1 00:00:05,760 --> 00:00:10,240 WELCOME TO ALL OF YOU WHO HAVE 2 00:00:10,240 --> 00:00:12,320 REGISTERED AND NOW ARE 3 00:00:12,320 --> 00:00:15,960 ATTENDING THIS REALLY VERY, 4 00:00:15,960 --> 00:00:17,720 VERY EXCITING WORKSHOP ON 5 00:00:17,720 --> 00:00:20,280 CURRENT AND FUTURE RESEARCH 6 00:00:20,280 --> 00:00:24,720 DIRECTIONS IN CYSTIC FIBROSIS. 7 00:00:24,720 --> 00:00:29,920 JIM KILEY, AHEAD OF THE LUNG 8 00:00:29,920 --> 00:00:32,680 DIVISION AT NDI AND IT IS 9 00:00:32,680 --> 00:00:34,680 REALLY A PLEASURE TO WELCOME 10 00:00:34,680 --> 00:00:35,680 YOU TO THIS WEBSITE. 11 00:00:35,680 --> 00:00:38,040 IT IS SUCH A PLEASURE TO BRING 12 00:00:38,040 --> 00:00:39,320 TOGETHER SUCH A GROUP OF 13 00:00:39,320 --> 00:00:41,400 PEOPLE, YOU MAY KNOW WE HAVE 14 00:00:41,400 --> 00:00:42,320 500 REGISTERED FOR THIS 15 00:00:42,320 --> 00:00:43,760 MEETING SO I THINK WE HIT THE 16 00:00:43,760 --> 00:00:45,840 NAIL ON THE HEAD WITH THE 17 00:00:45,840 --> 00:00:46,880 TOPIC AND INTEREST ON BEHALF 18 00:00:46,880 --> 00:00:48,640 OF THE COMMUNITY AND WE'RE 19 00:00:48,640 --> 00:00:51,200 REALLY LOOKING FORWARD TO SOME 20 00:00:51,200 --> 00:00:52,240 VERY EXCITING PRESENTATIONS, 21 00:00:52,240 --> 00:00:52,960 DISCUSSIONS AND THEN 22 00:00:52,960 --> 00:00:54,440 RECOMMENDATIONS FROM ALL OF 23 00:00:54,440 --> 00:00:55,600 YOU IN TERMS OF THE DIRECTIONS 24 00:00:55,600 --> 00:00:58,160 WE NEED TO GO IN THIS FIELD. 25 00:00:58,160 --> 00:01:00,680 SO I AM GOING TO DO SOMETHING 26 00:01:00,680 --> 00:01:02,280 A LITTLE BIT OPPOSITE THAN 27 00:01:02,280 --> 00:01:04,640 USUALLY YOU DO WITH WELCOMES 28 00:01:04,640 --> 00:01:09,000 BY JUST SAYING HELLO TO ALL OF 29 00:01:09,000 --> 00:01:11,680 YOU, TO REALLY EXTEND A VERY 30 00:01:11,680 --> 00:01:12,520 SPECIAL, SPECIAL THANKS TO ALL 31 00:01:12,520 --> 00:01:15,080 OF THE PEOPLE WHO HAVE WORKED 32 00:01:15,080 --> 00:01:15,960 TIRELESSLY TO PUT THIS 33 00:01:15,960 --> 00:01:18,800 ALTOGETHER AND THIS IS A 34 00:01:18,800 --> 00:01:20,080 OUTSTANDING AGENDA WITH SOME 35 00:01:20,080 --> 00:01:20,600 WONDERFUL SPEAKERS. 36 00:01:20,600 --> 00:01:22,280 WE HAVE ALL THE EXPERTS REALLY 37 00:01:22,280 --> 00:01:23,760 IN THIS FIELD WITH US AND I 38 00:01:23,760 --> 00:01:25,760 THINK THIS IS GOING TO BE 39 00:01:25,760 --> 00:01:27,520 QUITE AN EXCITING COUPLE OF 40 00:01:27,520 --> 00:01:28,080 DAYS. 41 00:01:28,080 --> 00:01:32,800 I HAVE TO EXTEND A SPECIAL 42 00:01:32,800 --> 00:01:43,400 THANKS TO OUR COCHAIRS SO THAT 43 00:01:44,480 --> 00:01:48,320 INCLUDES DOCTORS INGLEHARDT, 44 00:01:48,320 --> 00:01:50,360 BURKETTE AND OTHER SPEAKERS 45 00:01:50,360 --> 00:01:52,520 FOR NOT ONLY HELPING WITH THE 46 00:01:52,520 --> 00:01:54,560 AGENDA BUT THE TIME THEY PUT 47 00:01:54,560 --> 00:01:58,240 INTO THIS WHICH IS NOT A SMALL 48 00:01:58,240 --> 00:02:00,360 TASK SO WE THANK THEM FOR 49 00:02:00,360 --> 00:02:03,080 DEVOTING TIME TO IT AND 50 00:02:03,080 --> 00:02:05,400 JOINING US WITH THE WORK ON 51 00:02:05,400 --> 00:02:06,400 THIS SPECIAL WORKSHOP. 52 00:02:06,400 --> 00:02:10,640 I ALSO WANT TO EXTEND A THANKS 53 00:02:10,640 --> 00:02:13,520 TO THE CYSTIC FIBROSIS 54 00:02:13,520 --> 00:02:14,160 FOUNDATION, Dr. CLANCY, I 55 00:02:14,160 --> 00:02:17,240 KNOW YOU ARE HERE SOMEWHERE, 56 00:02:17,240 --> 00:02:18,520 Dr. ROWE, THANK YOU FOR ALL 57 00:02:18,520 --> 00:02:20,600 YOUR HELP WITH THIS AND 58 00:02:20,600 --> 00:02:21,720 PARTNERSHIP OVER THE YEARS AS 59 00:02:21,720 --> 00:02:24,840 WE HAVE HAD SUCH A 60 00:02:24,840 --> 00:02:26,320 LONGSTANDING RELATIONSHIP WITH 61 00:02:26,320 --> 00:02:28,280 THE CF FOUNDATION AND HOPE TO 62 00:02:28,280 --> 00:02:29,880 BUILD OFF OF THAT GOING 63 00:02:29,880 --> 00:02:30,240 FORWARD. 64 00:02:30,240 --> 00:02:32,520 ONE OF THE THINGS YOU HAVE 65 00:02:32,520 --> 00:02:34,920 NOTICED RIGHT AWAY IS THIS IS 66 00:02:34,920 --> 00:02:37,000 A TOPIC OF INTEREST TO SEVERAL 67 00:02:37,000 --> 00:02:38,600 INSTITUTES AT THE NIH AND I 68 00:02:38,600 --> 00:02:44,440 HAVE TO SAY OUR COMMITTEE 69 00:02:44,440 --> 00:02:54,960 INCLUDES Dr. EGGERMAN FROM 70 00:02:55,920 --> 00:02:57,720 NAIAD AND OTHERS DONE A LOT OF 71 00:02:57,720 --> 00:02:59,120 THE HEAVY LIFTING TO BRING 72 00:02:59,120 --> 00:03:00,120 THIS ALTOGETHER WITH THE 73 00:03:00,120 --> 00:03:01,280 AGENDA WE HAVE TODAY. 74 00:03:01,280 --> 00:03:05,040 SO I AM REALLY THANKFUL TO ALL 75 00:03:05,040 --> 00:03:08,120 OF YOU, FOR THE LONDON 76 00:03:08,120 --> 00:03:15,800 DIVISION AND ALSO AT THE NHAI, 77 00:03:15,800 --> 00:03:17,520 WELCOME TO THIS WONDERFUL 78 00:03:17,520 --> 00:03:18,200 TOPIC. 79 00:03:18,200 --> 00:03:20,840 LET ME MOVE ALONG SINCE WE 80 00:03:20,840 --> 00:03:23,080 HAVE A PACKED AGENDA, BUT ONE 81 00:03:23,080 --> 00:03:25,520 OF THE THINGS WE IDENTIFIED 82 00:03:25,520 --> 00:03:27,400 FOR TOMORROW IN WATCHING THE 83 00:03:27,400 --> 00:03:28,720 SCIENCE AND THE LANDSCAPE AND 84 00:03:28,720 --> 00:03:31,120 REALLY HELPING TO IDENTIFY 85 00:03:31,120 --> 00:03:32,600 DIRECTIONS, PUT TOGETHER A 86 00:03:32,600 --> 00:03:34,280 WORKING GROUP THAT INCLUDED 87 00:03:34,280 --> 00:03:37,440 ALL OF YOU AND OUR SISTER 88 00:03:37,440 --> 00:03:40,800 AGENCY AT THE INSTITUTES AT 89 00:03:40,800 --> 00:03:42,080 NIH. 90 00:03:42,080 --> 00:03:44,160 WHEN WE REALIZED THERE WAS A 91 00:03:44,160 --> 00:03:46,560 PRETTY GOOD SEA CHANGE IN THE 92 00:03:46,560 --> 00:03:50,600 RESEARCH LANDSCAPE AFTER THE 93 00:03:50,600 --> 00:03:53,520 APPROVAL OF TRICAPTA BY THE 94 00:03:53,520 --> 00:03:56,480 FDA IN 2013 SO THAT MEANT WE 95 00:03:56,480 --> 00:03:58,280 REALLY NEEDED TO REASSESS WITH 96 00:03:58,280 --> 00:04:00,240 ALL OF YOU WITH THE EXPERTS IN 97 00:04:00,240 --> 00:04:01,880 THE FIELD TO ADDRESS THE 98 00:04:01,880 --> 00:04:03,280 CRITICAL QUESTIONS THAT WE 99 00:04:03,280 --> 00:04:04,880 FORM THE FIELD FOR FUTURE 100 00:04:04,880 --> 00:04:06,480 RESEARCH AS WE MOVE FORWARD 101 00:04:06,480 --> 00:04:11,360 AND LOOK AT THESE HIGHLY 102 00:04:11,360 --> 00:04:12,880 EFFECTIVE MODULATED THERAPIES 103 00:04:12,880 --> 00:04:13,720 FOR TREATMENT OF CF. 104 00:04:13,720 --> 00:04:15,560 AND I THINK THIS IS A TIME FOR 105 00:04:15,560 --> 00:04:17,040 US TO REALLY TAKE STOCK IN 106 00:04:17,040 --> 00:04:19,320 WHERE WE HAVE BEEN, WHERE WE 107 00:04:19,320 --> 00:04:21,760 ARE TODAY AFTER SOME MAJOR, 108 00:04:21,760 --> 00:04:23,600 MAJOR ADVANCES AND TO BRING 109 00:04:23,600 --> 00:04:26,080 TOGETHER THIS PANEL'S EXPERT 110 00:04:26,080 --> 00:04:27,240 AND COMMITTEE, LOOKING WITH 111 00:04:27,240 --> 00:04:29,680 THE PWA*ED OF SCIENCE THAT 112 00:04:29,680 --> 00:04:32,160 NEEDS TO ADDRESS THE PROBLEM 113 00:04:32,160 --> 00:04:34,240 FROM BASIC TRANSLATION WITH 114 00:04:34,240 --> 00:04:35,840 CLINICAL BACKGROUND AND REALLY 115 00:04:35,840 --> 00:04:37,360 LOOK AT CRITICAL QUESTIONS IN 116 00:04:37,360 --> 00:04:38,200 GAPS AND OPPORTUNITIES THAT 117 00:04:38,200 --> 00:04:41,320 NEED TO BE ADDRESSED GOING 118 00:04:41,320 --> 00:04:41,840 FORWARD. 119 00:04:41,840 --> 00:04:43,240 SO THAT BASICALLY SETS THE 120 00:04:43,240 --> 00:04:45,120 STAGE FOR THIS WORKSHOP AND 121 00:04:45,120 --> 00:04:48,000 THE GOAL IS TO HIGHLIGHT THE 122 00:04:48,000 --> 00:04:48,920 CHALLENGES AND OPPORTUNITIES 123 00:04:48,920 --> 00:04:51,120 FOR RESEARCH IN THE CONTEXT OF 124 00:04:51,120 --> 00:04:51,920 THIS RAPIDLY SHIFTING 125 00:04:51,920 --> 00:04:52,880 TREATMENT OPTIONS FOR ALL 126 00:04:52,880 --> 00:04:54,640 PEOPLE WITH CYSTIC FIBROSIS 127 00:04:54,640 --> 00:04:56,640 INCLUDING THOSE NOT CREDIBLY 128 00:04:56,640 --> 00:05:00,720 ELIGIBLE FOR THE VARIETY OF 129 00:05:00,720 --> 00:05:03,280 MODULATED THEIRS THAT EXIST 130 00:05:03,280 --> 00:05:03,760 TODAY. 131 00:05:03,760 --> 00:05:06,880 SO WE WILL GIVE PERSPECTIVES 132 00:05:06,880 --> 00:05:11,080 OF INDIVIDUALS WITH CF, SOME 133 00:05:11,080 --> 00:05:14,280 OF THE CAREGIVERS, SOME WILL 134 00:05:14,280 --> 00:05:15,920 SPEAK ON THE THERAPY WHO ARE 135 00:05:15,920 --> 00:05:17,680 NOT ELIGIBLE AND BOTH 136 00:05:17,680 --> 00:05:18,720 PERSPECTIVES WILL HELP US 137 00:05:18,720 --> 00:05:21,000 UNDERSTAND WHAT RESEARCH IS 138 00:05:21,000 --> 00:05:23,800 NEEDED TO ADDRESS FUTURE 139 00:05:23,800 --> 00:05:25,960 CRITICAL CLINICAL CARE FOR ALL 140 00:05:25,960 --> 00:05:26,400 PEOPLE WITH CF. 141 00:05:26,400 --> 00:05:29,840 SO IT IS A BROAD-RANGING 142 00:05:29,840 --> 00:05:31,160 AGENDA, INVOLVES WHAT WE THINK 143 00:05:31,160 --> 00:05:32,880 ARE THE KEY STAKEHOLDERS AND 144 00:05:32,880 --> 00:05:34,400 REALLY DESIGNED TO GIVE US A 145 00:05:34,400 --> 00:05:36,920 LITTLE BIT OF A BLUEPRINT OR 146 00:05:36,920 --> 00:05:38,320 ROAD MAP, AT LEAST THE SENSE 147 00:05:38,320 --> 00:05:40,200 OF WHERE THE MOST CRITICAL 148 00:05:40,200 --> 00:05:41,920 QUESTIONS ARE THAT COULD BE 149 00:05:41,920 --> 00:05:43,760 IMPACTFUL AS WE MOVE PAST OUR 150 00:05:43,760 --> 00:05:45,360 CURRENT STATE OF KNOWLEDGE AND 151 00:05:45,360 --> 00:05:46,760 UNDERSTANDING OF THIS DISEASE 152 00:05:46,760 --> 00:05:51,400 BOTH FROM A MECHANISTIC 153 00:05:51,400 --> 00:05:52,240 PATHOBIOLOGY, GENETIC AND ALL 154 00:05:52,240 --> 00:05:55,720 THE WAY UP TO HOW DO WE 155 00:05:55,720 --> 00:05:58,600 IMPLEMENT IN THE POPULATION 156 00:05:58,600 --> 00:05:59,280 THAT WE'RE TESTING. 157 00:05:59,280 --> 00:06:01,400 SO I HOPE ALL OF YOU CAN 158 00:06:01,400 --> 00:06:03,000 REALLY FOCUS ON THAT. 159 00:06:03,000 --> 00:06:05,400 I KNOW THESE WORKSHOPS TEND TO 160 00:06:05,400 --> 00:06:06,800 BE A CATCH-ALL SO YOU OFTEN 161 00:06:06,800 --> 00:06:08,880 WILL COME UP WITH A LAUNDRY 162 00:06:08,880 --> 00:06:11,320 LIST AT THE END OF SOMEWHERE 163 00:06:11,320 --> 00:06:15,320 AROUND 15, 20 OPPORTUNITIES, 164 00:06:15,320 --> 00:06:16,720 GAPS, RESEARCH DIRECTIONS, BUT 165 00:06:16,720 --> 00:06:18,320 TRY TO GIVE SOME THOUGHT TO 166 00:06:18,320 --> 00:06:18,920 PRIORITIZATION A BIT. 167 00:06:18,920 --> 00:06:22,400 WHAT I LIKE TO LEAVE PEOPLE 168 00:06:22,400 --> 00:06:26,360 WITH IS WHAT ARE THE REALLY 169 00:06:26,360 --> 00:06:27,320 HIGHEST IMPLEMENTABLE AREAS WE 170 00:06:27,320 --> 00:06:29,200 NEED TO FOCUS ON THAT WILL 171 00:06:29,200 --> 00:06:30,480 REALLY HAVE AN IMPACT AND MAKE 172 00:06:30,480 --> 00:06:34,840 A DIFFERENCE AND NOT BE JUST 173 00:06:34,840 --> 00:06:36,320 INCREMENTAL BUT ADVANCE OUR 174 00:06:36,320 --> 00:06:38,240 SCIENCE IN A SUBSTANTIVE 175 00:06:38,240 --> 00:06:38,520 WAIVE. 176 00:06:38,520 --> 00:06:40,360 SO THINK ABOUT IT IN THOSE 177 00:06:40,360 --> 00:06:40,920 TERMS. 178 00:06:40,920 --> 00:06:43,840 THE GOAL OF THIS WORKSHOP WILL 179 00:06:43,840 --> 00:06:46,080 BE A PUBLICATION THAT I KNOW 180 00:06:46,080 --> 00:06:47,400 WILL BE EXCITING AND IMPORTANT 181 00:06:47,400 --> 00:06:48,480 IN SETTING THE STAGE WHERE WE 182 00:06:48,480 --> 00:06:50,640 ARE AND OUR UNDERSTANDING OF 183 00:06:50,640 --> 00:06:52,520 THE SCIENCE TO DATE BUT ALSO I 184 00:06:52,520 --> 00:06:53,920 HOPE WILL GIVE THE COMMUNITY A 185 00:06:53,920 --> 00:06:55,560 SENSE OF DIRECTION, WHERE WE 186 00:06:55,560 --> 00:06:57,960 NEED TO FOCUS OUR RESEARCH 187 00:06:57,960 --> 00:06:58,480 EFFORTS. 188 00:06:58,480 --> 00:07:00,920 WHEN WE DO THESE WORKSHOPS IN 189 00:07:00,920 --> 00:07:02,760 PERSON, WE HAVE 30, 40, 50 190 00:07:02,760 --> 00:07:04,400 PEOPLE IN THE ROOM AND 191 00:07:04,400 --> 00:07:05,560 OFTENTIMES YOU CAN'T GET THE 192 00:07:05,560 --> 00:07:06,400 WORD OUT TO EVERYONE ABOUT 193 00:07:06,400 --> 00:07:08,160 WHAT YOU HAVE RECOMMENDED OR 194 00:07:08,160 --> 00:07:10,880 SUGGESTED IN TERMS OF RESEARCH 195 00:07:10,880 --> 00:07:12,080 DIRECTION. 196 00:07:12,080 --> 00:07:19,760 WHEN WE DO THE VIRTUAL ONES, 197 00:07:19,760 --> 00:07:22,400 WE HAVE EVERYBODY, FOUR, 500 198 00:07:22,400 --> 00:07:23,520 PEOPLE TO HEAR THE 199 00:07:23,520 --> 00:07:25,880 RECOMMENDATIONS AND THAT IS AN 200 00:07:25,880 --> 00:07:29,760 INVITATION TO EVERYONE TO 201 00:07:29,760 --> 00:07:31,360 THINK NOT WAIT FOR 202 00:07:31,360 --> 00:07:32,240 SOLICITATIONS BUT THINK ABOUT 203 00:07:32,240 --> 00:07:33,680 THE NEXT STEPS AND YOU CAN 204 00:07:33,680 --> 00:07:35,840 THINK ABOUT THE NEXT STEPS ON 205 00:07:35,840 --> 00:07:37,600 YOUR OWN AND THAT WE ARE OPEN 206 00:07:37,600 --> 00:07:39,000 FOR BUSINESS. 207 00:07:39,000 --> 00:07:40,160 THE ROBUST MECHANISM IS THERE 208 00:07:40,160 --> 00:07:42,080 FOR EVERYONE TO SUBMIT 209 00:07:42,080 --> 00:07:43,480 APPLICATIONS ACROSS NIH AND 210 00:07:43,480 --> 00:07:45,320 WE'RE VERY INTERESTED IN 211 00:07:45,320 --> 00:07:46,160 RECEIVING THOSE APPLICATIONS 212 00:07:46,160 --> 00:07:46,520 FROM YOU. 213 00:07:46,520 --> 00:07:49,480 SO I WILL STOP THERE AND TURN 214 00:07:49,480 --> 00:07:51,960 IT BACK TO I THINK MARRAH AND 215 00:07:51,960 --> 00:07:53,880 AGAIN, I WELCOME ALL OF YOU, 216 00:07:53,880 --> 00:07:55,640 THANK YOU FOR YOUR TIME AND 217 00:07:55,640 --> 00:07:57,040 ATTENTION AND I LOOK FORWARD 218 00:07:57,040 --> 00:07:57,840 TO HEARING SOME OF THE 219 00:07:57,840 --> 00:07:58,720 DISCUSSIONS OVER THE NEXT 220 00:07:58,720 --> 00:08:00,680 COUPLE OF DAYS AND OUTPUT FROM 221 00:08:00,680 --> 00:08:02,320 THIS WORKSHOP SO THANK YOU ALL 222 00:08:02,320 --> 00:08:03,360 VERY MUCH AGAIN. 223 00:08:03,360 --> 00:08:06,240 >> THANK YOU Dr. KILEY FOR 224 00:08:06,240 --> 00:08:07,520 THAT TERRIFIC INTRODUCTION AND 225 00:08:07,520 --> 00:08:09,200 START TO THIS WORKSHOP. 226 00:08:09,200 --> 00:08:09,840 GOOD MORNING. 227 00:08:09,840 --> 00:08:18,640 FOR THOSE WHO DON'T KNOW ME, I 228 00:08:18,640 --> 00:08:19,920 AM MARRAH LACHOWICZ-SCROGGINS, 229 00:08:19,920 --> 00:08:23,200 I AM THE PROGRAM DIRECTOR AT 230 00:08:23,200 --> 00:08:24,240 AIRWAY BIOLOGY DISEASE BRANCH 231 00:08:24,240 --> 00:08:26,480 AND IT IS MY PLEASURE TO 232 00:08:26,480 --> 00:08:28,480 WELCOME YOU TO THIS WORKSHOP. 233 00:08:28,480 --> 00:08:29,120 NEXT SLIDE. 234 00:08:29,120 --> 00:08:31,680 SO AS Dr. KILEY MENTIONED, 235 00:08:31,680 --> 00:08:34,640 WE ARE HERE TO BRING TOGETHER 236 00:08:34,640 --> 00:08:36,680 SUBJECT MATTER EXPERTS FROM 237 00:08:36,680 --> 00:08:41,880 THE CLOSE COMMUNITY TO DISCUSS 238 00:08:41,880 --> 00:08:44,320 NEEDS FOR RESEARCH IN THE AREA 239 00:08:44,320 --> 00:08:50,440 OF HIGHLY EFFECTIVE MODULATOR 240 00:08:50,440 --> 00:08:51,080 THERAPIES. 241 00:08:51,080 --> 00:08:55,240 WE HAVE ASSEMBLED A DIVERSE 242 00:08:55,240 --> 00:08:58,080 TEAM OF RESEARCHERS, CARE 243 00:08:58,080 --> 00:09:01,600 PROVIDERS AND ADDRESS GAPS IN 244 00:09:01,600 --> 00:09:04,080 RESEARCH AND CLINICAL CARE FOR 245 00:09:04,080 --> 00:09:05,320 PEOPLE WITH CF. 246 00:09:05,320 --> 00:09:09,400 WE ASKED FOR YOUR HELP AS 247 00:09:09,400 --> 00:09:11,000 SUBJECT MATTER EXPERTS TO 248 00:09:11,000 --> 00:09:12,680 SHIFT THE FOCUS TOWARDS THE 249 00:09:12,680 --> 00:09:14,640 UNDERSTANDING OF THE CLINICAL 250 00:09:14,640 --> 00:09:17,200 COURSE WE UNDERSTAND IN THIS 251 00:09:17,200 --> 00:09:19,400 ERA FOR INDIVIDUALS WITH CF. 252 00:09:19,400 --> 00:09:22,520 FOR THOSE WHO ARE ELIGIBLE FOR 253 00:09:22,520 --> 00:09:24,240 MODULATOR THEIRS AND FOR THOSE 254 00:09:24,240 --> 00:09:28,120 WHO ARE NOT SO WE WANTED TO 255 00:09:28,120 --> 00:09:30,520 ADDRESS GAPS IN CARE INCLUDING 256 00:09:30,520 --> 00:09:32,240 HEALTH EQUITY AND SPECIAL 257 00:09:32,240 --> 00:09:33,040 POPULATIONS. 258 00:09:33,040 --> 00:09:34,400 WE'RE LOOKING FOR YOUR 259 00:09:34,400 --> 00:09:36,160 KNOWLEDGE TO MOVE THIS FIELD 260 00:09:36,160 --> 00:09:37,960 FORWARD THE NEXT FIVE TO TEN 261 00:09:37,960 --> 00:09:38,280 YEARS. 262 00:09:38,280 --> 00:09:41,080 WITH THAT, I HOPE THIS GROUP 263 00:09:41,080 --> 00:09:42,280 WILL MOVE FORWARD WITH 264 00:09:42,280 --> 00:09:44,400 COLLABORATION AND BE BOLD IN 265 00:09:44,400 --> 00:09:45,880 THE IDEAS THAT YOU SHARE 266 00:09:45,880 --> 00:09:46,160 TODAY. 267 00:09:46,160 --> 00:09:47,200 NEXT. 268 00:09:47,200 --> 00:09:50,440 I WILL BRIEFLY EXPLAIN SOME OF 269 00:09:50,440 --> 00:09:51,480 OUR MEETING LOGISTICS. 270 00:09:51,480 --> 00:09:54,200 THIS MEETING IS BEING 271 00:09:54,200 --> 00:09:55,040 RECORDED. 272 00:09:55,040 --> 00:09:56,840 SOME RESEARCHERS MAY SHARE 273 00:09:56,840 --> 00:09:58,960 CONFIDENTIAL DATA SO WE ASK 274 00:09:58,960 --> 00:10:01,400 YOU MAINTAIN INTEGRITY AND 275 00:10:01,400 --> 00:10:06,120 CONFIDENTIALITY IN THE 276 00:10:06,120 --> 00:10:06,480 WORKSHOP. 277 00:10:06,480 --> 00:10:11,520 WE ASK YOU USE THE CHAT IF YOU 278 00:10:11,520 --> 00:10:13,520 NEED TECHNICAL QUESTIONS AND 279 00:10:13,520 --> 00:10:16,160 TO REGISTER YOUR QUESTION. 280 00:10:16,160 --> 00:10:20,600 AS YOU ENTER THIS MEETING AND 281 00:10:20,600 --> 00:10:22,920 WORKSHOP, YOU ARE OFF CAMERA 282 00:10:22,920 --> 00:10:25,840 AND WE ASK YOU STAY THAT WAY 283 00:10:25,840 --> 00:10:26,640 TO INCREASE BANDWIDTH. 284 00:10:26,640 --> 00:10:28,920 YOU CAN COME OFF AT THE END OF 285 00:10:28,920 --> 00:10:33,360 THE DAY WITH MODERATORS TO 286 00:10:33,360 --> 00:10:35,600 FACILITATE DISCUSSION AND 287 00:10:35,600 --> 00:10:36,040 COLLABORATION. 288 00:10:36,040 --> 00:10:36,440 NEXT SLIDE. 289 00:10:36,440 --> 00:10:37,960 WE ALSO HAVE A PROGRAM BOOK 290 00:10:37,960 --> 00:10:39,880 FOR THIS WORKSHOP WHICH WILL 291 00:10:39,880 --> 00:10:42,840 HAVE THE SPEAKER BIOS AND 292 00:10:42,840 --> 00:10:43,240 MATERIALS. 293 00:10:43,240 --> 00:10:46,120 TO STAY ON TIME, WE ASK YOU 294 00:10:46,120 --> 00:10:47,920 USE THIS RESOURCE AS SESSION 295 00:10:47,920 --> 00:10:51,120 MODERATORS WILL NOT GIVE FULL 296 00:10:51,120 --> 00:10:52,840 BIOS DURING THE SESSION. 297 00:10:52,840 --> 00:10:54,720 FOR THE ORGANIZATION OF THIS 298 00:10:54,720 --> 00:10:57,160 WORKSHOP, WE WILL HAVE 299 00:10:57,160 --> 00:10:57,840 15-MINUTE BACK-TO-BACK 300 00:10:57,840 --> 00:10:59,920 PRESENTATIONS FOLLOWED BY A 301 00:10:59,920 --> 00:11:01,800 DEDICATED Q&A FOR EACH 302 00:11:01,800 --> 00:11:02,120 SESSION. 303 00:11:02,120 --> 00:11:03,640 AGAIN, PLEASE USE THE CHAT 304 00:11:03,640 --> 00:11:04,880 TOOL FOR THE QUESTIONS YOU 305 00:11:04,880 --> 00:11:06,040 WANT DIRECTED TO THAT SESSION. 306 00:11:06,040 --> 00:11:09,000 LATER IN THE DAY, WE WILL HAVE 307 00:11:09,000 --> 00:11:10,560 THREE BREAKOUT SESSIONS AND 308 00:11:10,560 --> 00:11:14,840 THESE WILL OCCUR 309 00:11:14,840 --> 00:11:15,320 SIMULTANEOUSLY. 310 00:11:15,320 --> 00:11:15,920 THESE BREAKOUTS WILL BE 311 00:11:15,920 --> 00:11:18,240 DESIGNED BY A TAN PANEL AND 312 00:11:18,240 --> 00:11:21,720 ARE DESIGNED TO BE BREAKOUTS 313 00:11:21,720 --> 00:11:23,040 WHERE WE WELCOME YOUR 314 00:11:23,040 --> 00:11:24,000 CONVERSATION AND DISCUSSION. 315 00:11:24,000 --> 00:11:28,360 YOU CAN USE ALL THE TOOLS LIKE 316 00:11:28,360 --> 00:11:30,080 HAND RAISE AND HOPE YOU WILL 317 00:11:30,080 --> 00:11:32,640 BE FULLY ENGAGED IN THE 318 00:11:32,640 --> 00:11:33,760 BREAKOUT GROUPS. 319 00:11:33,760 --> 00:11:35,840 IF YOU HAVE ANY ISSUES WITH 320 00:11:35,840 --> 00:11:37,040 THE BREAKOUT SESSIONS, YOU CAN 321 00:11:37,040 --> 00:11:39,080 ALWAYS COME BACK TO THE MAIN 322 00:11:39,080 --> 00:11:41,440 MEETING ROOM AND ASK FOR 323 00:11:41,440 --> 00:11:41,880 ASSISTANCE. 324 00:11:41,880 --> 00:11:42,600 NEXT SLIDE. 325 00:11:42,600 --> 00:11:44,480 AS I SAID, WE'LL FREQUENTLY 326 00:11:44,480 --> 00:11:45,480 POST THE AGENDA AND PROGRAM 327 00:11:45,480 --> 00:11:48,080 BOOK IN THE CHAT AS A RESOURCE 328 00:11:48,080 --> 00:11:49,320 FOR THE WORKSHOP PARTICIPANTS 329 00:11:49,320 --> 00:11:52,240 AND FOR THE STRUCTURE OF 330 00:11:52,240 --> 00:11:54,120 TODAY, WE WILL HAVE THREE 331 00:11:54,120 --> 00:11:54,480 SESSIONS. 332 00:11:54,480 --> 00:11:59,040 OUR FIRST SESSION IS A PLENARY 333 00:11:59,040 --> 00:12:00,560 HOSTED BY THE CYSTIC FIBROSIS 334 00:12:00,560 --> 00:12:00,960 FOUNDATION. 335 00:12:00,960 --> 00:12:02,360 THIS SETS THE STAGE FOR THE 336 00:12:02,360 --> 00:12:04,320 WORKSHOP TO LET YOU KNOW WHERE 337 00:12:04,320 --> 00:12:08,640 WE ARE IN THE LANDSCAPE AND 338 00:12:08,640 --> 00:12:09,480 HIGHLY EFFECTIVE MODULATOR 339 00:12:09,480 --> 00:12:10,680 THEIRS. 340 00:12:10,680 --> 00:12:12,440 AS Dr. KILEY SAID, WE WILL 341 00:12:12,440 --> 00:12:13,640 SEE WHERE WE HAVE BEEN, WHERE 342 00:12:13,640 --> 00:12:16,080 WE ARE AND WHERE WE ARE GOING. 343 00:12:16,080 --> 00:12:19,360 WE ALSO WILL HEAR ABOUT 344 00:12:19,360 --> 00:12:23,680 CLINICAL TRIALS FOR THE 345 00:12:23,680 --> 00:12:25,320 MODULATOR THEIRS. 346 00:12:25,320 --> 00:12:27,600 WE WILL HAVE ANIMAL MODEL 347 00:12:27,600 --> 00:12:28,760 SYSTEMS TO UNDERSTAND THE 348 00:12:28,760 --> 00:12:31,840 CLINICAL COURSE AND HOW WE CAN 349 00:12:31,840 --> 00:12:33,360 USE THESE FOR RESEARCH 350 00:12:33,360 --> 00:12:34,040 OPPORTUNITIES. 351 00:12:34,040 --> 00:12:38,160 SESSION 2 WILL DISCUSS 352 00:12:38,160 --> 00:12:43,960 LATE-STAGE CYSTIC FIBROSIS 353 00:12:43,960 --> 00:12:45,200 PATHOGENESIS AND PROCESSES. 354 00:12:45,200 --> 00:12:47,520 WE WILL HAVE THE BREAKOUT 355 00:12:47,520 --> 00:12:49,600 SESSIONS FOLLOWED BY A REGROUP 356 00:12:49,600 --> 00:12:53,000 AND REPORT OUT BY THE DAY 1 357 00:12:53,000 --> 00:12:53,360 PANELISTS. 358 00:12:53,360 --> 00:12:53,760 NEXT SLIDE. 359 00:12:53,760 --> 00:12:54,840 AS WE HAVE ALREADY SAID 360 00:12:54,840 --> 00:12:56,600 SEVERAL TIMES THIS MORNING, WE 361 00:12:56,600 --> 00:12:58,680 REALLY DO WANT TO HEAR FROM 362 00:12:58,680 --> 00:12:59,320 YOU. 363 00:12:59,320 --> 00:13:00,960 WE HAVE THESE BREAKOUTS 364 00:13:00,960 --> 00:13:01,800 DESIGNED FOR YOUR 365 00:13:01,800 --> 00:13:04,160 PARTICIPATION BUT YOU CAN ALSO 366 00:13:04,160 --> 00:13:07,640 SEND YOUR THOUGHTS USING THE 367 00:13:07,640 --> 00:13:11,040 MEETING HASHTAG, OR YOU CAN 368 00:13:11,040 --> 00:13:12,320 E-MAIL US DIRECTLY FOR 369 00:13:12,320 --> 00:13:13,520 COMMENTS, IDEAS AND FEEDBACK. 370 00:13:13,520 --> 00:13:14,680 WE WILL POST THIS INFORMATION 371 00:13:14,680 --> 00:13:17,240 IN THE CHAT THROUGHOUT THE 372 00:13:17,240 --> 00:13:17,600 WORKSHOP. 373 00:13:17,600 --> 00:13:18,360 NEXT SLIDE. 374 00:13:18,360 --> 00:13:21,760 NOW, I KNOW Dr. KILEY 375 00:13:21,760 --> 00:13:22,480 ALREADY GAVE ACKNOWLEDGEMENTS 376 00:13:22,480 --> 00:13:23,640 BUT I WANTED TO SEND ANOTHER 377 00:13:23,640 --> 00:13:26,080 HUGE THANKS TO THE WORKSHOP 378 00:13:26,080 --> 00:13:27,680 PLANNING TEAM, CO-CHAIR, ALL 379 00:13:27,680 --> 00:13:30,520 OF OUR SPEAKERS AND BREAKOUT 380 00:13:30,520 --> 00:13:30,920 MODERATORS. 381 00:13:30,920 --> 00:13:32,120 THEY HAVE PUT A LOT OF TIME 382 00:13:32,120 --> 00:13:33,520 AND EFFORT IN PLANNING THIS 383 00:13:33,520 --> 00:13:34,520 EVENT AND VERY MUCH LOOK 384 00:13:34,520 --> 00:13:35,880 FORWARD TO WHAT WE HAVE IN 385 00:13:35,880 --> 00:13:38,560 STORE THE NEXT TWO DAYS. 386 00:13:38,560 --> 00:13:39,480 FINALLY THIS WORKSHOP WOULD 387 00:13:39,480 --> 00:13:41,640 NOT BE POSSIBLE WITHOUT THE 388 00:13:41,640 --> 00:13:44,600 SUPPORT OF OUR SUPPORT GROUP 389 00:13:44,600 --> 00:13:46,560 AND OUR TECHNICAL TEAM MEMBERS 390 00:13:46,560 --> 00:13:48,720 WHO HAVE BEEN NOTHING SHORT OF 391 00:13:48,720 --> 00:13:49,040 AMAZING. 392 00:13:49,040 --> 00:13:50,440 WITH THAT, I WOULD LIKE TO 393 00:13:50,440 --> 00:13:52,520 THANK YOU ALL FOR REGISTERING 394 00:13:52,520 --> 00:13:55,080 AND I WILL TURN OVER THE FLOOR 395 00:13:55,080 --> 00:13:58,240 TO Dr. CLANCY FROM THE 396 00:13:58,240 --> 00:14:01,240 CYSTIC FIBROSIS FOUNDATION TO 397 00:14:01,240 --> 00:14:03,520 KICK OFF OUR SESSION. 398 00:14:03,520 --> 00:14:06,560 >> HELLO EVERYONE, THANK YOU, 399 00:14:06,560 --> 00:14:09,160 MARRAH, VERY EXCITED TO KICK 400 00:14:09,160 --> 00:14:13,280 THIS OFF, I AM Dr. CLANCY, 401 00:14:13,280 --> 00:14:15,680 VICE PRESIDENT OF CLINICAL 402 00:14:15,680 --> 00:14:16,760 RESEARCH WITH THE CYSTIC 403 00:14:16,760 --> 00:14:18,200 FIBROSIS FOUNDATION, THANK YOU 404 00:14:18,200 --> 00:14:20,160 FOR ADVANCING THAT NEXT SLIDE, 405 00:14:20,160 --> 00:14:22,240 SO I WANT TO TALK ABOUT OUR 406 00:14:22,240 --> 00:14:23,800 RESEARCH AND HOW THE FIELD IS 407 00:14:23,800 --> 00:14:24,160 CHANGING. 408 00:14:24,160 --> 00:14:28,480 I WILL BE KICKING THINGS OFF 409 00:14:28,480 --> 00:14:35,560 FOLLOWED BY A PRESENTATION BY 410 00:14:35,560 --> 00:14:38,160 STEVE ROWE WHO IS AT THE 411 00:14:38,160 --> 00:14:39,720 CYSTIC FIBROSIS AND GIVING US 412 00:14:39,720 --> 00:14:41,360 A GLIMPSE OF THE FUTURE 413 00:14:41,360 --> 00:14:44,240 DIRECTIONS AND THEN WE HAVE AN 414 00:14:44,240 --> 00:14:45,560 ASSOCIATE PROFESSOR AT 415 00:14:45,560 --> 00:14:46,160 UNIVERSITY CAMPUS MEDICAL 416 00:14:46,160 --> 00:14:47,640 CENTER AND WE WILL BE FOCUSING 417 00:14:47,640 --> 00:14:53,600 ON SOME OF THOSE FINDINGS AND 418 00:14:53,600 --> 00:14:55,880 CLINICAL TRIALS OF HIGHLY 419 00:14:55,880 --> 00:14:59,840 EFFECTIVE MODULATORS AND THEN 420 00:14:59,840 --> 00:15:04,280 WE WILL COMPLETE THE 421 00:15:04,280 --> 00:15:05,360 PERSPECTIVE WITH MELANIE WHO 422 00:15:05,360 --> 00:15:07,920 HAS BEEN A KEY PARTNER IN THIS 423 00:15:07,920 --> 00:15:09,680 RESEARCH AS WELL AS A VOICE IN 424 00:15:09,680 --> 00:15:14,800 THE COMMUNITY TO HELP EDUCATE 425 00:15:14,800 --> 00:15:16,000 US AS RESEARCHERS -- 426 00:15:16,000 --> 00:15:16,480 [INDISCERNIBLE] 427 00:15:16,480 --> 00:15:18,240 WE WILL THEN HAVE A Q&A 428 00:15:18,240 --> 00:15:22,600 SESSION AND THAT WILL COMPLETE 429 00:15:22,600 --> 00:15:23,400 OUR FIRST SESSION. 430 00:15:23,400 --> 00:15:24,280 THANK YOU. 431 00:15:24,280 --> 00:15:26,440 SO NEXT SLIDE, PLEASE. 432 00:15:26,440 --> 00:15:30,880 JUST A QUICK 'TIS CLOSURE THAT 433 00:15:30,880 --> 00:15:33,080 THE CF FOUNDATION DOES INVEST 434 00:15:33,080 --> 00:15:34,800 IN EARLY DRUG DEVELOPMENT AND 435 00:15:34,800 --> 00:15:36,080 IF THOSE INVESTMENTS LEAD TO 436 00:15:36,080 --> 00:15:40,440 PRODUCTS THAT MAKE IT TO THE 437 00:15:40,440 --> 00:15:44,720 MARKET AFTER APPROVAL IN SOME 438 00:15:44,720 --> 00:15:47,040 MARKETS, YOU CAN RECEIVE FUNDS 439 00:15:47,040 --> 00:15:49,360 BACK TO THE CF FOUNDATION AND 440 00:15:49,360 --> 00:15:50,400 WE HAVE MORE INFORMATION IF 441 00:15:50,400 --> 00:15:53,160 YOU WOULD LIKE TO HEAR ABOUT 442 00:15:53,160 --> 00:15:54,760 THAT ON OUR CF WEBSITE. 443 00:15:54,760 --> 00:15:55,680 NEXT SLIDE. 444 00:15:55,680 --> 00:15:58,480 SO I WILL KICK US OFF TALKING 445 00:15:58,480 --> 00:16:02,360 A LITTLE BIT ABOUT THE 446 00:16:02,360 --> 00:16:05,040 RESEARCH IMPACT TODAY AND 447 00:16:05,040 --> 00:16:05,800 HIGHLY EFFECTIVE MODULATORS, 448 00:16:05,800 --> 00:16:08,160 STEVE WILL TALK ABOUT THE 449 00:16:08,160 --> 00:16:09,760 FOUNDATION RESEARCH PRIORITIES 450 00:16:09,760 --> 00:16:13,760 GOING FORWARD INCLUDING 451 00:16:13,760 --> 00:16:17,800 SYMPTOMATIC THEIRS, PTA C AND 452 00:16:17,800 --> 00:16:18,480 LOOKING AT MEDICATION. 453 00:16:18,480 --> 00:16:18,920 NEXT SLIDE. 454 00:16:18,920 --> 00:16:21,160 THIS IS A SLIDE THAT IS NOT 455 00:16:21,160 --> 00:16:22,480 SURPRISING OR NEW TO ANYONE 456 00:16:22,480 --> 00:16:24,640 BUT REALLY TO HELP US REMEMBER 457 00:16:24,640 --> 00:16:28,320 THE STEPS THAT ARE INVOLVED 458 00:16:28,320 --> 00:16:30,160 BETWEEN THE CFTR GENE DEFECT 459 00:16:30,160 --> 00:16:36,760 WHICH LEADS TO THE CFTR 460 00:16:36,760 --> 00:16:39,280 PROTEIN DEFECT AND DEHYDRATED 461 00:16:39,280 --> 00:16:40,440 AIRWAY SURFACES. 462 00:16:40,440 --> 00:16:42,760 I HAVE HIGHLIGHTED THE LUNGS 463 00:16:42,760 --> 00:16:45,040 HERE AND THESE ABNORMALITIES 464 00:16:45,040 --> 00:16:49,280 AFFECT MANY ASPECTS OF LIFE 465 00:16:49,280 --> 00:16:52,920 WITH PEOPLE WITH CF. 466 00:16:52,920 --> 00:16:55,840 THE MUCOUS BUILDUP AND 467 00:16:55,840 --> 00:16:58,040 INFECTION THAT LEADS TO 468 00:16:58,040 --> 00:16:59,720 INFLAMMATION AND PROGRESSION 469 00:16:59,720 --> 00:17:01,760 OF THE DISEASE. 470 00:17:01,760 --> 00:17:03,600 IT IS PROGRESSIVE, NEXT SLIDE. 471 00:17:03,600 --> 00:17:08,880 AND WHAT WE HAVE LEARNED WITH 472 00:17:08,880 --> 00:17:12,560 THE MODULATORS THAT ADDRESS AN 473 00:17:12,560 --> 00:17:14,640 UPSTREAM TARGET IN THIS 474 00:17:14,640 --> 00:17:19,080 CASCADE REALLY HAVE AMAZING 475 00:17:19,080 --> 00:17:23,080 EFFECTS AND ARE HIGHLY 476 00:17:23,080 --> 00:17:23,600 EFFECTIVE. 477 00:17:23,600 --> 00:17:24,520 YOU CAN ADVANCE. 478 00:17:24,520 --> 00:17:27,040 AND SPECIFICALLY THE HIGH LIE 479 00:17:27,040 --> 00:17:31,560 EFFECTIVE MODULATORS ARE DRUGS 480 00:17:31,560 --> 00:17:32,400 WHICH REALLY HAVE A DRAMATIC 481 00:17:32,400 --> 00:17:36,520 EFFECT ACROSS A VARIETY OF 482 00:17:36,520 --> 00:17:46,560 EFFECTS SUCH AS LUNG FUNCTION, 483 00:17:46,560 --> 00:17:48,880 APEX, SYMPTOMS, WEIGHT, 484 00:17:48,880 --> 00:17:52,160 MICROBIOLOGY, TRANSPLANT AND 485 00:17:52,160 --> 00:17:54,000 SURVIVAL. 486 00:17:54,000 --> 00:17:55,760 THE TESTED THEIRS INCLUDING 487 00:17:55,760 --> 00:17:57,040 ALL THESE BENEFITS ARE 488 00:17:57,040 --> 00:18:03,840 MANIFEST AND REALLY HELP US 489 00:18:03,840 --> 00:18:05,600 FIND THE EFFECTIVE THEIRS. 490 00:18:05,600 --> 00:18:07,440 NEXT SLIDE. 491 00:18:07,440 --> 00:18:10,280 SO WITH THAT, BASED ON THIS 492 00:18:10,280 --> 00:18:12,560 TYPE OF INFORMATION, IT IS 493 00:18:12,560 --> 00:18:13,280 ESTIMATED APPROXIMATELY 494 00:18:13,280 --> 00:18:16,600 93 PERCENT OF PEOPLE WITH CF 495 00:18:16,600 --> 00:18:19,800 SHOULD POTENTIALLY BECOME 496 00:18:19,800 --> 00:18:23,680 CANDIDATES FOR MODULATORS. 497 00:18:23,680 --> 00:18:26,640 THAT IS OBVIOUSLY BASED ON AGE 498 00:18:26,640 --> 00:18:29,080 AND APPROVALS AND NOT EVERYONE 499 00:18:29,080 --> 00:18:30,560 CAN BENEFIT FROM MODULATORS 500 00:18:30,560 --> 00:18:34,120 BUT WE KNOW THEY HAVE SHIFTED 501 00:18:34,120 --> 00:18:37,080 THE LANDSCAPE DRAMATICALLY AND 502 00:18:37,080 --> 00:18:37,840 RENDER HIGHLY EFFECTIVE 503 00:18:37,840 --> 00:18:40,160 THERAPY TO PEOPLE WITH CF AT 504 00:18:40,160 --> 00:18:41,360 YOUNGER AND YOUNGER AGES. 505 00:18:41,360 --> 00:18:43,640 IT DOES RAISE THE QUESTION, IS 506 00:18:43,640 --> 00:18:45,880 THE CF RESEARCH OVER? 507 00:18:45,880 --> 00:18:47,120 AND NEXT SLIDE. 508 00:18:47,120 --> 00:18:49,320 I HOPE I CAN LAY THE GROUND 509 00:18:49,320 --> 00:18:51,200 WORK THAT THIS IS NOT THE CASE 510 00:18:51,200 --> 00:18:53,320 AND IN FACT IS ABSOLUTELY NOT 511 00:18:53,320 --> 00:18:55,440 THE CASE. 512 00:18:55,440 --> 00:19:00,360 I WOULD SAY THAT CF HAS 513 00:19:00,360 --> 00:19:01,480 FUNDAMENTALLY CHANGED AND WE 514 00:19:01,480 --> 00:19:03,520 KNOW THERE ARE NUMEROUS VERY, 515 00:19:03,520 --> 00:19:04,800 VERY BASIC QUESTIONS THAT NEED 516 00:19:04,800 --> 00:19:07,120 TO BE ANSWERED FOR US TO 517 00:19:07,120 --> 00:19:09,280 REALLY BE ABLE TO UNDERSTAND 518 00:19:09,280 --> 00:19:11,560 MODULATORS AND UNDERSTAND 519 00:19:11,560 --> 00:19:13,880 THEIR BENEFITS AND ALSO THE 520 00:19:13,880 --> 00:19:16,320 ROLE OF OTHER THEIRS. 521 00:19:16,320 --> 00:19:20,360 AS AN EXAMPLE, NO SYMPTOMATIC 522 00:19:20,360 --> 00:19:22,680 CF THEY WERE HAS EVER BEEN 523 00:19:22,680 --> 00:19:28,320 STUDIED IN CF IN THE CONTEXT 524 00:19:28,320 --> 00:19:30,480 OF FUNCTIONAL CFTR. 525 00:19:30,480 --> 00:19:32,800 WHAT IS THE LIFE COURSE OF 526 00:19:32,800 --> 00:19:35,720 LUNG DISEASE, WHAT ASPECTS ARE 527 00:19:35,720 --> 00:19:36,440 REVERSIBLE AND NOT 528 00:19:36,440 --> 00:19:37,200 RESERIOUSABLE? 529 00:19:37,200 --> 00:19:41,960 WHY IS THE VAPOR INDIVIDUAL 530 00:19:41,960 --> 00:19:42,560 BENEFIT AND TOLERANCE? 531 00:19:42,560 --> 00:19:44,240 WHAT IS THE IMPACT ON 532 00:19:44,240 --> 00:19:47,480 INFECTION AND WHAT IS THE ROLE 533 00:19:47,480 --> 00:19:48,240 OF SYMPTOMATIC THEIRS? 534 00:19:48,240 --> 00:19:50,400 ALL OF THOSE QUESTIONS AND YOU 535 00:19:50,400 --> 00:19:51,400 WILL HEAR MORE INDEPTH 536 00:19:51,400 --> 00:19:52,320 QUESTIONS THROUGHOUT THIS 537 00:19:52,320 --> 00:19:53,760 MEETING AND THAT IS ULTIMATELY 538 00:19:53,760 --> 00:19:56,400 OUR GOAL, TO IDENTIFY THOSE 539 00:19:56,400 --> 00:19:58,520 QUESTIONS BUT I ALSO WANTED TO 540 00:19:58,520 --> 00:20:03,840 HIGHLIGHT THE CF FOUNDATION 541 00:20:03,840 --> 00:20:09,480 REMAINS ABSOLUTELY COMMITTED 542 00:20:09,480 --> 00:20:12,680 TO CURE THEIRS FOR PERSONS 543 00:20:12,680 --> 00:20:15,120 WITH CF. 544 00:20:15,120 --> 00:20:18,120 SO LOOKING AT THE NUMBERS OF 545 00:20:18,120 --> 00:20:20,680 PERSONS WITH CF, THE GREEN 546 00:20:20,680 --> 00:20:23,080 BEING PEDIATRIC PATIENTS AND 547 00:20:23,080 --> 00:20:24,920 THE BLUE ARE ADULT DISEASE AND 548 00:20:24,920 --> 00:20:26,920 OVER 30 YEARS TO TODAY, YOU 549 00:20:26,920 --> 00:20:29,920 CAN SEE CF HAS FUNDAMENTALLY 550 00:20:29,920 --> 00:20:30,240 CHANGED. 551 00:20:30,240 --> 00:20:33,240 THE DEMOGRAPHICS ARE 552 00:20:33,240 --> 00:20:35,440 FUNDAMENTALLY DIFFERENT. 553 00:20:35,440 --> 00:20:38,760 IT WAS PREDOMINANTLY PEDIATRIC 554 00:20:38,760 --> 00:20:44,800 DISEASE YEARS AGO, NOW IT IS 555 00:20:44,800 --> 00:20:45,680 AN ADULT DISEASE. 556 00:20:45,680 --> 00:20:46,360 NEXT SLIDE. 557 00:20:46,360 --> 00:20:50,080 YOU CAN ADVANCE ONE MORE. 558 00:20:50,080 --> 00:20:51,720 LOOKING AT THAT DATA -- OR 559 00:20:51,720 --> 00:20:54,600 MOVING FROM THAT DATA TO THE 560 00:20:54,600 --> 00:20:56,200 FUTURE, ESTIMATES OF PEOPLE 561 00:20:56,200 --> 00:21:00,000 ARE CF IN THE PEDIATRIC GROUP 562 00:21:00,000 --> 00:21:04,120 UNDER AGE 18 AND IN THE LIGHT, 563 00:21:04,120 --> 00:21:05,440 THE ADULTS AND WHAT WE HAVE 564 00:21:05,440 --> 00:21:09,320 SEEN IS A FIVE-YEAR MARCH 565 00:21:09,320 --> 00:21:11,280 FORWARD, THIS SLIDE WAS PUT 566 00:21:11,280 --> 00:21:13,880 TOGETHER IN 2016 BUT I THINK 567 00:21:13,880 --> 00:21:15,840 IT IS STILL TRUE TODAY. 568 00:21:15,840 --> 00:21:20,880 IF YOU LOOK ON THE LEFT GROUP, 569 00:21:20,880 --> 00:21:25,960 5 YEARS, 10 YEARS, WE DON'T 570 00:21:25,960 --> 00:21:29,400 SEE A DIFFERENCE BUT WE SEE A 571 00:21:29,400 --> 00:21:31,000 SIGNIFICANT IMPROVEMENT AS 572 00:21:31,000 --> 00:21:35,640 TIME GOES BY AND MODULATORS 573 00:21:35,640 --> 00:21:37,440 BECOME AVAILABLE FOR 574 00:21:37,440 --> 00:21:38,200 PEDIATRICS. 575 00:21:38,200 --> 00:21:40,760 WHAT WE SEE IS THOSE WITH 576 00:21:40,760 --> 00:21:43,280 NORMAL LUNG FUNCTION AND THE 577 00:21:43,280 --> 00:21:46,360 REDUCTION OF PATIENTS WHO HAVE 578 00:21:46,360 --> 00:21:47,080 MODERATOR EXPERIENCE. 579 00:21:47,080 --> 00:21:48,920 ON THE RIGHT SIDE, WE'RE 580 00:21:48,920 --> 00:21:49,960 LOOKING AT THE ADULT 581 00:21:49,960 --> 00:21:52,280 POPULATION AND I THINK THE 582 00:21:52,280 --> 00:21:53,920 TAKEHOME POINT HERE IS IT IS 583 00:21:53,920 --> 00:21:56,360 GOING TO GROW, THE NUMBER OF 584 00:21:56,360 --> 00:21:57,400 PEOPLE SURVIVING WITH CF AND 585 00:21:57,400 --> 00:21:59,800 THE NUMBER OF ADULTS WILL GET 586 00:21:59,800 --> 00:22:02,040 LARGER AND BE A 40 TO 587 00:22:02,040 --> 00:22:03,000 50 PERCENT INCREASE IN THE 588 00:22:03,000 --> 00:22:05,040 NUMBER OF ADULTS WITH CF OVER 589 00:22:05,040 --> 00:22:06,560 THE NEXT 20 YEARS. 590 00:22:06,560 --> 00:22:07,960 AND THE OTHER POINT I WANTED 591 00:22:07,960 --> 00:22:10,200 TO MAKE IS PEOPLE WITH CF ARE 592 00:22:10,200 --> 00:22:13,840 GOING TO HAVE LUNG DISEASE. 593 00:22:13,840 --> 00:22:16,320 CERTAINLY THE NUMBER WITHOUT 594 00:22:16,320 --> 00:22:17,880 LUNG DISEASE OR LOW LUNG 595 00:22:17,880 --> 00:22:19,440 DISEASE WILL GROW BUT THOSE 596 00:22:19,440 --> 00:22:24,920 WITH MODERATE OR ADVANCED LUNG 597 00:22:24,920 --> 00:22:28,280 DISEASE NEED OUR CARE AND IN 598 00:22:28,280 --> 00:22:31,800 FACT WE SEE THAT AS A GROWING 599 00:22:31,800 --> 00:22:34,360 NEED OVER THE NEXT 10 TO 20 600 00:22:34,360 --> 00:22:34,640 YEARS. 601 00:22:34,640 --> 00:22:35,040 NEXT SLIDE. 602 00:22:35,040 --> 00:22:38,280 SO THERE ARE A NUMBER OF 603 00:22:38,280 --> 00:22:40,960 SLIDES FUNDED BY OUR 604 00:22:40,960 --> 00:22:41,360 FOUNDATION. 605 00:22:41,360 --> 00:22:43,480 I WILL NOT SPEND TIME WITH ALL 606 00:22:43,480 --> 00:22:44,880 OF THESE AS WE WILL HEAR FROM 607 00:22:44,880 --> 00:22:46,760 THEM LATER ON BUT TRYING TO 608 00:22:46,760 --> 00:22:49,360 UNDERSTAND THE ASPECTS IN THE 609 00:22:49,360 --> 00:22:57,120 CONTEXT OF MODULATOR USE 610 00:22:57,120 --> 00:22:59,160 LOOKING AT SYMPTOMOTOLOGY 611 00:22:59,160 --> 00:23:03,960 CARE, THE MEASURE OF OUTCOME 612 00:23:03,960 --> 00:23:04,600 INDICATORS, DECENTRALIZED 613 00:23:04,600 --> 00:23:06,080 STUDIES REGARDING WHAT PEOPLE 614 00:23:06,080 --> 00:23:08,360 ARE DOING ON THEIR OWN UNDER 615 00:23:08,360 --> 00:23:11,000 THE CONTEXT OF CARE AND THE 616 00:23:11,000 --> 00:23:12,280 IMPACT OF PREGNANCY. 617 00:23:12,280 --> 00:23:13,720 WE ACKNOWLEDGE AS MANY AS A 618 00:23:13,720 --> 00:23:14,880 QUARTER OF THE POPULATION IN 619 00:23:14,880 --> 00:23:18,440 THE U.S. MAY BE PARTICIPATING 620 00:23:18,440 --> 00:23:22,040 IN THESE STUDIES IN ONE WAY OR 621 00:23:22,040 --> 00:23:22,960 THE OTHER. 622 00:23:22,960 --> 00:23:23,480 NEXT SLIDE. 623 00:23:23,480 --> 00:23:26,600 SORRY, THAT WAS A LEFTOVER, IF 624 00:23:26,600 --> 00:23:28,920 YOU COULD MOVE FORWARD THE 625 00:23:28,920 --> 00:23:29,280 SLIDES. 626 00:23:29,280 --> 00:23:29,720 MY APOLOGIES. 627 00:23:29,720 --> 00:23:31,560 BUT I WANTED TO HIGHLIGHT 628 00:23:31,560 --> 00:23:32,960 WHERE RESEARCH FUNDS ARE BEING 629 00:23:32,960 --> 00:23:35,520 SPENT CURRENTLY AND THIS IS 630 00:23:35,520 --> 00:23:37,520 LOOKING AT OUR 2021 BUDGET, 631 00:23:37,520 --> 00:23:38,760 LOOKING AT MEDICAL AND 632 00:23:38,760 --> 00:23:40,440 RESEARCH ON THE TOP RIGHT AND 633 00:23:40,440 --> 00:23:41,960 THEN RESEARCH DOWN BELOW WHICH 634 00:23:41,960 --> 00:23:44,400 IS BROKEN DOWN IN THE 635 00:23:44,400 --> 00:23:46,160 DIFFERENT TOPIC AREAS HERE AND 636 00:23:46,160 --> 00:23:47,800 THE CF FOUNDATION IS FUNDING A 637 00:23:47,800 --> 00:23:51,560 LOT OF THESE ASPECTS AND YOU 638 00:23:51,560 --> 00:23:56,680 CAN SEE THE CURRENT CFTR 639 00:23:56,680 --> 00:23:58,880 MODULATORS ALONG WITH THE 640 00:23:58,880 --> 00:24:01,920 OTHER ASPECT TENDS TO BE THE 641 00:24:01,920 --> 00:24:03,520 LARGEST BECAUSE OF THE IMPACT 642 00:24:03,520 --> 00:24:13,960 AND WE CAN SEE BELOW THE 643 00:24:14,960 --> 00:24:16,120 CLINICAL RESEARCH SUPPORT. 644 00:24:16,120 --> 00:24:16,520 NEXT SLIDE. 645 00:24:16,520 --> 00:24:18,880 BUT I ALSO WANT TO EMPHASIZE 646 00:24:18,880 --> 00:24:21,720 IT GOES BEYOND RESEARCH. 647 00:24:21,720 --> 00:24:22,520 NEXT SLIDE. 648 00:24:22,520 --> 00:24:23,800 OUR MISSION REALLY CUTS ACROSS 649 00:24:23,800 --> 00:24:28,440 WHAT WE CALL THE THREE C'S, 650 00:24:28,440 --> 00:24:29,560 CURE, CARE OF THE PATIENTS AND 651 00:24:29,560 --> 00:24:32,400 THE COMMUNITY AND YOU CAN SEE 652 00:24:32,400 --> 00:24:35,640 UNDER EACH OF THESE AREAS THAT 653 00:24:35,640 --> 00:24:37,800 THE CF FOUNDATION SUPPORTS, 654 00:24:37,800 --> 00:24:38,760 SIGNIFICANT ACTIVITY. 655 00:24:38,760 --> 00:24:41,080 THE CURE IS VERY INVOLVED IN 656 00:24:41,080 --> 00:24:43,520 INDUSTRY PROGRAMS AND ALSO 657 00:24:43,520 --> 00:24:44,440 INVESTIGATOR-INITIATED 658 00:24:44,440 --> 00:24:44,800 RESEARCH. 659 00:24:44,800 --> 00:24:48,360 CARE IS FOCUSED ON PROVIDING 660 00:24:48,360 --> 00:24:51,720 SUPPORT CARE CENTERS, CFF 661 00:24:51,720 --> 00:24:56,840 REGISTRY AND ON THE RIGHT, 662 00:24:56,840 --> 00:24:59,880 PATIENT SUPPORT GROUPS AND 663 00:24:59,880 --> 00:25:00,360 ADVOCACY. 664 00:25:00,360 --> 00:25:00,800 ADVANCE. 665 00:25:00,800 --> 00:25:05,560 BUT I ALSO WANT TO HIGHLIGHT 666 00:25:05,560 --> 00:25:06,240 THE INVESTIGATOR-INITIATED 667 00:25:06,240 --> 00:25:08,520 RESEARCH IS A CLEAR 668 00:25:08,520 --> 00:25:12,440 OPPORTUNITY FOR US TO BE 669 00:25:12,440 --> 00:25:15,320 FUNDED BY NIH AND REALLY 670 00:25:15,320 --> 00:25:18,120 IMPACT ALL THREE ASPECTS OF 671 00:25:18,120 --> 00:25:18,560 PEOPLE WITH CF. 672 00:25:18,560 --> 00:25:20,960 SO I WOULD LIKE TO ADVANCE AND 673 00:25:20,960 --> 00:25:22,080 TURN THE SPOTLIGHT OF THE 674 00:25:22,080 --> 00:25:25,080 MICROPHONE OVER TO MY 675 00:25:25,080 --> 00:25:26,520 COLLEAGUE STEVE ROWE WHO WILL 676 00:25:26,520 --> 00:25:31,520 BE TAKING A LOOK FORWARD AT 677 00:25:31,520 --> 00:25:33,800 THE FUTURE OF CF PRIORITIES. 678 00:25:33,800 --> 00:25:34,800 ARE YOU READY? 679 00:25:34,800 --> 00:25:36,520 >> YES, THANK YOU VERY MUCH, 680 00:25:36,520 --> 00:25:37,640 Dr. CLANCY, HAPPY TO JOIN 681 00:25:37,640 --> 00:25:37,880 YOU. 682 00:25:37,880 --> 00:25:42,440 I ALSO WANT TO CONGRATULATE 683 00:25:42,440 --> 00:25:47,720 THE NIH AND PARTNERS NIAD FOR 684 00:25:47,720 --> 00:25:48,720 HOSTING THIS. 685 00:25:48,720 --> 00:25:52,520 IT IS REALLY A PERFECT TIME TO 686 00:25:52,520 --> 00:25:54,960 LOOK AT PEOPLE WITH CF AND 687 00:25:54,960 --> 00:25:55,920 WHAT THE RESEARCH PRIORITIES 688 00:25:55,920 --> 00:25:58,080 SHOULD BE FOR THE FUTURE. 689 00:25:58,080 --> 00:25:59,440 IN THE TRANSITION PERIOD, I 690 00:25:59,440 --> 00:26:02,000 WANT TO THANK Dr. CLANCY AND 691 00:26:02,000 --> 00:26:02,680 OTHERS FOR PUTTING TOGETHER 692 00:26:02,680 --> 00:26:03,920 THE MATERIALS FOR THIS. 693 00:26:03,920 --> 00:26:07,400 THE PURPOSE IS TO GIVE A HIGH 694 00:26:07,400 --> 00:26:09,720 OVERVIEW OF THE THERAPEUTIC 695 00:26:09,720 --> 00:26:11,800 LANDSCAPE AND I LOOK FORWARD 696 00:26:11,800 --> 00:26:13,680 TO LEARNING FROM ALL OF YOU AS 697 00:26:13,680 --> 00:26:15,240 WE CONSIDER THE RESEARCH 698 00:26:15,240 --> 00:26:16,120 PRIORITIES GOING FORWARD. 699 00:26:16,120 --> 00:26:17,720 HOPEFULLY I WILL PLANNED SOME 700 00:26:17,720 --> 00:26:20,280 SEED HERE AND LET IT GROW 701 00:26:20,280 --> 00:26:23,360 THROUGH THIS GREAT SYMPOSIA WE 702 00:26:23,360 --> 00:26:24,320 HAVE TODAY. 703 00:26:24,320 --> 00:26:25,640 NEXT SLIDE. 704 00:26:25,640 --> 00:26:28,160 SO IT IS CONSIDERED DRUG 705 00:26:28,160 --> 00:26:30,760 DEVELOPMENT IN THE HIGHLY 706 00:26:30,760 --> 00:26:34,800 EFFECTIVE MODULATOR ERA, THERE 707 00:26:34,800 --> 00:26:35,440 ARE OBVIOUSLY SYMPTOMATIC 708 00:26:35,440 --> 00:26:36,440 THEIRS THAT WILL CONTINUE TO 709 00:26:36,440 --> 00:26:39,320 BE IMPORTANT AS WELL AS 710 00:26:39,320 --> 00:26:46,880 THERAPEUTICS DRIVEN TOWARDS 711 00:26:46,880 --> 00:26:51,560 CORRECTING CFPR, BOTH GENETIC 712 00:26:51,560 --> 00:26:53,520 AND THE MODULATOR THEIRS WE 713 00:26:53,520 --> 00:26:55,600 KNOW ABOUT THAT HAVE BROUGHT A 714 00:26:55,600 --> 00:27:00,360 BROAD *EUFRP TUGS FOR 715 00:27:00,360 --> 00:27:00,760 ASSESSMENT. 716 00:27:00,760 --> 00:27:03,000 AND I THINK IT IS BEEN POINTED 717 00:27:03,000 --> 00:27:05,200 OUT HOW THIS GROUP OF PATIENTS 718 00:27:05,200 --> 00:27:07,600 IS GROWING AND HOW THEY NEED 719 00:27:07,600 --> 00:27:10,000 TO HAVE SOME LOW DISEASE 720 00:27:10,000 --> 00:27:12,440 PROGRESSION THAT INVOLVES OVER 721 00:27:12,440 --> 00:27:15,080 TIME AND THESE SYMPTOMATIC 722 00:27:15,080 --> 00:27:16,680 THEIRS WILL BE MORE IMPORTANT 723 00:27:16,680 --> 00:27:25,480 TO THAT POPULATION AS IT GROWS 724 00:27:25,480 --> 00:27:29,280 INCLUDING ANTI-INEFFECTIVES, 725 00:27:29,280 --> 00:27:31,480 MUCOLYTICS, HIDE DATERS, 726 00:27:31,480 --> 00:27:35,440 ANTI-INFLAMMATORIES AND GI AND 727 00:27:35,440 --> 00:27:36,600 NUTRITIONAL NEEDS. 728 00:27:36,600 --> 00:27:37,600 AND TO FIGURE OUT HOW MUCH 729 00:27:37,600 --> 00:27:39,000 THEY NEED AND WHEN THEY NEED 730 00:27:39,000 --> 00:27:40,880 IT WILL BE A MAJOR PRIORITY. 731 00:27:40,880 --> 00:27:42,000 NEXT SLIDE. 732 00:27:42,000 --> 00:27:43,760 IF WE LOOK AT THE DRUG 733 00:27:43,760 --> 00:27:45,400 DEVELOPMENT PIPELINE, YOU CAN 734 00:27:45,400 --> 00:27:46,840 SEE THIS LANDSCAPE OF THEIRS 735 00:27:46,840 --> 00:27:49,680 THAT ARE IN DEVELOPMENT, THE 736 00:27:49,680 --> 00:27:52,120 APPROVED THEIRS ARE ON TOP OF 737 00:27:52,120 --> 00:27:52,400 IT. 738 00:27:52,400 --> 00:27:54,840 THOSE IN DEVELOPMENT REMAIN 739 00:27:54,840 --> 00:27:56,880 QUITE ROBUST WHICH IS EXCITED 740 00:27:56,880 --> 00:28:01,520 TO THINK ABOUT, BRINGING 741 00:28:01,520 --> 00:28:02,920 THERAPIES NEEDED FOR THIS 742 00:28:02,920 --> 00:28:04,360 GROWING GROUP OF INDIVIDUALS 743 00:28:04,360 --> 00:28:06,400 BUT NOT WITHOUT CHALLENGES TO 744 00:28:06,400 --> 00:28:07,120 SUCCESSFULLY DEVELOP THESE 745 00:28:07,120 --> 00:28:10,800 DRUGS AND FIGURE OUT THE RIGHT 746 00:28:10,800 --> 00:28:12,600 PEOPLE WITH CF WHICH CAN 747 00:28:12,600 --> 00:28:16,080 PARTICIPATE AND THE BEST 748 00:28:16,080 --> 00:28:21,000 CANDIDATES TO ASSESS THESE 749 00:28:21,000 --> 00:28:31,200 THEIRS. 750 00:28:35,240 --> 00:28:35,520 THERAPIES. 751 00:28:35,520 --> 00:28:36,160 IN PURPLE, THERE ARE MORE 752 00:28:36,160 --> 00:28:37,040 ADVANCED STAGES WITH TRIALS 753 00:28:37,040 --> 00:28:37,760 ONGOING AND TO HIGHLIGHT SOME 754 00:28:37,760 --> 00:28:38,320 OF THE TRIALS IN EARLY 755 00:28:38,320 --> 00:28:39,000 DEVELOPMENT OR IN THE STARTUP 756 00:28:39,000 --> 00:28:39,640 PHASE THROUGHOUT THE TALK. 757 00:28:39,640 --> 00:28:43,360 THERE'S ALSO THEIRS IN THE 758 00:28:43,360 --> 00:28:47,560 SYMPTOMATIC GROUPS AS WELL AS 759 00:28:47,560 --> 00:28:49,000 ANTI-INFLAMMATORY IN GREEN AND 760 00:28:49,000 --> 00:28:52,280 BLUE THAT ARE RESPECTIVELY 761 00:28:52,280 --> 00:28:52,640 ADVANCING. 762 00:28:52,640 --> 00:28:53,520 THE INFECTION RESEARCH 763 00:28:53,520 --> 00:28:54,840 INITIATIVE WHICH I WILL 764 00:28:54,840 --> 00:28:56,880 HIGHLIGHT IN THE SLIDE GOING 765 00:28:56,880 --> 00:28:58,000 FORWARD IS EXTENSIVE AND 766 00:28:58,000 --> 00:29:06,320 INCLUDES A NUMBER OF ANT 767 00:29:06,320 --> 00:29:08,640 FIVECROBIALS THAT CAN ADDRESS 768 00:29:08,640 --> 00:29:11,760 THE INFECTION THAT PEOPLE HAVE 769 00:29:11,760 --> 00:29:12,960 AND MOST LIKELY DEAL WITH THE 770 00:29:12,960 --> 00:29:14,600 SEVERITY OF THE DISEASE AS IT 771 00:29:14,600 --> 00:29:17,880 ADVANCES EVEN IN THE CONTEXT 772 00:29:17,880 --> 00:29:22,080 OF HIGHLY EFFECTIVE MODULATOR 773 00:29:22,080 --> 00:29:25,320 THERAPY. 774 00:29:25,320 --> 00:29:28,240 EVEN NUTRITIONAL THERAPY AS 775 00:29:28,240 --> 00:29:28,560 WELL. 776 00:29:28,560 --> 00:29:30,120 NEXT SLIDE. 777 00:29:30,120 --> 00:29:35,920 SO AS WE LOOK AT THE LARGE AND 778 00:29:35,920 --> 00:29:43,160 GROWING POPULATION OF ADULTS 779 00:29:43,160 --> 00:29:45,520 WITH LUNG DISEASE, IT IS 780 00:29:45,520 --> 00:29:48,480 UNCLEAR EXACTLY WHO NEEDS 781 00:29:48,480 --> 00:29:49,280 WHAT. 782 00:29:49,280 --> 00:29:54,960 SO HOW DO WE DEVELOP NEW 783 00:29:54,960 --> 00:30:03,640 THERAPIES FOR THESE SUBPOPULAT. 784 00:30:03,640 --> 00:30:05,720 AND ENROLL THE HIGHLY 785 00:30:05,720 --> 00:30:10,000 EFFECTIVE AND NONE HIGHLY 786 00:30:10,000 --> 00:30:11,280 EFFECTIVE MODULATOR SUBJECTS 787 00:30:11,280 --> 00:30:15,960 AND WHAT IS THE REGULATORY 788 00:30:15,960 --> 00:30:16,400 PATH. 789 00:30:16,400 --> 00:30:20,520 ALSO STUDIES INCLUDE THE CF 790 00:30:20,520 --> 00:30:22,800 AND NONCF SUBJECTS AND THEN 791 00:30:22,800 --> 00:30:25,200 THERE ARE PATIENTS IN WHICH 792 00:30:25,200 --> 00:30:26,040 DOSING IS NOT APPLICABLE AND 793 00:30:26,040 --> 00:30:28,960 THIS WILL BE A URGENT NEED TO 794 00:30:28,960 --> 00:30:29,320 APPROVE. 795 00:30:29,320 --> 00:30:31,440 IF ANYTHING, THIS POPULATION 796 00:30:31,440 --> 00:30:35,000 HAS ONLY INCREASED WITH THE 797 00:30:35,000 --> 00:30:36,840 DEVELOPMENT OF MODULATOR 798 00:30:36,840 --> 00:30:37,600 THERAPY FOR OTHERS. 799 00:30:37,600 --> 00:30:39,680 SO WHAT WE REALLY NEED TO DO 800 00:30:39,680 --> 00:30:43,960 IS DEFINE WHO NEEDS WHICH 801 00:30:43,960 --> 00:30:45,360 THERAPIES AND HOW WE DEVELOP 802 00:30:45,360 --> 00:30:47,240 THEM IN THE SUBPOPULATION. 803 00:30:47,240 --> 00:30:49,880 WE NEED TO FIND PATIENTS WHO 804 00:30:49,880 --> 00:30:51,640 ARE CONTINUING TO PROGRESS AND 805 00:30:51,640 --> 00:30:52,800 THEN CONSIDER WHETHER WE WANT 806 00:30:52,800 --> 00:30:55,200 TO ENROLL PATIENTS WHO ARE ON 807 00:30:55,200 --> 00:30:57,160 AND OFF HIGHLY EFFECTIVE 808 00:30:57,160 --> 00:30:58,800 MODULATOR THERAPY, SHOULD THEY 809 00:30:58,800 --> 00:30:59,360 BE SEPARATED? 810 00:30:59,360 --> 00:31:02,360 I THINK IT WILL DEPEND ON THE 811 00:31:02,360 --> 00:31:03,760 SOURCE OF THEIRS BEING 812 00:31:03,760 --> 00:31:07,760 DEVELOPED, BUT THAT WILL BE A 813 00:31:07,760 --> 00:31:13,440 KEY QUESTION OF WHAT WILL THE 814 00:31:13,440 --> 00:31:14,480 APPROACHING FOR THESE 815 00:31:14,480 --> 00:31:16,680 PATIENTS. 816 00:31:16,680 --> 00:31:19,520 CAN WE HELP FACILITATE THAT 817 00:31:19,520 --> 00:31:23,440 FOR THESE PATIENTS WITH URGENT 818 00:31:23,440 --> 00:31:23,800 NEED. 819 00:31:23,800 --> 00:31:27,000 STUDIES INCLUDING CF AND NONCF 820 00:31:27,000 --> 00:31:30,000 SUBJECTS ARE ON THE HORIZON AS 821 00:31:30,000 --> 00:31:32,080 THEY BECOME MORE SIMILAR WITH 822 00:31:32,080 --> 00:31:36,360 PATIENTS WHO HAVE PARTIAL 823 00:31:36,360 --> 00:31:37,720 DYSFUNCTION, AND HOW THEY ARE 824 00:31:37,720 --> 00:31:40,600 SIMILAR TO MANY PATIENTS WITH 825 00:31:40,600 --> 00:31:45,200 CF THAT IS CAUSED BY 826 00:31:45,200 --> 00:31:49,840 PARTIAL CF DYSFUNCTION, AS A 827 00:31:49,840 --> 00:31:54,320 EXAMPLE. 828 00:31:54,320 --> 00:31:57,440 AND THEN -- PEOPLE WITH CF AND 829 00:31:57,440 --> 00:32:05,600 BEYOND WILL BE A PRIORITY. 830 00:32:05,600 --> 00:32:06,680 NEXT SLIDE. 831 00:32:06,680 --> 00:32:09,120 NOW TO HIGH LIE LIGHT THE 832 00:32:09,120 --> 00:32:10,600 INFECTION RESEARCH INITIATIVE, 833 00:32:10,600 --> 00:32:11,800 ESTABLISHED IN 2018 AND IT 834 00:32:11,800 --> 00:32:13,280 CAME FROM THE COMMUNITY AFTER 835 00:32:13,280 --> 00:32:18,400 A LARGE SURVEY BOTH OF 836 00:32:18,400 --> 00:32:19,880 PROVIDERS AND PATIENTS WITH 837 00:32:19,880 --> 00:32:20,680 FAMILIES WHO IDENTIFIED 838 00:32:20,680 --> 00:32:21,520 CONTINUED PROBLEMS WITH 839 00:32:21,520 --> 00:32:23,720 INFECTION AND EVEN AS THAT 840 00:32:23,720 --> 00:32:29,360 TIME IN THE EARLY DAYS OF THE 841 00:32:29,360 --> 00:32:31,160 CF MODULATOR THERAPY WAS OF 842 00:32:31,160 --> 00:32:33,360 CONCERN SO TO ADDRESS THIS, 843 00:32:33,360 --> 00:32:36,080 THERE WAS A LARGE FINANCIAL 844 00:32:36,080 --> 00:32:37,760 COMMITMENT AND IT IS LIKELY 845 00:32:37,760 --> 00:32:41,000 THIS INITIATIVE WILL CONTINUE 846 00:32:41,000 --> 00:32:42,080 FOR SOMETIME. 847 00:32:42,080 --> 00:32:44,520 WE'RE GOING TO NEED EFFORTS TO 848 00:32:44,520 --> 00:32:45,280 IMPROVE DETECTION AND 849 00:32:45,280 --> 00:32:45,640 DIAGNOSIS. 850 00:32:45,640 --> 00:32:49,560 THIS IS ONLY BECOME MORE ACUTE 851 00:32:49,560 --> 00:32:55,960 AS SOME PATIENTS HAVE LESS 852 00:32:55,960 --> 00:33:00,400 OBVIOUS EXPECTORATION SO HOW 853 00:33:00,400 --> 00:33:04,600 DO WE IDENTIFY DRUGS AND KNOW 854 00:33:04,600 --> 00:33:07,920 THAT IS ERADICATED WITH MORE 855 00:33:07,920 --> 00:33:09,800 ROBUST METHODS? 856 00:33:09,800 --> 00:33:10,840 WE UNDERSTAND MICROORGANISMS 857 00:33:10,840 --> 00:33:13,040 WORKING TOGETHER TO GENERATE 858 00:33:13,040 --> 00:33:14,960 THE CF ENVIRONMENT THAT CAUSES 859 00:33:14,960 --> 00:33:15,600 THE GREATEST PROGRESSION. 860 00:33:15,600 --> 00:33:18,680 WE WILL NEED TO UNDERSTAND 861 00:33:18,680 --> 00:33:19,000 THAT. 862 00:33:19,000 --> 00:33:20,240 OPTIMIZE CURRENT TREATMENTS AS 863 00:33:20,240 --> 00:33:26,600 WELL AS DEVELOP NEW 864 00:33:26,600 --> 00:33:28,560 ANTIMICROBIALS THAT WE WILL 865 00:33:28,560 --> 00:33:30,600 IDENTIFY, THE LOW HANGING 866 00:33:30,600 --> 00:33:33,280 FRUIT THAT HAVE AVAILABLE AS 867 00:33:33,280 --> 00:33:36,000 WELL AS IN OTHER FORMS AND 868 00:33:36,000 --> 00:33:37,640 IDENTIFY THAT BROAD SPECTRUM 869 00:33:37,640 --> 00:33:44,640 OF CF FOR THE LANDSCAPE. 870 00:33:44,640 --> 00:33:45,800 EVALUATE THE ANTIMICROBIAL USE 871 00:33:45,800 --> 00:33:46,840 AND INFECTION. 872 00:33:46,840 --> 00:33:48,400 WE KNOW THIS IS CURRENTLY 873 00:33:48,400 --> 00:33:52,920 CHANGING BUT NOT GOING AWAY, 874 00:33:52,920 --> 00:33:54,560 SO WHAT PATHOGENS ARE 875 00:33:54,560 --> 00:33:56,520 PROBLEMATIC AND WHICH ARE 876 00:33:56,520 --> 00:33:57,800 CAUSING PROGRESSION WILL 877 00:33:57,800 --> 00:33:58,960 BECOME AN URGENT QUESTION TO 878 00:33:58,960 --> 00:34:00,040 ADDRESS AND THEN FINALLY I 879 00:34:00,040 --> 00:34:03,360 THINK AS WE HAVE SEEN, SOME 880 00:34:03,360 --> 00:34:09,680 PATIENTS HAVE SPONTANEOUS 881 00:34:09,680 --> 00:34:16,240 ERADICATION OF THEIR 882 00:34:16,240 --> 00:34:17,520 DELETERIOUS PATHOGENS AND I 883 00:34:17,520 --> 00:34:24,680 THINK THIS MIGHT SHOW HOW WE 884 00:34:24,680 --> 00:34:28,120 ERADICATE LONG-TERM THOSE ON 885 00:34:28,120 --> 00:34:30,720 HIGHLY EFFECTIVE MODULATOR 886 00:34:30,720 --> 00:34:32,080 THERAPY. 887 00:34:32,080 --> 00:34:33,440 NEXT SLIDE. 888 00:34:33,440 --> 00:34:38,680 SO WE HAVE A TABLE OF THE 889 00:34:38,680 --> 00:34:41,000 VARIOUS THINGS IN DEVELOPMENT, 890 00:34:41,000 --> 00:34:42,840 OBVIOUSLY IN TRIALS WHICH THE 891 00:34:42,840 --> 00:34:48,440 RESEARCH COMMUNITY IS PURSUING 892 00:34:48,440 --> 00:34:49,680 BUT ALSO IDENTIFYING 893 00:34:49,680 --> 00:34:50,600 APPROPRIATE PATIENT 894 00:34:50,600 --> 00:34:51,320 POPULATION. 895 00:34:51,320 --> 00:34:53,200 YOU CAN SEE BY THE CLASS 896 00:34:53,200 --> 00:34:59,640 GROUPINGS ON THE RIGHT SIDE OF 897 00:34:59,640 --> 00:35:08,000 THE SLIDE, THE ESTABLISHED 898 00:35:08,000 --> 00:35:11,320 THERAPY BUT CASE STUDIES THAT 899 00:35:11,320 --> 00:35:12,440 IT BECOMES TRANSFORMATIVE FOR 900 00:35:12,440 --> 00:35:13,920 CERTAIN INDIVIDUALS. 901 00:35:13,920 --> 00:35:16,960 SO WE REALLY TRY TO HELP BRING 902 00:35:16,960 --> 00:35:18,160 CLARITY WITH RANDOMIZED 903 00:35:18,160 --> 00:35:19,640 CONTROL STUDIES THAT ARE WELL 904 00:35:19,640 --> 00:35:20,640 DESIGNED IN THIS AREA AND YOU 905 00:35:20,640 --> 00:35:23,960 CAN SEE THERE ARE A NUMBER OF 906 00:35:23,960 --> 00:35:26,880 STUDIES ONGOING WITH VARIOUS 907 00:35:26,880 --> 00:35:28,480 FORMS OF PHAGE IN TRYING TO 908 00:35:28,480 --> 00:35:29,640 ADDRESS THIS. 909 00:35:29,640 --> 00:35:35,640 THERE ARE ALSO BROAD SPECTRUM 910 00:35:35,640 --> 00:35:37,080 ANTIMICROBIALS THAT WORK WITH 911 00:35:37,080 --> 00:35:39,360 THE E MECHANISM ALONG WITH 912 00:35:39,360 --> 00:35:42,800 DRUGS THAT HAVE NO MECHANISM. 913 00:35:42,800 --> 00:35:45,920 NEXT SLIDE. 914 00:35:45,920 --> 00:35:48,320 THE ANTI-INEFFECTIVE PORTFOLIO 915 00:35:48,320 --> 00:35:50,200 IS ROBUST SO AGAIN A SECOND 916 00:35:50,200 --> 00:35:53,760 SLIDE SHOWING THE VARIOUS 917 00:35:53,760 --> 00:35:55,160 PATHWAYS BEING ATTACKED IN 918 00:35:55,160 --> 00:35:59,760 TRYING TO ADDRESS THIS. 919 00:35:59,760 --> 00:36:00,760 BIODISRUPTORS IS ONE EXAMPLE 920 00:36:00,760 --> 00:36:04,200 WHERE WE HAVE THE NEW SCIENCE 921 00:36:04,200 --> 00:36:12,640 EMERGING BUT THERE IS ALSO THE 922 00:36:12,640 --> 00:36:17,000 MR SA OR ANTI-FUNGAL THERAPY 923 00:36:17,000 --> 00:36:25,760 AND A NOVEL TECHNIQUE WITH 924 00:36:25,760 --> 00:36:27,320 ANTIMICROBIAL TECHNOLOGY THAT 925 00:36:27,320 --> 00:36:28,600 CAN MAKE THESE DRUGS AVAILABLE 926 00:36:28,600 --> 00:36:31,720 SO THAT WILL BE AN AREA OF 927 00:36:31,720 --> 00:36:34,000 INTEREST ESPECIALLY FOR 928 00:36:34,000 --> 00:36:37,760 PATHOGENS THAT HAVE BEEN 929 00:36:37,760 --> 00:36:41,840 DIFFICULT TO TREAT AND 930 00:36:41,840 --> 00:36:42,640 ERADICATE IT. 931 00:36:42,640 --> 00:36:49,640 NEXT SLIDE. 932 00:36:49,640 --> 00:36:50,600 ADDITIONAL SYMPTOMATIC 933 00:36:50,600 --> 00:36:51,480 THERAPIES ARE IMPORTANT BUT 934 00:36:51,480 --> 00:36:54,320 THIS IS IN THE LANDSCAPE WITH 935 00:36:54,320 --> 00:36:58,520 PATIENTS AT THE LEVEL OF 936 00:36:58,520 --> 00:37:02,280 EXPECTORATION RESOLVED IN SOME 937 00:37:02,280 --> 00:37:06,280 BUT NOT OTHERS. 938 00:37:06,280 --> 00:37:09,840 THE MUCOLYTICS WITH DISRUPTO 939 00:37:09,840 --> 00:37:11,840 RS AND REDUCERS. 940 00:37:11,840 --> 00:37:18,080 THERE ARE ALSO HIDE TRAITORS 941 00:37:18,080 --> 00:37:24,240 WITH THE CELL EXPRESSION 942 00:37:24,240 --> 00:37:26,000 INCLUDING ENAC INHIBITION, 943 00:37:26,000 --> 00:37:29,120 ALTERNATE CI CHANNEL ACT 944 00:37:29,120 --> 00:37:29,760 VARIETIES, ANTI-INFLAMMATORY 945 00:37:29,760 --> 00:37:30,120 AGENTS. 946 00:37:30,120 --> 00:37:32,480 ONE THAT MIGHT BE PARTICULARLY 947 00:37:32,480 --> 00:37:33,960 CHALLENGING TO DEVELOP FOR CF 948 00:37:33,960 --> 00:37:38,000 BECAUSE OF THE LONG-TERM 949 00:37:38,000 --> 00:37:40,480 THERAPY NEEDED AND I POINT OUT 950 00:37:40,480 --> 00:37:42,840 THE NEED FOR SHORTER ENDPOINTS 951 00:37:42,840 --> 00:37:45,240 WITH THIS BUT ALSO LONG-TERM 952 00:37:45,240 --> 00:37:47,560 PRIORITIES FOR THOSE WITH CF. 953 00:37:47,560 --> 00:37:49,800 OTHER PRIORITIES NEED TO BE 954 00:37:49,800 --> 00:37:50,120 DEFINED. 955 00:37:50,120 --> 00:37:53,080 A CLEAR PICTURE OF WHAT PEOPLE 956 00:37:53,080 --> 00:37:58,880 ARE HIGHLY EFFECTIVE MODULATOR 957 00:37:58,880 --> 00:38:00,120 THERAPY ARE EXPERIENCING, 958 00:38:00,120 --> 00:38:02,800 DEFINING THE POPULATION WITH 959 00:38:02,800 --> 00:38:04,560 PROGRESSIVE DISEASE OR UNMET 960 00:38:04,560 --> 00:38:06,840 NEEDS, INFORMED BY THE 961 00:38:06,840 --> 00:38:08,760 CATEGORY OR WHO RESPOND FOR 962 00:38:08,760 --> 00:38:10,400 UNKNOWN REASONS AND THEN THE 963 00:38:10,400 --> 00:38:12,000 RESULTS OF OUR ONGOING 964 00:38:12,000 --> 00:38:13,440 CLINICAL TRIALS THAT ARE 965 00:38:13,440 --> 00:38:16,720 STUDYING PATIENTS ON HIGHLY 966 00:38:16,720 --> 00:38:18,640 EFFECTIVE MODULATOR THERAPY AS 967 00:38:18,640 --> 00:38:21,720 THE FIELD HAS CHANGED 968 00:38:21,720 --> 00:38:24,480 THROUGHOUT THE DESIGNS OF THE 969 00:38:24,480 --> 00:38:24,800 STUDY. 970 00:38:24,800 --> 00:38:25,400 NEXT SLIDE. 971 00:38:25,400 --> 00:38:31,440 IF YOU LOOK AT THE LANDSCAPE 972 00:38:31,440 --> 00:38:32,720 OF MUCOCILIARY AND 973 00:38:32,720 --> 00:38:33,400 ANTI-INFLAMMATORY PROGRAMS, 974 00:38:33,400 --> 00:38:35,040 YOU CAN SEE THERE ARE ALSO 975 00:38:35,040 --> 00:38:41,200 QUITE A FEW AND SPAN VARIOUS 976 00:38:41,200 --> 00:38:41,960 CLASSES OF ANTI-INFLAMMATORY 977 00:38:41,960 --> 00:38:44,520 AGENTS AND AT THE BOTTOM 978 00:38:44,520 --> 00:38:46,200 INCLUDES PATHWAYS THAT ARE 979 00:38:46,200 --> 00:38:48,520 TRIED AND TRUE BUT MAYBE SOME 980 00:38:48,520 --> 00:38:49,960 THAT HAVE BEEN RECENTLY 981 00:38:49,960 --> 00:38:52,760 IDENTIFIED AND SHOWN TO BE 982 00:38:52,760 --> 00:38:53,120 EFFECTIVE. 983 00:38:53,120 --> 00:39:03,720 THERE IS ALSO MUCOUS HYDRATION 984 00:39:05,720 --> 00:39:07,960 AGENTS, MUCOLYTIC CAN AND SOME 985 00:39:07,960 --> 00:39:11,160 WE HEARD ABOUT EARLIER TO 986 00:39:11,160 --> 00:39:13,640 IMPROVE ELASTICITY. 987 00:39:13,640 --> 00:39:15,400 NEXT SLIDE. 988 00:39:15,400 --> 00:39:17,080 NOW OUR TRANSITION TO THE PATH 989 00:39:17,080 --> 00:39:19,000 TO A CURE TREATMENT. 990 00:39:19,000 --> 00:39:20,080 OBVIOUSLY IT INVOLVES MANY 991 00:39:20,080 --> 00:39:21,200 DIFFERENT WAYS TO GET THERE 992 00:39:21,200 --> 00:39:25,720 BUT WITH THE ULTIMATE MISSION 993 00:39:25,720 --> 00:39:27,440 OF RESTORING CFPR FUNCTION FOR 994 00:39:27,440 --> 00:39:29,440 ALL AND TO NORMAL LEVELS. 995 00:39:29,440 --> 00:39:31,880 THIS IS A LARGE INVESTMENT FOR 996 00:39:31,880 --> 00:39:32,800 THE FOUNDATION TO ACCELERATE 997 00:39:32,800 --> 00:39:34,680 THIS BUT IT CAN'T BE DONE 998 00:39:34,680 --> 00:39:37,120 WITHOUT THE PARTNERSHIP OF NIH 999 00:39:37,120 --> 00:39:37,920 TO UNDERSTAND THE BASIC 1000 00:39:37,920 --> 00:39:48,440 BIOLOGY ON HOW TO EXECUTE 1001 00:39:49,800 --> 00:39:51,840 GENETIC THERAPY RESOURCES 1002 00:39:51,840 --> 00:39:52,400 ABOVE AND BEYOND. 1003 00:39:52,400 --> 00:39:54,240 AND THIS IS BUILT ON A PREMISE 1004 00:39:54,240 --> 00:39:57,080 WE MAY EVEN NEED TO ADDRESS 1005 00:39:57,080 --> 00:39:58,280 OTHER GENETIC DISEASES WITH 1006 00:39:58,280 --> 00:40:00,240 THE PROMISE IT COULD 1007 00:40:00,240 --> 00:40:01,600 ACCELERATE DRUG THERAPY FOR 1008 00:40:01,600 --> 00:40:07,640 PEOPLE WITH CF IN PARTICULAR 1009 00:40:07,640 --> 00:40:08,080 CASES. 1010 00:40:08,080 --> 00:40:08,760 NEXT SLIDE. 1011 00:40:08,760 --> 00:40:10,160 WE CAN CONSIDER THE MAJOR 1012 00:40:10,160 --> 00:40:12,120 STRAT WE DO AND IF YOU WILL 1013 00:40:12,120 --> 00:40:16,040 ADVANCE, YOU CAN SEE THE PATH 1014 00:40:16,040 --> 00:40:22,080 TO A CURE THERAPIES INVOLVES A 1015 00:40:22,080 --> 00:40:26,520 LOOK AT DNA THAT COULD BE 1016 00:40:26,520 --> 00:40:30,760 DIFFERED BY GENE DELIVERY OR 1017 00:40:30,760 --> 00:40:32,600 EDITING. 1018 00:40:32,600 --> 00:40:39,040 OUR RNA MODALITY AS WELL AS 1019 00:40:39,040 --> 00:40:42,480 THE WAY TO ADDRESS RNA 1020 00:40:42,480 --> 00:40:46,360 REPLACEMENT OR INHIBITION OF 1021 00:40:46,360 --> 00:40:47,200 PATHWAYS IRRELEVANT TO 1022 00:40:47,200 --> 00:40:47,680 CORRECTION. 1023 00:40:47,680 --> 00:40:49,120 AND WE HAVE SEEN QUITE A FEW 1024 00:40:49,120 --> 00:40:55,760 OF THESE IN THE LANDSCAPE AND 1025 00:40:55,760 --> 00:40:56,640 OBVIOUSLY EFFECTIVE MODULATORS 1026 00:40:56,640 --> 00:41:03,760 HAVE BECOME A VERY IMPORTANT 1027 00:41:03,760 --> 00:41:07,880 CORNERSTONE WITH CF 1028 00:41:07,880 --> 00:41:08,640 MANIFESTATIONS AND THERAPY. 1029 00:41:08,640 --> 00:41:09,040 NEXT SLIDE. 1030 00:41:09,040 --> 00:41:12,040 YOU CAN SEE THE AMOUNT OF 1031 00:41:12,040 --> 00:41:17,240 RESEARCH IN THE PRECLINICAL 1032 00:41:17,240 --> 00:41:20,120 STAGE AND INVESTMENT IS REALLY 1033 00:41:20,120 --> 00:41:21,360 UNPRECEDENTED. 1034 00:41:21,360 --> 00:41:22,560 IT INCLUDES MULTIPLE PROGRAMS 1035 00:41:22,560 --> 00:41:26,400 IN EACH OF THE CATEGORIES ON 1036 00:41:26,400 --> 00:41:30,400 THE SLIDE INCLUDING CRISPR AND 1037 00:41:30,400 --> 00:41:32,960 TRANSMITTING NOT ONLY SHORT 1038 00:41:32,960 --> 00:41:36,880 TERM BUT LONG-TERM GENETIC 1039 00:41:36,880 --> 00:41:40,040 MODULATION TYPE THERAPY BEING 1040 00:41:40,040 --> 00:41:42,040 A MAJOR PRIORITY AND THUS A 1041 00:41:42,040 --> 00:41:44,240 HEAVY AREA OF INFLUENCE. 1042 00:41:44,240 --> 00:41:47,680 THIS INCLUDES BOTH VIRALS, 1043 00:41:47,680 --> 00:41:49,200 NONVIRALS AND OTHER PROGRAMS 1044 00:41:49,200 --> 00:41:51,280 TO ACCOMPLISH THIS. 1045 00:41:51,280 --> 00:41:52,920 GENE EDITING INCLUDING TAKING 1046 00:41:52,920 --> 00:41:57,280 ADVANTAGE OF THE REMARKABLE 1047 00:41:57,280 --> 00:42:02,960 CRISPR TECHNOLOGY AS WELL AS 1048 00:42:02,960 --> 00:42:05,440 NON-CRISPR TECHNOLOGY THAT IS 1049 00:42:05,440 --> 00:42:07,440 RISING VERY RAPIDLY FOR THOSE 1050 00:42:07,440 --> 00:42:09,240 CURRENTLY UNTREATED. 1051 00:42:09,240 --> 00:42:11,320 OTHER MODELS AND TOOL 1052 00:42:11,320 --> 00:42:12,480 PROGRAMS, ACCELERATE RESEARCH 1053 00:42:12,480 --> 00:42:16,520 AS WELL AS UNIQUE PARTNERSHIPS 1054 00:42:16,520 --> 00:42:21,800 WITH VENTURE FIRMS TO TRY TO 1055 00:42:21,800 --> 00:42:23,920 GENERATE MULTIINSTITUTIONAL 1056 00:42:23,920 --> 00:42:26,120 AND PA*RPLA COLLABORATIVES TO 1057 00:42:26,120 --> 00:42:30,240 ADDRESS THE PROBLEMS IN A 1058 00:42:30,240 --> 00:42:36,640 UNIQUE WAY -- PHARMA 1059 00:42:36,640 --> 00:42:37,120 COLLABORATIVES. 1060 00:42:37,120 --> 00:42:37,520 NEXT SLIDE. 1061 00:42:37,520 --> 00:42:41,680 A LOOK AT THE NEW MODULATOR 1062 00:42:41,680 --> 00:42:46,400 PROGRAMS REPRESENTED IN THIS 1063 00:42:46,400 --> 00:42:50,280 SLIDE, PHASE 3 OF THE PROGRAM 1064 00:42:50,280 --> 00:42:53,680 IS IN PROGRESS AND IT MAY BE 1065 00:42:53,680 --> 00:42:55,280 THAT DIFFERENT COMBINATIONS 1066 00:42:55,280 --> 00:42:57,800 WILL BE AVAILABLE TO TREAT 1067 00:42:57,800 --> 00:43:01,040 VERY DIFFICULT AND CORRECT 1068 00:43:01,040 --> 00:43:02,360 MUTATIONS WHICH THEORETICALLY 1069 00:43:02,360 --> 00:43:04,240 HAS BEEN POSSIBLE BUT 1070 00:43:04,240 --> 00:43:07,760 DIFFICULT TO ACHIEVE IN THE 1071 00:43:07,760 --> 00:43:18,320 THERAPEUTIC RANGE FOR SOME 1072 00:43:23,120 --> 00:43:25,640 PATIENTS, THE PRE-K EXAMPLE IS 1073 00:43:25,640 --> 00:43:27,720 FEASIBLE WHERE IT COULD 1074 00:43:27,720 --> 00:43:30,400 ADDRESS ONE OR MORE MOLECULES. 1075 00:43:30,400 --> 00:43:31,440 NEXT SLIDE. 1076 00:43:31,440 --> 00:43:36,880 WE CAN ALSO CONSIDER A 1077 00:43:36,880 --> 00:43:39,480 READTHROUGH, YOU CAN SEE THIS 1078 00:43:39,480 --> 00:43:41,560 IS ALSO GROWING FROM THE 1079 00:43:41,560 --> 00:43:44,080 CLINIC INCLUDING ONE THAT HAS 1080 00:43:44,080 --> 00:43:45,920 SHOWN A SMALL CHANGE THAT AT 1081 00:43:45,920 --> 00:43:48,880 LEAST ESTABLISHES THE PROOF OF 1082 00:43:48,880 --> 00:43:50,280 CONCEPT THAT THESE PATIENTS 1083 00:43:50,280 --> 00:43:53,640 MAY ALSO BE AMENABLE TO THESE 1084 00:43:53,640 --> 00:43:55,240 SORTS OF MODULATION TECHNIQUES 1085 00:43:55,240 --> 00:43:59,000 AND THERE ARE OTHER 1086 00:43:59,000 --> 00:44:01,960 PRECLINICAL PROGRAMS MOVING 1087 00:44:01,960 --> 00:44:03,320 TOWARDS CLINICAL CANDIDATES. 1088 00:44:03,320 --> 00:44:07,920 AND THEN THE NUCLEOTIDE 1089 00:44:07,920 --> 00:44:10,080 THERAPY REMAINS AN APPROACH 1090 00:44:10,080 --> 00:44:13,360 FOR SOME PATIENTS, HIKE THE 1091 00:44:13,360 --> 00:44:14,080 3849 PATIENTS LISTED WHERE 1092 00:44:14,080 --> 00:44:19,080 THEY ARE ABLE TO TAKE CERTAIN 1093 00:44:19,080 --> 00:44:22,800 CF MODULATORS BUT THE 1094 00:44:22,800 --> 00:44:24,640 POTENTIAL THERAPY HAS NOT YET 1095 00:44:24,640 --> 00:44:26,320 BEEN ACHIEVED FOR NORMAL 1096 00:44:26,320 --> 00:44:26,680 FUNCTION. 1097 00:44:26,680 --> 00:44:27,320 NEXT SLIDE. 1098 00:44:27,320 --> 00:44:29,440 THIS IS A SCHEMATIC YOU HAVE 1099 00:44:29,440 --> 00:44:31,920 SEEN BEFORE THAT LOOKS AT HOW 1100 00:44:31,920 --> 00:44:39,800 WE MIGHT REPAIR OR REPLACE THE 1101 00:44:39,800 --> 00:44:46,160 CF DEFECTIVE CFTR GENE CAN 1102 00:44:46,160 --> 00:44:47,560 DNA-TARGETED THEIRS AND IN 1103 00:44:47,560 --> 00:44:49,040 ASSOCIATION WITH THAT, LOOKING 1104 00:44:49,040 --> 00:44:51,400 AT THE VEHICLE, THE DURATION 1105 00:44:51,400 --> 00:44:53,720 AND AS WELL HOW WE MIGHT 1106 00:44:53,720 --> 00:44:56,400 DELIVER THAT IN THE CF LUNG AS 1107 00:44:56,400 --> 00:45:02,480 WELL AS TECHNOLOGIES THAT ARE 1108 00:45:02,480 --> 00:45:04,360 TARGETING THE CORRECT ZONE, 1109 00:45:04,360 --> 00:45:07,360 LOOKING AT THOSE BEYOND OR 1110 00:45:07,360 --> 00:45:08,760 CERTAIN CELL TYPES OR THOSE WE 1111 00:45:08,760 --> 00:45:10,480 HAVE LEARNED ABOUT THE LAST 1112 00:45:10,480 --> 00:45:13,080 FEW YEARS ABOUT WHICH CELL 1113 00:45:13,080 --> 00:45:16,120 TYPES ARE PARTICULARLY 1114 00:45:16,120 --> 00:45:17,360 IMPORTANT FOR CFTR EXPRESSIONS 1115 00:45:17,360 --> 00:45:20,400 TO BE PRESENT IN WHICH NORMAL 1116 00:45:20,400 --> 00:45:22,120 PHYSIOLOGY WILL BE NEEDED FOR 1117 00:45:22,120 --> 00:45:26,160 THAT TO OCCUR, AS WELL AS 1118 00:45:26,160 --> 00:45:28,080 ULTIMATELY TARGETING CFR 1119 00:45:28,080 --> 00:45:30,160 THROUGHOUT THE BODY AND HAVING 1120 00:45:30,160 --> 00:45:32,240 THE SORTS OF TARGETING VECTOR 1121 00:45:32,240 --> 00:45:35,240 THAT WOULD ALLOW THAT TO OCCUR 1122 00:45:35,240 --> 00:45:40,160 AND ULTIMATELY PROVIDE A CURE. 1123 00:45:40,160 --> 00:45:41,720 NEXT SLIDE. 1124 00:45:41,720 --> 00:45:43,480 OTHER-- SOME NOTABLE RESEARCH 1125 00:45:43,480 --> 00:45:45,960 PRIORITIES OF THE GENETIC 1126 00:45:45,960 --> 00:45:49,560 THERAPY ERA THAT WE ARE HIGHLY 1127 00:45:49,560 --> 00:45:52,120 ENCOURAGING AND LOOK IN PART 1128 00:45:52,120 --> 00:45:54,560 FOR NIH TO ACCELERATE IS 1129 00:45:54,560 --> 00:45:55,760 UNDERSTANDING THE EPITHELIAL 1130 00:45:55,760 --> 00:45:57,880 BIOLOGY, CELL TYPES AND 1131 00:45:57,880 --> 00:46:05,760 TARGETING TECHNOLOGIES 1132 00:46:05,760 --> 00:46:07,160 NECESSARY TO ACHIEVE. 1133 00:46:07,160 --> 00:46:09,840 SO THRESHOLDS REQUIRED FOR 1134 00:46:09,840 --> 00:46:20,000 EFFICACY, WE HAVE LEARNED 1135 00:46:20,000 --> 00:46:23,000 THIS, ON THIS TOPIC AND 1136 00:46:23,000 --> 00:46:25,000 OTHERS, THE CF MODULATION AND 1137 00:46:25,000 --> 00:46:30,320 NOW WE CAN LOOK AT THE 1138 00:46:30,320 --> 00:46:34,720 HEITEROGENEITY IN CELL TYPES 1139 00:46:34,720 --> 00:46:38,040 AND RESTORING FUNCTIONAL 1140 00:46:38,040 --> 00:46:38,480 BIOLOGY. 1141 00:46:38,480 --> 00:46:39,880 VECTOR TECHNOLOGIES TO 1142 00:46:39,880 --> 00:46:42,360 ACCOMPLISH EFFICIENT DELIVERY, 1143 00:46:42,360 --> 00:46:45,480 A STEP FOR MANY. 1144 00:46:45,480 --> 00:46:52,520 ADVANCES IN GENETIC CAR GO, 1145 00:46:52,520 --> 00:46:57,960 THAT IS ACCELERATING QUICKLY, 1146 00:46:57,960 --> 00:47:00,640 INCLUDING ANIMAL MODELS TO 1147 00:47:00,640 --> 00:47:02,280 FACILITATE AND PREDICT 1148 00:47:02,280 --> 00:47:04,480 CLINICAL TRANSLATION. 1149 00:47:04,480 --> 00:47:10,480 LOOKING AT OUTCOME MEASURES 1150 00:47:10,480 --> 00:47:12,200 FOR GENETIC-BASED THERAPIES, 1151 00:47:12,200 --> 00:47:13,920 CLINIC TALL TRIAL DESIGNS, I 1152 00:47:13,920 --> 00:47:15,800 HAVE ALREADY SPOKEN TO THAT 1153 00:47:15,800 --> 00:47:17,520 AND THEN FINALLY DEFINING 1154 00:47:17,520 --> 00:47:22,400 RISKS OF TRANSIENT AND 1155 00:47:22,400 --> 00:47:24,240 TERMMENT THERAPIES GIVEN THE 1156 00:47:24,240 --> 00:47:24,960 POTENTIAL FOR RISK. 1157 00:47:24,960 --> 00:47:25,680 NEXT SLIDE. 1158 00:47:25,680 --> 00:47:30,200 SO THIS IS THE LANDSCAPE OF 1159 00:47:30,200 --> 00:47:31,360 GENETIC THERAPIES. 1160 00:47:31,360 --> 00:47:33,600 WE OBVIOUSLY HAVE LEARNINGS 1161 00:47:33,600 --> 00:47:35,000 FROM THE MODULATOR PROGRAM AS 1162 00:47:35,000 --> 00:47:38,640 WELL AS A NUMBER OF GENETIC 1163 00:47:38,640 --> 00:47:42,080 THERAPY APPROACHES THAT ARE 1164 00:47:42,080 --> 00:47:43,120 REACHING THE CLINIC AND 1165 00:47:43,120 --> 00:47:46,920 STARTING TO LEARN NOW AS WELL 1166 00:47:46,920 --> 00:47:48,760 AS THE RESEARCH EXPERIENCE OF 1167 00:47:48,760 --> 00:47:53,880 A COMPOUND NOT EFFECTIVE BUT 1168 00:47:53,880 --> 00:47:55,040 WILL PROVIDE SOME EXPERIENCE 1169 00:47:55,040 --> 00:47:55,560 MOVING FORWARD. 1170 00:47:55,560 --> 00:47:56,680 NEXT SLIDE. 1171 00:47:56,680 --> 00:47:59,120 SO WE'RE WORKING TO PROVIDE 1172 00:47:59,120 --> 00:48:01,000 GUIDANCE FOR INDUSTRY, LOOKING 1173 00:48:01,000 --> 00:48:03,000 TO DEVELOP A NETWORK FOR 1174 00:48:03,000 --> 00:48:04,360 EDUCATION PRIORITIES AMONG THE 1175 00:48:04,360 --> 00:48:05,280 COMMUNITY, RESEARCH TEAMS AND 1176 00:48:05,280 --> 00:48:06,960 CARE TEAMS AND THEN WE WILL BE 1177 00:48:06,960 --> 00:48:09,440 SPENDING A LOT OF TIME 1178 00:48:09,440 --> 00:48:12,960 CONSIDERING HOW THE NOVEL 1179 00:48:12,960 --> 00:48:14,360 CLINICAL TRIAL DESIGNS AND END 1180 00:48:14,360 --> 00:48:16,280 OPINIONS WILL BE EXECUTED AND 1181 00:48:16,280 --> 00:48:22,920 THAT WILL BE A CONSIDERABLE 1182 00:48:22,920 --> 00:48:23,600 AMOUNT GOING FORWARD. 1183 00:48:23,600 --> 00:48:30,600 SO YOU CAN SEE HERE IN 1184 00:48:30,600 --> 00:48:34,320 PARTNERSHIP WITH NIH ON 1185 00:48:34,320 --> 00:48:35,920 FUNDAMENTAL RESEARCH QUESTIONS 1186 00:48:35,920 --> 00:48:39,360 WHICH WILL ENABLE EVALUATION, 1187 00:48:39,360 --> 00:48:43,200 TESTING AND DEVELOPMENT OF 1188 00:48:43,200 --> 00:48:46,440 GENETIC BASED THERAPIES IS 1189 00:48:46,440 --> 00:48:47,000 CRUCIAL. 1190 00:48:47,000 --> 00:48:48,520 CRITICAL ACADEMIC INNOVATION 1191 00:48:48,520 --> 00:48:50,840 IS NEEDED IN PARTNERSHIP WITH 1192 00:48:50,840 --> 00:48:53,840 THE NIH AND WE LOOK FORWARD TO 1193 00:48:53,840 --> 00:48:56,560 THAT ROLE. 1194 00:48:56,560 --> 00:48:59,120 LABORATORIES OF CFF AND 1195 00:48:59,120 --> 00:49:00,400 ACADEMIC PARTNERS POISED TO 1196 00:49:00,400 --> 00:49:04,720 MAKE REAL PROGRESS IN 1197 00:49:04,720 --> 00:49:06,600 COLLABORATIVE RESEARCH AREAS 1198 00:49:06,600 --> 00:49:07,080 AND SUCCESS. 1199 00:49:07,080 --> 00:49:08,920 THANKS VERY MUCH AND I AM 1200 00:49:08,920 --> 00:49:19,480 HAPPY TO PASS IT ALONG TO OUR 1201 00:50:04,160 --> 00:50:05,200 NEXT SPEAKER. 1202 00:50:05,200 --> 00:50:11,000 >> SO WE ARE DISCUSSING THE 1203 00:50:11,000 --> 00:50:18,080 RESEARCH FOR CYSTIC FIBROSIS 1204 00:50:18,080 --> 00:50:21,240 AND DRUGS THAT CAN TURN THE 1205 00:50:21,240 --> 00:50:23,160 DEADLY DISEASE INTO A 1206 00:50:23,160 --> 00:50:24,800 MANAGEABLE CONDITION AND WE 1207 00:50:24,800 --> 00:50:26,440 HAVE THE TIMELINE HERE 1208 00:50:26,440 --> 00:50:28,880 STARTING WITH APPROVAL IN 1984 1209 00:50:28,880 --> 00:50:31,000 AND ADVANCING FORWARD IN 2012 1210 00:50:31,000 --> 00:50:35,560 WITH THE FIRST APPROVAL OF THE 1211 00:50:35,560 --> 00:50:41,960 HIGHLY EFFECTIVE MODULATOR 1212 00:50:41,960 --> 00:50:49,800 THERAPY AND THEN LEADING US TO 1213 00:50:49,800 --> 00:50:50,920 THE PRESENT DAY. 1214 00:50:50,920 --> 00:50:52,520 NEXT SLIDE. 1215 00:50:52,520 --> 00:50:55,960 SO THE GOAL TODAY IS TO 1216 00:50:55,960 --> 00:50:56,960 PRESENT KEY EVIDENCE FROM 1217 00:50:56,960 --> 00:51:00,760 PHASE 3 AND OBSERVATIONAL 1218 00:51:00,760 --> 00:51:02,800 STUDIES WITH FUNCTIONAL AND 1219 00:51:02,800 --> 00:51:04,080 MECHANISTIC OUTCOMES AND AS 1220 00:51:04,080 --> 00:51:14,680 YOU CAN SEE ON THE SIDE, THE 1221 00:51:23,040 --> 00:51:26,120 FUNCTION WE HAVE, ASSESSING 1222 00:51:26,120 --> 00:51:32,800 INFECTION AND INFLAMMATION AND 1223 00:51:32,800 --> 00:51:34,800 THE NUTRITIONAL PART OF THAT. 1224 00:51:34,800 --> 00:51:37,640 THIS IS REALLY A SUMMARY OF 1225 00:51:37,640 --> 00:51:44,280 INFORMATION COMING FROM PHASE 1226 00:51:44,280 --> 00:51:46,440 3 RANDOMIZED CONTROL TRIALS, 1227 00:51:46,440 --> 00:51:47,960 THE REGISTRY DATA TO REFLECT 1228 00:51:47,960 --> 00:51:49,800 WHERE WE ARE NOW BUT REALLY 1229 00:51:49,800 --> 00:51:51,520 THIS IS LOOKING FORWARD AT 1230 00:51:51,520 --> 00:51:53,160 OPPORTUNITIES TO UNDERSTAND 1231 00:51:53,160 --> 00:52:00,560 MORE IN GAPS IN OUR HIGHLY 1232 00:52:00,560 --> 00:52:01,760 EFFECTIVE MODULATOR THERAPY 1233 00:52:01,760 --> 00:52:11,160 AND WHERE WE ARE GOING WITH 1234 00:52:11,160 --> 00:52:12,840 INFECTION, INFLAMMATION, THE 1235 00:52:12,840 --> 00:52:15,280 LIVER EFFECTS, LOOKING AT 1236 00:52:15,280 --> 00:52:17,560 TOLERANCE AND ADHERENCE AND 1237 00:52:17,560 --> 00:52:19,080 ALL OF THESE WILL IN THE 1238 00:52:19,080 --> 00:52:25,240 FUTURE CONVEY WHERE WE ARE 1239 00:52:25,240 --> 00:52:25,520 GOING. 1240 00:52:25,520 --> 00:52:26,520 NEXT SLIDE. 1241 00:52:26,520 --> 00:52:28,040 SO TO START THIS SUMMARY, WE 1242 00:52:28,040 --> 00:52:31,040 HAVE TO LOOK BACK TO THE FIRST 1243 00:52:31,040 --> 00:52:33,440 BREATHTAKING DATA THAT WERE 1244 00:52:33,440 --> 00:52:36,880 PUBLISHED IN 2011 INCLUDING 1245 00:52:36,880 --> 00:52:40,040 IVACAFTOR, THE FIRST HIGHLY 1246 00:52:40,040 --> 00:52:40,800 EFFECTIVE MODULATOR THERAPY 1247 00:52:40,800 --> 00:52:42,360 AND IT IS HARD NOT TO NOTICE 1248 00:52:42,360 --> 00:52:45,120 IN EVERY ONE OF THESE PANELS 1249 00:52:45,120 --> 00:52:49,440 THE KEY OBSERVATIONS OF THE 1250 00:52:49,440 --> 00:52:52,080 IMPACT OF THERARY ON CF. 1251 00:52:52,080 --> 00:52:54,560 YOU CAN SEE IT STARTS WITH 1252 00:52:54,560 --> 00:52:55,680 JUST 10 PERCENT IMPROVEMENT 1253 00:52:55,680 --> 00:52:59,480 RELATIVE TO THE PLACEBO GROUP 1254 00:52:59,480 --> 00:53:06,000 AND THEN CONTINUING ON THROUGH 1255 00:53:06,000 --> 00:53:07,880 THE 48 PERIOD TIME COURSE AS 1256 00:53:07,880 --> 00:53:13,640 WELL AS PANEL B, REFLECTION OF 1257 00:53:13,640 --> 00:53:21,520 THE EFFECT, THOSE TREATED WITH 1258 00:53:21,520 --> 00:53:22,880 IVACAFTOR AND ANTIBIOTICS. 1259 00:53:22,880 --> 00:53:27,880 YOU CAN SEE IN C OVER TIME, 1260 00:53:27,880 --> 00:53:29,640 MARKED IMPROVEMENT AND IN 1261 00:53:29,640 --> 00:53:30,560 PANEL D, THE FIRST 1262 00:53:30,560 --> 00:53:32,320 IMPROVEMENTS WE HAD SEEN OF 1263 00:53:32,320 --> 00:53:35,080 THIS NATURE IN BODY MASS INDEX 1264 00:53:35,080 --> 00:53:38,480 AND FRANKLY A CHANGE IN WEIGHT 1265 00:53:38,480 --> 00:53:40,400 BUT WHEN WE STARTED TO LOOK AT 1266 00:53:40,400 --> 00:53:42,160 THE MECHANISM OF THIS CLINICAL 1267 00:53:42,160 --> 00:53:43,600 BENEFIT, YOU CAN SEE IN PANELS 1268 00:53:43,600 --> 00:53:54,120 A AND B ON THE RIGHT THAT 1269 00:53:56,760 --> 00:54:00,400 FLUORIDE WAS DROPPED IN THIS 1270 00:54:00,400 --> 00:54:01,040 MARKED INDICATOR. 1271 00:54:01,040 --> 00:54:06,560 SO YOU CAN SEE IN PANEL A THE 1272 00:54:06,560 --> 00:54:10,480 FLUORIDE AND THEN IN PANEL B, 1273 00:54:10,480 --> 00:54:16,360 THE REDUCTION AND THEN IN D, 1274 00:54:16,360 --> 00:54:18,000 CONSIDERED AS A DIAGNOSIS WHEN 1275 00:54:18,000 --> 00:54:20,000 TAKEN TOGETHER WITH CLINICAL 1276 00:54:20,000 --> 00:54:21,640 SYMPTOMS AT THE TIME. 1277 00:54:21,640 --> 00:54:25,200 SO WE FOLLOWED THE PATIENT FOR 1278 00:54:25,200 --> 00:54:28,520 FIVE YEARS IN U.S. AND UK 1279 00:54:28,520 --> 00:54:34,240 REGISTRY DATA AND CONTINUED TO 1280 00:54:34,240 --> 00:54:36,360 SEE IMPROVEMENT WITH THERAPY. 1281 00:54:36,360 --> 00:54:41,120 A AND B ON THE LEFT ARE THE 1282 00:54:41,120 --> 00:54:45,880 PROPORTION OF PATIENTS TREATED 1283 00:54:45,880 --> 00:54:49,640 WITH IVACAFTOR WERE LOWER THAN 1284 00:54:49,640 --> 00:54:51,800 THE PHENOTYPE IN THE U.S. AND 1285 00:54:51,800 --> 00:54:53,360 U.K. OVER FIVE YEARS. 1286 00:54:53,360 --> 00:54:56,320 AND THEN YOU CAN SEE IT WAS 1287 00:54:56,320 --> 00:54:59,000 DECREASED AFTER ONE YEAR AND 1288 00:54:59,000 --> 00:54:59,960 REMAINS SLIGHTLY DECREASED 1289 00:54:59,960 --> 00:55:00,840 OVER TIME. 1290 00:55:00,840 --> 00:55:03,520 SO SOME OF THE DATA WE WILL 1291 00:55:03,520 --> 00:55:06,040 GET INTO FURTHER IN THIS 1292 00:55:06,040 --> 00:55:09,280 DISCUSSION WILL SHOW IN MORE 1293 00:55:09,280 --> 00:55:10,760 GRANULAR DETAIL AND FINALLY IN 1294 00:55:10,760 --> 00:55:15,120 THE RIGHT PANEL WHAT WE CAN 1295 00:55:15,120 --> 00:55:19,680 SEE AS WE LEARN ABOUT IN THIS 1296 00:55:19,680 --> 00:55:24,800 ERA FOR THE MAJORITY IF NOT 1297 00:55:24,800 --> 00:55:26,640 ALL OF THE PANELS. 1298 00:55:26,640 --> 00:55:30,200 SO YOU CAN SEE THAT THERE HAS 1299 00:55:30,200 --> 00:55:32,560 BEEN AN INCREASE OVER THE 1300 00:55:32,560 --> 00:55:34,800 INITIAL PERIOD BUT AS FOLLOWED 1301 00:55:34,800 --> 00:55:36,920 OVER THE FIVE-YEAR PERIOD, YOU 1302 00:55:36,920 --> 00:55:44,480 CAN SEE THERE IS SOME SLIDE IN 1303 00:55:44,480 --> 00:55:47,720 FV1 AND THAT WAS ALSO SEEN IN 1304 00:55:47,720 --> 00:55:51,000 THE UNITED KINGDOM IN THE 1305 00:55:51,000 --> 00:55:51,960 INITIAL YEAR BUT FOLLOWING 1306 00:55:51,960 --> 00:55:54,120 THAT OVER THE COURSE OF TIME. 1307 00:55:54,120 --> 00:55:55,680 SO TO TRY TO UNDERSTAND WHAT 1308 00:55:55,680 --> 00:55:57,320 IS LEADING TO THAT, WE WILL 1309 00:55:57,320 --> 00:56:00,440 HAVE TO LOOK FURTHER AT THIS 1310 00:56:00,440 --> 00:56:01,160 WITH -- 1311 00:56:01,160 --> 00:56:02,160 [INDISCERNIBLE] 1312 00:56:02,160 --> 00:56:05,040 SO IF WE GO TO THE NEXT SLIDE. 1313 00:56:05,040 --> 00:56:11,360 THE LONG-TERM EFFECTS OF 1314 00:56:11,360 --> 00:56:15,360 IVACAFTOR WERE HOOKED IN A 1315 00:56:15,360 --> 00:56:16,080 LONG-TERM OBSERVATIONAL STUDY 1316 00:56:16,080 --> 00:56:17,720 AND OVER THE COURSE OF SIX 1317 00:56:17,720 --> 00:56:21,800 MONTHS, IT WAS EVIDENT THE 1318 00:56:21,800 --> 00:56:27,280 MEASURES CHANGE IN PMI, BLOOD 1319 00:56:27,280 --> 00:56:29,160 CLOTTING MEASURES WERE ALL 1320 00:56:29,160 --> 00:56:30,160 PRESERVED ALTHOUGH THERE WAS 1321 00:56:30,160 --> 00:56:35,120 SOME DECREASE IN THE 1322 00:56:35,120 --> 00:56:37,200 RESPIRATORY IN PANEL B. 1323 00:56:37,200 --> 00:56:41,320 WHAT WE HAVE SEEN IN A SET OF 1324 00:56:41,320 --> 00:56:42,520 31 PATIENTS INDICATING 1325 00:56:42,520 --> 00:56:44,920 INFLAMMATORY MEASURES AS SHOWN 1326 00:56:44,920 --> 00:56:47,560 IN THESE BIOMARKERS IN EACH OF 1327 00:56:47,560 --> 00:56:55,480 THESE PANELS AS WELL AS OTHER 1328 00:56:55,480 --> 00:56:59,040 ORGANISMS WERE NOT HIGHLY 1329 00:56:59,040 --> 00:57:01,920 EFFECTIVE AND THIS MAY SHOW US 1330 00:57:01,920 --> 00:57:10,040 THE HIGHLY EFFECTIVE MODULATOR 1331 00:57:10,040 --> 00:57:11,280 THERAPY OVER TIME. 1332 00:57:11,280 --> 00:57:13,560 NEXT SLIDE. 1333 00:57:13,560 --> 00:57:24,080 SO IT DOES APPEAR THAT I IT IS 1334 00:57:24,080 --> 00:57:24,840 HERE TO STAY. 1335 00:57:24,840 --> 00:57:28,560 IN THE WHITE PANEL ON THE LEFT 1336 00:57:28,560 --> 00:57:33,080 OF EACH OF THESE, THE 24 WEEK 1337 00:57:33,080 --> 00:57:35,840 DATA FOLLOWED BY THE SHADED 1338 00:57:35,840 --> 00:57:37,760 DATA IN THE ENSUING 24 WEEKS 1339 00:57:37,760 --> 00:57:39,400 OF THE STUDY AND YOU CAN SEE 1340 00:57:39,400 --> 00:57:40,920 IN THE BOTTOM RIGHT THERE IS A 1341 00:57:40,920 --> 00:57:51,520 BIT OF A POSTER BY Dr. 1342 00:57:51,520 --> 00:57:52,880 COREY DAINES AND WHILE THAT IS 1343 00:57:52,880 --> 00:57:59,000 NOT AVAILABLE IN THE DATA, I 1344 00:57:59,000 --> 00:58:01,600 CAN HYPOTHESIZE ON THAT DATA. 1345 00:58:01,600 --> 00:58:03,760 AS YOU CAN SEE HERE IN BOTH OF 1346 00:58:03,760 --> 00:58:06,800 THESE PANELS AT THE TOP, THESE 1347 00:58:06,800 --> 00:58:08,880 APPEAR TO BE STABLE AT 24 1348 00:58:08,880 --> 00:58:12,440 WEEKS AND THEN AS SHOWN IN THE 1349 00:58:12,440 --> 00:58:15,080 POSTER FROM Dr. DAINES, 1350 00:58:15,080 --> 00:58:17,640 THERE DOES NOT SEEM TO BE A 1351 00:58:17,640 --> 00:58:21,800 SIGNIFICANT CHANGE IN THE 24 1352 00:58:21,800 --> 00:58:32,080 WEEK PATH. 1353 00:58:33,880 --> 00:58:35,040 SIMILARLY YOU CAN SEE THE 1354 00:58:35,040 --> 00:58:35,720 REDUCTION OF THE FLUORIDE AND 1355 00:58:35,720 --> 00:58:36,400 FOLLOWED BY ANOTHER 24-WEEK 1356 00:58:36,400 --> 00:58:41,360 PERIOD AND IT DOES PERSIST 1357 00:58:41,360 --> 00:58:44,200 SHOWN IN THE POSTER IN THE 1358 00:58:44,200 --> 00:58:44,960 FALL OF 2021. 1359 00:58:44,960 --> 00:58:45,440 NEXT SLIDE. 1360 00:58:45,440 --> 00:58:47,640 SO ONE OF THE QUESTIONS WE 1361 00:58:47,640 --> 00:58:50,640 PHASE NOW IS, IS IT POSSIBLE 1362 00:58:50,640 --> 00:58:52,120 TO BUILD ON BETTER? 1363 00:58:52,120 --> 00:58:55,880 AND THIS IS A PHASE 3 STUDY 1364 00:58:55,880 --> 00:59:00,600 WITH 132 PATIENTS GLOBALLY 1365 00:59:00,600 --> 00:59:04,440 ALREADY TAKING A CF MODULATOR 1366 00:59:04,440 --> 00:59:10,200 AND FEIGNING FUNCTION SO IT 1367 00:59:10,200 --> 00:59:12,840 WAS A COMBINATION. 1368 00:59:12,840 --> 00:59:23,400 AND IN THIS STUDY, WE ADDED 1369 00:59:25,320 --> 00:59:32,400 THE MODULATOR AND SAW A . 1370 00:59:32,400 --> 00:59:33,440 5 PERCENT EFFECT. 1371 00:59:33,440 --> 00:59:38,160 AND THE PROPORTION ON THE LEFT 1372 00:59:38,160 --> 00:59:42,720 PANEL OF PATIENTS THAT HAD 1373 00:59:42,720 --> 00:59:44,680 SWEAT CHLORIDE DECREASES ARE 1374 00:59:44,680 --> 00:59:52,160 SHOWN IN THIS BLUE COLUMN, 1375 00:59:52,160 --> 00:59:54,640 83.3 PERCENT OVERALL FOR 1376 00:59:54,640 --> 00:59:56,120 PATIENTS TREATED ON THIS 1377 00:59:56,120 --> 00:59:56,480 THERAPY. 1378 00:59:56,480 --> 00:59:59,520 AND WHAT IS EVEN PERHAPS 1379 00:59:59,520 --> 01:00:00,760 FURTHER REMARKABLE WHEN WE 1380 01:00:00,760 --> 01:00:03,040 CONSIDER THE RIGHTHAND PANEL 1381 01:00:03,040 --> 01:00:04,360 FOR THE PROPORTION OF PATIENTS 1382 01:00:04,360 --> 01:00:07,000 WITH THE SWEAT CHLORIDE LEVEL 1383 01:00:07,000 --> 01:00:17,760 THAT ENDED WITH LESS THAN 30ML 1384 01:00:17,760 --> 01:00:18,480 PER LITER. 1385 01:00:18,480 --> 01:00:21,760 WHAT WE SEE IS THAT 50 PERCENT 1386 01:00:21,760 --> 01:00:23,720 OF THE STUDIED POPULATION 1387 01:00:23,720 --> 01:00:25,120 OVERALL ACHIEVED THESE LOW 1388 01:00:25,120 --> 01:00:31,320 LEVELS OF SWEAT CHLORIDE AND 1389 01:00:31,320 --> 01:00:35,560 AGAIN 65.1 PERCENT EFFECTIVE 1390 01:00:35,560 --> 01:00:39,120 FOR THEIR GENOTYPES AND 1391 01:00:39,120 --> 01:00:42,600 MODULATOR THERAPY. 1392 01:00:42,600 --> 01:00:43,720 SO NEXT SLIDE. 1393 01:00:43,720 --> 01:00:45,280 LOOKING AT THESE SLIDES, WHAT 1394 01:00:45,280 --> 01:00:46,760 DOES THE DATA MEAN? 1395 01:00:46,760 --> 01:00:50,640 WHEN YOU LOOK AT THE FIVE-YEAR 1396 01:00:50,640 --> 01:00:51,800 SURVIVAL IN CF PATIENTS, 1397 01:00:51,800 --> 01:00:54,320 CLEARLY WE CAN SEE THERE IS AN 1398 01:00:54,320 --> 01:00:55,720 INCREASE OVERALL. 1399 01:00:55,720 --> 01:00:57,800 IN 1989 ALL WAIT TO THE LEFT 1400 01:00:57,800 --> 01:01:04,120 OF THIS Y AXIS WHEN CF WAS 1401 01:01:04,120 --> 01:01:07,520 FIRST DISCOVERED, THE MEDIAN 1402 01:01:07,520 --> 01:01:09,400 AGE WAS ALMOST 30 YEARS OLD. 1403 01:01:09,400 --> 01:01:14,880 IF YOU LOOK TO THE FAR RIGHT 1404 01:01:14,880 --> 01:01:17,640 IN THE 2018-19 ANALYSIS, THIS 1405 01:01:17,640 --> 01:01:19,240 IS REACHING 40 YEARS OLD AND 1406 01:01:19,240 --> 01:01:24,960 THIS IS FOR THE FDA APPROVAL 1407 01:01:24,960 --> 01:01:25,520 OF IVACAFTOR. 1408 01:01:25,520 --> 01:01:28,840 SO YOU CAN SEE THE 20-YEAR 1409 01:01:28,840 --> 01:01:30,120 INCREASE IN SURVIVAL AGE WHICH 1410 01:01:30,120 --> 01:01:33,640 IS JUST STARTING TO ENCOMPASS 1411 01:01:33,640 --> 01:01:35,520 THE EFFECTS OF ETI. 1412 01:01:35,520 --> 01:01:38,440 AND ALSO ON THE RIGHT YOU CAN 1413 01:01:38,440 --> 01:01:42,440 SEE THE SIMILAR DECREASE 1414 01:01:42,440 --> 01:01:44,280 BETWEEN 2019 AND 2020 WITH THE 1415 01:01:44,280 --> 01:01:45,280 A MORTALITY RATE. 1416 01:01:45,280 --> 01:01:46,800 WHAT IS CHALLENGING TO 1417 01:01:46,800 --> 01:01:49,120 DECIPHER IS WHAT ARE THE 1418 01:01:49,120 --> 01:01:51,280 CONFOUNDING FACTORS AS THE 1419 01:01:51,280 --> 01:01:52,360 COVID-19 PARTLY CLOUDY SPREAD 1420 01:01:52,360 --> 01:01:54,520 WORLDWIDE AND THE EFFECTS OF 1421 01:01:54,520 --> 01:01:57,800 SOCIAL DISTANCING AND 1422 01:01:57,800 --> 01:01:59,400 QUARANTINE WERE DIFFICULT TO 1423 01:01:59,400 --> 01:02:02,080 PARSE AS YOU LOOK AT MORTALITY 1424 01:02:02,080 --> 01:02:04,400 OVER TIME AND ALSO OVERLAP THE 1425 01:02:04,400 --> 01:02:10,600 START OF WIDELY ACCEPTED ETI 1426 01:02:10,600 --> 01:02:11,560 THERAPY. 1427 01:02:11,560 --> 01:02:12,280 NEXT SLIDE 1428 01:02:12,280 --> 01:02:13,080 >> TWO-MINUTE WARNING. 1429 01:02:13,080 --> 01:02:15,120 >> THANK YOU SO THIS SLIDE 1430 01:02:15,120 --> 01:02:16,520 MAY PROVIDE US SOME FIRST 1431 01:02:16,520 --> 01:02:27,000 CLUES AS WE LOOK AT THE 1432 01:02:29,160 --> 01:02:30,040 COMPARATOR OF PULMONARY 1433 01:02:30,040 --> 01:02:33,320 DISEASE, WE SEE A SHARP 1434 01:02:33,320 --> 01:02:36,720 DROPOFF IN 2020 AND WHILE WE 1435 01:02:36,720 --> 01:02:40,400 SEE COPD ALSO INCREASED IN 1436 01:02:40,400 --> 01:02:42,840 2020, BUT ALSO DURING A TIME 1437 01:02:42,840 --> 01:02:53,320 OF SOCIAL DISTANCING AND 1438 01:02:54,080 --> 01:02:54,360 QUARANTINE. 1439 01:02:54,360 --> 01:02:56,240 NEXT SLIDE. 1440 01:02:56,240 --> 01:02:58,640 SO 478 INDIVIDUALS IN A 1441 01:02:58,640 --> 01:03:01,680 SIX-MONTH PLANNED ANALYSIS AND 1442 01:03:01,680 --> 01:03:02,920 OBSERVATIONAL STUDY OF 1443 01:03:02,920 --> 01:03:07,480 PATIENTS WHO WERE PRIOR TO 1444 01:03:07,480 --> 01:03:11,280 MODULATOR THERAPY OR WERE ON 1445 01:03:11,280 --> 01:03:14,240 MODULATOR THERA PY AND WHAT WE 1446 01:03:14,240 --> 01:03:18,160 SEE IS AT THREE MONTHS AND SIX 1447 01:03:18,160 --> 01:03:20,280 MONTHS, RAISES THAT TO 1448 01:03:20,280 --> 01:03:21,440 OBSERVATIONAL STUDIES SO WE 1449 01:03:21,440 --> 01:03:24,720 ARE STARTING TO SEE THAT THERE 1450 01:03:24,720 --> 01:03:26,560 IS SOME RISE THAT IS RELATED 1451 01:03:26,560 --> 01:03:29,120 TO TREATMENT AND CARE AND THIS 1452 01:03:29,120 --> 01:03:30,080 STUDY IS ONGOING. 1453 01:03:30,080 --> 01:03:31,600 AND IF YOU ADVANCE THE SLIDE, 1454 01:03:31,600 --> 01:03:37,800 YOU CAN SEE RELATIVE 1455 01:03:37,800 --> 01:03:48,400 COMPARISONS TO THESE DATA WITH 1456 01:03:48,840 --> 01:03:50,160 G551D AND IVACASTOR. 1457 01:03:50,160 --> 01:03:52,720 NEXT SLIDE. 1458 01:03:52,720 --> 01:03:57,240 SWEAT CHLORIDE VALUES HAS BEEN 1459 01:03:57,240 --> 01:03:59,560 ANALYZED INDEPENDENTLY, THESE 1460 01:03:59,560 --> 01:04:01,880 ARE UNPUBLISHED DATA OF 26 1461 01:04:01,880 --> 01:04:05,960 INDIVIDUALS AND WHAT WE SEE 1462 01:04:05,960 --> 01:04:09,120 INDIVIDUALLY IS THESE 1463 01:04:09,120 --> 01:04:11,440 INDIVIDUALS ARE TRACKING THOSE 1464 01:04:11,440 --> 01:04:19,480 WITH THE DECREASE IN SWEAT 1465 01:04:19,480 --> 01:04:22,720 CHLORIDE AFTER THER APIES. 1466 01:04:22,720 --> 01:04:23,920 SO QUICKLY, NEXT SLIDE, I 1467 01:04:23,920 --> 01:04:27,960 WOULD SAY IF YOU LOOK AT THE 1468 01:04:27,960 --> 01:04:33,960 COMBINATION OF THESE AND THE 1469 01:04:33,960 --> 01:04:41,520 THE IVACAFTOR OR TRIKAFTA TONE 1470 01:04:41,520 --> 01:04:47,560 AS A COMBINED THERAPY SHOWING 1471 01:04:47,560 --> 01:04:48,520 HIGHLY MODULATED EFFECTS AT 1472 01:04:48,520 --> 01:04:50,240 THE SIX MONTH LEVEL AND WILL 1473 01:04:50,240 --> 01:04:55,600 CLINICALLY AT THE OUTCOME OF 1474 01:04:55,600 --> 01:04:58,120 TREATING THE UNDERLYING CF. 1475 01:04:58,120 --> 01:04:59,640 NEXT SLIDE. 1476 01:04:59,640 --> 01:05:02,440 BUT APPARENTLY ALL THAT 1477 01:05:02,440 --> 01:05:04,960 GLITTERS IS NOT GOLD. 1478 01:05:04,960 --> 01:05:09,480 IN STUDYING THIS DATA, WE KNOW 1479 01:05:09,480 --> 01:05:14,600 WE ARE LOOKING AT A FUTURE OF 1480 01:05:14,600 --> 01:05:18,400 BMI FOR ADULTS AND WHERE THIS 1481 01:05:18,400 --> 01:05:21,760 IS GOING AND SEEING THIS LIKE 1482 01:05:21,760 --> 01:05:22,640 NEVER BEFORE. 1483 01:05:22,640 --> 01:05:23,040 NEXT SLIDE. 1484 01:05:23,040 --> 01:05:27,120 AND THERE ARE A NUMBER OF 1485 01:05:27,120 --> 01:05:27,760 INTOLERANT CONSIDERATIONS 1486 01:05:27,760 --> 01:05:32,640 CONSIDERED FOR PEOPLE WHO 1487 01:05:32,640 --> 01:05:36,800 CANNOT TAKE THE MODULATOR 1488 01:05:36,800 --> 01:05:38,640 THERAPY AND WHERE THAT LEAVES 1489 01:05:38,640 --> 01:05:39,680 THEM TODAY. 1490 01:05:39,680 --> 01:05:42,800 NEXT SLIDE. 1491 01:05:42,800 --> 01:05:52,400 SO I WILL TRANSITION OVER TO 1492 01:05:52,400 --> 01:05:55,200 THE NEXT SPEAKER ON THE MANY 1493 01:05:55,200 --> 01:05:56,560 STUDIES CURRENTLY REFLECTED 1494 01:05:56,560 --> 01:05:59,640 HERE WITH MORE THAN 7800 1495 01:05:59,640 --> 01:06:05,520 PARTICIPANT TO BEGIN 1496 01:06:05,520 --> 01:06:06,360 ADDRESSING THIS AND IT HAS 1497 01:06:06,360 --> 01:06:08,160 BEEN A LOW PRESSURE SURE TO BE 1498 01:06:08,160 --> 01:06:09,200 ABLE TO PRESENT. 1499 01:06:09,200 --> 01:06:10,280 THANK YOU. 1500 01:06:10,280 --> 01:06:11,880 >> THANK YOU SO MUCH. 1501 01:06:11,880 --> 01:06:13,080 GOOD MORNING EVERYONE, WE ARE 1502 01:06:13,080 --> 01:06:14,440 THROWING A LOT OF INFORMATION 1503 01:06:14,440 --> 01:06:16,680 AT YOU REALLY FAST SO I JUST 1504 01:06:16,680 --> 01:06:19,240 WANTED TO TAKE A BREATH THAT 1505 01:06:19,240 --> 01:06:21,280 WE'RE ALL SO FORTUNATE TO TAKE 1506 01:06:21,280 --> 01:06:25,880 BEFORE I DIVE INTO MY STORY. 1507 01:06:25,880 --> 01:06:28,160 [ EXHALING HEAVILY ] 1508 01:06:28,160 --> 01:06:29,720 >> OKAY, MY NAME IS MELANIE 1509 01:06:29,720 --> 01:06:30,080 LAWRENCE. 1510 01:06:30,080 --> 01:06:32,840 I AM AN ADULT LIVING WITH CF. 1511 01:06:32,840 --> 01:06:36,040 I AM 41, JUST TURNED 42, 1512 01:06:36,040 --> 01:06:38,360 SORRY, HAVEN'T CAUGHT UP YET, 1513 01:06:38,360 --> 01:06:42,920 LIVING WITH CF AND I LIVE WITH 1514 01:06:42,920 --> 01:06:45,480 MY 11-YEAR-OLD SON MILES WHICH 1515 01:06:45,480 --> 01:06:45,880 IS AMAZING. 1516 01:06:45,880 --> 01:06:50,760 I HAVE BEEN WORKING WITH THE 1517 01:06:50,760 --> 01:06:52,600 CF FOUNDATION AT BOSTON 1518 01:06:52,600 --> 01:06:54,640 HOSPITAL FOR SEVERAL YEARS 1519 01:06:54,640 --> 01:06:56,120 NOW, QUALITY IMPROVEMENT 1520 01:06:56,120 --> 01:06:57,920 WORKSHOPS AND RESEARCH 1521 01:06:57,920 --> 01:07:01,480 OPPORTUNITIES AS WELL AS SIT 1522 01:07:01,480 --> 01:07:05,800 OINK ON THE SUCCESSFUL 1523 01:07:05,800 --> 01:07:07,160 THERAPIES RESEARCH CONSORTIUM 1524 01:07:07,160 --> 01:07:07,880 STEERING COMMITTEE. 1525 01:07:07,880 --> 01:07:13,400 I AM PASSIONATE ABOUT 1526 01:07:13,400 --> 01:07:14,920 COPRODUCTION CLINICAL 1527 01:07:14,920 --> 01:07:16,480 STRATEGIES AND HUMANIZING CF 1528 01:07:16,480 --> 01:07:16,800 CARE. 1529 01:07:16,800 --> 01:07:18,360 I HAVE PARTICIPATED IN 1530 01:07:18,360 --> 01:07:19,760 CLINICAL RESEARCH FOR DECADES 1531 01:07:19,760 --> 01:07:21,840 AND WITNESSED THE AMAZING 1532 01:07:21,840 --> 01:07:23,880 PROGRESS BEING MADE FIRSTHAND. 1533 01:07:23,880 --> 01:07:26,880 IT HAS BEEN BOTH AN HONOR AND 1534 01:07:26,880 --> 01:07:28,520 A PRIVILEGE TO CONTRIBUTE TO 1535 01:07:28,520 --> 01:07:30,000 THAT RESEARCH AND ALSO TO 1536 01:07:30,000 --> 01:07:30,720 BENEFIT. 1537 01:07:30,720 --> 01:07:35,880 I HAVE PERSONALLY BENEFITTED 1538 01:07:35,880 --> 01:07:37,040 AND I AM CURRENTLY 1539 01:07:37,040 --> 01:07:38,680 PARTICIPATING IN A NEW 1540 01:07:38,680 --> 01:07:40,480 CLINICAL TRIAL THAT GIVES ME 1541 01:07:40,480 --> 01:07:41,840 GREAT HOPE FOR WHERE WE ARE 1542 01:07:41,840 --> 01:07:44,760 GOING AND FOR THAT, I AM 1543 01:07:44,760 --> 01:07:45,880 DEEPLY GRATEFUL TO THE 1544 01:07:45,880 --> 01:07:48,400 ATTENTION BEING PAID TO OUR 1545 01:07:48,400 --> 01:07:49,040 COMMUNITY TRULY. 1546 01:07:49,040 --> 01:07:51,280 THANK YOU FOR PUTTING THIS 1547 01:07:51,280 --> 01:07:53,480 WORKSHOP TOGETHER AND SHEDDING 1548 01:07:53,480 --> 01:07:56,560 LIGHT ON THE EVOLVING NEEDS OF 1549 01:07:56,560 --> 01:07:57,640 OUR WORLD. 1550 01:07:57,640 --> 01:07:59,000 I UNDERSTAND THINGS ARE 1551 01:07:59,000 --> 01:08:00,400 CHANGING AT SUCH AN 1552 01:08:00,400 --> 01:08:01,400 ACCELERATED RATE THAT WE ARE 1553 01:08:01,400 --> 01:08:02,240 ALL LEARNING TOGETHER AND 1554 01:08:02,240 --> 01:08:03,200 TRYING TO KEEP UP. 1555 01:08:03,200 --> 01:08:05,360 THERE IS NO QUESTION THAT 1556 01:08:05,360 --> 01:08:06,760 MODULATORS HAVE CHANGED THE 1557 01:08:06,760 --> 01:08:08,480 LANDSCAPE AND THAT THE 1558 01:08:08,480 --> 01:08:10,880 MODELING NEEDS TO CHANGE WITH 1559 01:08:10,880 --> 01:08:11,360 IT. 1560 01:08:11,360 --> 01:08:12,480 MY MODULATOR EXPERIENCE HAS 1561 01:08:12,480 --> 01:08:14,440 BEEN OVERALL VERY POSITIVE BUT 1562 01:08:14,440 --> 01:08:16,280 IT HAS NOT BEEN THE MIRACLE 1563 01:08:16,280 --> 01:08:23,840 DRUG FOR ME THAT IT HAS BEEN 1564 01:08:23,840 --> 01:08:24,200 FOR MOST. 1565 01:08:24,200 --> 01:08:25,840 I HAD SOME -- 1566 01:08:25,840 --> 01:08:26,480 [INDISCERNIBLE] 1567 01:08:26,480 --> 01:08:34,160 -- WHEN I STARTED SEVERAL 1568 01:08:34,160 --> 01:08:40,560 YEARS AGO AND TRIKAFTA HAS 1569 01:08:40,560 --> 01:08:42,280 STABILIZED MY CITIES AND NO 1570 01:08:42,280 --> 01:08:46,800 DOUBT GIVEN ME BETTER QUALITY 1571 01:08:46,800 --> 01:08:49,880 OF LIFE. 1572 01:08:49,880 --> 01:08:54,120 MY CFPS HAVE BECOME STEADY, MY 1573 01:08:54,120 --> 01:08:56,160 BREEZING IS BETTER AND ARE MY 1574 01:08:56,160 --> 01:08:57,320 SINUSES ARE MUCH HEALTHIER. 1575 01:08:57,320 --> 01:08:59,720 I DON'T WANT TO MINIMIZE THESE 1576 01:08:59,720 --> 01:09:00,600 BENEFITS BECAUSE THESE ARE 1577 01:09:00,600 --> 01:09:02,640 HUGE AND I AM GREATFUL FOR 1578 01:09:02,640 --> 01:09:06,440 THEM EACH AND EVERY DAY. 1579 01:09:06,440 --> 01:09:09,400 TRIKAFTA HAS GIVEN ME THE 1580 01:09:09,400 --> 01:09:11,440 ABILITY TO INDEPENDENTLY 1581 01:09:11,440 --> 01:09:13,160 IMPROVE MY HEALTH AND I AM 1582 01:09:13,160 --> 01:09:15,280 ABLE TO DEVOTE MORE TIME TO 1583 01:09:15,280 --> 01:09:18,280 EXERCISE AND MY MENTAL AND 1584 01:09:18,280 --> 01:09:21,320 EMOTIONAL WELL-BEING AND TO 1585 01:09:21,320 --> 01:09:23,040 CONTRIBUTE TO THINGS LIKE 1586 01:09:23,040 --> 01:09:24,800 MAKING ME FEEL LIKE I HAVE A 1587 01:09:24,800 --> 01:09:28,280 PURPOSE AND LIVING A FULL 1588 01:09:28,280 --> 01:09:29,080 LIFE. 1589 01:09:29,080 --> 01:09:31,720 I CAN SPEND LESS TIME FEELING 1590 01:09:31,720 --> 01:09:32,880 AWFUL OR EXPERIENCING SIDE 1591 01:09:32,880 --> 01:09:34,280 EFFECTS OF DRUGS AND SPEND 1592 01:09:34,280 --> 01:09:36,640 MORE TIME WITH OTHERS IN THE 1593 01:09:36,640 --> 01:09:37,480 HUMAN CONNECTION. 1594 01:09:37,480 --> 01:09:39,320 THAT BEING SAID, WE STILL HAVE 1595 01:09:39,320 --> 01:09:40,920 OUR WORK CUT OUT FOR US AND 1596 01:09:40,920 --> 01:09:43,920 THERE ARE MANY AREAS THAT WE 1597 01:09:43,920 --> 01:09:46,480 CAN IMPROVE UPON. 1598 01:09:46,480 --> 01:09:48,920 WHILE TRIKAFTA HAS HELPED TO 1599 01:09:48,920 --> 01:09:51,880 STABILIZE ME, IT DID NOT 1600 01:09:51,880 --> 01:09:54,960 DECREASE MY EPISODES AND HAS 1601 01:09:54,960 --> 01:09:58,400 NOT HELPED WHAT SEEMS TO BE 1602 01:09:58,400 --> 01:10:04,720 CAUSING MY CHRONIC EDEMA, HAS 1603 01:10:04,720 --> 01:10:08,520 NOT CHANGED MY CULTURAL 1604 01:10:08,520 --> 01:10:11,120 BACTERIA AND HAS NOT -- 1605 01:10:11,120 --> 01:10:11,640 [INDISCERNIBLE] 1606 01:10:11,640 --> 01:10:14,560 I STILL EXPERIENCE MORE THAN I 1607 01:10:14,560 --> 01:10:15,120 LIKE. 1608 01:10:15,120 --> 01:10:18,560 I ALSO EXPERIENCE THE SIDE 1609 01:10:18,560 --> 01:10:21,280 EFFECTS THAT HAS AFFECTED MY 1610 01:10:21,280 --> 01:10:23,560 FOOD INTAKE AND QUALITY OF 1611 01:10:23,560 --> 01:10:25,600 LIFE. 1612 01:10:25,600 --> 01:10:36,080 WHILE I CONSIDER MYSELF 1613 01:10:42,600 --> 01:10:44,400 SUCCESSFUL -- 1614 01:10:44,400 --> 01:10:44,880 [INDISCERNIBLE] 1615 01:10:44,880 --> 01:10:49,280 I RECENTLY PARTICIPATED IN A 1616 01:10:49,280 --> 01:10:51,000 WORKING GROUP ON THE 1617 01:10:51,000 --> 01:10:53,600 EXPERIENCE OF POST MODULATOR 1618 01:10:53,600 --> 01:10:54,960 ERA AND VERY MUCH LOOKING 1619 01:10:54,960 --> 01:10:56,360 FORWARD TO THE FINDINGS. 1620 01:10:56,360 --> 01:10:58,520 I THINK THIS COULD BE THE 1621 01:10:58,520 --> 01:11:02,160 FUTURE FOR US WITH FUTURE 1622 01:11:02,160 --> 01:11:03,080 RESEARCH IN EF. 1623 01:11:03,080 --> 01:11:04,440 ONE SENTIMENTS THAT HAS BEEN 1624 01:11:04,440 --> 01:11:06,240 ECHOED FOR A WHILE NOW IS HOW 1625 01:11:06,240 --> 01:11:08,640 ADULTS WITH MODERATE TO 1626 01:11:08,640 --> 01:11:15,680 ADVANCED DISEASE ARE STARTING 1627 01:11:15,680 --> 01:11:17,280 TO SEE -- 1628 01:11:17,280 --> 01:11:17,760 [INDISCERNIBLE] 1629 01:11:17,760 --> 01:11:23,400 -- AND I AM GREATFUL TO SHARE 1630 01:11:23,400 --> 01:11:27,520 THE CHANGE WITH MODULATORS SO 1631 01:11:27,520 --> 01:11:30,200 MUCH, BUT OUR GENERATION IS 1632 01:11:30,200 --> 01:11:30,920 BEING DISREGARDED. 1633 01:11:30,920 --> 01:11:33,680 MANY HAVE SAID AND I AGREE 1634 01:11:33,680 --> 01:11:39,040 THAT WE NEED NEW ANTIBIOTICS 1635 01:11:39,040 --> 01:11:42,760 AND NEW THERAPY TO TREAT WHAT 1636 01:11:42,760 --> 01:11:46,720 HAS ALREADY BEEN DONE. 1637 01:11:46,720 --> 01:11:51,520 I AM RESISTANT TO EVERY 1638 01:11:51,520 --> 01:11:58,560 ANTIBIOTIC FOR MY BACTERIA AND 1639 01:11:58,560 --> 01:12:01,800 THE EFFECTS THAT ARE WORSE 1640 01:12:01,800 --> 01:12:05,800 PREVENT MY WANTING TO USE 1641 01:12:05,800 --> 01:12:06,160 THEM. 1642 01:12:06,160 --> 01:12:08,000 MANY STRUGGLE WITH RFD. 1643 01:12:08,000 --> 01:12:10,800 YES, IT IS AN ABSOLUTELY 1644 01:12:10,800 --> 01:12:12,920 AMAZING GIFT WE ARE LIVING IN 1645 01:12:12,920 --> 01:12:23,680 OUR LIVES BUT IT IS FAR FROM A 1646 01:12:23,680 --> 01:12:23,880 CURE. 1647 01:12:23,880 --> 01:12:25,440 YOU WILL HEAR MEANINGFUL 1648 01:12:25,440 --> 01:12:27,200 STORIES FROM OUR COMMUNITY, 1649 01:12:27,200 --> 01:12:29,680 ESPECIALLY THOSE NOT ELIGIBLE 1650 01:12:29,680 --> 01:12:30,320 FOR MODULATORS. 1651 01:12:30,320 --> 01:12:34,960 I HAVE NO DOUBT THIS WORKSHOP 1652 01:12:34,960 --> 01:12:36,560 WILL BE IMPACTFUL. 1653 01:12:36,560 --> 01:12:38,080 AS YOU SPOKE IN THE 1654 01:12:38,080 --> 01:12:40,440 INFORMATION YOU SHARED, I DO 1655 01:12:40,440 --> 01:12:42,600 CHALLENGE YOU TO DO THIS WORK 1656 01:12:42,600 --> 01:12:43,840 WITH A DIFFERENT LENS. 1657 01:12:43,840 --> 01:12:46,880 I ASK YOU NOT TO JUST LOOK AT 1658 01:12:46,880 --> 01:12:48,640 WHERE RESEARCH CAN GO BUT HOW 1659 01:12:48,640 --> 01:12:50,280 WE CAN MAKE RESEARCH BETTER, 1660 01:12:50,280 --> 01:12:55,520 MORE EFFECTIVE AND MORE 1661 01:12:55,520 --> 01:12:55,880 INCLUSIVE. 1662 01:12:55,880 --> 01:12:58,400 I IMPLORE YOU TO BUILD A 1663 01:12:58,400 --> 01:13:00,920 FRAMEWORK OF COMMUNITY AND 1664 01:13:00,920 --> 01:13:02,840 COPRODUCTION WITH YOUR WORK. 1665 01:13:02,840 --> 01:13:04,800 I RECENTLY HAD THE HONOR OF 1666 01:13:04,800 --> 01:13:06,120 SPEAKING AT A RESEARCH 1667 01:13:06,120 --> 01:13:09,600 CONFERENCE AND HIGHLIGHTING 1668 01:13:09,600 --> 01:13:12,040 THE DISCONNECT BETWEEN THE 1669 01:13:12,040 --> 01:13:15,200 ALGORITHM OF ADVICE AND HOW 1670 01:13:15,200 --> 01:13:17,040 LITTLE EFFECT TRICKLES DOWN TO 1671 01:13:17,040 --> 01:13:17,880 THE PATIENT EXPERIENCE. 1672 01:13:17,880 --> 01:13:21,040 RESEARCH NEEDS TO BE 1673 01:13:21,040 --> 01:13:22,840 SYMBIOTIC, HOWEVER YOU WANT TO 1674 01:13:22,840 --> 01:13:23,480 SAY IT. 1675 01:13:23,480 --> 01:13:25,680 YOU NEED US AND WE NEED YOU 1676 01:13:25,680 --> 01:13:28,240 AND PROGRESS HAPPENS WHEN WE 1677 01:13:28,240 --> 01:13:28,720 WORK TOGETHER. 1678 01:13:28,720 --> 01:13:33,120 SO MUCH OF OUR COMMUNITY 1679 01:13:33,120 --> 01:13:38,560 FEELSY HUMANIZED BY THEIR 1680 01:13:38,560 --> 01:13:39,840 EXPERIENCES, LEAVING AN OPEN 1681 01:13:39,840 --> 01:13:42,400 DOOR TO GROW AS A FIELD. 1682 01:13:42,400 --> 01:13:45,800 AS RESEARCHERS, PLEASE REMAIN 1683 01:13:45,800 --> 01:13:47,280 COGNIZANT OF HOW MUCH PATIENTS 1684 01:13:47,280 --> 01:13:48,960 ARE PUTTING ON THE LINE TO GET 1685 01:13:48,960 --> 01:13:50,400 THE DATA YOU NEED, TO REMEMBER 1686 01:13:50,400 --> 01:13:52,760 WE ARE ALL HUMAN BEINGS WITH 1687 01:13:52,760 --> 01:13:55,040 FULL LIVES WHO DESPERATELY 1688 01:13:55,040 --> 01:13:58,600 WANT TO WORK TOWARD THE SAME 1689 01:13:58,600 --> 01:14:00,400 GOALS YOU DO. 1690 01:14:00,400 --> 01:14:03,160 SHARING OUR ENVIRONMENT WITH 1691 01:14:03,160 --> 01:14:03,880 COMPASSION AND UNDERSTANDING, 1692 01:14:03,880 --> 01:14:06,560 IT IS SAID WE WILL BRING MORE 1693 01:14:06,560 --> 01:14:08,160 PARTICIPANTS INTO THE FOLD AND 1694 01:14:08,160 --> 01:14:09,720 WORK TOGETHER MORE 1695 01:14:09,720 --> 01:14:10,320 EFFICIENTLY. 1696 01:14:10,320 --> 01:14:12,520 IT IS NOT ONLY THE QUESTION OF 1697 01:14:12,520 --> 01:14:16,000 WHAT WE CAN ACCOMPLISH BUT HOW 1698 01:14:16,000 --> 01:14:17,360 WE WANT TO ACCOMPLISH. 1699 01:14:17,360 --> 01:14:19,920 I HOPE YOU CAN CARRY THIS 1700 01:14:19,920 --> 01:14:21,560 INCENTIVE WITH YOU DURING THIS 1701 01:14:21,560 --> 01:14:23,800 WORKSHOP AND WORK TO IMPLEMENT 1702 01:14:23,800 --> 01:14:24,880 MORE HUMANITY INTO YOUR 1703 01:14:24,880 --> 01:14:25,240 PRACTICES. 1704 01:14:25,240 --> 01:14:27,800 I THANK YOU SO MUCH FOR YOUR 1705 01:14:27,800 --> 01:14:29,560 TIME AND OPPORTUNITY TO SPEAK 1706 01:14:29,560 --> 01:14:30,680 WITH YOU TODAY. 1707 01:14:30,680 --> 01:14:32,280 WE NOW WILL WELCOME ANY 1708 01:14:32,280 --> 01:14:34,000 QUESTIONS YOU MAY HAVE AND I 1709 01:14:34,000 --> 01:14:40,480 PROMISE NO QUESTION IS 1710 01:14:40,480 --> 01:14:41,480 OFFLIMITS. 1711 01:14:41,480 --> 01:14:44,320 >> THANK YOU SO MUCH MELANIE 1712 01:14:44,320 --> 01:14:45,800 FOR THAT WONDERFUL SUMMARY AND 1713 01:14:45,800 --> 01:14:54,880 THANKS TO ALL OF THE SPEAKERS 1714 01:14:54,880 --> 01:14:55,680 PROVIDING INFORMATION, REALLY 1715 01:14:55,680 --> 01:14:57,800 POWERFUL WORK TO REMEMBER AS 1716 01:14:57,800 --> 01:15:02,240 RESEARCHERS AND ALSO -- 1717 01:15:02,240 --> 01:15:02,680 [INDISCERNIBLE] 1718 01:15:02,680 --> 01:15:03,360 [ AUDIO DROPPING ] 1719 01:15:03,360 --> 01:15:04,720 I DO SEE WE HAVE A FEW 1720 01:15:04,720 --> 01:15:08,120 QUESTIONS THAT HAVE STARTED TO 1721 01:15:08,120 --> 01:15:10,040 COME IN AND ONE I CAN START 1722 01:15:10,040 --> 01:15:13,040 WITH, I THINK THERE WAS A 1723 01:15:13,040 --> 01:15:14,960 QUESTION EARLY ON, COULDN'T 1724 01:15:14,960 --> 01:15:17,920 FIND EXACTLY WHERE IT WAS 1725 01:15:17,920 --> 01:15:19,240 BECAUSE MARRAH PROVIDED SO 1726 01:15:19,240 --> 01:15:23,000 MANY WONDERFUL LINKS TO 1727 01:15:23,000 --> 01:15:24,960 EVERYBODY ON RESEARCH BUT IT 1728 01:15:24,960 --> 01:15:32,240 WAS ON THE SERIOUSNESS OF 1729 01:15:32,240 --> 01:15:35,280 SYMPTOMATIC THERAPIES WITH 1730 01:15:35,280 --> 01:15:40,520 HIGHLY EFFECTIVE MODULATORS 1731 01:15:40,520 --> 01:15:42,800 AND I POINTED TO THE FACT THAT 1732 01:15:42,800 --> 01:15:44,960 ALL THESE DRUGS WERE DEVELOPED 1733 01:15:44,960 --> 01:15:47,160 WERE DEVELOPED FOR MODULATORS 1734 01:15:47,160 --> 01:15:50,440 SO THERE ARE ADDED BENEFITS ON 1735 01:15:50,440 --> 01:15:53,560 TOP OF THAT SO I THINK THAT IS 1736 01:15:53,560 --> 01:15:56,960 KIND OF THE CONTEXT. 1737 01:15:56,960 --> 01:16:01,520 I THINK THE QUESTION I AM 1738 01:16:01,520 --> 01:16:04,520 GOING TO PROBABLY POSE IS 1739 01:16:04,520 --> 01:16:07,200 BETTER UNDERSTANDING SOME OF 1740 01:16:07,200 --> 01:16:08,800 THE RELATIONSHIPS BETWEEN 1741 01:16:08,800 --> 01:16:13,360 SWEAT CHLORIDE AND LONGER TERM 1742 01:16:13,360 --> 01:16:15,880 CLINICAL OUTCOMES, Dr. 1743 01:16:15,880 --> 01:16:20,200 DEEPIKA, DO YOU KNOW WHAT DATA 1744 01:16:20,200 --> 01:16:24,120 HAS BEEN ASPIRED IN THOSE 1745 01:16:24,120 --> 01:16:25,720 TOPIC AREAS? 1746 01:16:25,720 --> 01:16:29,360 >> I WAS ON MUTE. 1747 01:16:29,360 --> 01:16:32,360 YES, I HAD HOPED TO COVER 1748 01:16:32,360 --> 01:16:32,680 THAT. 1749 01:16:32,680 --> 01:16:37,600 ONE OF THE THINGS I DID AT 1750 01:16:37,600 --> 01:16:38,920 CHILDREN'S MERCY HOSPITAL, AND 1751 01:16:38,920 --> 01:16:41,920 THERE WERE MANY SO I ENCOURAGE 1752 01:16:41,920 --> 01:16:44,440 PEOPLE TO LOOK AT THE 1753 01:16:44,440 --> 01:16:46,160 MANUSCRIPT BECAUSE THERE ARE A 1754 01:16:46,160 --> 01:16:48,680 NUMBER OF STUDIES IN THAT DATA 1755 01:16:48,680 --> 01:16:53,920 BUT THE SWEAT CHLORIDE 1756 01:16:53,920 --> 01:16:55,080 MODULATION AT SIX MONTHS, IT 1757 01:16:55,080 --> 01:16:56,560 WILL BE VERY INTERESTING TO 1758 01:16:56,560 --> 01:16:59,440 SEE IF THAT CORRELATION 1759 01:16:59,440 --> 01:17:00,040 PERSISTS. 1760 01:17:00,040 --> 01:17:10,320 WE KNOW THESE ARE VERY COMPLEX 1761 01:17:10,320 --> 01:17:12,640 VARIABLES, FP1 AND SWEAT 1762 01:17:12,640 --> 01:17:13,040 CHLORIDE. 1763 01:17:13,040 --> 01:17:16,840 SO I THINK WE STILL FACE 1764 01:17:16,840 --> 01:17:17,760 CHALLENGES WITHIN THE SUBJECT 1765 01:17:17,760 --> 01:17:20,520 AND STILL NEED TO LOOK AT 1766 01:17:20,520 --> 01:17:23,760 CORRELATION OF SWEAT CHLORIDES 1767 01:17:23,760 --> 01:17:25,160 WITH CLINICAL OUTCOMES 1768 01:17:25,160 --> 01:17:26,880 GENERALLY SPEAKING BUT WE CAN 1769 01:17:26,880 --> 01:17:29,080 CERTAINLY SEE IT AFFECTS THE 1770 01:17:29,080 --> 01:17:32,560 BROADER POPULATION LEVEL AND I 1771 01:17:32,560 --> 01:17:34,760 THINK WE'RE LEARNING MORE ON 1772 01:17:34,760 --> 01:17:36,520 THE SWEAT CHLORIDE LEVEL. 1773 01:17:36,520 --> 01:17:37,760 SOMETIMES THESE ARE LINKED 1774 01:17:37,760 --> 01:17:40,520 TOGETHER IN THESE STUDIES AND 1775 01:17:40,520 --> 01:17:42,160 SOMETIMES NOT -- 1776 01:17:42,160 --> 01:17:42,600 [INDISCERNIBLE] 1777 01:17:42,600 --> 01:17:45,680 ZO SO I THINK WE'RE STILL 1778 01:17:45,680 --> 01:17:46,240 LOOKING AT THAT. 1779 01:17:46,240 --> 01:17:53,080 >> GREAT, THANK YOU SO MUCH. 1780 01:17:53,080 --> 01:17:56,920 NEXT QUESTION I THINK I WILL 1781 01:17:56,920 --> 01:17:58,240 BRING TO STEVE BUT MAYBE YOU 1782 01:17:58,240 --> 01:18:00,120 CAN WEIGH IN A LITTLE BIT, THE 1783 01:18:00,120 --> 01:18:06,160 QUESTION WHETHER WE HAVE THE 1784 01:18:06,160 --> 01:18:14,200 DYNAMICS OF MODULATORS AND 1785 01:18:14,200 --> 01:18:15,760 PHARMACO MODULATORS, IF THERE 1786 01:18:15,760 --> 01:18:17,800 IS A CLARIFICATION, PLEASE PUT 1787 01:18:17,800 --> 01:18:20,560 IT IN THE CHAT. 1788 01:18:20,560 --> 01:18:22,440 >> YEAH, I THINK IT IS AN AREA 1789 01:18:22,440 --> 01:18:23,920 WE STILL DON'T KNOW FULLY 1790 01:18:23,920 --> 01:18:24,840 ABOUT BECAUSE MONITORING THE 1791 01:18:24,840 --> 01:18:27,240 LEVELS IN THE TISSUES HAS BEEN 1792 01:18:27,240 --> 01:18:27,920 MORE CHALLENGING ALTHOUGH WE 1793 01:18:27,920 --> 01:18:31,000 CAN START TO SEE SOME EMERGING 1794 01:18:31,000 --> 01:18:33,880 TECHNOLOGIES TRYING TO DO 1795 01:18:33,880 --> 01:18:34,440 THAT. 1796 01:18:34,440 --> 01:18:36,720 CERTAINLY IN THE DRUG DOSE 1797 01:18:36,720 --> 01:18:39,160 PATH, THE TK RELATIONSHIP 1798 01:18:39,160 --> 01:18:41,080 ESPECIALLY WITH THESE 1799 01:18:41,080 --> 01:18:44,760 MULTIDRUG COMBINATIONS HAS 1800 01:18:44,760 --> 01:18:47,080 BEEN COMPLICATED AND 1801 01:18:47,080 --> 01:18:47,680 PARTICULARLY COMPLICATED 1802 01:18:47,680 --> 01:18:49,760 BECAUSE THEY INTERACT WITH ONE 1803 01:18:49,760 --> 01:18:52,360 ANOTHER AND LEAD TO THE 1804 01:18:52,360 --> 01:18:56,080 METABOLISM OF ONE ANOTHER. 1805 01:18:56,080 --> 01:18:59,000 BUT NONETHELESS, THE 1806 01:18:59,000 --> 01:19:00,720 PREPONDERANCE OF THE DATA HAS 1807 01:19:00,720 --> 01:19:03,720 SHOWN ONCE THE THRESHOLD IS 1808 01:19:03,720 --> 01:19:06,000 ACHIEVED FOR DRUG LEVELS, THAT 1809 01:19:06,000 --> 01:19:07,400 IS GENERALLY CORRELATED WITH 1810 01:19:07,400 --> 01:19:09,120 IMPROVEMENT IN SWEAT CHLORIDE. 1811 01:19:09,120 --> 01:19:12,920 SO WE KNOW THE MAJOR EFFECT 1812 01:19:12,920 --> 01:19:15,240 HAS BEEN GETTING ABOVE THE 1813 01:19:15,240 --> 01:19:16,320 THRESHOLD. 1814 01:19:16,320 --> 01:19:25,200 HAVING SAID THAT, THERE ARE 1815 01:19:25,200 --> 01:19:27,360 NOW EMERGING CASES FOR 1816 01:19:27,360 --> 01:19:28,760 RESPONSE, DRUG INTERACTION 1817 01:19:28,760 --> 01:19:33,640 CASES RECORDED THAT SHOW IN 1818 01:19:33,640 --> 01:19:35,320 SOME CASES, THE SUBOPTIMAL 1819 01:19:35,320 --> 01:19:38,600 RESPONSE MAY BE AT LOW LEVELS 1820 01:19:38,600 --> 01:19:41,800 DESPITE THE DOSING BEING 1821 01:19:41,800 --> 01:19:43,840 NORMAL. 1822 01:19:43,840 --> 01:19:46,080 WE CAN IMAGINE THAT HAPPENING 1823 01:19:46,080 --> 01:19:47,800 BECAUSE OF THE METABOLISM OF 1824 01:19:47,800 --> 01:19:58,400 THESE DRUGS AND THEN FINALLY, 1825 01:20:00,640 --> 01:20:02,400 WE CAN SEE IT HAPPEN IN THE 1826 01:20:02,400 --> 01:20:07,080 LIVER BUT THEN THERE IS SOME 1827 01:20:07,080 --> 01:20:08,000 EARLY METABOLISM CONSIDERING 1828 01:20:08,000 --> 01:20:09,600 THAT MAY BE DIFFERENT FROM 1829 01:20:09,600 --> 01:20:10,760 WHAT YOU PREDICT FROM THE 1830 01:20:10,760 --> 01:20:16,800 SERUM AND IT MAY BE THAT A 1831 01:20:16,800 --> 01:20:17,840 METABOLIZING ENZYME VARIANCE 1832 01:20:17,840 --> 01:20:20,560 IS PART OF THAT STORY EXISTING 1833 01:20:20,560 --> 01:20:21,040 IN THE ARRAY. 1834 01:20:21,040 --> 01:20:24,360 SO I THINK THERE IS MORE TO 1835 01:20:24,360 --> 01:20:24,760 LEARN. 1836 01:20:24,760 --> 01:20:26,800 I CERTAINLY LOOK FOR FUTURE 1837 01:20:26,800 --> 01:20:29,320 SCIENCE TO SEE IN A 1838 01:20:29,320 --> 01:20:31,440 NONRESPONSIVE OR LESS 1839 01:20:31,440 --> 01:20:36,880 RESPONSIVE POPULATION IF DRUG 1840 01:20:36,880 --> 01:20:38,480 LEVELS OVER THE HISTORY LEVEL 1841 01:20:38,480 --> 01:20:42,200 HAVE AN EFFECT ON THE ORGANS. 1842 01:20:42,200 --> 01:20:52,760 >> THANK YOU FOR THAT -- [ 1843 01:20:53,480 --> 01:20:53,840 INDISCERNIBLE ] 1844 01:20:53,840 --> 01:20:54,200 [ AUDIO. 1845 01:20:54,200 --> 01:20:57,560 >> I AM SORRY, I DON'T THINK I 1846 01:20:57,560 --> 01:20:58,680 CAN ANSWER THAT BETTER THAN 1847 01:20:58,680 --> 01:21:01,200 STEVE BUT I WANT TO ADD ON 1848 01:21:01,200 --> 01:21:02,760 GOING FORWARD, THE QUESTION OF 1849 01:21:02,760 --> 01:21:07,000 BEING ABLE TO UNDERSTAND WHO 1850 01:21:07,000 --> 01:21:08,480 WILL BE A RESPONDER WILL BE 1851 01:21:08,480 --> 01:21:12,680 MORE IMPORTANT AS WE SEE 1852 01:21:12,680 --> 01:21:14,880 THERAPIES BROADEN ON THE 1853 01:21:14,880 --> 01:21:15,200 HORIZON. 1854 01:21:15,200 --> 01:21:19,240 SO IN ADDITION TO THE POINT 1855 01:21:19,240 --> 01:21:21,520 STEVE BROUGHT UP, I WOULD ADD 1856 01:21:21,520 --> 01:21:23,120 THAT UNDERSTANDING THE 1857 01:21:23,120 --> 01:21:24,720 GENOMICS IS GOING TO BE 1858 01:21:24,720 --> 01:21:27,320 CRITICAL AND WE HOPE TO HAVE A 1859 01:21:27,320 --> 01:21:28,720 BETTER PREDICTION OF TREATMENT 1860 01:21:28,720 --> 01:21:31,080 RESPONSE OR OPTIMAL TREATMENT. 1861 01:21:31,080 --> 01:21:32,720 >> GREAT, VERY GOOD POINT, 1862 01:21:32,720 --> 01:21:37,080 THANK YOU FOR BRINGING THAT 1863 01:21:37,080 --> 01:21:39,680 UP. 1864 01:21:39,680 --> 01:21:40,760 ALSO MELANIE, I APPRECIATE 1865 01:21:40,760 --> 01:21:42,920 YOUR TALK AND HOPE YOU CAN SEE 1866 01:21:42,920 --> 01:21:46,480 HOW MANY APPRECIATED IT IN THE 1867 01:21:46,480 --> 01:21:46,800 CHAT. 1868 01:21:46,800 --> 01:21:48,120 COULD YOU SPEAK A LITTLE MORE 1869 01:21:48,120 --> 01:21:50,440 ABOUT HOW WE CAN BRING MORE 1870 01:21:50,440 --> 01:22:01,000 HUMANITY TO HOW WE CONDUCT OUR 1871 01:22:03,880 --> 01:22:04,160 RESEARCH -- 1872 01:22:04,160 --> 01:22:05,400 >> WELL, YOU FROZE THERE AT 1873 01:22:05,400 --> 01:22:07,520 THE END BUT I SAW THE QUESTION 1874 01:22:07,520 --> 01:22:09,400 AND I AM HAPPY TO ANSWER. 1875 01:22:09,400 --> 01:22:12,360 THERE ARE WAYS TO BRING MORE 1876 01:22:12,360 --> 01:22:13,640 HUMANITY TO RESEARCH. 1877 01:22:13,640 --> 01:22:17,440 THE CF FOUNDATION HAS THIS 1878 01:22:17,440 --> 01:22:20,600 PROGRAM CALLED THE PEP 1879 01:22:20,600 --> 01:22:22,160 PROGRAM, THE PARTNERSHIP 1880 01:22:22,160 --> 01:22:25,120 ENHANCEMENT PROGRAM IN WHICH 1881 01:22:25,120 --> 01:22:27,520 TRAINING CLINICIANS AND 1882 01:22:27,520 --> 01:22:28,800 RESEARCHERS ON CONCRETE 1883 01:22:28,800 --> 01:22:31,440 METHODS TO COMMUNICATE FOR A 1884 01:22:31,440 --> 01:22:33,280 MORE EMPATHETIC PLACE AND TO 1885 01:22:33,280 --> 01:22:37,080 ENGAGE ON A DEEPER LEVEL WITH 1886 01:22:37,080 --> 01:22:37,440 PATIENTS. 1887 01:22:37,440 --> 01:22:39,520 THAT ASIDE, I DO THINK IT IS 1888 01:22:39,520 --> 01:22:41,400 REALLY SO SIMPLE, AND IF YOU 1889 01:22:41,400 --> 01:22:46,120 THINK ABOUT IT, IT IS LIKE A 1890 01:22:46,120 --> 01:22:48,320 MICROKOES MOST OF HUMAN 1891 01:22:48,320 --> 01:22:48,760 EXPERIENCE. 1892 01:22:48,760 --> 01:22:50,160 RESEARCH IS SO CONCISE AND YOU 1893 01:22:50,160 --> 01:22:52,720 HAVE SO MUCH TO GET DONE IN A 1894 01:22:52,720 --> 01:22:54,360 SHORT AMOUNT OF TIME AND WE 1895 01:22:54,360 --> 01:22:55,080 FEEL THAT. 1896 01:22:55,080 --> 01:22:58,640 SO MAYBE BEFORE YOU GO INTO 1897 01:22:58,640 --> 01:23:01,120 THE ROOM, STOP, TAKE A BREATH 1898 01:23:01,120 --> 01:23:02,200 AND THEN CONNECT WITH THE 1899 01:23:02,200 --> 01:23:04,040 PATIENT ON A HUMAN LEVEL 1900 01:23:04,040 --> 01:23:06,960 BEFORE YOU DRIVE IN TO ALL OF 1901 01:23:06,960 --> 01:23:08,680 THE RESEARCH QUESTIONS. 1902 01:23:08,680 --> 01:23:09,800 ACKNOWLEDGE THEIR SACRIFICE. 1903 01:23:09,800 --> 01:23:13,360 YOU KNOW, WE'RE PUTTING OUR 1904 01:23:13,360 --> 01:23:15,800 BODIES ON THE LINE TO GIVE YOU 1905 01:23:15,800 --> 01:23:17,680 DATA AND PROGRESS, JUST 1906 01:23:17,680 --> 01:23:19,200 ACKNOWLEDGE AND APPRECIATE 1907 01:23:19,200 --> 01:23:22,720 THAT BUT ALSO LIKE I CONNECTED 1908 01:23:22,720 --> 01:23:25,240 A LOT MORE WITH RESEARCHERS 1909 01:23:25,240 --> 01:23:27,000 AFTER I LEARNED WHAT THEY 1910 01:23:27,000 --> 01:23:29,040 LIKED ABOUT RESEARCH, WHAT 1911 01:23:29,040 --> 01:23:32,400 DROVE THEM TO DO IT, WAS IT A 1912 01:23:32,400 --> 01:23:34,120 REWARDING JOB OR A GRUELING 1913 01:23:34,120 --> 01:23:36,200 JOB SO THAT ALLOWED ME TO 1914 01:23:36,200 --> 01:23:38,280 CONNECT WITH THEM AS A HUMAN 1915 01:23:38,280 --> 01:23:41,360 BEING SO SHARE A LITTLE MORE 1916 01:23:41,360 --> 01:23:42,960 ABOUT YOURSELF AND CONNECT 1917 01:23:42,960 --> 01:23:44,800 WITH YOUR PATIENTS AS WELL. 1918 01:23:44,800 --> 01:23:46,240 >> THIS IS MARRAH. 1919 01:23:46,240 --> 01:23:48,080 I WILL GO AHEAD AND JUMP IN 1920 01:23:48,080 --> 01:23:49,680 BECAUSE I THINK WE HAVE LOST 1921 01:23:49,680 --> 01:23:52,240 JP BUT I HAVE BEEN COLLECTING 1922 01:23:52,240 --> 01:23:53,000 THE QUESTIONS. 1923 01:23:53,000 --> 01:23:53,920 MELANIE, WE HAVE ANOTHER 1924 01:23:53,920 --> 01:23:58,240 QUESTION FOR YOU THAT COMES 1925 01:23:58,240 --> 01:24:00,080 FROM Dr. ROSENTHAL, SHE 1926 01:24:00,080 --> 01:24:02,960 WANTED TO TACK ON TO TERRY'S 1927 01:24:02,960 --> 01:24:05,440 QUESTION WHICH IS DO YOU SEE 1928 01:24:05,440 --> 01:24:06,240 DECENTRALIZATION OF TRIALS 1929 01:24:06,240 --> 01:24:07,960 LIKE BEING ABLE TO COLLECT 1930 01:24:07,960 --> 01:24:13,720 ENDPOINTS AT HOME SUCH AS 1931 01:24:13,720 --> 01:24:16,520 SPIROMETRY AT HOME AS A WAY TO 1932 01:24:16,520 --> 01:24:17,640 IMPROVE CLINICAL TRIAL 1933 01:24:17,640 --> 01:24:18,040 EXPERIENCE. 1934 01:24:18,040 --> 01:24:18,760 >> IT IS INTERESTING BECAUSE 1935 01:24:18,760 --> 01:24:20,200 I THINK IT IS A WHETHER HE 1936 01:24:20,200 --> 01:24:22,480 ISING AND A CURSE. 1937 01:24:22,480 --> 01:24:25,120 IT CAN BRING MORE PATIENTS 1938 01:24:25,120 --> 01:24:26,920 INTO RESEARCH FROM THAT 1939 01:24:26,920 --> 01:24:29,440 STANDPOINT, TO GET A DIFFERENT 1940 01:24:29,440 --> 01:24:31,000 POOL OF PARTICIPANTS BUT I DO 1941 01:24:31,000 --> 01:24:34,320 THINK THERE IS SOMETHING THAT 1942 01:24:34,320 --> 01:24:36,480 IS LOST IN THE FACE TO PACE 1943 01:24:36,480 --> 01:24:36,880 EXPERIENCE. 1944 01:24:36,880 --> 01:24:43,640 I THINK THAT THERE'S A NUANCE, 1945 01:24:43,640 --> 01:24:44,560 BEING FACE-TO-FACE WITH 1946 01:24:44,560 --> 01:24:45,760 SOMEONE, THAT MORE WILL COME 1947 01:24:45,760 --> 01:24:47,400 UP AND IF YOU ARE JUST 1948 01:24:47,400 --> 01:24:52,640 COUNTING ON HOME DATA, LIKE 1949 01:24:52,640 --> 01:24:55,240 HOME SPIROMETRY THERE ARE MANY 1950 01:24:55,240 --> 01:24:57,000 NUANCES THAT ARE LOST AND 1951 01:24:57,000 --> 01:24:57,920 SYMPTOMS NOT SHARED OR 1952 01:24:57,920 --> 01:24:59,000 EXPERIENCES THAT MIGHT BE LEFT 1953 01:24:59,000 --> 01:24:59,240 OUT. 1954 01:24:59,240 --> 01:25:08,880 SO I THINK IT IS HELPFUL BUT 1955 01:25:08,880 --> 01:25:10,960 NOT THE FULL ANSWER EITHER. 1956 01:25:10,960 --> 01:25:13,000 >> THANK YOU, THAT IS A GREAT 1957 01:25:13,000 --> 01:25:15,000 PERSPECTIVE AND THE VALUE OF 1958 01:25:15,000 --> 01:25:15,720 MAKING THE PERSONAL CONNECTION 1959 01:25:15,720 --> 01:25:19,240 AS YOU SAID IN YOUR TALK IS 1960 01:25:19,240 --> 01:25:21,040 REALLY IMPORTANT AND YIELDS 1961 01:25:21,040 --> 01:25:21,560 ADDITIONAL INSIGHT. 1962 01:25:21,560 --> 01:25:23,720 SO I HAVE A QUESTION FOR Dr. 1963 01:25:23,720 --> 01:25:25,400 ROWE AND NOT SURE YOU CAN 1964 01:25:25,400 --> 01:25:27,320 ANSWER BUT IT POPPED UP IN THE 1965 01:25:27,320 --> 01:25:34,040 CHAT BUT HOW EFFECTIVE IS 1966 01:25:34,040 --> 01:25:36,200 EDD20 AS A HIDE TRAITOR? 1967 01:25:36,200 --> 01:25:39,320 >> FOR THOSE NOT FAMILIAR, 1968 01:25:39,320 --> 01:25:42,160 THIS IS A COMPOUND PRESENTED 1969 01:25:42,160 --> 01:25:46,840 AT THE CF MEETING FOR CLINICAL 1970 01:25:46,840 --> 01:25:49,320 DEVELOPMENT, A DRUG COULD BE 1971 01:25:49,320 --> 01:25:52,320 ON THE HORIZON, MEANING IT 1972 01:25:52,320 --> 01:25:54,360 ACTIVATES OF ALTERNATIVE 1973 01:25:54,360 --> 01:25:55,640 CHLORIDE CHANNEL AND WHAT HAS 1974 01:25:55,640 --> 01:25:58,040 BEEN SHOWN IS THAT IN VITRO, 1975 01:25:58,040 --> 01:26:04,200 IT IS A QUITE POTENT AND 1976 01:26:04,200 --> 01:26:07,480 EFFICACIOUS DRUG AND DOES SO 1977 01:26:07,480 --> 01:26:11,960 DIRECTLY IN THE CHANNEL AS 1978 01:26:11,960 --> 01:26:14,800 OPPOSED TO OTHER INDIRECT 1979 01:26:14,800 --> 01:26:15,160 CHANNELS. 1980 01:26:15,160 --> 01:26:20,520 IT HAS BEEN SHOWN TO AUGMENT 1981 01:26:20,520 --> 01:26:21,560 AIRWAY SURFACE LIQUID DEPTH 1982 01:26:21,560 --> 01:26:28,720 AND DO SO STRONGLY AND IT HAS 1983 01:26:28,720 --> 01:26:33,360 ALSO BEEN REPORTED TO KNOCK 1984 01:26:33,360 --> 01:26:35,840 THE MUCOUS SECRETION WHICH HAS 1985 01:26:35,840 --> 01:26:41,720 BEEN A POTENTIAL RISK ON THE 1986 01:26:41,720 --> 01:26:42,120 PATHWAYS -- 1987 01:26:42,120 --> 01:26:42,600 [INDISCERNIBLE] 1988 01:26:42,600 --> 01:26:46,760 SO I THINK IN VITRO IT LOOKS 1989 01:26:46,760 --> 01:26:47,680 PROMISING. 1990 01:26:47,680 --> 01:26:52,160 WE KNOW THAT THE EMAM CHANNEL 1991 01:26:52,160 --> 01:26:54,800 AND SWEAT CHLORIDE ON THE 1992 01:26:54,800 --> 01:26:56,640 SURFACE ARE EFFECTIVE BUT WE 1993 01:26:56,640 --> 01:26:59,280 DON'T YET KNOW WHETHER THAT 1994 01:26:59,280 --> 01:27:01,000 WILL TRANSLATE TO MUCOUS 1995 01:27:01,000 --> 01:27:02,600 CLEARANCE. 1996 01:27:02,600 --> 01:27:05,760 IT IS EXPRESSED IN SIMILAR IPR 1997 01:27:05,760 --> 01:27:08,040 SO THAT IS A GOOD SIGN IT 1998 01:27:08,040 --> 01:27:09,360 SHOULD AND WE'LL KNOW MORE 1999 01:27:09,360 --> 01:27:11,000 WHEN IT REACHES THE CLINIC. 2000 01:27:11,000 --> 01:27:12,840 IT CERTAINLY CHECKS THE RIGHT 2001 01:27:12,840 --> 01:27:16,040 BOXES AS FAR AS THE PHYSIOLOGY 2002 01:27:16,040 --> 01:27:18,040 SEEN IN THE STUDIES. 2003 01:27:18,040 --> 01:27:20,160 >> SO LOOKS LIKE WE HAVE TWO 2004 01:27:20,160 --> 01:27:20,600 MINUTES LEFT. 2005 01:27:20,600 --> 01:27:23,400 I WILL POSE THIS LAST QUESTION 2006 01:27:23,400 --> 01:27:25,360 BEFORE WE MOVE TON FROM 2007 01:27:25,360 --> 01:27:27,000 SESSION 1 AND THIS IS FROM THE 2008 01:27:27,000 --> 01:27:29,960 CHAT. 2009 01:27:29,960 --> 01:27:37,320 CAN YOU TALK'HOW WE ARE SYSTEM 2010 01:27:37,320 --> 01:27:40,160 ATICALLY STARTING MODULATORS 2011 01:27:40,160 --> 01:27:44,000 EARLY IN LIFE AND HOW THIS CAN 2012 01:27:44,000 --> 01:27:45,640 BE ADDSES, THIS IS ALSO A 2013 01:27:45,640 --> 01:27:46,400 QUESTION FROM OTHER SESSIONS 2014 01:27:46,400 --> 01:27:50,560 BUT I THINK YOU GUYS CAN TALK 2015 01:27:50,560 --> 01:27:52,880 ABOUT IT NOW. 2016 01:27:52,880 --> 01:27:53,760 >> Dr. POLINENI, YOU WANT 2017 01:27:53,760 --> 01:27:57,160 TO START IT OR YOU WANT ME TO 2018 01:27:57,160 --> 01:27:57,440 TRY? 2019 01:27:57,440 --> 01:27:58,960 >> SURE, SO I NOTICED THIS 2020 01:27:58,960 --> 01:28:00,360 QUESTION FROM DENNIS IN THE 2021 01:28:00,360 --> 01:28:03,040 CHAT AS WELL AND I THINK THE 2022 01:28:03,040 --> 01:28:05,000 TWO APPEAR TOGETHER BECAUSE 2023 01:28:05,000 --> 01:28:08,120 WHEN WE'RE STARTING TO THINK 2024 01:28:08,120 --> 01:28:13,600 ABOUT VERY EARLY ON IN 2025 01:28:13,600 --> 01:28:15,520 THERAPY, WE LOOK AT ACTIVATION 2026 01:28:15,520 --> 01:28:18,000 BUT IT LEADS US TO CONSIDER 2027 01:28:18,000 --> 01:28:28,560 WHEN DO WE START THE TREATMENT 2028 01:28:34,880 --> 01:28:35,760 AND IN WHICH PATIENT. 2029 01:28:35,760 --> 01:28:36,440 THERE ARE CERTAIN PATIENTS 2030 01:28:36,440 --> 01:28:37,120 THAT HAVE BEEN APPROVED FOR 2031 01:28:37,120 --> 01:28:37,760 THE MODULATOR THERAPY BUT WE 2032 01:28:37,760 --> 01:28:38,480 DON'T SEE THAT TOGETHER WITH 2033 01:28:38,480 --> 01:28:38,920 THE PROTEINS. 2034 01:28:38,920 --> 01:28:39,600 SO IT MAKES US QUESTION AT 2035 01:28:39,600 --> 01:28:43,280 WHAT POINT DO WE INITIATE 2036 01:28:43,280 --> 01:28:43,760 THERAPY. 2037 01:28:43,760 --> 01:28:45,720 AND TO THE CONVERSE, WE HAVE 2038 01:28:45,720 --> 01:28:50,040 PATIENTS THAT ARE PRESENTING 2039 01:28:50,040 --> 01:28:52,800 SOME SPECTRUM OF CFPR BUT 2040 01:28:52,800 --> 01:28:54,000 THEIR SYMPTOMS ARE FINE. 2041 01:28:54,000 --> 01:28:57,200 SO I THINK THE TREATMENT AND 2042 01:28:57,200 --> 01:29:01,880 STUDY OF LONG-TERM RISK BEN 2043 01:29:01,880 --> 01:29:05,200 PHYSICIAN ARE REALLY ONE OF 2044 01:29:05,200 --> 01:29:05,960 RESEARCH AND EXPERIENCE. 2045 01:29:05,960 --> 01:29:07,400 >> THANK YOU, AT THIS TIME I 2046 01:29:07,400 --> 01:29:10,760 WOULD LIKE TO THANK THE 2047 01:29:10,760 --> 01:29:12,600 PLENARY SPEAKERS FOR THEIR 2048 01:29:12,600 --> 01:29:13,160 TIME AND PERSPECTIVE. 2049 01:29:13,160 --> 01:29:15,440 WE WILL MOVE ON FROM SESSION 1 2050 01:29:15,440 --> 01:29:16,560 BUT I DO ENCOURAGE THOSE 2051 01:29:16,560 --> 01:29:17,440 PARTICIPATING IF YOU HAVE A 2052 01:29:17,440 --> 01:29:18,600 QUESTION THAT WAS NOT 2053 01:29:18,600 --> 01:29:20,160 ANSWERED, YOU CAN 2054 01:29:20,160 --> 01:29:21,560 DIRECT-MESSAGE THE SPEAKER OR 2055 01:29:21,560 --> 01:29:23,960 YOU CAN POST IT IN THE CHAT 2056 01:29:23,960 --> 01:29:26,320 AND THE SPEAKERS CAN ANSWER IT 2057 01:29:26,320 --> 01:29:36,280 LIKE THAT. 2058 01:29:36,280 --> 01:29:37,080 THANK YOU. 2059 01:29:37,080 --> 01:29:38,960 >> ALL RIGHT, SO THANKS 2060 01:29:38,960 --> 01:29:42,120 EVERYBODY FOR JOINING OUR NEXT 2061 01:29:42,120 --> 01:29:44,520 SYSTEM, WHICH IS THE MOUSE 2062 01:29:44,520 --> 01:29:50,560 MODELS FOR UNDERSTANDING THE 2063 01:29:50,560 --> 01:29:51,960 HIGHLY EFFECTIVE MODULATOR 2064 01:29:51,960 --> 01:29:55,080 THER APY. 2065 01:29:55,080 --> 01:30:05,400 OUR NEXT SPEAKER WILL BE CRAIG 2066 01:30:05,400 --> 01:30:10,480 HODGES AT THE CASE WESTERN 2067 01:30:10,480 --> 01:30:12,200 RESERVE UNIVERSITY. 2068 01:30:12,200 --> 01:30:16,680 AND WE HAVE A SLIDE UP FOR HOW 2069 01:30:16,680 --> 01:30:20,560 HAD MODELS FOR CF, NOT SURE I 2070 01:30:20,560 --> 01:30:21,760 SEE MY CO-HOST. 2071 01:30:21,760 --> 01:30:23,120 >> I AM HERE. 2072 01:30:23,120 --> 01:30:24,760 >> ARE REINTRODUCING ALL THE 2073 01:30:24,760 --> 01:30:26,080 SPEAKERS AT ONCE OR -- 2074 01:30:26,080 --> 01:30:30,440 >> ONE BY ONE, I THINK. 2075 01:30:30,440 --> 01:30:31,120 >> OKAY, SO CRAIG, GO AHEAD. 2076 01:30:31,120 --> 01:30:31,800 >> ALL RIGHT, THANK YOU VERY 2077 01:30:31,800 --> 01:30:33,720 MUCH, I WOULD LIKE TO THANK 2078 01:30:33,720 --> 01:30:35,320 THE ORGANIZERS FOR THE 2079 01:30:35,320 --> 01:30:37,880 INVITATION TO SPEAK TODAY AND 2080 01:30:37,880 --> 01:30:40,040 AS MENTIONED, WE ARE FOCUSED 2081 01:30:40,040 --> 01:30:45,760 ON USING THE MOUSE MODEL FOR 2082 01:30:45,760 --> 01:30:48,280 HIGHLY EFFECTIVE MODULATOR 2083 01:30:48,280 --> 01:30:49,440 THERAPY. 2084 01:30:49,440 --> 01:30:51,160 SOME OF THE ADVANTAGES SHOWN 2085 01:30:51,160 --> 01:30:53,000 HERE IN THIS SLIDE, THE 2086 01:30:53,000 --> 01:30:55,320 ABILITY TO CONTROL MOST 2087 01:30:55,320 --> 01:31:00,600 CONDITIONS WITH A 2088 01:31:00,600 --> 01:31:01,280 DISTINCTIVELY GENETIC 2089 01:31:01,280 --> 01:31:03,400 BACKGROUND, A SHORT TIME TO 2090 01:31:03,400 --> 01:31:07,480 SEXUAL MAT TUTOR, PRODUCING 2091 01:31:07,480 --> 01:31:09,760 MANY GENETICALLY IDENTICAL 2092 01:31:09,760 --> 01:31:12,720 OFFSPRING, A FULLY SEQUENCED 2093 01:31:12,720 --> 01:31:13,040 GENOME. 2094 01:31:13,040 --> 01:31:16,760 AND AS FAR AS THE MOUSE AS A 2095 01:31:16,760 --> 01:31:21,840 MODEL FOR CYSTIC FIBROSIS, THE 2096 01:31:21,840 --> 01:31:25,840 PHENOTYPE SHOWS THE ASPECTS OF 2097 01:31:25,840 --> 01:31:27,880 ALMOST EVERY PHENOTYPE OF THE 2098 01:31:27,880 --> 01:31:29,120 DISEASE. 2099 01:31:29,120 --> 01:31:38,480 WHILE IN LATE STAGE, ONE OF 2100 01:31:38,480 --> 01:31:46,280 THE DISEASES IS NOT OBSERVED 2101 01:31:46,280 --> 01:31:50,040 IN THE MICE WITH LUNG DISEASE 2102 01:31:50,040 --> 01:32:00,560 BUT THERE ARE SIMILAR SO THE 2103 01:32:06,520 --> 01:32:08,160 MAIN QUESTION HERE TODAY IS 2104 01:32:08,160 --> 01:32:13,720 ARE MICE USEFUL IN THE STUDY 2105 01:32:13,720 --> 01:32:14,560 OF CFTR MODULATORS? 2106 01:32:14,560 --> 01:32:16,440 THE FIRST POINT I WANT TO MAKE 2107 01:32:16,440 --> 01:32:19,120 IS HUMAN AND MOUSE CFTR ARE 2108 01:32:19,120 --> 01:32:20,240 NOT IDENTICAL. 2109 01:32:20,240 --> 01:32:22,320 SO ON THE GENE LEVEL, THEY 2110 01:32:22,320 --> 01:32:26,000 HAVE A 82 PERCENT SEQUENCE 2111 01:32:26,000 --> 01:32:27,600 THAT IS IDENTICAL IN THE 2112 01:32:27,600 --> 01:32:28,720 CODING REGION. 2113 01:32:28,720 --> 01:32:32,120 FROM THE HUMAN STANDPOINT, 2114 01:32:32,120 --> 01:32:36,960 AMINO AS SAID IS 78 PERCENT 2115 01:32:36,960 --> 01:32:37,760 SIMILAR. 2116 01:32:37,760 --> 01:32:43,760 SO IS IT ENOUGH IN THE MOUSE? 2117 01:32:43,760 --> 01:32:48,480 SOME STUDIES SHOW THAT IT DOES 2118 01:32:48,480 --> 01:32:50,320 NOT POTENTIATE THE CFTR. 2119 01:32:50,320 --> 01:32:53,880 THERE IS ONE STUDY, AND THERE 2120 01:32:53,880 --> 01:33:00,440 ARE MANY BUT LOOKING AT THE 2121 01:33:00,440 --> 01:33:06,680 CFTR CELLS, HUMOR MOUSE, THE 2122 01:33:06,680 --> 01:33:17,240 STRONGEST RESPONSE FROM HUMAN 2123 01:33:18,080 --> 01:33:20,000 FACTORS. 2124 01:33:20,000 --> 01:33:20,920 AND GENISTEIN CONTROLLED THIS 2125 01:33:20,920 --> 01:33:22,840 VERY WELL. 2126 01:33:22,840 --> 01:33:30,880 ON THE OTHER HAND, WE FOUND 15 2127 01:33:30,880 --> 01:33:34,240 CORRECT TORSION RESCUED HUMAN 2128 01:33:34,240 --> 01:33:35,680 AND MOUSE CFTR. 2129 01:33:35,680 --> 01:33:39,760 HOWEVER TESTING THE HUMAN TO 2130 01:33:39,760 --> 01:33:41,840 MOUSE CFTRS HAVE BEEN 2131 01:33:41,840 --> 01:33:43,240 OVEREXPRESSING RATHER THAN 2132 01:33:43,240 --> 01:33:45,760 USING PRIMARY CELLS IN THE 2133 01:33:45,760 --> 01:33:46,080 MOUSE. 2134 01:33:46,080 --> 01:33:50,080 MY LAB HAS BEEN INTERESTED IN 2135 01:33:50,080 --> 01:33:58,680 USING THE CFTR MODULATORS AND 2136 01:33:58,680 --> 01:34:02,840 INTESTINAL ORGANISMS. 2137 01:34:02,840 --> 01:34:03,920 CFTR IS PREDOMINANTLY 2138 01:34:03,920 --> 01:34:08,120 EXPRESSED AT THE APICAL POINT 2139 01:34:08,120 --> 01:34:12,760 OF THE STEM CELLS WHERE 2140 01:34:12,760 --> 01:34:20,360 FORSKOLIN DRIVES THE SECRETION 2141 01:34:20,360 --> 01:34:25,160 AND IF CFTR IS NOT EMPHASIZED, 2142 01:34:25,160 --> 01:34:26,640 NO EXPRESSION IS OBSERVED. 2143 01:34:26,640 --> 01:34:30,720 I AM GIVING AN EXAMINER HERE 2144 01:34:30,720 --> 01:34:34,680 OF NONCF ANIMALS AND ABOUT 2145 01:34:34,680 --> 01:34:37,400 FORSKOLIN IS ADDED, YOU CAN 2146 01:34:37,400 --> 01:34:39,600 SEE THAT THEY SWELL LIKE 2147 01:34:39,600 --> 01:34:40,000 BALLOONS. 2148 01:34:40,000 --> 01:34:41,240 THIS HAPPENS VERY QUICKLY, 2149 01:34:41,240 --> 01:34:43,520 LIKE IN TEN MINUTES AND WE CAN 2150 01:34:43,520 --> 01:34:45,280 MEASURE HOW MUCH THEY EXPAND. 2151 01:34:45,280 --> 01:34:47,560 AND WHEN WE DO THAT, WE GET A 2152 01:34:47,560 --> 01:34:50,600 FIGURE LIKE THIS IN WHICH THE 2153 01:34:50,600 --> 01:34:52,240 PERCENT AREA NORMALIZED IS 2154 01:34:52,240 --> 01:34:54,840 INCREASING OVER TIME. 2155 01:34:54,840 --> 01:35:02,320 THIS FIGURE SHOWS ADULT F508 2156 01:35:02,320 --> 01:35:03,240 MOUSE EMULATERS AND WHAT YOU 2157 01:35:03,240 --> 01:35:07,360 WILL SEE IS THE NO TREATMENT 2158 01:35:07,360 --> 01:35:09,280 AND THE VX-'70 GROUP ARE 2159 01:35:09,280 --> 01:35:13,240 IDENTICAL SUGGESTING THAT YES, 2160 01:35:13,240 --> 01:35:15,520 MICE WHO DON'T HAVE THE 2161 01:35:15,520 --> 01:35:22,240 SYMPTOMS DON'T RESPOND TO THE 2162 01:35:22,240 --> 01:35:25,800 THERAPY, HOWEVER THERE IS A 2163 01:35:25,800 --> 01:35:33,200 RESULT FROM THE VX-445 AND 661 2164 01:35:33,200 --> 01:35:33,640 ABOVE. 2165 01:35:33,640 --> 01:35:36,040 AND USING BOTH CORRECT TORSION 2166 01:35:36,040 --> 01:35:40,280 ON THE MOUSE HAVE BEEN 2167 01:35:40,280 --> 01:35:41,160 OBSERVED. 2168 01:35:41,160 --> 01:35:43,560 SO DOES CFTR MODULATORS WORK 2169 01:35:43,560 --> 01:35:49,520 ON THE MOUSE CFTR? 2170 01:35:49,520 --> 01:35:49,760 YES. 2171 01:35:49,760 --> 01:35:53,760 BUT THERE IS DIFFERENCES IN 2172 01:35:53,760 --> 01:35:54,080 GATING. 2173 01:35:54,080 --> 01:35:56,800 CORRECT TORSION HAVE A VERY 2174 01:35:56,800 --> 01:35:57,520 SIMILAR RESPONSIVENESS IN 2175 01:35:57,520 --> 01:36:01,440 HUMANS BUT WHAT ABOUT THE 2176 01:36:01,440 --> 01:36:03,720 OTHER CFTR MODULATORS? 2177 01:36:03,720 --> 01:36:11,640 THIS MAY DEPEND ON THE HUMAN 2178 01:36:11,640 --> 01:36:16,160 PART BUT WE DECIDE TO BUILD A 2179 01:36:16,160 --> 01:36:18,760 MODEL THAT EXPRESS BOTH MOUSE 2180 01:36:18,760 --> 01:36:19,760 AND HUMAN CFTR. 2181 01:36:19,760 --> 01:36:21,960 WE ACCOMPLISHED THIS WITH A 2182 01:36:21,960 --> 01:36:28,400 RANDOM SEARCH OF THE WHOLE 2183 01:36:28,400 --> 01:36:31,480 258KB HUMAN CFTR GENE THAT WAS 2184 01:36:31,480 --> 01:36:32,880 CONTAINED IN THE ARTIFICIAL 2185 01:36:32,880 --> 01:36:36,440 CHROMOSOME ESPECIALLY SO MANY. 2186 01:36:36,440 --> 01:36:39,080 THIS SHOWS THAT IT WOULD BE 2187 01:36:39,080 --> 01:36:43,040 EXPRESSED IN THE CFTR PROMOTER 2188 01:36:43,040 --> 01:36:49,600 AS WELL AS MOST NONREGULATORY 2189 01:36:49,600 --> 01:36:53,440 FUNCTION. 2190 01:36:53,440 --> 01:36:57,520 SO THE CF MOUSE BACKGROUND, IT 2191 01:36:57,520 --> 01:37:00,840 EXPRESSES THE CFTR IN MAIN 2192 01:37:00,840 --> 01:37:01,920 TISSUES AND DISPLAYS THE 2193 01:37:01,920 --> 01:37:04,960 FUNCTION IN AIRWAY AND 2194 01:37:04,960 --> 01:37:05,360 INTESTINE. 2195 01:37:05,360 --> 01:37:07,960 THIS LEADS US TO CREATE 2196 01:37:07,960 --> 01:37:09,440 SEVERAL HUMAN IMPLEMENTATIONS 2197 01:37:09,440 --> 01:37:15,040 IN HOPES THEY WOULD REACT IN 2198 01:37:15,040 --> 01:37:18,120 VIVO SIMILAR TO HUMANS. 2199 01:37:18,120 --> 01:37:20,160 THE TWO MUTATIONS I WILL TALK 2200 01:37:20,160 --> 01:37:25,880 ABOUT TODAY ARE SHOWN HERE, 2201 01:37:25,880 --> 01:37:34,360 THE HCFTR AND THE HCFTRG551D. 2202 01:37:34,360 --> 01:37:36,840 THAT IS SHOWN HERE. 2203 01:37:36,840 --> 01:37:45,760 WHILE THE WILD TYPE OF HUMAN 2204 01:37:45,760 --> 01:37:47,960 HCFTR SHOWED THE FUNCTION IN 2205 01:37:47,960 --> 01:37:52,080 THE MOUSE, IN THE HUMAN 2206 01:37:52,080 --> 01:37:55,120 MUTATION, IT SHOWED VERY 2207 01:37:55,120 --> 01:37:55,480 LITTLE. 2208 01:37:55,480 --> 01:37:59,840 SO OF COURSE WE WANTED TO USE 2209 01:37:59,840 --> 01:38:03,960 FTA APPROVED DRUGS, VX-770 OR 2210 01:38:03,960 --> 01:38:06,600 661 ON THE MOUSE TO SEE IF WE 2211 01:38:06,600 --> 01:38:09,280 COULD CORRECT THIS HUMAN CFTR 2212 01:38:09,280 --> 01:38:09,800 FUNCTION. 2213 01:38:09,800 --> 01:38:12,240 FIRST WE TESTED THE MODULATORS 2214 01:38:12,240 --> 01:38:17,600 IN VITRO USING THE AFORE 2215 01:38:17,600 --> 01:38:18,880 MENTIONED INTESTINE ORGAN 2216 01:38:18,880 --> 01:38:21,120 MODEL IN THE MICE. 2217 01:38:21,120 --> 01:38:25,040 HERE IS AN EXAMPLE OF THE 2218 01:38:25,040 --> 01:38:28,360 FUNCTION IN THE INTESTINE 2219 01:38:28,360 --> 01:38:30,680 ASSAY AND IF THERE IS NO 2220 01:38:30,680 --> 01:38:32,400 TREATMENT, THESE DO NOT SWELL 2221 01:38:32,400 --> 01:38:38,120 AT ALL EVEN IN A 24-HOUR 2222 01:38:38,120 --> 01:38:38,480 PERIOD. 2223 01:38:38,480 --> 01:38:42,920 HOWEVER IF THEY ARE PUT IN IN 2224 01:38:42,920 --> 01:38:46,160 24 HOURS, THEY DISPLAY 2225 01:38:46,160 --> 01:38:48,600 RESTORED CFTR FUNCTION. 2226 01:38:48,600 --> 01:38:50,480 AND SHOWING HERE HAVING THE 2227 01:38:50,480 --> 01:38:51,480 STRONGEST EFFECT AND WHILE I 2228 01:38:51,480 --> 01:38:52,880 DON'T HAVE TIME TO PRESENT ALL 2229 01:38:52,880 --> 01:38:58,240 OF THE DATA, I CAN SAY THE 2230 01:38:58,240 --> 01:39:03,760 VX-770 WORKS SIMILARLY ON THE 2231 01:39:03,760 --> 01:39:04,760 DEHAO*UPLIZED MOUSE. 2232 01:39:04,760 --> 01:39:08,800 WE THEN SHOW THE HCFTR 2233 01:39:08,800 --> 01:39:11,280 FUNCTION IN THE MOUSE FOR 2234 01:39:11,280 --> 01:39:16,960 THREE DAYS AND IMPROVED 2235 01:39:16,960 --> 01:39:17,760 FUNCTION, USING CHAMBERS FOR 2236 01:39:17,760 --> 01:39:19,280 MICE THAT WERE NOT TREATED IN 2237 01:39:19,280 --> 01:39:22,880 BLACK AND WERE TREATED IN RED. 2238 01:39:22,880 --> 01:39:25,560 SO SHOWN HERE WITH THE ARROW, 2239 01:39:25,560 --> 01:39:32,400 SHOULD INCREASE THE SHORT KIRK 2240 01:39:32,400 --> 01:39:35,760 FUNCTION AND THAT IS WHAT WE 2241 01:39:35,760 --> 01:39:37,080 FOUND HERE. 2242 01:39:37,080 --> 01:39:40,840 WHEN WE ADDED THE HCFTR IN AT 2243 01:39:40,840 --> 01:39:41,920 LEAST FOUR MICE, IT SHOWS THAT 2244 01:39:41,920 --> 01:39:47,240 IT IS VERY STRONG IN WILD TYPE 2245 01:39:47,240 --> 01:39:50,920 MICE, THE HUMAN CFTR MICE WITH 2246 01:39:50,920 --> 01:39:55,880 THE AGAIN BUT NOT MUCH CHANGE 2247 01:39:55,880 --> 01:39:59,560 IN THE VX-770 OR 661 MICE. 2248 01:39:59,560 --> 01:40:01,880 HOWEVER WHEN WE ADD THE 2249 01:40:01,880 --> 01:40:03,440 IMPORTANT MODULATORS, YOU TO 2250 01:40:03,440 --> 01:40:05,000 SEE N INCREASE IN THE FUNCTION 2251 01:40:05,000 --> 01:40:08,720 ALMOST TO THE LEVEL OF THE 2252 01:40:08,720 --> 01:40:09,480 WILD TYPE MICE. 2253 01:40:09,480 --> 01:40:10,960 THIS IS SUGGESTED THESE 2254 01:40:10,960 --> 01:40:14,600 MUTATIONS CAN BE CORRECTED IN 2255 01:40:14,600 --> 01:40:18,160 VIVO USING THIS MODEL. 2256 01:40:18,160 --> 01:40:19,280 NOW, WITH EVERYTHING I HAVE 2257 01:40:19,280 --> 01:40:20,440 SHOWN YOU BEFORE, WE WANTED TO 2258 01:40:20,440 --> 01:40:21,960 ASSESS THE FUNCTION OF THE 2259 01:40:21,960 --> 01:40:22,320 AIRWAY. 2260 01:40:22,320 --> 01:40:25,600 SO WE LOOKED AT THE NASAL 2261 01:40:25,600 --> 01:40:26,560 POTENTIAL DIFFERENCE AND IT 2262 01:40:26,560 --> 01:40:28,600 WAS MEASURED BEFORE AND AFTER 2263 01:40:28,600 --> 01:40:32,240 THE ADDITION OF CHLORIDE-FREE 2264 01:40:32,240 --> 01:40:38,400 SOLUTIONS INCLUDING PORCELAIN 2265 01:40:38,400 --> 01:40:42,480 IN THE MOUTH. 2266 01:40:42,480 --> 01:40:44,120 NONCFTR SHOWED A RESPONSE IN 2267 01:40:44,120 --> 01:40:47,200 THE WILD TYPE AND HCFTR MICE, 2268 01:40:47,200 --> 01:40:48,480 HOWEVER THERE IS NO RESPONSE 2269 01:40:48,480 --> 01:40:51,320 IN THE TWO MUTATED MICE AND 2270 01:40:51,320 --> 01:40:54,960 THIS IS AN IN VIVO ASS AY, I 2271 01:40:54,960 --> 01:40:57,640 WANT TO SAY. 2272 01:40:57,640 --> 01:41:01,160 BUT ONCE THEY WERE TRANSMITTED 2273 01:41:01,160 --> 01:41:04,360 FOR THREE DAYS, WE SEE A 2274 01:41:04,360 --> 01:41:05,960 DIFFERENCE IN THE RESPONSE FOR 2275 01:41:05,960 --> 01:41:07,120 THE CORRECTED DIFFERENCE 2276 01:41:07,120 --> 01:41:10,360 SHOWING THE MICE DO RESPOND IN 2277 01:41:10,360 --> 01:41:11,720 VIVO TO THE MODULATORS. 2278 01:41:11,720 --> 01:41:17,120 SO WE NEED TO KEEP IN MIND 2279 01:41:17,120 --> 01:41:18,880 THERE ARE STILL CONDITIONS NOT 2280 01:41:18,880 --> 01:41:21,160 POINTED OUT IN THE MODULATOR. 2281 01:41:21,160 --> 01:41:28,600 I WOULD ALSO POINT OUT WE HAVE 2282 01:41:28,600 --> 01:41:35,400 CREATED SPLICING MUTATION WITH 2283 01:41:35,400 --> 01:41:39,400 THE F508D EL AND G55 AND 2284 01:41:39,400 --> 01:41:41,120 HOPEFULLY THIS WILL BE 2285 01:41:41,120 --> 01:41:43,240 IMPORTANT IN THE FUTURE OF 2286 01:41:43,240 --> 01:41:46,240 MOUSE MODELS. 2287 01:41:46,240 --> 01:41:49,000 SO NOW TO ANSWER THE QUESTIONS 2288 01:41:49,000 --> 01:41:58,240 USING MOUSE MODELS, WE CAN 2289 01:41:58,240 --> 01:41:59,720 ADDRESS IMPORTANT POINTS. 2290 01:41:59,720 --> 01:42:03,760 ONE IS THAT IT ALLOWS THE 2291 01:42:03,760 --> 01:42:08,800 MOUSE TO DEVELOP OF HUMAN TO 2292 01:42:08,800 --> 01:42:09,120 ADULT. 2293 01:42:09,120 --> 01:42:11,200 THE CF MOUSE SHOWN HERE ARE 2294 01:42:11,200 --> 01:42:13,360 LITTERING FOR THE CF AND A 2295 01:42:13,360 --> 01:42:14,040 NONCF MOUSE. 2296 01:42:14,040 --> 01:42:18,240 THE SMALLER BEING THE CF 2297 01:42:18,240 --> 01:42:18,800 MOUSE. 2298 01:42:18,800 --> 01:42:21,680 HERE IS AN AVERAGE WEIGHT OF 2299 01:42:21,680 --> 01:42:23,680 POPULATION OF MICE FROM DAY 10 2300 01:42:23,680 --> 01:42:25,880 TO 40 BUT WE KNOW THIS 2301 01:42:25,880 --> 01:42:27,080 REDUCTION IN WEIGHT ACTUALLY 2302 01:42:27,080 --> 01:42:32,120 EXTENDS ALL THE WAY BEFORE 2303 01:42:32,120 --> 01:42:33,000 BIRTH IN UTERO. 2304 01:42:33,000 --> 01:42:38,160 WE KNOW IF WE RESTORE THAT 2305 01:42:38,160 --> 01:42:39,560 HALFWAY THROUGH IN THE MOUSE 2306 01:42:39,560 --> 01:42:42,640 MODEL SHOWN HERE IN RED, WE 2307 01:42:42,640 --> 01:42:44,480 CORRECT THIS. 2308 01:42:44,480 --> 01:42:47,560 WILL MODULATORS HAVE THE SAME 2309 01:42:47,560 --> 01:42:51,000 EFFECT ON THE HAO*UPLHUMANIZED 2310 01:42:51,000 --> 01:42:52,440 MOUSE MODEL? 2311 01:42:52,440 --> 01:42:53,880 POTENTIALLY AND NOW WE HAVE 2312 01:42:53,880 --> 01:42:55,360 MORE INFORMATION ON WHAT IT 2313 01:42:55,360 --> 01:42:56,480 WILL CORRECT DURING THE 2314 01:42:56,480 --> 01:42:58,360 LIFETIME OF THE MOUSE. 2315 01:42:58,360 --> 01:43:00,920 AND THE OTHER ASPECT IS MOUSE 2316 01:43:00,920 --> 01:43:03,880 LITTERS WILL BE ABLE TO 2317 01:43:03,880 --> 01:43:07,880 ADDRESS WHETHER THERE IS ANY 2318 01:43:07,880 --> 01:43:08,440 CHANGE IN UTERO. 2319 01:43:08,440 --> 01:43:10,640 THE MOUSE CAN BE USEFUL IN 2320 01:43:10,640 --> 01:43:13,240 STUDYING THIS VERY QUICKLY. 2321 01:43:13,240 --> 01:43:15,800 ALSO WHAT DOES LONG-TERM OF 2322 01:43:15,800 --> 01:43:17,720 MODULATORS LOOK LIKE? 2323 01:43:17,720 --> 01:43:20,600 DOES THIS DECREASE OVER TIME 2324 01:43:20,600 --> 01:43:24,320 WHEN THE CFTR GETS AWAY TO 2325 01:43:24,320 --> 01:43:25,040 TOTAL ABSENCE? 2326 01:43:25,040 --> 01:43:32,800 THE MOUSE HAS A 2-YEAR 2327 01:43:32,800 --> 01:43:35,120 LIFESPAN, THEY ARE LESS 2328 01:43:35,120 --> 01:43:36,800 EXPENSIVE AND QUITE SMALL 2329 01:43:36,800 --> 01:43:40,280 COMPARED TO OTHER ANIMAL 2330 01:43:40,280 --> 01:43:40,640 PATIENTS. 2331 01:43:40,640 --> 01:43:41,960 ANOTHER QUESTION IS WHAT IS 2332 01:43:41,960 --> 01:43:46,160 THE EFFECT OF THE MODULATORS 2333 01:43:46,160 --> 01:43:47,640 ON INTESTINAL SYMPTOMS. 2334 01:43:47,640 --> 01:43:50,800 DATA SHOWING AFTER SIX MONTHS, 2335 01:43:50,800 --> 01:43:53,600 THE PATIENT SHOWED NO CLINICAL 2336 01:43:53,600 --> 01:43:55,840 CHANGE IN SYMPTOMS SUGGESTING 2337 01:43:55,840 --> 01:43:58,840 WHILE LUNG FUNCTIONS IMPROVE, 2338 01:43:58,840 --> 01:44:01,120 THE GI SYMPTOMS MAY HAVE 2339 01:44:01,120 --> 01:44:04,040 LITTLE TOLL NO IMPACT. 2340 01:44:04,040 --> 01:44:05,640 THE MOUSE MAKES THIS A GOOD 2341 01:44:05,640 --> 01:44:08,720 MODEL FOR TESTING AND ONE LAST 2342 01:44:08,720 --> 01:44:12,600 QUESTION WE MIGHT BE ABLE TO 2343 01:44:12,600 --> 01:44:14,560 ASSIST WITH CONCERNING THE 2344 01:44:14,560 --> 01:44:16,880 IMPACT OF MODULATORS IS WHAT I 2345 01:44:16,880 --> 01:44:19,880 CALL THE UNDER STUDIED MAN 2346 01:44:19,880 --> 01:44:21,400 TESTATIONS AND THESE ARE VERY 2347 01:44:21,400 --> 01:44:21,760 IMPORTANT. 2348 01:44:21,760 --> 01:44:26,800 ONE EXAMPLE IS SLEEP. 2349 01:44:26,800 --> 01:44:30,440 FOR CLINICIIANS WHO ARE 2350 01:44:30,440 --> 01:44:31,760 STUDYING PATIENTS WITH CF, 2351 01:44:31,760 --> 01:44:38,560 THEY KNOW THERE IS A SLEEP 2352 01:44:38,560 --> 01:44:40,080 DISRUPTION. 2353 01:44:40,080 --> 01:44:41,520 SOME OF MY COLLEAGUES THAT 2354 01:44:41,520 --> 01:44:44,160 HEAR THE CASE HYPOTHESIZE THAT 2355 01:44:44,160 --> 01:44:46,840 LOSS OF CFTR CAUSES THE 2356 01:44:46,840 --> 01:44:47,920 DISRUPTION OF THE GENE 2357 01:44:47,920 --> 01:44:48,560 EXPRESSION REGULATION AND 2358 01:44:48,560 --> 01:44:51,040 FOUND THIS WAS INDEED THE CASE 2359 01:44:51,040 --> 01:44:51,920 IN CF MICE. 2360 01:44:51,920 --> 01:44:55,760 THEY HAVE EXPANDED ON THIS 2361 01:44:55,760 --> 01:44:58,960 INITIAL SUBJECT AND FOUND THAT 2362 01:44:58,960 --> 01:45:02,760 SIMILAR TO CF PATIENTS, THE 2363 01:45:02,760 --> 01:45:04,040 MICE SHOWED ALTERED SLEEP 2364 01:45:04,040 --> 01:45:04,360 PARTIES. 2365 01:45:04,360 --> 01:45:08,040 HERE IS SOME OF THE DATA THAT 2366 01:45:08,040 --> 01:45:12,760 HAS NOT BEEN PUBLISHED YET, SO 2367 01:45:12,760 --> 01:45:18,520 WITH THE CF MOUSE OVER 14 2368 01:45:18,520 --> 01:45:19,920 DAYS, THE CYCLES INDICATED 2369 01:45:19,920 --> 01:45:22,440 HERE BY THE WHITE AND THE 2370 01:45:22,440 --> 01:45:24,560 BLACK MARK. 2371 01:45:24,560 --> 01:45:27,600 THE PLAQUE LINES ARE THE 2372 01:45:27,600 --> 01:45:29,120 ACTIVITY IN THE MOUSE DURING 2373 01:45:29,120 --> 01:45:30,600 THE SAY. 2374 01:45:30,600 --> 01:45:33,320 SINCE THEY ARE NOT TURN, YOU 2375 01:45:33,320 --> 01:45:37,320 WILL SEE LESS ACTIVITY IN THE 2376 01:45:37,320 --> 01:45:37,640 DARK. 2377 01:45:37,640 --> 01:45:39,040 HOWEVER, ACTIVITY IS LESS 2378 01:45:39,040 --> 01:45:41,120 CONTAINED IN THE DARK CYCLE 2379 01:45:41,120 --> 01:45:42,960 AND STARTS BEFORE THE DARK 2380 01:45:42,960 --> 01:45:45,160 CYCLE IS OVER SHOWN HERE. 2381 01:45:45,160 --> 01:45:47,600 IN ADDITION, WHEN THE MICE ARE 2382 01:45:47,600 --> 01:45:50,000 SWITCHED TO A CONSTANT DARK 2383 01:45:50,000 --> 01:45:53,000 CYCLE INDICATED BY ONE DARK 2384 01:45:53,000 --> 01:46:01,000 BLACK BAR, THE NORMAL PART 2385 01:46:01,000 --> 01:46:03,160 PATTERN DECREASED THEIR 2386 01:46:03,160 --> 01:46:04,600 ACTIVITY AND SHORTENED THEIR 2387 01:46:04,600 --> 01:46:05,360 CYCLE. 2388 01:46:05,360 --> 01:46:09,560 BUT THE DELTA F MICE HAVE A 2389 01:46:09,560 --> 01:46:12,600 DIFFERENT OUTCOME AND THAT IS 2390 01:46:12,600 --> 01:46:14,800 SHOWN HERE ON THE RIGHT. 2391 01:46:14,800 --> 01:46:19,280 TO SEE THE CIRCADIAN RHYTHM 2392 01:46:19,280 --> 01:46:22,320 CORRECTED BY THE MODERATE 2393 01:46:22,320 --> 01:46:30,160 LATER, THE ABILITY TO CONTROL 2394 01:46:30,160 --> 01:46:37,680 THE MICE SHOULD ACCELERATE AND 2395 01:46:37,680 --> 01:46:38,200 FACILITATE RESEARCH. 2396 01:46:38,200 --> 01:46:40,200 I WOULD LIKE TO THANK AND 2397 01:46:40,200 --> 01:46:41,120 ACKNOWLEDGE ALL THE PEOPLE 2398 01:46:41,120 --> 01:46:44,400 INVOLVED IN THE RESEARCH AND 2399 01:46:44,400 --> 01:46:50,400 IF YOU ARE INTERESTED IN MORE 2400 01:46:50,400 --> 01:46:53,480 INFORMATION, PLEASE CONTACT 2401 01:46:53,480 --> 01:46:53,720 ME. 2402 01:46:53,720 --> 01:47:04,160 THANK YOU VERY MUCH. 2403 01:47:09,800 --> 01:47:10,600 >> OKLAHOMA, SHALL REMOVE ON 2404 01:47:10,600 --> 01:47:12,160 TO THE NEXT TALK? 2405 01:47:12,160 --> 01:47:12,960 THANK YOU, CRAIG. 2406 01:47:12,960 --> 01:47:20,000 SO OUR NEXT SPEAKER IS SUSAN 2407 01:47:20,000 --> 01:47:21,920 BIRKET AND WHILE I DON'T HAVE 2408 01:47:21,920 --> 01:47:24,160 HER TITLE, WE KNOW SHE WILL BE 2409 01:47:24,160 --> 01:47:27,840 SPEAKING TO US ABOUT THE MOUSE 2410 01:47:27,840 --> 01:47:28,160 MODEL. 2411 01:47:28,160 --> 01:47:38,520 PLEASE PROCEED. 2412 01:47:39,400 --> 01:47:49,640 >> THANK YOU. 2413 01:47:59,280 --> 01:48:01,720 ITCH MY OWN SLIDES IF YOU NEED 2414 01:48:01,720 --> 01:48:05,000 ME TO. 2415 01:48:05,000 --> 01:48:05,560 >> NO, WE'RE GOOD. 2416 01:48:05,560 --> 01:48:07,960 >> SO THANK YOU FOR HAVING ME 2417 01:48:07,960 --> 01:48:10,520 TO TALK ABOUT THE RAT MODELS 2418 01:48:10,520 --> 01:48:15,320 FOR HIGHLY EFFECTIVE MODULATOR 2419 01:48:15,320 --> 01:48:16,040 THERAPY. 2420 01:48:16,040 --> 01:48:17,840 NEXT SLIDE. 2421 01:48:17,840 --> 01:48:20,840 SO THE RAT AS A MODEL OF CF 2422 01:48:20,840 --> 01:48:22,840 AIRWAY DISEASE WAS GENUINE 2423 01:48:22,840 --> 01:48:25,160 RAPED BACK IN 2011. 2424 01:48:25,160 --> 01:48:28,400 THE RAT SPECIES HAS SEVERAL 2425 01:48:28,400 --> 01:48:28,960 ADVANTAGES. 2426 01:48:28,960 --> 01:48:31,120 THEY ARE LARGER AND LIVE A 2427 01:48:31,120 --> 01:48:33,280 LITTLE LONGER THAN MOUSE WHICH 2428 01:48:33,280 --> 01:48:36,480 ENABLE A LONGER STUDY. 2429 01:48:36,480 --> 01:48:42,840 IT ENABLES INDEPTH OF THEERAPY 2430 01:48:42,840 --> 01:48:45,280 AND TESTING AND THE 2431 01:48:45,280 --> 01:48:45,960 TRADITIONAL MODELS INCLUDING 2432 01:48:45,960 --> 01:48:46,960 IN THE LUNG WHICH MEANS THERE 2433 01:48:46,960 --> 01:48:49,200 IS A WEALTH OF DATA FROM 2434 01:48:49,200 --> 01:48:53,320 DECADES AGO ABOUT SORT OF THE 2435 01:48:53,320 --> 01:48:54,840 BASELINE EFFECT OF THE WILD 2436 01:48:54,840 --> 01:48:59,520 TYPE BUT ALSO MEAN THERE IS AN 2437 01:48:59,520 --> 01:49:04,240 ABUNDANCE OF ANTIBEEN ODIES TO 2438 01:49:04,240 --> 01:49:06,240 USE IN THE CONDUCTOR STUDIES. 2439 01:49:06,240 --> 01:49:10,200 IT IS VERY EASY TO MOVE BACK 2440 01:49:10,200 --> 01:49:17,360 AND FORTH BETWEEN 2441 01:49:17,360 --> 01:49:18,480 FIREMANACALOGICAL AND 2442 01:49:18,480 --> 01:49:20,160 TOXICOLOGY STUDIES AS WE MOVE 2443 01:49:20,160 --> 01:49:21,760 FORWARD WITH THE NOVEL 2444 01:49:21,760 --> 01:49:22,480 STUDIES. 2445 01:49:22,480 --> 01:49:26,080 SO WE INITIATED THIS MODEL 2446 01:49:26,080 --> 01:49:31,040 WITH THE CF KNOCKOUT NULL 2447 01:49:31,040 --> 01:49:35,160 WHICH HAS THE EXPRESSION AND 2448 01:49:35,160 --> 01:49:43,920 LEADS TO A STOP IN EXON4 AND 2449 01:49:43,920 --> 01:49:44,640 5. 2450 01:49:44,640 --> 01:49:45,520 NEXT SLIDE. 2451 01:49:45,520 --> 01:49:48,800 SO WE FOCUSED OUR STUDIES 2452 01:49:48,800 --> 01:49:52,880 PRIMARILY ON THE LUNG AND THE 2453 01:49:52,880 --> 01:49:53,960 MANIFESTATION OF MUCOUS 2454 01:49:53,960 --> 01:49:57,040 ABNORMALITY AS THE RAT AGES. 2455 01:49:57,040 --> 01:49:59,080 WE FOCUSED OR STUDY PRIMARILY 2456 01:49:59,080 --> 01:50:02,440 ON TRANSPORT OF THE LARGE 2457 01:50:02,440 --> 01:50:04,240 AIRWAYS AND WHAT WE FOUND WAS 2458 01:50:04,240 --> 01:50:07,360 THAT AT UP WITH MONTH OF AGE, 2459 01:50:07,360 --> 01:50:15,440 THE WILD TYPE AND CF RAT ARE 2460 01:50:15,440 --> 01:50:16,160 VERY DISSIMILAR. 2461 01:50:16,160 --> 01:50:18,520 AS WE MOVE TO THREE MONTHS OF 2462 01:50:18,520 --> 01:50:20,240 AGE IN THE MIDDLE OF THE 2463 01:50:20,240 --> 01:50:22,840 GRAPH, YOU CAN SEE THE CF IN 2464 01:50:22,840 --> 01:50:25,280 THE RED SCARE THAT SEPARATES 2465 01:50:25,280 --> 01:50:28,600 FROM THE WILD TYPE A EFFECTIVE 2466 01:50:28,600 --> 01:50:31,000 IN TRANSPORT AND BY SIX MONTHS 2467 01:50:31,000 --> 01:50:34,000 OF AGE, IT HAS AIRWAYS 2468 01:50:34,000 --> 01:50:35,840 SEVERELY DELAYED AT SIX MONTHS 2469 01:50:35,840 --> 01:50:46,320 OF AGE AS WELL AS HIGHLY 2470 01:50:48,640 --> 01:50:49,240 DEFECTIVE. 2471 01:50:49,240 --> 01:50:53,760 SO WE LOOK AT THE RED STAGE 2472 01:50:53,760 --> 01:50:55,320 INDICATED BY RED ARROWS. 2473 01:50:55,320 --> 01:50:57,840 MANY OF OUR STUDIES START AT 2474 01:50:57,840 --> 01:51:00,360 TWO MONTHS OF AGE AND PROGRESS 2475 01:51:00,360 --> 01:51:02,760 TO SIX MONTHS OF AGE IN WHICH 2476 01:51:02,760 --> 01:51:07,760 THE MUCOUS IS VERY STATIC AND 2477 01:51:07,760 --> 01:51:08,080 EVASIVE. 2478 01:51:08,080 --> 01:51:08,480 NEXT SLIDE. 2479 01:51:08,480 --> 01:51:10,280 SO ONE OF THE PRIMARY OUTCOMES 2480 01:51:10,280 --> 01:51:12,440 THAT WE HAVE LOOKED AT IS 2481 01:51:12,440 --> 01:51:19,680 INFECTION IN THE LUNG AND WE 2482 01:51:19,680 --> 01:51:22,800 STARTED WHEN WE INFECTED 2483 01:51:22,800 --> 01:51:26,120 KNOCKOUT RATS AT TWO MONTHS OF 2484 01:51:26,120 --> 01:51:28,960 AGE, WE SEE HIGH RATES OF 2485 01:51:28,960 --> 01:51:30,240 INFECTION, NO DIFFERENCE. 2486 01:51:30,240 --> 01:51:37,520 BY DAY 7 OF INFECTION, THE 2487 01:51:37,520 --> 01:51:39,400 CFES HAVE SIGNIFICANTLY 2488 01:51:39,400 --> 01:51:45,880 INCREASED IN THE WILD TYPE. 2489 01:51:45,880 --> 01:51:48,880 AT TWO MONTHS OF AGE, HAVE 2490 01:51:48,880 --> 01:51:51,720 CLEAR LUNGS BY DAY 28 2491 01:51:51,720 --> 01:51:52,920 INDICATING WHATEVER EFFECTS 2492 01:51:52,920 --> 01:51:56,920 THE LUNGS WERE SUBJECTED TO, 2493 01:51:56,920 --> 01:51:58,720 THE INFECTION TOTALLY RESOLVED 2494 01:51:58,720 --> 01:52:00,400 BY THE END OF THE EXPERIMENT. 2495 01:52:00,400 --> 01:52:03,120 ON THE RIGHTHAND SIDE OF THE 2496 01:52:03,120 --> 01:52:04,640 SLIDE, WE SEE A DIFFERENCE 2497 01:52:04,640 --> 01:52:06,840 WHEN RATS ARE INFECTED AT SIX 2498 01:52:06,840 --> 01:52:07,880 MONTHS OF AGE. 2499 01:52:07,880 --> 01:52:15,160 AS MENTIONED THE DOTTED LINE 2500 01:52:15,160 --> 01:52:25,120 INDICATES THE CURRICULUM, AT 2501 01:52:25,120 --> 01:52:29,680 AGE 9, DAY 7, IT HAS 2502 01:52:29,680 --> 01:52:36,720 COMPLETELY REMOVED THE 2503 01:52:36,720 --> 01:52:38,280 INFECTION. 2504 01:52:38,280 --> 01:52:41,280 DAY 28, THE CF IN THE LUNG IS 2505 01:52:41,280 --> 01:52:43,720 EQUAL TO THE KNOCKOUT. 2506 01:52:43,720 --> 01:52:46,760 SO IF YOU LOOK AT THE 2507 01:52:46,760 --> 01:52:48,760 HISTOLOGY BELOW, YOU CAN SEE 2508 01:52:48,760 --> 01:52:51,240 THE WILD TYPE HAS CLEAR BONES 2509 01:52:51,240 --> 01:52:54,120 END KATE HILLARY CLINTON ANY 2510 01:52:54,120 --> 01:52:58,320 DAMAGE BUT THE KNOCKOUTS 2511 01:52:58,320 --> 01:52:59,120 SPECIFICALLY DEVELOP 2512 01:52:59,120 --> 01:53:01,320 AATTACHMENTS AND BY DAY 28, WE 2513 01:53:01,320 --> 01:53:06,920 CAN SEE THE SMALL AREAS THAT 2514 01:53:06,920 --> 01:53:07,760 COMPLETELY OCCLUDED. 2515 01:53:07,760 --> 01:53:08,200 NEXT SLIDE. 2516 01:53:08,200 --> 01:53:12,000 SO HOW CAN WE USE THIS. 2517 01:53:12,000 --> 01:53:13,480 >> Moderator: DEL TO PREDICT 2518 01:53:13,480 --> 01:53:17,240 THE PATIENT'S RESPONSE TO 2519 01:53:17,240 --> 01:53:17,680 THERAPEUTICS? 2520 01:53:17,680 --> 01:53:23,240 WE WANTED TO KNOW IF CFR WOULD 2521 01:53:23,240 --> 01:53:25,200 CORRECT IN HUMANS LIKE THE 2522 01:53:25,200 --> 01:53:27,240 MOUSE COULD YOU TELL COMES 2523 01:53:27,240 --> 01:53:28,480 AFFECTED IN THIS MODEL. 2524 01:53:28,480 --> 01:53:35,320 SO TO DO THAT, WE TOOK THE 2525 01:53:35,320 --> 01:53:42,520 HUMAN CFTR WITH THE EXON2, 2526 01:53:42,520 --> 01:53:44,800 INCERTAIN THIS GENE INTO THE 2527 01:53:44,800 --> 01:53:51,760 RAT GENOME SO THIS IS 2528 01:53:51,760 --> 01:53:58,160 ESSENTIALLY A GENE, BEHIND THE 2529 01:53:58,160 --> 01:54:07,280 LOADER AND ANDOGENOUS EXON1 2530 01:54:07,280 --> 01:54:07,720 AND INTRON1. 2531 01:54:07,720 --> 01:54:09,680 WE WENT RIGHT TO THE REPORTS 2532 01:54:09,680 --> 01:54:15,080 THAT IT MAY NOT BE RESPONSIVE 2533 01:54:15,080 --> 01:54:16,160 TO EITHER. 2534 01:54:16,160 --> 01:54:17,160 NEXT SLIDE. 2535 01:54:17,160 --> 01:54:18,640 SO THE DATA THAT I AM 2536 01:54:18,640 --> 01:54:21,360 PRESENTING HERE IN THE SLIDE 2537 01:54:21,360 --> 01:54:27,000 IS PRIMARILY AIR EXPRESSION OF 2538 01:54:27,000 --> 01:54:29,280 HG551D, THE HUMANIZED VERSION. 2539 01:54:29,280 --> 01:54:31,240 WE HAVE ALSO LOOKED AT THE 2540 01:54:31,240 --> 01:54:34,600 CORRECTIONS AND SEE THIS IS A 2541 01:54:34,600 --> 01:54:36,600 GLOBAL INFECTION OF THE 2542 01:54:36,600 --> 01:54:37,280 HUMANIZET GENE. 2543 01:54:37,280 --> 01:54:40,960 AS WE START AT THE TOP LEFT, 2544 01:54:40,960 --> 01:54:44,120 WE LOOKED AT THE MRNA. 2545 01:54:44,120 --> 01:54:47,520 WHEN YOU USE RAT SPECIFIC 2546 01:54:47,520 --> 01:54:52,640 SEQUENCES, WE HAVE VERY LITTLE 2547 01:54:52,640 --> 01:54:55,280 RAT MRNA EXPRESSION IN THE TWO 2548 01:54:55,280 --> 01:54:57,600 COMPARED TO THE WILD TYPE. 2549 01:54:57,600 --> 01:55:02,680 WHEN YOU USE THE HUMAN CORRECT 2550 01:55:02,680 --> 01:55:06,880 TORSION, YOU CAN SEE 2551 01:55:06,880 --> 01:55:07,760 SIGNIFICANT ABUNDANCE COMPARED 2552 01:55:07,760 --> 01:55:11,400 TO THE WILD TYPE AND THE 2553 01:55:11,400 --> 01:55:15,320 KNOCKOUT AND HERE WE CAN SEE 2554 01:55:15,320 --> 01:55:18,360 THE DEFECT EXPRESSES 2555 01:55:18,360 --> 01:55:21,960 APPROXIMATELY AS MUCH 2556 01:55:21,960 --> 01:55:25,720 CFTR MRNA AS THE WILD TYPE 2557 01:55:25,720 --> 01:55:28,840 SPECIFIED TO THE CFTR IN THE 2558 01:55:28,840 --> 01:55:29,200 KNOCKOUT. 2559 01:55:29,200 --> 01:55:31,000 AND AS WE HOOK AT THE 2560 01:55:31,000 --> 01:55:32,240 EXPRESSION, COMPARED TO THE 2561 01:55:32,240 --> 01:55:35,040 WILD TYPE, WE HAVE SIMILAR 2562 01:55:35,040 --> 01:55:42,640 LEVELS OF CFTR EXPRESSION IN 2563 01:55:42,640 --> 01:55:44,040 THE THOSE COMPARED. 2564 01:55:44,040 --> 01:55:47,480 SO WE HAVE IT EXPRESSED 2565 01:55:47,480 --> 01:55:48,600 APPROPRIATELY IN THE CELL 2566 01:55:48,600 --> 01:55:49,880 TYPE. 2567 01:55:49,880 --> 01:55:52,520 WE ALSO LOOKED AT THE TRACHEA 2568 01:55:52,520 --> 01:55:56,080 AND ASSESSED THE CFTR ACTIVITY 2569 01:55:56,080 --> 01:55:59,080 IN THE GRAPH AT THE BOTTOM. 2570 01:55:59,080 --> 01:56:02,880 THE WILD TYPE AT THE TOP, HIGH 2571 01:56:02,880 --> 01:56:04,960 CFTR ACTIVITY AND THE PACE 2572 01:56:04,960 --> 01:56:08,960 LINE STARTING AROUND 350 THAT 2573 01:56:08,960 --> 01:56:10,720 IS PARTIALLY DECREASED IN IT 2574 01:56:10,720 --> 01:56:12,840 THE BLOCK IN THE PANELS AND 2575 01:56:12,840 --> 01:56:15,800 THEN INCREASED BY THE CFTR AND 2576 01:56:15,800 --> 01:56:18,880 YOU CAN SEE ON THE RIGHT SIDE 2577 01:56:18,880 --> 01:56:20,640 THERE ARE HARDLY ANY OR 2578 01:56:20,640 --> 01:56:21,520 MINIMAL EFFECTS. 2579 01:56:21,520 --> 01:56:24,720 IN THE RED SQUARES, WE HAVE 2580 01:56:24,720 --> 01:56:26,320 THE KNOCKOUT RATS THAT START 2581 01:56:26,320 --> 01:56:31,600 VERY LOW AT PACE LINE AND HAVE 2582 01:56:31,600 --> 01:56:33,280 NO CHANGE WHATSOEVER WITH 2583 01:56:33,280 --> 01:56:34,280 EITHER ADDED IN. 2584 01:56:34,280 --> 01:56:39,800 BUT WHEN WE ASSESS THE 2585 01:56:39,800 --> 01:56:46,720 HUMANIZED EXPRESSION, WE SEE 2586 01:56:46,720 --> 01:56:48,560 LOW STARTUP ACTIVITY AT 2587 01:56:48,560 --> 01:56:55,520 BASELINE BUT INCREASED IN A 2588 01:56:55,520 --> 01:56:56,520 DOSE-DEPENDENT MANNER FOR 2589 01:56:56,520 --> 01:56:57,520 EITHER FACTOR. 2590 01:56:57,520 --> 01:56:58,440 NEXT SLIDE. 2591 01:56:58,440 --> 01:57:04,960 AND WHEN WE DOSE THESE RATS 2592 01:57:04,960 --> 01:57:08,400 SYSTEMICALLY FOR 14 DAYS WITH 2593 01:57:08,400 --> 01:57:09,680 VX-770, WE SAW A DIFFERENCE 2594 01:57:09,680 --> 01:57:12,320 AND ABLE TO SEE AN INCREASE IN 2595 01:57:12,320 --> 01:57:14,440 THE ACTIVITY AND THE GRAPH AT 2596 01:57:14,440 --> 01:57:20,040 THE TOP, YOU HAVE THE DELTAS 2597 01:57:20,040 --> 01:57:21,280 FROM BASELINE AND WHEN YOU 2598 01:57:21,280 --> 01:57:23,960 LOOK AT THE SUMMARY DATA, THE 2599 01:57:23,960 --> 01:57:28,720 TWO GRAPHS ON THE BOTTOM, YOU 2600 01:57:28,720 --> 01:57:30,360 CAN SEE UNTREATED IT IS VERY 2601 01:57:30,360 --> 01:57:35,200 LOW COMPARED TO THE WILD TYPE 2602 01:57:35,200 --> 01:57:39,560 AND INCREASES TO ABOUT 2603 01:57:39,560 --> 01:57:41,400 50 PERCENT WILD RAT ACTIVITY. 2604 01:57:41,400 --> 01:57:42,200 NEXT SLIDE. 2605 01:57:42,200 --> 01:57:47,640 AND WE WANTED TO KNOW IF WE 2606 01:57:47,640 --> 01:57:50,440 CAN RESTORE AS SHOWN IN THE 2607 01:57:50,440 --> 01:57:51,080 LAST SLIDE. 2608 01:57:51,080 --> 01:57:59,560 TO DO THAT WE USE 2609 01:57:59,560 --> 01:58:04,720 MICROSPECTOMETRY AND SHOW THE 2610 01:58:04,720 --> 01:58:05,640 TRANSPORT AND VISCOSITY OF THE 2611 01:58:05,640 --> 01:58:08,720 MUSIC CAN YOU SAY. 2612 01:58:08,720 --> 01:58:17,120 BOTH ARE RESTORED IN THE G551D 2613 01:58:17,120 --> 01:58:27,680 AND IN THE BOTTOM SQUARE, THE 2614 01:58:38,480 --> 01:58:39,280 TRANSPORT AND EXPECTORATION 2615 01:58:39,280 --> 01:58:40,600 AFTER THE ADDITION OF 2616 01:58:40,600 --> 01:58:40,960 IVACAFTOR. 2617 01:58:40,960 --> 01:58:41,720 SO WE WANT TO KNOW HOW THIS 2618 01:58:41,720 --> 01:58:52,200 INFLUENCES THE INFECTION 2619 01:59:07,480 --> 01:59:09,000 IN THIS CASE ON THE BOTTOM, WE 2620 01:59:09,000 --> 01:59:12,280 SAW A DECREASE OF CFUs IN THE 2621 01:59:12,280 --> 01:59:14,240 IVACAFTOR-TREATED RATS AND A 2622 01:59:14,240 --> 01:59:15,440 DECREASE OF NEUTROPHILS. 2623 01:59:15,440 --> 01:59:19,160 WE ALSO SAW THAT IN THE 2624 01:59:19,160 --> 01:59:20,360 IVACAFTOR-TREATED RATS, ABOUT 2625 01:59:20,360 --> 01:59:22,680 50% OF THE BACTERIA CONVERTED TO 2626 01:59:22,680 --> 01:59:28,160 A NON-MUCOID PHENOTYPE. 2627 01:59:28,160 --> 01:59:30,840 IN THE CHRONIC INFECTION, WHICH 2628 01:59:30,840 --> 01:59:32,400 ACTUALLY INITIATED -- OH, I'M 2629 01:59:32,400 --> 01:59:34,360 SORRY, THIS IS A PRE-TREATMENT 2630 01:59:34,360 --> 01:59:36,120 INFECTION, WE INITIATED 2631 01:59:36,120 --> 01:59:37,320 IVACAFTOR ABOUT SEVEN DAYS 2632 01:59:37,320 --> 01:59:43,920 BEFORE WITH SACRIFICE AT DAY 14. 2633 01:59:43,920 --> 01:59:46,600 AGAIN WE SAW CFUs, DECREASE 2634 01:59:46,600 --> 01:59:48,000 ALTHOUGH NOT STATISTICALLY IN 2635 01:59:48,000 --> 01:59:53,400 THE PERCENT NEUTROPHILS. 2636 01:59:53,400 --> 01:59:54,600 HERE'S THE CHRONIC INFECTION 2637 01:59:54,600 --> 01:59:56,800 DATA WHERE WE INFECTED AT DAY 2638 01:59:56,800 --> 01:59:58,880 ZERO AND BEGAN TREATMENT AT DAY 2639 01:59:58,880 --> 02:00:01,040 7 WITH SACRIFICE AT DAY 28. 2640 02:00:01,040 --> 02:00:02,040 IN THIS CASE UNFORTUNATELY WE 2641 02:00:02,040 --> 02:00:03,880 DID NOT SEE A DECREASE IN CFUs 2642 02:00:03,880 --> 02:00:06,320 IN THE IVACAFTOR-TREAT THED RATS 2643 02:00:06,320 --> 02:00:12,240 OR DECREASE IN THE PERCENTAGE OF 2644 02:00:12,240 --> 02:00:12,520 NEUTROPHILS. 2645 02:00:12,520 --> 02:00:13,880 SO FROM THIS WORK, WE CAN 2646 02:00:13,880 --> 02:00:15,600 CONCLUDE THAT WE HAVE ACHIEVED 2647 02:00:15,600 --> 02:00:20,120 TARGETED INSERTION OF THE HUME 2648 02:00:20,120 --> 02:00:21,320 NIEZED G551D SEQUENCE WHICH 2649 02:00:21,320 --> 02:00:25,760 APPEARS TO BE EXPRESSED 2650 02:00:25,760 --> 02:00:26,640 APPROPRIATELY TO IVACAFTOR. 2651 02:00:26,640 --> 02:00:34,000 THE TREATMENT CORRECTS CFTR 2652 02:00:34,000 --> 02:00:34,600 CURRENT MUCOCILIARY TRANSPORT 2653 02:00:34,600 --> 02:00:39,560 AND ALTHOUGH IT DOES NOT LEAD TO 2654 02:00:39,560 --> 02:00:40,520 COMPLETE ERADICATION IT DOES 2655 02:00:40,520 --> 02:00:42,080 SEEM TO AMELIORATE THE FORCE OF 2656 02:00:42,080 --> 02:00:43,160 DISEASE. 2657 02:00:43,160 --> 02:00:43,840 FUTURE STUDIES WILL CONTINUE TO 2658 02:00:43,840 --> 02:00:45,040 LOOK AT THIS IN DEPTH TO 2659 02:00:45,040 --> 02:00:47,960 UNDERSTAND IF WE CAN USE HIGHLY 2660 02:00:47,960 --> 02:00:50,520 EFFECTIVE MODULATORS TO CONTINUE 2661 02:00:50,520 --> 02:00:56,160 TO DECREASE INFECTION. 2662 02:00:56,160 --> 02:00:57,520 MOVING FORWARD, SO WE CLEARLY 2663 02:00:57,520 --> 02:01:01,760 HAVE SOME UNMET NEEDS IN THIS 2664 02:01:01,760 --> 02:01:02,920 COMMUNITY AND WE THINK THE RAT 2665 02:01:02,920 --> 02:01:04,040 CAN ADDRESS THESE AS WELL. 2666 02:01:04,040 --> 02:01:06,440 WE'VE CREATED SEVERAL ADDITIONAL 2667 02:01:06,440 --> 02:01:07,880 MODELS OR IN THE PROCESS OF 2668 02:01:07,880 --> 02:01:09,200 CREATING ADDITIONAL MODELS. 2669 02:01:09,200 --> 02:01:12,600 THE FIRST ONE IS A G542X 2670 02:01:12,600 --> 02:01:16,280 MUTATION WHICH IS A POINT 2671 02:01:16,280 --> 02:01:18,080 MUTATION, THIS IS THE RAT GENOME 2672 02:01:18,080 --> 02:01:19,240 BUT IT HAS ONLY THE POINT 2673 02:01:19,240 --> 02:01:22,520 MUTATION SO IT PRESERVES ALL THE 2674 02:01:22,520 --> 02:01:25,280 SEQUENCES SURROUNDING. 2675 02:01:25,280 --> 02:01:27,560 THIS MODEL WILL BE USED TO TEST 2676 02:01:27,560 --> 02:01:29,000 BOTH MODEL AGENTS AND GENE 2677 02:01:29,000 --> 02:01:32,160 REPLACEMENT STRATEGIES MOVING 2678 02:01:32,160 --> 02:01:37,320 FORWARD. 2679 02:01:37,320 --> 02:01:39,080 SO WHAT ARE THE GAPS AND THE 2680 02:01:39,080 --> 02:01:41,240 LONG TERM QUESTIONS THAT THESE 2681 02:01:41,240 --> 02:01:48,160 RAT MODELS CAN HELP ADDRESS. 2682 02:04:54,480 --> 02:04:59,280 [TEST] 2683 02:05:07,600 --> 02:05:11,480 [TEST] 2684 02:07:29,080 --> 02:07:31,280 FOR EXAMPLE, I HAVE 2685 02:07:31,280 --> 02:07:41,640 NON-CORONAVIRUS AND CORONAVIRUSF 2686 02:07:41,640 --> 02:07:44,040 AIRWAYS, ONE CAN INACTIVATE CFTR 2687 02:07:44,040 --> 02:07:45,800 JUST IN THAT CELL TYPE AND STUDY 2688 02:07:45,800 --> 02:07:47,880 DISEASE PROGRESSION OR ONE CAN 2689 02:07:47,880 --> 02:07:49,760 REACTIVATE CFTR WITHIN THOSE 2690 02:07:49,760 --> 02:07:52,840 CELL TYPES ON A CF BACKGROUND 2691 02:07:52,840 --> 02:07:54,880 AND FOR EXAMPLE MODEL A GENETIC 2692 02:07:54,880 --> 02:07:56,440 THERAPY THAT'S TARGETING 2693 02:07:56,440 --> 02:07:58,720 CORRECTION OF CFTR IN EITHER OF 2694 02:07:58,720 --> 02:08:00,120 KNOWS TWO CELL TYPES. 2695 02:08:00,120 --> 02:08:02,080 NOW, TO MOVE ON TO THE RELEVANCE 2696 02:08:02,080 --> 02:08:08,120 OF THESE MODELS TO MODULATE 2697 02:08:08,120 --> 02:08:11,520 THERAPY, WE'VE DEVELOPED A GFF1D 2698 02:08:11,520 --> 02:08:12,840 MODEL IN THE ABSENCE OF 2699 02:08:12,840 --> 02:08:14,560 MODULATOR, IT DEVELOPS AIRWAY 2700 02:08:14,560 --> 02:08:18,000 DISEASE AND GLAND PLUGGING YOU 2701 02:08:18,000 --> 02:08:19,720 MUCH LIKE KNOCKOUT FERRETS AS 2702 02:08:19,720 --> 02:08:23,240 COMPARED TO NORMALS. 2703 02:08:23,240 --> 02:08:25,080 IF THEY'RE MAINTAINED, IT 2704 02:08:25,080 --> 02:08:26,480 PREVENTS LUNG DISEASE AND 2705 02:08:26,480 --> 02:08:28,680 PANCREATIC DISEASE. 2706 02:08:28,680 --> 02:08:30,320 NOW WHEN THESE ANIMALS ARE 2707 02:08:30,320 --> 02:08:33,400 REMOVED FROM MODULATOR, THEY 2708 02:08:33,400 --> 02:08:34,680 BECOME COLONIZED, HERE SHOWN AS 2709 02:08:34,680 --> 02:08:37,160 THE AMOUNT OF BACTERIA BOTH IN 2710 02:08:37,160 --> 02:08:38,720 THE LUNG WHEN THE ANIMALS ARE 2711 02:08:38,720 --> 02:08:43,240 EUTHANIZED ON THE RIGHT, OR THE% 2712 02:08:43,240 --> 02:08:47,160 OF VARIOUS TAXONS WITHIN THE 2713 02:08:47,160 --> 02:08:48,040 LUNG, DIFFERENT TYPES OF 2714 02:08:48,040 --> 02:08:48,480 BACTERIA. 2715 02:08:48,480 --> 02:08:52,080 SO THEY GET COLONIZED WITH TIME, 2716 02:08:52,080 --> 02:08:58,440 AND ON VX770 WE CAN RECOVER 2717 02:08:58,440 --> 02:09:01,400 ABOUT 75% OF CFTR ACTIVITY HERE 2718 02:09:01,400 --> 02:09:04,360 IN GREEN COMPARED TO WILD TYPE. 2719 02:09:04,360 --> 02:09:07,920 NOW, THIS MODEL IS PARTICULARLY 2720 02:09:07,920 --> 02:09:09,360 RELEVANT AND IMPORTANT IN 2721 02:09:09,360 --> 02:09:11,600 STUDYING BOTH THE ONSET AS WELL 2722 02:09:11,600 --> 02:09:14,080 AS THE REVERSIBILITY OF DISEASE 2723 02:09:14,080 --> 02:09:16,560 PROCESSES USING THESE MODULATOR 2724 02:09:16,560 --> 02:09:19,440 THERAPY. 2725 02:09:19,440 --> 02:09:21,160 WE'VE ALSO LEARNED THAT THESE 2726 02:09:21,160 --> 02:09:23,240 ANIMALS AS THEY AGE CAN 2727 02:09:23,240 --> 02:09:27,320 SPONTANEOUSLY ACQUIRE MUCOID 2728 02:09:27,320 --> 02:09:27,600 PSEUDOMONAS. 2729 02:09:27,600 --> 02:09:29,720 THESE ARE MUTATIONS WITHIN 2730 02:09:29,720 --> 02:09:31,680 PSEUDOMONAS THAT OCCUR MOST 2731 02:09:31,680 --> 02:09:34,640 OFTEN WITHIN HUMANS, AND IN THIS 2732 02:09:34,640 --> 02:09:37,080 PARTICULAR CASE, IN THE LUNG 2733 02:09:37,080 --> 02:09:40,200 TISSUE, NEARLY ALL THE BACTERIA 2734 02:09:40,200 --> 02:09:44,280 RESIDENT WITHIN THE CF -- THIS 2735 02:09:44,280 --> 02:09:47,120 IS DELTA F508, WAS PSEUDOMONAS. 2736 02:09:47,120 --> 02:09:51,160 NOW WE CAN STUDY BOTH THE ONSET 2737 02:09:51,160 --> 02:09:55,760 OF DISEASE PROCESSES AS WELL AS 2738 02:09:55,760 --> 02:09:57,400 THE ABILITY OF MODULATORS TO 2739 02:09:57,400 --> 02:09:58,800 REVERSE THOSE PROCESSES AS SHOWN 2740 02:09:58,800 --> 02:09:59,000 HERE. 2741 02:09:59,000 --> 02:10:05,400 THIS IS AN IMAGING OF A WILD 2742 02:10:05,400 --> 02:10:07,240 TYPE TRACHEA, MONITORED OVER 2743 02:10:07,240 --> 02:10:09,760 TIME MOVING UP. 2744 02:10:09,760 --> 02:10:15,320 AND HERE WE'RE COMPARING CF 2745 02:10:15,320 --> 02:10:17,200 FERRETS, EITHER ON MODULATOR 2746 02:10:17,200 --> 02:10:20,360 THAT'S BASELINE OR REMOVED AT 2747 02:10:20,360 --> 02:10:22,360 ONE, TWO OR THREE WEEKS HERE IN 2748 02:10:22,360 --> 02:10:25,520 YELLOW, ORANGE AND PURPLE, AND 2749 02:10:25,520 --> 02:10:26,920 YOU CAN SEE THERE'S A DECLINE IN 2750 02:10:26,920 --> 02:10:29,440 CLEARANCE WITH TIME. 2751 02:10:29,440 --> 02:10:31,600 THEN THESE ANIMALS WERE PUT BACK 2752 02:10:31,600 --> 02:10:32,600 ON MODULATOR, AND YOU CAN SEE 2753 02:10:32,600 --> 02:10:34,600 THIS REVERSE. 2754 02:10:34,600 --> 02:10:37,440 THIS IS JUST QUANTIFYING THAT AS 2755 02:10:37,440 --> 02:10:39,040 PERCENT REMAINING IN THE 2756 02:10:39,040 --> 02:10:39,720 TRACHEA. 2757 02:10:39,720 --> 02:10:41,360 NOW, THIS IS A VERY SHORT 2758 02:10:41,360 --> 02:10:43,440 EXPERIMENT OF ABOUT A MONTH, AND 2759 02:10:43,440 --> 02:10:47,600 IT'S UNCLEAR WHETHER OR NOT THE 2760 02:10:47,600 --> 02:10:48,720 EXTENSIVE DISEASE HERE SEEN IN 2761 02:10:48,720 --> 02:10:50,880 THIS REMODELED CF AIRWAY IS 2762 02:10:50,880 --> 02:10:53,840 REVERSIBLE WITH HIGHLY EFFECTIVE 2763 02:10:53,840 --> 02:10:55,280 MODULATOR THERAPY. 2764 02:10:55,280 --> 02:10:56,560 SO IT WOULD BE IMPOSSIBLE AT 2765 02:10:56,560 --> 02:10:58,960 LEAST FOR ME TO TALK ABOUT THE 2766 02:10:58,960 --> 02:11:00,160 EFFECTIVENESS OF MODULATORS 2767 02:11:00,160 --> 02:11:04,000 WITHOUT TALKING ABOUT PANCREATIC 2768 02:11:04,000 --> 02:11:06,080 DISEASE STATES. 2769 02:11:06,080 --> 02:11:06,840 PANCREATIC INSUFFICIENCY IS 2770 02:11:06,840 --> 02:11:08,880 KNOWN TO LEAD TO CF-RELATED 2771 02:11:08,880 --> 02:11:11,560 DIABETES AND THIS WORSENS LUNG 2772 02:11:11,560 --> 02:11:15,160 FUNCTION, AND WE'VE STUDIED 2773 02:11:15,160 --> 02:11:17,040 PANCREATIC RETENTION AND 2774 02:11:17,040 --> 02:11:19,400 PANCREATIC FUNCTION ON THESE 2775 02:11:19,400 --> 02:11:25,680 TYPES OF MODULATORS IN BOTH THE 2776 02:11:25,680 --> 02:11:27,440 G551D AND IF THEY'RE REMOVED 2777 02:11:27,440 --> 02:11:29,040 FROM THE MODULATOR, DISEASE 2778 02:11:29,040 --> 02:11:30,680 PROGRESSES AND YOU GET THE 2779 02:11:30,680 --> 02:11:32,120 TYPICAL FIBROSIS WITHIN THE 2780 02:11:32,120 --> 02:11:32,360 PANCREAS. 2781 02:11:32,360 --> 02:11:37,480 SO HOW DOES THE AGE OF 2782 02:11:37,480 --> 02:11:39,200 PANCREATITIS ONSET IMPACT THE 2783 02:11:39,200 --> 02:11:40,640 DEVELOPMENT OF CFR D? 2784 02:11:40,640 --> 02:11:41,920 SO WE DID THE FOLLOWING 2785 02:11:41,920 --> 02:11:47,960 EXPERIMENT IN WHICH WE BIRTHED 2786 02:11:47,960 --> 02:11:53,240 G551D FERRETS ON VX770 AND KEPT 2787 02:11:53,240 --> 02:11:55,720 IT ON IT FOR FOUR MONTHS AND 2788 02:11:55,720 --> 02:11:59,240 THEN REMOVED THE VX-770 AND 2789 02:11:59,240 --> 02:12:01,720 FOLLOWED THE GLYCEMIC STATUS 2790 02:12:01,720 --> 02:12:02,360 WITHIN THESE FERRETS. 2791 02:12:02,360 --> 02:12:03,600 WHAT WE SAW WAS THE GROUP THAT 2792 02:12:03,600 --> 02:12:08,120 CAME OFF VX-770 VERY EARLY HAD A 2793 02:12:08,120 --> 02:12:09,520 GLYCEMIC CRISIS THAT IS VERY 2794 02:12:09,520 --> 02:12:11,720 TYPICAL OR IS ALWAYS SEEN WITHIN 2795 02:12:11,720 --> 02:12:13,440 CFTR KNOCKOUT FERRETS BUT THE 2796 02:12:13,440 --> 02:12:14,440 GROUP THAT WAS OLDER WHEN THEY 2797 02:12:14,440 --> 02:12:19,680 CAME OFF VX-770 DID NOT HAVE 2798 02:12:19,680 --> 02:12:20,680 THIS CRISIS. 2799 02:12:20,680 --> 02:12:25,800 THIS IS FAST ONE OUR 2800 02:12:25,800 --> 02:12:26,600 POSTPRANDIAL BUT WHAT YOU CAN 2801 02:12:26,600 --> 02:12:28,320 SEE IS THE GROUP THAT CAME OFF 2802 02:12:28,320 --> 02:12:31,840 LATE PROGRESSED TO THE POINT OF 2803 02:12:31,840 --> 02:12:34,480 WORSE GLUCOSE OR GLUCOSE 2804 02:12:34,480 --> 02:12:40,320 HANDLING AS THEY AGE, AND SO 2805 02:12:40,320 --> 02:12:43,120 FIVE MNTS AF MONTHS AFTER DETERN 2806 02:12:43,120 --> 02:12:44,480 OF THE MODULATOR, ONE CAN SEE 2807 02:12:44,480 --> 02:12:46,160 THE ANIMALS THAT CAME OFF EARLY 2808 02:12:46,160 --> 02:12:48,120 IN LIFE ACTUALLY FAIRED BETTER 2809 02:12:48,120 --> 02:12:52,640 AND WERE CLASSIFIED AS 2810 02:12:52,640 --> 02:12:53,640 INDETERMINANT AS THOSE THAT CAME 2811 02:12:53,640 --> 02:12:55,040 OFF LATER IN LIFE WERE 2812 02:12:55,040 --> 02:12:56,240 CLASSIFIED AS CFR D. 2813 02:12:56,240 --> 02:12:57,440 THESE ARE JUST THE NUMBERS IN 2814 02:12:57,440 --> 02:12:59,200 THOSE VARIOUS GROUPS, SHOWING 2815 02:12:59,200 --> 02:13:02,120 THAT NONE THAT CAME OFF EARLY 2816 02:13:02,120 --> 02:13:05,520 ACTUALLY HAD A CFR D PHENOTYPE. 2817 02:13:05,520 --> 02:13:07,720 SO AGE OF PANCREATIC ONSET 2818 02:13:07,720 --> 02:13:10,360 IMPACTS LONGER TERM ISLET 2819 02:13:10,360 --> 02:13:13,160 FUNCTION AND ACQUISITION OF CFR 2820 02:13:13,160 --> 02:13:17,120 D STATE, AND THE IMPACT OF THESE 2821 02:13:17,120 --> 02:13:18,200 CHANGES ON THE LUNG ARE 2822 02:13:18,200 --> 02:13:19,320 CURRENTLY UNKNOWN BUT WE'RE 2823 02:13:19,320 --> 02:13:20,520 HOPING TO BE ABLE TO ADDRESS 2824 02:13:20,520 --> 02:13:26,320 THIS THROUGH MORE STUDIES. 2825 02:13:26,320 --> 02:13:28,960 ANOTHER -- ANOTHER FINDING THAT 2826 02:13:28,960 --> 02:13:32,880 WE HAD IS THAT WHEN ANIMALS WERE 2827 02:13:32,880 --> 02:13:36,200 REMOVED FROM VX-770 EARLY IN 2828 02:13:36,200 --> 02:13:40,040 LIFE, THERE WAS SIGNIFICANTLY 2829 02:13:40,040 --> 02:13:43,320 INCREASED HEALTH PROBLEMS THAT 2830 02:13:43,320 --> 02:13:45,040 REQUIRED TERMINATION OR REQUIRED 2831 02:13:45,040 --> 02:13:45,960 EUTHANASIA OF THE ANIMALS. 2832 02:13:45,960 --> 02:13:48,000 THIS OCCURRED IN TWO DIFFERENT 2833 02:13:48,000 --> 02:13:48,440 PHASING. 2834 02:13:48,440 --> 02:13:50,640 ONE MORE IMMEDIATE FOLLOWING 2835 02:13:50,640 --> 02:13:52,400 REMOVAL WHICH INVOLVED 2836 02:13:52,400 --> 02:13:54,160 OBSTRUCTION RECTAL PROLAPSE AND 2837 02:13:54,160 --> 02:13:58,480 ANOTHER INVOLVING SEVERE 2838 02:13:58,480 --> 02:13:59,720 ENTERITIS AND ELEVATED LIVER 2839 02:13:59,720 --> 02:14:00,600 FUNCTION TESTS. 2840 02:14:00,600 --> 02:14:05,080 THIS IS JUST AN EXAMPLE OF THE 2841 02:14:05,080 --> 02:14:08,600 ONTOLOGY, SLOUGHING VILLI, 2842 02:14:08,600 --> 02:14:09,760 SIGNIFICANT AMOUNT OF 2843 02:14:09,760 --> 02:14:10,880 INFLAMMATION AND ANIMALS THAT 2844 02:14:10,880 --> 02:14:13,840 HAD THIS PHENOTYPE SUCCUMBED TO 2845 02:14:13,840 --> 02:14:16,240 DISEASE AT THIS TIME POINT HAD 2846 02:14:16,240 --> 02:14:17,880 ELEVATED LIVER FUNCTION TESTS. 2847 02:14:17,880 --> 02:14:20,960 ANOTHER FINDING THAT WE'VE HAD 2848 02:14:20,960 --> 02:14:24,000 IN REARING THESE ANIMALS ON 2849 02:14:24,000 --> 02:14:25,000 VX-770 IS THE FACT THAT 2850 02:14:25,000 --> 02:14:27,160 COMPARING ONES THAT HAD BEEN ON 2851 02:14:27,160 --> 02:14:28,800 IT FOR LIFE OR TERMINATION AT 2852 02:14:28,800 --> 02:14:30,760 ONE MONTH OF AGE, WE CAN SEE 2853 02:14:30,760 --> 02:14:34,040 HERE THAT MOST ANIMALS BUT NOT 2854 02:14:34,040 --> 02:14:38,760 ALL THAT ARE PLAIN TA MAINTAINEE 2855 02:14:38,760 --> 02:14:42,600 ONE TO TWO-MONTH TIME POINT ARE 2856 02:14:42,600 --> 02:14:43,080 PANCREATIC-SUFFICIENT. 2857 02:14:43,080 --> 02:14:44,560 OBVIOUSLY ONCE THEY COME OFF, 2858 02:14:44,560 --> 02:14:46,320 LOSE PANCREATIC FUNCTION, THIS 2859 02:14:46,320 --> 02:14:48,800 IS FECAL LASTASE I'M SHOWING 2860 02:14:48,800 --> 02:14:49,920 HERE BUT IN THIS PARTICULAR 2861 02:14:49,920 --> 02:14:51,120 EXAMPLE, THESE FOUR ANIMALS THAT 2862 02:14:51,120 --> 02:14:54,760 ARE DOWN HERE CLASSIFIED AS 2863 02:14:54,760 --> 02:14:56,120 PANCREATIC-INSUFFICIENT, 2864 02:14:56,120 --> 02:14:56,760 RECOVERED PANCREATIC FUNCTION 2865 02:14:56,760 --> 02:14:59,640 LATER IN LIFE. 2866 02:14:59,640 --> 02:15:04,320 SO IVACAFTOR TREATMENT OF 2867 02:15:04,320 --> 02:15:05,120 HOMOZYGOUS G551D FERRETS ONLY 2868 02:15:05,120 --> 02:15:06,360 PARTIALLY PROTECTS THE PANCREAS. 2869 02:15:06,360 --> 02:15:09,920 I THINK THIS IS IMPORTANT WHEN 2870 02:15:09,920 --> 02:15:10,480 CONSIDERING THAT PARTIAL 2871 02:15:10,480 --> 02:15:11,680 PROTECTION IS PROBABLY ALSO THE 2872 02:15:11,680 --> 02:15:15,280 CASE IN THE LUNG, EVEN IF THESE 2873 02:15:15,280 --> 02:15:19,240 ANIMALS WERE KEPT ON VX- 2874 02:15:19,240 --> 02:15:20,760 770 FOR THEIR ENTIRE LIFE AND IN 2875 02:15:20,760 --> 02:15:21,080 UTERO. 2876 02:15:21,080 --> 02:15:23,560 YOU CAN SEE HERE JUST AREAS OF 2877 02:15:23,560 --> 02:15:27,000 THE PANCREAS THAT HAVE HAD -- 2878 02:15:27,000 --> 02:15:29,840 THAT HAVE LOST CELL MASS. 2879 02:15:29,840 --> 02:15:30,920 ANOTHER ISSUE IS PREGNANCY. 2880 02:15:30,920 --> 02:15:32,480 PREGNANCY IS RISING IN CF 2881 02:15:32,480 --> 02:15:33,400 PATIENTS AND THIS IS PROBABLY 2882 02:15:33,400 --> 02:15:35,400 GOING TO POP UP HERE EVEN MORE. 2883 02:15:35,400 --> 02:15:37,040 WE'RE GOING TO HEAR ABOUT THIS 2884 02:15:37,040 --> 02:15:39,040 LATER IN THE SESSION, BUT WE 2885 02:15:39,040 --> 02:15:41,000 FOUND THAT ANIMALS THAT WERE 2886 02:15:41,000 --> 02:15:46,880 TREATED WITH VX-770 IN UTERO AND 2887 02:15:46,880 --> 02:15:48,640 POSTNATALLY, BOTH -- FOR LIFE 2888 02:15:48,640 --> 02:15:51,280 WERE FERTILE AND COULD GIVE RISE 2889 02:15:51,280 --> 02:15:52,120 TO KITS. 2890 02:15:52,120 --> 02:15:53,920 WE FOUND THAT WE CAN -- THIS IS 2891 02:15:53,920 --> 02:15:58,440 LOOKING AT VX-770 DRUG LEVELS IN 2892 02:15:58,440 --> 02:16:01,880 THE MILK AS THEY'RE NURSING 2893 02:16:01,880 --> 02:16:03,600 THEIR KITS OR IN THEIR BLOOD, 2894 02:16:03,600 --> 02:16:06,920 IT'S ABOUT THREE FOLD LOWER BUT 2895 02:16:06,920 --> 02:16:09,880 CAN REAR KITS DELIVERING THE 2896 02:16:09,880 --> 02:16:12,920 DRUG THROUGH THE JILL'S MILK. 2897 02:16:12,920 --> 02:16:17,320 WE ALSO FOUND OUT THAT G551D 2898 02:16:17,320 --> 02:16:19,600 FERRETS THAT WE WERE AGING FOR 2899 02:16:19,600 --> 02:16:23,320 LUNG DISEASE AND WERE 2900 02:16:23,320 --> 02:16:24,920 PANCREATIC-INSI FUSHT, THEY'D 2901 02:16:24,920 --> 02:16:26,800 COME INTO ESTRUS, WE BRED THEM 2902 02:16:26,800 --> 02:16:30,320 AND FOUND THIS UNIQUE PHENOTYPE 2903 02:16:30,320 --> 02:16:33,080 OF ACUTE FATTY LIVER OF 2904 02:16:33,080 --> 02:16:34,480 PREGNANCY HERE, YOU CAN SEE 2905 02:16:34,480 --> 02:16:36,200 HEPATOCYTES FILLED WITH LIPIDS, 2906 02:16:36,200 --> 02:16:37,640 SIGNIFICANT INFLAMMATION AND 2907 02:16:37,640 --> 02:16:39,200 PLUGGING OF THE BILE DUCTS. 2908 02:16:39,200 --> 02:16:49,680 SO DRAMATIC STEATOSIS COULD BE 2909 02:16:49,960 --> 02:16:54,080 CAUSED BY GALLBLADDER 2910 02:16:54,080 --> 02:16:55,920 DYSFUNCTION, NUTRITIONAL DEMAND 2911 02:16:55,920 --> 02:16:58,440 AND/OR DEFECT IN FAT EE ACID 2912 02:16:58,440 --> 02:16:59,960 OXIDATION CORRELATED WITH LARGER 2913 02:16:59,960 --> 02:17:00,840 LITTERS, WHICH IS IMPORTANT 2914 02:17:00,840 --> 02:17:02,920 BECAUSE THE INCIDENCE OF ACUTE 2915 02:17:02,920 --> 02:17:04,560 FATTY LIVER IN PREGNANCY IS LOW 2916 02:17:04,560 --> 02:17:07,840 IN HUMANS, IT'S HIGHER WHEN 2917 02:17:07,840 --> 02:17:12,320 THERE ARE TWINS IN UTERO. 2918 02:17:12,320 --> 02:17:13,960 THESE NEW PHENOTYPES ARE GOING 2919 02:17:13,960 --> 02:17:15,400 TO BECOME INCREASINGLY IMPORTANT 2920 02:17:15,400 --> 02:17:17,440 IN PATIENT CARE. 2921 02:17:17,440 --> 02:17:18,640 SO THIS BRINGS ME TO MY 2922 02:17:18,640 --> 02:17:21,280 KNOWLEDGE GAPS. 2923 02:17:21,280 --> 02:17:25,680 IS IN UTERO HIGHLY EFFECTIVE 2924 02:17:25,680 --> 02:17:27,200 MODULATOR SAFE AND DOES IT LEAD 2925 02:17:27,200 --> 02:17:29,080 TO GREATER PRESERVATION OF ORGAN 2926 02:17:29,080 --> 02:17:31,480 FUNCTION POST-NATALLY IN THE 2927 02:17:31,480 --> 02:17:33,120 MULTIPLE ORGANS AFFECTED IN CF? 2928 02:17:33,120 --> 02:17:34,840 WHAT ARE THE LONG TERM CON 2929 02:17:34,840 --> 02:17:38,000 QENSES OF CONTINUOUS TURNOVER OF 2930 02:17:38,000 --> 02:17:39,880 EXOCRINE PANCREATIC CELLS WHILE 2931 02:17:39,880 --> 02:17:40,800 ON THERAPY? 2932 02:17:40,800 --> 02:17:43,080 DOES THIS ENHANCE LUNG 2933 02:17:43,080 --> 02:17:46,360 INFLAMMATION DUE TO S SECRETED 2934 02:17:46,360 --> 02:17:49,280 CYTOKINES, DOES IT PREDISPOSE TO 2935 02:17:49,280 --> 02:17:50,600 DIABETES, EVEN PANCREATIC 2936 02:17:50,600 --> 02:17:50,920 CANCER? 2937 02:17:50,920 --> 02:17:55,440 AND SHOULD WE BE THINKING MORE 2938 02:17:55,440 --> 02:17:56,200 AGGRESSIVELY ABOUT THERAPIES 2939 02:17:56,200 --> 02:17:58,360 THAT SHOULD BE USED IN 2940 02:17:58,360 --> 02:18:01,440 CONJUNCTION WITH HIGHLY 2941 02:18:01,440 --> 02:18:04,400 EFFECTIVE MODULATOR THERAPY IF 2942 02:18:04,400 --> 02:18:06,680 THEY'RE REALLY JUST PARTIALLY 2943 02:18:06,680 --> 02:18:07,920 EFFECTIVE, EITHER 2944 02:18:07,920 --> 02:18:09,560 PROPHYLACTICALLY OR DURING VIRAL 2945 02:18:09,560 --> 02:18:11,520 EX-EXACERBATIONS, FOR EXAMPLE. 2946 02:18:11,520 --> 02:18:13,760 SO I'LL END THERE. 2947 02:18:13,760 --> 02:18:17,560 AND I'D LIKE TO THANK -- THIS 2948 02:18:17,560 --> 02:18:19,040 TYPE OF RESEARCH REALLY TAKES A 2949 02:18:19,040 --> 02:18:19,480 TEAM. 2950 02:18:19,480 --> 02:18:24,080 I'D LIKE TO CALL OUT THE TEAM 2951 02:18:24,080 --> 02:18:26,240 FOR MUCH OF THE DATA THAT ARE 2952 02:18:26,240 --> 02:18:26,720 PRESENTED HERE. 2953 02:18:26,720 --> 02:18:30,320 THANK YOU. 2954 02:18:30,320 --> 02:18:31,400 >> JOHN, THANK YOU VERY MUCH. 2955 02:18:31,400 --> 02:18:32,400 THERE ARE PLENTY OF QUESTIONS IN 2956 02:18:32,400 --> 02:18:33,920 THE BOX WHICH WE CAN CIRCLE BACK 2957 02:18:33,920 --> 02:18:35,480 TO LATER ON IF YOU'D LIKE TO 2958 02:18:35,480 --> 02:18:38,640 TAKE A LOOK AT THEM. 2959 02:18:38,640 --> 02:18:41,480 AND OUR NEXT SPEAKER IS ALSO 2960 02:18:41,480 --> 02:18:47,280 FROM IOWA, SARAH ERNST, RESEARCH 2961 02:18:47,280 --> 02:18:48,360 ASSOCIATE IN THE UNIVERSITY OF 2962 02:18:48,360 --> 02:18:48,560 IOWA. 2963 02:18:48,560 --> 02:18:51,400 AND SHE'S GOING TO TALK TO US 2964 02:18:51,400 --> 02:18:55,880 ABOUT THE G551D PIG MODEL. 2965 02:18:55,880 --> 02:18:56,440 SARAH, PLEASE. 2966 02:18:56,440 --> 02:18:59,720 >> OKAY, THANK YOU. 2967 02:18:59,720 --> 02:19:03,800 I THINK AS WE CONSIDER CURRENT 2968 02:19:03,800 --> 02:19:05,600 AND FUTURE RESEARCH NEEDS, ONE 2969 02:19:05,600 --> 02:19:08,680 OF THE QUESTIONS WE'RE ASKING 2970 02:19:08,680 --> 02:19:10,280 IS, WHAT ARE THE CHALLENGES IN 2971 02:19:10,280 --> 02:19:13,520 THE ERA OF HIGHLY EFFICIENT 2972 02:19:13,520 --> 02:19:14,080 MODULATOR THERAPY. 2973 02:19:14,080 --> 02:19:16,680 AND WE KNOW THAT FOR THE CASE OF 2974 02:19:16,680 --> 02:19:18,560 ESTABLISHED DISEASE, MANY PEOPLE 2975 02:19:18,560 --> 02:19:21,160 HAVE BENEFITED FROM MODULATORS. 2976 02:19:21,160 --> 02:19:22,800 THEY SEE AN INCREASE IN LUNG 2977 02:19:22,800 --> 02:19:24,000 FUNCTION BUT THE CHALLENGE FOR 2978 02:19:24,000 --> 02:19:28,280 US IS TO ADDRESS HOW CAN WE HELP 2979 02:19:28,280 --> 02:19:31,040 THEM IMPROVE EVEN FURTHER. 2980 02:19:31,040 --> 02:19:33,000 THE SECOND CHALLENGE IS THAT 2981 02:19:33,000 --> 02:19:35,480 SOME PEOPLE AREN'T ELIGIBLE FOR 2982 02:19:35,480 --> 02:19:35,960 MODULATORS. 2983 02:19:35,960 --> 02:19:38,120 THIS MAY BE BECAUSE THEIR 2984 02:19:38,120 --> 02:19:40,640 GENOTYPE ISN'T COMPATIBLE OR 2985 02:19:40,640 --> 02:19:42,280 POSSIBLY BECAUSE THEY'VE HAD TO 2986 02:19:42,280 --> 02:19:44,240 DISCONTINUE THERAPY DUE TO SIDE 2987 02:19:44,240 --> 02:19:45,320 EFFECTS. 2988 02:19:45,320 --> 02:19:49,080 AND A THIRD CHALLENGE IS THAT 2989 02:19:49,080 --> 02:19:50,160 NOW, WE HAVE PEOPLE WHO ARE 2990 02:19:50,160 --> 02:19:54,200 BEING TREATED WITH MODULATORS 2991 02:19:54,200 --> 02:19:56,040 EARLY, BEFORE THE ONSET OF 2992 02:19:56,040 --> 02:19:57,160 SEVERE DISEASE AND WE DON'T KNOW 2993 02:19:57,160 --> 02:19:58,360 WHAT PROBLEMS MAY DEVELOP FOR 2994 02:19:58,360 --> 02:20:02,080 THEM IN THE FUTURE. 2995 02:20:02,080 --> 02:20:03,640 SO ONE WAY TO OVERCOME SOME OF 2996 02:20:03,640 --> 02:20:05,240 THESE CHALLENGES IS THROUGH THE 2997 02:20:05,240 --> 02:20:09,520 USE OF ANIMAL MODELS. 2998 02:20:09,520 --> 02:20:12,120 SO OUR GOAL WAS TO DEVELOP A 2999 02:20:12,120 --> 02:20:15,720 G551D PIG THAT WOULD BE 3000 02:20:15,720 --> 02:20:16,160 MODULATOR-SENSITIVE. 3001 02:20:16,160 --> 02:20:17,920 IN THE PAST, WE HAVE DEVELOPED 3002 02:20:17,920 --> 02:20:19,560 CFTR KNOCKOUT PIGS THAT LACKED 3003 02:20:19,560 --> 02:20:21,640 THE CFTR PROTEIN. 3004 02:20:21,640 --> 02:20:24,280 AS WE EVALUATE THE G551D PIG, 3005 02:20:24,280 --> 02:20:25,600 I'LL REFERENCE THESE ANIMALS SO 3006 02:20:25,600 --> 02:20:26,440 I'M JUST GOING TO PROVIDE A 3007 02:20:26,440 --> 02:20:27,760 LITTLE BIT OF BACKGROUND ON THAT 3008 02:20:27,760 --> 02:20:30,840 MODEL. 3009 02:20:30,840 --> 02:20:32,800 SO THOSE INITIAL CFTR KNOCKOUT 3010 02:20:32,800 --> 02:20:34,680 ANIMALS DID NOT HAVE EVIDENCE OF 3011 02:20:34,680 --> 02:20:38,840 LUNG DISEASE AT BIRTH, HOWEVER, 3012 02:20:38,840 --> 02:20:40,360 THEY DID HAVE HOST DEFENSE 3013 02:20:40,360 --> 02:20:40,800 DEFECTS. 3014 02:20:40,800 --> 02:20:44,120 WE MEASURED REDUCED ASL PH IN 3015 02:20:44,120 --> 02:20:45,160 THE CF ANIMALS. 3016 02:20:45,160 --> 02:20:49,320 THIS CONTRIBUTED TO AN INCREASE 3017 02:20:49,320 --> 02:20:51,320 IN -- OR A DECREASE IN BACTERIAL 3018 02:20:51,320 --> 02:20:52,520 KILLING, AND WE ALSO FOUND THAT 3019 02:20:52,520 --> 02:20:57,440 THOSE ANIMALS HAD A DEFECT IN 3020 02:20:57,440 --> 02:21:00,160 MUCOCILIARY TRAPT. 3021 02:21:00,160 --> 02:21:00,480 TRANSPORT. 3022 02:21:00,480 --> 02:21:05,520 SO THIS HOST DEFENSE DEFECTS LED 3023 02:21:05,520 --> 02:21:07,600 TO DEVELOPING SPONTANEOUS AIRWAY 3024 02:21:07,600 --> 02:21:08,680 DISEASE OVER TIME. 3025 02:21:08,680 --> 02:21:10,240 HERE ARE SOME IMAGES FROM THOSE 3026 02:21:10,240 --> 02:21:12,280 ANIMALS SHOWING AIRWAY DISEASE 3027 02:21:12,280 --> 02:21:14,160 VERY SIMILAR TO HUMANS. 3028 02:21:14,160 --> 02:21:16,040 SINCE THIS MODEL LACKS 3029 02:21:16,040 --> 02:21:17,680 FUNCTIONAL CFTR, IT MAY NOT BE 3030 02:21:17,680 --> 02:21:19,280 USEFUL FOR US TO STUDY THE 3031 02:21:19,280 --> 02:21:20,920 CURRENT MODULATORS SO THAT'S WHY 3032 02:21:20,920 --> 02:21:26,720 WE DEVELOPED THE G551D ANIMAL. 3033 02:21:26,720 --> 02:21:29,160 BUT BEFORE WE STARTED MAKING 3034 02:21:29,160 --> 02:21:31,000 THAT PIG, WE DID SOME STUDIES IN 3035 02:21:31,000 --> 02:21:33,840 CELLS TO FIND OUT IF G551D WOULD 3036 02:21:33,840 --> 02:21:37,360 CAUSE A GATING DEFECT IN PIG 3037 02:21:37,360 --> 02:21:38,640 CFTR SIMILAR TO HUMANS. 3038 02:21:38,640 --> 02:21:41,040 SO HERE'S AN EXAMPLE OF A PATCH 3039 02:21:41,040 --> 02:21:43,440 CLAMP TRACE WHERE WE'RE STUDYING 3040 02:21:43,440 --> 02:21:45,640 WILD TYPE CFTR, AND YOU CAN SEE 3041 02:21:45,640 --> 02:21:49,840 HERE THAT THE CHANNEL OPENS AND 3042 02:21:49,840 --> 02:21:51,320 CLOSES, SO THIS IS A PATTERN FOR 3043 02:21:51,320 --> 02:21:53,080 A NORMALLY FUNCTIONING CHANNEL. 3044 02:21:53,080 --> 02:21:54,840 WHEN WE REPEAT THESE EXPERIMENTS 3045 02:21:54,840 --> 02:22:00,200 WITH THE G551D CFTR FROM PIGS WE 3046 02:22:00,200 --> 02:22:01,920 FIND INDEED THEY DO HAVE A 3047 02:22:01,920 --> 02:22:06,560 GATING DEFECT AND FORTUNATELY 3048 02:22:06,560 --> 02:22:08,720 THIS DEFECT IS PREVENTED OR 3049 02:22:08,720 --> 02:22:10,400 RESCUED WHEN WE TREAT THEM WITH 3050 02:22:10,400 --> 02:22:11,240 IVACAFTOR. 3051 02:22:11,240 --> 02:22:12,360 SO THIS PROVIDED THE EVIDENCE 3052 02:22:12,360 --> 02:22:15,200 THAT WE NEEDED TO PROCEED TO 3053 02:22:15,200 --> 02:22:19,440 MAKE OUR G551D PIGS. 3054 02:22:19,440 --> 02:22:22,200 THE FIRST STEP HERE IS FOR US TO 3055 02:22:22,200 --> 02:22:23,920 MAKE HETEROZYGOUS PIGS. 3056 02:22:23,920 --> 02:22:27,680 TO THIS, WE USED PIG FETAL 3057 02:22:27,680 --> 02:22:28,640 FIBROBLASTS, INFECTED THEM WITH 3058 02:22:28,640 --> 02:22:30,520 A VIRAL CFTR TARGETING VECTOR. 3059 02:22:30,520 --> 02:22:31,480 SOME OF THOSE CELLS WILL BE 3060 02:22:31,480 --> 02:22:35,080 APPROPRIATAPPROPRIATELY TARGETEE 3061 02:22:35,080 --> 02:22:38,480 USED THOSE TO MAKE OUR FIRST 3062 02:22:38,480 --> 02:22:40,120 HETEROZYGOUS PIGS. 3063 02:22:40,120 --> 02:22:41,320 ONCE THEY GROW UP WE CAN MATE 3064 02:22:41,320 --> 02:22:45,680 THEM AND THIS PRODUCED OUR FIRST 3065 02:22:45,680 --> 02:22:46,920 G551D HOMOZYGOUS ANIMALS. 3066 02:22:46,920 --> 02:22:50,520 AS WE STUDY THESE PIGLETS, WE 3067 02:22:50,520 --> 02:22:53,560 NEED TO KNOW IF THEY'LL HAVE A 3068 02:22:53,560 --> 02:22:54,360 CF PHENOTYPE AT BIRTH. 3069 02:22:54,360 --> 02:22:57,080 SO LIKE OUR OTHER ANIMAL -- OUR 3070 02:22:57,080 --> 02:22:58,480 OTHER KNOCK WITHOUT MODEL, THEY 3071 02:22:58,480 --> 02:23:00,800 DIDN'T HAVE LUNG DISEASE AT 3072 02:23:00,800 --> 02:23:02,520 BIRTH, BUT WE DID FIND DISEASE 3073 02:23:02,520 --> 02:23:03,880 OF OTHER ORGANS. 3074 02:23:03,880 --> 02:23:06,120 SO HERE WE'RE LOOKING AT SOME 3075 02:23:06,120 --> 02:23:07,120 HISTOLOGICAL IMAGES FROM THE 3076 02:23:07,120 --> 02:23:07,920 PANCREAS. 3077 02:23:07,920 --> 02:23:10,320 THE FIRST IMAGES OF WILD TYPE 3078 02:23:10,320 --> 02:23:14,920 PANCREAS FOR COMPARISON, OUR 3079 02:23:14,920 --> 02:23:18,400 CFGR KNOCKOUT MODEL HAS EXOCRINE 3080 02:23:18,400 --> 02:23:19,600 PANCREATIC DESTRUCTION AND SAME 3081 02:23:19,600 --> 02:23:21,600 WITH OUR G551D. 3082 02:23:21,600 --> 02:23:24,080 SIMILARLY, WE FOUND THAT THESE 3083 02:23:24,080 --> 02:23:26,040 PIGS HAVE HEPATOBILIARY DISEASE, 3084 02:23:26,040 --> 02:23:29,880 SO YOU CAN SEE A NORMAL WILD 3085 02:23:29,880 --> 02:23:33,920 TYPE GALLBLADDER, AND THEN FOR 3086 02:23:33,920 --> 02:23:35,680 COMPARISON, OUR KNOCKOUT ANIMAL 3087 02:23:35,680 --> 02:23:38,120 HAS A GALLBLADDER VERY REDUCED 3088 02:23:38,120 --> 02:23:40,720 IN SIZE AND OUR G551D SHOW A 3089 02:23:40,720 --> 02:23:43,680 SIMILAR PHENOTYPE. 3090 02:23:43,680 --> 02:23:45,560 ADDITIONALLY WHEN WE STUDIED THE 3091 02:23:45,560 --> 02:23:46,840 INTESTINE, WE FOUND THESE 3092 02:23:46,840 --> 02:23:49,680 ANIMALS HAVE LETHAL MECONIUM 3093 02:23:49,680 --> 02:23:55,040 ILEUS OR INTESTINAL O OBSTRUCTI, 3094 02:23:55,040 --> 02:23:57,440 SO THE WILD TYPE, THE BLACK 3095 02:23:57,440 --> 02:23:59,000 ARROW IS INDICATING A NORMAL 3096 02:23:59,000 --> 02:24:01,480 SPIRAL COLON, OUR CFTR KNOCKOUT 3097 02:24:01,480 --> 02:24:02,920 ANIMALS, THE RED STAR IS 3098 02:24:02,920 --> 02:24:05,200 INDICATING AN AREA WHERE WE HAVE 3099 02:24:05,200 --> 02:24:06,000 INTESTINAL OBSTRUCTION AND IN 3100 02:24:06,000 --> 02:24:10,320 OUR CF ANIMALS WE HAVE A MICRO 3101 02:24:10,320 --> 02:24:11,560 COLON, WE SEE THE SAME 3102 02:24:11,560 --> 02:24:14,200 OBSTRUCTION IN OUR G551D 3103 02:24:14,200 --> 02:24:16,040 ANIMALS. 3104 02:24:16,040 --> 02:24:23,160 SOL IF OUR GOALSO IF OUR GOAL IA 3105 02:24:23,160 --> 02:24:24,240 MODULATOR-SENSITIVE ANIMAL WE 3106 02:24:24,240 --> 02:24:28,280 NEED TO MAKE SURE THE MRNA AND 3107 02:24:28,280 --> 02:24:32,440 PROTEIN LEVELS ARE WHAT WE HAVE 3108 02:24:32,440 --> 02:24:34,640 SEEN AND WE ASK ARE THOSE LEVELS 3109 02:24:34,640 --> 02:24:35,400 SIMILAR TO WILD TYPE. 3110 02:24:35,400 --> 02:24:38,120 WHEN WE MEASURE MRNA FROM THE 3111 02:24:38,120 --> 02:24:40,760 INTESTINE WE FIND THE MRNA 3112 02:24:40,760 --> 02:24:44,120 LEVELS ARE SIMILAR BETWEEN G551D 3113 02:24:44,120 --> 02:24:44,600 AND WILD TYPE. 3114 02:24:44,600 --> 02:24:47,240 THEN WE WENT ON TO TEST WHETHER 3115 02:24:47,240 --> 02:24:48,760 OR NOT THIS EXPRESSED CFTR WOULD 3116 02:24:48,760 --> 02:24:49,760 BE FUNCTIONAL. 3117 02:24:49,760 --> 02:24:52,560 TSO HERE WE'RE LOOKING AT 3118 02:24:52,560 --> 02:24:53,360 SHORT-CIRCUIT CURRENT. 3119 02:24:53,360 --> 02:24:54,640 WE'VE GOT WILD TYPE HERE IN BLUE 3120 02:24:54,640 --> 02:24:58,920 AND IN RESPONSE WE SEE A LARGE 3121 02:24:58,920 --> 02:25:01,320 INCREASE SO THIS WOULD INDICATE 3122 02:25:01,320 --> 02:25:03,960 CFTR ACTIVITY. 3123 02:25:03,960 --> 02:25:06,880 THEN ADDITIONALLY WE ADD 3124 02:25:06,880 --> 02:25:07,880 IVACAFTOR, IN WILD TYPE WE DON'T 3125 02:25:07,880 --> 02:25:09,080 SEE AN INCREASE, HOWEVER, WHEN 3126 02:25:09,080 --> 02:25:13,480 WE LOOK AT G551D IN GREEN, WE 3127 02:25:13,480 --> 02:25:17,200 SEE THAT THE G551D INTESTINE HAS 3128 02:25:17,200 --> 02:25:19,160 A REDUCED RESPONSE AND WITH 3129 02:25:19,160 --> 02:25:21,760 ADDITION OF I' IVACAFTOR, WE SEE 3130 02:25:21,760 --> 02:25:22,960 THIS CURRENT IS INCREASED TO 3131 02:25:22,960 --> 02:25:24,600 NEAR WILD TYPE LEVELS. 3132 02:25:24,600 --> 02:25:26,280 SO THAT'S THE INTESTINE. 3133 02:25:26,280 --> 02:25:27,800 WE ALSO WANTED TO LOOK FOR 3134 02:25:27,800 --> 02:25:30,320 PROTEIN LEVELS IN THE AIRWAY. 3135 02:25:30,320 --> 02:25:33,800 SO HERE WE'RE LOOKING FOR CFTR 3136 02:25:33,800 --> 02:25:35,240 IMMUNOSTAINING IN AIRWAY 3137 02:25:35,240 --> 02:25:35,560 CULTURES. 3138 02:25:35,560 --> 02:25:38,200 FIRST WE'LL LOOK AT WILD TYPE, 3139 02:25:38,200 --> 02:25:39,480 CFTR IS STAINED WITH GREEN, SO 3140 02:25:39,480 --> 02:25:42,240 THIS IS A NORMAL CFTR EXPRESSION 3141 02:25:42,240 --> 02:25:44,640 PATTERN WHERE WE SEE THAT CFTR 3142 02:25:44,640 --> 02:25:46,080 IS LOCALIZED TO THE APICAL 3143 02:25:46,080 --> 02:25:46,720 MEMBRANE. 3144 02:25:46,720 --> 02:25:49,920 OUR CFTR KNOCKOUT ANIMALS LACK 3145 02:25:49,920 --> 02:25:51,880 CFTR PROTEIN SO WE DON'T SEE 3146 02:25:51,880 --> 02:25:52,520 CFTR STAINING HERE. 3147 02:25:52,520 --> 02:25:55,880 THIS IS JUST A GOOD NEGATIVE 3148 02:25:55,880 --> 02:25:56,360 CONTROL. 3149 02:25:56,360 --> 02:25:59,560 THEN WHEN WE LOOK AT OUR G551D 3150 02:25:59,560 --> 02:26:02,320 CULTURES, WE SEE THEY HAVE 3151 02:26:02,320 --> 02:26:06,280 NORMAL PROTEIN EXPRESSION. 3152 02:26:06,280 --> 02:26:08,160 THEN WE CAN GO ON TO LOOK AT THE 3153 02:26:08,160 --> 02:26:10,760 FUNCTION IN OUR AIRWAY CULTURES. 3154 02:26:10,760 --> 02:26:11,960 HERE WE'RE LOOKING AT THE CHANGE 3155 02:26:11,960 --> 02:26:15,040 IN SHORT-CIRCUIT CURRENT AND WE 3156 02:26:15,040 --> 02:26:17,880 SEE THAT FORCE CLIN INDUCED 3157 02:26:17,880 --> 02:26:19,640 SHORT-CIRCUIT CURRENT IS REDUCED 3158 02:26:19,640 --> 02:26:30,160 IN THE G551D -- THIS FUNCTIONAL 3159 02:26:35,560 --> 02:26:37,560 RESCUE WE'VE SEEN IN OUR AIRWAY 3160 02:26:37,560 --> 02:26:39,080 CULTURE, WE WANT TO KNOW IF THIS 3161 02:26:39,080 --> 02:26:40,400 FUNCTIONAL RESCUE WILL ALSO 3162 02:26:40,400 --> 02:26:41,800 RESCUE SOME OF THE HOST DEFENSE 3163 02:26:41,800 --> 02:26:49,040 DEFECTS THAT WE'VE SEEN. 3164 02:26:49,040 --> 02:26:52,040 HERE WE SEE THE G551D ANIMALS 3165 02:26:52,040 --> 02:26:55,920 HAVE A REDUCED ASL PH IN THE 3166 02:26:55,920 --> 02:26:58,440 WILD TYPE AND WITH THE ADDITION 3167 02:26:58,440 --> 02:27:01,200 OF EYE VO CALF TORE, WE SEE IT 3168 02:27:01,200 --> 02:27:01,640 INCREASES. 3169 02:27:01,640 --> 02:27:03,320 WE ALSO MEASURED BACTERIAL 3170 02:27:03,320 --> 02:27:06,960 KILLING AND WE SEE THAT WHEN WE 3171 02:27:06,960 --> 02:27:08,160 LOOK AT THE PERCENTAGE OF 3172 02:27:08,160 --> 02:27:12,000 BACTERIA THAT ARE KILLED, THIS 3173 02:27:12,000 --> 02:27:14,600 KILLING IS INCREASED WHEN WE ADD 3174 02:27:14,600 --> 02:27:20,200 EYE VO CALF TORE. 3175 02:27:20,200 --> 02:27:24,360 SO OUR NEXT QUESTION IS WILL 3176 02:27:24,360 --> 02:27:25,800 IVACAFTOR RESCUE THE CF 3177 02:27:25,800 --> 02:27:26,440 PHENOTYPE? 3178 02:27:26,440 --> 02:27:28,880 WE KNOW IN UTERO ADMINISTRATION 3179 02:27:28,880 --> 02:27:30,920 OF IVACAFTOR HAS CORRECTED THE 3180 02:27:30,920 --> 02:27:32,240 CF PHENOTYPE IN OTHER ANIMAL 3181 02:27:32,240 --> 02:27:32,720 MODELS. 3182 02:27:32,720 --> 02:27:34,840 AND WE WANT TO KNOW IF IT WILL 3183 02:27:34,840 --> 02:27:43,320 WORK IN PIG. 3184 02:27:43,320 --> 02:27:45,400 WE WANTED TO KNOW IF THE PIGS 3185 02:27:45,400 --> 02:27:47,680 WILL RESPOND TO IVACAFTOR 3186 02:27:47,680 --> 02:27:51,760 SIMILAR TO HUMANS, SO FOR THIS, 3187 02:27:51,760 --> 02:27:53,960 WE DID DOSE-RESPONSE OF 3188 02:27:53,960 --> 02:27:57,440 IVACAFTOR SO WE'RE MEASURING 3189 02:27:57,440 --> 02:27:58,960 NORMALIZED TRANS EPITHELIAL 3190 02:27:58,960 --> 02:28:00,840 CURRENT WITH INCREASING DOSES OF 3191 02:28:00,840 --> 02:28:03,560 IVACAFTOR AND WE CAN COMPARE 3192 02:28:03,560 --> 02:28:05,320 HUMAN AIRWAY CULTURES TO PIG 3193 02:28:05,320 --> 02:28:09,560 AIRWAY CULTURES AND WE FIND THAT 3194 02:28:09,560 --> 02:28:11,440 BOTH SPECIES RESPOND SIMILARLY. 3195 02:28:11,440 --> 02:28:15,160 SO WE THINK A SIMILAR DOSE FOR 3196 02:28:15,160 --> 02:28:16,920 PIGS WILL BE EFFECTIVE. 3197 02:28:16,920 --> 02:28:19,520 WE ALSO DID SOME OTHER STUDIES 3198 02:28:19,520 --> 02:28:22,160 WHERE WE GAVE ANIMALS DIFFERENT 3199 02:28:22,160 --> 02:28:24,040 DOSES OF IVACAFTOR AND TESTED 3200 02:28:24,040 --> 02:28:27,520 PLASMA LESMS TO MAKE LEVELS TO Y 3201 02:28:27,520 --> 02:28:28,840 WERE SIMILAR TO WHAT'S BEEN 3202 02:28:28,840 --> 02:28:29,720 REPORTED IN HUMAN. 3203 02:28:29,720 --> 02:28:34,000 SO WE BEGAN TO TREAT OUR G551D 3204 02:28:34,000 --> 02:28:37,800 PIG LET'S WITH IVACAFTOR IN 3205 02:28:37,800 --> 02:28:38,320 UTERO. 3206 02:28:38,320 --> 02:28:40,720 A NORMAL PIG PREGNANCY IS 114 3207 02:28:40,720 --> 02:28:42,160 DAYS SO WE BEGAN TO TREAT OUR 3208 02:28:42,160 --> 02:28:45,000 ANIMALS AT DAY 35. 3209 02:28:45,000 --> 02:28:47,200 THIS IS BEFORE MECONIUM IS 3210 02:28:47,200 --> 02:28:47,480 OBSERVED. 3211 02:28:47,480 --> 02:28:49,640 SO WE CONTINUED TREATMENT UNTIL 3212 02:28:49,640 --> 02:28:51,160 THE ANIMALS WERE BORN. 3213 02:28:51,160 --> 02:28:55,840 SO NOW WE HAVE OUR HETEROZYGOUS 3214 02:28:55,840 --> 02:28:58,800 SOWS RECEIVING THE IVACAFTOR, 3215 02:28:58,800 --> 02:29:01,080 G551D PIG LET'S EXPOSED IN UTERO 3216 02:29:01,080 --> 02:29:02,840 AND WE'RE ASKING IS THERE 3217 02:29:02,840 --> 02:29:03,160 CORRECTION. 3218 02:29:03,160 --> 02:29:04,360 SO THESE ARE SOME OF THE SAME 3219 02:29:04,360 --> 02:29:05,880 IMAGES WE LOOKED AT BEFORE FOR 3220 02:29:05,880 --> 02:29:06,880 THE PANCREAS. 3221 02:29:06,880 --> 02:29:08,960 THE WILD TYPE, THE G551D THAT 3222 02:29:08,960 --> 02:29:12,800 HAD AREAS OF DESTRUCTION, AND 3223 02:29:12,800 --> 02:29:14,880 NOW WHEN WE LOOK AT THE G551D 3224 02:29:14,880 --> 02:29:16,480 WITH FETAL IVACAFTOR TREATMENT, 3225 02:29:16,480 --> 02:29:22,400 WE SEE THE PHENOTYPE IS RESCUED. 3226 02:29:22,400 --> 02:29:23,960 WE FIND THE SAME THING IN THE 3227 02:29:23,960 --> 02:29:24,280 GALLBLADDER. 3228 02:29:24,280 --> 02:29:27,360 BEFORE WE HAD A GALLBLADDER 3229 02:29:27,360 --> 02:29:30,200 SEVERELY REDUCED IN SIZE, YOUR 3230 02:29:30,200 --> 02:29:32,600 THEY HAVE A MORE NORMAL 3231 02:29:32,600 --> 02:29:37,880 APPEARING GALLBLADDER. 3232 02:29:37,880 --> 02:29:39,480 WE ALSO LOOKED AT THE INTESTINE. 3233 02:29:39,480 --> 02:29:41,040 IT WAS OBVIOUS PRETTY EARLY ON 3234 02:29:41,040 --> 02:29:43,760 THAT THESE ANIMALS HAD A RESCUE 3235 02:29:43,760 --> 02:29:45,280 OF MECONIUM ILEUS. 3236 02:29:45,280 --> 02:29:46,800 THESE ANIMALS WERE ABLE TO PASS 3237 02:29:46,800 --> 02:29:49,000 MECONIUM AND WERE ABLE TO 3238 02:29:49,000 --> 02:29:56,800 SURVIVE FOR A LATER STUDY. 3239 02:29:56,800 --> 02:29:57,800 SO A REALLY IMPORTANT QUESTION 3240 02:29:57,800 --> 02:30:02,920 NOW IS THAT NOW THAT THE CF 3241 02:30:02,920 --> 02:30:05,000 PHENOTYPE HAS BEEN RESCUED IN 3242 02:30:05,000 --> 02:30:07,640 UTERO, IF WE WITHDRAW IVACAFTOR, 3243 02:30:07,640 --> 02:30:09,120 WILL THESE PIGS GO ON TO DEVELOP 3244 02:30:09,120 --> 02:30:10,360 AIRWAY DISEASE WITH TIME? 3245 02:30:10,360 --> 02:30:11,720 SO WE'VE HAD THE OPPORTUNITY TO 3246 02:30:11,720 --> 02:30:13,720 DO THIS A FEW TIMES. 3247 02:30:13,720 --> 02:30:16,800 SO THIS IS PRELIMINARY EVIDENCE. 3248 02:30:16,800 --> 02:30:19,200 THESE ARE HISTOLOGICAL IMAMONGS 3249 02:30:19,200 --> 02:30:22,920 IMAGESFROM THE LUNG, THE WHITE S 3250 02:30:22,920 --> 02:30:25,200 THE AIRWAY LUMEN IN A WILD TYPE 3251 02:30:25,200 --> 02:30:27,080 ANIMAL, THIS IS THE EPITHELIA. 3252 02:30:27,080 --> 02:30:28,800 YOU CAN SEE IN A WILD TYPE 3253 02:30:28,800 --> 02:30:30,000 ANIMAL THE AREAS ARE 3254 02:30:30,000 --> 02:30:32,440 MUCOUS-FREE. 3255 02:30:32,440 --> 02:30:36,000 IN OUR G551D ANIMAL, YOU CAN SEE 3256 02:30:36,000 --> 02:30:37,040 MUCUS IS STARTING TO ACCUMULATE 3257 02:30:37,040 --> 02:30:38,880 ON THE SURFACE AND WE HAVE THE 3258 02:30:38,880 --> 02:30:40,240 PRESENCE OF SCATTERED 3259 02:30:40,240 --> 02:30:41,000 NEUTROPHILS. 3260 02:30:41,000 --> 02:30:42,480 SO SOME BENEFITS AND LIMITATIONS 3261 02:30:42,480 --> 02:30:43,840 OF THE PIG. 3262 02:30:43,840 --> 02:30:46,560 FL CF PIGS HAVE DISEASE SIMILAR 3263 02:30:46,560 --> 02:30:49,480 TO HUMANS, IVACAFTOR TREATMENT 3264 02:30:49,480 --> 02:30:52,040 HAS PREVENTED THE CF PHENOTYPE 3265 02:30:52,040 --> 02:30:54,640 AND THESE PIGS CAN NOW BE RAISED 3266 02:30:54,640 --> 02:30:56,160 WITHOUT IVACAFTOR TO STUDY 3267 02:30:56,160 --> 02:30:57,160 DISEASE HOWEVER, LIKE HUMANS, 3268 02:30:57,160 --> 02:30:58,480 THE PRESENTATION, SEVERITY AND 3269 02:30:58,480 --> 02:31:00,080 TIMING TO PROGRESSION ARE 3270 02:31:00,080 --> 02:31:01,120 VARIABLE. 3271 02:31:01,120 --> 02:31:02,520 SO JUST TO FINISH UP, I'M GOING 3272 02:31:02,520 --> 02:31:06,360 TO COME BACK TO THE CHAT EPTION 3273 02:31:06,360 --> 02:31:12,880 THE CHALLENGESWE'RE FACING AND L 3274 02:31:12,880 --> 02:31:14,760 MODELS CAN HELP US OVER COME 3275 02:31:14,760 --> 02:31:16,440 THEM. 3276 02:31:16,440 --> 02:31:17,720 UNDERSTANDING MECHANISM OFS OF 3277 02:31:17,720 --> 02:31:24,800 OFPERSISTENT INFECTION, 3278 02:31:24,800 --> 02:31:25,800 INFLAMMATION AND REMODELING TO 3279 02:31:25,800 --> 02:31:27,680 DEVELOP NEW TREATMENTS. 3280 02:31:27,680 --> 02:31:32,600 REPEATED HIGH RESOLUTION CT, 3281 02:31:32,600 --> 02:31:35,560 MUCOCILIARY THERAPY IN LARGE AND 3282 02:31:35,560 --> 02:31:36,640 SMALL AIRWAYS, WE CAN DO 3283 02:31:36,640 --> 02:31:39,160 REPEATED BAL, AND WE CAN DO 3284 02:31:39,160 --> 02:31:42,120 REPEATED LUNG TISSUE SAMPLES AND 3285 02:31:42,120 --> 02:31:43,320 CONTROLLED NECROPSY AND 3286 02:31:43,320 --> 02:31:44,520 HISTOPATHOLOGY. 3287 02:31:44,520 --> 02:31:45,960 SO THESE ASSAYS CAN HELP US 3288 02:31:45,960 --> 02:31:47,600 DEVELOP NEW TREATMENTS. 3289 02:31:47,600 --> 02:31:50,240 ANIMAL MODELS CAN ALSO HELP US 3290 02:31:50,240 --> 02:31:52,400 TEST NEW MODULATORS OR CURRENT 3291 02:31:52,400 --> 02:31:54,040 MODULATORS PLUS ADDITIONAL 3292 02:31:54,040 --> 02:31:55,880 THERAPIES LIKE 3293 02:31:55,880 --> 02:31:56,880 ANTI-INFLAMMATORIES, 3294 02:31:56,880 --> 02:31:57,960 ANTIBIOTICS, AND FUNGALS, AND 3295 02:31:57,960 --> 02:32:01,040 THEY CAN ALSO HELP US DEVELOP 3296 02:32:01,040 --> 02:32:02,920 NEW THERAPIES THAT COULD IMPROVE 3297 02:32:02,920 --> 02:32:07,520 HOST DEFENSE DEFECTS. 3298 02:32:07,520 --> 02:32:09,360 AND THEN THE LAST THING HERE IS 3299 02:32:09,360 --> 02:32:11,560 JUST HOW CAN ANIMAL MODELS HELP 3300 02:32:11,560 --> 02:32:15,400 US WITH DISEASE PREVENTION FOR 3301 02:32:15,400 --> 02:32:17,680 THOSE WHO AREN'T ELIGIBLE FOR 3302 02:32:17,680 --> 02:32:18,000 MODULATORS. 3303 02:32:18,000 --> 02:32:19,640 THEY CAN HELP US ANSWER THE 3304 02:32:19,640 --> 02:32:20,800 QUESTION, WHERE IS THE 3305 02:32:20,800 --> 02:32:21,280 APPROPRIATE TARGET? 3306 02:32:21,280 --> 02:32:24,360 SHOULD IT BE LARGE AIRWAYS, 3307 02:32:24,360 --> 02:32:25,880 SUBMUCOSAL GLANDS, SMALL 3308 02:32:25,880 --> 02:32:28,200 AIRWAYS, OR ALL OF THESE? 3309 02:32:28,200 --> 02:32:29,280 ALSO IMPORTANT QUESTIONS ARE, 3310 02:32:29,280 --> 02:32:30,280 WHICH CELLS ARE THE MOST 3311 02:32:30,280 --> 02:32:31,000 IMPORTANT TO TARGET? 3312 02:32:31,000 --> 02:32:37,480 SHOULD IT BE SECRETORY CELLS OR 3313 02:32:37,480 --> 02:32:39,360 OTHER TYPES, IT CAN HELP US TEST 3314 02:32:39,360 --> 02:32:41,080 NEW THERAPEUTIC APPROACHES AND 3315 02:32:41,080 --> 02:32:42,720 ALSO TEST DIFFERENT DELIVERY 3316 02:32:42,720 --> 02:32:46,440 STRATEGIES. 3317 02:32:46,440 --> 02:32:49,920 AND THE G551D PIG COULD HELP US 3318 02:32:49,920 --> 02:32:51,160 WITH THE QUESTIONS SURROUNDING 3319 02:32:51,160 --> 02:32:54,200 EARLY MODULATOR TREATMENT, BUT I 3320 02:32:54,200 --> 02:32:55,520 THINK AS PROBLEMS DEVELOP IN 3321 02:32:55,520 --> 02:32:57,160 PEOPLE AND MODULATORS, THESE 3322 02:32:57,160 --> 02:32:58,600 ANIMAL MODELS MAY AID IN THE 3323 02:32:58,600 --> 02:33:00,760 DISCOVERY OF MECHANISMS AND 3324 02:33:00,760 --> 02:33:05,120 OTHER THERAPY PEW THERAPEUTIC T. 3325 02:33:05,120 --> 02:33:08,120 SO JUST -- THIS IS THE VERY LAST 3326 02:33:08,120 --> 02:33:10,960 SLIDE, THE EXAMPLE OF THAT WE'VE 3327 02:33:10,960 --> 02:33:13,160 USED IS LUNG FUNCTION BUT CF IS 3328 02:33:13,160 --> 02:33:15,080 A MULTISYSTEM DISEASE, SO THE 3329 02:33:15,080 --> 02:33:16,160 ANIMAL MODELS AND THE THINGS 3330 02:33:16,160 --> 02:33:17,840 THAT WE DISCOVER USING THE 3331 02:33:17,840 --> 02:33:19,240 ANIMAL MODELS CAN HELP US 3332 02:33:19,240 --> 02:33:21,880 TRANSLATE TREATMENTS TO OTHER 3333 02:33:21,880 --> 02:33:23,720 ORGANS, LIKE EXOCRINE AND 3334 02:33:23,720 --> 02:33:30,200 ENDOCRINE PANCREATIC DISEASE, 3335 02:33:30,200 --> 02:33:31,720 HEPATOBILIARY DISEASE, AND 3336 02:33:31,720 --> 02:33:32,280 INTESTINAL DISEASE. 3337 02:33:32,280 --> 02:33:32,840 AND THAT'S IT. 3338 02:33:32,840 --> 02:33:34,880 I'M A MEMBER OF THE UNIVERSITY 3339 02:33:34,880 --> 02:33:37,400 OF IOWA CF RESEARCH GROUP AND 3340 02:33:37,400 --> 02:33:39,800 THIS WORK IS -- A LOT OF PEOPLE 3341 02:33:39,800 --> 02:33:40,720 HAVE CONTRIBUTED TO THIS WORK. 3342 02:33:40,720 --> 02:33:44,320 SO THANK YOU. 3343 02:33:44,320 --> 02:33:45,320 >> THANK YOU, SARAH. 3344 02:33:45,320 --> 02:33:47,920 THAT WAS A GREAT TALK. 3345 02:33:47,920 --> 02:33:49,200 WITH THAT, I'D LIKE TO INTRODUCE 3346 02:33:49,200 --> 02:33:50,880 THE FINAL SPEAKERS FOR THIS 3347 02:33:50,880 --> 02:33:51,400 SESSION. 3348 02:33:51,400 --> 02:33:54,600 THE LAST TALK WILL BE GIVEN BY 3349 02:33:54,600 --> 02:33:58,000 DR. IRINA POLEJAEVA, PROFESSOR 3350 02:33:58,000 --> 02:34:01,040 OF DEVELOPMENTAL BIOLOGY AT UTAH 3351 02:34:01,040 --> 02:34:03,440 STATE UNIVERSITY AND ANN HARRIS, 3352 02:34:03,440 --> 02:34:04,680 PROFESSOR AND VICE CHAIR FOR 3353 02:34:04,680 --> 02:34:08,200 RESEARCH AT CASE WESTERN 3354 02:34:08,200 --> 02:34:13,640 RESERVE. 3355 02:34:13,640 --> 02:34:15,040 >> DO YOU SEE MY SLIDES? 3356 02:34:15,040 --> 02:34:17,920 >> WE SEE YOUR SLIDES, IRINA, 3357 02:34:17,920 --> 02:34:19,200 BUT NOT YOU. 3358 02:34:19,200 --> 02:34:20,720 >> THE SLIDES ARE ALSO NOT IN 3359 02:34:20,720 --> 02:34:25,440 PRESENTATION MODE. 3360 02:34:25,440 --> 02:34:27,200 >> THAT'S WHAT I'M TRYING TO 3361 02:34:27,200 --> 02:34:35,040 SWITCH. 3362 02:34:35,040 --> 02:34:36,440 ALL RIGHT. 3363 02:34:36,440 --> 02:34:38,000 THANK YOU FOR THE INTRODUCTION, 3364 02:34:38,000 --> 02:34:39,440 AND I ALSO WOULD LIKE TO THANK 3365 02:34:39,440 --> 02:34:41,480 THE ORGANIZING COMMITTEE FOR 3366 02:34:41,480 --> 02:34:44,000 INVITATION TO PRESENT. 3367 02:34:44,000 --> 02:34:46,320 THE SHEEP MODEL IS ONE OF THE 3368 02:34:46,320 --> 02:34:47,520 RECENT -- MOST RECENT MODEL 3369 02:34:47,520 --> 02:34:49,040 DEVELOPED IN THE FIELD, AND IT'S 3370 02:34:49,040 --> 02:34:52,440 A COLLABORATIVE PROJECT BETWEEN 3371 02:34:52,440 --> 02:34:53,960 UTAH STATE AND CASE WESTERN 3372 02:34:53,960 --> 02:34:55,400 RESERVE UNIVERSITY. 3373 02:34:55,400 --> 02:34:58,160 SO THE MODEL ACTUALLY WAS 3374 02:34:58,160 --> 02:35:03,720 INSPIRED BY WORK -- ANN HARRIS' 3375 02:35:03,720 --> 02:35:07,640 WORK, AND THE QUESTION THAT WE 3376 02:35:07,640 --> 02:35:09,640 ALWAYS -- WE OFTEN HEAR IS WHY 3377 02:35:09,640 --> 02:35:14,000 DO WE DEVELOP NEW MODELS AND I 3378 02:35:14,000 --> 02:35:15,080 CANNOT FOR SOME REASON ADVANCE 3379 02:35:15,080 --> 02:35:19,920 MY SLIDES. 3380 02:35:19,920 --> 02:35:24,360 >> I SEE AN ARROW ON THE BOTTOM 3381 02:35:24,360 --> 02:35:24,560 LEFT. 3382 02:35:24,560 --> 02:35:29,840 >> THANK YOU. 3383 02:35:29,840 --> 02:35:32,240 SO WHY ARE WE DEVELOPING A NEW 3384 02:35:32,240 --> 02:35:37,200 CF MODEL AND THE ANSWER WAS 3385 02:35:37,200 --> 02:35:39,240 SPECIFICALLY SHEEP IS QUITE 3386 02:35:39,240 --> 02:35:43,200 OBVIOUS, SO THE SHEEP HAS BEEN 3387 02:35:43,200 --> 02:35:44,400 USED AS ONE OF THE PRIMARY 3388 02:35:44,400 --> 02:35:46,920 MODELS TO STUDY HUMAN LUNG 3389 02:35:46,920 --> 02:35:51,160 DEVELOPMENT DUE TO A LOT OF 3390 02:35:51,160 --> 02:35:54,480 SIMILARITY IN PHYSIOLOGY AND 3391 02:35:54,480 --> 02:35:55,960 ACTUALLY JOHN GAVE AN EXCELLENT 3392 02:35:55,960 --> 02:35:57,080 OVERVIEW SLIDE ABOUT LARGE 3393 02:35:57,080 --> 02:35:58,160 ANIMAL MODELS AND THEIR 3394 02:35:58,160 --> 02:36:00,160 SIMILARITY TO HUMAN. 3395 02:36:00,160 --> 02:36:02,200 SO IN FACT, MUCH OF OUR 3396 02:36:02,200 --> 02:36:03,560 KNOWLEDGE IN HUMAN LUNG 3397 02:36:03,560 --> 02:36:09,320 DEVELOPMENT IS BASED ON THE SEMI 3398 02:36:09,320 --> 02:36:11,640 SEMINAL STUDIES ON SHEEP. 3399 02:36:11,640 --> 02:36:12,520 THE UNIQUENESS OF SHEEP IS 3400 02:36:12,520 --> 02:36:15,680 ALLOWING US TO MONITOR 3401 02:36:15,680 --> 02:36:19,680 DEVELOPMENT IN CLOSE CONDITIONS 3402 02:36:19,680 --> 02:36:22,040 OR CLOSER PREGNANCY LENGTH TO 3403 02:36:22,040 --> 02:36:23,640 HUMANS, SO SHEEP HAS NEARLY FIVE 3404 02:36:23,640 --> 02:36:25,080 MONTHS OF GESTATION COMPARED TO 3405 02:36:25,080 --> 02:36:27,720 LESS THAN FOUR MONTHS IN PIGS, 3406 02:36:27,720 --> 02:36:29,800 AND THEY ALSO HAVE SIMILAR 3407 02:36:29,800 --> 02:36:31,200 NUMBER OF OFFSPRING. 3408 02:36:31,200 --> 02:36:35,040 IT'S TYPICALLY ONE OR TWO LAMBS. 3409 02:36:35,040 --> 02:36:37,560 RARELY THREE, DEPENDING ON THE 3410 02:36:37,560 --> 02:36:42,240 BREED, WHICH MIGHT BE BENEFICIAL 3411 02:36:42,240 --> 02:36:45,640 TO TESTING PRENATAL THERAPEUTIC 3412 02:36:45,640 --> 02:36:48,480 INTERVENTION AND INDIVIDUAL 3413 02:36:48,480 --> 02:36:54,840 FETAL MONITORING. 3414 02:36:54,840 --> 02:36:56,720 SO ONE OF THE FIRST MODELS WE 3415 02:36:56,720 --> 02:36:58,920 DEVELOPED USED IN CRISPR/CAS 3416 02:36:58,920 --> 02:37:04,560 MEDIATED APPROACH TO SHEEP 3417 02:37:04,560 --> 02:37:05,760 FIBROBLAST IN VITRO, COMMONLY 3418 02:37:05,760 --> 02:37:07,840 USED FOR GENETIC MODIFICATIONS 3419 02:37:07,840 --> 02:37:12,440 IN COMBINATION WITH SOMATIC CELL 3420 02:37:12,440 --> 02:37:13,040 NUCLEOTRANSFER. 3421 02:37:13,040 --> 02:37:15,080 THE INITIAL MODEL WE DEVELOPED 3422 02:37:15,080 --> 02:37:18,600 WAS SIMPLE INTRODUCTION OF -- IN 3423 02:37:18,600 --> 02:37:22,840 EITHER IN EXON 2 OR EXON 11. 3424 02:37:22,840 --> 02:37:26,560 SO WE DESIGN GUIDE RNA TARGETING 3425 02:37:26,560 --> 02:37:33,240 TO DIFFERENT AXONS AND 3426 02:37:33,240 --> 02:37:35,880 TRANSVECTED FIBROBLAST CELL 3427 02:37:35,880 --> 02:37:38,280 FOLLOWED BY POPULATION OF THE 3428 02:37:38,280 --> 02:37:41,360 CELLS AND -- CELLS THAT HAVE 3429 02:37:41,360 --> 02:37:42,320 DESIRED GENOTYPE, SPECIFICALLY 3430 02:37:42,320 --> 02:37:46,440 WE'RE LOOKING FOR -- TO 3431 02:37:46,440 --> 02:37:51,480 FUNCTIONAL KNOCKOUT IN -- AND WE 3432 02:37:51,480 --> 02:37:55,520 USE THESE CELLS FOR FUTURE SCNT 3433 02:37:55,520 --> 02:37:55,720 WORK. 3434 02:37:55,720 --> 02:37:58,600 SO BASICALLY CELLS WERE 3435 02:37:58,600 --> 02:38:01,760 CONFIRMED BY -- ASSAYS AND A 3436 02:38:01,760 --> 02:38:04,520 SEQUENCE CONFIRMATION FOR THE 3437 02:38:04,520 --> 02:38:06,600 PRESENCE OF THESE. 3438 02:38:06,600 --> 02:38:10,400 FOR CLONING WE USE -- OOCYTES 3439 02:38:10,400 --> 02:38:14,480 WHICH WE ENUCLEATE OR USE IN 3440 02:38:14,480 --> 02:38:16,200 REMOVAL OF -- FACEPLATE FROM 3441 02:38:16,200 --> 02:38:20,920 THESE OOCYTES BY ASPIRATIONAL 3442 02:38:20,920 --> 02:38:22,880 DNA MATERIAL AND INTRODUCE 3443 02:38:22,880 --> 02:38:29,320 GENETICALLY MODIFIED CELLS, NULL 3444 02:38:29,320 --> 02:38:39,720 CELLS INTO -- OOCYTES THAT -- BY 3445 02:38:39,720 --> 02:38:41,560 FUSION, THESE TRANSFER INTO 3446 02:38:41,560 --> 02:38:43,000 ESTRUS SYNCHRONIZED RECIPIENTS 3447 02:38:43,000 --> 02:38:45,640 WHICH WOULD CARRY PREGNANCIES TO 3448 02:38:45,640 --> 02:38:47,280 TERM, AFTER ABOUT FIVE MONTHS OF 3449 02:38:47,280 --> 02:38:51,880 GESTATION, WE PRODUCED THE CFTR 3450 02:38:51,880 --> 02:38:52,640 NULL LAMBS. 3451 02:38:52,640 --> 02:38:54,600 SO INITIALLY WE PRODUCED A SET 3452 02:38:54,600 --> 02:38:58,560 OF TWO DIFFERENT TYPE OF ANIMALS 3453 02:38:58,560 --> 02:39:02,480 WITH CFTR NULL MUTATION IN THE 3454 02:39:02,480 --> 02:39:03,440 EXON 2 OR 11. 3455 02:39:03,440 --> 02:39:07,640 AND WE ALSO PRODUCED NOT ONLY 3456 02:39:07,640 --> 02:39:10,240 ANIMALS WITH -- KNOCKOUTS BUT 3457 02:39:10,240 --> 02:39:11,760 ALSO HETEROZYGOUS ANIMALS FOR 3458 02:39:11,760 --> 02:39:17,920 FUTURE LINE EN EXPANSION. 3459 02:39:17,920 --> 02:39:27,760 SINCE THEN WE HAVE 5508DEL AND 3460 02:39:27,760 --> 02:39:30,400 G542X, WE ALSO DESIGN THE 3461 02:39:30,400 --> 02:39:33,120 TEMPLATE TOGETHER WITH THAT 3462 02:39:33,120 --> 02:39:35,080 COCKTAIL OF RNP THAT WILL ALLOW 3463 02:39:35,080 --> 02:39:36,480 US TO INTRODUCE SPECIFIC 3464 02:39:36,480 --> 02:39:40,880 MUTATIONS AND TO USE THAT AS A 3465 02:39:40,880 --> 02:39:43,280 TEMPLATE FOR --. 3466 02:39:43,280 --> 02:39:45,240 SO CURRENTLY WE HAVE ABILITY TO 3467 02:39:45,240 --> 02:39:48,640 PRODUCE THESE DIFFERENT FOUR 3468 02:39:48,640 --> 02:39:51,560 TYPE OF CLONE ANIMALS, AND ALSO 3469 02:39:51,560 --> 02:39:53,680 HAVE FETAL FIBROBLAST CELLS THAT 3470 02:39:53,680 --> 02:39:57,280 COULD BE PROVIDED FOR IF YOU 3471 02:39:57,280 --> 02:39:59,240 DESIRE TO GENERATE PREGNANCY 3472 02:39:59,240 --> 02:40:01,200 USING THESE FETAL FIBROBLAST 3473 02:40:01,200 --> 02:40:01,640 CELLS. 3474 02:40:01,640 --> 02:40:04,720 WE ALSO HAVE HETEROZYGOUS 3475 02:40:04,720 --> 02:40:08,840 ANIMALS THAT CAN BE USED FOR -- 3476 02:40:08,840 --> 02:40:11,080 TO GENERATE HOMOZYGOUS ANIMALS 3477 02:40:11,080 --> 02:40:12,480 WITH CF GENOTYPE. 3478 02:40:12,480 --> 02:40:16,200 JUST A QUICK REVIEW OF PATHOLOGY 3479 02:40:16,200 --> 02:40:17,120 COLLABORATIONS THAT WERE DONE ON 3480 02:40:17,120 --> 02:40:19,160 THE ANIMALS AND WHAT WE 3481 02:40:19,160 --> 02:40:20,360 CURRENTLY OBSERVE. 3482 02:40:20,360 --> 02:40:26,160 SO IT'S VERY SIMILAR TO JUST 3483 02:40:26,160 --> 02:40:28,760 DESCRIBED BY PREVIOUS SPEAKER, 3484 02:40:28,760 --> 02:40:32,800 WE SEE MECONIUM ILEUS IN 100% OF 3485 02:40:32,800 --> 02:40:35,640 CF ANIMALS, WHICH IS WILD TYPE 3486 02:40:35,640 --> 02:40:38,760 ON THE LEFT PANEL, AND YOU SEE 3487 02:40:38,760 --> 02:40:44,520 IN B AND D PANELS, CF MECONIUM 3488 02:40:44,520 --> 02:40:44,960 ILEUS. 3489 02:40:44,960 --> 02:40:50,000 THE ARROW POINTING HERE SHOWING 3490 02:40:50,000 --> 02:40:58,120 THE ACCUMULATION OF MECONIUM IN 3491 02:40:58,120 --> 02:41:00,400 SMALL INTESTINE AND HISTOLOGICAL 3492 02:41:00,400 --> 02:41:01,560 OBSERVATION HERE SHOWN IN 3493 02:41:01,560 --> 02:41:03,440 DILATED SMALL INTESTINE. 3494 02:41:03,440 --> 02:41:07,280 IMAGES OF COLON SHOWN HERE WILL 3495 02:41:07,280 --> 02:41:08,400 OBSERVE SIMILAR HOW IT WAS SHOWN 3496 02:41:08,400 --> 02:41:12,080 IN PIG'S MICRO COLON AND ALSO 3497 02:41:12,080 --> 02:41:17,040 VERY CLEAR CHANGES IN COLONIC 3498 02:41:17,040 --> 02:41:19,000 GLANDS FILLED AND DISTENDED WITH 3499 02:41:19,000 --> 02:41:20,200 LARGE AMOUNT OF MUCUS. 3500 02:41:20,200 --> 02:41:22,920 AGAIN SIMILAR TO PIGS, WE 3501 02:41:22,920 --> 02:41:24,520 CEELITIONS IN THE PANCREAS ON 3502 02:41:24,520 --> 02:41:28,160 THE BOTTOM PANEL, THE TWO IMAGES 3503 02:41:28,160 --> 02:41:30,040 ON THE LEFT SHOW WILD TYPE 3504 02:41:30,040 --> 02:41:32,960 PANCREAS AND THEN 3505 02:41:32,960 --> 02:41:34,960 DIFFERENT DEGREE OF FIBROTIC 3506 02:41:34,960 --> 02:41:35,720 CHANGES. 3507 02:41:35,720 --> 02:41:38,800 THE MIDDLE IS MORE MODERATE 3508 02:41:38,800 --> 02:41:39,640 CHANGES WITH SOME -- WHERE WE 3509 02:41:39,640 --> 02:41:42,960 CAN SEE THAT INCREASE IN SPACE 3510 02:41:42,960 --> 02:41:47,000 BETWEEN PANCREATIC -- AND ON THE 3511 02:41:47,000 --> 02:41:49,920 RIGHT BOTTOM PANEL WE SEE MUCH 3512 02:41:49,920 --> 02:41:53,680 MORE SEVERE GU FIBROTIC CHANGESN 3513 02:41:53,680 --> 02:41:56,080 THE PANCREAS. 3514 02:41:56,080 --> 02:41:58,360 WAS ALSO OBSERVED IN CF LAMBS. 3515 02:41:58,360 --> 02:42:01,640 SHOWN ON THE TOP HERE, NORMAL 3516 02:42:01,640 --> 02:42:04,280 WILD TYPE, LIVER, AND 3517 02:42:04,280 --> 02:42:08,120 VARIOUS DEGREE OF CHANGES WITH 3518 02:42:08,120 --> 02:42:09,360 BILIARY FIBROSIS IN THE LIVER OF 3519 02:42:09,360 --> 02:42:14,640 THE CF LAMBS AND SEVERE 3520 02:42:14,640 --> 02:42:15,840 INTRAHEPATIC CHOLESTASIS 3521 02:42:15,840 --> 02:42:16,520 APPEARS. 3522 02:42:16,520 --> 02:42:18,920 SO SUMMARIZING THE OBSERVATION 3523 02:42:18,920 --> 02:42:22,640 IN -- USING OUR 3524 02:42:22,640 --> 02:42:24,600 HISTOPATHOLOGICAL ASSESSMENT, I 3525 02:42:24,600 --> 02:42:26,160 ALREADY MENTIONED THE CHANGES IN 3526 02:42:26,160 --> 02:42:32,400 INTESS TIRNINTESTINE, PANCREAS , 3527 02:42:32,400 --> 02:42:35,960 ALSO OBSERVED SIMILARLY TO PIGS, 3528 02:42:35,960 --> 02:42:37,720 MODEL HYPOPLASIA IN GALLBLADDER 3529 02:42:37,720 --> 02:42:40,920 AND WE ALSO OBSERVE THE ABSENCE 3530 02:42:40,920 --> 02:42:44,600 OF VAS DEFERENS IN THE CF MALES. 3531 02:42:44,600 --> 02:42:46,720 NO LESIONS AT BIRTH WERE 3532 02:42:46,720 --> 02:42:49,560 OBSERVED IN CF LAMB, AND WE ALSO 3533 02:42:49,560 --> 02:42:52,840 FREQUENTLY SEE HYDRONEPHROSIS, 3534 02:42:52,840 --> 02:42:56,760 WHICH IS RELATED TO COLON BUT 3535 02:42:56,760 --> 02:42:58,960 IT'S NOT A CF PHENOTYPE. 3536 02:42:58,960 --> 02:43:01,040 SO WITH THAT, I WILL PASS THE 3537 02:43:01,040 --> 02:43:02,120 MIC TO ANN. 3538 02:43:02,120 --> 02:43:03,760 ARE YOU READY, ANN? 3539 02:43:03,760 --> 02:43:10,760 >> YES, I'M HERE. 3540 02:43:10,760 --> 02:43:13,160 DO YOU SEE MY SCREEN? 3541 02:43:13,160 --> 02:43:14,240 >> YES, LOOKS GOOD. 3542 02:43:14,240 --> 02:43:15,560 >> THANK YOU VERY MUCH. 3543 02:43:15,560 --> 02:43:17,440 HOKAY. 3544 02:43:17,440 --> 02:43:18,520 SO I'M GOING TO DRILL DOWN A 3545 02:43:18,520 --> 02:43:21,600 LITTLE BIT MORE DETAIL ON SHEEP 3546 02:43:21,600 --> 02:43:24,240 CFTR AND THE USE THAT WE'RE 3547 02:43:24,240 --> 02:43:27,160 PUTTING THE CF SHEEP MODEL TO 3548 02:43:27,160 --> 02:43:29,800 ADVANCE UNDERSTANDING REALLY OF 3549 02:43:29,800 --> 02:43:31,880 HUMAN EARLY LUNG DISEASE, AND 3550 02:43:31,880 --> 02:43:36,160 OTHER ORGANS PRENATALLY WITH A 3551 02:43:36,160 --> 02:43:37,560 HOPE THIS WILL BE USEFUL GOING 3552 02:43:37,560 --> 02:43:39,200 FORWARD FOR HEMT. 3553 02:43:39,200 --> 02:43:42,360 SO JUST TO TELL YOU THAT THE 3554 02:43:42,360 --> 02:43:45,760 SHEEP CFTR PROTEIN IS REMARKABLY 3555 02:43:45,760 --> 02:43:48,160 SIMILAR TO THE HUMAN CFTR 3556 02:43:48,160 --> 02:43:50,160 PROTEIN, THESE ARE EXPERIMENTS 3557 02:43:50,160 --> 02:43:54,840 THAT WERE DONE BY CALVIN WHEN HE 3558 02:43:54,840 --> 02:43:58,040 WAS AT CASE SHOWING THE CONDUCT 3559 02:43:58,040 --> 02:44:01,200 CONDUCTANCE OF THE SHEEP CFTR 3560 02:44:01,200 --> 02:44:05,040 AND SHEEP TRACHEAL EPITHELIAL 3561 02:44:05,040 --> 02:44:06,280 CELLS, SHORT-CIRCUIT CURRENT 3562 02:44:06,280 --> 02:44:06,600 MEASUREMENTS. 3563 02:44:06,600 --> 02:44:09,160 WITH TIME, YOU CAN SEE THE RED 3564 02:44:09,160 --> 02:44:13,000 TRACES, THE CF SHEEP TRACHEAL 3565 02:44:13,000 --> 02:44:14,200 EPITHELIAL CELLS AND THE BLACK 3566 02:44:14,200 --> 02:44:15,320 DOTTED LINE THE WILD TYPE. 3567 02:44:15,320 --> 02:44:19,960 THESE ARE IN THE NULL ANIMALS 3568 02:44:19,960 --> 02:44:22,160 THAT IRINA SHOWED A MINUTE AGO. 3569 02:44:22,160 --> 02:44:27,440 FIRST BLOCKING SODIUM TRANSPORT 3570 02:44:27,440 --> 02:44:30,360 IN THE WILD TYPE WHEN YOU GET 3571 02:44:30,360 --> 02:44:31,880 FORSKALIN, YOU SEE AN ACTIVATION 3572 02:44:31,880 --> 02:44:34,440 OF THE CFTR CHANNEL, AND IN FACT 3573 02:44:34,440 --> 02:44:40,440 THAT'S INHIBITED NOT BY THE THE 3574 02:44:40,440 --> 02:44:47,200 INHIBITOR 172 BUT BY GLYH-101. 3575 02:44:47,200 --> 02:44:50,920 YOU CAN SEE DOWN HERE A SIMILAR 3576 02:44:50,920 --> 02:44:52,440 SHORT-CIRCUIT CURRENT TRACE FOR 3577 02:44:52,440 --> 02:44:54,760 HUMAN NASAL EPITHELIAL CELLS. 3578 02:44:54,760 --> 02:44:56,840 THE SHEEP CFTR CHANNEL ITSELF IS 3579 02:44:56,840 --> 02:45:00,800 A SLIGHTLY MORE ACTIVE CFTR 3580 02:45:00,800 --> 02:45:02,400 CHANNEL THAN THE HUMAN CHANNEL 3581 02:45:02,400 --> 02:45:07,600 BUT ESSENTIALLY THE MUTATIONS IN 3582 02:45:07,600 --> 02:45:09,640 THE HUMAN PROTEIN HAVE A SIMILAR 3583 02:45:09,640 --> 02:45:13,480 EFFECT ON THE SHEEP PROTEIN. 3584 02:45:13,480 --> 02:45:15,880 SO OUR INTEREST IN USING THIS 3585 02:45:15,880 --> 02:45:19,040 MODEL TO STUDY EARLY DISEASE, 3586 02:45:19,040 --> 02:45:20,920 EARLY CF DISEASE, RELATES 3587 02:45:20,920 --> 02:45:22,320 PRIMARILY TO THE FACT THAT MANY 3588 02:45:22,320 --> 02:45:26,240 YEARS AGO, WE STUDIED CFTR 3589 02:45:26,240 --> 02:45:27,240 EXPRESSION IN UTERO IN SHEEP, 3590 02:45:27,240 --> 02:45:30,160 AND WE FOUND THAT THOUGH THERE 3591 02:45:30,160 --> 02:45:33,600 IS VERY LITTLE CFTR IN THE LUNG, 3592 02:45:33,600 --> 02:45:34,880 AND OF COURSE NOW WE KNOW MUCH 3593 02:45:34,880 --> 02:45:36,560 MORE ABOUT THE CELL TYPES AND 3594 02:45:36,560 --> 02:45:42,080 THE LUNG THAT DO EXPRESS CFTR, 3595 02:45:42,080 --> 02:45:43,440 IN UTERO IN MID GESTATION IN THE 3596 02:45:43,440 --> 02:45:45,080 SHEEP AND ACTUALLY IN HUMAN, YOU 3597 02:45:45,080 --> 02:45:47,480 SEE QUITE AN ABUNDANCE OF CFTR 3598 02:45:47,480 --> 02:45:48,800 MESSENGER RNA. 3599 02:45:48,800 --> 02:45:50,440 SO THE QUESTION IS IF IT'S 3600 02:45:50,440 --> 02:45:52,400 MAKING MESSENGER RNA, LIKELY 3601 02:45:52,400 --> 02:45:55,560 MAKING PROTEIN, WHAT IS DOING 3602 02:45:55,560 --> 02:46:02,000 DURING EARLY DEVELOPMENT? 3603 02:46:02,000 --> 02:46:06,840 SO WE'VE DONE A DEVELOPMENTAL 3604 02:46:06,840 --> 02:46:08,240 TIME COURSE WITH THE TEAM IN 3605 02:46:08,240 --> 02:46:11,320 UTAH HAVE SET THIS UP FOR US, 3606 02:46:11,320 --> 02:46:15,120 AND ESSENTIALLY WE'RE TAKING 3607 02:46:15,120 --> 02:46:17,320 TISSUES FROM ALL ORGANS IN THE 3608 02:46:17,320 --> 02:46:18,960 SHEEP AT TIME POINTS THROUGH 3609 02:46:18,960 --> 02:46:20,280 GESTATION, BOTH FROM WILD TYPE 3610 02:46:20,280 --> 02:46:23,680 SHEEP AND FROM CF NULL SHEEP, 3611 02:46:23,680 --> 02:46:25,200 AND ON THIS SLIDE I JUST SHOW 3612 02:46:25,200 --> 02:46:30,240 YOU IN BLUE BASICALLY THE 3613 02:46:30,240 --> 02:46:32,200 PHENOTYPES, PANCREAS, INTESTINE, 3614 02:46:32,200 --> 02:46:35,040 LUNG, LIVER AND THE MALE GENITAL 3615 02:46:35,040 --> 02:46:36,560 DUCT IN WILD TYPE ANIMALS IN 3616 02:46:36,560 --> 02:46:40,000 BLUE, AND THE CFs IN A BUFF 3617 02:46:40,000 --> 02:46:40,520 COLOR. 3618 02:46:40,520 --> 02:46:42,800 AND WHAT YOU CAN SEE IS THAT 3619 02:46:42,800 --> 02:46:44,880 ALREADY BY BETWEEN 80 AND 100 3620 02:46:44,880 --> 02:46:46,640 DAYS OF GESTATION, WE SEE EARLY 3621 02:46:46,640 --> 02:46:54,640 PAN KPANCREATIC DISEASE, AS WE T 3622 02:46:54,640 --> 02:46:55,720 NO VISIBLE LESIONS IN THE LUNG, 3623 02:46:55,720 --> 02:46:59,440 WE SEE THE EARLY GALLBLADDER 3624 02:46:59,440 --> 02:47:00,520 DISEASE BEING REPORTED IN THE 3625 02:47:00,520 --> 02:47:02,520 OTHER LARGE ANIMAL MODELS. 3626 02:47:02,520 --> 02:47:05,440 SO WHAT WE'RE DOING HERE IS 3627 02:47:05,440 --> 02:47:06,440 WE'RE TRYING TO DRILL DOWN AND 3628 02:47:06,440 --> 02:47:08,600 THOUGH WE SEE NO ANATOMICAL 3629 02:47:08,600 --> 02:47:11,600 DEFECTS OR PATHOLOGICAL 3630 02:47:11,600 --> 02:47:12,680 HISTOLOGICAL DEFECTS IN THE 3631 02:47:12,680 --> 02:47:15,960 EARLY GESTATIONAL STAGES, WE'RE 3632 02:47:15,960 --> 02:47:17,840 LOOKING AT MORE DETAIL BY 3633 02:47:17,840 --> 02:47:19,800 LOOKING AT TRANSCRIPTOMIC 3634 02:47:19,800 --> 02:47:21,760 CHANGES, SO CHANGES IN GENE 3635 02:47:21,760 --> 02:47:22,960 EXPRESSION, BOTH IN BULK TISSUE 3636 02:47:22,960 --> 02:47:24,680 AND I'LL SHOW YOU IN A MINUTE AT 3637 02:47:24,680 --> 02:47:25,600 THE SINGLE CELL LEVEL. 3638 02:47:25,600 --> 02:47:28,200 AND THIS ENABLES US TO ASK, ARE 3639 02:47:28,200 --> 02:47:29,720 THERE SPECIFIC PATHWAYS OR 3640 02:47:29,720 --> 02:47:35,000 SPECIFIC GENES THAT ARE EITHER 3641 02:47:35,000 --> 02:47:36,200 MISREGULATED OR ALTERED IN SOME 3642 02:47:36,200 --> 02:47:39,160 WAY WHEN YOU COMPARE SHEEP WITH 3643 02:47:39,160 --> 02:47:40,440 CF TO WILD TYPE SHEEP. 3644 02:47:40,440 --> 02:47:47,680 AND THIS JUST SHOWS YOU ON THE 3645 02:47:47,680 --> 02:47:50,760 LEFT SIDE, WE'RE COMPARING LUNG 3646 02:47:50,760 --> 02:47:53,440 TYPE, LUNG 120 DAYS VERSUS 100 3647 02:47:53,440 --> 02:47:53,920 DAYS GESTATION. 3648 02:47:53,920 --> 02:47:58,080 THIS IS THE TOP IS DISTAL LUNG, 3649 02:47:58,080 --> 02:47:59,680 THE BOTTOM ONE IS PROXIMAL LUNG, 3650 02:47:59,680 --> 02:48:04,720 AND THIS VOLCANIC PLOT SHOWS 3651 02:48:04,720 --> 02:48:07,240 DIFFERENTIALLY EXPRESSED GENES, 3652 02:48:07,240 --> 02:48:12,400 DOWN REGULATED HUNDRED DAYS OR 3653 02:48:12,400 --> 02:48:13,800 UPREGULATED VERSUS 100 AND WE 3654 02:48:13,800 --> 02:48:16,560 SEE SPECIFIC GENES IN THERE LIKE 3655 02:48:16,560 --> 02:48:18,520 AQUAPORIN 5 INVOLVED IN WATER 3656 02:48:18,520 --> 02:48:19,840 TRANSPORT IN THE DISTAL LUNG AND 3657 02:48:19,840 --> 02:48:22,000 DOWN HERE WE SEE UNUSUAL 3658 02:48:22,000 --> 02:48:24,080 APPEARANCE OF SOME OF THE 3659 02:48:24,080 --> 02:48:25,520 SURFACTANT PROTEINS THAT WE'RE 3660 02:48:25,520 --> 02:48:27,600 NOT EXPECTING TO SEE AT THAT 3661 02:48:27,600 --> 02:48:27,760 AGE. 3662 02:48:27,760 --> 02:48:29,120 WE CAN ALSO, FROM THESE DATA, 3663 02:48:29,120 --> 02:48:32,400 GET A FANTASTIC IDEA OF GENE 3664 02:48:32,400 --> 02:48:33,480 EXPRESSION PROFILES, IN OTHER 3665 02:48:33,480 --> 02:48:36,040 WORDS, TAKING ALL THE DATA, AND 3666 02:48:36,040 --> 02:48:40,080 USING A PROGRAM THAT POOLS THE 3667 02:48:40,080 --> 02:48:42,360 DATABASED ON GENE EXPRESSION 3668 02:48:42,360 --> 02:48:45,520 VALUES, SO GENE EXPRESSION WITH 3669 02:48:45,520 --> 02:48:45,960 TIME. 3670 02:48:45,960 --> 02:48:47,360 WE SEE OBVIOUSLY GROUPS OF GENES 3671 02:48:47,360 --> 02:48:48,920 THAT GO DOWN WITH GESTATION, 3672 02:48:48,920 --> 02:48:50,360 OTHERS THAT GO UP, AND IN SOME 3673 02:48:50,360 --> 02:48:51,360 CASES ONES THAT ARE MOST 3674 02:48:51,360 --> 02:48:52,600 INTERESTING ARE THE ONES THAT GO 3675 02:48:52,600 --> 02:48:54,280 UP AND DOWN. 3676 02:48:54,280 --> 02:48:57,880 SO THIS CLASS OF GENES ARE 3677 02:48:57,880 --> 02:49:00,520 HIGHER 80 DAYS LOWER TO 100 THEN 3678 02:49:00,520 --> 02:49:01,840 THEY GO UP 120 AND THEN THEY 3679 02:49:01,840 --> 02:49:02,280 FALL OFF. 3680 02:49:02,280 --> 02:49:04,680 SO WE CAN USE ADVANCED 3681 02:49:04,680 --> 02:49:08,480 BIOINFORMATIC PROTOCOLS TO STUDY 3682 02:49:08,480 --> 02:49:09,600 BOTH INDIVIDUAL GENES AND ALSO 3683 02:49:09,600 --> 02:49:11,120 THE FUNCTIONAL PATHWAYS THAT 3684 02:49:11,120 --> 02:49:13,880 THEY BELONG TO. 3685 02:49:13,880 --> 02:49:15,920 WE'RE ALSO DOING SINGLE CELL 3686 02:49:15,920 --> 02:49:18,760 ANALYSIS TO TRY AND FIND OUT 3687 02:49:18,760 --> 02:49:22,080 WHETHER -- WHAT CELL TYPES MAY 3688 02:49:22,080 --> 02:49:23,720 BE SHOWING DIFFERENCES EARLY ON 3689 02:49:23,720 --> 02:49:25,120 IN GESTATION IN THE CF SHEEP 3690 02:49:25,120 --> 02:49:27,000 LUNG AND IF THAT PANCREAS AS 3691 02:49:27,000 --> 02:49:31,040 WELL COMPARED TO THE WILD TYPE 3692 02:49:31,040 --> 02:49:32,440 SHEEP AT THE SAME AGE. 3693 02:49:32,440 --> 02:49:34,200 THESE ARE SOME OF OUR EARLY DATA 3694 02:49:34,200 --> 02:49:37,840 SHOWING VERY NICELY THAT WE CAN 3695 02:49:37,840 --> 02:49:40,800 NOT EASILY BUT WE CAN DO ROBUST 3696 02:49:40,800 --> 02:49:42,120 SINGLE CELL RNA SEQUENCING ON 3697 02:49:42,120 --> 02:49:42,720 THE SHEEP LUNG. 3698 02:49:42,720 --> 02:49:47,920 THIS IS JUST TWIN LUNGS FROM 120 3699 02:49:47,920 --> 02:49:54,200 DAY WILD TYPE SHEEP, WE SEE NICE 3700 02:49:54,200 --> 02:49:56,760 DONOR CONTRIBUTION TO ALL THE 3701 02:49:56,760 --> 02:49:57,960 CLUSTERS, AND WHEN WE LOOK AT 3702 02:49:57,960 --> 02:49:59,680 THE DIFFERENT CLUSTERS OF 3703 02:49:59,680 --> 02:50:02,200 INDIVIDUAL CELLS ON THIS U MAP 3704 02:50:02,200 --> 02:50:04,560 PLOT, WE CAN IDENTIFY MOST OF 3705 02:50:04,560 --> 02:50:06,240 THE CELL TYPES THAT WE WOULD BE 3706 02:50:06,240 --> 02:50:09,760 EXPECTING TO SEE IN A DEVELOPING 3707 02:50:09,760 --> 02:50:10,280 LUNG. 3708 02:50:10,280 --> 02:50:13,160 BUT THIS HAS NEVER BEEN DONE 3709 02:50:13,160 --> 02:50:14,480 BEFORE AT SUCH A LEVEL OF 3710 02:50:14,480 --> 02:50:15,720 RESOLUTION THAT WE CAN LOOK AT, 3711 02:50:15,720 --> 02:50:17,360 FOR EXAMPLE, WE COULD TAKE ANY 3712 02:50:17,360 --> 02:50:20,240 ONE OF THESE CLUSTERS AND 3713 02:50:20,240 --> 02:50:22,880 COMPARE GENE EXPRESSION IN CF 3714 02:50:22,880 --> 02:50:25,080 AND NON-CF ANIMALS AND LOOK AT 3715 02:50:25,080 --> 02:50:27,800 THE SINGLE CELL AND THE SINGLE 3716 02:50:27,800 --> 02:50:33,160 GENE LEVEL TO LOOK FOR CHANGES 3717 02:50:33,160 --> 02:50:36,000 THAT RELATE TO THE CF PHENOTYPE. 3718 02:50:36,000 --> 02:50:38,640 SO JUST THIS POINTS THIS OUT, 3719 02:50:38,640 --> 02:50:40,040 THIS JUST IS THE SAME PLOT AS I 3720 02:50:40,040 --> 02:50:41,160 SHOWED YOU ON THE PREVIOUS 3721 02:50:41,160 --> 02:50:43,560 SLIDE, THE SAME U MAP PLOTS 3722 02:50:43,560 --> 02:50:45,520 WHERE WE'RE JUST HIGHLIGHTING 3723 02:50:45,520 --> 02:50:48,680 THE EXPRESSION OF THE ONE, TWO, 3724 02:50:48,680 --> 02:50:50,080 THREE, FOUR DIFFERENT SURFACTANT 3725 02:50:50,080 --> 02:50:51,000 PROTEIN GENES AND YOU SEE THEY 3726 02:50:51,000 --> 02:50:53,080 DO HAVE A SLIGHTLY DIFFERENT 3727 02:50:53,080 --> 02:51:00,960 CELLULAR EXPRESSION PATTERN IN 3728 02:51:00,960 --> 02:51:02,480 THE ONE TIME POINT BUT THE 3729 02:51:02,480 --> 02:51:06,600 DIFFERENT CELL TYPES AT THAT 3730 02:51:06,600 --> 02:51:08,080 TIME POINT. 3731 02:51:08,080 --> 02:51:09,360 AND THIS IS SOMETHING WE CAN DO 3732 02:51:09,360 --> 02:51:10,600 FOR ANY OF THE GENES THAT WE'RE 3733 02:51:10,600 --> 02:51:11,800 INTERESTED IN. 3734 02:51:11,800 --> 02:51:13,520 WE ALSO HAVE ORGANOIDS FROM BOTH 3735 02:51:13,520 --> 02:51:15,680 THE PANCREAS AND THE LUNG, WHICH 3736 02:51:15,680 --> 02:51:17,320 WE'RE USING FOR FUNCTIONAL 3737 02:51:17,320 --> 02:51:23,880 STUDIES NOT ONLY FOR EYE ON ION 3738 02:51:23,880 --> 02:51:26,200 TRANSPORT BUT WE CAN MAKE 3739 02:51:26,200 --> 02:51:27,400 ORGANOIDS OF DIFFERENT LINEAGE 3740 02:51:27,400 --> 02:51:30,600 CELL TYPES TO ESSENTIALLY ASSAY 3741 02:51:30,600 --> 02:51:34,080 WHATEVER PATHWAYS WE FIND TO BE 3742 02:51:34,080 --> 02:51:35,840 DIFFERENTIALLY EXPRESSED IN THE 3743 02:51:35,840 --> 02:51:37,240 CF LUNG VERSUS THE WILD TYPE 3744 02:51:37,240 --> 02:51:38,120 LUNG. 3745 02:51:38,120 --> 02:51:41,200 SO THAT'S A QUICK RUNTHROUGH 3746 02:51:41,200 --> 02:51:44,600 SOME OF OUR INITIAL EXPERIMENTS, 3747 02:51:44,600 --> 02:51:46,120 INITIAL DATA, TO SUMMARIZE WHAT 3748 02:51:46,120 --> 02:51:50,600 I'VE SAID TO YOU, THE -- OR 3749 02:51:50,600 --> 02:51:52,480 IRINA AND I HAVE BOTH SAID THE 3750 02:51:52,480 --> 02:51:54,160 CF SHEEP HAS A SEVERE PHENOTYPE 3751 02:51:54,160 --> 02:51:56,640 THAT MIRRORS SEVERAL KEY ASPECTS 3752 02:51:56,640 --> 02:51:59,240 OF THE HUMAN PHENOTIE. AT BIRTH, 3753 02:51:59,240 --> 02:52:01,880 PANCREATIC DISEASE IS SIMILAR, 3754 02:52:01,880 --> 02:52:03,080 INTESTINAL AND LIVER DISEASE ARE 3755 02:52:03,080 --> 02:52:06,480 MORE SEVERE, MALE GENITAL DUCTS 3756 02:52:06,480 --> 02:52:07,560 ARE ALSO ABSENT. 3757 02:52:07,560 --> 02:52:09,160 IN PEOPLE WITH CF, THERE'S A 3758 02:52:09,160 --> 02:52:11,920 LACK OF GROSS LUNG PATHOLOGY AT 3759 02:52:11,920 --> 02:52:15,080 BIRTH. 3760 02:52:15,080 --> 02:52:16,840 OUR GOAL ARE TO INVESTIGATE THE 3761 02:52:16,840 --> 02:52:18,200 EARLY DEVELOPMENT OF CF DISEASE 3762 02:52:18,200 --> 02:52:19,800 IN THE KEY ORGAN SYSTEMS. 3763 02:52:19,800 --> 02:52:22,080 WE ARE ALSO TRYING TO RESTORE 3764 02:52:22,080 --> 02:52:24,920 WILD TYPE EXPRESSION IN THE 3765 02:52:24,920 --> 02:52:27,560 DIGESTIVE TRACT TO OVERCOME THE 3766 02:52:27,560 --> 02:52:28,760 PROFOUND MECONIUM ILEUS THAT 3767 02:52:28,760 --> 02:52:31,160 YOU'VE SEEN. 3768 02:52:31,160 --> 02:52:33,480 AND WE'D ALSO LIKE TO MAKE THE 3769 02:52:33,480 --> 02:52:35,440 CF SHEEP ACCESSIBLE MORE BROADLY 3770 02:52:35,440 --> 02:52:36,880 TO THE RESEARCH COMMUNITY. 3771 02:52:36,880 --> 02:52:41,360 AND AS PEOPLE PLAN FUTURE 3772 02:52:41,360 --> 02:52:45,600 EXPERIMENTS IN THE LIGHT OF THE 3773 02:52:45,600 --> 02:52:47,000 HEMT PROPOSALS, PLEASE THINK 3774 02:52:47,000 --> 02:52:49,880 ABOUT THE SHEEP BECAUSE IT 3775 02:52:49,880 --> 02:52:51,520 ACTUALLY CAN PROVIDE A RESOURCE 3776 02:52:51,520 --> 02:52:54,160 THAT -- ANOTHER LARGE ANIMAL 3777 02:52:54,160 --> 02:52:56,440 RESOURCE THAT CAN BE VERY 3778 02:52:56,440 --> 02:53:00,160 PROFOUNDLY IMPORTANT IN MAKING 3779 02:53:00,160 --> 02:53:01,680 ADVANCES. 3780 02:53:01,680 --> 02:53:03,320 MY LAST SLIDE IS JUST A -- IF I 3781 02:53:03,320 --> 02:53:07,360 CAN GET TO ADVANCE, MY LAST 3782 02:53:07,360 --> 02:53:10,320 SLIDE WAS THE SUMMARY OF 3783 02:53:10,320 --> 02:53:11,640 EVERYONE WHO'S BEEN INVOLVED. 3784 02:53:11,640 --> 02:53:13,280 THIS IS A PROJECT THAT'S BEEN 3785 02:53:13,280 --> 02:53:17,200 GOING ON FOR MANY YEARS BETWEEN 3786 02:53:17,200 --> 02:53:22,040 UNIVERSITY OF UTAH AND MOST 3787 02:53:22,040 --> 02:53:22,840 RECENTLY AT CASE WESTERN. 3788 02:53:22,840 --> 02:53:32,240 THANK YOU. 3789 02:53:32,240 --> 02:53:35,480 >> OKAY, THANK YOU, ANNE AND 3790 02:53:35,480 --> 02:53:35,680 IRINA. 3791 02:53:35,680 --> 02:53:36,960 THAT WAS A GREAT PRESENTATION ON 3792 02:53:36,960 --> 02:53:40,120 THE SHEEP MODEL. 3793 02:53:40,120 --> 02:53:41,480 SO JUMPING INTO THE Q & A 3794 02:53:41,480 --> 02:53:42,440 SESSION, WE HAVE OBVIOUSLY A 3795 02:53:42,440 --> 02:53:43,720 NUMBER OF QUESTIONS IN THE CHAT 3796 02:53:43,720 --> 02:53:48,880 SO WE THANK EVERYBODY FOR ASKING 3797 02:53:48,880 --> 02:53:49,360 THOSE. 3798 02:53:49,360 --> 02:53:50,520 SOME OF THE ANSWERS HAVE BEEN 3799 02:53:50,520 --> 02:53:51,600 DIRECTED BACK TO THE CHAT, SO 3800 02:53:51,600 --> 02:53:53,160 LOOK THERE IF YOU HAVE A 3801 02:53:53,160 --> 02:53:55,560 QUESTION THAT YOU DIDN'T HEAR AS 3802 02:53:55,560 --> 02:53:57,600 WE GO THROUGH THIS PANEL. 3803 02:53:57,600 --> 02:53:59,280 BUT THERE WERE A LOT OF 3804 02:53:59,280 --> 02:54:00,600 QUESTIONS THAT CAME THROUGH THE 3805 02:54:00,600 --> 02:54:02,640 CHAT THAT REALLY WERE TARGETED 3806 02:54:02,640 --> 02:54:04,960 TO ALL OF THE SPEAKERS, SO I 3807 02:54:04,960 --> 02:54:06,840 THINK WE'RE GOING TO START WITH 3808 02:54:06,840 --> 02:54:07,120 THOSE. 3809 02:54:07,120 --> 02:54:08,560 SO THE FIRST QUESTION FOR ALL 3810 02:54:08,560 --> 02:54:14,160 THE SPEAKERS IS FOR THE USE OF 3811 02:54:14,160 --> 02:54:17,320 ETI COMPOUNDS OR HE MT COMPOUNDS 3812 02:54:17,320 --> 02:54:19,160 IN ANIMAL OR IN VITRO MODELS, 3813 02:54:19,160 --> 02:54:20,600 WHAT'S THE SOURCE OF THE 3814 02:54:20,600 --> 02:54:24,320 MOLECULES FOR YOUR STUDIES? 3815 02:54:24,320 --> 02:54:28,800 AND IS THIS EMERGING CONSENSUS 3816 02:54:28,800 --> 02:54:30,200 FOR SOURCING THE COMPOUNDS OR 3817 02:54:30,200 --> 02:54:33,600 DOSING AMOUNTS AND REGIMENS? 3818 02:54:33,600 --> 02:54:34,600 WHO WANTS TO START WITH THAT? 3819 02:54:34,600 --> 02:54:37,880 >> I CAN SAY FOR SOURCE, I'M NOT 3820 02:54:37,880 --> 02:54:39,400 GOING TO PROMOTE ONE COMPANY 3821 02:54:39,400 --> 02:54:40,960 OVER ANOTHER, BUT IF YOU PUT IN 3822 02:54:40,960 --> 02:54:43,480 THE VX NUMBERS INTO GOOGLE AND 3823 02:54:43,480 --> 02:54:44,760 SAY FOR SALE, YOU CAN FIND 3824 02:54:44,760 --> 02:54:45,640 SEVERAL COMPANIES WHO ARE 3825 02:54:45,640 --> 02:54:46,720 SELLING THEM. 3826 02:54:46,720 --> 02:54:49,360 I'VE CHOSEN NOT TO GO THROUGH 3827 02:54:49,360 --> 02:54:50,520 VERTEX BECAUSE I FEEL LIKE SOME 3828 02:54:50,520 --> 02:54:53,400 OF THE COMPANIES THAT YOU GET 3829 02:54:53,400 --> 02:54:55,800 THE DRUGS FOR OR FROM HAVE YOU 3830 02:54:55,800 --> 02:54:57,240 KIND OF JUMP THROUGH HOOPS WHEN 3831 02:54:57,240 --> 02:55:00,800 YOU HAVE TO PUBLISH OR GET 3832 02:55:00,800 --> 02:55:02,160 EVERYTHING APPROVED, SO THAT'S 3833 02:55:02,160 --> 02:55:05,840 JUST WHAT I'LL SAY ON THAT. 3834 02:55:05,840 --> 02:55:07,800 >> YES, I'VE ACTUALLY DONE IT IN 3835 02:55:07,800 --> 02:55:09,880 MORE OF A MIXED MODEL. 3836 02:55:09,880 --> 02:55:12,960 SOME OF THE COMPOUND I'VE USED 3837 02:55:12,960 --> 02:55:14,280 STRAIGHT FROM VERTEX AND THEY 3838 02:55:14,280 --> 02:55:15,560 ACTUALLY HELPED, FOR THE RAT 3839 02:55:15,560 --> 02:55:17,960 THEY HELPED ME WITH THE INITIAL 3840 02:55:17,960 --> 02:55:19,400 DOSING CHOICE FOR IVACAFTOR. 3841 02:55:19,400 --> 02:55:23,000 AND THEN SINCE THEN, I'VE DONE 3842 02:55:23,000 --> 02:55:25,880 THE SAME SORT OF STRATEGY AS 3843 02:55:25,880 --> 02:55:27,040 CRAIG WHERE I LOOKED FOR 3844 02:55:27,040 --> 02:55:28,480 COMPANIES THAT CAN MAKE THESE 3845 02:55:28,480 --> 02:55:31,400 CHEMICALS IN BULK. 3846 02:55:31,400 --> 02:55:31,600 JOHN? 3847 02:55:31,600 --> 02:55:33,600 >> YEAH, I MEAN, WE HAVE A 3848 02:55:33,600 --> 02:55:37,440 SOURCE WHERE WE GET IT IN BULK. 3849 02:55:37,440 --> 02:55:38,840 THERE ARE MULTIPLE PLACES WHERE 3850 02:55:38,840 --> 02:55:44,240 YOU CAN BUY IT. 3851 02:55:44,240 --> 02:55:46,080 >> I THINK THE DOSING IS A 3852 02:55:46,080 --> 02:55:46,640 BIGGER CHALLENGE. 3853 02:55:46,640 --> 02:55:51,000 I THINK WHEN I STARTED THE 3854 02:55:51,000 --> 02:55:53,960 EXPERIMENTS I ASKED VERTEX, WE 3855 02:55:53,960 --> 02:55:55,240 DID FIND SOME GOOD INFORMATION 3856 02:55:55,240 --> 02:55:58,560 IN THE PRODUCT INSERT. 3857 02:55:58,560 --> 02:56:00,840 IN TERMS OF THE LARGER ANIMALS, 3858 02:56:00,840 --> 02:56:02,800 SARAH, HOW HAVE YOU HANDLED THE 3859 02:56:02,800 --> 02:56:04,480 SOURCING AND DOSING FOR YOUR 3860 02:56:04,480 --> 02:56:04,720 MODELS? 3861 02:56:04,720 --> 02:56:09,040 >> SO WE ALSO PURCHASE OURS IN 3862 02:56:09,040 --> 02:56:10,600 BULK, JUST FREE AGENT GRADE AND 3863 02:56:10,600 --> 02:56:12,000 HAVE COLLABORATED WITH SOMEONE 3864 02:56:12,000 --> 02:56:15,640 TO COMPOUND IT FOR US, AND IN 3865 02:56:15,640 --> 02:56:19,880 CHOOSING A DOSE, WE'VE MEASURED 3866 02:56:19,880 --> 02:56:20,960 PLASMA LEVELS AND JUST TO 3867 02:56:20,960 --> 02:56:23,280 MAKE -- I MEAN, OUR FIRST 3868 02:56:23,280 --> 02:56:26,240 EXPERIMENTS WERE KIND OF A 3869 02:56:26,240 --> 02:56:27,720 GUESS, AND WE WERE LUCKY THAT 3870 02:56:27,720 --> 02:56:28,960 SOME OF THE FIRST THINGS THAT WE 3871 02:56:28,960 --> 02:56:32,920 TRIED WERE SUFFICIENT TO PROVIDE 3872 02:56:32,920 --> 02:56:36,760 CORRECTION. 3873 02:56:36,760 --> 02:56:39,240 >> I'D JUST ECHO THAT THE 3874 02:56:39,240 --> 02:56:40,200 FORMULATION IS PROBABLY THE MOST 3875 02:56:40,200 --> 02:56:41,080 DIFFICULT PART OF IT ALL. 3876 02:56:41,080 --> 02:56:43,400 I MEAN, YOU HAVE TO DO THE PK, 3877 02:56:43,400 --> 02:56:46,040 AND KNOW WHERE YOU'RE AT IF YOU 3878 02:56:46,040 --> 02:56:50,720 WANT TO USE IT IN AN ANIMAL. 3879 02:56:50,720 --> 02:56:52,160 >> AND FOR THE SHEEP, ARE THERE 3880 02:56:52,160 --> 02:56:58,600 ANY DOSING INTRICACIES THAT 3881 02:56:58,600 --> 02:56:59,920 SHOULD BE TAKEN INTO 3882 02:56:59,920 --> 02:57:00,280 CONSIDERATION? 3883 02:57:00,280 --> 02:57:01,880 >> WE HAVEN'T TAKEN ON MUCH OF 3884 02:57:01,880 --> 02:57:02,760 THAT AT THE MOMENT. 3885 02:57:02,760 --> 02:57:05,720 ALTHOUGH YOU KNOW I THINK THE 3886 02:57:05,720 --> 02:57:07,480 SHEEP -- THE LAMBS ARE ABOUT THE 3887 02:57:07,480 --> 02:57:09,400 SAME SIZE AS -- BOTH ARE ABOUT 3888 02:57:09,400 --> 02:57:14,360 THE SAME SIZE AS HUMANS ARE. 3889 02:57:14,360 --> 02:57:16,000 I'M GOING TO SLIGHTLY DEFLECT 3890 02:57:16,000 --> 02:57:16,800 THAT QUESTION BECAUSE I THINK 3891 02:57:16,800 --> 02:57:18,280 ONE OF THE ISSUES THAT WE'VE HAD 3892 02:57:18,280 --> 02:57:22,320 IS WANTING TO TRY AND HELP WITH 3893 02:57:22,320 --> 02:57:25,200 THE COMPANIES WHO'VE GOT MAYBE 3894 02:57:25,200 --> 02:57:27,560 OTHER DRUGS IN THEIR PIPELINE 3895 02:57:27,560 --> 02:57:29,560 THAT AREN'T SPECIFICALLY -- FOR 3896 02:57:29,560 --> 02:57:32,640 EXAMPLE, FOR G551D, BUT FOR 3897 02:57:32,640 --> 02:57:33,840 OTHER APPROACHES TO NEW 3898 02:57:33,840 --> 02:57:37,960 THERAPIES THAT I THINK THINGS 3899 02:57:37,960 --> 02:57:40,240 DON'T SEEM AS EASY AS ONE MIGHT 3900 02:57:40,240 --> 02:57:42,480 HOPE IN TERMS OF SETTING UP 3901 02:57:42,480 --> 02:57:43,960 COLLABORATIONS THAT MIGHT 3902 02:57:43,960 --> 02:57:47,200 ADVANCE THE SUBJECT. 3903 02:57:47,200 --> 02:57:49,120 >> I THINK I SEE SOME ADDITIONAL 3904 02:57:49,120 --> 02:57:50,000 QUESTIONS ABOUT THE SPECIFIC 3905 02:57:50,000 --> 02:57:51,080 SOURCE IN THE CHAT. 3906 02:57:51,080 --> 02:57:54,720 I THINK TO AVOID MAYBE PROMOTING 3907 02:57:54,720 --> 02:57:55,600 ONE COMPANY OVER THE OTHER, IF 3908 02:57:55,600 --> 02:57:57,120 ANYBODY WANTS TO EMAIL ME OR 3909 02:57:57,120 --> 02:57:58,520 JOHN OR ANYONE ON THE PANEL TO 3910 02:57:58,520 --> 02:58:00,080 SEE EXACTLY WHERE WE'RE GETTING 3911 02:58:00,080 --> 02:58:01,360 AT, WE'D BE HAPPY TO SHARE 3912 02:58:01,360 --> 02:58:04,120 PRODUCT INFORMATION. 3913 02:58:04,120 --> 02:58:06,520 MOVING ON TO THE SECOND QUESTION 3914 02:58:06,520 --> 02:58:08,280 THEN, THIS IS ALSO FOR 3915 02:58:08,280 --> 02:58:08,800 EVERYBODY. 3916 02:58:08,800 --> 02:58:10,800 IS THERE CONSENSUS REGARDING THE 3917 02:58:10,800 --> 02:58:13,120 HIGHLY EFFECTIVE MODULATOR 3918 02:58:13,120 --> 02:58:14,760 THERAPY ON INFLAMMATORY 3919 02:58:14,760 --> 02:58:16,560 RESPONSES IN THE LUNG AND OTHER 3920 02:58:16,560 --> 02:58:18,560 ORGANS CROSSING IN VITRO AND IN 3921 02:58:18,560 --> 02:58:20,640 VIVO MODELS AND RELATING THAT 3922 02:58:20,640 --> 02:58:25,880 BACK TO THE PATIENTS? 3923 02:58:25,880 --> 02:58:34,120 ANYBODY WANT TO TAKE THIS ONE? 3924 02:58:34,120 --> 02:58:37,040 >> THAT'S A COMPLICATED ONE. 3925 02:58:37,040 --> 02:58:39,120 SO REPEAT PART OF THE QUESTION. 3926 02:58:39,120 --> 02:58:42,320 SO IT'S EVALUATING THE STATUS OF 3927 02:58:42,320 --> 02:58:43,720 INFLAMMATION TO START AND THE 3928 02:58:43,720 --> 02:58:46,000 RESPONSE OF THE HIGHLY EFFECTIVE 3929 02:58:46,000 --> 02:58:47,360 MODULATOR, IS THAT CORRECT? 3930 02:58:47,360 --> 02:58:47,880 >> RIGHT. 3931 02:58:47,880 --> 02:58:52,920 >> YOU KNOW, I'D SAY IF YOU 3932 02:58:52,920 --> 02:58:54,440 CONSIDER INFLAMMATION IN THE 3933 02:58:54,440 --> 02:58:58,240 PANCREAS, WE FIND THAT FIRST 3934 02:58:58,240 --> 02:58:59,360 THREE MONTHS OF LIFE WHERE 3935 02:58:59,360 --> 02:59:01,520 ANIMALS ARE BEING WEANED AT TWO 3936 02:59:01,520 --> 02:59:06,120 MONTHS OF LIFE, THAT THERE'S A 3937 02:59:06,120 --> 02:59:08,560 CRITICAL WINDOW WHERE IT WILL 3938 02:59:08,560 --> 02:59:10,720 DETERMINE LONGER TERM IF THE 3939 02:59:10,720 --> 02:59:12,720 ANIMAL MAINTAINS PANCREATIC 3940 02:59:12,720 --> 02:59:15,320 SUFFICIENCY, BUT UNTIL THE 3941 02:59:15,320 --> 02:59:16,720 ANIMAL IS ALMOST FULLY GROWN, 3942 02:59:16,720 --> 02:59:20,920 THERE'S THIS UNDERLYING RESIDUAL 3943 02:59:20,920 --> 02:59:24,280 INFLAMMATION THAT'S NOT 3944 02:59:24,280 --> 02:59:26,040 CORRECTED BY -- AT LEAST IN ALL 3945 02:59:26,040 --> 02:59:27,560 ANIMALS BY THE MODULATORS. 3946 02:59:27,560 --> 02:59:30,000 I SEE IT AS UNTIL THE ANIMALS 3947 02:59:30,000 --> 02:59:31,800 ARE FULLY GROWN, THE STRESS ON 3948 02:59:31,800 --> 02:59:33,600 THE PANCREAS CAN BE GREAT. 3949 02:59:33,600 --> 02:59:36,440 I MEAN, ESPECIALLY AT WEANING. 3950 02:59:36,440 --> 02:59:38,840 AND SO IF YOU DON'T HAVE ENOUGH 3951 02:59:38,840 --> 02:59:42,000 CFTR, THE PIPES GET CLOGGED AND 3952 02:59:42,000 --> 02:59:46,720 THEN -- BUT IF THE ANIMAL GOES 3953 02:59:46,720 --> 02:59:47,480 PANCREATIC-INSUFFICIENT LATER IN 3954 02:59:47,480 --> 02:59:48,560 LIFE, THEY'RE LIKELY NOT GOING 3955 02:59:48,560 --> 02:59:49,880 TO COME BACK. 3956 02:59:49,880 --> 02:59:50,760 SO IF YOU TAKE AWAY THE 3957 02:59:50,760 --> 02:59:52,760 MODULATOR, YOU'LL GET 3958 02:59:52,760 --> 02:59:58,640 INFLAMMATION. 3959 02:59:58,640 --> 03:00:00,040 -- IT BACK, BUT THEY WON'T 3960 03:00:00,040 --> 03:00:00,280 RECOVER. 3961 03:00:00,280 --> 03:00:02,800 >> SO JOHN, CAN I JUST ASK IN 3962 03:00:02,800 --> 03:00:04,320 THAT CONTEXT WHETHER YOU'VE 3963 03:00:04,320 --> 03:00:05,200 LOOKED -- I'M SURE YOU HAVE 3964 03:00:05,200 --> 03:00:07,400 LOOKED VERY CAREFULLY TO CHECK, 3965 03:00:07,400 --> 03:00:09,240 BUT YOU SAID THE TUBES GET 3966 03:00:09,240 --> 03:00:10,240 BLOCKED, BUT YOU ARE SURE 3967 03:00:10,240 --> 03:00:11,680 THERE'S NO COMPONENT OF THE 3968 03:00:11,680 --> 03:00:12,880 TUBES NOT FORMING PROPERLY IN 3969 03:00:12,880 --> 03:00:14,960 THE FIRST PLACE? 3970 03:00:14,960 --> 03:00:18,680 >> WELL, WE TREAT -- 80% OF CF 3971 03:00:18,680 --> 03:00:20,080 FERRETS, REGARDLESS OF THE 3972 03:00:20,080 --> 03:00:21,720 GENOTYPE, HAVE MECONIUM ILEUS 3973 03:00:21,720 --> 03:00:23,680 AND THERE'S SOME GENETIC 3974 03:00:23,680 --> 03:00:25,000 COMPONENT THAT PROTECTS THE 20% 3975 03:00:25,000 --> 03:00:25,640 THAT DON'T. 3976 03:00:25,640 --> 03:00:27,760 SO ALL THE ANIMALS WE'RE 3977 03:00:27,760 --> 03:00:28,760 BIRTHING, JUST BECAUSE THE 3978 03:00:28,760 --> 03:00:30,160 LOSSES ARE SO GREAT AND THE COST 3979 03:00:30,160 --> 03:00:33,960 IS TO GREAT, ARE BORN ON SOME 3980 03:00:33,960 --> 03:00:37,880 COMBINATION OF MODULATORS AT 3981 03:00:37,880 --> 03:00:38,080 BIRTH. 3982 03:00:38,080 --> 03:00:39,880 SO THIRD TRIMESTER, THEY GO ON 3983 03:00:39,880 --> 03:00:44,360 AND IT LARGELY PREVENTS MECONIUM 3984 03:00:44,360 --> 03:00:44,560 ILEUS. 3985 03:00:44,560 --> 03:00:47,080 >> AND HOW ABOUT IN THE 3986 03:00:47,080 --> 03:00:47,360 PANCREAS? 3987 03:00:47,360 --> 03:00:48,640 BECAUSE I MEAN, THAT'S THE 3988 03:00:48,640 --> 03:00:50,600 SAME -- IN PART THAT'S THE SAME 3989 03:00:50,600 --> 03:00:52,240 QUESTION, IS THAT OTHER 3990 03:00:52,240 --> 03:00:53,520 PANCREATIC DUCTS GETTING 3991 03:00:53,520 --> 03:00:54,720 OBSTRUCTED OR ARE THEY NOT 3992 03:00:54,720 --> 03:00:55,560 FORMING PROPERLY? 3993 03:00:55,560 --> 03:00:57,600 >> WE DON'T SEE -- UNLIKE THE 3994 03:00:57,600 --> 03:01:00,360 PIG AND THE SHEEP, THE AMOUNT OF 3995 03:01:00,360 --> 03:01:01,960 INJURY IN THE PANCREAS AT BIRTH 3996 03:01:01,960 --> 03:01:04,560 IS PRETTY MINIMAL IN A CF 3997 03:01:04,560 --> 03:01:06,120 FERRET, KNOCKOUT OR OTHERWISE. 3998 03:01:06,120 --> 03:01:08,000 THERE IS SOME INCREASED 3999 03:01:08,000 --> 03:01:11,640 INFLAMMATION BUT THERE'S NOT A 4000 03:01:11,640 --> 03:01:12,440 LOT OF CELL LOSS. 4001 03:01:12,440 --> 03:01:15,320 IF YOU'RE NOT ON MODULATOR, THAT 4002 03:01:15,320 --> 03:01:16,440 PROGRESSES EXTREMELY QUICKLY, 4003 03:01:16,440 --> 03:01:18,800 FIRST MONTH OF LIFE, BUT TO 4004 03:01:18,800 --> 03:01:20,720 BECOME PANCREATIC-INSUFFICIENT 4005 03:01:20,720 --> 03:01:22,960 VERY RAPIDLY. 4006 03:01:22,960 --> 03:01:26,800 THAT'S A BIT DIFFERENT THAN 4007 03:01:26,800 --> 03:01:31,520 HUMAN, WHERE THERE'S SORT OF -- 4008 03:01:31,520 --> 03:01:34,760 WE'LL WAX AND WANE, ABOVE OR 4009 03:01:34,760 --> 03:01:38,600 BELOW THAT 200 LEVEL OF FECAL 4010 03:01:38,600 --> 03:01:41,000 LASTASE THAT DEFINES PANCREATIC 4011 03:01:41,000 --> 03:01:41,360 INSUFFICIENCY. 4012 03:01:41,360 --> 03:01:44,960 SO WE DON'T SEE DEVELOPMENTAL 4013 03:01:44,960 --> 03:01:46,400 ABNORMALITIES IN THE PANCREAS. 4014 03:01:46,400 --> 03:01:46,920 >> INTERESTING. 4015 03:01:46,920 --> 03:01:48,800 THANK YOU. 4016 03:01:48,800 --> 03:01:52,160 >> THE VAS DEFERENS, YOU DO. 4017 03:01:52,160 --> 03:01:52,400 >> YES. 4018 03:01:52,400 --> 03:01:56,320 >> SUSAN, WHEN YOU'VE -- NEXT 4019 03:01:56,320 --> 03:01:57,480 QUESTION, CAN YOU GIVE US THE 4020 03:01:57,480 --> 03:01:58,840 TIME STAMP THAT'S ON THE CHAT 4021 03:01:58,840 --> 03:02:00,520 BECAUSE IT'S ACTUALLY QUITE HARD 4022 03:02:00,520 --> 03:02:01,480 TO FOLLOW WHERE YOU'RE WORKING 4023 03:02:01,480 --> 03:02:01,800 FROM. 4024 03:02:01,800 --> 03:02:03,880 >> SO ACTUALLY MARA HAS SENT ME 4025 03:02:03,880 --> 03:02:04,400 THE QUESTIONS. 4026 03:02:04,400 --> 03:02:04,960 >> I SEE. 4027 03:02:04,960 --> 03:02:06,360 THAT'S WHY I CAN'T SEE THEM. 4028 03:02:06,360 --> 03:02:06,920 THAT'S FINE. 4029 03:02:06,920 --> 03:02:08,360 >> THE QUESTIONS ARE BURIED IN 4030 03:02:08,360 --> 03:02:12,000 THE CHAT ABOVE. 4031 03:02:12,000 --> 03:02:13,720 BUT THEY ARE HARD TO FIND. 4032 03:02:13,720 --> 03:02:15,360 SO MOVING ON TO THE THIRD 4033 03:02:15,360 --> 03:02:17,320 QUESTION THEN, THIS IS, AGAIN, 4034 03:02:17,320 --> 03:02:18,320 FOR EVERYBODY. 4035 03:02:18,320 --> 03:02:23,880 GIVEN THE INCREASE IN IN UTERO 4036 03:02:23,880 --> 03:02:25,200 EXPOSURE HIGHLY EFFECTIVE 4037 03:02:25,200 --> 03:02:26,840 MODULATOR THERAPY, WHAT CAN THE 4038 03:02:26,840 --> 03:02:29,560 ANIMAL MODELS TELL US ABOUT 4039 03:02:29,560 --> 03:02:31,080 POTENTIAL NEGATIVE EFFECTS FROM 4040 03:02:31,080 --> 03:02:32,880 WITHDRAWAL FROM THE DRUG AT 4041 03:02:32,880 --> 03:02:34,920 BIRTH, BOTH FROM THE AFFECTED 4042 03:02:34,920 --> 03:02:35,920 AND NON-AFFECTED BABIES? 4043 03:02:35,920 --> 03:02:37,160 I THINK THIS WOULD BE DIRECTED 4044 03:02:37,160 --> 03:02:39,880 TOWARDS THE PIG AND FERRET 4045 03:02:39,880 --> 03:02:44,160 EXPERIMENTS PRIMARILY. 4046 03:02:44,160 --> 03:02:50,920 >> I'LL TAKE IT FIRST. 4047 03:02:50,920 --> 03:02:56,040 HETEROZYGOUS ANIMALS AREN'T 4048 03:02:56,040 --> 03:02:57,680 AFFECTED IN UTERO AFTER BIRTH. 4049 03:02:57,680 --> 03:03:03,920 CF ANIMALS BORN ON MODULATORS DO 4050 03:03:03,920 --> 03:03:06,120 VERY POORLY IF THE MODULATOR IS 4051 03:03:06,120 --> 03:03:06,960 REMOVED AT BIRTH. 4052 03:03:06,960 --> 03:03:10,600 THERE'S LIKE ZERO SURVIVAL. 4053 03:03:10,600 --> 03:03:11,920 AND THAT'S DUE TO A LOT OF 4054 03:03:11,920 --> 03:03:13,760 DIFFERENT THINGS, BUT MOSTLY THE 4055 03:03:13,760 --> 03:03:17,160 GUT, ONSET OF GUT OBSTRUCTION. 4056 03:03:17,160 --> 03:03:21,160 SO AN ANIMAL BORN OFF MODULATOR 4057 03:03:21,160 --> 03:03:25,600 AND REARED IS EASIER TO REAR 4058 03:03:25,600 --> 03:03:27,560 THAN ONE THAT'S BORN ON 4059 03:03:27,560 --> 03:03:31,160 MODULATOR AND TAKEN OFF THE 4060 03:03:31,160 --> 03:03:33,040 MODULATOR AT BIRTH, PROVIDED 4061 03:03:33,040 --> 03:03:36,080 THAT AGAIN WE LOSE 80% IF YOU'RE 4062 03:03:36,080 --> 03:03:38,720 BORN OFF MODULATOR TO MECONIUM 4063 03:03:38,720 --> 03:03:40,800 ILEUS, SO IT'S THAT SELECT 20% 4064 03:03:40,800 --> 03:03:43,520 THAT WILL BE EASIER TO REAR THAN 4065 03:03:43,520 --> 03:03:47,360 AN ANIMAL COMING OFF MODULATOR. 4066 03:03:47,360 --> 03:03:50,840 >> SO IN THE PIGS, I THINK THE 4067 03:03:50,840 --> 03:03:55,560 WILD TYPE AND HETEROZYGOUS 4068 03:03:55,560 --> 03:03:56,960 ANIMALS HAVEN'T -- IT DOESN'T 4069 03:03:56,960 --> 03:03:58,520 MATTER WHEN THEY COME OFF OF 4070 03:03:58,520 --> 03:03:59,160 MODULATORS AT BIRTH. 4071 03:03:59,160 --> 03:04:06,480 FOR THE CF ANIMALS, ONE OF THE 4072 03:04:06,480 --> 03:04:08,200 THINGS THAT WE NOTICE IS A 4073 03:04:08,200 --> 03:04:10,640 DIFFERENCE IN WEIGHT GAIN. 4074 03:04:10,640 --> 03:04:12,280 I THINK THAT'S PRETTY OBVIOUS 4075 03:04:12,280 --> 03:04:15,680 WITHIN THE FIRST WEEK. 4076 03:04:15,680 --> 03:04:16,760 OTHER THINGS ARE A LITTLE BIT 4077 03:04:16,760 --> 03:04:19,520 MORE VARIABLE. 4078 03:04:19,520 --> 03:04:21,000 SO I WOULD SAY THE WEIGHT GAIN 4079 03:04:21,000 --> 03:04:22,800 IS THE THING WE NOTICE FIRST. 4080 03:04:22,800 --> 03:04:25,520 >> I'D ALSO COMMENT THAT IF WE 4081 03:04:25,520 --> 03:04:27,160 TAKE AN ANIMAL OFF MODULATOR, 4082 03:04:27,160 --> 03:04:29,120 THEY'RE GOING ON PANCREATIC 4083 03:04:29,120 --> 03:04:29,440 ENZYMES. 4084 03:04:29,440 --> 03:04:31,000 WE'RE DOING EVERYTHING TO 4085 03:04:31,000 --> 03:04:32,440 PREVENT -- AND LAXATIVES, TO 4086 03:04:32,440 --> 03:04:38,080 PREVENT GUT AND IMPROVE WEIGHT 4087 03:04:38,080 --> 03:04:42,080 GAIN. 4088 03:04:42,080 --> 03:04:45,880 >> HAVE YOU DONE ANY MOUSE IN 4089 03:04:45,880 --> 03:04:47,600 UTERO EXPOSURES LIKE THIS? 4090 03:04:47,600 --> 03:04:49,800 >> WE'VE STARTED DOING THAT WITH 4091 03:04:49,800 --> 03:04:51,440 THE HUMANIZED AND SIMILAR TO 4092 03:04:51,440 --> 03:04:52,880 JOHN AND SARAH, WE HAVEN'T 4093 03:04:52,880 --> 03:04:57,840 REALLY SEEN ANY DIFFERENCES WHEN 4094 03:04:57,840 --> 03:04:59,760 IT COMES TO TAKING THEM OFF 4095 03:04:59,760 --> 03:05:00,760 MODULATORS ONCE THEY'RE BORN. 4096 03:05:00,760 --> 03:05:02,040 BUT THEN AGAIN, WE HAVEN'T 4097 03:05:02,040 --> 03:05:03,920 LOOKED AT SOME OF THE THINGS 4098 03:05:03,920 --> 03:05:06,680 THAT AT LEAST I'VE SEEN ONE 4099 03:05:06,680 --> 03:05:11,440 POSTER ON MAYBE ISSUES WITH LUNG 4100 03:05:11,440 --> 03:05:14,520 DEVELOPMENT WITH IN UTERO, 4101 03:05:14,520 --> 03:05:16,080 WHETHER IT'S NON-CF, I GUESS, 4102 03:05:16,080 --> 03:05:16,560 MICE. 4103 03:05:16,560 --> 03:05:19,200 WE HAVEN'T LOOKED AT THAT SO. 4104 03:05:19,200 --> 03:05:21,160 BUT AS FAR AS THEM LIVING, 4105 03:05:21,160 --> 03:05:22,560 THEY'RE JUST FINE OFF THE 4106 03:05:22,560 --> 03:05:24,000 MODULATORS. 4107 03:05:24,000 --> 03:05:26,320 THE CF MICE, ONCE YOU TAKE THEM 4108 03:05:26,320 --> 03:05:28,360 OFF, THE MODULATORS, IF YOU TAKE 4109 03:05:28,360 --> 03:05:30,120 THEM OFF EARLY ENOUGH, YEAH, 4110 03:05:30,120 --> 03:05:31,360 THEY'LL OBSTRUCT AND HAVE 4111 03:05:31,360 --> 03:05:35,960 REDUCED GROWTH. 4112 03:05:35,960 --> 03:05:37,000 >> GREAT. 4113 03:05:37,000 --> 03:05:38,320 SO THIS QUESTION ACTUALLY LEADS 4114 03:05:38,320 --> 03:05:40,840 VERY WELL INTO THE NEXT 4115 03:05:40,840 --> 03:05:45,880 QUESTION, WHICH AGAIN IS FOR 4116 03:05:45,880 --> 03:05:46,320 EVERYBODY. 4117 03:05:46,320 --> 03:05:48,920 AS DISCUSSED IN MULTIPLE 4118 03:05:48,920 --> 03:05:51,320 PRESENTATION, SOME ANIMAL MODELS 4119 03:05:51,320 --> 03:05:54,400 SHOW A MUCH HIGHER FREQUENCY OF 4120 03:05:54,400 --> 03:05:55,920 MECONIUM ILEUS OR SEVERITY OF 4121 03:05:55,920 --> 03:05:57,160 THE GI SYMPTOMS THAN THE HUMANS 4122 03:05:57,160 --> 03:05:57,920 MAY EXPERIENCE. 4123 03:05:57,920 --> 03:05:59,560 ARE THERE KNOWN FACTORS THAT 4124 03:05:59,560 --> 03:06:02,200 MITIGATE INTESTINAL PHENOTYPE IN 4125 03:06:02,200 --> 03:06:03,360 HUMAN RELATIVE TO THESE OTHER 4126 03:06:03,360 --> 03:06:10,600 MODELS? 4127 03:06:10,600 --> 03:06:12,240 >> WE KNOW IN MICE, ONCE YOU 4128 03:06:12,240 --> 03:06:14,520 START HAVING THEM NOT ON 4129 03:06:14,520 --> 03:06:17,680 GENETICALLY DISTINCT BACKGROUND, 4130 03:06:17,680 --> 03:06:18,800 THEY'LL ACTUALLY DO BETTER. 4131 03:06:18,800 --> 03:06:21,200 IN MICE, YOU WON'T HAVE AS MUCH 4132 03:06:21,200 --> 03:06:23,200 OBSTRUCTION ON WHAT WE CALL A 4133 03:06:23,200 --> 03:06:24,120 MIXED BACKGROUND, AND THAT'S 4134 03:06:24,120 --> 03:06:25,600 WHAT I WOULD SAY HUMANS ARE. 4135 03:06:25,600 --> 03:06:29,320 SO THAT WOULD BE MY ANSWER. 4136 03:06:29,320 --> 03:06:31,720 >> THERE ARE KNOWN GENETIC 4137 03:06:31,720 --> 03:06:32,240 FACTORS. 4138 03:06:32,240 --> 03:06:38,640 GAIR FACTORS, THAT IMPACT MECONM 4139 03:06:38,640 --> 03:06:38,960 ILEUS. 4140 03:06:38,960 --> 03:06:42,400 I THINK IN THE FERRET, WE KNOW 4141 03:06:42,400 --> 03:06:44,280 THESE GENETIC FACTORS OR 4142 03:06:44,280 --> 03:06:46,160 MODIFIER GENES EXIST. 4143 03:06:46,160 --> 03:06:49,080 WE'VE SEEN KNOCKOUT FERRETS, 4144 03:06:49,080 --> 03:06:53,880 VERY FEW BUT CFTR KNOCKOUT THAT 4145 03:06:53,880 --> 03:06:55,680 ARE PANCREATIC SUFFICIENT BUT 4146 03:06:55,680 --> 03:06:57,840 GET LUNG DISEASE JUST AS AN 4147 03:06:57,840 --> 03:06:58,280 EXAMPLE. 4148 03:06:58,280 --> 03:07:01,560 THERE ARE HERITABLE TRAITS IN 4149 03:07:01,560 --> 03:07:05,160 THE MECONIUM ILEUS THAT AFFECTS 4150 03:07:05,160 --> 03:07:06,160 PREDISPOSITION IN UTERO TO THAT 4151 03:07:06,160 --> 03:07:06,720 IN FERRETS. 4152 03:07:06,720 --> 03:07:08,240 SO IT'S JUST VERY DIFFICULT TO 4153 03:07:08,240 --> 03:07:10,960 TRACK DOWN THESE GENES FROM A 4154 03:07:10,960 --> 03:07:12,960 COST STANDPOINT, THE BREEDING, I 4155 03:07:12,960 --> 03:07:18,400 THINK YOU CAN ONLY DO THAT IN 4156 03:07:18,400 --> 03:07:18,720 MICE. 4157 03:07:18,720 --> 03:07:22,240 >> I AGREE THAT -- I'VE SORT OF 4158 03:07:22,240 --> 03:07:23,760 TRIED TO GO DOWN THAT PATH FOR 4159 03:07:23,760 --> 03:07:26,720 THE RAT TO FIGURE OUT IF I CAN 4160 03:07:26,720 --> 03:07:28,880 NUDGE THE INTESTINAL DISEASE TO 4161 03:07:28,880 --> 03:07:30,280 BE A LITTLE BIT MORE FAVORABLE, 4162 03:07:30,280 --> 03:07:35,480 AND IT'S A REALLY DIFFICULT 4163 03:07:35,480 --> 03:07:36,520 TOPIC. 4164 03:07:36,520 --> 03:07:37,880 >> JUST TO POINT OUT THAT IT'S 4165 03:07:37,880 --> 03:07:40,400 NOT JUST A STRAIGHTFORWARD 4166 03:07:40,400 --> 03:07:41,800 MECONIUM ILEUS, AT LEAST IN THE 4167 03:07:41,800 --> 03:07:42,800 SHEEP AND I THINK ALSO IN THE 4168 03:07:42,800 --> 03:07:43,160 PIG. 4169 03:07:43,160 --> 03:07:46,000 THERE'S ACTUALLY THIS MICRO 4170 03:07:46,000 --> 03:07:47,280 COLON PHENOMENON AND THE 4171 03:07:47,280 --> 03:07:48,480 OBSTRUCTION IS REALLY VERY HIGH 4172 03:07:48,480 --> 03:07:50,560 UP IN THE INTESTINE. 4173 03:07:50,560 --> 03:07:53,520 AND SO THERE MAY BE LOCAL 4174 03:07:53,520 --> 03:07:56,440 EFFECTS ON THE ACTUAL -- THE 4175 03:07:56,440 --> 03:07:57,680 BORDER BETWEEN THE SMALL 4176 03:07:57,680 --> 03:07:59,320 INTESTINE AND THE COLON, AND 4177 03:07:59,320 --> 03:08:02,160 THERE MAY BE DIFFERENT 4178 03:08:02,160 --> 03:08:03,600 DIFFERENCES THERE THAT MAY BE 4179 03:08:03,600 --> 03:08:07,480 CONTRIBUTING TO IT. 4180 03:08:07,480 --> 03:08:08,960 >> WHAT I'VE SEEN ACTUALLY IN 4181 03:08:08,960 --> 03:08:10,480 THE RAT IS THAT WE -- THE RAT 4182 03:08:10,480 --> 03:08:12,680 HAS LESS MECONIUM ILEUS OR SORT 4183 03:08:12,680 --> 03:08:14,320 OF INTESTINAL PROBLEMS AT BIRTH 4184 03:08:14,320 --> 03:08:19,880 LIKE SOME OF THE OTHER SPEE, BUT 4185 03:08:19,880 --> 03:08:22,000 THE INCIDENCE OF MORE OF A D IOS 4186 03:08:22,000 --> 03:08:26,680 SYNDROME LATER IN LIFE, 4187 03:08:26,680 --> 03:08:28,320 INTESTINAL OBSTRUCTIVE SYMPTOM 4188 03:08:28,320 --> 03:08:29,640 IS REALLY PERVASIVE. 4189 03:08:29,640 --> 03:08:31,880 A LOT OF THE ANIMALS THAT HAVE 4190 03:08:31,880 --> 03:08:33,400 SEVERE LUNG DISEASE ACTUALLY 4191 03:08:33,400 --> 03:08:35,280 HAVE WORSENED GI EFFECTS SOON 4192 03:08:35,280 --> 03:08:35,720 AFTER. 4193 03:08:35,720 --> 03:08:37,920 SO IT DOES SEEM LIKE THERE'S 4194 03:08:37,920 --> 03:08:39,800 SOME INTERACTION BETWEEN THE 4195 03:08:39,800 --> 03:08:42,520 WHOLE BODY PHYSIOLOGY AND THE 4196 03:08:42,520 --> 03:08:48,360 HEALTH OF THE INTESTINE AS WELL. 4197 03:08:48,360 --> 03:08:48,760 ALL RIGHT. 4198 03:08:48,760 --> 03:08:50,520 SO MOVING ON TO QUESTION FIVE, 4199 03:08:50,520 --> 03:08:52,600 FOR THE ANIMAL MODELS THAT HAVE 4200 03:08:52,600 --> 03:08:54,800 BENEFITED FROM OR REQUIRED 4201 03:08:54,800 --> 03:08:56,760 ANTIBIOTIC SUPPRESSION TO 4202 03:08:56,760 --> 03:08:57,600 IMPROVE SURVIVAL, HAS THE EARLY 4203 03:08:57,600 --> 03:08:59,480 USE OF HIGHLY EFFECTIVE 4204 03:08:59,480 --> 03:09:00,240 MODULATORS AFFECTED THE NEEDS 4205 03:09:00,240 --> 03:09:03,440 FOR THE ANTIBIOTICS OR THE 4206 03:09:03,440 --> 03:09:04,440 MICROBIOLOGY OF THE LUNG AT TIME 4207 03:09:04,440 --> 03:09:09,800 OF SACRIFICE? 4208 03:09:09,800 --> 03:09:11,960 >> I CAN MAKE A COMMENT ON THAT. 4209 03:09:11,960 --> 03:09:15,240 YOU KNOW, EARLY ON WHEN WE'VE 4210 03:09:15,240 --> 03:09:17,960 BEEN REARING CFTR KNOCKOUT 4211 03:09:17,960 --> 03:09:20,160 FERRET, WE HAD TO KEEP THEM ON 4212 03:09:20,160 --> 03:09:21,920 ANTIBIOTICS OR THEY WOULD GET 4213 03:09:21,920 --> 03:09:24,200 LUNG INFECTIONS AND DIE VERY 4214 03:09:24,200 --> 03:09:24,760 RAPIDLY. 4215 03:09:24,760 --> 03:09:26,800 MOST OF THEM WERE ENTERIC 4216 03:09:26,800 --> 03:09:28,240 BACTERIA, ENDOGENOUS TO FERRETS. 4217 03:09:28,240 --> 03:09:30,560 MORE RECENTLY, AS WE HAVE BEEN 4218 03:09:30,560 --> 03:09:34,840 REARING ANIMALS ON HIGHLY 4219 03:09:34,840 --> 03:09:36,040 EFFECTIVE MODULATORS AND TAKING 4220 03:09:36,040 --> 03:09:38,240 THEM OFF THREE MONTHS OF AGE TO 4221 03:09:38,240 --> 03:09:40,200 DEVELOP LUNG DISEASE, WHEN WE 4222 03:09:40,200 --> 03:09:41,840 FIND TO DEVELOP THE CHRONIC 4223 03:09:41,840 --> 03:09:45,200 DISEASE STATE AND LIKELY WITH 4224 03:09:45,200 --> 03:09:46,840 PSEUDOMONAS AS I SHOWED WITH 4225 03:09:46,840 --> 03:09:50,120 MUCOID CONVERSION, YOU NEED TO 4226 03:09:50,120 --> 03:09:53,320 RESCUE THEM EARLY IN LIFE. 4227 03:09:53,320 --> 03:09:58,800 AND WE RESCUE WITH MODULATORS AT 4228 03:09:58,800 --> 03:10:01,080 LEAST AT FIRST RATHER THAN 4229 03:10:01,080 --> 03:10:03,160 ANTIBIOTICS, BUT I THINK THAT 4230 03:10:03,160 --> 03:10:07,000 PROCESS THAT IS -- THAT OCCURS 4231 03:10:07,000 --> 03:10:09,920 IN HUMANS ALL THE TIME IS WHAT 4232 03:10:09,920 --> 03:10:10,880 EVOLVES THAT CHRONIC DISEASE 4233 03:10:10,880 --> 03:10:12,680 STATE WITH BACTERIA THAT DON'T 4234 03:10:12,680 --> 03:10:14,880 KILL THE HOST AS RAPIDLY AS WE 4235 03:10:14,880 --> 03:10:18,120 HAD SEEN WITH EARLY LUNG DISEASE 4236 03:10:18,120 --> 03:10:23,320 IN CFTR KNOCKOUT FERRETS. 4237 03:10:23,320 --> 03:10:25,520 >> HAVE ANY OF THE OTHER MODELS 4238 03:10:25,520 --> 03:10:29,320 USED ANTIBIOTICS IN THIS SIMILAR 4239 03:10:29,320 --> 03:10:37,840 WAY? 4240 03:10:37,840 --> 03:10:39,400 THIS LEADS ON TO WHAT WILL 4241 03:10:39,400 --> 03:10:41,240 LIKELY BE THE LAST QUESTION AS 4242 03:10:41,240 --> 03:10:42,560 WE ONLY HAVE 3 MINUTES LEFT. 4243 03:10:42,560 --> 03:10:45,440 THE QUESTION IS THAT IT'S A 4244 03:10:45,440 --> 03:10:47,280 MAJOR ADVANCE THAT SEVERAL CF 4245 03:10:47,280 --> 03:10:50,240 ANIMAL MODELS DEVELOP -- DO ANY 4246 03:10:50,240 --> 03:10:52,200 DEVELOP TRUE CHRONIC INFECTION 4247 03:10:52,200 --> 03:10:54,280 WITH THE SINGLE PERSISTENT 4248 03:10:54,280 --> 03:10:56,560 LINEAGES OF BA BACTERIA THAT 4249 03:10:56,560 --> 03:11:01,720 PRODUCE WAXING AND WANING 4250 03:11:01,720 --> 03:11:03,560 MANIFESTATIONS LIKE SEEN IN 4251 03:11:03,560 --> 03:11:03,800 HUMANS? 4252 03:11:03,800 --> 03:11:06,760 >> THE ANSWER WOULD BE NO, WE 4253 03:11:06,760 --> 03:11:09,680 HAVE TO EXOGENOUSLY PUT IN THE 4254 03:11:09,680 --> 03:11:11,560 BACTERIA TO GET THEM HAVE ANY 4255 03:11:11,560 --> 03:11:13,840 KIND OF INFLAMMATORY RESPONSE OR 4256 03:11:13,840 --> 03:11:14,200 LUNG DISEASE. 4257 03:11:14,200 --> 03:11:18,080 >> I THINK WHAT'S INTERESTING 4258 03:11:18,080 --> 03:11:20,080 WHAT WE'VE SEEN WITH THE RATS, 4259 03:11:20,080 --> 03:11:23,040 WHEN WE PUT THE BACTERIA IN, 4260 03:11:23,040 --> 03:11:25,000 MOST OF THE RATS THAT LIVE PAST 4261 03:11:25,000 --> 03:11:27,080 FOUR TO SIX WEEKS OF AGE HAVE 4262 03:11:27,080 --> 03:11:27,960 PRETTY CLEAN LUNGS BUT WHEN WE 4263 03:11:27,960 --> 03:11:29,920 DO PUT THE BACTERIA IN, IT 4264 03:11:29,920 --> 03:11:33,120 LARGELY STAYS THERE. 4265 03:11:33,120 --> 03:11:37,240 NOW WE'VE GOTTEN DETECTABLE AT 4266 03:11:37,240 --> 03:11:38,360 DAY 56 AFTER INFECTION. 4267 03:11:38,360 --> 03:11:39,880 BUP WHAT'S INTERESTING, AND IT 4268 03:11:39,880 --> 03:11:41,320 COULD BE JUST A FACTOR OF THE 4269 03:11:41,320 --> 03:11:45,000 MODEL ITSELF, WE DON'T SEE A LOT 4270 03:11:45,000 --> 03:11:46,800 OF WORSENING OF THE OVERALL 4271 03:11:46,800 --> 03:11:47,320 ANIMAL CONDITION. 4272 03:11:47,320 --> 03:11:50,240 SO WE DON'T -- WE SEE AN INITIAL 4273 03:11:50,240 --> 03:11:50,720 WEIGHT DROP. 4274 03:11:50,720 --> 03:11:52,760 OF THE ONES THAT STAY INFECTED, 4275 03:11:52,760 --> 03:11:55,280 YOU KNOW, THEY NEVER QUITE 4276 03:11:55,280 --> 03:11:57,840 RECOVER BACK TO THEIR UNINFECTED 4277 03:11:57,840 --> 03:11:59,720 LITTER MATE OR COUNTERPARTS, BUT 4278 03:11:59,720 --> 03:12:02,200 WE DON'T REALLY SEE LIKE A SLOW 4279 03:12:02,200 --> 03:12:02,520 DECLINE. 4280 03:12:02,520 --> 03:12:04,280 THEY GET THE BACTERIA IN THEIR 4281 03:12:04,280 --> 03:12:05,680 LUNGS AND THEY SORT OF COPE WITH 4282 03:12:05,680 --> 03:12:05,920 IT. 4283 03:12:05,920 --> 03:12:08,440 THEY SORT OF LIVE WITH IT. 4284 03:12:08,440 --> 03:12:10,920 I THINK WHAT'S INTERESTING ABOUT 4285 03:12:10,920 --> 03:12:12,000 THE QUESTION THE WAY IT'S POSED 4286 03:12:12,000 --> 03:12:15,320 IS THAT A LOT OF -- THE HUMAN 4287 03:12:15,320 --> 03:12:17,720 LUNG DISEASE MAY BE AFFECTED 4288 03:12:17,720 --> 03:12:20,120 POSITIVELY OR OTHERWISE BY THE 4289 03:12:20,120 --> 03:12:21,240 ANTIBIOTIC REGIMENS THAT THESE 4290 03:12:21,240 --> 03:12:22,760 PATIENTS ARE GOING ON AND COMING 4291 03:12:22,760 --> 03:12:24,840 OFF OF, AND SO ONE OF THE THINGS 4292 03:12:24,840 --> 03:12:26,080 THAT I AM INTERESTED IN MODELING 4293 03:12:26,080 --> 03:12:28,840 IN THE RATS IS RECAPITULATING 4294 03:12:28,840 --> 03:12:31,160 SOME OF THOSE ANTIBIOTIC 4295 03:12:31,160 --> 03:12:33,720 EXPOSURES TO ASK DO THE RATS 4296 03:12:33,720 --> 03:12:37,200 IMPROVE DURING ANTIBIOTIC 4297 03:12:37,200 --> 03:12:38,600 TREATMENTS OR WORSEN ONCE THEY 4298 03:12:38,600 --> 03:12:42,240 COME OFF, AND THAT KIND OF 4299 03:12:42,240 --> 03:12:45,560 THING. 4300 03:12:45,560 --> 03:12:47,240 >> IN THE FERRET, THEY GET 4301 03:12:47,240 --> 03:12:47,920 CHRONICALLY DISEASED. 4302 03:12:47,920 --> 03:12:50,760 I THINK THE NARROWING OF 4303 03:12:50,760 --> 03:12:52,440 PARDEEP'S QUESTION ABOUT IS 4304 03:12:52,440 --> 03:12:53,600 THERE CLONAL EXPANSION, WE CAN'T 4305 03:12:53,600 --> 03:12:55,800 SAY THAT FOR SURE, BUT THE 4306 03:12:55,800 --> 03:12:57,640 NARROWING OF THE TYPES OF 4307 03:12:57,640 --> 03:12:59,400 BACTERIA THAT ARE IN THE LUNG 4308 03:12:59,400 --> 03:13:02,040 TAKES QUITE A WHILE. 4309 03:13:02,040 --> 03:13:04,520 THE ONE I SHOWED WITH THE MUCOID 4310 03:13:04,520 --> 03:13:05,720 PSEUDOMONAS WHERE IT WAS PREDOM 4311 03:13:05,720 --> 03:13:07,360 NAPTLY ALL THE SAME MUTATION, WE 4312 03:13:07,360 --> 03:13:08,720 DON'T KNOW IF IT WAS CLONAL IN 4313 03:13:08,720 --> 03:13:10,560 THAT PARTICULAR CASE, BUT SAME 4314 03:13:10,560 --> 03:13:12,760 MUTATION WITHIN THE PSEUDOMONAS 4315 03:13:12,760 --> 03:13:15,480 GENOME THAT LED TO THE MUCOID 4316 03:13:15,480 --> 03:13:18,440 PHENOTYPE, THAT WAS 95% OF ALL 4317 03:13:18,440 --> 03:13:19,000 THE BACTERIA IN THE LUNG. 4318 03:13:19,000 --> 03:13:22,600 NOW THERE WERE OTHER BACTERIA IN 4319 03:13:22,600 --> 03:13:25,440 THE FLUID LINING THAT -- IT WAS 4320 03:13:25,440 --> 03:13:27,280 IN THE BOWEL, BUT THE 4321 03:13:27,280 --> 03:13:30,040 PSEUDOMONAS IS IN THE LUNG. 4322 03:13:30,040 --> 03:13:30,440 >> ALL RIGHT. 4323 03:13:30,440 --> 03:13:34,480 IT LOOKS LIKE WE'RE AT TIME. 4324 03:13:34,480 --> 03:13:36,520 THANK YOU ALL TO THE SESSION ONE 4325 03:13:36,520 --> 03:13:38,640 SPEAKERS. 4326 03:13:38,640 --> 03:13:39,960 WELCOME TO SESSION 2. 4327 03:13:39,960 --> 03:13:41,800 IN THIS SESSION WE'LL TAKE YOU 4328 03:13:41,800 --> 03:13:45,200 THROUGH A SPECTRUM OF CLINICAL 4329 03:13:45,200 --> 03:13:47,080 AND TRANSLATIONAL RESEARCH ON CF 4330 03:13:47,080 --> 03:13:49,280 LUNG DISEASE PATHOPHYSIOLOGY AND 4331 03:13:49,280 --> 03:13:50,760 PROCESSES INCLUDING STRUCTURAL 4332 03:13:50,760 --> 03:13:52,200 CHANGES WITH CHRONIC INFECTION 4333 03:13:52,200 --> 03:13:54,080 AND CROSS-TALK WITH ENDOCRINE 4334 03:13:54,080 --> 03:13:56,560 SYSTEMS AND NUTRITION AND 4335 03:13:56,560 --> 03:13:58,640 METABOLISM, THE GOAL TO DEFINE 4336 03:13:58,640 --> 03:14:05,000 CLINICAL CHALLENGES FOR CF 4337 03:14:05,000 --> 03:14:11,640 PATIENTS ON HIGHLY EFFECTIVE. 4338 03:14:11,640 --> 03:14:14,280 I'LL BE MODERATING WITH OUR 4339 03:14:14,280 --> 03:14:17,600 WORKSHOP CO-CHAIR DR. KATHERINE 4340 03:14:17,600 --> 03:14:19,960 HISERT, SCIENTIST AT NATIONAL 4341 03:14:19,960 --> 03:14:21,280 JEWISH HEALTH. 4342 03:14:21,280 --> 03:14:26,120 SO I'LL INTRODUCE THE SPEAKERS 4343 03:14:26,120 --> 03:14:26,920 AND THEY WILL PRESENT BACK TO 4344 03:14:26,920 --> 03:14:27,800 BACK AS THE FIRST SESSION AND 4345 03:14:27,800 --> 03:14:30,000 WE'LL DO THE Q&A AFTER EVERYONE 4346 03:14:30,000 --> 03:14:30,640 HAS PRESENTED. 4347 03:14:30,640 --> 03:14:35,960 WE'LL START THE SESSION WITH DR. 4348 03:14:35,960 --> 03:14:37,840 FRANK McKEON, UNIVERSITY OF 4349 03:14:37,840 --> 03:14:41,240 HOUSTON, WITH DR. WA XIAN, ALSO 4350 03:14:41,240 --> 03:14:42,440 ASSOCIATE PROFESSOR AT STEM CELL 4351 03:14:42,440 --> 03:14:48,160 CENTER AND THEY WILL COVER 4352 03:14:48,160 --> 03:14:51,640 PATHOGENIC STEM CELL VARIANTS. 4353 03:14:51,640 --> 03:14:55,840 NEXT DR. ESZTER VLADAR, 4354 03:14:55,840 --> 03:14:58,000 ASSISTANT PROFESSOR IN 4355 03:14:58,000 --> 03:14:58,880 MEDICINE-PULMONARY SCIENCE, 4356 03:14:58,880 --> 03:15:02,280 UNIVERSITY OF COLORADO ANSCHUTZ 4357 03:15:02,280 --> 03:15:04,560 MEDICAL CAMPUS, COVERING 4358 03:15:04,560 --> 03:15:06,680 EPITHELIAL AND FUNCTIONAL 4359 03:15:06,680 --> 03:15:10,160 RESPONSES OF HIGHLY EFFECTIVE 4360 03:15:10,160 --> 03:15:20,360 MODULATOR THERAPY. 4361 03:15:20,360 --> 03:15:25,920 DR. PRADEEP SINGH AND DR. ANDREA 4362 03:15:25,920 --> 03:15:26,160 KELLY. 4363 03:15:26,160 --> 03:15:28,560 AND I'LL END WITH CURRENT 4364 03:15:28,560 --> 03:15:30,200 NUTRITIONAL CHALLENGES AND GAPS 4365 03:15:30,200 --> 03:15:32,360 IN CF IN THIS POST-MODULATOR 4366 03:15:32,360 --> 03:15:33,680 WORLD. 4367 03:15:33,680 --> 03:15:41,760 WITH THAT I WILL LET DR. 4368 03:15:41,760 --> 03:15:44,520 McKEON TAKE OVER. 4369 03:15:44,520 --> 03:15:46,120 >> THANK YOU VERY MUCH. 4370 03:15:46,120 --> 03:15:47,320 TODAY I'M GOING TO TALK ABOUT 4371 03:15:47,320 --> 03:15:54,240 NEW WORK IN THE LABORATORY. 4372 03:15:54,240 --> 03:15:55,040 NONE IS PUBLISHED. 4373 03:15:55,040 --> 03:15:58,880 GOD WILLING, IT WILL BE, FOCUSED 4374 03:15:58,880 --> 03:16:01,240 ON ADVANCED POTENTIALLY 4375 03:16:01,240 --> 03:16:04,920 MODULATOR RESISTANT DISEASE. 4376 03:16:04,920 --> 03:16:06,680 4377 03:16:06,680 --> 03:16:09,600 SO, THE POINTS I WANT TO COVER 4378 03:16:09,600 --> 03:16:13,320 TODAY ARE SINGLE CELL CLONING 4379 03:16:13,320 --> 03:16:18,040 TECHNOLOGY ADAPTED TO CYSTIC 4380 03:16:18,040 --> 03:16:19,680 CYSTIC FIBROSIS LUNGS, ALL FROM 4381 03:16:19,680 --> 03:16:24,400 THE UNIVERSITY OF IOWA, FROM THE 4382 03:16:24,400 --> 03:16:26,800 TRANSPLANT CENTER THERE, BY 4383 03:16:26,800 --> 03:16:29,280 DEFINITION THEY ARE ADVANCED 4384 03:16:29,280 --> 03:16:32,280 STAGE CYSTIC FIBROSIS LUNGS, AND 4385 03:16:32,280 --> 03:16:33,680 THIS MAY ADDRESS SOME OF THE 4386 03:16:33,680 --> 03:16:39,320 ISSUES RAISED IN THAT STUNNING 4387 03:16:39,320 --> 03:16:41,120 TALK BY MELANIE LAWRENCE. 4388 03:16:41,120 --> 03:16:43,520 BUT JUST TO SUMMARIZE ALL OF 4389 03:16:43,520 --> 03:16:45,920 THIS, I'M GOING TO PRESENT, 4390 03:16:45,920 --> 03:16:48,760 CYSTIC FIBROSIS IS DOMINANT BY 4391 03:16:48,760 --> 03:16:51,400 FIVE PATHOGENIC VARIANTS, STEM 4392 03:16:51,400 --> 03:16:55,560 CELL VARIANTS WHICH IN AGGREGATE 4393 03:16:55,560 --> 03:16:57,760 RECAPITULATE THE CYSTIC FIBROSIS 4394 03:16:57,760 --> 03:16:59,040 LUNG PATHOLOGY. 4395 03:16:59,040 --> 03:17:02,760 BREAKING IT DOWN FURTHER INTO 4396 03:17:02,760 --> 03:17:05,840 SINGLE TYPES, THERE ARE THREE 4397 03:17:05,840 --> 03:17:08,240 PRO-INFLAMMATORY VARIANTS, TWO 4398 03:17:08,240 --> 03:17:12,200 PRO FIBROTIC, TWO THAT ARE 4399 03:17:12,200 --> 03:17:13,400 CONSTITUATIVELY PRODUCING MUCIN. 4400 03:17:13,400 --> 03:17:15,160 THREE OF THOSE VARIANTS ARE 4401 03:17:15,160 --> 03:17:17,760 COMING TO THOSE THAT WE'VE SEEN 4402 03:17:17,760 --> 03:17:21,640 IN COPD, AND TWO ARE NOVEL 4403 03:17:21,640 --> 03:17:24,920 PRO-INFLAMMATORY VARIANTS WE'VE 4404 03:17:24,920 --> 03:17:26,880 ONLY FAR SEEN IN CYSTIC 4405 03:17:26,880 --> 03:17:27,640 FIBROSIS. 4406 03:17:27,640 --> 03:17:28,760 SHOULD NOTE THE PATHOGENIC 4407 03:17:28,760 --> 03:17:32,400 FEATURES OF THEY CELLS ARE 4408 03:17:32,400 --> 03:17:35,040 UNAFFECTED BY CFTR GENE 4409 03:17:35,040 --> 03:17:36,280 COMPLEMENTATION OR CFTR 4410 03:17:36,280 --> 03:17:36,640 MODULATORS. 4411 03:17:36,640 --> 03:17:40,120 AND AT THE END I'LL TALK ABOUT 4412 03:17:40,120 --> 03:17:43,880 DRUG DISCOVERY FOR PARTICULARLY 4413 03:17:43,880 --> 03:17:47,120 TARGETING THESE PATHOGENIC 4414 03:17:47,120 --> 03:17:47,400 VARIANTS. 4415 03:17:47,400 --> 03:17:48,920 SO, PRETTY MUCH THIS IS A 4416 03:17:48,920 --> 03:17:56,040 SUMMARY OF HOW WE GENERATE CLONE 4417 03:17:56,040 --> 03:18:01,400 LIBRARIES, 1/1,000 OF THE 4418 03:18:01,400 --> 03:18:02,920 EPITHELIAL CELLS, THE CLONOGENIC 4419 03:18:02,920 --> 03:18:04,000 ONE OF ONES DEVELOPED IN THE 4420 03:18:04,000 --> 03:18:06,080 '70s BY HOWARD GREEN. 4421 03:18:06,080 --> 03:18:08,440 IN A STUNNING NOT A FORMAL 4422 03:18:08,440 --> 03:18:12,560 MENTORSHIP BUT ONE OF THESE 4423 03:18:12,560 --> 03:18:13,920 INTERESTING INFORMAL 4424 03:18:13,920 --> 03:18:15,160 MENTORSHIPS, WA XIAN AT THE BIG 4425 03:18:15,160 --> 03:18:21,440 HAM AND WOMEN'S - BRIGHAM AND 4426 03:18:21,440 --> 03:18:26,600 WOMEN'S AT THE TIME WANTED 4427 03:18:26,600 --> 03:18:30,760 INVESTIGATE HIGH GRADE OVARIAN 4428 03:18:30,760 --> 03:18:34,480 CANCER, NOW STEM CELL IN CHRONIC 4429 03:18:34,480 --> 03:18:36,120 INFLAMMATORY DISEASES. 4430 03:18:36,120 --> 03:18:39,960 YOU GENERATE LIBRARIES, IT'S A 4431 03:18:39,960 --> 03:18:42,360 POSITIVE SELECTION FOR 4432 03:18:42,360 --> 03:18:43,200 CLONOGENIC CELLS, DIFFERENTIATED 4433 03:18:43,200 --> 03:18:44,800 CELLS DON'T SHOW UP. 4434 03:18:44,800 --> 03:18:46,520 YOU'RE LOOKING AT JUST THE STEM 4435 03:18:46,520 --> 03:18:48,520 CELL COMPONENT. 4436 03:18:48,520 --> 03:18:51,040 BY A SINGLE CELL RNAseq 4437 03:18:51,040 --> 03:18:53,680 ANALYSIS THESE ARE FOUR CASE 4438 03:18:53,680 --> 03:18:57,280 CONTROLS FROM BOTH UNIVERSITY OF 4439 03:18:57,280 --> 03:18:57,960 CONNECTICUT AND HOUSTON 4440 03:18:57,960 --> 03:19:00,680 METHODIST HOSPITAL. 4441 03:19:00,680 --> 03:19:03,400 THESE WERE LUNG DONORS THAT 4442 03:19:03,400 --> 03:19:04,400 DIDN'T FIND RECIPIENTS. 4443 03:19:04,400 --> 03:19:05,920 THEY DON'T HAVE ANY OBVIOUS LUNG 4444 03:19:05,920 --> 03:19:06,400 DISEASE. 4445 03:19:06,400 --> 03:19:08,680 THEY HAVE SOME OF THESE 4446 03:19:08,680 --> 03:19:09,000 VARIANTS. 4447 03:19:09,000 --> 03:19:11,440 SO THESE VARIANTS ARE ALL 4448 03:19:11,440 --> 03:19:13,520 PREEXISTING, NOT ONLY IN CONTROL 4449 03:19:13,520 --> 03:19:20,360 CASES BUT THEY ARE PRESENT IN 4450 03:19:20,360 --> 03:19:21,720 MID-GESTATION, FETAL DEMISE 4451 03:19:21,720 --> 03:19:22,080 LUNG. 4452 03:19:22,080 --> 03:19:25,120 AND BUT NOW YOU LOOK AT A CYSTIC 4453 03:19:25,120 --> 03:19:26,280 FIBROSIS LUNG. 4454 03:19:26,280 --> 03:19:28,800 SO HERE IS THE NORMAL LUNG STEM 4455 03:19:28,800 --> 03:19:30,080 CELL, THIS BLUE ONE. 4456 03:19:30,080 --> 03:19:32,560 IN ALL THE NORMAL CASES IT'S THE 4457 03:19:32,560 --> 03:19:33,920 DOMINANT ONE. 4458 03:19:33,920 --> 03:19:36,200 IF YOU LOOK AT CYSTIC FIBROSIS 4459 03:19:36,200 --> 03:19:39,160 THE NORMAL GUYS ARE OVERWHELMED 4460 03:19:39,160 --> 03:19:40,960 BY THESE VARIANTS. 4461 03:19:40,960 --> 03:19:46,160 AND THESE ARE THE FOUR CYSTIC 4462 03:19:46,160 --> 03:19:47,680 FIBROSIS CASES THAT CAL PAREK 4463 03:19:47,680 --> 03:19:48,240 SENT OVER. 4464 03:19:48,240 --> 03:19:50,320 THESE VERY LITTLE IN THE WAY OF 4465 03:19:50,320 --> 03:19:51,280 NORMAL STEM CELLS ANYMORE IN 4466 03:19:51,280 --> 03:19:51,640 THESE. 4467 03:19:51,640 --> 03:19:54,120 IF YOU LOOK AT THESE WHOLE 4468 03:19:54,120 --> 03:19:58,640 LIBRARIES AS A SINGLE ENTITY, 4469 03:19:58,640 --> 03:20:00,720 XENOGRAFT INTO HIGHLY 4470 03:20:00,720 --> 03:20:02,720 IMMUNODEFICIENT MICE, THEY 4471 03:20:02,720 --> 03:20:04,000 SELF-ASSEMBLE INTO EPITHELIAL 4472 03:20:04,000 --> 03:20:04,320 CYSTS. 4473 03:20:04,320 --> 03:20:07,520 AND YOU CAN SEE THAT THE 4474 03:20:07,520 --> 03:20:12,880 EPITHELIA HERE IS PRETTY NORMAL. 4475 03:20:12,880 --> 03:20:16,200 THERE'S SOME CILIATED CELLS, 4476 03:20:16,200 --> 03:20:17,040 SOMEWHAT MUCIN-POSITIVE CELLS. 4477 03:20:17,040 --> 03:20:20,640 IF YOU DO THE SAME THING WITH 4478 03:20:20,640 --> 03:20:24,920 CYSTIC FIBROSIS LIBRARIES YOU 4479 03:20:24,920 --> 03:20:33,240 GET MASSIVE FIBROSIS, THEY 4480 03:20:33,240 --> 03:20:35,200 ATTRACT MURINE NEUTROPHILS, THE 4481 03:20:35,200 --> 03:20:38,560 ONLY IMMUNE CELL LEFT IN THE 4482 03:20:38,560 --> 03:20:39,240 IMMUNODEFICIENT NSG MOUSE, 4483 03:20:39,240 --> 03:20:41,440 PRODUCE A TREMENDOUS AMOUNT OF 4484 03:20:41,440 --> 03:20:41,880 MUCINS. 4485 03:20:41,880 --> 03:20:45,720 THAT'S JUST AT THE WHOLE LIBRARY 4486 03:20:45,720 --> 03:20:45,920 LEVEL. 4487 03:20:45,920 --> 03:20:47,640 YOU CAN USE SINGLE CELL -- 4488 03:20:47,640 --> 03:20:48,960 BECAUSE THESE ARE STEM CELLS 4489 03:20:48,960 --> 03:20:51,400 THEY ARE P 63 POSITIVE, AS IS 4490 03:20:51,400 --> 03:20:53,160 THE NORMAL LUNG STEM CELL. 4491 03:20:53,160 --> 03:20:55,240 YOU CAN USE FACT SORTING TO 4492 03:20:55,240 --> 03:21:02,360 SINGLE CELLS, THEY ARE HIGHLY 4493 03:21:02,360 --> 03:21:03,800 CLONOGENIC, YOU CAN EXPAND THEM 4494 03:21:03,800 --> 03:21:06,040 IN INFINITE MANNER AND LOOK AT 4495 03:21:06,040 --> 03:21:07,720 THEIR PROPERTIES. 4496 03:21:07,720 --> 03:21:09,680 THEY ARE CLUSTERED AS STEM CELLS 4497 03:21:09,680 --> 03:21:12,960 BUT WHEN YOU DIFFERENTIATE THEM 4498 03:21:12,960 --> 03:21:14,800 THEY ALL HAVE THESE DIFFERENT 4499 03:21:14,800 --> 03:21:15,920 POPULATIONS. 4500 03:21:15,920 --> 03:21:18,760 WE'VE BEEN ABLE TO IDENTIFY 4501 03:21:18,760 --> 03:21:21,760 THESE SIX POPULATIONS, NORMAL 4502 03:21:21,760 --> 03:21:22,520 AND FIVE VARIANTS. 4503 03:21:22,520 --> 03:21:24,560 SO WHEN YOU START EXAMINING 4504 03:21:24,560 --> 03:21:27,840 THESE AT A SINGLE CLONE LEVEL, 4505 03:21:27,840 --> 03:21:31,880 YOU REALIZE THAT CLONE 1 IS THE 4506 03:21:31,880 --> 03:21:34,400 NORMAL ONE, YOU KNOW, CLONE 2 4507 03:21:34,400 --> 03:21:36,480 GIVES A VERY SIMILAR EPITHELIUM. 4508 03:21:36,480 --> 03:21:40,720 IN FACT NORMAL DISTAL AIRWAY 4509 03:21:40,720 --> 03:21:41,040 EPITHELIUM. 4510 03:21:41,040 --> 03:21:45,240 CLONE 3 AND 4 GIVE RISE TO 4511 03:21:45,240 --> 03:21:49,200 GOBLET CELL METAPLASIA, AND 4512 03:21:49,200 --> 03:21:57,800 CLONES 5 AND 6 GIVE RISE TO 4513 03:21:57,800 --> 03:22:02,200 SQUAMOUS, ALL FIT CRITERIA FOR 4514 03:22:02,200 --> 03:22:04,480 STEM CELLS, UNIFORMLY EXPRESS 4515 03:22:04,480 --> 03:22:12,360 P62, THE STEM CELLMARKER. 4516 03:22:12,360 --> 03:22:13,320 THEY ARE INTRINSICALLY IMMORTAL, 4517 03:22:13,320 --> 03:22:15,320 NOT THE FIRST STEP TO 4518 03:22:15,320 --> 03:22:21,960 TRANSFORMATION, WE'RE NOW 4519 03:22:21,960 --> 03:22:26,280 FINDING THIS LIKE EMBRYONIC STEM 4520 03:22:26,280 --> 03:22:30,200 CELLS THESE ARE IMMORTAL. 4521 03:22:30,200 --> 03:22:31,920 VERY HIGH CLONOGENICICITY, IN 4522 03:22:31,920 --> 03:22:33,680 THIS CASE 50%, THAT NUMBER 4523 03:22:33,680 --> 03:22:35,320 DOESN'T CHANGE WITH INCREASED 4524 03:22:35,320 --> 03:22:36,640 PASSAGES. 4525 03:22:36,640 --> 03:22:39,040 THEY HAVE GENOMIC STABILITY. 4526 03:22:39,040 --> 03:22:41,920 ABSENCE OF COPY-NUMBER VARIATION 4527 03:22:41,920 --> 03:22:44,400 OR SIGNIFICANT SINGLE-NUCLEOTIDE 4528 03:22:44,400 --> 03:22:44,840 VARIATION. 4529 03:22:44,840 --> 03:22:48,880 LOOK AT THESE GENOMES OF ALL OF 4530 03:22:48,880 --> 03:22:49,760 THESE. 4531 03:22:49,760 --> 03:22:53,040 THERE'S NO COPY-NUMBER 4532 03:22:53,040 --> 03:22:54,720 VARIATION, VERY FEW SOMATIC 4533 03:22:54,720 --> 03:22:55,680 SINGLE NUCLEOTIDE POLYMORPHISMS, 4534 03:22:55,680 --> 03:22:58,720 AND YOU CAN GROW THESE CELLS 4535 03:22:58,720 --> 03:23:02,360 FOR -- THIS IS PASSAGE 25, WHICH 4536 03:23:02,360 --> 03:23:03,320 IS ROUGHLY 250 DAYS, 4537 03:23:03,320 --> 03:23:04,600 DIFFERENTIATE THEM, AND THEY 4538 03:23:04,600 --> 03:23:05,600 DON'T GET CONFUSED. 4539 03:23:05,600 --> 03:23:06,920 THEY ALWAYS KNOW WHAT THEY 4540 03:23:06,920 --> 03:23:09,120 SHOULD DO. 4541 03:23:09,120 --> 03:23:13,960 IN THIS CASE GOBLET CELL 4542 03:23:13,960 --> 03:23:15,480 METAPLASIA, SQUAMOUS CELL FOR 4543 03:23:15,480 --> 03:23:18,920 THESE TWO, APPARENTLY NORMAL 4544 03:23:18,920 --> 03:23:25,240 DISTAL AIRWAY EPITHELIUM. 4545 03:23:25,240 --> 03:23:26,200 >> FIVE MINUTE WARNING. 4546 03:23:26,200 --> 03:23:28,760 >> ALL OF THESE -- HERE IS P62 4547 03:23:28,760 --> 03:23:31,360 STEM CELLS IN THE NORMAL LUNG. 4548 03:23:31,360 --> 03:23:35,760 HERE IS THE ONES WE SEE A 4549 03:23:35,760 --> 03:23:40,560 SQUAMOUS CELL METAPLASIA AND 4550 03:23:40,560 --> 03:23:43,840 GOBLET CELL METAPLASIA. 4551 03:23:43,840 --> 03:23:44,680 THIS PRO-INFLAMMATORY OF VARIANT 4552 03:23:44,680 --> 03:23:47,680 2, 4, AND 6, THAT'S REFLECTED IN 4553 03:23:47,680 --> 03:23:49,080 THEIR GENE EXPRESSION PROFILES 4554 03:23:49,080 --> 03:23:51,720 AND MANY OF THESE ARE PART OF 4555 03:23:51,720 --> 03:23:53,920 INNATE IMMUNE RESPONSE. 4556 03:23:53,920 --> 03:24:02,120 YOU CAN SEE RESPONSES TO 4557 03:24:02,120 --> 03:24:04,080 L ESHMANIASIS, WE THINK THESE 4558 03:24:04,080 --> 03:24:06,400 ARE INTRINSIC PART. 4559 03:24:06,400 --> 03:24:07,680 THESE PRO-INFLAMMATORY ONES 4560 03:24:07,680 --> 03:24:10,320 DRIVE THE ACTIVATION OF 4561 03:24:10,320 --> 03:24:15,320 HUVECs, FIRST SITE IN 4562 03:24:15,320 --> 03:24:17,320 LEUKOCYTE ROLLING. 4563 03:24:17,320 --> 03:24:18,560 FIBROSIS ONES TRIGGER FIBROSIS 4564 03:24:18,560 --> 03:24:24,440 IN VITRO AND IN VIVO. 4565 03:24:24,440 --> 03:24:28,600 IMPORTANTLY, IF YOU NOW CORRECT 4566 03:24:28,600 --> 03:24:30,320 THE PROPERTIES, COMPLEMENT THE 4567 03:24:30,320 --> 03:24:32,200 CFTR MUTATION IN THESE, AND JOHN 4568 03:24:32,200 --> 03:24:34,280 ENGELHARDT AND GROUP HAVE DONE 4569 03:24:34,280 --> 03:24:35,560 THE BIOPHYSICS ON THIS, THESE 4570 03:24:35,560 --> 03:24:36,560 ARE CORRECTED. 4571 03:24:36,560 --> 03:24:39,760 YOU PUT THE SAME CORRECTED ONES 4572 03:24:39,760 --> 03:24:42,840 BACK INTO MICE. 4573 03:24:42,840 --> 03:24:44,640 THEY ARE STILL PRO-INFLAMMATORY. 4574 03:24:44,640 --> 03:24:46,320 GENE EXPRESSION PROFILES ARE 4575 03:24:46,320 --> 03:24:47,400 STILL PRO-INFLAMMATORY. 4576 03:24:47,400 --> 03:24:51,880 HASN'T CHANGED THAT AT ALL. 4577 03:24:51,880 --> 03:24:54,400 THE SAME WITH THE ACTIVATION OF 4578 03:24:54,400 --> 03:24:57,040 HUVACs, THERE'S NO CHANGE IN 4579 03:24:57,040 --> 03:24:59,240 THE ABILITY OF A NORMAL CFTR 4580 03:24:59,240 --> 03:25:01,400 GENE TO DO ANYTHING THERE. 4581 03:25:01,400 --> 03:25:05,920 AND IN VIVO WE PRETTY MUCH SEE 4582 03:25:05,920 --> 03:25:06,880 THE SAME THING. 4583 03:25:06,880 --> 03:25:08,720 IN THIS CASE IT'S THE 4584 03:25:08,720 --> 03:25:09,520 MODULATORS. 4585 03:25:09,520 --> 03:25:15,200 WE DON'T SEE ANY IMPACT 4586 03:25:15,200 --> 03:25:19,240 MODULATORS ON PATHOGENIC 4587 03:25:19,240 --> 03:25:20,200 FEATURES, STILL HYPER-MUCINOUS, 4588 03:25:20,200 --> 03:25:21,520 PRO-INFLAMMATORY, PRO FIBROTIC. 4589 03:25:21,520 --> 03:25:26,120 DO WE NEED A PLAN B FOR 4590 03:25:26,120 --> 03:25:28,080 ADVANCED PLAN? 4591 03:25:28,080 --> 03:25:35,680 WE BELIEVE THE VARIANTS DOMINATE 4592 03:25:35,680 --> 03:25:37,520 ADVANCED LUNG CONDITIONS. 4593 03:25:37,520 --> 03:25:40,720 IPF IS UNDER REVIEW RIGHT NOW. 4594 03:25:40,720 --> 03:25:42,560 AND CYSTIC FIBROSIS. 4595 03:25:42,560 --> 03:25:43,880 WE PREDICT THE DISEASE IS 4596 03:25:43,880 --> 03:25:45,320 MAINTAINED BY EXPANSION OF THESE 4597 03:25:45,320 --> 03:25:46,200 VARIANTS. 4598 03:25:46,200 --> 03:25:49,000 THE QUESTION IS CAN YOU 4599 03:25:49,000 --> 03:25:52,080 SELECTIVELY ELIMINATE THESE. 4600 03:25:52,080 --> 03:25:54,200 SO WE'VE NOW LEVERAGED THE 4601 03:25:54,200 --> 03:25:58,520 IMMORTALITY OF THESE CELLS TO DO 4602 03:25:58,520 --> 03:25:59,760 HIGH-THROUGHPUT DRUG SCREENING. 4603 03:25:59,760 --> 03:26:03,240 AND IT'S VERY EASY TO DO WITH 4604 03:26:03,240 --> 03:26:05,760 THESE CLONAL VARIANTS. 4605 03:26:05,760 --> 03:26:08,200 WE HAVE COME TO WHAT WE THINK 4606 03:26:08,200 --> 03:26:10,280 ARE EXCITING LEADS, DRUG 4607 03:26:10,280 --> 03:26:13,120 COMBINATIONS THAT DO NOT AFFECT 4608 03:26:13,120 --> 03:26:15,280 THE NORMAL DISTAL AIRWAY STEM 4609 03:26:15,280 --> 03:26:19,240 CELL BUT AFFECT PRETTY MUCH 4610 03:26:19,240 --> 03:26:22,960 ACROSS THESE LUNG CONDITIONS, 4611 03:26:22,960 --> 03:26:26,880 WHETHER IT'S COPD OR CYSTIC 4612 03:26:26,880 --> 03:26:28,440 FIBROSIS OR COVID VARIANTS, 4613 03:26:28,440 --> 03:26:31,360 SEVERE ASTHMA VARIANTS OR SINGLE 4614 03:26:31,360 --> 03:26:32,040 IPF VARIANT. 4615 03:26:32,040 --> 03:26:34,000 AND JUST FOLLOWING UP ON OUR 4616 03:26:34,000 --> 03:26:36,320 LAST SESSION, I THINK WE 4617 03:26:36,320 --> 03:26:41,680 ABSOLUTELY NEED TO BRING THIS 4618 03:26:41,680 --> 03:26:43,440 TECHNOLOGY INTO ANIMAL MODELS TO 4619 03:26:43,440 --> 03:26:45,360 VALIDATE THE CONCEPT THAT 4620 03:26:45,360 --> 03:26:49,560 PATHOGENIC VARIANTS IS A COMMON 4621 03:26:49,560 --> 03:26:50,960 THEME IN SEVERE DISEASE. 4622 03:26:50,960 --> 03:26:53,680 WE NEED TO MONITOR DYNAMICS OF 4623 03:26:53,680 --> 03:26:54,760 VARIANTS WITH DISEASE PROGRESS, 4624 03:26:54,760 --> 03:26:56,320 MONITOR DYNAMICS IN RESPONSE TO 4625 03:26:56,320 --> 03:26:57,520 ACUTE INFECTION, WE BELIEVE 4626 03:26:57,520 --> 03:26:59,520 THESE CELLS ARE ALL PREEXISTING. 4627 03:26:59,520 --> 03:27:01,600 THEY ARE PRESENT IN ALL OF US, 4628 03:27:01,600 --> 03:27:03,240 AT LOW LEVELS. 4629 03:27:03,240 --> 03:27:06,960 BUT IN RESPONSE TO ACUTE 4630 03:27:06,960 --> 03:27:08,280 INFECTION, WE IMAGINE THEY COME 4631 03:27:08,280 --> 03:27:09,600 UP, WE HAVEN'T DONE THOSE 4632 03:27:09,600 --> 03:27:09,880 EXPERIMENTS. 4633 03:27:09,880 --> 03:27:14,400 OF COURSE WE WANT TO ASSESS THE 4634 03:27:14,400 --> 03:27:16,920 IMPACT OF THE CFTR MODULATORS OR 4635 03:27:16,920 --> 03:27:18,320 PROSPECTIVE DRUGS WE AND OTHERS 4636 03:27:18,320 --> 03:27:19,960 WILL BE DEVELOPING AGAINST THESE 4637 03:27:19,960 --> 03:27:20,400 VARIANTS. 4638 03:27:20,400 --> 03:27:23,560 THIS IS JUST SOME OF THE WORK 4639 03:27:23,560 --> 03:27:26,320 WE'RE DOING WITH JOHN ENGELHARDT 4640 03:27:26,320 --> 03:27:27,320 AND COLLEAGUES. 4641 03:27:27,320 --> 03:27:31,920 WE'VE NOW DEVELOPED A NEW MEDIA 4642 03:27:31,920 --> 03:27:35,000 TO CAPTURE THE STEM CELL 4643 03:27:35,000 --> 03:27:38,440 VARIANTS OF THIS, AND GOD 4644 03:27:38,440 --> 03:27:40,440 WILLING, THAT WILL PROGRESS. 4645 03:27:40,440 --> 03:27:42,080 THIS HAS INVOLVED A TON OF 4646 03:27:42,080 --> 03:27:45,280 PEOPLE FROM UNIVERSITY OF IOWA, 4647 03:27:45,280 --> 03:27:50,920 M.D. ANDERSON CANCER CENTER, 4648 03:27:50,920 --> 03:27:56,080 HOUSTON METHODIST, NATIONAL 4649 03:27:56,080 --> 03:27:59,760 JEWISH, MARK METERSKY, GROUPS AT 4650 03:27:59,760 --> 03:28:03,200 UNC, CHRIS CRUM, A NUMBER OF 4651 03:28:03,200 --> 03:28:04,280 EXCELLENT SYNTHETIC CHEMISTS 4652 03:28:04,280 --> 03:28:05,240 HELPING US. 4653 03:28:05,240 --> 03:28:08,320 I WANT TO THANK MARA FOR 4654 03:28:08,320 --> 03:28:11,400 RESCUING US FROM CERTAIN DEMISE, 4655 03:28:11,400 --> 03:28:18,520 AND MAKING SURE WE'RE FUNDING 4656 03:28:18,520 --> 03:28:20,640 FOR ALL THEIR GENEROUS SUPPORT. 4657 03:28:20,640 --> 03:28:25,520 THANK YOU. 4658 03:28:25,520 --> 03:28:31,360 4659 03:28:31,360 --> 03:28:32,240 4660 03:28:32,240 --> 03:28:37,760 >> NEXT WE HAVE DR. VLADAR 4661 03:28:37,760 --> 03:28:39,880 TALKING. 4662 03:28:39,880 --> 03:28:45,880 4663 03:28:45,880 --> 03:28:50,880 4664 03:28:50,880 --> 03:28:52,480 >> CAN YOU ADVANCE THE SLIDES? 4665 03:28:52,480 --> 03:28:53,720 >> WE'RE GETTING YOUR SLIDES UP. 4666 03:28:53,720 --> 03:28:54,120 >> ALL RIGHT. 4667 03:28:54,120 --> 03:28:56,280 THANK YOU SO MUCH FOR THE 4668 03:28:56,280 --> 03:28:59,720 ORGANIZERS AND THE REST OF THE 4669 03:28:59,720 --> 03:29:00,560 SPEAKERS FOR THIS WONDERFUL 4670 03:29:00,560 --> 03:29:00,760 PROGRAM. 4671 03:29:00,760 --> 03:29:03,080 IT'S MY PLEASURE TO TELL YOU 4672 03:29:03,080 --> 03:29:09,080 ABOUT WHAT WE COULD LEARN FROM 4673 03:29:09,080 --> 03:29:10,480 THE EPITHELIAL TRANSCRIPTIONAL 4674 03:29:10,480 --> 03:29:12,800 AND RESPONSES TO MODULATOR 4675 03:29:12,800 --> 03:29:16,440 THERAPY IN CYSTIC FIBROSIS LUNG 4676 03:29:16,440 --> 03:29:16,840 DISEASE. 4677 03:29:16,840 --> 03:29:19,680 I HAVE NO -- NEXT SLIDE PLEASE. 4678 03:29:19,680 --> 03:29:25,000 I HAVE NO DISCLOSURES. 4679 03:29:25,000 --> 03:29:25,200 NEXT. 4680 03:29:25,200 --> 03:29:27,040 BUT I HAVE A LOT OF 4681 03:29:27,040 --> 03:29:33,040 ACKNOWLEDGMENTS, A TEAM OF 4682 03:29:33,040 --> 03:29:36,800 COLLABORATORS LED BY JEN TAYLOR 4683 03:29:36,800 --> 03:29:42,240 AND KATIE HISERT AND MAX 4684 03:29:42,240 --> 03:29:42,720 SEIBOLD. 4685 03:29:42,720 --> 03:29:43,000 NEXT. 4686 03:29:43,000 --> 03:29:43,800 ALL RIGHT. 4687 03:29:43,800 --> 03:29:45,440 I WILL START WITH THE PROBLEM 4688 03:29:45,440 --> 03:29:47,280 THAT WE'RE TRYING TO ADDRESS 4689 03:29:47,280 --> 03:29:52,440 WHICH IS THE EXTENSIVE 4690 03:29:52,440 --> 03:29:54,280 STRUCTURAL AND FUNCTIONAL DEFECT 4691 03:29:54,280 --> 03:29:57,360 CHARACTERIZED EPITHELIUM. 4692 03:29:57,360 --> 03:29:58,480 AS ILLUSTRATED BY SCANNING 4693 03:29:58,480 --> 03:30:06,200 IMAGES OF THE APICAL SURFACE OF 4694 03:30:06,200 --> 03:30:08,160 TURBINATES, CF AIR WAY FROM A 4695 03:30:08,160 --> 03:30:13,440 SINGLE DONOR IS HIGHLY VARIABLE 4696 03:30:13,440 --> 03:30:15,840 RANGING FROM NEARLY NORMAL TO 4697 03:30:15,840 --> 03:30:22,640 HIGHLY ABNORMAL. 4698 03:30:22,640 --> 03:30:24,000 THESE ARE ASSOCIATED WITH 4699 03:30:24,000 --> 03:30:26,160 DISEASE PHENOTYPES AS WELL. 4700 03:30:26,160 --> 03:30:27,480 THERE'S SOME EVIDENCE THAT SOME 4701 03:30:27,480 --> 03:30:33,120 TYPE OR EXTENT OF REMODELING MAY 4702 03:30:33,120 --> 03:30:33,720 BE IRREVERSIBLE. 4703 03:30:33,720 --> 03:30:35,400 WE PRIMARILY STUDY CF EPITHELIUM 4704 03:30:35,400 --> 03:30:36,680 AND I'LL COME BACK TO 4705 03:30:36,680 --> 03:30:37,400 SPECIFICALLY ADDRESS THE 4706 03:30:37,400 --> 03:30:38,840 RELATIONSHIP AND RELEVANCE OF 4707 03:30:38,840 --> 03:30:42,920 THAT TO LOWER AIRWAY DISEASE. 4708 03:30:42,920 --> 03:30:43,120 NEXT. 4709 03:30:43,120 --> 03:30:49,440 NEXT SLIDE. 4710 03:30:49,440 --> 03:30:51,520 I WILL BRIEFLY MENTION THAT 4711 03:30:51,520 --> 03:30:52,840 REMODELING PHENOTYPES IN VIVO 4712 03:30:52,840 --> 03:31:00,480 AIRWAYS ARE REFLECTED IN PRIMARY 4713 03:31:00,480 --> 03:31:03,880 CULTURE, ISOLATED FROM DONOR 4714 03:31:03,880 --> 03:31:05,320 TISSUE TO STUDY FUNCTIONAL 4715 03:31:05,320 --> 03:31:05,680 OUTCOMES. 4716 03:31:05,680 --> 03:31:08,840 YOU CAN SEE DISEASE DONOR TISSUE 4717 03:31:08,840 --> 03:31:12,440 LEADS TO POORLY DIFFERENTIATED 4718 03:31:12,440 --> 03:31:12,880 CULTURES. 4719 03:31:12,880 --> 03:31:14,120 NEXT PLEASE. 4720 03:31:14,120 --> 03:31:16,360 WHILE REMODELING MECHANISMS ARE 4721 03:31:16,360 --> 03:31:17,280 NOT COMPLETELY WELL UNDERSTOOD, 4722 03:31:17,280 --> 03:31:18,840 THEY ARE LIKELY TO BE COMPLEX, 4723 03:31:18,840 --> 03:31:21,400 THIS IS HOW I THINK ABOUT HOW IT 4724 03:31:21,400 --> 03:31:22,520 EVOLVES AND HOW CORRECTORS MAY 4725 03:31:22,520 --> 03:31:24,480 PLAY A ROLE IN IMPACTING IT. 4726 03:31:24,480 --> 03:31:30,080 CAN YOU JUST KEEP MOVING THROUGH 4727 03:31:30,080 --> 03:31:30,520 THE ANIMATIONS? 4728 03:31:30,520 --> 03:31:34,800 INC, 4729 03:31:34,800 --> 03:31:41,800 WE START IN EARLY LIFE, 4730 03:31:41,800 --> 03:31:43,120 DIFFICULTY CLEARING MUCUS, 4731 03:31:43,120 --> 03:31:44,680 LEADING TO REMODELING. 4732 03:31:44,680 --> 03:31:48,360 IT REMAINS UNKNOWN TO WHAT 4733 03:31:48,360 --> 03:31:50,880 EXTENT CF MODULATOR THERAPY 4734 03:31:50,880 --> 03:31:52,880 WHICH IS THE TRIPLE COMBINATION 4735 03:31:52,880 --> 03:31:55,960 IS ABLE TO RECTIFY THESE CHANGES 4736 03:31:55,960 --> 03:31:57,360 ESPECIALLY WHEN INITIATED IN 4737 03:31:57,360 --> 03:31:58,360 ADULT POPULATION WITH 4738 03:31:58,360 --> 03:32:00,320 ESTABLISHED DISEASE. 4739 03:32:00,320 --> 03:32:01,720 NEXT PLEASE. 4740 03:32:01,720 --> 03:32:06,080 WITH THIS WORKSHOP IN MIND, I 4741 03:32:06,080 --> 03:32:09,600 OUTLINED FIVE BIG GAPS FOR 4742 03:32:09,600 --> 03:32:10,880 DISCUSSION CONCERNING INITIATING 4743 03:32:10,880 --> 03:32:13,200 MODULATORS IN FOLKS WITH 4744 03:32:13,200 --> 03:32:15,160 ESTABLISHED DISEASE. 4745 03:32:15,160 --> 03:32:16,080 FIRST EPITHELIAL REMODELING, 4746 03:32:16,080 --> 03:32:17,920 DOES IT IMPROVE UPON STARTING 4747 03:32:17,920 --> 03:32:18,240 MODULATORS? 4748 03:32:18,240 --> 03:32:20,440 SECOND, WHAT IS EXTENT OF THIS 4749 03:32:20,440 --> 03:32:22,400 IMPROVEMENT OVER TIME? 4750 03:32:22,400 --> 03:32:23,720 AND IMPORTANTLY, HOW HEALTHY DO 4751 03:32:23,720 --> 03:32:26,360 WE GET COMPARED TO HEALTHY 4752 03:32:26,360 --> 03:32:26,760 INDIVIDUALS? 4753 03:32:26,760 --> 03:32:31,160 THIRD AND FOURTH, HOW USEFUL ARE 4754 03:32:31,160 --> 03:32:34,560 TRANSCRIPT OMIC METRICS, PRIMARY 4755 03:32:34,560 --> 03:32:35,960 CULTURE MODELS, CHARACTERIZING 4756 03:32:35,960 --> 03:32:37,640 AND MONITORING CF LUNG DISEASE 4757 03:32:37,640 --> 03:32:38,840 RESPONSE TO MODULATORS. 4758 03:32:38,840 --> 03:32:42,240 FINALLY HOW DO WE USE THIS INFO 4759 03:32:42,240 --> 03:32:44,640 AND APPROACHES CURRENTLY BEING 4760 03:32:44,640 --> 03:32:49,240 DEVELOPED TO ASSESS FUTURE 4761 03:32:49,240 --> 03:32:51,080 MODULATOR OUTCOME WITH MILD OR 4762 03:32:51,080 --> 03:32:52,520 DISEASE OR AGING CF IN THE 4763 03:32:52,520 --> 03:32:52,840 FUTURE. 4764 03:32:52,840 --> 03:32:56,480 I STRUCTURED THE TALK ADDRESS 4765 03:32:56,480 --> 03:32:58,360 THESE QUESTIONS. 4766 03:32:58,360 --> 03:33:01,080 NEXT PLEASE. 4767 03:33:01,080 --> 03:33:03,400 AND THEN JUST PLEASE DO ALL THE 4768 03:33:03,400 --> 03:33:03,800 ANIMATIONS. 4769 03:33:03,800 --> 03:33:05,440 ALL RIGHT. 4770 03:33:05,440 --> 03:33:08,200 I WILL JUMP INTO THIS. 4771 03:33:08,200 --> 03:33:09,640 STUDIES TO ASSESS MODULATOR 4772 03:33:09,640 --> 03:33:12,120 RESPONSE IN ADULT COHORT. 4773 03:33:12,120 --> 03:33:14,760 FIRST IS A TIMECOURSE RESPONSE 4774 03:33:14,760 --> 03:33:16,960 STUDY IN COLLABORATION TO TEST 4775 03:33:16,960 --> 03:33:19,240 HYPOTHESIS MODULATORS WILL LEAD 4776 03:33:19,240 --> 03:33:21,240 TO IMPROVEMENT IN CF-RELATED 4777 03:33:21,240 --> 03:33:22,120 SINUS DISEASE AND 4778 03:33:22,120 --> 03:33:24,120 PATIENT-REPORTED OUTCOMES AS 4779 03:33:24,120 --> 03:33:26,280 WELL AS ACCOMPANYING 4780 03:33:26,280 --> 03:33:27,280 TRANSCRIPTOMICS AND FUNCTIONAL 4781 03:33:27,280 --> 03:33:29,120 CHANGES IN THE MUCOSA AT SIX 4782 03:33:29,120 --> 03:33:32,200 MONTHS AND TWO YEARS COMPARED TO 4783 03:33:32,200 --> 03:33:32,480 BASELINE. 4784 03:33:32,480 --> 03:33:35,800 CLINICAL STUDIES HAVE BEEN 4785 03:33:35,800 --> 03:33:37,240 CARRIED OUT AND I WOULD LIKE TO 4786 03:33:37,240 --> 03:33:41,200 REFER YOU TO THE EXCELLENT 4787 03:33:41,200 --> 03:33:43,040 PAPERS BELOW WHICH DEMONSTRATE 4788 03:33:43,040 --> 03:33:45,440 TRUE TO ITS NATURE MODULATORS 4789 03:33:45,440 --> 03:33:46,800 LEAD TO SUBSTANTIAL IMPROVEMENT 4790 03:33:46,800 --> 03:33:47,880 IN SINUS DISEASE. 4791 03:33:47,880 --> 03:33:51,600 I WILL TALK ABOUT THE THIRD AIM 4792 03:33:51,600 --> 03:33:53,240 OF THE STUDY, CARRIED OUT BY MY 4793 03:33:53,240 --> 03:33:54,440 LAB. 4794 03:33:54,440 --> 03:33:56,200 WE HAVE A SECOND INDEPENDENT 4795 03:33:56,200 --> 03:33:58,080 STUDY WHICH WE CONDUCTED WITH 4796 03:33:58,080 --> 03:34:01,160 KATIE HISERT AND MAX TO TEST 4797 03:34:01,160 --> 03:34:08,120 HYPOTHESIS THE UP -- EPITHELIUM 4798 03:34:08,120 --> 03:34:08,960 WILL HAVE ALTERED FUNCTION 4799 03:34:08,960 --> 03:34:11,640 COMPARED TO HEALTHY INDIVIDUALS. 4800 03:34:11,640 --> 03:34:12,440 NEXT PLEASE. 4801 03:34:12,440 --> 03:34:15,800 BRIEFLY, THIS IS THE MODULATOR 4802 03:34:15,800 --> 03:34:20,840 TIME COURSE, WE COLLECTED NASAL 4803 03:34:20,840 --> 03:34:27,720 BRUSH BIOPSIES FROM 25 SUBJECTS, 4804 03:34:27,720 --> 03:34:34,800 RED FOR BULK RNAseq, LEFT WAS 4805 03:34:34,800 --> 03:34:35,760 USED FOR PRIMARY CULTURE. 4806 03:34:35,760 --> 03:34:38,080 AND THEN WE HAVE OUR MODULATOR 4807 03:34:38,080 --> 03:34:41,400 VERSUS HEALTHY STUDY WHERE WE 4808 03:34:41,400 --> 03:34:42,640 ENROLLED ADDITIONAL 10 CF 4809 03:34:42,640 --> 03:34:45,920 SUBJECTS AT SIX MONTHS AFTER ETI 4810 03:34:45,920 --> 03:34:50,200 THERAPY, AND NINE HEALTHY AGE 4811 03:34:50,200 --> 03:34:53,800 MATCHED SUBJECTS, RIGHT CARRIED 4812 03:34:53,800 --> 03:34:56,680 OUT SINGLE CELL SEQUENCING, LEFT 4813 03:34:56,680 --> 03:34:57,760 NOSE DID CULTURES. 4814 03:34:57,760 --> 03:35:00,720 THEN LET'S START WITH OUR FIRST 4815 03:35:00,720 --> 03:35:05,640 KNOWLEDGE GAP, DO MODULATORS 4816 03:35:05,640 --> 03:35:06,720 RECTIFY INFLAMMATORY REMODELING, 4817 03:35:06,720 --> 03:35:07,960 TIME COURSE DATA INDICATES IT 4818 03:35:07,960 --> 03:35:10,880 DOES ALTHOUGH RESPONSE IS HIGHLY 4819 03:35:10,880 --> 03:35:11,400 VARIABLE. 4820 03:35:11,400 --> 03:35:13,600 I'M SHOWING ONLY THE DATA FOR 4821 03:35:13,600 --> 03:35:18,320 THE SIX MONTHS TO BASELINE WHICH 4822 03:35:18,320 --> 03:35:20,960 LED TO 1500 DIFFERENTIALLY 4823 03:35:20,960 --> 03:35:23,880 REGULATED GENES, DOMINATED BY 4824 03:35:23,880 --> 03:35:24,320 REDUCED NEUTROPHILIC 4825 03:35:24,320 --> 03:35:24,920 INFILTRATION. 4826 03:35:24,920 --> 03:35:27,480 THIS IS A HEAT MAP THOSE THE 4827 03:35:27,480 --> 03:35:30,280 GENES, BLUE IS DOWN, RED IS UP. 4828 03:35:30,280 --> 03:35:32,320 GENES ARE BY ROWS, SUBJECT BY 4829 03:35:32,320 --> 03:35:32,560 COLUMNS. 4830 03:35:32,560 --> 03:35:34,720 YOU CAN SEE THERE IS QUITE A 4831 03:35:34,720 --> 03:35:35,840 HETEROGENEOUS RESPONSE AMONGST 4832 03:35:35,840 --> 03:35:37,920 THE SUBJECTS WHICH WE ASSIGN TO 4833 03:35:37,920 --> 03:35:41,000 GROUPS, A, B,C, AND D. 4834 03:35:41,000 --> 03:35:42,960 GOOD NEWS, VAST MAJORITY OF 4835 03:35:42,960 --> 03:35:52,400 SUBJECTS, THOSE IN B-D, 4836 03:35:52,400 --> 03:35:53,040 DECREASED INFLAMMATION, HALLMARK 4837 03:35:53,040 --> 03:35:58,960 OF ABERRANT STRUCTURE, 4838 03:35:58,960 --> 03:36:00,800 CONSISTENT WITH IMPROVED 4839 03:36:00,800 --> 03:36:01,120 REMODELING. 4840 03:36:01,120 --> 03:36:02,200 UNDERSTANDING VARIABILITY AND 4841 03:36:02,200 --> 03:36:04,600 DURABILITY OF THIS RESPONSE OVER 4842 03:36:04,600 --> 03:36:06,280 TIME AND MECHANISMS THAT DRIVE 4843 03:36:06,280 --> 03:36:07,680 CHANGES WILL BE CRITICAL TO 4844 03:36:07,680 --> 03:36:10,200 DECIPHER IN THE FUTURE AND 4845 03:36:10,200 --> 03:36:13,280 HOPEFULLY BASED ON HYPOTHESIS WE 4846 03:36:13,280 --> 03:36:14,240 CAN GENERATE FROM EXPRESSION 4847 03:36:14,240 --> 03:36:15,440 DATA. 4848 03:36:15,440 --> 03:36:16,640 NEXT PLEASE. 4849 03:36:16,640 --> 03:36:20,680 THE NEXT SECOND CRITICAL 4850 03:36:20,680 --> 03:36:22,440 KNOWLEDGE GAP IS TO KNOW WHAT IS 4851 03:36:22,440 --> 03:36:26,040 THE EXTENT OF THE IMPROVEMENT 4852 03:36:26,040 --> 03:36:28,120 OVER TIME, IMPORTANTLY WHAT IS 4853 03:36:28,120 --> 03:36:29,120 IT COMPARED TO HEALTHY 4854 03:36:29,120 --> 03:36:30,440 INDIVIDUALS THAT ARE AGE 4855 03:36:30,440 --> 03:36:31,440 MATCHED. 4856 03:36:31,440 --> 03:36:34,280 I'LL START WITH DISCLAIMER, OUR 4857 03:36:34,280 --> 03:36:41,160 TWO-YEAR SAMPLES HAVE BEEN 4858 03:36:41,160 --> 03:36:43,480 SEQUENCED, I CAN'T COMMENT ON 4859 03:36:43,480 --> 03:36:47,240 LONG-TERM CHANGES AND HOPEFULLY 4860 03:36:47,240 --> 03:36:48,360 WILL HAVE THOSE RESULTS. 4861 03:36:48,360 --> 03:36:51,560 WE'VE BEEN ABLE TO GENERATE 4862 03:36:51,560 --> 03:36:54,840 ROBUST SINGLE CELL TRANSCRIPT 4863 03:36:54,840 --> 03:36:57,800 OPENS FROM IMMUNE CELL 4864 03:36:57,800 --> 03:36:59,040 POPULATIONS, FROM CF SUBJECTS 4865 03:36:59,040 --> 03:37:01,120 ABOUT SIX MONTHS ON MODULATORS 4866 03:37:01,120 --> 03:37:03,640 AND HEALTHY INDIVIDUALS. 4867 03:37:03,640 --> 03:37:04,920 THIS PROJECTION SHOWS CELL 4868 03:37:04,920 --> 03:37:08,520 STATES RECOVERED IN OUR 4869 03:37:08,520 --> 03:37:09,080 SUBJECTS. 4870 03:37:09,080 --> 03:37:09,960 NEXT PLEASE. 4871 03:37:09,960 --> 03:37:12,040 PERHAPS NOT SURPRISINGLY WHAT WE 4872 03:37:12,040 --> 03:37:16,640 FOUND IS THAT THE CF EPITHELIUM 4873 03:37:16,640 --> 03:37:18,600 REMAINED DISTINCT FROM HEALTHY, 4874 03:37:18,600 --> 03:37:21,360 TO OUTLINE THREE EXAMPLES I'M 4875 03:37:21,360 --> 03:37:23,560 SHOWING HERE THE EXPRESSION OF 4876 03:37:23,560 --> 03:37:25,840 SPECIFIC MARKER GENES LAID ON 4877 03:37:25,840 --> 03:37:28,000 HEALTHY VERSUS CF CELL 4878 03:37:28,000 --> 03:37:32,480 POPULATIONS TO SHOW THAT FIRST 4879 03:37:32,480 --> 03:37:37,280 THE CF SINONASAL MUCOSA DISPLACE 4880 03:37:37,280 --> 03:37:40,360 SUBSTANTIAL NEUTROPHIL DOMINANT 4881 03:37:40,360 --> 03:37:42,240 INFLAMMATION, HALLMARKS OF 4882 03:37:42,240 --> 03:37:43,440 SQUAMOUS METAPLASIA. 4883 03:37:43,440 --> 03:37:46,840 NEXT PLEASE. 4884 03:37:46,840 --> 03:37:48,080 >> FIVE-MINUTE WARNING. 4885 03:37:48,080 --> 03:37:49,120 >> TO MORE BROADLY DEFINE 4886 03:37:49,120 --> 03:37:53,320 MECHANISMS THAT DRIVE THESE 4887 03:37:53,320 --> 03:38:00,040 CHANGES CARRIED OUT CELL CHAT 4888 03:38:00,040 --> 03:38:01,520 ANALYSIS, CELL-CELL SIGNALING 4889 03:38:01,520 --> 03:38:02,040 RELATIONSHIP. 4890 03:38:02,040 --> 03:38:02,960 I DON'T EXPECT YOU TO INTERPRET 4891 03:38:02,960 --> 03:38:04,600 THE DATA ON THE SCREEN BUT THIS 4892 03:38:04,600 --> 03:38:07,560 IS JUST TO SHOW THAT WE DETECT 4893 03:38:07,560 --> 03:38:13,680 SIGNIFICANT DIFFERENCE IN IMMUNE 4894 03:38:13,680 --> 03:38:14,760 SIGNALING AND EPITHELIAL 4895 03:38:14,760 --> 03:38:15,640 DIFFERENTIAL PATHWAYS, HOPING TO 4896 03:38:15,640 --> 03:38:18,480 USE MODELS TO PICK APART 4897 03:38:18,480 --> 03:38:21,880 MECHANISTIC DETAILS. 4898 03:38:21,880 --> 03:38:22,440 NEXT PLEASE. 4899 03:38:22,440 --> 03:38:24,600 THEN THIS IS A GREAT SEGUE INTO 4900 03:38:24,600 --> 03:38:26,760 THE THIRD KNOWLEDGE GAP, HOW 4901 03:38:26,760 --> 03:38:29,400 WELL THE TRANSCRIPTOMIC AND 4902 03:38:29,400 --> 03:38:30,440 PRIMARY CULTURE DATA REFLECT 4903 03:38:30,440 --> 03:38:33,000 MODULATOR RESPONSE IN PEOPLE. 4904 03:38:33,000 --> 03:38:34,120 GOING BACK TO OUR MODULATOR 4905 03:38:34,120 --> 03:38:36,880 RESPONSE TIME COURSE WE CARRIED 4906 03:38:36,880 --> 03:38:39,160 OUT EXTENSIVE ANALYSES TO SEE IF 4907 03:38:39,160 --> 03:38:39,920 THERE'S CORRELATION BETWEEN OUR 4908 03:38:39,920 --> 03:38:43,000 GENE EXPRESSION DATA AND ANY OF 4909 03:38:43,000 --> 03:38:44,560 THE SUBJECT CHARACTERISTICS OR 4910 03:38:44,560 --> 03:38:46,160 CLINICAL AND PATIENT-REPORTED 4911 03:38:46,160 --> 03:38:46,680 OUTCOMES. 4912 03:38:46,680 --> 03:38:54,800 FOCUSING ON TWO CRITICAL 4913 03:38:54,800 --> 03:38:58,120 METRICS, NEXT PLEASE, WHICH IS 4914 03:38:58,120 --> 03:38:59,760 MEASURE OF SINUS DISEASE 4915 03:38:59,760 --> 03:39:01,160 SEVERITY BY SCAN WE SAW 4916 03:39:01,160 --> 03:39:03,240 SUBSTANTIAL IMPROVEMENT IN MOST 4917 03:39:03,240 --> 03:39:04,880 BUT ONLY DETECTED SIGNIFICANT 4918 03:39:04,880 --> 03:39:06,080 CORRELATION WITH CHANGES IN 4919 03:39:06,080 --> 03:39:07,000 SINUS DISEASE SEVERITY. 4920 03:39:07,000 --> 03:39:09,680 IN FACT WE WERE ABLE TO SHOW 4921 03:39:09,680 --> 03:39:10,680 THIS CAN BE DRIVEN AND DRILLED 4922 03:39:10,680 --> 03:39:21,240 DOWN TO A A SINGLE GENE PROK2, 4923 03:39:22,360 --> 03:39:25,240 FUNCTION NOT CLEAR BUT SHOWN TO 4924 03:39:25,240 --> 03:39:27,640 BE UPREGULATED IN NEUTROPHILS BY 4925 03:39:27,640 --> 03:39:29,840 GSFT AND TO BE HIGHLY EXPRESSED 4926 03:39:29,840 --> 03:39:37,160 IN THE CF LUNG AND SUGGEST LOWER 4927 03:39:37,160 --> 03:39:43,080 PROK2 REPRESENTS REDUCTION OF 4928 03:39:43,080 --> 03:39:48,160 INFLAMMATION, AND WHY WE DIDN'T 4929 03:39:48,160 --> 03:39:50,000 DESECRETARY PROK 1A SUBJECT 4930 03:39:50,000 --> 03:39:50,440 LATER. 4931 03:39:50,440 --> 03:39:54,640 ADDRESSING PRIMARY CULTURES TO 4932 03:39:54,640 --> 03:39:57,040 STUDY MODULATOR RESPONSE USED 4933 03:39:57,040 --> 03:39:58,680 CULTURE MODEL, NOT OVERLY 4934 03:39:58,680 --> 03:40:00,120 SUPPORTIVE OF DIFFERENTIATION 4935 03:40:00,120 --> 03:40:03,160 LIKE COMMERCIAL FORMULATIONS AND 4936 03:40:03,160 --> 03:40:04,280 FOUND CONSISTENT FOR 4937 03:40:04,280 --> 03:40:08,080 TRANSCRIPTOMIC DATA SIX MONTH 4938 03:40:08,080 --> 03:40:12,240 CULTURES IMPROVED, CILIATED CELL 4939 03:40:12,240 --> 03:40:21,120 DIVERSITY, -- DIFFERENTIATION. 4940 03:40:21,120 --> 03:40:23,320 HERE INTERESTINGLY CULTURES ETI 4941 03:40:23,320 --> 03:40:29,320 COMPOUND TREATED IN VITRO HAD AN 4942 03:40:29,320 --> 03:40:30,000 EFFECT ON DIFFERENTIATION, VERY 4943 03:40:30,000 --> 03:40:32,160 INTERESTING TO UNDERSTAND IN THE 4944 03:40:32,160 --> 03:40:33,520 FUTURE, SUGGESTING STEM CELL 4945 03:40:33,520 --> 03:40:36,760 POOL ISOLATED FROM THE SAME AREA 4946 03:40:36,760 --> 03:40:39,160 SIX MONTHS APART HAVE IMPROVED 4947 03:40:39,160 --> 03:40:40,600 DIFFERENTIATION CAPACITY AT SIX 4948 03:40:40,600 --> 03:40:43,120 MONTHS COMPARED TO BASELINE AND 4949 03:40:43,120 --> 03:40:43,800 WE'RE ACTIVELY CHARACTERIZING 4950 03:40:43,800 --> 03:40:45,840 COMPOSITION AND FUNCTION OF THIS 4951 03:40:45,840 --> 03:40:48,040 POPULATION AS WELL AS PATHWAYS 4952 03:40:48,040 --> 03:40:49,040 THAT CONTROL DIFFERENTIATION 4953 03:40:49,040 --> 03:40:52,280 WHICH WILL BE CRITICAL AS WE 4954 03:40:52,280 --> 03:40:56,600 CONSIDER THESE FOR FUTURE GENE 4955 03:40:56,600 --> 03:40:58,080 THERAPY APPLICATIONS FOR 4956 03:40:58,080 --> 03:41:00,200 AGING-RELATED PHENOTYPES. 4957 03:41:00,200 --> 03:41:01,160 NEXT ONE PLEASE. 4958 03:41:01,160 --> 03:41:04,040 BRIEFLY I WANT TO TOUCH ON THIS 4959 03:41:04,040 --> 03:41:05,760 STUDY OF THE SINONASAL 4960 03:41:05,760 --> 03:41:08,160 EPITHELIUM AS PROXY FOR CF LUNG 4961 03:41:08,160 --> 03:41:09,920 DISEASE. 4962 03:41:09,920 --> 03:41:15,320 WE USE NASAL BRUSH BIOPSIES, THE 4963 03:41:15,320 --> 03:41:18,440 ARGUMENT FOR USE RESTS IN 4964 03:41:18,440 --> 03:41:20,000 UNIFIED AIR WAY HYPOTHESIS, 4965 03:41:20,000 --> 03:41:24,240 UPPER AND LOWER AIRWAYS COMPRISE 4966 03:41:24,240 --> 03:41:26,680 SINGLE UNIT AND ARISING FROM 4967 03:41:26,680 --> 03:41:28,640 COMMON INFLAMMATORY PROCESS, NOT 4968 03:41:28,640 --> 03:41:30,640 THAT THE PHENOMENON THERE'S BOTH 4969 03:41:30,640 --> 03:41:34,720 SINONASAL AND LUNG DISEASE BUT 4970 03:41:34,720 --> 03:41:36,480 TRULY A UNIFIED MECHANISM. 4971 03:41:36,480 --> 03:41:37,720 AND THERE'S REALLY A LOT TO BE 4972 03:41:37,720 --> 03:41:41,360 SAID FOR THE USE OF NASAL 4973 03:41:41,360 --> 03:41:43,040 BRUSHES CONSISTENT, IT'S EASY, 4974 03:41:43,040 --> 03:41:45,320 ALLOWS LONGITUDINAL SAMPLING. 4975 03:41:45,320 --> 03:41:48,080 NEXT PLEASE. 4976 03:41:48,080 --> 03:41:49,720 AND ONE MORE. 4977 03:41:49,720 --> 03:41:51,680 AND IT'S WIDESPREAD AND THERE'S 4978 03:41:51,680 --> 03:41:54,000 BEEN A GOOD PRECEDENT FOR THEIR 4979 03:41:54,000 --> 03:41:55,040 USE IN CF. 4980 03:41:55,040 --> 03:41:57,440 AND OTHER DISEASES LIKE ASTHMA, 4981 03:41:57,440 --> 03:41:59,120 CAREFUL STUDIES COMPARED NASAL 4982 03:41:59,120 --> 03:42:00,560 AND BRONCHIAL EPITHELIA FROM THE 4983 03:42:00,560 --> 03:42:02,040 SAME DONORS AND DIFFERENT WAYS 4984 03:42:02,040 --> 03:42:04,360 AND FOUND THEM TO BE REASONABLY 4985 03:42:04,360 --> 03:42:06,040 SIMILAR BUT NOT THE SAME. 4986 03:42:06,040 --> 03:42:08,000 WHICH THEN LEADS US TO CONSIDER 4987 03:42:08,000 --> 03:42:11,160 THIS REALLY HASN'T BEEN 4988 03:42:11,160 --> 03:42:12,360 CAREFULLY EVALUATED IN CF IN ALL 4989 03:42:12,360 --> 03:42:15,320 CASES WHERE THERE'S EVIDENCE 4990 03:42:15,320 --> 03:42:17,400 THAT SINONASAL INFLAMMATION 4991 03:42:17,400 --> 03:42:20,720 ESPECIALLY MICROBIOME MAY BE 4992 03:42:20,720 --> 03:42:21,640 QUITE DISTINCT. 4993 03:42:21,640 --> 03:42:22,560 >> ONE-MINUTE WARNING. 4994 03:42:22,560 --> 03:42:23,360 >> ALL RIGHT. 4995 03:42:23,360 --> 03:42:25,520 SO THEN WITH THAT I WILL 4996 03:42:25,520 --> 03:42:30,440 CONCLUDE THAT OUR DATA INDICATE 4997 03:42:30,440 --> 03:42:31,920 THAT MODULATOR INITIATION PEOPLE 4998 03:42:31,920 --> 03:42:32,840 WITH CF ESTABLISHED DISEASE 4999 03:42:32,840 --> 03:42:36,480 LEADS TO IMPROVEMENT IN 5000 03:42:36,480 --> 03:42:37,640 REMODELING BUT TRANSCRIPTIONAL 5001 03:42:37,640 --> 03:42:39,960 RESPONSES ARE VARIABLE AND NOT 5002 03:42:39,960 --> 03:42:41,720 FULLY CORRELATED. 5003 03:42:41,720 --> 03:42:42,640 NEXT. 5004 03:42:42,640 --> 03:42:45,240 AND WITH MY FINAL SLIDE, I DREW 5005 03:42:45,240 --> 03:42:47,320 A FEW WHAT I THINK ARE PRIORITY 5006 03:42:47,320 --> 03:42:49,320 AREAS THAT WILL HELP INCREASE 5007 03:42:49,320 --> 03:42:51,160 OUR UNDERSTANDING OF LONG-TERM 5008 03:42:51,160 --> 03:42:52,280 MODULATOR USE. 5009 03:42:52,280 --> 03:42:55,480 WE NEED TO UNDERSTAND WHAT 5010 03:42:55,480 --> 03:43:00,400 MECHANISMS DRIVE REMODELING, HOW 5011 03:43:00,400 --> 03:43:01,600 MODULATORS RECTIFY CHANGES. 5012 03:43:01,600 --> 03:43:07,840 IRREVERSIBLE CHANGES LIKE THOSE 5013 03:43:07,840 --> 03:43:14,680 ASSOCIATED WITH BRONCHIAL 5014 03:43:14,680 --> 03:43:17,240 REGIONS, CAN THIS REVEAL EARLY 5015 03:43:17,240 --> 03:43:20,320 SIGNS OF NEW LUNG DISEASE. 5016 03:43:20,320 --> 03:43:25,560 AS PEOPLE WILL LIVE LONGER AND 5017 03:43:25,560 --> 03:43:26,560 TO POTENTIALLY BENEFIT FROM GENE 5018 03:43:26,560 --> 03:43:34,200 THERAPY, WE HAVE A LOT TO DO IN 5019 03:43:34,200 --> 03:43:41,320 TERMS OF METHODOLOGY, AND 5020 03:43:41,320 --> 03:43:42,840 CROSS-COMPARISON OR MULTIOMICS 5021 03:43:42,840 --> 03:43:44,040 WITH BE CRITICAL. 5022 03:43:44,040 --> 03:43:45,760 IF ANYBODY IS INTERESTED IN 5023 03:43:45,760 --> 03:43:46,480 COLLABORATING PLEASE GET IN 5024 03:43:46,480 --> 03:43:46,680 TOUCH. 5025 03:43:46,680 --> 03:43:48,880 THIS IS THE END OF MY 5026 03:43:48,880 --> 03:43:49,360 PRESENTATION. 5027 03:43:49,360 --> 03:43:54,920 THANK FOR YOUR TIME. 5028 03:43:54,920 --> 03:44:01,560 NEXT SPEAKER IS DR. PRADEEP 5029 03:44:01,560 --> 03:44:08,400 SINGH. 5030 03:44:08,400 --> 03:44:10,400 >> I'M GETTING A MESSAGE SAYING 5031 03:44:10,400 --> 03:44:12,600 THE HOST STOPPED ME FROM SHOWING 5032 03:44:12,600 --> 03:44:14,640 VIDEO. 5033 03:44:14,640 --> 03:44:15,720 THERE WE GO. 5034 03:44:15,720 --> 03:44:16,640 GREAT. 5035 03:44:16,640 --> 03:44:16,840 THANKS. 5036 03:44:16,840 --> 03:44:21,760 CAN YOU SEE ME AND HEAR ME OKAY? 5037 03:44:21,760 --> 03:44:22,040 >> YES. 5038 03:44:22,040 --> 03:44:23,640 >> ALL RIGHT. 5039 03:44:23,640 --> 03:44:25,480 THANK YOU. 5040 03:44:25,480 --> 03:44:29,840 I'M GOING TO TALK TODAY ABOUT CF 5041 03:44:29,840 --> 03:44:32,560 MODULATORS AND EFFECTS ON CF 5042 03:44:32,560 --> 03:44:32,840 INFECTION. 5043 03:44:32,840 --> 03:44:35,440 I THINK A LOT OF US WOULD AGREE 5044 03:44:35,440 --> 03:44:38,400 CF INFECTIONS ARE PROBABLY AMONG 5045 03:44:38,400 --> 03:44:41,040 THE MOST IMPORTANT CLINICAL 5046 03:44:41,040 --> 03:44:41,680 MANIFESTATIONS OF CYSTIC 5047 03:44:41,680 --> 03:44:44,640 FIBROSIS BUT WE REALLY DON'T 5048 03:44:44,640 --> 03:44:47,280 REALLY KNOW YET HOW MODULATORS 5049 03:44:47,280 --> 03:44:48,040 AFFECT INFECTION OUTCOMES. 5050 03:44:48,040 --> 03:44:50,040 THERE'S BEEN A NUMBER OF SMALL 5051 03:44:50,040 --> 03:44:53,560 STUDIES THAT LOOK AT SPUTUM 5052 03:44:53,560 --> 03:44:54,880 PROSPECTIVELY TO MEASURE 5053 03:44:54,880 --> 03:44:57,720 MICROBIOLOGY AFTER MODULATORS 5054 03:44:57,720 --> 03:45:00,000 AND SOME SHOW MODULATORS REDUCE 5055 03:45:00,000 --> 03:45:01,520 SPUTUM BACTERIA, OTHER STUDIES 5056 03:45:01,520 --> 03:45:05,920 HAVE SHOWN NO CHANGE AFTER 5057 03:45:05,920 --> 03:45:07,560 MODULATOR TREATMENT. 5058 03:45:07,560 --> 03:45:10,160 I'LL START AND GIVE SOME HIGH 5059 03:45:10,160 --> 03:45:12,800 LEVEL RESULTS FROM THE PROMISE 5060 03:45:12,800 --> 03:45:15,560 OF STUDY, PROMISE OF 5061 03:45:15,560 --> 03:45:16,640 MICROBIOLOGY SUBSTUDY, PROMISE 5062 03:45:16,640 --> 03:45:20,160 IS LED BY STEVE ROWE AND DAVE 5063 03:45:20,160 --> 03:45:22,760 NICHOLS, AND THIS STUDY 5064 03:45:22,760 --> 03:45:24,440 COLLECTED INDUCED SPUTUM BEFORE 5065 03:45:24,440 --> 03:45:25,520 AND DURING ETI TREATMENT, 5066 03:45:25,520 --> 03:45:28,680 SCHEDULED TO GO ON NOW FOR FOUR 5067 03:45:28,680 --> 03:45:28,880 YEARS. 5068 03:45:28,880 --> 03:45:30,680 RIGHT NOW I'LL TALK ABOUT THE 5069 03:45:30,680 --> 03:45:32,520 FIRST SIX MONTHS OF DATA. 5070 03:45:32,520 --> 03:45:34,520 I THINK NOTABLE POINT THIS IS A 5071 03:45:34,520 --> 03:45:36,280 LARGE STUDY, THE LARGEST STUDY 5072 03:45:36,280 --> 03:45:40,200 WE HAVE SO FAR LOOKING 5073 03:45:40,200 --> 03:45:42,800 PROSPECTIVELY AT WHAT HAPPENS TO 5074 03:45:42,800 --> 03:45:43,480 SPUTUM MICROBIOLOGY AFTER 5075 03:45:43,480 --> 03:45:45,040 MODULATORS, THERE'S A WIDE RANGE 5076 03:45:45,040 --> 03:45:46,200 OF STUDY PARTICIPANTS. 5077 03:45:46,200 --> 03:45:50,920 YOU CAN SEE THE FEV1 FROM LOW TO 5078 03:45:50,920 --> 03:45:53,120 HIGH, AN IMPORTANT POINT IS THIS 5079 03:45:53,120 --> 03:45:54,960 STUDY INCLUDED PATIENTS THAT DID 5080 03:45:54,960 --> 03:45:56,560 AND DID NOT HAVE OR MEET 5081 03:45:56,560 --> 03:45:58,080 DEFINITION OF CHRONIC INFECTION. 5082 03:45:58,080 --> 03:46:00,240 IT WAS A REAL WORLD STUDY 5083 03:46:00,240 --> 03:46:02,440 LOOKING AT ALL COMERS INITIATING 5084 03:46:02,440 --> 03:46:02,600 ETI. 5085 03:46:02,600 --> 03:46:04,720 AS I SAID, THIS IS THE FIRST SIX 5086 03:46:04,720 --> 03:46:06,520 MONTHS OF A TWO-YEAR NOW GOING 5087 03:46:06,520 --> 03:46:07,920 TO BE FOUR-YEAR STUDY. 5088 03:46:07,920 --> 03:46:10,400 TO START WITH I THINK ONE OF THE 5089 03:46:10,400 --> 03:46:12,920 MOST STRIKING FINDINGS IS THE 5090 03:46:12,920 --> 03:46:14,760 EFFECTS ON SPUTUM DENSITY OF KEY 5091 03:46:14,760 --> 03:46:16,320 CF PATHOGENS. 5092 03:46:16,320 --> 03:46:19,280 WHAT'S PLOTTED ON THE Y-AXIS IS 5093 03:46:19,280 --> 03:46:22,640 THE GRAMS OF SPUTUM, SORRY, CFU 5094 03:46:22,640 --> 03:46:24,960 PER GRAM OF SPUTUM ON A LOG 5095 03:46:24,960 --> 03:46:25,400 SCALE. 5096 03:46:25,400 --> 03:46:27,680 X-AXIS IS TIME AFTER STARTING 5097 03:46:27,680 --> 03:46:28,040 ETI. 5098 03:46:28,040 --> 03:46:30,440 THIS FIRST PANEL SHOALS EFFECT 5099 03:46:30,440 --> 03:46:32,480 ON STAPH AUREUS IN THIS COHORT. 5100 03:46:32,480 --> 03:46:34,600 YOU CAN SEE THERE'S A MARKED 5101 03:46:34,600 --> 03:46:37,840 REDUCTION THAT OCCURS IN THE 5102 03:46:37,840 --> 03:46:45,440 FIRST MONTH IN STAPH AUREUS CFU 5103 03:46:45,440 --> 03:46:47,320 DENSITY, MAINTAINED THROUGHOUT 5104 03:46:47,320 --> 03:46:51,720 SIX-MONTH OBSERVATION PERIOD. 5105 03:46:51,720 --> 03:46:52,560 SIMILAR WITH P AERUGINOSA, A 5106 03:46:52,560 --> 03:46:54,200 HUNDRED FOLD IN THE FIRST MONTH, 5107 03:46:54,200 --> 03:46:56,800 STABILITY AFTER THAT ON AVERAGE, 5108 03:46:56,800 --> 03:47:03,520 AND MORE PRONOUNCED BUT SIMILAR 5109 03:47:03,520 --> 03:47:05,040 EFFECT ON S MALTOPHILIA. 5110 03:47:05,040 --> 03:47:06,880 WHEN WE LOOK AT MAGNITUDE OF 5111 03:47:06,880 --> 03:47:08,840 THESE DECLINES IN THE FIRST 5112 03:47:08,840 --> 03:47:14,560 MONTH OF TREATMENT THEY ARE 5113 03:47:14,560 --> 03:47:15,200 PRONOUNCED. 5114 03:47:15,200 --> 03:47:16,760 YOU'RE SEEING CONSISTENT 5115 03:47:16,760 --> 03:47:19,080 IRRESPECTIVE OF PATHOGEN, YOU'RE 5116 03:47:19,080 --> 03:47:22,920 SEEING TWO TO THREE LOG TEN 5117 03:47:22,920 --> 03:47:24,680 REDUCTION OF SPUTUM CFU DENSITY 5118 03:47:24,680 --> 03:47:26,080 IN FIRST MONTH OF TREATMENT. 5119 03:47:26,080 --> 03:47:27,320 UNFORTUNATELY SO FAR WE'VE NOT 5120 03:47:27,320 --> 03:47:30,160 OBSERVED THAT A LARGE NUMBER OF 5121 03:47:30,160 --> 03:47:30,920 SUBJECTS BECOME PERSISTENTLY 5122 03:47:30,920 --> 03:47:31,920 CULTURE NEGATIVE. 5123 03:47:31,920 --> 03:47:33,840 THIS IS ONLY THE SIX-MONTH 5124 03:47:33,840 --> 03:47:35,840 INTERIM REPORT SO WE'LL NEED 5125 03:47:35,840 --> 03:47:38,880 MORE DATA TO REALLY ANSWER THIS 5126 03:47:38,880 --> 03:47:40,000 QUESTION DEFINITIVELY, WHETHER 5127 03:47:40,000 --> 03:47:41,280 PATIENTS ARE CONVERTING TO 5128 03:47:41,280 --> 03:47:43,400 CULTURE NEGATIVE BUT LET ME SHOW 5129 03:47:43,400 --> 03:47:45,680 YOU WHAT WE'VE SEEN SO FAR. 5130 03:47:45,680 --> 03:47:49,920 WE HAVE 49 SUBJECTS RIGHT NOW, 5131 03:47:49,920 --> 03:47:51,720 P.A. POSITIVE, CULTURE POSITIVE 5132 03:47:51,720 --> 03:47:54,760 AT STUDY ENTRY, PROVIDED AT 5133 03:47:54,760 --> 03:47:56,760 LEAST TWO SPUTUM SAMPLES, 5134 03:47:56,760 --> 03:47:57,520 ADDITIONAL SAMPLES OVER THE 5135 03:47:57,520 --> 03:48:00,680 FIRST SIX MONTHS OF TREATMENT, 5136 03:48:00,680 --> 03:48:02,360 THOSE 49 REPRESENT GREEN DOTS, 5137 03:48:02,360 --> 03:48:03,640 EACH IS A SUBJECT. 5138 03:48:03,640 --> 03:48:07,400 WE LOOK AT SUBJECTS THAT BECAME 5139 03:48:07,400 --> 03:48:08,840 REPEATEDLY CULTURE NEGATIVE, IT 5140 03:48:08,840 --> 03:48:11,480 WAS RELATIVELY SMALL. 5141 03:48:11,480 --> 03:48:13,080 ONLY 14 OUT OF 49. 5142 03:48:13,080 --> 03:48:15,880 WE SEE EVEN WORSE OUTCOMES I 5143 03:48:15,880 --> 03:48:18,600 THINK FOR STAPH AUREUS. 5144 03:48:18,600 --> 03:48:20,640 83 SUBJECTS REPRESENTED BY THESE 5145 03:48:20,640 --> 03:48:22,080 GREEN DOTS TO CULTURE POSITIVE 5146 03:48:22,080 --> 03:48:26,120 FOR STAPH AUREUS ON STUDY ENTRY, 5147 03:48:26,120 --> 03:48:28,880 GAVE WHO SAMPLES, SO FAR ONLY 6 5148 03:48:28,880 --> 03:48:30,360 HAVE BECOME REPEATEDLY CULTURE 5149 03:48:30,360 --> 03:48:30,640 NEGATIVE. 5150 03:48:30,640 --> 03:48:33,120 MOST PEOPLE WHO COME IN A 5151 03:48:33,120 --> 03:48:35,120 PATHOGEN APPEAR TO RETAIN THAT 5152 03:48:35,120 --> 03:48:37,200 PATHOGEN AT LEAST THE FIRST SIX 5153 03:48:37,200 --> 03:48:39,160 MONTHS OF OBSERVATION. 5154 03:48:39,160 --> 03:48:41,560 SO, THAT WAS SOME CULTURE-BASED 5155 03:48:41,560 --> 03:48:41,800 DATA. 5156 03:48:41,800 --> 03:48:43,520 WE'VE LOOKED USING DNA METHODS 5157 03:48:43,520 --> 03:48:46,440 TO ASK MORE BROADLY HOW DOES ETI 5158 03:48:46,440 --> 03:48:50,280 CHANGE ALL THE OTHER ORGANISMS 5159 03:48:50,280 --> 03:48:55,120 THAT CAN BE DETECTED IN SPUTUM 5160 03:48:55,120 --> 03:48:55,360 SAMPLES. 5161 03:48:55,360 --> 03:48:59,960 WE SEQUENCED 16S R-RNA AND 5162 03:48:59,960 --> 03:49:01,160 CALCULATED TAXA ABSOLUTE 5163 03:49:01,160 --> 03:49:10,320 ABUNDANCE LEVELS BY MULTIPLYING 5164 03:49:10,320 --> 03:49:12,760 TIMES INDIVIDUAL GENERA, ON THE 5165 03:49:12,760 --> 03:49:16,240 Y-AXIS I'M SHOWING CHANGE IN THE 5166 03:49:16,240 --> 03:49:18,240 ABSOLUTE ABUNDANCE IN THESE 5167 03:49:18,240 --> 03:49:20,440 ORGANISMS, THAT WERE PRESENT AT 5168 03:49:20,440 --> 03:49:21,880 GREATER THAN 1% RELATIVE 5169 03:49:21,880 --> 03:49:25,120 ABUNDANCE IN THE STARTING SPUTUM 5170 03:49:25,120 --> 03:49:26,200 SAMPLE, PRE-TREATMENT SPUTUM 5171 03:49:26,200 --> 03:49:27,680 SAMPLE, THOSE ORGANISMS. 5172 03:49:27,680 --> 03:49:31,080 AND THE Y-AXIS IS PLOTTED CHANGE 5173 03:49:31,080 --> 03:49:32,560 IN ABSOLUTE ABUNDANCE AFTER A 5174 03:49:32,560 --> 03:49:32,760 MONTH. 5175 03:49:32,760 --> 03:49:34,360 THIS LOOKS SIMILAR TO WHAT 5176 03:49:34,360 --> 03:49:36,760 OCCURS AT THREE MONTHS AND SIX 5177 03:49:36,760 --> 03:49:37,520 MONTHS. 5178 03:49:37,520 --> 03:49:38,720 IT'S REPRESENTATIVE OF THE 5179 03:49:38,720 --> 03:49:39,520 OVERALL CHANGE. 5180 03:49:39,520 --> 03:49:43,400 WHAT YOU CAN SEE IS THAT THERE'S 5181 03:49:43,400 --> 03:49:45,400 A CLEAR DIFFERENTIATION IN 5182 03:49:45,400 --> 03:49:47,240 RESPONSE TO ETI. 5183 03:49:47,240 --> 03:49:49,360 WE LOOK AT THE CF PATHOGENS 5184 03:49:49,360 --> 03:49:50,840 PLOTTED ON THE RIGHT SIDE. 5185 03:49:50,840 --> 03:50:00,600 YOU CAN SEE ALL OF THEM WITH 5186 03:50:00,600 --> 03:50:03,240 EXCEPTION ONE EXHIBIT CHANGES, 5187 03:50:03,240 --> 03:50:08,160 OTHER LIKE STREP, PREVOTELLA, 5188 03:50:08,160 --> 03:50:10,000 GAMELLA, PART OF THE ORAL 5189 03:50:10,000 --> 03:50:14,400 MICROBIOME, DON'T CHANGE AT ALL 5190 03:50:14,400 --> 03:50:15,920 SIGNIFICANTLY AFTER ETI IS 5191 03:50:15,920 --> 03:50:16,200 INITIATED. 5192 03:50:16,200 --> 03:50:19,840 LOOKING ANOTHER WAY BY GROUPING 5193 03:50:19,840 --> 03:50:21,280 TOGETHER TRADITIONAL PATHOGENS 5194 03:50:21,280 --> 03:50:22,600 AND OTHER BACTERIA, AND WHEN WE 5195 03:50:22,600 --> 03:50:26,280 DO THIS NOW I'M SHOWING ON THE 5196 03:50:26,280 --> 03:50:28,160 Y-AXIS CALCULATED ABSOLUTE 5197 03:50:28,160 --> 03:50:31,480 ABUNDANCE IN GENOME COPY PER MIL 5198 03:50:31,480 --> 03:50:32,360 OF TRADITIONAL PATHOGENS GROUPED 5199 03:50:32,360 --> 03:50:32,840 TOGETHER. 5200 03:50:32,840 --> 03:50:34,720 YOU CAN SEE THE LIST AT THE TOP. 5201 03:50:34,720 --> 03:50:40,360 AGAIN YOU'RE SEEING ABOUT A 1 5202 03:50:40,360 --> 03:50:41,920 1/2-ISH, 2-LOG REDUCTION AFTER A 5203 03:50:41,920 --> 03:50:44,520 MONTH, THAT STAYS STABLE. 5204 03:50:44,520 --> 03:50:47,240 ALL THE OTHER BACTERIA NOT 5205 03:50:47,240 --> 03:50:48,120 TRADITIONALLY CONSIDERED CF 5206 03:50:48,120 --> 03:50:51,520 PATHOGENS DIDN'T EXHIBIT ANY 5207 03:50:51,520 --> 03:50:52,600 CHANGE. 5208 03:50:52,600 --> 03:50:54,880 TO SUMMARIZE SO FAR, ETI 5209 03:50:54,880 --> 03:50:56,880 TREATMENT REDUCED ALL CF 5210 03:50:56,880 --> 03:51:02,360 PATHOGENS BY 2 OR 3 LOGS, 5211 03:51:02,360 --> 03:51:03,120 INCLUDING STAPH AUREUS, 5212 03:51:03,120 --> 03:51:07,600 PSEUDOMONAS, AND A SMALL NUMBER 5213 03:51:07,600 --> 03:51:09,360 OF PATIENTS WHO HAD OTHER 5214 03:51:09,360 --> 03:51:09,720 SPECIES. 5215 03:51:09,720 --> 03:51:10,960 WHEN WE LOOKED BY SEQUENCING 5216 03:51:10,960 --> 03:51:15,280 FOUND THE SAME THING FOR THE CF 5217 03:51:15,280 --> 03:51:17,080 PATHOGENS, ETI REDUCED ABSOLUTE 5218 03:51:17,080 --> 03:51:19,760 ABUNDANCE OF TRADITIONAL 5219 03:51:19,760 --> 03:51:21,200 PATHOGEN SPUTUM, BUT DIDN'T 5220 03:51:21,200 --> 03:51:22,360 PRODUCE CHANGE OR PRODUCED NO 5221 03:51:22,360 --> 03:51:25,120 CHANGE IN ANY OF THE OTHER GENRE 5222 03:51:25,120 --> 03:51:26,000 DETECTED THERE. 5223 03:51:26,000 --> 03:51:27,760 I DIDN'T HAVE TIME TO SHOW THIS 5224 03:51:27,760 --> 03:51:31,240 DATA BUT ETI DID PRODUCE A 5225 03:51:31,240 --> 03:51:39,120 SLIGHT INCREASE IN SPUTUM 5226 03:51:39,120 --> 03:51:41,760 MICROBIAL DIVERSITY BUT WHEN WE 5227 03:51:41,760 --> 03:51:42,840 INCREASE, THIS CHANGE OR 5228 03:51:42,840 --> 03:51:44,680 INCREASE IN DIVERSITY IS ALL 5229 03:51:44,680 --> 03:51:47,240 DRIVEN BY REDUCTION IN THE 5230 03:51:47,240 --> 03:51:49,320 TRADITIONAL CF PATHOGENS AFTER 5231 03:51:49,320 --> 03:51:52,040 ETI TREATMENT. 5232 03:51:52,040 --> 03:51:54,920 I'M GOING TO END WITH FIVE KEY 5233 03:51:54,920 --> 03:51:57,760 QUESTIONS ABOUT CF INFECTIONS IN 5234 03:51:57,760 --> 03:51:59,480 THE POST-MODULATOR ERA. 5235 03:51:59,480 --> 03:52:03,400 FIRST IMPORTANT QUESTION HOW 5236 03:52:03,400 --> 03:52:04,280 DURABLE ARE PATHOGEN REDUCTIONS? 5237 03:52:04,280 --> 03:52:05,960 IS THAT GOING TO BE THE NEW 5238 03:52:05,960 --> 03:52:07,920 NORMAL OR IS IT A POSSIBILITY 5239 03:52:07,920 --> 03:52:10,080 THEY COULD IMPROVE FURTHER OR 5240 03:52:10,080 --> 03:52:11,880 MAYBE EVEN GET WORSE? 5241 03:52:11,880 --> 03:52:18,880 SO WE HAVE DATA FROM THE DUBLIN 5242 03:52:18,880 --> 03:52:21,160 STUDY GROUP, HISERT WAS FIRST 5243 03:52:21,160 --> 03:52:22,480 OFF ON SOME. 5244 03:52:22,480 --> 03:52:25,960 THAT SHOWED -- A SMALL STUDY, 12 5245 03:52:25,960 --> 03:52:28,400 PEOPLE TOTAL, THAT AFTER ABOUT A 5246 03:52:28,400 --> 03:52:29,080 YEAR, SOMETIME BETWEEN A YEAR 5247 03:52:29,080 --> 03:52:35,640 AND A HALF AND TWO YEARS AFTER 5248 03:52:35,640 --> 03:52:37,160 STARTING IVACAFTOR SUBJECTS WITH 5249 03:52:37,160 --> 03:52:40,240 THE MUTATIONS EXHIBITED A 5250 03:52:40,240 --> 03:52:41,680 REBOUND IN PSEUDOMONAS DENSITY 5251 03:52:41,680 --> 03:52:43,760 FOUND IN SPUTUM. 5252 03:52:43,760 --> 03:52:45,480 Y-AXIS IS PSEUDOMONAS DENSITY 5253 03:52:45,480 --> 03:52:47,160 MEASURED BY CULTURE, X-AXIS IS 5254 03:52:47,160 --> 03:52:47,360 TIME. 5255 03:52:47,360 --> 03:52:50,200 THIS IS IN YEARS NOW. 5256 03:52:50,200 --> 03:52:52,600 WE SAW INITIAL DECLINE LIKE WE 5257 03:52:52,600 --> 03:52:55,760 SAW WITH ETI, AND THEN REBOUND 5258 03:52:55,760 --> 03:52:56,440 INCREASED DENSITY. 5259 03:52:56,440 --> 03:52:59,760 WE DON'T FLOW IF THAT'S GOING TO 5260 03:52:59,760 --> 03:53:04,360 HAPPEN WITH ETI OR NOT. 5261 03:53:04,360 --> 03:53:06,280 THE NADIR WAS AROUND A YEAR, 5262 03:53:06,280 --> 03:53:07,440 DON'T KNOW EXACTLY WHEN, 5263 03:53:07,440 --> 03:53:08,840 FOLLOWED BY REBOUND. 5264 03:53:08,840 --> 03:53:11,160 WE ALSO SAW SIMILAR PHENOMENA 5265 03:53:11,160 --> 03:53:13,520 WITH INFLAMMATION. 5266 03:53:13,520 --> 03:53:15,080 ON THE Y-AXIS NEUTROPHIL 5267 03:53:15,080 --> 03:53:16,480 ELASTICS LEVEL IN SPUTUM 5268 03:53:16,480 --> 03:53:18,360 MEASURED ON LOG SCALE, X-AXIS IS 5269 03:53:18,360 --> 03:53:20,680 TIME IN YEARS. 5270 03:53:20,680 --> 03:53:22,120 WE SAW SIMILAR REBOUND OCCURRING 5271 03:53:22,120 --> 03:53:30,760 A BIT LATER IT APPEARS IN SPUTUM 5272 03:53:30,760 --> 03:53:31,080 INFLAMMATION. 5273 03:53:31,080 --> 03:53:33,800 SECOND KEY QUESTION RAISED BY 5274 03:53:33,800 --> 03:53:36,200 THE DATA AND RELEVANT TO POST 5275 03:53:36,200 --> 03:53:38,760 MODULATOR ERA, WHY DO WE SEE 5276 03:53:38,760 --> 03:53:41,880 THESE MARKED REDUCTION IN 5277 03:53:41,880 --> 03:53:45,960 PATHOGENS BRUCE TROMBERG ARE BUT 5278 03:53:45,960 --> 03:53:49,560 -- BUT OTHER TAXA REMAIN 5279 03:53:49,560 --> 03:53:50,160 CONSTANT. 5280 03:53:50,160 --> 03:53:53,520 ONE POSSIBILITY IS THAT ETI, 5281 03:53:53,520 --> 03:53:55,560 MODULATORS IN GENERAL, CORRECT 5282 03:53:55,560 --> 03:53:58,320 DEFENSES THAT ONLY ACT ON 5283 03:53:58,320 --> 03:54:07,960 PATHOGENS, LEAVE THE OTHER BUGS 5284 03:54:07,960 --> 03:54:10,160 UNTOUCHED. 5285 03:54:10,160 --> 03:54:11,880 MODULATORS IMPROVE CLEARANCE AND 5286 03:54:11,880 --> 03:54:12,840 SHOULD CLEAR BACTERIA, 5287 03:54:12,840 --> 03:54:18,800 MODULATORS ARE SHOWN TO REDUCE 5288 03:54:18,800 --> 03:54:22,480 MUCUS PLUGGING, SHOULD REDUCE 5289 03:54:22,480 --> 03:54:25,680 GROWTH NICHE FOR ANAEROBES. 5290 03:54:25,680 --> 03:54:26,480 ANOTHER POSSIBILITY PATHOGENS 5291 03:54:26,480 --> 03:54:29,720 ARE COMING LARGELY FROM THE LUNG 5292 03:54:29,720 --> 03:54:32,280 WHERE ETI IS WORKING AND 5293 03:54:32,280 --> 03:54:33,560 IMPROVING HOST DEFENSES, WHEREAS 5294 03:54:33,560 --> 03:54:35,200 THE OTHER BACTERIA WE FIND IN 5295 03:54:35,200 --> 03:54:36,840 SPUTUM ARE LARGELY COMING FROM 5296 03:54:36,840 --> 03:54:39,920 THE ORAL PHARYNX. 5297 03:54:39,920 --> 03:54:42,920 WE KNOW SALIVA CONTAINS 5298 03:54:42,920 --> 03:54:43,680 ASTRONOMICAL CONCENTRATIONS, 10 5299 03:54:43,680 --> 03:54:46,800 TO THE 8th, 10 TO THE 10th 5300 03:54:46,800 --> 03:54:47,880 IN SOME STUDIES. 5301 03:54:47,880 --> 03:54:49,760 IF YOU REDUCE PATHOGENS IN THE 5302 03:54:49,760 --> 03:54:53,800 LUNG, THE OTHER BACTERIA IN THE 5303 03:54:53,800 --> 03:54:56,680 SPUTUM CONTAMINANTS WERE 5304 03:54:56,680 --> 03:55:01,280 UNCHANGED, NET EFFECT, REDUCED 5305 03:55:01,280 --> 03:55:04,920 PATHOGENS BUT OTHER BACTERIA 5306 03:55:04,920 --> 03:55:07,760 UNCHANGED IN ABSOLUTE ABUNDANCE. 5307 03:55:07,760 --> 03:55:10,800 QUESTION 3, HAVE THESE SUBJECTS 5308 03:55:10,800 --> 03:55:12,880 WHO CONVERTED TO 5309 03:55:12,880 --> 03:55:13,920 CULTURE-NEGATIVITY, HAVE THEY 5310 03:55:13,920 --> 03:55:15,640 TRULY CLEARED THEIR INFECTION? 5311 03:55:15,640 --> 03:55:17,280 ARE THEY INFECTION FREE? IT'S A 5312 03:55:17,280 --> 03:55:18,400 TOUGH QUESTION TO ANSWER WITH 5313 03:55:18,400 --> 03:55:21,760 SPUTUM BUT WE TRY TO GET MORE 5314 03:55:21,760 --> 03:55:23,000 INFORMATION ABOUT THAT BY 5315 03:55:23,000 --> 03:55:24,640 STUDYING SPUTUM OF SUBJECT WHO 5316 03:55:24,640 --> 03:55:29,240 IS CONVERTED TO CULTURE NEGATIVE 5317 03:55:29,240 --> 03:55:32,000 AFTER ETI WITH VERY SENSITIVE 5318 03:55:32,000 --> 03:55:35,360 SPECIES-SPECIFIC DROPLET DIGITAL 5319 03:55:35,360 --> 03:55:39,080 PCR STUDIES ON CULTURE NEGATIVE 5320 03:55:39,080 --> 03:55:39,520 SPUTUMS. 5321 03:55:39,520 --> 03:55:40,400 >> TWO-MINUTE WARNING. 5322 03:55:40,400 --> 03:55:42,280 >> FIVE OR ONE? 5323 03:55:42,280 --> 03:55:44,880 >> TWO-MINUTE WARNING. 5324 03:55:44,880 --> 03:55:45,200 >> THANKS. 5325 03:55:45,200 --> 03:55:47,280 THAT'S PERFECT. 5326 03:55:47,280 --> 03:55:48,480 I'VE SHOWN THIS DOT PLOT, THESE 5327 03:55:48,480 --> 03:55:51,800 ARE THE PATIENTS WHO CAME IN 5328 03:55:51,800 --> 03:55:52,520 WITH PSEUDOMONAS CULTURE 5329 03:55:52,520 --> 03:55:53,400 POSITIVE. 5330 03:55:53,400 --> 03:55:55,480 THESE ARE THE PATIENTS, 14 THAT 5331 03:55:55,480 --> 03:55:56,880 BECAME REPEATEDLY CULTURE 5332 03:55:56,880 --> 03:56:00,400 NEGATIVE, WHEN WE LOOK BY 5333 03:56:00,400 --> 03:56:02,280 SENSITIVE DIGITAL DROP PCR NOW 5334 03:56:02,280 --> 03:56:05,560 ONLY FIVE SUBJECTS WHO ARE 5335 03:56:05,560 --> 03:56:08,200 DIGITAL PCR NEGATIVE FOR P 5336 03:56:08,200 --> 03:56:08,520 AERUGINOSA. 5337 03:56:08,520 --> 03:56:09,840 SIMILAR WITH STAPH AUREUS. 5338 03:56:09,840 --> 03:56:11,920 HERE IS 6 THAT BECAME CULTURE 5339 03:56:11,920 --> 03:56:16,320 NEGATIVE, NOW WHEN I LOOK WITH 5340 03:56:16,320 --> 03:56:18,160 SENSITIVE DIGITAL DROPLET PCR ON 5341 03:56:18,160 --> 03:56:23,600 SAMPLES ONLY 3 OF THESE SUBJECTS 5342 03:56:23,600 --> 03:56:24,840 WERE NEGATIVE FOR STAPH AUREUS 5343 03:56:24,840 --> 03:56:26,680 SUGGESTING THERE MAY BE 5344 03:56:26,680 --> 03:56:28,040 PERSISTENT INFECTION EVEN IN 5345 03:56:28,040 --> 03:56:29,240 CULTURE NEGATIVE SUBJECTS. 5346 03:56:29,240 --> 03:56:30,840 ANOTHER IMPORTANT POINT IS THAT 5347 03:56:30,840 --> 03:56:32,720 WE HAVE OBSERVED SMALL NUMBER OF 5348 03:56:32,720 --> 03:56:34,720 SUBJECTS WHO DEVELOP WHAT 5349 03:56:34,720 --> 03:56:39,480 APPEARS TO BE NEW P.A. AND S A 5350 03:56:39,480 --> 03:56:40,640 INFECTIONS AFTER STARTING ETI. 5351 03:56:40,640 --> 03:56:43,120 PREVIOUS DATA SUGGESTS THEY WERE 5352 03:56:43,120 --> 03:56:45,320 UNINFECTED, AND MAYBE THEY HAVE 5353 03:56:45,320 --> 03:56:47,320 DEVELOPED NEW INFECTIONS 5354 03:56:47,320 --> 03:56:48,760 SUGGESTING PERSISTENT DEFECT. 5355 03:56:48,760 --> 03:56:52,640 SO, QUESTION 4, WHY DO MOST 5356 03:56:52,640 --> 03:56:53,760 PATIENTS REMAIN PERSISTENTLY 5357 03:56:53,760 --> 03:56:57,080 INFECTED, DESPITE MARKET 5358 03:56:57,080 --> 03:56:59,800 IMPROVEMENT IN CFTR ACTIVITY? 5359 03:56:59,800 --> 03:57:02,640 THE LEADING HYPOTHESIS IN THE 5360 03:57:02,640 --> 03:57:05,360 FIELD IS DUE TO SEVERE AREAS OF 5361 03:57:05,360 --> 03:57:07,880 LUNG DAMAGE, THESE REMAIN 5362 03:57:07,880 --> 03:57:10,280 INFECTED WHEREAS THE MILD AREAS 5363 03:57:10,280 --> 03:57:14,960 CLEAR, AND WE'VE STARTED TO 5364 03:57:14,960 --> 03:57:18,280 INVESTIGATE THAT USING 5365 03:57:18,280 --> 03:57:20,440 BRONCHOSCOPY TO SAMPLE MOST AND 5366 03:57:20,440 --> 03:57:21,440 LEAST DAMAGED REGIONS. 5367 03:57:21,440 --> 03:57:23,520 WE'RE FINDING A PATTERN IN A 5368 03:57:23,520 --> 03:57:24,560 SUBJECT EITHER ALL THE AREAS 5369 03:57:24,560 --> 03:57:27,560 CLEAR OR NONE OF THE AREAS 5370 03:57:27,560 --> 03:57:28,680 CLEAR. 5371 03:57:28,680 --> 03:57:30,080 SO THE SEVERELY DAMAGED REGIONS 5372 03:57:30,080 --> 03:57:32,400 ARE MARKED IN RED, MILDEST 5373 03:57:32,400 --> 03:57:36,080 DAMAGE REGION IN YELLOW, AND YOU 5374 03:57:36,080 --> 03:57:38,200 CAN SEE SUBJECT A ALL REGIONS 5375 03:57:38,200 --> 03:57:39,920 CLEAR, SUBJECT B NONE OF THE 5376 03:57:39,920 --> 03:57:41,280 REGIONS CLEARED. 5377 03:57:41,280 --> 03:57:43,240 HERE IS CLEARANCE DATABASED ON 5378 03:57:43,240 --> 03:57:44,440 HIGHEST DAMAGED REGIONS AND 5379 03:57:44,440 --> 03:57:46,200 LOWEST DAMAGED REGIONS AND WE 5380 03:57:46,200 --> 03:57:50,800 SEE ABOUT 40% OF REGIONS CLEARED 5381 03:57:50,800 --> 03:57:52,880 REGARDLESS OF MILD OR SEVERE 5382 03:57:52,880 --> 03:57:53,160 DISEASE. 5383 03:57:53,160 --> 03:57:55,040 THE LAST QUESTION IS DOES 5384 03:57:55,040 --> 03:57:57,160 INFLAMMATION PERSIST IN LUNG 5385 03:57:57,160 --> 03:57:58,760 REGIONS THAT CLEAR INFECTION? 5386 03:57:58,760 --> 03:58:02,400 AGAIN WE'VE USED A BRONCO SCOPEY 5387 03:58:02,400 --> 03:58:07,320 STUDY, WE'VE MEASURED NEUTROPHIL 5388 03:58:07,320 --> 03:58:09,600 ELASTASE, AND WHAT WE FIND IS 5389 03:58:09,600 --> 03:58:11,680 THAT IN THE AREAS OF LUNG WHERE 5390 03:58:11,680 --> 03:58:14,440 P.A. PERSISTS WE CAN STILL SEE 5391 03:58:14,440 --> 03:58:18,600 ELEVATED LEVELS OF NEUTROPHIL 5392 03:58:18,600 --> 03:58:23,200 ELASTASE, THOSE WHO CLEAR DON'T 5393 03:58:23,200 --> 03:58:25,360 HAVE DETECTABLE LEVELS. 5394 03:58:25,360 --> 03:58:27,240 CONCLUDING, WE FOUND ETI 5395 03:58:27,240 --> 03:58:31,280 MARKEDLY REDUCES CF PATHOGENS IN 5396 03:58:31,280 --> 03:58:33,800 SPUTUM BUT MOST REMAIN 5397 03:58:33,800 --> 03:58:35,200 PERSISTENTLY INFECTED AND SOME 5398 03:58:35,200 --> 03:58:37,840 NEW INFECTIONS OCCUR. 5399 03:58:37,840 --> 03:58:38,640 POST-MODULATOR INFECTIONS MAY 5400 03:58:38,640 --> 03:58:40,840 NOT BE DUE TO COLONIZATION OF 5401 03:58:40,840 --> 03:58:42,120 HIGHLY DAMAGED LUNG REGIONS, A 5402 03:58:42,120 --> 03:58:45,840 SMALL STUDY, WE NEED LARGER 5403 03:58:45,840 --> 03:58:46,640 STUDIES TO REALLY INVESTIGATE 5404 03:58:46,640 --> 03:58:47,400 THIS IDEA. 5405 03:58:47,400 --> 03:58:50,680 IT'S A KEY POINT FOR THE FUTURE. 5406 03:58:50,680 --> 03:58:55,160 WE FOUND SO THAT ARE THAT 5407 03:58:55,160 --> 03:58:56,720 ELASTASE BECOMES UNDEFECT AL IN 5408 03:58:56,720 --> 03:58:59,680 REGIONS THAT CLEAR POST ETI, A 5409 03:58:59,680 --> 03:59:01,080 SMALL STUDY, NEED MORE WORK ON 5410 03:59:01,080 --> 03:59:01,520 THIS. 5411 03:59:01,520 --> 03:59:03,840 WE DON'T KNOW WHAT THE 5412 03:59:03,840 --> 03:59:06,000 DURABILITY OF RESPONSE AND 5413 03:59:06,000 --> 03:59:07,640 MECHANISM OF PERSISTENT 5414 03:59:07,640 --> 03:59:08,320 INFECTION AFTER MODULATOR 5415 03:59:08,320 --> 03:59:10,480 TREATMENT ARE AND THIS ALSO 5416 03:59:10,480 --> 03:59:12,000 NEEDS MORE STUDY. 5417 03:59:12,000 --> 03:59:16,640 I SHOWED SOME DATA FROM THE 5418 03:59:16,640 --> 03:59:18,240 PROMISE MICROBIOLOGY STUDY LED 5419 03:59:18,240 --> 03:59:23,400 DIE DAVE AND SARAH, SONIA, 5420 03:59:23,400 --> 03:59:25,480 MICHELE CONTRIBUTED, BAL STUDY 5421 03:59:25,480 --> 03:59:27,720 LED BY SAM AND COLLABORATORS AT 5422 03:59:27,720 --> 03:59:28,680 UNIVERSITY OF WASHINGTON, 5423 03:59:28,680 --> 03:59:32,920 UNIVERSITY OF IOWA 5424 03:59:32,920 --> 03:59:35,760 THANKS FOR YOUR ATTENTION. 5425 03:59:35,760 --> 03:59:45,800 5426 03:59:49,400 --> 03:59:50,320 5427 03:59:50,320 --> 03:59:52,480 >> I WANT TO THANK THE 5428 03:59:52,480 --> 03:59:54,360 ORGANIZERS FOR INVITING ME TO 5429 03:59:54,360 --> 03:59:58,440 PRESENT ON THE POTENTIAL 5430 03:59:58,440 --> 04:00:00,000 INTERSECTION OF ENDOCRINE 5431 04:00:00,000 --> 04:00:01,960 COMORBIDITIES AND MODULATOR 5432 04:00:01,960 --> 04:00:02,200 THERAPY. 5433 04:00:02,200 --> 04:00:04,480 AND FOR THE PURPOSES OF THIS 5434 04:00:04,480 --> 04:00:05,280 PRESENTATION I WILL HIGHLIGHT 5435 04:00:05,280 --> 04:00:08,760 DATA I THINK ARE RELEVANT FOR 5436 04:00:08,760 --> 04:00:10,160 ADDRESSING KNOWLEDGE GAPS IN 5437 04:00:10,160 --> 04:00:11,440 SEVERAL CONDITIONS. 5438 04:00:11,440 --> 04:00:14,760 AND THE FIRST IS CAN HIGHLY 5439 04:00:14,760 --> 04:00:16,160 EFFECTIVE MODULATOR THERAPY 5440 04:00:16,160 --> 04:00:18,800 IMPROVE, DELAY, EVEN PREVENT 5441 04:00:18,800 --> 04:00:22,520 CF-RELATED DIABETES? 5442 04:00:22,520 --> 04:00:23,720 CAN MODULATOR THERAPY INFECT 5443 04:00:23,720 --> 04:00:26,880 RELATED LOW BONE DENSITY AND 5444 04:00:26,880 --> 04:00:29,200 WHAT ARE UNDERLYING MECHANISMS 5445 04:00:29,200 --> 04:00:31,600 ARE WILL CHARACTERISTICS THAT 5446 04:00:31,600 --> 04:00:33,800 PORTEND FAVORABLE OUTCOMES, AND 5447 04:00:33,800 --> 04:00:36,320 WHAT IS THE TIME FRAME. 5448 04:00:36,320 --> 04:00:39,360 IN CONTRAST IS TRADITIONAL 5449 04:00:39,360 --> 04:00:40,240 PROTECTION AGAINST 5450 04:00:40,240 --> 04:00:41,760 CARDIOMETABOLIC AND 5451 04:00:41,760 --> 04:00:45,600 CARDIOVASCULAR RISK WE'VE LONG 5452 04:00:45,600 --> 04:00:46,800 CELEBRATED MITIGATED BY 5453 04:00:46,800 --> 04:00:48,800 MODULATOR THERAPY. 5454 04:00:48,800 --> 04:00:56,400 MANY OF US WERE EXCITED WHEN 5455 04:00:56,400 --> 04:01:00,240 CASE REPORTS IMPROVED GLUCOSE 5456 04:01:00,240 --> 04:01:05,240 EMERGED FOLLOWING IVACAFTOR. 5457 04:01:05,240 --> 04:01:12,560 HERE IS BELLIN, FIVE ADULTS WHO 5458 04:01:12,560 --> 04:01:18,040 UNDERWENT TESTING AND ACUTE 5459 04:01:18,040 --> 04:01:23,200 INSULIN RESPONSE, INDIVIDUALS 5460 04:01:23,200 --> 04:01:26,240 WITHOUT CFRD IMPROVEMENTS UNDER 5461 04:01:26,240 --> 04:01:29,000 ORAL AND INTRAVENOUS GLUCOSE 5462 04:01:29,000 --> 04:01:29,760 CONDITIONS. 5463 04:01:29,760 --> 04:01:35,320 BUT DATA WERE LESS COMPELLING IN 5464 04:01:35,320 --> 04:01:35,840 CFRD, SUGGESTING MINIMAL 5465 04:01:35,840 --> 04:01:37,440 FUNCTION MUST BE AVAILABLE IN 5466 04:01:37,440 --> 04:01:42,920 ORDER FOR MODULATOR THERAPY TO 5467 04:01:42,920 --> 04:01:43,880 IMPART IMPROVEMENTS. 5468 04:01:43,880 --> 04:01:47,280 U.S. AND U.K. REGISTRY DATA 5469 04:01:47,280 --> 04:01:48,560 DEMONSTRATED TRENDS IN LOWER 5470 04:01:48,560 --> 04:01:51,200 CFRD RATES OVER THE FOUR TO FIVE 5471 04:01:51,200 --> 04:01:55,000 YEARS AFTER INTRODUCTION OF 5472 04:01:55,000 --> 04:01:56,880 IVACAFTOR IN INDIVIDUALS WITH CF 5473 04:01:56,880 --> 04:02:01,480 COMPARED TO INDIVIDUALS WITH CF 5474 04:02:01,480 --> 04:02:02,880 NOT TREATED WITH IVACAFTOR SHOWN 5475 04:02:02,880 --> 04:02:05,080 ON THE RIGHT. 5476 04:02:05,080 --> 04:02:08,040 GIVEN THIS ENTHUSIASM LARGER 5477 04:02:08,040 --> 04:02:12,080 PERSPECTIVE SUBSTUDY WAS 5478 04:02:12,080 --> 04:02:13,840 INCLUDED IN A STUDY, 39 5479 04:02:13,840 --> 04:02:15,080 INDIVIDUALS WITH VARIABLE 5480 04:02:15,080 --> 04:02:20,160 GLUCOSE TOLERANCE AT BASELINE 5481 04:02:20,160 --> 04:02:22,120 UNDERWENT TWO-HOUR TESTING. 5482 04:02:22,120 --> 04:02:24,560 AND OF THE 30 COMPLETERS AT 12 5483 04:02:24,560 --> 04:02:27,520 MONTHS THERE DID NOT APPEAR TO 5484 04:02:27,520 --> 04:02:28,720 BE IMPROVEMENT IN OVERALL 5485 04:02:28,720 --> 04:02:30,760 GLUCOSE TOLERANCE. 5486 04:02:30,760 --> 04:02:34,280 AND THAT DATA IS CONFIRMED BY NO 5487 04:02:34,280 --> 04:02:36,520 IMPROVEMENTS IN FASTING GLUCOSE, 5488 04:02:36,520 --> 04:02:38,240 TWO HOUR GLUCOSE, GLUCOSE AREA 5489 04:02:38,240 --> 04:02:44,240 UNDER THE CURVE DURING THE OGTT 5490 04:02:44,240 --> 04:02:46,240 AND NEW IMPROVEMENT UNDER THE 5491 04:02:46,240 --> 04:02:47,520 CURVE. 5492 04:02:47,520 --> 04:02:51,800 THIS WAS NOT SURPRISING GIVEN 5493 04:02:51,800 --> 04:02:55,200 LESS ROBUST IMPACT ON CF 5494 04:02:55,200 --> 04:02:55,560 OUTCOMES. 5495 04:02:55,560 --> 04:02:57,960 SO DESPITE THIS INITIAL 5496 04:02:57,960 --> 04:02:59,040 DISAPPOINTMENT, WE REMAINED 5497 04:02:59,040 --> 04:03:03,760 HOPEFUL WE WOULD SEE 5498 04:03:03,760 --> 04:03:07,840 IMPROVEMENTS IN DIABETES-RELATED 5499 04:03:07,840 --> 04:03:11,440 OUTCOMES WITH ELEXACAFTOR AND 5500 04:03:11,440 --> 04:03:13,600 TEZA AND IVACAFTOR. 5501 04:03:13,600 --> 04:03:15,280 A STUDY USED CONTINUOUS GLUCOSE 5502 04:03:15,280 --> 04:03:17,000 MONITORING AND HERE AT THE 5503 04:03:17,000 --> 04:03:19,520 BOTTOM FOR THOSE LESS FAMILIAR 5504 04:03:19,520 --> 04:03:24,320 WITH THIS TOOL IS THREE-DAY 5505 04:03:24,320 --> 04:03:27,080 OUTPUT OVERLAID OF GLUCOSE 5506 04:03:27,080 --> 04:03:31,040 EXCURSION IN INDIVIDUALS WITH 5507 04:03:31,040 --> 04:03:31,360 DIABETES. 5508 04:03:31,360 --> 04:03:32,760 WHAT KEVIN DEMONSTRATED 5509 04:03:32,760 --> 04:03:34,200 FOLLOWING TWO WEEKS OF 5510 04:03:34,200 --> 04:03:35,840 CONTINUOUS GLUCOSE MONITORING 5511 04:03:35,840 --> 04:03:38,800 PRIOR TO ETI AND THEN IN THE 5512 04:03:38,800 --> 04:03:47,440 SEVERAL WEEKS FOLLOWING ETI 5513 04:03:47,440 --> 04:03:48,880 GLUCOSE EXCURSION IMPROVED WITH 5514 04:03:48,880 --> 04:03:49,080 THERAPY. 5515 04:03:49,080 --> 04:03:52,560 WASHINGTON UNIVERSITY GROUP IN A 5516 04:03:52,560 --> 04:03:54,760 RETROSPECTIVE ANALYSIS OF 5517 04:03:54,760 --> 04:03:56,080 CLINICALLY AVAILABLE DATA IN 139 5518 04:03:56,080 --> 04:03:59,000 INDIVIDUALS, NOT TREATED WITH 5519 04:03:59,000 --> 04:04:01,400 ETI FOR APPROXIMATELY 12 MONTHS 5520 04:04:01,400 --> 04:04:05,160 DEMONSTRATED NOT SURPRISINGLY 5521 04:04:05,160 --> 04:04:06,440 INCREASES IN WEIGHT, BMI, 5522 04:04:06,440 --> 04:04:07,760 INCREASING RATES OF OVERWEIGHT 5523 04:04:07,760 --> 04:04:12,400 AND TO LESSER EXTENT OBESITY. 5524 04:04:12,400 --> 04:04:14,160 HIGHER RATES OF HYPERTENSION. 5525 04:04:14,160 --> 04:04:19,840 IN SUBSET OF 20 OR SO 5526 04:04:19,840 --> 04:04:28,240 INDIVIDUALS WITH DIABETES, THEY 5527 04:04:28,240 --> 04:04:30,680 DEMONSTRATED INCREASES IN 5528 04:04:30,680 --> 04:04:32,120 CHOLESTEROL. 5529 04:04:32,120 --> 04:04:39,560 PUTNAM LOOKED AT IMPACT OF 5530 04:04:39,560 --> 04:04:42,480 IVACAFTOR, AT THE RADIUS AND 5531 04:04:42,480 --> 04:04:43,680 TIBIA. 5532 04:04:43,680 --> 04:04:47,880 AND THIS TOOL GIVES CORTICAL AND 5533 04:04:47,880 --> 04:04:49,000 TRABECULAR VOLUME, CORTICAL AREA 5534 04:04:49,000 --> 04:04:51,240 AS WELL AS CORTICAL THICKNESS, 5535 04:04:51,240 --> 04:04:53,240 MUCH MORE INFORMATIVE WITH 5536 04:04:53,240 --> 04:04:55,080 RESPECT TO BONE FRAGILITY THAN 5537 04:04:55,080 --> 04:04:55,960 TRADITIONAL DEXA. 5538 04:04:55,960 --> 04:04:59,480 HERE IS AN EXAMPLE OF AN 5539 04:04:59,480 --> 04:05:02,000 OTHERWISE HEALTHY FEMALE SHOWING 5540 04:05:02,000 --> 04:05:04,600 CORTICAL AND TRABECULAR BONE, 5541 04:05:04,600 --> 04:05:06,560 COMPARABLE AGE WITH CF, SMALLER 5542 04:05:06,560 --> 04:05:11,600 BONES, CORTICAL BONE IS LOWER, 5543 04:05:11,600 --> 04:05:14,600 FEWER TREBEKULAE. 5544 04:05:14,600 --> 04:05:17,280 TWO-YEAR CHANGES IN PARAMETERS, 5545 04:05:17,280 --> 04:05:18,280 AND DEMONSTRATING INCREASES IN 5546 04:05:18,280 --> 04:05:24,960 CORTICAL AREA AS WELL AS 5547 04:05:24,960 --> 04:05:25,640 CORTICAL THICKNESS. 5548 04:05:25,640 --> 04:05:31,000 PROMISE , WHICH PREVIOUS 5549 04:05:31,000 --> 04:05:32,280 PRESENTERS DISCUSSED, A 5550 04:05:32,280 --> 04:05:33,840 PROSPECTIVE STUDY TO EVALUATE 5551 04:05:33,840 --> 04:05:36,520 EFFECTS OF ETI ON MULTIPLE 5552 04:05:36,520 --> 04:05:38,840 OUTCOME, STUDY STARTED IN THE 5553 04:05:38,840 --> 04:05:43,200 FALL OF 2019 FOLLOWING FDA 5554 04:05:43,200 --> 04:05:44,560 APPROVAL, AND HERE INCLUDED IN 5555 04:05:44,560 --> 04:05:46,840 DATA I WILL SHOW ARE THOSE 5556 04:05:46,840 --> 04:05:48,600 SUBSET OF INDIVIDUALS AGE 12 AND 5557 04:05:48,600 --> 04:05:51,120 OLDER WHEN THEY WERE PRESCRIBED 5558 04:05:51,120 --> 04:05:51,880 ETI CLINICALLY. 5559 04:05:51,880 --> 04:05:55,720 I'M GOING TO FOCUS ON ENDOCRINE 5560 04:05:55,720 --> 04:05:59,560 SUBSTUDY, DATA AT 0, 12-18, 5561 04:05:59,560 --> 04:06:01,080 24-30 MONTHS, THAT COLLECTION IS 5562 04:06:01,080 --> 04:06:04,520 GOING ON NOW, AND THIS IS 5563 04:06:04,520 --> 04:06:08,120 EXTENDED OUT TO 54 MONTHS. 5564 04:06:08,120 --> 04:06:09,720 WE'RE OBTAINING THREE-OUR OGTT 5565 04:06:09,720 --> 04:06:13,880 AND DEXA FOR BONE AND BODY 5566 04:06:13,880 --> 04:06:14,200 COMPOSITION. 5567 04:06:14,200 --> 04:06:16,640 AND WE RECOGNIZE THAT BASED UPON 5568 04:06:16,640 --> 04:06:17,480 CLINICAL EXPERIENCE AND CASE 5569 04:06:17,480 --> 04:06:19,280 REPORTS THAT WE PROBABLY NEED A 5570 04:06:19,280 --> 04:06:20,640 LONGER TIME FRAME TO SEE CHANGES 5571 04:06:20,640 --> 04:06:25,640 AND SO THAT'S WHY WE HAVE GONE 5572 04:06:25,640 --> 04:06:30,640 TO 12 TO 18 MONTHS AND 24 TO 30 5573 04:06:30,640 --> 04:06:32,240 MONTHS VERSUS LOOKING AT ACUTE 5574 04:06:32,240 --> 04:06:34,160 CHANGES TO MODULATOR THERAPY. 5575 04:06:34,160 --> 04:06:37,240 I'LL SHOW HERE 12-18 MONTH DATA, 5576 04:06:37,240 --> 04:06:39,920 WHICH WE RECENTLY HAVE 5577 04:06:39,920 --> 04:06:40,280 AVAILABLE. 5578 04:06:40,280 --> 04:06:43,120 I'LL SHOW GLUCOSE TOLERANCE TEST 5579 04:06:43,120 --> 04:06:45,320 DATA AND EARLY PHASE INSULIN 5580 04:06:45,320 --> 04:06:45,960 SECRETION DATA. 5581 04:06:45,960 --> 04:06:48,920 BECAUSE MOST OF YOU IN THE 5582 04:06:48,920 --> 04:06:54,280 AUDIENCE HAVE NOT THOUGHT ABOUT 5583 04:06:54,280 --> 04:06:56,840 GLUCOSE EXCURSION ALL WALK YOU 5584 04:06:56,840 --> 04:06:58,640 THROUGH DATA. 5585 04:06:58,640 --> 04:07:01,840 ON THE LEFT-HAND PANEL IN GRAY 5586 04:07:01,840 --> 04:07:03,240 SHOWING THE NORMAL PLASMA 5587 04:07:03,240 --> 04:07:05,440 GLUCOSE IN RESPONSE TO A MEAL, 5588 04:07:05,440 --> 04:07:08,280 GLUCOSE PEAKS AT 30 MINUTES, 5589 04:07:08,280 --> 04:07:09,600 LOWER THAN BASELINE, GENERALLY 5590 04:07:09,600 --> 04:07:11,800 BY 2 HOURS. 5591 04:07:11,800 --> 04:07:15,680 AND THIS ARISES BECAUSE OF 5592 04:07:15,680 --> 04:07:17,880 INSULIN SECRETORY PROFILE ON THE 5593 04:07:17,880 --> 04:07:19,240 RIGHT, INSULIN PEAKS IN THE 5594 04:07:19,240 --> 04:07:21,960 FIRST 30 MINUTES, REFERRED TO AS 5595 04:07:21,960 --> 04:07:23,520 EARLY PHASE INSULIN SECRETION, 5596 04:07:23,520 --> 04:07:29,200 AND SECOND PHASE LESS ROBUST 5597 04:07:29,200 --> 04:07:32,160 INSULIN SECRETION PEAKING AT 60 5598 04:07:32,160 --> 04:07:32,800 MINUTES. 5599 04:07:32,800 --> 04:07:34,440 WITH NORMAL GLUCOSE TOLERANCE 5600 04:07:34,440 --> 04:07:37,040 WITH BLOOD GLUCOSE LESS THAN 155 5601 04:07:37,040 --> 04:07:39,480 AT ONE HOUR AND LESS THAN 140 AT 5602 04:07:39,480 --> 04:07:44,200 TWO HOURS YOU CAN SEE ONE-HOUR 5603 04:07:44,200 --> 04:07:46,360 GLUCOSE IS HIGH RELATIVE TO 5604 04:07:46,360 --> 04:07:48,240 OTHERWISE HEALTHY INDIVIDUAL 5605 04:07:48,240 --> 04:07:52,480 WITHOUT CF CAN DAMPENING OF 5606 04:07:52,480 --> 04:07:56,040 SECRETION ACCOMPANIED BY ROBUST 5607 04:07:56,040 --> 04:07:58,680 BUT DELAYED COMPENSATORY SECOND 5608 04:07:58,680 --> 04:07:59,400 PHASE SECRETION. 5609 04:07:59,400 --> 04:08:06,760 INDIVIDUALS WITH EARLY 5610 04:08:06,760 --> 04:08:08,520 TOLERANCE, PURPOSING SHOWS 5611 04:08:08,520 --> 04:08:12,640 DAMPENING OF EARLY FACE 5612 04:08:12,640 --> 04:08:13,080 SECRETION. 5613 04:08:13,080 --> 04:08:16,280 RED AND ORANGE IMPAIRED 5614 04:08:16,280 --> 04:08:19,800 TOLERANCE, EARLY PHASE INSULIN 5615 04:08:19,800 --> 04:08:23,840 SECRETION IS LEST, SECOND PHASE 5616 04:08:23,840 --> 04:08:26,120 IS ROBUST BUT DELAYED AND 5617 04:08:26,120 --> 04:08:28,440 GRADUAL DECLINE IN SECOND PHASE 5618 04:08:28,440 --> 04:08:32,800 SECRETION IS ASSOCIATED WITH 5619 04:08:32,800 --> 04:08:34,760 WORSEN OF CFRD. 5620 04:08:34,760 --> 04:08:36,760 >> FIVE-MINUTE WARNING. 5621 04:08:36,760 --> 04:08:38,400 >> INDIVIDUALS WITH NORMAL 5622 04:08:38,400 --> 04:08:40,160 TOLERANCE, FOUR WORSENED DURING 5623 04:08:40,160 --> 04:08:42,920 OF THE 12-18 MONTHS ETI. 5624 04:08:42,920 --> 04:08:45,440 23 WITH EARLY GLUCOSE 5625 04:08:45,440 --> 04:08:46,400 INTOLERANCE, FIVE WORSENED, ONE 5626 04:08:46,400 --> 04:08:46,840 IMPROVED. 5627 04:08:46,840 --> 04:08:52,200 AS WE GET TO WORSENING 5628 04:08:52,200 --> 04:08:53,960 TOLERANCE, SEEING GREATER 5629 04:08:53,960 --> 04:08:58,680 IMPROVEMENTS, 11 IMPROVED, THREE 5630 04:08:58,680 --> 04:09:01,480 CFRD PATIENTS IMPROVED. 5631 04:09:01,480 --> 04:09:03,360 THERE'S NORMAL VARIABILITY BUT 5632 04:09:03,360 --> 04:09:07,520 MANY HAVE APPRECIATED SUBSET OF 5633 04:09:07,520 --> 04:09:09,440 PATIENTS WHO IMPROVED GLUCOSE 5634 04:09:09,440 --> 04:09:10,920 TOLERANCE WITH ETI. 5635 04:09:10,920 --> 04:09:13,320 A LITTLE BIT MORE GRANULAR DATA 5636 04:09:13,320 --> 04:09:20,320 THE AREA UNDER THE CURVE FOR 5637 04:09:20,320 --> 04:09:21,960 GLUCOSE, SECRETORY RATES, NEW 5638 04:09:21,960 --> 04:09:24,680 CHANGES IN INSULIN SENSITIVITY 5639 04:09:24,680 --> 04:09:26,560 WITH ETI. 5640 04:09:26,560 --> 04:09:28,440 OTHER GLUCOSE PARAMETERS, I'LL 5641 04:09:28,440 --> 04:09:29,720 HIGHLIGHT SUBSET OF 50+ 5642 04:09:29,720 --> 04:09:31,280 INDIVIDUALS WHO WERE NOT TREATED 5643 04:09:31,280 --> 04:09:34,120 WITH INSULIN DURING THE 12-18 5644 04:09:34,120 --> 04:09:34,440 MONTHS. 5645 04:09:34,440 --> 04:09:37,080 THERE WAS A DECREASE IN FASTING 5646 04:09:37,080 --> 04:09:42,600 GLUCOSE, 3 1/2 MILLIGRAMS PER 5647 04:09:42,600 --> 04:09:45,600 DECILITER, ETI MAY HAVE 5648 04:09:45,600 --> 04:09:48,400 FAVORABLE IMPACTS UPON GLUCOSE 5649 04:09:48,400 --> 04:09:49,320 BEYOND MEAL-RELATED INSULIN 5650 04:09:49,320 --> 04:09:49,640 SECRETION. 5651 04:09:49,640 --> 04:09:54,280 WE FOUND OUT ABOUT A QUARTER 5652 04:09:54,280 --> 04:09:55,320 PERCENT DECREASE IN HEMOGLOBIN 5653 04:09:55,320 --> 04:10:05,840 AI 1 D -- A1c, COMPARABLE FROM 5654 04:10:15,240 --> 04:10:19,120 SWITCHING INJECTION TO PUMP. 5655 04:10:19,120 --> 04:10:20,320 SWITCHING GEARS, CARDIOMETABOLIC 5656 04:10:20,320 --> 04:10:21,600 HEALTH, JESSICA ALVAREZ WILL 5657 04:10:21,600 --> 04:10:23,040 TALK ABOUT NUTRITION BODY 5658 04:10:23,040 --> 04:10:25,280 COMPOSITION AND BMI. 5659 04:10:25,280 --> 04:10:26,760 I'M FOCUSING ON 50 INDIVIDUALS 5660 04:10:26,760 --> 04:10:29,800 FROM PROMISE WHO HAD FASTING 5661 04:10:29,800 --> 04:10:32,280 LIPIDS, LDL LESS THAN 100 IS 5662 04:10:32,280 --> 04:10:34,160 CONSIDERED FAVORABLE FOR PEOPLE 5663 04:10:34,160 --> 04:10:35,600 WITH ESTABLISHED CARDIOVASCULAR 5664 04:10:35,600 --> 04:10:37,800 DISEASE, LEVELS LESS THAN 70 ARE 5665 04:10:37,800 --> 04:10:38,120 TARGETED. 5666 04:10:38,120 --> 04:10:40,400 AND HOPEFULLY YOU CAN APPRECIATE 5667 04:10:40,400 --> 04:10:42,520 MANY PATIENTS HAVE REALLY GOOD 5668 04:10:42,520 --> 04:10:43,360 LDL. 5669 04:10:43,360 --> 04:10:46,880 THERE WAS AN OVERALL INCREASE IN 5670 04:10:46,880 --> 04:10:48,840 LDL WITH ETI TREATMENT, BUT THAT 5671 04:10:48,840 --> 04:10:51,000 WAS LARGELY EXPLAINED BY CHANGES 5672 04:10:51,000 --> 04:10:52,640 IN BMI. 5673 04:10:52,640 --> 04:10:55,960 IN CONTRAST HDL ALSO INCREASED 5674 04:10:55,960 --> 04:10:57,800 OVER THAT TIME FRAME, BUT WAS 5675 04:10:57,800 --> 04:11:01,640 NOT ASSOCIATED WITH BMI AND THAT 5676 04:11:01,640 --> 04:11:03,080 INCREASE PERSISTED AFTER 5677 04:11:03,080 --> 04:11:04,160 ADJUSTMENT FOR BMI. 5678 04:11:04,160 --> 04:11:08,200 I THINK THIS RAISES SOME 5679 04:11:08,200 --> 04:11:11,840 QUESTIONS, INCLUDING ARE THE LOW 5680 04:11:11,840 --> 04:11:13,920 CHOLESTEROL THAT WE 5681 04:11:13,920 --> 04:11:16,360 TRADITIONALLY SEE IN CF RELATED 5682 04:11:16,360 --> 04:11:20,600 TO MALNUTRITION AND 5683 04:11:20,600 --> 04:11:28,240 MALABSORPTION, D DOES ETI 5684 04:11:28,240 --> 04:11:33,520 IMPROVE, AND ARE WE GOING TO SEE 5685 04:11:33,520 --> 04:11:35,280 EMERGENCE OF DYSLIPIDEMIA IN 5686 04:11:35,280 --> 04:11:41,520 YOUTH AND ADULTS IN CF. 5687 04:11:41,520 --> 04:11:42,120 THE FOUNDATION RECOMMENDS 5688 04:11:42,120 --> 04:11:46,040 LUMBAR SPINE AND HIP DEXA, WE 5689 04:11:46,040 --> 04:11:51,280 OBTAINED WHOLE BODY DEXA. 5690 04:11:51,280 --> 04:11:57,200 LESS THAN NEGATIVE 2 BONE 5691 04:11:57,200 --> 04:11:57,720 DENSITY. 5692 04:11:57,720 --> 04:11:59,600 WHAT I WANTED TO HIGHLIGHT ON 5693 04:11:59,600 --> 04:12:02,280 AVERAGE NO DIFFERENCE AT ANY OF 5694 04:12:02,280 --> 04:12:04,080 THE SKELETAL SITES WAS 5695 04:12:04,080 --> 04:12:05,560 IDENTIFIED 12 TO 18 MONTHS OF 5696 04:12:05,560 --> 04:12:07,040 ETI BUT I WANT TO ACKNOWLEDGE 5697 04:12:07,040 --> 04:12:10,200 THERE ARE A GOOD NUMBER OF 5698 04:12:10,200 --> 04:12:12,720 PEOPLE WHO HAVE LOW HIP DEXA, 5699 04:12:12,720 --> 04:12:15,760 MAKING ME CONCERNED ABOUT 5700 04:12:15,760 --> 04:12:21,160 INCREASED RISK FOR FRAGILITY 5701 04:12:21,160 --> 04:12:24,320 FRACTURE AT THE HIP WITH AGE. 5702 04:12:24,320 --> 04:12:28,800 WE'RE SEEING DECREASES IN Z 5703 04:12:28,800 --> 04:12:30,400 SCORES, SURPRISINGLY WITH 12 TO 5704 04:12:30,400 --> 04:12:32,600 18 MONTHS OF ETI THERAPY, AND 5705 04:12:32,600 --> 04:12:35,240 THAT WAS CONFIRMED WITH HIP, 5706 04:12:35,240 --> 04:12:37,240 ALSO SEEING THESE SUBTLE 5707 04:12:37,240 --> 04:12:38,800 DECREASES IN Z SCORES, I HAVE 5708 04:12:38,800 --> 04:12:43,480 NOTIONS OF WHY, BEYOND THE SCOPE 5709 04:12:43,480 --> 04:12:45,240 OF THIS CONVERSATION. 5710 04:12:45,240 --> 04:12:49,920 IN THIS EXCITING TIME, WE NEED 5711 04:12:49,920 --> 04:12:52,120 TO REASSESS WELL ESTABLISHED 5712 04:12:52,120 --> 04:12:53,200 COMORBIDITIES AND CONCERN 5713 04:12:53,200 --> 04:12:54,520 OURSELVES WITH POTENTIAL MASK OF 5714 04:12:54,520 --> 04:12:58,160 NEW CONDITIONS, RESPOND TO 5715 04:12:58,160 --> 04:12:59,720 CHANGING PHENOTYPES AND 5716 04:12:59,720 --> 04:13:01,600 SCREENING AND MANAGE 5717 04:13:01,600 --> 04:13:02,200 ACCORDINGLY. 5718 04:13:02,200 --> 04:13:05,240 MODULATOR THERAPY MAY IMPACT 5719 04:13:05,240 --> 04:13:06,640 CFRD RISK, MAY IMPACT 5720 04:13:06,640 --> 04:13:07,840 CARDIOMETABOLIC RISK, MAY NEED 5721 04:13:07,840 --> 04:13:09,080 TO RECONSIDER MANAGEMENT 5722 04:13:09,080 --> 04:13:12,240 INCLUDING USE OF TYPE 2 DIABETES 5723 04:13:12,240 --> 04:13:12,840 WITH MEDICATIONS, NUTRITIONAL 5724 04:13:12,840 --> 04:13:14,680 CHANGES, AND THEN CONSIDER A 5725 04:13:14,680 --> 04:13:15,440 SCREENING FOR COMPLICATIONS AND 5726 04:13:15,440 --> 04:13:19,800 WE MAY NEED TO BE ADDRESSING 5727 04:13:19,800 --> 04:13:20,680 MORE AGGRESSIVELY HYPERTENSION, 5728 04:13:20,680 --> 04:13:21,880 DYSLIPIDEMIA, OBESITY. 5729 04:13:21,880 --> 04:13:24,200 ALSO THE IMPACT OF MODULATOR 5730 04:13:24,200 --> 04:13:26,800 THERAPY ON BONE HEALTH AND RISK 5731 04:13:26,800 --> 04:13:28,320 OF FRACTURE WITH INCREASING AGE 5732 04:13:28,320 --> 04:13:29,080 IN OUR POPULATION. 5733 04:13:29,080 --> 04:13:31,640 WITH THAT I WOULD LIKE TO THANK 5734 04:13:31,640 --> 04:13:33,360 MY COLLABORATORS AND AGAIN THE 5735 04:13:33,360 --> 04:13:35,600 CF FOUNDATION AND NIH FOR THEIR 5736 04:13:35,600 --> 04:13:37,760 SUPPORT. 5737 04:13:37,760 --> 04:13:43,800 5738 04:13:43,800 --> 04:13:49,040 5739 04:13:49,040 --> 04:13:52,080 I'M SUPPOSED TO INTRODUCE 5740 04:13:52,080 --> 04:13:54,880 JESSICA ALVAREZ TALKING ABOUT 5741 04:13:54,880 --> 04:13:59,560 BMI AND BODY COMPOSITION. 5742 04:13:59,560 --> 04:14:01,200 >> THANK YOU, DR. KELLY. 5743 04:14:01,200 --> 04:14:05,680 WHILE SLIDES ARE COMING UP, I'LL 5744 04:14:05,680 --> 04:14:09,200 END WITH WHERE I THINK WE SHOULD 5745 04:14:09,200 --> 04:14:11,200 GO FOR NUTRITION RESEARCH IN 5746 04:14:11,200 --> 04:14:12,920 CYSTIC FIBROSIS. 5747 04:14:12,920 --> 04:14:20,360 I HAVE NO CONFLICT OF INTEREST 5748 04:14:20,360 --> 04:14:22,680 OR DISCLOSURES RELATED TO THIS 5749 04:14:22,680 --> 04:14:23,200 PRESENTATION. 5750 04:14:23,200 --> 04:14:24,960 WHAT ARE OUR KNOWLEDGE GAPS? 5751 04:14:24,960 --> 04:14:27,280 I'LL SPEAK TO EACH OF THESE BUT 5752 04:14:27,280 --> 04:14:29,560 TO START HOW DO WE DETERMINE 5753 04:14:29,560 --> 04:14:30,480 OPTIMAL NUTRITION STATUS FOR 5754 04:14:30,480 --> 04:14:31,960 HEALTH AND LONGEVITY FOR PEOPLE 5755 04:14:31,960 --> 04:14:33,480 WITH CF? 5756 04:14:33,480 --> 04:14:35,160 KEY HERE IS LONGEVITY, RIGHT? 5757 04:14:35,160 --> 04:14:37,720 WHAT IS THE OPTIMAL DIET FOR 5758 04:14:37,720 --> 04:14:39,160 PEOPLE WITH CYSTIC FIBROSIS? 5759 04:14:39,160 --> 04:14:41,160 I'M A DIETITIAN SO I LOVE FOOD. 5760 04:14:41,160 --> 04:14:44,800 AND THAT'S WHAT I LIKE TO 5761 04:14:44,800 --> 04:14:46,080 CONCENTRATE ON. 5762 04:14:46,080 --> 04:14:48,280 WHAT A LONG-TERM EFFECTS OF 5763 04:14:48,280 --> 04:14:53,000 MODULATOR THERAPY ON NUTRITION 5764 04:14:53,000 --> 04:14:53,640 STATUS. 5765 04:14:53,640 --> 04:14:56,080 NEXT SLIDE. 5766 04:14:56,080 --> 04:14:57,160 SEMINAL STUDIES SHOWS BETTER 5767 04:14:57,160 --> 04:14:58,280 NUTRITION STATUS AS DETERMINED 5768 04:14:58,280 --> 04:15:01,640 BY HEIGHT AND WEIGHT AND BMI IN 5769 04:15:01,640 --> 04:15:04,960 EARLY LIFE PREDICTS IMPROVED 5770 04:15:04,960 --> 04:15:08,560 SURVIVAL AND CLINICAL OUTCOMES. 5771 04:15:08,560 --> 04:15:10,520 WE SEE SURVIVAL CURVES SHOWING 5772 04:15:10,520 --> 04:15:11,480 HIGHER WEIGHT PERCENTILE AT 4 5773 04:15:11,480 --> 04:15:13,280 YEARS OF AGE WAS ASSOCIATED WITH 5774 04:15:13,280 --> 04:15:17,400 SURVIVAL AT 18 YEARS OF AGE. 5775 04:15:17,400 --> 04:15:18,520 NEXT SLIDE. 5776 04:15:18,520 --> 04:15:20,240 AND THIS LINK BETWEEN BMI AND 5777 04:15:20,240 --> 04:15:23,640 HEIGHT AND WEIGHT PARAMETERS AND 5778 04:15:23,640 --> 04:15:26,480 CLINICAL OUTCOMES HAS GUIDED 5779 04:15:26,480 --> 04:15:28,120 MANAGEMENT TO DATE. 5780 04:15:28,120 --> 04:15:29,200 THIS HAS BEEN THE 5781 04:15:29,200 --> 04:15:30,520 RECOMMENDATIONS HAVE BEEN A HIGH 5782 04:15:30,520 --> 04:15:33,480 CALORIE HIGH FAT DIET WITH 5783 04:15:33,480 --> 04:15:36,120 APPROPRIATE PANCREATIC ENZYMES, 5784 04:15:36,120 --> 04:15:37,440 SALT SUPPLEMENTATION, FAT 5785 04:15:37,440 --> 04:15:39,600 SOLUBLE VITAMIN SUPPLEMENTATION. 5786 04:15:39,600 --> 04:15:41,560 TO MEET MINIMUM BMI GOALS OF 5787 04:15:41,560 --> 04:15:50,880 50th PERCENTILE FOR CHILDREN, 5788 04:15:50,880 --> 04:15:56,360 22 AND 23 FOR MEN AND WOMEN. 5789 04:15:56,360 --> 04:15:58,240 THIS DIET QUITE OFTEN TRANSLATED 5790 04:15:58,240 --> 04:16:01,280 TO ONE WHERE NO CALORIE IS A BAD 5791 04:16:01,280 --> 04:16:03,560 CALORIE, AND YOU MIGHT SEE THIS 5792 04:16:03,560 --> 04:16:06,760 OR HEAR THIS REFERRED TO AS THE 5793 04:16:06,760 --> 04:16:07,960 LEGACY CF DIET. 5794 04:16:07,960 --> 04:16:10,920 WE KNOW THINGS ARE STARTING TO 5795 04:16:10,920 --> 04:16:13,960 CHANGE AND PEOPLE ARE STARTING 5796 04:16:13,960 --> 04:16:15,400 TO MAKE RECOMMENDATIONS ON 5797 04:16:15,400 --> 04:16:19,800 IMPROVING DIET QUALITY IN THIS 5798 04:16:19,800 --> 04:16:20,360 ASPECT. 5799 04:16:20,360 --> 04:16:21,440 NEXT SLIDE. 5800 04:16:21,440 --> 04:16:24,280 BUT HISTORICAL PLAN MADE SENSE. 5801 04:16:24,280 --> 04:16:27,160 SO LOOKING AT OLDER CYSTIC 5802 04:16:27,160 --> 04:16:28,240 FIBROSIS PATIENT REGISTRY 5803 04:16:28,240 --> 04:16:30,080 REPORTS YOU COULD ALWAYS SEE 5804 04:16:30,080 --> 04:16:32,400 THIS POSITIVE RELATIONSHIP 5805 04:16:32,400 --> 04:16:35,120 BETWEEN BODY MASS INDEX, 5806 04:16:35,120 --> 04:16:38,680 PERCENTILE AND LUNGS FUNCTION IN 5807 04:16:38,680 --> 04:16:40,880 CHILDREN FROM 2016. 5808 04:16:40,880 --> 04:16:42,440 NEXT SLIDE. 5809 04:16:42,440 --> 04:16:44,960 BUT WHEN WE COMPARE THE 2016 5810 04:16:44,960 --> 04:16:47,040 GRAPH ON THE LEFT-HAND SIDE TO 5811 04:16:47,040 --> 04:16:50,360 THE LATEST FROM THE YEAR 2020, 5812 04:16:50,360 --> 04:16:51,520 THE RELATIONSHIP BETWEEN BMI AND 5813 04:16:51,520 --> 04:16:53,640 LUNG FUNCTION STARTS TO LOOK 5814 04:16:53,640 --> 04:16:54,920 PRETTY DIFFERENT. 5815 04:16:54,920 --> 04:16:56,280 THIS HASN'T BEEN SCIENTIFICALLY 5816 04:16:56,280 --> 04:16:57,880 TESTED, I HAVEN'T DONE 5817 04:16:57,880 --> 04:16:59,200 STATISTICAL ANALYSIS BUT JUST 5818 04:16:59,200 --> 04:17:01,640 LOOKING AT THESE TWO HERE, IT 5819 04:17:01,640 --> 04:17:03,880 MAKES ME WONDER IF WE'RE SEEING 5820 04:17:03,880 --> 04:17:06,040 ALMOST IN THIS POST MODULATOR 5821 04:17:06,040 --> 04:17:11,680 ERA UNCOUPLING OF BMI FROM LUNG 5822 04:17:11,680 --> 04:17:13,840 FUNCTION AT LEAST IN CHILDREN AT 5823 04:17:13,840 --> 04:17:15,280 HIGHER PERCENTILES. 5824 04:17:15,280 --> 04:17:17,000 NEXT SLIDE. 5825 04:17:17,000 --> 04:17:18,760 AND ADULTS, THIS SLOPE BETWEEN 5826 04:17:18,760 --> 04:17:20,120 LUNGS FUNCTION AND BMI REMAINS, 5827 04:17:20,120 --> 04:17:24,680 WE CAN SEE THAT THERE. 5828 04:17:24,680 --> 04:17:25,000 NEXT SLIDE. 5829 04:17:25,000 --> 04:17:27,840 BUT STUDIES HAVE LOOKED MORE 5830 04:17:27,840 --> 04:17:30,040 RIGOROUSLY AT THIS RELATIONSHIP 5831 04:17:30,040 --> 04:17:32,240 TO SEE WHAT THAT EXTENT OF THE 5832 04:17:32,240 --> 04:17:33,800 RELATIONSHIP IS. 5833 04:17:33,800 --> 04:17:35,160 AND THEY ARE INDEED POSITIVELY 5834 04:17:35,160 --> 04:17:37,280 CORRELATED BUT A LOT OF STUDIES 5835 04:17:37,280 --> 04:17:38,360 SHOW THAT RELATIONSHIP ONLY 5836 04:17:38,360 --> 04:17:40,360 EXISTS AT A CERTAIN POINT. 5837 04:17:40,360 --> 04:17:43,400 SO SOME STUDIES LISTED HERE ON 5838 04:17:43,400 --> 04:17:45,840 THE RIGHT-HAND SIDE PUBLISHED 5839 04:17:45,840 --> 04:17:49,000 THRESHOLDS BEYOND WHICH 5840 04:17:49,000 --> 04:17:50,120 RELATIONSHIP BETWEEN BMI AND 5841 04:17:50,120 --> 04:17:52,440 LUNGS FUNCTION SEEMED TO BE 5842 04:17:52,440 --> 04:17:55,560 BLUNTED, RANGING BETWEEN 23 TO 5843 04:17:55,560 --> 04:17:56,760 29, BUT WHAT I'M SHOWING IS ONE 5844 04:17:56,760 --> 04:17:58,840 OF THE MOST RECENT STUDIES OUT 5845 04:17:58,840 --> 04:18:00,560 OF MINNESOTA SUGGESTING A 5846 04:18:00,560 --> 04:18:01,920 PLATEAU IN THAT RELATIONSHIP 5847 04:18:01,920 --> 04:18:04,320 BETWEEN BMI AND LUNG FUNCTION AT 5848 04:18:04,320 --> 04:18:07,320 ABOVE -- RIGHT AROUND 28 OR 29 5849 04:18:07,320 --> 04:18:08,920 KILOGRAMS PER METER SQUARED. 5850 04:18:08,920 --> 04:18:10,240 SO, AGAIN, THESE STUDIES SUGGEST 5851 04:18:10,240 --> 04:18:12,320 THAT TO A CERTAIN POINT 5852 04:18:12,320 --> 04:18:14,040 INCREASING BMI MAY NOT IMPROVE 5853 04:18:14,040 --> 04:18:15,800 LUNGS FUNCTION, AT LEAST AT THE 5854 04:18:15,800 --> 04:18:18,880 POPULATION LEVEL. 5855 04:18:18,880 --> 04:18:19,880 NEXT SLIDE. 5856 04:18:19,880 --> 04:18:22,160 ALMOST IN CONTRAST TO THAT 5857 04:18:22,160 --> 04:18:23,560 MESSAGE, A RECENTLY PUBLISHED 5858 04:18:23,560 --> 04:18:28,600 META-ANALYSIS OUT OF HUNGRY 5859 04:18:28,600 --> 04:18:29,960 SUGGESTED BETTER LUNGS FUNCTION 5860 04:18:29,960 --> 04:18:32,160 COMPARED TO THOSE WHO WERE 5861 04:18:32,160 --> 04:18:33,000 NORMAL WEIGHT. 5862 04:18:33,000 --> 04:18:34,880 HOWEVER, I WILL SAY THIS WAS 5863 04:18:34,880 --> 04:18:37,080 ONLY BASED ON CATEGORIES OF BMI 5864 04:18:37,080 --> 04:18:38,640 AND NOT AS A CONTINUOUS FUNCTION 5865 04:18:38,640 --> 04:18:41,600 LIKE I SHOWED IN THE SLIDE 5866 04:18:41,600 --> 04:18:42,360 EARLIER. 5867 04:18:42,360 --> 04:18:43,760 SO, A THRESHOLD WASN'T 5868 04:18:43,760 --> 04:18:46,040 DESCRIBED, AND YOU CAN SEE THAT 5869 04:18:46,040 --> 04:18:47,680 THE VARIABILITY OF THE 5870 04:18:47,680 --> 04:18:48,880 RELATIONSHIP, IT'S MUCH WIDER 5871 04:18:48,880 --> 04:18:51,640 WHEN THEY MOVED FROM LOOKING AT 5872 04:18:51,640 --> 04:18:52,720 NORMAL WEIGHT VERSUS OVERWEIGHT 5873 04:18:52,720 --> 04:18:56,240 TO LOOKING AT NORMAL WEIGHT 5874 04:18:56,240 --> 04:18:57,120 VERSUS OBESITY. 5875 04:18:57,120 --> 04:18:58,880 ANOTHER THING TO REMEMBER IF 5876 04:18:58,880 --> 04:19:02,040 YOU'RE READING THIS IS THAT THIS 5877 04:19:02,040 --> 04:19:03,400 META-ANALYSIS INCLUDED STUDIES 5878 04:19:03,400 --> 04:19:04,760 PUBLISHED BEFORE NOVEMBER 2020. 5879 04:19:04,760 --> 04:19:07,400 SO THE STUDIES ARE OLDER, AND 5880 04:19:07,400 --> 04:19:10,080 MORE HEAVILY WEIGHED BY THE 5881 04:19:10,080 --> 04:19:13,120 PRE-HIGHLY EFFECTIVE MODULATOR 5882 04:19:13,120 --> 04:19:13,600 DATA. 5883 04:19:13,600 --> 04:19:14,640 NEXT SLIDE. 5884 04:19:14,640 --> 04:19:16,280 SO, A BIG LIMITATION OF THE 5885 04:19:16,280 --> 04:19:18,160 STUDIES I'VE HIGHLIGHTED IS THAT 5886 04:19:18,160 --> 04:19:20,040 BMI DOESN'T PROVIDE ANY 5887 04:19:20,040 --> 04:19:21,240 INFORMATION ABOUT BODY 5888 04:19:21,240 --> 04:19:21,560 COMPOSITION. 5889 04:19:21,560 --> 04:19:23,680 IT'S A GREAT TOOL FOR SCREENING 5890 04:19:23,680 --> 04:19:25,080 AND IDENTIFYING PEOPLE AT THE 5891 04:19:25,080 --> 04:19:28,080 EXTREME ENDS OF MALNUTRITION AND 5892 04:19:28,080 --> 04:19:29,440 OVERWEIGHT, BUT IT DOESN'T 5893 04:19:29,440 --> 04:19:33,160 DISTINGUISH BETWEEN FAT MASS OR 5894 04:19:33,160 --> 04:19:36,480 MUSCLE AND FAT-FREE MASS, OR FAT 5895 04:19:36,480 --> 04:19:38,120 MASS OR FAT-FREE MASS. 5896 04:19:38,120 --> 04:19:39,600 WE HAVE MUSCLE, BONE, CONNECTIVE 5897 04:19:39,600 --> 04:19:42,680 TISSUE AND ORGANS WE CAN LOOK 5898 04:19:42,680 --> 04:19:42,960 AT. 5899 04:19:42,960 --> 04:19:44,520 WHAT WE'RE MOST CONCERNED ABOUT 5900 04:19:44,520 --> 04:19:46,960 WHEN THINKING ABOUT HEALTH AND 5901 04:19:46,960 --> 04:19:49,120 LONGEVITY IN CF AND OTHER 5902 04:19:49,120 --> 04:19:51,640 DISEASE STATES IS THE 5903 04:19:51,640 --> 04:19:53,480 PRESERVATION OF FAT-FREE MASS, 5904 04:19:53,480 --> 04:19:56,160 PRESERVATION OF BONE AND MUSCLE. 5905 04:19:56,160 --> 04:19:58,080 NEXT SLIDE. 5906 04:19:58,080 --> 04:20:00,720 ON A POSITIVE NOTE BMI IS A 5907 04:20:00,720 --> 04:20:02,480 USEFUL SURROGATE FOR FAT-FREE 5908 04:20:02,480 --> 04:20:04,000 MASS, BUT DOES CORRELATE WITH 5909 04:20:04,000 --> 04:20:04,920 FAT MASS. 5910 04:20:04,920 --> 04:20:06,880 AND WHEN WE COMPARE FAT-FREE 5911 04:20:06,880 --> 04:20:10,920 MASS VERSUS FAT MASS VERSUS BODY 5912 04:20:10,920 --> 04:20:14,200 MASS INDEX TO CLINICAL OUTCOMES 5913 04:20:14,200 --> 04:20:15,960 FAT-FREE MOST OFTEN PERFORMS 5914 04:20:15,960 --> 04:20:16,400 BETTER. 5915 04:20:16,400 --> 04:20:18,680 STUDIES IN CF HAVE SHOWN 5916 04:20:18,680 --> 04:20:22,000 FAT-FREE OR LEAN MASS, I USE 5917 04:20:22,000 --> 04:20:23,280 THOSE WORDS INTERCHANGEABLY, IS 5918 04:20:23,280 --> 04:20:24,920 A STRONGER CORRELATE OF LUNG 5919 04:20:24,920 --> 04:20:26,600 FUNCTION COMPARED TO BMI, 5920 04:20:26,600 --> 04:20:29,480 COMPARED TO FAT MASS. 5921 04:20:29,480 --> 04:20:30,760 SEVERAL STUDIES HAVE SHOWN FOR 5922 04:20:30,760 --> 04:20:34,080 THE LAST 20 YEARS THAT BMI HAS A 5923 04:20:34,080 --> 04:20:35,320 LOW SENSITIVITY FOR DETECTING 5924 04:20:35,320 --> 04:20:37,720 FAT-FREE MASS IN PEOPLE WITH CF 5925 04:20:37,720 --> 04:20:38,920 ACROSS ALL AGES. 5926 04:20:38,920 --> 04:20:42,560 AND THIS HASN'T BEEN STUDIED IN 5927 04:20:42,560 --> 04:20:46,560 CF YET BUT IN OTHER PULMONARY 5928 04:20:46,560 --> 04:20:50,520 DISEASES SUCH AS COPD FAT-FREE 5929 04:20:50,520 --> 04:20:53,240 MASS IS STRONGER PREDICTOR OF 5930 04:20:53,240 --> 04:20:55,880 MORTALITY. 5931 04:20:55,880 --> 04:20:57,080 NEXT SLIDE. 5932 04:20:57,080 --> 04:20:59,280 SO, LOOKING AT BODY COMPOSITION 5933 04:20:59,280 --> 04:21:01,160 AND RELATIONSHIPS WITH LUNG 5934 04:21:01,160 --> 04:21:03,680 FUNCTION AND CLINICAL OUTCOMES, 5935 04:21:03,680 --> 04:21:07,200 HERE IS A STUDY WE PUBLISHED IN 5936 04:21:07,200 --> 04:21:09,840 2016 THAT SHOWED THE EXPECTED 5937 04:21:09,840 --> 04:21:10,720 POSITIVE RELATIONSHIP BETWEEN 5938 04:21:10,720 --> 04:21:12,560 BMI AND LUNG FUNCTION. 5939 04:21:12,560 --> 04:21:13,800 WE ALSO FOUND FAT-FREE MASS, 5940 04:21:13,800 --> 04:21:16,560 LOOKED AT THAT ALSO AND FOUND 5941 04:21:16,560 --> 04:21:20,040 SIMILAR POSITIVE RELATIONSHIP. 5942 04:21:20,040 --> 04:21:21,480 BUT VERY SURPRISING FINDING 5943 04:21:21,480 --> 04:21:23,000 THERE WAS INVERSE RELATIONSHIP 5944 04:21:23,000 --> 04:21:25,080 BETWEEN OUR MEASURES OF ADIPOSE 5945 04:21:25,080 --> 04:21:27,160 TISSUES, PERCENT BODY FAT, EVEN 5946 04:21:27,160 --> 04:21:29,840 LOOKING AT FAT MASS ON ITS OWN, 5947 04:21:29,840 --> 04:21:31,240 IT WAS INVERSELY ASSOCIATED WITH 5948 04:21:31,240 --> 04:21:33,440 LUNG FUNCTION. 5949 04:21:33,440 --> 04:21:34,640 HIGHER BODY FAT, LOWER LUNG 5950 04:21:34,640 --> 04:21:35,080 FUNCTION. 5951 04:21:35,080 --> 04:21:38,040 THIS STARTED TO GIVE MORE DETAIL 5952 04:21:38,040 --> 04:21:39,480 ABOUT LUNG FUNCTION AND STUFF WE 5953 04:21:39,480 --> 04:21:41,240 COULDN'T SEE WHEN JUST LOOKING 5954 04:21:41,240 --> 04:21:44,400 AT BODY MASS INDEX. 5955 04:21:44,400 --> 04:21:45,720 NEXT SLIDE. 5956 04:21:45,720 --> 04:21:48,760 AND THIS JUST SHOWS A MORE 5957 04:21:48,760 --> 04:21:53,920 RECENT COHORT STUDY LED BY DR. 5958 04:21:53,920 --> 04:21:54,960 PUTNAM AT HARVARD, SUPPORTED 5959 04:21:54,960 --> 04:21:56,760 POSITIVE RELATIONSHIP WITH LEAN 5960 04:21:56,760 --> 04:21:58,480 MASS, INVERSE RELATIONSHIP WITH 5961 04:21:58,480 --> 04:22:02,640 FAT MASS INDICES. 5962 04:22:02,640 --> 04:22:03,640 NEXT SLIDE. 5963 04:22:03,640 --> 04:22:06,920 WE SPENT TIME FOCUSING ON MUSCLE 5964 04:22:06,920 --> 04:22:08,040 MASS OR MUSCLE SIZE, SOMETIMES 5965 04:22:08,040 --> 04:22:09,320 MUSCLE FUNCTION CAN BE 5966 04:22:09,320 --> 04:22:09,680 OVERLOOKED. 5967 04:22:09,680 --> 04:22:13,160 MY LAB AND OTHERS HAVE LOOKED AT 5968 04:22:13,160 --> 04:22:15,760 HOW HAND GRIP STRENGTH, MEASURE 5969 04:22:15,760 --> 04:22:19,720 OF MUSCLE FUNCTION, CAN 5970 04:22:19,720 --> 04:22:20,720 CORRELATE CAN DEXA-DERIVED 5971 04:22:20,720 --> 04:22:22,000 MEASURES OF BODY COMPOSITION. 5972 04:22:22,000 --> 04:22:24,680 ON THE LEFT-HAND PANEL IS WE 5973 04:22:24,680 --> 04:22:29,640 DIDN'T FIND -- THIS WAS AN 5974 04:22:29,640 --> 04:22:31,400 ABSTRACT WE, NO RELATIONSHIP 5975 04:22:31,400 --> 04:22:35,640 BETWEEN HAND GRIP STRENGTH AND 5976 04:22:35,640 --> 04:22:36,880 BMI BUT STRONG RELATIONSHIP WITH 5977 04:22:36,880 --> 04:22:40,200 STRENGTH AND LEAN MASS AND TOTAL 5978 04:22:40,200 --> 04:22:41,400 BONE MARROW DENSITY. 5979 04:22:41,400 --> 04:22:43,800 AND SIMILAR TO WHAT SOME OTHER 5980 04:22:43,800 --> 04:22:45,440 FINDINGS WE FOUND INVERSE 5981 04:22:45,440 --> 04:22:46,880 RELATIONSHIP BETWEEN HAND GRIP 5982 04:22:46,880 --> 04:22:49,920 STRENGTH AND PERCENT BODY FAT. 5983 04:22:49,920 --> 04:22:50,480 NEXT SLIDE. 5984 04:22:50,480 --> 04:22:53,400 SO IN KEEPING WITH THE THEME BMI 5985 04:22:53,400 --> 04:22:55,720 DOESN'T TELL ALL, WE'VE LOOKED 5986 04:22:55,720 --> 04:22:57,920 AT NORMAL WEIGHT OBESITY IN 5987 04:22:57,920 --> 04:23:00,000 ADULTS WITH CF, BASICALLY HAVING 5988 04:23:00,000 --> 04:23:03,920 A NORMAL WEIGHT BMI IN NUMBERS 5989 04:23:03,920 --> 04:23:04,920 BUT DISPROPORTIONATELY HIGH 5990 04:23:04,920 --> 04:23:06,200 PERCENTAGE BODY FAT, ALMOST A 5991 04:23:06,200 --> 04:23:08,000 THIRD OF OUR GROUP THAT WE 5992 04:23:08,000 --> 04:23:10,960 STUDIED HERE HAD NORMAL WEIGHT 5993 04:23:10,960 --> 04:23:11,240 OBESITY. 5994 04:23:11,240 --> 04:23:13,640 WHEN WE LOOKED AT GROUP 5995 04:23:13,640 --> 04:23:15,520 DIFFERENCES HOWEVER IN LUNG 5996 04:23:15,520 --> 04:23:17,080 FUNCTION BETWEEN BMI CATEGORIES 5997 04:23:17,080 --> 04:23:19,120 IT WAS THE NORMAL WEIGHT OBESE 5998 04:23:19,120 --> 04:23:21,640 GROUP, THIS PINK BAR, THAT HAD 5999 04:23:21,640 --> 04:23:24,080 THE LOWEST LUNG FUNCTION, ALSO 6000 04:23:24,080 --> 04:23:25,040 NOT COINCIDENTALLY WAS ALSO THE 6001 04:23:25,040 --> 04:23:27,840 GROUP THAT HAD THE LOWEST 6002 04:23:27,840 --> 04:23:29,680 FAT-FREE MASS, LOWEST MUSCLE. 6003 04:23:29,680 --> 04:23:31,360 NEXT SLIDE. 6004 04:23:31,360 --> 04:23:32,360 >> FIVE-MINUTE WARNING. 6005 04:23:32,360 --> 04:23:32,960 >> OKAY. 6006 04:23:32,960 --> 04:23:34,920 IN A MORE RECENT STUDY COMPARED 6007 04:23:34,920 --> 04:23:36,640 BODY COMPOSITION TO HEALTHY 6008 04:23:36,640 --> 04:23:37,800 CONTROLS USING DEXA. 6009 04:23:37,800 --> 04:23:41,040 IN THE STUDY I'M SHOWING HERE WE 6010 04:23:41,040 --> 04:23:43,040 HAD GROUPS WELL MATCHED FOR BMI 6011 04:23:43,040 --> 04:23:45,000 AND FAT MASS AND LEAN MASS BUT 6012 04:23:45,000 --> 04:23:47,520 SOMETHING PRETTY SHOCKING TO US 6013 04:23:47,520 --> 04:23:49,760 WAS A MUCH HIGHER VISCERAL 6014 04:23:49,760 --> 04:23:51,360 ADIPOSE TISSUE, FAT IN THE 6015 04:23:51,360 --> 04:23:53,560 ORGANS, WHEN THE VISCERAL AREA 6016 04:23:53,560 --> 04:23:54,800 IN OUR ADULTS CAN CYSTIC 6017 04:23:54,800 --> 04:23:58,920 FIBROSIS COMPARED TO CONTROLS. 6018 04:23:58,920 --> 04:23:59,800 NEXT SLIDE. 6019 04:23:59,800 --> 04:24:01,680 AND THEN DATA THAT DR. KELLY 6020 04:24:01,680 --> 04:24:04,760 SHOWED US, WE FOUND A POSITIVE 6021 04:24:04,760 --> 04:24:05,600 RELATIONSHIP BETWEEN VISCERAL 6022 04:24:05,600 --> 04:24:11,040 ADIPOSE TISSUE IN SAME SUBJECTS, 6023 04:24:11,040 --> 04:24:21,560 MEASURES OF FASTING GLUCOSE. 6024 04:24:23,080 --> 04:24:24,560 NEXT SLIDE. 6025 04:24:24,560 --> 04:24:26,080 WHAT ABOUT DIET? 6026 04:24:26,080 --> 04:24:28,400 IN THE SAME COHORT OF ADULTS WE 6027 04:24:28,400 --> 04:24:29,520 DIDN'T FIND ANY DIFFERENCES 6028 04:24:29,520 --> 04:24:34,120 AFTER WE ADJUSTED FOR CALORIE IN 6029 04:24:34,120 --> 04:24:34,760 OVERALL MACRONUTRIENTS, 6030 04:24:34,760 --> 04:24:35,680 CARBOHYDRATES, FAT, PROTEIN. 6031 04:24:35,680 --> 04:24:38,040 BUT WHEN WE DUG DEEPER AND 6032 04:24:38,040 --> 04:24:39,800 LOOKED AT DIET QUALITY, 6033 04:24:39,800 --> 04:24:42,200 INDICATORS OF QUALITY, WE FOUND 6034 04:24:42,200 --> 04:24:44,400 OVERALL MEASURES OF DIET QUALITY 6035 04:24:44,400 --> 04:24:47,040 WERE WORSE IN OUR ADULTS WITH CF 6036 04:24:47,040 --> 04:24:49,120 COMPARED TO OUR HEALTHY 6037 04:24:49,120 --> 04:24:50,000 CONTROLS. 6038 04:24:50,000 --> 04:24:55,280 AND THAT INCLUDED ADDED SUGAR 6039 04:24:55,280 --> 04:24:58,000 INTAKE, GLYCEMIC LOAD, FIBER AND 6040 04:24:58,000 --> 04:25:01,200 FATTY INTAKE, LOOKED AT HEALTHY 6041 04:25:01,200 --> 04:25:02,520 EATING INDEX, LOWER IN CF 6042 04:25:02,520 --> 04:25:03,840 COMPARED TO CONTROLS. 6043 04:25:03,840 --> 04:25:07,200 NEXT SLIDE. 6044 04:25:07,200 --> 04:25:08,640 WE'VE ALSO LOOKED AT 6045 04:25:08,640 --> 04:25:09,760 RELATIONSHIP BETWEEN DIET AND 6046 04:25:09,760 --> 04:25:19,800 BODY COMPOSITION, ADDED SUGAR 6047 04:25:19,800 --> 04:25:20,440 INTAKE WAS ASSOCIATED, 6048 04:25:20,440 --> 04:25:23,400 HIGHLIGHTING WE NEED TO FOCUS ON 6049 04:25:23,400 --> 04:25:25,240 NUTRITION, SHIFTING FOCUS TO 6050 04:25:25,240 --> 04:25:26,560 NUTRITION ASSESSMENT TOWARDS 6051 04:25:26,560 --> 04:25:28,680 BODY COMPOSITION AND DIET 6052 04:25:28,680 --> 04:25:30,080 QUALITY AS OPPOSED TO HEIGHT AND 6053 04:25:30,080 --> 04:25:32,840 WEIGHT AND TOTAL CALORIE INTAKE. 6054 04:25:32,840 --> 04:25:34,600 AND AS DR. KELLY SHOWED THERE'S 6055 04:25:34,600 --> 04:25:36,520 GOOD BIT OF VARIABILITY IN 6056 04:25:36,520 --> 04:25:37,520 EFFECTS OF MODULATORS ON 6057 04:25:37,520 --> 04:25:38,640 ENDOCRINE FUNCTION, SO WE NEED 6058 04:25:38,640 --> 04:25:41,040 TO START THINKING ABOUT OTHER 6059 04:25:41,040 --> 04:25:42,160 MODIFIERS, OTHER POTENTIAL 6060 04:25:42,160 --> 04:25:44,240 MODIFIERS TO CF DIABETES RISK. 6061 04:25:44,240 --> 04:25:46,320 DIET QUALITY COULD WELL BE ONE 6062 04:25:46,320 --> 04:25:49,040 OF THEM. 6063 04:25:49,040 --> 04:25:49,760 NEXT SLIDE. 6064 04:25:49,760 --> 04:25:54,080 AS DR. KELLY SHOWED US, 6065 04:25:54,080 --> 04:25:57,160 MODULATORS ARE EFFECTIVE AT 6066 04:25:57,160 --> 04:26:00,640 INCREASING BMI SOME MECHANISMS 6067 04:26:00,640 --> 04:26:08,000 OF WEIGHT GAIN PROPOSED ARE 6068 04:26:08,000 --> 04:26:10,080 DECREASED MALABSORPTION, 6069 04:26:10,080 --> 04:26:19,320 DECREASED GUT INFLAMMATION, 6070 04:26:19,320 --> 04:26:20,160 DECREASED ENERGY EXPENDITURE. 6071 04:26:20,160 --> 04:26:22,120 IS IT WEIGHT GAIN, FAT, MUSCLE 6072 04:26:22,120 --> 04:26:22,800 OR BOTH. 6073 04:26:22,800 --> 04:26:24,000 >> ONE-MINUTE WARNING. 6074 04:26:24,000 --> 04:26:26,600 >> THIS IS JUST A STUDY FROM 6075 04:26:26,600 --> 04:26:30,640 KING OUT OF AUSTRALIA SHOWING 6076 04:26:30,640 --> 04:26:35,720 CHANGES OVER 28 DAYS IN FAT-FREE 6077 04:26:35,720 --> 04:26:43,520 MASS, NOT FAT MOSS FOLLOWING 6078 04:26:43,520 --> 04:26:45,680 IVACAFTOR USE, BY SIX MONTHS 64% 6079 04:26:45,680 --> 04:26:48,840 OF THE TOTAL WEIGHT GAIN WAS FAT 6080 04:26:48,840 --> 04:26:50,600 MASS, AND THEN BY 2 1/2 YEARS NO 6081 04:26:50,600 --> 04:26:53,120 FURTHER CHANGES IN BODY 6082 04:26:53,120 --> 04:26:53,880 COMPOSITION. 6083 04:26:53,880 --> 04:26:59,680 I'LL SKIP OVER THE NEXT SLIDE 6084 04:26:59,680 --> 04:27:02,640 WHICH SHOWS SIMILAR FINDINGS OF 6085 04:27:02,640 --> 04:27:05,480 INCREASED FAT MASS BUT NOT 6086 04:27:05,480 --> 04:27:07,400 FAT-FREE MASS IN ADULTS 6087 04:27:07,400 --> 04:27:09,480 FOLLOWING IVACAFTOR US A. 6088 04:27:09,480 --> 04:27:12,720 I'M GOING TO END HERE WITH 6089 04:27:12,720 --> 04:27:13,920 READDRESSING OUR CF NUTRITION 6090 04:27:13,920 --> 04:27:14,920 KNOWLEDGE GAPS. 6091 04:27:14,920 --> 04:27:16,760 WE KNOW MAINTENANCE OF ADEQUATE 6092 04:27:16,760 --> 04:27:18,320 NUTRITION IS CRITICAL FOR CF. 6093 04:27:18,320 --> 04:27:21,720 HOW DO WE BEST ASSESS NUTRITION 6094 04:27:21,720 --> 04:27:24,160 NOW IN THIS POST-MODULATOR ERA? 6095 04:27:24,160 --> 04:27:26,960 BMI REMAINS A USEFUL SCREENING 6096 04:27:26,960 --> 04:27:28,640 TOOL, CAN LONGITUDINAL BODY 6097 04:27:28,640 --> 04:27:30,680 COMPOSITION FAT DISTRIBUTION ADD 6098 04:27:30,680 --> 04:27:32,000 FURTHER INSIGHT INTO PROGRESSION 6099 04:27:32,000 --> 04:27:36,280 OF CF HEALTH AND DISEASE NOW? 6100 04:27:36,280 --> 04:27:37,840 GIVEN IMPROVEMENTS IN LUNG 6101 04:27:37,840 --> 04:27:40,520 FUNCTION POST MOD MODULATOR 6102 04:27:40,520 --> 04:27:44,080 DOES IT REMAIN A GOOD ENDPOINT 6103 04:27:44,080 --> 04:27:46,280 FOR NUTRITION STUDIES? 6104 04:27:46,280 --> 04:27:47,480 MOST NUTRITION RECOMMENDATIONS 6105 04:27:47,480 --> 04:27:49,120 FOR ENERGY EXPENDITURE, DIETARY 6106 04:27:49,120 --> 04:27:51,520 NEEDS AND TARGET NUTRITION GOALS 6107 04:27:51,520 --> 04:27:53,360 COME FROM WONDERFUL RESEARCH, 6108 04:27:53,360 --> 04:27:55,240 ABSOLUTELY WONDERFUL RESEARCH 6109 04:27:55,240 --> 04:27:56,920 DONE BEFORE CFTR MODULATOR 6110 04:27:56,920 --> 04:27:58,160 THERAPY WAS AVAILABLE SO NOW 6111 04:27:58,160 --> 04:28:00,800 THERE'S A HUGE NEED TO DETERMINE 6112 04:28:00,800 --> 04:28:03,120 THESE NEW BASELINE NUTRITION 6113 04:28:03,120 --> 04:28:04,640 STATUS, AND IN TERMS OF DIET 6114 04:28:04,640 --> 04:28:06,720 WHAT ARE MACRO AND MICRO 6115 04:28:06,720 --> 04:28:08,400 NUTRIENT NEEDS NOW, HOW DO THESE 6116 04:28:08,400 --> 04:28:11,040 DIFFER WITH COMORBIDITIES SUCH 6117 04:28:11,040 --> 04:28:13,440 AS CF-RELATED DIABETES? 6118 04:28:13,440 --> 04:28:16,640 AND FINALLY HOW DO MODULATORS 6119 04:28:16,640 --> 04:28:18,480 AFFECT NUTRITION FOR PEOPLE WITH 6120 04:28:18,480 --> 04:28:22,400 CF, IS OVERWEIGHT OBESITY A 6121 04:28:22,400 --> 04:28:22,640 CONCERN? 6122 04:28:22,640 --> 04:28:25,160 WHAT ARE LONG-TERM EFFECTS OF 6123 04:28:25,160 --> 04:28:28,320 MODULATORS ON BODY COMPOSITION 6124 04:28:28,320 --> 04:28:29,440 AND CARDIOMETABOLIC RISK. 6125 04:28:29,440 --> 04:28:31,200 BOTTOM LINE NEW STUDIES ARE 6126 04:28:31,200 --> 04:28:33,080 NEEDED TO BETTER DEFINE OPTIMAL 6127 04:28:33,080 --> 04:28:34,720 NUTRITION STATUS FOR HEALTH AND 6128 04:28:34,720 --> 04:28:36,920 LONGEVITY IN PEOPLE WITH CF. 6129 04:28:36,920 --> 04:28:40,200 SO I WILL END WITH 6130 04:28:40,200 --> 04:28:40,560 ACKNOWLEDGMENTS. 6131 04:28:40,560 --> 04:28:42,640 NEXT SLIDE. 6132 04:28:42,640 --> 04:28:45,360 WONDERFUL STUDY TEAM AND GEORGIA 6133 04:28:45,360 --> 04:28:47,080 CF CENTER, THAT'S BEEN 6134 04:28:47,080 --> 04:28:48,400 SUPPORTIVE MUCH NUTRITION 6135 04:28:48,400 --> 04:28:52,320 RESEARCH AS WELL AS MY MANY 6136 04:28:52,320 --> 04:28:54,320 COLLABORATORS OUTSIDE EMORY WHO 6137 04:28:54,320 --> 04:28:55,520 I'VE LOVED WORKING WITH. 6138 04:28:55,520 --> 04:28:57,720 I THINK THAT'S IT. 6139 04:28:57,720 --> 04:29:01,840 WE WILL MOVE ON TO THE Q&A 6140 04:29:01,840 --> 04:29:02,080 SESSION. 6141 04:29:02,080 --> 04:29:03,160 >> THANK YOU, JESSICA, FOR THE 6142 04:29:03,160 --> 04:29:03,360 TALK. 6143 04:29:03,360 --> 04:29:06,520 THANK YOU TO ALL THE SPEAKERS IN 6144 04:29:06,520 --> 04:29:07,120 THIS SESSION. 6145 04:29:07,120 --> 04:29:08,840 I THINK YOU'LL NOTICE AS WE MOVE 6146 04:29:08,840 --> 04:29:11,240 FORWARD THAT UNLIKE THE FIRST 6147 04:29:11,240 --> 04:29:13,320 SESSION THERE'S DISPARATE TALKS 6148 04:29:13,320 --> 04:29:14,320 THAT COVER BROAD CATEGORIES IN 6149 04:29:14,320 --> 04:29:15,840 EACH OF THESE SESSIONS AS WE 6150 04:29:15,840 --> 04:29:17,280 MOVE FORWARD. 6151 04:29:17,280 --> 04:29:19,160 WE'LL START WITH SOME QUESTIONS 6152 04:29:19,160 --> 04:29:20,440 THAT HOPEFULLY ALL OF THE 6153 04:29:20,440 --> 04:29:22,520 SPEAKERS CAN ADDRESS AND WE HAVE 6154 04:29:22,520 --> 04:29:26,720 SPECIFIC QUESTIONS FOR EACH OF 6155 04:29:26,720 --> 04:29:29,640 THE INDIVIDUAL SPEAKERS, AS WELL 6156 04:29:29,640 --> 04:29:31,320 AS DIRECTING QUESTIONS TO 6157 04:29:31,320 --> 04:29:36,000 SPEAKERS, SOME BEING ANSWERED 6158 04:29:36,000 --> 04:29:37,960 IN THE CHAT. 6159 04:29:37,960 --> 04:29:39,280 FIRST QUESTION, BIG QUESTIONS 6160 04:29:39,280 --> 04:29:40,480 ACROSS THE BOARD, ANYONE WHO 6161 04:29:40,480 --> 04:29:42,000 WANTS TO ANSWER IT, DOES ANYONE 6162 04:29:42,000 --> 04:29:49,880 THINK THAT WE WILL BE ABLE TO 6163 04:29:49,880 --> 04:29:50,560 REVERSE BRONCHIECTASIS, 6164 04:29:50,560 --> 04:29:53,040 REMODELING INTO A MORE 6165 04:29:53,040 --> 04:29:57,840 FUNCTIONAL AIRWAY? 6166 04:29:57,840 --> 04:29:59,400 FRANK OR ESZTER, PRADEEP? 6167 04:29:59,400 --> 04:30:01,320 >> WE HAVEN'T SEEN ANY TENDENCY 6168 04:30:01,320 --> 04:30:04,640 OF THEM WANTING TO DO THAT. 6169 04:30:04,640 --> 04:30:09,040 WE HAVE NOT -- WE DON'T SEE 6170 04:30:09,040 --> 04:30:10,880 EVIDENCE OF PLASTICITY. 6171 04:30:10,880 --> 04:30:13,920 THEY SEEMED TO BE SO 6172 04:30:13,920 --> 04:30:14,520 EPIGENETICALLY FIXED. 6173 04:30:14,520 --> 04:30:22,960 I THINK THAT'S GOING TO BE A 6174 04:30:22,960 --> 04:30:23,240 CHALLENGE. 6175 04:30:23,240 --> 04:30:24,840 >> CONTEXT OF AIR-LIQUID 6176 04:30:24,840 --> 04:30:25,600 INTERFACE CULTURE 6177 04:30:25,600 --> 04:30:26,880 DIFFERENTIATION WE'VE DONE 6178 04:30:26,880 --> 04:30:29,080 STUDIES WHERE WE'VE MODULATED 6179 04:30:29,080 --> 04:30:30,840 DEVELOPMENTAL SIGNALING PATHWAYS 6180 04:30:30,840 --> 04:30:33,560 LIKE NOTCH AND WNT SIGNALING IN 6181 04:30:33,560 --> 04:30:35,520 CF CULTURES WHICH HAVE ALLOWED 6182 04:30:35,520 --> 04:30:37,680 THEM TO FORM A MORE NORMAL 6183 04:30:37,680 --> 04:30:39,920 EPITHELIUM AS LEAST IN TERMS OF 6184 04:30:39,920 --> 04:30:40,480 COMPOSITION. 6185 04:30:40,480 --> 04:30:42,280 BUT WHETHER THAT IS SOMETHING 6186 04:30:42,280 --> 04:30:47,040 YOU CAN, LIKE FRANK SAID, 6187 04:30:47,040 --> 04:30:50,200 PROGRAM INTO PROGENITOR 6188 04:30:50,200 --> 04:30:51,520 POPULATION, THAT'S THE 6189 04:30:51,520 --> 04:30:51,800 CHALLENGE. 6190 04:30:51,800 --> 04:30:53,000 >> I DON'T KNOW IF IN THE 6191 04:30:53,000 --> 04:30:55,720 PROMISE STUDY YOU DID -- WE'VE 6192 04:30:55,720 --> 04:30:56,960 BEEN LOOKING AT CAT SCANS LIKE 6193 04:30:56,960 --> 04:30:58,240 THE IRISH COHORT. 6194 04:30:58,240 --> 04:31:00,640 MY UNDERSTANDING IS THE CURRENT 6195 04:31:00,640 --> 04:31:02,080 UNDERSTANDING IS THAT FOLLOWING 6196 04:31:02,080 --> 04:31:05,360 CAT SCANS WE DON'T SEE 6197 04:31:05,360 --> 04:31:06,360 BRONCHIECTASIS RESOLVE, IS THAT 6198 04:31:06,360 --> 04:31:06,840 CORRECT? 6199 04:31:06,840 --> 04:31:09,600 >> THANKS FOR THE QUESTION. 6200 04:31:09,600 --> 04:31:11,520 UNFORTUNATELY PROMISE DOES NOT 6201 04:31:11,520 --> 04:31:12,920 HAVE AN IMAGING ARM, SO I DON'T 6202 04:31:12,920 --> 04:31:14,480 THINK WE'LL BE ABLE TO ANSWER 6203 04:31:14,480 --> 04:31:16,160 THAT ON A LARGE SCALE WITH 6204 04:31:16,160 --> 04:31:16,360 PROMISE. 6205 04:31:16,360 --> 04:31:21,040 I THINK YOU'RE RIDE -- RIGHT 6206 04:31:21,040 --> 04:31:22,680 THAT'S THE DOGMA BRONCHIECTASIS 6207 04:31:22,680 --> 04:31:23,640 CAN BE CONSIDERED IRREVERSIBLE 6208 04:31:23,640 --> 04:31:23,880 LESION. 6209 04:31:23,880 --> 04:31:24,880 I DON'T KNOW IF IT'S TRUE. 6210 04:31:24,880 --> 04:31:26,200 WE NEED TO KNOW THAT. 6211 04:31:26,200 --> 04:31:27,800 THAT'S A KEY QUESTION THAT MAY 6212 04:31:27,800 --> 04:31:30,040 DIFFER DEPENDING ON WHAT THE 6213 04:31:30,040 --> 04:31:36,640 PATHOGENS ARE PRESENT OR ABSENT, 6214 04:31:36,640 --> 04:31:39,560 WE NEED TO KNOW THAT. 6215 04:31:39,560 --> 04:31:42,440 >> ANOTHER UNIFIED QUESTION, 6216 04:31:42,440 --> 04:31:45,160 OBVIOUSLY, CLEARS THE LUNGS, 6217 04:31:45,160 --> 04:31:45,800 SYSTEMIC METABOLISM, THESE 6218 04:31:45,800 --> 04:31:47,240 THINGS INTERRELATE. 6219 04:31:47,240 --> 04:31:48,680 AS THINGS ARE CHANGING WITH 6220 04:31:48,680 --> 04:31:51,280 MODULATORS THIS MAY BE MORE 6221 04:31:51,280 --> 04:31:53,360 ABOUT THE GENERAL LITERATURE, 6222 04:31:53,360 --> 04:31:54,160 INFLAMMATION, METABOLISM, WHAT 6223 04:31:54,160 --> 04:31:55,960 DO WE THINK IS HAPPENING IN 6224 04:31:55,960 --> 04:31:59,840 TERMS OF MEDIATORS IN THE 6225 04:31:59,840 --> 04:32:02,160 PLASMA, METABOLITES, GLUCOSE 6226 04:32:02,160 --> 04:32:04,120 LEVELS, LUNG INFLAMMATION, 6227 04:32:04,120 --> 04:32:05,080 ABILITY TO REPAIR, DIFFERENT 6228 04:32:05,080 --> 04:32:06,400 KINDS OF INFECTION, DO WE THINK 6229 04:32:06,400 --> 04:32:07,600 INFECTIONS IN THE LUNG AND 6230 04:32:07,600 --> 04:32:09,280 INFLAMMATION IN THE LUNG IS 6231 04:32:09,280 --> 04:32:13,480 GOING TO AFFECT METABOLICS 6232 04:32:13,480 --> 04:32:13,960 SYNDROME, METABOLISM? 6233 04:32:13,960 --> 04:32:14,600 BIG QUESTION. 6234 04:32:14,600 --> 04:32:16,920 ANY OF YOU CAN ANSWER. 6235 04:32:16,920 --> 04:32:19,120 >> I'LL START WITH -- I CAN'T 6236 04:32:19,120 --> 04:32:23,560 SPEAK TO INFECTION OR EPITHELIA 6237 04:32:23,560 --> 04:32:25,880 BUT OLDER STUDIES BY STEVE 6238 04:32:25,880 --> 04:32:27,400 FRIEDMAN AND OTHERS AT HARVARD 6239 04:32:27,400 --> 04:32:30,440 LOOKING AT ESSENTIAL FATTY ACID 6240 04:32:30,440 --> 04:32:31,640 DEFICIENCIES AND THEIR 6241 04:32:31,640 --> 04:32:36,240 RELATIONSHIP TO HELP IN CF, DONE 6242 04:32:36,240 --> 04:32:41,640 YEARS AGO, AND ANOTHER TOPIC WE 6243 04:32:41,640 --> 04:32:46,080 NEED TO REVISIT AS MALABSORPTION 6244 04:32:46,080 --> 04:32:48,240 IMPROVED WITH HIGHLY EFFECTIVE 6245 04:32:48,240 --> 04:32:50,720 MODULATOR THERAPY OVERALL. 6246 04:32:50,720 --> 04:32:51,920 6247 04:32:51,920 --> 04:32:53,880 >> ANY OTHER THOUGHTS, GLUCOSE 6248 04:32:53,880 --> 04:32:57,760 LEVELS, CHANGING HOW THE LUNG 6249 04:32:57,760 --> 04:32:58,120 FUNCTION -- 6250 04:32:58,120 --> 04:33:01,120 >> I THINK IT'S A GREAT 6251 04:33:01,120 --> 04:33:01,720 QUESTION. 6252 04:33:01,720 --> 04:33:04,400 YOU KNOW, AS WE WERE PROBING THE 6253 04:33:04,400 --> 04:33:05,640 DATA FROM PROMISE, ONE OF THE 6254 04:33:05,640 --> 04:33:07,320 QUESTIONS THAT WE WERE TRYING TO 6255 04:33:07,320 --> 04:33:10,880 ANSWER AT LEAST IN THE 12-18 6256 04:33:10,880 --> 04:33:13,960 MONTH DATA WERE IMPROVEMENTS IN 6257 04:33:13,960 --> 04:33:15,440 PULMONARY FUNCTION ASSOCIATED 6258 04:33:15,440 --> 04:33:18,240 WITH BETTER IMPROVEMENTS IN 6259 04:33:18,240 --> 04:33:18,960 GLUCOSE EXCURSION, THAT DID NOT 6260 04:33:18,960 --> 04:33:19,880 PAN OUT. 6261 04:33:19,880 --> 04:33:23,520 WE HAVE NOT YET LOOKED AT EARLY 6262 04:33:23,520 --> 04:33:29,520 INSULIN SECRETION, WHICH I THINK 6263 04:33:29,520 --> 04:33:32,240 MAY BE QUITE RELEVANT AND 6264 04:33:32,240 --> 04:33:34,800 HAVEN'T PAIRED DATA WITH 6265 04:33:34,800 --> 04:33:36,560 SYSTEMIC INFLAMMATORY MARKERS 6266 04:33:36,560 --> 04:33:38,960 BUT GIVEN INFLAMMATION UNDERLIES 6267 04:33:38,960 --> 04:33:42,760 AT LEAST PARTLY SOME OF THE BETA 6268 04:33:42,760 --> 04:33:44,760 CELL DYSFUNCTION AS THAT 6269 04:33:44,760 --> 04:33:45,440 INFLAMMATION IMPROVES 6270 04:33:45,440 --> 04:33:46,640 SYSTEMICALLY WILL WE ALSO SEE 6271 04:33:46,640 --> 04:33:49,280 THAT AT THE LEVEL OF THE 6272 04:33:49,280 --> 04:33:50,560 PANCREAS, CERTAINLY IN PEOPLE 6273 04:33:50,560 --> 04:33:53,880 THERE HAVE BEEN SUBSET OF PEOPLE 6274 04:33:53,880 --> 04:33:56,040 WHO HAVE SOME RESIDUAL 6275 04:33:56,040 --> 04:33:57,040 PANCREATIC EXOCRINE FUNCTION 6276 04:33:57,040 --> 04:33:58,600 THAT SEEM TO HAVE IMPROVEMENT 6277 04:33:58,600 --> 04:33:59,520 WITH MODULATOR THERAPY. 6278 04:33:59,520 --> 04:34:01,440 AND THAT BEGS THE QUESTION, 6279 04:34:01,440 --> 04:34:04,280 COULD THAT SORT OF STALLING OF 6280 04:34:04,280 --> 04:34:06,360 THAT INFLAMMATION THERE ALSO 6281 04:34:06,360 --> 04:34:07,680 FLOW OVER TO IMPROVEMENTS IN 6282 04:34:07,680 --> 04:34:08,640 BETA CELL FUNCTION, SO I THINK 6283 04:34:08,640 --> 04:34:09,880 IT'S A BIG QUESTION THAT NEEDS 6284 04:34:09,880 --> 04:34:11,840 TO BE ANSWERED BUT WE DON'T HAVE 6285 04:34:11,840 --> 04:34:15,320 THE DATA YET TO SUPPORT EITHER 6286 04:34:15,320 --> 04:34:15,880 WAY. 6287 04:34:15,880 --> 04:34:20,160 >> ONE POINT TO ADD, THE WAY THE 6288 04:34:20,160 --> 04:34:22,680 PROMISE STUDY WAS DESIGNED, 6289 04:34:22,680 --> 04:34:24,200 EVENTUALLY ALL THESE PARAMETERS 6290 04:34:24,200 --> 04:34:27,920 WILL BE ABLE TO BE 6291 04:34:27,920 --> 04:34:30,440 CROSS-CORRELATED TO LOOK AT LUNG 6292 04:34:30,440 --> 04:34:32,400 INFLAMMATION, LUNG INFECTION, 6293 04:34:32,400 --> 04:34:33,640 METABOLIC PARAMETERS, GROWTH 6294 04:34:33,640 --> 04:34:35,040 PARAMETERS, G.I. PARAMETERS, SO 6295 04:34:35,040 --> 04:34:37,360 HOPEFULLY THAT WILL AT LEAST 6296 04:34:37,360 --> 04:34:40,080 START GETTING TO THE ASSOCIATION 6297 04:34:40,080 --> 04:34:41,280 LEVEL IN ANSWER TO YOUR 6298 04:34:41,280 --> 04:34:41,560 QUESTION. 6299 04:34:41,560 --> 04:34:42,040 >> THAT'S GREAT. 6300 04:34:42,040 --> 04:34:46,080 GLAD WE HAVE ALL THAT DATA. 6301 04:34:46,080 --> 04:34:47,160 SOME SPECIFIC QUESTIONS, FRANK, 6302 04:34:47,160 --> 04:34:48,480 I'M GOING TO SEE IF I GET THESE 6303 04:34:48,480 --> 04:34:49,680 QUESTIONS RIGHT. 6304 04:34:49,680 --> 04:34:52,640 IF THE CF VARIANTS HAVE LIMITED 6305 04:34:52,640 --> 04:34:58,400 DIFFERENTIATION POTENTIATION 6306 04:34:58,400 --> 04:35:00,320 ARE THEY TISSUE STEM CELLS? 6307 04:35:00,320 --> 04:35:04,600 AND CAN YOU FORCE THEM TO MAKE 6308 04:35:04,600 --> 04:35:07,000 CILIATED CELLS FOR EXAMPLE WITH 6309 04:35:07,000 --> 04:35:07,800 NOTCH INHIBITORS? 6310 04:35:07,800 --> 04:35:09,680 >> THE LAST PART, THEY ARE STEM 6311 04:35:09,680 --> 04:35:11,640 CELLS BY ALL CRITERIA. 6312 04:35:11,640 --> 04:35:14,720 THEY ARE P63 POSITIVE AS IS THE 6313 04:35:14,720 --> 04:35:17,160 NORMAL DISTAL AIRWAY STEM CELL. 6314 04:35:17,160 --> 04:35:23,240 AND YOU CAN SEE THEM IN VIVO. 6315 04:35:23,240 --> 04:35:25,440 YOU KNOW, SUBTENDING MET PLASTIC 6316 04:35:25,440 --> 04:35:27,840 LESIONS IN THE CF LUNG. 6317 04:35:27,840 --> 04:35:31,080 SO, OUR SENSE RIGHT NOW IS THEY 6318 04:35:31,080 --> 04:35:34,560 HAVE ALL THE PROPERTIES OF 6319 04:35:34,560 --> 04:35:39,920 FORMAL STEM CELL WITH HIGH 6320 04:35:39,920 --> 04:35:45,280 CLONOGENICICITY TO BOOT. 6321 04:35:45,280 --> 04:35:48,760 WHETHER WE CAN TWISTER THEM, USE 6322 04:35:48,760 --> 04:35:49,640 VARIOUS PATHWAY INHIBITORS TO 6323 04:35:49,640 --> 04:35:53,200 GET THEM TO BEHAVE IN A MORE 6324 04:35:53,200 --> 04:35:54,760 NORMAL FASHION WE DON'T HAVE ANY 6325 04:35:54,760 --> 04:35:57,640 INFORMATION ON THAT YET. 6326 04:35:57,640 --> 04:35:59,080 IT'S REALLY INTERESTING. 6327 04:35:59,080 --> 04:36:02,160 >> AND THEN ALSO HOW LONG HAVE 6328 04:36:02,160 --> 04:36:03,040 WE OBSERVED ABNORMAL CF-SPECIFIC 6329 04:36:03,040 --> 04:36:07,080 STEM CELL VARIANTS IN A NORMAL 6330 04:36:07,080 --> 04:36:09,920 ENVIRONMENT, IS THERE INDICATION 6331 04:36:09,920 --> 04:36:11,760 PERSISTENT GROWTH CAN REPROGRAM 6332 04:36:11,760 --> 04:36:14,840 THEM, BACK TO BRONCHIECTASIS 6333 04:36:14,840 --> 04:36:17,080 QUESTIONS, NORMAL STEM CELL 6334 04:36:17,080 --> 04:36:21,320 VARIANTS COMPETITIVE ADVANTAGE? 6335 04:36:21,320 --> 04:36:22,960 >> WE'VE GROWN THEM FOR I THINK 6336 04:36:22,960 --> 04:36:26,880 PASSAGE 25 WHICH IS ALMOST A 6337 04:36:26,880 --> 04:36:27,120 YEAR. 6338 04:36:27,120 --> 04:36:30,280 AND THEY DON'T CHANGE DURING 6339 04:36:30,280 --> 04:36:32,040 THAT TIME. 6340 04:36:32,040 --> 04:36:33,880 THEY ARE ALSO GENOMICALLY STABLE 6341 04:36:33,880 --> 04:36:39,040 DURING THAT TIME, DON'T SEEM TO 6342 04:36:39,040 --> 04:36:39,800 CARE ABOUT ANYTHING. 6343 04:36:39,800 --> 04:36:42,720 AND SO WE JUST DON'T SEE ANY 6344 04:36:42,720 --> 04:36:43,040 PLASTICITY. 6345 04:36:43,040 --> 04:36:44,520 THEY SEEM TO BE ABSOLUTELY 6346 04:36:44,520 --> 04:36:45,040 FIXED. 6347 04:36:45,040 --> 04:36:46,240 WE DON'T SEE THEM DIFFERENT FROM 6348 04:36:46,240 --> 04:36:53,240 THE ONES WE CAN ISOLATE FROM 6349 04:36:53,240 --> 04:36:53,760 21-WEEK-OLD FETAL LUNGS. 6350 04:36:53,760 --> 04:36:56,400 I THINK THEY ARE JUST PART OF 6351 04:36:56,400 --> 04:36:57,880 OUR INNATE IMMUNE SYSTEM. 6352 04:36:57,880 --> 04:37:02,040 AND FOR GOD KNOWS WHAT REASON, 6353 04:37:02,040 --> 04:37:04,560 THEY STAY HIGH IN ALL THESE 6354 04:37:04,560 --> 04:37:06,600 CHRONIC INFLAMMATORY DISEASES. 6355 04:37:06,600 --> 04:37:09,680 AND I THINK, YOU KNOW, AT LEAST 6356 04:37:09,680 --> 04:37:13,240 THE DRUG DEVELOPMENT WE'RE DOING 6357 04:37:13,240 --> 04:37:16,640 SOMEHOW HAS HIT ON SOME ASPECT 6358 04:37:16,640 --> 04:37:20,000 OF WHY THEY STAY PRESENT. 6359 04:37:20,000 --> 04:37:22,080 SO WE'RE VERY INTERESTED IN THE 6360 04:37:22,080 --> 04:37:26,280 ONES WE SEE FOR CYSTIC FIBROSIS 6361 04:37:26,280 --> 04:37:29,560 ARE THE SAME AS -- HAVE THE SAME 6362 04:37:29,560 --> 04:37:32,840 SENSITIVITY TOWARDS THE VARIANT 6363 04:37:32,840 --> 04:37:33,920 IN IDIOPATHIC PULMONARY FIBROSIS 6364 04:37:33,920 --> 04:37:36,680 SO THERE'S SOMETHING ABOUT THESE 6365 04:37:36,680 --> 04:37:40,040 VARIANTS THAT STAY HIGH THAT 6366 04:37:40,040 --> 04:37:40,840 RENDERS THEM VULNERABLE, YOU 6367 04:37:40,840 --> 04:37:42,440 KNOW, THEY SHOULDN'T BE DOING 6368 04:37:42,440 --> 04:37:45,240 THAT, THEY SHOULD BE 6369 04:37:45,240 --> 04:37:48,840 DISAPPEARING AFTER INFECTION. 6370 04:37:48,840 --> 04:37:49,720 >> THANK YOU. 6371 04:37:49,720 --> 04:37:51,680 SIMILAR SORT OF IDEA ABOUT CAN 6372 04:37:51,680 --> 04:37:55,400 WE CHANGE THINGS, CAN WE 6373 04:37:55,400 --> 04:37:56,400 INTERVENE FOR ESZTER, GREAT 6374 04:37:56,400 --> 04:37:59,440 TALK, AS YOU KNOW WE FOUND THE 6375 04:37:59,440 --> 04:38:02,720 SINUS DISEASE IMPROVED SUBSTANCE 6376 04:38:02,720 --> 04:38:04,680 BUT WE COULDN'T REVERSE ANOSMIA 6377 04:38:04,680 --> 04:38:06,640 IN ADULTS. 6378 04:38:06,640 --> 04:38:11,480 HAVE YOU LOOKED AT HOW NASAL 6379 04:38:11,480 --> 04:38:15,080 EPITHELIUM COMPARES TO ADULTS, 6380 04:38:15,080 --> 04:38:17,880 ARE THERE CLUES TO PREVENT IF WE 6381 04:38:17,880 --> 04:38:19,280 ADMINISTER HEMP EARLIER? 6382 04:38:19,280 --> 04:38:20,600 >> THAT'S THE CRITICAL THING. 6383 04:38:20,600 --> 04:38:22,720 I HAVEN'T DONE THE EXPERIMENT. 6384 04:38:22,720 --> 04:38:24,720 WE'VE ONLY LOOKED AT THE ONE 6385 04:38:24,720 --> 04:38:28,880 ADULT POPULATION, BUT THE IDEA 6386 04:38:28,880 --> 04:38:32,040 HERE IS THE TIMING AND WHETHER 6387 04:38:32,040 --> 04:38:34,520 THERE IS IRREVERSIBLE DAMAGE IN 6388 04:38:34,520 --> 04:38:36,440 A TERMINALLY DIFFERENTIATED CELL 6389 04:38:36,440 --> 04:38:39,920 TYPE THAT YOU CAN REPOPULATE 6390 04:38:39,920 --> 04:38:41,600 POTENTIALLY. 6391 04:38:41,600 --> 04:38:43,640 OR EVEN THE EXTENT, WHICH WE'VE 6392 04:38:43,640 --> 04:38:45,840 TUSHED ON DURING THIS MEETING A 6393 04:38:45,840 --> 04:38:48,560 COUPLE WAYS, WHICH WE STILL 6394 04:38:48,560 --> 04:38:50,160 DON'T 100% KNOW IN THE DIFFERENT 6395 04:38:50,160 --> 04:38:51,520 COMPARTMENTS AND WHAT IS THE 6396 04:38:51,520 --> 04:38:53,480 THRESHOLD LEVEL OF CORRECTION 6397 04:38:53,480 --> 04:38:56,560 THAT YOU NEED IN DIFFERENT 6398 04:38:56,560 --> 04:38:58,280 TISSUES TO GET A PHENOTYPIC 6399 04:38:58,280 --> 04:39:00,400 CHANGE. 6400 04:39:00,400 --> 04:39:03,920 6401 04:39:03,920 --> 04:39:04,960 6402 04:39:04,960 --> 04:39:06,160 >> JESSICA, DO YOU WANT TO TAKE 6403 04:39:06,160 --> 04:39:09,040 OVER FOR THE NEXT FEW? 6404 04:39:09,040 --> 04:39:12,560 >> THIS IS A QUESTION FOR 6405 04:39:12,560 --> 04:39:12,880 PRADEEP. 6406 04:39:12,880 --> 04:39:15,720 ANY THOUGHTS TO WHY ETI REDUCES 6407 04:39:15,720 --> 04:39:19,040 ONLY CF PATHOGENS AND NOT OTHER 6408 04:39:19,040 --> 04:39:21,080 BACTERIA IN THE AIRWAY? 6409 04:39:21,080 --> 04:39:22,160 AND THERE ARE FOLLOW-UP 6410 04:39:22,160 --> 04:39:22,840 QUESTIONS. 6411 04:39:22,840 --> 04:39:25,480 RELATED TO THAT QUESTION, DOES 6412 04:39:25,480 --> 04:39:28,480 THE ENVIRONMENT CHANGE DUE TO 6413 04:39:28,480 --> 04:39:30,160 ETI TREATMENT THAT NOW SELECTS 6414 04:39:30,160 --> 04:39:31,000 AGAINST PATHOGENS? 6415 04:39:31,000 --> 04:39:33,320 ARE PATIENTS NOT BEING TREATED 6416 04:39:33,320 --> 04:39:38,960 WITH ANTIBIOTICS AS OFTEN SINCE 6417 04:39:38,960 --> 04:39:39,840 SOME CLINICAL PARAMETERS ARE 6418 04:39:39,840 --> 04:39:40,520 IMPROVING? 6419 04:39:40,520 --> 04:39:42,640 >> I THINK WE DON'T KNOW THE 6420 04:39:42,640 --> 04:39:45,840 ANSWER AS TO WHY CF PATHOGENS GO 6421 04:39:45,840 --> 04:39:49,920 DOWN AND THE OTHER BACTERIA IN 6422 04:39:49,920 --> 04:39:51,520 SPUTUM STAY THE SAME. 6423 04:39:51,520 --> 04:39:52,840 I THINK THE PREPONDERANCE OF 6424 04:39:52,840 --> 04:39:57,880 EVIDENCE FROM MY POINT OF VIEW 6425 04:39:57,880 --> 04:39:59,680 WOULD SUGGEST THAT MOST LIKELY 6426 04:39:59,680 --> 04:40:01,400 MECHANISM IS THAT THOSE OTHER AT 6427 04:40:01,400 --> 04:40:05,000 LEAST MOST OF THOSE OTHER 6428 04:40:05,000 --> 04:40:06,600 BACTERIA ARE CONTAMINANTS COMING 6429 04:40:06,600 --> 04:40:07,760 FROM THE ORAL PHARYNX. 6430 04:40:07,760 --> 04:40:12,160 THERE'S BEEN A FEW STUDIES THAT 6431 04:40:12,160 --> 04:40:15,120 LOOKED DIRECTLY IN LUNGS BY 6432 04:40:15,120 --> 04:40:16,080 DIRECT SAMPLING. 6433 04:40:16,080 --> 04:40:18,800 WE FIND CF PATHOGENS ARE 6434 04:40:18,800 --> 04:40:20,680 ABUNDANT, THE OTHER BACTERIA 6435 04:40:20,680 --> 04:40:22,400 PRESENT IN SPUTUM ARE EITHER 6436 04:40:22,400 --> 04:40:24,320 ABSENT OR MUCH LESS ABUNDANT. 6437 04:40:24,320 --> 04:40:26,200 I THINK WHAT'S PROBABLY 6438 04:40:26,200 --> 04:40:28,040 HAPPENING IS THAT ETI IS WORKING 6439 04:40:28,040 --> 04:40:30,480 IN THE LUNGS, THAT'S WHERE THE 6440 04:40:30,480 --> 04:40:31,560 LUNG PATHOGENS ARE. 6441 04:40:31,560 --> 04:40:32,960 THEY ARE GOING DOWN. 6442 04:40:32,960 --> 04:40:38,320 AS THAT SPUTUM SAMPLE COMES UP, 6443 04:40:38,320 --> 04:40:41,520 IT GETS ADMIXED WITH SALIVA AND 6444 04:40:41,520 --> 04:40:43,760 UPPER AIRWAY SECRETIONS THAT 6445 04:40:43,760 --> 04:40:48,920 HAVE HUGE CONCENTRATIONS OF ORAL 6446 04:40:48,920 --> 04:40:51,680 ANAEROBES, UP TO 10 TO THE 6447 04:40:51,680 --> 04:40:53,320 10th GENOME COPIES PER MIL. 6448 04:40:53,320 --> 04:40:55,800 IF YOU GOT A MIL OF SPUTUM 6449 04:40:55,800 --> 04:40:59,240 COMING UP, IT GETS CONTAMINATED 6450 04:40:59,240 --> 04:41:01,280 WITH 10% SALIVA, THAT WILL GIVE 6451 04:41:01,280 --> 04:41:06,680 A SIGNAL OF 10 TO THE EIGHTH, 10 6452 04:41:06,680 --> 04:41:17,200 TO THE SEVENTH, A BIG SIGNAL OF 6453 04:41:19,240 --> 04:41:20,080 ORAL ANAEROBES. 6454 04:41:20,080 --> 04:41:21,440 IT COULD BE WE CAN'T SEE THE 6455 04:41:21,440 --> 04:41:24,440 CHANGE BECAUSE THEY ARE DWARFED 6456 04:41:24,440 --> 04:41:27,160 BY CONTAMINANT SIGNAL. 6457 04:41:27,160 --> 04:41:28,480 EVERYTHING WE KNOW ABOUT 6458 04:41:28,480 --> 04:41:30,320 MECHANISM OF CORRECTORS AND 6459 04:41:30,320 --> 04:41:34,600 MODULATORS IS THEY SHOULD LIKELY 6460 04:41:34,600 --> 04:41:38,360 IMPROVE BROAD SPECTRUM 6461 04:41:38,360 --> 04:41:41,920 INDISCRIMINATE LUNG DEFENSES, SO 6462 04:41:41,920 --> 04:41:43,560 CLEARANCE REMOVES PARTICLES, 6463 04:41:43,560 --> 04:41:45,040 DOESN'T CARE THE SPECIES, IT'S 6464 04:41:45,040 --> 04:41:48,080 GOING TO REMOVE PHYSICALLY. 6465 04:41:48,080 --> 04:41:50,560 IMPROVED AIR WAY pH WILL 6466 04:41:50,560 --> 04:41:51,960 INCREASE ACTIVITY OF MICROBIALS 6467 04:41:51,960 --> 04:41:53,840 IN THE AIRWAY WITH BROAD 6468 04:41:53,840 --> 04:41:56,040 SPECTRUM ACTIVITY. 6469 04:41:56,040 --> 04:41:57,800 PUTTING THOSE IDEAS TOGETHER, I 6470 04:41:57,800 --> 04:41:59,000 THINK THE MOST LIKELY 6471 04:41:59,000 --> 04:42:00,320 EXPLANATION IS THOSE OTHER BUGS 6472 04:42:00,320 --> 04:42:03,040 DON'T CHANGE BECAUSE OF 6473 04:42:03,040 --> 04:42:03,840 CONTAMINANTS. 6474 04:42:03,840 --> 04:42:05,240 BECAUSE THEY ARE CONTAMINANTS. 6475 04:42:05,240 --> 04:42:07,320 AS FAR AS ANTIBIOTIC USE, I 6476 04:42:07,320 --> 04:42:11,320 DEFER TO OTHERS TO ANSWER THAT 6477 04:42:11,320 --> 04:42:13,760 MORE DEFINITIVELY, PRELIMINARY 6478 04:42:13,760 --> 04:42:15,160 DATA FROM THE PROMISE STUDY 6479 04:42:15,160 --> 04:42:17,880 SUGGESTS THERE IS A DECLINE IN 6480 04:42:17,880 --> 04:42:20,000 INHALED ANTIBIOTIC USE AT THE 6481 04:42:20,000 --> 04:42:20,960 SIX-MONTH TIME POINT. 6482 04:42:20,960 --> 04:42:24,720 SO IT COULD BE THAT THE, YOU 6483 04:42:24,720 --> 04:42:27,120 KNOW, THE CHANGES COULD BE 6484 04:42:27,120 --> 04:42:28,800 GREATER PERHAPS, IF ANTIBIOTIC 6485 04:42:28,800 --> 04:42:31,000 USE HAD CONTINUED, COULD BE 6486 04:42:31,000 --> 04:42:32,400 ANTIBIOTIC IS IMMATERIAL, WE 6487 04:42:32,400 --> 04:42:34,440 HAVE MODULATORS, DON'T KNOW THAT 6488 04:42:34,440 --> 04:42:34,960 QUESTION. 6489 04:42:34,960 --> 04:42:36,000 WE NEED A CONTROL STUDY TO 6490 04:42:36,000 --> 04:42:38,840 ANSWER THAT. 6491 04:42:38,840 --> 04:42:39,600 >> THANK YOU. 6492 04:42:39,600 --> 04:42:41,040 WE HAVE SOME MORE QUESTIONS FOR 6493 04:42:41,040 --> 04:42:44,320 YOU IF YOU'RE OKAY WITH THAT. 6494 04:42:44,320 --> 04:42:46,640 IT LOOKS LIKE THE DATA THAT WAS 6495 04:42:46,640 --> 04:42:47,600 PRESENTED IS AMONG PARTICIPANTS 6496 04:42:47,600 --> 04:42:51,920 WHO WERE STILL ABLE TO PRODUCE 6497 04:42:51,920 --> 04:42:58,440 SPUTUM AFTER STARTING ETI, CAN 6498 04:42:58,440 --> 04:43:00,520 THIS BE EXTRAPOLATED TO THOSE 6499 04:43:00,520 --> 04:43:05,920 WHO NO LONGER PRODUCE SPUTUM? 6500 04:43:05,920 --> 04:43:10,960 >> THE WISDOM WAS TO COME UP WAS 6501 04:43:10,960 --> 04:43:15,200 USE INDUCED SPUTUM, ALL SUBJECTS 6502 04:43:15,200 --> 04:43:16,760 GET INHALATION INDUCED SPUTUM 6503 04:43:16,760 --> 04:43:18,160 SAMPLES THROUGHOUT THE STUDY. 6504 04:43:18,160 --> 04:43:20,680 COVID PANDEMIC MESSED THAT UP 6505 04:43:20,680 --> 04:43:21,880 BECAUSE IT'S AN 6506 04:43:21,880 --> 04:43:24,040 AEROSOL-GENERATING PROCEDURE, WE 6507 04:43:24,040 --> 04:43:25,960 STARTED TO ACCEPT INDUCED AND 6508 04:43:25,960 --> 04:43:28,640 SPONTANEOUS SPUTUM LATER IN THE 6509 04:43:28,640 --> 04:43:29,480 STUDY. 6510 04:43:29,480 --> 04:43:33,720 IT'S A MIXTURE OF PEOPLE THAT -- 6511 04:43:33,720 --> 04:43:35,360 MIXTURE OF SPUTUM SAMPLES THAT I 6512 04:43:35,360 --> 04:43:35,720 PRESENTED. 6513 04:43:35,720 --> 04:43:38,080 I THINK WE NEED TO KNOW THAT, 6514 04:43:38,080 --> 04:43:38,520 YEAH. 6515 04:43:38,520 --> 04:43:41,360 WE'VE CERTAINLY SEEN THE BAL 6516 04:43:41,360 --> 04:43:44,520 STUDIES, A PATIENT OR TWO, WHO 6517 04:43:44,520 --> 04:43:45,720 HAVE BECOME CLINICALLY 6518 04:43:45,720 --> 04:43:46,720 NON-PRODUCTIVE, SO CLINIC SAYS 6519 04:43:46,720 --> 04:43:50,480 THEY CAN'T GET ANY SPUTUM, WE GO 6520 04:43:50,480 --> 04:43:53,520 IN WITH A BRONCHOSCOPE AND FIND 6521 04:43:53,520 --> 04:43:55,240 CF PATHOGEN THAT PREEXISTED 6522 04:43:55,240 --> 04:43:57,800 BEFORE ETI, WE SEQUENCE THAT 6523 04:43:57,800 --> 04:44:00,000 PATHOGEN WE FIND IT'S THE SAME 6524 04:44:00,000 --> 04:44:02,960 STRAIN, SAME LINEAGE. 6525 04:44:02,960 --> 04:44:04,920 IT'S A CLONAL DESCENDANT OF THE 6526 04:44:04,920 --> 04:44:06,760 BUGS THAT PREEXISTED. 6527 04:44:06,760 --> 04:44:08,360 SO I THINK THAT THE IMPLI 6528 04:44:08,360 --> 04:44:13,200 QUAILINGS -- IMPLICATION OF THE 6529 04:44:13,200 --> 04:44:15,840 QUESTION IS CORRECT, PROBABLY A 6530 04:44:15,840 --> 04:44:17,240 NUMBER OF PEOPLE, SIGNIFICANT 6531 04:44:17,240 --> 04:44:18,600 PROPORTION THAT CAN'T PRODUCE 6532 04:44:18,600 --> 04:44:21,200 SPUTUM BUT CONTINUE TO HARBOR A 6533 04:44:21,200 --> 04:44:22,640 PATHOGEN IN THE LUNG, THE ONLY 6534 04:44:22,640 --> 04:44:25,400 WAY TO ANSWER IS BY DIRECT 6535 04:44:25,400 --> 04:44:28,520 SAMPLING. 6536 04:44:28,520 --> 04:44:32,640 >> I'M GOING TO MOVE TO 6537 04:44:32,640 --> 04:44:35,520 QUESTIONS FOR DR. KELLY. 6538 04:44:35,520 --> 04:44:38,600 FIRST ONE, WHAT CAUSES THAT 6539 04:44:38,600 --> 04:44:43,880 DELAY IN INSULIN SECRETION, 6540 04:44:43,880 --> 04:44:48,400 DELAY YET ROBUST -- DELAYED 6541 04:44:48,400 --> 04:44:50,240 SECRETION AMONG THOSE EVEN WITH 6542 04:44:50,240 --> 04:44:51,560 NORMAL GLUCOSE TOLERANCE. 6543 04:44:51,560 --> 04:44:52,160 >> GREAT QUESTION. 6544 04:44:52,160 --> 04:44:53,960 STUDIES ARE ACTIVELY GOING ON TO 6545 04:44:53,960 --> 04:44:56,160 TRY AND IDENTIFY WHY THERE IS 6546 04:44:56,160 --> 04:44:59,880 THAT LOSS OF EARLY PHASE INSULIN 6547 04:44:59,880 --> 04:45:00,120 SECRETION. 6548 04:45:00,120 --> 04:45:02,360 WE SEE THIS IN OTHER FORMS OF 6549 04:45:02,360 --> 04:45:02,680 DIABETES. 6550 04:45:02,680 --> 04:45:04,320 AND THERE'S INCREASING DATA 6551 04:45:04,320 --> 04:45:06,200 EMERGING IN TYPE 2 DIABETES THAT 6552 04:45:06,200 --> 04:45:09,760 EARLY PHASE IS PROBABLY QUITE 6553 04:45:09,760 --> 04:45:11,280 RELEVANT. 6554 04:45:11,280 --> 04:45:16,520 THAT EARLY PHASE REPRESENTS THE 6555 04:45:16,520 --> 04:45:19,920 GRANULES READILY AVAILABLE AT 6556 04:45:19,920 --> 04:45:22,440 BETA CELL MEMBRANE, MAY REFLECT 6557 04:45:22,440 --> 04:45:23,960 PROCESSING ISSUES WITH PRO 6558 04:45:23,960 --> 04:45:24,960 INSULIN NORMALLY GETTING TO 6559 04:45:24,960 --> 04:45:28,040 INSULIN BECAUSE IF WE LOOK AT 6560 04:45:28,040 --> 04:45:29,440 THE PRO INSULIN TO INSULIN RATIO 6561 04:45:29,440 --> 04:45:32,080 WHICH TELLS US ABOUT THAT 6562 04:45:32,080 --> 04:45:33,160 PROCESSING, THAT'S ABNORMAL EVEN 6563 04:45:33,160 --> 04:45:36,320 IN THE PATIENTS WITH CF, NORMAL 6564 04:45:36,320 --> 04:45:37,680 GLUCOSE TOLERANCE, MAY NOT BE 6565 04:45:37,680 --> 04:45:39,920 SIMPLY A REDUCTION IN NUMBER OF 6566 04:45:39,920 --> 04:45:42,560 BETA CELLS AVAILABLE BUT THERE'S 6567 04:45:42,560 --> 04:45:43,760 A STRESS, ONGOING STRESS ON 6568 04:45:43,760 --> 04:45:47,960 THOSE BETA CELLS THAT DON'T 6569 04:45:47,960 --> 04:45:49,480 ALLOW THAT GRANULES TO BE 6570 04:45:49,480 --> 04:45:51,440 READILY AVAILABLE AT THE BETA 6571 04:45:51,440 --> 04:45:54,160 CELL MEMBRANE FOR QUICK RELEASE. 6572 04:45:54,160 --> 04:45:56,200 BEYOND THAT, I DON'T THINK THAT 6573 04:45:56,200 --> 04:45:59,840 WE UNDERSTAND THOUGH THE 6574 04:45:59,840 --> 04:46:01,120 MECHANISMS UNDERLYING THAT 6575 04:46:01,120 --> 04:46:01,440 REDUCTION. 6576 04:46:01,440 --> 04:46:03,080 >> THANK YOU. 6577 04:46:03,080 --> 04:46:04,520 ANOTHER QUESTION FOR YOU, IN THE 6578 04:46:04,520 --> 04:46:07,280 PROMISE DATA, DID YOU GUYS TRACK 6579 04:46:07,280 --> 04:46:11,640 PHYSICAL ACTIVITY AND WAS THIS 6580 04:46:11,640 --> 04:46:13,080 RELATED TO INSULIN GLUCOSE? 6581 04:46:13,080 --> 04:46:13,840 >> GREAT QUESTION. 6582 04:46:13,840 --> 04:46:15,480 WE DID NOT. 6583 04:46:15,480 --> 04:46:18,160 AND IN HINDSIGHT WE WISH WE 6584 04:46:18,160 --> 04:46:19,640 WOULD HAVE. 6585 04:46:19,640 --> 04:46:20,840 BUT THE PROMISE PARTICIPANTS ARE 6586 04:46:20,840 --> 04:46:23,600 ALREADY DOING A LOT, AS YOU CAN 6587 04:46:23,600 --> 04:46:29,160 SEE, JUST WHAT PRADEEP HAS 6588 04:46:29,160 --> 04:46:31,320 PRESENTED AND OTHER ARMS OF THE 6589 04:46:31,320 --> 04:46:31,840 STUDY. 6590 04:46:31,840 --> 04:46:35,640 WE NEEDED TO BALANCE HAVING 6591 04:46:35,640 --> 04:46:39,000 PERFECT WITH WHAT'S PRACTICAL IN 6592 04:46:39,000 --> 04:46:40,760 THIS BIG STUDY. 6593 04:46:40,760 --> 04:46:44,480 >> TWO MORE QUESTIONS, ONE 6594 04:46:44,480 --> 04:46:45,720 RELATED TO -- DURING THE PROMISE 6595 04:46:45,720 --> 04:46:46,760 STUDY ANY RELATIONSHIP BETWEEN 6596 04:46:46,760 --> 04:46:49,280 WHAT YOU SAW IN THE DEVELOPMENT 6597 04:46:49,280 --> 04:46:51,160 OF OBESITY AND ONSET OF 6598 04:46:51,160 --> 04:46:51,800 CF-RELATED DIABETES? 6599 04:46:51,800 --> 04:46:54,600 HAVE YOU LOOKED AT THAT DATA 6600 04:46:54,600 --> 04:46:55,240 YET? 6601 04:46:55,240 --> 04:46:55,920 >> GREAT QUESTION. 6602 04:46:55,920 --> 04:46:58,760 WE HAD TWO OR THREE INDIVIDUALS 6603 04:46:58,760 --> 04:47:01,880 WHO PROGRESSED TO CFRD. 6604 04:47:01,880 --> 04:47:04,960 IF WE LOOK AT -- I HAVE ACCESS 6605 04:47:04,960 --> 04:47:09,440 TO A LIMITED DATASET SUGGESTING 6606 04:47:09,440 --> 04:47:13,280 ENDOCRINE SUBSTUDY WITH 75 6607 04:47:13,280 --> 04:47:14,480 INDIVIDUALS WITH OGTT AND 135 6608 04:47:14,480 --> 04:47:16,280 WITH DEXA. 6609 04:47:16,280 --> 04:47:20,360 SO TALK ABOUT THE DATA THAT I 6610 04:47:20,360 --> 04:47:23,320 HAVE, ABOUT 13% WERE OVERWEIGHT, 6611 04:47:23,320 --> 04:47:24,200 AT BASELINE. 6612 04:47:24,200 --> 04:47:26,520 ONE OR TWO OBESE. 6613 04:47:26,520 --> 04:47:31,440 AND THEN AFTER 12-18 MONTHS, 6614 04:47:31,440 --> 04:47:32,360 ABOUT 25% WERE OVERWEIGHT WITH 6615 04:47:32,360 --> 04:47:35,280 ONE OR TWO WHO WERE OBESE. 6616 04:47:35,280 --> 04:47:40,200 WE COULD NOT FIND A RELATIONSHIP 6617 04:47:40,200 --> 04:47:44,920 BETWEEN BMI OR CHANGE IN BMI AND 6618 04:47:44,920 --> 04:47:45,680 RELATIONSHIP WITH WORSENING 6619 04:47:45,680 --> 04:47:46,680 GLUCOSE TOLERANCE BASED ON THE 6620 04:47:46,680 --> 04:47:48,120 DATA WE HAVE THUS FAR. 6621 04:47:48,120 --> 04:47:53,080 >> THE LAST QUESTION I'LL ASK 6622 04:47:53,080 --> 04:47:54,240 YOU IS ABOUT BONE. 6623 04:47:54,240 --> 04:47:58,120 DO YOU HAVE ANY EVIDENCE THAT 6624 04:47:58,120 --> 04:47:59,760 EFFECTS OF CF-RELATED DIABETES 6625 04:47:59,760 --> 04:48:01,600 ON BONE ALSO IMPACTS IMMUNE CELL 6626 04:48:01,600 --> 04:48:08,160 PRODUCTION OR CAUSES DAMAGE TO 6627 04:48:08,160 --> 04:48:10,240 BONE MARROW-DERIVED STEM CELLS? 6628 04:48:10,240 --> 04:48:13,000 >> I DON'T THINK WE HAVE DATA 6629 04:48:13,000 --> 04:48:14,960 WITH RESPECT TO CF-RELATED 6630 04:48:14,960 --> 04:48:16,320 DIABETES. 6631 04:48:16,320 --> 04:48:18,800 WE KNOW IN NON-CF DIABETES IS 6632 04:48:18,800 --> 04:48:21,520 ASSOCIATED WITH INCREASED RISK 6633 04:48:21,520 --> 04:48:32,000 OF FRACTURE AND BONE FRAGILITY. 6634 04:48:32,000 --> 04:48:33,200 MECHANISMS INCLUDE CALCIUM LOSS, 6635 04:48:33,200 --> 04:48:36,960 GLYCATION OF COLLAGEN THAT 6636 04:48:36,960 --> 04:48:39,600 CAUSES BONE FRAGILITY, AND NOW 6637 04:48:39,600 --> 04:48:44,520 THERE'S EMERGING EVIDENCE FOR 6638 04:48:44,520 --> 04:48:46,600 THE ROLE OF THE ENTEROBONE 6639 04:48:46,600 --> 04:48:49,800 ACCESS, THERE ARE RECEPTORS ON 6640 04:48:49,800 --> 04:48:51,640 OSTEOBLASTS RESPONSIVE NOT ONLY 6641 04:48:51,640 --> 04:48:55,480 TO INSULIN BUT ALSO TO THE 6642 04:48:55,480 --> 04:48:58,440 HORMONES SECRETE AND AUGMENT 6643 04:48:58,440 --> 04:48:59,720 NORMAL INSULIN SECRETION. 6644 04:48:59,720 --> 04:49:02,400 I CAN'T TELL YOU THERE'S DATA IN 6645 04:49:02,400 --> 04:49:04,440 CF AND MOST OF THE DATA IN CF 6646 04:49:04,440 --> 04:49:06,960 WITH RESPECT TO DIABETES WILL BE 6647 04:49:06,960 --> 04:49:09,480 OLDER DATA. 6648 04:49:09,480 --> 04:49:12,320 WE KNOW INDIVIDUALS WHO PRIOR TO 6649 04:49:12,320 --> 04:49:13,400 ETI WHO HAD CF-RELATED DIABETES 6650 04:49:13,400 --> 04:49:15,280 ALSO TEND TO BE SICKER, MORE 6651 04:49:15,280 --> 04:49:17,600 LIKELY TO HAVE BONE FRAGILITY SO 6652 04:49:17,600 --> 04:49:22,280 I THINK IT'S DIFFICULT TO 6653 04:49:22,280 --> 04:49:23,920 UNTEASE THOSE AND WE'LL HAVE 6654 04:49:23,920 --> 04:49:29,400 BETTER INSIGHT INTO WHAT'S GOING 6655 04:49:29,400 --> 04:49:30,120 GOING FORWARD BETWEEN 6656 04:49:30,120 --> 04:49:31,360 ENTEROINSULAR ACCESS AND BONE. 6657 04:49:31,360 --> 04:49:33,120 A LOT OF "I DON'T KNOW" THERE. 6658 04:49:33,120 --> 04:49:34,680 >> THINGS WE STILL NEED TO 6659 04:49:34,680 --> 04:49:35,760 FIGURE OUT. 6660 04:49:35,760 --> 04:49:37,920 I'LL ASK QUESTIONS TO JESSICA 6661 04:49:37,920 --> 04:49:38,600 NOW. 6662 04:49:38,600 --> 04:49:39,560 ARE THERE ANY EMERGING 6663 04:49:39,560 --> 04:49:44,480 GUIDELINES FOR CHANGES IN BMI 6664 04:49:44,480 --> 04:49:47,000 FOR KIDS OR ADULTS TRIGGERING 6665 04:49:47,000 --> 04:49:48,200 ADDITIONAL MONITORING? 6666 04:49:48,200 --> 04:49:51,840 >> THE CF FOUNDATION IS WORKING 6667 04:49:51,840 --> 04:49:53,080 CURRENTLY ON NEW GUIDELINES. 6668 04:49:53,080 --> 04:49:56,720 THERE'S A GROUP WORKING ON THAT 6669 04:49:56,720 --> 04:49:57,600 ONE. 6670 04:49:57,600 --> 04:49:59,360 THE AMERICAN ACADEMY ON 6671 04:49:59,360 --> 04:50:01,480 NUTRITION DIETETICS PUT OUT 6672 04:50:01,480 --> 04:50:04,080 GUIDELINES ABOUT ONE OR TWO 6673 04:50:04,080 --> 04:50:06,240 YEARS AGO, AND THE BOTTOM LINE 6674 04:50:06,240 --> 04:50:08,640 FOR THAT GUIDELINE, I HAVE A 6675 04:50:08,640 --> 04:50:10,520 FEELING BOTTOM LINE FOR UPCOMING 6676 04:50:10,520 --> 04:50:12,800 GUIDELINES WILL BE TO MONITOR 6677 04:50:12,800 --> 04:50:16,680 WEIGHT AND BMI, AND A LOT WILL 6678 04:50:16,680 --> 04:50:19,240 BE MORE INDIVIDUAL 6679 04:50:19,240 --> 04:50:19,600 RECOMMENDATIONS. 6680 04:50:19,600 --> 04:50:22,000 SO IF SOMEONE IS GAINING TOO 6681 04:50:22,000 --> 04:50:26,840 MUCH WEIGHT, YOU KNOW, WE SORT 6682 04:50:26,840 --> 04:50:30,520 OF PULL BACK ON THE CALORIES 6683 04:50:30,520 --> 04:50:33,160 OR -- THAT'S FOR ADULTS BUT VERY 6684 04:50:33,160 --> 04:50:33,880 CAREFUL PERSONALIZED TREATMENT 6685 04:50:33,880 --> 04:50:36,520 IS WHERE THINGS ARE MOVING WITH 6686 04:50:36,520 --> 04:50:38,720 CYSTIC FIBROSIS BECAUSE IT'S NO 6687 04:50:38,720 --> 04:50:43,560 LONGER GOING TO BE EVERYONE EAT 6688 04:50:43,560 --> 04:50:44,560 EVERYTHING THAT YOU CAN. 6689 04:50:44,560 --> 04:50:46,520 >> AND RELATED TO THAT WHAT DO 6690 04:50:46,520 --> 04:50:48,160 WE UNDERSTAND ABOUT IMPACT OF 6691 04:50:48,160 --> 04:50:49,360 EXERCISE INDEPENDENT OF DIE OAT 6692 04:50:49,360 --> 04:50:51,440 LEAN BODY MASS OR FAT, IS 6693 04:50:51,440 --> 04:50:59,200 DIETARY CHANGE ALONE ADEQUATE TO 6694 04:50:59,200 --> 04:51:00,400 RELATE HEALTH GOALS? 6695 04:51:00,400 --> 04:51:02,800 >> NOT ENOUGH STUDIES LOOKING AT 6696 04:51:02,800 --> 04:51:04,560 EXERCISE AND ACTIVITY IN CF AND 6697 04:51:04,560 --> 04:51:05,680 SEDENTARY ACTIVITY BUT STUDIES 6698 04:51:05,680 --> 04:51:11,680 IN GENERAL HAVE SHOWN RESISTANCE 6699 04:51:11,680 --> 04:51:20,000 EXERCISE, EXERCISE IN GENERAL 6700 04:51:20,000 --> 04:51:21,760 IMPROVES HEALTH, STUDIES OUT OF 6701 04:51:21,760 --> 04:51:24,680 AUGUSTA HAVE SHOWN THIS. 6702 04:51:24,680 --> 04:51:26,200 I'M BIASED, I THINK ABOUT FOOD 6703 04:51:26,200 --> 04:51:31,680 ONLY, BUT IT IS BOTH EXERCISE 6704 04:51:31,680 --> 04:51:33,120 AND DIET, FOR THE GENERATION 6705 04:51:33,120 --> 04:51:34,320 POPULATION ALSO, IMPORTANT FOR 6706 04:51:34,320 --> 04:51:36,520 LUNG HEALTH AND OVERALL 6707 04:51:36,520 --> 04:51:36,800 LONGEVITY. 6708 04:51:36,800 --> 04:51:42,280 >> AND THEN ONE MORE AND WE HAVE 6709 04:51:42,280 --> 04:51:47,120 MORE FOR PRADEEP, WHAT ABOUT 6710 04:51:47,120 --> 04:51:49,160 NEEDS DURING PERIODS OF INTENSE 6711 04:51:49,160 --> 04:51:50,320 GROWTH LIKE PUBERTY? 6712 04:51:50,320 --> 04:51:51,600 >> THAT'S ANOTHER AREA WHERE 6713 04:51:51,600 --> 04:51:54,240 WE'LL HAVE TO DO A LOT OF 6714 04:51:54,240 --> 04:51:56,560 INDIVIDUAL MONITORING. 6715 04:51:56,560 --> 04:52:00,400 I DO BELIEVE IN CHILDREN WITH CF 6716 04:52:00,400 --> 04:52:03,600 WE STILL WANT TO GROW THE LUNGS, 6717 04:52:03,600 --> 04:52:05,440 WE WANT OUR KIDS TO GROW AS MUCH 6718 04:52:05,440 --> 04:52:07,240 AS THEY POSSIBLY CAN. 6719 04:52:07,240 --> 04:52:11,240 WE'LL BE MONITORING THAT. 6720 04:52:11,240 --> 04:52:12,240 INDIVIDUALLY ASSESSING FOR 6721 04:52:12,240 --> 04:52:13,080 CALORIE NEEDS. 6722 04:52:13,080 --> 04:52:17,000 MY SHORT ANSWER, IT WILL BE 6723 04:52:17,000 --> 04:52:18,760 INDIVIDUAL DEPENDING ON THE 6724 04:52:18,760 --> 04:52:21,520 GROWTH OF THE CHILD, BUT THAT 6725 04:52:21,520 --> 04:52:23,800 BEING SAID, ANOTHER QUESTION 6726 04:52:23,800 --> 04:52:27,160 THAT REMAINS IS WHETHER -- DO WE 6727 04:52:27,160 --> 04:52:29,280 STRIVE TO HIT BMI PERCENTILE 6728 04:52:29,280 --> 04:52:30,400 GOAL OF 50%? 6729 04:52:30,400 --> 04:52:32,000 WHAT ARE NEW TARGET GOALS? 6730 04:52:32,000 --> 04:52:35,920 DO WE NEED TO CHANGE THE 6731 04:52:35,920 --> 04:52:36,320 THRESHOLD? 6732 04:52:36,320 --> 04:52:39,560 STILL A LOT OF QUESTIONS I THINK 6733 04:52:39,560 --> 04:52:42,720 I'LL DEFER TO DR. KELLY, A LOT 6734 04:52:42,720 --> 04:52:44,280 OF "I DON'T KNOWS," AND THINGS 6735 04:52:44,280 --> 04:52:48,760 ARE COMING IN THIS NEW WORLD. 6736 04:52:48,760 --> 04:52:49,600 >> I APPRECIATE -- THERE'S SO 6737 04:52:49,600 --> 04:52:50,840 MANY QUESTIONS IN THE CHAT. 6738 04:52:50,840 --> 04:52:52,800 WE'RE TRYING TO MIX IT UP 6739 04:52:52,800 --> 04:52:53,920 BETWEEN SPEAKERS. 6740 04:52:53,920 --> 04:52:55,720 I WANT TO ASK PRADEEP, A 6741 04:52:55,720 --> 04:52:58,040 QUESTION YOU'VE BEEN INTERESTED 6742 04:52:58,040 --> 04:53:01,920 IN, ARE THERE ANY DATA OR IDEAS 6743 04:53:01,920 --> 04:53:08,000 ABOUT THE DIFFERENCES GENETIC, 6744 04:53:08,000 --> 04:53:15,760 METABOLIC OR VIRULENCE WITH HEMP 6745 04:53:15,760 --> 04:53:16,760 AND PERSIST AFTER TREATMENT? 6746 04:53:16,760 --> 04:53:18,960 >> I'LL ADD TO THE CHORUS OF I 6747 04:53:18,960 --> 04:53:19,480 DON'T KNOW. 6748 04:53:19,480 --> 04:53:24,240 WE'VE DONE A LITTLE BIT OF 6749 04:53:24,240 --> 04:53:27,040 PRELIMINARY ANALYSIS, VERY CRUDE 6750 04:53:27,040 --> 04:53:28,480 MICROPARAMETERS TO ASK, DO ANY 6751 04:53:28,480 --> 04:53:32,960 OF THEM THAT ARE -- WE CAN 6752 04:53:32,960 --> 04:53:38,560 QUICKLY GAUGE BY EYE, CORRELATE 6753 04:53:38,560 --> 04:53:45,440 WITH PROPENSITY TO CLEAR 6754 04:53:45,440 --> 04:53:45,760 INFECTION. 6755 04:53:45,760 --> 04:53:48,680 THE ONLY THING SO FAR THAT SHOWS 6756 04:53:48,680 --> 04:53:50,680 AN ASSOCIATION, AGAIN THIS IS 6757 04:53:50,680 --> 04:53:54,720 EARLY DAYS IN THE STUDY, IS 6758 04:53:54,720 --> 04:53:56,200 STARTING DENSITY OF THE 6759 04:53:56,200 --> 04:53:56,560 BACTERIA. 6760 04:53:56,560 --> 04:53:59,320 THERE APPEARS TO BE A BIT OF 6761 04:53:59,320 --> 04:54:02,880 THRESHOLD SOMEWHERE AROUND 10 TO 6762 04:54:02,880 --> 04:54:05,360 THE 6th OR SO, CF USE PER MIL 6763 04:54:05,360 --> 04:54:11,080 OF PSEUDOMONAS, IN THE SPUTUM. 6764 04:54:11,080 --> 04:54:12,920 IF YOU'RE STARTING PRE-ETI 6765 04:54:12,920 --> 04:54:17,320 SPUTUM COUNTS BELOW THAT HIGHER 6766 04:54:17,320 --> 04:54:21,160 PROBABILITY OF GOING TO 6767 04:54:21,160 --> 04:54:22,040 INFLECTION CLEARANCE THAN IF 6768 04:54:22,040 --> 04:54:23,680 SIGNIFICANTLY ABOVE THAT. 6769 04:54:23,680 --> 04:54:26,960 COULD BE MECHANISTIC. 6770 04:54:26,960 --> 04:54:29,080 WE KNOW HIGHER DENSITY CULTURES 6771 04:54:29,080 --> 04:54:31,680 ARE HARDER TO KILL. 6772 04:54:31,680 --> 04:54:33,440 COULD BE EPIPHENOMENON TRACKING 6773 04:54:33,440 --> 04:54:36,160 WITH SOMETHING ELSE, COULD BE 6774 04:54:36,160 --> 04:54:38,440 EPIPHENOMENON RELATED TO 6775 04:54:38,440 --> 04:54:41,960 DURATION OF INFECTION, EXTENT OF 6776 04:54:41,960 --> 04:54:42,840 GENETIC DIVERSIFICATION OF 6777 04:54:42,840 --> 04:54:43,800 ORGANISMS, BUT DON'T KNOW A LOT 6778 04:54:43,800 --> 04:54:45,680 BUT THAT'S THE ONLY THING WE'VE 6779 04:54:45,680 --> 04:54:48,960 SEEN SO FAR AS SHAKING OUT AS 6780 04:54:48,960 --> 04:54:50,640 PREDICTIVE. 6781 04:54:50,640 --> 04:54:51,000 >> THANK YOU. 6782 04:54:51,000 --> 04:54:53,560 WE'RE EAGER TO LEARN MORE ABOUT 6783 04:54:53,560 --> 04:54:53,800 THAT. 6784 04:54:53,800 --> 04:54:56,040 JESSICA, THERE'S ANOTHER 6785 04:54:56,040 --> 04:54:56,840 QUESTION FOR YOU. 6786 04:54:56,840 --> 04:54:58,600 WE'LL BE TALKING MORE ABOUT 6787 04:54:58,600 --> 04:55:01,480 PREGNANCY TOMORROW, BUT IS THERE 6788 04:55:01,480 --> 04:55:03,200 EVIDENCE THAT SUGGESTS LEGACY 6789 04:55:03,200 --> 04:55:04,320 DIET CONTRIBUTES TO INCREASED 6790 04:55:04,320 --> 04:55:10,760 RISK OF CONGENITAL 6791 04:55:10,760 --> 04:55:11,560 ABNORMALLALITIES COMPARED TO 6792 04:55:11,560 --> 04:55:12,160 WITHOUT CFS? 6793 04:55:12,160 --> 04:55:13,240 >> I DON'T KNOW THE ANSWER. 6794 04:55:13,240 --> 04:55:15,960 I DON'T THINK THERE'S EVIDENCE 6795 04:55:15,960 --> 04:55:23,920 IN OUR CF WORLD REGARDING THE 6796 04:55:23,920 --> 04:55:25,640 PREGNANCY AND OTHER OUTCOMES. 6797 04:55:25,640 --> 04:55:31,000 THERE'S A LOT OF INFORMATION ON 6798 04:55:31,000 --> 04:55:33,560 DIET AND OBESITY STATUS OF THE 6799 04:55:33,560 --> 04:55:36,080 MOTHER AND EPIGENETIC CHANGES 6800 04:55:36,080 --> 04:55:38,000 THAT OCCUR IN THEIR INFANTS. 6801 04:55:38,000 --> 04:55:40,120 I THINK THERE'S A LOT WE CAN 6802 04:55:40,120 --> 04:55:42,760 LEARN AND SHOULD LEARN FROM THE 6803 04:55:42,760 --> 04:55:45,360 GENERAL OBESITY AND GENERAL TYPE 6804 04:55:45,360 --> 04:55:47,360 2 DIABETES EFFECTS ON PREGNANCY 6805 04:55:47,360 --> 04:55:50,320 THERE. 6806 04:55:50,320 --> 04:55:50,600 >> GREAT. 6807 04:55:50,600 --> 04:55:52,840 AND THEN LASTLY, I THINK -- OH, 6808 04:55:52,840 --> 04:55:54,360 SO MANY QUESTIONS HERE. 6809 04:55:54,360 --> 04:55:57,080 HAVE WE SEEN INCREASED NEED FOR 6810 04:55:57,080 --> 04:55:59,840 GLUTEN-FREE DIETS OR ANY OTHER 6811 04:55:59,840 --> 04:56:06,280 CHANGES IN PEOPLE'S DIETS WHEN 6812 04:56:06,280 --> 04:56:09,040 PEOPLE START HEMPT? 6813 04:56:09,040 --> 04:56:10,560 ARE WE UNEARTHING TOLERANCES OF 6814 04:56:10,560 --> 04:56:11,520 THINGS THEIR BODIES WEREN'T 6815 04:56:11,520 --> 04:56:12,400 SEEING BEFORE? 6816 04:56:12,400 --> 04:56:18,360 >> IT'S A REALLY GOOD QUESTION. 6817 04:56:18,360 --> 04:56:28,880 HISTORICALLY, THERE IS A HIGHER 6818 04:56:29,360 --> 04:56:30,280 PREVALENCE OF CELIAC DISEASE, 6819 04:56:30,280 --> 04:56:31,680 NOTHING HAS BEEN PUBLISHED, 6820 04:56:31,680 --> 04:56:33,120 SOMETHING WE CAN LOOK TOWARDS IN 6821 04:56:33,120 --> 04:56:39,120 LOOKING AT CHANGES IN DIET AND 6822 04:56:39,120 --> 04:56:39,680 TOLERANCES. 6823 04:56:39,680 --> 04:56:40,040 >> EXCELLENT. 6824 04:56:40,040 --> 04:56:42,320 MARA, HAVE WE MANAGED TO HIT THE 6825 04:56:42,320 --> 04:56:44,080 QUESTIONS? 6826 04:56:44,080 --> 04:56:44,320 >> YES. 6827 04:56:44,320 --> 04:56:46,800 WE STILL HAVE QUITE A BIT OF 6828 04:56:46,800 --> 04:56:49,760 QUESTIONS THAT WE WILL TRY TO 6829 04:56:49,760 --> 04:56:51,600 ANSWER IN THE CHAT BECAUSE WE'RE 6830 04:56:51,600 --> 04:56:54,040 NEARING THE END OF THIS SESSION. 6831 04:56:54,040 --> 04:56:57,520 SO BE ON THE LOOKOUT FOR THOSE. 6832 04:56:57,520 --> 04:56:58,800 WE DID GET TO MOST. 6833 04:56:58,800 --> 04:57:09,600 SO THANK YOU VERY MUCH. 6834 04:57:09,600 --> 04:57:10,680 WELCOME BACK. 6835 04:57:10,680 --> 04:57:13,880 WE'RE GOING TO HAVE ANOTHER 6836 04:57:13,880 --> 04:57:16,720 SESSION OF COMMUNITY MEMBER 6837 04:57:16,720 --> 04:57:20,040 PERSPECTIVES HOSTED BY DR. 6838 04:57:20,040 --> 04:57:20,520 CLANCY. 6839 04:57:20,520 --> 04:57:24,560 I'LL TURN IT OVER TO THE GUEST 6840 04:57:24,560 --> 04:57:27,080 SPEAKERS NOW. 6841 04:57:27,080 --> 04:57:32,440 >>HANK YOU, MARA, AND EVERYONE 6842 04:57:32,440 --> 04:57:35,160 FOR AN OUTSTANDING WORKSHOP. 6843 04:57:35,160 --> 04:57:36,920 AN EXCELLENT SCIENCE AND GREAT 6844 04:57:36,920 --> 04:57:39,080 QUESTIONS BEING ASKED. 6845 04:57:39,080 --> 04:57:40,200 NEXT SESSION IS ONLY 15 MINUTES 6846 04:57:40,200 --> 04:57:47,120 BEFORE WE GO BACK INTO 6847 04:57:47,120 --> 04:57:47,440 BREAKOUTS. 6848 04:57:47,440 --> 04:57:50,160 AN OPPORTUNITY TO HEAR FROM 6849 04:57:50,160 --> 04:57:51,320 PEOPLE NOT SPECIFICALLY 6850 04:57:51,320 --> 04:57:53,440 BENEFITED FROM CF CARE 6851 04:57:53,440 --> 04:57:54,000 MODULATORS. 6852 04:57:54,000 --> 04:57:55,840 WE WANTED TO ENSURE THAT VOICE 6853 04:57:55,840 --> 04:57:56,840 WAS HEARD NOW. 6854 04:57:56,840 --> 04:57:59,920 THIS IS AN EXCITING TIME FOR SO 6855 04:57:59,920 --> 04:58:07,880 MANY PEOPLE WITH CF, ALSO 6856 04:58:07,880 --> 04:58:09,800 PERSPECTIVE WE NEED AS WE LOOK 6857 04:58:09,800 --> 04:58:12,160 TO THE FUTURE. 6858 04:58:12,160 --> 04:58:14,280 I'M JOINED BY PARENTS OF CF 6859 04:58:14,280 --> 04:58:16,200 PATIENTS WHO ARE CURRENTLY ARE 6860 04:58:16,200 --> 04:58:20,160 NOT ELIGIBLE FOR MODULATORS AND 6861 04:58:20,160 --> 04:58:22,560 WILL LEAVE IT TO THEM AND WOULD 6862 04:58:22,560 --> 04:58:24,880 LIKE TO INVITE OR INTRODUCE LISA 6863 04:58:24,880 --> 04:58:26,080 HAMBURGER, JOINING US I BELIEVE 6864 04:58:26,080 --> 04:58:27,040 FROM MARYLAND. 6865 04:58:27,040 --> 04:58:29,480 IS THAT CORRECT? 6866 04:58:29,480 --> 04:58:30,440 >> THAT'S CORRECT. 6867 04:58:30,440 --> 04:58:32,840 >> AND KATE, I FORGOT WHERE 6868 04:58:32,840 --> 04:58:33,600 YOU'RE FROM. 6869 04:58:33,600 --> 04:58:36,800 WHERE IS HOME FOR YOU? 6870 04:58:36,800 --> 04:58:39,800 >> IOWA FOR ME. 6871 04:58:39,800 --> 04:58:40,920 >> I'M FROM IOWA, ALL RIGHT. 6872 04:58:40,920 --> 04:58:43,240 I'LL TURN IT OVER TO YOU. 6873 04:58:43,240 --> 04:58:50,400 THANK YOU FOR JOINING US, YOUR 6874 04:58:50,400 --> 04:58:54,520 PERSPECTIVES WILL BE VALUABLE. 6875 04:58:54,520 --> 04:58:57,480 OVER TO YOU. 6876 04:58:57,480 --> 04:58:58,000 >> HI, EVERYONE. 6877 04:58:58,000 --> 04:58:59,560 I WANT TO THANK EVERYONE FOR 6878 04:58:59,560 --> 04:59:02,960 LETTING ME SPEAK WITH YOU TODAY. 6879 04:59:02,960 --> 04:59:05,440 MY SON MATTHEW IS 30 YEARS OLD, 6880 04:59:05,440 --> 04:59:06,200 RECENTLY GOT MARRIED. 6881 04:59:06,200 --> 04:59:09,040 A DAY I NEVER THOUGHT I WOULD 6882 04:59:09,040 --> 04:59:10,160 SEE OR COULD EVEN IMAGINE. 6883 04:59:10,160 --> 04:59:12,160 I HOPE TO SEE MANY MORE 6884 04:59:12,160 --> 04:59:14,200 MILESTONES LIKE THIS ONE. 6885 04:59:14,200 --> 04:59:20,680 HE HAS TWO NONSENSE MUTATIONS, G 6886 04:59:20,680 --> 04:59:26,560 542X AND W 1282X, NO CURRENT 6887 04:59:26,560 --> 04:59:29,600 MODULATOR AT 8 WEEKS OLD, GENE 6888 04:59:29,600 --> 04:59:30,600 THERAPY WAS CONSIDERED A 6889 04:59:30,600 --> 04:59:31,560 POTENTIAL CURE. 6890 04:59:31,560 --> 04:59:33,880 I WAS TOLD AT THE TIME THAT 6891 04:59:33,880 --> 04:59:35,080 WITHIN 7 TO 10 YEARS THERE WOULD 6892 04:59:35,080 --> 04:59:36,400 BE A CURE. 6893 04:59:36,400 --> 04:59:38,360 OBVIOUSLY THAT DID NOT HAPPEN. 6894 04:59:38,360 --> 04:59:40,040 AS GENE THERAPY DID NOT WORK OUT 6895 04:59:40,040 --> 04:59:42,560 AS PLANNED DURING THAT TIME 6896 04:59:42,560 --> 04:59:42,840 PERIOD. 6897 04:59:42,840 --> 04:59:44,400 I REMAINED HOPEFUL AS I DO 6898 04:59:44,400 --> 04:59:44,720 TODAY. 6899 04:59:44,720 --> 04:59:47,920 THERE HAVE BEEN OTHER ADVANCES 6900 04:59:47,920 --> 04:59:49,440 IN RESEARCH WITH MEDICATIONS, 6901 04:59:49,440 --> 04:59:51,080 BUT DO NOT TREAT UNDERLYING 6902 04:59:51,080 --> 04:59:53,280 CAUSE OF CF. 6903 04:59:53,280 --> 04:59:55,600 MY SON HAS HAD CHALLENGES, 6904 04:59:55,600 --> 04:59:57,800 MOSTLY WITH G.I. ISSUES 6905 04:59:57,800 --> 04:59:59,880 INCLUDING RUPTURED BOWEL AT 14 6906 04:59:59,880 --> 05:00:03,800 WHERE WE ALMOST LOST HIM, SEVERE 6907 05:00:03,800 --> 05:00:04,560 SINUS ISSUES. 6908 05:00:04,560 --> 05:00:06,560 HE'S COMPLIANCE WHICH HELPS 6909 05:00:06,560 --> 05:00:09,040 MAINTAIN A HIGH PULMONARY 6910 05:00:09,040 --> 05:00:10,680 FUNCTION AND FEW EXACERBATIONS 6911 05:00:10,680 --> 05:00:12,440 FEELS THE OLDER HE GETS THERE 6912 05:00:12,440 --> 05:00:14,400 WILL BE MORE CHALLENGES HARDER 6913 05:00:14,400 --> 05:00:16,920 TO MAINTAIN HELP WITHOUT A 6914 05:00:16,920 --> 05:00:17,200 MODULATOR. 6915 05:00:17,200 --> 05:00:19,120 SO WHAT DOES THIS MEAN FOR THOSE 6916 05:00:19,120 --> 05:00:23,240 LIKE MY SON WHO ARE NOT 6917 05:00:23,240 --> 05:00:23,720 ELIGIBLE? 6918 05:00:23,720 --> 05:00:25,880 MEDIAN LIFE EXPECTANCY IS AROUND 6919 05:00:25,880 --> 05:00:28,000 50 YEARS OLD, OBVIOUSLY NOT GOOD 6920 05:00:28,000 --> 05:00:28,320 ENOUGH. 6921 05:00:28,320 --> 05:00:33,040 ALTHOUGH I LOOK AT THIS AND HOW 6922 05:00:33,040 --> 05:00:34,520 THIS RELATES TO INDIVIDUALS 6923 05:00:34,520 --> 05:00:35,320 WITHOUT CURRENT MODULATORS, THIS 6924 05:00:35,320 --> 05:00:37,520 MAY NOT BE A TRUE INDICATOR 6925 05:00:37,520 --> 05:00:43,040 WITHOUT A MODULATOR. 6926 05:00:43,040 --> 05:00:45,560 THEY HAVE INCREASED ABILITY FOR 6927 05:00:45,560 --> 05:00:47,040 WOMEN TO HAVE CHILDREN, 6928 05:00:47,040 --> 05:00:48,000 MODULATORS HAVE BEEN DIRECT 6929 05:00:48,000 --> 05:00:50,480 CAUSE FOR TRIPLING IN THE LAST 6930 05:00:50,480 --> 05:00:52,560 YEAR, FOR THOSE WITHOUT WHERE DO 6931 05:00:52,560 --> 05:00:54,640 THEY STAND? 6932 05:00:54,640 --> 05:01:00,880 WE KNOW THE OBVIOUS RESULTS ARE 6933 05:01:00,880 --> 05:01:04,480 FEWER HOSPITALIZATIONS, LESS 6934 05:01:04,480 --> 05:01:15,080 LUNG AS EXACERBATION AND. 6935 05:01:15,080 --> 05:01:17,640 THEY HAVE BEEN SHOWN TO ENHANCE 6936 05:01:17,640 --> 05:01:19,880 ONE'S QUALITY OF LIFE BUT 6937 05:01:19,880 --> 05:01:21,880 WITHOUT THE MODULATOR THIS IS 6938 05:01:21,880 --> 05:01:23,520 NOT THE CASE. 6939 05:01:23,520 --> 05:01:25,200 THE BIGGEST DIFFERENCE WOULD BE 6940 05:01:25,200 --> 05:01:26,440 CHILDREN BEING BORN TODAY. 6941 05:01:26,440 --> 05:01:27,680 IF THEY HAVE A CHANCE AT AN 6942 05:01:27,680 --> 05:01:29,440 EARLY AGE TO START A MODULATOR 6943 05:01:29,440 --> 05:01:31,400 THERE'S LESS OF A CHANCE FOR 6944 05:01:31,400 --> 05:01:34,160 LUNG DAMAGE AND MANY OTHER 6945 05:01:34,160 --> 05:01:35,120 COMPLICATIONS ASSOCIATED WITH 6946 05:01:35,120 --> 05:01:35,280 CF. 6947 05:01:35,280 --> 05:01:37,440 THIS IS WHY WORK NEEDS TO 6948 05:01:37,440 --> 05:01:39,320 ACCELERATE SO ALL BABIES BEING 6949 05:01:39,320 --> 05:01:42,120 BORN WITH CF TODAY HAVE THE SAME 6950 05:01:42,120 --> 05:01:42,480 RESULTS. 6951 05:01:42,480 --> 05:01:44,840 I SPEAK WITH MANY ADULTS WHO 6952 05:01:44,840 --> 05:01:45,960 DISCUSSED TRANSFORMATION NOT 6953 05:01:45,960 --> 05:01:48,480 ONLY OF THEIR HEALTH BUT MENTAL 6954 05:01:48,480 --> 05:01:50,560 HEALTH IN THAT THEY NOW LOOK 6955 05:01:50,560 --> 05:01:51,880 FORWARD TO REACHING MILESTONES 6956 05:01:51,880 --> 05:01:53,400 THAT THEY NEVER THOUGHT 6957 05:01:53,400 --> 05:01:53,800 POSSIBLE. 6958 05:01:53,800 --> 05:01:55,960 VERSUS THOSE WHO DON'T HAVE A 6959 05:01:55,960 --> 05:01:57,120 MODULATOR THAT WORRY ABOUT THEIR 6960 05:01:57,120 --> 05:01:59,000 FUTURE AND WHAT IT HOLDS FOR 6961 05:01:59,000 --> 05:01:59,520 THEM. 6962 05:01:59,520 --> 05:02:01,840 THEY DO NOT REBOUND AS QUICKLY 6963 05:02:01,840 --> 05:02:04,880 AS BEFORE AS EACH EXASPERATION 6964 05:02:04,880 --> 05:02:05,120 BUILDS. 6965 05:02:05,120 --> 05:02:06,440 CF TAKES A TOLL ON PHYSICAL AND 6966 05:02:06,440 --> 05:02:07,680 MENTAL HEALTH AND THOSE WHO 6967 05:02:07,680 --> 05:02:09,480 CURRENTLY DO NOT HAVE A 6968 05:02:09,480 --> 05:02:11,240 MODULATOR FEEL LIKE THEY CAN NOT 6969 05:02:11,240 --> 05:02:13,320 NECESSARILY PLAN FOR THE FUTURE. 6970 05:02:13,320 --> 05:02:17,240 FOR SOME, THERE'S A WEIGHT OF 6971 05:02:17,240 --> 05:02:18,440 BEING LEFT BEHIND, THAT NEEDS TO 6972 05:02:18,440 --> 05:02:20,760 BE CHANGED SO ALL PEOPLE WITH CF 6973 05:02:20,760 --> 05:02:24,360 HAVE THE SAME OPPORTUNITIES 6974 05:02:24,360 --> 05:02:25,920 MOVING FORWARD. 6975 05:02:25,920 --> 05:02:27,120 WITH mRNA TECHNOLOGY IN THE 6976 05:02:27,120 --> 05:02:31,800 NEWS TODAY DUE TO AC SELL 6977 05:02:31,800 --> 05:02:33,160 ACCELERATION OF COVID VACCINE 6978 05:02:33,160 --> 05:02:37,520 WE'RE LOOKING FORWARD TO SIMILAR 6979 05:02:37,520 --> 05:02:38,000 TECHNOLOGY. 6980 05:02:38,000 --> 05:02:38,720 THERE'S BEEN DISCUSSIONS THAT 6981 05:02:38,720 --> 05:02:40,680 MAY CONNECT THE CURE WITH 6982 05:02:40,680 --> 05:02:44,640 FINDING SOMETHING FOR THOSE WITH 6983 05:02:44,640 --> 05:02:46,080 NONSENSE MUTATION, UTMOST 6984 05:02:46,080 --> 05:02:47,320 IMPORTANCE RESEARCH ACCELERATES 6985 05:02:47,320 --> 05:02:48,480 AT A BRISK PACE. 6986 05:02:48,480 --> 05:02:50,400 OVER THE 30 YEARS I'VE BEEN 6987 05:02:50,400 --> 05:02:52,600 INVOLVED WITH THE CF FOUNDATION, 6988 05:02:52,600 --> 05:02:55,000 AS A PARENT, VOLUNTEER, BOARD 6989 05:02:55,000 --> 05:02:57,120 MEMBER, I'VE WITNESSED GROWTH IN 6990 05:02:57,120 --> 05:02:57,760 RESEARCH DEVELOPMENT AND 6991 05:02:57,760 --> 05:03:00,080 COMMITMENT TO FINDING A CURE FOR 6992 05:03:00,080 --> 05:03:02,480 ALL REGARDLESS OF ONE'S 6993 05:03:02,480 --> 05:03:02,800 MUTATION. 6994 05:03:02,800 --> 05:03:04,200 NO ONE WILL REST UNTIL THERE'S A 6995 05:03:04,200 --> 05:03:06,960 CURE FOR ALL PEOPLE WITH CF. 6996 05:03:06,960 --> 05:03:09,600 WE MUST STAY ON COURSE. 6997 05:03:09,600 --> 05:03:11,120 WE KNOW AS RESEARCHERS YOU WON'T 6998 05:03:11,120 --> 05:03:13,080 STOP UNTIL THERE'S A CURE FOR 6999 05:03:13,080 --> 05:03:15,840 EVERYONE WITH CF BUT IN THE 7000 05:03:15,840 --> 05:03:17,000 MEANTIME THOSE WITHOUT A 7001 05:03:17,000 --> 05:03:18,680 MODULATOR NEED TO KEEP FIGHTING 7002 05:03:18,680 --> 05:03:20,320 UNTIL THEY GET THEIR MODULATOR 7003 05:03:20,320 --> 05:03:23,560 AND A CURE. 7004 05:03:23,560 --> 05:03:25,320 THANK YOU. 7005 05:03:25,320 --> 05:03:27,840 >> THANK YOU, LISA. 7006 05:03:27,840 --> 05:03:33,000 I'M KADE HAMMES, HERE IN IOWA, 7007 05:03:33,000 --> 05:03:34,800 OUR CARE CENTER IS UNIVERSITY OF 7008 05:03:34,800 --> 05:03:37,600 IOWA 7009 05:03:37,600 --> 05:03:39,040 OUR DAUGHTER MILA IS 3 YEARS 7010 05:03:39,040 --> 05:03:42,120 OLD, WE GOVERNMENT THE DREAD -- 7011 05:03:42,120 --> 05:03:45,840 GOT THE DREADED PHONE CALL AT 10 7012 05:03:45,840 --> 05:03:48,280 DAYS OLD, THE FIRST STEP IN 7013 05:03:48,280 --> 05:03:49,680 LEARNING, OUR CALL WAS -- MY 7014 05:03:49,680 --> 05:03:53,160 WIFE IS A NURSE PRACTITIONER, 7015 05:03:53,160 --> 05:03:54,800 SHE WAS BAWLING AND CRYING, I 7016 05:03:54,800 --> 05:03:57,760 HAD NO IDEA WHAT CF WAS. 7017 05:03:57,760 --> 05:03:59,960 I'M CURIOUS WHY MY WIFE IS 7018 05:03:59,960 --> 05:04:00,200 BAWLING. 7019 05:04:00,200 --> 05:04:03,360 THE LADY ON THE PHONE TELLS US 7020 05:04:03,360 --> 05:04:04,880 DON'T RESEARCH WITH GOOGLE, 7021 05:04:04,880 --> 05:04:06,760 DON'T LOOK UP WHAT CF IS. 7022 05:04:06,760 --> 05:04:07,840 YOU'LL REGRET IT. 7023 05:04:07,840 --> 05:04:10,400 HERE IS MY WIFE, SHE'S BAWLING, 7024 05:04:10,400 --> 05:04:12,440 WHAT DO I DO? 7025 05:04:12,440 --> 05:04:14,280 WE GOOGLE IT. 7026 05:04:14,280 --> 05:04:16,360 AND SO YOU QUICKLY LEARN KIND OF 7027 05:04:16,360 --> 05:04:18,360 THE OLD STATISTICS, ALL THE OLD 7028 05:04:18,360 --> 05:04:22,960 OUT OF DATE THINGS THAT CF, 7029 05:04:22,960 --> 05:04:23,640 NOBODY'S LIVING BEYOND 7030 05:04:23,640 --> 05:04:25,360 CHILDHOOD, ALL OF THESE OLD 7031 05:04:25,360 --> 05:04:27,120 STATS THAT PROBABLY DON'T MEAN 7032 05:04:27,120 --> 05:04:28,320 MUCH ANYMORE. 7033 05:04:28,320 --> 05:04:31,720 SO IT INSTANTLY PUT THE FEAR IN 7034 05:04:31,720 --> 05:04:34,680 MYSELF AND MY WIFE, SHE WAS 7035 05:04:34,680 --> 05:04:35,640 FAMILIAR, BUT DIDN'T TOTALLY 7036 05:04:35,640 --> 05:04:36,440 UNDERSTAND IT. 7037 05:04:36,440 --> 05:04:44,360 MY DAUGHTER WAS BORN THE YEAR 7038 05:04:44,360 --> 05:04:45,280 TRI CAFTA CAME OUT. 7039 05:04:45,280 --> 05:04:46,760 SHE WAS BORN IN APRIL, IT CAME 7040 05:04:46,760 --> 05:04:48,720 OUT IN OCTOBER. THERE WAS 7041 05:04:48,720 --> 05:04:50,600 EXCITEMENT IN THE RESEARCH TEAM 7042 05:04:50,600 --> 05:04:52,720 WITH EVERYBODY WE WERE TALKING 7043 05:04:52,720 --> 05:04:54,720 TO ABOUT CF. 7044 05:04:54,720 --> 05:04:55,720 IT'S A TOTALLY DIFFERENT DISEASE 7045 05:04:55,720 --> 05:04:57,600 TODAY, YOU CAN'T LOOK AT GOOGLE, 7046 05:04:57,600 --> 05:04:59,320 IT'S ONE OF THOSE THINGS BECAUSE 7047 05:04:59,320 --> 05:05:01,160 OF THE MODULATORS THESE KIDS 7048 05:05:01,160 --> 05:05:02,600 COULD LIVE VERY LONG LIVES, WE 7049 05:05:02,600 --> 05:05:04,720 HAVE NO IDEA WHAT THE CEILING 7050 05:05:04,720 --> 05:05:07,000 IS, AGE IS JUST A NUMBER. 7051 05:05:07,000 --> 05:05:08,760 BUT THE PROBLEM WAS I KEPT 7052 05:05:08,760 --> 05:05:10,720 DIGGING IN AND TRYING TO 7053 05:05:10,720 --> 05:05:14,640 UNDERSTAND AND RESEARCH FOR MY 7054 05:05:14,640 --> 05:05:15,520 OWN BENEFIT, EVERYTHING I'M 7055 05:05:15,520 --> 05:05:16,800 UNDERSTANDING IS IT'S ABOUT 7056 05:05:16,800 --> 05:05:17,600 CERTAIN MUTATIONS AND OUR 7057 05:05:17,600 --> 05:05:19,160 DAUGHTER SEEMS TO HAVE A 7058 05:05:19,160 --> 05:05:22,080 MUTATION THAT THESE DON'T WORK. 7059 05:05:22,080 --> 05:05:24,040 OUR CARE TEAM WASN'T 100% SURE 7060 05:05:24,040 --> 05:05:26,520 AT THE TIME BUT HELPED US DIG IN 7061 05:05:26,520 --> 05:05:27,760 AND START TO RESEARCH AND THAT 7062 05:05:27,760 --> 05:05:29,880 WAS KIND OF THE TRUTH WE ENDED 7063 05:05:29,880 --> 05:05:32,520 UP FINDING WAS SHE JUST HAS TWO 7064 05:05:32,520 --> 05:05:34,360 CLASS 1 MUTATIONS, ONE IS A 7065 05:05:34,360 --> 05:05:36,120 FRAME SHIFT, ONE IS A SPLICE. 7066 05:05:36,120 --> 05:05:39,160 BUT NEITHER OF THEM ARE ON THE 7067 05:05:39,160 --> 05:05:42,000 LIST OF THINGS THAT TRICATFA 7068 05:05:42,000 --> 05:05:46,520 WILL BENEFIT EVEN WITH THERA 7069 05:05:46,520 --> 05:05:49,440 TYPING, THEY ARE WORKING ON THE 7070 05:05:49,440 --> 05:05:50,560 NONSENSE WITH THE READ-THROUGH, 7071 05:05:50,560 --> 05:05:52,640 NEITHER OF HERS WOULD BE 7072 05:05:52,640 --> 05:05:55,040 BENEFITING FROM THOSE MODULATORS 7073 05:05:55,040 --> 05:05:56,680 SO IT'S BECOME THAT GUT FEELING 7074 05:05:56,680 --> 05:05:59,520 OF, OKAY, WHAT ABOUT US? 7075 05:05:59,520 --> 05:06:00,720 WHERE IS THE MODULATOR THAT'S 7076 05:06:00,720 --> 05:06:03,040 GOING TO CHANGE OUR LIFE? 7077 05:06:03,040 --> 05:06:05,240 ALL AROUND US IT'S GREAT TO BE 7078 05:06:05,240 --> 05:06:06,960 EXCITED FOR EVERYBODY ELSE AND 7079 05:06:06,960 --> 05:06:08,720 SEEING HOW HAPPY EVERYBODY IS 7080 05:06:08,720 --> 05:06:10,240 AND SEEING THE ADVANCEMENTS THAT 7081 05:06:10,240 --> 05:06:12,360 ARE HAPPENING, AND SO MANY IN 7082 05:06:12,360 --> 05:06:14,360 THIS CF COMMUNITY ARE JUST -- 7083 05:06:14,360 --> 05:06:15,840 IT'S A WONDERFUL FAMILY, A 7084 05:06:15,840 --> 05:06:17,800 FAMILY WE DIDN'T WANT BUT THEY 7085 05:06:17,800 --> 05:06:20,000 ARE AMAZING PEOPLE WITHIN OUR 7086 05:06:20,000 --> 05:06:21,400 FAMILY OF CF AND THEY ARE 7087 05:06:21,400 --> 05:06:22,760 TELLING US, HEY, WE'RE NOT 7088 05:06:22,760 --> 05:06:23,800 STOPPING TILL THE FIGHT IS DONE. 7089 05:06:23,800 --> 05:06:27,200 WE'RE GOING TO BE WITH YOU EVERY 7090 05:06:27,200 --> 05:06:28,880 STEP OF THE WAY. 7091 05:06:28,880 --> 05:06:30,520 THEY GIVE US THE ENCOURAGEMENT 7092 05:06:30,520 --> 05:06:32,840 THAT BACK WHEN WE FOUND OUT WE 7093 05:06:32,840 --> 05:06:34,680 HAD CF THERE WAS NO HOPE, AT 7094 05:06:34,680 --> 05:06:36,680 LEAST THAT'S THE WAY IT FELT. 7095 05:06:36,680 --> 05:06:38,720 WE'VE SEEN THE ADVANCEMENTS IN 7096 05:06:38,720 --> 05:06:39,160 PROGRESSION. 7097 05:06:39,160 --> 05:06:41,120 SO FROM OUR STANDPOINT MY WIFE 7098 05:06:41,120 --> 05:06:43,520 AND MYSELF, IT'S LEARNING TO 7099 05:06:43,520 --> 05:06:44,320 TRUST EVERYBODY ELSE'S 7100 05:06:44,320 --> 05:06:45,160 EXPERIENCE THAT WE'RE GOING TO 7101 05:06:45,160 --> 05:06:47,960 GET THERE AND WE'RE GOING TO SEE 7102 05:06:47,960 --> 05:06:48,360 THIS. 7103 05:06:48,360 --> 05:06:49,560 SO IT'S CONSTANTLY TRYING TO 7104 05:06:49,560 --> 05:06:51,640 EDUCATE OURSELVES. 7105 05:06:51,640 --> 05:06:54,040 I'VE ACTUALLY ATTENDED MANY 7106 05:06:54,040 --> 05:06:55,600 RESEARCH OPPORTUNITIES WITH AT 7107 05:06:55,600 --> 05:06:57,560 LEAST VIDEOS AND LEARNING FROM 7108 05:06:57,560 --> 05:06:59,200 JP BEFORE, I'VE SEEN HIM QUITE A 7109 05:06:59,200 --> 05:07:00,560 FEW TIMES NOW, TRYING TO 7110 05:07:00,560 --> 05:07:02,160 UNDERSTAND I HAVE A LIST OF LIKE 7111 05:07:02,160 --> 05:07:03,360 EVERY COMPANY THAT HAS A DRUG 7112 05:07:03,360 --> 05:07:06,080 THAT THEY ARE WORKING ON WHETHER 7113 05:07:06,080 --> 05:07:07,480 CLINICAL OR PRE-CLINICAL, THAT 7114 05:07:07,480 --> 05:07:10,120 COULD POTENTIALLY HELP MY 7115 05:07:10,120 --> 05:07:10,480 DAUGHTER. 7116 05:07:10,480 --> 05:07:14,160 LIKE THE mRNAs, THE GENE 7117 05:07:14,160 --> 05:07:16,480 THERAPY SPLICE SENSE IN ISRAEL, 7118 05:07:16,480 --> 05:07:17,320 ANYTHING THAT COULD POTENTIALLY 7119 05:07:17,320 --> 05:07:18,320 HELP HER IN THE FUTURE IS 7120 05:07:18,320 --> 05:07:20,760 SOMETHING I KEEP TRACK OF. 7121 05:07:20,760 --> 05:07:22,280 WHAT'S PROBABLY INTERESTS ME THE 7122 05:07:22,280 --> 05:07:24,880 MOST, EVERY YEAR ATTENDING 7123 05:07:24,880 --> 05:07:26,000 RESEARCH CON, AND LIKE I SAID, 7124 05:07:26,000 --> 05:07:28,280 IT'S ONE OF THOSE THINGS WHERE 7125 05:07:28,280 --> 05:07:29,840 WE'RE VERY ENCOURAGED BY THE 7126 05:07:29,840 --> 05:07:31,360 QUICK ADVANCEMENTS IN THE 7127 05:07:31,360 --> 05:07:33,120 RESEARCH AND EVERYTHING, AND NOT 7128 05:07:33,120 --> 05:07:35,440 BEING LEFT BEHIND, BUT IN THE 7129 05:07:35,440 --> 05:07:36,960 SAME SENSE THERE IS THAT NATURAL 7130 05:07:36,960 --> 05:07:39,360 GUT FEELING OF BEING LEFT 7131 05:07:39,360 --> 05:07:40,160 BEHIND. 7132 05:07:40,160 --> 05:07:41,880 RESEARCH CON WITH THE CYSTIC 7133 05:07:41,880 --> 05:07:42,680 FIBROSIS FOUNDATION TWO YEARS 7134 05:07:42,680 --> 05:07:44,960 AGO WAS ABOUT THE PATH TO THE 7135 05:07:44,960 --> 05:07:46,720 CURE, AND HERE ARE ALL THE DRUGS 7136 05:07:46,720 --> 05:07:47,560 WE'RE WORKING ON. 7137 05:07:47,560 --> 05:07:52,280 TO BASICALLY GET EVERYBODY 7138 05:07:52,280 --> 05:07:52,760 THERE. 7139 05:07:52,760 --> 05:07:54,040 THIS YEAR IT FELT LIKE THE 7140 05:07:54,040 --> 05:07:57,760 RESEARCH CON WAS ABOUT WHAT IS 7141 05:07:57,760 --> 05:07:58,960 LIFE LIKE ON MODULATORS BECAUSE 7142 05:07:58,960 --> 05:08:00,600 THERE'S A LOT OF RESEARCH FOR 7143 05:08:00,600 --> 05:08:01,800 THOSE THAT HAVE MODULATORS AND 7144 05:08:01,800 --> 05:08:03,400 WHAT IS LIFE LIKE FOR THEM. 7145 05:08:03,400 --> 05:08:05,600 AND WE'VE TALKED TO A FEW OF 7146 05:08:05,600 --> 05:08:05,840 THEM. 7147 05:08:05,840 --> 05:08:06,920 WE JUST HAD OUR WALK. 7148 05:08:06,920 --> 05:08:09,480 THERE WAS ANOTHER FAMILY WE WERE 7149 05:08:09,480 --> 05:08:12,240 TALKING ABOUT HOW WE MAYBE PUT 7150 05:08:12,240 --> 05:08:13,880 OUR CHILD IN MORE OF A BUBBLE 7151 05:08:13,880 --> 05:08:17,480 THAN THE NEXT FAMILY, BUT OUR 7152 05:08:17,480 --> 05:08:18,800 STANDPOINT ONCE SHE LOSES LUNG 7153 05:08:18,800 --> 05:08:20,880 FUNCTION WE CAN'T GET IT BACK. 7154 05:08:20,880 --> 05:08:22,200 IF A MODULATOR'S IN HER FUTURE 7155 05:08:22,200 --> 05:08:23,720 CAN WE KEEP HER LUNG FUNCTION AS 7156 05:08:23,720 --> 05:08:25,480 GOOD AS POSSIBLE UNTIL WE CAN 7157 05:08:25,480 --> 05:08:27,880 GET ON THAT MODULATOR, SO WE TRY 7158 05:08:27,880 --> 05:08:29,200 VERY HARD. 7159 05:08:29,200 --> 05:08:31,960 WE CULTURE STAPH FREQUENTLY BUT 7160 05:08:31,960 --> 05:08:34,600 LUCKILY HAVE NOT HAD TO DEAL 7161 05:08:34,600 --> 05:08:35,400 WITH PSEUDOMONAS, A LOT OF 7162 05:08:35,400 --> 05:08:37,720 FAMILIES IN OUR AREA HAVE BEEN 7163 05:08:37,720 --> 05:08:38,600 DEALING WITH PSEUDOMONAS, 7164 05:08:38,600 --> 05:08:40,240 CULTURING IT NOW, CAN'T GET RID 7165 05:08:40,240 --> 05:08:40,920 OF IT. 7166 05:08:40,920 --> 05:08:44,440 ONE PARENT TOLD ME MY SON HAS 7167 05:08:44,440 --> 05:08:46,400 BEEN ON MODULATOR VERY EARLY ON, 7168 05:08:46,400 --> 05:08:49,280 HE'S LIKE I THINK MAYBE WE 7169 05:08:49,280 --> 05:08:50,120 RELAXED TOO MUCH BECAUSE OF 7170 05:08:50,120 --> 05:08:51,080 BEING ON IT. 7171 05:08:51,080 --> 05:08:52,760 SO THERE'S A LOT OF RESEARCH 7172 05:08:52,760 --> 05:08:55,080 HAPPENING THAT NEEDS TO HAPPEN 7173 05:08:55,080 --> 05:08:57,240 FOR THOSE THAT QUALIFY, BUT THAT 7174 05:08:57,240 --> 05:08:58,760 RESEARCH CON THIS YEAR LIKE I'M 7175 05:08:58,760 --> 05:09:00,520 SO USED TO TALKING ABOUT 7176 05:09:00,520 --> 05:09:01,760 MODULATORS IN DEVELOPMENT AND 7177 05:09:01,760 --> 05:09:04,560 THINGS THAT COULD GO FOR HER TO 7178 05:09:04,560 --> 05:09:07,000 IT WAS LIKE IT FELT LIKE A SHIFT 7179 05:09:07,000 --> 05:09:08,200 TO EVERYBODY'S JUST CONCERNED 7180 05:09:08,200 --> 05:09:09,800 ABOUT WHAT IS LIFE LIKE AFTER 7181 05:09:09,800 --> 05:09:10,920 THE MODULATORS. 7182 05:09:10,920 --> 05:09:13,800 THAT WAS KIND OF THE, OH, CRAP, 7183 05:09:13,800 --> 05:09:15,840 ARE WE BEING LEFT BEHIND MOMENT, 7184 05:09:15,840 --> 05:09:17,200 A SINKING FEELING. 7185 05:09:17,200 --> 05:09:19,280 I KNOW I'VE READ IT ENOUGH 7186 05:09:19,280 --> 05:09:22,640 PLACES NOW THAT WE WON'T BE LEFT 7187 05:09:22,640 --> 05:09:24,280 FIND, THE CF FOUNDATION AS 7188 05:09:24,280 --> 05:09:25,840 REPEATEDLY SAID IT, EVERY PARENT 7189 05:09:25,840 --> 05:09:27,760 EVEN THOUGH THEIR CHILD HAS A 7190 05:09:27,760 --> 05:09:29,200 MODULATOR NOBODY IS GOING TO 7191 05:09:29,200 --> 05:09:29,680 STOP. 7192 05:09:29,680 --> 05:09:31,720 SO THAT'S ALL VERY ENCOURAGING, 7193 05:09:31,720 --> 05:09:33,760 AND I JUST -- WE WANT TO TALK TO 7194 05:09:33,760 --> 05:09:35,560 THE RESEARCHERS AND ANYBODY WE 7195 05:09:35,560 --> 05:09:37,960 CAN ENCOURAGE TO KEEP THAT FOCUS 7196 05:09:37,960 --> 05:09:40,280 ON THAT LAST, IT'S STILL LIKE 7197 05:09:40,280 --> 05:09:42,400 10% THAT ARE LOOKING FOR THAT 7198 05:09:42,400 --> 05:09:43,920 THING TO HELP THEM UNTIL A CURE 7199 05:09:43,920 --> 05:09:45,320 CAN BE FOUND LATER ON. 7200 05:09:45,320 --> 05:09:47,520 LET'S NOT GIVE UP ON THEM. 7201 05:09:47,520 --> 05:09:49,240 THERE'S THINGS OUT THERE THAT 7202 05:09:49,240 --> 05:09:51,880 CAN WORK AND WE KNOW THERE ARE 7203 05:09:51,880 --> 05:09:53,440 SO LET'S KEEP THE FOCUS UNTIL 7204 05:09:53,440 --> 05:09:56,160 THERE'S AT LEAST SOMETHING FOR 7205 05:09:56,160 --> 05:09:56,560 EVERYBODY. 7206 05:09:56,560 --> 05:09:57,800 THAT'S MY BIG PLEA. 7207 05:09:57,800 --> 05:10:00,320 I GUESS WHY I'M HERE ATTENDING, 7208 05:10:00,320 --> 05:10:04,320 BUT I'M HAPPY TO TAKE QUESTIONS 7209 05:10:04,320 --> 05:10:05,440 ANYTIME, JP. 7210 05:10:05,440 --> 05:10:07,560 >> THANK YOU BOTH SO MUCH FOR 7211 05:10:07,560 --> 05:10:09,160 GIVING US THAT REALLY VALUABLE 7212 05:10:09,160 --> 05:10:12,040 PERSPECTIVE AND I HOPE THE 7213 05:10:12,040 --> 05:10:14,640 MESSAGE, YOU'VE BEEN ABLE TO 7214 05:10:14,640 --> 05:10:16,520 LISTEN TO SESSIONS TODAY, THE 7215 05:10:16,520 --> 05:10:18,680 RESEARCH COMMUNITY AND THE CARE 7216 05:10:18,680 --> 05:10:21,800 COMMUNITY IS COMMITTED TO ALL 7217 05:10:21,800 --> 05:10:24,480 PEOPLE WITH CF AND EXTENDS WELL 7218 05:10:24,480 --> 05:10:26,120 BEYOND THE BORDERS OF CF 7219 05:10:26,120 --> 05:10:30,280 FOUNDATION BUT THE ENTIRE 7220 05:10:30,280 --> 05:10:30,560 COMMUNITY. 7221 05:10:30,560 --> 05:10:31,920 I GUESS WE HAVE TWO MINUTES 7222 05:10:31,920 --> 05:10:33,720 BEFORE WE BREAK INTO BREAKOUTS. 7223 05:10:33,720 --> 05:10:38,600 I WOULD ASK IS THERE ANY -- I 7224 05:10:38,600 --> 05:10:40,800 THINK KADE, YOU MENTIONED THAT. 7225 05:10:40,800 --> 05:10:44,760 LISA, ANYTHING YOU'D LIKE TO 7226 05:10:44,760 --> 05:10:46,200 SHARE OR TELL RESEARCHERS FROM 7227 05:10:46,200 --> 05:10:49,000 YOUR HEART ABOUT WHAT WOULD BE 7228 05:10:49,000 --> 05:10:50,320 MEANINGFUL TO YOU? 7229 05:10:50,320 --> 05:10:52,080 THAT'S MAYBE ONE PIECE I WOULD 7230 05:10:52,080 --> 05:10:53,640 LOVE TO HEAR. 7231 05:10:53,640 --> 05:10:55,360 >> WELL, THE FACT THAT, YOU 7232 05:10:55,360 --> 05:10:59,440 KNOW, MY SON IS 30, AND, YOU 7233 05:10:59,440 --> 05:11:01,600 KNOW, IF THE TIME ISN'T RUNNING 7234 05:11:01,600 --> 05:11:03,600 OUT, BUT IT FEELS LIKE TIME IS 7235 05:11:03,600 --> 05:11:08,400 RUNNING OUT, THE OLDER HE GETS. 7236 05:11:08,400 --> 05:11:11,040 AND I WOULD SAY, YOU KNOW, I 7237 05:11:11,040 --> 05:11:12,120 HAVE THE STRONG BELIEF, HAVE 7238 05:11:12,120 --> 05:11:13,200 BEEN INVOLVED LONG ENOUGH WITH 7239 05:11:13,200 --> 05:11:14,960 THE FOUNDATION TO KNOW WE WILL 7240 05:11:14,960 --> 05:11:17,360 NOT BE LEFT BEHIND, AND IT'S A 7241 05:11:17,360 --> 05:11:19,640 SPEECH, YOU KNOW, WHEN I ATTEND 7242 05:11:19,640 --> 05:11:21,600 ANYTHING LIKE VLC OR ANYTHING 7243 05:11:21,600 --> 05:11:23,600 ELSE THAT, YOU KNOW, WE KEEP 7244 05:11:23,600 --> 05:11:25,920 GIVING, THAT WE'RE STILL HERE, 7245 05:11:25,920 --> 05:11:28,000 WE'RE THE 10%. 7246 05:11:28,000 --> 05:11:31,400 SO, I FEEL STRONGLY THAT PEOPLE 7247 05:11:31,400 --> 05:11:32,240 ARE COMMITTED. 7248 05:11:32,240 --> 05:11:34,680 IT'S JUST THE TIME FRAME OF 7249 05:11:34,680 --> 05:11:36,680 GETTING TO THAT POINT, YOU KNOW, 7250 05:11:36,680 --> 05:11:38,360 THAT I GUESS WORRIES ME THE 7251 05:11:38,360 --> 05:11:41,280 MOST, YOU KNOW, HOW MUCH LONGER 7252 05:11:41,280 --> 05:11:47,160 CAN MY SON HANG ON TO HIS 93% 7253 05:11:47,160 --> 05:11:49,160 LUNG FUNCTION AND, YOU KNOW, 7254 05:11:49,160 --> 05:11:51,200 WHILE IT'S HIGH FOR SOMEONE HIS 7255 05:11:51,200 --> 05:11:55,400 AGE IT'S GETTING HARDER AND 7256 05:11:55,400 --> 05:11:55,840 HARDER. 7257 05:11:55,840 --> 05:11:58,000 AND, YOU KNOW, WE JUST ALL WANT 7258 05:11:58,000 --> 05:12:00,160 OUR SOMETHING, WHETHER IT'S A 7259 05:12:00,160 --> 05:12:04,600 MODULATOR, CURE, WHATEVER IT IS. 7260 05:12:04,600 --> 05:12:08,440 AND, YOU KNOW, WE'RE A LITTLE 7261 05:12:08,440 --> 05:12:10,160 BIT HOPEFUL ABOUT THE ELOCK 7262 05:12:10,160 --> 05:12:12,480 STUDY AND OTHER STUDIES GOING ON 7263 05:12:12,480 --> 05:12:16,320 FOR SOMETHING SPECIFIC FOR HIS 7264 05:12:16,320 --> 05:12:17,600 MUTATION BUT, YOU KNOW, WE'RE 7265 05:12:17,600 --> 05:12:21,960 TRYING TO HANG IN THERE, BUT 7266 05:12:21,960 --> 05:12:23,640 HOPEFULLY EVERYONE HERE IS ON 7267 05:12:23,640 --> 05:12:27,600 BOARD AND WILL TRY TO HELP US 7268 05:12:27,600 --> 05:12:29,000 ACCELERATE, YOU KNOW, CLOSER TO 7269 05:12:29,000 --> 05:12:33,840 THE MODULATORS OF THE CURES WE 7270 05:12:33,840 --> 05:12:34,040 NEED. 7271 05:12:34,040 --> 05:12:37,080 >> THOSE ARE GREAT WORDS OF 7272 05:12:37,080 --> 05:12:37,320 WISDOM. 7273 05:12:37,320 --> 05:12:40,480 AND ALSO MARCHING ORDERS FOR US 7274 05:12:40,480 --> 05:12:41,480 TO KEEP GOING. 7275 05:12:41,480 --> 05:12:44,720 THANK YOU BOTH. 7276 05:12:44,720 --> 05:12:45,840 LISA, KADE, REALLY APPRECIATE 7277 05:12:45,840 --> 05:12:47,520 YOU SHARING PERSPECTIVES. 7278 05:12:47,520 --> 05:12:48,800 WE'LL HAVE BREAKOUTS COMING NOW. 7279 05:12:48,800 --> 05:12:51,920 MARA WILL COME BACK AND GIVE US 7280 05:12:51,920 --> 05:12:56,560 A BIT MORE DIRECTION. 7281 05:12:56,560 --> 05:13:00,280 I THINK YOU HAVE SORT OF THE 7282 05:13:00,280 --> 05:13:01,200 LINKS. 7283 05:13:01,200 --> 05:13:05,200 THANK YOU. 7284 05:13:05,200 --> 05:13:06,640 WELCOME BACK TO THE MAIN 7285 05:13:06,640 --> 05:13:07,520 WORKSHOP ROOM. 7286 05:13:07,520 --> 05:13:10,360 THANK YOU ALL FOR PARTICIPATING 7287 05:13:10,360 --> 05:13:11,880 IN OUR BREAKOUTS THIS AFTERNOON. 7288 05:13:11,880 --> 05:13:13,760 I WANT TO GIVE YOU LOGISTICS 7289 05:13:13,760 --> 05:13:14,840 ABOUT WHAT WE'RE DOING OVER THE 7290 05:13:14,840 --> 05:13:17,600 NEXT HOUR BEFORE WE CLOSE OUT 7291 05:13:17,600 --> 05:13:18,560 THE WORKSHOP. 7292 05:13:18,560 --> 05:13:19,160 >> RECORDING IN PROGRESS. 7293 05:13:19,160 --> 05:13:22,480 >> WE'RE HERE TO REGROUP AND 7294 05:13:22,480 --> 05:13:25,040 RECAP FROM THE BREAKOUT ROOMS. 7295 05:13:25,040 --> 05:13:26,440 WE'LL DISPLAY THE BOARDS FROM 7296 05:13:26,440 --> 05:13:30,960 EACH BREAKOUT ROOM AND WE WILL 7297 05:13:30,960 --> 05:13:32,280 HAVE THE SESSION MODERATORS 7298 05:13:32,280 --> 05:13:33,840 DISCUSS THE DISCUSSION THAT 7299 05:13:33,840 --> 05:13:34,760 HAPPENED WITHIN THAT ROOM. 7300 05:13:34,760 --> 05:13:37,080 AND SOME OF THE TOPICS THAT ROSE 7301 05:13:37,080 --> 05:13:38,400 TO HIGH PRIORITY FOR EACH OF 7302 05:13:38,400 --> 05:13:39,920 THOSE ROOMS. 7303 05:13:39,920 --> 05:13:42,480 SO WE'RE ASKING THAT EACH OF THE 7304 05:13:42,480 --> 05:13:44,120 BREAKOUT ROOMS REPORT OUT FOR 7305 05:13:44,120 --> 05:13:45,960 ABOUT TEN MINUTES EACH. 7306 05:13:45,960 --> 05:13:49,440 AND THEN AT THE END WE WILL BE 7307 05:13:49,440 --> 05:13:52,600 SHOWING A FOURTH BOARD, AND THAT 7308 05:13:52,600 --> 05:13:55,920 WILL HAVE THREE TO FIVE OF THE 7309 05:13:55,920 --> 05:13:56,800 TOP-VOTED TOPICS THAT CAME OUT 7310 05:13:56,800 --> 05:13:59,040 FROM EACH OF THE BREAKOUT ROOMS. 7311 05:13:59,040 --> 05:14:00,840 SO, THAT WILL GIVE US AN 7312 05:14:00,840 --> 05:14:04,920 OPPORTUNITY TO SPEND THE LAST 30 7313 05:14:04,920 --> 05:14:06,120 MINUTES OF THE MEETING IN A 7314 05:14:06,120 --> 05:14:08,080 GENERAL DISCUSSION THAT WILL BE 7315 05:14:08,080 --> 05:14:09,920 LED BY WORKSHOP CO-CHAIRS ABOUT 7316 05:14:09,920 --> 05:14:11,040 SOME TOPIC THAT ROSE TO THE TOP 7317 05:14:11,040 --> 05:14:12,880 FROM EACH OF THE ROOMS. 7318 05:14:12,880 --> 05:14:16,280 NOW, I WANT TO LET YOU KNOW THAT 7319 05:14:16,280 --> 05:14:18,360 WE'RE KEEPING ALL IDEAS, SO 7320 05:14:18,360 --> 05:14:19,360 THANK YOU FOR YOUR 7321 05:14:19,360 --> 05:14:19,800 PARTICIPATION. 7322 05:14:19,800 --> 05:14:21,120 I THOUGHT THERE WAS A LOT OF 7323 05:14:21,120 --> 05:14:21,960 GREAT IDEAS ON THESE BOARDS, 7324 05:14:21,960 --> 05:14:23,600 FROM EACH OF THE ROOMS, BUT WE 7325 05:14:23,600 --> 05:14:26,560 DO WANT TO HAVE A MORE 7326 05:14:26,560 --> 05:14:27,360 NARROW-FOCUSED DISCUSSION ON 7327 05:14:27,360 --> 05:14:28,320 SOME THINGS THAT GOT MORE VOTES 7328 05:14:28,320 --> 05:14:29,440 FROM EACH OF THE ROOMS. 7329 05:14:29,440 --> 05:14:31,360 WE'LL DO THAT IN THE LAST HALF. 7330 05:14:31,360 --> 05:14:33,240 SO THAT'S GOING TO BE THE 7331 05:14:33,240 --> 05:14:34,640 STRUCTURE FOR THE DISCUSSION FOR 7332 05:14:34,640 --> 05:14:37,480 THE NEXT HOUR. 7333 05:14:37,480 --> 05:14:40,240 AND WITH THAT, LET'S PULL UP THE 7334 05:14:40,240 --> 05:14:41,280 BOARD FROM BREAKOUT 1. 7335 05:14:41,280 --> 05:14:43,480 I WILL TURN IT OVER TO THE 7336 05:14:43,480 --> 05:14:47,440 MODERATORS FOR THAT ROOM. 7337 05:14:47,440 --> 05:14:53,480 7338 05:14:53,480 --> 05:15:01,120 7339 05:15:01,120 --> 05:15:04,080 7340 05:15:04,080 --> 05:15:04,960 >> IS AP HERE? 7341 05:15:04,960 --> 05:15:08,040 >> WE HAD A GREAT DISCUSSION. 7342 05:15:08,040 --> 05:15:13,960 I WAS CO-MODERATING WITH AMY 7343 05:15:13,960 --> 05:15:15,720 RYAN, AND AP NAREN, SUMMARIZING 7344 05:15:15,720 --> 05:15:18,120 THE MAIN FINDINGS AND WE'LL 7345 05:15:18,120 --> 05:15:19,920 CHIME IN. 7346 05:15:19,920 --> 05:15:22,160 >> THANK YOU VERY MUCH. 7347 05:15:22,160 --> 05:15:24,920 THIS WAS A WONDERFUL SESSION. 7348 05:15:24,920 --> 05:15:26,560 WE ENJOYED IT. 7349 05:15:26,560 --> 05:15:30,280 IT WAS PATIENT-DERIVED MODEL 7350 05:15:30,280 --> 05:15:30,520 SYSTEMS. 7351 05:15:30,520 --> 05:15:33,560 WE WENT OFF FOUR TOPICS, CURRENT 7352 05:15:33,560 --> 05:15:35,320 USES OF PATIENT DERIVED MODELS 7353 05:15:35,320 --> 05:15:37,480 AND SYSTEMS, AND MODEL SYSTEMS 7354 05:15:37,480 --> 05:15:39,800 AND ADVANTAGES AND LIMITATIONS, 7355 05:15:39,800 --> 05:15:41,240 RELEVANCE OF PERSONALIZED MODEL 7356 05:15:41,240 --> 05:15:42,960 TO THE CLINIC. 7357 05:15:42,960 --> 05:15:45,160 AND OTHER TOPICS. 7358 05:15:45,160 --> 05:15:46,480 THE DISCUSSION WAS VERY LIVELY. 7359 05:15:46,480 --> 05:15:49,200 WE HAD A LOT OF INPUT FROM 7360 05:15:49,200 --> 05:15:49,560 EVERYBODY. 7361 05:15:49,560 --> 05:15:52,120 SO, ONE OF THE HIGHEST VOTE 7362 05:15:52,120 --> 05:15:58,160 GETTERS WAS DO WE NEED A COMPLEX 7363 05:15:58,160 --> 05:15:58,720 MODEL INCORPORATING 7364 05:15:58,720 --> 05:16:03,080 BIOENGINEERING, TO WE NEED MORE 7365 05:16:03,080 --> 05:16:04,520 COMPLEX MODELS INCORPORATING 7366 05:16:04,520 --> 05:16:05,440 BIOENGINEERING INFLAMMATION THAT 7367 05:16:05,440 --> 05:16:06,400 BETTER REFLECTS IN VIVO 7368 05:16:06,400 --> 05:16:08,560 SITUATION, CAN THAT BE ADAPTED 7369 05:16:08,560 --> 05:16:09,600 TO HIGH-THROUGHPUT? 7370 05:16:09,600 --> 05:16:20,040 WHAT DID WE MEAN BY THAT? 7371 05:16:21,000 --> 05:16:23,000 CAN WE SEE WHAT WE SEE IN THE 7372 05:16:23,000 --> 05:16:24,440 AIRWAY IN MOUSE MODELS, RELATED 7373 05:16:24,440 --> 05:16:25,720 BACK TO DIFFERENT ANIMAL MODEL? 7374 05:16:25,720 --> 05:16:30,360 CAN WE HAVE A MORE COMPLEX MODEL 7375 05:16:30,360 --> 05:16:32,760 LIKE LUNG OR PANCREAS IN A CHIP, 7376 05:16:32,760 --> 05:16:36,400 IS THE THROUGHPUT FOR THESE 7377 05:16:36,400 --> 05:16:38,680 LIMITING USE, NEED COLLABORATION 7378 05:16:38,680 --> 05:16:40,680 BETWEEN INFLAMMATION AND 7379 05:16:40,680 --> 05:16:41,120 EPITHELIAL EXPERTS, 7380 05:16:41,120 --> 05:16:45,880 BIOENGINEERING COLLABORATIONS. 7381 05:16:45,880 --> 05:16:48,200 THIS IS A COMPLEX SET OF STUDIES 7382 05:16:48,200 --> 05:16:50,840 BUT I THINK A LOT OF INTEREST 7383 05:16:50,840 --> 05:16:52,880 WAS SHOWN IN THIS PARTICULAR 7384 05:16:52,880 --> 05:16:53,440 VISIT. 7385 05:16:53,440 --> 05:16:56,440 THE SECOND MOST HIGHLY VOTED WAS 7386 05:16:56,440 --> 05:17:01,040 THIS PARTICULAR TOPIC IN WHICH 7387 05:17:01,040 --> 05:17:03,360 ARE PERSONALIZED MODEL SYSTEMS 7388 05:17:03,360 --> 05:17:05,000 CRITICAL IN DEVELOPING 7389 05:17:05,000 --> 05:17:07,600 THERAPEUTIC OPTIONS FOR RARE 7390 05:17:07,600 --> 05:17:08,280 MUTATION, INFLAMMATION AND 7391 05:17:08,280 --> 05:17:09,680 INFECTION, AND SEE IF YOU'RE 7392 05:17:09,680 --> 05:17:10,240 UNDERSTANDING INFECTION. 7393 05:17:10,240 --> 05:17:13,640 ONE OF THE IDEAS, NOT ONLY TO 7394 05:17:13,640 --> 05:17:17,480 LOOK AT SPECIFIC PATIENT-DERIVED 7395 05:17:17,480 --> 05:17:18,240 MODEL SYSTEM, INCORPORATE iPSC 7396 05:17:18,240 --> 05:17:19,560 TECHNOLOGY AS WELL. 7397 05:17:19,560 --> 05:17:22,280 IN SOME CASES IT WOULD BE 7398 05:17:22,280 --> 05:17:24,720 IMPOSSIBLE TO GET PRIMARY CELLS 7399 05:17:24,720 --> 05:17:27,080 AND THE IDEA IS WHETHER THERE 7400 05:17:27,080 --> 05:17:29,200 ARE SOME LIMITATIONS TO THAT, 7401 05:17:29,200 --> 05:17:34,120 WHETHER IT WOULD MIMIC PRIMARY 7402 05:17:34,120 --> 05:17:35,720 CELLS WAS THE QUESTION. 7403 05:17:35,720 --> 05:17:39,160 RELEVANCE OF NASAL CELLS TO 7404 05:17:39,160 --> 05:17:39,840 PREDICT BRONCHIAL RESPONSES, 7405 05:17:39,840 --> 05:17:41,200 SOME QUESTIONS WERE ASKED. 7406 05:17:41,200 --> 05:17:46,720 AND THE THIRD MOST HIGHLY VOTED 7407 05:17:46,720 --> 05:17:48,120 TOPIC, SHOULD STANDARDIZED 7408 05:17:48,120 --> 05:17:50,640 METHOD BE DEVELOPED TO ALLOW 7409 05:17:50,640 --> 05:17:51,520 COMPARISON ACROSS LABORATORIES. 7410 05:17:51,520 --> 05:17:54,920 THERE WAS A LOT OF INTEREST IN 7411 05:17:54,920 --> 05:17:57,480 THIS BECAUSE THE IDEA IF WE WERE 7412 05:17:57,480 --> 05:17:59,280 GOING INTO TESTING IN PATIENT 7413 05:17:59,280 --> 05:18:03,280 DERIVED SYSTEMS, THAT WE NEEDED 7414 05:18:03,280 --> 05:18:05,240 TO HAVE STANDARDIZED ASSAYS 7415 05:18:05,240 --> 05:18:06,520 REPRODUCED BETWEEN LABS, AMONG 7416 05:18:06,520 --> 05:18:07,720 LABS, WITHIN LABS, SO THERE WAS 7417 05:18:07,720 --> 05:18:09,800 A LOT OF INTEREST IN THAT. 7418 05:18:09,800 --> 05:18:12,000 THERE WERE SEVERAL OTHER TOPICS 7419 05:18:12,000 --> 05:18:13,640 THAT GOT A LOT OF VOTES BUT I'M 7420 05:18:13,640 --> 05:18:15,600 NOT GOING TO HIGHLIGHT THAT. 7421 05:18:15,600 --> 05:18:18,800 THESE WERE THE THREE TOP 7422 05:18:18,800 --> 05:18:21,120 VOTE-GETTING TOPICS, I WILL 7423 05:18:21,120 --> 05:18:30,000 PAUSE AND SEE IF MARTINA OR AMY 7424 05:18:30,000 --> 05:18:36,440 WANTS TO CHIME IN. 7425 05:18:36,440 --> 05:18:38,600 7426 05:18:38,600 --> 05:18:49,160 >> AP SUMMARIZED WELL , GETTING 7427 05:18:54,120 --> 05:18:56,120 MORE COMPLEX MODELS, TRANSLATION 7428 05:18:56,120 --> 05:18:56,840 TO CLINIC, MISSING INFLAMMATION 7429 05:18:56,840 --> 05:19:07,320 WHICH WAS A LARGE PART OF THE 7430 05:19:13,360 --> 05:19:13,600 DISCUSSION. 7431 05:19:13,600 --> 05:19:18,120 >> AND FUNCTION WHICH BETTER 7432 05:19:18,120 --> 05:19:20,760 MODELS MIGHT MAKE FEASIBLE, AND 7433 05:19:20,760 --> 05:19:23,600 COMPLEXITY OF MODELS COULD 7434 05:19:23,600 --> 05:19:24,360 BETTER REFLECT TISSUE STRUCTURE, 7435 05:19:24,360 --> 05:19:27,840 THERE WAS THE IDEA OF 7436 05:19:27,840 --> 05:19:30,600 INCORPORATING NEUTROPHILS TO GET 7437 05:19:30,600 --> 05:19:34,720 MORE TO THE REALITY OF 7438 05:19:34,720 --> 05:19:35,800 INFLAMMATORY RESPONSES, AND 7439 05:19:35,800 --> 05:19:40,680 MAYBE NOT REFLECTED IN THE TOP 7440 05:19:40,680 --> 05:19:42,520 VOTES BUT RELATED TO IMPROVING 7441 05:19:42,520 --> 05:19:47,720 MODELS, TO GET A MORE 7442 05:19:47,720 --> 05:19:48,560 HIGH-THROUGHPUT PLATFORM FOR 7443 05:19:48,560 --> 05:19:50,640 TESTING. 7444 05:19:50,640 --> 05:19:55,760 7445 05:19:55,760 --> 05:19:59,080 WHAT WAS ALREADY MENTIONED, WAS 7446 05:19:59,080 --> 05:20:01,280 REPEATEDLY DISCUSSED, MODELS 7447 05:20:01,280 --> 05:20:04,440 SHOULD REALLY REFLECT IN VIVO 7448 05:20:04,440 --> 05:20:07,720 ENVIRONMENT OF CF EPITHELIA 7449 05:20:07,720 --> 05:20:11,720 WHICH IS OBVIOUSLY INFECTION 7450 05:20:11,720 --> 05:20:14,520 INFLAMMATION, SO COULD BE 7451 05:20:14,520 --> 05:20:16,160 ADVANCED BY CULTURE, BACTERIA, 7452 05:20:16,160 --> 05:20:20,200 LOOKING AT INFLAMED MODELS TO 7453 05:20:20,200 --> 05:20:24,240 STUDY ANTI-INFLAMMATORY AND ALSO 7454 05:20:24,240 --> 05:20:24,920 THERAPEUTICS. 7455 05:20:24,920 --> 05:20:27,000 THERE WAS DISCUSSION ABOUT 7456 05:20:27,000 --> 05:20:28,080 PARTICLE DELIVERY IN 7457 05:20:28,080 --> 05:20:29,160 RELATIONSHIP TO MACHINE THERAPY, 7458 05:20:29,160 --> 05:20:33,600 AND THIS COULD ALSO BE MUCH MORE 7459 05:20:33,600 --> 05:20:39,040 RELEVANT STUDIED IN MODELS THAT 7460 05:20:39,040 --> 05:20:43,600 REFLECT THE TISSUE BY HAVING 7461 05:20:43,600 --> 05:20:47,640 PHARMACOKINETICS MORE RELATED TO 7462 05:20:47,640 --> 05:20:54,520 THE EPITHELIA IN VIVO AND ALSO 7463 05:20:54,520 --> 05:20:57,040 RELEVANT SYSTEM. 7464 05:20:57,040 --> 05:20:59,240 7465 05:20:59,240 --> 05:21:02,400 >> ANOTHER TOPIC THAT WAS 7466 05:21:02,400 --> 05:21:04,280 DISCUSSED, PERSONALIZED MODELS 7467 05:21:04,280 --> 05:21:08,440 ASPECT, WAS HOW GOOD ARE NASAL 7468 05:21:08,440 --> 05:21:11,040 EPITHELIAL CELLS WHICH ARE MORE 7469 05:21:11,040 --> 05:21:11,840 SUCCESSFUL AT PREDICTING IN 7470 05:21:11,840 --> 05:21:13,680 OTHER AREAS OF THE AIRWAY AND 7471 05:21:13,680 --> 05:21:16,880 OTHER TISSUES, CAN THEY BE USED 7472 05:21:16,880 --> 05:21:20,080 AS FIRST STEP IN SCREENING IN A 7473 05:21:20,080 --> 05:21:21,040 PERSONALIZED MANNER. 7474 05:21:21,040 --> 05:21:22,680 THAT THAT CAME UP UNDER A FEW OF 7475 05:21:22,680 --> 05:21:24,600 THE COMMENTS THAT ARE THERE BUT 7476 05:21:24,600 --> 05:21:26,640 DOESN'T APPLY TO THE 7477 05:21:26,640 --> 05:21:27,640 PERSONALIZED MODELS. 7478 05:21:27,640 --> 05:21:29,280 >> IN REGARD TO IMPROVING MODELS 7479 05:21:29,280 --> 05:21:32,120 THERE WAS ALSO THE IDEA USING 7480 05:21:32,120 --> 05:21:35,080 DIFFERENT SECTIONS OF THE G.I. 7481 05:21:35,080 --> 05:21:36,720 TRACT BECAUSE THEY ARE DIFFERENT 7482 05:21:36,720 --> 05:21:39,200 WHICH GETS BACK TO MAYBE NASAL 7483 05:21:39,200 --> 05:21:49,720 AND BRONCHIAL ARE NOT REALLY 7484 05:21:53,080 --> 05:21:55,960 IDENTICAL, WITH NUCLEOTIDES. 7485 05:21:55,960 --> 05:22:00,040 >> ALSO UPPER AND LOWER AIRWAYS. 7486 05:22:00,040 --> 05:22:00,920 >> SMALL AND LARGE AIRWAYS, 7487 05:22:00,920 --> 05:22:03,320 YEAH. 7488 05:22:03,320 --> 05:22:07,000 7489 05:22:07,000 --> 05:22:08,880 WHAT DIDN'T GET THE MOST VOTES, 7490 05:22:08,880 --> 05:22:12,800 AP MIGHT HAVE MENTIONED QUICKLY, 7491 05:22:12,800 --> 05:22:16,000 COMPARISON OF ANIMAL MODELS TO 7492 05:22:16,000 --> 05:22:18,960 IN VITRO MODELS. 7493 05:22:18,960 --> 05:22:22,440 PARTICULARLY HUMAN PRIMARY 7494 05:22:22,440 --> 05:22:25,960 CULTURES TO FINDINGS IN ANIMAL 7495 05:22:25,960 --> 05:22:26,920 MODELS. 7496 05:22:26,920 --> 05:22:30,000 I THINK ALEXANDRA WANTED TO ASK 7497 05:22:30,000 --> 05:22:30,760 SOMETHING. 7498 05:22:30,760 --> 05:22:34,120 >> JUST A COMMENT, MARTINA, BUT 7499 05:22:34,120 --> 05:22:36,120 VERY ENDS OF OUR SESSION, ANIMAL 7500 05:22:36,120 --> 05:22:38,320 MODELS SESSION, SOMEONE POPPED A 7501 05:22:38,320 --> 05:22:41,520 COMMENT ABOUT DO WE NEED SOME IN 7502 05:22:41,520 --> 05:22:44,600 VITRO MODEL TO REPLICATE 7503 05:22:44,600 --> 05:22:45,760 SPECIFIC ASPECT OF THE -- WHAT 7504 05:22:45,760 --> 05:22:47,840 WE FIND IN ANIMAL MODELS, SO IT 7505 05:22:47,840 --> 05:22:49,720 LOOKS LIKE THE CONVERSATION IS 7506 05:22:49,720 --> 05:22:51,480 CONVERGING ON A CONTINUUM THAT 7507 05:22:51,480 --> 05:22:53,720 GOES FROM IN VIVO TO IN VITRO, 7508 05:22:53,720 --> 05:22:54,720 AND EVERYTHING IN BETWEEN. 7509 05:22:54,720 --> 05:22:56,080 I THINK ONE OF THE BIG THINGS 7510 05:22:56,080 --> 05:22:58,680 THAT CAME OUT OF OUR DISCUSSION 7511 05:22:58,680 --> 05:23:01,880 WAS IF WHAT YOU FIND IS 7512 05:23:01,880 --> 05:23:02,760 REPLICATED IN DIFFERENT MODELS, 7513 05:23:02,760 --> 05:23:06,800 YOU CAN TRUST IT A LITTLE BIT 7514 05:23:06,800 --> 05:23:07,480 MORE. 7515 05:23:07,480 --> 05:23:09,480 SO, I'M HAPPY TO HEAR THAT. 7516 05:23:09,480 --> 05:23:10,520 >> THAT'S A GOOD POINT. 7517 05:23:10,520 --> 05:23:12,960 >> THIS IS ALSO A GREAT SEGUE TO 7518 05:23:12,960 --> 05:23:17,360 MOVING INTO THE REPORT OUT FROM 7519 05:23:17,360 --> 05:23:24,640 THE SECOND SESSION. 7520 05:23:24,640 --> 05:23:25,400 >> SUPER. 7521 05:23:25,400 --> 05:23:27,800 >> THEY WILL CALL UP THE BOARD 7522 05:23:27,800 --> 05:23:30,720 FROM BREAKOUT 2. 7523 05:23:30,720 --> 05:23:32,560 >> I HAVE IT OPEN. 7524 05:23:32,560 --> 05:23:38,000 I CAN SHARE IT RIGHT NOW. 7525 05:23:38,000 --> 05:23:39,640 >> IF YOU HAVE SCREEN SHARING 7526 05:23:39,640 --> 05:23:40,920 CAPABILITIES, THAT'S FINE. 7527 05:23:40,920 --> 05:23:44,160 >> HERE WE GO. 7528 05:23:44,160 --> 05:23:48,040 SO, ANIMAL MODEL SESSION HAD A 7529 05:23:48,040 --> 05:23:49,240 GOOD DISCUSSION. 7530 05:23:49,240 --> 05:23:51,800 WE STARTED WITH THREE MAJOR 7531 05:23:51,800 --> 05:23:53,040 AREAS THAT WE DISCUSSED, I'M 7532 05:23:53,040 --> 05:23:58,680 GOING TO GO OVER THE TOP FIVE. 7533 05:23:58,680 --> 05:24:00,440 WHAT PRESSING CLINICALLY 7534 05:24:00,440 --> 05:24:03,480 RELEVANT QUESTIONS REGARDING 7535 05:24:03,480 --> 05:24:05,240 HIGHLY EFFECTIVE MODULATOR 7536 05:24:05,240 --> 05:24:09,720 THERAPIES REQUIRE 7537 05:24:09,720 --> 05:24:11,920 EXPERIMENTATION IN ANIMALS. 7538 05:24:11,920 --> 05:24:13,360 ONE OF THE HIGHEST SOURCE, 7539 05:24:13,360 --> 05:24:15,320 SECOND FROM THE TOP, WAS USING 7540 05:24:15,320 --> 05:24:18,400 THE ANIMAL MODELS TO GET A 7541 05:24:18,400 --> 05:24:20,720 PATHOLOGY OF NON-EPITHELIAL CELL 7542 05:24:20,720 --> 05:24:24,360 COMPARTMENTS, AND I INTERPRET 7543 05:24:24,360 --> 05:24:28,800 THIS THAT OFTEN PROBABLY THE NIH 7544 05:24:28,800 --> 05:24:31,800 STUDY SECTIONS, YOU KNOW, FAVOR 7545 05:24:31,800 --> 05:24:34,640 ORGAN -- YOU KNOW, THE STUDY OF 7546 05:24:34,640 --> 05:24:36,480 ORGANS THAT GET EPITHELIAL 7547 05:24:36,480 --> 05:24:39,000 DISEASE WHERE CFTR IS MOST 7548 05:24:39,000 --> 05:24:41,520 CHARACTERIZED, BUT I THINK IT'S 7549 05:24:41,520 --> 05:24:42,680 RELEVANT TO THE FACT THAT THERE 7550 05:24:42,680 --> 05:24:45,920 ARE GOING TO BE MANY NEW 7551 05:24:45,920 --> 05:24:48,000 PHENOTYPES EMERGING FROM HIGHLY 7552 05:24:48,000 --> 05:24:49,320 EFFECTIVE MODULATOR THERAPY IN 7553 05:24:49,320 --> 05:24:50,760 CF PATIENTS THAT WE DON'T 7554 05:24:50,760 --> 05:24:52,920 UNDERSTAND, AND IT'S POSSIBLE 7555 05:24:52,920 --> 05:24:57,760 THAT THIS TYPE OF -- THESE TYPES 7556 05:24:57,760 --> 05:25:00,000 OF EPITHELIAL POPULATIONS, 7557 05:25:00,000 --> 05:25:01,000 SMOOTH MUSCLE, BONE, VASCULAR, 7558 05:25:01,000 --> 05:25:04,520 COULD BE VERY IMPORTANT TO THOSE 7559 05:25:04,520 --> 05:25:05,720 NEW PHENOTYPES. 7560 05:25:05,720 --> 05:25:09,800 THERE'S ALSO COMMENTED OVER HERE 7561 05:25:09,800 --> 05:25:13,200 TOO UNDER -- ABOUT 7562 05:25:13,200 --> 05:25:13,920 CARDIOVASCULAR DISEASE, 7563 05:25:13,920 --> 05:25:16,240 INCREASED INCIDENCE IN CF 7564 05:25:16,240 --> 05:25:16,480 PATIENTS. 7565 05:25:16,480 --> 05:25:19,960 SECOND REALLY HAS TO DO WITH 7566 05:25:19,960 --> 05:25:22,480 CHRONIC DISEASE STATE, 7567 05:25:22,480 --> 05:25:23,080 DISCUSSION ABOUT REVERSIBILITY 7568 05:25:23,080 --> 05:25:30,800 EVER BRONCHIECTASIS. 7569 05:25:30,800 --> 05:25:33,000 HOW ANIMAL MODELS COULD BE USED 7570 05:25:33,000 --> 05:25:33,960 TO ADDRESS THAT. 7571 05:25:33,960 --> 05:25:36,040 THERE WAS ANOTHER SESSION THAT 7572 05:25:36,040 --> 05:25:39,680 WAS TALKING ABOUT CHRONIC 7573 05:25:39,680 --> 05:25:41,320 DISEASE STATES, THIS MIGHT BE A 7574 05:25:41,320 --> 05:25:46,800 TOPIC WE CAN TALK ABOUT HERE IN 7575 05:25:46,800 --> 05:25:49,080 THE COMMON DISCUSSION. 7576 05:25:49,080 --> 05:25:49,840 HIGHLY EFFECTIVE MODULATOR 7577 05:25:49,840 --> 05:25:52,280 THERAPIES IN PREGNANCY AND 7578 05:25:52,280 --> 05:25:54,000 POST-NATAL CARE, DISCUSSIONS 7579 05:25:54,000 --> 05:25:58,040 ABOUT THE TIMING OF, YOU KNOW, 7580 05:25:58,040 --> 05:26:02,880 WHEN IN UTERO EITHER CONGENITAL 7581 05:26:02,880 --> 05:26:13,440 ABNORMALITIES SUCH AS ABSENCE OF 7582 05:26:14,840 --> 05:26:19,640 VAS DEFERENS OR EPIDIDYMIS 7583 05:26:19,640 --> 05:26:20,680 PRE-MODULATOR THAT CONGENITAL 7584 05:26:20,680 --> 05:26:22,360 ABNORMALITIES ARE MORE ABUNDANT 7585 05:26:22,360 --> 05:26:25,640 IN THAT POPULATION THAN NORMAL 7586 05:26:25,640 --> 05:26:26,400 NON-CF INDIVIDUALS. 7587 05:26:26,400 --> 05:26:28,800 SECOND MAJOR AREA THAT I'LL TALK 7588 05:26:28,800 --> 05:26:31,640 ABOUT IS WHAT CF MODEL 7589 05:26:31,640 --> 05:26:33,760 PHENOTYPES CAN INFORM CLINICALLY 7590 05:26:33,760 --> 05:26:34,480 RELEVANT KNOWLEDGE GAPS. 7591 05:26:34,480 --> 05:26:36,920 I THINK THIS WOULD BENEFIT 7592 05:26:36,920 --> 05:26:41,480 SIGNIFICANTLY FROM HEARING 7593 05:26:41,480 --> 05:26:43,640 DURING THE DISCUSSION AT THE END 7594 05:26:43,640 --> 05:26:45,000 OF THESE PRESENTATIONS WITH ALL 7595 05:26:45,000 --> 05:26:47,520 THE CLINICIANS IN THE AUDIENCE. 7596 05:26:47,520 --> 05:26:50,800 THERE WAS DISCUSSION ABOUT CF 7597 05:26:50,800 --> 05:26:52,600 PATIENTS ARE NOW -- MALE CF 7598 05:26:52,600 --> 05:26:56,520 PATIENTS ARE GETTING MUCH MORE 7599 05:26:56,520 --> 05:26:58,680 INTERESTED IN UNDERSTANDING 7600 05:26:58,680 --> 05:27:01,200 THEIR FERTILITY PROSPECTS ON 7601 05:27:01,200 --> 05:27:05,920 CFTR MODULATORS, AND IT'S THE 7602 05:27:05,920 --> 05:27:08,440 CONSENSUS OF THE PIG AND FERRET 7603 05:27:08,440 --> 05:27:10,280 GROUPS MODULATORS WOULD HAVE TO 7604 05:27:10,280 --> 05:27:13,880 INITIATE IN UTERO IN ORDER TO 7605 05:27:13,880 --> 05:27:15,400 PREVENT INFERTILITY IN MALES AT 7606 05:27:15,400 --> 05:27:20,240 BIRTH BASED ON THE ANIMAL 7607 05:27:20,240 --> 05:27:21,000 MODELS. 7608 05:27:21,000 --> 05:27:25,160 SOMEWHAT SIMILAR WITH COULD THE 7609 05:27:25,160 --> 05:27:26,080 CHRONIC BRONCHIECTASIS COMMENT, 7610 05:27:26,080 --> 05:27:28,040 CHRONIC DISEASE STATES AND 7611 05:27:28,040 --> 05:27:29,680 BIOMARKERS THAT COULD PREDICT 7612 05:27:29,680 --> 05:27:32,400 NEW CONDITIONS ASSOCIATED IN CF 7613 05:27:32,400 --> 05:27:33,600 PATIENTS ON HIGHLY EFFECTIVE 7614 05:27:33,600 --> 05:27:34,720 MODULATOR THERAPY. 7615 05:27:34,720 --> 05:27:37,440 WE HEARD A LOT IN THE EARLIER 7616 05:27:37,440 --> 05:27:38,160 SESSIONS, YOU KNOW, ABOUT SOME 7617 05:27:38,160 --> 05:27:39,600 OF THESE. 7618 05:27:39,600 --> 05:27:41,480 WE'RE GOING TO HEAR MORE LATER, 7619 05:27:41,480 --> 05:27:43,600 BUT I THINK IT'S IMPORTANT BOTH 7620 05:27:43,600 --> 05:27:46,080 IN THE CONTEXT OF VERY EARLY 7621 05:27:46,080 --> 05:27:50,040 DISEASE PROGRESSION AND THE 7622 05:27:50,040 --> 05:27:52,760 PREDICTION OF WHAT CF 7623 05:27:52,760 --> 05:27:54,520 PATIENTS -- WHAT THEIR CLINICAL 7624 05:27:54,520 --> 05:27:56,600 SITUATION MIGHT BE, MANY YEARS 7625 05:27:56,600 --> 05:28:00,080 FROM THE TIME THAT THEY STARTED 7626 05:28:00,080 --> 05:28:01,080 HIGHLY EFFECTIVE MODULATOR 7627 05:28:01,080 --> 05:28:03,040 THERAPY, THE CF ANIMALS THAT 7628 05:28:03,040 --> 05:28:04,920 HAVE SHORTER LIFESPANS COULD 7629 05:28:04,920 --> 05:28:07,080 HELP IN THIS. 7630 05:28:07,080 --> 05:28:10,320 I MENTIONED THIS PREVIOUSLY AS 7631 05:28:10,320 --> 05:28:11,240 WELL, CARDIOVASCULAR DISEASE, 7632 05:28:11,240 --> 05:28:13,640 THIS IS A COMMENT BY JEN, 7633 05:28:13,640 --> 05:28:19,360 STARTING TO SEE A LOT MORE 7634 05:28:19,360 --> 05:28:20,400 MYOCARDIAL INFARCTIONS, AND WILL 7635 05:28:20,400 --> 05:28:24,440 CANCER RISE BOTH G.I., CERVICAL, 7636 05:28:24,440 --> 05:28:26,120 BUT ALSO PANCREATIC CANCER, 7637 05:28:26,120 --> 05:28:30,480 BECAUSE THE MODULATOR THERAPIES 7638 05:28:30,480 --> 05:28:36,080 ARE PARTIALLY EFFECTIVE BUT 7639 05:28:36,080 --> 05:28:38,080 ORGANS HAVE INCREASED 7640 05:28:38,080 --> 05:28:39,280 PROLIFERATION AND TURNOVER. 7641 05:28:39,280 --> 05:28:42,920 ALSO COMPARING THE FACT THAT 7642 05:28:42,920 --> 05:28:45,840 WE'RE, AS A FIELD LUCKY TO HAVE 7643 05:28:45,840 --> 05:28:47,240 SEVEN ANIMAL MODELS, AND 7644 05:28:47,240 --> 05:28:48,480 COMPARING THE SIMILARITIES AND 7645 05:28:48,480 --> 05:28:50,560 DIFFERENCES BETWEEN THOSE MODELS 7646 05:28:50,560 --> 05:28:53,640 CAN BE VERY INFORMATIVE, EVEN IF 7647 05:28:53,640 --> 05:28:55,040 THE ANIMAL MODEL DOESN'T GET 7648 05:28:55,040 --> 05:28:57,680 DISEASE IN THAT PARTICULAR ORGAN 7649 05:28:57,680 --> 05:29:00,240 IT'S PROBABLY INFORMING GENETIC 7650 05:29:00,240 --> 05:29:01,760 DIVERSITY IN HUMANS, AND THE 7651 05:29:01,760 --> 05:29:06,600 WIDE RANGE OF PHENOTYPES THAT WE 7652 05:29:06,600 --> 05:29:14,000 SEE IN CF PATIENTS AND THE LAST 7653 05:29:14,000 --> 05:29:15,680 TOP HITTER, AGAIN, RELEVANT 7654 05:29:15,680 --> 05:29:16,760 BIOMARKERS HERE, MENTIONED 7655 05:29:16,760 --> 05:29:20,360 EARLIER, BUT CAN NEW BIOMARKERS 7656 05:29:20,360 --> 05:29:22,680 BE DISCOVERED THAT ARE 7657 05:29:22,680 --> 05:29:24,760 PREDICTING THESE EARLY -- 7658 05:29:24,760 --> 05:29:26,400 PREDICTING THESE NEW DISEASE 7659 05:29:26,400 --> 05:29:27,600 STATES, I THINK IDEALLY THOSE 7660 05:29:27,600 --> 05:29:28,440 TYPE OF BIOMARKERS WOULD BE 7661 05:29:28,440 --> 05:29:31,000 SOMETHING THAT WOULD BE IN THE 7662 05:29:31,000 --> 05:29:35,800 BLOOD, AND I THINK IT COULD BE 7663 05:29:35,800 --> 05:29:38,760 EXTREMELY USEFUL WITH NEW 7664 05:29:38,760 --> 05:29:40,880 SEQUENCING, HIGH-THROUGHPUT 7665 05:29:40,880 --> 05:29:45,240 SEQUENCING TECHNOLOGY, IF THINGS 7666 05:29:45,240 --> 05:29:46,760 LIKE NON-CODING RNAs OR 7667 05:29:46,760 --> 05:29:47,760 microRNAs REACHED OUT OF 7668 05:29:47,760 --> 05:29:52,160 CELLS AS THEY TURN OVER COULD 7669 05:29:52,160 --> 05:29:53,680 INDEX PARTICULAR PATHWAYS THAT 7670 05:29:53,680 --> 05:29:54,880 ARE BEING ACTIVATED THAT PREDICT 7671 05:29:54,880 --> 05:29:57,600 THE COURSE OF THE DISEASE STATE. 7672 05:29:57,600 --> 05:30:00,800 I UNDERSTAND THIS IS KIND OF 7673 05:30:00,800 --> 05:30:02,360 HARD TO FUND THROUGH NIH BECAUSE 7674 05:30:02,360 --> 05:30:04,960 IT'S DISCOVERY, BUT I THINK IT'S 7675 05:30:04,960 --> 05:30:07,560 RELEVANT TO PUT THE IMPORTANCE 7676 05:30:07,560 --> 05:30:08,560 DOWN HERE. 7677 05:30:08,560 --> 05:30:10,480 WHY DON'T I TURN IT OVER OR ASK 7678 05:30:10,480 --> 05:30:17,120 BRUCE AND SUE, THE OTHER 7679 05:30:17,120 --> 05:30:18,200 CO-CHAIRS, ON THIS SESSION, DO 7680 05:30:18,200 --> 05:30:19,640 YOU HAVE ANY COMMENTS, BRUCE, 7681 05:30:19,640 --> 05:30:20,160 SUE? 7682 05:30:20,160 --> 05:30:22,720 >> YOU DID A GREAT JOB, JOHN, 7683 05:30:22,720 --> 05:30:26,920 COVERING THE HIGH POINTS OF OUR 7684 05:30:26,920 --> 05:30:27,520 DISCUSSION. 7685 05:30:27,520 --> 05:30:28,440 THANKS. 7686 05:30:28,440 --> 05:30:28,760 >> GREAT. 7687 05:30:28,760 --> 05:30:33,320 >> YEAH, I AGREE. 7688 05:30:33,320 --> 05:30:33,600 >> OKAY. 7689 05:30:33,600 --> 05:30:34,960 >> MAYBE BEFORE YOU HAVE LIKE 7690 05:30:34,960 --> 05:30:36,800 THREE MINUTES IN YOUR 7691 05:30:36,800 --> 05:30:39,120 REPORT-OUT, MAYBE BEFORE WE DO 7692 05:30:39,120 --> 05:30:41,560 THAT YOU COULD ADDRESS FELIX'S 7693 05:30:41,560 --> 05:30:43,520 QUESTION IN THE CHAT. 7694 05:30:43,520 --> 05:30:46,360 DO WE NEWS A ROBUST CF 7695 05:30:46,360 --> 05:30:47,320 BRONCHIECTASIS ANIMAL MODEL? 7696 05:30:47,320 --> 05:30:48,960 I THINK IT RELATES TO SOME OF 7697 05:30:48,960 --> 05:30:50,720 THE PRIORITIES THAT YOU RAISED 7698 05:30:50,720 --> 05:30:52,520 FOR YOUR ROOM. 7699 05:30:52,520 --> 05:30:53,200 >> YEAH, ROBUST BRONCHIECTASIS, 7700 05:30:53,200 --> 05:30:55,440 SORRY, I CAN'T SEE THE CHAT. 7701 05:30:55,440 --> 05:31:00,920 >> DO WE NEED A ROBUST CF 7702 05:31:00,920 --> 05:31:03,280 BRONCHIECTASIS OR GENERAL 7703 05:31:03,280 --> 05:31:05,760 BRONCHIECTASIS MODEL? 7704 05:31:05,760 --> 05:31:09,600 >> WELL, YOU KNOW, THE PIGS AND 7705 05:31:09,600 --> 05:31:10,760 FERRETS DEVELOP BRONCHIECTASIS. 7706 05:31:10,760 --> 05:31:11,840 THIS WAS DISCUSSED, IT'S 7707 05:31:11,840 --> 05:31:13,040 PROBABLY ON HERE SOMEWHERE IN 7708 05:31:13,040 --> 05:31:17,480 ONE OF THE LOWER LEVEL ONES. 7709 05:31:17,480 --> 05:31:18,800 IT'S HIGHLY COSTLY. 7710 05:31:18,800 --> 05:31:23,360 I MEAN, THE ANIMAL I SHOWED IN 7711 05:31:23,360 --> 05:31:26,440 MY PREVIOUS TALK THAT DEVELOPED 7712 05:31:26,440 --> 05:31:29,280 MUCOID PSEUDOMONAS WAS PRETTY 7713 05:31:29,280 --> 05:31:29,720 HEALTHY. 7714 05:31:29,720 --> 05:31:31,920 COEXISTING WITH EXTREMELY HIGH 7715 05:31:31,920 --> 05:31:33,640 TITERS OF BACTERIA IN THE LUNG, 7716 05:31:33,640 --> 05:31:35,160 THREE YEARS OLD, TAKEN OFF 7717 05:31:35,160 --> 05:31:36,040 MODULATORS EARLY IN LIFE, THREE 7718 05:31:36,040 --> 05:31:39,120 TO FOUR MONTHS OF AGE. 7719 05:31:39,120 --> 05:31:41,200 SO, THE MODELS ARE HERE. 7720 05:31:41,200 --> 05:31:43,280 I THINK IT'S A MATTER OF 7721 05:31:43,280 --> 05:31:44,680 FIGURING OUT HOW TO ACCELERATE 7722 05:31:44,680 --> 05:31:45,800 DISEASE PROCESS, WE'RE WORKING 7723 05:31:45,800 --> 05:31:49,240 WITH THAT IN THE FERRETS, BY 7724 05:31:49,240 --> 05:31:52,720 CO-HOUSING AND, YOU KNOW, THE 7725 05:31:52,720 --> 05:31:55,040 TRANSMISSION OF THESE BUGS THAT 7726 05:31:55,040 --> 05:31:57,760 COME IN A SERIES, AN ORDER THAT 7727 05:31:57,760 --> 05:32:00,280 DEVELOP THE STABLE COEXISTENCE 7728 05:32:00,280 --> 05:32:04,120 OF PSEUDOMONAS, AND THERE'S VERY 7729 05:32:04,120 --> 05:32:05,320 SIGNIFICANT INFLAMMATION IN LATE 7730 05:32:05,320 --> 05:32:05,960 STAGE DISEASE. 7731 05:32:05,960 --> 05:32:07,600 DAVID, I'M NOT SURE IF YOU WANT 7732 05:32:07,600 --> 05:32:08,560 TO COMMENT ABOUT SOMETHING, YOU 7733 05:32:08,560 --> 05:32:15,280 WERE IN THIS SESSION AS WELL. 7734 05:32:15,280 --> 05:32:17,760 7735 05:32:17,760 --> 05:32:21,440 OKAY. 7736 05:32:21,440 --> 05:32:22,440 >> ALL RIGHT. 7737 05:32:22,440 --> 05:32:25,360 WE'LL MOVE ON TO THE REPORT-OUT 7738 05:32:25,360 --> 05:32:26,680 FROM BREAKOUT 3, AND THEN AFTER 7739 05:32:26,680 --> 05:32:29,760 THIS WE'LL HAVE A GENERAL 7740 05:32:29,760 --> 05:32:30,520 DISCUSSION FROM EACH, COVERING 7741 05:32:30,520 --> 05:32:32,720 ALL OF THE TOPICS FROM EACH OF 7742 05:32:32,720 --> 05:32:36,080 THE ROOMS. 7743 05:32:36,080 --> 05:32:41,360 7744 05:32:41,360 --> 05:32:44,520 >> THANKS, I'LL BE TALKING ABOUT 7745 05:32:44,520 --> 05:32:47,120 OUR DISCUSSION IN BREAKOUT 3, 7746 05:32:47,120 --> 05:32:53,040 LUNG DISEASE ON HIGHLY EFFECTIVE 7747 05:32:53,040 --> 05:32:54,880 MODULATOR THERAPY, THE 7748 05:32:54,880 --> 05:32:59,480 DISCUSSION WITH GINA AND MANU. 7749 05:32:59,480 --> 05:33:01,560 WE BROKE THE DISCUSSION INTO 7750 05:33:01,560 --> 05:33:03,080 FOUR MAIN TOPICS, YOU CAN SEE 7751 05:33:03,080 --> 05:33:03,760 HERE. 7752 05:33:03,760 --> 05:33:05,600 WE TALKED ABOUT THEMES RELATED 7753 05:33:05,600 --> 05:33:07,720 TO EMERGING CHALLENGES WITH 7754 05:33:07,720 --> 05:33:09,760 KNOWN ORGANISMS, CHANGES IN 7755 05:33:09,760 --> 05:33:11,320 BACKGROUND AND MAINTENANCE 7756 05:33:11,320 --> 05:33:12,280 THERAPY, POST HIGHLY EFFECTIVE 7757 05:33:12,280 --> 05:33:12,920 MODULATOR TREATMENT. 7758 05:33:12,920 --> 05:33:14,600 WE TALKED ABOUT WHAT WE DO AND 7759 05:33:14,600 --> 05:33:16,120 DON'T KNOW ABOUT STARTING AND 7760 05:33:16,120 --> 05:33:18,000 STOPPING THERAPIES, AND WE 7761 05:33:18,000 --> 05:33:19,760 TALKED ABOUT IMPORTANT QUESTIONS 7762 05:33:19,760 --> 05:33:20,800 FOR UNDERSTANDING DAMAGED 7763 05:33:20,800 --> 05:33:22,520 EPITHELIAL CELLS FROM PATIENTS 7764 05:33:22,520 --> 05:33:23,600 WITH LONGSTANDING AIRWAY 7765 05:33:23,600 --> 05:33:23,920 DISEASE. 7766 05:33:23,920 --> 05:33:25,560 THERE WERE A NUMBER OF COMMON 7767 05:33:25,560 --> 05:33:28,400 THEMES THAT CAME UP ACROSS THESE 7768 05:33:28,400 --> 05:33:30,240 DIFFERENT TOPICS, AND SO WE 7769 05:33:30,240 --> 05:33:31,240 SUMMARIZED THE OVERALL 7770 05:33:31,240 --> 05:33:33,280 DISCUSSION TO A COUPLE DIFFERENT 7771 05:33:33,280 --> 05:33:33,640 THEMES. 7772 05:33:33,640 --> 05:33:35,680 THE FIRST GENERAL THEME WAS HOW 7773 05:33:35,680 --> 05:33:38,240 DO WE RETHINK OUR GENERAL 7774 05:33:38,240 --> 05:33:40,720 APPROACH TO MONITORING CF 7775 05:33:40,720 --> 05:33:41,280 DISEASE, AND MONITORING 7776 05:33:41,280 --> 05:33:43,360 INFECTION WAS A BIG PART OF THAT 7777 05:33:43,360 --> 05:33:44,000 DISCUSSION. 7778 05:33:44,000 --> 05:33:46,120 SO WE TALKED ABOUT THE DECREASE 7779 05:33:46,120 --> 05:33:47,760 IN SPUTUM PRODUCTION IN PEOPLE 7780 05:33:47,760 --> 05:33:49,840 WITH CF ON HIGHLY EFFECTIVE 7781 05:33:49,840 --> 05:33:51,920 MODULATORS, AND HOW DO WE GET 7782 05:33:51,920 --> 05:33:55,200 AROUND THAT, HOW DO WE DETECT CF 7783 05:33:55,200 --> 05:33:57,400 PATHOGENS AND OTHER POTENTIAL 7784 05:33:57,400 --> 05:33:59,240 INFECTIONS THAT MAY BE DISEASE 7785 05:33:59,240 --> 05:34:06,800 CAUSING, DO WE NEED TO DO MORE 7786 05:34:06,800 --> 05:34:08,640 BRONCHIOSCOPES, SWABS AND HOW WE 7787 05:34:08,640 --> 05:34:14,440 LIKELY NEED MORE DATA ON HOW TO 7788 05:34:14,440 --> 05:34:16,320 USE OP SWABS, HOME SPUTUM 7789 05:34:16,320 --> 05:34:17,120 COLLECTION, SPUTUM COLLECTION IN 7790 05:34:17,120 --> 05:34:19,160 GENERAL IN TERMS OF TIMING, HOW 7791 05:34:19,160 --> 05:34:21,160 OFTEN, WHAT TESTS IN SPUTUM, DO 7792 05:34:21,160 --> 05:34:22,680 WE NEED NEW MARKERS OF 7793 05:34:22,680 --> 05:34:24,760 INFECTION, NEW WAYS OF DEFECTING 7794 05:34:24,760 --> 05:34:26,080 INFECTION IN PEOPLE WITH CF. 7795 05:34:26,080 --> 05:34:28,680 WE TALKED ABOUT UNDER THE THEME 7796 05:34:28,680 --> 05:34:31,240 OF HOW TO MONITOR CF DISEASE DO 7797 05:34:31,240 --> 05:34:35,600 WE NEED NOVEL WAYS OF MONITORING 7798 05:34:35,600 --> 05:34:37,880 LUNG DISEASE THAT SPIROMETRY 7799 05:34:37,880 --> 05:34:41,720 WILL BE IMPORTANT WAYS TO 7800 05:34:41,720 --> 05:34:43,800 MONITOR BUT NOT AS SENSITIVE AS 7801 05:34:43,800 --> 05:34:44,560 OTHER THINGS. 7802 05:34:44,560 --> 05:34:47,080 DO WE NEED NEW IMAGING 7803 05:34:47,080 --> 05:34:49,120 APPROACHES SUCH AS MRI, MORE USE 7804 05:34:49,120 --> 05:34:53,400 OF LCI, DO WE NEED WAYS TO DO 7805 05:34:53,400 --> 05:34:54,840 MORE MONITORING OF INFLAMMATION 7806 05:34:54,840 --> 05:34:57,000 OF OVER TIME, POTENTIALLY 7807 05:34:57,000 --> 05:35:01,120 GENERALLY DISCUSSION AROUND 7808 05:35:01,120 --> 05:35:03,280 NOVEL WAYS AND MORE SENSITIVE 7809 05:35:03,280 --> 05:35:05,360 WAYS TO MONITOR CF LUNG DISEASE 7810 05:35:05,360 --> 05:35:07,000 GOING FORWARD. 7811 05:35:07,000 --> 05:35:09,400 SECOND BIG TOPIC, HOW DO WE 7812 05:35:09,400 --> 05:35:11,080 ASSESS CF THERAPIES, THIS 7813 05:35:11,080 --> 05:35:13,920 RELATED TO CHANGES IN 7814 05:35:13,920 --> 05:35:14,800 MAINTENANCE THERAPIES, AND ALSO 7815 05:35:14,800 --> 05:35:17,680 HOW WE SHOULD BE USING THERAPIES 7816 05:35:17,680 --> 05:35:18,920 IN PEOPLE WITH CF. 7817 05:35:18,920 --> 05:35:21,240 A LOT OF THIS CONVERSATION WAS 7818 05:35:21,240 --> 05:35:22,440 AROUND KIDS, AND WHEN KIDS ARE 7819 05:35:22,440 --> 05:35:25,960 GOING TO BE STARTING HIGHLY 7820 05:35:25,960 --> 05:35:26,960 EFFECTIVE MODULATORS EARLY IN 7821 05:35:26,960 --> 05:35:28,520 LIFE, HOW DO WE DETERMINE WHEN 7822 05:35:28,520 --> 05:35:36,000 TO START THE DAILY THERAPIES, 7823 05:35:36,000 --> 05:35:37,120 THIS INCLUDED MUCOLYTICS, 7824 05:35:37,120 --> 05:35:38,720 DECISIONS IN TERMS OF WHAT ARE 7825 05:35:38,720 --> 05:35:41,240 THEY GOING TO BENEFIT VERSUS 7826 05:35:41,240 --> 05:35:42,560 MORE BURDEN WITH MINIMAL BENEFIT 7827 05:35:42,560 --> 05:35:44,240 IN DAILY THERAPIES. 7828 05:35:44,240 --> 05:35:46,280 WE TALKED ABOUT FURTHER DOWN THE 7829 05:35:46,280 --> 05:35:48,680 LUNG DISEASE SPECTRUM, SIMILAR 7830 05:35:48,680 --> 05:35:53,720 QUESTIONS REGARDING USE OF DAILY 7831 05:35:53,720 --> 05:35:55,600 THERAPIES, MUCOLYTICS, AND HOW 7832 05:35:55,600 --> 05:35:59,120 DO WE DETERMINE WHEN TO 7833 05:35:59,120 --> 05:36:01,920 CONTINUE, WHEN TO USE AS NEEDED, 7834 05:36:01,920 --> 05:36:03,040 WILL DIFFERENCES HELP DETERMINE 7835 05:36:03,040 --> 05:36:04,000 RELATIVE BENEFIT SUCH AS 7836 05:36:04,000 --> 05:36:06,560 PATIENTS WITH DIFFERENT DEGREES 7837 05:36:06,560 --> 05:36:08,400 OF ESTABLISHED BRONCHIECTASIS 7838 05:36:08,400 --> 05:36:10,720 VERSUS DIFFERENT CHRONIC 7839 05:36:10,720 --> 05:36:11,920 INFECTIONS, WILL THEY 7840 05:36:11,920 --> 05:36:12,920 DIFFERENTIALLY BENEFIT. 7841 05:36:12,920 --> 05:36:13,760 AND MOVING BACK TO THE FIRST 7842 05:36:13,760 --> 05:36:16,720 POINT OF HOW DO WE MONITOR CF 7843 05:36:16,720 --> 05:36:18,680 LUNG DISEASE, WHAT WILL WE USE 7844 05:36:18,680 --> 05:36:20,000 TO DETERMINE WHICH OF THESE 7845 05:36:20,000 --> 05:36:21,960 THERAPIES WILL BE THE MOST 7846 05:36:21,960 --> 05:36:24,280 BENEFICIAL IN SHORT TERM WITH 7847 05:36:24,280 --> 05:36:25,240 ONGOING STUDIES BUT THEN OVER 7848 05:36:25,240 --> 05:36:28,440 THE LONGER TERM TOO TO MAKE SURE 7849 05:36:28,440 --> 05:36:29,840 WE'RE STILL KEEPING PEOPLE 7850 05:36:29,840 --> 05:36:30,960 HEALTHY BUT MINIMIZING BURDENS 7851 05:36:30,960 --> 05:36:33,160 OF CARE THAT MAYBE AREN'T AS 7852 05:36:33,160 --> 05:36:33,480 BENEFICIAL. 7853 05:36:33,480 --> 05:36:36,640 AND THEN THE THIRD BIG TOPIC 7854 05:36:36,640 --> 05:36:39,160 THAT WE WENT OVER WAS THE NEED 7855 05:36:39,160 --> 05:36:41,760 STILL FOR NEW APPROACHES TO 7856 05:36:41,760 --> 05:36:43,640 TREATING CF DISEASE, AND SO ONE 7857 05:36:43,640 --> 05:36:46,400 OF THE TOP POINTS WE DISCUSSED 7858 05:36:46,400 --> 05:36:51,760 WAS ONGOING NEED FOR NOVEL 7859 05:36:51,760 --> 05:36:54,280 ANTIMICROBIALS FOR MULTI-DRUG 7860 05:36:54,280 --> 05:36:54,880 RESISTANT INFECTIONS, 7861 05:36:54,880 --> 05:36:56,120 HIGHLIGHTED BY THE SPEAKER EARLY 7862 05:36:56,120 --> 05:36:57,080 BUT CONTINUED NEED FOR 7863 05:36:57,080 --> 05:36:59,320 DEVELOPMENT OF NEW APPROACHES TO 7864 05:36:59,320 --> 05:37:01,640 CF INFECTION TREATMENT, BUT ALSO 7865 05:37:01,640 --> 05:37:03,800 IN THE NEW THERAPEUTIC 7866 05:37:03,800 --> 05:37:05,560 APPROACHES TOPIC WE TALKED ABOUT 7867 05:37:05,560 --> 05:37:10,040 HOW CAN WE OPTIMIZE CURRENT 7868 05:37:10,040 --> 05:37:11,880 TREATMENT APPROACHES FOR 7869 05:37:11,880 --> 05:37:12,800 EXACERBATION, ANTIBIOTIC 7870 05:37:12,800 --> 05:37:14,800 TOXICITIES, NEED TO WORK TOWARDS 7871 05:37:14,800 --> 05:37:21,040 REDUCING ANTIBIOTIC BURDEN AND 7872 05:37:21,040 --> 05:37:21,840 REDUCING ANTIBIOTIC TOXICITY 7873 05:37:21,840 --> 05:37:22,840 WITH EXACERBATION TREATMENT. 7874 05:37:22,840 --> 05:37:26,600 WE TALKED ABOUT ONGOING NEEDS TO 7875 05:37:26,600 --> 05:37:28,040 DEVELOP IMPROVED TREATMENT 7876 05:37:28,040 --> 05:37:30,320 APPROACHES FOR FUNGAL INFECTION, 7877 05:37:30,320 --> 05:37:31,640 DETERMINING OTHER INFECTIONS. 7878 05:37:31,640 --> 05:37:34,040 HOW DO WE TREAT, WHEN DO WE 7879 05:37:34,040 --> 05:37:40,080 TREAT, HOW DO WE HELP OPTIMIZE 7880 05:37:40,080 --> 05:37:40,360 OUTCOMES. 7881 05:37:40,360 --> 05:37:42,720 THOSE WERE THE HIGH POINTS THAT 7882 05:37:42,720 --> 05:37:44,440 WE HAD HERE. 7883 05:37:44,440 --> 05:37:46,000 MANU OR GINA, ANYTHING ELSE TO 7884 05:37:46,000 --> 05:37:50,640 ADD TO THE DISCUSSION ON THIS? 7885 05:37:50,640 --> 05:37:52,320 >> NO, THAT WAS GREAT. 7886 05:37:52,320 --> 05:37:56,680 ONE THING I WOULD ADD IS THAT 7887 05:37:56,680 --> 05:37:59,520 FOR NOVEL MICROBIALS, THE TOPIC 7888 05:37:59,520 --> 05:38:01,640 OF FINDING NEWER BETTER 7889 05:38:01,640 --> 05:38:02,680 TOLERATED NTM THERAPIES WAS ALSO 7890 05:38:02,680 --> 05:38:06,960 BROUGHT UP BY A COUPLE PEOPLE. 7891 05:38:06,960 --> 05:38:09,160 7892 05:38:09,160 --> 05:38:13,640 >> YEAH, THE ONLY THING TO ADD, 7893 05:38:13,640 --> 05:38:16,600 JUST TO PIGGYBACK WHAT LINDSAY 7894 05:38:16,600 --> 05:38:17,160 MENTIONED, WE TALKED ABOUT 7895 05:38:17,160 --> 05:38:21,200 WHETHER OR NOT THIS WAS 7896 05:38:21,200 --> 05:38:24,360 MENTIONED EARLY ON, BY J.P., 7897 05:38:24,360 --> 05:38:26,880 ABOUT RETHINKING BECAUSE A LOT 7898 05:38:26,880 --> 05:38:28,560 OF SYMPTOMATIC THERAPIES WERE -- 7899 05:38:28,560 --> 05:38:32,680 LIKE EFFICACY WAS TESTED IN THE 7900 05:38:32,680 --> 05:38:33,480 SETTING OF LIKE PRE-MODULATORS, 7901 05:38:33,480 --> 05:38:37,960 SO WHETHER OR NOT WE REALLY EVEN 7902 05:38:37,960 --> 05:38:39,320 SHOULD BE CONSIDERING CLINICAL 7903 05:38:39,320 --> 05:38:40,920 TRIALS IN PEOPLE WITH CF WITH 7904 05:38:40,920 --> 05:38:43,400 MODULATORS FOR SOME OF THESE 7905 05:38:43,400 --> 05:38:48,080 EXISTING APPROVED THERAPIES. 7906 05:38:48,080 --> 05:38:49,360 EVERYTHING ELSE WAS SUMMARIZED 7907 05:38:49,360 --> 05:38:52,120 NICELY BY LINDSAY. 7908 05:38:52,120 --> 05:38:56,040 7909 05:38:56,040 --> 05:38:57,920 7910 05:38:57,920 --> 05:38:59,880 >> WE'LL MOVE INTO THE GENERAL 7911 05:38:59,880 --> 05:39:00,640 DISCUSSION. 7912 05:39:00,640 --> 05:39:04,400 SO WE'LL OPEN UP THE BOARD THAT 7913 05:39:04,400 --> 05:39:06,200 HAS THE TOP-VOTED TOPICS FROM 7914 05:39:06,200 --> 05:39:07,680 EACH OF THE ROOMS. 7915 05:39:07,680 --> 05:39:10,200 AND SO I WOULD INVITE OUR 7916 05:39:10,200 --> 05:39:11,960 WORKSHOP CO-CHAIRS TO HELP 7917 05:39:11,960 --> 05:39:15,120 MODERATE THE DISCUSSION HERE AND 7918 05:39:15,120 --> 05:39:17,840 DISCUSS SOME TOPICS THAT 7919 05:39:17,840 --> 05:39:22,240 HARMONIZED ACROSS SOME OF THE 7920 05:39:22,240 --> 05:39:24,120 BREAKOUTS OR MAY BE DIFFERENT, 7921 05:39:24,120 --> 05:39:26,800 AND ALSO YOU CAN SEE IN THE 7922 05:39:26,800 --> 05:39:29,040 PARENTHESES HERE HOW MANY VOTES 7923 05:39:29,040 --> 05:39:30,480 EACH OF THE TOPICS GOT. 7924 05:39:30,480 --> 05:39:32,800 WE WILL ALSO BE MONITORING THE 7925 05:39:32,800 --> 05:39:34,640 CHAT AS WELL, IF OTHERS WANT TO 7926 05:39:34,640 --> 05:39:36,280 ASK QUESTIONS OR GIVE FEEDBACK 7927 05:39:36,280 --> 05:39:38,680 AS WELL. 7928 05:39:38,680 --> 05:39:45,000 7929 05:39:45,000 --> 05:39:48,840 7930 05:39:48,840 --> 05:39:49,960 >> I'LL START AND OPEN A 7931 05:39:49,960 --> 05:39:52,920 QUESTION TO THE ENTIRE AUDIENCE 7932 05:39:52,920 --> 05:39:53,760 HERE. 7933 05:39:53,760 --> 05:39:56,960 FROM THE CONTEXT OF THE ANIMAL 7934 05:39:56,960 --> 05:40:00,800 MODELS SECTION, WHAT ARE THE 7935 05:40:00,800 --> 05:40:03,800 KNOWLEDGE GAPS OR PHENOTYPES OR 7936 05:40:03,800 --> 05:40:04,760 BIOMARKERS ASSOCIATED WITH 7937 05:40:04,760 --> 05:40:07,200 PARTICULAR DISEASE STATES THAT 7938 05:40:07,200 --> 05:40:09,360 WOULD BE MOST USEFUL CLINICALLY 7939 05:40:09,360 --> 05:40:14,760 TO CF PATIENTS? 7940 05:40:14,760 --> 05:40:17,800 AND THEIR CAREGIVERS? 7941 05:40:17,800 --> 05:40:23,600 7942 05:40:23,600 --> 05:40:26,520 MARRAH, I ASSUME ANYBODY IN THE 7943 05:40:26,520 --> 05:40:27,880 AUDIENCE CAN TALK, RIGHT? 7944 05:40:27,880 --> 05:40:28,320 >> NO. 7945 05:40:28,320 --> 05:40:31,920 SO, I THINK THAT IF YOU'RE IN 7946 05:40:31,920 --> 05:40:34,320 THE MAIN DISCUSSION, MAIN 7947 05:40:34,320 --> 05:40:36,520 PARTICIPANTS, YOU WOULD USE THE 7948 05:40:36,520 --> 05:40:36,720 CHAT. 7949 05:40:36,720 --> 05:40:42,400 BUT ANY OF OUR PANEL TESTS FROM 7950 05:40:42,400 --> 05:40:46,480 TODAY ARE WELCOME TO WEIGH IN. 7951 05:40:46,480 --> 05:40:53,080 >> I HATE TO INTERRUPT. 7952 05:40:53,080 --> 05:40:57,840 THE FUNCTION TO SPEAK. 7953 05:40:57,840 --> 05:40:59,280 >> THEY CAN CHAT. 7954 05:40:59,280 --> 05:41:02,320 >> WE'RE SEEING THE LEAST VOTED 7955 05:41:02,320 --> 05:41:03,880 CATEGORY. 7956 05:41:03,880 --> 05:41:06,360 >> WE CAN'T UP-SORT THESE. 7957 05:41:06,360 --> 05:41:09,560 >> CAN YOU ROLL THE SCREEN? 7958 05:41:09,560 --> 05:41:10,960 >> THIS IS IT. 7959 05:41:10,960 --> 05:41:12,600 WE PULLED OUT THE TOP CATEGORIES 7960 05:41:12,600 --> 05:41:14,240 FROM EACH OF THE ROOMS. 7961 05:41:14,240 --> 05:41:15,440 YOU'RE SEEING THE ENTIRETY OF 7962 05:41:15,440 --> 05:41:15,880 THEM. 7963 05:41:15,880 --> 05:41:18,080 WE CAN'T SORT BY VOTES BECAUSE 7964 05:41:18,080 --> 05:41:20,160 THE FOURTH BOARD DOESN'T HAVE 7965 05:41:20,160 --> 05:41:21,680 THE VOTES, IT JUST HAS THE VOTES 7966 05:41:21,680 --> 05:41:24,520 THAT CAME FROM THE MAIN ROOM, IN 7967 05:41:24,520 --> 05:41:24,840 PARENTHESES. 7968 05:41:24,840 --> 05:41:26,080 THESE WERE PULLED FROM EACH OF 7969 05:41:26,080 --> 05:41:28,360 THE BREAKOUT ROOMS. 7970 05:41:28,360 --> 05:41:30,680 SO WE HAVE SESSION 1 ON THE 7971 05:41:30,680 --> 05:41:32,320 LEFT, ANIMAL MODELS IS 2 IN THE 7972 05:41:32,320 --> 05:41:35,480 MIDDLE, THE THIRD IS LUNG 7973 05:41:35,480 --> 05:41:41,040 DISEASE IN THE THIRD COLUMN. 7974 05:41:41,040 --> 05:41:44,320 7975 05:41:44,320 --> 05:41:45,760 >> FELIX, DO YOU WANT TO SPEAK 7976 05:41:45,760 --> 05:41:46,240 UP? 7977 05:41:46,240 --> 05:41:49,160 ARE YOU ABLE TO UNMUTE? 7978 05:41:49,160 --> 05:41:50,760 >> YOU USUALLY AM ABLE TO SPEAK 7979 05:41:50,760 --> 05:41:52,360 UP BUT I DON'T THINK I CAN DO IT 7980 05:41:52,360 --> 05:41:52,600 RYE NOW. 7981 05:41:52,600 --> 05:41:53,680 >> YOU'RE ON. 7982 05:41:53,680 --> 05:41:57,800 WE CAN HEAR YOU. 7983 05:41:57,800 --> 05:41:58,560 >> THANK YOU. 7984 05:41:58,560 --> 05:42:00,000 JUST BECAUSE JOHN WAS ASKING 7985 05:42:00,000 --> 05:42:01,640 THIS QUESTION, WE HAVE THIS 7986 05:42:01,640 --> 05:42:04,960 DISCUSSION IN THE FIRST SESSION 7987 05:42:04,960 --> 05:42:06,760 ABOUT PRE-CLINICAL MODELS FOR 7988 05:42:06,760 --> 05:42:07,120 INFLAMMATION. 7989 05:42:07,120 --> 05:42:09,640 J.P. ALSO BROUGHT THIS UP 7990 05:42:09,640 --> 05:42:13,000 BECAUSE WE REALLY LACK RELIABLE 7991 05:42:13,000 --> 05:42:13,240 MODELS. 7992 05:42:13,240 --> 05:42:16,000 AND IF ONE OF THE -- HOPEFULLY 7993 05:42:16,000 --> 05:42:18,640 MORE AFFORDABLE ANIMAL MODELS 7994 05:42:18,640 --> 05:42:19,320 COULD REPRESENT THAT RELIABLY 7995 05:42:19,320 --> 05:42:22,440 THAT WOULD BE VERY HELPFUL FOR 7996 05:42:22,440 --> 05:42:24,760 THE PRE-CLINICAL DEVELOPMENT OF 7997 05:42:24,760 --> 05:42:27,280 ANTI-INFLAMMATORY THERAPIES. 7998 05:42:27,280 --> 05:42:35,600 7999 05:42:35,600 --> 05:42:36,360 >> I'LL ADD. 8000 05:42:36,360 --> 05:42:37,680 EXACERBATIONS ARE DIFFERENT WITH 8001 05:42:37,680 --> 05:42:38,880 PEOPLE ON MODULATORS NOW, BUT 8002 05:42:38,880 --> 05:42:40,240 THERE'S SEVERAL TIMES OF 8003 05:42:40,240 --> 05:42:43,720 INFLAMMATIONS WE THINK ABOUT. 8004 05:42:43,720 --> 05:42:48,800 THERE'S THE BASELINE SMOLDERING 8005 05:42:48,800 --> 05:42:50,800 INFLAMMATION, EXACERBATION ADDS 8006 05:42:50,800 --> 05:42:53,680 ANOTHER WRINKLE HARD TO MODEL IN 8007 05:42:53,680 --> 05:42:54,840 ANIMALS BUT THAT WOULD BE AMAZE 8008 05:42:54,840 --> 05:42:56,160 FIGURE WE COULD DO THAT. 8009 05:42:56,160 --> 05:43:00,440 AND THEN AS WE DISCUSSED IN 8010 05:43:00,440 --> 05:43:02,720 GROUP 3, UNDERSTANDING WHAT AN 8011 05:43:02,720 --> 05:43:03,920 EXACERBATION IS, PREDICTING IT 8012 05:43:03,920 --> 05:43:05,000 IN THIS ERA, YOU KNOW, THAT 8013 05:43:05,000 --> 05:43:06,320 WOULD BE A GOOD REASON TO HAVE 8014 05:43:06,320 --> 05:43:08,720 THAT KIND OF MODEL BUT I'M NOT 8015 05:43:08,720 --> 05:43:10,360 SURE HOW WE ACHIEVE THAT WAXING 8016 05:43:10,360 --> 05:43:13,360 AND WANING IN AN ANIMAL MODEL. 8017 05:43:13,360 --> 05:43:14,680 >> , YEAH THERE'S ANOTHER 8018 05:43:14,680 --> 05:43:16,160 COMMENT THAT ECHOES THAT IN THE 8019 05:43:16,160 --> 05:43:16,400 CHAT. 8020 05:43:16,400 --> 05:43:20,800 YOU KNOW, THINKING ABOUT HOW TO 8021 05:43:20,800 --> 05:43:23,840 USE ANIMAL MODELS TO ASSESS 8022 05:43:23,840 --> 05:43:24,920 DISEASE IN CLINICALLY RELEVANT 8023 05:43:24,920 --> 05:43:26,720 WAYS SO WE'RE GOING TO HAVE A 8024 05:43:26,720 --> 05:43:28,880 SESSION ON SOME OF THE ENDPOINTS 8025 05:43:28,880 --> 05:43:31,480 AND SOME OF THE THINGS LISTED IN 8026 05:43:31,480 --> 05:43:35,040 THERE, IN THE CHAT, LIKE 8027 05:43:35,040 --> 05:43:35,640 NON-CULTURE-BASED OP SWABS, 8028 05:43:35,640 --> 05:43:37,280 URINE, THINGS LIKE THAT. 8029 05:43:37,280 --> 05:43:40,120 HOW WE WOULD USE THE ANIMAL 8030 05:43:40,120 --> 05:43:41,480 MODELS TO VALIDATE SOME OF THOSE 8031 05:43:41,480 --> 05:43:43,080 AND THEN TRANSLATE THOSE INTO 8032 05:43:43,080 --> 05:43:45,240 THE CLINIC, I THINK THAT'S WHAT 8033 05:43:45,240 --> 05:43:48,000 THAT COMMENT IS REFLECTING. 8034 05:43:48,000 --> 05:43:52,200 8035 05:43:52,200 --> 05:43:55,680 >> SO, FELIX, WE DO HAVE CF 8036 05:43:55,680 --> 05:43:58,960 ANIMAL MODELS, MULTIPLE ONES 8037 05:43:58,960 --> 05:44:02,720 THAT INDEX INFLAMMATION, 8038 05:44:02,720 --> 05:44:03,360 BRONCHIECTASIS, CHRONIC 8039 05:44:03,360 --> 05:44:04,040 LONG-TERM PERMANENT 8040 05:44:04,040 --> 05:44:05,080 COLONIZATION. 8041 05:44:05,080 --> 05:44:06,600 YOU KNOW, THE FERRET, THE PIG 8042 05:44:06,600 --> 05:44:07,360 BOTH DO. 8043 05:44:07,360 --> 05:44:09,840 THEY HAVE CHALLENGES, THEY ARE 8044 05:44:09,840 --> 05:44:12,920 MORE EXPENSIVE. 8045 05:44:12,920 --> 05:44:16,680 SUE BURKETT HAS THE RAT MODEL 8046 05:44:16,680 --> 05:44:18,600 THAT GETS MUCUS OBSTRUCTION. 8047 05:44:18,600 --> 05:44:20,680 SHE COULD COMMENT ON THE -- I 8048 05:44:20,680 --> 05:44:21,960 CAN'T REMEMBER THE INFLAMMATORY 8049 05:44:21,960 --> 05:44:24,960 STATE, BUT EVEN THE MOUSE MODELS 8050 05:44:24,960 --> 05:44:27,560 HAVE SOME ELEVATED INFLAMMATION 8051 05:44:27,560 --> 05:44:31,040 THAT MIGHT BE IN THE LUNG WHEN 8052 05:44:31,040 --> 05:44:31,360 CHALLENGED. 8053 05:44:31,360 --> 05:44:31,960 IT'S RELATIVE. 8054 05:44:31,960 --> 05:44:33,120 IF YOU WANT AN ANIMAL MODEL THAT 8055 05:44:33,120 --> 05:44:36,320 YOU'RE GOING TO BE ABLE TO RUN A 8056 05:44:36,320 --> 05:44:37,200 SMALL ANIMAL CLINICAL STUDY, FOR 8057 05:44:37,200 --> 05:44:41,160 EXAMPLE, THAT YOU WANT TO DO IN 8058 05:44:41,160 --> 05:44:42,480 HUMANS, WITH THE VERY CLOSE 8059 05:44:42,480 --> 05:44:44,360 DISEASE STATE TO WHAT IS SEEN IN 8060 05:44:44,360 --> 05:44:46,800 HUMANS, THEN, YOU KNOW, YOU HAVE 8061 05:44:46,800 --> 05:44:48,840 TO PICK THE RIGHT STATE OF 8062 05:44:48,840 --> 05:44:49,920 DISEASE, IF THAT'S CHRONIC 8063 05:44:49,920 --> 05:44:52,120 PSEUDOMONAS OR WHATEVER IT MIGHT 8064 05:44:52,120 --> 05:44:52,360 BE. 8065 05:44:52,360 --> 05:44:53,640 BUT THEY ARE AVAILABLE. 8066 05:44:53,640 --> 05:44:54,560 THEY ARE JUST EXPENSIVE, WHICH 8067 05:44:54,560 --> 05:44:57,920 IS ONE OF THE TOPICS THAT CAME 8068 05:44:57,920 --> 05:44:59,840 UP IN OUR -- IN THE ANIMAL MODEL 8069 05:44:59,840 --> 05:45:01,960 SECTION AS WELL. 8070 05:45:01,960 --> 05:45:03,360 >> I THINK THAT'S RIGHT, JOHN. 8071 05:45:03,360 --> 05:45:05,040 I THINK WE HAVE A LOT OF MODELS 8072 05:45:05,040 --> 05:45:07,240 THAT CAN ANSWER THE QUESTION, IF 8073 05:45:07,240 --> 05:45:08,280 THE EXPERIMENT IS DESIGNED THE 8074 05:45:08,280 --> 05:45:09,040 RIGHT WAY. 8075 05:45:09,040 --> 05:45:13,000 AND WHAT WE WOULD NEED IS HELP 8076 05:45:13,000 --> 05:45:16,400 FROM THE CLINICIANS TO LOOK 8077 05:45:16,400 --> 05:45:20,320 EXACTLY WHEN IS IMPORTANT AND IN 8078 05:45:20,320 --> 05:45:21,400 WHAT CONTEXT IS IMPORTANT. 8079 05:45:21,400 --> 05:45:24,120 >> SOUNDED TO ME THE RAT MODEL 8080 05:45:24,120 --> 05:45:28,240 HAS SOME ADVANTAGES OF BEING A 8081 05:45:28,240 --> 05:45:30,760 BIT MORE EXPOUNDABLE IN TERMS OF 8082 05:45:30,760 --> 05:45:33,280 NUMBER OF ANIMALS AND COSTS 8083 05:45:33,280 --> 05:45:35,000 ASSOCIATED WITH THAT. 8084 05:45:35,000 --> 05:45:40,720 SO, IT WOULD JUST BE NICE TO DO 8085 05:45:40,720 --> 05:45:43,120 THAT WITH AN ANTI-INFLAMMATORY 8086 05:45:43,120 --> 05:45:45,320 THERAPY THAT WE THINK OR KNOW 8087 05:45:45,320 --> 05:45:48,720 WOULD WORK, TO SEE THAT IT 8088 05:45:48,720 --> 05:45:49,360 ACTUALLY RECAPITULATES WHAT 8089 05:45:49,360 --> 05:45:52,520 COULD BE SEEN IN HUMANS BECAUSE 8090 05:45:52,520 --> 05:45:54,960 THIS IS ALWAYS THE DISCUSSION 8091 05:45:54,960 --> 05:45:55,560 ANTI-INFLAMMATORY DEVELOPMENT 8092 05:45:55,560 --> 05:45:57,360 CURRENTLY WE DON'T REALLY HAVE A 8093 05:45:57,360 --> 05:46:00,440 GOOD PRE-CLINICAL MODEL THAT WE 8094 05:46:00,440 --> 05:46:01,960 COULD RELY ON, EVEN THOUGH THERE 8095 05:46:01,960 --> 05:46:03,520 ARE ANIMAL MODELS, THEY HAVEN'T 8096 05:46:03,520 --> 05:46:05,360 BEEN UTILIZED IN ANY OF THESE 8097 05:46:05,360 --> 05:46:08,000 SETTINGS BEFORE, BUT I DON'T 8098 05:46:08,000 --> 05:46:09,640 WANT TO DOMINATE THE DISCUSSION 8099 05:46:09,640 --> 05:46:12,360 ANYMORE WITH THAT. 8100 05:46:12,360 --> 05:46:15,080 8101 05:46:15,080 --> 05:46:17,880 >> YEAH, I MIGHT JUST WANT TO 8102 05:46:17,880 --> 05:46:20,120 ADD THAT IT'S MUCH MORE 8103 05:46:20,120 --> 05:46:23,440 SIMPLIFIED MODEL IN VITRO 8104 05:46:23,440 --> 05:46:24,720 PERSONALIZED MEDICINE MODEL THAT 8105 05:46:24,720 --> 05:46:28,680 WE HAD ALSO A VERY HOT TOPIC 8106 05:46:28,680 --> 05:46:30,120 CREATING MODELS OF INFLAMMATION 8107 05:46:30,120 --> 05:46:32,960 IN VARIOUS REGARDS BECAUSE IT'S 8108 05:46:32,960 --> 05:46:36,880 A MORE COMPLEX MODEL THAT 8109 05:46:36,880 --> 05:46:38,640 REPRESENTS THE CF AIRWAY 8110 05:46:38,640 --> 05:46:48,040 EPITHELIA AND WOULD ALLOW TO 8111 05:46:48,040 --> 05:46:49,640 STUDY VARIOUS THERAPEUTICS, 8112 05:46:49,640 --> 05:46:53,640 ANTI-INFLAMMATORY STIMULI OR 8113 05:46:53,640 --> 05:46:55,040 CONDITIONS. 8114 05:46:55,040 --> 05:46:55,840 IT'S NOT AS SOPHISTICATED AS 8115 05:46:55,840 --> 05:46:58,680 ANIMAL MODEL BUT I THOUGHT I 8116 05:46:58,680 --> 05:47:00,120 WOULD ADD IT BECAUSE IT WAS A 8117 05:47:00,120 --> 05:47:01,320 BIG HOT TOPIC OF DISCUSSION. 8118 05:47:01,320 --> 05:47:05,360 >> IF I COULD COMMENT ON THAT, I 8119 05:47:05,360 --> 05:47:07,960 FIND ORGAN ON A CHIP 8120 05:47:07,960 --> 05:47:08,320 FASCINATING. 8121 05:47:08,320 --> 05:47:10,360 IN OUR SESSION, THE MULTI-ORGAN 8122 05:47:10,360 --> 05:47:11,560 NATURE OF THE DISEASE CAME UP 8123 05:47:11,560 --> 05:47:13,280 WHICH IS GOING TO BE DIFFERENT 8124 05:47:13,280 --> 05:47:14,200 BETWEEN THE DIFFERENT ANIMAL 8125 05:47:14,200 --> 05:47:17,240 MODELS IF THEY DON'T HAVE 8126 05:47:17,240 --> 05:47:18,840 PANCREATIC DISEASE OR DON'T 8127 05:47:18,840 --> 05:47:21,320 DEVELOP SPONTANEOUS LUNG 8128 05:47:21,320 --> 05:47:23,720 DISEASE. 8129 05:47:23,720 --> 05:47:24,360 BUT UNDERSTANDING THE 8130 05:47:24,360 --> 05:47:25,920 INTERACTIONS BETWEEN STATES THAT 8131 05:47:25,920 --> 05:47:29,080 ARE NOT FULLY PROTECTED ON 8132 05:47:29,080 --> 05:47:30,960 HIGHLY AFFECTED MODULATORS, 8133 05:47:30,960 --> 05:47:32,160 INTERACTIONS BETWEEN EPITHELIUM, 8134 05:47:32,160 --> 05:47:35,840 FOR EXAMPLE, LIKE HOW DOES THE 8135 05:47:35,840 --> 05:47:36,920 PANCREATITIS AFFECT COLONIZATION 8136 05:47:36,920 --> 05:47:38,160 IN THE LUNG, WE KNOW THOSE 8137 05:47:38,160 --> 05:47:41,960 PATIENTS DO WORSE IF THEY GET 8138 05:47:41,960 --> 05:47:42,160 CFRD. 8139 05:47:42,160 --> 05:47:44,840 AND SO BACK TO FELIX'S COMMENT, 8140 05:47:44,840 --> 05:47:46,040 I THINK, YOU KNOW, THERE ARE A 8141 05:47:46,040 --> 05:47:46,880 LOT OF MODELS HERE. 8142 05:47:46,880 --> 05:47:48,520 YOU START WITH THE ONE THAT 8143 05:47:48,520 --> 05:47:50,600 GIVERS YOU MAYBE THE BROADEST 8144 05:47:50,600 --> 05:47:52,200 DIRECTION AND WHERE YOU WANT TO 8145 05:47:52,200 --> 05:47:54,640 GO, MAYBE THAT'S LUNG ON A CHIP, 8146 05:47:54,640 --> 05:47:57,520 MOVE TO MOUSE OR RAT, AND THEN 8147 05:47:57,520 --> 05:47:59,280 THE CLOSER YOU GET TO FEELING 8148 05:47:59,280 --> 05:48:00,280 CONFIDENT ABOUT THE DRUG YOU'RE 8149 05:48:00,280 --> 05:48:01,760 GOING TO DEVELOP YOU PULL THE 8150 05:48:01,760 --> 05:48:03,240 TRIGGER AND DECIDE, YOU KNOW, DO 8151 05:48:03,240 --> 05:48:07,360 YOU HAVE TO GO INTO ONE OF THESE 8152 05:48:07,360 --> 05:48:09,480 MORE EXPENSIVE MODELS, AND TO 8153 05:48:09,480 --> 05:48:11,000 EVALUATE IT PRIOR TO CONVINCING 8154 05:48:11,000 --> 05:48:12,200 YOURSELF THAT IT'S TIME FOR A 8155 05:48:12,200 --> 05:48:14,520 CLINICAL TRIAL. 8156 05:48:14,520 --> 05:48:16,920 AT LEAST THAT'S HOW THE 8157 05:48:16,920 --> 05:48:21,400 INTERACTIONS THAT WE HAVE AT 8158 05:48:21,400 --> 05:48:22,520 IOWA WITH COMPANIES AND ACADEMIC 8159 05:48:22,520 --> 05:48:25,560 GROUPS THAT WANT TO USE THE 8160 05:48:25,560 --> 05:48:26,560 FERRET MODEL. 8161 05:48:26,560 --> 05:48:28,040 >> THERE'S A NUMBER OF COMMENTS 8162 05:48:28,040 --> 05:48:29,960 IN THE CHAT ABOUT OTHER WAYS 8163 05:48:29,960 --> 05:48:31,600 THESE KIND OF MODELS CAN BE 8164 05:48:31,600 --> 05:48:33,680 USED, CONTINUING ON THE THEME OF 8165 05:48:33,680 --> 05:48:35,960 EVEN JUST LOOKING FOR 8166 05:48:35,960 --> 05:48:36,600 ANTI-INFLAMMATORIES, ONE OF THE 8167 05:48:36,600 --> 05:48:38,800 ANIMAL MODELS COULD HELP US 8168 05:48:38,800 --> 05:48:41,640 LOOKING AT SIDE EFFECT, 8169 05:48:41,640 --> 05:48:43,600 OFF-TARGET EFFECTS WE MIGHT NOT 8170 05:48:43,600 --> 05:48:44,720 BE EXPECTING. 8171 05:48:44,720 --> 05:48:46,680 THE OTHER THING ESZTER BROUGHT 8172 05:48:46,680 --> 05:48:51,160 UP, I WILL BACK THIS UP, I THINK 8173 05:48:51,160 --> 05:48:56,000 THAT FOR -- IN A PETRI DISH WE 8174 05:48:56,000 --> 05:48:57,200 HAVE GOOD MODELS FOR 8175 05:48:57,200 --> 05:49:01,800 ANTI-INFLAMMATORIES BUT FOR 8176 05:49:01,800 --> 05:49:08,880 HUMANS VIEWING FV-1, AND CRP AND 8177 05:49:08,880 --> 05:49:09,560 BIOMARKERS. 8178 05:49:09,560 --> 05:49:14,280 AZITHROMYCIN, THE WORKHORSE, 8179 05:49:14,280 --> 05:49:15,800 DECREASED EXACERBATION, ESZTER 8180 05:49:15,800 --> 05:49:16,920 BRINGS UP AN ANIMAL MODEL WE 8181 05:49:16,920 --> 05:49:17,760 COULD COME UP WITH NOVEL 8182 05:49:17,760 --> 05:49:18,760 BIOMARKERS THAT WE COULD LOOK 8183 05:49:18,760 --> 05:49:21,360 FOR IN HUMANS THAT MIGHT BE MORE 8184 05:49:21,360 --> 05:49:23,880 PREDICTIVE OF LONG-TERM BENEFIT 8185 05:49:23,880 --> 05:49:26,640 OF ANTI-INFLAMMATORY AS A BETTER 8186 05:49:26,640 --> 05:49:28,080 BIOMARKER AND SO USING AN ANIMAL 8187 05:49:28,080 --> 05:49:30,400 MODEL THAT WAY TO HELP US WITH 8188 05:49:30,400 --> 05:49:33,320 OUR HUMAN CLINICAL TRIALS AS AN 8189 05:49:33,320 --> 05:49:33,880 ENDPOINT GENERATOR. 8190 05:49:33,880 --> 05:49:36,600 >> GOOD POINT. 8191 05:49:36,600 --> 05:49:40,320 8192 05:49:40,320 --> 05:49:42,360 >> THERE'S ALSO A LOT OF 8193 05:49:42,360 --> 05:49:44,520 COMMENTS IN HERE IN THE CHATTELS 8194 05:49:44,520 --> 05:49:47,240 ABOUT THE UTILITY OF USING THESE 8195 05:49:47,240 --> 05:49:49,000 MODELS TO ADDRESS THE OTHER 10%, 8196 05:49:49,000 --> 05:49:52,480 HOW WE COULD USE THEM FOR GENE 8197 05:49:52,480 --> 05:49:56,120 THERAPIES, LOOKING AT A COMMENT 8198 05:49:56,120 --> 05:49:59,000 HERE BY STEVE IS OFF TARGET 8199 05:49:59,000 --> 05:50:01,680 EFFECTS AND, YOU KNOW, 8200 05:50:01,680 --> 05:50:04,400 DIFFERENTIAL CFTR EXPRESSION 8201 05:50:04,400 --> 05:50:07,240 AFTER GENE THERAPY, IN DIFFERENT 8202 05:50:07,240 --> 05:50:09,680 ORGANS, AND POTENTIALLY OTHER 8203 05:50:09,680 --> 05:50:11,440 COMMENTS HERE ABOUT, YOU KNOW, 8204 05:50:11,440 --> 05:50:14,120 REALLY THINKING ABOUT HOW THE 8205 05:50:14,120 --> 05:50:16,400 MODELS CAN TRANSLATE INTO 8206 05:50:16,400 --> 05:50:16,680 CLINIC. 8207 05:50:16,680 --> 05:50:19,680 AND ANOTHER COMMENT WAS RAISED 8208 05:50:19,680 --> 05:50:21,320 HERE THAT MODULATORS DIDN'T 8209 05:50:21,320 --> 05:50:23,160 NECESSARILY NEED MODELS TO BE 8210 05:50:23,160 --> 05:50:25,280 DEVELOPED, AND SO MAYBE WE WON'T 8211 05:50:25,280 --> 05:50:28,320 BE USING ANIMALS IN THAT WAY TO 8212 05:50:28,320 --> 05:50:29,640 DEVELOP NEW DRUGS NECESSARILY, 8213 05:50:29,640 --> 05:50:34,880 BUT MIGHT BE OF MORE UTILITY FOR 8214 05:50:34,880 --> 05:50:35,320 ANTI-INFLAMMATORIES, 8215 05:50:35,320 --> 05:50:36,840 ANTIBIOTICS, AND POTENTIALLY 8216 05:50:36,840 --> 05:50:39,360 GENE THERAPIES. 8217 05:50:39,360 --> 05:50:43,640 8218 05:50:43,640 --> 05:50:45,400 >> THOSE ARE GOOD POINTS. 8219 05:50:45,400 --> 05:50:48,560 IN THE ANIMAL MODEL SECTION WE 8220 05:50:48,560 --> 05:50:50,960 TALKED ABOUT THE VIRAL TROPISM 8221 05:50:50,960 --> 05:50:52,080 AND HOW TO BETTER DETERMINE, YOU 8222 05:50:52,080 --> 05:50:54,560 KNOW, IF YOU'RE USING A VIRUS TO 8223 05:50:54,560 --> 05:50:57,120 DO GENE THERAPY, BETTER 8224 05:50:57,120 --> 05:51:00,120 DETERMINE WHAT WILL REPRESENT 8225 05:51:00,120 --> 05:51:03,920 THAT TROPISM IN HUMANS. 8226 05:51:03,920 --> 05:51:05,640 AND TO DATE, THAT'S GOING TO 8227 05:51:05,640 --> 05:51:06,960 INVOLVE MULTIPLE -- THE MORE 8228 05:51:06,960 --> 05:51:08,480 SPECIES YOU HAVE, THAT YOU CAN 8229 05:51:08,480 --> 05:51:10,000 TEST YOUR VIRUS IN, IT GOES TO 8230 05:51:10,000 --> 05:51:12,240 THE RIGHT CELL TYPES, AND THEN 8231 05:51:12,240 --> 05:51:15,480 YOU TEST IT IN A DISEASE STATE 8232 05:51:15,480 --> 05:51:16,920 AND REVERSES DISEASE IT'S GOING 8233 05:51:16,920 --> 05:51:20,520 TO HAVE HIGHER LOOKLY HOOD OF -- 8234 05:51:20,520 --> 05:51:21,720 LIKELIHOOD OF WORKING IN HUMANS. 8235 05:51:21,720 --> 05:51:23,440 IS THERE A WAY TO DO THAT WITH 8236 05:51:23,440 --> 05:51:24,800 LUNG ON A CHIP? 8237 05:51:24,800 --> 05:51:26,880 YOU KNOW, WHERE YOU GOT ALL THE 8238 05:51:26,880 --> 05:51:29,600 MODELS ON THE PLATE TO TEST YOUR 8239 05:51:29,600 --> 05:51:32,920 THERAPY, AND YOU EVOLVE VIRUSES 8240 05:51:32,920 --> 05:51:35,960 THAT, YOU KNOW, ACROSS MULTIPLE 8241 05:51:35,960 --> 05:51:37,120 SPECIES AT ONCE, INTERESTING TO 8242 05:51:37,120 --> 05:51:40,520 THINK ABOUT. 8243 05:51:40,520 --> 05:51:44,720 8244 05:51:44,720 --> 05:51:47,240 >> ONE OF THE THINGS THAT CAME 8245 05:51:47,240 --> 05:51:48,960 UP IN OUR SECTION WAS ALSO WHAT 8246 05:51:48,960 --> 05:51:52,160 ARE THE RIGHT CELL TYPES TO BE 8247 05:51:52,160 --> 05:51:56,440 TARGETING, BECAUSE IF WE JUST 8248 05:51:56,440 --> 05:51:57,520 HAVE A PATIENT-DERIVED SYSTEM 8249 05:51:57,520 --> 05:51:59,360 LIKE ORGANOID IS THAT GOOD 8250 05:51:59,360 --> 05:52:01,560 ENOUGH FOR ANY OF THE GENE 8251 05:52:01,560 --> 05:52:03,440 THERAPY OR ANY OF THE -- WOULD 8252 05:52:03,440 --> 05:52:06,320 IT MIMIC WHAT HAPPENS IN AN 8253 05:52:06,320 --> 05:52:06,840 ANIMAL MODEL? 8254 05:52:06,840 --> 05:52:08,640 THAT WAS THE QUESTION THAT WAS 8255 05:52:08,640 --> 05:52:12,200 BEING ASKED. 8256 05:52:12,200 --> 05:52:13,520 >> YEAH, I MEAN, PROBABLY NOT, 8257 05:52:13,520 --> 05:52:16,440 UNTIL YOU TEST IT AND SHOW THAT 8258 05:52:16,440 --> 05:52:22,160 IT DOES THE SAME THING IN VIVO. 8259 05:52:22,160 --> 05:52:23,240 BUT IT'S ESPECIALLY TRUE FOR 8260 05:52:23,240 --> 05:52:25,200 ANYTHING THAT'S A VIRUS THAT HAS 8261 05:52:25,200 --> 05:52:29,160 A RECEPTOR THAT HAS TO BE 8262 05:52:29,160 --> 05:52:29,440 CONSERVED. 8263 05:52:29,440 --> 05:52:30,920 EITHER ACROSS SPECIES OR WITH 8264 05:52:30,920 --> 05:52:34,960 THE CELL PHENOTYPE. 8265 05:52:34,960 --> 05:52:37,720 >> WE HAVE TWO OTHER BREAKOUT 8266 05:52:37,720 --> 05:52:38,560 SESSIONS THAT HAPPENED, BEFORE 8267 05:52:38,560 --> 05:52:39,560 WE RUN OUT OF TIME. 8268 05:52:39,560 --> 05:52:40,880 DOES ANYONE WANT TO CHIME IN 8269 05:52:40,880 --> 05:52:43,840 ABOUT THE TOPICS FROM EITHER OF 8270 05:52:43,840 --> 05:52:45,240 THE OTHER BREAKOUT SESSIONS TO 8271 05:52:45,240 --> 05:52:45,800 DISCUSS? 8272 05:52:45,800 --> 05:52:47,440 >> I MIGHT CALL YOUR ATTENTION 8273 05:52:47,440 --> 05:52:49,520 TO ONE COMMENT THAT FELIX RAISES 8274 05:52:49,520 --> 05:52:53,040 IN THE CHAT THAT HE SAID THAT 8275 05:52:53,040 --> 05:52:54,240 FOR THE LUNG DISEASE SECTION, IT 8276 05:52:54,240 --> 05:52:58,080 WAS INTERESTING THAT THERE WAS A 8277 05:52:58,080 --> 05:53:00,040 FOCUS ON EARLY DISEASE. 8278 05:53:00,040 --> 05:53:03,320 BUT WHAT WAS THE DISCUSSION ON 8279 05:53:03,320 --> 05:53:05,400 ASSESSING THE REVERSIBILITY OF 8280 05:53:05,400 --> 05:53:07,160 MORE ADVANCED DISEASE? 8281 05:53:07,160 --> 05:53:09,120 IF SOMEONE FROM THAT SESSION, 8282 05:53:09,120 --> 05:53:11,000 THE LUNG SESSION, BREAKOUT 3, 8283 05:53:11,000 --> 05:53:13,920 COULD DISCUSS THAT QUESTION? 8284 05:53:13,920 --> 05:53:19,320 8285 05:53:19,320 --> 05:53:21,360 >> GO AHEAD, GINA. 8286 05:53:21,360 --> 05:53:23,560 >> I WAS GOING TO SAY WE DIDN'T 8287 05:53:23,560 --> 05:53:34,080 SPECIFICALLY TALK ABOUT THE TERM 8288 05:53:35,000 --> 05:53:37,120 "REVERSIBILITY" BUT ABOUT 8289 05:53:37,120 --> 05:53:39,120 TREATING AND MODERATING 8290 05:53:39,120 --> 05:53:39,880 ESTABLISHED DISEASE, 8291 05:53:39,880 --> 05:53:42,520 ANTICIPATING FOR INDIVIDUALS 8292 05:53:42,520 --> 05:53:44,560 WITH THIS ESTABLISHED DISEASE. 8293 05:53:44,560 --> 05:53:48,160 BUT WE DIDN'T -- I MEAN MY 8294 05:53:48,160 --> 05:53:52,600 CO-CHAIRS COULD CHIME IN BUT WE 8295 05:53:52,600 --> 05:53:53,880 DIDN'T TALK ABOUT REVERSIBILITY 8296 05:53:53,880 --> 05:53:54,560 PER SE. 8297 05:53:54,560 --> 05:53:56,360 WE DID TALK ABOUT STOPPAGE OF 8298 05:53:56,360 --> 05:53:59,400 THERAPIES, WHEN THAT SHOULD BE 8299 05:53:59,400 --> 05:54:00,880 CONSIDERED IN BOTH THE EARLY 8300 05:54:00,880 --> 05:54:03,520 LUNG DISEASE AND THE ADVANCED 8301 05:54:03,520 --> 05:54:05,160 LUNG DISEASE POPULATIONS, OR IN 8302 05:54:05,160 --> 05:54:09,200 MORE SIMPLER TERMS THE PEDIATRIC 8303 05:54:09,200 --> 05:54:10,960 AND ADULT POPULATIONS. 8304 05:54:10,960 --> 05:54:15,320 SO I JUST OPENED THAT UP TO MY 8305 05:54:15,320 --> 05:54:17,760 CO-MODERATORS TO COMMENT TOO. 8306 05:54:17,760 --> 05:54:19,400 >> YOU KNOW, ONE OF THE THINGS 8307 05:54:19,400 --> 05:54:24,560 THAT CAME THROUGH FOR US IS THAT 8308 05:54:24,560 --> 05:54:27,280 FED-1 MAY NOT BE AS SENSITIVE A 8309 05:54:27,280 --> 05:54:28,520 MARKER AND THERE WAS DISCUSSION 8310 05:54:28,520 --> 05:54:31,880 ABOUT LOOKING AT OTHER WAYS TO 8311 05:54:31,880 --> 05:54:33,080 ASSESS LUNG HEALTH. 8312 05:54:33,080 --> 05:54:37,480 YOU KNOW, MOSTLY THE CONTEXT OF 8313 05:54:37,480 --> 05:54:39,000 ASSESSING PROGRESSION OF DISEASE 8314 05:54:39,000 --> 05:54:43,800 , IN THE CONTEXT OF MAYBE FED-1 8315 05:54:43,800 --> 05:54:44,480 WOULDN'T NECESSARILY REFLECT 8316 05:54:44,480 --> 05:54:46,120 PROGRESSION, THINGS COULD GET 8317 05:54:46,120 --> 05:54:46,320 WORSE. 8318 05:54:46,320 --> 05:54:48,200 CERTAINLY ALONG THAT DISCUSSION 8319 05:54:48,200 --> 05:54:49,320 IF THINGS GOT BETTER, WHATEVER 8320 05:54:49,320 --> 05:54:50,920 WORK WE DID IN TERMS OF 8321 05:54:50,920 --> 05:54:52,120 IDENTIFYING OTHER OUTCOMES COULD 8322 05:54:52,120 --> 05:54:56,160 ALSO BE USED TO SEE HOW IT'S 8323 05:54:56,160 --> 05:54:58,520 REVERSIBLE IT IS, WHETHER 8324 05:54:58,520 --> 05:55:02,200 IMAGING OR OTHER TYPES OF 8325 05:55:02,200 --> 05:55:03,200 MODALITIES. 8326 05:55:03,200 --> 05:55:09,840 LOOKING AT OTHER OUTCOMES IS AN 8327 05:55:09,840 --> 05:55:11,600 IMPORTANT OUTCOME TO GO FORWARD. 8328 05:55:11,600 --> 05:55:13,480 >> THANKS, THAT HELPS IN MY TALK 8329 05:55:13,480 --> 05:55:16,720 TOMORROW ON THESE TOPICS. 8330 05:55:16,720 --> 05:55:19,360 >> I THINK ALSO I MIGHT CALL 8331 05:55:19,360 --> 05:55:20,800 ATTENTION TO SOMETHING THAT 8332 05:55:20,800 --> 05:55:23,200 MARTINA PUTS IN THE CHAT ABOUT 8333 05:55:23,200 --> 05:55:25,720 THE COMPLEXITY OF THESE MODELS 8334 05:55:25,720 --> 05:55:28,800 AND THINKING ABOUT BRINGING IN 8335 05:55:28,800 --> 05:55:31,320 DIFFERENT TEAMS OF EXPERTISE. 8336 05:55:31,320 --> 05:55:37,320 SHE NOTES IN THERE EPITHELIAL 8337 05:55:37,320 --> 05:55:38,000 BIOLOGISTS, INFLAMMATION 8338 05:55:38,000 --> 05:55:38,640 EXPERTS, BIOINFORMATICS EXPERTS, 8339 05:55:38,640 --> 05:55:39,440 ET CETERA. 8340 05:55:39,440 --> 05:55:42,960 SO I GUESS MY QUESTION TO THE 8341 05:55:42,960 --> 05:55:46,960 GROUP IS, ARE SOME OF THESE 8342 05:55:46,960 --> 05:55:48,320 AREAS THAT YOU BROUGHT UP, IS 8343 05:55:48,320 --> 05:55:51,680 THERE A GAP IN THE TYPE OF TEAM 8344 05:55:51,680 --> 05:55:53,720 SCIENCE THAT WE COULD BE 8345 05:55:53,720 --> 05:55:55,840 SUPPORTING OR SOLICITING OR 8346 05:55:55,840 --> 05:55:56,920 THINKING ABOUT MORE CREATIVELY 8347 05:55:56,920 --> 05:55:59,680 TO MOVE SOME OF THESE AREAS 8348 05:55:59,680 --> 05:56:00,080 FORWARD? 8349 05:56:00,080 --> 05:56:03,720 I KNOW THIS IS A VERY TIGHT 8350 05:56:03,720 --> 05:56:05,240 CLOSE COMMUNITY, BUT THAT 8351 05:56:05,240 --> 05:56:06,880 PARTICULAR COMMENT, YOU KNOW, 8352 05:56:06,880 --> 05:56:10,400 RAISED TO ME, THAT QUESTION OF 8353 05:56:10,400 --> 05:56:12,840 WHAT YOU THINK ABOUT TEAM 8354 05:56:12,840 --> 05:56:14,400 SCIENCE AND HOW WE MIGHT BE ABLE 8355 05:56:14,400 --> 05:56:17,200 TO SUPPORT THAT. 8356 05:56:17,200 --> 05:56:21,280 8357 05:56:21,280 --> 05:56:25,520 >> I'LL MAKE ONE COMMENT. 8358 05:56:25,520 --> 05:56:26,920 THIS DID COME UP IN THE ANIMAL 8359 05:56:26,920 --> 05:56:29,320 MODEL SECTION, IT WAS ABOUT HOW 8360 05:56:29,320 --> 05:56:31,960 REALLY MOST OF THE MODELS, NOT 8361 05:56:31,960 --> 05:56:33,800 PROBABLY ALL, EXCEPT FOR THE 8362 05:56:33,800 --> 05:56:37,200 MOUSE, MAYBE THE RAT TOO, YOU 8363 05:56:37,200 --> 05:56:38,760 KNOW, ARE AN ORPHAN GENOME. 8364 05:56:38,760 --> 05:56:43,560 IN THIS DAY AND AGE, FULLY 8365 05:56:43,560 --> 05:56:45,760 TAPPING THE OMICS TECHNOLOGIES 8366 05:56:45,760 --> 05:56:48,840 TO UNDERSTAND THE DISEASE STATE 8367 05:56:48,840 --> 05:56:51,560 IS -- THERE'S SO MUCH POTENTIAL. 8368 05:56:51,560 --> 05:56:54,280 BUT THE LIMITATION IS HAVING A 8369 05:56:54,280 --> 05:56:55,600 REALLY ACCURATE GENOME. 8370 05:56:55,600 --> 05:56:59,320 WE STRUGGLE WITH THIS IN THE 8371 05:56:59,320 --> 05:57:00,200 FERRET. 8372 05:57:00,200 --> 05:57:01,920 BUT IT NEEDS TO HAVE MONEY 8373 05:57:01,920 --> 05:57:05,160 THROWN AT IT TO COMPLETE IT, AND 8374 05:57:05,160 --> 05:57:09,160 GET ALTERNATIVE SPLICE FORMS, 8375 05:57:09,160 --> 05:57:11,360 ORTHOLOGS, YOU KNOW, ANNOTATED 8376 05:57:11,360 --> 05:57:13,600 CORRECTLY. 8377 05:57:13,600 --> 05:57:17,600 8378 05:57:17,600 --> 05:57:18,400 8379 05:57:18,400 --> 05:57:21,120 >> YEAH, I WANTED TO REALLY PUT 8380 05:57:21,120 --> 05:57:23,840 THE IMPORTANCE ON INTERACTION OF 8381 05:57:23,840 --> 05:57:26,280 DIFFERENT EXPERTS FOR THE 8382 05:57:26,280 --> 05:57:30,960 COMPLEX MODELS, WHAT MARRAH JUST 8383 05:57:30,960 --> 05:57:32,360 SAID, EPITHELIAL BIOLOGISTS, 8384 05:57:32,360 --> 05:57:34,040 THINKING ABOUT OTHERS THAT KNOW 8385 05:57:34,040 --> 05:57:38,440 MORE ABOUT NEUTROPHILS AND 8386 05:57:38,440 --> 05:57:41,480 INFLAMMATION, SINGLE CELL DATA, 8387 05:57:41,480 --> 05:57:42,480 BIOINFORMATICS, BIOENGINEERS. 8388 05:57:42,480 --> 05:57:43,760 BESIDES THAT IT CAME ALSO 8389 05:57:43,760 --> 05:57:47,200 CLEARLY TO THE SURFACE THAT EVEN 8390 05:57:47,200 --> 05:57:48,360 INTERACTION BETWEEN THE BASIC 8391 05:57:48,360 --> 05:57:50,120 RESEARCHERS THAT USE IN VITRO 8392 05:57:50,120 --> 05:57:51,880 MODELS AND OTHERS THAT USE 8393 05:57:51,880 --> 05:57:54,200 ANIMAL MODELS WOULD BE VERY 8394 05:57:54,200 --> 05:57:54,800 IMPORTANT. 8395 05:57:54,800 --> 05:57:56,920 THERE WAS A COMMENT I THINK BY 8396 05:57:56,920 --> 05:57:59,320 J.P. SAID ANIMAL MODEL OUTCOMES 8397 05:57:59,320 --> 05:58:03,920 AND IN VITRO MODEL OUTCOMES 8398 05:58:03,920 --> 05:58:04,880 SHOULD BE COMPARABLE, EVEN MORE 8399 05:58:04,880 --> 05:58:07,920 REALLY THIS IS ONE OF OUR POINTS 8400 05:58:07,920 --> 05:58:09,640 HERE, HOW CAN LABORATORY 8401 05:58:09,640 --> 05:58:11,960 FINDINGS BE BETTER LEVERAGED TO 8402 05:58:11,960 --> 05:58:13,480 MOVE FROM PRE-CLINICAL STUDIES 8403 05:58:13,480 --> 05:58:15,560 TO THE CLINIC. 8404 05:58:15,560 --> 05:58:17,960 SO EVEN THE COLLABORATION OF 8405 05:58:17,960 --> 05:58:18,600 BASIC RESEARCHERS WITH 8406 05:58:18,600 --> 05:58:20,480 CLINICIANS WHICH IS ALREADY 8407 05:58:20,480 --> 05:58:25,240 HAPPENING A LOT BY OBTAINING THE 8408 05:58:25,240 --> 05:58:26,920 PRIMARY TISSUES FROM THE CLINIC 8409 05:58:26,920 --> 05:58:29,440 BUT THERE COULD BE EVEN MORE 8410 05:58:29,440 --> 05:58:30,800 COLLABORATION THAT CLINICAL 8411 05:58:30,800 --> 05:58:35,680 READOUTS ARE DIRECTLY CORRELATED 8412 05:58:35,680 --> 05:58:38,320 TO LABORATORY EVALUATIONS. 8413 05:58:38,320 --> 05:58:39,400 AND COLLABORATIONS BETWEEN 8414 05:58:39,400 --> 05:58:40,840 DIFFERENT EXPERTS IN CF 8415 05:58:40,840 --> 05:58:41,920 COMMUNITY WILL DEFINITELY MOVE 8416 05:58:41,920 --> 05:58:43,120 THE FIELD FORWARD IN MANY 8417 05:58:43,120 --> 05:58:45,320 REGARDS. 8418 05:58:45,320 --> 05:58:49,480 8419 05:58:49,480 --> 05:58:52,400 >> ANN, DID YOU WANT TO SAY 8420 05:58:52,400 --> 05:58:52,680 SOMETHING? 8421 05:58:52,680 --> 05:58:53,600 >> YEAH, WANTING TO SECOND WHAT 8422 05:58:53,600 --> 05:58:55,600 JOHN SAID ABOUT THE GENOMES. 8423 05:58:55,600 --> 05:58:59,080 I MEAN, IF WE COULD BRING IN A 8424 05:58:59,080 --> 05:59:03,240 LITTLE BIT MORE POWER ON 8425 05:59:03,240 --> 05:59:04,440 SEQUENCING, IN-DEPTH SEQUENCING, 8426 05:59:04,440 --> 05:59:05,400 GETTING A REALLY GOOD COMPLETE 8427 05:59:05,400 --> 05:59:08,920 MAP FOR SOME OF THE MODELS THAT 8428 05:59:08,920 --> 05:59:10,480 ARE RELEVANT TO CF, IT IS A 8429 05:59:10,480 --> 05:59:11,000 CHALLENGE. 8430 05:59:11,000 --> 05:59:12,640 IT TAKES MUCH LONGER THAN IT 8431 05:59:12,640 --> 05:59:15,560 NEEDS TO WHEN YOU DON'T HAVE A 8432 05:59:15,560 --> 05:59:19,080 COMPLETE GENOME, AND WE HAVE 8433 05:59:19,080 --> 05:59:20,360 SPOKEN TO NHGRI, I'M NOT SURE 8434 05:59:20,360 --> 05:59:21,360 ANY MODELS WE'RE TALKING ABOUT 8435 05:59:21,360 --> 05:59:37,120 HERE ARE TOP OF THEIR LIST. 8436 05:59:37,120 --> 05:59:38,120 >> I MIGHT RAISE ESZTER'S 8437 05:59:38,120 --> 05:59:41,640 COMMENT FROM THE CHAT AS WELL 8438 05:59:41,640 --> 05:59:44,400 FOR DISCUSSION. 8439 05:59:44,400 --> 05:59:47,120 SHE MENTIONS SENESCENCE AS SORT 8440 05:59:47,120 --> 05:59:50,640 OF A SIGNATURE THAT PERSISTS IN 8441 05:59:50,640 --> 05:59:51,720 THE EPITHELIUM DESPITE 8442 05:59:51,720 --> 05:59:54,160 CORRECTORS, AND THINKING ABOUT 8443 05:59:54,160 --> 05:59:56,480 SOME OF THE TALKS INCLUDING 8444 05:59:56,480 --> 05:59:59,760 FRANK'S EARLIER FROM TODAY OF 8445 05:59:59,760 --> 06:00:01,200 THESE SIGNATURES THAT REALLY 8446 06:00:01,200 --> 06:00:02,800 CAN'T BE CORRECTED, AND SO I 8447 06:00:02,800 --> 06:00:04,200 WONDER IF ANYBODY WANTS TO 8448 06:00:04,200 --> 06:00:05,880 DISCUSS THAT IN THE TYPE OF 8449 06:00:05,880 --> 06:00:06,960 RESEARCH GAPS AND OPPORTUNITIES 8450 06:00:06,960 --> 06:00:10,120 THAT THERE MIGHT BE THERE. 8451 06:00:10,120 --> 06:00:16,160 8452 06:00:16,160 --> 06:00:21,720 8453 06:00:21,720 --> 06:00:22,840 >> PROBABLY ONE THING I WOULD 8454 06:00:22,840 --> 06:00:27,400 ADD TO THAT IS THAT FOLKS WITH 8455 06:00:27,400 --> 06:00:30,360 CF WHO START CORRECTORS WITH 8456 06:00:30,360 --> 06:00:31,680 ESTABLISHED DISEASE PROBABLY 8457 06:00:31,680 --> 06:00:36,160 HAVE HAD THE EQUIVALENT OF AN 8458 06:00:36,160 --> 06:00:38,360 ENTIRE LIFESPAN-PLUS OF 8459 06:00:38,360 --> 06:00:38,880 INFLECTION, INFLAMMATION, 8460 06:00:38,880 --> 06:00:39,640 REPEATED INJURY, MOST -- YOU 8461 06:00:39,640 --> 06:00:41,320 KNOW, WHAT WE COULD NEVER 8462 06:00:41,320 --> 06:00:43,040 COUNTER IN OUR NORMAL LIVES. 8463 06:00:43,040 --> 06:00:46,480 THAT'S GOT TO LEAVE POTENTIALLY 8464 06:00:46,480 --> 06:00:50,400 SOME SORT OF EPIGENETIC LOAD OR 8465 06:00:50,400 --> 06:00:51,640 IRREVERSIBLE STRUCTURAL DAMAGE 8466 06:00:51,640 --> 06:00:52,600 THAT YOU CAN'T OVERCOME. 8467 06:00:52,600 --> 06:00:56,520 AND I THINK THAT TRANSCRIPTIONAL 8468 06:00:56,520 --> 06:00:58,280 SIGNATURES COULD BE REALLY 8469 06:00:58,280 --> 06:00:59,600 POWERFUL AT DETECTING THESE, 8470 06:00:59,600 --> 06:01:02,360 EVEN IF THERE ARE NECESSARILY 8471 06:01:02,360 --> 06:01:04,000 VERY OBVIOUS SIGNATURES LIKE 8472 06:01:04,000 --> 06:01:06,000 THERE ARE WITH BRONCHIECTASIS. 8473 06:01:06,000 --> 06:01:12,960 A LOT OF THESE MAY BE EARLY 8474 06:01:12,960 --> 06:01:14,280 PRECURSORS TO CHRONIC LUNG 8475 06:01:14,280 --> 06:01:15,520 DISEASES OF AGING THAT COULD 8476 06:01:15,520 --> 06:01:18,640 COME. 8477 06:01:18,640 --> 06:01:20,400 >> I AGREE. 8478 06:01:20,400 --> 06:01:23,480 I'LL JUST MAKE A COMMENT TO WHAT 8479 06:01:23,480 --> 06:01:25,000 YOU SAID TOO, MARRAH. 8480 06:01:25,000 --> 06:01:26,480 I COLLABORATE WITH FRANK, SO I 8481 06:01:26,480 --> 06:01:29,600 KNOW WHAT HE'S DOING. 8482 06:01:29,600 --> 06:01:31,800 AND, YOU KNOW, THE DISCOVERY OF 8483 06:01:31,800 --> 06:01:34,400 EPIGENETIC CHANGES IN THE STEM 8484 06:01:34,400 --> 06:01:36,280 CELL COMPARTMENTS OF THE LUNG IS 8485 06:01:36,280 --> 06:01:39,480 INCREDIBLY IMPORTANT TO GENE 8486 06:01:39,480 --> 06:01:40,360 THERAPY, GENE EDITING. 8487 06:01:40,360 --> 06:01:45,720 AND, YOU KNOW, I CAN'T SEE A 8488 06:01:45,720 --> 06:01:47,400 PATH TO TESTING A DRUG WITHOUT 8489 06:01:47,400 --> 06:01:49,040 IT FIRST GOING THROUGH THE 8490 06:01:49,040 --> 06:01:49,880 DISEASE MODEL. 8491 06:01:49,880 --> 06:01:53,480 YOU KNOW, EVEN IF YOU COULD 8492 06:01:53,480 --> 06:01:56,080 SPECIFICALLY REVERSE THAT 8493 06:01:56,080 --> 06:01:56,920 EPIGENETIC PROGRAMMING, THAT 8494 06:01:56,920 --> 06:01:58,880 PROGRAM IS SO IMPORTANT TO THE 8495 06:01:58,880 --> 06:02:00,600 BODY. 8496 06:02:00,600 --> 06:02:02,680 I MEAN, UNDERSTANDING OFF-TARGET 8497 06:02:02,680 --> 06:02:04,120 EFFECTS, IT'S GOING TO TAKE 8498 06:02:04,120 --> 06:02:05,960 ANIMAL MODELS THAT CAN WE 8499 06:02:05,960 --> 06:02:06,880 PRODUCE THE HUMAN PHENOTYPE 8500 06:02:06,880 --> 06:02:08,240 DISEASE MODELS TO GO IN AND TEST 8501 06:02:08,240 --> 06:02:09,640 AND MAKE SURE THAT THE DRUGS ARE 8502 06:02:09,640 --> 06:02:13,600 SAFE AND THEY DO WHAT YOU THINK 8503 06:02:13,600 --> 06:02:15,360 AND THEY KILL ONLY 8504 06:02:15,360 --> 06:02:19,520 PRO-INFLAMMATORY BASAL CELLS, 8505 06:02:19,520 --> 06:02:19,880 FOR EXAMPLE. 8506 06:02:19,880 --> 06:02:23,120 SO I THINK IT'S IMPORTANT. 8507 06:02:23,120 --> 06:02:24,680 8508 06:02:24,680 --> 06:02:32,440 >> I'M NOTICING ROBERT GRAY'S 8509 06:02:32,440 --> 06:02:33,720 COMMENT IMMUNOSENESCE AND 8510 06:02:33,720 --> 06:02:34,520 EPITHELIAL SENESCENCE ARE AREAS 8511 06:02:34,520 --> 06:02:36,600 TO FOCUS ON. 8512 06:02:36,600 --> 06:02:37,680 DO WE THINK POST-MODULATOR CF 8513 06:02:37,680 --> 06:02:41,080 AIRWAYS ARE THE SAME THING AS 8514 06:02:41,080 --> 06:02:42,680 NON-CF BRONCHIECTASIS? 8515 06:02:42,680 --> 06:02:46,360 OR DOES THE -- IN ADULT WITH CF, 8516 06:02:46,360 --> 06:02:48,520 WHO HAD CF FOR THE FIRST 25 8517 06:02:48,520 --> 06:02:51,600 YEARS OF THEIR LIFE AND START 8518 06:02:51,600 --> 06:02:53,040 MODULATORS ONCE THEY START 8519 06:02:53,040 --> 06:02:54,320 MODULATORS IS BRONCHIECTASIS 8520 06:02:54,320 --> 06:02:55,440 GOING TO BE FUNDAMENTALLY 8521 06:02:55,440 --> 06:02:56,080 DIFFERENT BECAUSE EPIGENETIC 8522 06:02:56,080 --> 06:02:57,120 CHANGES MAY HAVE HAPPENED? 8523 06:02:57,120 --> 06:03:00,280 OR IS THAT THE SAME THING THAT'S 8524 06:03:00,280 --> 06:03:00,920 HAPPENING IN NON-CF 8525 06:03:00,920 --> 06:03:03,280 BRONCHIECTASIS? 8526 06:03:03,280 --> 06:03:09,320 8527 06:03:09,320 --> 06:03:13,480 8528 06:03:13,480 --> 06:03:15,600 >> IT'S A GOOD POINT, PROBABLY 8529 06:03:15,600 --> 06:03:18,320 SOMEWHERE IN BETWEEN BECAUSE THE 8530 06:03:18,320 --> 06:03:23,880 CFTR MODULATORS ARE NOT 100%, 8531 06:03:23,880 --> 06:03:32,440 EVEN IF YOU'RE HETEROZYGOTE FOR 8532 06:03:32,440 --> 06:03:32,880 MUTATIONS, INCLUDING 8533 06:03:32,880 --> 06:03:33,480 PANCREATITIS, DIABETES, AND SO 8534 06:03:33,480 --> 06:03:35,880 ON. 8535 06:03:35,880 --> 06:03:41,920 8536 06:03:41,920 --> 06:03:42,280 8537 06:03:42,280 --> 06:03:44,000 >> I THINK THE UNDERSTANDING OF 8538 06:03:44,000 --> 06:03:50,160 REPAIRING THE LUNG AND 8539 06:03:50,160 --> 06:03:51,360 PREVENTING DAMAGE AND THE USE OF 8540 06:03:51,360 --> 06:03:53,400 ANIMAL MODELS FOR THAT IS VERY 8541 06:03:53,400 --> 06:03:54,560 USEFUL. 8542 06:03:54,560 --> 06:03:55,960 AS AN ADULT PROVIDER, I THINK 8543 06:03:55,960 --> 06:03:57,480 OF -- WHEN I THINK ABOUT WHAT'S 8544 06:03:57,480 --> 06:03:59,440 THE FUTURE ON PEOPLE WITH HEMT, 8545 06:03:59,440 --> 06:04:02,600 I'M JUST THINKING ABOUT THE 8546 06:04:02,600 --> 06:04:04,680 CONTINUED STATE OF THE AIRWAY, 8547 06:04:04,680 --> 06:04:07,320 SO ARE WE LOOKING FOR THE SAME 8548 06:04:07,320 --> 06:04:09,440 DRUGS AND TREATMENTS AS NON-CF 8549 06:04:09,440 --> 06:04:11,080 BRONCHIECTASIS OR IS THIS GOING 8550 06:04:11,080 --> 06:04:13,600 TO BE -- CONTINUE TO BE A UNIQUE 8551 06:04:13,600 --> 06:04:14,240 POPULATION BECAUSE OUR PATIENTS 8552 06:04:14,240 --> 06:04:16,120 ARE GOING TO BE LIVING LONGER, 8553 06:04:16,120 --> 06:04:17,480 WE'LL HAVE MORE ADULT PATIENTS, 8554 06:04:17,480 --> 06:04:19,960 AND WE'RE GOING TO HAVE A FAIRER 8555 06:04:19,960 --> 06:04:22,240 PROPORTION OF PATIENTS WITH 8556 06:04:22,240 --> 06:04:23,000 DAMAGED LUNGS, LIVING LONGER, 8557 06:04:23,000 --> 06:04:25,520 THAT WE'RE GOING TO HAVE TO 8558 06:04:25,520 --> 06:04:26,600 UNDERSTAND AND TREAT. 8559 06:04:26,600 --> 06:04:37,120 SO-- ROBERT, YOU SHOULD SPEAK 8560 06:04:38,000 --> 06:04:38,080 UP. 8561 06:04:38,080 --> 06:04:41,080 ROBERT GRAY. 8562 06:04:41,080 --> 06:04:46,440 8563 06:04:46,440 --> 06:04:47,120 8564 06:04:47,120 --> 06:04:49,200 CAN YOU EXPLAIN MORE CF PATIENTS 8565 06:04:49,200 --> 06:04:52,240 ON HEMT FOR ONE YEAR DON'T LOOK 8566 06:04:52,240 --> 06:04:52,960 LIKE NON-CF BRONCHIECTASIS ON 8567 06:04:52,960 --> 06:04:56,520 CAT SCAN? 8568 06:04:56,520 --> 06:05:00,200 8569 06:05:00,200 --> 06:05:01,880 OR IF ANYONE ELSE WANTS TO WEIGH 8570 06:05:01,880 --> 06:05:04,400 IN ON THAT? 8571 06:05:04,400 --> 06:05:07,160 >> CAN YOU HEAR ME? 8572 06:05:07,160 --> 06:05:08,120 >> YES, WE CAN. 8573 06:05:08,120 --> 06:05:09,240 >> SORRY, I'VE BEEN DEALING WITH 8574 06:05:09,240 --> 06:05:14,480 A VOMITING CHILD ALL DAY IN 8575 06:05:14,480 --> 06:05:15,560 SCOTLAND. 8576 06:05:15,560 --> 06:05:17,520 WE'VE BEEN DOING A LOT OF 8577 06:05:17,520 --> 06:05:18,080 OBSERVATIONAL EXPERIMENTS 8578 06:05:18,080 --> 06:05:19,160 LOOKING AT THESE PATIENTS. 8579 06:05:19,160 --> 06:05:22,520 WE'VE GOT TEN PATIENTS 8580 06:05:22,520 --> 06:05:25,480 COMPLETELY MODULATOR NAIVE THAT 8581 06:05:25,480 --> 06:05:32,720 WE LOOK PRE AND POST ONE YEAR 8582 06:05:32,720 --> 06:05:36,960 TRICAFTA AS WE CALL IT. 8583 06:05:36,960 --> 06:05:39,440 THE BRONCHIECTASIS LOOKS 8584 06:05:39,440 --> 06:05:41,320 DIFFERENT. 8585 06:05:41,320 --> 06:05:42,200 THEY HAVE DILATED AIRWAYS BUT 8586 06:05:42,200 --> 06:05:45,680 THEY LOST THE WALL THICKENING. 8587 06:05:45,680 --> 06:05:47,680 LOOKS LIKE A DIFFERENT PROSPECT 8588 06:05:47,680 --> 06:05:49,280 IN TERMS OF THE RADIOLOGY. 8589 06:05:49,280 --> 06:05:51,040 WHICH WE WERE NOT EXPECTING. 8590 06:05:51,040 --> 06:05:56,080 I WAS EXPECTING TO MAKE OUR 8591 06:05:56,080 --> 06:05:56,960 PATIENTS INTO NON-CF 8592 06:05:56,960 --> 06:05:59,040 BRONCHIECTASIS BUT APPEAR TO 8593 06:05:59,040 --> 06:06:01,200 HAVE MADE OUR PATIENTS WHO 8594 06:06:01,200 --> 06:06:10,760 COMPLETE THERAPIES INTO A 8595 06:06:10,760 --> 06:06:11,400 DIFFERENT CATEGORY. 8596 06:06:11,400 --> 06:06:15,240 A SHOUT OUT TO EX VIVO MODELS. 8597 06:06:15,240 --> 06:06:18,960 WE NEED TO GET MORE AMBITIOUS, 8598 06:06:18,960 --> 06:06:20,480 LOSS OF CO-CULTURE AND LOSS OF 8599 06:06:20,480 --> 06:06:22,040 BRINGING IN EXPERTISE BECAUSE WE 8600 06:06:22,040 --> 06:06:27,080 CAN DO SOME GOOD GOOD STUFF IN 8601 06:06:27,080 --> 06:06:27,560 EX VIVO MODELING. 8602 06:06:27,560 --> 06:06:30,560 I'LL BE QUITE NOW. 8603 06:06:30,560 --> 06:06:36,560 8604 06:06:36,560 --> 06:06:40,200 8605 06:06:40,200 --> 06:06:42,280 >> FRANK, DID YOU WANT TO SAY 8606 06:06:42,280 --> 06:06:50,400 SOMETHING? 8607 06:06:50,400 --> 06:06:51,360 >> I'M JUST LISTENING. 8608 06:06:51,360 --> 06:06:59,280 THERE IS SIGNIFICANT OVERLAP 8609 06:06:59,280 --> 06:07:01,240 BETWEEN VARIETIES IN COPD AND 8610 06:07:01,240 --> 06:07:11,080 CYSTIC FIBROSIS, YET TWO NEW 8611 06:07:11,080 --> 06:07:21,520 ONES THAT WE HAVEN'T SEEN. 8612 06:07:24,360 --> 06:07:34,760 THE COMPLETE GESTALT WILL BE 8613 06:07:50,200 --> 06:07:51,160 DISEASE SPECIFIC. 8614 06:07:51,160 --> 06:08:01,680 WHAT DOES AN EARLY STAGE LOOK 8615 06:08:31,560 --> 06:08:31,800 LIKE? 8616 06:08:31,800 --> 06:08:38,360 THIS IS WHAT THE ANIMAL MODEL 8617 06:08:38,360 --> 06:08:38,920 WILLS KEY. 8618 06:08:38,920 --> 06:08:40,160 ALSO CLINICAL EXPERIENCE NOW 8619 06:08:40,160 --> 06:08:43,760 GOING ON. 8620 06:08:43,760 --> 06:08:46,280 I THINK IT'S GOING TO BE 8621 06:08:46,280 --> 06:08:48,800 IMPORTANT TO WATCH. 8622 06:08:48,800 --> 06:08:49,920 >> MARRAH, THAT'S A GOOD 8623 06:08:49,920 --> 06:08:50,440 COMMENT, FRANK. 8624 06:08:50,440 --> 06:08:51,920 IF I COULD MAKE A COMMENT. 8625 06:08:51,920 --> 06:08:55,240 THERE'S BEEN A LOT OF ACTIVITY 8626 06:08:55,240 --> 06:08:58,800 ON RENAL DISEASE, AND 8627 06:08:58,800 --> 06:09:01,400 NEPHROTOXICITY AND STATING THIS 8628 06:09:01,400 --> 06:09:04,360 IS IT'S AN UNDER STUDIED AREA, 8629 06:09:04,360 --> 06:09:06,680 IMPORTANT IN THE FUTURE WITH 8630 06:09:06,680 --> 06:09:08,200 PATIENTS ON HEMT. 8631 06:09:08,200 --> 06:09:09,840 CAN ANYBODY -- I DIDN'T THINK 8632 06:09:09,840 --> 06:09:15,080 THERE WAS KIDNEY DISEASE IN CF 8633 06:09:15,080 --> 06:09:15,320 PATIENTS. 8634 06:09:15,320 --> 06:09:18,480 I FEEL UNINFORMED OTHER THE FACT 8635 06:09:18,480 --> 06:09:19,400 IT'S ANTIBIOTIC USAGE, 8636 06:09:19,400 --> 06:09:20,960 OFF-TARGET DRUG USAGE. 8637 06:09:20,960 --> 06:09:21,520 IS THERE SOMETHING THAT'S 8638 06:09:21,520 --> 06:09:27,800 FUNDAMENTAL TO THE LACK OF CFTR 8639 06:09:27,800 --> 06:09:29,520 IN THE KIDNEY THAT LEADS TO 8640 06:09:29,520 --> 06:09:30,400 DISEASE STATE? 8641 06:09:30,400 --> 06:09:35,320 FELIX OR SOMEBODY THAT'S A 8642 06:09:35,320 --> 06:09:35,600 CLINICIAN? 8643 06:09:35,600 --> 06:09:35,760 JEN? 8644 06:09:35,760 --> 06:09:38,720 >> CAN YOU HEAR ME? 8645 06:09:38,720 --> 06:09:45,640 8646 06:09:45,640 --> 06:09:46,160 8647 06:09:46,160 --> 06:09:48,040 >> THIS IS AGNES, A PRINCIPAL 8648 06:09:48,040 --> 06:09:48,600 INVESTIGATOR NEPHROLOGIST, 8649 06:09:48,600 --> 06:09:58,920 WATCHING THIS AREA TO DEVELOP. 8650 06:09:58,920 --> 06:10:07,480 CFTR IS EXPRESSING SEGMENTS, IT 8651 06:10:07,480 --> 06:10:18,000 HAS DEVELOPED -- IT IS POORLY 8652 06:10:20,880 --> 06:10:21,120 UNDERSTAND. 8653 06:10:21,120 --> 06:10:22,560 IT MUST HAVE HAVE A ROLE, 8654 06:10:22,560 --> 06:10:24,520 PRESENT IN THE KIDNEY. 8655 06:10:24,520 --> 06:10:25,920 MORE FOCUS ON UNDERSTANDING 8656 06:10:25,920 --> 06:10:27,240 DEVELOPMENTAL ROLE IN THE KIDNEY 8657 06:10:27,240 --> 06:10:30,320 WILL BE VERY IMPORTANT TO INFORM 8658 06:10:30,320 --> 06:10:30,960 WHAT TO EXPECT. 8659 06:10:30,960 --> 06:10:41,440 I THINK AS WE'RE GOING TO BE 8660 06:12:58,760 --> 06:13:00,200 AGED, WE CAN MODULATE. 8661 06:13:00,200 --> 06:13:02,200 >> FOR PATIENTS WITH DIFFERENT 8662 06:13:02,200 --> 06:13:04,480 MUTATIONS, WHO RESPOND 8663 06:13:04,480 --> 06:13:05,680 DIFFERENTLY TO MODULATORS OR WHO 8664 06:13:05,680 --> 06:13:10,920 MAY NOT BE ON MODULATORS, MAKING 8665 06:13:10,920 --> 06:13:12,920 SURE THAT WE'RE CAPTURING IT'S 8666 06:13:12,920 --> 06:13:14,240 RIGHT RESEARCH QUESTIONS FOR ALL 8667 06:13:14,240 --> 06:13:18,720 GROUPS, AND SO THAT COMMENT WAS 8668 06:13:18,720 --> 06:13:20,600 ALSO RAISED EARLIER, I'M GOING 8669 06:13:20,600 --> 06:13:23,560 TO READ THIS, IT'S DIFFICULT TO 8670 06:13:23,560 --> 06:13:25,400 COMPLETELY ADJUST SURVIVAL 8671 06:13:25,400 --> 06:13:27,480 MODELS FOR THIS PROBLEM. 8672 06:13:27,480 --> 06:13:29,800 BECAUSE IT TAKES TIME TO ACCRUE 8673 06:13:29,800 --> 06:13:36,240 THE DISEASE IN THE PHENOTYPE. 8674 06:13:36,240 --> 06:13:37,520 THINKING ABOUT ADDITIONAL GAPS 8675 06:13:37,520 --> 06:13:39,400 MOVING INTO DAY 2 WILL BE MORE 8676 06:13:39,400 --> 06:13:40,720 THAN, ADDING TO THE DISCUSSION 8677 06:13:40,720 --> 06:13:41,280 FOR TOMORROW. 8678 06:13:41,280 --> 06:13:44,880 SO I WANT TO THANK YOU ALL FOR 8679 06:13:44,880 --> 06:13:46,320 YOUR PARTICIPATION TODAY AND 8680 06:13:46,320 --> 06:13:47,000 LOOK FORWARD TO ANOTHER LIVELY 8681 06:13:47,000 --> 00:00:00,000 AND FULL DAY TOMORROW.