 9363 05:55:15,920 --> 05:55:19,520 SHOULD BE AN EXPERT IN MANAGING 9364 05:55:19,520 --> 05:55:21,760 THE PHYSICAL SYMPTOM OF SICKLE 9365 05:55:21,760 --> 05:55:23,920 CELL DISEASE. 9366 05:55:23,920 --> 05:55:26,160 AND THEN 70% AGREE THAT THE 9367 05:55:26,160 --> 05:55:28,080 SICKLE CELL PROVIDER SHOULD BE 9368 05:55:28,080 --> 05:55:34,160 AN EXPERT IN THE MANAGEMENT -- 9369 05:55:34,160 --> 05:55:34,640 SICKLE CELL DISEASE. 9370 05:55:34,640 --> 05:55:37,000 BUT INTERESTING ENOUGH AS WELL, 9371 05:55:37,000 --> 05:55:38,440 80% DISAGREED THAT SICKLE CELL 9372 05:55:38,440 --> 05:55:39,920 PROVIDERS ARE THE BEST PEOPLE OR 9373 05:55:39,920 --> 05:55:41,760 THE BEST PERSON TO PROVIDE 9374 05:55:41,760 --> 05:55:42,680 PALLIATIVE CARE TO THEIR 9375 05:55:42,680 --> 05:55:43,680 PATIENTS. 9376 05:55:43,680 --> 05:55:48,640 AGAIN, I THINK THIS HIGHLIGHTS 9377 05:55:48,640 --> 05:55:49,520 THE OPPORTUNITY TO COLLABORATE 9378 05:55:49,520 --> 05:55:51,840 WITH EACH OTHER TO ENSURE THAT 9379 05:55:51,840 --> 05:55:53,400 THE SYMPTOMS OF OUR PATIENTS ARE 9380 05:55:53,400 --> 05:55:54,040 ADDRESSED. 9381 05:55:54,040 --> 05:55:57,400 AND THEN THE LAST DOMAIN IS 9382 05:55:57,400 --> 05:55:58,720 PROVIDERS' PERCEPTION OF 9383 05:55:58,720 --> 05:56:00,800 PATIENTS AB REACTION TO 9384 05:56:00,800 --> 05:56:02,120 PALLIATIVE CARE. 9385 05:56:02,120 --> 05:56:04,280 SO THE QUESTION IF A PALLIATIVE 9386 05:56:04,280 --> 05:56:05,800 CARE REFERRAL WAS SUGGESTED TO 9387 05:56:05,800 --> 05:56:08,360 MY PATIENT WITH SICKLE CELL 9388 05:56:08,360 --> 05:56:10,800 DISEASE, THEY MIGHT, AND THE 9389 05:56:10,800 --> 05:56:13,520 RESPONSES ARE AGREE, HIGHLY 9390 05:56:13,520 --> 05:56:15,080 AGREE, DISAGREE AND STRONGLY 9391 05:56:15,080 --> 05:56:15,720 DISAGREE. 9392 05:56:15,720 --> 05:56:18,720 PROVIDERS FELT THAT A GOOD CHUNK 9393 05:56:18,720 --> 05:56:21,280 OF PATIENTS -- NOTHING CAN BE 9394 05:56:21,280 --> 05:56:26,520 DONE FOR HAIR -- WILL TALK TO 9395 05:56:26,520 --> 05:56:28,200 THEM ABOUT DYING. 9396 05:56:28,200 --> 05:56:29,560 THESE RESPONSES, I WILL SAY OVER 9397 05:56:29,560 --> 05:56:32,280 70% OF RESPONSES THAT SAID 9398 05:56:32,280 --> 05:56:34,520 HIGHLLY AGREEABLE, AGREE. 9399 05:56:34,520 --> 05:56:35,160 ON THE OTHER HAND AS WELL, IF 9400 05:56:35,160 --> 05:56:36,160 YOU LOOK AT THE BOTTOM OF THIS 9401 05:56:36,160 --> 05:56:39,080 CHART, OF THIS GRAPH, IT ALSO -- 9402 05:56:39,080 --> 05:56:40,680 THE PROVIDERS REPORT THEY FELT 9403 05:56:40,680 --> 05:56:43,640 IF THEY REFERRED THEIR PATIENTS 9404 05:56:43,640 --> 05:56:45,440 TO PALLIATIVE CARE, THAT THEY 9405 05:56:45,440 --> 05:56:47,040 MIGHT THINK THE MORE SUPPORT 9406 05:56:47,040 --> 05:56:48,960 THEY GOT, THE BETTER THEY WILL 9407 05:56:48,960 --> 05:56:51,080 FEEL, AND ALSO THE PATIENT MIGHT 9408 05:56:51,080 --> 05:56:53,120 FEEL THAT THEY'RE MORE IN 9409 05:56:53,120 --> 05:56:56,120 CONTROL OF THEIR SITUATION. 9410 05:56:56,120 --> 05:56:58,240 SO HOW HOW PATIENTS RESPOND TO 9411 05:56:58,240 --> 05:57:00,840 PALLIATIVE CARE. 9412 05:57:00,840 --> 05:57:02,280 I WILL STIP THE SLIDE. 9413 05:57:02,280 --> 05:57:06,280 SO JUST TO GIVE A BIRD'S EYE 9414 05:57:06,280 --> 05:57:08,360 OVERVIEW OF THE DOMAINS, WE HAVE 9415 05:57:08,360 --> 05:57:10,560 THE MEAN OF THE COMPOSITE 9416 05:57:10,560 --> 05:57:11,840 SCORES, THE STANDARD DEVIATION 9417 05:57:11,840 --> 05:57:13,560 AND RANGE, AND THEN LIKE I 9418 05:57:13,560 --> 05:57:14,840 MENTIONED, WE DID THE 9419 05:57:14,840 --> 05:57:16,120 CORRELATION ANALYSIS TO SEE IF 9420 05:57:16,120 --> 05:57:20,400 THERE WAS ANY RELATIONSHIP 9421 05:57:20,400 --> 05:57:22,840 BETWEEN THE DIFFERENT DOMAINS. 9422 05:57:22,840 --> 05:57:25,520 WE HAVE SOME STATISTIC LITTLE 9423 05:57:25,520 --> 05:57:27,760 SIGNIFICANT FINDINGS, WHAT THE 9424 05:57:27,760 --> 05:57:30,720 CORRELATIONS WERE WEAK OR 9425 05:57:30,720 --> 05:57:31,280 NEGLIGIBLE. 9426 05:57:31,280 --> 05:57:34,840 SO AT THIS TIME WHAT WE LOOK 9427 05:57:34,840 --> 05:57:37,760 FORWARD TO DOING IS A SEEING 9428 05:57:37,760 --> 05:57:38,880 THAT THERE'S A RELATIONSHIP 9429 05:57:38,880 --> 05:57:40,600 BETWEEN THOSE AND THE DOMAINS 9430 05:57:40,600 --> 05:57:43,720 THAT WE HAVE THERE FOR THE 9431 05:57:43,720 --> 05:57:43,960 SURVEY. 9432 05:57:43,960 --> 05:57:46,480 SO IN CONCLUSION, SICKLE CELL 9433 05:57:46,480 --> 05:57:48,360 PROVIDERS REPORT FREQUENT 9434 05:57:48,360 --> 05:57:49,680 INVOLVEMENT IN SYMPTOM 9435 05:57:49,680 --> 05:57:51,080 MANAGEMENT. 9436 05:57:51,080 --> 05:57:53,080 THEY ALSO REPORT LESS 9437 05:57:53,080 --> 05:57:54,480 INVOLVEMENT IN END OF LIFE 9438 05:57:54,480 --> 05:57:56,200 DISCUSSION AND CARE. 9439 05:57:56,200 --> 05:57:58,440 AND MOST SICKLE CELL PROVIDERS 9440 05:57:58,440 --> 05:58:00,280 THINK THAT THEIR PATIENTS WOULD 9441 05:58:00,280 --> 05:58:01,400 BENEFIT TO EARLY INTRODUCTION TO 9442 05:58:01,400 --> 05:58:02,840 PALLIATIVE CARE. 9443 05:58:02,840 --> 05:58:04,040 HOWEVER, PROVIDERS ALSO STAY 9444 05:58:04,040 --> 05:58:09,040 CONCERNED THAT THEIR SO -- 9445 05:58:09,040 --> 05:58:11,600 >>LEAKING, SO -- 9446 05:58:11,600 --> 05:58:17,120 >>SO MORE STUDIES ARE NEEDED 9447 05:58:17,120 --> 05:58:20,400 TO -- I WILL SAY WE DID A FOCUS 9448 05:58:20,400 --> 05:58:22,200 GROUP STUDY THAT RAN PARALLEL TO 9449 05:58:22,200 --> 05:58:25,600 THIS SURVEY STUDY AND WE DO 9450 05:58:25,600 --> 05:58:27,120 HOPE -- ON BARRIERS, AND WE HOPE 9451 05:58:27,120 --> 05:58:29,280 TO SHARE THE RESULTS OF THAT 9452 05:58:29,280 --> 05:58:31,120 QUALITATIVE STUDY IN THE NEAR 9453 05:58:31,120 --> 05:58:33,640 FUTURE. 9454 05:58:33,640 --> 05:58:35,160 LASTLY DISCUSSIONS ARE NEEDED 9455 05:58:35,160 --> 05:58:38,280 BETWEEN PALLIATIVE CARE 9456 05:58:38,280 --> 05:58:39,560 PROVIDERS AND -- TO IDENTIFY 9457 05:58:39,560 --> 05:58:42,640 WAYS IN WHICH PALLIATIVE CARE 9458 05:58:42,640 --> 05:58:43,520 CAN BENEFIT INDIVIDUALS WITH 9459 05:58:43,520 --> 05:58:44,680 SICKLE CELL DISEASE. 9460 05:58:44,680 --> 05:58:47,400 AND WITH THAT SAID, I WOULD LIKE 9461 05:58:47,400 --> 05:58:50,240 TO ACKNOWLEDGE THE PRIDE-FTG 9462 05:58:50,240 --> 05:58:53,600 PROGRAM WHICH FUNDED THIS STUDY. 9463 05:58:53,600 --> 05:58:56,800 DR. BETTY PACE, DIRECTOR OF THAT 9464 05:58:56,800 --> 05:59:06,560 PROGRAM, DR. IFY OSUNKWO, MY 9465 05:59:06,560 --> 05:59:10,320 MENTOR, AND I THINK A LOT OF 9466 05:59:10,320 --> 05:59:12,480 WHAT WE'RE HOPING TO DO IS TO 9467 05:59:12,480 --> 05:59:16,560 INCREASE EX-PE SURE OF CALTIVE 9468 05:59:16,560 --> 05:59:19,360 CARE AND SICKLE CELL DISEASE 9469 05:59:19,360 --> 05:59:19,960 THROUGH SICKLE CELL 9470 05:59:19,960 --> 05:59:20,520 PRESENTATION. 9471 05:59:20,520 --> 05:59:22,160 WE LAUNCHED A PALLIATIVE CARE 9472 05:59:22,160 --> 05:59:23,600 AND SICKLE CELL WORKING GROUP 9473 05:59:23,600 --> 05:59:24,400 WHERE A LOT OF PROVIDERS IN 9474 05:59:24,400 --> 05:59:25,520 PALLIATIVE CARE WERE INTERESTED 9475 05:59:25,520 --> 05:59:26,920 IN THIS AREA OR WORKING TOGETHER 9476 05:59:26,920 --> 05:59:29,400 TO SEE HOW WE CAN BRING 9477 05:59:29,400 --> 05:59:32,240 INCREASED EXPOSURE TO THIS AREA 9478 05:59:32,240 --> 05:59:33,080 IN OUR FIELD. 9479 05:59:33,080 --> 05:59:36,360 AND THEN WE'LL ALSO LOOK INTO 9480 05:59:36,360 --> 05:59:39,280 ONE DEFINE THE ROLE OF 9481 05:59:39,280 --> 05:59:42,480 PALLIATIVE CARE IN SICKLE CELL, 9482 05:59:42,480 --> 05:59:44,200 TO BETTER DEFINE WHAT IS OUR 9483 05:59:44,200 --> 05:59:47,160 ROLE IN THIS DISEASE MANAGEMENT. 9484 05:59:47,160 --> 05:59:53,360 AND THEN LASTLY, KREE HEN SIEVE 9485 05:59:53,360 --> 05:59:54,280 SICKLE CELL CLINICS, WE'RE 9486 05:59:54,280 --> 05:59:57,120 HOPING TO DEVELOP MORE HOW-TO 9487 05:59:57,120 --> 05:59:59,600 GUIDES TO GUIDE OUR CLINICAL 9488 05:59:59,600 --> 06:00:00,600 MANAGEMENT AND SYMPTOM 9489 06:00:00,600 --> 06:00:01,600 MANAGEMENT OF THIS POPULATION. 9490 06:00:01,600 --> 06:00:04,240 SO AGAIN, THANK YOU ALL SO MUCH 9491 06:00:04,240 --> 06:00:05,440 FOR YOUR ATTENTION, AND WE 9492 06:00:05,440 --> 06:00:06,440 REALLY DO APPRECIATE THIS 9493 06:00:06,440 --> 06:00:11,000 PLATFORM TO TALK ABOUT THIS. 9494 06:00:11,000 --> 06:00:13,960 >>THANK YOU. 9495 06:00:13,960 --> 06:00:15,280 ANY QUESTIONS FROM THE AUDIENCE? 9496 06:00:15,280 --> 06:00:17,720 OKAY. 9497 06:00:17,720 --> 06:00:19,200 >>HI, THAT WAS A GREAT 9498 06:00:19,200 --> 06:00:19,680 QUESTION. 9499 06:00:19,680 --> 06:00:22,160 I'M FROM UCSF-OAKLAND. 9500 06:00:22,160 --> 06:00:24,000 I WANTED TO KNOW FROM YOU -- WE 9501 06:00:24,000 --> 06:00:27,720 HAVE PSYCHOLOGY IN OUR CLINIC. 9502 06:00:27,720 --> 06:00:30,760 WE ALSO HAVE AN INTEGRATIVE PAIN 9503 06:00:30,760 --> 06:00:31,400 LINK. 9504 06:00:31,400 --> 06:00:34,160 SO WE UTILIZE THAT ARE MORE THAN 9505 06:00:34,160 --> 06:00:36,320 OUR PALLIATIVE TEAM, SO I WANTED 9506 06:00:36,320 --> 06:00:39,360 TO HEAR FROM YOU, WHERE DO YOU 9507 06:00:39,360 --> 06:00:42,200 SEE THOSE TEAMS COLLABORATING 9508 06:00:42,200 --> 06:00:42,640 MAYBE TOGETHER? 9509 06:00:42,640 --> 06:00:43,880 BECAUSE IT SEEMS LIKE A LOT OF 9510 06:00:43,880 --> 06:00:45,080 THINGS THAT YOU WERE ADDRESSING 9511 06:00:45,080 --> 06:00:46,520 ARE ADDRESSED BY OUR PSYCHOLOGY 9512 06:00:46,520 --> 06:00:48,520 TEAM AND PAIN TEAM. 9513 06:00:48,520 --> 06:00:51,120 >>DEFINITELY, THERE'S AN 9514 06:00:51,120 --> 06:00:53,080 OVERLAP BETWEEN THOSE 9515 06:00:53,080 --> 06:00:54,840 DISCIPLINES, WHICH IS WHY WE SAY 9516 06:00:54,840 --> 06:00:56,800 PALLIATIVE CARE IS A 9517 06:00:56,800 --> 06:00:58,160 MULTIDISCIPLINARY FIELD N A 9518 06:00:58,160 --> 06:00:58,960 PALLIATIVE CARE TEAM, YOU COULD 9519 06:00:58,960 --> 06:01:01,360 HAVE A PSYCHOLOGIST PART OF OUR 9520 06:01:01,360 --> 06:01:01,680 TEAM. 9521 06:01:01,680 --> 06:01:04,600 WE COULD HAVE PHARMACISTS AS 9522 06:01:04,600 --> 06:01:05,800 PART OF OUR TEAM OR A NURSE. 9523 06:01:05,800 --> 06:01:08,000 SO HAVING THOSE MEMBERS OF THE 9524 06:01:08,000 --> 06:01:11,840 TEAM IN YOUR INSTITUTION, THEY 9525 06:01:11,840 --> 06:01:13,240 ARE FILLING THE ROLE THAT WE 9526 06:01:13,240 --> 06:01:16,080 COULD FILL BUT ADDING ADDITIONAL 9527 06:01:16,080 --> 06:01:16,840 PALLIATIVE CARE PROVIDERS TO 9528 06:01:16,840 --> 06:01:19,080 TALK ABOUT OTHER ASPECTS OF 9529 06:01:19,080 --> 06:01:19,640 THEIR CARE WILL BE 9530 06:01:19,640 --> 06:01:20,160 COMPLEMENTARY. 9531 06:01:20,160 --> 06:01:21,280 IT DOESN'T DISTRACT, IT JUST 9532 06:01:21,280 --> 06:01:23,680 ADDS TO THE LAYER OF SUPPORT 9533 06:01:23,680 --> 06:01:25,280 THAT THE PATIENT GETS. 9534 06:01:25,280 --> 06:01:27,240 IT'S A LAYER OF SUPPORT THAT WE 9535 06:01:27,240 --> 06:01:28,560 WOULD PROVIDE TO OUR PATIENT. 9536 06:01:28,560 --> 06:01:31,760 THAT'S HOW I WOULD LOOK AT THAT. 9537 06:01:31,760 --> 06:01:33,000 >>ONE -- 9538 06:01:33,000 --> 06:01:33,640 >>THANK YOU SO MUCH. 9539 06:01:33,640 --> 06:01:35,640 THIS WAS REALLY GREAT AND I'M SO 9540 06:01:35,640 --> 06:01:39,200 GLAD THAT WILL YOU FIND THAT 9541 06:01:39,200 --> 06:01:39,760 PALLIATIVE CARE AT THE VERY 9542 06:01:39,760 --> 06:01:42,800 BEGINNING IS WHERE WE NEED TO 9543 06:01:42,800 --> 06:01:43,440 BE. 9544 06:01:43,440 --> 06:01:45,000 ONE OF THE THINGS THAT WE'VE 9545 06:01:45,000 --> 06:01:47,680 FOUND IN ALL OUR ADVOCATING WORK 9546 06:01:47,680 --> 06:01:49,520 OF WELL OVER, I DON'T KNOW, 9547 06:01:49,520 --> 06:01:51,000 2,000 HOURS AT POINT OF CARE, IS 9548 06:01:51,000 --> 06:01:53,040 THAT WHEN WE HAVE A PALLIATIVE 9549 06:01:53,040 --> 06:01:57,520 CARE TEAM INVOLVED, IT PROVIDES 9550 06:01:57,520 --> 06:01:59,120 PROTECTION FOR PARTICULARLY OUR 9551 06:01:59,120 --> 06:02:03,040 ADULTS, AND BY THAT, I MEAN 9552 06:02:03,040 --> 06:02:06,120 ANYBODY THAT COMES IN CAN EFFECT 9553 06:02:06,120 --> 06:02:06,560 THE CARE. 9554 06:02:06,560 --> 06:02:08,960 IF THEY HAVE A PALLIATIVE CARE 9555 06:02:08,960 --> 06:02:15,040 TEAM, THEN HE ARE AVOID ALL THAT 9556 06:02:15,040 --> 06:02:16,440 INTERFERENCE AND HAVE THAT 9557 06:02:16,440 --> 06:02:17,760 CONNECTIVITY AND CARE, SO I 9558 06:02:17,760 --> 06:02:18,760 THINK THAT'S SOMETHING THAT YOU 9559 06:02:18,760 --> 06:02:21,560 NEED TO REALLY SERIOUSLY --, YOU 9560 06:02:21,560 --> 06:02:22,240 KNOW, LOOK AT. 9561 06:02:22,240 --> 06:02:23,760 THE OTHER IS, A CLEARER 9562 06:02:23,760 --> 06:02:28,120 DEFINITION OF PALLIATIVE CARE, 9563 06:02:28,120 --> 06:02:32,280 HOSPICE, AND I SUE YOU USE SAW E 9564 06:02:32,280 --> 06:02:33,760 CURATIVE, WE USE CHRONIC CARE. 9565 06:02:33,760 --> 06:02:35,120 SOMETHING LIKE THAT THAT'S 9566 06:02:35,120 --> 06:02:36,520 REALLY CLEAR WILL HELP EDUCATE 9567 06:02:36,520 --> 06:02:38,160 BOTH THE PATIENTS AND THE DOCS. 9568 06:02:38,160 --> 06:02:38,960 THANK YOU. 9569 06:02:38,960 --> 06:02:39,960 >>THANK YOU FOR THOSE POINTS. 9570 06:02:39,960 --> 06:02:40,400 >>THANK YOU. 9571 06:02:40,400 --> 06:02:42,040 THANK YOU, EVERYBODY. 9572 06:02:42,040 --> 06:02:43,680 OKAY. 9573 06:02:43,680 --> 06:02:45,240 SO WE'RE MOVE ON TO THE NEXT 9574 06:02:45,240 --> 06:02:45,440 TALK. 9575 06:02:45,440 --> 06:02:47,040 WE'RE GOING TO CHANGE A LITTLE 9576 06:02:47,040 --> 06:02:47,600 GEARS HERE. 9577 06:02:47,600 --> 06:02:53,400 SO THE NEXT TALK IS FROM 9578 06:02:53,400 --> 06:02:56,520 DR. SERGEI NEKHAI FROM HOWARD 9579 06:02:56,520 --> 06:02:57,560 UNIVERSITY, HIV INFECTION IN 9580 06:02:57,560 --> 06:03:07,920 SICKLE CELL DISEASE. 9581 06:03:15,600 --> 06:03:26,080 CAN WE GO TO THE NEXT SLIDE SET? 9582 06:03:39,720 --> 06:03:41,920 >>I'D LIKE TO THANK THE 9583 06:03:41,920 --> 06:03:42,640 ORGANIZERS, EVERYBODY WHO STAYED 9584 06:03:42,640 --> 06:03:45,000 TO THE END OF THE SESSIONS, IT'S 9585 06:03:45,000 --> 06:03:48,760 MY PLEASURE TO TALK HERE ABOUT 9586 06:03:48,760 --> 06:03:49,960 THE -- 9587 06:03:49,960 --> 06:03:54,240 [ZOOM INTERRUPTION] 9588 06:03:54,240 --> 06:03:55,720 >>CAN YOU MUTE YOUR PHONE, 9589 06:03:55,720 --> 06:04:00,920 PLEASE? 9590 06:04:00,920 --> 06:04:03,360 GREAT YOU THOO. YOU LET ME 9591 06:04:03,360 --> 06:04:04,840 THANK YOU. 9592 06:04:04,840 --> 06:04:05,720 I THOUGHT IT WAS SOMETHING ABOUT 9593 06:04:05,720 --> 06:04:06,520 ME. 9594 06:04:06,520 --> 06:04:08,520 I'M GOING TO TALK TO YOU ABOUT 9595 06:04:08,520 --> 06:04:09,800 THE HIV INFECTION IN PATIENTS 9596 06:04:09,800 --> 06:04:10,600 WITH SICKLE CELL DISEASE. 9597 06:04:10,600 --> 06:04:11,680 I DON'T HAVE CONFLICTS OF 9598 06:04:11,680 --> 06:04:14,840 INTEREST. 9599 06:04:14,840 --> 06:04:17,920 SO THE STORY GOES WHA BACK TO TE 9600 06:04:17,920 --> 06:04:21,600 LATE 80s AND EARLY 90s WHEN 9601 06:04:21,600 --> 06:04:22,440 DR. CASTRO, DIRECTOR OF THE 9602 06:04:22,440 --> 06:04:25,440 SICKLE CELL CENTER NOTICED THAT 9603 06:04:25,440 --> 06:04:27,840 PATIENTS WITH SICKLE CELL 9604 06:04:27,840 --> 06:04:30,400 DISEASE HAD LOWER LEVELS OF 9605 06:04:30,400 --> 06:04:31,280 ANTIBODIES AGAINST HIV AS 9606 06:04:31,280 --> 06:04:36,880 OPPOSED TO THE HIGH LEVELS OF 9607 06:04:36,880 --> 06:04:41,320 ANTIBODIES AGAINST --. 9608 06:04:41,320 --> 06:04:45,920 STUDY WAS CONDUCTED WITH THE 9609 06:04:45,920 --> 06:04:47,040 PATIENTS, SEVERAL PATIENTS WERE 9610 06:04:47,040 --> 06:04:48,360 IDENTIFIED WITH HIV INFECTION 9611 06:04:48,360 --> 06:04:50,560 AND SICKLE CELL DISEASE AND 9612 06:04:50,560 --> 06:04:51,480 THOSE PATIENTS SEEM TO PROGRESS 9613 06:04:51,480 --> 06:04:56,600 SLOWER TO THE AIDS, BASICALLY TO 9614 06:04:56,600 --> 06:04:58,840 BE NON-PROGRESSERS COMPARED TO 9615 06:04:58,840 --> 06:05:00,280 THE CONTROL PARTICIPANTS WITH 9616 06:05:00,280 --> 06:05:04,240 JUST HIV INFECTION. 9617 06:05:04,240 --> 06:05:06,760 SO WE LATER ANALYZED THESE 9618 06:05:06,760 --> 06:05:07,680 CHALLENGES FROM THE HOSPITALS 9619 06:05:07,680 --> 06:05:12,800 WHERE WE LOOKED AT THE CHANCES 9620 06:05:12,800 --> 06:05:15,080 OF HAVING SICKLE CELL DISEASE 9621 06:05:15,080 --> 06:05:18,240 AND HIV AND THE ODDS WERE LOWER 9622 06:05:18,240 --> 06:05:19,760 FOR THE HIV AND SICKLE CELL 9623 06:05:19,760 --> 06:05:24,160 DISEASE COMPARED TO THE -- 9624 06:05:24,160 --> 06:05:24,440 INFECTION. 9625 06:05:24,440 --> 06:05:29,280 THERE WAS A RECENT STUDY FROM 9626 06:05:29,280 --> 06:05:32,920 SHAWN KELLY AT UCSF-OAKLAND 9627 06:05:32,920 --> 06:05:34,600 WHERE THEY FOUND SICKLE CELL 9628 06:05:34,600 --> 06:05:36,120 PATIENTS HAVE AGAIN LOWER RISK 9629 06:05:36,120 --> 06:05:37,640 OF INFECTION COMPARED TO THE 9630 06:05:37,640 --> 06:05:41,480 OTHER GROUPS OF PEOPLE WHERE WE 9631 06:05:41,480 --> 06:05:45,360 WERE RECEIVING MUCH BLOOD 9632 06:05:45,360 --> 06:05:46,240 TRANSFUSIONS. 9633 06:05:46,240 --> 06:05:47,440 ALSO A COUPLE REPORTS FROM 9634 06:05:47,440 --> 06:05:48,440 AFRICA WHERE SICKLE CELL 9635 06:05:48,440 --> 06:05:50,200 PATIENTS WERE FOUND TO HAVE LOW 9636 06:05:50,200 --> 06:05:55,800 RISK OF INFECTION SO THIS WAS IN 9637 06:05:55,800 --> 06:05:57,200 THE DEMOCRATIC REPUBLIC OF CONGO 9638 06:05:57,200 --> 06:05:58,440 AND ALSO NIGERIA. 9639 06:05:58,440 --> 06:06:02,400 SO A FEW YEARS AGO WE ANALYZED 9640 06:06:02,400 --> 06:06:04,760 EX VIVO HIV INFECTION, SO WE 9641 06:06:04,760 --> 06:06:10,000 USED HIV VIRUS WHICH HAS 9642 06:06:10,000 --> 06:06:16,520 MUTATION -- PART OF GENOME, AND 9643 06:06:16,520 --> 06:06:22,320 ALSO IN CONTRAST TO THE STUDY BY 9644 06:06:22,320 --> 06:06:26,400 SHAWN KELLY ACTUATED PBMCs -- 9645 06:06:26,400 --> 06:06:28,720 INFECTION ONLY -- ACTIVATE 9646 06:06:28,720 --> 06:06:29,160 PBMCs. 9647 06:06:29,160 --> 06:06:32,920 SO WE SEE DECREASE IN THE 9648 06:06:32,920 --> 06:06:34,360 HA1 ROUND INFECTION AND ALSO CAN 9649 06:06:34,360 --> 06:06:40,160 DETECT ALL OF THE HIV -- LOWER 9650 06:06:40,160 --> 06:06:41,800 RATE OF TRANSCRIPTION AND WE 9651 06:06:41,800 --> 06:06:44,040 COULD ALSO DETECT LESS HIV 9652 06:06:44,040 --> 06:06:47,440 ADVERSE TRANSCRIPTION INDICATING 9653 06:06:47,440 --> 06:06:50,000 THAT THE EARLY POST INFECTIOUS 9654 06:06:50,000 --> 06:06:50,800 STEP OF HIV INFECTION. 9655 06:06:50,800 --> 06:06:53,520 SO INITIALLY WE FOCUSED ON THE 9656 06:06:53,520 --> 06:07:03,560 ROLE OF IRON, SO WE USED CALLS 9657 06:07:03,560 --> 06:07:04,480 YUM, WHICH -- FOR IRON INSIDE 9658 06:07:04,480 --> 06:07:12,040 THE CELLS, SO WE SEE FRACTION, 9659 06:07:12,040 --> 06:07:16,840 WE HAVE LESS INTA -- SUPPORTED 9660 06:07:16,840 --> 06:07:20,320 BY THE INCREASED LEVEL OF -- 9661 06:07:20,320 --> 06:07:24,680 MARKER OF THE INTRACELLULAR IRON 9662 06:07:24,680 --> 06:07:30,920 TO THE ROLE OF IRON IN CELLS. 9663 06:07:30,920 --> 06:07:33,360 THIS WAS ALL SUPPORTED BY THE -- 9664 06:07:33,360 --> 06:07:36,360 NO CHANGE IN DECREASE -- IN THE 9665 06:07:36,360 --> 06:07:40,040 PATIENTS. 9666 06:07:40,040 --> 06:07:42,920 SO OUR PREVIOUS STUDIES SHOW IF 9667 06:07:42,920 --> 06:07:49,040 YOU BLOCK IRON IN CELLS USING 9668 06:07:49,040 --> 06:07:51,800 IRON -- ONE OF THE CELL CYCLE 9669 06:07:51,800 --> 06:07:53,240 KINASES AND WE LOOKED WHAT 9670 06:07:53,240 --> 06:07:54,000 HAPPENED IN SICKLE CELL 9671 06:07:54,000 --> 06:07:59,240 PATIENTS, WE SEE DECREASE IN THE 9672 06:07:59,240 --> 06:08:04,160 CDK2 ACTIVITY, SO THE SELL 9673 06:08:04,160 --> 06:08:07,240 CYCLES IS INVOLVED IN THE -- 9674 06:08:07,240 --> 06:08:13,560 WHICH IS ONE OF THE -- FACTORS. 9675 06:08:13,560 --> 06:08:18,560 DECREASED IN SICKLE CELL 9676 06:08:18,560 --> 06:08:21,760 PATIENTS -- SO HERE WE SEE -- 9677 06:08:21,760 --> 06:08:25,680 ONE ACTIVITY GOES UP, IT REDUCES 9678 06:08:25,680 --> 06:08:29,080 NUCLEOTIDES IN CELLS AND CAN 9679 06:08:29,080 --> 06:08:30,440 BLOCK REVERSE TRANSCRIPTIONS. 9680 06:08:30,440 --> 06:08:32,840 SO WE WANTED TO CONTINUE THE 9681 06:08:32,840 --> 06:08:39,080 STUDY WITH FULLY -- EFFECT 9682 06:08:39,080 --> 06:08:41,400 AGAINST SICKLE CELL DISEASE 9683 06:08:41,400 --> 06:08:45,440 DERIVED PBMCs TO CONTROL WE 9684 06:08:45,440 --> 06:08:50,600 SEE -- WHICH WE CAN DETECT -- 9685 06:08:50,600 --> 06:08:57,600 MRNA AND WE CAN ALSO DETECT P24 9686 06:08:57,600 --> 06:09:04,600 IN PBMCS AND WE CAN ALSO 9687 06:09:04,600 --> 06:09:10,160 DETECT -- INCLUDING -- 9688 06:09:10,160 --> 06:09:11,760 TRANSCRIPTION, CIRCLES AND 9689 06:09:11,760 --> 06:09:16,680 INTEGRATION OF -- DNA. 9690 06:09:16,680 --> 06:09:20,160 SO WE WANTED TO DIG INTO THE -- 9691 06:09:20,160 --> 06:09:20,400 FACTORS. 9692 06:09:20,400 --> 06:09:23,320 THIS IS THE RNA SEQ. 9693 06:09:23,320 --> 06:09:25,960 PBMCs WHICH ARE ACTIVATED SO 9694 06:09:25,960 --> 06:09:28,560 MY SICKLE CELL PATIENT DERIVED 9695 06:09:28,560 --> 06:09:29,320 SAMPLES. 9696 06:09:29,320 --> 06:09:33,120 SO WE DETECTED AROUND 2,000 9697 06:09:33,120 --> 06:09:36,160 GENES WHICH WERE UP AND DOWN 9698 06:09:36,160 --> 06:09:38,360 REGULATED, 1900 GENES WERE 9699 06:09:38,360 --> 06:09:43,360 UPREGULATED, ABOUT 200 GENES 9700 06:09:43,360 --> 06:09:50,040 WERE DOWNREGULATED. 9701 06:09:50,040 --> 06:09:55,200 SO THE TOP WE DETECT WAS -- 9702 06:09:55,200 --> 06:09:59,800 WHICH IS KNOWN FOR ITS ANTIVIRAL 9703 06:09:59,800 --> 06:10:04,000 ACTIVITY AGAINST PARVO VIRUSES, 9704 06:10:04,000 --> 06:10:14,480 AND THE HAV, ACTUALLY IT LEADS 9705 06:10:15,720 --> 06:10:19,320 TO -- SOME OTHER FACTORS -- 9706 06:10:19,320 --> 06:10:25,160 RECEPTORS IN DIFFERENT FACTORS, 9707 06:10:25,160 --> 06:10:27,040 WE'LL ALSO SEE CONSISTENTLY 9708 06:10:27,040 --> 06:10:30,200 HIGHER LEVELS OF P21. 9709 06:10:30,200 --> 06:10:34,840 SO WE CHOSE -- THEN WE ALSO DID 9710 06:10:34,840 --> 06:10:39,600 THE ANALYSIS WHICH BASICALLY WAS 9711 06:10:39,600 --> 06:10:42,760 ALSO KIND OF CLOSE LOOK AT THE 9712 06:10:42,760 --> 06:10:43,440 DIFFERENT FACTORS IN SICKLE 9713 06:10:43,440 --> 06:10:43,720 CELL. 9714 06:10:43,720 --> 06:10:47,680 SO WE PUT TOGETHER CLOSE TO 50 9715 06:10:47,680 --> 06:10:50,720 KNOWN RESTRICTION -- FACTORS 9716 06:10:50,720 --> 06:10:52,320 INVOLVED IN -- AND SEE THOSE 9717 06:10:52,320 --> 06:10:56,560 FACTORS ARE HIGHLY -- PBMCs TO 9718 06:10:56,560 --> 06:11:00,160 CONTROLS WITH HIGH NORMALIZED 9719 06:11:00,160 --> 06:11:04,000 ENRICHMENT, ADDITIONAL -- ON THE 9720 06:11:04,000 --> 06:11:04,880 TOP OF THE LIST, I SEE NOT ONE 9721 06:11:04,880 --> 06:11:07,480 WHICH IS NOT ACTUALLY THE ISSUE 9722 06:11:07,480 --> 06:11:14,080 HERE, IT'S A SENSOR -- DURING 9723 06:11:14,080 --> 06:11:16,960 BACTERIAL INFECTION, WE SEE P21, 9724 06:11:16,960 --> 06:11:25,800 CH25H AND THEN NUMBER OF 9725 06:11:25,800 --> 06:11:27,040 INDUCIBLE FACTORS. 9726 06:11:27,040 --> 06:11:29,920 WE CHOSE SEVERAL FACTORS 9727 06:11:29,920 --> 06:11:34,720 INCLUDING APOBEC3A, HO-1, CH25H 9728 06:11:34,720 --> 06:11:39,400 AND P21 AND WE VALIDATED -- WE 9729 06:11:39,400 --> 06:11:47,480 CAN ALSO SEE -- ANALYSIS AT THE 9730 06:11:47,480 --> 06:11:47,840 PROTEIN LEVEL. 9731 06:11:47,840 --> 06:11:50,040 SO THE PATIENT WAS -- WHAT DOES 9732 06:11:50,040 --> 06:11:52,440 IT COST FOR THESE FACTORS? 9733 06:11:52,440 --> 06:11:54,360 SO WE LOOKED AT THE INTERFERON 9734 06:11:54,360 --> 06:11:57,320 PRODUCTION, SO WE CAN SEE 9735 06:11:57,320 --> 06:12:00,360 INTERFERON CIRCULATION, BUT WE 9736 06:12:00,360 --> 06:12:05,360 DIDN'T SEE INTERFERON -- PBMCs 9737 06:12:05,360 --> 06:12:07,080 WAS THE -- LEVEL OR THE GENE 9738 06:12:07,080 --> 06:12:08,960 EXPRESSION LEVEL. 9739 06:12:08,960 --> 06:12:11,160 SO WE HYPOTHESIZED THAT 9740 06:12:11,160 --> 06:12:12,480 INTERFERE ON MIGHT BE PRODUCED 9741 06:12:12,480 --> 06:12:15,240 BY MACROPHAGES WHICH SENSE 9742 06:12:15,240 --> 06:12:19,640 HEMOGLOBIN SO THEY USE -- 9743 06:12:19,640 --> 06:12:21,480 DERIVED MACROPHAGES, TREATED 9744 06:12:21,480 --> 06:12:25,200 THEM WITH -- S, RNA SEQ ANALYSIS 9745 06:12:25,200 --> 06:12:27,840 AND LOOK AT THE DIFFERENT 9746 06:12:27,840 --> 06:12:29,360 FACTORS IN THE STATION, SO WE 9747 06:12:29,360 --> 06:12:33,160 SEE A NUMBER OF FACTORS. 9748 06:12:33,160 --> 06:12:35,240 IF WE PLUG THOSE FACTORS INTO 9749 06:12:35,240 --> 06:12:37,240 THE ANALYSIS, WE CAN ACTUALLY 9750 06:12:37,240 --> 06:12:40,960 SEE NICELY THAT THEY POINT TO 9751 06:12:40,960 --> 06:12:47,960 THE INTERFERON INDUCTION, RF7, 9752 06:12:47,960 --> 06:12:49,080 F1, SOME OTHER FACTORS WHICH 9753 06:12:49,080 --> 06:12:51,640 LEAD TO THE INTERFERON 9754 06:12:51,640 --> 06:12:52,400 INDUCTION. 9755 06:12:52,400 --> 06:12:55,280 WE CAN ALSO DO JUST ENRICHMENT 9756 06:12:55,280 --> 06:12:57,760 ANALYSIS USING HALLMARK 9757 06:12:57,760 --> 06:13:00,400 INTERFERON GEN SET AND WE CAN 9758 06:13:00,400 --> 06:13:04,280 SEE AGAIN THOSE ARE ENRICHED IN 9759 06:13:04,280 --> 06:13:06,040 THE MACROPHAGES WHICH WE WOULD 9760 06:13:06,040 --> 06:13:08,760 TREAT WITH HEMOGLOBIN S BUT NOT 9761 06:13:08,760 --> 06:13:11,800 HEMOGLOBIN A AND WE CAN SEE -- 9762 06:13:11,800 --> 06:13:13,560 FACTORS. 9763 06:13:13,560 --> 06:13:16,600 SORE WE NEXT LOOKED IN THE MOUSE 9764 06:13:16,600 --> 06:13:20,880 MODEL, SICKLE CELL DISEASE MOUSE 9765 06:13:20,880 --> 06:13:23,560 MODEL, AND SO THIS MODEL CAN BE 9766 06:13:23,560 --> 06:13:28,480 INFECTED WITH MOUSE ABDUCTED 9767 06:13:28,480 --> 06:13:33,200 VIRUS, ECOTROPIC VIRUS ENVELOPE 9768 06:13:33,200 --> 06:13:39,560 INSTEAD OF HIV ENVELOPE, WE CAN 9769 06:13:39,560 --> 06:13:46,400 SEE INFECTION OF SPLEEN, BUT WE 9770 06:13:46,400 --> 06:13:47,640 DON'T SEE ANY INFECTION IN THE 9771 06:13:47,640 --> 06:13:49,000 SICKLE CELL MICE SPLEAN. 9772 06:13:49,000 --> 06:13:52,640 AND WE COMPANY ANALYZE THIS -- 9773 06:13:52,640 --> 06:13:55,320 THE LEVEL OF GENE EXPRESSION 9774 06:13:55,320 --> 06:13:58,200 DURING THE DECREASE IN 9775 06:13:58,200 --> 06:14:00,480 EXPRESSION, WE CAN SEE ALSO 9776 06:14:00,480 --> 06:14:08,800 DECREASE IN P24 AND WE CAN SEE 9777 06:14:08,800 --> 06:14:10,640 BLOCK IN THE -- REVERSE 9778 06:14:10,640 --> 06:14:12,800 TRANSCRIPTION AND INTEGRATION. 9779 06:14:12,800 --> 06:14:14,680 WE CAN ALSO KIND OF SEE IN 9780 06:14:14,680 --> 06:14:15,680 PARALLEL WITH WHAT WE HAVE SEEN 9781 06:14:15,680 --> 06:14:24,560 IN PATIENTS, WE CAN SEE -- 9782 06:14:24,560 --> 06:14:26,600 RECEPTOR IN SPLEEN OF SICKLE 9783 06:14:26,600 --> 06:14:32,520 CELL MICE, REGULATION OF CH25H, 9784 06:14:32,520 --> 06:14:38,080 P21, AND THEN --. 9785 06:14:38,080 --> 06:14:41,480 AND WE SEE DOWN REGULATION AT 9786 06:14:41,480 --> 06:14:47,400 THE -- LEVEL. 9787 06:14:47,400 --> 06:14:52,680 HOWEVER MICE ONLY HAVE ONE -- 9788 06:14:52,680 --> 06:14:55,480 GENE WHEREAS DISOSH MOUSE MODEL 9789 06:14:55,480 --> 06:14:57,840 DOES NOT REPLICATE WHAT WE SEE 9790 06:14:57,840 --> 06:14:59,280 IN HUMANS. 9791 06:14:59,280 --> 06:15:05,320 SO OUR MODEL IS THAT IN SICKLE 9792 06:15:05,320 --> 06:15:07,480 CELL, NUCLEAR CELLS, WE HAVE A 9793 06:15:07,480 --> 06:15:12,880 NUMBER OF CELLS UPREGULATED 9794 06:15:12,880 --> 06:15:17,440 INCLUDING APOBEC3A, CH25H, BUT 9795 06:15:17,440 --> 06:15:22,960 ALSO FACTORS WHICH HIGH BER LOW 9796 06:15:22,960 --> 06:15:30,400 LATE, INCLUDING P21, HMOX1, SO 9797 06:15:30,400 --> 06:15:31,880 THE INTERFERON IS LIKELY TO COME 9798 06:15:31,880 --> 06:15:38,040 FROM THE MACROPHAGES -- INDUCE 9799 06:15:38,040 --> 06:15:42,720 INTERFATHER ON PRODUCTION, AND 9800 06:15:42,720 --> 06:15:44,280 ALL GIVES MUCH PROTECTION 9801 06:15:44,280 --> 06:15:46,080 AGAINST HIV INFECTION AND I 9802 06:15:46,080 --> 06:15:49,080 GUESS LACK OF HIV INFECTION IN 9803 06:15:49,080 --> 06:15:49,600 PATIENTS WITH SICKLE CELL 9804 06:15:49,600 --> 06:15:54,320 DISEASE. 9805 06:15:54,320 --> 06:15:58,720 SO WE THINK -- AND THIS DUE TO 9806 06:15:58,720 --> 06:16:04,600 DECREASED -- INTERFERON INDUCED 9807 06:16:04,600 --> 06:16:07,640 FACTORS IN THE -- IN PATIENTS 9808 06:16:07,640 --> 06:16:10,400 LEADING TO INHIBITION, AND THIS 9809 06:16:10,400 --> 06:16:12,280 CAN BE -- LACK OF INFECTION BY 9810 06:16:12,280 --> 06:16:13,280 SICKLE CELL MICE. 9811 06:16:13,280 --> 06:16:15,000 I WOULD LIKE TO STOP AND THANK 9812 06:16:15,000 --> 06:16:18,160 OUR MEMBERS OF THE SICKLE CELL 9813 06:16:18,160 --> 06:16:19,600 CENTER. 9814 06:16:19,600 --> 06:16:22,080 NAMITA KUMARI WHO DID MOST OF 9815 06:16:22,080 --> 06:16:24,520 THE WORK AND POSTDOC THAT 9816 06:16:24,520 --> 06:16:27,160 CONTRIBUTED TO THE STUDY, 9817 06:16:27,160 --> 06:16:32,560 MARINA, FUNDING, AND GENOMICS 9818 06:16:32,560 --> 06:16:33,720 FACILITY AT GEORGE WASHINGTON 9819 06:16:33,720 --> 06:16:34,000 UNIVERSITY. 9820 06:16:34,000 --> 06:16:34,360 THANK YOU. 9821 06:16:34,360 --> 06:16:36,880 >>THANK YOU, SERGEI. 9822 06:16:36,880 --> 06:16:40,240 ANY QUESTIONS FOR SUR JAY? 9823 06:16:40,240 --> 06:16:40,920 SERGEI. 9824 06:16:40,920 --> 06:16:41,960 ANYTHING ONLINE? 9825 06:16:41,960 --> 06:16:42,120 NO? 9826 06:16:42,120 --> 06:16:42,640 THANK YOU SO MUCH AGAIN. 9827 06:16:42,640 --> 06:16:46,040 SO LET'S MOVE ON TO OUR NEXT 9828 06:16:46,040 --> 06:16:46,240 TALK. 9829 06:16:46,240 --> 06:16:49,440 THIS PANEL OF MULTIPLE URINARY 9830 06:16:49,440 --> 06:16:50,680 BIOMARKERS FOR EARLY DETECTION 9831 06:16:50,680 --> 06:16:52,200 OF CHRONIC KIDNEY DISEASE IN 9832 06:16:52,200 --> 06:16:57,080 SICKLE CELL ANEMIA. 9833 06:16:57,080 --> 06:16:59,400 MARINA JEREBTSOVA, ALSO FROM 9834 06:16:59,400 --> 06:17:09,720 HOWARD UNIVERSITY. 9835 06:17:19,440 --> 06:17:24,080 >>GO ON TO THE NEXT SLIDE. 9836 06:17:24,080 --> 06:17:26,480 >>NEXT SLIDE, PLEASE. 9837 06:17:26,480 --> 06:17:36,920 >>JUST CLICK TO ADVANCE. 9838 06:17:42,840 --> 06:17:45,600 >>OKAY, THANK YOU. 9839 06:17:45,600 --> 06:17:47,000 SO THANK YOU FOR HAVING ME HERE 9840 06:17:47,000 --> 06:17:55,120 TO PRESENT ON THIS CONFERENCE. 9841 06:17:55,120 --> 06:17:56,680 THIS IS ONE OF THE MAJOR 9842 06:17:56,680 --> 06:17:57,960 COMPLICATIONS IN SICKLE CELL 9843 06:17:57,960 --> 06:17:58,400 DISEASE. 9844 06:17:58,400 --> 06:17:59,840 PATIENTS WITH SICKLE CELL ANEMIA 9845 06:17:59,840 --> 06:18:02,200 HAVE APPROXIMATELY THREE FOURTHS 9846 06:18:02,200 --> 06:18:04,720 HIGHER RISK OF DEVELOPING 9847 06:18:04,720 --> 06:18:05,520 CHRONIC KIDNEY DISEASE THAN THE 9848 06:18:05,520 --> 06:18:15,840 GENERAL POPULATION. 9849 06:18:24,360 --> 06:18:25,720 OKAY. 9850 06:18:25,720 --> 06:18:28,880 30 TO 60% OF SICKLE CELL ANEMIA 9851 06:18:28,880 --> 06:18:30,400 PATIENTS DEVELOP CHRONIC KIDNEY 9852 06:18:30,400 --> 06:18:30,720 DISEASE. 9853 06:18:30,720 --> 06:18:32,240 14 TO 18% OF THEM PROGRESS TO 9854 06:18:32,240 --> 06:18:37,120 THE END STAGE OF RENAL DISEASE. 9855 06:18:37,120 --> 06:18:41,920 RENAL DISEASE IN SICKLE CELL 9856 06:18:41,920 --> 06:18:43,000 DISEASE PATIENTS AFFECT ALL 9857 06:18:43,000 --> 06:18:51,000 PARTS OF THE NEPHRON. 9858 06:18:51,000 --> 06:18:55,280 IT'S NOT WORKING. 9859 06:18:55,280 --> 06:18:57,440 >>NEXT SLIDE. 9860 06:18:57,440 --> 06:18:58,200 >>USE THE MOUSE TO CLICK 9861 06:18:58,200 --> 06:19:08,320 FORWARD. 9862 06:19:27,800 --> 06:19:30,280 THE CURR 9863 06:19:30,280 --> 06:19:32,360 >>THE CURRENT STANDARD OF CARE 9864 06:19:32,360 --> 06:19:38,160 FOR KIDNEY DISEASE BEGINNING AT 9865 06:19:38,160 --> 06:19:42,640 AGE 10 FOR SICKLE CELL DISEASE 9866 06:19:42,640 --> 06:19:43,600 PATIENTS -- IF PROTEIN AMOUNT IN 9867 06:19:43,600 --> 06:19:48,960 THE YOU' URINE IS HIGHER THAN 9868 06:19:48,960 --> 06:19:49,920 30 MILLIGRAMS BER DL, PATIENTS 9869 06:19:49,920 --> 06:19:55,800 ARE REFERRED TO A FR NEPHROLOGI. 9870 06:19:55,800 --> 06:19:58,120 SICKLE CELL ANEMIA PATIENTS, 9871 06:19:58,120 --> 06:20:02,680 TRAIT PATIENTS, DEVELOP 9872 06:20:02,680 --> 06:20:03,760 HYPOSTENURIA, INABILITY TO 9873 06:20:03,760 --> 06:20:05,080 CONCENTRATE URINE, THAT AFFECTS 9874 06:20:05,080 --> 06:20:08,040 DETECTION OF THE PROTEIN BY 9875 06:20:08,040 --> 06:20:08,960 DIPSTICK. 9876 06:20:08,960 --> 06:20:12,480 SO THE PATIENTS WHO REFER TO 9877 06:20:12,480 --> 06:20:15,040 NEPHROLOGIST USUALLY HAVE ALL 9878 06:20:15,040 --> 06:20:16,320 THEIR ADVANCED STAGE OF CHRONIC 9879 06:20:16,320 --> 06:20:21,000 KIDNEY DISEASE. 9880 06:20:21,000 --> 06:20:24,600 WHEN PATIENT IS REFERRED TO 9881 06:20:24,600 --> 06:20:25,920 NEPHROLOGIST, THEY DETECT THE 9882 06:20:25,920 --> 06:20:28,000 STAGE OF CHRONIC KIDNEY DISEASE 9883 06:20:28,000 --> 06:20:31,400 BASED ON THE STANDARD 9884 06:20:31,400 --> 06:20:31,800 GUIDELINES. 9885 06:20:31,800 --> 06:20:39,480 THESE GUIDELINES ARE BASED ON 9886 06:20:39,480 --> 06:20:45,840 THE GLOMERULAR FILTRATION RATE. 9887 06:20:45,840 --> 06:20:48,640 MORE THAN 40% OF SICKLE CELL 9888 06:20:48,640 --> 06:20:54,440 ANEMIA PATIENTS HAVE 9889 06:20:54,440 --> 06:20:55,200 HYPERFILTRATION. 9890 06:20:55,200 --> 06:20:57,400 HYPER FILTRATION IS DEFINED AS 9891 06:20:57,400 --> 06:21:01,640 THE EGFR RATE MORE THAN 9892 06:21:01,640 --> 06:21:04,520 130-MILLILITER PER MINUTE PER 9893 06:21:04,520 --> 06:21:09,400 1.73 SQUARE METERS, GREATER THAN 9894 06:21:09,400 --> 06:21:10,800 140 FOR MALES. 9895 06:21:10,800 --> 06:21:12,560 SO THIS HYPERFILTRATION MASKS 9896 06:21:12,560 --> 06:21:16,080 THE STAGE OF RENAL CHRONIC -- OF 9897 06:21:16,080 --> 06:21:21,280 CHRONIC KIDNEY DISEASE, AND THEN 9898 06:21:21,280 --> 06:21:25,400 THE GLOMERULAR FILTRATION -- 9899 06:21:25,400 --> 06:21:27,160 DROP IN THE LATE STAGE OF 9900 06:21:27,160 --> 06:21:30,880 CHRONIC DISEASE. 9901 06:21:30,880 --> 06:21:38,480 -- THE EGFR CALCULATION IS NOTL 9902 06:21:38,480 --> 06:21:43,200 PATIENTS. 9903 06:21:43,200 --> 06:21:46,120 -- RESULTS ARE NOT COMPATIBLE. 9904 06:21:46,120 --> 06:21:49,520 BECAUSE OF THIS, A LOT OF 9905 06:21:49,520 --> 06:21:52,040 PATIENT ARE UNDETECTED AND RENAL 9906 06:21:52,040 --> 06:21:53,520 DISEASE IS NOT TREATED IN THESE 9907 06:21:53,520 --> 06:21:55,720 PATIENTS. 9908 06:21:55,720 --> 06:21:59,200 OR EVEN PREVENTED. 9909 06:21:59,200 --> 06:22:00,520 THE EFFECTIVENESS OF RENAL 9910 06:22:00,520 --> 06:22:02,160 DISEASE TREATMENT IS LIMITED BY 9911 06:22:02,160 --> 06:22:09,200 THE LEVEL OF -- MARKERS. 9912 06:22:09,200 --> 06:22:12,000 SO THE DISCOVERY OF KNOWN 9913 06:22:12,000 --> 06:22:14,160 BIOMARKERS FOR CHRONIC KIDNEY 9914 06:22:14,160 --> 06:22:15,680 DISEASE IN SICKLE CELL DISEASE 9915 06:22:15,680 --> 06:22:23,560 PATIENTS ARE URGENTLY NEEDED. 9916 06:22:23,560 --> 06:22:25,200 URINE PROTEOMICS FOR DISCOVERY 9917 06:22:25,200 --> 06:22:27,800 OF MARKERS FOR CHRONIC KIDNEY 9918 06:22:27,800 --> 06:22:28,880 DISEASE FOR SICKLE CELL 9919 06:22:28,880 --> 06:22:31,080 PATIENTS. 9920 06:22:31,080 --> 06:22:32,920 WHY URINE? 9921 06:22:32,920 --> 06:22:39,160 URINE IS AN EASILY ACCESSIBLE 9922 06:22:39,160 --> 06:22:39,400 BIOFLUID. 9923 06:22:39,400 --> 06:22:41,560 IT'S MAINLY FROM THE KIDNEY AND 9924 06:22:41,560 --> 06:22:44,400 LOW URINARY TRACT ORGANS, SO 9925 06:22:44,400 --> 06:22:48,880 IT'S VERY RELEVANT TO WHAT'S 9926 06:22:48,880 --> 06:22:49,840 HAPPENING IN THE KIDNEY. 9927 06:22:49,840 --> 06:22:51,840 UNFORTUNATELY THERE ARE SEVERAL 9928 06:22:51,840 --> 06:22:54,280 MAJOR OBSTACLES FOR DEVELOPMENT 9929 06:22:54,280 --> 06:22:58,040 OF CLINICALLY RELEVANT URINARY 9930 06:22:58,040 --> 06:22:58,320 BIOMARKERS. 9931 06:22:58,320 --> 06:23:01,640 URINE HAS A HIGH LEVEL OF 9932 06:23:01,640 --> 06:23:03,920 VARIABILITY IN VOLUME AND 9933 06:23:03,920 --> 06:23:06,240 PROTEIN CONCENTRATION. 9934 06:23:06,240 --> 06:23:07,960 DEBRIS OF SPONTANEOUSLY DYING 9935 06:23:07,960 --> 06:23:10,280 RENAL CELLS IS RELEASED INTO THE 9936 06:23:10,280 --> 06:23:12,120 URINE AND UNCONTROLLED AMOUNTS 9937 06:23:12,120 --> 06:23:16,240 OF THESE PEPTIDES FROM CELL 9938 06:23:16,240 --> 06:23:23,400 DEBRIS IS DETECTED. 9939 06:23:23,400 --> 06:23:24,240 AND -- NORMALIZED. 9940 06:23:24,240 --> 06:23:26,080 PATIENTS WITH CHRONIC KIDNEY 9941 06:23:26,080 --> 06:23:27,440 DISEASE RELEASE LARGE AMOUNT OF 9942 06:23:27,440 --> 06:23:29,080 SERUM PROTEINS INTO THE URINE, 9943 06:23:29,080 --> 06:23:33,480 MAKING IT DIFFICULT TO FIND THE 9944 06:23:33,480 --> 06:23:36,280 RELIABLE MARKER IN THE LIST OF 9945 06:23:36,280 --> 06:23:40,440 THE PROTEIN. 9946 06:23:40,440 --> 06:23:47,320 SO WE USE QUANTITATIVE 9947 06:23:47,320 --> 06:23:48,960 PROTEOMICS IN HOWARD UNIVERSITY. 9948 06:23:48,960 --> 06:23:54,400 THIS IS THEIR SCHEME FOR -- OF 9949 06:23:54,400 --> 06:23:55,280 QUANTITATIVE PROTEOMICS. 9950 06:23:55,280 --> 06:24:00,240 IT STARTS WITH THE URINE 9951 06:24:00,240 --> 06:24:06,400 COLLECTION -- OF THE PROTEINS, 9952 06:24:06,400 --> 06:24:09,120 AND HE USED SEVERAL PLATFORMS 9953 06:24:09,120 --> 06:24:12,440 FOR ANALYSIS OF THIS DATA, 9954 06:24:12,440 --> 06:24:18,320 INCLUDING THE SIEVE LABEL-FREE 9955 06:24:18,320 --> 06:24:20,960 QUANTIFICATION, INGENUITYRATE 9956 06:24:20,960 --> 06:24:21,560 ANALYSIS. 9957 06:24:21,560 --> 06:24:28,560 THESE ANALYSES GIVE US A -- 9958 06:24:28,560 --> 06:24:32,800 FOR -- OF CHRONIC KIDNEY 9959 06:24:32,800 --> 06:24:33,040 DISEASE. 9960 06:24:33,040 --> 06:24:39,080 SO FOR THIS STUDY YOU USE SAMPLE 9961 06:24:39,080 --> 06:24:40,600 FROM 54 PATIENTS FROM UNIVERSITY 9962 06:24:40,600 --> 06:24:40,880 OF CHICAGO. 9963 06:24:40,880 --> 06:24:42,080 SPOT URINE SAMPLES WERE 9964 06:24:42,080 --> 06:24:43,720 COLLECTED DURING A CLINIC VISIT 9965 06:24:43,720 --> 06:24:45,120 WHEN THE PATIENTS WERE IN A 9966 06:24:45,120 --> 06:24:47,120 STEADY STATE. 9967 06:24:47,120 --> 06:24:51,480 AS I TOLD ONE OF THE MAJOR 9968 06:24:51,480 --> 06:24:54,360 CHALLENGES FOR THE PROTEOMIC 9969 06:24:54,360 --> 06:24:56,600 STUDY, THE PATIENTS WITH CHRONIC 9970 06:24:56,600 --> 06:24:59,240 KIDNEY DISEASE RELEASE A LARGE 9971 06:24:59,240 --> 06:25:04,480 AMOUNT OF SERUM PROTEINS IN 9972 06:25:04,480 --> 06:25:05,240 URINE. 9973 06:25:05,240 --> 06:25:06,840 LARGE LIST OF THE PROTEINS 9974 06:25:06,840 --> 06:25:08,280 COMPARED TO THE PATIENTS WHO 9975 06:25:08,280 --> 06:25:10,720 DON'T HAVE ANY CHRONIC KIDNEY 9976 06:25:10,720 --> 06:25:14,200 DISEASE, SO THAT SELECTION OF 9977 06:25:14,200 --> 06:25:16,800 RELIABLE MARKERS FOR THESE 9978 06:25:16,800 --> 06:25:20,400 PATIENTS IS VERY DIFFICULT. 9979 06:25:20,400 --> 06:25:21,920 SO TO SOLVE THIS PROBLEM, WE 9980 06:25:21,920 --> 06:25:23,760 DECIDE TO USE SAMPLES FROM 9981 06:25:23,760 --> 06:25:27,840 SICKLE CELL ANEMIA PATIENTS 9982 06:25:27,840 --> 06:25:30,120 WITHOUT PROTEINURIA. 9983 06:25:30,120 --> 06:25:32,400 BUT WE DECIDE TO SEPARATE THEM 9984 06:25:32,400 --> 06:25:35,840 IN TWO GROUPS THAT HAVE AT LEAST 9985 06:25:35,840 --> 06:25:38,000 ONE FACTOR OF PREDISPOSITION TO 9986 06:25:38,000 --> 06:25:43,560 DEVELOPMENT OF RENAL DISEASE. 9987 06:25:43,560 --> 06:25:44,840 COMPARED TO PATIENTS WHO DON'T 9988 06:25:44,840 --> 06:25:46,400 HAVE ANY KNOWN FACTORS THAT 9989 06:25:46,400 --> 06:25:47,480 PREDISPOSE THEM TO DEVELOPMENT 9990 06:25:47,480 --> 06:25:52,400 OF RENAL DISEASE. 9991 06:25:52,400 --> 06:26:01,560 SO 20-SOME SAMPLES WITH 9992 06:26:01,560 --> 06:26:04,720 UNDETECTABLE URINARY PROTEIN 9993 06:26:04,720 --> 06:26:08,120 LEVELS WERE USED FOR MASS 9994 06:26:08,120 --> 06:26:09,600 SPECTROMETRY ANALYSIS. 9995 06:26:09,600 --> 06:26:13,240 FROM THESE SAMPLES, WE DETECTED 9996 06:26:13,240 --> 06:26:17,480 PEPTIDES FROM 270 PROTEINS. 9997 06:26:17,480 --> 06:26:18,600 UNFORTUNATELY MOST OF THESE 9998 06:26:18,600 --> 06:26:20,880 PROTEINS WERE STILL FROM THE 9999 06:26:20,880 --> 06:26:27,480 TUBULAR EPITHELIAL CELL DEBREA. 10000 06:26:27,480 --> 06:26:35,600 SO AT THIS STAGE, WE DECIDED TO 10001 06:26:35,600 --> 06:26:37,720 APPLY ADDITIONAL CRITERIA FOR 10002 06:26:37,720 --> 06:26:39,600 URINARY BIOMARKER DISCOVERY. 10003 06:26:39,600 --> 06:26:40,800 THE FIRST WOULD BE BIOMARKERS 10004 06:26:40,800 --> 06:26:43,840 SHOULD BE SOLUBLE PROTEINS, LIVE 10005 06:26:43,840 --> 06:26:45,640 CELLS, NOT THE DEAD CELLS. 10006 06:26:45,640 --> 06:26:46,640 BIOMARKERS SHOULD CORRELATE WITH 10007 06:26:46,640 --> 06:26:48,840 THE KNOWN FACTORS OF 10008 06:26:48,840 --> 06:26:49,680 PREDISPOSITION TO DEVELOPMENT OF 10009 06:26:49,680 --> 06:26:51,440 CHRONIC KIDNEY DISEASE. 10010 06:26:51,440 --> 06:26:53,480 AND BIOMARKERS SHOULD REFLECT 10011 06:26:53,480 --> 06:26:56,000 KNOWN PATHOLOGY OF SICKLE CELL 10012 06:26:56,000 --> 06:27:04,120 ANEMIA. 10013 06:27:04,120 --> 06:27:11,320 SO -- WE DECIDED TO USE 10014 06:27:11,320 --> 06:27:12,720 HEMOGLOBIN AS A RISK FACTOR FOR 10015 06:27:12,720 --> 06:27:16,560 DEVELOPMENT OF CHRONIC KIDNEY 10016 06:27:16,560 --> 06:27:17,560 DISEASE. 10017 06:27:17,560 --> 06:27:19,320 IRON, INFLAMMATION ARE TWO 10018 06:27:19,320 --> 06:27:20,360 WELL-KNOWN PATHOLOGY CONDITION 10019 06:27:20,360 --> 06:27:26,160 IN SICKLE CELL ANEMIA. 10020 06:27:26,160 --> 06:27:30,000 SO BASED ON THESE CRITERIA, WE 10021 06:27:30,000 --> 06:27:32,920 SELECTED 14 PROTEINS FROM THE 10022 06:27:32,920 --> 06:27:33,120 LIST. 10023 06:27:33,120 --> 06:27:43,200 TWO OF THEM -- PROTEIN THAT 10024 06:27:43,200 --> 06:27:49,440 EXPRESS IN THE -- THIS IS IMMUNE 10025 06:27:49,440 --> 06:27:53,240 PROTEIN, CERULOPLASMIN IS A 10026 06:27:53,240 --> 06:27:56,520 PROTEIN INVOLVED IN THE 10027 06:27:56,520 --> 06:28:00,120 REGULATION OF HOMEOSTASIS. 10028 06:28:00,120 --> 06:28:02,240 SO WE CONCENTRATED ON THESE TWO 10029 06:28:02,240 --> 06:28:05,040 PROTEINS BECAUSE THEY WERE 10030 06:28:05,040 --> 06:28:05,520 CONNECTED WITH THE KNOWN 10031 06:28:05,520 --> 06:28:06,800 PATHOLOGY IN SICKLE CELL DISEASE 10032 06:28:06,800 --> 06:28:09,520 PATIENTS. 10033 06:28:09,520 --> 06:28:17,600 THIS IS JUST A SCHEME HOW LABEL 10034 06:28:17,600 --> 06:28:20,000 FREE QUANTIFICATION OF MASS 10035 06:28:20,000 --> 06:28:22,840 SPECTROMETRY RESULTS. 10036 06:28:22,840 --> 06:28:24,160 -- DIVIDED INTO GROUPS, 10037 06:28:24,160 --> 06:28:27,560 PATIENTS WITH HIGH HEMOGLOBIN 10038 06:28:27,560 --> 06:28:34,200 AND PATIENTS WITHOUT 10039 06:28:34,200 --> 06:28:35,400 HEMOGLOBINURIA, TO CHOOSE THREE 10040 06:28:35,400 --> 06:28:44,520 SAMPLES FROM EACH GROUP. 10041 06:28:44,520 --> 06:28:52,680 -- THE LEVEL OF PROTEINS 10042 06:28:52,680 --> 06:28:54,640 ANALYSIS BY LCMS. 10043 06:28:54,640 --> 06:28:55,880 SO THIS IS A REPRESENTATIVE 10044 06:28:55,880 --> 06:28:58,880 PICTURE OF THE RESULT FROM THE 10045 06:28:58,880 --> 06:29:00,800 SIEVE LABEL FREE QUANTIFICATION. 10046 06:29:00,800 --> 06:29:04,800 THE FIRST GRAPH SHOW A PLOT THAT 10047 06:29:04,800 --> 06:29:07,320 DEMONSTRATES A LOT OF PEPTIDES 10048 06:29:07,320 --> 06:29:14,840 ARE DIFFERENT BETWEEN THE HIGH 10049 06:29:14,840 --> 06:29:15,920 HEMOGLOBIN AND LOW HEMOGLOBIN 10050 06:29:15,920 --> 06:29:17,920 GROUPS. 10051 06:29:17,920 --> 06:29:18,560 THE SECOND PRESENT 10052 06:29:18,560 --> 06:29:22,960 QUANTIFICATION FOR ONE OF THE 10053 06:29:22,960 --> 06:29:24,360 SERULOPLASMIN GUIDE, IT 10054 06:29:24,360 --> 06:29:26,840 DEMONSTRATED THAT THE LEVEL WAS 10055 06:29:26,840 --> 06:29:30,800 SIGNIFICANTLY HIGHER IN THE 10056 06:29:30,800 --> 06:29:31,440 SAMPLES WITH HIGH HEMOGLOBIN 10057 06:29:31,440 --> 06:29:33,080 COMPARED TO THE SAMPLES WITH LOW 10058 06:29:33,080 --> 06:29:39,240 HEMOGLOBIN. 10059 06:29:39,240 --> 06:29:41,920 WE VALIDATE URINE BIOMARKERS BY 10060 06:29:41,920 --> 06:29:47,680 ELI IS A. 10061 06:29:47,680 --> 06:29:48,880 ELISA. 10062 06:29:48,880 --> 06:29:56,400 SO BIOMARKERS -- THEY ARE 10063 06:29:56,400 --> 06:29:58,280 INCREASED IRON METABOLISM. 10064 06:29:58,280 --> 06:29:59,600 SO PLASMIN WAS SIGNIFICANTLY 10065 06:29:59,600 --> 06:30:04,000 HIGH IN THE SICKLE CELL DISEASE 10066 06:30:04,000 --> 06:30:07,880 PATIENT SAMPLES COMPARED TO THE 10067 06:30:07,880 --> 06:30:08,760 CONTROL PATIENTS. 10068 06:30:08,760 --> 06:30:12,280 THERE WAS A -- FOR THE HIGH 10069 06:30:12,280 --> 06:30:16,720 LEVEL OF CERULOPLASMIN -- 10070 06:30:16,720 --> 06:30:17,640 COMPARED TO THE PATIENTS WITH 10071 06:30:17,640 --> 06:30:18,360 LOW HEMOGLOBIN. 10072 06:30:18,360 --> 06:30:19,800 BOTH OF THEM ARE SICKLE CELL 10073 06:30:19,800 --> 06:30:25,160 DISEASE PATIENTS. 10074 06:30:25,160 --> 06:30:28,240 WE'RE INTERESTED THAT -- RELATES 10075 06:30:28,240 --> 06:30:29,800 WITH CHRONIC KIDNEY DISEASE IN 10076 06:30:29,800 --> 06:30:36,440 SICKLE CELL DISEASE PATIENTS. 10077 06:30:36,440 --> 06:30:38,960 -- HIGH SENSITIVITY AND 10078 06:30:38,960 --> 06:30:44,560 SPECIFICITY OF THESE MARKERS TO 10079 06:30:44,560 --> 06:30:46,280 DISCRIMINATE BETWEEN THEIR -- 10080 06:30:46,280 --> 06:30:48,280 CHRONIC KIDNEY DISEASE AND -- 10081 06:30:48,280 --> 06:30:55,280 CHRONIC KIDNEY DISEASE. 10082 06:30:55,280 --> 06:30:58,760 -- THEY ARE BOTH MARKERS OF 10083 06:30:58,760 --> 06:31:01,400 INCREASED METABOLISM. 10084 06:31:01,400 --> 06:31:06,320 THE LEVEL OF -- BIOMARKER, THE 10085 06:31:06,320 --> 06:31:08,080 LEVELS WERE SIGNIFICANTLY HIGHER 10086 06:31:08,080 --> 06:31:11,680 IN SICKLE CELL DISEASE -- THEY 10087 06:31:11,680 --> 06:31:15,400 DID NOT CORRELATE BECAUSE OF 10088 06:31:15,400 --> 06:31:16,720 CHRONIC KIDNEY DISEASE 10089 06:31:16,720 --> 06:31:18,240 PROGRESSION. 10090 06:31:18,240 --> 06:31:21,360 WE ALSO -- WITH LIKE A BIOMARKER 10091 06:31:21,360 --> 06:31:31,640 OF INFLAMMATION. 10092 06:31:32,040 --> 06:31:36,320 OROSOMUCOID WAS SI -- STAGE OF 10093 06:31:36,320 --> 06:31:41,360 CHRONIC KIDNEY DISEASE, AND IT 10094 06:31:41,360 --> 06:31:42,360 PRODUCES EVEN HIGHER SENSITIVITY 10095 06:31:42,360 --> 06:31:48,240 AND SPECIFICITY COMPARED TO THE 10096 06:31:48,240 --> 06:31:49,480 CERULOPLASMIN. 10097 06:31:49,480 --> 06:31:52,400 NEXT WE DECIDED TO TEST IF THE 10098 06:31:52,400 --> 06:31:55,320 COMBINATION OF TWO OR THREE 10099 06:31:55,320 --> 06:31:58,840 BIOMARKERS WILL INCREASE THEIR 10100 06:31:58,840 --> 06:32:01,920 ACCURACY OF DIFFERENT -- OF 10101 06:32:01,920 --> 06:32:03,640 SINGLE BIOMARKERS TO 10102 06:32:03,640 --> 06:32:10,000 DISCRIMINATE BETWEEN THE 10103 06:32:10,000 --> 06:32:11,160 PRESSURES -- STAGE OF CHRONIC 10104 06:32:11,160 --> 06:32:11,760 KIDNEY DISEASE. 10105 06:32:11,760 --> 06:32:14,240 THE COMBINATION OF ALL THREE 10106 06:32:14,240 --> 06:32:16,640 BIOMARKERS SIGNIFICANTLY 10107 06:32:16,640 --> 06:32:19,240 INCREASE THEIR -- UNDER THEIR -- 10108 06:32:19,240 --> 06:32:23,120 IN THE ANALYSIS. 10109 06:32:23,120 --> 06:32:28,280 INTERESTING -- COMBINATION OF -- 10110 06:32:28,280 --> 06:32:31,920 ALSO SIGNIFICANTLY INCREASE 10111 06:32:31,920 --> 06:32:34,800 THE -- UNDER THE -- ANALYSIS. 10112 06:32:34,800 --> 06:32:38,560 SO IT'S MORE ACCURATE FOR 10113 06:32:38,560 --> 06:32:40,760 DETECTION OF STAGE OF CHRONIC IK 10114 06:32:40,760 --> 06:32:41,400 DISEASE. 10115 06:32:41,400 --> 06:32:48,640 IN CONCLUSION, CERUMOPLASMIN, 10116 06:32:48,640 --> 06:32:53,160 ORM AND HEMOGLOBINURIA ARE GOOD 10117 06:32:53,160 --> 06:32:54,800 CANDIDATES FOR NONINVASIVE 10118 06:32:54,800 --> 06:32:56,760 BIOMARKERS OF YEARLY STAGES OF 10119 06:32:56,760 --> 06:32:58,800 CHRONIC KIDNEY DISEASE IN SICKLE 10120 06:32:58,800 --> 06:32:59,280 CELL PATIENTS. 10121 06:32:59,280 --> 06:33:01,040 EACH OF THESE PROTEINS REFLECTS 10122 06:33:01,040 --> 06:33:02,800 A DISTINCT PATHOLOGICAL PROCESS 10123 06:33:02,800 --> 06:33:05,160 IN THE KIDNEY OF SICKLE CELL 10124 06:33:05,160 --> 06:33:05,440 PATIENTS. 10125 06:33:05,440 --> 06:33:07,920 THE USE OF COMBINED BIOMARKERS 10126 06:33:07,920 --> 06:33:09,000 SIGNIFICANTLY IMPROVES THE 10127 06:33:09,000 --> 06:33:10,640 ACCURACY OF DETECTION OF EARLIER 10128 06:33:10,640 --> 06:33:12,880 STAGE CHRONIC KIDNEY DISEASE. 10129 06:33:12,880 --> 06:33:16,680 SO WHAT'S THE NEXT STEP? 10130 06:33:16,680 --> 06:33:22,600 WE STILL HAVE -- WE WANT TO 10131 06:33:22,600 --> 06:33:28,760 STUDY THESE BIOMARKERS 10132 06:33:28,760 --> 06:33:30,080 DISCOVERED IN PROTEOMICS OF 10133 06:33:30,080 --> 06:33:30,560 URINE. 10134 06:33:30,560 --> 06:33:32,560 NOT ALL BIOMARKERS CAN BE FOUND 10135 06:33:32,560 --> 06:33:35,200 BY MASS SPECTROMETRY. 10136 06:33:35,200 --> 06:33:37,320 SO THE STUDY OF OTHER BIOMARKERS 10137 06:33:37,320 --> 06:33:41,720 OF CHRONIC KIDNEY DISEASE IN THE 10138 06:33:41,720 --> 06:33:43,560 LITERATURE -- TWO OF THEM, 10139 06:33:43,560 --> 06:33:47,720 SOLUBLE UROKINASE-TYPE 10140 06:33:47,720 --> 06:33:52,520 PLASMINOGEN ACTIVATOR RECEPTOR, 10141 06:33:52,520 --> 06:33:53,840 AND -- LIMITATION OF THIS STUDY. 10142 06:33:53,840 --> 06:33:58,520 IT'S SMALL SAMPLE SIZE. 10143 06:33:58,520 --> 06:33:59,120 IT'S CROSS-SECTIONAL NATURE OF 10144 06:33:59,120 --> 06:34:00,520 THE STUDY. 10145 06:34:00,520 --> 06:34:02,840 LIMITED NUMBER OF THE TESTED 10146 06:34:02,840 --> 06:34:04,040 BIOMARKERS. 10147 06:34:04,040 --> 06:34:06,520 AND LONGITUDINAL STUDIES IN 10148 06:34:06,520 --> 06:34:08,720 LARGE COHORT ARE NEEDED FOR 10149 06:34:08,720 --> 06:34:10,160 VALIDATION OF THIS STUDY. 10150 06:34:10,160 --> 06:34:14,000 SO I ACKNOWLEDGE THE SICKLE CELL 10151 06:34:14,000 --> 06:34:16,200 DISEASE CENTER AND ALSO STUDENTS 10152 06:34:16,200 --> 06:34:24,840 THAT WORK IN MY LAB, UNIVERSITY 10153 06:34:24,840 --> 06:34:26,400 OF ILLINOIS AT CHICAGO. 10154 06:34:26,400 --> 06:34:28,560 THANK YOU. 10155 06:34:28,560 --> 06:34:35,320 >>THANK YOU, DR. JEREBTSOVA. 10156 06:34:35,320 --> 06:34:36,760 QUESTIONS? 10157 06:34:36,760 --> 06:34:38,960 ANY QUESTIONS ONLINE? 10158 06:34:38,960 --> 06:34:40,600 NO QUESTION ONLINE. 10159 06:34:40,600 --> 06:34:45,520 THANK YOU SO MUCH FOR YOUR TALK. 10160 06:34:45,520 --> 06:34:46,920 SO OUR NEXT -- WE'VE SAVED THE 10161 06:34:46,920 --> 06:34:48,440 BEST FOR THE LAST. 10162 06:34:48,440 --> 06:34:53,000 STEPPING UP INTO ADULT CARE: AN 10163 06:34:53,000 --> 06:34:58,520 UPDATE ON THE ST3P UP STUDY. 10164 06:34:58,520 --> 06:35:02,520 PRESENTING IS DR. IFY OSUNKOWO. 10165 06:35:02,520 --> 06:35:03,880 >>GOOD EVENING, EVERYBODY. 10166 06:35:03,880 --> 06:35:05,560 I'M STANDING BETWEEN YOU AND 10167 06:35:05,560 --> 06:35:06,640 YOUR SHUTTLE RIDE RECEPTION AT 10168 06:35:06,640 --> 06:35:09,160 THE DOUBLETREE SO I'M GOING TO 10169 06:35:09,160 --> 06:35:11,160 MAKE THIS SHORT AND SWEET AND 10170 06:35:11,160 --> 06:35:11,600 PRETTY INTERESTING. 10171 06:35:11,600 --> 06:35:16,960 MY NAME IS DR. IFY OSUNKOWO. 10172 06:35:16,960 --> 06:35:19,080 THE VIEWS AND OPINIONS EXPRESSED 10173 06:35:19,080 --> 06:35:20,120 IN THIS PRESENTATION REPRESENT 10174 06:35:20,120 --> 06:35:21,480 MY OWN AND NOT THOSE OF MY 10175 06:35:21,480 --> 06:35:22,440 CURRENT OR PREVIOUS EMPLOYERS, 10176 06:35:22,440 --> 06:35:24,120 AND THESE ARE THE DISCLOSURES 10177 06:35:24,120 --> 06:35:25,200 FOR BOTH MYSELF AROUND THE 10178 06:35:25,200 --> 06:35:26,640 COLLABORATORS WHO WORKED ON THIS 10179 06:35:26,640 --> 06:35:28,800 AMAZING STUDY. 10180 06:35:28,800 --> 06:35:30,560 I DO WANT TO TAKE A MINUTE TO 10181 06:35:30,560 --> 06:35:32,000 RECOGNIZE SOME OF OUR 10182 06:35:32,000 --> 06:35:33,200 COLLABORATORS AND 10183 06:35:33,200 --> 06:35:34,720 CO-INVESTIGATORS WHO PASSED AWAY 10184 06:35:34,720 --> 06:35:35,640 OVER THE PAST SIX YEARS. 10185 06:35:35,640 --> 06:35:37,720 THIS IS PROBABLY THE MOST 10186 06:35:37,720 --> 06:35:38,480 HEART-WRENCHING PART OF THIS 10187 06:35:38,480 --> 06:35:40,400 PRESENTATION IN MY CAREER AS A 10188 06:35:40,400 --> 06:35:40,840 HEMATOLOGIST. 10189 06:35:40,840 --> 06:35:42,360 WHERE SOME STELLAR INVESTIGATORS 10190 06:35:42,360 --> 06:35:43,680 AND PEOPLE IN THE SICKLE CELL 10191 06:35:43,680 --> 06:35:46,680 SPACE GAVE THEIR LIFE TO THE 10192 06:35:46,680 --> 06:35:48,560 CAUSE OF SICKLE CELL DISEASE. 10193 06:35:48,560 --> 06:35:50,400 TREVOR THOMPSON WAS A COI. ON 10194 06:35:50,400 --> 06:35:50,880 THE GRANT. 10195 06:35:50,880 --> 06:35:52,400 HE DIED AS WE WERE WRITING THE 10196 06:35:52,400 --> 06:35:53,320 GRANT. 10197 06:35:53,320 --> 06:35:55,840 SHARON LEWIS AND JOHNSON HAYNES 10198 06:35:55,840 --> 06:35:58,520 WERE CO-AIs IN ALABAMA AND 10199 06:35:58,520 --> 06:36:00,000 THEY BOTH PASSED AWAY DURING THE 10200 06:36:00,000 --> 06:36:03,080 STUDY, AND CATHY NORCOTT PASSED 10201 06:36:03,080 --> 06:36:03,680 AWAY EARLY THIS MONTH AND SHE 10202 06:36:03,680 --> 06:36:05,600 WAS ONE OF OUR COIs IN NORTH 10203 06:36:05,600 --> 06:36:05,960 CAROLINA. 10204 06:36:05,960 --> 06:36:16,480 CAN YOU QUEUE THE VIDEO, PLEASE. 10205 06:36:20,680 --> 06:36:23,600 >>ONE SECOND. 10206 06:36:23,600 --> 06:36:25,120 >>I'M SHOWING YOU A VIDEO OF A 10207 06:36:25,120 --> 06:36:26,720 PUBLIC SERVICE ANNOUNCEMENT THAT 10208 06:36:26,720 --> 06:36:27,600 HIGHLIGHTS THE CHALLENGES OF 10209 06:36:27,600 --> 06:36:28,560 TRANSITION IN SICKLE CELL 10210 06:36:28,560 --> 06:36:30,440 DISEASE AND REALLY BRINGS THIS 10211 06:36:30,440 --> 06:36:31,440 HOME THAT THIS IS SOMETHING THAT 10212 06:36:31,440 --> 06:36:33,960 IS NOT A YESTERDAY PROBLEM, BUT 10213 06:36:33,960 --> 06:36:35,360 A TODAY AND A TOMORROW PROBLEM. 10214 06:36:35,360 --> 06:36:36,920 THE GOAL IS FOR US TO TRY TO 10215 06:36:36,920 --> 06:36:38,800 SOLVE FOR TRANSITION IN SICKLE 10216 06:36:38,800 --> 06:36:46,240 CELL DISEASE. 10217 06:36:46,240 --> 06:36:56,440 ANY LUCK? 10218 06:37:21,880 --> 06:37:25,200 IF YOU WOULD CARE TO LOOK AT THE 10219 06:37:25,200 --> 06:37:27,600 PUBLIC SERVICE -- IT'S ON THE 10220 06:37:27,600 --> 06:37:29,280 SCD WEBSITE, IT TALKS ABOUT A 10221 06:37:29,280 --> 06:37:31,920 TEENAGE BOY IN COLLEGE AND WHAT 10222 06:37:31,920 --> 06:37:33,000 LIFE IS LIKE WITH SICKLE CELL 10223 06:37:33,000 --> 06:37:34,760 DISEASE AND WHY IT'S IMPORTANT 10224 06:37:34,760 --> 06:37:36,600 THAT WE ENCOURAGE OUR PROVIDERS 10225 06:37:36,600 --> 06:37:38,160 TO BELIEVE THEM WHEN THEY SAY 10226 06:37:38,160 --> 06:37:41,440 THEY HAVE PAIN. 10227 06:37:41,440 --> 06:37:45,200 SO THR ST3P-UP STUDY BEGAN IN 10228 06:37:45,200 --> 06:37:49,280 2016 RIGHT AT THE NHLBI MEETING. 10229 06:37:49,280 --> 06:37:50,400 CAME ON THE TUESDAY AT THE 10230 06:37:50,400 --> 06:37:52,120 MEETING AND THE TEAM ASSEMBLED 10231 06:37:52,120 --> 06:37:54,640 AND WE HAD TO PUT IN A LETTER OF 10232 06:37:54,640 --> 06:37:56,640 INTENT IN A MONTH, PUT IN THE 10233 06:37:56,640 --> 06:37:57,680 GRANT WITHIN TWO MONTHS AND 10234 06:37:57,680 --> 06:37:59,120 QUICK TURN AROUND TIME, WE WERE 10235 06:37:59,120 --> 06:38:02,520 AWARDED A $9.8 MILLION GRANT FOR 10236 06:38:02,520 --> 06:38:03,640 A MULTICENTER COMPARATIVE 10237 06:38:03,640 --> 06:38:05,400 EFFECTIVE STUDY OF TRANSITIONING 10238 06:38:05,400 --> 06:38:06,720 IN ADULTS WITH SICKLE CELL 10239 06:38:06,720 --> 06:38:08,400 DISEASE ACROSS 14 SITES IN THE 10240 06:38:08,400 --> 06:38:10,120 SOUTHEAST AND THE NORTHEAST USA. 10241 06:38:10,120 --> 06:38:13,200 THESE ARE THE PIs OF THIS 10242 06:38:13,200 --> 06:38:14,760 GRANT. 10243 06:38:14,760 --> 06:38:15,480 RAYMONA LAWRENCE IS SITTING IN 10244 06:38:15,480 --> 06:38:15,840 THE BACK. 10245 06:38:15,840 --> 06:38:18,120 SHE WAS MY PARTNER IN CRIME FOR 10246 06:38:18,120 --> 06:38:20,480 THE FIRST 4 1/2 YEARS, AND AS I 10247 06:38:20,480 --> 06:38:22,560 WAS LEAVING CLINICAL PRACTICE, 10248 06:38:22,560 --> 06:38:26,160 WE CONVINCED PAYAL DESAI TO JOIN 10249 06:38:26,160 --> 06:38:28,040 AT NOW WE HAVE A TRIAD PI TEAM. 10250 06:38:28,040 --> 06:38:30,160 THESE ARE THE GROUPS THAT WORKED 10251 06:38:30,160 --> 06:38:40,320 WITH US. 10252 06:38:42,920 --> 06:38:44,360 SICKLE CELL REMAINS A DISEASE OF 10253 06:38:44,360 --> 06:38:47,120 YUJ PEOPLE. 10254 06:38:47,120 --> 06:38:51,400 YOUNG PEOPLE. 10255 06:38:51,400 --> 06:38:52,000 THIS IS A PROBLEM WE HAVE TO 10256 06:38:52,000 --> 06:38:52,920 SOLVE FOR IN THE FUTURE. 10257 06:38:52,920 --> 06:38:54,120 WE WANT THESE PEOPLE TO LIVE 10258 06:38:54,120 --> 06:38:54,720 LONG. 10259 06:38:54,720 --> 06:38:56,360 IT'S ALSO A GLOBAL DISEASE. 10260 06:38:56,360 --> 06:38:57,360 IT'S NOT JUST AN AMERICAN 10261 06:38:57,360 --> 06:38:58,240 PROBLEM. 10262 06:38:58,240 --> 06:39:00,320 SO WHAT DO WE TRY TO SOLVE FOR 10263 06:39:00,320 --> 06:39:01,640 IN ST3P UP? 10264 06:39:01,640 --> 06:39:03,280 WE KNEW THERE WERE POOR OUTCOMES 10265 06:39:03,280 --> 06:39:07,000 TO TRANSITION. 10266 06:39:07,000 --> 06:39:08,960 THREE TIMES ACU, TWO TIMES 10267 06:39:08,960 --> 06:39:11,040 READMISSION RATE, THEY DON'T DO 10268 06:39:11,040 --> 06:39:12,360 WELL ON STANDARDIZED TESTING BUT 10269 06:39:12,360 --> 06:39:13,920 THERE WAS ALSO NO MODEL FOR 10270 06:39:13,920 --> 06:39:14,960 TRANSITION FOR SICKLE CELL 10271 06:39:14,960 --> 06:39:15,960 DISEASE THAT WAS WELL 10272 06:39:15,960 --> 06:39:18,080 ESTABLISHED AND APPLIED IN THE 10273 06:39:18,080 --> 06:39:19,760 POPULATION OF CLINICAL CARE. 10274 06:39:19,760 --> 06:39:21,800 THERE WAS ALSO VERY SHORT TERM 10275 06:39:21,800 --> 06:39:22,560 FOLLOW-UP AMONG PILOTS THAT WERE 10276 06:39:22,560 --> 06:39:24,560 DONE. 10277 06:39:24,560 --> 06:39:25,400 NO TWO PROGRAMS DID IT THE SAME 10278 06:39:25,400 --> 06:39:25,600 WAY. 10279 06:39:25,600 --> 06:39:26,920 THERE WAS NO DEFINITION OF 10280 06:39:26,920 --> 06:39:28,440 SUCCESS IN TRANSITION. 10281 06:39:28,440 --> 06:39:30,440 AND IT ALL RELIED ON THE 10282 06:39:30,440 --> 06:39:32,080 HEALTHCARE SYSTEM TO EXECUTE. 10283 06:39:32,080 --> 06:39:34,640 NOW LIFE HAPPENS MOSTLY OUTSIDE 10284 06:39:34,640 --> 06:39:36,520 OF HEALTHCARE. 10285 06:39:36,520 --> 06:39:37,280 ALSO, WHO REALLY CARED? 10286 06:39:37,280 --> 06:39:38,480 WHO'S GOING TO PAY FOR THIS 10287 06:39:38,480 --> 06:39:38,920 EFFORT? 10288 06:39:38,920 --> 06:39:40,960 AND WE WANTED TO SOLVE FOR THAT 10289 06:39:40,960 --> 06:39:41,720 AS WELL AS PART OF THE ST3P UP 10290 06:39:41,720 --> 06:39:42,920 STUDY. 10291 06:39:42,920 --> 06:39:44,640 BUT WE DID A NEEDS ASSESSMENT OF 10292 06:39:44,640 --> 06:39:46,280 THE COMMUNITY, A 10293 06:39:46,280 --> 06:39:46,920 MULTI-STAKEHOLDER ASSESSMENT, 10294 06:39:46,920 --> 06:39:48,680 MEDICAL PROVIDERS, 10295 06:39:48,680 --> 06:39:49,960 ADMINISTRATORS, PATIENTS, 10296 06:39:49,960 --> 06:39:51,960 COMMUNITIES, ORGANIZATIONS, AND 10297 06:39:51,960 --> 06:39:52,600 WE FOUND TWO MAIN THINGS. 10298 06:39:52,600 --> 06:39:54,160 EVERYBODY WANTED THERE TO BE A 10299 06:39:54,160 --> 06:39:55,480 CARE STANDARD, AND EVERYBODY 10300 06:39:55,480 --> 06:39:57,880 WANTED TO HAVE MULTI-STAKEHOLDER 10301 06:39:57,880 --> 06:39:59,320 ENGAGEMENT IN THE PROCESS OF 10302 06:39:59,320 --> 06:40:01,400 TRANSITION. 10303 06:40:01,400 --> 06:40:05,200 AND THE GOAL WAS TO ACHIEVE 10304 06:40:05,200 --> 06:40:05,600 INTERDEEPEN DENSE. 10305 06:40:05,600 --> 06:40:06,440 WHEN YOU TALK TO THE COMMUNITY, 10306 06:40:06,440 --> 06:40:08,480 THEY SAY I DON'T WANT TO BE 10307 06:40:08,480 --> 06:40:09,680 DEPENDENT ON MY DOCTOR TO 10308 06:40:09,680 --> 06:40:10,480 SURVIVE. 10309 06:40:10,480 --> 06:40:15,080 I WANT TO KNOW WHERE I CAN GET 10310 06:40:15,080 --> 06:40:17,160 HELP, USE IT WHEN I NEED IT -- 10311 06:40:17,160 --> 06:40:19,120 WHEN IT COMES TO IND DEPENDENCE 10312 06:40:19,120 --> 06:40:25,320 INTERDEPENDENCEWAS THE BEDROCK S 10313 06:40:25,320 --> 06:40:26,920 YOU GET OLDER, YOU BUILD SKILLS 10314 06:40:26,920 --> 06:40:28,880 OF SELF MANAGEMENT, SELF-CARE, 10315 06:40:28,880 --> 06:40:30,000 SELF-EFFICACY, BUT YOU COULD TAP 10316 06:40:30,000 --> 06:40:32,400 INTO YOUR FAMILY, YOUR CBU, YOUR 10317 06:40:32,400 --> 06:40:33,600 MEDICAL PROVIDER WHEN AND IF YOU 10318 06:40:33,600 --> 06:40:36,040 NEEDED TO BE ABLE TO LIVE A FULL 10319 06:40:36,040 --> 06:40:36,640 LIFE UNLIMITED BY SICKLE CELL 10320 06:40:36,640 --> 06:40:37,960 DISEASE. 10321 06:40:37,960 --> 06:40:43,760 SO OUR STUDY WAS DESIGNED AS A 10322 06:40:43,760 --> 06:40:45,200 PERSPECTIVE RANDOMIZED STUDY 10323 06:40:45,200 --> 06:40:47,080 LOOKING AT A STANDARDIZED ARM 10324 06:40:47,080 --> 06:40:49,480 INTERVENTION WHICH WAS PUT IN 10325 06:40:49,480 --> 06:40:51,240 PLACE ACROSS ALL 14 CLINICS, 10326 06:40:51,240 --> 06:40:52,040 THEN WE'RE GOING TO COMPARE IS 10327 06:40:52,040 --> 06:40:53,920 IT EVEN BETTER IF YOU ADD PEER 10328 06:40:53,920 --> 06:40:56,120 MENTORING, AND THE OUTCOME OF 10329 06:40:56,120 --> 06:40:57,200 INTEREST WAS ACUTE CARE 10330 06:40:57,200 --> 06:40:58,400 UTILIZATION AND QUALITY OF LIFE. 10331 06:40:58,400 --> 06:41:00,160 EACH TEAM WAS MADE UP OF THREE 10332 06:41:00,160 --> 06:41:01,760 COMPONENTS: THE PROVIDER TEAM, 10333 06:41:01,760 --> 06:41:05,440 THE MEDICAL, SO PEDS AND ADULTS 10334 06:41:05,440 --> 06:41:07,000 TOGETHER, THE ORGANIZATION AS A 10335 06:41:07,000 --> 06:41:08,800 SOCIAL SUPPORT OUTSIDE OF 10336 06:41:08,800 --> 06:41:09,400 HEALTHCARE, AND THEN THE 10337 06:41:09,400 --> 06:41:09,760 PATIENT. 10338 06:41:09,760 --> 06:41:12,680 AND YOU WILL HEAR MORE ABOUT THE 10339 06:41:12,680 --> 06:41:17,360 TRIAD IN THE SYMPOSIUM TOMORROW. 10340 06:41:17,360 --> 06:41:20,760 SO WE CAME UP WITH A STRUCTURED 10341 06:41:20,760 --> 06:41:26,240 PROGRAM BASED ON ELEMENTS 10342 06:41:26,240 --> 06:41:28,120 DESIGNED BY CORE TRANSITION. 10343 06:41:28,120 --> 06:41:28,720 WE DECIDED TO USE QUALITY 10344 06:41:28,720 --> 06:41:30,360 IMPROVEMENT TO IMPLEMENT THIS 10345 06:41:30,360 --> 06:41:32,600 STANDARD ACROSS 14 SITES AND OF 10346 06:41:32,600 --> 06:41:33,800 COURSE THE PEER MENTORING ARM 10347 06:41:33,800 --> 06:41:35,160 WAS GIVEN TO SEVEN SITES OF THE 10348 06:41:35,160 --> 06:41:36,560 14. 10349 06:41:36,560 --> 06:41:38,800 WHY DO WE PICK PEER MENTORING? 10350 06:41:38,800 --> 06:41:40,960 BECAUSE THERE IS A LOT OF DATA 10351 06:41:40,960 --> 06:41:41,920 OUTSIDE OF SICKLE CELL DISEASE 10352 06:41:41,920 --> 06:41:43,360 THAT IF YOU HAVE A MENTOR WHO IS 10353 06:41:43,360 --> 06:41:45,600 A PEER, YOU'RE MORE LIKELY TO 10354 06:41:45,600 --> 06:41:47,440 GET INFORMATION FROM THIS, I'M 10355 06:41:47,440 --> 06:41:48,720 MOTIONAL SUPPORT AND ACHIEVE 10356 06:41:48,720 --> 06:41:50,640 RECIPROCITY AND THIS LEADS TO 10357 06:41:50,640 --> 06:41:51,480 BETTER OUTCOMES IN TERMS OF 10358 06:41:51,480 --> 06:41:57,400 QUALITY OF LIFE, IMPROVED HEALTH 10359 06:41:57,400 --> 06:41:58,720 BEHAVIOR AND -- FOR CHRONIC 10360 06:41:58,720 --> 06:42:00,080 DISEASES, WE NEED TO SEE IF THIS 10361 06:42:00,080 --> 06:42:01,920 DATA IS TRUE IN SICKLE CELL 10362 06:42:01,920 --> 06:42:02,160 DISEASE. 10363 06:42:02,160 --> 06:42:04,680 SO WHAT WAS THE STRUCTURED 10364 06:42:04,680 --> 06:42:06,640 PROCESS IN TRANSITIONING OUR 10365 06:42:06,640 --> 06:42:06,840 STUDY? 10366 06:42:06,840 --> 06:42:08,600 GETTING ENGAGED AND FOSTER 10367 06:42:08,600 --> 06:42:09,280 COMMUNICATION ACROSS THE THREE 10368 06:42:09,280 --> 06:42:10,800 PARTS OF THE TRIAD. 10369 06:42:10,800 --> 06:42:11,400 SO YOU HAVE TO TALK TO EACH 10370 06:42:11,400 --> 06:42:12,400 OTHER. 10371 06:42:12,400 --> 06:42:13,400 COMMUNICATE WELL AND ENGAGE EACH 10372 06:42:13,400 --> 06:42:15,120 OTHER TO BE ABLE TO BUILD A 10373 06:42:15,120 --> 06:42:16,760 PROGRAM THAT IS SERVED BY ALL OF 10374 06:42:16,760 --> 06:42:18,440 YOU FOR THE PATIENT COMMUNITY. 10375 06:42:18,440 --> 06:42:24,000 WE HAD TO PUT UP A STANDARD. 10376 06:42:24,000 --> 06:42:26,120 WHAT DOES -- FOR A 16-YEAR-OLD 10377 06:42:26,120 --> 06:42:27,440 WITH SICKLE CELL DISEASE? 10378 06:42:27,440 --> 06:42:28,720 WHAT SHOULD YOU DO AT EACH 10379 06:42:28,720 --> 06:42:29,840 VISIT, WHAT SCREENING TESTS DO 10380 06:42:29,840 --> 06:42:30,800 YOU DO? 10381 06:42:30,800 --> 06:42:32,120 AND WE WANTED THIS FOR NOT JUST 10382 06:42:32,120 --> 06:42:35,040 SS BUT FOR SC AND SB -- WE 10383 06:42:35,040 --> 06:42:37,040 ESTABLISHED A MODEL WHERE EVERY 10384 06:42:37,040 --> 06:42:39,720 PATIENT SAW THE DRR EITHER 10385 06:42:39,720 --> 06:42:41,360 VIRTUALLY OR IN PERSON, BECAUSE 10386 06:42:41,360 --> 06:42:43,200 IF YOU DON'T SEE YOUR PROVIDER, 10387 06:42:43,200 --> 06:42:45,280 YOU MAY MISS OUT ON CRITICAL 10388 06:42:45,280 --> 06:42:46,520 EDUCATION YOU NEED TO LEARN HOW 10389 06:42:46,520 --> 06:42:48,240 TO MANAGE YOUR DISEASE OR TO BE 10390 06:42:48,240 --> 06:42:49,920 LINKED TO THE COMMUNITY 10391 06:42:49,920 --> 06:42:50,200 RESOURCES. 10392 06:42:50,200 --> 06:42:51,520 WE ASSESSED THEIR READINESS NOT 10393 06:42:51,520 --> 06:42:54,280 JUST IN PEDIATRICS BUT ADULT 10394 06:42:54,280 --> 06:42:55,760 CARE. 10395 06:42:55,760 --> 06:42:57,120 YOU LOSE SKILLS YOU THOUGHT YOU 10396 06:42:57,120 --> 06:42:57,840 GAINED BECAUSE IT'S A DIFFERENT 10397 06:42:57,840 --> 06:42:58,760 ENVIRONMENT AND WE ALL HAVE 10398 06:42:58,760 --> 06:42:59,960 YOUNG ADULTS IN OUR LIVES WHO 10399 06:42:59,960 --> 06:43:03,480 ARE OUR CHILDREN THAT WE KNOW 10400 06:43:03,480 --> 06:43:04,720 WHEN THEY'RE 21 THEY LEARN 10401 06:43:04,720 --> 06:43:06,320 SOMETHING, WHEN THEY'RE 25, THEY 10402 06:43:06,320 --> 06:43:08,240 FORGET IT SO YOU WANT TO MAKE 10403 06:43:08,240 --> 06:43:09,000 SURE YOU RE-BOOST THEIR 10404 06:43:09,000 --> 06:43:10,200 KNOWLEDGE AS THEY MOVE ON TO 10405 06:43:10,200 --> 06:43:11,880 DIFFERENT PHASES OF LIFE. 10406 06:43:11,880 --> 06:43:12,960 USE THEIR KNOWLEDGE AND SKILL 10407 06:43:12,960 --> 06:43:14,160 BUILDING TO FIX THE GAPS YOU 10408 06:43:14,160 --> 06:43:15,720 FIND OUT IN YOUR ASSESSMENT AND 10409 06:43:15,720 --> 06:43:16,800 ALSO SHOW WITH THEM WHAT IS 10410 06:43:16,800 --> 06:43:18,560 DIFFERENT IN PEDIATRIC CARE AND 10411 06:43:18,560 --> 06:43:18,840 ADULT CARE. 10412 06:43:18,840 --> 06:43:19,600 THEY NEED TO KNOW THIS. 10413 06:43:19,600 --> 06:43:21,120 WE NEED TO KNOW THIS I NEED TO 10414 06:43:21,120 --> 06:43:25,200 KNOW AS A PEDIATRICIAN -- ADULT 10415 06:43:25,200 --> 06:43:26,160 CARE AND VICE VERSA BECAUSE IF 10416 06:43:26,160 --> 06:43:27,600 NOT, WE SET UP THE WRONG 10417 06:43:27,600 --> 06:43:28,240 EXPECTATION. 10418 06:43:28,240 --> 06:43:30,160 CONNECT AND REFER. 10419 06:43:30,160 --> 06:43:31,280 MOST PATIENTS LEAVE HEALTHCARE 10420 06:43:31,280 --> 06:43:33,680 BEFORE THEY TURN 16. 10421 06:43:33,680 --> 06:43:38,440 THE SC, THE S BETA PLUS THAL AND 10422 06:43:38,440 --> 06:43:39,960 THE -- PATIENTS ARE NOT IN 10423 06:43:39,960 --> 06:43:40,400 HEALTHCARE. 10424 06:43:40,400 --> 06:43:42,480 SO HOW DO WE GET THEM BACK INTO 10425 06:43:42,480 --> 06:43:44,480 HEALTHCARE WHEN THEY NEED TO 10426 06:43:44,480 --> 06:43:46,120 MANAGE THEIR LIFE? 10427 06:43:46,120 --> 06:43:47,560 THE STE IS THAT SCAFFOLD AND 10428 06:43:47,560 --> 06:43:48,880 THEN REFERS THEM BACK INTO 10429 06:43:48,880 --> 06:43:49,280 HEALTHCARE. 10430 06:43:49,280 --> 06:43:50,880 AND OF COURSE THE MEDICAL CENTER 10431 06:43:50,880 --> 06:43:53,520 SHOULD REFER TO THE CBO FOR 10432 06:43:53,520 --> 06:43:54,360 SOCIETAL SUPPORT THAT YOU CANNOT 10433 06:43:54,360 --> 06:43:57,560 GIVE IN THE CLINIC. 10434 06:43:57,560 --> 06:43:58,640 EQUIPPING THE CARE TEAM, NOT 10435 06:43:58,640 --> 06:44:00,160 JUST THE PATIENTS BUT THE 10436 06:44:00,160 --> 06:44:02,520 DOCTOR, THE ER, THE HOSPITAL, 10437 06:44:02,520 --> 06:44:03,400 THEY NEED TO KNOW, HOW DO I TAKE 10438 06:44:03,400 --> 06:44:04,160 CARE OF THE PATIENT? 10439 06:44:04,160 --> 06:44:05,120 WHAT IS A CARE PLAN? 10440 06:44:05,120 --> 06:44:07,080 GIVE ME A STRUCTURED PLAN, WHEN 10441 06:44:07,080 --> 06:44:09,280 SOMETHING GOES WRONG, DO XYZ. 10442 06:44:09,280 --> 06:44:10,920 AND UPDATE THIS ANNUALLY, MAKE 10443 06:44:10,920 --> 06:44:12,360 THIS ACCESSIBLE IN THE MEDICAL 10444 06:44:12,360 --> 06:44:13,720 RECORD OR IN WHATEVER FORMAT YOU 10445 06:44:13,720 --> 06:44:16,040 HAVE, BUT ALSO ADD SOMETHING 10446 06:44:16,040 --> 06:44:17,360 SPECIAL ABOUT EACH PATIENT. 10447 06:44:17,360 --> 06:44:18,800 WHAT MAKES JOHN DIFFERENT FROM 10448 06:44:18,800 --> 06:44:19,880 JANE, DIFFERENT FROM OSCAR, 10449 06:44:19,880 --> 06:44:20,880 DIFFERENT FROM VICTOR? 10450 06:44:20,880 --> 06:44:21,640 BECAUSE THAT'S GOING TO MAKE 10451 06:44:21,640 --> 06:44:24,040 THEM DO WELL OR NOT DO WELL WHEN 10452 06:44:24,040 --> 06:44:24,760 THEY GET ADMITTED TO THE 10453 06:44:24,760 --> 06:44:25,040 HOSPITAL. 10454 06:44:25,040 --> 06:44:27,160 AND THEN MONITOR AND TRACK HOW 10455 06:44:27,160 --> 06:44:28,200 WELL YOUR PLAN IS DOING WITH 10456 06:44:28,200 --> 06:44:29,800 THIS PROCESS, HOW WELL YOUR 10457 06:44:29,800 --> 06:44:31,880 TRIAD IS WORKING TOGETHER 10458 06:44:31,880 --> 06:44:32,880 SEAMLESSLY, AND THEN HOW ARE YOU 10459 06:44:32,880 --> 06:44:34,640 DOING WITH PUTTING THIS 10460 06:44:34,640 --> 06:44:35,240 STRUCTURE IN PLACE FOR YOUR 10461 06:44:35,240 --> 06:44:36,080 PATIENTS? 10462 06:44:36,080 --> 06:44:36,640 DATA IS KING. 10463 06:44:36,640 --> 06:44:38,480 THE MORE DATA YOU HAVE, THE MORE 10464 06:44:38,480 --> 06:44:40,280 YOU CAN GET THIS PAID FOR BY 10465 06:44:40,280 --> 06:44:41,480 PUBLIC AND PRIVATE INSURANCE. 10466 06:44:41,480 --> 06:44:42,680 AND THEN TRACK WHAT WORKS AND 10467 06:44:42,680 --> 06:44:44,680 DIDN'T WORK, AND THAT'S WHAT QI 10468 06:44:44,680 --> 06:44:45,000 IS ALL ABOUT. 10469 06:44:45,000 --> 06:44:46,040 SO HOW DO WE DO IT? 10470 06:44:46,040 --> 06:44:47,680 WE PUT TOGETHER A QI PROCESS, WE 10471 06:44:47,680 --> 06:44:49,920 BUILT A TEAM AT EACH SITE. 10472 06:44:49,920 --> 06:44:51,080 WE HAD A QI COORDINATOR WHO'S IN 10473 06:44:51,080 --> 06:44:52,320 THE BACK WHO HELPED COACH THESE 10474 06:44:52,320 --> 06:44:53,640 SITES ON HOW TO IMPLEMENT 10475 06:44:53,640 --> 06:44:55,520 QUALITY IMPROVEMENT BEGINNING 10476 06:44:55,520 --> 06:44:57,120 WITH QI101. 10477 06:44:57,120 --> 06:45:01,720 AND THE GOAL WAS TO PUT IN PLACE 10478 06:45:01,720 --> 06:45:04,840 THESE SIX CORE ELEMENTS IN THE 10479 06:45:04,840 --> 06:45:08,520 PEDIATRIC CLINIC AND THE ATULT T 10480 06:45:08,520 --> 06:45:08,760 CLINIC. 10481 06:45:08,760 --> 06:45:10,240 HOW TO COLLECT DATA, HOW TO MAKE 10482 06:45:10,240 --> 06:45:11,440 CHANGES, HOW TO ACCESSORY 10483 06:45:11,440 --> 06:45:12,720 SOURCES IN OUR CHANGE PACKAGE, 10484 06:45:12,720 --> 06:45:14,480 AND PUT THEM IN PLACE IN THEIR 10485 06:45:14,480 --> 06:45:14,800 CLINIC. 10486 06:45:14,800 --> 06:45:17,640 HOW TO TRY SK THAT DOESN'T WORK, 10487 06:45:17,640 --> 06:45:20,680 DON'T WASTE TIME -- AND THEN 10488 06:45:20,680 --> 06:45:22,440 MOVE ON WITH THE NEXT ITERATION. 10489 06:45:22,440 --> 06:45:23,360 THEN WE ALSO HAD MONTHLY 10490 06:45:23,360 --> 06:45:24,240 MEETINGS WHERE WE TALKED ABOUT 10491 06:45:24,240 --> 06:45:25,040 WHAT WAS HAPPENING IN EACH 10492 06:45:25,040 --> 06:45:26,000 CLINIC. 10493 06:45:26,000 --> 06:45:29,240 WE HAD EVERY SIX MONTHS SITE 10494 06:45:29,240 --> 06:45:31,000 VISIT, AND ANNUAL INVESTIGATIVE 10495 06:45:31,000 --> 06:45:33,400 CONFERENCE, AND A HEALTHY DOSE 10496 06:45:33,400 --> 06:45:34,200 OF COMPETITION. 10497 06:45:34,200 --> 06:45:35,680 SITES WANT TO DO WELL COMPARED 10498 06:45:35,680 --> 06:45:36,400 TO THEIR PEERS. 10499 06:45:36,400 --> 06:45:39,280 YOU KNOW HOW DOCTORS ARE. 10500 06:45:39,280 --> 06:45:41,640 SO THE AIM STATEMENT IS THAT 10501 06:45:41,640 --> 06:45:42,720 SICKLE CELL DISEASE IS A COMPLEX 10502 06:45:42,720 --> 06:45:47,560 DISEASE AND YOU NEED TO IMPROVE 10503 06:45:47,560 --> 06:45:49,000 THE TEAMS IN BOTH THE PEDIATRIC 10504 06:45:49,000 --> 06:45:50,640 CLINIC AND THE ADULT CLINIC, WE 10505 06:45:50,640 --> 06:45:52,280 HAD A TIMELINE, AND WE HAD A 10506 06:45:52,280 --> 06:45:55,320 MODEL THAT WE WERE GOING TO USE. 10507 06:45:55,320 --> 06:45:56,080 WE PICKED OUR PROCESS MEASURE, 10508 06:45:56,080 --> 06:45:57,920 WHICH IS WHAT WILL WE DO TO SHOW 10509 06:45:57,920 --> 06:46:00,080 THAT WE SUCCEEDED, AND THEN WE 10510 06:46:00,080 --> 06:46:04,200 PICKED OUR OUTCOME MESSAGE, HOW 10511 06:46:04,200 --> 06:46:04,880 WE GOT THERE. 10512 06:46:04,880 --> 06:46:06,400 AND THIS IS OUR OUT COME 10513 06:46:06,400 --> 06:46:08,000 MEASURE, THE PROCESS MEASUREMENT 10514 06:46:08,000 --> 06:46:08,440 TOOL. 10515 06:46:08,440 --> 06:46:09,760 EVERY CLINIC HAD TO SCORE 10516 06:46:09,760 --> 06:46:11,160 THEMSELVES ALONG THESE SIX CORE 10517 06:46:11,160 --> 06:46:13,840 ELEMENTS WITH PACKUP DATA, I 10518 06:46:13,840 --> 06:46:14,960 THINK HE WITH ACTUALLY MET THIS 10519 06:46:14,960 --> 06:46:15,600 CRITERIA. 10520 06:46:15,600 --> 06:46:16,880 THE POLICY. 10521 06:46:16,880 --> 06:46:18,680 DO YOU HAVE A POLICY, WAS IT 10522 06:46:18,680 --> 06:46:20,840 DEVELOPED WITH YOUNG ADULTS IN 10523 06:46:20,840 --> 06:46:22,480 MIND, WITH PATIENT ENGAGEMENT, 10524 06:46:22,480 --> 06:46:24,280 COMMUNITY, WAS IT A 10525 06:46:24,280 --> 06:46:25,160 MULTI-STAKEHOLDER PROCESS, AND 10526 06:46:25,160 --> 06:46:28,120 IS IT VISIBLE IN YOUR CLINIC AND 10527 06:46:28,120 --> 06:46:29,400 DO THEY KNOW ABOUT IT. 10528 06:46:29,400 --> 06:46:31,160 THAT'S JUST ONE EXAMPLE. 10529 06:46:31,160 --> 06:46:31,760 WE HAD ONE FOR THE PIED TRICK 10530 06:46:31,760 --> 06:46:35,360 CPEDIATRICCLINIC AND ONE FOR THT 10531 06:46:35,360 --> 06:46:37,160 CLINIC. 10532 06:46:37,160 --> 06:46:37,840 WHAT DO WE DO WITH THE PMT? 10533 06:46:37,840 --> 06:46:39,800 WE SCORE CLINICS EVERY SIX 10534 06:46:39,800 --> 06:46:40,200 MONTHS. 10535 06:46:40,200 --> 06:46:42,560 THE PEDS AND THE ADULT CLINIC, 10536 06:46:42,560 --> 06:46:46,240 AND WE ASK PEOPLE TO SCORE 10537 06:46:46,240 --> 06:46:47,600 THEMSELVES AND SEND IN THEIR 10538 06:46:47,600 --> 06:46:49,400 DATA, AND THEN THE DCC WOULD NOW 10539 06:46:49,400 --> 06:46:50,880 SCORE THEM AND VALIDATE THOSE 10540 06:46:50,880 --> 06:46:51,320 SCORES. 10541 06:46:51,320 --> 06:46:52,560 I'LL SHOW YOU THE DATA IN A 10542 06:46:52,560 --> 06:46:54,040 LITTLE BIT, BUT THE GOAL WAS TO 10543 06:46:54,040 --> 06:46:54,760 MAKE SURE THAT EVERYBODY 10544 06:46:54,760 --> 06:46:55,880 UNDERSTOOD HOW TO MEASURE 10545 06:46:55,880 --> 06:46:56,960 YOURSELF AND IF YOU'RE REALLY 10546 06:46:56,960 --> 06:47:00,840 PUTTING IN PLACE THIS PROCESS IN 10547 06:47:00,840 --> 06:47:02,720 A SYSTEM THAT WOULD BE 10548 06:47:02,720 --> 06:47:03,000 SUSTAINABLE. 10549 06:47:03,000 --> 06:47:05,120 WE HAVE A MONTHLY CALL, WE HAVE 10550 06:47:05,120 --> 06:47:06,800 THE BIANNUAL SITE VISIT, 10551 06:47:06,800 --> 06:47:07,920 INVESTIGATOR MEETING, AND EVERY 10552 06:47:07,920 --> 06:47:09,440 SIX MONTHS WE RE-SCORE THE SITES 10553 06:47:09,440 --> 06:47:11,280 UNTIL THE END OF THE STUDY. 10554 06:47:11,280 --> 06:47:13,200 NOW THIS IS HOW PEOPLE SCORE 10555 06:47:13,200 --> 06:47:16,280 THEMSELVES IN THE BEGINNING 10556 06:47:16,280 --> 06:47:18,520 VERSUS WHAT WE VALIDATED. 10557 06:47:18,520 --> 06:47:20,400 SO THE BLUE LINES CAME DOWN 10558 06:47:20,400 --> 06:47:23,560 DRASTICALLY IN SOME SITE. 10559 06:47:23,560 --> 06:47:25,520 ONLY ONE SITE WAS QUITE ACCURATE 10560 06:47:25,520 --> 06:47:26,880 IN THEIR SCORE. 10561 06:47:26,880 --> 06:47:27,520 BUT AFTER TWO YEARS IT LOOKED 10562 06:47:27,520 --> 06:47:28,080 LIKE THIS. 10563 06:47:28,080 --> 06:47:30,080 THEY WERE ABLE TO TRULY ASSESS 10564 06:47:30,080 --> 06:47:31,840 THEMSELVES AGAINST SEMI SEFS AND 10565 06:47:31,840 --> 06:47:32,520 SEE WHAT THEY ARE REALLY DOING 10566 06:47:32,520 --> 06:47:34,160 AND THAT THEY VALIDATE THEIR 10567 06:47:34,160 --> 06:47:35,360 DATA BEFORE THEY PUT IT OUT 10568 06:47:35,360 --> 06:47:35,680 THERE. 10569 06:47:35,680 --> 06:47:38,360 NOW THIS IS OUR OVERALL SUMMIT 10570 06:47:38,360 --> 06:47:39,240 OF OUR RESULTS. 10571 06:47:39,240 --> 06:47:42,000 SO OVER THE FIRST TWO YEARS OF 10572 06:47:42,000 --> 06:47:46,080 THE STUDY -- OVER THE FIVE YEARS 10573 06:47:46,080 --> 06:47:50,400 OF THE STUDY, WE NOTICED AN 10574 06:47:50,400 --> 06:47:51,240 INCREASE -- THIS TELLS ME THEY 10575 06:47:51,240 --> 06:47:54,040 WERE ABLE TO PUT IN PLACE THIS 10576 06:47:54,040 --> 06:47:54,640 STRUCTURED PROGRAM 80% OF THE 10577 06:47:54,640 --> 06:47:56,880 TIME. 10578 06:47:56,880 --> 06:47:58,240 SORRY, 80% OF THE CLINICS WERE 10579 06:47:58,240 --> 06:48:00,080 ABLE TO PUT THIS PROCESS IN 10580 06:48:00,080 --> 06:48:00,280 PLACE. 10581 06:48:00,280 --> 06:48:01,360 IN THE PEDIATRIC PROGRAM, WE HAD 10582 06:48:01,360 --> 06:48:06,280 A RISE IN THEIR SCORE OF 76%, 10583 06:48:06,280 --> 06:48:14,000 AND THE ADULT SIDE BY 84%. 10584 06:48:14,000 --> 06:48:16,640 SO IT'S NOT AN ADULT PROBLEM OR 10585 06:48:16,640 --> 06:48:18,000 A PEDIATRIC PROBLEM, IT'S A KNOW 10586 06:48:18,000 --> 06:48:21,720 HOW T TO DO WHAT TO DO PROBLEM. 10587 06:48:21,720 --> 06:48:23,480 THIS IS THE SCORES OVER TIME. 10588 06:48:23,480 --> 06:48:27,640 AT THE END OF OUR STUDY, 13 OUT 10589 06:48:27,640 --> 06:48:33,640 OF THE 14 ADULT PROGRAMS REACHED 10590 06:48:33,640 --> 06:48:34,240 THE RESULT -- WE HAD ONE SITE 10591 06:48:34,240 --> 06:48:36,160 WHO HAD MULTIPLE P.I. CHANGES 10592 06:48:36,160 --> 06:48:37,520 AND SOME OTHER CHANGES WE HAD TO 10593 06:48:37,520 --> 06:48:39,320 DEAL WITH THAT NEVER MET THE 10594 06:48:39,320 --> 06:48:41,520 SCORE BUT OVERALL IT IS 10595 06:48:41,520 --> 06:48:43,360 POSSIBLE, FEASIBLE AND ACTUALLY 10596 06:48:43,360 --> 06:48:45,440 DOABLE TO PUT THIS 10597 06:48:45,440 --> 06:48:46,600 SYSTEM/PROCESS IN PLACE IN YOUR 10598 06:48:46,600 --> 06:48:47,280 CLINICS, NO MATTER WHERE YOU 10599 06:48:47,280 --> 06:48:47,600 ARE. 10600 06:48:47,600 --> 06:48:51,960 WE HAVE PEOPLE IN RURAL, URBAN, 10601 06:48:51,960 --> 06:48:52,520 ACADEMIC CLINICS, IT DIDN'T 10602 06:48:52,520 --> 06:48:53,160 REALLY MATTER. 10603 06:48:53,160 --> 06:48:54,280 SO AT THE END OF THE DAY, WE 10604 06:48:54,280 --> 06:48:56,280 KNOW THE TRANSITION IS A BIG 10605 06:48:56,280 --> 06:48:56,520 PROBLEM. 10606 06:48:56,520 --> 06:48:57,400 YOU CAN ACTUALLY IMPLEMENT AND 10607 06:48:57,400 --> 06:48:59,520 YOU SHOULD IMPLEMENT A 10608 06:48:59,520 --> 06:49:01,360 STRUCTURED PROGRAM FOR YOUR 10609 06:49:01,360 --> 06:49:03,880 SICKLE CELL PROGRAMS BOTH ON -- 10610 06:49:03,880 --> 06:49:04,160 ADULT CARE. 10611 06:49:04,160 --> 06:49:06,480 IT IS VERY, VERY IMPORTANT THAT 10612 06:49:06,480 --> 06:49:07,600 YOU USE THESE COMMUNITY 10613 06:49:07,600 --> 06:49:08,680 ORGANIZATIONS AS PART OF THIS 10614 06:49:08,680 --> 06:49:10,040 MODEL, BECAUSE HEALTHCARE 10615 06:49:10,040 --> 06:49:11,120 HAPPENS NOT JUST IN HEALTHCARE 10616 06:49:11,120 --> 06:49:12,560 BUT ALSO OUTSIDE OF HEALTHCARE. 10617 06:49:12,560 --> 06:49:14,400 LIFE HAPPENS. 10618 06:49:14,400 --> 06:49:15,840 AND WE NEEDED A COORDINATOR TO 10619 06:49:15,840 --> 06:49:17,120 BE ABLE TO PUT THESE PIECES 10620 06:49:17,120 --> 06:49:20,760 TOGETHER, BE THE BRIDGE BETWEEN 10621 06:49:20,760 --> 06:49:22,640 THE COMMUNITY, BETWEEN THE PEDS 10622 06:49:22,640 --> 06:49:24,960 AND ADULTS PROGRAM AND PROVIDES 10623 06:49:24,960 --> 06:49:26,160 A STRONG IMPLEMENTATION FOR 10624 06:49:26,160 --> 06:49:27,600 THESE KINDS OF PROGRAMS, BUT 10625 06:49:27,600 --> 06:49:30,560 YOU'VE GOT TO -- WE SPENT A LOT 10626 06:49:30,560 --> 06:49:34,000 OF TIME WORKING ON RELATIONSHIP 10627 06:49:34,000 --> 06:49:35,840 BUILDING, TRUST BUILDING, 10628 06:49:35,840 --> 06:49:40,400 PSYCHOLOGICAL SAFETY ACROSS -- 10629 06:49:40,400 --> 06:49:41,640 IN ANY PROGRAM WE DON'T TRUST 10630 06:49:41,640 --> 06:49:42,640 EACH OTHER, WE DON'T BELIEVE 10631 06:49:42,640 --> 06:49:44,160 YOU'RE DOING AS GOOD A JOB FOR 10632 06:49:44,160 --> 06:49:45,320 MY PATIENT AS I THINK YOU SHOULD 10633 06:49:45,320 --> 06:49:46,520 S AND VICE VERSA. 10634 06:49:46,520 --> 06:49:49,480 AND WE ALL COME TO TRYING TO DO 10635 06:49:49,480 --> 06:49:50,320 THE RIGHT THING FOR OUR PATIENTS 10636 06:49:50,320 --> 06:49:51,560 SO WE SPENT A LOT OF TIME 10637 06:49:51,560 --> 06:49:52,480 WORKING ON THAT PIECE AND I 10638 06:49:52,480 --> 06:49:55,360 THINK THAT'S ONE OF THE KEYS 10639 06:49:55,360 --> 06:49:56,160 THAT WORKED VERY WELL. 10640 06:49:56,160 --> 06:50:00,000 I WANT TO THANK OUR PATIENTS 10641 06:50:00,000 --> 06:50:05,240 FIRST AND FOREMOST, THE CBOs, 10642 06:50:05,240 --> 06:50:06,480 AT OUR SITES, ALL OF OUR 10643 06:50:06,480 --> 06:50:07,440 CONSULTANTS, AND I WANT TO SAY 10644 06:50:07,440 --> 06:50:09,320 THANK YOU, I HAVE 3 MINUTE FOR 10645 06:50:09,320 --> 06:50:09,600 QUESTIONS. 10646 06:50:09,600 --> 06:50:09,840 I DID IT. 10647 06:50:09,840 --> 06:50:15,280 THANK YOU VERY MUCH, EVERYBODY. 10648 06:50:15,280 --> 06:50:17,000 >>THANK YOU SO MUCH, IFY, FOR 10649 06:50:17,000 --> 06:50:18,200 AN EXCITING TALK. 10650 06:50:18,200 --> 06:50:24,480 QUESTIONS FOR IFY? 10651 06:50:24,480 --> 06:50:25,280 ANYTHING ONLINE? 10652 06:50:25,280 --> 06:50:27,120 NO? 10653 06:50:27,120 --> 06:50:28,960 I GUESS YOU WERE VERY CLEAR. 10654 06:50:28,960 --> 06:50:29,600 BUT IT WAS A GREAT SEGUE FOR 10655 06:50:29,600 --> 06:50:29,960 TOMORROW. 10656 06:50:29,960 --> 06:50:31,920 SO WE'RE GOING TO START TOMORROW 10657 06:50:31,920 --> 06:50:33,680 WITH GLOBAL SICKLE CELL DISEASE 10658 06:50:33,680 --> 06:50:38,240 FROM INDIA, FROM AFRICA, FROM 10659 06:50:38,240 --> 06:50:40,200 BRAZIL, AND ALSO TALK ABOUT GGIT 10660 06:50:40,200 --> 06:50:42,920 AND ALL THAT, SO IT SHOULD BE AN 10661 06:50:42,920 --> 06:50:43,240 EXCITING DAY. 10662 06:50:43,240 --> 06:50:45,120 SEE YOU TOMORROW, ALL, AT 9:00. 10663 06:50:45,120 --> 06:50:46,480 WE START THE SESSION TOMORROW 10664 06:50:46,480 --> 06:50:48,080 HERE AT 9:00. 10665 06:50:48,080 --> 06:50:49,560 THANK YOU VERY MUCH. 10666 06:50:49,560 --> 06:50:59,800 >>THANK YOU.