1 00:00:05,080 --> 00:00:06,680 >> WELCOME EVERYONE TO THE 2 00:00:06,680 --> 00:00:08,320 SECOND DAY OF OUR SYMPOSIUM. 3 00:00:08,320 --> 00:00:10,640 WE'RE VERY EXCITED WITH ALL THE 4 00:00:10,640 --> 00:00:13,800 WONDERFUL PRESENTATIONS AND 5 00:00:13,800 --> 00:00:15,320 DISCUSSION FROM YESTERDAY SO WE 6 00:00:15,320 --> 00:00:16,680 KNOW TODAY WILL BE EQUALLY AS 7 00:00:16,680 --> 00:00:18,520 EXCITING. 8 00:00:18,520 --> 00:00:24,120 SO I WANTED TO INTRODUCE THE 9 00:00:24,120 --> 00:00:31,920 MODERATOR FOR THE PART THREE AND 10 00:00:31,920 --> 00:00:40,240 THAT'S DR. MAY MALICDAN AND SHE 11 00:00:40,240 --> 00:00:46,160 IS QUITE AN EXPERT REGARDING 12 00:00:46,160 --> 00:00:47,920 PERIPHERAL NERVOUS SYSTEM AND 13 00:00:47,920 --> 00:00:51,880 NEURO MUSCULAR DISEASES AND AN 14 00:00:51,880 --> 00:00:54,360 EXPERT ON A RARE DISEASE CALLED 15 00:00:54,360 --> 00:00:58,720 SPG3A AND HAPPY TO HAVE HER AS A 16 00:00:58,720 --> 00:01:00,120 SCIENTIST STUDYING RARE 17 00:01:00,120 --> 00:01:00,480 DISEASES. 18 00:01:00,480 --> 00:01:01,720 I'LL LET HER TAKE OVER. 19 00:01:01,720 --> 00:01:03,800 THANK YOU VERY MUCH. 20 00:01:03,800 --> 00:01:05,360 >> THANK YOU VERY MUCH. 21 00:01:05,360 --> 00:01:11,680 IT'S A VERY NICE INTRODUCTION. 22 00:01:11,680 --> 00:01:13,680 THIS MORNING WE HAVE SIX VERY 23 00:01:13,680 --> 00:01:17,160 EXCITE BEING TOPICS GOING FROM 24 00:01:17,160 --> 00:01:18,080 PATIENT-DERIVED CELLS TO MOUSE 25 00:01:18,080 --> 00:01:19,720 MODELS YOU'LL HEAR LATER AND THE 26 00:01:19,720 --> 00:01:22,440 GOALS OF UNDERSTANDING THE 27 00:01:22,440 --> 00:01:24,360 MECHANISM OF EFFECTS AND THE 28 00:01:24,360 --> 00:01:29,720 OVERALL GOAL AND AIM OF 29 00:01:29,720 --> 00:01:30,640 IDENTIFYING AVENUES FOR FUTURE 30 00:01:30,640 --> 00:01:31,440 TREATMENT. 31 00:01:31,440 --> 00:01:35,720 OUR FIRST TWO SPEAKERS WOULD 32 00:01:35,720 --> 00:01:39,760 PRESENT AS ARIANE SAID AND A 33 00:01:39,760 --> 00:01:42,120 BRIEF QUESTION AND ANSWER AND 34 00:01:42,120 --> 00:01:44,920 THE FIRST IS DR. TRAYNOR AT THE 35 00:01:44,920 --> 00:01:46,920 NATIONAL INSTITUTES ON AGING. 36 00:01:46,920 --> 00:01:50,200 A MEMBER OF THE NIH GENE THERAPY 37 00:01:50,200 --> 00:01:51,520 TASK FORCE. 38 00:01:51,520 --> 00:01:54,160 HE LED THE CONSORTIUM THAT 39 00:01:54,160 --> 00:02:01,280 IDENTIFIED THE NUCLEO PEPTIDES 40 00:02:01,280 --> 00:02:05,920 IN THE GENE AND RECEIVED HIS MTD 41 00:02:05,920 --> 00:02:09,280 FROM THE UNIVERSITY OF COLLEGE 42 00:02:09,280 --> 00:02:12,840 LONDON AND HE CON COMPLETED A 43 00:02:12,840 --> 00:02:14,520 NEUROLOGY RESIDENCY AT THE 44 00:02:14,520 --> 00:02:19,280 CHILDREN'S HOSPITAL AT BRIGHAM 45 00:02:19,280 --> 00:02:23,640 AND WOMEN'S HOSPITAL IN BOSTON. 46 00:02:23,640 --> 00:02:26,320 AFTER DR. BLACKSTONE WILL BE 47 00:02:26,320 --> 00:02:26,720 PRESENTING. 48 00:02:26,720 --> 00:02:30,120 HE RECEIVED HIS Ph.D. FROM JOHNS 49 00:02:30,120 --> 00:02:30,760 HOPKINS UNIVERSITY AND HE 50 00:02:30,760 --> 00:02:34,120 COMPLETED A FELLOWSHIP IN 51 00:02:34,120 --> 00:02:35,080 CLINICAL MOVEMENT DISORDER AT 52 00:02:35,080 --> 00:02:35,920 THE MASSACHUSETTS GENERAL 53 00:02:35,920 --> 00:02:36,280 HOSPITAL. 54 00:02:36,280 --> 00:02:39,200 DURING THIS TIME HE ALSO 55 00:02:39,200 --> 00:02:39,920 CONDUCTED POST-DOCTORAL RESEARCH 56 00:02:39,920 --> 00:02:41,040 AT HARVARD MEDICAL SCHOOL 57 00:02:41,040 --> 00:02:43,920 INVESTIGATING THE FUNCTIONS OF 58 00:02:43,920 --> 00:02:45,800 PROTEINS IMPLICATED IN 59 00:02:45,800 --> 00:02:48,280 HEREDITARY DEPLOYMENTS AN JOINED 60 00:02:48,280 --> 00:02:52,880 AS AN INVESTIGATOR AND HIS 61 00:02:52,880 --> 00:02:55,920 LABORATORY INVESTIGATED CELLULAR 62 00:02:55,920 --> 00:02:59,920 MECHANISMS UNDERLYING 63 00:02:59,920 --> 00:03:09,760 INHEREDITARY MOVEMENT DISORDER 64 00:03:09,760 --> 00:03:16,760 AND HE LOOKS AT HEREDITARY PERI 65 00:03:16,760 --> 00:03:18,600 >>I WANT TO SAY UP 66 00:03:18,600 --> 00:03:22,960 FRONT THANK YOU SO MUCH FOR THE 67 00:03:22,960 --> 00:03:27,680 INVITATION TO PRESENT TO YOU 68 00:03:27,680 --> 00:03:35,160 THIS MORNING AND THANK YOU FOR 69 00:03:35,160 --> 00:03:38,000 YOUR TIME LISTENING. 70 00:03:38,000 --> 00:03:43,360 NIA AND NCATS LINE FOR RARE 71 00:03:43,360 --> 00:03:44,400 DISEASE THERAPEUTICS. 72 00:03:44,400 --> 00:03:45,520 IF YOU THINK ABOUT IT, IT'S 73 00:03:45,520 --> 00:03:46,800 REALLY WHAT I WANT TO TALK ABOUT 74 00:03:46,800 --> 00:03:49,800 TODAY IS OUR WORK IN THE GENE 75 00:03:49,800 --> 00:03:53,840 THERAPY SPACE. 76 00:03:53,840 --> 00:03:57,480 AND OUR DEVELOPMENT TRYING TO 77 00:03:57,480 --> 00:04:01,680 HELP PLATFORMS FOR TREATMENTS 78 00:04:01,680 --> 00:04:05,480 FOR RARE AND ULTRA RARE 79 00:04:05,480 --> 00:04:05,760 DISEASES. 80 00:04:05,760 --> 00:04:07,320 I LIKE TO START BY GIVING A 81 00:04:07,320 --> 00:04:08,720 SUMMARY UP FRONT WHAT I'M GOING 82 00:04:08,720 --> 00:04:13,280 TO TALK ABOUT BECAUSE I THINK 83 00:04:13,280 --> 00:04:15,360 THAT SERVES TO ORIENTATE 84 00:04:15,360 --> 00:04:18,200 EVERYBODY BECAUSE IT'S NOT GOING 85 00:04:18,200 --> 00:04:23,160 TO BE A TALK FOCUSSED ON SPG4 86 00:04:23,160 --> 00:04:25,960 IT'S BROADER AND APPLIES TO THE 87 00:04:25,960 --> 00:04:27,320 DISEASE OF INTEREST AT THIS 88 00:04:27,320 --> 00:04:28,960 PARTICULAR CONFERENCE. 89 00:04:28,960 --> 00:04:30,600 REALLY, THE MESSAGE WANT TO 90 00:04:30,600 --> 00:04:34,000 CONVEY IS THAT WE HAVE SET UP A 91 00:04:34,000 --> 00:04:37,520 NEW LABORATORY OVER AT NCATS THE 92 00:04:37,520 --> 00:04:40,080 NAME IS THE RNA THERAPEUTICS 93 00:04:40,080 --> 00:04:42,000 LABORATORY AND AS THE NAME 94 00:04:42,000 --> 00:04:43,560 SUGGESTS THE REAL AIM HERE AND 95 00:04:43,560 --> 00:04:47,840 OVER ARCHING PURPOSE OF THIS 96 00:04:47,840 --> 00:04:52,560 LABORATORY IS TO DEVELOP ASO FOR 97 00:04:52,560 --> 00:04:54,280 RARE AND ULTRA RARE DISEASES. 98 00:04:54,280 --> 00:05:00,000 THERE'S MANY FACET TO THIS 99 00:05:00,000 --> 00:05:01,680 PARTICULAR PROGRAM IN TERMS OF 100 00:05:01,680 --> 00:05:05,360 DELIVERY AND MANUFACTURING BUT 101 00:05:05,360 --> 00:05:10,960 THE ONE I WANT TO TALK IS IN 102 00:05:10,960 --> 00:05:13,400 VITRO CELL-BASED MODELS TO 103 00:05:13,400 --> 00:05:16,640 PREVENT THE TOXICOLOGY WITH THIS 104 00:05:16,640 --> 00:05:19,520 NEW CLASS OF THERAPIES. 105 00:05:19,520 --> 00:05:21,160 IT'S TOXICOLOGY THAT PREVENTED 106 00:05:21,160 --> 00:05:23,400 THE WIDER USE OF ASOs IN THE 107 00:05:23,400 --> 00:05:25,200 GENERAL POPULATION. 108 00:05:25,200 --> 00:05:27,320 IF WE CAN LICK THAT, I THINK WE 109 00:05:27,320 --> 00:05:27,920 CAN START TO USE THESE MORE 110 00:05:27,920 --> 00:05:35,560 BROADLY. 111 00:05:35,560 --> 00:05:37,520 THE OTHER POINT AND I KNOW MANY 112 00:05:37,520 --> 00:05:39,360 ON THE CALL YOU ARE ALL VERY 113 00:05:39,360 --> 00:05:46,040 USED TO ME TALKING ABOUT LOU 114 00:05:46,040 --> 00:05:48,880 GHERIG'S DISEASE ALL THE TIME. 115 00:05:48,880 --> 00:05:51,360 THOUGH ALS IS STILL CLOSE TO MY 116 00:05:51,360 --> 00:05:57,200 HEART AND WE'RE STILL USING ALS 117 00:05:57,200 --> 00:05:59,360 AS A TEST BED FOR TREATMENT OF 118 00:05:59,360 --> 00:06:05,160 ACUTE NEUROLOGICAL OR CHRONIC 119 00:06:05,160 --> 00:06:07,360 NEURODEGENERATIVE DISEASES, THIS 120 00:06:07,360 --> 00:06:09,360 HAS A BROADER SCOPE, THIS WHOLE 121 00:06:09,360 --> 00:06:09,600 PROGRAM. 122 00:06:09,600 --> 00:06:15,320 IT'S MORE FOCUSSED ON RARE AND 123 00:06:15,320 --> 00:06:17,760 ULTRA RARE DISEASES NOT JUST 124 00:06:17,760 --> 00:06:18,040 ALS. 125 00:06:18,040 --> 00:06:19,960 SO WITH THAT IN MIND, I JUST 126 00:06:19,960 --> 00:06:24,680 WANT TO START OFF BY TALKING A 127 00:06:24,680 --> 00:06:25,960 LITTLE BIT ABOUT WHAT IS -- WHY 128 00:06:25,960 --> 00:06:28,640 IS IT IMPORTANT TO GO AFTER AND 129 00:06:28,640 --> 00:06:30,040 TRY TO TREAT THESE RARE AND 130 00:06:30,040 --> 00:06:31,360 ULTRA RARE DISEASES. 131 00:06:31,360 --> 00:06:33,560 I THINK THE NEXT COUPLE OF 132 00:06:33,560 --> 00:06:35,880 STARTS WE'LL TRY TO GET ACROSS 133 00:06:35,880 --> 00:06:38,560 HOW IMPORTANT THESE ARE TO THE 134 00:06:38,560 --> 00:06:38,880 COMMUNITY. 135 00:06:38,880 --> 00:06:42,000 YOU SEE HERE ON THE RIGHT-HAND 136 00:06:42,000 --> 00:06:47,640 SIDE A SCREEN SHOT FROM THE 137 00:06:47,640 --> 00:06:48,160 WEBSITE THAT TRACKS THE 138 00:06:48,160 --> 00:06:50,360 OCCURRENCE OF THE DEFINITION OF 139 00:06:50,360 --> 00:06:53,560 RARE AND ULTRA RARE DISEASES 140 00:06:53,560 --> 00:06:55,840 GLOBALLY AND THEY REPORT THERE'S 141 00:06:55,840 --> 00:06:56,760 NEARLY 10,000 TYPES OF RARE 142 00:06:56,760 --> 00:06:59,360 DISEASES FOR WHICH WE KNOW THE 143 00:06:59,360 --> 00:07:02,800 UNDERLYING GENETIC DEFECT IN 144 00:07:02,800 --> 00:07:04,440 ABOUT 7,000 TO 8,000. 145 00:07:04,440 --> 00:07:06,920 WHILE THE NUMBERS ARE HIGH, I 146 00:07:06,920 --> 00:07:09,080 DON'T THINK THEY CONVEY THE 147 00:07:09,080 --> 00:07:10,640 MASSIVE SCALE OF THE PROBLEM. 148 00:07:10,640 --> 00:07:13,720 WHEN YOU THINK OF IT IN ABSOLUTE 149 00:07:13,720 --> 00:07:15,760 NUMBERS IT TURNS OUT ACCORDING 150 00:07:15,760 --> 00:07:18,040 TO THE BEST ESTIMATES THERE'S 151 00:07:18,040 --> 00:07:27,360 HALF A BILLION PEOPLE WORLDWIDE 152 00:07:27,360 --> 00:07:29,040 WHO SUFFER FROM RARE DISEASES 153 00:07:29,040 --> 00:07:30,800 AND THAT'S RARE ULTRA RARE BUT 154 00:07:30,800 --> 00:07:32,640 I'M TALKING ABOUT THE ULTRA 155 00:07:32,640 --> 00:07:33,680 RARE, THE RAREST OF THE RARE 156 00:07:33,680 --> 00:07:37,160 TYPES OF DISEASES, THAT NUMBER 157 00:07:37,160 --> 00:07:39,160 SHRINKS TO ABOUT 4 MILLION. 158 00:07:39,160 --> 00:07:40,680 I STILL THINK IS QUITE A BIG 159 00:07:40,680 --> 00:07:43,120 NUMBER BECAUSE IT'S ABOUT THE 160 00:07:43,120 --> 00:07:45,560 POPULATION OF IRELAND AND OF 161 00:07:45,560 --> 00:07:53,680 COURSE I'M IRISH SO I THINK 162 00:07:53,680 --> 00:07:57,840 IT'S A BIG NUMBER AND ASSOCIATED 163 00:07:57,840 --> 00:07:58,920 WITH THAT AS THE MASSIVE HEALTH 164 00:07:58,920 --> 00:08:00,480 CARE COSTS TO THE COMMUNITY. 165 00:08:00,480 --> 00:08:02,960 I THINK THE NIH AND IN 166 00:08:02,960 --> 00:08:03,520 PARTICULAR THE INTRAMURAL 167 00:08:03,520 --> 00:08:05,960 PROGRAM IS A REALLY GOOD PLACE 168 00:08:05,960 --> 00:08:09,520 TO GO AFTER THESE TYPES OF 169 00:08:09,520 --> 00:08:10,600 DISEASES BECAUSE THE LOW NUMBER 170 00:08:10,600 --> 00:08:12,360 OF THEM, THE LOW NUMBER OF 171 00:08:12,360 --> 00:08:15,880 OCCURRENCE OF PATIENTS FOR EACH 172 00:08:15,880 --> 00:08:18,760 PARTICULAR RARE DISEASES MEANS 173 00:08:18,760 --> 00:08:20,560 THEY'RE NOT GOING ATTRACTIVE ANY 174 00:08:20,560 --> 00:08:21,560 COMMERCIAL INTEREST AT LEAST NOT 175 00:08:21,560 --> 00:08:23,160 IN THE NEAR TERM. 176 00:08:23,160 --> 00:08:25,160 MAYBE 10 YEARS FROM NOW BUT NOT 177 00:08:25,160 --> 00:08:26,080 IN THE NEAR TERM. 178 00:08:26,080 --> 00:08:29,520 I THINK BECAUSE OF THAT THE NIH 179 00:08:29,520 --> 00:08:30,840 CAN FILL IN THAT PARTICULAR 180 00:08:30,840 --> 00:08:31,080 VACUUM. 181 00:08:31,080 --> 00:08:32,840 THE OTHER POINT IS BECAUSE WARE 182 00:08:32,840 --> 00:08:34,760 TALKING ABOUT SO MANY DITCH 183 00:08:34,760 --> 00:08:38,280 TYPES OF DISEASES, 10,000, IT 184 00:08:38,280 --> 00:08:40,520 LENDS TO SELF TO THIS NOTION OF 185 00:08:40,520 --> 00:08:41,960 A PLATFORM DEVELOPMENT SO WE'RE 186 00:08:41,960 --> 00:08:44,840 NOT GOING AFTER TRYING TO DO ONE 187 00:08:44,840 --> 00:08:46,480 DISEASE AT A TIME BUT RATHER DO 188 00:08:46,480 --> 00:08:51,320 IT ACROSS THE GAMUT OF RARE AND 189 00:08:51,320 --> 00:08:52,440 ULTRA RARE DISEASES. 190 00:08:52,440 --> 00:08:55,320 NOW ONE OF THE KEY POINTS ABOUT 191 00:08:55,320 --> 00:08:58,360 THE RARE DISEASES IS IF YOU GO 192 00:08:58,360 --> 00:09:01,440 DOWN AND LOOK AT IT, THE VAST 193 00:09:01,440 --> 00:09:03,960 MAJORITY OF RARE AND ULTRA RARE 194 00:09:03,960 --> 00:09:06,880 DISEASES, THEY AFFECT THE 195 00:09:06,880 --> 00:09:07,560 CENTRAL NERVOUS SYSTEM IN ONE 196 00:09:07,560 --> 00:09:08,880 FORM OR ANOTHER. 197 00:09:08,880 --> 00:09:10,400 THE REASON WHY THAT'S IMPORTANT 198 00:09:10,400 --> 00:09:15,080 IS IS BECAUSE IN ORDER TO TREAT 199 00:09:15,080 --> 00:09:20,680 THEM WITH ANTISENSE OLIGOS WE 200 00:09:20,680 --> 00:09:23,960 HAVE TO TREAT THEM THROUGH THE 201 00:09:23,960 --> 00:09:25,360 LUMBAR SPINE AND THE NEUROTOX 202 00:09:25,360 --> 00:09:28,000 SIDE EFFECTS ONE SEES WITH THIS 203 00:09:28,000 --> 00:09:33,280 TYPE OF MEDICATION IS SOMETHING 204 00:09:33,280 --> 00:09:34,840 WE HAVE TO CONSIDER AND CAN 205 00:09:34,840 --> 00:09:35,880 BECOME A LIMITING FACTOR IN 206 00:09:35,880 --> 00:09:38,760 TERMS OF WHAT WE CAN ADMINISTER. 207 00:09:38,760 --> 00:09:41,560 THE OTHER KEY FACT AND 208 00:09:41,560 --> 00:09:42,480 COMMONALITY THE RARE AND YOU 209 00:09:42,480 --> 00:09:46,480 WILL RA RARE DISEASE HAVE IN 210 00:09:46,480 --> 00:09:48,520 COMMON IS FOR THE VAST MAJORITY 211 00:09:48,520 --> 00:09:50,080 NO EFFECT OF TREATMENT FOR MANY 212 00:09:50,080 --> 00:09:51,320 OF THEM. 213 00:09:51,320 --> 00:09:55,760 WE'RE TALKING PREDOMINANTLY 214 00:09:55,760 --> 00:09:58,120 SYMPTOMATIC TREATMENT FOR THIS 215 00:09:58,120 --> 00:09:58,400 POPULATION. 216 00:09:58,400 --> 00:09:59,720 THAT BEING SAID, THERE ARE 217 00:09:59,720 --> 00:10:03,280 ACTUAL GLIMMERS OF HOPE. 218 00:10:03,280 --> 00:10:06,520 THIS IS A PICTURE YOU SEE ON THE 219 00:10:06,520 --> 00:10:10,720 LEFT OF YOUR SCREEN WHO IS A 220 00:10:10,720 --> 00:10:12,240 NEUROLOGIST AT BOSTON CHILDREN'S 221 00:10:12,240 --> 00:10:13,640 HOSPITAL AND SAW THIS YOUNG GIRL 222 00:10:13,640 --> 00:10:18,000 IN HIS CLINIC WITH A PROFOUND 223 00:10:18,000 --> 00:10:19,880 EPILEPSY DISORDER. 224 00:10:19,880 --> 00:10:22,840 HE SEQUENCED MILA'S GENOME, 225 00:10:22,840 --> 00:10:24,360 FOUND THE UNDERLYING MUTATION 226 00:10:24,360 --> 00:10:28,120 AND THEN TURNED HIS LABORATORY 227 00:10:28,120 --> 00:10:30,040 AROUND AND SPENT ABOUT 9 TO 18 228 00:10:30,040 --> 00:10:36,000 MONTHS DEVELOPING A TREATMENT 229 00:10:36,000 --> 00:10:37,880 FOR THIS YOUNGER GIRL AND WAS 230 00:10:37,880 --> 00:10:39,200 ELEGANTLY SHOW HIS TREATMENT WAS 231 00:10:39,200 --> 00:10:46,000 ABLE TO DECREASE THE SEIZURE 232 00:10:46,000 --> 00:10:47,160 RATE UNFORTUNATELY SHE SUCCUMBED 233 00:10:47,160 --> 00:10:49,800 TO HER DISEASE LAST YEAR BUT HE 234 00:10:49,800 --> 00:10:52,120 SHOWED ELEGANTLY THE SCIENCE IS 235 00:10:52,120 --> 00:10:52,920 POSSIBLE. 236 00:10:52,920 --> 00:10:56,040 THE SCIENCE OF DEVELOPING AN ASO 237 00:10:56,040 --> 00:10:57,680 THERAPY PERSONALIZED TO ONE 238 00:10:57,680 --> 00:10:58,160 PATIENT IS POSSIBLE. 239 00:10:58,160 --> 00:10:59,960 THE PROBLEM FACING US NOW IS HOW 240 00:10:59,960 --> 00:11:01,320 DO WE OPERATIONALIZE THIS AND 241 00:11:01,320 --> 00:11:04,480 MOVE IT FROM A ONE-OFF FOR ONE 242 00:11:04,480 --> 00:11:08,640 PATIENT TO BE ABLE TO ACTUALLY 243 00:11:08,640 --> 00:11:10,160 DEVELOP IT FOR VIRTUALLY EVERY 244 00:11:10,160 --> 00:11:12,000 PATIENT WOULD PRESENTS TO US 245 00:11:12,000 --> 00:11:14,040 WITH A KNOWN RARE DISEASE AND 246 00:11:14,040 --> 00:11:16,200 KNOWN UNDERLYING GENETIC 247 00:11:16,200 --> 00:11:17,000 MUTATION? 248 00:11:17,000 --> 00:11:19,360 AGAIN, WHAT WE'RE TALKING ABOUT 249 00:11:19,360 --> 00:11:20,760 HERE IS REALLY DEVELOPING 250 00:11:20,760 --> 00:11:23,120 PLATFORMS TO REALLY TREAT ACROSS 251 00:11:23,120 --> 00:11:27,160 THE GAMUT OF RARE AND ULTRA RARE 252 00:11:27,160 --> 00:11:27,440 DISEASES. 253 00:11:27,440 --> 00:11:30,080 NOW, WHEN YOU LOOK AT WHAT TIM 254 00:11:30,080 --> 00:11:31,840 DID, IT CAUSED HIM ABOUT $2 255 00:11:31,840 --> 00:11:33,360 MILLION AND TO BE HONEST THAT 256 00:11:33,360 --> 00:11:36,800 WAS THE BARGAIN BASEMENT LEVEL 257 00:11:36,800 --> 00:11:38,800 OF DEVELOPMENT AND IT TOOK HIM 258 00:11:38,800 --> 00:11:40,080 AS I SAY NINE AND 12 MONTHS TO 259 00:11:40,080 --> 00:11:42,000 DO THAT. 260 00:11:42,000 --> 00:11:44,480 NOW, IF YOU DELVE DOWN INTO 261 00:11:44,480 --> 00:11:46,200 THIS, A LOT OF WHAT HAS TO 262 00:11:46,200 --> 00:11:48,320 HAPPEN BETWEEN THE DISCOVERY OF 263 00:11:48,320 --> 00:11:50,440 THE ACTUAL MUTATION AND GETTING 264 00:11:50,440 --> 00:11:55,320 YOUR TREATMENT INTO THE PATIENTS 265 00:11:55,320 --> 00:11:58,240 FOR THEIR FIRST IN-HUMAN STUDIES 266 00:11:58,240 --> 00:11:59,880 AND A LOT HAS TO HAPPEN BUT WHEN 267 00:11:59,880 --> 00:12:05,080 YOU DRILL DOWN THERE ARE TWO 268 00:12:05,080 --> 00:12:08,760 PARTS TO IT. 269 00:12:08,760 --> 00:12:12,760 THEY ACT AS LINCHPINS THAT DRIVE 270 00:12:12,760 --> 00:12:15,760 THE COST AND TAKE TIME TO 271 00:12:15,760 --> 00:12:16,760 ACTUALLY COMPLETE. 272 00:12:16,760 --> 00:12:20,360 THEY ARE GMP MANUFACTURING AND 273 00:12:20,360 --> 00:12:21,400 EXPLORATORY ANIMAL TOXICOLOGY 274 00:12:21,400 --> 00:12:23,360 WHICH IS MANDATED BY THE FDA 275 00:12:23,360 --> 00:12:25,560 BEFORE YOU CAN ACTUALLY PUT 276 00:12:25,560 --> 00:12:28,520 THESE THERAPIES INTO HUMANS. 277 00:12:28,520 --> 00:12:32,080 AS I SAY, NOT ONLY ARE THEY COST 278 00:12:32,080 --> 00:12:33,840 SENSE BUT TIME SENSE. 279 00:12:33,840 --> 00:12:40,600 WE WANT TO NARROW THAT DOWN AS 280 00:12:40,600 --> 00:12:41,560 MUCH POSSIBLE BECAUSE WE HAVE 281 00:12:41,560 --> 00:12:44,320 THE SENSE OF URGENCY TO TRY AND 282 00:12:44,320 --> 00:12:47,360 GET THE TREATMENT INTO THE 283 00:12:47,360 --> 00:12:48,080 PATIENT AS QUICKLY AS POSSIBLE. 284 00:12:48,080 --> 00:12:51,360 SO OF COURSE THIS IS ACTUALLY 285 00:12:51,360 --> 00:12:53,000 WHERE NCATS ENTERS INTO THE 286 00:12:53,000 --> 00:12:53,200 STORY. 287 00:12:53,200 --> 00:12:55,880 SO NCATS, AS MANY OF YOU KNOW, 288 00:12:55,880 --> 00:12:57,520 THE NATIONAL CENTER FOR 289 00:12:57,520 --> 00:12:58,760 ADVANCING TRANSLATIONAL SCIENCES 290 00:12:58,760 --> 00:13:06,000 IS AN INSTITUTE AND THE CORE 291 00:13:06,000 --> 00:13:08,400 MISSION IS TO DRIVE TREATMENTS 292 00:13:08,400 --> 00:13:10,160 FROM THE LABORATORY INTO THE 293 00:13:10,160 --> 00:13:12,280 PATIENTS AS QUICKLY AS POSSIBLE. 294 00:13:12,280 --> 00:13:14,000 OF COURSE WE SAW AN OPPORTUNITY 295 00:13:14,000 --> 00:13:15,360 HERE IN OUR CRAZY WAY OF 296 00:13:15,360 --> 00:13:18,040 THINKING ABOUT IT, WHAT COULD WE 297 00:13:18,040 --> 00:13:21,320 DO TO INSTEAD OF COST -- TAKE 18 298 00:13:21,320 --> 00:13:23,320 MONTHS AND $2 MILLION, WHAT 299 00:13:23,320 --> 00:13:25,720 COULD WE DO TO DRIVE IT DOWN TO 300 00:13:25,720 --> 00:13:27,360 6 MONTHS AND $100,000? 301 00:13:27,360 --> 00:13:28,440 SOMETHING THAT COULD BE RAISED 302 00:13:28,440 --> 00:13:31,360 BY A LOCAL KICK STARTER 303 00:13:31,360 --> 00:13:32,000 CAMPAIGN. 304 00:13:32,000 --> 00:13:34,360 OF COURSE, THIS IS A NAIVE WAY 305 00:13:34,360 --> 00:13:37,400 OF THINKING ABOUT IT AND THIS IS 306 00:13:37,400 --> 00:13:37,800 HIGH-RISK SCIENCE. 307 00:13:37,800 --> 00:13:40,080 WE DO NOT KNOW IF WE'RE GOING 308 00:13:40,080 --> 00:13:41,760 SUCCESS BUT IF WE SUCCESS EVEN 309 00:13:41,760 --> 00:13:43,360 PARTIALLY I THINK WE'LL CHANGE 310 00:13:43,360 --> 00:13:45,840 THE LANDSCAPE FOR TREATMENT OF 311 00:13:45,840 --> 00:13:49,560 RARE AND ULTRA RARE DISEASES AND 312 00:13:49,560 --> 00:13:52,520 THE REAL FOCUS WAS TO DECREASE 313 00:13:52,520 --> 00:13:55,520 THE COST OF THE DEVELOPMENT TIME 314 00:13:55,520 --> 00:13:57,080 ASSOCIATED WITH THIS AND THIS IS 315 00:13:57,080 --> 00:13:58,760 ONE THING I LOVE ABOUT WORKING 316 00:13:58,760 --> 00:14:01,960 WITH THE NIH I GET TO COMBINE MY 317 00:14:01,960 --> 00:14:07,240 SKILLS AS A PHYSICIAN AND 318 00:14:07,240 --> 00:14:10,360 SCIENTIST AND WORK 319 00:14:10,360 --> 00:14:11,000 TRANSLATIONALLY AND COMBINE TO 320 00:14:11,000 --> 00:14:15,440 BRING THE STRENGTHS OF BOTH 321 00:14:15,440 --> 00:14:18,080 PROGRAMS TO BEAR ON THIS REAL 322 00:14:18,080 --> 00:14:24,360 CHALLENGE FOR HEALTH CARE. 323 00:14:24,360 --> 00:14:30,000 I WAS ABLE TO WORK WITH DON LOWE 324 00:14:30,000 --> 00:14:31,360 AT NCATS AND WE ESTABLISHED THIS 325 00:14:31,360 --> 00:14:33,160 RNA THERAPEUTICS LABORATORY 326 00:14:33,160 --> 00:14:35,360 WHICH HAS A REAL GOAL TO MAKE 327 00:14:35,360 --> 00:14:38,560 THESE ASOs ACCESSIBLE TO 328 00:14:38,560 --> 00:14:40,640 EVERYBODY REGARDLESS OF THEIR 329 00:14:40,640 --> 00:14:42,000 INCOME AND STATUS. 330 00:14:42,000 --> 00:14:43,920 NOW, ONE OF THE KEY ADVANTAGES 331 00:14:43,920 --> 00:14:46,640 THAT WE HAVE AT NCATS AND THE 332 00:14:46,640 --> 00:14:48,560 NIH IS WE'RE ACTUALLY A 333 00:14:48,560 --> 00:14:51,360 GOVERNMENT ENTITY, RIGHT. 334 00:14:51,360 --> 00:14:54,000 BECAUSE WE'RE A GOVERNMENT 335 00:14:54,000 --> 00:14:55,760 ENTITY WE CAN WORK MORE CLOSELY 336 00:14:55,760 --> 00:15:00,000 WITH THE FDA OUR SISTER 337 00:15:00,000 --> 00:15:02,480 GOVERNMENT ENTITY AND DISCUSS 338 00:15:02,480 --> 00:15:08,480 WITH THEM AT AN EARLY STAGE THE 339 00:15:08,480 --> 00:15:09,760 REGULATORY ASPECTS WITH THIS. 340 00:15:09,760 --> 00:15:11,600 AND WE SHARE A FELLOW WHO YOU'LL 341 00:15:11,600 --> 00:15:13,760 SEE A PICTURE OF LATER ON, SHE'S 342 00:15:13,760 --> 00:15:19,480 A SHARED FELLOW BETWEEN THE FDA 343 00:15:19,480 --> 00:15:22,080 AND NCATS AND THE FDA WHEN TALK 344 00:15:22,080 --> 00:15:24,040 TO THEM THEY'RE REALLY SMART 345 00:15:24,040 --> 00:15:27,400 SCIENTISTS AND PHYSICIANS AND 346 00:15:27,400 --> 00:15:29,120 KNOW THEY'RE FACING THIS TITLE 347 00:15:29,120 --> 00:15:31,360 WAVE, THIS TSUNAMI OF INDs AND 348 00:15:31,360 --> 00:15:32,720 APPROVAL APPLICATIONS COMING IN 349 00:15:32,720 --> 00:15:34,680 FOR ASOs. 350 00:15:34,680 --> 00:15:36,040 SO THEY REALLY WANT TO GET TO 351 00:15:36,040 --> 00:15:37,800 THE BOTTOM OF THIS AND THEY'RE 352 00:15:37,800 --> 00:15:39,360 VERY SMART AND VERY INTERESTED 353 00:15:39,360 --> 00:15:41,200 AND MOTIVATED TO TRY AND 354 00:15:41,200 --> 00:15:42,800 UNDERSTAND THE TOXICOLOGY OF 355 00:15:42,800 --> 00:15:54,000 THIS NEW CLASS OF MEDICATIONS. 356 00:15:54,000 --> 00:15:56,840 NOW, NCATS IS KNOWN FOR THE 357 00:15:56,840 --> 00:15:58,680 SCREENING AND WE WANT TO PLAY TO 358 00:15:58,680 --> 00:16:00,280 THAT AND A LARGE PART OF WHAT WE 359 00:16:00,280 --> 00:16:02,560 DO FOCUSES ON THE DEVELOPMENT OF 360 00:16:02,560 --> 00:16:06,960 WHAT IS A SUITE OF ASSESSES TO 361 00:16:06,960 --> 00:16:08,640 UNDERSTAND TOXICOLOGY ASSOCIATED 362 00:16:08,640 --> 00:16:11,800 WITH ASOs MORE FULLY. 363 00:16:11,800 --> 00:16:14,400 IN THE INTEREST OF TIME I'M 364 00:16:14,400 --> 00:16:15,400 GOING TO GIVE YOU ONE SUCH 365 00:16:15,400 --> 00:16:16,280 EXAMPLE OF IT. 366 00:16:16,280 --> 00:16:21,240 I THINK IT'S AN IMPORTANT ONE. 367 00:16:21,240 --> 00:16:26,440 IT'S THE ACUTE NEUROTOXICITY 368 00:16:26,440 --> 00:16:28,640 ASSOCIATED WITH ASSOS. 369 00:16:28,640 --> 00:16:31,360 AT THE 370 00:16:34,120 --> 00:16:36,360 ASOs AND MANY RARE DISEASES ARE 371 00:16:36,360 --> 00:16:37,480 ASSOCIATED WITH CNS EFFECTS AND 372 00:16:37,480 --> 00:16:42,000 BECAUSE OF THAT WE'LL HAVE TO 373 00:16:42,000 --> 00:16:45,160 INJECT THOSE ASOs INTRAFECALLY. 374 00:16:45,160 --> 00:16:47,360 THE PROBLEM IS YOU GET THIS 375 00:16:47,360 --> 00:16:50,600 ACUTE NEUROTOXICITY. 376 00:16:50,600 --> 00:16:52,600 LET ME DESCRIBE THIS. 377 00:16:52,600 --> 00:16:56,040 IF YOU INJECT A BAD OR TOXIC ASO 378 00:16:56,040 --> 00:16:58,640 INTO A MOUSE YOU GET A 379 00:16:58,640 --> 00:17:00,400 STEREOTYPED PHENOTYPE WHICH 380 00:17:00,400 --> 00:17:01,960 CONSISTS OF PARALYSIS THAT COMES 381 00:17:01,960 --> 00:17:03,200 ON WITHIN MINUTES AND LASTS FOR 382 00:17:03,200 --> 00:17:05,360 A NUMBER OF HOURS AND THEN WANES 383 00:17:05,360 --> 00:17:05,560 OFF. 384 00:17:05,560 --> 00:17:08,840 AND IT'S A VERY STEREOTYPED ONE. 385 00:17:08,840 --> 00:17:11,400 SO REGARDLESS OF WHICH GENE 386 00:17:11,400 --> 00:17:14,640 YOU'RE ASO IS TARGETING IT 387 00:17:14,640 --> 00:17:16,920 HAPPENS THE SAME WAY EVERY TIME 388 00:17:16,920 --> 00:17:19,200 YOU INJECT A BAD ASO. 389 00:17:19,200 --> 00:17:20,960 YOU DON'T WANT TO INJECT IT INTO 390 00:17:20,960 --> 00:17:23,360 A HUMAN, YOU'RE TRYING TO AVOID 391 00:17:23,360 --> 00:17:25,280 THAT BUT I'M TALKING ABOUT 392 00:17:25,280 --> 00:17:26,400 INJECTING THESE INTO MICE AND 393 00:17:26,400 --> 00:17:27,640 THE REASON WHY THIS HAPPENS OR 394 00:17:27,640 --> 00:17:29,960 WHAT WE THINK IS HAPPENING IS 395 00:17:29,960 --> 00:17:31,840 THE ASO BINDS TO THE SURFACE OF 396 00:17:31,840 --> 00:17:35,360 THE NEURON AND WHEN IT BINDS IT 397 00:17:35,360 --> 00:17:36,960 CAUSES ELECTRICAL SILENCING OF 398 00:17:36,960 --> 00:17:38,360 THAT NEURON BECAUSE OF THE 399 00:17:38,360 --> 00:17:41,800 MEMBRANE AND AS THE ASO GETS 400 00:17:41,800 --> 00:17:45,880 ABSORBED INTO THE NEURON BY 401 00:17:45,880 --> 00:17:47,600 ENDOCYTOSIS THE ELECTRICAL 402 00:17:47,600 --> 00:17:50,320 SILENCING GOES WAY AND THE 403 00:17:50,320 --> 00:17:52,760 NEURON CORRECTS ITSELF AND ABLE 404 00:17:52,760 --> 00:17:53,600 TO START OVER. 405 00:17:53,600 --> 00:17:56,240 THE REASONY EMPHASIZE THIS IS 406 00:17:56,240 --> 00:17:59,360 BECAUSE THIS PARTICULAR SIDE 407 00:17:59,360 --> 00:18:02,120 EFFECT LIMITS OUR SELECTION OF 408 00:18:02,120 --> 00:18:05,960 ASOs BROADLY LOOKING ACROSS THE 409 00:18:05,960 --> 00:18:08,200 GENOME AND ONCE HAVE YOU THE ASO 410 00:18:08,200 --> 00:18:10,680 IN HAND AND INJECT TO HUMANS IT 411 00:18:10,680 --> 00:18:13,320 LIMITS THE DOSE YOU CAN 412 00:18:13,320 --> 00:18:14,160 ADMINISTER. 413 00:18:14,160 --> 00:18:17,920 THIS IS THE KEY LINCHPIN IN 414 00:18:17,920 --> 00:18:20,840 TERMS OF TOXICITIES ASSOCIATED 415 00:18:20,840 --> 00:18:23,600 WITH THESE DISEASES AND TREATING 416 00:18:23,600 --> 00:18:25,680 THEM WITH ASOs. 417 00:18:25,680 --> 00:18:27,960 THE GOOD NEWS IS THIS IS 418 00:18:27,960 --> 00:18:29,320 SEQUENCE CONTENT AND CHEMISTRY 419 00:18:29,320 --> 00:18:29,920 SPECIFIC. 420 00:18:29,920 --> 00:18:32,360 AND BECAUSE OF THAT WE ACTUALLY 421 00:18:32,360 --> 00:18:35,600 THINK WE CAN PREDICT WITH THIS 422 00:18:35,600 --> 00:18:36,240 PARTICULAR TYPE OF TOXICITY 423 00:18:36,240 --> 00:18:42,720 USING IF WE GENERATE ENOUGH IN 424 00:18:42,720 --> 00:18:44,680 VITRO DATA AND APPLY THAT IN 425 00:18:44,680 --> 00:18:46,040 TERMS OF MACHINE LEARNING WE MAY 426 00:18:46,040 --> 00:18:50,120 BE ABLE TO PREDICT AHEAD OF TIME 427 00:18:50,120 --> 00:18:52,240 WHICH ASOs ARE BAD AND THE 428 00:18:52,240 --> 00:18:53,760 ABILITY TO PREDICT THIS MEANS 429 00:18:53,760 --> 00:18:58,200 THE ASOs CAN GET WEEDED OUT 430 00:18:58,200 --> 00:18:59,280 EARLY IN THE PROCESS. 431 00:18:59,280 --> 00:19:03,280 IT WILL SPEED UP OUR PROCESS AS 432 00:19:03,280 --> 00:19:10,440 WE GO ALONG AND INCREASE THE 433 00:19:10,440 --> 00:19:16,680 COST SOCIETIED WITH THE 434 00:19:16,680 --> 00:19:19,160 DEVELOPMENT -- ASSOCIATED WITH 435 00:19:19,160 --> 00:19:23,320 THIS DEVELOPMENT OF ASO. 436 00:19:23,320 --> 00:19:26,920 WE HAVE BEEN FORTUNATE TO WORK 437 00:19:26,920 --> 00:19:31,320 WITH A GROUP AT THE HEAD OF THE 438 00:19:31,320 --> 00:19:34,120 STEM CELL LABORATORY AT NCATS 439 00:19:34,120 --> 00:19:36,280 AND HAS AN ORGANOID ASSAY WE'VE 440 00:19:36,280 --> 00:19:39,680 ADAPTED TO SCREEN FOR THIS ACUTE 441 00:19:39,680 --> 00:19:40,160 TOXICITY. 442 00:19:40,160 --> 00:19:43,000 AND EACH OF THESE IS A LITTLE 443 00:19:43,000 --> 00:19:46,400 BALL ABOUT 300 MICRONS IN 444 00:19:46,400 --> 00:19:47,760 DIAMETER CONTAINING ABOUT 10,000 445 00:19:47,760 --> 00:19:52,640 NEURONS AND 1,000 ASTROCYTES AND 446 00:19:52,640 --> 00:19:56,440 IN EACH WELL YOU CAN SEE A 447 00:19:56,440 --> 00:19:56,720 SPHEROID. 448 00:19:56,720 --> 00:20:00,880 AND THE REAL BEAUTY OF WHAT HIS 449 00:20:00,880 --> 00:20:04,760 TEAM HAS ACCOMPLISHED IS THEY'RE 450 00:20:04,760 --> 00:20:09,160 REMARKABLY CONSISTENT LITERALLY 451 00:20:09,160 --> 00:20:17,280 CARBON COPIES TO EACH OTHER AND 452 00:20:17,280 --> 00:20:19,640 HERE HE SEEMED TO HAVE LICKED 453 00:20:19,640 --> 00:20:21,920 THE PROBLEM AND FORMED IT FROM 454 00:20:21,920 --> 00:20:23,760 WELL TO WELL. 455 00:20:23,760 --> 00:20:25,800 THE OTHER COOL ASPECT IS BECAUSE 456 00:20:25,800 --> 00:20:30,000 IT'S A BALL OF NEURONS YOU GET 457 00:20:30,000 --> 00:20:32,480 SPONTANEOUS AND SYNCHRONIZED 458 00:20:32,480 --> 00:20:37,080 ELECTRICAL ACTIVITY FROM THEOID 459 00:20:40,400 --> 00:20:45,320 THE SPHEROID AND YOU CAN SEE THE 460 00:20:45,320 --> 00:20:47,360 SPIKES THAT COME OUT 461 00:20:47,360 --> 00:20:50,400 SYNCHRONIZED ACTIVITY ASSOCIATED 462 00:20:50,400 --> 00:20:58,520 WITH THIS NEURO ORGANOID OR 463 00:20:58,520 --> 00:21:02,560 SPHEROID AND WHEN YOU HAVE THIS 464 00:21:02,560 --> 00:21:08,440 ASO5 OF 3 MICROMOLES YOU SEE 465 00:21:08,440 --> 00:21:09,320 ELECTRICAL FLATTENING WITHIN 466 00:21:09,320 --> 00:21:11,360 THREE MINUTES OF ADMINISTERING 467 00:21:11,360 --> 00:21:15,360 THE ASO IF YOU FOLLOW IT OUT YOU 468 00:21:15,360 --> 00:21:19,480 SEE IT GO BACK TO BASELINE IN 469 00:21:19,480 --> 00:21:23,160 HOURS AND WE REALLY IDENTIFY 470 00:21:23,160 --> 00:21:29,040 THOSE TOXICITY ASO TO THEN 471 00:21:29,040 --> 00:21:31,360 PREDICT AHEAD OF TIME OR SCREEN 472 00:21:31,360 --> 00:21:38,000 FROM OUR FILTERING PROCESS. 473 00:21:38,000 --> 00:21:40,000 AND WE'RE TRYING TO DEVELOP IT 474 00:21:40,000 --> 00:21:43,320 FOR THE FIELD BECAUSE YOU WANT 475 00:21:43,320 --> 00:21:46,640 TO TAKE IT OPEN AND SOURCED SO 476 00:21:46,640 --> 00:21:47,960 EVERY OTHER ACADEMIC HOSPITAL 477 00:21:47,960 --> 00:21:50,920 CAN USE THE METHOD TO SCREEN 478 00:21:50,920 --> 00:21:51,880 THEIR ASOs WHEN I THEY SEE A 479 00:21:51,880 --> 00:22:03,040 PATIENT. 480 00:22:03,040 --> 00:22:07,360 IS A PICTURE OF OUTSTANDING 481 00:22:07,360 --> 00:22:11,360 POST-DOCS LEADING THIS EFFORT 482 00:22:11,360 --> 00:22:19,400 OVER AT NCATS AND WE HAVE A NEW 483 00:22:19,400 --> 00:22:23,200 LABORATORY WITH A PARTICULAR 484 00:22:23,200 --> 00:22:25,200 FOCUS ON RARE AND ULTRA RARE 485 00:22:25,200 --> 00:22:26,800 DISEASES AND DEVELOPING ASOs IN 486 00:22:26,800 --> 00:22:29,120 A RAPID AND CHEAP MANNER SO THEY 487 00:22:29,120 --> 00:22:31,360 CAN GET INTO PATIENTS AND OPEN 488 00:22:31,360 --> 00:22:34,440 UP THE FIELD IN TERMS OF 489 00:22:34,440 --> 00:22:37,160 INCLUSIVITY AND ACCESS. 490 00:22:37,160 --> 00:22:39,360 REALLY A FOCUS ON DECREASING 491 00:22:39,360 --> 00:22:41,680 COST AND OPERATIONALIZING THIS 492 00:22:41,680 --> 00:22:42,240 TYPE OF TREATMENT. 493 00:22:42,240 --> 00:22:43,880 OF COURSE, THERE'S LOTS OF 494 00:22:43,880 --> 00:22:50,240 ACKNOWLEDGE MAMENTS HERE ALL OF 495 00:22:50,240 --> 00:22:52,040 WHOM HAVE BEEN WORKING HARD 496 00:22:52,040 --> 00:22:53,960 DURING THE PANDEMIC. 497 00:22:53,960 --> 00:22:55,960 IT'S BEEN A HARD TIME TO BE 498 00:22:55,960 --> 00:22:57,440 HONEST IN TERMS OF GETTING THIS 499 00:22:57,440 --> 00:22:59,080 SORTED OUT. 500 00:22:59,080 --> 00:23:00,840 WE'VE COME A LONG WAY ALREADY IN 501 00:23:00,840 --> 00:23:02,040 A RELATIVELY SHORT PERIOD OF 502 00:23:02,040 --> 00:23:02,240 TIME. 503 00:23:02,240 --> 00:23:05,960 AND I DO WANT TO GIVE MENTION TO 504 00:23:05,960 --> 00:23:06,560 THE CONSORTIA. 505 00:23:06,560 --> 00:23:09,680 I THINK THIS IS A VERY IMPORTANT 506 00:23:09,680 --> 00:23:11,840 AND I SEE REBECCA SCHULE IN THE 507 00:23:11,840 --> 00:23:16,720 AUDIENCE WHO IS ALSO A MEMBER OF 508 00:23:16,720 --> 00:23:18,480 THIS N EQUALS 1 COLLABORATIVE 509 00:23:18,480 --> 00:23:21,160 NETWORK AND ONE THING I LIKE 510 00:23:21,160 --> 00:23:22,560 ABOUT THE ASO FIELD RATHER THAN 511 00:23:22,560 --> 00:23:23,440 TRYING TO COMPETE AGAINST EACH 512 00:23:23,440 --> 00:23:25,280 OTHER WE'RE COMING TOGETHER AND 513 00:23:25,280 --> 00:23:27,840 RECOGNIZING NO ONE GROUP WILL 514 00:23:27,840 --> 00:23:28,800 HAVE SUFFICIENT BANDWIDTH TO 515 00:23:28,800 --> 00:23:31,040 ADDRESS ALL OF THIS SO WE'RE 516 00:23:31,040 --> 00:23:32,000 REALLY PUTTING OUR MINDS 517 00:23:32,000 --> 00:23:33,120 TOGETHER AND TRYING TO THINK 518 00:23:33,120 --> 00:23:34,920 ABOUT HOW WE CAN ACTUALLY MOVE 519 00:23:34,920 --> 00:23:39,080 THIS FORWARD FOR OUR PATIENTS AS 520 00:23:39,080 --> 00:23:39,320 WELL. 521 00:23:39,320 --> 00:23:41,160 AND OF COURSE I WANT TO TALK 522 00:23:41,160 --> 00:23:45,480 ABOUT -- I MENTIONED THE VARIOUS 523 00:23:45,480 --> 00:23:46,080 PHARMACEUTICAL COMPANIES WE 524 00:23:46,080 --> 00:23:48,000 COLLABORATE WITH AND PATIENTS 525 00:23:48,000 --> 00:23:49,360 AND FAMILIES WITHOUT WHOM THIS 526 00:23:49,360 --> 00:23:53,120 WOULD NOT ACTUALLY WORK. 527 00:23:53,120 --> 00:23:55,840 ONE LAST HOUSEKEEPING ITEM, WE 528 00:23:55,840 --> 00:23:58,760 RUN A MONTHLY GENE THERAPY 529 00:23:58,760 --> 00:23:59,440 SPECIAL INTEREST GROUP AND I 530 00:23:59,440 --> 00:24:01,760 JUST WANT TO PUT IT ON YOUR 531 00:24:01,760 --> 00:24:02,960 CALENDARS THAT THE NEXT MEETING 532 00:24:02,960 --> 00:24:07,360 IS GOING TO BE GIVEN BY CHRIS 533 00:24:07,360 --> 00:24:09,360 BOSSOFF TALKING ABOUT THE URGENT 534 00:24:09,360 --> 00:24:11,360 NETWORK INITIATIVE THAT HE HAS 535 00:24:11,360 --> 00:24:14,360 BEEN SPEARHEADING AND THAT'S 536 00:24:14,360 --> 00:24:21,280 GOING TO TAKE PLACE MAY 12 AT 537 00:24:21,280 --> 00:24:22,880 12:00 NOON FOR ANYONE WHO WANTS 538 00:24:22,880 --> 00:24:23,760 TO JOIN. 539 00:24:23,760 --> 00:24:25,040 I'M HAPPY TO PAUSE THERE AND 540 00:24:25,040 --> 00:24:25,520 TAKE QUESTIONS. 541 00:24:25,520 --> 00:24:28,600 >> WE'LL TAKE QUESTIONS AFTER 542 00:24:28,600 --> 00:24:33,680 DR. BLACKSTONE'S PRESENTATION. 543 00:24:33,680 --> 00:24:37,320 IT'S A PLEASURE TO SPEAK TO THIS 544 00:24:37,320 --> 00:24:39,680 GROUP TODAY AND THANK YOU TO 545 00:24:39,680 --> 00:24:42,000 ARIANE AND BRINGING US TOGETHER 546 00:24:42,000 --> 00:24:43,680 AND WE HAVEN'T HAD MANY 547 00:24:43,680 --> 00:24:44,520 OPPORTUNITIES THE LAST COUPLE 548 00:24:44,520 --> 00:24:47,000 YEARS AND IT'S GREAT WE GET A 549 00:24:47,000 --> 00:24:47,560 CHANCE TO BE TOGETHER. 550 00:24:47,560 --> 00:24:55,000 LI 551 00:24:55,000 --> 00:24:59,640 LIKE BRYAN, I'M GOING DRILL DOWN 552 00:24:59,640 --> 00:25:00,880 INTO SPG4 DE NOVO CASES WHICH I 553 00:25:00,880 --> 00:25:03,040 KNOW IS THE TOPIC OF THIS 554 00:25:03,040 --> 00:25:07,240 MEETING BUT I ALSO WANT TO TALK 555 00:25:07,240 --> 00:25:07,800 A LITTLE BIT ABOUT DE NOVO 556 00:25:07,800 --> 00:25:08,000 SPG3A. 557 00:25:08,000 --> 00:25:09,800 YOU MAY BE LESS FAMILIAR WITH 558 00:25:09,800 --> 00:25:13,520 THAT BUT I WANTED TO EMPHASIZE 559 00:25:13,520 --> 00:25:16,320 THERE'S SOME COMMONALITIES I 560 00:25:16,320 --> 00:25:20,680 THINK WILL BE HELPFUL IN MAKING 561 00:25:20,680 --> 00:25:33,680 PROGRESS IN SPG4. 562 00:25:33,680 --> 00:25:41,600 I'LL START TALKING ABOUT SPASTIC 563 00:25:41,600 --> 00:25:42,760 PARAPLEGIA AND THERE'S IMPORTANT 564 00:25:42,760 --> 00:25:43,600 DISTINCTIONS WE HAVE TO THINK 565 00:25:43,600 --> 00:25:46,360 ABOUT WHEN WE THINK ABOUT THE 566 00:25:46,360 --> 00:25:49,680 PATIENTS WITH DE NOVO FORMS. 567 00:25:49,680 --> 00:25:57,080 THE HISTORIC PARAPLEGIAS AFFECT 568 00:25:57,080 --> 00:25:59,480 THE LEGS AND THERE ARE PATIENT 569 00:25:59,480 --> 00:26:01,160 WHO'S HAVE COMPLICATED ONES WITH 570 00:26:01,160 --> 00:26:03,680 OTHER NEUROLOGICAL SYMPTOMS BUT 571 00:26:03,680 --> 00:26:10,080 FOR THE MOST PART WE THINK OF 572 00:26:10,080 --> 00:26:12,000 SPGs AS AFFECTING WALKING AND 573 00:26:12,000 --> 00:26:13,880 FOR DE NOVO FORMS IT'S MORE 574 00:26:13,880 --> 00:26:14,880 EXTENSIVE AND IT'S IMPORTANT TO 575 00:26:14,880 --> 00:26:18,640 THINK OF THEM AS POTENTIALLY 576 00:26:18,640 --> 00:26:20,800 RELATED TO SPASTIC PARAPLEGIA 577 00:26:20,800 --> 00:26:22,120 AND THERE'S OTHER TYPES OF 578 00:26:22,120 --> 00:26:26,760 DISORDERS AND WE HAVE TO THINK 579 00:26:26,760 --> 00:26:28,320 ABOUT DIFFERENT MECHANISMS AND 580 00:26:28,320 --> 00:26:29,680 THE DIFFERENT WAYS THE MUTATIONS 581 00:26:29,680 --> 00:26:31,120 MAY BE AFFECTING PEOPLE. 582 00:26:31,120 --> 00:26:33,280 ONE OF THE DRAMATIC THINGS I 583 00:26:33,280 --> 00:26:37,880 THINK GREAT THINGS ABOUT THE 584 00:26:37,880 --> 00:26:41,000 HEREDITARY SPASTIC PARAPLEGIAS 585 00:26:41,000 --> 00:26:41,720 THERE'S DIFFERENT GENES. 586 00:26:41,720 --> 00:26:45,960 THERE'S 90 DIFFERENT GENETIC 587 00:26:45,960 --> 00:26:50,400 LOCI AND THAT ALLOWS US TO 588 00:26:50,400 --> 00:26:56,480 IDENTIFY PROTEINS AND MAKE 589 00:26:56,480 --> 00:26:59,440 RELATIONS AND I HAVE A PICTURE 590 00:26:59,440 --> 00:27:04,120 OF A SCHEMATIC PERSON AND 591 00:27:04,120 --> 00:27:06,920 CORTICOSPINAL TRACT AND NEURONS 592 00:27:06,920 --> 00:27:09,680 FROM YOUR CORTEX TO THE SPINAL 593 00:27:09,680 --> 00:27:12,760 CORD AND MAKE CONNECTIONS OR 594 00:27:12,760 --> 00:27:14,080 SYNAPSES THAT MOVE YOUR MUSCLES 595 00:27:14,080 --> 00:27:16,200 AND THE LONGEST ONES ARE THE 596 00:27:16,200 --> 00:27:18,600 ONES THAT CONTROL YOUR LEGS AND 597 00:27:18,600 --> 00:27:20,800 WE THOUGHT OF THESE AS 598 00:27:20,800 --> 00:27:22,280 LEG-DEPENDENT DISORDERS. 599 00:27:22,280 --> 00:27:26,240 OTHER FORMS MAY NOT SHOW THAT 600 00:27:26,240 --> 00:27:26,920 QUITE AS MUCH AND WE NEED TO 601 00:27:26,920 --> 00:27:35,720 KEEP THAT IN MIND. 602 00:27:35,720 --> 00:27:38,680 SO AGAIN, IT'S IMPORTANT TO 603 00:27:38,680 --> 00:27:41,080 THINK ABOUT THESE DE NOVO FORMS 604 00:27:41,080 --> 00:27:44,320 BOTH AS HEREDITARY SPASTIC 605 00:27:44,320 --> 00:27:45,800 PARAPLEGIAS AND THINK OF THE 606 00:27:45,800 --> 00:27:47,760 DIFFERENT MECHANISMS AND 607 00:27:47,760 --> 00:27:48,800 TREATMENTS. 608 00:27:48,800 --> 00:27:49,720 ONE THINGS WE HAVE HISTORICALLY 609 00:27:49,720 --> 00:27:52,040 DONE BECAUSE OF ALL THE GENES 610 00:27:52,040 --> 00:27:55,320 WE'VE IDENTIFIED IS TO GROUP 611 00:27:55,320 --> 00:27:57,680 THEM INTO CLUSTERS AS PARTS OF 612 00:27:57,680 --> 00:27:59,640 THE CELL AND CELLULAR DISORDER 613 00:27:59,640 --> 00:28:01,600 AND LONG CELLS ARE AFFECT THE 614 00:28:01,600 --> 00:28:02,480 MOST AND IT'S IMPORTANT TO 615 00:28:02,480 --> 00:28:04,240 REMEMBER JUST BECAUSE WE'RE 616 00:28:04,240 --> 00:28:06,600 THINKING ABOUT A LONG NEURON 617 00:28:06,600 --> 00:28:08,960 DOESN'T MEAN THE PATHOLOGY IS IN 618 00:28:08,960 --> 00:28:13,440 THE NEURON AND WE LOOK AT OLIGO 619 00:28:13,440 --> 00:28:18,400 DENDROCYTES AND OTHER NEURONS 620 00:28:18,400 --> 00:28:21,480 CAN IMPACT THE FUNCTION OF 621 00:28:21,480 --> 00:28:22,680 NEURONS SO WE HAVE TO KEEP AN 622 00:28:22,680 --> 00:28:25,320 OPEN MIND WHEN WE THINK OF MODEL 623 00:28:25,320 --> 00:28:26,760 SYSTEMS TO THINK HOW THE OTHER 624 00:28:26,760 --> 00:28:28,640 CELLS ARE AFFECTING LONG NEURONS 625 00:28:28,640 --> 00:28:30,280 THAT GIVE RISE TO THE SYMPTOMS 626 00:28:30,280 --> 00:28:30,960 WE SEE. 627 00:28:30,960 --> 00:28:32,880 NOW, OF COURSE THE ONES WE'RE 628 00:28:32,880 --> 00:28:35,640 GOING TO TALK ABOUT TODAY, SPG3A 629 00:28:35,640 --> 00:28:37,080 AND SPG4 HAVE A RELATIONSHIP 630 00:28:37,080 --> 00:28:37,560 WITH ONE ANOTHER. 631 00:28:37,560 --> 00:28:40,760 AS YOU CAN SEE IN MY SESSION 632 00:28:40,760 --> 00:28:44,320 THEY'RE BOTH LISTED THERE BUT 633 00:28:44,320 --> 00:28:49,600 YOU'LL NOTICE IT'S LISTED OTHER 634 00:28:49,600 --> 00:28:51,560 PLACES AND THIS UNDERLYING SPG4 635 00:28:51,560 --> 00:28:54,840 AND SPG3A. 636 00:28:54,840 --> 00:28:55,680 THE COMMONALITIES AND 637 00:28:55,680 --> 00:28:56,920 DIFFERENCES AND THEY CAN BE 638 00:28:56,920 --> 00:28:58,920 IMPORTANT AS WE COMPARE AND 639 00:28:58,920 --> 00:29:00,880 CONTRAST HOW WE MIGHT APPROACH 640 00:29:00,880 --> 00:29:02,200 THEM THERAPEUTICALLY. 641 00:29:02,200 --> 00:29:05,400 ONE THING THAT IS CLEAR IS THAT 642 00:29:05,400 --> 00:29:07,640 SEVERAL OF THESE SPASTIC 643 00:29:07,640 --> 00:29:11,080 PARAPLEGIC GENES ALL WORK 644 00:29:11,080 --> 00:29:12,840 TOGETHER TO FORM COMMON CELLULAR 645 00:29:12,840 --> 00:29:13,440 FUNCTIONS. 646 00:29:13,440 --> 00:29:17,240 AND I THINK WE GOT A REALLY 647 00:29:17,240 --> 00:29:18,480 INTERESTING SERIES OF TALKS 648 00:29:18,480 --> 00:29:19,400 YESTERDAY ABOUT DRAMATIC 649 00:29:19,400 --> 00:29:22,880 ADVANCES IN GENETICS OF THE 650 00:29:22,880 --> 00:29:29,800 SPAST IIC PARAPLEGIAS IN TERMS OF 651 00:29:29,800 --> 00:29:31,480 UNDERSTANDING HOW DIFFERENT 652 00:29:31,480 --> 00:29:32,800 MUTATIONS CORRELATE WITH 653 00:29:32,800 --> 00:29:34,280 DIFFERENT TYPES OF CLINIC 654 00:29:34,280 --> 00:29:34,760 SYNDROMES. 655 00:29:34,760 --> 00:29:37,280 I THINK IT'S AN IMPORTANT THEME 656 00:29:37,280 --> 00:29:39,120 TO BUILD OFF OF AS WE CREATE 657 00:29:39,120 --> 00:29:40,600 MODEL SYSTEMS AND GET CLOSER TO 658 00:29:40,600 --> 00:29:41,640 UNDERSTANDING WHAT OUR TARGETS 659 00:29:41,640 --> 00:29:43,680 SHOULD BE FOR THERAPY. 660 00:29:43,680 --> 00:29:47,040 AGAIN, BRYAN OUTLINED NICELY ONE 661 00:29:47,040 --> 00:29:50,040 FORM OF GENE THERAPY ASOs AND WE 662 00:29:50,040 --> 00:29:50,720 HEARD YESTERDAY ABOUT OTHER 663 00:29:50,720 --> 00:29:54,160 TYPES OF GENE THERAPY AND 664 00:29:54,160 --> 00:29:56,040 DELIVER GENES TO REPLACE A 665 00:29:56,040 --> 00:29:57,040 MISSING PROTEIN AND I'LL TALK 666 00:29:57,040 --> 00:29:58,080 ABOUT A THIRD. 667 00:29:58,080 --> 00:29:59,880 THERE'S MANY TYPES OF GENE 668 00:29:59,880 --> 00:30:02,240 THERAPIES AND MANY TYPES OF 669 00:30:02,240 --> 00:30:03,080 PHARMACOLOGIC THERAPIES. 670 00:30:03,080 --> 00:30:04,320 ALL THESE THINGS TO CONSIDER. 671 00:30:04,320 --> 00:30:05,680 BECAUSE IT'S A RARE DISEASE WE 672 00:30:05,680 --> 00:30:07,400 DON'T HAVE THE LUXURY OF TRYING 673 00:30:07,400 --> 00:30:08,640 A WHOLE BUNCH OF THEM. 674 00:30:08,640 --> 00:30:10,920 I THINK IT'S ONE OF THOSE WHERE 675 00:30:10,920 --> 00:30:12,520 WE WANT TO USE OUR MODEL 676 00:30:12,520 --> 00:30:14,480 SYSTEMS, WHICH IS A BIG PART OF 677 00:30:14,480 --> 00:30:17,440 MY TALK TO NARROW DOWN THE 678 00:30:17,440 --> 00:30:18,880 POSSIBILITIES OR THE MOST LIKELY 679 00:30:18,880 --> 00:30:21,480 POSSIBILITIES FOR SUCCESS AND BE 680 00:30:21,480 --> 00:30:24,800 ABLE TO PURSUE THOSE. 681 00:30:24,800 --> 00:30:28,400 NOW, ONE THING AND BRYAN SHOWED 682 00:30:28,400 --> 00:30:30,200 ONE TOO AND A LOT OF US TALK 683 00:30:30,200 --> 00:30:31,280 ABOUT MODEL SYSTEMS BUT A LOT OF 684 00:30:31,280 --> 00:30:33,280 PEOPLE ON THE CALL MAY NOT HAVE 685 00:30:33,280 --> 00:30:35,080 SEEN WHAT THE MODEL SYSTEMS AND 686 00:30:35,080 --> 00:30:36,160 WHAT DO WE MEAN. 687 00:30:36,160 --> 00:30:37,480 IN THE CASE OF THIS MOUSE, THIS 688 00:30:37,480 --> 00:30:41,440 IS A MOUSE WE MADE TO MIMIC 689 00:30:41,440 --> 00:30:42,880 HEREDITARY SPASTIC PARAPLEGIA 690 00:30:42,880 --> 00:30:45,160 AND WE HEARD YESTERDAY SOMETIMES 691 00:30:45,160 --> 00:30:48,400 THE GENES MIGHT COMBINE TO CAUSE 692 00:30:48,400 --> 00:30:50,720 A MORE SEVERE SYNDROME AND WE 693 00:30:50,720 --> 00:30:53,440 USED THAT TO THIS DISEASE AND 694 00:30:53,440 --> 00:30:56,680 TRIED TO CREATE A MORE SEVERE 695 00:30:56,680 --> 00:30:57,920 MODEL WHERE THE MICE GET 696 00:30:57,920 --> 00:30:59,320 SYMPTOMS EARLIER TO START 697 00:30:59,320 --> 00:31:00,480 TESTING QUICKER RATHER THAN 698 00:31:00,480 --> 00:31:02,280 WAITING FOR THE MOUSE TO GET TO 699 00:31:02,280 --> 00:31:03,320 A CERTAIN AGE TO SPEED THE 700 00:31:03,320 --> 00:31:03,680 PROCESS UP. 701 00:31:03,680 --> 00:31:05,720 TO GIVE YOU AN IDEA WHAT WE LOOK 702 00:31:05,720 --> 00:31:07,320 FOR IN THE MODEL SYSTEM, THE 703 00:31:07,320 --> 00:31:08,720 MOUSE IS WALKING, HOPEFULLY YOU 704 00:31:08,720 --> 00:31:11,280 CAN SEE THE VIDEO AND HE'S 705 00:31:11,280 --> 00:31:12,200 MOVING FINE AND YOU'LL NOTICE 706 00:31:12,200 --> 00:31:15,480 THE MOUSE AT THE BOTTOM HAS 707 00:31:15,480 --> 00:31:18,400 MUTATIONS IN THE SPG GENES AND 708 00:31:18,400 --> 00:31:20,360 THIS MOUSE HAS MORE STRUGGLE 709 00:31:20,360 --> 00:31:20,840 MOVING. 710 00:31:20,840 --> 00:31:23,640 IN FACT THE TREADMILL IS MOVING 711 00:31:23,640 --> 00:31:25,080 SEVEN TIMES SLOWER AND YOU STILL 712 00:31:25,080 --> 00:31:27,360 SEE ALL THE STRUGGLES. 713 00:31:27,360 --> 00:31:30,120 THOSE TYPE OF PHENOTYPES OR 714 00:31:30,120 --> 00:31:31,640 BEHAVIORAL ABNORMALITIES WE LOOK 715 00:31:31,640 --> 00:31:35,680 FOR AND TRY TO SUPPRESS LIKE IN 716 00:31:35,680 --> 00:31:36,440 PEOPLE WE SEE A WALKING 717 00:31:36,440 --> 00:31:38,240 DIFFICULTY AND WANT TO MAKE IT 718 00:31:38,240 --> 00:31:38,480 BETTER. 719 00:31:38,480 --> 00:31:40,160 IN MICE AND OTHER ORGANISMS WE 720 00:31:40,160 --> 00:31:41,560 HAVE THE ABILITY TO DELVE DEEPER 721 00:31:41,560 --> 00:31:43,680 AND DO STUDIES TO UNDERSTAND 722 00:31:43,680 --> 00:31:44,600 WHAT'S HAPPENING AT DIFFERENT 723 00:31:44,600 --> 00:31:46,360 LEVELS. 724 00:31:46,360 --> 00:31:48,680 AT THE LEVELS OF INDIVIDUAL 725 00:31:48,680 --> 00:31:50,880 CELLS AND DIFFERENT ORGANS AND 726 00:31:50,880 --> 00:31:54,080 YOU CAN SEE THIS IS JUST A 727 00:31:54,080 --> 00:31:55,680 QUANTIFICATION BEFORE I MOVE ON 728 00:31:55,680 --> 00:31:57,880 IN THE SAME WAY WE HAVE AND WE 729 00:31:57,880 --> 00:31:59,600 HEARD ABOUT THESE YESTERDAY, 730 00:31:59,600 --> 00:32:00,320 SPECIFIC ASSESSMENT TOOLS FOR 731 00:32:00,320 --> 00:32:02,400 PEOPLE THAT WE WANT TO 732 00:32:02,400 --> 00:32:04,480 ULTIMATELY SEE IF THOSE 733 00:32:04,480 --> 00:32:05,400 IMPROVEMENTS IN THOSE IN 734 00:32:05,400 --> 00:32:07,000 RESPONSE TO THERAPY WE DO THE 735 00:32:07,000 --> 00:32:08,280 SAME FOR OUR MODEL SYSTEMS IN 736 00:32:08,280 --> 00:32:11,160 THIS CASE A MOUSE. 737 00:32:11,160 --> 00:32:14,080 YOU'LL SEE WE CAN HAVE SPEED 738 00:32:14,080 --> 00:32:15,480 TEST OR ROTOR ROD A SPINNING 739 00:32:15,480 --> 00:32:17,920 DRUM TO SEE HOW LONG THEY CAN 740 00:32:17,920 --> 00:32:22,040 STAY ON IT. 741 00:32:22,040 --> 00:32:25,040 A LEDGE TEST TO WALK ALONG AN 742 00:32:25,040 --> 00:32:27,280 EDGE AND CAN COMPARE THEM TO 743 00:32:27,280 --> 00:32:29,400 NORMAL MICE AND MUTANT MICE AND 744 00:32:29,400 --> 00:32:31,600 THE BIGGER THE EFFECT THE EASIER 745 00:32:31,600 --> 00:32:33,520 TO SEE WHETHER A DRUG OR THERAPY 746 00:32:33,520 --> 00:32:33,880 IS HELPING. 747 00:32:33,880 --> 00:32:36,800 SO THESE ARE JUST THE TYPES OF 748 00:32:36,800 --> 00:32:37,040 THINGS. 749 00:32:37,040 --> 00:32:38,320 I WON'T GO THROUGH THE DETAILS 750 00:32:38,320 --> 00:32:40,360 OF THIS BUT THIS IS THE TYPE OF 751 00:32:40,360 --> 00:32:42,560 MODEL AND READOUT THAT IS 752 00:32:42,560 --> 00:32:44,680 VALUABLE FOR US AS WE TRY NEW 753 00:32:44,680 --> 00:32:44,960 THERAPIES. 754 00:32:44,960 --> 00:32:47,480 THIS IS ANOTHER THING WE CAN DO 755 00:32:47,480 --> 00:32:49,200 IN AN ANIMAL MODEL WE CAN'T DO 756 00:32:49,200 --> 00:32:51,000 IN PEOPLE WE CONDITION ACTUALLY 757 00:32:51,000 --> 00:32:58,880 RECONSTRUCT PART OF THE SPINAL ACTUALLY 758 00:32:58,880 --> 00:32:59,680 RECONSTRUCT PART OF THE SPINAL ACTUALLY 759 00:32:59,680 --> 00:33:00,440 RECONSTRUCT PART OF THE SPINAL ACTUALLY 760 00:33:00,440 --> 00:33:01,080 RECONSTRUCT PART OF THE SPINAL 761 00:33:01,080 --> 00:33:01,400 CO 762 00:33:01,400 --> 00:33:07,480 SPINALCOCORACORD AND YOU'LL NOTICE ON 763 00:33:07,480 --> 00:33:10,280 THE LEFT IS JUST THE WHAT THE 764 00:33:10,280 --> 00:33:12,720 WHOLE TRACT LOOKS LIKE AND THE 765 00:33:12,720 --> 00:33:18,960 ORANGE IS THE ENDOPLASMIC 766 00:33:18,960 --> 00:33:24,200 RETICULUM AND THE BLUE IS 767 00:33:24,200 --> 00:33:26,280 MITOCHONDRIA AND YOU NOTICE THE 768 00:33:26,280 --> 00:33:28,240 STRANDS GOING UP AND DOWN AND IN 769 00:33:28,240 --> 00:33:30,320 THE MUTANT FORM IN PANEL B, 770 00:33:30,320 --> 00:33:32,480 THERE'S ALL THESE LATERAL-LIKE 771 00:33:32,480 --> 00:33:32,760 STRUCTURES. 772 00:33:32,760 --> 00:33:35,280 THIS IS REMARKABLE. 773 00:33:35,280 --> 00:33:40,160 WE CAN SEE THE ABNORMALITY THAT 774 00:33:40,160 --> 00:33:41,680 CAUSES THIS DISEASE IN THE 775 00:33:41,680 --> 00:33:43,240 ACTUAL NEURONS INVOLVED MOST. 776 00:33:43,240 --> 00:33:45,480 THAT ALLOWS US TO START WHEN WE 777 00:33:45,480 --> 00:33:47,920 START THINKING ABOUT THERAPY, IT 778 00:33:47,920 --> 00:33:49,880 ALLOWS US TO HAVE A READ-OUT 779 00:33:49,880 --> 00:33:52,360 THAT IS NOT JUST BEHAVIORAL, NOT 780 00:33:52,360 --> 00:33:55,680 JUST SYMPTOMS WE SEE BUT ALSO 781 00:33:55,680 --> 00:33:57,600 SORT OF MORE MEC NIFTILY 782 00:33:58,360 --> 00:33:58,480 783 00:34:03,680 --> 00:34:04,680 MECHANISTICALLY AND WHAT WAS 784 00:34:04,680 --> 00:34:10,320 USED AS MARKERS BEFORE AND THE 785 00:34:10,320 --> 00:34:13,280 BOTTOM COMPARES WILD TYPE TO A 786 00:34:13,280 --> 00:34:15,680 MUTANT FORM AND THERE'S DRAMATIC 787 00:34:15,680 --> 00:34:16,920 DIFFERENCES AND THEY'RE SO EASY 788 00:34:16,920 --> 00:34:19,320 TO SEE THAT IF WE HAVE A 789 00:34:19,320 --> 00:34:23,120 THERAPY, WE REALLY HAVE THE 790 00:34:23,120 --> 00:34:23,760 RELATIVE 791 00:34:23,760 --> 00:34:25,480 RELATIVELY STRAIGHTFORWARD 792 00:34:25,480 --> 00:34:27,640 ABILITY TO ASSESS WHETHER THE 793 00:34:27,640 --> 00:34:29,880 THERAPY IS IMPROVING THESE 794 00:34:29,880 --> 00:34:31,640 CHANGES AS WELL AS THE 795 00:34:31,640 --> 00:34:33,040 BEHAVIORAL CHANGES AND THINK 796 00:34:33,040 --> 00:34:34,480 ABOUT IN THE HUMAN AS BIOMARKERS 797 00:34:34,480 --> 00:34:38,400 AND THINGS WE CAN FOLLOW AS 798 00:34:38,400 --> 00:34:40,760 CLINICAL OUTCOMES AND WE DO THAT 799 00:34:40,760 --> 00:34:42,560 ALSO IN MODEL SYMPTOMS. 800 00:34:42,560 --> 00:34:45,680 HERE'S A YOUNG GIRL WITH DE NOVO 801 00:34:45,680 --> 00:34:46,400 MUTATION AND SPG3A. 802 00:34:46,400 --> 00:34:53,680 YOU CAN SEE SHE'S WALKING IN A 803 00:34:53,680 --> 00:34:56,520 THEY'RE MARATHON AND MILDLY 804 00:34:56,520 --> 00:34:58,080 AFFECTS COMPARED TO SOME WE 805 00:34:58,080 --> 00:34:58,840 TALKED ABOUT AND UNDERSTAND 806 00:34:58,840 --> 00:34:59,760 EVERYTHING THE MUTATION IN TERMS 807 00:34:59,760 --> 00:35:03,360 OF HOW IT WORKS AND WE CAN MODEL 808 00:35:03,360 --> 00:35:05,320 THIS DISEASE ALSO IN USING CELLS 809 00:35:05,320 --> 00:35:07,440 FROM PATIENTS LIKE THIS YOUNG 810 00:35:07,440 --> 00:35:07,680 GIRL. 811 00:35:07,680 --> 00:35:16,320 THIS WAS DONE BY JUNE LI LATER 812 00:35:16,320 --> 00:35:19,040 ABOUT TAKING CELLS FROM A PERSON 813 00:35:19,040 --> 00:35:20,120 AFFECTED AND MAKE THEM INTO STEM 814 00:35:20,120 --> 00:35:22,320 CELLS AND THEN MAKE THEM INTO 815 00:35:22,320 --> 00:35:26,080 NERVE CELLS SO IT ALLOWS US TO 816 00:35:26,080 --> 00:35:27,680 GET ACCESS TO THE NERVOUS SYSTEM 817 00:35:27,680 --> 00:35:33,480 WITHOUT HAVING TO DO ANYTHING 818 00:35:33,480 --> 00:35:36,400 INVASIVE AND THERE'S THIS YOUNG 819 00:35:36,400 --> 00:35:37,600 GIRL'S CELLS MADE INTO A CELL 820 00:35:37,600 --> 00:35:40,880 AND UP TOP IS A HEALTHY 821 00:35:40,880 --> 00:35:41,160 VOLUNTEER. 822 00:35:41,160 --> 00:35:43,080 ON THE BOTTOM THE PROCESSES FROM 823 00:35:43,080 --> 00:35:46,960 THE NERVE SMALL AND THOSE CAN BE 824 00:35:46,960 --> 00:35:48,240 REVERSED WITH DIFFERENT DRUG 825 00:35:48,240 --> 00:35:48,680 THERAPIES. 826 00:35:48,680 --> 00:35:50,360 THIS IS ANOTHER WAY TO SCREEN 827 00:35:50,360 --> 00:35:53,480 FOR COMPOUNDS FOR THERAPIES THAT 828 00:35:53,480 --> 00:35:55,200 MIGHT ACTUALLY HELP REVERSE SOME 829 00:35:55,200 --> 00:35:57,320 OF THE ABNORMALITIES WE SEE. 830 00:35:57,320 --> 00:35:58,360 AND AGAIN IT'S A MODEL. 831 00:35:58,360 --> 00:36:01,440 OF COURSE THE CELLS DON'T HAVE 832 00:36:01,440 --> 00:36:01,600 HSP. 833 00:36:01,600 --> 00:36:02,920 IT'S NOT IMPORTANT TO THINK 834 00:36:02,920 --> 00:36:04,960 ABOUT IT THEY WAY BUT THE TOOLS 835 00:36:04,960 --> 00:36:06,680 THAT ALLOW TO US TEST IDEAS THAT 836 00:36:06,680 --> 00:36:07,680 CAN ULTIMATELY LEAD TO 837 00:36:07,680 --> 00:36:11,680 THERAPIES. 838 00:36:11,680 --> 00:36:13,800 NOW, JUST LIKE IN THE CASE OF 839 00:36:13,800 --> 00:36:14,880 SPG4 THE FOCUS OF THIS MEETING 840 00:36:14,880 --> 00:36:21,080 THERE'S BEEN A GROUP OF PATIENTS 841 00:36:21,080 --> 00:36:24,480 WITH VERY SEVERE PHENOTYPES WITH 842 00:36:24,480 --> 00:36:25,880 PREDOMINANTLY MISSED SENSES AND 843 00:36:25,880 --> 00:36:27,440 YOU CAN SEE FROM THE ARTICLE 844 00:36:27,440 --> 00:36:28,760 THIS WAS DONE 15 YEARS AGO. 845 00:36:28,760 --> 00:36:31,680 I THINK THERE'S AN INCREASING 846 00:36:31,680 --> 00:36:34,960 REALIZATION NOW THAT THESE 847 00:36:34,960 --> 00:36:36,240 SEVERE PHENOTYPES CAN BE THOUGHT 848 00:36:36,240 --> 00:36:38,000 OF DIFFERENT DISEASES. 849 00:36:38,000 --> 00:36:39,520 WE SHOULDN'T THINK OF THEM AS ON 850 00:36:39,520 --> 00:36:43,360 THE SAME SPECTRUM BUT FROM THE 851 00:36:43,360 --> 00:36:44,000 THERAPEUTIC POINT OF VIEW AS 852 00:36:44,000 --> 00:36:44,680 INTERESTING DISORDERS. 853 00:36:44,680 --> 00:36:46,680 AND DARIUS DIDN'T TALK ABOUT IT 854 00:36:46,680 --> 00:36:47,600 YESTERDAY BUT HE AND HIS 855 00:36:47,600 --> 00:36:49,960 COLLEAGUES HAVE DONE A 856 00:36:49,960 --> 00:36:50,880 REMARKABLE JOB WITH SPG3A 857 00:36:50,880 --> 00:36:55,160 LOOKING AT ABOUT 500 DIFFERENT 858 00:36:55,160 --> 00:36:56,320 PATIENTS AND IDENTIFYING THOSE 859 00:36:56,320 --> 00:36:59,160 WITH SEVERE FORMS AND BE ABLE TO 860 00:36:59,160 --> 00:37:00,800 NARROW THE AREAS OR TYPES OF 861 00:37:00,800 --> 00:37:01,680 MUTATIONS DOWN TO SPECIFIC PARTS 862 00:37:01,680 --> 00:37:05,040 OF THE PROTEIN THAT REALLY GIVES 863 00:37:05,040 --> 00:37:07,280 INSIGHTS INTO HOW WE MIGHT 864 00:37:07,280 --> 00:37:10,360 ADDRESS THERAPY FOR THIS 865 00:37:10,360 --> 00:37:11,560 COMPARED TO THE MORE COMMON 866 00:37:11,560 --> 00:37:13,280 FORMS WHICH ARE LESS SEVERE. 867 00:37:13,280 --> 00:37:15,080 ONE OF THE THINGS WE'VE BEEN 868 00:37:15,080 --> 00:37:17,440 DOING AS PART OF THIS SPG3A DE 869 00:37:17,440 --> 00:37:19,240 NOVO EFFORT IS WORKING WITH A 870 00:37:19,240 --> 00:37:22,000 FOUNDATION CALLED THE CARTER 871 00:37:22,000 --> 00:37:23,480 FOUNDATION AND I'M AN ADVISER 872 00:37:23,480 --> 00:37:25,480 FOR THAT FOUNDATION AND THINKING 873 00:37:25,480 --> 00:37:26,880 MUCH THE SAME WAY YOU ARE IN THE 874 00:37:26,880 --> 00:37:31,320 MEETING HOW WE CAN COME UP WITH 875 00:37:31,320 --> 00:37:33,400 WAYS TO DO RESEARCH, IMPROVE 876 00:37:33,400 --> 00:37:35,680 OPTIONS FOR THERAPIES FOR THE 877 00:37:35,680 --> 00:37:38,320 MORE SEVERE DE NOVO PATIENTS IN 878 00:37:38,320 --> 00:37:38,720 PARTICULAR. 879 00:37:38,720 --> 00:37:40,560 ONE OF THE THINGS WE'VE DONE AS 880 00:37:40,560 --> 00:37:43,160 PART OF THIS AGAIN IT COULD BE 881 00:37:43,160 --> 00:37:44,720 COMPARED AND CONTRAST TO WHAT 882 00:37:44,720 --> 00:37:47,280 YOU'RE DOING IS DEVELOPING 883 00:37:47,280 --> 00:37:50,840 SEVERAL MODEL SYSTEMS INCLUDING 884 00:37:50,840 --> 00:37:55,640 A FLY MODEL AND WE MADE AN 885 00:37:55,640 --> 00:37:56,320 INTERESTING MOUSE MODEL AND I'LL 886 00:37:56,320 --> 00:37:57,440 TELL YOU ABOUT THAT BECAUSE IT'S 887 00:37:57,440 --> 00:38:02,360 A UNIQUE WAY TO THINK OF GENE 888 00:38:02,360 --> 00:38:03,640 THERAPY. 889 00:38:03,640 --> 00:38:11,040 THE PROMISING THERAPEUTICS IS 890 00:38:11,040 --> 00:38:15,640 WHAT WE LEARNED FROM PLASTIC 891 00:38:15,640 --> 00:38:18,800 PARAPLEGIA AND JUNE IS NOW 892 00:38:18,800 --> 00:38:19,440 SCREENING FOR A LOT OF THESE 893 00:38:19,440 --> 00:38:21,600 TYPES OF PATHWAYS TO SEE IF THEY 894 00:38:21,600 --> 00:38:24,320 WORK IN CELLS FROM PATIENTS WITH 895 00:38:24,320 --> 00:38:26,480 THIS MORE SEVERE DE NOVO FORM. 896 00:38:26,480 --> 00:38:28,520 AND I WANTED TO EMPHASIZE AT THE 897 00:38:28,520 --> 00:38:30,680 BOTTOM AND I TALKED AT THE 898 00:38:30,680 --> 00:38:31,840 BOTTOM ABOUT DARIUS' GREAT WORK 899 00:38:31,840 --> 00:38:35,040 IN TERMS OF LIKE WE HEARD 900 00:38:35,040 --> 00:38:38,280 YESTERDAY FOR SPG4 AS WELL. 901 00:38:38,280 --> 00:38:41,280 UNDERSTANDING BROADLY THE TYPES 902 00:38:41,280 --> 00:38:44,760 OF SYMPTOMS THAT PATIENTS GET IN 903 00:38:44,760 --> 00:38:47,480 TRYING TO CORRELATE THAT WITH 904 00:38:47,480 --> 00:38:50,080 THE TYPES OF GENETIC CHANGES AND 905 00:38:50,080 --> 00:38:52,080 LOOK AT STUDY THIS FURTHER. 906 00:38:52,080 --> 00:38:53,640 I WANTED TO EMPHASIZE ONE 907 00:38:53,640 --> 00:38:56,520 INTERESTING NEW TYPE OF GENE 908 00:38:56,520 --> 00:39:00,360 THERAPY AND AGAIN BRYAN TALKED 909 00:39:00,360 --> 00:39:03,080 ABOUT ASOs AND SOME THAT ARE 910 00:39:03,080 --> 00:39:04,160 PROMISING FOR CERTAIN DISORDERS 911 00:39:04,160 --> 00:39:05,080 BUT WE HAVE TO UNDERSTAND WHAT 912 00:39:05,080 --> 00:39:07,160 OUR GOALS ARE. 913 00:39:07,160 --> 00:39:11,040 ONE THING ABOUT THESE DISORDERS, 914 00:39:11,040 --> 00:39:14,640 SPG3A AND SPG4 AND WE HAVE 915 00:39:14,640 --> 00:39:16,320 MUTATION OFTEN AND THOSE ARE 916 00:39:16,320 --> 00:39:18,080 AMENABLE TO JUST AT A BASIC 917 00:39:18,080 --> 00:39:20,720 LEVEL WHAT IF WE COULD GO IN AND 918 00:39:20,720 --> 00:39:24,240 JUST CHANGE THE ABNORMALITY AND 919 00:39:24,240 --> 00:39:25,520 MAKE IT BETTER. 920 00:39:25,520 --> 00:39:26,960 WE WANT TO DO THAT AS MUCH 921 00:39:26,960 --> 00:39:28,440 POSSIBLE BUT IF WE CAN DO THAT 922 00:39:28,440 --> 00:39:31,040 AND THE TECHNOLOGY EXISTS TO DO 923 00:39:31,040 --> 00:39:31,280 THAT. 924 00:39:31,280 --> 00:39:36,880 WE'RE FORTUNATE TO WORK WITH AN 925 00:39:36,880 --> 00:39:47,800 INVESTIGATOR AT THE BRODE -- 926 00:39:47,800 --> 00:39:51,480 BROAD INSTITUTE AND WE MADE THIS 927 00:39:51,480 --> 00:39:55,040 MOUSE MODEL AND JACKSON 928 00:39:55,040 --> 00:39:56,560 LABORATORY WERE NICE ENOUGH TO 929 00:39:56,560 --> 00:39:58,160 MAKE IT FOR US INSTEAD OF 930 00:39:58,160 --> 00:39:59,560 CHARGING US AND INSTEAD OF 931 00:39:59,560 --> 00:40:02,280 MAKING THE MUTATION IN THE MOUSE 932 00:40:02,280 --> 00:40:04,320 WE ACTUALLY PUT A CHUNK OF THE 933 00:40:04,320 --> 00:40:07,640 HUMAN GENE INTO THE MOUSE SO WE 934 00:40:07,640 --> 00:40:12,920 CAN TEST THE EXACT SORT OF 935 00:40:12,920 --> 00:40:18,320 CHEMICAL BIOLOGY RE-AGENTS AS IN 936 00:40:18,320 --> 00:40:21,160 THE MOUSE WITH DAVID LU'S LAB. 937 00:40:21,160 --> 00:40:22,680 THIS IS AN AREA WHERE THERE'S A 938 00:40:22,680 --> 00:40:24,960 LOT OF INTEREST IN TERMS OF 939 00:40:24,960 --> 00:40:27,080 TRANSLATING THESE CHANGES INTO 940 00:40:27,080 --> 00:40:28,240 BENEFITS FOR PEOPLE. 941 00:40:28,240 --> 00:40:29,520 AN UNUSUAL APPROACH HERE BUT 942 00:40:29,520 --> 00:40:32,520 IT'S ONE THAT COULD DEFINITELY 943 00:40:32,520 --> 00:40:33,840 FIT IN AS WELL TO SPG4 WHERE A 944 00:40:33,840 --> 00:40:35,520 LOT OF THE CHANGES ARE SORT OF 945 00:40:35,520 --> 00:40:38,760 THESE SINGLE CHANGES THAT GIVE 946 00:40:38,760 --> 00:40:43,440 RISE TO AMINO ACID CHANGE AND IN 947 00:40:43,440 --> 00:40:45,160 MY LAST FEW SLIDES I WANTED TO 948 00:40:45,160 --> 00:40:48,680 FOCUS ON SO THAT'S WHAT I'VE 949 00:40:48,680 --> 00:40:50,760 DONE WITH SPG3A AND CREATED 950 00:40:50,760 --> 00:40:52,080 DIFFERENT MODEL SYSTEMS AND 951 00:40:52,080 --> 00:40:53,240 ORGANISMS AND TRIED TO 952 00:40:53,240 --> 00:40:54,320 UNDERSTAND THE AFFECTS OF THEM 953 00:40:54,320 --> 00:40:55,480 ON THE BIOLOGY OF THE PROTEIN 954 00:40:55,480 --> 00:40:57,600 AND THE PROTEIN IS AN ENZYME. 955 00:40:57,600 --> 00:40:59,200 AND IN ONE OF THE DISCUSSIONS 956 00:40:59,200 --> 00:41:00,960 YESTERDAY IS THIS GAIN OF 957 00:41:00,960 --> 00:41:03,480 FUNCTION, LOSS OF FUNCTION, IT'S 958 00:41:03,480 --> 00:41:05,360 IMPORTANT TO REMEMBER WITH 959 00:41:05,360 --> 00:41:06,800 ENZYMES IS YOU CAN EITHER HAVE 960 00:41:06,800 --> 00:41:08,920 TOO MUCH ACTIVITY OR TOO LITTLE. 961 00:41:08,920 --> 00:41:11,560 YOU MAY NOT GET THE SAME 962 00:41:11,560 --> 00:41:11,840 SYMPTOMS. 963 00:41:11,840 --> 00:41:14,000 FOR SPG3A THERE'S SOME 964 00:41:14,000 --> 00:41:15,640 SPECULATION THE DE NOVO PATIENTS 965 00:41:15,640 --> 00:41:19,360 MAY HAVE TOO MUCH ACTIVITY AND 966 00:41:19,360 --> 00:41:20,720 THE TRADITIONAL ONES MAY HAVE 967 00:41:20,720 --> 00:41:21,200 TOO LITTLE. 968 00:41:21,200 --> 00:41:25,280 YOU CAN SEE THAT AS BOTH TOXIC 969 00:41:25,280 --> 00:41:27,200 GAIN OF FUNCTION BUT IT'S 970 00:41:27,200 --> 00:41:28,280 DIFFERENT BECAUSE ONE IS LOSS OF 971 00:41:28,280 --> 00:41:31,120 ENZYME ACTIVITY AND ONE IS TOO 972 00:41:31,120 --> 00:41:31,320 MUCH. 973 00:41:31,320 --> 00:41:33,240 BUT THEY'RE BOTH TOXIC IN 974 00:41:33,240 --> 00:41:33,600 DIFFERENT WAYS. 975 00:41:33,600 --> 00:41:37,640 THE SPG4 PROTEIN HAS AN 976 00:41:37,640 --> 00:41:38,080 IMPORTANT DISTINCTION. 977 00:41:38,080 --> 00:41:42,200 AS I WAS LISTENING TO THE TALKS 978 00:41:42,200 --> 00:41:44,280 YESTERDAY I WAS STRUCK ABOUT 979 00:41:44,280 --> 00:41:46,600 TALK ABOUT HOW THERE'S VARIATION 980 00:41:46,600 --> 00:41:48,120 OR WHY THESE CERTAIN MUTATIONS 981 00:41:48,120 --> 00:41:51,000 SHOULD GIVE RISE TO A MORE 982 00:41:51,000 --> 00:41:52,920 SEVERE FORM OR OTHERS DON'T. 983 00:41:52,920 --> 00:41:55,360 IS IT AS SIMPLE AS CHANGES IN A 984 00:41:55,360 --> 00:41:56,280 CERTAIN AREA OR IS THERE 985 00:41:56,280 --> 00:41:59,200 SOMETHING MORE TO IT AND AGAIN 986 00:41:59,200 --> 00:42:04,280 WE'RE TALKING ABOUT GENETIC 987 00:42:04,280 --> 00:42:04,880 MODIFIE 988 00:42:04,880 --> 00:42:05,120 MODIFIERS. 989 00:42:05,120 --> 00:42:06,120 IT'S IMPORTANT TO REMEMBER SPG4 990 00:42:06,120 --> 00:42:10,920 HAS ITS OWN MODIFIER AND ONE 991 00:42:10,920 --> 00:42:14,640 mRNA AND WE CALL M1 AND M87. 992 00:42:14,640 --> 00:42:17,760 WE THINK OF THEM AS USING 993 00:42:17,760 --> 00:42:18,680 DIFFERENT TRANSLATION START 994 00:42:18,680 --> 00:42:19,680 SITES BUT WHAT WE'VE DONE 995 00:42:19,680 --> 00:42:21,680 RECENTLY IS COME UP WITH WAYS TO 996 00:42:21,680 --> 00:42:25,320 GENETICALLY CHANGE A CELL TO 997 00:42:25,320 --> 00:42:28,000 TAKE ON M1 AND M87 SEPARATELY 998 00:42:28,000 --> 00:42:32,920 AND YOU CAN'T DO WITH SRNA 999 00:42:32,920 --> 00:42:34,280 APPROACH BECAUSE THEY HAVE THE 1000 00:42:34,280 --> 00:42:36,920 SAME BUT YOU CAN IF YOU EDIT THE 1001 00:42:36,920 --> 00:42:39,440 GENOME. 1002 00:42:39,440 --> 00:42:40,720 I WANT TO SHOW YOU PICTURES AT 1003 00:42:40,720 --> 00:42:43,680 THE BOTTOM AND YOU SEE THIS TINY 1004 00:42:43,680 --> 00:42:48,440 BAND AND M87 IS REALLY BIG. 1005 00:42:48,440 --> 00:42:52,200 WHEN WE KNOCKOUT M1 WE SEE A 1006 00:42:52,200 --> 00:42:56,240 HUGE DIFFERENCE IN ENDOPLASMIC 1007 00:42:56,240 --> 00:42:57,840 RETICULUM AND IF YOU KNOCKOUT 1008 00:42:57,840 --> 00:42:59,680 M87 IT HAS NO EFFECT. 1009 00:42:59,680 --> 00:43:00,800 THEY'RE TWO DIFFERENT PROTEINS 1010 00:43:00,800 --> 00:43:03,560 MADE OFF THE SAME GENE AND THEY 1011 00:43:03,560 --> 00:43:04,880 HAVE DIFFERENT FUNCTIONS. 1012 00:43:04,880 --> 00:43:05,880 SO IF YOU THINK ABOUT THAT AND 1013 00:43:05,880 --> 00:43:09,480 ANOTHER THING WE FOUND IS THE 1014 00:43:09,480 --> 00:43:12,160 EFFECT OF M1 ON ER DOESN'T 1015 00:43:12,160 --> 00:43:13,960 DEPEND ON THE ACTIVITY AND OTHER 1016 00:43:13,960 --> 00:43:15,200 FUNCTIONS OF M87 DO. 1017 00:43:15,200 --> 00:43:17,480 THAT'S A WAY TO IMAGINE AN 1018 00:43:17,480 --> 00:43:17,920 EXPLANATION. 1019 00:43:17,920 --> 00:43:21,000 IF YOU THINK ABOUT IT YOU HAVE 1020 00:43:21,000 --> 00:43:22,680 AN MUTATION THAT IS AFFECTING 1021 00:43:22,680 --> 00:43:24,000 TWO DIFFERENT PROTEINS IN TWO 1022 00:43:24,000 --> 00:43:24,480 DIFFERENT WAYS. 1023 00:43:24,480 --> 00:43:25,880 YOU CAN IMAGINE DIFFERENT 1024 00:43:25,880 --> 00:43:27,280 MUTATIONS CAN AFFECT ONE MORE 1025 00:43:27,280 --> 00:43:28,960 THAN THE OTHER OR BOTH AT THE 1026 00:43:28,960 --> 00:43:31,640 SAME RATE AND YOU COULD GET 1027 00:43:31,640 --> 00:43:34,440 DIFFERENT LEVELS OF SEVERITY AND 1028 00:43:34,440 --> 00:43:37,680 DIFFERENT TYPES OF SYMPTOMS. 1029 00:43:37,680 --> 00:43:40,440 I WANTED TO EMPHASIZE TO A LOT 1030 00:43:40,440 --> 00:43:44,280 OF THE PEOPLE ON THE CALL TODAY 1031 00:43:44,280 --> 00:43:46,480 THAT THERE'S SEVERAL VERY 1032 00:43:46,480 --> 00:43:48,920 DEDICATED PEOPLE WORKING ON 1033 00:43:48,920 --> 00:43:50,400 SPASTIC PARAPLEGIA AND DOING 1034 00:43:50,400 --> 00:43:52,040 THIS ALL THEIR LIFE BUT THERE'S 1035 00:43:52,040 --> 00:43:52,960 ALSO A LOT OF SUPPORT WE GET 1036 00:43:52,960 --> 00:43:56,760 FROM PEOPLE WHO AREN'T WORKING 1037 00:43:56,760 --> 00:44:02,600 ON SPGs AND DON'T NEUROLOGIC 1038 00:44:02,600 --> 00:44:04,000 DISEASE BUT PROVIDE EXPERTISE 1039 00:44:04,000 --> 00:44:06,280 THAT IS CRITICAL YOU WON'T SEE 1040 00:44:06,280 --> 00:44:07,680 THEM AT THESE TYPES OF MEETINGS 1041 00:44:07,680 --> 00:44:10,680 BECAUSE THEY'RE OFTEN ENGINEERS 1042 00:44:10,680 --> 00:44:15,280 OR INFORMATICIANS. 1043 00:44:15,280 --> 00:44:16,800 A LOT OF DIFFERENT ROLES AND I 1044 00:44:16,800 --> 00:44:18,280 WANT TO HIGHLIGHT A GROUP THAT'S 1045 00:44:18,280 --> 00:44:21,080 BEEN CRUCIAL TO ME EN ADVANCING 1046 00:44:21,080 --> 00:44:22,920 RESEARCH AND SEVERAL PEOPLE AT 1047 00:44:22,920 --> 00:44:25,680 HOWARD HUGHES MEDICAL INSTITUTE 1048 00:44:25,680 --> 00:44:28,480 AND A STUDENT SPEARHEADED A LOT 1049 00:44:28,480 --> 00:44:31,680 OF THESE COLLABORATIONS AND HE 1050 00:44:31,680 --> 00:44:34,280 WAS IN THE GROUP AS WELL. 1051 00:44:34,280 --> 00:44:35,480 BUT THOUGH IT'S IT'S A RARE 1052 00:44:35,480 --> 00:44:37,280 DISEASE WE HAVE SOME OF THE 1053 00:44:37,280 --> 00:44:38,280 GREATEST MINDS ON EARTH WORKING 1054 00:44:38,280 --> 00:44:40,680 ON THIS AND WE HAVE A NOBEL 1055 00:44:40,680 --> 00:44:43,680 PRIZE WINNER AND ONE OF THE BEST 1056 00:44:43,680 --> 00:44:48,600 CELL BIOLOGISTS ON EARTH AND 1057 00:44:48,600 --> 00:44:50,680 SOME ARE CREATED ADVANCED 1058 00:44:50,680 --> 00:44:51,400 IMAGING TECHNOLOGIES INCLUDING 1059 00:44:51,400 --> 00:44:52,720 THE ONE I SHOWED FOR 1060 00:44:52,720 --> 00:44:57,680 RECONSTRUCTING THE SPINAL CORD. 1061 00:44:57,680 --> 00:44:59,680 THESE ARE PEOPLE WHO AREN'T AT 1062 00:44:59,680 --> 00:45:01,480 THE CLINICAL MEETINGS BUT 1063 00:45:01,480 --> 00:45:03,320 PROVIDE EXPERTISE AS THAT WILL 1064 00:45:03,320 --> 00:45:04,800 CRITICAL AS WE ANALYZE THE MODEL 1065 00:45:04,800 --> 00:45:06,040 SYSTEMS. 1066 00:45:06,040 --> 00:45:07,680 I WANTED TO GIVE THEM A SHOUT 1067 00:45:07,680 --> 00:45:09,680 OUT AND PEOPLE BEHIND THE SCENES 1068 00:45:09,680 --> 00:45:12,280 THAT ARE REALLY TALENTED. 1069 00:45:12,280 --> 00:45:13,920 THOUGH IT'S A REALLY RARE 1070 00:45:13,920 --> 00:45:15,280 DISEASE WE'RE TALKING ABOUT WE 1071 00:45:15,280 --> 00:45:17,160 HAVE SOME OF THE GREATEST MINDS 1072 00:45:17,160 --> 00:45:18,880 ON EARTH HELPING OUT WITH IT. 1073 00:45:18,880 --> 00:45:23,720 HERE'S AGE -- AN EXAMPLE OF WHAT 1074 00:45:23,720 --> 00:45:27,080 WE CAN DO NOW LOOKING AT A 1075 00:45:27,080 --> 00:45:29,760 PROTEIN MOVING AND THE DOTS ARE 1076 00:45:29,760 --> 00:45:30,680 INDIVIDUAL PROTEINS MOVING ON 1077 00:45:30,680 --> 00:45:31,480 THE ER. 1078 00:45:31,480 --> 00:45:33,080 ONE THING WE THINK ABOUT WHEN WE 1079 00:45:33,080 --> 00:45:34,680 THINK OF MODEL SYSTEMS IS HOW WE 1080 00:45:34,680 --> 00:45:36,760 ASSESS THEM. 1081 00:45:36,760 --> 00:45:39,480 WE LOOK A LOT PERSON AND WE THEM 1082 00:45:39,480 --> 00:45:42,080 WALK AND TEST THEIR MOTION AND 1083 00:45:42,080 --> 00:45:44,160 CELLS SHOW A STATIC PICTURE. 1084 00:45:44,160 --> 00:45:45,520 I DOESN'T HAVE TO BE LIKE THAT. 1085 00:45:45,520 --> 00:45:47,320 WE HAVE THE ABILITY NOW TO LOOK 1086 00:45:47,320 --> 00:45:49,200 AT PROTEINS DYNAMICALLY AND IN 1087 00:45:49,200 --> 00:45:52,080 THE LAST SLIDE OR TWO I'LL SHOW 1088 00:45:52,080 --> 00:45:55,680 WHAT A SPAST MUTATION LOOKS LIKE 1089 00:45:55,680 --> 00:45:56,680 AND THAT'S THE INDIVIDUAL 1090 00:45:56,680 --> 00:45:58,320 MOLECULE MOVING, ON THE LEFT IS 1091 00:45:58,320 --> 00:45:59,520 A NORMAL ONE. 1092 00:45:59,520 --> 00:46:01,120 THE ONE ON THE RIGHT IS MUTANT 1093 00:46:01,120 --> 00:46:03,680 FORM AND THE ONE ON THE LEFT IS 1094 00:46:03,680 --> 00:46:04,760 WILD TYPE, NORMAL. 1095 00:46:04,760 --> 00:46:06,480 LOOK AT THE DRAMATIC DIFFERENCE. 1096 00:46:06,480 --> 00:46:08,240 THE ONE ON THE RIGHT IS MOVING 1097 00:46:08,240 --> 00:46:09,600 IT'S JUST NOT GOING WHERE AND 1098 00:46:09,600 --> 00:46:10,760 THE ONE ON THE LEFT IS GOING ALL 1099 00:46:10,760 --> 00:46:11,360 OVER THE PLACE. 1100 00:46:11,360 --> 00:46:14,720 IT GIVES ANOTHER WAY TO LOOK AT 1101 00:46:14,720 --> 00:46:15,600 SPAST IN FUNCTION. 1102 00:46:15,600 --> 00:46:17,280 IT'S ANOTHER WAY TO EMPHASIZE 1103 00:46:17,280 --> 00:46:19,040 WE'VE HAD GREAT COLLABORATORS 1104 00:46:19,040 --> 00:46:21,280 WHO CONTRIBUTED REALLY THE MOST 1105 00:46:21,280 --> 00:46:23,480 CUTTING-EDGE TECHNOLOGY TO OUR 1106 00:46:23,480 --> 00:46:24,920 ABILITY TO STUDY SPG4 AND OF 1107 00:46:24,920 --> 00:46:27,600 COURSE THIS RELATES TO THE DE 1108 00:46:27,600 --> 00:46:29,360 NOVO PATIENTS AS WELL. 1109 00:46:29,360 --> 00:46:31,760 WE CAN COMPARE DE NOVO MUTATIONS 1110 00:46:31,760 --> 00:46:33,600 TO THE TRADITIONAL ONES IN NEW 1111 00:46:33,600 --> 00:46:33,800 WAYS. 1112 00:46:33,800 --> 00:46:37,960 I THINK THAT WILL ALLOW US TO 1113 00:46:37,960 --> 00:46:40,360 AGAIN UNDERSTAND WHAT THE 1114 00:46:40,360 --> 00:46:41,920 DIFFERENCE MORE AND THAT 1115 00:46:41,920 --> 00:46:43,360 UNDERSTANDING WILL DIRECTLY 1116 00:46:43,360 --> 00:46:45,320 APPLY TO HOW WE ULTIMATELY TREAT 1117 00:46:45,320 --> 00:46:46,400 THIS. 1118 00:46:46,400 --> 00:46:47,720 I WANTED TO END WITH THOSE. 1119 00:46:47,720 --> 00:46:51,080 A FINAL SLIDE, I THINK ONE OF 1120 00:46:51,080 --> 00:46:52,160 THE IMPORTANT SLIDE AND TAKE 1121 00:46:52,160 --> 00:47:01,720 HOME MESS AG -- MESSAGE OF MY 1122 00:47:01,720 --> 00:47:02,840 SLIDE AS WE NEED TO LOOK AT THIS 1123 00:47:02,840 --> 00:47:04,400 AS TRADITIONAL DISEASE WE NEED 1124 00:47:04,400 --> 00:47:07,680 TO LOOK AT M1 AND M87 AS TWO 1125 00:47:07,680 --> 00:47:08,520 DIFFERENT PROTEINS AND WHEN YOU 1126 00:47:08,520 --> 00:47:11,080 LOOK AT ONE GENE MAKING TWO 1127 00:47:11,080 --> 00:47:14,560 DIFFERENT PROTEINS IT GETS 1128 00:47:14,560 --> 00:47:15,680 EASIER TO UNDERSTAND HOW THE 1129 00:47:15,680 --> 00:47:16,720 MUTATION WILL AFFECT THE PROTEIN 1130 00:47:16,720 --> 00:47:19,680 IN DIFFERENT WAYS AND THOSE CAN 1131 00:47:19,680 --> 00:47:20,800 ALSO IF WE DON'T STUDY THEM 1132 00:47:20,800 --> 00:47:22,360 SEPARATELY IT CAN GET MORE 1133 00:47:22,360 --> 00:47:25,520 CONFUSING IN TERMS OF 1134 00:47:25,520 --> 00:47:27,520 UNDERSTANDING THE BASIC BIOLOGY 1135 00:47:27,520 --> 00:47:28,360 THAT UNDER LIES THE SPG4. 1136 00:47:28,360 --> 00:47:30,400 I WANT TO THANK THE PEOPLE I 1137 00:47:30,400 --> 00:47:31,160 WORK WITH. 1138 00:47:31,160 --> 00:47:33,560 I WANT TO EMPHASIZE SOME OF THE 1139 00:47:33,560 --> 00:47:36,480 GROUPS THAT REALLY PROVIDE 1140 00:47:36,480 --> 00:47:37,680 CUTTING-EDGE TECHNOLOGY THAT 1141 00:47:37,680 --> 00:47:42,760 WOULD BE AVAILABLE NOWHERE ELSE 1142 00:47:42,760 --> 00:47:44,520 AND I WANTED TO EMPHASIZE FOR 1143 00:47:44,520 --> 00:47:46,200 THOSE LISTENING ON THE CALL HOW 1144 00:47:46,200 --> 00:47:50,280 IMPORTANT THE NIH UDP, 1145 00:47:50,280 --> 00:47:51,880 UNDIAGNOSED DISEASE PROGRAM HAS 1146 00:47:51,880 --> 00:47:52,080 BEEN. 1147 00:47:52,080 --> 00:47:58,120 I REMEMBER WHEN CAMILA AND I 1148 00:47:58,120 --> 00:47:59,560 WERE TALKING ABOUT THE FIRST 1149 00:47:59,560 --> 00:48:00,960 PATIENTS WITH THE DE NOVO FORMS 1150 00:48:00,960 --> 00:48:02,520 THE UNDIAGNOSED DISEASES PROGRAM 1151 00:48:02,520 --> 00:48:05,720 HAS ALWAYS BEEN THERE IN TERMS 1152 00:48:05,720 --> 00:48:07,480 OF PROVIDING THE ABILITY TO LOOK 1153 00:48:07,480 --> 00:48:09,920 AT NEW DISEASES IN VERY DETAILED 1154 00:48:09,920 --> 00:48:13,040 AND NEW WAYS AND I THINK HAS 1155 00:48:13,040 --> 00:48:14,160 ALLOWED US TO THINK OF THE 1156 00:48:14,160 --> 00:48:17,080 CONCEPT OF SOME OF THESE TYPES 1157 00:48:17,080 --> 00:48:22,000 OF DISORDERS AND THE NEW 1158 00:48:22,000 --> 00:48:24,880 MECHANISMS AND IT'S BECAUSE OF 1159 00:48:24,880 --> 00:48:27,600 THEIR LEADERSHIP I DON'T KNOW BY 1160 00:48:27,600 --> 00:48:29,520 HOW MANY YEARS BUT AT SOMEONE AS 1161 00:48:29,520 --> 00:48:31,560 NIH FOR 20 YEARS, I WANTED TO 1162 00:48:31,560 --> 00:48:35,160 EMPHASIZE THE IMPORTANCE OF THAT 1163 00:48:35,160 --> 00:48:38,680 PROGRAM IN RARE DISEASE RESEARCH 1164 00:48:38,680 --> 00:48:40,360 AND IN TERMS OF JUMP STARTING 1165 00:48:40,360 --> 00:48:42,840 RESEARCH INTO RARE DISEASES LIKE 1166 00:48:42,840 --> 00:48:43,880 THIS DE NOVO FORM OF SPG4 IN 1167 00:48:43,880 --> 00:48:45,160 PARTICULAR. 1168 00:48:45,160 --> 00:48:46,320 AGAIN, THANK YOU AND I KNOW AT 1169 00:48:46,320 --> 00:48:47,880 SOME POINT I'LL BE ABLE TO 1170 00:48:47,880 --> 00:48:56,160 ANSWER QUESTIONS. 1171 00:48:56,160 --> 00:48:56,760 >> THANK YOU VERY MUCH. 1172 00:48:56,760 --> 00:48:57,920 VERY EXCITING TALK. 1173 00:48:57,920 --> 00:48:59,640 THERE'S A FEW QUESTIONS FOR 1174 00:48:59,640 --> 00:49:01,720 BRYAN IN THE CHAT AND I'LL START 1175 00:49:01,720 --> 00:49:04,320 READING ONE OF THEM. 1176 00:49:04,320 --> 00:49:06,520 BRYAN, ARE THE BRAIN SPEAROIDS 1177 00:49:06,520 --> 00:49:09,120 GENERATE FROM CELLS OR NEURONS 1178 00:49:09,120 --> 00:49:10,960 FROM THE RARE DISEASED PATIENTS 1179 00:49:10,960 --> 00:49:11,720 AND NEURONS OR CELLS THAT 1180 00:49:11,720 --> 00:49:19,040 GENERATE IN THEIR DISEASES? 1181 00:49:19,040 --> 00:49:20,640 >> THAT'S EXACTLY WHAT YOU DON'T 1182 00:49:20,640 --> 00:49:21,920 WANT TO DO BECAUSE WE'RE TALKING 1183 00:49:21,920 --> 00:49:23,640 ABOUT 10,000 RARE DISEASES. 1184 00:49:23,640 --> 00:49:28,280 WHAT YOU ABSOLUTELY DO NOT WANT 1185 00:49:28,280 --> 00:49:30,680 TO DO IN THIS INSTANCE IS START 1186 00:49:30,680 --> 00:49:32,600 MAKING DISEASE-SPECIFIC ASSAYS. 1187 00:49:32,600 --> 00:49:36,080 THIS HAS TO WORK ACROSS THE 1188 00:49:36,080 --> 00:49:39,440 GAMUT OF NEUROLOGICAL AND RARE 1189 00:49:39,440 --> 00:49:39,920 DISEASES. 1190 00:49:39,920 --> 00:49:41,240 SO THEY'RE NOT DISEASE SPECIFIC. 1191 00:49:41,240 --> 00:49:46,760 THEY'RE ACTUALLY TAKEN FROM -- 1192 00:49:46,760 --> 00:49:51,480 THEY'RE TAKEN FROM A NORMAL 1193 00:49:51,480 --> 00:49:55,320 HEALTHY INDIVIDUAL AND TO JUMP 1194 00:49:55,320 --> 00:49:56,360 FORWARD BECAUSE I SAW A QUESTION 1195 00:49:56,360 --> 00:49:59,680 IN THE CHAT BOX THERE, ONE OF 1196 00:49:59,680 --> 00:50:01,600 THE KEY FEATURES WE'RE TRYING TO 1197 00:50:01,600 --> 00:50:04,240 DEVELOP IS WE'LL MAKE ALL THE 1198 00:50:04,240 --> 00:50:05,760 PROTOCOLS AND ALL THE DATA 1199 00:50:05,760 --> 00:50:08,520 PUBLICLY AVAILABLE AS QUICKLY AS 1200 00:50:08,520 --> 00:50:11,240 POSSIBLE BECAUSE WE WANT THESE 1201 00:50:11,240 --> 00:50:13,200 PROTOCOLS TO BE OPEN AND SHARED 1202 00:50:13,200 --> 00:50:14,080 WIDELY BECAUSE IT BASICALLY 1203 00:50:14,080 --> 00:50:18,040 MEANS THAT IF YOU'RE WORKING IN 1204 00:50:18,040 --> 00:50:21,200 AN ACADEMIC HOSPITAL IN OHIO OWE 1205 00:50:21,200 --> 00:50:24,200 YOU CAN PICK UP THE BALL AND RUN 1206 00:50:24,200 --> 00:50:26,800 DOWN THE FIELD FURTHER WITH IT 1207 00:50:26,800 --> 00:50:29,640 WHEN YOUR PATIENT PRESENTS IN 1208 00:50:29,640 --> 00:50:30,040 CLINIC. 1209 00:50:30,040 --> 00:50:33,800 ANOTHER ASPECT OF THE GENE 1210 00:50:33,800 --> 00:50:39,040 THERAPY ONGOING AT NCATS IS 1211 00:50:39,040 --> 00:50:42,440 CALLED PAVED GP AND THE IDEA 1212 00:50:42,440 --> 00:50:45,680 THERE IS THIS IS TO DEVELOP AAB 1213 00:50:45,680 --> 00:50:47,280 VIRAL VECTORS FOR DISEASES. 1214 00:50:47,280 --> 00:50:49,680 AND EVERYTHING HAS BEEN MADE 1215 00:50:49,680 --> 00:50:51,680 PUBLICLY AVAILABLE EVEN FOR ONE 1216 00:50:51,680 --> 00:50:53,680 OF THE FIRST TIMES THE FEEDBACK 1217 00:50:53,680 --> 00:50:56,280 FROM THE FDA WHEN THEY SUBMITTED 1218 00:50:56,280 --> 00:50:59,680 THEIR IND APPLICATION. 1219 00:50:59,680 --> 00:51:03,440 THE FDA VERY KINDLY ALLOWED US 1220 00:51:03,440 --> 00:51:05,640 TO PUT THEIR COMMENTS UP ONLINE 1221 00:51:05,640 --> 00:51:07,440 SO PEOPLE COULD SEE IN REAL TIME 1222 00:51:07,440 --> 00:51:08,880 WHAT THE COMMENTS COMING BACK 1223 00:51:08,880 --> 00:51:11,640 FROM THE FDA WERE AND HOW WE 1224 00:51:11,640 --> 00:51:13,960 WOULD ACTUALLY RESPOND TO THEM 1225 00:51:13,960 --> 00:51:15,640 IN ORDER TO ADDRESS THEIR 1226 00:51:15,640 --> 00:51:15,880 CONCERNS. 1227 00:51:15,880 --> 00:51:17,920 I THINK THAT OPENNESS IS REAL 1228 00:51:17,920 --> 00:51:21,480 IMPORTANT HERE AND ALSO HAVING A 1229 00:51:21,480 --> 00:51:22,080 COMPATIBLE ACROSS THE GAMUT OF 1230 00:51:22,080 --> 00:51:23,840 RARE DISEASES. 1231 00:51:23,840 --> 00:51:27,640 >> AND I GUESS THERE'S A SIMILAR 1232 00:51:27,640 --> 00:51:29,120 QUESTION FROM PETER. 1233 00:51:29,120 --> 00:51:31,280 ARE THE ASO'S SPECIFIC TO THE 1234 00:51:31,280 --> 00:51:34,720 MUTANT GENE SO EXPRESSION OCCURS 1235 00:51:34,720 --> 00:51:37,160 FROM THE WILD TYPE GENE AND IS 1236 00:51:37,160 --> 00:51:39,680 TO THE ASO LIMITED BY PROTEINS 1237 00:51:39,680 --> 00:51:41,760 AGGREGATE AND BECOME LONG LIVED. 1238 00:51:41,760 --> 00:51:43,240 >> THAT'S A SLIGHTLY SEPARATE 1239 00:51:43,240 --> 00:51:44,120 QUESTION BECAUSE THAT'S MORE 1240 00:51:44,120 --> 00:51:46,360 TALKING ABOUT THE EFFICACY AND 1241 00:51:46,360 --> 00:51:48,840 WHAT DO YOU WANT TO TARGET. 1242 00:51:48,840 --> 00:51:50,200 AND I THINK THAT IS ESSENTIALLY 1243 00:51:50,200 --> 00:51:52,360 THAT'S AN UNANSWERED QUESTIONS 1244 00:51:52,360 --> 00:51:54,160 WITHIN THE FIELD. 1245 00:51:54,160 --> 00:51:56,360 AND THERE IT PROBABLY IS A 1246 00:51:56,360 --> 00:51:57,040 LITTLE BIT MORE DISEASE SPECIFIC 1247 00:51:57,040 --> 00:52:00,240 IN HOW YOU WANT TO APPROACH IT. 1248 00:52:00,240 --> 00:52:01,720 THERE ARE GOING TO BE INSTANTES 1249 00:52:01,720 --> 00:52:03,320 WHERE YOU WANT TO TAKE IT -- 1250 00:52:03,320 --> 00:52:05,040 INSTANCES WHERE YOU WANT TO TAKE 1251 00:52:05,040 --> 00:52:09,080 OUT THE WILD TYPE AND MUTANT 1252 00:52:09,080 --> 00:52:09,960 ALLELES AND THERE'S TIMES YOU 1253 00:52:09,960 --> 00:52:12,480 WANT TO TAKE BOTH OUT AND 1254 00:52:12,480 --> 00:52:14,480 INSTANCE WHERE'S YOU'LL WANT TO 1255 00:52:14,480 --> 00:52:16,320 BE MORE SELECTIVE AND EVEN 1256 00:52:16,320 --> 00:52:17,360 INSTANCES TO INCREASE UP 1257 00:52:17,360 --> 00:52:20,480 EXPRESSION BY TARGETING WHAT IS 1258 00:52:20,480 --> 00:52:23,640 KNOWN AS NATURAL ANTI-SENSE 1259 00:52:23,640 --> 00:52:23,920 TRANSCRIPTS. 1260 00:52:23,920 --> 00:52:26,080 IT'S ALMOST LIKE NATURAL 1261 00:52:26,080 --> 00:52:27,040 PREDICTED AHEAD OF TIME WHAT 1262 00:52:27,040 --> 00:52:30,520 ASOs WOULD BE LIKE AND ACTUALLY 1263 00:52:30,520 --> 00:52:33,440 PUT A LITTLE ASO IN FRONT OF OR 1264 00:52:33,440 --> 00:52:35,560 ADJACENT TO ABOUT 30% OF THE 1265 00:52:35,560 --> 00:52:36,400 GENES. 1266 00:52:36,400 --> 00:52:38,120 AND WHAT IS ACTUALLY INTERESTING 1267 00:52:38,120 --> 00:52:40,400 IS WHAT'S EMERGING NOW IS 1268 00:52:40,400 --> 00:52:41,680 ACTUALLY A LOT OF THE GENES THAT 1269 00:52:41,680 --> 00:52:44,880 ARE IMPORTANT IN NEUROLOGICAL 1270 00:52:44,880 --> 00:52:45,480 DISEASES AND THEIR EXPRESSED IN 1271 00:52:45,480 --> 00:52:49,120 THE CNS, THEY'RE THE VERY ONES 1272 00:52:49,120 --> 00:52:54,040 THAT ACTUALLY HAVE THESE NATURAL 1273 00:52:54,040 --> 00:52:55,680 ANTI-SENSE TRANSCRIPTS. 1274 00:52:55,680 --> 00:52:57,000 VIROLOGY AND EVOLUTION MAY BE 1275 00:52:57,000 --> 00:52:57,800 TRYING TO TELL US SOMETHING 1276 00:52:57,800 --> 00:52:58,880 ABOUT IMPORTANCE OF THESE. 1277 00:52:58,880 --> 00:53:02,080 TO SPEAK TO PETER'S QUESTION 1278 00:53:02,080 --> 00:53:02,960 ABOUT INCLUSIONS, I ACTUALLY 1279 00:53:02,960 --> 00:53:04,320 DON'T KNOW THE ANSWER TO THAT 1280 00:53:04,320 --> 00:53:06,560 AND I DON'T THINK ANYBODY DOES. 1281 00:53:06,560 --> 00:53:07,240 LET'S WAIT AND SEE WHAT HAPPENS 1282 00:53:07,240 --> 00:53:09,600 THERE. 1283 00:53:09,600 --> 00:53:14,600 I WILL SAY JUST COMING FROM THE 1284 00:53:14,600 --> 00:53:16,680 NS FIELD WE KNOW THERE'S 1285 00:53:16,680 --> 00:53:18,400 INCLUSIONS THOUGH WE THINK OF 1286 00:53:18,400 --> 00:53:19,560 THEMES BOWLS OF PROTEIN. 1287 00:53:19,560 --> 00:53:21,400 THEY'RE QUITE ACTIVE. 1288 00:53:21,400 --> 00:53:24,040 THERE'S STUFF GOING IN AND STUFF 1289 00:53:24,040 --> 00:53:25,800 COMING OUT. 1290 00:53:25,800 --> 00:53:27,640 ONE HOPES IF YOU CAN CHANGE THE 1291 00:53:27,640 --> 00:53:31,000 UNDERLYING PROCESS MAYBE THE 1292 00:53:31,000 --> 00:53:31,920 PROTEIN CLUMPS WILL GO AWAY. 1293 00:53:31,920 --> 00:53:32,960 I DON'T KNOW. 1294 00:53:32,960 --> 00:53:35,600 MAYBE IT'S AN OPEN QUESTION. 1295 00:53:35,600 --> 00:53:42,560 >> THE NEXT QUESTION IS IN TERMS 1296 00:53:42,560 --> 00:53:45,640 OF LIKE SHARING SAMPLES AND 1297 00:53:45,640 --> 00:53:48,560 PROVIDING FEE FOR SERVICE AND 1298 00:53:48,560 --> 00:53:52,360 THE SECOND SECOND IS A 1299 00:53:52,360 --> 00:53:53,240 FOLLOW-UP. 1300 00:53:53,240 --> 00:53:55,280 DO YOU THINK YOUR IN VITRO TOX 1301 00:53:55,280 --> 00:53:57,880 ASSAYS AT SOME POINT REPLACE IN 1302 00:53:57,880 --> 00:53:58,960 VIVO APPLICATION AND DO YOU SEE 1303 00:53:58,960 --> 00:53:59,680 FDA MOVING THAT WAY IN THE 1304 00:53:59,680 --> 00:54:10,360 FORESEEABLE FUTURE. 1305 00:54:10,360 --> 00:54:11,680 >> I'LL ADDRESS THE FIRST 1306 00:54:11,680 --> 00:54:14,040 QUESTION BECAUSE THE SECOND HAS 1307 00:54:14,040 --> 00:54:14,760 BEEN ANSWERED ALREADY AND 1308 00:54:14,760 --> 00:54:16,960 DR. SCHULE IS BASED IN GERMANY 1309 00:54:16,960 --> 00:54:18,560 AND THE RULES ARE SLIGHTLY 1310 00:54:18,560 --> 00:54:20,760 DIFFERENT OVER THERE. 1311 00:54:20,760 --> 00:54:23,680 THEY DON'T REQUIRE IND APPROVAL 1312 00:54:23,680 --> 00:54:27,000 TO PUT DRUGS INTO HUMANS WHICH 1313 00:54:27,000 --> 00:54:31,920 IS A STEP THE FDA REQUIRES. 1314 00:54:31,920 --> 00:54:35,280 REBECCA AND MYSELF HAVE TALKED 1315 00:54:35,280 --> 00:54:36,720 ABOUT THIS A LOT AND THIS IS 1316 00:54:36,720 --> 00:54:38,280 WHAT WE'RE HOPING. 1317 00:54:38,280 --> 00:54:39,680 WE HOPE AT SOME STAGE IN THE 1318 00:54:39,680 --> 00:54:41,560 FUTURE WE CAN CONVINCE THE FDA 1319 00:54:41,560 --> 00:54:43,880 OUR CELL-BASED ASSAYS ARE JUST 1320 00:54:43,880 --> 00:54:49,680 AS GOOD AS THE ANIMAL TOX. 1321 00:54:49,680 --> 00:54:52,280 THAT'S THE PLATONIC IDEAL WE'RE 1322 00:54:52,280 --> 00:54:53,120 AIMING FOR BUT IT'S HIGH RISK 1323 00:54:53,120 --> 00:54:56,880 RESEARCH AND I DON'T KNOW WE'LL 1324 00:54:56,880 --> 00:54:58,040 SUCCEED BUT IF WE DO WE'LL 1325 00:54:58,040 --> 00:55:03,680 CERTAINLY CHANGE THE LANDSCAPE 1326 00:55:03,680 --> 00:55:04,040 SOMEWHAT. 1327 00:55:04,040 --> 00:55:07,440 >> AND DO THINK ABOUT WHEN 1328 00:55:07,440 --> 00:55:09,480 YOU'RE READY TO DESIGN AN ASO IS 1329 00:55:09,480 --> 00:55:13,960 IT ABLE TO DESIGN IT AGAINST THE 1330 00:55:13,960 --> 00:55:17,960 M87 ISOFORM AGAINST THE OTHER. 1331 00:55:17,960 --> 00:55:19,720 >> YOU'RE SHAKE YOUR HEAD BUT I 1332 00:55:19,720 --> 00:55:26,280 THINK IT'S POSSIBLE. 1333 00:55:26,280 --> 00:55:29,200 MAYBE YOU CAN HIT THE PROMOTER. 1334 00:55:29,200 --> 00:55:31,480 IF YOU KNOW WHICH ONE DRIVES THE 1335 00:55:31,480 --> 00:55:36,160 M1 VERSUS M87 YOU MAY BE ABLE TO 1336 00:55:36,160 --> 00:55:41,240 SWITCH THAT RATIO A LITTLE BIT, 1337 00:55:41,240 --> 00:55:41,440 CRAIG. 1338 00:55:41,440 --> 00:55:44,080 >> YOU MIGHT BE ABLE TO BUT HOW 1339 00:55:44,080 --> 00:55:46,520 CONSISTENTLY CAN YOU DO THAT? 1340 00:55:46,520 --> 00:55:49,280 IT'S MORE COMPLICATED BECAUSE 1341 00:55:49,280 --> 00:55:51,280 IT'S MORE THAN ONE TRANSCRIPT. 1342 00:55:51,280 --> 00:55:55,480 IT'S NOT IMPOSSIBLE. 1343 00:55:55,480 --> 00:55:57,880 ONE ADDITIONAL POINT IS ONE 1344 00:55:57,880 --> 00:55:59,680 THING AND WITH YOU ARE 1345 00:55:59,680 --> 00:56:00,960 EMPHASIZING PLATFORMS TO BE USED 1346 00:56:00,960 --> 00:56:03,240 WITH HSPs WE HAVE LOTS OF 1347 00:56:03,240 --> 00:56:04,440 DIFFERENT MUTATIONS. 1348 00:56:04,440 --> 00:56:06,680 BUT IF YOU COULD USE AN 1349 00:56:06,680 --> 00:56:07,800 ASO-BASED APPROACH, YOU DON'T 1350 00:56:07,800 --> 00:56:10,280 HAVE TO TARGET THE MUTANT 1351 00:56:10,280 --> 00:56:10,560 MUTATION. 1352 00:56:10,560 --> 00:56:12,920 YOU CAN TARGET -- THERE'S 1353 00:56:12,920 --> 00:56:16,360 CERTAIN POLYMORPHISMS YOU CAN 1354 00:56:16,360 --> 00:56:18,720 OCCASIONALLY TARGET WITH A 1355 00:56:18,720 --> 00:56:20,960 CERTAIN PREVALENCE AND IF 1356 00:56:20,960 --> 00:56:23,080 THEY'RE ON THAT ALLELE YOU CAN 1357 00:56:23,080 --> 00:56:24,840 HAVE A SMALLER NUMBER OF PERHAPS 1358 00:56:24,840 --> 00:56:26,080 ASOs YOU COULD USE WITHOUT 1359 00:56:26,080 --> 00:56:29,280 HAVING TO HAVE A DIFFERENT ONE 1360 00:56:29,280 --> 00:56:30,480 FOR EVERY DIFFERENT FORM. 1361 00:56:30,480 --> 00:56:32,840 WE DON'T WANT TO MAYBE GET RID 1362 00:56:32,840 --> 00:56:35,720 OF THE WHOLE PROTEIN JUST GET 1363 00:56:35,720 --> 00:56:40,400 RID OF MUTANT ALLELE. 1364 00:56:40,400 --> 00:56:42,160 >> THIS IS -- TO BE FAIR WE 1365 00:56:42,160 --> 00:56:46,400 CHANGE THE NAME OF OUR 1366 00:56:46,400 --> 00:56:46,800 LABORATORY. 1367 00:56:46,800 --> 00:56:48,280 INITIALLY WAS THE RAPID ASO 1368 00:56:48,280 --> 00:56:52,400 DEVELOPMENT AND CHANGED IT TO 1369 00:56:52,400 --> 00:56:55,280 THE RNA THERAPEUTICS LABORATORY 1370 00:56:55,280 --> 00:56:58,040 BECAUSE I THINK THERE'S OTHER 1371 00:56:58,040 --> 00:56:59,960 APPROACHES OTHER THAN ASOs TO 1372 00:56:59,960 --> 00:57:01,160 BRING IN AND WE'RE ESSENTIALLY 1373 00:57:01,160 --> 00:57:03,080 ON THE SAME PAGE. 1374 00:57:03,080 --> 00:57:06,400 I SEE A QUESTION ABOUT USING 1375 00:57:06,400 --> 00:57:08,160 MONKEYS, THE FDA REQUIRING 1376 00:57:08,160 --> 00:57:08,400 MONKEYS. 1377 00:57:08,400 --> 00:57:10,360 IF I CAN ADDRESS THAT QUICKLY. 1378 00:57:10,360 --> 00:57:12,880 THEY REQUIRED MONKEY STUDIES FOR 1379 00:57:12,880 --> 00:57:14,920 WHEN YOU ARE ADMINISTERING ASOs 1380 00:57:14,920 --> 00:57:17,120 TO RELATIVELY COMMON DISEASES. 1381 00:57:17,120 --> 00:57:19,680 SO IF YOU WANTED TO DO STUDIES 1382 00:57:19,680 --> 00:57:23,160 FOR THERE'S A NEW ASO COMING OUT 1383 00:57:23,160 --> 00:57:28,480 TO TREAT HYPERLIPIDEMIA THE U.K. 1384 00:57:28,480 --> 00:57:34,360 AND THEY JUST BOUGHT 100,000 1385 00:57:34,360 --> 00:57:39,280 ZEROS -- DOSES AND MONKEY 1386 00:57:39,280 --> 00:57:40,840 DISORDERS ARE REQUIRED FOR THAT 1387 00:57:40,840 --> 00:57:42,080 AND THE FDA ONLY REQUIRES A 1388 00:57:42,080 --> 00:57:46,400 MOUSE OR SOME SORT OF RODENT 1389 00:57:46,400 --> 00:57:47,680 STUDY. 1390 00:57:47,680 --> 00:57:53,200 THEY DON'T REQUIRE ANY MORE AS 1391 00:57:53,200 --> 00:57:55,640 LONG AS IT'S A RARE AND ULTRA 1392 00:57:55,640 --> 00:57:58,080 RARE DISEASES A NON-HUMAN 1393 00:57:58,080 --> 00:57:58,480 PRIMATE STUDY. 1394 00:57:58,480 --> 00:58:00,320 >> FOR CRAIG THERE'S A QUESTION 1395 00:58:00,320 --> 00:58:02,360 FROM DARIUS. 1396 00:58:02,360 --> 00:58:04,280 IS THERE ANYTHING KNOWN ABOUT 1397 00:58:04,280 --> 00:58:07,200 THE CELL TYPE SPECIFIC 1398 00:58:07,200 --> 00:58:07,480 EXPRESSION. 1399 00:58:07,480 --> 00:58:08,640 FOR INSTANCE, NEURONAL 1400 00:58:08,640 --> 00:58:11,440 SUBPOPULATIONS OF M1 AND M87 IN 1401 00:58:11,440 --> 00:58:12,880 THE CONTEXT OF BRAIN 1402 00:58:12,880 --> 00:58:13,160 DEVELOPMENT? 1403 00:58:13,160 --> 00:58:14,880 >> VERY GOOD QUESTION. 1404 00:58:14,880 --> 00:58:17,520 BASICALLY BECAUSE M1 HAS BEEN SO 1405 00:58:17,520 --> 00:58:19,280 HARD TO SEE USING TRADITIONAL 1406 00:58:19,280 --> 00:58:20,480 APPROACHES, WE DON'T REALLY 1407 00:58:20,480 --> 00:58:20,800 KNOW. 1408 00:58:20,800 --> 00:58:23,880 BECAUSE AS I SHOWED YOU, YOU 1409 00:58:23,880 --> 00:58:26,200 ALMOST HAVE TO OVER EXPOSE ANY 1410 00:58:26,200 --> 00:58:28,000 GELS TO BE ABLE TO SEE IT. 1411 00:58:28,000 --> 00:58:29,640 THERE'S NO SPECIFIC ANTIBODIES 1412 00:58:29,640 --> 00:58:30,560 THAT ALLOW TO YOU TELL THEM 1413 00:58:30,560 --> 00:58:34,800 APART AND I CAN TELL YOU WE CAN 1414 00:58:34,800 --> 00:58:36,280 SEE PHENOTYPIC DIFFERENCES EVEN 1415 00:58:36,280 --> 00:58:39,680 WHEN WE CAN'T DETECT THE PROTEIN 1416 00:58:39,680 --> 00:58:40,840 ANY OTHER WAY. 1417 00:58:40,840 --> 00:58:43,160 WE KNOW IT'S THERE. 1418 00:58:43,160 --> 00:58:45,520 IT'S JUST SUCH LOW COPY NUMBERS 1419 00:58:45,520 --> 00:58:46,880 OR LOW NUMBERS OF MOLECULES WE 1420 00:58:46,880 --> 00:58:47,760 CAN'T SEE IT. 1421 00:58:47,760 --> 00:58:52,400 BUT IT DOES EMPHASIZE THE FACT 1422 00:58:52,400 --> 00:58:54,320 THAT WE DO NEED TO BE COGNIZANT 1423 00:58:54,320 --> 00:58:56,680 OF THE FACT IT EXISTS AND THINK 1424 00:58:56,680 --> 00:58:57,640 THE M1 IS THE MOST IMPORTANT 1425 00:58:57,640 --> 00:58:58,680 FORM FOR THE DISEASE. 1426 00:58:58,680 --> 00:59:00,640 WE DON'T KNOW THAT FOR SURE BUT 1427 00:59:00,640 --> 00:59:03,640 WE HAVE THE ABILITY NOW TO 1428 00:59:03,640 --> 00:59:05,480 SEPARATE THE TWO FORMS TO THINK 1429 00:59:05,480 --> 00:59:07,640 OF THEM AS TWO DIFFERENT 1430 00:59:07,640 --> 00:59:10,080 PROTEINS AND ASK QUESTIONS HOW 1431 00:59:10,080 --> 00:59:13,040 MUTATIONS AFFECT DIFFERENT FORMS 1432 00:59:13,040 --> 00:59:14,000 AND THEIR FUNCTIONS ARE 1433 00:59:14,000 --> 00:59:14,280 DIFFERENT. 1434 00:59:14,280 --> 00:59:15,360 IT'S A GOOD POINT. 1435 00:59:15,360 --> 00:59:17,720 WE WOULD LIKE TO KNOW THAT. 1436 00:59:17,720 --> 00:59:19,640 IT'S JUST BEEN HARD BECAUSE THE 1437 00:59:19,640 --> 00:59:22,000 M1 FORM IS SO LOW ABUNDANCE AND 1438 00:59:22,000 --> 00:59:25,000 THE M87 FORM IS SO HIGH. 1439 00:59:25,000 --> 00:59:25,880 IT'S JUST EXPERIMENTALLY 1440 00:59:25,880 --> 00:59:26,880 DIFFICULT TO DO BUT IT'S A VERY 1441 00:59:26,880 --> 00:59:29,200 IMPORTANT QUESTION. 1442 00:59:29,200 --> 00:59:31,720 >> AND AS A FOLLOW-UP YOU CAN 1443 00:59:31,720 --> 00:59:37,920 SEE IN THE CHAT, CAN YOU CLARIFY 1444 00:59:37,920 --> 00:59:41,600 THE MECHANISM BETWEEN M1 AND 1445 00:59:41,600 --> 00:59:42,040 M87. 1446 00:59:42,040 --> 00:59:47,800 ARE THERE TWO DIFFERENT 1447 00:59:47,800 --> 01:00:06,880 PROMOTERS. 1448 01:00:06,880 --> 01:00:11,280 >> BY STRENGTHENING THE COZAK 1449 01:00:11,280 --> 01:00:12,440 CONSEQUENCE WE CAN INCREASE THE 1450 01:00:12,440 --> 01:00:15,640 AMOUNT OF M1 PRODUCED. 1451 01:00:15,640 --> 01:00:18,040 I THINK THE DIFFERENTIAL 1452 01:00:18,040 --> 01:00:19,400 TRANSLATION START SITES AND PART 1453 01:00:19,400 --> 01:00:22,640 IS THE STRENGTH OF THE COZAK 1454 01:00:22,640 --> 01:00:23,640 SEQUENCE AT LEAST THAT'S ONE 1455 01:00:23,640 --> 01:00:26,480 THING WE'VE SEEN SO FAR BUT IT'S 1456 01:00:26,480 --> 01:00:27,800 NOT LIKE WE ALWAYS HEAR ABOUT 1457 01:00:27,800 --> 01:00:30,280 SPLICE VARIANTS AND SO ON. 1458 01:00:30,280 --> 01:00:35,280 THIS IS THE SAME TRANSCRIPT JUST 1459 01:00:35,280 --> 01:00:37,080 THE DIFFERENT TRANSLATION START 1460 01:00:37,080 --> 01:00:39,680 SITES AND ONE WAY WE'VE BEEN 1461 01:00:39,680 --> 01:00:41,760 ABLE TO ADJUST THAT IS ADJUSTING 1462 01:00:41,760 --> 01:00:45,720 THE COZAK SEQUENCE THAT PLAYS AN 1463 01:00:45,720 --> 01:00:51,680 IMPORTANT ROLE FOR TRANSLATION 1464 01:00:51,680 --> 01:01:03,680 INITIATION. 1465 01:01:03,680 --> 01:01:06,480 >> I MISSED A QUESTION. 1466 01:01:06,480 --> 01:01:07,520 >> I ANSWERED THAT EARLIER. 1467 01:01:07,520 --> 01:01:08,480 >> THERE'S ONE MORE QUESTION 1468 01:01:08,480 --> 01:01:09,200 FROM THE AUDIENCE. 1469 01:01:09,200 --> 01:01:11,640 >> I WANTED TO ASK A QUESTION. 1470 01:01:11,640 --> 01:01:15,640 KIM WHO IS THE MOM OF OWEN THE 1471 01:01:15,640 --> 01:01:18,520 YOUNG ADULT AFFECTED SPG4. 1472 01:01:18,520 --> 01:01:20,840 SHE SAID HER SON WAS SELECTED 1473 01:01:20,840 --> 01:01:22,840 FOR A TRIAL REGARDING AN ASO BUT 1474 01:01:22,840 --> 01:01:26,840 PUT ON HOLD BECAUSE THERE WAS 1475 01:01:26,840 --> 01:01:28,360 CONCERN THE ASO WOULD NOT HAVE 1476 01:01:28,360 --> 01:01:31,640 THE MUTANT GENE AND THE 1477 01:01:31,640 --> 01:01:33,720 NON-MUTATED COPY OF SPAST. 1478 01:01:33,720 --> 01:01:35,680 CAN YOU COMMENT FROM A FAMILY 1479 01:01:35,680 --> 01:01:37,040 PERSPECTIVE WHICH PATIENTS MAY 1480 01:01:37,040 --> 01:01:42,720 BE ELIGIBLE FOR ASOs AND WHAT 1481 01:01:42,720 --> 01:01:54,120 THE CONSIDERATIONS ARE. 1482 01:01:54,120 --> 01:01:56,600 GENERAL TERMS THIS IS THE ISSUE 1483 01:01:56,600 --> 01:01:58,200 THAT FACES THE FIELD. 1484 01:01:58,200 --> 01:02:00,880 CAN YOU BE SPECIFIC TO KNOCKING 1485 01:02:00,880 --> 01:02:03,080 DOWN MUTANT VERSUS WILD TYPE. 1486 01:02:03,080 --> 01:02:03,760 THERE'LL BE TIMES WHERE THAT'S 1487 01:02:03,760 --> 01:02:05,400 WHAT YOU NEED TO DO AND OTHER 1488 01:02:05,400 --> 01:02:10,560 TIMES WHEN IT DOESN'T MATTER AND 1489 01:02:10,560 --> 01:02:13,560 YOU CAN JUST KNOCK DOWN 1490 01:02:13,560 --> 01:02:14,360 INDISCRIMINATELY THE TRANSCRIPT. 1491 01:02:14,360 --> 01:02:19,680 IT'S THE ISSUE THAT FACE THE 1492 01:02:19,680 --> 01:02:21,160 FIELD. 1493 01:02:21,160 --> 01:02:22,800 AND THEY GO HAND IN HAND. 1494 01:02:22,800 --> 01:02:25,200 WHEN YOU WANT TO -- WE KNOW WE 1495 01:02:25,200 --> 01:02:27,520 CAN KNOCK DOWN TRANSCRIPTS 1496 01:02:27,520 --> 01:02:27,840 SELECTIVELY. 1497 01:02:27,840 --> 01:02:30,120 THE PROBLEM IS WHEN YOU GO AND 1498 01:02:30,120 --> 01:02:31,880 DO THAT WITH THOSE PARTICULAR 1499 01:02:31,880 --> 01:02:33,320 TRANSCRIPTS THEY'RE ALSO TOXIC. 1500 01:02:33,320 --> 01:02:36,960 SO IF WE COULD FIND SOME WAY TO 1501 01:02:36,960 --> 01:02:39,080 MITIGATE THAT TOXICOLOGY 1502 01:02:39,080 --> 01:02:41,080 ASSOCIATED WITH IT, IT WOULD 1503 01:02:41,080 --> 01:02:43,640 OPEN UP THE SCOPE OF ASOs WE CAN 1504 01:02:43,640 --> 01:02:44,800 ADMINISTER TO OUR PATIENTS. 1505 01:02:44,800 --> 01:02:48,960 IT'S REALLY THE AREA AND PROBLEM 1506 01:02:48,960 --> 01:02:50,640 THAT FACES THE FIELD. 1507 01:02:50,640 --> 01:02:53,600 JUST TO PUT IT IN PERSPECTIVE, 1508 01:02:53,600 --> 01:02:57,560 WE IN SILICO MADE EVERY SINGLE 1509 01:02:57,560 --> 01:02:59,680 ASO YOU CAN POSSIBLY MAKE 1510 01:02:59,680 --> 01:03:01,360 AGAINST EVERY SINGLE GENE YOU 1511 01:03:01,360 --> 01:03:06,480 CAN POSSIBLY THINK OF. 1512 01:03:06,480 --> 01:03:19,000 THEN WE HAD CAN PRE CALCULATE 1513 01:03:19,000 --> 01:03:25,880 AND ONLY 0.07% WERE SAFE AND 1514 01:03:25,880 --> 01:03:28,280 SHOWS IS THE NARROWNESS OF THE 1515 01:03:28,280 --> 01:03:33,440 GENE AND THAT'S STOPPING THE NEW 1516 01:03:33,440 --> 01:03:36,480 CLASS OF THERAPIES.% WERE SAFE AND 1517 01:03:36,480 --> 01:03:37,080 SHOWS IS THE NARROWNESS OF THE 1518 01:03:37,080 --> 01:03:37,720 GENE AND THAT'S STOPPING THE NEW 1519 01:03:37,720 --> 01:03:38,480 CLASS OF THERAPIES.2% WERE SAFE AND 1520 01:03:38,480 --> 01:03:39,080 SHOWS IS THE NARROWNESS OF THE 1521 01:03:39,080 --> 01:03:39,720 GENE AND THAT'S STOPPING THE NEW 1522 01:03:39,720 --> 01:03:40,160 CLASS OF THERAPIES. 1523 01:03:40,160 --> 01:03:40,800 AND IF I CAN HAVE ONE MORE 1524 01:03:40,800 --> 01:03:43,320 MINUTE TO MAKE THE POINT. 1525 01:03:43,320 --> 01:03:45,560 IN SMALL MOLECULES WE KNOW WE 1526 01:03:45,560 --> 01:03:47,200 CAN GET THEM TO THE TISSUE AND 1527 01:03:47,200 --> 01:03:49,080 KNOW THE TOXICOLOGY. 1528 01:03:49,080 --> 01:03:51,360 WE JUST DON'T KNOW WHETHER THE 1529 01:03:51,360 --> 01:03:53,920 SMALL MOLECULE HAS AN EFFECT ON 1530 01:03:53,920 --> 01:03:55,680 SOMETHING INSIDE THE CELL AND 1531 01:03:55,680 --> 01:03:59,080 THAT'S FACED THE PHARMACOLOGIC 1532 01:03:59,080 --> 01:04:01,240 INDUSTRY FOR YEARS AND IN GENE 1533 01:04:01,240 --> 01:04:15,240 THERAPY IT TURNS IT ON ITS HEAD. 1534 01:04:15,240 --> 01:04:19,680 20,000 GENES WE CAN DELIVER BUT 1535 01:04:19,680 --> 01:04:23,680 WE CAN'T DELIVER WITHOUT 1536 01:04:23,680 --> 01:04:26,880 TOXICOLOGY AND IT'S TURNED IT ON 1537 01:04:26,880 --> 01:04:31,400 ITS HEAD. 1538 01:04:31,400 --> 01:04:32,760 >> THANK YOU SO MUCH. 1539 01:04:32,760 --> 01:04:33,880 THAT WRAPS THE FIRST TWO 1540 01:04:33,880 --> 01:04:35,680 SPEAKERS SO WE CAN CATCH UP ON 1541 01:04:35,680 --> 01:04:39,680 TIME IF THERE'S NO FINAL 1542 01:04:39,680 --> 01:04:44,440 QUESTIONS. 1543 01:04:44,440 --> 01:04:46,440 WE HAVE FOUR MORE SPEAKERS FOR 1544 01:04:46,440 --> 01:04:47,240 THE SESSION. 1545 01:04:47,240 --> 01:04:50,280 THE NEXT SPEAKER IS DR. JUNE LI 1546 01:04:50,280 --> 01:04:53,120 WHO HAS POST-DOC TRAINING IN 1547 01:04:53,120 --> 01:04:55,680 STEM CELL RESEARCH. 1548 01:04:55,680 --> 01:04:59,680 SHE'S CURRENTLY AN ASSOCIATE 1549 01:04:59,680 --> 01:05:01,960 PROFESSOR AT THE DEPARTMENT OF 1550 01:05:01,960 --> 01:05:03,680 BIOMEDICAL SCIENCES AT THE 1551 01:05:03,680 --> 01:05:10,400 COLLEGE OF MEDICINE RUTFORD. 1552 01:05:10,400 --> 01:05:14,280 HER LEE FOCUSES ON NEURONAL SUB 1553 01:05:14,280 --> 01:05:17,280 TIMES OF STEM CELLS AND USING 1554 01:05:17,280 --> 01:05:24,360 THE STEM CELLS TO STUDY AXONAL 1555 01:05:24,360 --> 01:05:24,680 DEGENERATION. 1556 01:05:24,680 --> 01:05:27,680 IN PARTICULAR HER LAB IS 1557 01:05:27,680 --> 01:05:31,400 INTERESTED IN MODELS OF 1558 01:05:31,400 --> 01:05:35,480 HEREDITARY SPASTIC PARAPLEGIAS. 1559 01:05:35,480 --> 01:05:37,960 THE FOURTH SPEAKER IS 1560 01:05:37,960 --> 01:05:41,640 DR. CHI-LUN CHANG WHO EARNED HIS 1561 01:05:41,640 --> 01:05:45,440 Ph.D. FROM THE UNIVERSITY OF 1562 01:05:45,440 --> 01:05:50,080 TEXAS STUDYING THE 1563 01:05:50,080 --> 01:06:00,400 INTER-ORGANELLE INTER FAFAC FACFAC FACFACE S AND 1564 01:06:00,400 --> 01:06:07,360 STUDIED PROTEIN TRAFFICKING AND 1565 01:06:07,360 --> 01:06:09,920 JOINED THE DEPARTMENT OF CELL 1566 01:06:09,920 --> 01:06:11,680 AND MOLECULAR BIOLOGY AND HIS 1567 01:06:11,680 --> 01:06:15,680 RESEARCH INTERESTS INCLUDE 1568 01:06:15,680 --> 01:06:19,680 SPATIAL TEMPORAL REGULATION OF 1569 01:06:19,680 --> 01:06:21,680 INTERORGANOIDS AND THE FIFTH 1570 01:06:21,680 --> 01:06:27,360 SPEAKER IS DR. PETER BAAS A 1571 01:06:27,360 --> 01:06:30,680 PROFESSOR AT DREXEL DEVELOP ALSO 1572 01:06:30,680 --> 01:06:33,720 THE DIRECTOR OF THE PROGRAM IN 1573 01:06:33,720 --> 01:06:36,480 NEUROSCIENCE AND THE DIRECTOR A 1574 01:06:36,480 --> 01:06:38,840 NIH-FUNDED TRAINING PROGRAM IN 1575 01:06:38,840 --> 01:06:41,080 SPINAL CORD INJURY. 1576 01:06:41,080 --> 01:06:44,040 HE HAS STUDIED SPG4 FOR THE PAST 1577 01:06:44,040 --> 01:06:49,480 YEARS AND FOCUSSED MAINLY ON THE 1578 01:06:49,480 --> 01:06:50,080 UNDERLYING MECHANISM OF THE 1579 01:06:50,080 --> 01:06:52,760 DISEASE AND DEVELOPED THE FIRST 1580 01:06:52,760 --> 01:06:54,200 ANIMAL MOUSE MODEL WITH LOSS OF 1581 01:06:54,200 --> 01:06:55,480 FUNCTION AND GAIN OF FUNCTION 1582 01:06:55,480 --> 01:06:57,400 PERFORMANCE AND HE'LL BE 1583 01:06:57,400 --> 01:06:58,000 PRESENTING HIS TALK ABOUT THE 1584 01:06:58,000 --> 01:07:04,680 MODELS TODAY. 1585 01:07:04,680 --> 01:07:13,200 LASTLY, DR. ERIC SAMARUT HAS TAY 1586 01:07:13,200 --> 01:07:18,880 DOCTORATE FROM THE UNIVERSITY OF 1587 01:07:18,880 --> 01:07:19,200 STRASBURG. 1588 01:07:19,200 --> 01:07:25,560 AND HE IS NOW THE CO-FOUNDER AND 1589 01:07:25,560 --> 01:07:27,680 CHIEF SCIENTIFIC OFFICER OF A 1590 01:07:27,680 --> 01:07:31,120 COMPANY FOR TREATMENT OF RARE 1591 01:07:31,120 --> 01:07:31,400 DISEASES. 1592 01:07:31,400 --> 01:07:32,280 HIS RESEARCH INTERESTS AIM TO 1593 01:07:32,280 --> 01:07:33,920 BETTER UNDERSTAND THE MECHANISMS 1594 01:07:33,920 --> 01:07:37,600 AND UNDERLYING NEUROLOGICAL 1595 01:07:37,600 --> 01:07:39,680 DISEASES AND TO DEVELOP 1596 01:07:39,680 --> 01:07:42,560 PRECISION MEDICINE STRATEGIES. 1597 01:07:42,560 --> 01:07:46,600 I'D LIKE TO CALL ON DR. JUNE LI 1598 01:07:46,600 --> 01:07:47,680 TO PRESENT HER TALK. 1599 01:07:47,680 --> 01:08:03,440 >> THANK YOU. 1600 01:08:03,440 --> 01:08:06,240 >> CAN YOU HEAR ME WELL? 1601 01:08:06,240 --> 01:08:06,960 >> YES. 1602 01:08:06,960 --> 01:08:08,680 >> I'M HONORED TO BE HERE. 1603 01:08:08,680 --> 01:08:11,640 I'M NEW TO THE TEAM. 1604 01:08:11,640 --> 01:08:16,960 I'D LIKE TO THANK DR. BLACKSTONE 1605 01:08:16,960 --> 01:08:19,000 AND THE ORGANIZERS OF THE 1606 01:08:19,000 --> 01:08:20,320 MEETING FOR THE OPPORTUNITY TO 1607 01:08:20,320 --> 01:08:22,680 PRESENT AT THIS WONDERFUL 1608 01:08:22,680 --> 01:08:23,080 SYMPOSIUM. 1609 01:08:23,080 --> 01:08:26,880 I'LL DISCUSS WITH YOU ABOUT OUR 1610 01:08:26,880 --> 01:08:31,240 WORK ON DIFFERENTIATING PLURI 1611 01:08:31,240 --> 01:08:40,400 PLURIPOTENT STEM CELLS FOR 1612 01:08:40,400 --> 01:08:51,400 COMPOUND SCREENING. 1613 01:08:51,400 --> 01:08:52,840 CHARACTERISTIC OF STEM CELLS IS 1614 01:08:52,840 --> 01:08:55,680 THEY HAVE THE CAPACITY TO 1615 01:08:55,680 --> 01:08:57,320 DIFFERENTIATE INTO DIFFERENT 1616 01:08:57,320 --> 01:08:59,120 TYPES OF CELL TISSUES. 1617 01:08:59,120 --> 01:09:00,760 BASED ON THEIR CAPACITY TO 1618 01:09:00,760 --> 01:09:09,720 GENERATE OTHER TYPE OF CELLS, 1619 01:09:09,720 --> 01:09:12,600 HERE ARE THREE TYPES. 1620 01:09:12,600 --> 01:09:16,360 AND THE RESEARCH IN MY LAB IS 1621 01:09:16,360 --> 01:09:18,200 FOCUSSED ON USING THE STEM CELL 1622 01:09:18,200 --> 01:09:20,880 BASED MODELS. 1623 01:09:20,880 --> 01:09:22,680 THE PLURIPOTENT STEM CELLS CAN 1624 01:09:22,680 --> 01:09:25,560 GENERATE ANY CELL TYPE IN OUR 1625 01:09:25,560 --> 01:09:25,760 BODY. 1626 01:09:25,760 --> 01:09:29,680 THESE OTHER CELL TYPES ARE 1627 01:09:29,680 --> 01:09:34,040 DERIVED FROM THE LAYERS AND THEY 1628 01:09:34,040 --> 01:09:37,040 CAN GENERATE THIS PROJECTION OF 1629 01:09:37,040 --> 01:09:37,680 NEURONS DEGENERATED AND CAN 1630 01:09:37,680 --> 01:09:39,680 CAUSE NEUROLOGICAL DISEASE AND 1631 01:09:39,680 --> 01:09:47,760 OTHER TYPES OF CELLS. 1632 01:09:47,760 --> 01:09:51,680 THERE'S TWO TYPES AND ONE IS 1633 01:09:51,680 --> 01:10:09,320 INDUCED. 1634 01:10:09,320 --> 01:10:11,920 THESE CELLS CAN BE ASSOCIATED ON 1635 01:10:11,920 --> 01:10:14,680 THE FEEDER CELLS FOR 1636 01:10:14,680 --> 01:10:18,280 SELF-RENEWAL AND FORCED THE 1637 01:10:18,280 --> 01:10:20,400 HUMAN EMBRYONIC STEM CELLS WERE 1638 01:10:20,400 --> 01:10:22,320 ESTABLISHED BY JIM JOHNSON FROM 1639 01:10:22,320 --> 01:10:27,640 UW MADISON PUBLISHED IN 1998. 1640 01:10:27,640 --> 01:10:30,080 THIS IS A UNIQUE SYSTEM TO 1641 01:10:30,080 --> 01:10:33,080 GENERATE THE DIFFERENT TYPE OF 1642 01:10:33,080 --> 01:10:36,400 CELLS INCLUDING THE CELLS THIS 1643 01:10:36,400 --> 01:10:39,720 EMBRYONIC STEM CELL LIMITED TO 1644 01:10:39,720 --> 01:10:40,080 AVAILABILITY. 1645 01:10:40,080 --> 01:10:46,400 THESE COME TO THE OTHER TYPE OF 1646 01:10:46,400 --> 01:10:49,480 PLURIPOTENT STEM CELLS WE CALL 1647 01:10:49,480 --> 01:10:56,240 INDUCED PLURIPOTENT PLURIPOTENT 1648 01:10:56,240 --> 01:10:57,360 STEM CELLS. 1649 01:10:57,360 --> 01:10:59,240 BUT IF THE CELLS ARE 1650 01:10:59,240 --> 01:11:02,040 DIFFERENTIATED AND THE STEM 1651 01:11:02,040 --> 01:11:03,280 CELLS AND THESE CELLS IT WOULD 1652 01:11:03,280 --> 01:11:04,720 BE HARD FOR THE CELLS TO GO BACK 1653 01:11:04,720 --> 01:11:07,920 TO BECOME STEM CELLS. 1654 01:11:07,920 --> 01:11:13,320 SO THIS DOGMA HAS BEEN 1655 01:11:13,320 --> 01:11:13,640 CHALLENGED. 1656 01:11:13,640 --> 01:11:17,880 IN 2006 A GROUP SHOWED FROM THE 1657 01:11:17,880 --> 01:11:19,640 MOUSE DIFFERENTIATED FIBROBLAST 1658 01:11:19,640 --> 01:11:25,960 CELLS CAN REPROGRAM BACK TO 1659 01:11:25,960 --> 01:11:27,680 PLURIPOTENT STEM CELLS AND A 1660 01:11:27,680 --> 01:11:30,680 2007 ANOTHER GROUP SHOWED IF YOU 1661 01:11:30,680 --> 01:11:32,960 CAN TAKE THIS HUMAN FIBROBLAST 1662 01:11:32,960 --> 01:11:38,360 CELLS WHICH ARE ALREADY 1663 01:11:38,360 --> 01:11:42,680 DIFFERENTIATED CELLS FROM TAKEN 1664 01:11:42,680 --> 01:11:47,680 FROM SKIN BIOPSY AND INDUCE 1665 01:11:47,680 --> 01:11:50,280 PLURIPOTENT FACTORS AND THEN 1666 01:11:50,280 --> 01:11:52,080 CULTURE IN A STEM CELL MEDIUM 1667 01:11:52,080 --> 01:11:55,440 THE CELLS WILL CHANGE THEIROLOGY 1668 01:11:55,440 --> 01:11:58,480 AND NOW LOOK SIMILAR TO 1669 01:11:58,480 --> 01:12:01,680 EMBRYONIC STEM CELLS AND HAVE 1670 01:12:01,680 --> 01:12:04,360 THE SAME GENE EXPRESSION PROFILE 1671 01:12:04,360 --> 01:12:08,880 AND GENETIC STATUS AND ARE 1672 01:12:08,880 --> 01:12:15,640 PLURIPOTENT AND CAN BECOME THIS 1673 01:12:15,640 --> 01:12:19,280 CELLS IN VIVO AND CAN START A 1674 01:12:19,280 --> 01:12:26,160 NEURO DEGENERATIVE DISEASE. 1675 01:12:26,160 --> 01:12:31,200 BECAUSE OF THIS THEY'VE 1676 01:12:31,200 --> 01:12:33,720 GENERATED HUMAN IPA CELLS AND 1677 01:12:33,720 --> 01:12:35,680 OTHERS WHO BROUGHT UP THE 1678 01:12:35,680 --> 01:12:36,480 PROGRAMMING CONCEPT THEY 1679 01:12:36,480 --> 01:12:39,840 TOGETHER WON A NOBEL PRIZE IN 1680 01:12:39,840 --> 01:12:45,680 MEDICINE IN 2012. 1681 01:12:45,680 --> 01:12:48,360 AS ILLUSTRATED HERE AND IN OUR 1682 01:12:48,360 --> 01:12:51,320 LAB WE COULD TAKE THIS PATIENT 1683 01:12:51,320 --> 01:12:54,240 CELLS AND USUALLY WE HAVE THE 1684 01:12:54,240 --> 01:12:58,160 FIBROBLAST CELLS WHICH CAN BE 1685 01:12:58,160 --> 01:13:00,320 DERIVED BY SKIN BIOPSY AND USE 1686 01:13:00,320 --> 01:13:10,960 BLADDER CELLS AND WE COULD 1687 01:13:10,960 --> 01:13:13,800 TRANSDUCE A SET ON THE PLURI-POE 1688 01:13:13,800 --> 01:13:18,040 PLURIPOTENCY FACTOR AND THEN 1689 01:13:18,040 --> 01:13:21,080 THEY CAN PROVIDE A SOURCE TO 1690 01:13:21,080 --> 01:13:23,880 GENERATE THE PATIENT-SPECIFIC 1691 01:13:23,880 --> 01:13:25,880 CELLS AND IN OUR LAB WHERE WE 1692 01:13:25,880 --> 01:13:27,000 DIFFERENTIATE THE CELLS INTO THE 1693 01:13:27,000 --> 01:13:31,200 NERVE CELLS AND USE THEM TO TEST 1694 01:13:31,200 --> 01:13:34,240 THIS DIFFERENT COMPOUNDS AND TO 1695 01:13:34,240 --> 01:13:34,880 ALSO IDENTIFY THE THERAPEUTIC 1696 01:13:34,880 --> 01:13:41,520 TARGET. 1697 01:13:41,520 --> 01:13:43,480 SO TO USE THIS IPSC MODELS THE 1698 01:13:43,480 --> 01:13:45,840 FIRST TIME IS TO EFFICIENTLY 1699 01:13:45,840 --> 01:13:47,800 GENERATE THE NERVE CELLS THAT 1700 01:13:47,800 --> 01:13:48,400 ARE SPECIFIC A FACTOR IN THE 1701 01:13:48,400 --> 01:13:49,080 DISEASE. 1702 01:13:49,080 --> 01:13:52,400 SO AS WE KNOW YOU HAVE A NERVOUS 1703 01:13:52,400 --> 01:13:57,120 SYSTEM AND DIFFERENT TYPES OF 1704 01:13:57,120 --> 01:13:58,480 NEURONS. 1705 01:13:58,480 --> 01:14:01,640 FOR EXAMPLE, LIKE DOPAMINE 1706 01:14:01,640 --> 01:14:03,680 NEURONS AND ONE IMPORTANT 1707 01:14:03,680 --> 01:14:04,760 QUESTION IN APPLYING THE STEM 1708 01:14:04,760 --> 01:14:07,640 CELL DERIVED MODEL TO START THE 1709 01:14:07,640 --> 01:14:14,280 DISEASE IS HOW WE'RE ABLE TO 1710 01:14:14,280 --> 01:14:15,080 HAVE NAIVE PLURIPOTENT STEM 1711 01:14:15,080 --> 01:14:17,360 CELLS AND AFTER APPLYING THEM TO 1712 01:14:17,360 --> 01:14:18,080 THE STEM CELLS CAN THEY BE 1713 01:14:18,080 --> 01:14:19,440 FURTHER DIFFERENTIATED INTO THE 1714 01:14:19,440 --> 01:14:24,080 DIFFERENT TYPE OF NEURONS. 1715 01:14:24,080 --> 01:14:25,680 FOR EXAMPLE, THERE'S HAS BEEN 1716 01:14:25,680 --> 01:14:28,160 REFERRED TO AS THE CORTICO 1717 01:14:28,160 --> 01:14:31,640 PROJECT NEURON DEGENERATED IN 1718 01:14:31,640 --> 01:14:32,800 THIS IPSC. 1719 01:14:32,800 --> 01:14:35,680 WE NEED TO LOOK AT WHAT ARE THE 1720 01:14:35,680 --> 01:14:37,720 KEY FACTORS REGULATING THIS 1721 01:14:37,720 --> 01:14:48,600 PROCESS DURING DEVELOPMENT. 1722 01:14:48,600 --> 01:15:07,640 AND WE HAVE ON THE KEY STEPS WE 1723 01:15:07,640 --> 01:15:15,640 CAN USE THIS AND GENERATE THIS 1724 01:15:15,640 --> 01:15:19,040 FINAL MOTOR NEURONS AND BY 1725 01:15:19,040 --> 01:15:21,120 REGULATING THE SIGNALS WE COULD 1726 01:15:21,120 --> 01:15:23,880 LOOK AT THE PROJECTION NEURONS 1727 01:15:23,880 --> 01:15:27,240 AND OTHER CELLS DEGENERATED IN 1728 01:15:27,240 --> 01:15:28,400 THE SPG3A AND SPG4. 1729 01:15:28,400 --> 01:15:31,640 I'LL TALK MORE ABOUT IT LATER. 1730 01:15:31,640 --> 01:15:34,480 AFTER WE ESTABLISHED THE SYSTEM 1731 01:15:34,480 --> 01:15:37,560 TO GENERATE THE NERVE CELLS A 1732 01:15:37,560 --> 01:15:39,560 FACTOR IN THE DISEASE WE CAN 1733 01:15:39,560 --> 01:15:41,280 FURTHER START THE DISEASE MODELS 1734 01:15:41,280 --> 01:15:46,680 TO TEST THE DRUGS. 1735 01:15:46,680 --> 01:15:51,640 PARTICULARLY IN COLLABORATION WE 1736 01:15:51,640 --> 01:15:55,160 STARTED SPG3A AS DR. BLACKSTONE 1737 01:15:55,160 --> 01:15:56,240 HAS INTRODUCED AND GAVE AN 1738 01:15:56,240 --> 01:16:00,640 INFORMATIVE AND INCLUSIVE 1739 01:16:00,640 --> 01:16:02,080 INTRODUCTION ABOUT IPSC IT'S THE 1740 01:16:02,080 --> 01:16:09,320 MOST ONSET FORM. 1741 01:16:09,320 --> 01:16:16,280 AND ONE CHARACTERISTIC CHANGE IS 1742 01:16:16,280 --> 01:16:20,880 THE AXONS WHICH CONTROL THE 1743 01:16:20,880 --> 01:16:25,560 SPINAL MOTOR NEURON FOR THE 1744 01:16:25,560 --> 01:16:25,800 MUSCLES. 1745 01:16:25,800 --> 01:16:26,920 THE SPG3A GENE ENCODES THE 1746 01:16:26,920 --> 01:16:34,480 PROTEIN AND THIS IS A MEMBER OF 1747 01:16:34,480 --> 01:16:43,480 THIS ER GTP PROTEIN AND BECAUSE 1748 01:16:43,480 --> 01:16:46,000 THIS IS IMPORTANT FOR THE LIPID 1749 01:16:46,000 --> 01:16:55,680 SYNTHESIS AND METABOLISM, SO I 1750 01:16:55,680 --> 01:17:11,280 THINK THE AND YOU CAN SEE THIS 1751 01:17:11,280 --> 01:17:13,840 OTHER FIBROBLAST CELLS WHICH 1752 01:17:13,840 --> 01:17:25,920 HAVE AN ELONGATED MORPHOLOGY. 1753 01:17:25,920 --> 01:17:31,640 WE USED THE METHOD AND WE USE 1754 01:17:31,640 --> 01:17:33,480 THE VIRUS MEASURED. 1755 01:17:33,480 --> 01:17:34,640 BY EXPRESSING THE FACTORS AND 1756 01:17:34,640 --> 01:17:36,560 THE CLONES AFTER ONE MONTH WE 1757 01:17:36,560 --> 01:17:39,880 START TO SEE THE STEM CELL 1758 01:17:39,880 --> 01:17:45,480 CLONES. 1759 01:17:45,480 --> 01:17:47,640 ARE STEM CELL CLONES AND THE 1760 01:17:47,640 --> 01:17:52,880 FIRST TIME WAS TO VALIDATE AND 1761 01:17:52,880 --> 01:17:54,880 CHARACTERIZE THE IPSC CELLS AND 1762 01:17:54,880 --> 01:17:59,560 THE CRITERIA TO CHARACTERIZE THE 1763 01:17:59,560 --> 01:18:03,640 CELLS IS THE PLURIPOTENCY AND WE 1764 01:18:03,640 --> 01:18:04,720 LOOK AT THE EXPRESS OF THE 1765 01:18:04,720 --> 01:18:06,960 PLURIPOTENT GENES AND PROTEINS. 1766 01:18:06,960 --> 01:18:11,640 I SHOW HERE SO WE CAN SEE THE 1767 01:18:11,640 --> 01:18:15,640 IPSC CLONES FORMULATE AND 1768 01:18:15,640 --> 01:18:17,160 EXPRESS THIS PLURIPOTENT 1769 01:18:17,160 --> 01:18:18,480 PROTEINS. 1770 01:18:18,480 --> 01:18:23,520 WE ALSO TESTED THE PLURIPOTENCY 1771 01:18:23,520 --> 01:18:26,080 USING THE FORMATION AND SHOW 1772 01:18:26,080 --> 01:18:29,800 THEY CAN FORM THE THREE GERM 1773 01:18:29,800 --> 01:18:31,600 LAYERS IN VIVO. 1774 01:18:31,600 --> 01:18:33,440 WE'LL CONFIRM THE CELLS ARE 1775 01:18:33,440 --> 01:18:34,280 PLURIPOTENT. 1776 01:18:34,280 --> 01:18:36,080 THE OTHER IMPORTANT THING IS TO 1777 01:18:36,080 --> 01:18:37,680 SEE WHETHER AFTER REPROGRAMMING 1778 01:18:37,680 --> 01:18:43,280 WHETHER THE CELLS STILL MAINTAIN 1779 01:18:43,280 --> 01:18:43,880 THE PATIENT SPAST MUTATION. 1780 01:18:43,880 --> 01:18:46,360 FOR THIS MALE PATIENT THE FIRST 1781 01:18:46,360 --> 01:18:47,640 ONE AS DR. BLACKSTONE ALSO 1782 01:18:47,640 --> 01:18:54,600 MENTIONED THIS IS A MUTATION A 1783 01:18:54,600 --> 01:19:01,840 DE NOVO MUTATION AND YOU CAN SEE 1784 01:19:01,840 --> 01:19:13,240 HERE IT HAS IPSC CELLS WE CAN 1785 01:19:13,240 --> 01:19:14,320 FURTHER GENERATE THE NEURONS 1786 01:19:14,320 --> 01:19:17,440 FROM THE CELLS TO FURTHER LOOK 1787 01:19:17,440 --> 01:19:23,640 AT WHAT ARE THE DISEASE SPECIFIC 1788 01:19:23,640 --> 01:19:30,680 PHENOTYPES IN THIS 1789 01:19:30,680 --> 01:19:33,080 PATIENT-DERIVED CELLS AND WE 1790 01:19:33,080 --> 01:19:35,480 HAVE SEEN THEY CAN REDUCE THIS 1791 01:19:35,480 --> 01:19:42,600 AT THE EARLY STAGE. 1792 01:19:42,600 --> 01:19:46,200 AND THIS WILL BE EXPRESSED FROM 1793 01:19:46,200 --> 01:19:50,640 THE AXONAL CONTROL GROUP TO 1794 01:19:50,640 --> 01:19:55,160 DIFFERENT CLONES FROM IS THE 1795 01:19:55,160 --> 01:19:57,600 PATIENT'S IPSC CELLS. 1796 01:19:57,600 --> 01:20:01,760 AND REDUCE THE CELLS. 1797 01:20:01,760 --> 01:20:04,080 ONE QUESTION USING IPSC CELLS TO 1798 01:20:04,080 --> 01:20:06,680 MODEL DISEASE IS WHETHER THE 1799 01:20:06,680 --> 01:20:08,800 PHENOTYPE WE SEE IS STILL 1800 01:20:08,800 --> 01:20:12,480 RELATED TO THIS MUTATION. 1801 01:20:12,480 --> 01:20:17,000 SO TO DO THAT WE USE THE CRISPR 1802 01:20:17,000 --> 01:20:19,120 GENE EDITING TO CORRECT THE 1803 01:20:19,120 --> 01:20:19,400 MUTATION. 1804 01:20:19,400 --> 01:20:23,520 IF YOU LOOK AT THE TWO PANELS 1805 01:20:23,520 --> 01:20:27,640 HERE SO THIS SHOWS LIKE THERE 1806 01:20:27,640 --> 01:20:31,120 CLONES AND THE PROTEIN AND THIS 1807 01:20:31,120 --> 01:20:31,400 MUTATION. 1808 01:20:31,400 --> 01:20:34,960 BY USING THE MEDIATED GENE AFTER 1809 01:20:34,960 --> 01:20:45,040 LIKE A GENE CORRECTION I SEE THE 1810 01:20:45,040 --> 01:20:49,000 CRITER CELLS AND THIS SHOWS THE 1811 01:20:49,000 --> 01:20:50,040 MUTANT CELLS. 1812 01:20:50,040 --> 01:20:52,960 OF THE CORRECTION THIS IS 1813 01:20:52,960 --> 01:20:53,840 RESTORED. 1814 01:20:53,840 --> 01:20:58,400 THIS SUGGESTS IMPAIRED CELLS ARE 1815 01:20:58,400 --> 01:21:06,240 DERIVED BY THE MUTATION. 1816 01:21:06,240 --> 01:21:08,560 WE ALSO KNOCK IN THE DIFFERENT 1817 01:21:08,560 --> 01:21:11,320 MUTATION TO THE PROTEIN FOR 161 1818 01:21:11,320 --> 01:21:13,480 AND WE CAN ALSO SEE THE CELLS 1819 01:21:13,480 --> 01:21:19,280 HAS A SIGNIFICANT REDUCE LENS 1820 01:21:19,280 --> 01:21:22,080 AND THE SUGGESTS THE MUTATIONS 1821 01:21:22,080 --> 01:21:26,480 CAN RESULT IN THE REDUCED AXON 1822 01:21:26,480 --> 01:21:27,240 OUTGROWTH. 1823 01:21:27,240 --> 01:21:31,640 ONE REASON FOR PATHOLOGICAL 1824 01:21:31,640 --> 01:21:38,360 CHANGE IS ACCUMULATIVE PARTICLES 1825 01:21:38,360 --> 01:21:42,360 CAUSED BY THE IMPAIRED AXON. 1826 01:21:42,360 --> 01:21:46,440 SO INTERESTINGLY IF YOU CULTURE 1827 01:21:46,440 --> 01:21:53,000 THIS CORTICAL NERVE CELLS WE CAN 1828 01:21:53,000 --> 01:21:55,640 SEE IN THE PATIENT-DERIVED CELLS 1829 01:21:55,640 --> 01:21:57,760 YOU CAN SEE IT FORMED THIS AND 1830 01:21:57,760 --> 01:22:01,920 CAN SEE THE BREAKDOWN OF THIS 1831 01:22:01,920 --> 01:22:02,280 AXON. 1832 01:22:02,280 --> 01:22:06,240 AND GET A SIGNIFICANT INCREASE 1833 01:22:06,240 --> 01:22:07,360 AND THEY'RE RESCUED IN THE 1834 01:22:07,360 --> 01:22:08,640 CORRECT CELLS. 1835 01:22:08,640 --> 01:22:09,520 THIS SUGGESTS THE MUTATION CAN 1836 01:22:09,520 --> 01:22:14,520 RESULT IN ACCUMULATED SWALLOWING 1837 01:22:14,520 --> 01:22:18,120 AND CAN SEE THE SWALLOWING OF 1838 01:22:18,120 --> 01:22:19,640 OTHER MUTATION. 1839 01:22:19,640 --> 01:22:28,920 AND THOUGH THIS AXONAL POUCH WE 1840 01:22:28,920 --> 01:22:32,440 LOOKED AT THE FUNCTIONAL CHANGE 1841 01:22:32,440 --> 01:22:35,080 BY USING THE IPSC DERIVED NERVE 1842 01:22:35,080 --> 01:22:37,920 CELLS WE CAN LOOK AT THE 1843 01:22:37,920 --> 01:22:39,880 FUNCTION IN IMAGING. 1844 01:22:39,880 --> 01:22:43,680 AN STEM CELLS WE DO A LIVE CELL 1845 01:22:43,680 --> 01:22:50,280 IMAGE FIVE MINUTES. 1846 01:22:50,280 --> 01:22:53,640 THIS X AXIS IN A DIFFERENT 1847 01:22:53,640 --> 01:22:56,600 POSITION AND IF THE MITOCHONDRIA 1848 01:22:56,600 --> 01:22:58,840 MOVES IT WILL CHANGE THE 1849 01:22:58,840 --> 01:23:02,360 POSITION ALONG THE X AXIS. 1850 01:23:02,360 --> 01:23:05,600 YOU CAN SEE IMMEDIATELY IN THE 1851 01:23:05,600 --> 01:23:07,640 CONTROL CELLS THERE'S A LOT OF 1852 01:23:07,640 --> 01:23:09,800 MITOCHONDRIA MOVES BUT IN THESE 1853 01:23:09,800 --> 01:23:11,680 PATIENTS MOST MOVE VERY LITTLE 1854 01:23:11,680 --> 01:23:13,440 OR DO NOT MOVE. 1855 01:23:13,440 --> 01:23:15,640 SO THERE'S A SIGNIFICANT 1856 01:23:15,640 --> 01:23:19,320 REDUCTION OF THIS MITOCHONDRIA 1857 01:23:19,320 --> 01:23:21,160 AND THE EVENTS OF MITOCHONDRIA. 1858 01:23:21,160 --> 01:23:26,880 WE CAN SEE MUTATION OF THESE HR1 1859 01:23:26,880 --> 01:23:29,160 RESULTS IN REDUCED OUTGROWTH 1860 01:23:29,160 --> 01:23:32,320 RESULTS AND THE IMPAIRED POUCH 1861 01:23:32,320 --> 01:23:37,560 WHICH RECAPITULATE THESE 1862 01:23:37,560 --> 01:23:38,680 SPECIFIC PHENOTYPES. 1863 01:23:38,680 --> 01:23:43,480 WE CAN USE THE MODEL TO TEST THE 1864 01:23:43,480 --> 01:23:43,920 THERAPEUTIC COMPOUNDS. 1865 01:23:43,920 --> 01:23:46,440 I'LL NOW GIVE AN EXAMPLE HOW WE 1866 01:23:46,440 --> 01:23:48,320 USE THIS ONE TO TEST THIS 1867 01:23:48,320 --> 01:23:49,400 COMPOUNDS AND WHAT ARE THE 1868 01:23:49,400 --> 01:23:51,640 CHALLENGES AND WHAT ARE THE 1869 01:23:51,640 --> 01:23:54,880 FUTURE PLANS WE'RE GOING TO DO 1870 01:23:54,880 --> 01:23:56,920 WHICH CAN SCREEN COMPOUNDS TO 1871 01:23:56,920 --> 01:23:59,640 RESCUE THE AXONAL DEGENERATION. 1872 01:23:59,640 --> 01:24:05,280 SO WE CAN SEE WE HAVE A PATIENT 1873 01:24:05,280 --> 01:24:08,800 WITH THIS MUTATION WITH THE 1874 01:24:08,800 --> 01:24:11,040 PROTEIN AND RECEIVE AND GENERATE 1875 01:24:11,040 --> 01:24:13,320 IPSC CELLS FROM ANOTHER 1876 01:24:13,320 --> 01:24:13,600 MUTATION. 1877 01:24:13,600 --> 01:24:16,160 CRAIG HAS MENTIONED THE 1878 01:24:16,160 --> 01:24:18,880 MUTATION. 1879 01:24:18,880 --> 01:24:24,520 THESE ARE SEVERE IPSC PATIENTS 1880 01:24:24,520 --> 01:24:27,480 AND ACTUALLY THIS MUTATION HAS 1881 01:24:27,480 --> 01:24:29,920 ALSO BEEN LOOKED AT BEFORE AND 1882 01:24:29,920 --> 01:24:32,680 THIS STARTED IN 2007. 1883 01:24:32,680 --> 01:24:39,480 THEY HAVE BEEN SCREENED OVER 100 1884 01:24:39,480 --> 01:24:41,960 PATIENTS WHICH DO NOT HAVE A 1885 01:24:41,960 --> 01:24:46,360 CLEAR MUTATION OF SPG4. 1886 01:24:46,360 --> 01:24:49,920 THE SCREEN FOUND THEY HAVE 1887 01:24:49,920 --> 01:24:50,880 MUTATION SPG3A. 1888 01:24:50,880 --> 01:24:52,280 AND THREE ARE DE NOVO MUTATIONS. 1889 01:24:52,280 --> 01:24:55,720 AND YOU CAN SEE THESE ARE THE 1890 01:24:55,720 --> 01:24:58,840 THREE DE NOVO AND THERE'S TWO IN 1891 01:24:58,840 --> 01:25:07,360 THE DTP AND THIS ONE IN THE ONE 1892 01:25:07,360 --> 01:25:10,880 MENTIONED AND WE HAVE ALSO HAVE 1893 01:25:10,880 --> 01:25:13,040 THIS PATIENT HAD SEVERE EARLY 1894 01:25:13,040 --> 01:25:22,760 ONSET AND SEVERE PHENOTYPES. 1895 01:25:22,760 --> 01:25:27,480 AND THESE PATIENTS HAVE A SEVERE 1896 01:25:27,480 --> 01:25:48,480 PHENOTYPE AND EARLY ONSET AND 1897 01:25:48,480 --> 01:25:54,120 AND WE SEE REDUCED THIS IN THE 1898 01:25:54,120 --> 01:26:00,080 PATIENT WITH OTHER DE NOVO 1899 01:26:00,080 --> 01:26:00,400 MUTATIONS. 1900 01:26:00,400 --> 01:26:04,600 AND ALSO LIKE WITH DIFFERENT 1901 01:26:04,600 --> 01:26:05,560 CLONES. 1902 01:26:05,560 --> 01:26:08,600 SO AS I TURN TO THIS FIGURE 1903 01:26:08,600 --> 01:26:12,680 SHOWED WE HAVE ALREADY TESTED AS 1904 01:26:12,680 --> 01:26:19,440 A PROOF OF CONTEST MACRO TUBULE 1905 01:26:19,440 --> 01:26:23,360 TARGETING COMPOUNDS AND THE 1906 01:26:23,360 --> 01:26:25,120 CELLS IN THE SPG3A IPSC-DERIVED 1907 01:26:25,120 --> 01:26:28,440 NEURONS AND WE SEE A SIGNIFICANT 1908 01:26:28,440 --> 01:26:33,360 OUTGROWTH OF THE PATIENT CELLS 1909 01:26:33,360 --> 01:26:39,720 AND WE SEE THE DEFECTS. 1910 01:26:39,720 --> 01:26:43,080 SO THIS SUGGESTS IT'S A 1911 01:26:43,080 --> 01:26:46,480 MICROTUBULE TARGETING CAN 1912 01:26:46,480 --> 01:26:49,120 MITIGATE THE GROWTH AND SUGGEST 1913 01:26:49,120 --> 01:27:02,080 THE PATIENT'S STEM CELLS IN CAN 1914 01:27:02,080 --> 01:27:06,080 HELP SCREEN THE DRUG AND WE CAN 1915 01:27:06,080 --> 01:27:10,480 USE A SYSTEM LIKE THIS COMPUTER 1916 01:27:10,480 --> 01:27:13,480 ALGORITHM TO ANALYZE THE 1917 01:27:13,480 --> 01:27:13,720 EXTENSION. 1918 01:27:13,720 --> 01:27:16,400 IN THIS WAY WE COULD TEST LIKE A 1919 01:27:16,400 --> 01:27:17,040 LARGE NUMBER OF COMPOUNDS IN THE 1920 01:27:17,040 --> 01:27:19,960 FUTURE. 1921 01:27:19,960 --> 01:27:22,640 SO I SHOW HERE LIKE NOT ONLY IN 1922 01:27:22,640 --> 01:27:24,280 ADDITION TO HAVING THE SYSTEM WE 1923 01:27:24,280 --> 01:27:28,480 WANT TO ALSO WANT TO DEVELOP 1924 01:27:28,480 --> 01:27:30,840 SOME SENSITIVE HIGH THROUGHPUT 1925 01:27:30,840 --> 01:27:31,080 METHOD. 1926 01:27:31,080 --> 01:27:35,040 WE HAVE SHOWN A SIGNIFICANT 1927 01:27:35,040 --> 01:27:36,320 ALTERATION OF THIS IN THE 1928 01:27:36,320 --> 01:27:36,560 MEDIUM. 1929 01:27:36,560 --> 01:27:41,200 SO WE WANT TO SEE LIKE WHETHER 1930 01:27:41,200 --> 01:27:45,120 WE COULD HAVE A MORE SENSITIVE 1931 01:27:45,120 --> 01:27:53,360 MEASURE AND WE'RE LOOKING AT A 1932 01:27:53,360 --> 01:27:55,640 TEST CASE IN THE CELLS. 1933 01:27:55,640 --> 01:27:57,800 IN THIS MORE SENSITIVE HIGH 1934 01:27:57,800 --> 01:28:01,080 THROUGHPUT MEASURE WE WILL BE 1935 01:28:01,080 --> 01:28:05,600 ABLE TO TEST A LARGE NUMBER OF 1936 01:28:05,600 --> 01:28:06,680 DIFFERENT COMPOUNDS AND COMPARE 1937 01:28:06,680 --> 01:28:08,080 THE COMPOUNDS TARGETED AT 1938 01:28:08,080 --> 01:28:11,080 DIFFERENT PATHWAYS AND 1939 01:28:11,080 --> 01:28:15,320 POTENTIALLY ALSO TEST THIS IN 1940 01:28:15,320 --> 01:28:16,400 THE FUTURE. 1941 01:28:16,400 --> 01:28:19,080 FOR EXAMPLE DR. BLACKSTONE 1942 01:28:19,080 --> 01:28:22,400 SHOWED THE TARGET DRUG WE CAN 1943 01:28:22,400 --> 01:28:24,200 TEST OTHER DRUGS. 1944 01:28:24,200 --> 01:28:30,480 AND WE CAN IDENTIFY THIS AND USE 1945 01:28:30,480 --> 01:28:33,560 ANALYSIS FOR THE CELLS. 1946 01:28:33,560 --> 01:28:36,120 AND WE CAN TEST THIS STEM CELL 1947 01:28:36,120 --> 01:28:37,880 DERIVED NEURONS. 1948 01:28:37,880 --> 01:28:42,880 ONE THING INTERESTINGLY IS ONE 1949 01:28:42,880 --> 01:28:44,480 ADVANTAGE FOR THE MODEL IS THE 1950 01:28:44,480 --> 01:28:47,720 CELLS CAN GENERATE OTHER TYPE OF 1951 01:28:47,720 --> 01:28:48,880 NERVE CELLS. 1952 01:28:48,880 --> 01:28:53,840 CLEAR CELLS AND ASTROCYTE AND 1953 01:28:53,840 --> 01:28:57,280 THE MUTATION THIS MUTATION CAN 1954 01:28:57,280 --> 01:29:03,080 IMPAIR THESE DROPLET IN 1955 01:29:03,080 --> 01:29:03,640 ASTROCYTES. 1956 01:29:03,640 --> 01:29:06,480 I'LL NOT TALK TOO MUCH DETAIL 1957 01:29:06,480 --> 01:29:11,640 BUT YOU SEE THE STEM CELL 1958 01:29:11,640 --> 01:29:16,120 DERIVED ASTROCYTE AND SEE THE 1959 01:29:16,120 --> 01:29:17,360 DROPLET IN THE CELLS. 1960 01:29:17,360 --> 01:29:18,720 AND THERE'S VERY FEW OF THESE 1961 01:29:18,720 --> 01:29:22,400 DROPLET AND FOR THE STUDY SHOW 1962 01:29:22,400 --> 01:29:25,080 IN THIS MUTANT CELLS THE DE NOVO 1963 01:29:25,080 --> 01:29:26,200 MUTANT CELLS WE SHOW THE SIZE OF 1964 01:29:26,200 --> 01:29:36,080 THE DROP LETSS -- DROPLETS ARE 1965 01:29:36,080 --> 01:29:39,640 REDUCED IN THE GLIAL CELLS. 1966 01:29:39,640 --> 01:29:43,640 WE KNOW AS WE SHOW HERE WITH THE 1967 01:29:43,640 --> 01:29:48,480 OTHER SCHEMATIC SHOWS THE GLIAL 1968 01:29:48,480 --> 01:29:51,400 CELLS AND THE NEURONS WITH LATER 1969 01:29:51,400 --> 01:29:54,480 DEVELOPMENT WHEN THEY ARE 1970 01:29:54,480 --> 01:29:57,440 MATURE, THEY ARE DEPENDENT ON 1971 01:29:57,440 --> 01:30:07,480 THIS ASTROCYTE AND GLIAL CELLS 1972 01:30:07,480 --> 01:30:12,280 SO THERE'S TRANSFER FROM THE 1973 01:30:12,280 --> 01:30:15,640 CELL TO THE NEURON AND THE 1974 01:30:15,640 --> 01:30:17,040 NEURONS HAVE A DEFICIENCY WHICH 1975 01:30:17,040 --> 01:30:20,520 LEAD TO THE DEFECTS. 1976 01:30:20,520 --> 01:30:26,200 THEREFORE BY USING THE MODELS AS 1977 01:30:26,200 --> 01:30:29,080 SUMMARIZED HERE WE CAN TRY TO 1978 01:30:29,080 --> 01:30:31,640 DEVELOP SOME SENSITIVITY METHOD 1979 01:30:31,640 --> 01:30:33,600 TO TEST COMPOUNDS TARGETED IN 1980 01:30:33,600 --> 01:30:37,160 DIFFERENT PATHWAYS AND IF THE 1981 01:30:37,160 --> 01:30:38,880 FUTURE TEST SOME LABORATORIES. 1982 01:30:38,880 --> 01:30:44,480 AND WE CAN FURTHER LOOK AT THE 1983 01:30:44,480 --> 01:30:47,360 ANALYSIS IN THE IPSC MODEL MORE 1984 01:30:47,360 --> 01:30:50,440 IMPORTANTLY WE CAN LOOK AT THE 1985 01:30:50,440 --> 01:30:51,080 GLIAL IN ACTION AND IN THE 1986 01:30:51,080 --> 01:30:53,080 FUTURE IT CAN BE TESTED IN 1987 01:30:53,080 --> 01:30:55,160 ANIMAL STUDIES. 1988 01:30:55,160 --> 01:30:58,440 SO WE CAN SEE THIS IS IPSC CELL 1989 01:30:58,440 --> 01:31:03,440 DERIVED MODELS CAN PROVIDE A 1990 01:31:03,440 --> 01:31:04,320 VERY POWERFUL TOOLS BY COMBINING 1991 01:31:04,320 --> 01:31:07,280 WITH DIFFERENT APPROACHES AND 1992 01:31:07,280 --> 01:31:10,840 OTHER MODELS IN THE FUTURE WILL 1993 01:31:10,840 --> 01:31:14,880 PROVIDE A SYSTEM TO IDENTIFY 1994 01:31:14,880 --> 01:31:19,000 SOME POTENTIAL AGENTS TO RESCUE 1995 01:31:19,000 --> 01:31:27,160 THE AXONAL DEFECTS IN THE SPG3A 1996 01:31:27,160 --> 01:31:27,440 PATIENTS. 1997 01:31:27,440 --> 01:31:30,200 I'D LIKE TO THANK THE PEOPLE IN 1998 01:31:30,200 --> 01:31:32,320 MY LAB AND I WANT THANK 1999 01:31:32,320 --> 01:31:39,760 DR. BLACKSTONE AND HIS TEAM. 2000 01:31:39,760 --> 01:31:44,480 AND UP PARTICULAR I WANT TO 2001 01:31:44,480 --> 01:31:46,040 THANK THE FUNDING AGENCIES 2002 01:31:46,040 --> 01:31:47,680 SPORING OUR WORK. 2003 01:31:47,680 --> 01:31:50,200 I'LL BE HAPPY TO ANSWER ANY 2004 01:31:50,200 --> 01:31:51,840 QUESTION US HAVE IN LATER 2005 01:31:51,840 --> 01:31:52,160 DISCUSSION. 2006 01:31:52,160 --> 01:31:55,040 THANK YOU. 2007 01:31:55,040 --> 01:31:57,800 >> THANK YOU, DR. LI. 2008 01:31:57,800 --> 01:32:01,480 WE CAN PROCEED WITH THE TALK 2009 01:32:01,480 --> 01:32:03,760 FROM DR. PETER BAAS. 2010 01:32:03,760 --> 01:32:05,760 IT'S A GREAT PLEASURE TO BE 2011 01:32:05,760 --> 01:32:09,680 HERE. 2012 01:32:09,680 --> 01:32:10,560 SO WONDERFUL OF THEM AND 2013 01:32:10,560 --> 01:32:13,320 TERRIFIC TO INTERACT WITH 2014 01:32:13,320 --> 01:32:15,080 PHYSICIANS AND PARENTS OF 2015 01:32:15,080 --> 01:32:15,840 CHILDREN SUFFERING FROM THIS 2016 01:32:15,840 --> 01:32:17,280 DISEASE AND SCIENTIST. 2017 01:32:17,280 --> 01:32:22,160 I'LL TALK ABOUT TODAY IS MOUSE 2018 01:32:22,160 --> 01:32:23,480 MODEL FOR SPG4. 2019 01:32:23,480 --> 01:32:26,280 IN DOING SO I THINK IT'S 2020 01:32:26,280 --> 01:32:28,440 IMPORTANT I TALK ABOUT 2021 01:32:28,440 --> 01:32:29,760 MECHANISMS UNDERLYING THE 2022 01:32:29,760 --> 01:32:31,360 DISEASE AND I ALSO WHERE THIS 2023 01:32:31,360 --> 01:32:34,120 GOES WITH REGARD TO POTENTIAL 2024 01:32:34,120 --> 01:32:38,720 THERAPIES. 2025 01:32:38,720 --> 01:32:44,600 I WAND TO REMIND THINGS WE HEARD 2026 01:32:44,600 --> 01:32:47,840 AND HEREDITARY SPASTIC 2027 01:32:47,840 --> 01:32:52,680 PARAPLEGIA HAS THINGS IN COMMON 2028 01:32:52,680 --> 01:33:04,640 AND HOW WE CATEGORIZE THESE ARE 2029 01:33:04,640 --> 01:33:06,680 GAIT DEFECTS AND WE'RE STARTING 2030 01:33:06,680 --> 01:33:08,360 TO UNDERSTAND OTHER 2031 01:33:08,360 --> 01:33:08,880 ABNORMALITIES. 2032 01:33:08,880 --> 01:33:10,280 USUALLY THE DISEASE IS ADULT 2033 01:33:10,280 --> 01:33:11,680 ONSET BUT NOT ALWAYS AND THAT'S 2034 01:33:11,680 --> 01:33:13,680 THE POINT OF THE MEETING TODAY. 2035 01:33:13,680 --> 01:33:19,560 THERE'S ALSO A GREAT DEAL OF 2036 01:33:19,560 --> 01:33:25,880 VARIABILITY EVEN WITHIN THE SAME 2037 01:33:25,880 --> 01:33:40,560 FAMILY. 2038 01:33:40,560 --> 01:33:46,480 THE MAIN THING THAT HAPPENS IS 2039 01:33:46,480 --> 01:33:49,080 DEFEND RATION OF THE SPINAL 2040 01:33:49,080 --> 01:33:53,040 MOTOR NEURONS AND THESE AXONS 2041 01:33:53,040 --> 01:33:57,840 DIE BACK FROM THE SYNAPSES AND 2042 01:33:57,840 --> 01:34:04,640 WHAT WE SEE CLASSICALLY IN 2043 01:34:04,640 --> 01:34:09,840 POSTMORTEM TISSUES IS 2044 01:34:09,840 --> 01:34:16,000 PATHOLOGICAL SWELLINGS. 2045 01:34:16,000 --> 01:34:17,200 IF YOU LOOK AT THE CAUSES FOR 2046 01:34:17,200 --> 01:34:18,080 THE SYMPTOMS THE NUMBER OF GENES 2047 01:34:18,080 --> 01:34:28,360 IS GROWING. 2048 01:34:28,360 --> 01:34:33,880 IT USED TO BE THOUGHT THERE WERE 2049 01:34:33,880 --> 01:34:37,880 NINE -- 12 AND NOW UP TO 92 AND 2050 01:34:37,880 --> 01:34:43,000 THE LIST GOES ON AND ON. 2051 01:34:43,000 --> 01:34:46,680 CODES FOR A PROTEIN CALLED 2052 01:34:46,680 --> 01:34:49,280 SPASTIN WHICH IS A PROTEIN BUT 2053 01:34:49,280 --> 01:34:51,120 IN THE CASE CRAIG POINTED OUT 2054 01:34:51,120 --> 01:34:53,840 WE'RE LEARNING MORE ABOUT THE 2055 01:34:53,840 --> 01:34:57,960 MULTIPLE FUNCTIONS OF THE 2056 01:34:57,960 --> 01:35:04,600 SPASTIN PROTEIN. 2057 01:35:04,600 --> 01:35:06,840 WE HEARD LOSS OF FUNCTION AND 2058 01:35:06,840 --> 01:35:09,000 GAIN OF FUNCTION IN THE 2059 01:35:09,000 --> 01:35:11,280 SYMPOSIUM AND IT'S RELEVANT TO 2060 01:35:11,280 --> 01:35:12,480 MAKE APPROPRIATE MOUSE MODEL FOR 2061 01:35:12,480 --> 01:35:13,080 THE DISEASE. 2062 01:35:13,080 --> 01:35:15,480 HERE'S AN EASY WAY I THINK ABOUT 2063 01:35:15,480 --> 01:35:16,000 IT. 2064 01:35:16,000 --> 01:35:18,840 IF IT'S A LOSS OF FUNCTION, THE 2065 01:35:18,840 --> 01:35:21,200 KID JUST DIDN'T SHOW UP FOR 2066 01:35:21,200 --> 01:35:22,600 CLASS, HE'S JUST NOT THERE. 2067 01:35:22,600 --> 01:35:23,640 BUT IF IT'S GAIN OF FUNCTION 2068 01:35:23,640 --> 01:35:26,080 HE'S THERE BUT MAKING TROUBLE. 2069 01:35:26,080 --> 01:35:28,680 SO DON'T THINK GAIN OF FUNCTION 2070 01:35:28,680 --> 01:35:29,920 MEANS IT'S SOMETHING GOOD. 2071 01:35:29,920 --> 01:35:32,760 GAIN OF FUNCTION USUALLY IN THE 2072 01:35:32,760 --> 01:35:34,600 DISEASE CONTEXT MEANS IT'S 2073 01:35:34,600 --> 01:35:37,480 MAKING SOME KIND OF TROUBLE. 2074 01:35:37,480 --> 01:35:40,560 SOMETIMES THE TROUBLE THE MUTANT 2075 01:35:40,560 --> 01:35:42,280 PROTEIN MAKES CAN BE PREDICTED 2076 01:35:42,280 --> 01:35:44,440 BY ITS NORMAL FUNCTION. 2077 01:35:44,440 --> 01:35:45,800 OTHER TIMES IT'S NOT SO EASY. 2078 01:35:45,800 --> 01:35:50,200 HAVE THIS MUTANT PROTEIN AND IT 2079 01:35:50,200 --> 01:35:56,240 DOES UNPREDICTED THINGS LIKE 2080 01:35:56,240 --> 01:35:57,880 HYPERACTIVATE KINASES OR OTHER 2081 01:35:57,880 --> 01:35:59,240 THINGS YOU'D NEVER PREDICT ON 2082 01:35:59,240 --> 01:36:03,480 THE OF ITS NORMAL FUNCTION. 2083 01:36:03,480 --> 01:36:05,960 IN THIS CASE IT GETS 2084 01:36:05,960 --> 01:36:07,280 PROGRESSIVELY WORSE AND USUALLY 2085 01:36:07,280 --> 01:36:09,360 BECAUSE MISFOLDED PROTEINS HAVE 2086 01:36:09,360 --> 01:36:11,760 A TENDENCY TO ABROGATE AND ONCE 2087 01:36:11,760 --> 01:36:14,200 THEY ABROGATE THEY ACCUMULATE 2088 01:36:14,200 --> 01:36:16,640 AND THEN THE STICK AROUND FOR A 2089 01:36:16,640 --> 01:36:18,800 LONG TIME. 2090 01:36:18,800 --> 01:36:20,200 THEY CAN GET WORSE. 2091 01:36:20,200 --> 01:36:25,840 AS CRAIG POINTED OUT EARLIER, 2092 01:36:25,840 --> 01:36:30,840 THE SPAST GENE ENCODES TO 2093 01:36:30,840 --> 01:36:31,200 PROTEIN. 2094 01:36:31,200 --> 01:36:33,840 ONE WE CALL THE M1, THE LONGER 2095 01:36:33,840 --> 01:36:34,800 OF THE TWO. 2096 01:36:34,800 --> 01:36:39,280 THE OTHER IS M87 JUST SLIGHTLY 2097 01:36:39,280 --> 01:36:42,880 SHORTER AND M87 PREDOMINANCE. 2098 01:36:42,880 --> 01:36:46,880 SO M87 IS IN VIRTUALLY EVERY 2099 01:36:46,880 --> 01:36:52,600 CELL OF THE BODY AND ENRICHED IN 2100 01:36:52,600 --> 01:36:55,320 THE SYSTEM AND LIVER AND SKIN 2101 01:36:55,320 --> 01:36:58,840 AND WIDELY EXPRESSED AND AN 2102 01:36:58,840 --> 01:37:03,240 IMPORTANT MICROTUBULE SEVERIN 2103 01:37:03,240 --> 01:37:05,720 PROTEIN AND THERE'S THE WHY 2104 01:37:05,720 --> 01:37:09,800 PERFECT ONE CRAIG MENTIONED. 2105 01:37:09,800 --> 01:37:11,440 IT'S EXPRESSED AT MUCH LOWER 2106 01:37:11,440 --> 01:37:13,800 LEVELS AND AS CRAIG POINTED OUT 2107 01:37:13,800 --> 01:37:16,480 YOU REALLY DON'T SEE IT BECAUSE 2108 01:37:16,480 --> 01:37:19,040 THERE'S SO LITTLE OF IT BUT WE 2109 01:37:19,040 --> 01:37:20,720 DO SEE IT IN CERTAIN INSTANCES 2110 01:37:20,720 --> 01:37:23,080 I'LL GET TO IN A MOMENT. 2111 01:37:23,080 --> 01:37:25,040 SO HERE'S A WESTERN BLOT AND AS 2112 01:37:25,040 --> 01:37:27,320 YOU CAN SEE IF YOU LOOK AT 2113 01:37:27,320 --> 01:37:30,920 CEREBRAL CORTEX, THIS IS FROM 2114 01:37:30,920 --> 01:37:35,040 RODENT, E18, P0, P12, THE BAND 2115 01:37:35,040 --> 01:37:39,520 YOU SEE THIS BAND IS ALL M87. 2116 01:37:39,520 --> 01:37:41,840 BUT HERE'S THE SPINAL CORD AND 2117 01:37:41,840 --> 01:37:45,240 REMEMBER THE SPINAL CORD 2118 01:37:45,240 --> 01:37:46,600 SOMEWHERE THE CORTICAL SPINAL 2119 01:37:46,600 --> 01:37:48,640 TRACKS LIE AND WHERE YOU START 2120 01:37:48,640 --> 01:37:53,920 TO SEE A BIT OF THE M1 BECOME 2121 01:37:53,920 --> 01:37:55,520 VISIBLE IN THE ADULT SPINAL CORD 2122 01:37:55,520 --> 01:37:57,240 AND WE THINK THERE'S SOMETHING 2123 01:37:57,240 --> 01:38:02,480 ABOUT THE SPINAL TRACTS THAT LIE 2124 01:38:02,480 --> 01:38:04,600 IN THE SPINAL CORD THAT HAVE THE 2125 01:38:04,600 --> 01:38:06,120 TENDENCY TO M1 AND THAT COULD BE 2126 01:38:06,120 --> 01:38:07,480 CRITICAL TO UNDERSTANDING THE 2127 01:38:07,480 --> 01:38:13,080 DISEASE AND WHY THE DISEASE HITS 2128 01:38:13,080 --> 01:38:15,560 THE CORTICAL SPINAL TRACKS. 2129 01:38:15,560 --> 01:38:20,760 WE PONDERED ON THE GAIN OF 2130 01:38:20,760 --> 01:38:21,840 FUNCTION AND LOSS OF FUNCTION 2131 01:38:21,840 --> 01:38:23,680 AND THE COMMUNITY IS GETTING 2132 01:38:23,680 --> 01:38:25,680 FRIENDLY ABOUT THE CONTROVERSY. 2133 01:38:25,680 --> 01:38:39,480 WHEN WE FIRST GOT INTO IT WAS A 2134 01:38:39,480 --> 01:38:41,720 CONTROVERSY AND THE PATIENT HAS 2135 01:38:41,720 --> 01:38:44,720 ONE GOOD GENE AND ONE NOW 2136 01:38:44,720 --> 01:38:45,320 FUNCTIONING GENE. 2137 01:38:45,320 --> 01:38:47,400 AND IT'S AS IF THE 2138 01:38:47,400 --> 01:38:49,840 MALFUNCTIONING GENE IS SIMPLY 2139 01:38:49,840 --> 01:38:51,960 NOT THERE AND SO THE PHENOTYPE 2140 01:38:51,960 --> 01:38:55,080 IN THIS MECHANISTIC SCENARIO IS 2141 01:38:55,080 --> 01:38:57,280 INTERPRETED IN TERMS OF NOT 2142 01:38:57,280 --> 01:38:58,600 ENOUGH FUNCTIONAL SPASTIN. 2143 01:38:58,600 --> 01:39:01,960 THAT COULD BE NOT ENOUGH 2144 01:39:01,960 --> 01:39:04,600 FUNCTIONAL M1 OR COULD BE NOT 2145 01:39:04,600 --> 01:39:06,760 ENOUGH FUNCTIONAL M87, WHATEVER 2146 01:39:06,760 --> 01:39:09,840 THE CASE IT'S NOT ENOUGH 2147 01:39:09,840 --> 01:39:14,920 FUNCTIONAL SPASTIN THEREFORE THE 2148 01:39:14,920 --> 01:39:15,640 SPINAL CORD PHENOTYPES SUFFER 2149 01:39:15,640 --> 01:39:19,400 AND TROUBLE ENSUES. 2150 01:39:19,400 --> 01:39:21,040 THERE'S NOT A LOT ABOUT THE 2151 01:39:21,040 --> 01:39:23,960 PHENOTYPE OVER THE YEARS WE 2152 01:39:23,960 --> 01:39:25,200 OBSERVED THAT WE DON'T THINK 2153 01:39:25,200 --> 01:39:26,440 FITS A LOSS OF FUNCTION SCENARIO 2154 01:39:26,440 --> 01:39:29,120 AT LEAST NOT EXCLUSIVELY. 2155 01:39:29,120 --> 01:39:29,880 ONE EXAMPLE IS THE KNOCKOUT 2156 01:39:29,880 --> 01:39:34,480 MOUSE. 2157 01:39:34,480 --> 01:39:37,160 SO MOST PEOPLE IN THE FIELD 2158 01:39:37,160 --> 01:39:40,640 PRIOR TO WHAT WE DEVELOPED USED 2159 01:39:40,640 --> 01:39:42,520 A SPASTIN KNOCKOUT MOUSE IN 2160 01:39:42,520 --> 01:39:47,080 ORDER TO MODEL THE DISEASE. 2161 01:39:47,080 --> 01:39:51,560 THE PROBLEM IS IT DOESN'T MIMIC 2162 01:39:51,560 --> 01:39:52,840 THE PHENOTYPE, THE SYMPTOMS OF 2163 01:39:52,840 --> 01:39:54,800 THE HUMAN DISEASE. 2164 01:39:54,800 --> 01:39:57,040 IT'S NOT A PERFECT MOUSE. 2165 01:39:57,040 --> 01:39:58,640 YOU CAN EITHER KNOCKOUT ONE OR 2166 01:39:58,640 --> 01:40:01,080 TWO GENES AND IT DOES HAVE SOME 2167 01:40:01,080 --> 01:40:04,080 NERVOUS SYSTEM DEFECTS BUT IT 2168 01:40:04,080 --> 01:40:05,840 REALLY DOESN'T MIMIC THE GAIT 2169 01:40:05,840 --> 01:40:08,400 DEFICIENCIES OF THE HUMAN 2170 01:40:08,400 --> 01:40:08,680 PATIENT. 2171 01:40:08,680 --> 01:40:12,080 WE COME AROUND TO THINKING 2172 01:40:12,080 --> 01:40:16,360 THOUGH IN RECENT YEARS THAT THE 2173 01:40:16,360 --> 01:40:17,280 LOSS OF FUNCTION IS A COMPONENT 2174 01:40:17,280 --> 01:40:18,120 OF THE DISEASE. 2175 01:40:18,120 --> 01:40:19,480 I'LL GIVE YOU MORE INFORMATION 2176 01:40:19,480 --> 01:40:22,680 AS TO WHY WE THINK THAT USING 2177 01:40:22,680 --> 01:40:25,560 OUR MOUSE MODELS BUT THESE DAYS 2178 01:40:25,560 --> 01:40:28,360 WE THINK THE GAIN OF FUNCTION 2179 01:40:28,360 --> 01:40:32,040 AND TOXIC PROPERTIES OF THE 2180 01:40:32,040 --> 01:40:33,200 MUTANT PROTEINS CAUSE THE 2181 01:40:33,200 --> 01:40:33,480 PHENOTYPE. 2182 01:40:33,480 --> 01:40:35,280 BUT THE LOSS OF FUNCTION, THE 2183 01:40:35,280 --> 01:40:37,840 FACT THAT HALF THE SPASTIN IS 2184 01:40:37,840 --> 01:40:40,640 NOT FUNCTIONING PROPERLY IS ALSO 2185 01:40:40,640 --> 01:40:43,160 A CONTRIBUTING FACTOR. 2186 01:40:43,160 --> 01:40:45,440 SO WE'RE BEGINNING TO SORT THIS 2187 01:40:45,440 --> 01:40:50,480 OUT AND WE'RE LOOKING AT LOSS OF 2188 01:40:50,480 --> 01:40:53,960 FUNCTION PATHWAYS AND LOOKING AT 2189 01:40:53,960 --> 01:41:03,280 LOSS OF FUNCTION FOR THE EXXON 2190 01:41:03,280 --> 01:41:04,600 -- 2191 01:41:09,840 --> 01:41:10,840 AXONAL FUNCTION AND THIS SLIDE 2192 01:41:10,840 --> 01:41:13,480 SHOWS A FEW OF THE MECHANISTIC 2193 01:41:13,480 --> 01:41:15,440 I'D THAT WE'RE PURSUING AS TO 2194 01:41:15,440 --> 01:41:19,600 WHY EACH OF THESE PATHWAYS 2195 01:41:19,600 --> 01:41:22,280 BECOMES CONSEQUENTIAL TO THE 2196 01:41:22,280 --> 01:41:32,720 DISEASE. 2197 01:41:32,720 --> 01:41:34,480 THE COLLABORATOR USED SQUID 2198 01:41:34,480 --> 01:41:37,840 AXALPLASM AND WE INFUSED MUTANT 2199 01:41:37,840 --> 01:41:44,680 M1 VERSUS MUTANT M8 7 AND FOUND 2200 01:41:44,680 --> 01:41:48,080 THE MUTANT M1 THAT PRODUCED 2201 01:41:48,080 --> 01:41:52,640 PROBLEMS WITH AXONAL TRANSPORT 2202 01:41:52,640 --> 01:41:57,400 AND THE MUTANT M87 WAS INCONS 2203 01:41:57,400 --> 01:42:01,320 INCONSEQUENTIAL AND NO 2204 01:42:01,320 --> 01:42:01,720 TRANSPORT. 2205 01:42:01,720 --> 01:42:03,680 WE USED A FLY MODEL AND 2206 01:42:03,680 --> 01:42:06,680 SIMILARLY IF WE KNOCKED IN THE 2207 01:42:06,680 --> 01:42:09,600 HUMAN MUTANT M87 THERE WAS 2208 01:42:09,600 --> 01:42:11,240 VIRTUALLY NO PHENOTYPE BUT IF WE 2209 01:42:11,240 --> 01:42:15,160 KNOCKED IN THE HUMAN MUTANT M1 2210 01:42:15,160 --> 01:42:17,080 THEN THE FLIES COULD NOT HOLD 2211 01:42:17,080 --> 01:42:19,320 THEIR WINGS PROPERLY OR FLY OR 2212 01:42:19,320 --> 01:42:22,680 FLIP OVER WHEN PUT ON THEIR 2213 01:42:22,680 --> 01:42:22,920 BACKS. 2214 01:42:22,920 --> 01:42:27,280 IT SEEMS THAT SPASTIN PROTEINS 2215 01:42:27,280 --> 01:42:30,640 IS TOXIC WHEN IT'S M1 BUT NOT 2216 01:42:30,640 --> 01:42:32,120 WHEN IT'S M87. 2217 01:42:32,120 --> 01:42:33,880 AND IT KIND OF MAKES SENSE 2218 01:42:33,880 --> 01:42:37,040 BECAUSE THE REGION OF M1 THAT IS 2219 01:42:37,040 --> 01:42:42,840 SPECIFIC TO M1 HAS THE 2220 01:42:42,840 --> 01:42:45,000 CHARACTERISTICS OF A PROTEIN 2221 01:42:45,000 --> 01:42:47,680 THAT WOULD BE PRONE TO 2222 01:42:47,680 --> 01:42:52,640 MISFOLDING AND TAKING ON TOXIC 2223 01:42:52,640 --> 01:42:57,280 PROPERTIES. 2224 01:42:57,280 --> 01:43:00,280 AND EVOLUTIONARILY TOO MUCH OF 2225 01:43:00,280 --> 01:43:02,080 IT IS NOT A GOOD THING. 2226 01:43:02,080 --> 01:43:04,480 SO WE SET FORTH TO CREATE A 2227 01:43:04,480 --> 01:43:04,880 KNOCK-IN ANIMAL. 2228 01:43:04,880 --> 01:43:08,640 WE WANTED TO MAKE A MOUSE THAT 2229 01:43:08,640 --> 01:43:10,960 WOULD KNOCK IN HUMAN MUTANT 2230 01:43:10,960 --> 01:43:11,320 SPASTIN. 2231 01:43:11,320 --> 01:43:14,960 THESE DAYS AS CRAIG MENTIONED, 2232 01:43:14,960 --> 01:43:16,800 THERE ARE SOPHISTICATED WAYS OF 2233 01:43:16,800 --> 01:43:21,880 GETTING INTO THE GENE OF THE 2234 01:43:21,880 --> 01:43:24,400 ANIMAL TO THE SPASTIN GENES AND 2235 01:43:24,400 --> 01:43:26,720 WHAT WE WANTED TO DO WAS LEAVE 2236 01:43:26,720 --> 01:43:30,000 THE ENDOGENOUS GENES ALONE AND 2237 01:43:30,000 --> 01:43:32,880 JUST KNOCK IN AND WE USE THIS 2238 01:43:32,880 --> 01:43:36,000 SYSTEM TO KNOCK IN HUMAN-MUTANT 2239 01:43:36,000 --> 01:43:36,920 SPASTIN. 2240 01:43:36,920 --> 01:43:41,400 WE WANTED TO START BY CREATE A 2241 01:43:41,400 --> 01:43:45,640 MOUSE THAT HAD ALL THE NORMAL 2242 01:43:45,640 --> 01:43:47,280 SPASTIN, MOUSE SPASTIN, BUT ON 2243 01:43:47,280 --> 01:43:49,360 TOP OF THAT HAS THE HUMAN MUTANT 2244 01:43:49,360 --> 01:43:49,720 SPASTIN. 2245 01:43:49,720 --> 01:43:52,040 SO WE CREATED A MOUSE NOT LOSS 2246 01:43:52,040 --> 01:43:52,680 OF FUNCTION. 2247 01:43:52,680 --> 01:44:01,080 IT'S ONLY GAIN OF FUNCTION. 2248 01:44:01,080 --> 01:44:02,360 HERE'S THE WILD TYPE MOUSE 2249 01:44:02,360 --> 01:44:04,720 WALKING ON A ROD AND IF I WANTED 2250 01:44:04,720 --> 01:44:08,280 TO FOOL YOU, I CAN SHOW YOU THE 2251 01:44:08,280 --> 01:44:10,480 SAME MOVIE WITH A KNOCKOUT MOUSE 2252 01:44:10,480 --> 01:44:11,480 AND IT WOULD LOOK THE SAME. 2253 01:44:11,480 --> 01:44:15,520 THERE'S NO WALKING DEFECT WITH 2254 01:44:15,520 --> 01:44:17,080 THE KNOCKOUT MOUSE. 2255 01:44:17,080 --> 01:44:19,920 LET ME SHOW YOU THE KNOCK-IN 2256 01:44:19,920 --> 01:44:20,120 MOUSE. 2257 01:44:20,120 --> 01:44:22,680 HERE'S THE KNOCK-IN MOUSE AND 2258 01:44:22,680 --> 01:44:25,880 NOTICE IT REALLY STRUGGLES TO 2259 01:44:25,880 --> 01:44:26,680 WALK. 2260 01:44:26,680 --> 01:44:31,920 ITS BODY IS SCRUNCHED UP BECAUSE 2261 01:44:31,920 --> 01:44:33,880 OF DIFFICULTY WALKING AND 2262 01:44:33,880 --> 01:44:37,640 STRUGGLES. 2263 01:44:37,640 --> 01:44:41,480 THIS IS AN ADULT EARLY ADULT HAS 2264 01:44:41,480 --> 01:44:44,320 THESE CHARACTERISTICS AND HAS A 2265 01:44:44,320 --> 01:44:45,840 TREMOR SOMEWHAT LIKE SPACTICITY. 2266 01:44:45,840 --> 01:44:47,760 WHAT I THINK THIS SHOWS IS YOU 2267 01:44:47,760 --> 01:44:53,760 CANNOT ACHIEVE THE HSP PHENOTYPE 2268 01:44:53,760 --> 01:44:56,760 WITH KNOCKOUT ALONE BUT YOU CAN 2269 01:44:56,760 --> 01:44:59,600 ACHIEVE THE HSP PHENOTYPE WITH 2270 01:44:59,600 --> 01:45:01,040 KNOCK-IN ALONE. 2271 01:45:01,040 --> 01:45:04,120 SO I THINK THIS IS THE STRONGEST 2272 01:45:04,120 --> 01:45:07,680 YET EVIDENCE IN FAVOR OF GAIN OF 2273 01:45:07,680 --> 01:45:08,720 FUNCTION BEING THE UNDERLYING 2274 01:45:08,720 --> 01:45:09,840 MECHANISM OF DISEASE. 2275 01:45:09,840 --> 01:45:12,280 I'M NOT GOING TO PUT A LOT OF 2276 01:45:12,280 --> 01:45:14,280 TIME INTO SHOWING DETAILS. 2277 01:45:14,280 --> 01:45:16,680 THESE THE SORTS OF THINGS WE 2278 01:45:16,680 --> 01:45:28,680 OBSERVE, ADULT ONSET, GAIT 2279 01:45:28,680 --> 01:45:34,680 DEFICIENCY AND HOMO ZYGOTES 2280 01:45:34,680 --> 01:45:40,240 WORSE HAND HETEROZYGOTES AND WE 2281 01:45:40,240 --> 01:45:42,400 DID TRACER STUDIES AND YOU 2282 01:45:42,400 --> 01:45:46,480 DETECT WHETHER THERE ARE FEWER 2283 01:45:46,480 --> 01:45:48,640 AXONS IN THE DISTAL REGION OF 2284 01:45:48,640 --> 01:45:51,360 THE SPINAL CORD AND WE SAW FEWER 2285 01:45:51,360 --> 01:45:53,280 AXONS IN THE DISTAL REGION 2286 01:45:53,280 --> 01:45:54,840 INDICATING THE AXONS ARE DYING 2287 01:45:54,840 --> 01:45:57,840 BACK FROM THEIR SYNAPSES AND 2288 01:45:57,840 --> 01:46:00,080 PULLING BACK. 2289 01:46:00,080 --> 01:46:07,080 HOW ABOUT THE AXONAL SWELLINGS I 2290 01:46:07,080 --> 01:46:08,680 MENTIONED? 2291 01:46:08,680 --> 01:46:09,840 CURIOUSLY WE DON'T SEE THEM IN 2292 01:46:09,840 --> 01:46:11,480 THE KNOCKOUT MOUSE BUT WE DO IN 2293 01:46:11,480 --> 01:46:13,520 THE KNOCK-IN MOUSE. 2294 01:46:13,520 --> 01:46:15,360 THE KNOCKOUT MOUSE SHARES THAT 2295 01:46:15,360 --> 01:46:19,480 FEATURE WITH THE HUMAN PATIENTS 2296 01:46:19,480 --> 01:46:22,680 WHEREAS THE KNOCKIN MOUSE DOES 2297 01:46:22,680 --> 01:46:24,560 N 2298 01:46:24,560 --> 01:46:25,840 NOT. 2299 01:46:25,840 --> 01:46:33,160 I THINK IT FORTIFIES THE LOV THIS THAT 2300 01:46:33,160 --> 01:46:38,120 IT FORTIFIES A ROLE AND WE SEE 2301 01:46:38,120 --> 01:46:41,240 THAT THE INSUFFICIENT LEVELS OF 2302 01:46:41,240 --> 01:46:46,640 SPASTIN IS NOT SUFFICIENT TO 2303 01:46:46,640 --> 01:46:49,840 CAUSE THE PHENOTYPE OF DISEASE 2304 01:46:49,840 --> 01:46:51,640 BUT WHEN YOU ADD THE MUTANT 2305 01:46:51,640 --> 01:47:00,760 SPASTIC PROTEIN THAT IS. 2306 01:47:00,760 --> 01:47:03,480 AND TO BELABOR THE DETAILS BUT 2307 01:47:03,480 --> 01:47:09,800 WE CROSSED THEM AND WE AN ANIMAL 2308 01:47:09,800 --> 01:47:12,160 INSUFFICIENT AND THE PROTEIN AND 2309 01:47:12,160 --> 01:47:13,800 EVERYTHING IS WORSE. 2310 01:47:13,800 --> 01:47:16,680 THE BEHAVIOR IS WORSE, EARLIER 2311 01:47:16,680 --> 01:47:21,120 ONSET, STRONGER BEHAVIORAL 2312 01:47:21,120 --> 01:47:23,520 DEFICITS AND CORTICAL SPINAL DIE 2313 01:47:23,520 --> 01:47:27,360 BACK IS MORE EXTREME AND THE 2314 01:47:27,360 --> 01:47:29,080 AXONS HAVE SWELLING. 2315 01:47:29,080 --> 01:47:31,440 THIS MOUSE THE CROSS OF TWO IS 2316 01:47:31,440 --> 01:47:32,840 THE BEST YET MOUSE FULLY 2317 01:47:32,840 --> 01:47:34,360 REPRESENTING THE FEATURES OF THE 2318 01:47:34,360 --> 01:47:34,840 DISEASE. 2319 01:47:34,840 --> 01:47:37,320 HOWEVER, THE OTHER TWO MICE ARE 2320 01:47:37,320 --> 01:47:39,080 REALLY STILL VERY USEFUL IF YOU 2321 01:47:39,080 --> 01:47:41,840 WANT TO DO STUDIES SPECIFICALLY 2322 01:47:41,840 --> 01:47:45,840 ON GAIN OF FUNCTION OR LOSS OF 2323 01:47:45,840 --> 01:47:46,920 FUNCTION FROM THE DISEASE. 2324 01:47:46,920 --> 01:47:49,040 WE USED A CAT WALK FOR 2325 01:47:49,040 --> 01:47:50,040 BEHAVIORAL TESTING. 2326 01:47:50,040 --> 01:47:53,120 THIS IS A HIGHLY SENSITIVE 2327 01:47:53,120 --> 01:47:53,680 METHOD. 2328 01:47:53,680 --> 01:47:58,640 YOU PUT THE ANIMAL THROUGH A 2329 01:47:58,640 --> 01:48:01,280 CHAMBER AND THE PAW PRINTS FROM 2330 01:48:01,280 --> 01:48:04,640 THE COMPUTER RECORD IT AND YOU 2331 01:48:04,640 --> 01:48:07,360 CAN GET ALL SORTS OF DATA AND 2332 01:48:07,360 --> 01:48:08,640 THIS WILL BE USEFUL FOR 2333 01:48:08,640 --> 01:48:10,280 ASSESSING THERAPY. 2334 01:48:10,280 --> 01:48:13,000 AGAIN, HERE ARE THE DATA THAT I 2335 01:48:13,000 --> 01:48:14,400 MENTIONED FROM THE DIE BACK. 2336 01:48:14,400 --> 01:48:17,520 I KNOW THIS IS COMPLICATED BUT 2337 01:48:17,520 --> 01:48:18,480 THINKING ABOUT WHAT I JUST SAID 2338 01:48:18,480 --> 01:48:20,480 RATHER THAN FOCUSSING ON THIS. 2339 01:48:20,480 --> 01:48:22,080 SO SCHEMATICALLY SPEAKING THIS 2340 01:48:22,080 --> 01:48:25,080 IS HOW WE'RE THINKING, THAT GAIN 2341 01:48:25,080 --> 01:48:26,520 OF FUNCTION IS THE MAIN DRIVER 2342 01:48:26,520 --> 01:48:28,920 OF THE DISEASE BUT LOSS OF 2343 01:48:28,920 --> 01:48:32,080 FUNCTION RENDERS THE AXONS MORE 2344 01:48:32,080 --> 01:48:33,840 VULNERABLE TO THE GAIN OF 2345 01:48:33,840 --> 01:48:37,560 FUNCTION TOXICITY. 2346 01:48:37,560 --> 01:48:39,000 THIS IS WHERE AN INTERESTING 2347 01:48:39,000 --> 01:48:41,840 QUESTION COMES IN AND WHAT ABOUT 2348 01:48:41,840 --> 01:48:45,280 THE PATIENTS WHO HAVE A FULL 2349 01:48:45,280 --> 01:48:47,120 DELETION ONE OF THE SPASTIN 2350 01:48:47,120 --> 01:48:47,800 GENES? 2351 01:48:47,800 --> 01:48:52,760 THEY ALSO HAVE HEREDITARY SPAST 2352 01:48:52,760 --> 01:48:55,760 SPASTIC PARAPLEGIA IS WHY IS 2353 01:48:55,760 --> 01:48:57,560 THAT WHEN THEY DON'T HAVE A GAIN 2354 01:48:57,560 --> 01:48:59,920 OF FUNCTION COMPONENT OF THE 2355 01:48:59,920 --> 01:49:00,600 SPASTIN? 2356 01:49:00,600 --> 01:49:02,120 IT GETS COMPLICATED BECAUSE GENE 2357 01:49:02,120 --> 01:49:03,960 DELETION NOT ONLY ONE PROTEIN. 2358 01:49:03,960 --> 01:49:05,080 THAT'S ONE THING BUT THE MAIN 2359 01:49:05,080 --> 01:49:07,040 THING I WANT TO REFER YOU TO IS 2360 01:49:07,040 --> 01:49:10,840 WHAT I SAID EARLIER ABOUT THE 2361 01:49:10,840 --> 01:49:12,560 LIST OF 92 GENES GROWING LONGER 2362 01:49:12,560 --> 01:49:14,640 AND LONGER AND LONGER AS TO WHAT 2363 01:49:14,640 --> 01:49:18,600 GENE MUTATIONS CAN CAUSE 2364 01:49:18,600 --> 01:49:23,960 HEREDITARY SPASTIC PARAPLEGIA 2365 01:49:23,960 --> 01:49:27,240 AND ARGUE THE PATIENTS WITH GENE 2366 01:49:27,240 --> 01:49:28,520 DELETION AND HSP PROBABLY HAVE 2367 01:49:28,520 --> 01:49:30,120 SOMETHING ELSE GOING ON IN THEIR 2368 01:49:30,120 --> 01:49:32,840 GENOME THAT ELICITS THAT 2369 01:49:32,840 --> 01:49:33,680 PHENOTYPE WITH THAT GROWING LIST 2370 01:49:33,680 --> 01:49:37,280 OF GENES IT WOULD BE SOMETHING 2371 01:49:37,280 --> 01:49:41,200 ON ITS OWN CAUSES THE SYSTEMS OR 2372 01:49:41,200 --> 01:49:41,680 COMBINATION. 2373 01:49:41,680 --> 01:49:43,560 THAT'S ONE OF THOSE COMPLICATED 2374 01:49:43,560 --> 01:49:45,920 FACTORS THAT'S GOING TO TAKE 2375 01:49:45,920 --> 01:49:47,800 WORK TO RESOLVE. 2376 01:49:47,800 --> 01:49:50,840 I'M WORKING WITH MIGUEL ESTEVEZ 2377 01:49:50,840 --> 01:49:53,840 ON GENE THERAPY AND A KNOW HE'S 2378 01:49:53,840 --> 01:49:55,760 SPEAK IN A LITTLE WHILE SO I 2379 01:49:55,760 --> 01:49:57,600 WON'T SPEND A LOT OF TIME ON 2380 01:49:57,600 --> 01:50:00,680 THIS AND THE GENE THERAPY WE 2381 01:50:00,680 --> 01:50:01,400 HEARD BEFORE IN WONDERFUL 2382 01:50:01,400 --> 01:50:06,400 PREVIOUS TALKS IS TO REPLACE THE 2383 01:50:06,400 --> 01:50:07,480 MUTANT GENE WITH A WILD TYPE 2384 01:50:07,480 --> 01:50:07,880 GENE. 2385 01:50:07,880 --> 01:50:11,520 SO WE'RE WORKING ON THAT AND 2386 01:50:11,520 --> 01:50:13,200 MIGUEL WILL TALK ABOUT THAT 2387 01:50:13,200 --> 01:50:13,640 SHORTLY. 2388 01:50:13,640 --> 01:50:16,280 AND I JUST WANT TO CLOSE BY 2389 01:50:16,280 --> 01:50:17,280 THANKING ALL OF THE VARIOUS 2390 01:50:17,280 --> 01:50:19,240 PEOPLE IN MY LAB OVER THE YEARS 2391 01:50:19,240 --> 01:50:21,520 WHO HAVE CONTRIBUTED TO THIS 2392 01:50:21,520 --> 01:50:28,680 WORK IN PARTICULAR I WANTED TO 2393 01:50:28,680 --> 01:50:38,280 THANK OSCAR AND EMMANUEL WHO DID 2394 01:50:38,280 --> 01:50:39,960 A LOT OF THE WORK AND THANK YOU 2395 01:50:39,960 --> 01:50:41,560 FOR YOUR KIND ATTENTION. 2396 01:50:41,560 --> 01:50:43,600 >> THANK YOU, PETER, FOR KEEPING 2397 01:50:43,600 --> 01:50:45,840 ON YOUR TIME AND AN EXCELLENT 2398 01:50:45,840 --> 01:50:46,880 TALK. 2399 01:50:46,880 --> 01:50:57,520 WE'LL TAKE A BREAK? 2400 01:50:57,520 --> 01:51:00,400 SAY THANK YOU FOR THE ORGANIZER 2401 01:51:00,400 --> 01:51:04,000 FOR THIS OPPORTUNITY, ESPECIALLY 2402 01:51:04,000 --> 01:51:07,640 ARUN FOR INTRODUCING ME TO THIS 2403 01:51:07,640 --> 01:51:09,040 COMMUNITY AND I HAVE TO SAY IT'S 2404 01:51:09,040 --> 01:51:14,200 A WONDERFUL EXPERIENCE SO FAR TO 2405 01:51:14,200 --> 01:51:16,160 LEARN ABOUT THIS FROM THE 2406 01:51:16,160 --> 01:51:18,840 PERSPECTIVE OF PATIENTS AND 2407 01:51:18,840 --> 01:51:21,680 FAMILY TO THE INITIAL FAMILY. 2408 01:51:21,680 --> 01:51:23,960 AS WAS MENTIONED I AM A 2409 01:51:23,960 --> 01:51:28,760 BIOLOGIST, SO I JUST SAW MY LAB 2410 01:51:28,760 --> 01:51:32,600 ABOUT A YEAR AGO, JUST WANT TO 2411 01:51:32,600 --> 01:51:34,280 TELL YOU A LITTLE BIT ABOUT THE 2412 01:51:34,280 --> 01:51:36,800 MANY SKILLS BIOLOGISTS HAVE 2413 01:51:36,800 --> 01:51:40,280 FOCUSED IN THE LABS WHICH REALLY 2414 01:51:40,280 --> 01:51:43,040 TO UNDERSTAND HOW PROTEIN 2415 01:51:43,040 --> 01:51:47,200 FUNCTION OR HOW PROTEINS BEHAVE 2416 01:51:47,200 --> 01:51:53,000 IN THEIR NATIVE ENVIRONMENT. SO 2417 01:51:53,000 --> 01:51:55,400 STRANGER IN THE CELL. SO 2418 01:51:55,400 --> 01:51:58,600 HOPEFULLY WE CAN PROVIDE SOME 2419 01:51:58,600 --> 01:52:01,360 INFORMATION SPECIAL ABOUT THIS 2420 01:52:01,360 --> 01:52:05,440 PROTEINS INVOLVING HSPD HOW THIS 2421 01:52:05,440 --> 01:52:06,960 PROTEIN NORMALLY FUNCTIONS 2422 01:52:06,960 --> 01:52:09,080 INSIDE THE CELL AND WE CAN START 2423 01:52:09,080 --> 01:52:10,640 TO UNDERSTAND HOW THEY'RE 2424 01:52:10,640 --> 01:52:12,800 REPAIRED AND HOPEFULLY WE CAN -- 2425 01:52:12,800 --> 01:52:15,800 THE KNOWLEDGE CAN LATER BE 2426 01:52:15,800 --> 01:52:20,040 APPLIED TO DEVELOP SOME 2427 01:52:20,040 --> 01:52:25,320 THERAPEUTIC AGENTSME AGENTSMENT. I WANT 2428 01:52:25,320 --> 01:52:29,320 TO INTRODUCE YOU HUMAN CELLS ARE 2429 01:52:29,320 --> 01:52:31,680 HIGHLY COMPARTMENTALIZED, DATA 2430 01:52:31,680 --> 01:52:37,120 INTO THE HUMAN CELLS, LOOKING AT 2431 01:52:37,120 --> 01:52:39,120 1.4 CUBIC MICRONS ABOUT 4.1 2432 01:52:39,120 --> 01:52:41,320 PERCENT OF CELLS. I HOPE YOU 2433 01:52:41,320 --> 01:52:43,160 CAN APPRECIATE THE HUMAN CELLS 2434 01:52:43,160 --> 01:52:46,320 ARE REALLY HIGHLY COMPONENT 2435 01:52:46,320 --> 01:52:46,960 WHEREAS EACH INDIVIDUALNAL LIS 2436 01:52:46,960 --> 01:52:50,360 FROM THE FACTORY THAT HAS HIGHLY 2437 01:52:50,360 --> 01:52:51,880 SPECIFIC FUNCTION, AND THIS IS 2438 01:52:51,880 --> 01:52:57,200 REALLY THE WHOLE MODEL ALLOW US 2439 01:52:57,200 --> 01:53:00,960 FROM SO MANY DIFFERENT OPTIONS, 2440 01:53:00,960 --> 01:53:04,920 BUT THIS IS ALSO POSE A VERY 2441 01:53:04,920 --> 01:53:08,800 CHALLENGING TO THE CELL HOW 2442 01:53:08,800 --> 01:53:13,120 USING A BIT OF RAW MATERIAL AND 2443 01:53:13,120 --> 01:53:15,080 HOW DO THEY DISTRIBUTE ALL 2444 01:53:15,080 --> 01:53:17,360 DIFFERENT PRODUCTS IN HERE FOR 2445 01:53:17,360 --> 01:53:19,200 PERFORMANCE SO THE CELL CAN 2446 01:53:19,200 --> 01:53:22,920 FUNCTION AS A UNIT. THIS IS 2447 01:53:22,920 --> 01:53:26,360 REALLY -- SO THE QUESTION HOW DO 2448 01:53:26,360 --> 01:53:38,200 CELL SOLVE INTER ORGANELLE LODGE 2449 01:53:38,200 --> 01:53:38,920 NI 2450 01:53:38,920 --> 01:53:40,520 LOGISTIC ISSUES, EVEN IN CELLS 2451 01:53:40,520 --> 01:53:42,080 IT'S THE SAME THING IF YOU HAVE 2452 01:53:42,080 --> 01:53:45,200 SOME LOGISTICS THAT YOU MIGHT 2453 01:53:45,200 --> 01:53:47,160 HAVE SOME DETRIMENTAL TO THE 2454 01:53:47,160 --> 01:53:51,720 CELL FUNCTION AND I'M GOING TO 2455 01:53:51,720 --> 01:53:54,040 SHARE A STORY INVOLVING THAT YOU 2456 01:53:54,040 --> 01:53:59,440 CAN FUNCTION LOGISTIC TO 2457 01:53:59,440 --> 01:54:03,480 FACILITATE BETWEEN FACILITY. SO 2458 01:54:03,480 --> 01:54:05,400 WHEN I STARTED THIS PROJECT I 2459 01:54:05,400 --> 01:54:07,280 WAS VERY VERY INTERESTING THAT 2460 01:54:07,280 --> 01:54:10,720 THIS START, BECAUSE IF YOU LOOK 2461 01:54:10,720 --> 01:54:15,720 AT TOPOLOGY THIS DOMAIN MEMBER 2462 01:54:15,720 --> 01:54:18,800 PROTEIN HAS MEMBRANE ASSOCIATION 2463 01:54:18,800 --> 01:54:22,360 TO HAVE HUGE CHUNK OF INTER 2464 01:54:22,360 --> 01:54:24,240 GREGS THAT INVOLVE 2465 01:54:24,240 --> 01:54:27,520 MICROORGANISM. SO I WAS VERY 2466 01:54:27,520 --> 01:54:29,840 NAÏVE IN ASKING THESE QUESTIONS. 2467 01:54:29,840 --> 01:54:36,000 TO DO THAT WE ACTUALLY HAVE THIS 2468 01:54:36,000 --> 01:54:37,360 PROTE 2469 01:54:37,360 --> 01:54:38,600 PROTEIN, AS YOU CAN SEE THE 2470 01:54:38,600 --> 01:54:45,320 IMAGE HERE YOU'RE LOOKING AT 2471 01:54:45,320 --> 01:54:50,400 M1SPASTIN EXPRESSING, AND THIS 2472 01:54:50,400 --> 01:54:55,520 IS AN HELA CELLS, LOCALIZED 2473 01:54:55,520 --> 01:54:57,240 MARKERS BOTH IN STEADY STATE AND 2474 01:54:57,240 --> 01:55:00,680 IN A STATE TRIGGERED A LITTLE 2475 01:55:00,680 --> 01:55:08,680 BIT OF BIOLOGY. SO THE -- SO 2476 01:55:08,680 --> 01:55:13,360 REALLY JUST TERMINAL MOTIF 2477 01:55:13,360 --> 01:55:16,560 FUNCTIONAL FOR DROPLETS HAVE A 2478 01:55:16,560 --> 01:55:20,000 FRAGMENT OF THE PATH THEY ARE 2479 01:55:20,000 --> 01:55:29,360 LOCALIZED TO THE FOCALIZED A 2480 01:55:29,360 --> 01:55:32,880 LITTLE INTRODUCTION DROPLETS ARE 2481 01:55:32,880 --> 01:55:34,160 INSIDE EACH INDIVIDUAL CELLS SO 2482 01:55:34,160 --> 01:55:36,640 AS WAS MENTIONED IN THE TALK. 2483 01:55:36,640 --> 01:55:38,480 SO AGAIN THIS IS ONLY A 2484 01:55:38,480 --> 01:55:39,680 WAREHOUSE SO YOU CAN THINK ABOUT 2485 01:55:39,680 --> 01:55:43,240 IT AS A REFRIGERATE NOR YOUR 2486 01:55:43,240 --> 01:55:46,280 HOUSE SO YOU KIND OF STORE THE 2487 01:55:46,280 --> 01:55:49,560 DROPLETS. SO FOR THE CELLS YOU 2488 01:55:49,560 --> 01:55:53,400 USE THIS MATERIAL YOU HAVE 2489 01:55:53,400 --> 01:55:58,000 TRAFFIC PROCESSES. 2490 01:55:58,000 --> 01:56:01,000 AND WE KNOW THIS TRAFFIC HAS 2491 01:56:01,000 --> 01:56:04,600 OCCURRED AT THIS ORGANELLE 2492 01:56:04,600 --> 01:56:10,240 COMPACT CITE. ADD 20 NANOS OFF 2493 01:56:10,240 --> 01:56:15,280 TO ALLOW THE RECORD AND 2494 01:56:15,280 --> 01:56:16,840 EFFICIENT MATERIAL. IT'S BETTER 2495 01:56:16,840 --> 01:56:20,800 THAN SITTING BETWEEN THE LIPID 2496 01:56:20,800 --> 01:56:22,600 DROPLETS TO FACILITATE THIS 2497 01:56:22,600 --> 01:56:24,280 LOGISTICALLY. SO HERE ARE SOME 2498 01:56:24,280 --> 01:56:25,920 EVIDENCE: FIRST SO NOW YOU'RE 2499 01:56:25,920 --> 01:56:31,000 LOOKING AT A CELL THAT LABELED 2500 01:56:31,000 --> 01:56:33,280 LIKE HERE AND HERE AND YOU SEE 2501 01:56:33,280 --> 01:56:35,480 THESE ARE THE BASAL INTERACTION 2502 01:56:35,480 --> 01:56:37,320 OR BASAL COMPOUND SITUATION 2503 01:56:37,320 --> 01:56:41,320 INSIDE THE CELL. AND ONCE WE 2504 01:56:41,320 --> 01:56:44,000 OVER EXPRESS YOU CAN START TO 2505 01:56:44,000 --> 01:56:47,960 SEE A CLUSTER OF HIGHLY SOC YAW 2506 01:56:47,960 --> 01:56:51,120 ACTIVE WITH THE DROPLETS. 2507 01:56:51,120 --> 01:56:53,360 SURELY INSIDE OF HERE. I SHOULD 2508 01:56:53,360 --> 01:56:55,720 QUANTIFY BY USING, WASN'T 2509 01:56:55,720 --> 01:56:57,400 OVERLAPPING, YOU CAN SEE 2510 01:56:57,400 --> 01:57:00,680 INCREASE OF THE DROPLETS ACROSS 2511 01:57:00,680 --> 01:57:02,280 SOME ASSOCIATION DURING M. 2512 01:57:02,280 --> 01:57:06,040 >> CHI-LUN CHANG: SPASTIN. 2513 01:57:06,040 --> 01:57:09,560 THIS IS TRADITIONAL IMAGING TO 2514 01:57:09,560 --> 01:57:12,840 SHOW THESE TWO ORGANELLES 2515 01:57:12,840 --> 01:57:15,000 DROPLET HERE, DROPLET HERE, 2516 01:57:15,000 --> 01:57:16,440 FORMING THIS INTER FACE BETWEEN 2517 01:57:16,440 --> 01:57:20,280 EACH OTHER SO THIS IS REALLY A 2518 01:57:20,280 --> 01:57:25,360 COMPACT WE ALSO MONITOR USING 2519 01:57:25,360 --> 01:57:31,800 TIME LAPSE MICROSCOPY TO MONITOR 2520 01:57:31,800 --> 01:57:33,200 THE COMPOUND. AS YOU CAN SEE 2521 01:57:33,200 --> 01:57:35,440 THIS IS A CONTROL SWACHLTHS SO 2522 01:57:35,440 --> 01:57:37,360 YOU CAN SEE THERE ARE COMPOUND 2523 01:57:37,360 --> 01:57:39,520 FORMATIONS SHOWN HERE AND HERE. 2524 01:57:39,520 --> 01:57:41,960 THIS IS ALSO STABLE COMPOUNDS 2525 01:57:41,960 --> 01:57:45,880 LIKE THAT EACH ORGANELLE OVER A 2526 01:57:45,880 --> 01:57:48,240 PERIOD OF TIME. AGAIN WE CAN 2527 01:57:48,240 --> 01:57:50,080 QUANTIFY THE DURATION HERE AND 2528 01:57:50,080 --> 01:57:52,680 THIS IS OVER EXPRESSING CELLS 2529 01:57:52,680 --> 01:57:54,160 NOW YOU CAN SEE ALL THIS 2530 01:57:54,160 --> 01:57:57,240 ASSOCIATION HIGHLY STABILIZED. 2531 01:57:57,240 --> 01:58:00,800 ALSO HOW THEY STAY TOGETHER. 2532 01:58:00,800 --> 01:58:06,040 AND WE CAN ALSO USE TO KNOCK 2533 01:58:06,040 --> 01:58:11,600 DOWN THIS IMPRESSION AND GET A 2534 01:58:11,600 --> 01:58:15,680 REDUCTION. SO THAT FASTING IS A 2535 01:58:15,680 --> 01:58:18,600 TYPE FOR LIPID DROPLETS. SO AS 2536 01:58:18,600 --> 01:58:23,480 I MENTIONED, SO WE ALSO FURTHER 2537 01:58:23,480 --> 01:58:26,560 IDENTIFY A REGION THAT INTERACT 2538 01:58:26,560 --> 01:58:30,600 WITH THE PROCESS ON THE 2539 01:58:30,600 --> 01:58:35,720 STAFFING, SO WE NAME THIS FOR 2540 01:58:35,720 --> 01:58:36,240 INTERA 2541 01:58:36,240 --> 01:58:39,400 INTERACTING, SO HERE DUE TO 2542 01:58:39,400 --> 01:58:44,080 TIME, TAG THIS PXI REGION, 2543 01:58:44,080 --> 01:58:47,560 SIMPLY HELPING A REGION FORM PXI 2544 01:58:47,560 --> 01:58:52,040 REGION, THIS IS FAIRLY LOCALIZED 2545 01:58:52,040 --> 01:58:54,840 DUE TO THE LIPID DROPLET WHERE 2546 01:58:54,840 --> 01:58:56,480 YOU CAN SEE THE ORGANIZATION 2547 01:58:56,480 --> 01:58:58,200 HERE IN THIS PROTEIN AND THE 2548 01:58:58,200 --> 01:59:01,840 LIPID DROPLET. AND ON LIPID 2549 01:59:01,840 --> 01:59:05,320 DROPLET THIS CAN ACTUALLY 2550 01:59:05,320 --> 01:59:07,760 ATTRACT OR BIND THROUGH A REGION 2551 01:59:07,760 --> 01:59:11,200 NOW YOU CAN SEE THERE'S MANY 2552 01:59:11,200 --> 01:59:14,440 MANY ASSOCIATED WITH THE LIPID 2553 01:59:14,440 --> 01:59:17,080 DROPLETS. AGAIN THIS IS A -- WE 2554 01:59:17,080 --> 01:59:19,840 DO SEE A SIGNIFICANT INDUCTION 2555 01:59:19,840 --> 01:59:21,960 OF THIS LIPID DROPLET 2556 01:59:21,960 --> 01:59:25,920 OVERLAPPING THIS PXI REGION. 2557 01:59:25,920 --> 01:59:31,000 AND WE WONDER ABOUT THE FATTY 2558 01:59:31,000 --> 01:59:33,360 ACID IN THESE CELL TWO HIGHLY 2559 01:59:33,360 --> 01:59:35,240 RELEVANT FATTY ACIDS BUT TO DO 2560 01:59:35,240 --> 01:59:38,800 THAT WE ACTUALLY DIVIDE THE 2561 01:59:38,800 --> 01:59:40,360 FATTY ACID WHERE WE JUST LABEL 2562 01:59:40,360 --> 01:59:43,400 THE CELL WITH THIS FATTY ACID 2563 01:59:43,400 --> 01:59:45,520 AND SHOW MODIFY AND THEN WE 2564 01:59:45,520 --> 01:59:49,000 ACTUALLY LOCALIZED TO LIPID 2565 01:59:49,000 --> 01:59:51,080 DROPLETS FIRST THEN WASH THIS 2566 01:59:51,080 --> 01:59:54,800 INSIDE OUT AND START MONITOR THE 2567 01:59:54,800 --> 01:59:59,800 FATE OF THE. THEN HERE IS JUST 2568 01:59:59,800 --> 02:00:01,320 WIDESPREAD SHOWING AFTER THE 2569 02:00:01,320 --> 02:00:04,680 POST OF THIS MBT FATTY ACID YOU 2570 02:00:04,680 --> 02:00:10,600 CAN SEE THE LOCALIZED FATTY ACID 2571 02:00:10,600 --> 02:00:11,680 STRUCTURE. AND THIS IS M1 2572 02:00:11,680 --> 02:00:14,760 ACTUALLY YOU CAN SEE THERE'S 2573 02:00:14,760 --> 02:00:16,840 MANY OF THIS WIDESPREAD HIGHLY 2574 02:00:16,840 --> 02:00:19,040 SOC WAITED WITH THIS LIQUID 2575 02:00:19,040 --> 02:00:22,480 DROPLETS. SO NOW LOOKING AT ONE 2576 02:00:22,480 --> 02:00:25,880 HOUR AFTER THE DIAL STILL YOU 2577 02:00:25,880 --> 02:00:29,160 SEE MANY OF THESE STILL REMAIN 2578 02:00:29,160 --> 02:00:32,680 INSIDE THE LIPID DROPLETS 2579 02:00:32,680 --> 02:00:34,280 LOCALIZED. BUT AFTER TWO HOURS 2580 02:00:34,280 --> 02:00:37,280 LATER NOW YOU CAN START TO SEE 2581 02:00:37,280 --> 02:00:40,120 THIS FATTY ACID TRAFFIC INSIDE 2582 02:00:40,120 --> 02:00:42,640 NOW YOU CAN SEE A LOCALIZATION 2583 02:00:42,640 --> 02:00:44,960 OF THE SIGNALS AT THE SAME TIME. 2584 02:00:44,960 --> 02:00:48,000 SO WE CAN AGAIN MONITOR OR 2585 02:00:48,000 --> 02:00:51,240 QUANTIFY THIS RELATIVELY 2586 02:00:51,240 --> 02:00:54,880 INTENSIVELY OF THE FATTY ACID 2587 02:00:54,880 --> 02:00:59,880 YOU CAN SEE THE SATURATION YOU 2588 02:00:59,880 --> 02:01:03,040 STUDY INCREASE OF THE FATTY ACID 2589 02:01:03,040 --> 02:01:05,200 INSIDE BECAUSE COMPARED TO CON 2590 02:01:05,200 --> 02:01:06,520 TROLL THERE'S NOT MUCH TRAFFIC. 2591 02:01:06,520 --> 02:01:10,800 AND THEN WE -- WE WONDER WHETHER 2592 02:01:10,800 --> 02:01:14,120 THIS BEHAVIOR OR THIS LOGISTICS 2593 02:01:14,120 --> 02:01:15,800 INVOLVING M1 IS ACTUALLY 2594 02:01:15,800 --> 02:01:17,000 RELEVANT TO THE SITUATION. SO I 2595 02:01:17,000 --> 02:01:21,320 THINK I'LL INTRODUCE THE MOST 2596 02:01:21,320 --> 02:01:28,280 COMMON CAUSE OF THIS MUTANT THE 2597 02:01:28,280 --> 02:01:31,480 MUTATION. SO WE ACTUALLY ARE 2598 02:01:31,480 --> 02:01:33,600 LOOKING AT A COMPACT FORMATION. 2599 02:01:33,600 --> 02:01:36,040 SO YOU CAN SEE THE MUTANT 2600 02:01:36,040 --> 02:01:41,200 EXPRESSING CELL MAKING THE 2601 02:01:41,200 --> 02:01:43,040 COMPACT, SO THIS IS JUST A 2602 02:01:43,040 --> 02:01:46,920 COMMUNICATION HERE YOU SEE THE 2603 02:01:46,920 --> 02:01:47,600 SIGNIFICANT DIFFERENCE BETWEEN 2604 02:01:47,600 --> 02:01:48,360 THE TWO. 2605 02:01:48,360 --> 02:01:51,800 AND ALSO THE FATTY ACID TRAFFIC 2606 02:01:51,800 --> 02:01:53,360 IS ALSO YOU CAN SEE THIS JUST 2607 02:01:53,360 --> 02:01:55,840 THE DATA IS SHOWN IN THE 2608 02:01:55,840 --> 02:01:57,800 PREVIOUS SLIDE AND THE MUTANT IT 2609 02:01:57,800 --> 02:02:00,000 COULDN'T REALLY TRAFFIC THE 2610 02:02:00,000 --> 02:02:03,600 FATTY ACID FROM THE DROPLETS. 2611 02:02:03,600 --> 02:02:06,840 AND HOW IS THIS RELEVANT TO 2612 02:02:06,840 --> 02:02:12,040 OTHER THINGS IN THE DEGEN RAGS. 2613 02:02:12,040 --> 02:02:14,560 SO WE KNOW FATTY ACID CAN BE 2614 02:02:14,560 --> 02:02:17,920 THROUGH ACTIVITIES, SO IT CAN BE 2615 02:02:17,920 --> 02:02:23,480 PROACTIVE SO WE'RE LOOK AT WHAT 2616 02:02:23,480 --> 02:02:26,000 IS PROJECT TILE FROM THE LIPID 2617 02:02:26,000 --> 02:02:30,000 BUILDUP. HERE A FLUORESCENT 2618 02:02:30,000 --> 02:02:33,320 ASSAY, SO INVOLVING FATTY OR 2619 02:02:33,320 --> 02:02:34,560 CONSTRUCT FROM THE DIVISION YOU 2620 02:02:34,560 --> 02:02:38,360 CAN SEE THAT REVIEWS OF THE 2621 02:02:38,360 --> 02:02:41,320 BUILDUP OF THE LIPIDS TO A 2622 02:02:41,320 --> 02:02:42,600 DEGREE IN THE SAME LINE THAT YOU 2623 02:02:42,600 --> 02:02:46,120 CAN ACTUALLY START TO SEE LIPID 2624 02:02:46,120 --> 02:02:48,080 DROPLETS COMPACT INCREASE UNDER 2625 02:02:48,080 --> 02:02:50,240 THE COMPOSITION SUGGESTING THAT 2626 02:02:50,240 --> 02:02:55,280 THIS PLATFORM AND FATTY ACID 2627 02:02:55,280 --> 02:02:57,000 TRAFFICKING INVOLVING TO PROTECT 2628 02:02:57,000 --> 02:03:00,200 OR ELIMINATE THE LIPID. 2629 02:03:00,200 --> 02:03:04,200 AND SO ACTUALLY NOT A SURPRISE 2630 02:03:04,200 --> 02:03:06,480 INTRO TUESDAY MUTATION THAT 2631 02:03:06,480 --> 02:03:07,920 COULD MAKE THE COMPACT PURSUANT 2632 02:03:07,920 --> 02:03:12,200 TO FATTY ACID DROPLETS YOU 2633 02:03:12,200 --> 02:03:13,880 UNDERSTAND THEY BUILDUP OF THE 2634 02:03:13,880 --> 02:03:15,440 ENVIRONMENT. SO HERE'S WHAT WE 2635 02:03:15,440 --> 02:03:19,080 THINK IS GOING ON IS ACTUALLY 2636 02:03:19,080 --> 02:03:21,080 SITTING IN BETWEEN INTERFACE OF 2637 02:03:21,080 --> 02:03:23,200 LIPID DROPLETS TO FACILITATE 2638 02:03:23,200 --> 02:03:27,600 FATTY ACID TRAFFICKING AND SOME 2639 02:03:27,600 --> 02:03:30,000 OF THE FATTY ACID GET TRAFFIC TO 2640 02:03:30,000 --> 02:03:35,000 GO OUT AND FURTHER DEGRADATION 2641 02:03:35,000 --> 02:03:38,600 AND IF YOU HAVE HYPO GENIC 2642 02:03:38,600 --> 02:03:42,200 MUTANT WE HAVE THE BUILDUP OF 2643 02:03:42,200 --> 02:03:44,440 LIPIDS PROTEINS LIPID DROPLETS 2644 02:03:44,440 --> 02:03:49,320 AND LIKELY MAY CAUSE NEURO 2645 02:03:49,320 --> 02:03:56,200 STRESS. EMPHASIZE ABOUT 2646 02:03:56,200 --> 02:04:05,960 THINKING THEY INVOLVING THE 2647 02:04:05,960 --> 02:04:07,720 ORGANELLE BIOLOGY AND INVOLVING 2648 02:04:07,720 --> 02:04:11,720 LIPIDS AND FATTY ACID 2649 02:04:11,720 --> 02:04:13,360 HOMEOSTASIS HERE JUST A LITTLE 2650 02:04:13,360 --> 02:04:19,000 FEW PROTEINS HAVE A LASTING SEEN 2651 02:04:19,000 --> 02:04:24,680 THE LIPIDS FATTY ACID HERE ARE 2652 02:04:24,680 --> 02:04:27,960 ISSUE TO AND ALSO FASTING AND 2653 02:04:27,960 --> 02:04:31,000 PURSUANT TO FATTY ACID 2654 02:04:31,000 --> 02:04:33,320 TRAFFICKING TO THE CHROME SOEMS 2655 02:04:33,320 --> 02:04:37,320 TO ELIMINATING THE BUILDUP AND 2656 02:04:37,320 --> 02:04:49,760 ALSO FACILITATE SO WE HAVE 2657 02:04:49,760 --> 02:04:53,400 EVIDENCE TO SUGGEST THAT THE MAY 2658 02:04:53,400 --> 02:04:56,400 LIKELY INVOLVE THIS MORE FOE 2659 02:04:56,400 --> 02:04:59,040 GENESIS TO SUPPORT FATTY ACID 2660 02:04:59,040 --> 02:05:00,400 TRAFFICKING ALSO LIMITED TO 2661 02:05:00,400 --> 02:05:04,200 SUPPORT THE IDEA THAT THE DOMAIN 2662 02:05:04,200 --> 02:05:09,000 CAN ACTUALLY FORM A COMPILATION 2663 02:05:09,000 --> 02:05:12,600 OF THE CULTURE TO EXPOSE THE PXI 2664 02:05:12,600 --> 02:05:15,920 REGION FOR -- SORRY -- FOR THE 2665 02:05:15,920 --> 02:05:19,800 LIPID DROPLET PROCESS AND 2666 02:05:19,800 --> 02:05:21,480 COMPACT. AND IN OTHER FRONTS 2667 02:05:21,480 --> 02:05:23,440 ACTUALLY WE ARE DEVELOPING FROM 2668 02:05:23,440 --> 02:05:25,560 TOOLS AND ACTUALLY COMPOUND AND 2669 02:05:25,560 --> 02:05:32,520 WE WANT TO USE THE HELP US UNDER 2670 02:05:32,520 --> 02:05:35,520 STON HOW IT IS RELEVANT TO 2671 02:05:35,520 --> 02:05:38,720 PHYSIOLOGY AND HOW THEY'RE 2672 02:05:38,720 --> 02:05:39,240 IMPAIRED. 2673 02:05:39,240 --> 02:05:44,000 I WANT TO THANK MY PH.D. -- 2674 02:05:44,000 --> 02:05:47,760 SORRY ADVISOR. SO THIS WORK WAS 2675 02:05:47,760 --> 02:05:50,600 DONE IN HER LAB WITH A GROUP OF 2676 02:05:50,600 --> 02:05:53,640 MANY PEOPLE. I WANT TO SAY 2677 02:05:53,640 --> 02:05:56,160 THANK YOU TO FOR THE MANY 2678 02:05:56,160 --> 02:05:58,040 DISCUSSIONS AND I HOPE TO 2679 02:05:58,040 --> 02:06:01,080 CONTINUE THE DISCUSSIONS AND TRY 2680 02:06:01,080 --> 02:06:03,480 TO MOVE FORWARD TO THE 2681 02:06:03,480 --> 02:06:06,040 THERAPEUTICS IN THIS FIELD. AND 2682 02:06:06,040 --> 02:06:09,200 ALSO IN RESEARCH PAPERS IN MY 2683 02:06:09,200 --> 02:06:13,360 LAB AT SAINT JUDE AND MY TWO 2684 02:06:13,360 --> 02:06:16,040 SENIOR PERSONNEL AND ALSO THE 2685 02:06:16,040 --> 02:06:17,800 FOUNDING AND THANK YOU I'M 2686 02:06:17,800 --> 02:06:21,800 LOOKING FORWARD TO THE Q AND A 2687 02:06:21,800 --> 02:06:22,000 SESSION. 2688 02:06:22,000 --> 02:06:25,360 >> THANK YOU DR. CHANG. SO OUR 2689 02:06:25,360 --> 02:06:29,360 NEXT SPEAKER IS ERIC, DR. 2690 02:06:29,360 --> 02:06:29,600 SAMARUT. 2691 02:06:29,600 --> 02:06:30,600 >> ERIC SAMARUT: YES, THANK 2692 02:06:30,600 --> 02:06:31,800 YOU. I'M SHARING MY SCREEN NOW. 2693 02:06:31,800 --> 02:06:35,160 CAN YOU SEE IT HERE? 2694 02:06:35,160 --> 02:06:35,600 >> YES. 2695 02:06:35,600 --> 02:06:38,600 >> ERIC SAMARUT: GRAY. WELL. 2696 02:06:38,600 --> 02:06:41,360 THANK YOU VERY MUCH. SO THANK 2697 02:06:41,360 --> 02:06:46,160 YOU FIRST TO INVITING ME. I'M A 2698 02:06:46,160 --> 02:06:48,000 SPECIALIST AND I LEARNED A LOT 2699 02:06:48,000 --> 02:06:49,040 TODAY AND YESTERDAY AND TODAY 2700 02:06:49,040 --> 02:06:50,360 I'M GOING TO SHOW YOU WHAT WE'VE 2701 02:06:50,360 --> 02:06:54,640 BEEN DOING IN A COMPANY I 2702 02:06:54,640 --> 02:06:57,360 COFOUNDED KOLD MODELIS WHERE 2703 02:06:57,360 --> 02:06:59,160 WE'RE PLAYING WITH IN VIVO 2704 02:06:59,160 --> 02:07:05,000 BIOLOGY AND DATA SCIENCE AND 2705 02:07:05,000 --> 02:07:08,000 TRYING TO IDENTIFY MECHANIC 2706 02:07:08,000 --> 02:07:09,120 INSIGHTS AND SPEED UP DRUG 2707 02:07:09,120 --> 02:07:11,880 DISCOVERY FOR RARE DISEASES. 2708 02:07:11,880 --> 02:07:13,320 AS A FIRST DISCUSSION SLIDE I'M 2709 02:07:13,320 --> 02:07:16,800 WEARING MULTIPLE HATS. I'M A 2710 02:07:16,800 --> 02:07:21,160 RESEARCHER OUT OF UNIVERSITY OF 2711 02:07:21,160 --> 02:07:23,360 MONTREAL. FOCUSSING ON GENOMICS 2712 02:07:23,360 --> 02:07:25,920 OF RARE DISORDERS BUT I'M ALSO A 2713 02:07:25,920 --> 02:07:27,760 COFOUNDER OF MULTIPLE BIO TEXT 2714 02:07:27,760 --> 02:07:29,440 AND I'M GOING TO SHOW YOU THE 2715 02:07:29,440 --> 02:07:31,640 WORK THAT WE HAVE BEEN -- WE ARE 2716 02:07:31,640 --> 02:07:35,000 DOING AT MODELIS THIS BIOTECH 2717 02:07:35,000 --> 02:07:36,800 COMPANY IS REALLY WILLING TO 2718 02:07:36,800 --> 02:07:39,120 ACCELERATE DRUG DISCOVERY FOR 2719 02:07:39,120 --> 02:07:41,360 FOCUSING ON RARE GENETIC 2720 02:07:41,360 --> 02:07:41,800 DISORDERS. 2721 02:07:41,800 --> 02:07:43,800 AND SO I'M SURE YOU WON'T LEARN 2722 02:07:43,800 --> 02:07:45,320 MUCH FROM THESE SLIDES, BUT YOU 2723 02:07:45,320 --> 02:07:46,600 ALL KNOW THAT RARE IS NOT RARE 2724 02:07:46,600 --> 02:07:48,800 AND SO THIS IS REALLY THE 2725 02:07:48,800 --> 02:07:50,240 PROBLEM THAT WE ARE TRYING TO 2726 02:07:50,240 --> 02:07:54,520 TACKLE AT MODELIS IS HOW CAN WE 2727 02:07:54,520 --> 02:07:56,400 JUST BRING ANSWERS OR TRY TO -- 2728 02:07:56,400 --> 02:07:58,800 TO START PROJECTS FOR ALL THESE 2729 02:07:58,800 --> 02:08:00,600 ORPHAN RARE DISEASES, SO YOU 2730 02:08:00,600 --> 02:08:03,360 KNOW THAT AMONG THE 700 MILLION 2731 02:08:03,360 --> 02:08:04,120 PEOPLE WORLD WIDE CONNECTED BY 2732 02:08:04,120 --> 02:08:07,040 RARE DISEASES HALF OF THEM ARE 2733 02:08:07,040 --> 02:08:10,200 CHILDREN, AND MANY OF THESE 2734 02:08:10,200 --> 02:08:12,800 DISEASES ARE REALLY LIFE 2735 02:08:12,800 --> 02:08:14,760 THREATENING. AND ONLY FIVE 2736 02:08:14,760 --> 02:08:17,400 PERCENT OF THEM HAVE SO-CALLED 2737 02:08:17,400 --> 02:08:19,320 TREATMENTS LEAVING 95 PERCENT OF 2738 02:08:19,320 --> 02:08:21,640 THESE DISEASES BEHIND AS ORPHAN 2739 02:08:21,640 --> 02:08:23,280 RARE DISEASES. 2740 02:08:23,280 --> 02:08:30,040 AT MODELIS WHAT WE THINKS IS 2741 02:08:30,040 --> 02:08:32,400 IMPAIRING DRUG DEVELOPMENT THE 2742 02:08:32,400 --> 02:08:33,640 DISEASES ARE SO RARE SOME ARE 2743 02:08:33,640 --> 02:08:35,600 EVEN MORE RARE THAN OTHERS, THAT 2744 02:08:35,600 --> 02:08:37,640 WE -- THE FACT THAT WE DON'T 2745 02:08:37,640 --> 02:08:38,960 KNOW MUCH ABOUT THE MECHANISM 2746 02:08:38,960 --> 02:08:41,360 AND WE DON'T KNOW EXACTLY WHAT 2747 02:08:41,360 --> 02:08:44,520 ARE THE UNDERLYING MECHANISM 2748 02:08:44,520 --> 02:08:45,960 IMPAIRING DEVELOPMENT TWO WAYS, 2749 02:08:45,960 --> 02:08:48,000 FIRST ONE REALLY LEADS TO 2750 02:08:48,000 --> 02:08:49,360 FAILURE IN CLINICAL TRIALS 2751 02:08:49,360 --> 02:08:51,840 BECAUSE MOST DRUGS THAT DO NOT 2752 02:08:51,840 --> 02:08:54,680 MAKE IT THEY FAIL FOR 2753 02:08:54,680 --> 02:08:56,040 PHARMACOLOGICAL REASON, THEY DO 2754 02:08:56,040 --> 02:09:01,400 NOT FAIL FOR PHARMACOLOGICAL 2755 02:09:01,400 --> 02:09:03,400 REASONS BUT EFFICACY REASONS, 2756 02:09:03,400 --> 02:09:05,960 THAT CREATES LIMITS IN THE 2757 02:09:05,960 --> 02:09:08,160 FIELD. THERE ARE SO MANY 2758 02:09:08,160 --> 02:09:10,520 DISEASES WE CAN'T JUST INITIATE 2759 02:09:10,520 --> 02:09:13,000 LIKE TARGET-BASED DRUG DISCOVERY 2760 02:09:13,000 --> 02:09:13,680 PROGRAM ON THEM. 2761 02:09:13,680 --> 02:09:17,040 AT MODELIS WE BELIEVE THAT TO 2762 02:09:17,040 --> 02:09:20,400 THE ABILITY TO IDENTIFY DISEASE 2763 02:09:20,400 --> 02:09:22,240 RELEVANT MAKE THEM A FACTION 2764 02:09:22,240 --> 02:09:24,560 INSTRUMENTAL AND HELP IDENTIFY 2765 02:09:24,560 --> 02:09:26,880 BETTER DRUGS FASTER AND IT CAN 2766 02:09:26,880 --> 02:09:30,720 ENABLE US TO WORK AND DEVELOP 2767 02:09:30,720 --> 02:09:33,120 DRUGS -- DRUG AGREEMENT PROGRAM 2768 02:09:33,120 --> 02:09:34,680 FOR DISEASES THAT HAVE BEEN 2769 02:09:34,680 --> 02:09:35,480 UNTOUCHED SO FAR. 2770 02:09:35,480 --> 02:09:38,800 HOW DO WE DO THIS? YOU SEE WE 2771 02:09:38,800 --> 02:09:40,480 WORK EXCLUSIVELY IN VIVO BUT 2772 02:09:40,480 --> 02:09:41,800 USING SIMPLE ANIMAL MODELS 2773 02:09:41,800 --> 02:09:43,440 BECAUSE WE WANT TO GO FAST AND 2774 02:09:43,440 --> 02:09:46,600 I'LL EXPLAIN LATER WHY THEY ARE 2775 02:09:46,600 --> 02:09:47,000 INTERESTING. 2776 02:09:47,000 --> 02:09:52,120 SO WE WORK WITH MICROSCOPIC 2777 02:09:52,120 --> 02:09:55,680 WORMS AND ZEBRA FISH. GENETIC 2778 02:09:55,680 --> 02:09:58,480 MODELS OF DISEASES I'LL EXPLAIN 2779 02:09:58,480 --> 02:10:00,360 LATER BUT FROM THESE IN VIVO 2780 02:10:00,360 --> 02:10:06,200 MODEL WE ACQUIRE DATA AND THEN 2781 02:10:06,200 --> 02:10:07,360 WE FEED IMAGINARY ALGORITHM WE 2782 02:10:07,360 --> 02:10:09,320 DEVELOPED AT THE COMPANY. THESE 2783 02:10:09,320 --> 02:10:11,880 IMAGINARY ALGORITHM MAKE SENSE 2784 02:10:11,880 --> 02:10:13,680 ABOUT THESE BIOLOGICAL IN VIVO 2785 02:10:13,680 --> 02:10:15,680 DATA. AND THE END HERE IS TO 2786 02:10:15,680 --> 02:10:17,200 START TO FIND THE PATH FOR THESE 2787 02:10:17,200 --> 02:10:20,000 RARE DISEASES FOR WHICH WE HAVE 2788 02:10:20,000 --> 02:10:23,960 NO IDEA WHAT'S GOING WRONG. SO 2789 02:10:23,960 --> 02:10:26,640 THE IDEA IS CAN WE IDENTIFY NOT 2790 02:10:26,640 --> 02:10:29,320 ONLY MECHANISMS FOR CONFIRM SOME 2791 02:10:29,320 --> 02:10:31,800 PREDICTED MECHANISMS AND -- AND 2792 02:10:31,800 --> 02:10:33,320 VALIDATE THE FACT THAT THEY ARE 2793 02:10:33,320 --> 02:10:35,280 PLAYING AN IMPORTANT ROLE IN THE 2794 02:10:35,280 --> 02:10:45,000 ET KNOW GENICIERAL NI -- LET ME PRESENT TH ESE 2795 02:10:45,000 --> 02:10:47,680 YOU'VE HEARD ABOUT THEM 2796 02:10:47,680 --> 02:10:48,960 MICROSCOPIC WORMS VERY NICE 2797 02:10:48,960 --> 02:10:50,120 BECAUSE THEY ARE TINY, SMALL 2798 02:10:50,120 --> 02:10:53,000 CHEAP TO HANDLE AND TO RAISE, 2799 02:10:53,000 --> 02:10:57,360 AND THEY SHARE QUITE A LOT OF 2800 02:10:57,360 --> 02:10:59,440 OUR GENES I'LL GET INTO THAT 2801 02:10:59,440 --> 02:11:03,360 LATER WE ALSO WORK WITH ZEBRA 2802 02:11:03,360 --> 02:11:05,680 FISH MAYBE MORE POPULAR. SMALL 2803 02:11:05,680 --> 02:11:07,680 TROPICAL FISH WE DON'T WORK WITH 2804 02:11:07,680 --> 02:11:11,360 ADULTS BUT WORK WITH AGE AND 2805 02:11:11,360 --> 02:11:13,600 LARVA AND THEY ARE A CONVENIENT 2806 02:11:13,600 --> 02:11:14,240 MODEL BECAUSE THEY ARE 2807 02:11:14,240 --> 02:11:15,360 RELATIVELY CHEAP AND YOU CAN DO 2808 02:11:15,360 --> 02:11:18,920 A LOT OF THINGS ON THOSE GUYS. 2809 02:11:18,920 --> 02:11:22,240 SO AS I SAID THEY ARE EASY TO 2810 02:11:22,240 --> 02:11:23,680 HANDLE, MICROSCOPIC HERE ARE A 2811 02:11:23,680 --> 02:11:26,240 LOT OF ADULT WORMS IN THERE THAT 2812 02:11:26,240 --> 02:11:29,200 YOU CAN'T EVEN SEE WITH YOUR 2813 02:11:29,200 --> 02:11:31,400 BARE EYES AND ZEBRA FISH AS I 2814 02:11:31,400 --> 02:11:35,280 SAID NOT WORKING WITH ADULT BUT 2815 02:11:35,280 --> 02:11:38,760 EMBRYO AND LARVAE BECAUSE THREE 2816 02:11:38,760 --> 02:11:42,000 DAY OLD LARVAE IS FUNCTIONAL 2817 02:11:42,000 --> 02:11:44,000 MINI ADULT BRAIN MUSCLE 2818 02:11:44,000 --> 02:11:45,240 EVERYTHING IS ALREADY 2819 02:11:45,240 --> 02:11:45,680 FUNCTIONAL. 2820 02:11:45,680 --> 02:11:48,240 AND WHEN YOU LOOK AT THE GENETIC 2821 02:11:48,240 --> 02:11:50,560 CONTENT OF THESE GUYS, THAT'S 2822 02:11:50,560 --> 02:11:52,720 SURPRISING THAT WE SHARE ABOUT 2823 02:11:52,720 --> 02:11:55,200 65 PERCENT OF OTHER GENES WITH 2824 02:11:55,200 --> 02:11:59,680 WORMS, 84 WITH FISH AND 90 ISH 2825 02:11:59,680 --> 02:12:01,240 WITH RODENTS, BUT WHAT'S 2826 02:12:01,240 --> 02:12:04,280 INTERESTING IS THE AMOUNT OF 2827 02:12:04,280 --> 02:12:07,520 EGGS THAT THESE GUYS PRODUCE, 2828 02:12:07,520 --> 02:12:12,000 YOU CAN HAVE 150 EGGS PER DAY, 2829 02:12:12,000 --> 02:12:15,280 200 EGGS PER WEEK FOR FEMALE 2830 02:12:15,280 --> 02:12:19,000 FISH WHILE ONLY TEN ISH PUPS FOR 2831 02:12:19,000 --> 02:12:21,360 A MOUSE MODEL. SPEED IS HIGH IN 2832 02:12:21,360 --> 02:12:23,560 THAT STAGE ALTHOUGH THE 2833 02:12:23,560 --> 02:12:27,160 COMPLEXITY IS QUITE LOW COMPARED 2834 02:12:27,160 --> 02:12:28,680 TO WORKING WITH MAMMALIAN MODEL. 2835 02:12:28,680 --> 02:12:30,440 THAT BRINGS ME TO PRESENT THAT 2836 02:12:30,440 --> 02:12:32,280 MODEL ON THAT GRAPH I LIKE THIS 2837 02:12:32,280 --> 02:12:33,800 ONE BECAUSE IT'S LIKE PLOTTING 2838 02:12:33,800 --> 02:12:34,800 THE HIGH FREQUENCY OF THE 2839 02:12:34,800 --> 02:12:36,600 DIFFERENT MODELS WE'RE WORKING 2840 02:12:36,600 --> 02:12:38,280 WITH COMPARED TO THEIR 2841 02:12:38,280 --> 02:12:41,120 PHYSIOLOGICAL COMPLEXITY SO ON 2842 02:12:41,120 --> 02:12:45,280 ONE HAND YOU HAVE THESE IN VITRO 2843 02:12:45,280 --> 02:12:47,400 MODELS EXTRAORDINARY MATTER IN 2844 02:12:47,400 --> 02:12:49,320 FOR HIGH FRU TOWS STUDIES 2845 02:12:49,320 --> 02:12:51,920 PROBLEM WITH BIOLOGICAL 2846 02:12:51,920 --> 02:12:53,080 RELEVANCE DEPEND DEPENDING ON 2847 02:12:53,080 --> 02:12:55,840 THE DISEASE YOU WANT TO STUDY ON 2848 02:12:55,840 --> 02:12:58,000 THE OTHER SIDE YOU HAVE HUMAN 2849 02:12:58,000 --> 02:13:01,360 NON HUMAN PRIMATES RODENTS THEY 2850 02:13:01,360 --> 02:13:04,640 ARE VALUABLE PHYSIOLOGICALLY 2851 02:13:04,640 --> 02:13:07,080 COMPLEX BUT THE MODELS CAN BE 2852 02:13:07,080 --> 02:13:08,760 CHALLENGIN 2853 02:13:08,760 --> 02:13:12,480 CHALLENGING, YOU SEE ME COMING, 2854 02:13:12,480 --> 02:13:15,280 ADDING HERE, PHYSIOLOGICALLY 2855 02:13:15,280 --> 02:13:17,360 COMPLEX ENOUGH AND THEY ARE 2856 02:13:17,360 --> 02:13:19,080 INTERESTINGLY POSITIONED ON THAT 2857 02:13:19,080 --> 02:13:24,920 CRAFT TO BE MODEL TO WORK WITH. 2858 02:13:24,920 --> 02:13:26,640 SO THEY ARE ALSO VERY EASY TO 2859 02:13:26,640 --> 02:13:29,680 WORK WITH IN TERMS OF GENETIC -- 2860 02:13:29,680 --> 02:13:31,720 I MEAN THEY ARE VERY ACCESSIBLE 2861 02:13:31,720 --> 02:13:34,800 FOR GENETIC STUDIES AND 2862 02:13:34,800 --> 02:13:37,320 PHARMACOLOGICAL STUDIES APPLY 2863 02:13:37,320 --> 02:13:39,200 ALL THE LATEST TECHNIQUES, SO 2864 02:13:39,200 --> 02:13:44,600 WHAT WE ARE DOING WHEN WE 2865 02:13:44,600 --> 02:13:45,280 STARTLEA 2866 02:13:45,280 --> 02:13:48,360 PROJECT GENERIC MODELS, THESE 2867 02:13:48,360 --> 02:13:49,040 MODELS WILL BE CARRYING PATIENT 2868 02:13:49,040 --> 02:13:50,640 SPECIFIC MUTATION. THEN WE CAN 2869 02:13:50,640 --> 02:13:52,800 CHARACTERIZE THE PHENOTYPE OF 2870 02:13:52,800 --> 02:13:58,000 THESE MODELS AND SEE IF ITWORTH 2871 02:13:58,000 --> 02:14:00,040 DOING DRUG SCREENING ON THEM. 2872 02:14:00,040 --> 02:14:01,280 THAT'S INTERESTING WHEN YOU 2873 02:14:01,280 --> 02:14:04,000 CONSIDER 80% OF THE GENES IN 2874 02:14:04,000 --> 02:14:06,000 HUMAN THAT ARE AS I SAID 2875 02:14:06,000 --> 02:14:09,000 DISEASES THESE 80% OF THESE 2876 02:14:09,000 --> 02:14:10,680 GENES ARE IN FISH AND WORM. SO 2877 02:14:10,680 --> 02:14:13,200 YOU CAN REALLY MODEL THE BROAD 2878 02:14:13,200 --> 02:14:15,280 SPECTRUM OF THE DISORDER GOING 2879 02:14:15,280 --> 02:14:20,200 FROM LIKE DEVELOPMENTAL DISEASES 2880 02:14:20,200 --> 02:14:21,000 NEUROLOGICAL METABOLISM 2881 02:14:21,000 --> 02:14:24,400 DISORDERS CANCER AND AGING. AT 2882 02:14:24,400 --> 02:14:27,160 MODELIS OUR MAIN EXPERTISE IS IN 2883 02:14:27,160 --> 02:14:28,880 NEUROSCIENCES, SO WE ARE 2884 02:14:28,880 --> 02:14:30,920 FOCUSING ON NEUROLOGICAL 2885 02:14:30,920 --> 02:14:33,160 DISORDERS AND NEURO METABOLIC 2886 02:14:33,160 --> 02:14:34,600 DISORDERS BUT NO LIMIT IN TERMS 2887 02:14:34,600 --> 02:14:36,640 OF WHAT KIND OF DISEASES WE 2888 02:14:36,640 --> 02:14:39,480 COULD MIMIC THE ONLY LIMITATION 2889 02:14:39,480 --> 02:14:41,880 IS THE GENE CONCERNED IN THESE 2890 02:14:41,880 --> 02:14:42,480 GUYS HERE. 2891 02:14:42,480 --> 02:14:44,400 SO WHAT ARE WE DOING ONCE WE 2892 02:14:44,400 --> 02:14:47,000 HAVE LIKE WORM AND FISH MODELS? 2893 02:14:47,000 --> 02:14:49,000 WE, AS I SAID, THEY ARE SMALL, 2894 02:14:49,000 --> 02:14:51,000 THEY ARE EASY TO WORK WITH. AND 2895 02:14:51,000 --> 02:14:53,280 SO WHAT WE CAN DO IS SCREEN THE 2896 02:14:53,280 --> 02:14:54,320 EFFECT OF THOUSANDS OF SMALL 2897 02:14:54,320 --> 02:14:56,520 MOLECULES ON THEM. SO WHAT WE 2898 02:14:56,520 --> 02:14:59,000 DO IS WE JUST TAKE LIKE 2899 02:14:59,000 --> 02:15:00,960 COMMERCIALLY AVAILABLE LIBRARIES 2900 02:15:00,960 --> 02:15:03,480 OR -- AND/OR SPECIFIC LIBRARIES 2901 02:15:03,480 --> 02:15:04,920 FROM PARTNERS THAT WE ESTABLISH, 2902 02:15:04,920 --> 02:15:08,320 SO WE -- WE GET ACCESS TO 2903 02:15:08,320 --> 02:15:09,360 PRIVATE MOLECULES FROM 2904 02:15:09,360 --> 02:15:10,440 PHARMACEUTICAL COMPANIES FOR 2905 02:15:10,440 --> 02:15:12,480 EXAMPLE, THEN YOU TEST THE 2906 02:15:12,480 --> 02:15:15,400 EFFICACY OF THESE MOLECULES ON A 2907 02:15:15,400 --> 02:15:16,920 SPECIFIC PHENOTYPE. YOU START 2908 02:15:16,920 --> 02:15:18,040 WITH WORMS BECAUSE THAT'S THE 2909 02:15:18,040 --> 02:15:19,600 EASIER TO START WITH. AND THEN 2910 02:15:19,600 --> 02:15:21,000 SELECT THE ONE HAVING A POSITIVE 2911 02:15:21,000 --> 02:15:23,680 EFFECT ON THESE WORMS AND 2912 02:15:23,680 --> 02:15:26,800 CONFIRM EFFECT IN A FISH MODEL 2913 02:15:26,800 --> 02:15:30,200 AND THEN GO INTO IPC OR RODENT 2914 02:15:30,200 --> 02:15:32,560 MODELS AND WHAT YOU ARE LEFT 2915 02:15:32,560 --> 02:15:35,240 WITH AT THE END ARE 2916 02:15:35,240 --> 02:15:36,200 INTERESTINGLY LEAD CANDIDATE 2917 02:15:36,200 --> 02:15:39,400 LEAD MOLECULES WORKING IN 2918 02:15:39,400 --> 02:15:40,640 EVOLUTIONARY DISTANT SPECIES, IF 2919 02:15:40,640 --> 02:15:44,720 IT WORKS THERE'S A GREAT CHANCE 2920 02:15:44,720 --> 02:15:46,120 IT'S CARVER A MECHANISM 2921 02:15:46,120 --> 02:15:46,480 EVOLUTION. 2922 02:15:46,480 --> 02:15:47,560 SO THESE LEADS ARE INTERESTING 2923 02:15:47,560 --> 02:15:49,600 ON THEIR OWN BECAUSE IF THESE 2924 02:15:49,600 --> 02:15:52,560 DRUGS ARE REPRODUCIBLE WE CAN 2925 02:15:52,560 --> 02:15:53,720 THINK ABOUT DOING DRUG 2926 02:15:53,720 --> 02:15:54,720 REPURPOSING AND MOVING FORWARD 2927 02:15:54,720 --> 02:15:56,880 INTO THE CLINIC WITH THESE 2928 02:15:56,880 --> 02:15:57,080 DRUGS. 2929 02:15:57,080 --> 02:15:59,680 BUT WE BELIEVE THAT THE MAIN 2930 02:15:59,680 --> 02:16:02,320 VALUE OF THIS SCREENING APPROACH 2931 02:16:02,320 --> 02:16:05,480 IS TO STUDY THIS IN VIVO DATA. 2932 02:16:05,480 --> 02:16:07,680 SO WHAT WE HAVE BEEN DEVELOPING 2933 02:16:07,680 --> 02:16:10,600 IS AN AI MACHINE LEARNING 2934 02:16:10,600 --> 02:16:11,880 APPROACH TO TRY TO MAKE SENSE 2935 02:16:11,880 --> 02:16:14,400 OUT OF THESE IN VIVO DATA. WE 2936 02:16:14,400 --> 02:16:16,560 HAVE SO MUCH DATA ABOUT THE 2937 02:16:16,560 --> 02:16:18,040 EFFECT OF INDIVIDUAL SMALL 2938 02:16:18,040 --> 02:16:21,200 MOLECULE THAT WE BELIEVE THERE 2939 02:16:21,200 --> 02:16:22,640 IS SOMETHING WE CAN DO HERE. SO 2940 02:16:22,640 --> 02:16:24,440 IF WE SEE THAT FROM A DIFFERENT 2941 02:16:24,440 --> 02:16:26,760 ANGLE AS I SAID THE FIRST STEP 2942 02:16:26,760 --> 02:16:29,360 IS GENERIC MODEL TO GENERIC DATA 2943 02:16:29,360 --> 02:16:31,640 COMPILE THEM SO FOR THAT WE ARE 2944 02:16:31,640 --> 02:16:32,960 INTEGRATING OUR DATA ACQUIRED IN 2945 02:16:32,960 --> 02:16:35,080 OUR MODEL BUT WE ALSO GETTING 2946 02:16:35,080 --> 02:16:39,000 ANY PUBLICLY AVAILABLE DATABASES 2947 02:16:39,000 --> 02:16:40,960 IF AVAILABLE FOR THESE DISEASE. 2948 02:16:40,960 --> 02:16:43,200 AND THEN THE NEXT BIG STEP IS 2949 02:16:43,200 --> 02:16:47,560 INTEGRATE THAT INTO A COMPUTER 2950 02:16:47,560 --> 02:16:49,320 AND MACHINERY ALGORITHM. SO 2951 02:16:49,320 --> 02:16:51,960 WHAT THE COMPUTER IS BASICALLY 2952 02:16:51,960 --> 02:16:53,680 DOING IS LOOK AT ALL THE 2953 02:16:53,680 --> 02:16:56,280 MOLECULE AND THE EFFECT ON A 2954 02:16:56,280 --> 02:16:58,120 SPECIFIC PHENOTYPE AND BY 2955 02:16:58,120 --> 02:17:00,080 PREDICTING THE MOLECULAR TARGETS 2956 02:17:00,080 --> 02:17:03,280 OF EACH OF THOSE MOLECULE CAN 2957 02:17:03,280 --> 02:17:06,080 BUILD A MAP RESEMBLE A 3D BAR 2958 02:17:06,080 --> 02:17:09,440 CODE I'LL SHOW YOU ONE LATER 2959 02:17:09,440 --> 02:17:11,680 CREATES A 3D BAR CODE THAT SHOWS 2960 02:17:11,680 --> 02:17:13,840 ALL THE TARGETS ARE PARTICULARLY 2961 02:17:13,840 --> 02:17:16,400 ENRICHED FROM A PARTICULAR 2962 02:17:16,400 --> 02:17:17,640 DISEASE. THESE TARGET 2963 02:17:17,640 --> 02:17:19,080 ENRICHMENT CLUSTERS YOU CAN 2964 02:17:19,080 --> 02:17:21,320 PREDICT SPECIFIC PATHWAYS AND 2965 02:17:21,320 --> 02:17:23,760 THESE PATHWAYS CAN BE SEEN AS 2966 02:17:23,760 --> 02:17:25,320 DISEASE INSIDES MEANS THESE 2967 02:17:25,320 --> 02:17:26,960 PATHWAYS ARE IMPORTANT FOR THE 2968 02:17:26,960 --> 02:17:29,000 DISEASE BECAUSE IF YOU MODULATE 2969 02:17:29,000 --> 02:17:30,960 THEM WITH DIFFERENT MOLECULES 2970 02:17:30,960 --> 02:17:33,960 IT'S HAVING AN EFFECT ON THE 2971 02:17:33,960 --> 02:17:34,280 PHENOTYPE. 2972 02:17:34,280 --> 02:17:36,400 SO ONCE WE HAVE THESE DISEASE 2973 02:17:36,400 --> 02:17:38,800 INSIGHTS IDENTIFIED WE CAN JUST 2974 02:17:38,800 --> 02:17:40,400 VALIDATE THEM PHARMACOLOGICALLY 2975 02:17:40,400 --> 02:17:42,360 AND GENETICALLY IN OUR MODEL AND 2976 02:17:42,360 --> 02:17:43,960 ONCE YOU CONFIRM THERE IS AN 2977 02:17:43,960 --> 02:17:45,240 INTERESTING NEW MECHANISM THAT 2978 02:17:45,240 --> 02:17:47,640 IS IMPORTANT FOR THE DISEASE YOU 2979 02:17:47,640 --> 02:17:48,920 CAN INITIATE THE DEVELOPMENT, 2980 02:17:48,920 --> 02:17:51,800 STRATEGIES SO AS I SAID IT COULD 2981 02:17:51,800 --> 02:17:54,120 BE DRUG REPURPOSING IF YOU HAVE 2982 02:17:54,120 --> 02:17:55,200 AN INTERESTING DRUG THAT EFFECTS 2983 02:17:55,200 --> 02:17:58,920 THESE PATHWAYS BUT YOU CAN THINK 2984 02:17:58,920 --> 02:18:01,240 ABOUT LIKE PERSON THERAPIES THAT 2985 02:18:01,240 --> 02:18:03,600 CAN BE SMALL MOLECULE FOR ASO OR 2986 02:18:03,600 --> 02:18:04,400 ANYTHING. 2987 02:18:04,400 --> 02:18:07,840 BUT THE BEAUTY OF THIS MODEL 2988 02:18:07,840 --> 02:18:09,960 LIKE A WILL SELF FED PLATFORM. 2989 02:18:09,960 --> 02:18:11,800 THESE DATA THAT FEED THE MODEL 2990 02:18:11,800 --> 02:18:15,360 FEED THE SOFTWARE, AND THAT THE 2991 02:18:15,360 --> 02:18:17,240 ALGORITHM IS GETTING EVEN MORE 2992 02:18:17,240 --> 02:18:19,000 ROBUST AT PREDICTING MECHANISM. 2993 02:18:19,000 --> 02:18:21,000 SO YOU REALLY HAVE LIKE A SNOW 2994 02:18:21,000 --> 02:18:22,600 BALL THAT IS GETTING FOREIGN AND 2995 02:18:22,600 --> 02:18:24,040 THAT YOUR MODEL IS GETTING 2996 02:18:24,040 --> 02:18:27,800 STRONGER AND STRONGER WITH THE 2997 02:18:27,800 --> 02:18:30,680 MODEL THAT YOU GENERATE. 2998 02:18:30,680 --> 02:18:31,720 SO WITH THOSE WE HAVE SORRY 2999 02:18:31,720 --> 02:18:33,760 DIFFERENT DRUG DISCOVERY 3000 02:18:33,760 --> 02:18:34,680 PROGRAMS, DIFFERENT STAGE, THE 3001 02:18:34,680 --> 02:18:37,280 ONE I'M GOING TO FOCUS ON 3002 02:18:37,280 --> 02:18:39,400 OBVIOUSLY TODAY ARE SPG4 PROGRAM 3003 02:18:39,400 --> 02:18:41,160 AS YOU SEE IT'S QUITE EARLY SO I 3004 02:18:41,160 --> 02:18:42,720 DON'T HAVE MUCH TO SHOW YOU BUT 3005 02:18:42,720 --> 02:18:44,280 I WILL SHOW YOU WHAT WE HAVE SO 3006 02:18:44,280 --> 02:18:44,480 FAR. 3007 02:18:44,480 --> 02:18:50,400 JUST TO SHOW YOU AN EXAMPLE OF 3008 02:18:50,400 --> 02:18:53,360 THE 3D BAR CODE THESE ARE THE 3009 02:18:53,360 --> 02:18:54,640 MAP THAT OUR MACHINE LEARNING 3010 02:18:54,640 --> 02:18:56,800 APPROACH IS GIVING. SO HERE YOU 3011 02:18:56,800 --> 02:18:59,200 HAVE ALL THE PREDICTIVE TARGETS 3012 02:18:59,200 --> 02:19:00,680 OF MOLECULE THAT IS HAVING A 3013 02:19:00,680 --> 02:19:02,520 POSITIVE OR NEGATIVE EFFECT ON 3014 02:19:02,520 --> 02:19:05,360 THE WORM PHENOTYPE AND THE 3015 02:19:05,360 --> 02:19:07,760 SOFTWARE IS TRYING TO PLOT THESE 3016 02:19:07,760 --> 02:19:08,600 TARGETS AGAINST THEMSELVES AND 3017 02:19:08,600 --> 02:19:11,320 SO YOU SEE THESE ENRICHMENT, 3018 02:19:11,320 --> 02:19:12,440 THESE SMALL LIKE HIGHLIGHTED 3019 02:19:12,440 --> 02:19:14,880 SQUARES THAT GETS FORMED AMONG 3020 02:19:14,880 --> 02:19:17,040 ALL THOSE TARGETS AND WHEN YOU 3021 02:19:17,040 --> 02:19:18,680 LOOK INTO A SPECIFIC SOME OF 3022 02:19:18,680 --> 02:19:21,080 THESE CLUSTERS YOU CAN SEE 3023 02:19:21,080 --> 02:19:22,800 PATHWAY ENRICHMENT. AND FOR 3024 02:19:22,800 --> 02:19:25,280 EXAMPLE IN THE CONTEXT OF 3025 02:19:25,280 --> 02:19:26,920 HUNTING TON WE IDENTIFY ONE 3026 02:19:26,920 --> 02:19:34,040 PATHWAY IN THE CONTEXT OF 3027 02:19:34,040 --> 02:19:35,560 HUNTINGTON I CAN DISCLOSE IT 3028 02:19:35,560 --> 02:19:37,320 HERE BUT YOU CAN TEST THE 3029 02:19:37,320 --> 02:19:40,920 EFFICACY OF THESE MOLECULES ON 3030 02:19:40,920 --> 02:19:43,840 MULTIPLE COMPLIMENTARY 3031 02:19:43,840 --> 02:19:45,120 PHENOTYPES. AS YOU SEE THE 3032 02:19:45,120 --> 02:19:46,760 NEURO PATHWAY OF THESE DISEASE 3033 02:19:46,760 --> 02:19:48,600 IS PERFORMING EVEN WELL AND 3034 02:19:48,600 --> 02:19:51,000 BETTER THAN SOME WELL KNOWN DRUG 3035 02:19:51,000 --> 02:19:52,760 THAT ARE CURRENTLY UNDER 3036 02:19:52,760 --> 02:19:54,760 CLINICAL TRIAL FOR HUNTINGTON. 3037 02:19:54,760 --> 02:19:57,360 A VALIDATION FOR THIS APPROACH 3038 02:19:57,360 --> 02:19:59,640 MAKES SENSE AND REUNRAVEL LIKE 3039 02:19:59,640 --> 02:20:01,760 NOVEL DISEASE INSIGHTS FOR 3040 02:20:01,760 --> 02:20:05,160 DISORDERS FOR WHICH THE 3041 02:20:05,160 --> 02:20:07,920 MECHANICS THE PATHOGENIC 3042 02:20:07,920 --> 02:20:09,600 MECHANICS NOT COMPLETELY 3043 02:20:09,600 --> 02:20:14,040 UNDERSTOOD UNBUYSED AND BIASED 3044 02:20:14,040 --> 02:20:16,440 APPROACH TO A. 3045 02:20:16,440 --> 02:20:22,160 LET ME JUMP INTO SPG4 COMPLEX AT 3046 02:20:22,160 --> 02:20:23,400 MODELIS THIS YOUNG LADY LIVING 3047 02:20:23,400 --> 02:20:25,320 IN FRANCE BEEN IN A WHEELCHAIR 3048 02:20:25,320 --> 02:20:27,880 SINCE HER YOUNG AGE. HER 3049 02:20:27,880 --> 02:20:30,760 PARENTS STARTED AN ASSOCIATION A 3050 02:20:30,760 --> 02:20:36,000 FOUNDATION CALLED ENORVV 3051 02:20:36,000 --> 02:20:41,280 CLINICALLY DIAGNOSED WITH 3052 02:20:41,280 --> 02:20:43,400 CEREBRAL PALSY, ALL THE TESTS 3053 02:20:43,400 --> 02:20:45,560 CAME BACK NEGATIVE, NO ANSWERS, 3054 02:20:45,560 --> 02:20:49,000 WE MET WITH THIS FAMILY AND WE 3055 02:20:49,000 --> 02:20:51,800 THOUGHT THAT WE SHOULD START A 3056 02:20:51,800 --> 02:20:53,880 PROJECT TRYING TO IDENTIFY NEW 3057 02:20:53,880 --> 02:20:55,200 VARIANT, NEW GENE BECAUSE 3058 02:20:55,200 --> 02:20:57,200 APPARENTLY SHE DIDN'T HAVE LIKE 3059 02:20:57,200 --> 02:21:00,800 A KNOWN GENE THAT WAS CAUSING 3060 02:21:00,800 --> 02:21:03,600 HSP. SO WE SENT THEM SWABS AND 3061 02:21:03,600 --> 02:21:05,400 THAT WAS PRE COVID SO SHE DIDN'T 3062 02:21:05,400 --> 02:21:07,920 KNOW THAT SHE WOULD QUICKLY KNOW 3063 02:21:07,920 --> 02:21:11,280 WHAT A SWAB IS, SO SHE SWABBED 3064 02:21:11,280 --> 02:21:14,520 AND WE DID SEQUENCING ON THE 3065 02:21:14,520 --> 02:21:16,560 TRIO AND WE DIDN'T HAVE TO DIG 3066 02:21:16,560 --> 02:21:19,360 MUCH FURTHER BECAUSE ACTUALLY WE 3067 02:21:19,360 --> 02:21:23,440 IDENTIFIED A WELL KNOWN PATH JOE 3068 02:21:23,440 --> 02:21:27,360 ANYONE NICK MUTATION IN R499H, 3069 02:21:27,360 --> 02:21:31,680 DOMINANT KNOWN TO BE CAUSING 3070 02:21:31,680 --> 02:21:37,720 SPG4. SO AS SPG4 SHE COULD PUT 3071 02:21:37,720 --> 02:21:40,360 A WORD ON THE DISEASE. 3072 02:21:40,360 --> 02:21:43,880 SO WE WORKED WITH THE PARENTS 3073 02:21:43,880 --> 02:21:46,360 AND THE FOUNDATION AND FAMILY TO 3074 02:21:46,360 --> 02:21:48,800 REALLY LIKE START A PROJECT 3075 02:21:48,800 --> 02:21:51,240 ON -- ON TRYING TO INITIATE A 3076 02:21:51,240 --> 02:21:54,120 PROJECT ON DRUG DISCOVERY AT 3077 02:21:54,120 --> 02:21:57,840 MODELIS ON SPG4 WE WORKED WITH 3078 02:21:57,840 --> 02:21:59,800 PROFESSIONALS TO DO A NICE STORY 3079 02:21:59,800 --> 02:22:01,360 TELLING, BECAUSE THIS NEW 3080 02:22:01,360 --> 02:22:02,400 DIAGNOSIS WAS A SPRING BOARD FOR 3081 02:22:02,400 --> 02:22:07,720 THE FAMILY. AND SO WE TRY TO 3082 02:22:07,720 --> 02:22:11,000 CLEARLY EXPLAIN WHAT WE WERE 3083 02:22:11,000 --> 02:22:13,280 WILLING TO DO USING FISHES AND 3084 02:22:13,280 --> 02:22:14,560 DRUG REPURPOSING AND IDENTIFY 3085 02:22:14,560 --> 02:22:17,080 THE DRUGS AND MAKING WORM AND 3086 02:22:17,080 --> 02:22:18,600 FISH SWIM BETTER. AND WE RAISED 3087 02:22:18,600 --> 02:22:20,120 A SIGNIFICANT AMOUNT OF MONEY 3088 02:22:20,120 --> 02:22:22,080 THAT ALLOWED US TO START THE 3089 02:22:22,080 --> 02:22:25,560 PROJECT. AND I'M ALWAYS AMAZED 3090 02:22:25,560 --> 02:22:26,800 ABOUT HOW DYNAMIC THESE FAMILIES 3091 02:22:26,800 --> 02:22:28,840 ARE AND TO SEE ALL THE EFFORTS 3092 02:22:28,840 --> 02:22:31,960 THEY ARE PUTTING IN, THEY'RE 3093 02:22:31,960 --> 02:22:34,560 REALLY, LIKE, SCIENTISTS. SO 3094 02:22:34,560 --> 02:22:36,560 WHAT WE STARTED WITH IS THE 3095 02:22:36,560 --> 02:22:39,360 GENERIC WORM MODELS AND WE 3096 02:22:39,360 --> 02:22:42,000 DECIDED TO DO TWO DIFFERENT WORM 3097 02:22:42,000 --> 02:22:47,320 MODELS, ONE WOULD BE A FULL GENE 3098 02:22:47,320 --> 02:22:49,320 DILUTION, AND THE OTHER ONE 3099 02:22:49,320 --> 02:22:52,800 WOULD MIMIC THE MUTATION THAT IS 3100 02:22:52,800 --> 02:22:54,880 AT POSITION 396 IN WORM BUT AS 3101 02:22:54,880 --> 02:22:57,360 YOU MIGHT NOT BE ABLE TO SEE ON 3102 02:22:57,360 --> 02:23:00,360 THIS ALIGNMENT THIS AMINO ACID 3103 02:23:00,360 --> 02:23:02,600 IS WELL CONSERVED IN FISH AND 3104 02:23:02,600 --> 02:23:05,400 WORM. SO WE DECIDED TO MIMIC 3105 02:23:05,400 --> 02:23:08,800 EXACTLY THE MUTATION IN A WORM 3106 02:23:08,800 --> 02:23:11,200 STRING. WHAT'S GREAT USING 3107 02:23:11,200 --> 02:23:14,080 MIMICS IS YOU HAVE A LIBRARY OF 3108 02:23:14,080 --> 02:23:18,080 CODES. THIS CHRISTMAS TREE HERE 3109 02:23:18,080 --> 02:23:22,360 YOU HAVE MIMICODES THAT CAN BE 3110 02:23:22,360 --> 02:23:25,000 VERY NICE FOR DOING LIKE THE 3111 02:23:25,000 --> 02:23:26,040 FUNCTIONAL STUDIES. 3112 02:23:26,040 --> 02:23:28,040 SO WE DID THESE MODELS AND THE 3113 02:23:28,040 --> 02:23:31,240 FIRST THING WE CHECKED SO AT 3114 02:23:31,240 --> 02:23:32,960 MODELIS WE HAVE ACCESS TO 3115 02:23:32,960 --> 02:23:35,160 SOFTWARE, DEVICES, ANYTHING THAT 3116 02:23:35,160 --> 02:23:37,000 CAN REALLY SCAN THE MORPHOLOGY 3117 02:23:37,000 --> 02:23:38,840 THE SHAPE EVERYTHING OF WORMS 3118 02:23:38,840 --> 02:23:42,440 YOU SEE LIKE GENETICALLY 3119 02:23:42,440 --> 02:23:43,560 TRACKED, IT'S BASICALLY WHEN YOU 3120 02:23:43,560 --> 02:23:45,000 CROSS THE SECURITY IN THE 3121 02:23:45,000 --> 02:23:49,240 AIRPORT AND YOU SCAN AND WE SEE 3122 02:23:49,240 --> 02:23:51,040 YOU NAKED THAT'S THE SAME THING 3123 02:23:51,040 --> 02:23:53,360 WE SEE EVERYTHING ON THESE GUYS. 3124 02:23:53,360 --> 02:23:55,640 THE FIRST THING WE REALIZE WHEN 3125 02:23:55,640 --> 02:23:57,360 LOOKING AT THEIR SIZE A DAY ONE 3126 02:23:57,360 --> 02:23:59,800 OF ADULT HOOD YOU DON'T SEE MUCH 3127 02:23:59,800 --> 02:24:01,360 OF A DIFFERENCE BUT THEN THEY 3128 02:24:01,360 --> 02:24:04,160 DON'T GROW AS GOOD AS THE DAY 3129 02:24:04,160 --> 02:24:08,160 ONE AND TWO, YOU SEE THE BODY IS 3130 02:24:08,160 --> 02:24:10,280 SIGNIFICANTLY SMALLER THAN THE 3131 02:24:10,280 --> 02:24:11,400 SIBLINGS, AND THESE DIFFERENCE 3132 02:24:11,400 --> 02:24:15,480 INCREASES WITH AGE. SO THAT'S 3133 02:24:15,480 --> 02:24:16,360 INTERESTING BECAUSE WE OBSERVE 3134 02:24:16,360 --> 02:24:19,920 THESE KIND OF BODY SIZE 3135 02:24:19,920 --> 02:24:21,400 REDUCTION IN AUTO SPASTIC 3136 02:24:21,400 --> 02:24:23,360 SYNDROMES WHERE IT'S AFFECTING 3137 02:24:23,360 --> 02:24:25,400 THE MUSCLE AND THE SPASTICITY IN 3138 02:24:25,400 --> 02:24:28,520 THE MUSCLE CAN MAKE THE MUSCLE 3139 02:24:28,520 --> 02:24:31,600 SHRINK AND THE WHOLE BODY NOT 3140 02:24:31,600 --> 02:24:33,520 GROWING AS IT SHOULD AND IT'S 3141 02:24:33,520 --> 02:24:34,920 SHRINKING, THAT'S THE FIRST 3142 02:24:34,920 --> 02:24:36,320 INDICATION THAT WE POTENTIALLY 3143 02:24:36,320 --> 02:24:37,520 HAD SOME INTERESTING HERE. 3144 02:24:37,520 --> 02:24:40,960 THE SECOND THING YOU WANTS TO 3145 02:24:40,960 --> 02:24:43,600 CHECK WHEN YOU WORK WITH MIM I 3146 02:24:43,600 --> 02:24:45,200 CANODES IS THE LIFE SPAN, ABOUT 3147 02:24:45,200 --> 02:24:47,360 30 DAYS AS YOU CAN SEE HERE IN 3148 02:24:47,360 --> 02:24:49,360 BLACK THESE GUYS THEY START TO 3149 02:24:49,360 --> 02:24:51,600 DIE AND THEY HAVE LIKE YOU HAVE 3150 02:24:51,600 --> 02:24:54,680 ONLY 50 PERCENT SURVIVAL ABOUT 3151 02:24:54,680 --> 02:24:57,200 20, 22 DAYS OF LIFE. BUT WHEN 3152 02:24:57,200 --> 02:24:59,440 WE LOOK AT THE LIFE SPAN OF THE 3153 02:24:59,440 --> 02:25:00,960 MUTATION OR POINT MUTATION HERE 3154 02:25:00,960 --> 02:25:02,440 YOU SEE THE MUTANT WORMS THEY 3155 02:25:02,440 --> 02:25:04,560 START TO DIE EARLIER, AND YOU 3156 02:25:04,560 --> 02:25:07,360 HAVE ABOUT 50% OF SURVIVAL AT 3157 02:25:07,360 --> 02:25:07,840 DAY 14. 3158 02:25:07,840 --> 02:25:09,400 SO THAT WAS ALSO AN INDICATION 3159 02:25:09,400 --> 02:25:10,800 THAT SOMETHING IS GOING WRONG IN 3160 02:25:10,800 --> 02:25:15,000 THOSE -- IN THOSE ANIMALS. 3161 02:25:15,000 --> 02:25:17,000 THE NEXT THING WE WANTED TO 3162 02:25:17,000 --> 02:25:19,000 CHECK IS HOW WERE THEY AGING? 3163 02:25:19,000 --> 02:25:22,200 WE KNOW HSP ARE AGE AGAIN DENT 3164 02:25:22,200 --> 02:25:24,080 AND PROGRESSIVE DISORDERS SO WE 3165 02:25:24,080 --> 02:25:25,200 WANTED TO SEE HOW THEY WERE 3166 02:25:25,200 --> 02:25:26,600 AGEING AND WHAT YOU NEED TO KNOW 3167 02:25:26,600 --> 02:25:29,400 IS THAT WORMS WHEN THEY AGE THEY 3168 02:25:29,400 --> 02:25:33,160 GET AS -- AS HUMAN THEY GET MORE 3169 02:25:33,160 --> 02:25:36,560 AND MORE -- LESS NIMBLE AND THEY 3170 02:25:36,560 --> 02:25:38,800 GET ULTIMATELY PARALYZED. 3171 02:25:38,800 --> 02:25:45,200 SO WHAT WE DO IS WE POKE A 3172 02:25:45,200 --> 02:25:46,800 LITTLE MIMIC TODAY AND SEE IF 3173 02:25:46,800 --> 02:25:49,000 IT'S REACTING AND MOVING AWAY 3174 02:25:49,000 --> 02:25:51,120 FROM THIS IF YOU DO THIS ON AN 3175 02:25:51,120 --> 02:25:53,440 OLD WORM THESE GUYS CANNOT MOVE 3176 02:25:53,440 --> 02:25:55,160 AWAY. THEY ARE NOT DEAD BECAUSE 3177 02:25:55,160 --> 02:26:00,360 IF YOU ZOOM IN YOU CAN SEE THE 3178 02:26:00,360 --> 02:26:02,160 IT'S STILL PUMPING, TOO OLD TO 3179 02:26:02,160 --> 02:26:04,440 MOVE AWAY SO KIND OF PARALYZED. 3180 02:26:04,440 --> 02:26:07,120 SO IF YOU QUANTIFY THE AMOUNT OF 3181 02:26:07,120 --> 02:26:09,400 PERCENTAGE OF WORM THAT GETS 3182 02:26:09,400 --> 02:26:11,000 PARALYZED OVER TIME YOU SEE THAT 3183 02:26:11,000 --> 02:26:16,000 FOR WILD TYPE HERE IN BLACK AT 3184 02:26:16,000 --> 02:26:17,800 12 DAYS OF ADULT HOODS 3185 02:26:17,800 --> 02:26:20,320 APPROXIMATELY HALF OF THEIR LIFE 3186 02:26:20,320 --> 02:26:23,040 YOU HAVE ABOUT 30% OF WORMS THAT 3187 02:26:23,040 --> 02:26:25,000 GET PARALYZED. BUT THIS AMOUNT 3188 02:26:25,000 --> 02:26:28,800 IS GOING UP TO 50 OR 60% FOR THE 3189 02:26:28,800 --> 02:26:30,440 MUTANT WORM SO THAT WAS AGAIN 3190 02:26:30,440 --> 02:26:33,400 ONE MORE SIGN THAT THESE WORM 3191 02:26:33,400 --> 02:26:38,360 ARE NOT IN GOOD SHAPE. 3192 02:26:38,360 --> 02:26:40,240 SO SORRY I GET BACK TO THE 3193 02:26:40,240 --> 02:26:41,560 PREVIOUS SLIDE THAT'S A 3194 02:26:41,560 --> 02:26:43,000 PHENOTYPE THAT'S INTERESTING BUT 3195 02:26:43,000 --> 02:26:46,480 HERE WE'RE LOOKING 12 DAYS AFTER 3196 02:26:46,480 --> 02:26:47,760 GETTING ADULT WORM AND THAT'S 3197 02:26:47,760 --> 02:26:49,360 TOO LONG TO DO DRUG SCREENING, 3198 02:26:49,360 --> 02:26:51,200 TOO LONG FOR US. WHAT WE WOULD 3199 02:26:51,200 --> 02:26:53,200 LIKE IS GET A VERY ACUTE AND 3200 02:26:53,200 --> 02:26:55,920 FAST PHENOTYPE. AND ACTUALLY 3201 02:26:55,920 --> 02:26:58,480 WHAT HAS DEVELOPED IN WORMS 3202 02:26:58,480 --> 02:27:00,120 THESE GUYS NORMALLY CRAWL ON 3203 02:27:00,120 --> 02:27:02,360 SOLID SURFACES BUT IF YOU PUT 3204 02:27:02,360 --> 02:27:04,600 THEM IN LIQUID CULTURE THEY TRY 3205 02:27:04,600 --> 02:27:07,480 TO SWIM AS YOU CAN SEE HERE. 3206 02:27:07,480 --> 02:27:08,800 THAT'S NOT THEIR NATURAL 3207 02:27:08,800 --> 02:27:10,320 BEHAVIOR THEY ARE SWIMMERS BUT 3208 02:27:10,320 --> 02:27:12,080 THEY DON'T LIKE TO DO THAT FOR 3209 02:27:12,080 --> 02:27:13,720 HOURSMENT BUT WE REALIZED IF YOU 3210 02:27:13,720 --> 02:27:16,240 PUT WORMS IN A LIQUID CULTURE 3211 02:27:16,240 --> 02:27:18,920 WELL LIKE THIS IF THESE WORMS 3212 02:27:18,920 --> 02:27:21,200 SHOW A PROBLEM OF MOTILITY 3213 02:27:21,200 --> 02:27:23,800 DEFECTS THIS DEFECT WILL BE SEEN 3214 02:27:23,800 --> 02:27:25,680 VERY QUICKLY BECAUSE THIS KIND 3215 02:27:25,680 --> 02:27:27,880 OF BEHAVIOR IS VERY ENERGY 3216 02:27:27,880 --> 02:27:30,520 CONSUMING. SO A PROGRESSIVE 3217 02:27:30,520 --> 02:27:33,160 PHENOTYPE THAT MIGHT TAKE DAYS 3218 02:27:33,160 --> 02:27:36,080 TO ALTER ON A PLATE ON WHICH 3219 02:27:36,080 --> 02:27:39,840 THEY ARE USUALLY CRAWLING AND 3220 02:27:39,840 --> 02:27:41,400 WITHIN MINUTES OR HOURS ON 3221 02:27:41,400 --> 02:27:43,920 LIQUID CULTURE. THIS IS WHAT WE 3222 02:27:43,920 --> 02:27:46,600 SAW. YOU CAN SEE GRAPHIC IN 3223 02:27:46,600 --> 02:27:48,440 DAYS BUT IN MINUTES. IF YOU 3224 02:27:48,440 --> 02:27:50,080 FOLLOW HOW THEY WERE SWIMMING OR 3225 02:27:50,080 --> 02:27:52,480 TRYING TO SWIM OVER 10 HOURS WE 3226 02:27:52,480 --> 02:27:54,520 SEE THAT THE WILD TYPE WORMS GET 3227 02:27:54,520 --> 02:27:56,400 A LITTLE BIT EXHAUSTED BUT THEY 3228 02:27:56,400 --> 02:27:57,960 SURVIVE. BUT YOU SEE THE 3229 02:27:57,960 --> 02:27:59,160 DECREASE AND THE SIGNIFICANT 3230 02:27:59,160 --> 02:28:00,800 REDUCTION IN THE MOTILITY OF 3231 02:28:00,800 --> 02:28:02,240 THESE WORMS WHEN THEY ARE ON 3232 02:28:02,240 --> 02:28:04,320 LIQUID CULTURE AND YOU SEE THE 3233 02:28:04,320 --> 02:28:05,440 DECREASE THAT WE SEE THAT THESE 3234 02:28:05,440 --> 02:28:07,040 GUYS ARE GETTING EXHAUSTED 3235 02:28:07,040 --> 02:28:09,120 FASTER THAN THE OTHERS AND SWIM 3236 02:28:09,120 --> 02:28:13,800 MUCH SLOWER THAN THEIR WILD TYPE 3237 02:28:13,800 --> 02:28:14,120 CONTROLS. 3238 02:28:14,120 --> 02:28:15,840 SO THIS IS A VERY INTERESTING 3239 02:28:15,840 --> 02:28:17,600 PHENOTYPE BECAUSE THIS IS FAST 3240 02:28:17,600 --> 02:28:21,400 AND THIS CAN BE PERFORMED ON 96 3241 02:28:21,400 --> 02:28:22,520 WELL PLATES SO MEANS THAT YOU 3242 02:28:22,520 --> 02:28:24,120 CAN JUST TEST THE EFFECT OF 3243 02:28:24,120 --> 02:28:25,280 DIFFERENT TREATMENT VERY QUICKLY 3244 02:28:25,280 --> 02:28:27,600 TO SEE IF IT'S HELPING THE WORMS 3245 02:28:27,600 --> 02:28:31,320 TO SWIM BETTER, BASICALLY. 3246 02:28:31,320 --> 02:28:33,400 AND TO BE SURE THAT THE 3247 02:28:33,400 --> 02:28:36,000 PHENOTYPE WAS SPECIFIC TO A 3248 02:28:36,000 --> 02:28:37,040 SPASTIC-RELATED SYNDROME WE 3249 02:28:37,040 --> 02:28:39,400 DECIDED TO TREAT -- SORRY -- WE 3250 02:28:39,400 --> 02:28:41,680 LOOKED AT THEIR MUSCLE HEALTH. 3251 02:28:41,680 --> 02:28:44,200 SO WE HAVE SOME TRANSGENIC WORM 3252 02:28:44,200 --> 02:28:47,080 STRAIN THAT EXPRESSED INTO MYO 3253 02:28:47,080 --> 02:28:49,120 GENERAL FIBERS AND YOU CAN 3254 02:28:49,120 --> 02:28:51,040 QUANTIFY QUALIFY MUSCLE AS LOW 3255 02:28:51,040 --> 02:28:52,880 DEFECTS, GOOD LOOKING YOU SEE 3256 02:28:52,880 --> 02:28:55,080 YOU HAVE A SMOOTH ORGANIZATION 3257 02:28:55,080 --> 02:28:57,400 OF THE DIFFERENT MUSCLE FIBERS 3258 02:28:57,400 --> 02:28:59,000 OR YOU CAN START TO SEE SOME 3259 02:28:59,000 --> 02:29:00,760 DEFECTS WITH LIKE THESE KIND OF 3260 02:29:00,760 --> 02:29:02,600 HOLES OR CLUSTERS OF FIBERS 3261 02:29:02,600 --> 02:29:04,400 TOGETHER AND WHEN WE LOOKED AT 3262 02:29:04,400 --> 02:29:06,360 HOW THE MUSCLE LOOKING IN OUR 3263 02:29:06,360 --> 02:29:09,400 WORM POPULATION WAS NOT A 3264 02:29:09,400 --> 02:29:11,360 DRASTIC PHENOTYPE BUT SAW 3265 02:29:11,360 --> 02:29:14,400 SIGNIFICANCE ON THE FIRST DAY OF 3266 02:29:14,400 --> 02:29:16,080 ADULT HOOD WHERE YOU HAD LESS 3267 02:29:16,080 --> 02:29:17,400 GOOD LOOKING MUSCLE FIBERS IN 3268 02:29:17,400 --> 02:29:19,160 THE POINT MUTATION, NOT 3269 02:29:19,160 --> 02:29:20,200 SIGNIFICANT IN THE KNOCK OUT 3270 02:29:20,200 --> 02:29:21,840 THAT COULD BE INTERESTING BUT A 3271 02:29:21,840 --> 02:29:24,320 TREND LIKE HAVING NOT HEALTHY 3272 02:29:24,320 --> 02:29:25,880 MUSCLE AND THAT'S AGAIN RELEVANT 3273 02:29:25,880 --> 02:29:29,400 IN A CONTEXT OF A SPASTIC 3274 02:29:29,400 --> 02:29:29,760 DISORDER. 3275 02:29:29,760 --> 02:29:32,160 TO BE SURE THIS PHENOTYPE WAS 3276 02:29:32,160 --> 02:29:36,080 RELATED TO SPASTICITY WE DECIDE 3277 02:29:36,080 --> 02:29:42,800 OD TO TREAT SWIMMING WORMS WITH 3278 02:29:42,800 --> 02:29:45,400 BACLOFEN, THE REDUCTION OF 3279 02:29:45,400 --> 02:29:47,040 MOTILITY THAT WE ARE SEEING IN 3280 02:29:47,040 --> 02:29:50,200 OUR FEN KNOW TYPE I JUST SHOWED 3281 02:29:50,200 --> 02:29:53,280 YOU, THIS LOOKS SPECIFIC TO A 3282 02:29:53,280 --> 02:29:57,000 SPASTIC PROBLEM IF YOU GIVE THEM 3283 02:29:57,000 --> 02:29:59,760 A MUSCLE RELAXANT THEY SWIM 3284 02:29:59,760 --> 02:30:00,000 BETTER. 3285 02:30:00,000 --> 02:30:01,280 THIS IS WHERE WE ARE AND I'M 3286 02:30:01,280 --> 02:30:02,440 SORRY I CANNOT SHOW YOU MORE 3287 02:30:02,440 --> 02:30:04,160 BECAUSE WE DON'T HAVE MORE AS I 3288 02:30:04,160 --> 02:30:06,120 SAID WE STARTED A LONG TIME AGO 3289 02:30:06,120 --> 02:30:09,040 SO WE ARE AT THAT STAGE AND WE 3290 02:30:09,040 --> 02:30:10,800 CAN'T WAIT TO GET THE FINAL -- 3291 02:30:10,800 --> 02:30:12,040 FINAL DRAWING. SO SOON ENOUGH 3292 02:30:12,040 --> 02:30:14,440 WE'LL HAVE ALL THE DATA. 3293 02:30:14,440 --> 02:30:17,080 SO WE HAD ALL THE SCREENING WITH 3294 02:30:17,080 --> 02:30:18,800 45,000 MOLECULES I TALKED TO YOU 3295 02:30:18,800 --> 02:30:20,840 ABOUT WE HAVE DONE ABOUT 1/3 OF 3296 02:30:20,840 --> 02:30:23,080 THIS ONCE WE HAVE ALL THE DATA 3297 02:30:23,080 --> 02:30:25,200 WE FEED THE MACHINE WITH THIS 3298 02:30:25,200 --> 02:30:28,400 AND HOPEFULLY GET A NICE 3D BIO 3299 02:30:28,400 --> 02:30:30,600 CODE POTENTIALLY NEW MECHANISMS 3300 02:30:30,600 --> 02:30:31,240 THAT WE MIGHT IDENTIFY. 3301 02:30:31,240 --> 02:30:33,400 SO THAT'S IT FOR ME. I WILL 3302 02:30:33,400 --> 02:30:38,040 THANKS OBVIOUSLY EVERYBODY AT 3303 02:30:38,040 --> 02:30:39,760 MODELIS ESPECIALLY SARAH LEADING 3304 02:30:39,760 --> 02:30:44,000 THE HPP PROGRAM, AND WE'VE BEEN 3305 02:30:44,000 --> 02:30:45,160 WORKING VERY INTERESTING 3306 02:30:45,160 --> 02:30:46,960 COLLABORATIVE PROJECT WE'VE BEEN 3307 02:30:46,960 --> 02:30:48,360 DOING WITH THE FAMILY THEMSELVES 3308 02:30:48,360 --> 02:30:50,280 AND PRESIDENT PEOPLE AT THE 3309 02:30:50,280 --> 02:30:52,400 UNIVERSITY HELPED IDENTIFYING 3310 02:30:52,400 --> 02:30:54,040 THE MUTE TAGS IN THE GENOME AND 3311 02:30:54,040 --> 02:30:55,800 THANK YOU VERY MUCH I'M WAITING 3312 02:30:55,800 --> 02:30:57,560 FOR THE ROUND TABLE FOR ASKING 3313 02:30:57,560 --> 02:31:01,840 QUESTIONS I GUESS FOR ANSWERING 3314 02:31:01,840 --> 02:31:02,160 QUESTIONS. 3315 02:31:02,160 --> 02:31:03,400 >> THANK YOU VERY MUCH. BACK TO 3316 02:31:03,400 --> 02:31:03,600 YOU. 3317 02:31:03,600 --> 02:31:04,960 >> THANK YOU VERY MUCH FOR A 3318 02:31:04,960 --> 02:31:06,040 WONDERFUL SESSION. SO WE'RE 3319 02:31:06,040 --> 02:31:09,200 GOING TO MOVE INTO THE LAST 3320 02:31:09,200 --> 02:31:10,640 SYMPOSIUM ON THERAPEUTICS AND 3321 02:31:10,640 --> 02:31:12,600 THREE EXCELLENT SPEAKERS AND 3322 02:31:12,600 --> 02:31:13,960 THEN Q AND A AND DISCUSSION FOR 3323 02:31:13,960 --> 02:31:15,280 THE WHOLE PANEL. 3324 02:31:15,280 --> 02:31:18,040 SO THE FIRST SPEAKER WILL BE DR. 3325 02:31:18,040 --> 02:31:19,600 KATHARINE ALTER WHO YOU MET 3326 02:31:19,600 --> 02:31:21,760 YESTERDAY FOR THOSE WHO WERE ON. 3327 02:31:21,760 --> 02:31:24,040 THOSE ARE NEW TODAY BOARD 3328 02:31:24,040 --> 02:31:27,520 CERTIFIED IN PEDIATRICS AND 3329 02:31:27,520 --> 02:31:29,400 NEURO MUSCULAR MEDICINE MEDICAL 3330 02:31:29,400 --> 02:31:32,280 DIRECTOR OF THE NIH REHAB 3331 02:31:32,280 --> 02:31:34,800 MEDICINE SHE HAS PARTICULAR 3332 02:31:34,800 --> 02:31:39,840 EXPERTISE IN CEREBRAL PALSY PASS 3333 02:31:39,840 --> 02:31:41,360 STICK OUTCOME MEASURES FOR A LOT 3334 02:31:41,360 --> 02:31:44,600 OF THE CLINICAL TRIALS CLINICAL 3335 02:31:44,600 --> 02:31:45,560 THERAPEUTIC TRIALS FOR RARE 3336 02:31:45,560 --> 02:31:48,000 DISEASE AT NIH AND SHE HAS SEEN 3337 02:31:48,000 --> 02:31:49,040 MANY OF THESE PATIENTS. 3338 02:31:49,040 --> 02:31:53,040 NEXT SPEAKER WILL BE MIGUEL 3339 02:31:53,040 --> 02:31:57,520 ESTEVESING AND HE IS IT A SOC 3340 02:31:57,520 --> 02:31:59,560 PROFESSORS HE RECEIVED HIS PH.D. 3341 02:31:59,560 --> 02:32:01,200 FROM THE UNIVERSITY OF PORT TOW 3342 02:32:01,200 --> 02:32:04,240 IN PORTUGAL WHERE HE STARTED HIS 3343 02:32:04,240 --> 02:32:07,640 WORK IN GENE THERAPY. 3344 02:32:07,640 --> 02:32:10,200 MASSACHUSETTS MEDICAL SCHOOL 3345 02:32:10,200 --> 02:32:12,080 FOCUSES ON DEVELOPMENT OF 3346 02:32:12,080 --> 02:32:15,480 LIPOSOME MAL STORAGE DISEASES, 3347 02:32:15,480 --> 02:32:18,040 HUNTINGTON'S DISEASE. ALS, 3348 02:32:18,040 --> 02:32:22,600 BRAIN TUMORS, NOVEL AV CAP LETS 3349 02:32:22,600 --> 02:32:24,040 ON TARGET TISSUES IN THESE 3350 02:32:24,040 --> 02:32:25,040 DISEASES WITH A PARTICULAR FOCUS 3351 02:32:25,040 --> 02:32:28,600 ON THE CNS. HE LEADS THE GENE 3352 02:32:28,600 --> 02:32:31,240 THERAPY CONSORTIUM WITH A 3353 02:32:31,240 --> 02:32:34,320 FOCUSED TO DEVELOP GENE THERAPY. 3354 02:32:34,320 --> 02:32:36,160 HE'S ALSO PART OF THE CLINICAL 3355 02:32:36,160 --> 02:32:41,360 TRIAL THAT DR. TIP SPOKE ABOUT 3356 02:32:41,360 --> 02:32:43,360 YESTERDAY FOR GN1 AND ALSO DOING 3357 02:32:43,360 --> 02:32:48,000 WORK ON SPG4 AND FINAL SPEAKER 3358 02:32:48,000 --> 02:32:52,280 IS DR. JAHANNAZ DASTGIR DID HER 3359 02:32:52,280 --> 02:32:54,520 PEDIATRIC TRAINING AT BOSTON'S 3360 02:32:54,520 --> 02:32:57,200 CHILDREN'S HOSPITAL. AT 3361 02:32:57,200 --> 02:32:57,880 MASSACHUSETTS GENERAL HOSPITAL 3362 02:32:57,880 --> 02:33:01,000 AT HARVARD CAME TO NIH TO DO AN 3363 02:33:01,000 --> 02:33:01,800 ADDITIONAL FELLOWSHIP IN RARE 3364 02:33:01,800 --> 02:33:05,520 NEURO MUSCULAR DISEASES IN 3365 02:33:05,520 --> 02:33:06,600 CHILDHOOD SECTION. SHE THEN 3366 02:33:06,600 --> 02:33:10,480 WENT TO COLUMBIA, WHERE SHE WAS 3367 02:33:10,480 --> 02:33:12,040 PROFESSOR FOR A FEW YEARS AND 3368 02:33:12,040 --> 02:33:14,240 NOW AT CHILDREN'S HOSPITAL IN 3369 02:33:14,240 --> 02:33:16,800 NEW JERSEY WHERE SHE DIRECTS THE 3370 02:33:16,800 --> 02:33:19,040 MUSCULAR DYSTROPHY CLINIC AND 3371 02:33:19,040 --> 02:33:20,680 PEDIATRIC NEURO MUSCULAR PROGRAM 3372 02:33:20,680 --> 02:33:22,920 AND EXPERTISE IN GENE THERAPY 3373 02:33:22,920 --> 02:33:25,200 FOR MANY SMA PATIENTS SHE TREATS 3374 02:33:25,200 --> 02:33:28,240 AND RECENTLY HAS MOVED TO 3375 02:33:28,240 --> 02:33:31,400 APPLIED THERAPEUTICS WHERE 3376 02:33:31,400 --> 02:33:32,920 MEDICAL DIRECTOR OF THE 3377 02:33:32,920 --> 02:33:34,400 DEFICIENCY SO GREAT PERSPECTIVE 3378 02:33:34,400 --> 02:33:37,000 ON RARE DISEASES FROM A 3379 02:33:37,000 --> 02:33:37,920 CLINICIAN PERSPECTIVE ALSO FROM 3380 02:33:37,920 --> 02:33:39,960 A PHARMACEUTICAL PERSPECTIVE. 3381 02:33:39,960 --> 02:33:44,520 WE THANK EVERYBODY N ON THE 3382 02:33:44,520 --> 02:33:47,560 PANEL AND WILL START WITH DR. 3383 02:33:47,560 --> 02:33:58,240 ALTER. DR. ALTER I THINK YOU'RE 3384 02:33:58,240 --> 02:34:03,200 MUTED. 3385 02:34:03,200 --> 02:34:05,560 >> KATHARINE ALTER: SORRY ARYAN 3386 02:34:05,560 --> 02:34:11,800 I HAD TO RESHARE. CAN YOU HEAR 3387 02:34:11,800 --> 02:34:13,320 ME NOW? 3388 02:34:13,320 --> 02:34:15,440 >> YES AND IF YOU DON'T MIND 3389 02:34:15,440 --> 02:34:18,000 PUTTING YOUR SLIDES IN? THANKS. 3390 02:34:18,000 --> 02:34:19,040 >> KATHARINE ALTER: THERE WE IT 3391 02:34:19,040 --> 02:34:21,400 GO. SORRY ABOUT THAT I'M ZOOMED 3392 02:34:21,400 --> 02:34:23,680 CHALLENGED LIKE SOME OTHER 3393 02:34:23,680 --> 02:34:24,760 CLINICIANS. I'M GOING TO BE 3394 02:34:24,760 --> 02:34:27,400 COVERING SWITCHING GEARS HERE A 3395 02:34:27,400 --> 02:34:31,200 LITTLE BIT FROM THE PHYSIOLOGY 3396 02:34:31,200 --> 02:34:33,320 AND GENETICS REALM INTO THE 3397 02:34:33,320 --> 02:34:34,720 CLINICAL REALM AND I'M PRIMARILY 3398 02:34:34,720 --> 02:34:37,000 A CLINICIAN WHO BACKED INTO 3399 02:34:37,000 --> 02:34:38,760 RESEARCH AND AM FULL TIME DOING 3400 02:34:38,760 --> 02:34:42,040 RESEARCH AT NIH NOW AND TALKING 3401 02:34:42,040 --> 02:34:45,080 ABOUT REHABILITATION CARE FOR 3402 02:34:45,080 --> 02:34:48,200 CHILDREN WITH HSP BUT REALLY 3403 02:34:48,200 --> 02:34:49,800 WANT TO TALK MORE 3404 02:34:49,800 --> 02:34:51,320 PHILOSOPHICALLY THAN ABOUT 3405 02:34:51,320 --> 02:34:52,800 INDIVIDUALIZED TREATMENT WHICH 3406 02:34:52,800 --> 02:34:54,080 YOU'LL UNDERSTAND MORE WHEN I GO 3407 02:34:54,080 --> 02:34:56,400 THROUGH MY TALK. I HAVE NO 3408 02:34:56,400 --> 02:34:57,440 DISCLOSURES, AND MY TALK WILL 3409 02:34:57,440 --> 02:35:00,160 PROBABLY -- I'M GOING TO TALK 3410 02:35:00,160 --> 02:35:01,480 ABOUT DIMENSIONS OF DISABILITY 3411 02:35:01,480 --> 02:35:03,000 AND THE IMPORTANCE OF 3412 02:35:03,000 --> 02:35:05,440 STANDARDIZED IN OUR ASSESSMENTS 3413 02:35:05,440 --> 02:35:06,800 AND COMMUNICATION TO TALK ABOUT 3414 02:35:06,800 --> 02:35:08,480 THE CURRENT EVIDENCE FOR 3415 02:35:08,480 --> 02:35:10,360 REHABILITATION THERAPY AND HOW 3416 02:35:10,360 --> 02:35:12,600 WE OPTIMIZE THE TREATMENT BOTH 3417 02:35:12,600 --> 02:35:13,560 FOR CLINICAL CARE AND GOING 3418 02:35:13,560 --> 02:35:14,800 FORWARD WITH RESEARCH. 3419 02:35:14,800 --> 02:35:16,600 ONE OF THE FOCUSES I GUESS I 3420 02:35:16,600 --> 02:35:19,800 SHOULD SAY IS FROM A 3421 02:35:19,800 --> 02:35:20,880 REHABILITATION PERSPECTIVE THAT 3422 02:35:20,880 --> 02:35:22,800 WE ALWAYS FOCUS ON A CHILD'S 3423 02:35:22,800 --> 02:35:26,400 ABILITY NOT DISABILITY. AND TRY 3424 02:35:26,400 --> 02:35:33,280 TO GIVE A CHILD INTER PENS IN 3425 02:35:33,280 --> 02:35:36,040 WHATEVER WAY WE CAN REGARDLESS 3426 02:35:36,040 --> 02:35:36,880 OF IMPAIRMENT. 3427 02:35:36,880 --> 02:35:38,600 MOST OF THE TALKS THAT HAVE GONE 3428 02:35:38,600 --> 02:35:43,480 BEFORE ME TALKING ABOUT 3429 02:35:43,480 --> 02:35:45,360 PATHOPHYSIOLOGY GENETICS AND 3430 02:35:45,360 --> 02:35:47,880 EMPATHY MODELMENT GOING TO SHIFT 3431 02:35:47,880 --> 02:35:49,840 GEARS TALKING ABOUT IMPAIRMENTS 3432 02:35:49,840 --> 02:35:52,200 PROBLEMS OF BODY STRUCTURE AND 3433 02:35:52,200 --> 02:35:56,440 FUNCTION CAUSED BY A CHANGE IN 3434 02:35:56,440 --> 02:35:58,640 PATHOPHYSIOLOGY AND MY PRIMARY 3435 02:35:58,640 --> 02:36:00,200 INTEREST IS TREATING IMPAIRMENTS 3436 02:36:00,200 --> 02:36:03,040 TO IMPROVE A CHILD'S ANNE 3437 02:36:03,040 --> 02:36:04,160 ABILITY TO FUNCTION AND THEIR 3438 02:36:04,160 --> 02:36:05,480 ACTIVITY LEVEL AND THEIR ABILITY 3439 02:36:05,480 --> 02:36:06,400 TO PARTICIPATE IN THEIR 3440 02:36:06,400 --> 02:36:07,880 COMMUNITY. BUT THERE'S ALSO A 3441 02:36:07,880 --> 02:36:09,440 NUMBER OF ENVIRONMENTAL FACTORS 3442 02:36:09,440 --> 02:36:10,600 AND PERSONAL FACTORS AND WE HAVE 3443 02:36:10,600 --> 02:36:13,080 TO DECIDE WHICH OF THESE TO 3444 02:36:13,080 --> 02:36:13,760 DEVELOP REHABILITATION WHICH OF 3445 02:36:13,760 --> 02:36:17,080 THESE ARE YOU TREATING. BECAUSE 3446 02:36:17,080 --> 02:36:19,840 WE'RE NOT JUST TREATING BODY 3447 02:36:19,840 --> 02:36:20,600 STRUCTURE AND FUNCTION ON ITS 3448 02:36:20,600 --> 02:36:23,520 OWN BUT FOR A PURPOSE TO IMPROVE 3449 02:36:23,520 --> 02:36:24,040 PATIENT FUNCTION. 3450 02:36:24,040 --> 02:36:28,480 WHEN WE TALK SPECIFICALLY ABOUT 3451 02:36:28,480 --> 02:36:31,560 UPPER MOTOR NEURON SYNDROMES IN 3452 02:36:31,560 --> 02:36:33,320 CHILDHOOD WE STILL HAVE A 3453 02:36:33,320 --> 02:36:34,640 VARIETY IMPAIRMENTS INCLUDING 3454 02:36:34,640 --> 02:36:36,200 POSITIVE AND NEGATIVE YOU CAN 3455 02:36:36,200 --> 02:36:37,720 LOOK AT THIS AS A GAIN OR LOSS 3456 02:36:37,720 --> 02:36:40,800 OF FUNCTION IN THIS REALM AS 3457 02:36:40,800 --> 02:36:42,040 WELL AS FAR AS IMPAIRMENT AND 3458 02:36:42,040 --> 02:36:43,640 THE THINGS WE SEE AND PATIENTS 3459 02:36:43,640 --> 02:36:46,800 SEE AND THERAPISTS OFTEN SEE 3460 02:36:46,800 --> 02:36:50,200 MOST -- MOST EASILY ARE THE 3461 02:36:50,200 --> 02:36:55,160 POSITIVE OR GAIN IN FUNCTION 3462 02:36:55,160 --> 02:37:02,400 ABNORMAL REFLEXES, BUT ALSO JUST 3463 02:37:02,400 --> 02:37:04,400 AS EQUALLY IMPORTANT ARE 3464 02:37:04,400 --> 02:37:06,040 NEGATIVE SIGNS AND SYMPTOMS OR 3465 02:37:06,040 --> 02:37:08,120 THE LOSS OF FUNCTION, INCLUDING 3466 02:37:08,120 --> 02:37:10,080 LOSS OF SELECTIVE MOTOR CONTROL, 3467 02:37:10,080 --> 02:37:12,600 WEAKNESS OR HYPO TONE YAW AND 3468 02:37:12,600 --> 02:37:14,600 SENSORY DEFICITS, REALLY THE 3469 02:37:14,600 --> 02:37:15,840 COMBINATION OF ALL THESE 3470 02:37:15,840 --> 02:37:17,960 IMPAIRMENTS THAT LEAD TO NOT 3471 02:37:17,960 --> 02:37:19,320 ONLY THE PATIENT'S FUNCTIONAL 3472 02:37:19,320 --> 02:37:20,520 LIMITATION BUT ALSO FOR CHILDREN 3473 02:37:20,520 --> 02:37:22,680 WHO ARE STILL GROWING AND 3474 02:37:22,680 --> 02:37:24,080 DEVELOPING INTO SECONDARY 3475 02:37:24,080 --> 02:37:27,920 IMPAIRMENT SUCH AS MUSCULAR 3476 02:37:27,920 --> 02:37:29,400 SKELETAL DISEASE AND 3477 02:37:29,400 --> 02:37:30,760 CONTRACTURES AND JOINT 3478 02:37:30,760 --> 02:37:31,400 DISLOCATION. 3479 02:37:31,400 --> 02:37:32,560 WHEN DEVELOPING A TREATMENT PLAN 3480 02:37:32,560 --> 02:37:34,480 WE ALWAYS HAVE TO START WITH 3481 02:37:34,480 --> 02:37:36,040 WHAT'S MOST IMPORTANT. AND 3482 02:37:36,040 --> 02:37:38,000 REALLY WHAT'S MOST IMPORTANT IS 3483 02:37:38,000 --> 02:37:39,800 THAT WE RECOGNIZE THE -- THAT 3484 02:37:39,800 --> 02:37:43,440 THESE PATIENTS HAVE MULTIPLE 3485 02:37:43,440 --> 02:37:46,040 IMPAIRMENTS NOT JUST SPASTICITY 3486 02:37:46,040 --> 02:37:47,040 AND SIGNIFICANT FUNGICIDE 3487 02:37:47,040 --> 02:37:49,360 VARIABILITY IN WHAT YOU SEE WITH 3488 02:37:49,360 --> 02:37:52,480 THESE IMPAIRMENTS AND THE 3489 02:37:52,480 --> 02:37:53,760 IMPAIRMENTS ARE AFFECT ALL 3490 02:37:53,760 --> 02:37:55,000 DOMAINS OF A PATIENT'S FUNCTION 3491 02:37:55,000 --> 02:37:57,040 SO IF YOU CHOOSE A TREATMENT FOR 3492 02:37:57,040 --> 02:37:58,280 AN IMPAIRMENT THAT REALLY ISN'T 3493 02:37:58,280 --> 02:37:59,320 CAUSE AGO PROBLEM FOR THAT 3494 02:37:59,320 --> 02:38:01,080 PATIENT OR A FUNCTIONAL GOAL 3495 02:38:01,080 --> 02:38:02,200 THAT REALLY ISN'T ACHIEVABLE FOR 3496 02:38:02,200 --> 02:38:03,200 THE PATIENT YOUR THERAPY IS 3497 02:38:03,200 --> 02:38:04,000 GOING TO FAIL. 3498 02:38:04,000 --> 02:38:06,120 SO YOU REALLY NEED TO CORRECTLY 3499 02:38:06,120 --> 02:38:09,200 IDENTIFY THE IMPAIRMENT, MEASURE 3500 02:38:09,200 --> 02:38:12,120 THE IMPAIRMENTS AND WHAT ARE THE 3501 02:38:12,120 --> 02:38:13,960 FUNCTIONAL GOALS FOR 3502 02:38:13,960 --> 02:38:14,680 REHABILITATION PROGRAM AND SET 3503 02:38:14,680 --> 02:38:17,400 REALISTIC GOALS FOR A PATIENT 3504 02:38:17,400 --> 02:38:19,880 FOR THERAPY TO REALLY SUCCEED. 3505 02:38:19,880 --> 02:38:21,400 SO TO BEGIN WITH AND I KNOW THIS 3506 02:38:21,400 --> 02:38:23,200 IS MENTIONED IN PREVIOUS TALKS 3507 02:38:23,200 --> 02:38:24,880 YESTERDAY, THAT TO START OFF WE 3508 02:38:24,880 --> 02:38:26,680 ALL NEED TO TALK AND COMMUNICATE 3509 02:38:26,680 --> 02:38:29,400 WITH ONE ANOTHER, AND WE NEED TO 3510 02:38:29,400 --> 02:38:30,920 USE THE SAME LANGUAGE. 3511 02:38:30,920 --> 02:38:33,400 AND PART OF THIS IS CORRECTLY 3512 02:38:33,400 --> 02:38:35,760 IDENTIFYING MEASURING AT THE 3513 02:38:35,760 --> 02:38:37,080 IMPAIRMENT LEVEL AND THEN 3514 02:38:37,080 --> 02:38:39,960 IDENTIFYING WHAT THE PATIENT'S 3515 02:38:39,960 --> 02:38:41,080 FUNCTIONAL LIMITATIONS ARE, ONE 3516 02:38:41,080 --> 02:38:44,600 OF THE THINGS I'M WORKING ON, 3517 02:38:44,600 --> 02:38:47,840 INCLUDING IN TRIALS WITH DR. 3518 02:38:47,840 --> 02:38:50,000 TIFTON AND OTHER CLINICS 3519 02:38:50,000 --> 02:38:52,480 RESEARCHERS THAT NIH ARE 3520 02:38:52,480 --> 02:38:54,000 ESTABLISHING QUANTITATIVE 3521 02:38:54,000 --> 02:38:55,880 BIOMARKERS WE CAN USE FOR 3522 02:38:55,880 --> 02:38:57,400 CLINICAL RESEARCH. INCLUDING 3523 02:38:57,400 --> 02:38:59,400 QUANTITATIVE MARKERS IN THE 3524 02:38:59,400 --> 02:39:00,040 REHABILITATION REALM. 3525 02:39:00,040 --> 02:39:01,680 THIS IS GOING TO HELP US IN THE 3526 02:39:01,680 --> 02:39:02,800 FUTURE DETERMINE WHICH 3527 02:39:02,800 --> 02:39:03,640 TREATMENTS ARE MOST EFFECTIVE 3528 02:39:03,640 --> 02:39:07,200 AND WHICH CAN BE -- WHICH 3529 02:39:07,200 --> 02:39:12,560 TREATMENTS CAN BE USED AND THEN 3530 02:39:12,560 --> 02:39:14,840 MARKETED I GUESS IN A PATIENT 3531 02:39:14,840 --> 02:39:16,360 SENSE FOR RESEARCH. 3532 02:39:16,360 --> 02:39:18,200 WE CAN MEASURE RESPONSE TO 3533 02:39:18,200 --> 02:39:20,600 TREATMENT MORE EASILY IF WE'RE 3534 02:39:20,600 --> 02:39:22,840 QUANTITATING THE EFFECTS OF THE 3535 02:39:22,840 --> 02:39:24,000 TREATMENT. AND I'M GOING TO 3536 02:39:24,000 --> 02:39:25,640 START BRIEFLY GOING BACK TO THE 3537 02:39:25,640 --> 02:39:26,800 IMPAIRMENT LEVEL BECAUSE I WANT 3538 02:39:26,800 --> 02:39:31,600 TO MAKE SURE WE'RE ALL USING THE 3539 02:39:31,600 --> 02:39:37,400 SAME LANGUAGE IF PASS CITIES 3540 02:39:37,400 --> 02:39:42,080 CITY YOU FEEL IT A BIT BUT MORE 3541 02:39:42,080 --> 02:39:44,200 RAPIDLY YOU MOVE THE LIMB IT'S 3542 02:39:44,200 --> 02:39:45,320 IMPORTANT YOU EXAMINE THE 3543 02:39:45,320 --> 02:39:49,360 PATIENT CORRECTLY IN THE CORRECT 3544 02:39:49,360 --> 02:39:52,960 POSITION IN TERMS FOR THE 3545 02:39:52,960 --> 02:39:54,400 QUADRICEPSES A POSITION PATIENT 3546 02:39:54,400 --> 02:40:08,600 PRONE ALWAYS USED FOR CLINICAL 3547 02:40:08,600 --> 02:40:09,640 TRIALS OR THERAPY BECAUSE IT'S 3548 02:40:09,640 --> 02:40:14,120 MANDATED BY THE FDA IS MODIFIED 3549 02:40:14,120 --> 02:40:15,880 OR STANDARD ASHWORTH SKILL. 3550 02:40:15,880 --> 02:40:18,040 DOESN'T USUALLY MEASURE PASS 3551 02:40:18,040 --> 02:40:20,040 CITIES CITY ONLY PERFORMED AT 3552 02:40:20,040 --> 02:40:21,960 ONE SPEED THE SPEED OF THE LIMB 3553 02:40:21,960 --> 02:40:22,920 FALLING THROUGH GRAVITY WHICH IS 3554 02:40:22,920 --> 02:40:28,520 NOT FAST. AND SO IT MEASURES 3555 02:40:28,520 --> 02:40:30,080 NOT ONLY POTENTIAL SPAS CITIES 3556 02:40:30,080 --> 02:40:33,800 FESS ELEMENTS OF THE MUSCLE. A 3557 02:40:33,800 --> 02:40:40,880 MORE SPECIFIC MEASURE IS 3558 02:40:40,880 --> 02:40:42,600 MODIFIED SCALE. EXAM HERE SEE 3559 02:40:42,600 --> 02:40:44,560 THIS SPASTIC CATCH WHEN I 3560 02:40:44,560 --> 02:40:46,640 RAPIDLY FLEX THE KNEE AT ABOUT 3561 02:40:46,640 --> 02:40:49,320 20 DEGREES THIS PATIENT HAS AN 3562 02:40:49,320 --> 02:40:52,800 R1 AT ABOUT 20 DEGREES. BECAUSE 3563 02:40:52,800 --> 02:40:55,920 OF SPASTICITY. SO THE TARDU 3564 02:40:55,920 --> 02:40:58,640 SCALE WHEN COMMUNICATING ONE 3565 02:40:58,640 --> 02:41:01,000 ANOTHER ABOUT SPASTICITY A MORE 3566 02:41:01,000 --> 02:41:02,600 SPECIFIC MEASURE OF SPASTICITY 3567 02:41:02,600 --> 02:41:04,120 THAN THE ASHER SCALE AND IF 3568 02:41:04,120 --> 02:41:06,880 WE'RE LOOKING FOR OTHER 3569 02:41:06,880 --> 02:41:08,800 IMPAIRMENTS MOTOR IMPAIRMENTS IN 3570 02:41:08,800 --> 02:41:11,000 MOVEMENT DISORDERS HYPER 20 3571 02:41:11,000 --> 02:41:12,240 ASSESSMENT TOOL IS A GREAT 3572 02:41:12,240 --> 02:41:14,000 DISCRIM NAH ACTIVE SCALE THAT 3573 02:41:14,000 --> 02:41:15,560 CAN HELP US IDENTIFY OTHER 3574 02:41:15,560 --> 02:41:17,600 MOVEMENT DISORDERS THAT MAY BE 3575 02:41:17,600 --> 02:41:19,760 PRESENT IN PATIENTS WITH HSP BUT 3576 02:41:19,760 --> 02:41:22,880 YOU WON'T SEE UNLESS YOU LOOK 3577 02:41:22,880 --> 02:41:30,400 FOR THEM. GIVING A SHOUT OUT TO 3578 02:41:30,400 --> 02:41:34,240 THE TOOLS WHEN WE TALK ABOUT 3579 02:41:34,240 --> 02:41:37,160 SPASTICITY EVERYONE'S CONCERNED 3580 02:41:37,160 --> 02:41:43,440 ABOUT THE NEGATIVE IMPACT SPAS 3581 02:41:43,440 --> 02:41:48,000 CITIES STEE. AQUINAS FEET BUT 3582 02:41:48,000 --> 02:41:49,800 SPASTICITY HAS POSITIVE BENEFITS 3583 02:41:49,800 --> 02:41:51,560 HELPS MAINTAIN MUSCLE TONE 3584 02:41:51,560 --> 02:41:56,160 CIRCULATORY FUNCTION TO PREVENT 3585 02:41:56,160 --> 02:42:01,240 DVT. S AND ASSIST FUNCTION. 3586 02:42:01,240 --> 02:42:02,000 PATIENT WITH CEREBRAL PALSY MAY 3587 02:42:02,000 --> 02:42:04,800 NOT LOOK LIKE IT HYPER FLEX YAW 3588 02:42:04,800 --> 02:42:09,400 AND SPASTICITY BUT PRIMARY 3589 02:42:09,400 --> 02:42:10,920 IMPAIRMENT HYPERTONIA. THE 3590 02:42:10,920 --> 02:42:13,200 TREATMENT IS VERY DIFFERENT. IF 3591 02:42:13,200 --> 02:42:18,080 YOU IDENTIFY THE IMPROVEMENT 3592 02:42:18,080 --> 02:42:22,320 IMPACT OF IMPAIRMENT ANDISM IN 3593 02:42:22,320 --> 02:42:26,400 CHILDREN YOU MAY DEVELOP THE 3594 02:42:26,400 --> 02:42:27,600 WRONG TREATMENT FOR THAT 3595 02:42:27,600 --> 02:42:27,840 PATIENT. 3596 02:42:27,840 --> 02:42:30,000 WHEN WE LOOK AT REHABILITATION 3597 02:42:30,000 --> 02:42:32,920 WE SEE OUR THERAPIES ARE 3598 02:42:32,920 --> 02:42:33,760 ADDRESSING PRIMARILY THE 3599 02:42:33,760 --> 02:42:37,360 IMPAIRMENT LEVEL WE'RE LOOKING 3600 02:42:37,360 --> 02:42:46,800 AT ACTIVITY BASED THERAPY 3601 02:42:46,800 --> 02:42:49,360 STRENGTHENING, MEDICAL SIDE 3602 02:42:49,360 --> 02:42:53,080 SPASTICITY MANAGEMENT ON THE 3603 02:42:53,080 --> 02:42:55,160 POSITIVE SIDE. REMEMBER OUR 3604 02:42:55,160 --> 02:42:56,720 FUNCTIONAL GOALS FOR TREATING 3605 02:42:56,720 --> 02:42:58,120 IMPAIRMENTS ARE IN THESE OTHER 3606 02:42:58,120 --> 02:43:00,800 REALMS, SO I'M TRYING TO 3607 02:43:00,800 --> 02:43:02,120 SEPARATE OUT OR SHOW THAT YOU 3608 02:43:02,120 --> 02:43:04,160 KNOW ALTHOUGH WE'RE LOOKING AT 3609 02:43:04,160 --> 02:43:05,400 IMPAIRMENT THAT THE GOAL REALLY 3610 02:43:05,400 --> 02:43:08,440 IS FUNCTIONAL INDEPENDENT AND 3611 02:43:08,440 --> 02:43:09,760 ADDRESSING THESE THROUGH 3612 02:43:09,760 --> 02:43:11,200 THERAPEUTIC WHATEVER MODALITIES 3613 02:43:11,200 --> 02:43:13,640 THAT WE CAN ACHIEVE IT'S FOR AN 3614 02:43:13,640 --> 02:43:14,520 INDIVIDUAL PATIENT. 3615 02:43:14,520 --> 02:43:17,400 AND IN -- WE'VE GOT MANY REALMS 3616 02:43:17,400 --> 02:43:20,760 THAT REHABILITATION OCCURS IN 3617 02:43:20,760 --> 02:43:22,920 NOT JUST IN A CENTER BUT IN THE 3618 02:43:22,920 --> 02:43:25,400 CENTER THE BAG OF CONTRIBUTION 3619 02:43:25,400 --> 02:43:26,880 INCLUDE STRENGTHENING FOREST 3620 02:43:26,880 --> 02:43:31,240 ACCEPT ACTIVE TREATMENT TO WORK 3621 02:43:31,240 --> 02:43:32,440 ON STRENGTH AND BALANCE MOBILITY 3622 02:43:32,440 --> 02:43:34,560 TRAINING AND FEEDING THERAPIES, 3623 02:43:34,560 --> 02:43:38,840 MOTOR TORE, WE ALSO HAVE 3624 02:43:38,840 --> 02:43:40,000 REHABILITATION TO SUPPORT 3625 02:43:40,000 --> 02:43:42,040 PATIENT FUNCTION IN RESEARCH 3626 02:43:42,040 --> 02:43:45,360 CLINICAL REALM COMMUNICATION 3627 02:43:45,360 --> 02:43:46,040 DIFFICULTIES. USING MEDICATION 3628 02:43:46,040 --> 02:43:48,200 TO IMPROVE ABILITY TO 3629 02:43:48,200 --> 02:43:49,800 COMMUNICATE NEEDS AND THOUGHTS 3630 02:43:49,800 --> 02:43:52,320 WITH OTHERS. USE REHABILITATION 3631 02:43:52,320 --> 02:43:58,000 ROBOTICS IN CHILDREN AN NIH LED 3632 02:43:58,000 --> 02:44:01,400 STUDY FOR AN EX SKOE SKELETON 3633 02:44:01,400 --> 02:44:02,600 DEVICE FOR PATIENTS TO ASSIST 3634 02:44:02,600 --> 02:44:05,000 PATIENTS IN WALKING AND A 3635 02:44:05,000 --> 02:44:06,800 FUNCTIONAL LEFT VENTRICLE 3636 02:44:06,800 --> 02:44:07,800 STIMULATION CAST AND/OR THOUGHT 3637 02:44:07,800 --> 02:44:09,680 TICKS AND A WHOLE REALM OF 3638 02:44:09,680 --> 02:44:12,800 MOBILITY ASSISTED DEVICES FROM 3639 02:44:12,800 --> 02:44:14,880 WALKERS CANES AND CRUTCHES TO 3640 02:44:14,880 --> 02:44:16,800 EARLY TREATMENT MOBILITY 3641 02:44:16,800 --> 02:44:18,080 LIMITATIONS IN CHILDREN 3642 02:44:18,080 --> 02:44:19,960 PROVIDING POWER MOBILITY TO VERY 3643 02:44:19,960 --> 02:44:21,600 YOUNG CHILDREN FOR WHEELCHAIR 3644 02:44:21,600 --> 02:44:25,360 POWER MOBILITY FOR OLDER 3645 02:44:25,360 --> 02:44:31,280 CHILDREN. 3646 02:44:31,280 --> 02:44:33,360 WE BILL TAGS IN THE COMMUNITY IS 3647 02:44:33,360 --> 02:44:35,520 IMPORTANT WE WANT KIDS TO BE 3648 02:44:35,520 --> 02:44:41,080 FUNCTIONAL IN COMMUNITY NOT JUST 3649 02:44:41,080 --> 02:44:42,840 THERAPY GYM. I DON'T WANT MY 3650 02:44:42,840 --> 02:44:45,840 KIDS WHO ARE IN REHAB TO BE JUST 3651 02:44:45,840 --> 02:44:48,000 IN A THERAPY GYM I WANT THEM OUT 3652 02:44:48,000 --> 02:44:49,640 IN THE COMMUNITY DOING GOLF 3653 02:44:49,640 --> 02:44:52,200 SWIMMING, DOING CLIMBING, 3654 02:44:52,200 --> 02:44:54,120 SKIING, BALLET PROGRAM AND 3655 02:44:54,120 --> 02:44:56,440 ADAPTIVE BALLET PROGRAM IN THE 3656 02:44:56,440 --> 02:44:57,640 WASHINGTON AREA AND AN ICE 3657 02:44:57,640 --> 02:44:59,000 SKATING PROGRAM AS WELL SO WHEN 3658 02:44:59,000 --> 02:45:00,920 A KID IS ASKED BY THEIR PEERS ON 3659 02:45:00,920 --> 02:45:03,040 MONDAY WHAT DID YOU DO THIS 3660 02:45:03,040 --> 02:45:04,880 WEEKEND I WENT SKIING AND I WENT 3661 02:45:04,880 --> 02:45:06,800 TO BALLET, YOU KNOW, I TOOK 3662 02:45:06,800 --> 02:45:09,280 SWIMMING CLASSES NOT THAT I WENT 3663 02:45:09,280 --> 02:45:13,160 TO PHYSICAL THERAPY OR 3664 02:45:13,160 --> 02:45:13,960 OCCUPATIONAL THERAPY. 3665 02:45:13,960 --> 02:45:14,960 ANOTHER CONSIDERATION BESIDES 3666 02:45:14,960 --> 02:45:17,400 TYPE OF THERAPY WE DO IS 3667 02:45:17,400 --> 02:45:20,720 INTENSITY AND DURATION. THE 3668 02:45:20,720 --> 02:45:22,400 QUESTION RAISED INTENSIVE 3669 02:45:22,400 --> 02:45:24,200 THERAPY ARE MORE EFFECTIVE OR 3670 02:45:24,200 --> 02:45:26,280 EQUALLY EFFECTIVE TO ROUTINE 3671 02:45:26,280 --> 02:45:30,080 THERAPIES THAT PERFORM ON A 3672 02:45:30,080 --> 02:45:36,440 REGULAR BASIS. ONGOING TRIALS 3673 02:45:36,440 --> 02:45:39,600 BUT CURRENTLY LIMITED 3674 02:45:39,600 --> 02:45:40,680 METAANALYSIS SHOWED A SMALL TO 3675 02:45:40,680 --> 02:45:44,240 MODE DES EFFECT SIZE OF BUNCHING 3676 02:45:44,240 --> 02:45:45,600 THERAPY TOGETHER TO DO INTENSIVE 3677 02:45:45,600 --> 02:45:47,760 TWO TO THREE TIMES A YEAR FOR A 3678 02:45:47,760 --> 02:45:49,200 COUPLE OF WEEKS RATHER THAN 3679 02:45:49,200 --> 02:45:51,560 DOING ONCE A WEEK THERAPY 3680 02:45:51,560 --> 02:45:51,800 FOREVER. 3681 02:45:51,800 --> 02:45:55,080 AND THERE ARE SOME FAMILIES THAT 3682 02:45:55,080 --> 02:45:57,400 TYPE OF THERAPY WORKS BETTER OR 3683 02:45:57,400 --> 02:45:59,520 IN ADDITION TO THEIR ROUTINE 3684 02:45:59,520 --> 02:45:59,760 THERAPY. 3685 02:45:59,760 --> 02:46:01,120 SO NOW THE QUESTION IS WHAT'S 3686 02:46:01,120 --> 02:46:02,800 THE EVIDENCE FOR REHABILITATION 3687 02:46:02,800 --> 02:46:04,240 THERAPIES? AND THE PROBLEM IS 3688 02:46:04,240 --> 02:46:07,400 THAT THERE ISN'T GREAT EVIDENCE. 3689 02:46:07,400 --> 02:46:09,400 PART OF THIS IS WHAT WORKS BEST 3690 02:46:09,400 --> 02:46:11,600 AND WHAT WORKS BEST FOR WHO. 3691 02:46:11,600 --> 02:46:14,760 THAT QUESTION IS REALLY NEEDS TO 3692 02:46:14,760 --> 02:46:22,760 BE ANSWERED. AGAIN ALL OF THESE 3693 02:46:22,760 --> 02:46:26,120 THINGS WE CAN DO BUT WHICH 3694 02:46:26,120 --> 02:46:27,720 INTERVENTIONS ARE GOING TO BE 3695 02:46:27,720 --> 02:46:29,160 EFFECTIVE. SOME THINGS ARE 3696 02:46:29,160 --> 02:46:29,960 COLORED RED AND SOME THINGS 3697 02:46:29,960 --> 02:46:33,400 GREEN WHEN I GO TO MY NEXT SLIDE 3698 02:46:33,400 --> 02:46:35,560 WHEN WE SELECT INTERVENTIONS WE 3699 02:46:35,560 --> 02:46:37,400 NEED TO DETERMINE WHETHER A 3700 02:46:37,400 --> 02:46:40,200 SPECIFIC TREATMENT CAN BE 3701 02:46:40,200 --> 02:46:42,000 EFFECTIVE. DOES THE INTENSITY 3702 02:46:42,000 --> 02:46:43,520 AND TREATMENT EFFECT EFFICACY 3703 02:46:43,520 --> 02:46:45,160 AND IF THAT THERAPY ISN'T 3704 02:46:45,160 --> 02:46:47,160 EFFECTIVE ARE THERE OTHER TYPES 3705 02:46:47,160 --> 02:46:48,960 OF THERAPIES THAT SHOULD BE 3706 02:46:48,960 --> 02:46:51,000 CONSIDERED FOR A PATIENT AND HOW 3707 02:46:51,000 --> 02:46:54,480 DO YOU ACHIEVE THIS? THIS IS A 3708 02:46:54,480 --> 02:46:59,000 SLIDE FROM A REVIEW PAPER BY 3709 02:46:59,000 --> 02:47:02,320 NOVAK PUBLISHED IN 2013 IN 3710 02:47:02,320 --> 02:47:05,040 DEVELOPMENTAL MEDICINE ALL THE 3711 02:47:05,040 --> 02:47:06,600 THERAPIES THROUGHOUT THERE IS 3712 02:47:06,600 --> 02:47:09,560 WITH CEREBRAL PALSY AND ANOTHER 3713 02:47:09,560 --> 02:47:11,320 UPPER MOTOR NEURON SYNDROME 3714 02:47:11,320 --> 02:47:13,200 WE'VE BEEN TALKING ABOUT THROUGH 3715 02:47:13,200 --> 02:47:14,600 THIS LAST TWO DAYS AND SHE 3716 02:47:14,600 --> 02:47:16,200 DEVISED THIS SCHEME WHICH I 3717 02:47:16,200 --> 02:47:17,760 THINK IS GREAT, WHICH IS A GREEN 3718 02:47:17,760 --> 02:47:18,720 LIGHT WHICH IS THERAPIES THAT 3719 02:47:18,720 --> 02:47:20,880 YOU SHOULD DEFINITELY CONSIDER 3720 02:47:20,880 --> 02:47:22,920 TO IMPROVE AND BE EFFECTIVE. 3721 02:47:22,920 --> 02:47:24,520 ORANGE WHICH IS THEY MIGHT BE 3722 02:47:24,520 --> 02:47:25,800 EFFECTIVE AND RED IS YOU 3723 02:47:25,800 --> 02:47:26,840 SHOULDN'T DO THEM BECAUSE THESE 3724 02:47:26,840 --> 02:47:32,240 THINGS DON'T WORK. AND THEY'VE 3725 02:47:32,240 --> 02:47:32,600 BE 3726 02:47:32,600 --> 02:47:34,320 BEEN PROVEN TO NOT WORK. 3727 02:47:34,320 --> 02:47:35,800 IS IT WORTH IT LINE. SOME 3728 02:47:35,800 --> 02:47:37,400 THINGS YOU SEE FOR THERAPY AND 3729 02:47:37,400 --> 02:47:39,800 MOTOR THERAPIES ARE DEFINITELY 3730 02:47:39,800 --> 02:47:42,000 WORTH IT AND HAVE BEEN PROVEN TO 3731 02:47:42,000 --> 02:47:45,360 BE EFFECTIVE. LIKE MOTOR 3732 02:47:45,360 --> 02:47:48,360 THERAPY OR HABIT THERAPIMENT 3733 02:47:48,360 --> 02:47:51,800 HOME PROGRAMS PROVEN TO BE 3734 02:47:51,800 --> 02:47:53,400 EFFECTIVE NAMED THERAPY NEURO 3735 02:47:53,400 --> 02:47:57,000 DON'T TALL TREATMENT NDT PROVEN 3736 02:47:57,000 --> 02:47:59,280 TO BE NECK EFFECTIVE BUT OFTEN 3737 02:47:59,280 --> 02:48:00,080 CONTINUALLY USED IN THE 3738 02:48:00,080 --> 02:48:02,320 COMMUNITY. SO I LIKE TO SET THE 3739 02:48:02,320 --> 02:48:03,680 FRAMEWORK OF HOW WE START 3740 02:48:03,680 --> 02:48:06,640 LOOKING AT WHAT THERAPIES TO 3741 02:48:06,640 --> 02:48:10,120 PROVIDE BASED ON THIS MEDIC 3742 02:48:10,120 --> 02:48:18,800 REVIEW. QUESTION BEYOND 3743 02:48:18,800 --> 02:48:20,400 EFFICACY INTERVENTION IS WHAT 3744 02:48:20,400 --> 02:48:22,520 CAN FAMILIES FEASIBLY DO? 3745 02:48:22,520 --> 02:48:24,120 BECAUSE THEY HAVE OTHER 3746 02:48:24,120 --> 02:48:26,400 CHILDREN, THEY HAVE WORK WE'VE 3747 02:48:26,400 --> 02:48:28,000 HEARD FROM SEVERAL FAMILY 3748 02:48:28,000 --> 02:48:29,000 MEMBERS THE AMOUNT OF BURDEN 3749 02:48:29,000 --> 02:48:31,680 THAT IT IS ON FAMILIES TO TRY TO 3750 02:48:31,680 --> 02:48:32,520 NEGOTIATE ALL THE THINGS THAT 3751 02:48:32,520 --> 02:48:34,560 THEY NEED TO DO IN THEIR LIFE 3752 02:48:34,560 --> 02:48:38,000 AND THEN TAKE THEIR KIDS TO AS 3753 02:48:38,000 --> 02:48:39,520 MANY THERAPIES AS WE PRESCRIBE 3754 02:48:39,520 --> 02:48:41,320 FOR THEM. AND TO GET INSURANCE 3755 02:48:41,320 --> 02:48:43,120 COVERAGE OR TO FIGHT WITH THE 3756 02:48:43,120 --> 02:48:45,400 INSURANCE COMPANY BECAUSE THE 3757 02:48:45,400 --> 02:48:46,720 INSURANCE COMPANY DENIES PIECES 3758 02:48:46,720 --> 02:48:47,600 OF EQUIPMENT OR THERAPY. 3759 02:48:47,600 --> 02:48:50,080 AND THE LAST PIECE OF THIS IS 3760 02:48:50,080 --> 02:48:52,240 REALLY THE CHILD CENTER PIECE OF 3761 02:48:52,240 --> 02:48:53,760 IT, WHICH IS KIDS NEED TO BE 3762 02:48:53,760 --> 02:48:55,840 KIDS. AND KIDS WITH HSP ALSO 3763 02:48:55,840 --> 02:48:57,360 NEED TO BE KIDS AND THEY NEED 3764 02:48:57,360 --> 02:48:59,520 TIME FOR UNSTRUCTURED PLAY AND 3765 02:48:59,520 --> 02:49:02,760 JUST TO BE A KID. AND YOU CAN'T 3766 02:49:02,760 --> 02:49:04,640 KEEP KIDS IN THERAPY 24/7 OR 3767 02:49:04,640 --> 02:49:15,880 THEY CAN'T BE A KID. SO 3768 02:49:15,880 --> 02:49:16,760 NARROWING THE EVIDENCE FOR 3769 02:49:16,760 --> 02:49:19,440 THERAPY DR. NOVAK DID ANOTHER 3770 02:49:19,440 --> 02:49:21,400 REVIEW IN 2019 AND A LOT MORE 3771 02:49:21,400 --> 02:49:23,000 THERAPIES THAT WE'VE HAD MORE 3772 02:49:23,000 --> 02:49:24,960 TRIALS ON, BUT WHEN WE NARROW 3773 02:49:24,960 --> 02:49:26,400 THE LIST OF INTERVENTIONS IT'S 3774 02:49:26,400 --> 02:49:28,280 REALLY BASED ON COMPARATIVE 3775 02:49:28,280 --> 02:49:30,120 TREATMENT TRIAL. SO WHEN WE 3776 02:49:30,120 --> 02:49:33,400 LOOK AT INTERVENTION A, 3777 02:49:33,400 --> 02:49:34,040 OFTENTIMES INTERVENTION A 3778 02:49:34,040 --> 02:49:36,120 BEGINNING IS SHOWN TO HAVE 3779 02:49:36,120 --> 02:49:38,600 POSITIVE RESULTS, BUT AND IT 3780 02:49:38,600 --> 02:49:41,800 LEAKS WHEN A NULLER OF LONG LIST 3781 02:49:41,800 --> 02:49:43,200 OF THERAPIES WE TRY AS YOU SEE 3782 02:49:43,200 --> 02:49:46,120 ON THE SLIDE ON THE RIGHT BUT 3783 02:49:46,120 --> 02:49:48,120 WHEN YOU DO COMPARATIVE TRIALS 3784 02:49:48,120 --> 02:49:51,200 OF INTERVENTION A AND B, THESE 3785 02:49:51,200 --> 02:49:52,600 ARE RANDOMIZED CLINICAL TRIALS 3786 02:49:52,600 --> 02:49:55,080 TO LOOK AT WHAT'S MORE EFFECTIVE 3787 02:49:55,080 --> 02:49:56,600 MANY TREATMENTS WE FOR YEARS 3788 02:49:56,600 --> 02:50:00,000 THOUGHT WERE EFFECTIVE NBT SHOWN 3789 02:50:00,000 --> 02:50:07,040 TO BE NEF TEKT ACTIVE E 3790 02:50:07,040 --> 02:50:09,640 INFECTIVE. RATHER THAN BASED ON 3791 02:50:09,640 --> 02:50:13,080 HISTORY AND WHAT WAS DONE IN THE 3792 02:50:13,080 --> 02:50:13,360 PAST. 3793 02:50:13,360 --> 02:50:16,720 SO WHO IS MOST LIKELY TO BEN 3794 02:50:16,720 --> 02:50:18,520 FISHT FROM WHAT THERAPY IS 3795 02:50:18,520 --> 02:50:21,120 DEPENDENT REALLY IN PART BASED 3796 02:50:21,120 --> 02:50:24,040 ON WHAT THEIR IMPAIRMENT IS, 3797 02:50:24,040 --> 02:50:26,920 THERE'S SO MUCH PHENOTYPIC 3798 02:50:26,920 --> 02:50:28,440 VARIABILITY HOW DO YOU SORT OUT 3799 02:50:28,440 --> 02:50:29,760 REGRESSION VARIABILITY BETWEEN 3800 02:50:29,760 --> 02:50:31,760 PATIENTS AND GROWTH AND 3801 02:50:31,760 --> 02:50:32,880 DEVELOPMENT, AND DETERMINE WHAT 3802 02:50:32,880 --> 02:50:36,040 THE EFFECTS ARE AND THESE 3803 02:50:36,040 --> 02:50:37,080 PATIENTS BOTH HAVE THE SAME 3804 02:50:37,080 --> 02:50:39,280 CONDITION BUT OBVIOUSLY THEIR 3805 02:50:39,280 --> 02:50:40,840 IMPAIRMENT LEVEL IS VERY 3806 02:50:40,840 --> 02:50:43,280 DIFFERENT. AND YOU NEED TO 3807 02:50:43,280 --> 02:50:44,920 DETERMINE WHETHER BENEFIT THE 3808 02:50:44,920 --> 02:50:48,280 SAME LEVEL OF BENEFIT CAN BE 3809 02:50:48,280 --> 02:50:49,880 MEASURED FOR BOTH OF THESE 3810 02:50:49,880 --> 02:50:51,000 PATIENTS IN THE CLINICAL TRIAL 3811 02:50:51,000 --> 02:50:53,120 WHEN THEY'RE SO DIFFERENT. 3812 02:50:53,120 --> 02:50:54,480 CAN YOU REALLY MEASURE AN EQUAL 3813 02:50:54,480 --> 02:50:56,200 AMOUNT OF BENEFIT OR IS THERE AN 3814 02:50:56,200 --> 02:50:57,000 ABSOLUTE AMOUNT OF CHANGE THAT 3815 02:50:57,000 --> 02:50:59,720 CAN BE APPLIED TO ALL KIDS? AND 3816 02:50:59,720 --> 02:51:03,200 THE ANSWER IS PROBABLY NO. 3817 02:51:03,200 --> 02:51:04,360 IT'S PROBABLY BETTER TO 3818 02:51:04,360 --> 02:51:05,760 DETERMINE A MORE PERSONAL 3819 02:51:05,760 --> 02:51:09,240 MEANINGFUL GOAL FOR AN 3820 02:51:09,240 --> 02:51:10,200 INDIVIDUAL PATIENT RATHER THAN 3821 02:51:10,200 --> 02:51:12,000 FOR A GROUP ITSELF. 3822 02:51:12,000 --> 02:51:14,920 AND THIS LEADS ME TO THE 3823 02:51:14,920 --> 02:51:16,040 DISCUSSION OF SKIP THAT IS TO 3824 02:51:16,040 --> 02:51:20,240 TALK ABOUT THIS ISSUE OF 3825 02:51:20,240 --> 02:51:22,720 VARIABILITY BETWEEN INDIVIDUALS 3826 02:51:22,720 --> 02:51:27,000 AND PERSONALIZED REHABILITATION 3827 02:51:27,000 --> 02:51:27,280 PROGRAMS. 3828 02:51:27,280 --> 02:51:28,280 BECAUSE THE TREATMENT REALLY 3829 02:51:28,280 --> 02:51:30,040 NEEDS FOR COMPLEX NEUROLOGICAL 3830 02:51:30,040 --> 02:51:31,680 DISORDERS MAY BE MORE EFFECTIVE 3831 02:51:31,680 --> 02:51:33,800 IF YOU ADJUST THE TREATMENT 3832 02:51:33,800 --> 02:51:37,640 BASED ON INDIVIDUAL PATIENT K 3833 02:51:37,640 --> 02:51:39,880 CONSCIOUSES AND WE KNOW THAT 3834 02:51:39,880 --> 02:51:41,080 SPANS FROM DREAMS FROM THE 3835 02:51:41,080 --> 02:51:43,200 PATIENT FUNCTIONAL GOALS WHAT 3836 02:51:43,200 --> 02:51:45,680 THAT THERAPY MIGHT BE. 3837 02:51:45,680 --> 02:51:46,640 PERSONALIZED MEDICINE IS -- GOES 3838 02:51:46,640 --> 02:51:51,200 BACK TO THE 1960S, WHEN IT WAS 3839 02:51:51,200 --> 02:51:52,520 FIRST IDENTIFIED THAT NOT ALL 3840 02:51:52,520 --> 02:51:54,120 MEDICATIONS WERE -- ARE 100 3841 02:51:54,120 --> 02:51:55,800 PERCENT EFFECTIVE FOR INDIVIDUAL 3842 02:51:55,800 --> 02:51:57,960 PEOPLE, AND THAT THERE'S GENETIC 3843 02:51:57,960 --> 02:51:59,880 VARIATIONS IN PEOPLE AND HOW 3844 02:51:59,880 --> 02:52:01,400 THEY METABOLIZE THE MEDICATIONS, 3845 02:52:01,400 --> 02:52:04,600 SO WE HAVE APPLIED THAT 3846 02:52:04,600 --> 02:52:06,680 PRINCIPLE TO REHABILITATION 3847 02:52:06,680 --> 02:52:07,800 SAYING ONE SIZE FITS ALL DOESN'T 3848 02:52:07,800 --> 02:52:09,280 WORK FOR OUR PATIENTS. AND IT 3849 02:52:09,280 --> 02:52:14,200 MAY BE MORE COST AND TIME 3850 02:52:14,200 --> 02:52:15,640 EFFICIENT TO FILE A TREATMENT 3851 02:52:15,640 --> 02:52:18,840 PLAN AND IT ALSO MAY REVIVE 3852 02:52:18,840 --> 02:52:21,200 THERAPIES THAT WERE FELT TO BE 3853 02:52:21,200 --> 02:52:22,760 INEFFECTIVE BECAUSE THEY WERE 3854 02:52:22,760 --> 02:52:24,080 ONLY EFFECTIVE FOR A SMALL 3855 02:52:24,080 --> 02:52:25,560 SUBGROUP OF PATIENTS. 3856 02:52:25,560 --> 02:52:28,000 BUT THAT TREATMENT IS VERY 3857 02:52:28,000 --> 02:52:29,920 EFFECTIVE FOR THAT SMALL SUBSET 3858 02:52:29,920 --> 02:52:33,360 AND IF YOU INDIVIDUAL THE 3859 02:52:33,360 --> 02:52:36,040 THERAPY AND REANALYZE THE DATA 3860 02:52:36,040 --> 02:52:37,680 YOU CAN SEE IT MAY WORK 3861 02:52:37,680 --> 02:52:39,000 PERSONALIZED DATA FOR RESEARCH 3862 02:52:39,000 --> 02:52:42,040 AND VARIABILITY AND HOW WE 3863 02:52:42,040 --> 02:52:43,600 MEASURE OUTCOMES HOW WE DO THIS 3864 02:52:43,600 --> 02:52:45,440 HOW WE SET UP PERSONALIZED 3865 02:52:45,440 --> 02:52:47,040 REHAB. LOOK AT DATA MINING, 3866 02:52:47,040 --> 02:52:49,000 LOOK AT ASSOCIATIONS FOR 3867 02:52:49,000 --> 02:52:50,560 INDIVIDUAL DATA AND DO 3868 02:52:50,560 --> 02:52:52,040 COMPARATIVE EFFECTIVENESS TRIALS 3869 02:52:52,040 --> 02:52:55,360 AND EVEN SINGLE SUBJECT DESIGN 3870 02:52:55,360 --> 02:52:56,040 AND WEIGHTLESS CONTROL TRIALS 3871 02:52:56,040 --> 02:52:58,640 CAN HELP US GET TO THIS 3872 02:52:58,640 --> 02:53:00,120 EFFICACY. 3873 02:53:00,120 --> 02:53:03,160 AN EXAMPLE OF THIS IS WHAT WAS 3874 02:53:03,160 --> 02:53:05,160 DONE IN THE ADULT STROKE WORLD, 3875 02:53:05,160 --> 02:53:09,400 WHERE THEY LOOKED AT -- AT THE 3876 02:53:09,400 --> 02:53:10,400 EFFICACY OF INTERVENTIONS AND 3877 02:53:10,400 --> 02:53:13,160 EFFICACY REALLY BASED ON THE 3878 02:53:13,160 --> 02:53:14,960 SEVERITY OF THE PATIENT 3879 02:53:14,960 --> 02:53:15,600 PREDICTED OUTCOME BETTER THAN 3880 02:53:15,600 --> 02:53:17,400 THE OUT ACTUAL TREATMENT THAT 3881 02:53:17,400 --> 02:53:18,400 WAS PERFORMED SO PATIENTS THAT 3882 02:53:18,400 --> 02:53:21,000 ARE MORE IMPAIRED HAD A 3883 02:53:21,000 --> 02:53:21,920 DIFFERENT FUNCTIONAL OUTCOME 3884 02:53:21,920 --> 02:53:23,640 THAN THOSE THAT ARE LESS 3885 02:53:23,640 --> 02:53:26,760 IMPAIRED AND ADJUSTMENTS OF 3886 02:53:26,760 --> 02:53:28,240 REHABILITATION PROGRAMS 3887 02:53:28,240 --> 02:53:29,360 IMPLEMENTED BASED ON THE RESULTS 3888 02:53:29,360 --> 02:53:31,600 OF THIS RESEARCH SO YOU CAN 3889 02:53:31,600 --> 02:53:33,360 ADJUST THE FUNCTIONAL GOALS FOR 3890 02:53:33,360 --> 02:53:35,600 A PATIENT WITH A MORE SEVERE 3891 02:53:35,600 --> 02:53:37,200 DISABILITY AND ONE WITH A 3892 02:53:37,200 --> 02:53:39,120 PATIENT WITH LESS SEVERE 3893 02:53:39,120 --> 02:53:39,400 DISABILITY. 3894 02:53:39,400 --> 02:53:42,080 AND P MY CONCLUSIONS REALLY ARE 3895 02:53:42,080 --> 02:53:45,760 REHABILITATIONS OR HABILITATION 3896 02:53:45,760 --> 02:53:47,200 IN YOUNG CHILDREN CRITICAL FOR 3897 02:53:47,200 --> 02:53:48,080 TREATMENT AND THE TREATMENT 3898 02:53:48,080 --> 02:53:49,360 SHOULDN'T BE CONSTRAINED BY THE 3899 02:53:49,360 --> 02:53:51,480 LACK OF EVIDENCE AS THEY ARE 3900 02:53:51,480 --> 02:53:53,400 NOW. I KNOW AS A CLINICIAN I 3901 02:53:53,400 --> 02:53:54,960 HEAR FROM INSURANCE COMPANIES 3902 02:53:54,960 --> 02:53:58,760 THAT THEY WON'T APPROVE CERTAIN 3903 02:53:58,760 --> 02:54:01,400 TREATMENTS BECAUSE THERE ARE NO 3904 02:54:01,400 --> 02:54:02,280 RESEARCH TO SUPPORT FOR INSTANCE 3905 02:54:02,280 --> 02:54:04,560 THE MOST RECENT ONE I HEARD WAS 3906 02:54:04,560 --> 02:54:05,880 FROM A MEDICAL INSURANCE COMPANY 3907 02:54:05,880 --> 02:54:09,560 WHO REFUSED TO PROVIDE A 3908 02:54:09,560 --> 02:54:11,440 WHEELCHAIR FOR A PATIENT BECAUSE 3909 02:54:11,440 --> 02:54:13,120 THE PATIENT WAS SIX YEARS OLD 3910 02:54:13,120 --> 02:54:14,280 AND THAT SOMEONE COULD JUST 3911 02:54:14,280 --> 02:54:17,000 CARRY THE CHILD TO AND FROM 3912 02:54:17,000 --> 02:54:17,640 WHATEVER IT WAS BECAUSE THERE 3913 02:54:17,640 --> 02:54:20,000 WAS ALWAYS AN ADULT WITH A 3914 02:54:20,000 --> 02:54:21,400 SIX-YEAR-OLD CHILD AND IT TOOK 3915 02:54:21,400 --> 02:54:22,600 ME ABOUT THREE HOURS WITH THE 3916 02:54:22,600 --> 02:54:24,040 DISCUSSION OF THE MEDICAL 3917 02:54:24,040 --> 02:54:24,600 DIRECTOR OF THE INSURANCE 3918 02:54:24,600 --> 02:54:29,000 PROGRAM FOR THEM TO UNDERSTAND 3919 02:54:29,000 --> 02:54:31,800 WHERE WHY THE CHILD NEEDED A 3920 02:54:31,800 --> 02:54:34,320 WHEELCHAIR. THAT GOES ON DAILY 3921 02:54:34,320 --> 02:54:35,840 FOR CLINICIANS TO GET APPROVAL 3922 02:54:35,840 --> 02:54:37,600 FOR THERAPY AND IT GOES ON DAILY 3923 02:54:37,600 --> 02:54:39,600 FOR FAMILIES AS WELL. 3924 02:54:39,600 --> 02:54:41,240 SO GOING FORWARD WE ALSO NEED TO 3925 02:54:41,240 --> 02:54:43,320 KNOW WHAT THERAPY AND HOW MUCH. 3926 02:54:43,320 --> 02:54:48,000 WHAT WORKS? THE CURRENT LEVEL 3927 02:54:48,000 --> 02:54:49,720 EVIDENCE IS INSUFFICIENT SO WE 3928 02:54:49,720 --> 02:54:51,360 NEED MORE HIGH QUALITY TRIALS TO 3929 02:54:51,360 --> 02:54:53,600 DO THAT WE REALLY NEED TO BETTER 3930 02:54:53,600 --> 02:54:59,600 MEASURE IMPRAICHAIRMENIMPAIRMENT, MEASURE 3931 02:54:59,600 --> 02:55:02,920 FUNCTION AND OUTCOMES AND 3932 02:55:02,920 --> 02:55:03,800 INDIVIDUALIZED TREATMENT TRIALS. 3933 02:55:03,800 --> 02:55:05,440 AND THANKS VERY MUCH TO ALL OF 3934 02:55:05,440 --> 02:55:08,000 OUR FAMILIES AND TO ALL THE 3935 02:55:08,000 --> 02:55:10,600 OTHER SPEAKERS AND TO DIANE WHO 3936 02:55:10,600 --> 02:55:12,480 IS MY LAB CHIEF WHO WAS INVOLVED 3937 02:55:12,480 --> 02:55:15,920 IN SOME OF THESE SLIDES. 3938 02:55:15,920 --> 02:55:17,400 THANK YOU. 3939 02:55:17,400 --> 02:55:18,800 >> THANK YOU SO MUCH FOR A 3940 02:55:18,800 --> 02:55:19,800 BEAUTIFUL PRESENTATION, SO 3941 02:55:19,800 --> 02:55:20,960 IMPORTANT FOR THE PATIENT'S 3942 02:55:20,960 --> 02:55:22,800 QUALITY OF LIFE TO CONSIDER 3943 02:55:22,800 --> 02:55:24,120 THESE REHAB INTERVENTIONSMENT 3944 02:55:24,120 --> 02:55:29,360 NEXT WE'LL MOVE ONTO MIGUEL 3945 02:55:29,360 --> 02:55:35,080 ESTEVES ABOUT GENE THERAPY. 3946 02:55:35,080 --> 02:55:35,880 >> MIGUEL ESTEVES: HELLO 3947 02:55:35,880 --> 02:55:37,200 EVERYONE. THANK YOU FOR THE 3948 02:55:37,200 --> 02:55:40,200 ORGANIZERS FOR INVITING ME. 3949 02:55:40,200 --> 02:55:41,120 I'LL TRY TO BE RELATIVELY BRIEF 3950 02:55:41,120 --> 02:55:42,720 ON THIS WE'RE RUNNING LATE I 3951 02:55:42,720 --> 02:55:49,040 WON'T JUST SAY WE'RE DOING AAV 3952 02:55:49,040 --> 02:55:51,720 GENE THERAPY. BUT I'LL BE MORE 3953 02:55:51,720 --> 02:55:55,520 BRIEF THAN WAS ANTICIPATED. 3954 02:55:55,520 --> 02:55:57,400 BRIEF INTRODUCTION TO ASSOCIATED 3955 02:55:57,400 --> 02:56:01,360 VIRUSES, STARTED AS A 3956 02:56:01,360 --> 02:56:03,080 CONTAMINANT DIDN'T DESERVE ITS 3957 02:56:03,080 --> 02:56:05,840 OWN NAME. WAS FOUND AS A 3958 02:56:05,840 --> 02:56:08,760 CONTAMINANT IN 1965 AND 3959 02:56:08,760 --> 02:56:11,400 MAINTAINED AS A CURIOSITY FOR 3960 02:56:11,400 --> 02:56:14,240 MOST OF ITS LIFE UNTIL DISCOVERY 3961 02:56:14,240 --> 02:56:18,400 THAT IT ACTUALLY CAN HANDLE 3962 02:56:18,400 --> 02:56:21,200 GENES QUITE EFFICIENTLY IN VIVO. 3963 02:56:21,200 --> 02:56:22,840 THE WILD TYPE VIRUS IS SIMPLE. 3964 02:56:22,840 --> 02:56:27,480 IT'S A SINGLE STRANDED DNA VIRUS 3965 02:56:27,480 --> 02:56:29,160 COMPOSED OF TWO GENES AND P 3966 02:56:29,160 --> 02:56:31,240 MAKES LINE PROTEINS AT LEAST AS 3967 02:56:31,240 --> 02:56:33,600 FAR AS WE KNOW IT'S SPENT MOST 3968 02:56:33,600 --> 02:56:36,800 OF ITS LIFE THINKING IT MADE 3969 02:56:36,800 --> 02:56:39,080 SEVEN WE DISCOVERED MORE 3970 02:56:39,080 --> 02:56:42,120 RECENTLY NINE PROTEINS, REALLY 0 3971 02:56:42,120 --> 02:56:47,720 TO 25 NAN MOMETERS AND THAT POSES 3972 02:56:47,720 --> 02:56:49,600 LIMITATIONS ON WHAT YOU CAN 3973 02:56:49,600 --> 02:56:52,320 ENCODE INTO THE VIRUS, THE SIZE 3974 02:56:52,320 --> 02:56:58,640 OF THE GENOME IS 4.7KB AND ONE 3975 02:56:58,640 --> 02:57:00,200 OF THE SAFETY FEATURES OF THE 3976 02:57:00,200 --> 02:57:02,800 ADD DEAN KNOW ASSOCIATED VIRUSES 3977 02:57:02,800 --> 02:57:05,120 THEY DON'T REPLICATE THEY DON'T 3978 02:57:05,120 --> 02:57:09,080 HAVE NECESSARY FUNCTIONS TO DO 3979 02:57:09,080 --> 02:57:10,840 SO THEREFORE CLASSIFIED BECAUSE 3980 02:57:10,840 --> 02:57:14,480 THEIR REPLICATION BEGINS ON THE 3981 02:57:14,480 --> 02:57:16,200 VIRUS HERPES SIMPLEX VIRUS. 3982 02:57:16,200 --> 02:57:19,840 IN TERMS OF HOW COMMON VECTORS 3983 02:57:19,840 --> 02:57:22,240 ARE MADE THE ONLY ELEMENTS OF 3984 02:57:22,240 --> 02:57:23,600 GENOME THAT WILD TYPE GENOME 3985 02:57:23,600 --> 02:57:27,840 THAT REMAIN THE RECOMBINANT 3986 02:57:27,840 --> 02:57:32,360 VIRUS TERMINAL PEAKS THAT TRANS 3987 02:57:32,360 --> 02:57:33,320 YET SET OF INTEREST THAT CARRIES 3988 02:57:33,320 --> 02:57:35,520 ALL THE ELEMENTS THAT YOU NEED 3989 02:57:35,520 --> 02:57:39,160 TO EXPRESS A GENE YOU KNOW CELL, 3990 02:57:39,160 --> 02:57:40,480 THE REASON THAT OF COURSE THEY 3991 02:57:40,480 --> 02:57:42,240 BECOME THE DOMINANT FORCE OR 3992 02:57:42,240 --> 02:57:51,360 DOMINANT PLATFORM FOR IN VIVO 3993 02:57:51,360 --> 02:57:52,360 GENE CLI 3994 02:57:52,360 --> 02:57:55,640 GENE DELIVERY. HIGHLY 3995 02:57:55,640 --> 02:57:57,400 EFFICIENT. ONE COULD ACTUALLY 3996 02:57:57,400 --> 02:58:00,560 CALCULATE THAT TO MOIS THE 3997 02:58:00,560 --> 02:58:02,720 ENTIRE BODY HUNDRED FOLD 3998 02:58:02,720 --> 02:58:04,040 DEFICIENCIES ARE RELATIVE THE 3999 02:58:04,040 --> 02:58:07,400 BEST WE HAVE CURRENTLY. ONE OF 4000 02:58:07,400 --> 02:58:09,400 THE ADVANTAGES IT HAZARDOUS NOT 4001 02:58:09,400 --> 02:58:10,560 INTEGRATE INTO THE GENOME AND 4002 02:58:10,560 --> 02:58:13,400 FOR THE MOST PART MAYBE A SMALL 4003 02:58:13,400 --> 02:58:18,120 PERCENTAGE OF THAT HAPPENS, IT'S 4004 02:58:18,120 --> 02:58:20,880 LOW GENEO TOXIC POTENTIAL, IT 4005 02:58:20,880 --> 02:58:25,200 CAN BE THE RIGHT TISSUE CAN BE 4006 02:58:25,200 --> 02:58:27,280 LONG-TERM GENE EXPRESSION. BUT 4007 02:58:27,280 --> 02:58:29,680 BECAUSE IT DOES NOT INTEGRATE 4008 02:58:29,680 --> 02:58:32,920 THE GENOME WRONG PLATFORM TO USE 4009 02:58:32,920 --> 02:58:35,160 FOR THE CELLS SUCH AS BONE 4010 02:58:35,160 --> 02:58:37,400 MARROW. SO OTHER PLATFORMS ARE 4011 02:58:37,400 --> 02:58:39,560 MORE ADEQUATE FOR THAT. 4012 02:58:39,560 --> 02:58:41,000 IN TERMS OF RESPONSES FOR THE 4013 02:58:41,000 --> 02:58:43,400 MOST PART CONTROLLED BY 4014 02:58:43,400 --> 02:58:45,840 EXPRESSION BUT WE ALSO HAVE THAT 4015 02:58:45,840 --> 02:58:48,080 FROM LATEST CLINICAL TRIALS 4016 02:58:48,080 --> 02:58:50,880 EXTREME DOSES THAT CAN BE 4017 02:58:50,880 --> 02:58:52,760 PROBLEMATIC AND HAVE RESULTED IN 4018 02:58:52,760 --> 02:58:56,120 SUCH CASES IN PATIENTS THAT MORE 4019 02:58:56,120 --> 02:58:56,600 RECENTLY. 4020 02:58:56,600 --> 02:59:02,000 IN THAMERMS OF -- ONE OF THE 4021 02:59:02,000 --> 02:59:02,680 INTERESTING PROPERTIES YOU CAN 4022 02:59:02,680 --> 02:59:05,360 USE THE SAME SET TO PUT IT 4023 02:59:05,360 --> 02:59:07,880 INSIDE PACKAGE INSIDE DIFFERENT 4024 02:59:07,880 --> 02:59:09,400 CAPSULES, IN TERMS OF THE 4025 02:59:09,400 --> 02:59:12,040 CENTRAL NERVOUS SYSTEM THE WORLD 4026 02:59:12,040 --> 02:59:13,240 CHANGED QUITE DRAMATICALLY IN 4027 02:59:13,240 --> 02:59:16,400 2009 WITH DISCOVERY THAT 89 4028 02:59:16,400 --> 02:59:19,400 CROSSES THE BLOOD BRAIN BARRIER 4029 02:59:19,400 --> 02:59:24,320 IN GENE THERAPY AB9 HAS THE 4030 02:59:24,320 --> 02:59:26,000 LEADING CAP SET TO DEVELOP 4031 02:59:26,000 --> 02:59:28,320 PROGRAMS TO TREAT NEUROLOGICAL 4032 02:59:28,320 --> 02:59:30,120 DISEASES ALTHOUGH IT'S FAR FROM 4033 02:59:30,120 --> 02:59:32,600 PERFECT IN TERMS OF THE 4034 02:59:32,600 --> 02:59:34,760 EFFICIENCY TRANSFER BUT THE BEST 4035 02:59:34,760 --> 02:59:36,800 WE HAVE IS FAR AND OF COURSE 4036 02:59:36,800 --> 02:59:39,760 QUITE A BIT OF CLINICAL 4037 02:59:39,760 --> 02:59:44,320 EXPERIENCE USING AAV9 GENE 4038 02:59:44,320 --> 02:59:45,400 TRANSFER. 4039 02:59:45,400 --> 02:59:48,120 IN ADDITION TO THE CHOICE OF CAP 4040 02:59:48,120 --> 02:59:49,480 SAID, THERE'S ALSO WILD TYPE 4041 02:59:49,480 --> 02:59:54,120 THAT CAN BE MODIFIED BY LEADING 4042 02:59:54,120 --> 02:59:55,560 SMALL SEQUENCE WHEREBY THE 4043 02:59:55,560 --> 03:00:00,080 GENOME IS PACKETED -- PACKAGED 4044 03:00:00,080 --> 03:00:05,120 IN THE DOUBLE STRAND SELF 4045 03:00:05,120 --> 03:00:06,080 COMPLEMENTARY GENOME, 4046 03:00:06,080 --> 03:00:07,880 DESCRIPTION OUT THERE DOUBLE 4047 03:00:07,880 --> 03:00:11,640 STRANDED CONTRARY TO THE SINGLE 4048 03:00:11,640 --> 03:00:12,280 STRAND GENOMES THAT HAVE TO BE 4049 03:00:12,280 --> 03:00:15,800 COMPORTED AND REALLY RENDERS 4050 03:00:15,800 --> 03:00:17,600 THEM CONSIDERABLY LESS 4051 03:00:17,600 --> 03:00:18,040 EFFICIENT. SEVERAL 4052 03:00:18,040 --> 03:00:19,360 CONSIDERATIONS WHEN DESIGNING 4053 03:00:19,360 --> 03:00:21,440 THE AAV VECTORS FROM THE CAP 4054 03:00:21,440 --> 03:00:23,760 SAID ALL THE WAY TO THE TYPE OF 4055 03:00:23,760 --> 03:00:25,160 GENOME THAT YOU'RE USING AND OF 4056 03:00:25,160 --> 03:00:28,600 COURSE LUNCH DOES NOT COME FREE 4057 03:00:28,600 --> 03:00:31,400 COMPLEMENTARY VECTORS ARE MORE 4058 03:00:31,400 --> 03:00:35,400 EFFICIENT BUT ALSO 2.4KB SO YOU 4059 03:00:35,400 --> 03:00:37,120 RENDER THAT TYPE OF DESIGN MAY 4060 03:00:37,120 --> 03:00:41,120 OR MAY NOT BE USEFUL OR USED 4061 03:00:41,120 --> 03:00:44,280 USABLE FOR EVERY GENE THAT ONE 4062 03:00:44,280 --> 03:00:47,080 WOULD WANT TO TRY AND DELIVER 4063 03:00:47,080 --> 03:00:49,040 FOR THERAPEUTIC PURPOSES. 4064 03:00:49,040 --> 03:00:50,960 OF COURSE THE BRAIN HAS THE 4065 03:00:50,960 --> 03:00:53,000 PERFECT DELIVERY VEHICLE, WHICH 4066 03:00:53,000 --> 03:01:01,400 IS THE BRAIN VAS SKVASCULAR SURE, 4067 03:01:01,400 --> 03:01:03,760 10 MICRONS AWAY FROM BLOOD 4068 03:01:03,760 --> 03:01:05,400 VESSEL WONDERFUL IT EXISTS 4069 03:01:05,400 --> 03:01:08,000 UNFORTUNATELY OR FORTUNATELY I 4070 03:01:08,000 --> 03:01:10,200 SUPPOSE WE HAVE A BLOOD BRAIN 4071 03:01:10,200 --> 03:01:11,520 BARRIER EFFICIENT TO DIFFUSING 4072 03:01:11,520 --> 03:01:13,800 INTO THE BRAIN. WE OFTEN IN A 4073 03:01:13,800 --> 03:01:17,360 GROUP THAT WORKING AND WITH 4074 03:01:17,360 --> 03:01:20,600 DISEASE WE ALWAYS SAY IF A WAS 4075 03:01:20,600 --> 03:01:22,200 ONLY CAUSED BY LIVER DISEASE WE 4076 03:01:22,200 --> 03:01:25,200 WOULD BE MUCH FURTHER AWAY THAN 4077 03:01:25,200 --> 03:01:25,920 WE ARE TODAY. 4078 03:01:25,920 --> 03:01:27,600 DELIVER VECTORS PRETTY MUCH FOR 4079 03:01:27,600 --> 03:01:30,080 EVERY OTHER MOLECULE IS 4080 03:01:30,080 --> 03:01:31,680 CHALLENGING THE BLOOD BRAIN 4081 03:01:31,680 --> 03:01:33,200 BARRIER PREVENTS US FROM DOING 4082 03:01:33,200 --> 03:01:36,920 SIMPLE IV ADMINISTRATIONS FOR 4083 03:01:36,920 --> 03:01:39,800 THE MOST PART, AND OFTEN IN 4084 03:01:39,800 --> 03:01:44,200 TERMS OF SMALL DRUGS THAT 4085 03:01:44,200 --> 03:01:46,120 MEDICINAL CHEMISTRY PROGRESSED 4086 03:01:46,120 --> 03:01:48,080 ENORMOUSLY WE KNOW WHAT CHEMICAL 4087 03:01:48,080 --> 03:01:50,520 MOIETIES AND FEATURES ALLOW 4088 03:01:50,520 --> 03:01:52,800 SMALL MOLECULES TO CROSS THE 4089 03:01:52,800 --> 03:01:54,560 BLOOD BRAIN BARRIER 4090 03:01:54,560 --> 03:01:55,800 UNDERSTANDING OF COURSE TALKING 4091 03:01:55,800 --> 03:01:58,440 ABOUT A VERY SMALL DOSE THAT 4092 03:01:58,440 --> 03:02:00,080 ENDS NUPT BRAIN OF COURSE ENDS 4093 03:02:00,080 --> 03:02:03,360 UP IN THE LIVER AND AAV NO 4094 03:02:03,360 --> 03:02:04,800 DIFFERENT THAT MOST OF IT ENDS 4095 03:02:04,800 --> 03:02:06,720 UP IN THE LIVER. 4096 03:02:06,720 --> 03:02:10,520 IN TERMS OF PHYSICAL METHODS TO 4097 03:02:10,520 --> 03:02:13,400 BYPASS, THE FIRST ITERATION FOR 4098 03:02:13,400 --> 03:02:15,680 NEUROLOGICAL DISEASES IT HAVE 4099 03:02:15,680 --> 03:02:19,200 THE APPROACH THAT WAS USED WAS 4100 03:02:19,200 --> 03:02:23,080 CERTAINLY THE INTERCRANIAL 4101 03:02:23,080 --> 03:02:27,440 DELIVERY CONTINUES TO BE USED, 4102 03:02:27,440 --> 03:02:28,040 PARKINS 4103 03:02:28,040 --> 03:02:30,000 PARKINSON'S DISEASE, UNDERSTAND 4104 03:02:30,000 --> 03:02:32,440 DIFFUSION, FROM LOCALIZED 4105 03:02:32,440 --> 03:02:35,080 DIFFUSION ALTERNATIVE APPROACH 4106 03:02:35,080 --> 03:02:37,720 CSF DELIVERY MULTIPLE ROUTES ONE 4107 03:02:37,720 --> 03:02:41,040 CAN USE MITRAL VENTRICLE, 4108 03:02:41,040 --> 03:02:43,480 POPULAR ONE RIGHT NOW FOR 4109 03:02:43,480 --> 03:02:45,680 DELIVERY OF AAV VECTORS FOR 4110 03:02:45,680 --> 03:02:49,320 NEUROLOGICAL DISEASE NOT JUST 4111 03:02:49,320 --> 03:02:51,760 FOR ME BUT WE USUALLY DELIVERING 4112 03:02:51,760 --> 03:02:54,160 THROUGH CSF WHICH CAUSE ISSUES 4113 03:02:54,160 --> 03:02:55,440 IN TERMS OF THE DISTRIBUTION AND 4114 03:02:55,440 --> 03:02:57,240 THE DOSES THAT NECESSARY. 4115 03:02:57,240 --> 03:03:01,880 NOW, I JUST WANTED TO MAKE SOME 4116 03:03:01,880 --> 03:03:03,560 CONSIDERATIONS THAT YOU'LL SEE 4117 03:03:03,560 --> 03:03:05,800 THAT I'LL TOUCH ON A FEW POINTS 4118 03:03:05,800 --> 03:03:07,800 RAISED BEFORE FOR DESIGNING AN 4119 03:03:07,800 --> 03:03:10,560 AV VECTOR TAKE A SIMPLE APPROACH 4120 03:03:10,560 --> 03:03:13,400 SLAP A CDMA TO THE VECTOR THAT 4121 03:03:13,400 --> 03:03:14,920 EVERYBODY USES TRY YOUR BEST 4122 03:03:14,920 --> 03:03:18,240 THAT'S PERFECTLY FINE TO DO, BUT 4123 03:03:18,240 --> 03:03:22,760 I THINK SPAST IS ONE PEOPLE 4124 03:03:22,760 --> 03:03:27,000 SHOULD TRY CAREFULLY MICRO JEWEL 4125 03:03:27,000 --> 03:03:28,080 PROTEIN I THINK STRONG POTENTIAL 4126 03:03:28,080 --> 03:03:30,120 FOR TOXICITY WITH OVER 4127 03:03:30,120 --> 03:03:33,040 EXPRESSION WE ENCOUNTERED THIS A 4128 03:03:33,040 --> 03:03:34,400 FEW YEARS AGO THAT ACTUALLY YOU 4129 03:03:34,400 --> 03:03:36,200 DO PAY A PRICE IF YOU ASK 4130 03:03:36,200 --> 03:03:39,360 NEURONS TO MAKE TOO MUCH OF A 4131 03:03:39,360 --> 03:03:41,360 PROTEIN MOST PEOPLE THINK IT'S 4132 03:03:41,360 --> 03:03:43,320 FAIRLY OFFENSIVE. 4133 03:03:43,320 --> 03:03:45,600 OTHER ASPECT OF COURSE WE HEARD 4134 03:03:45,600 --> 03:03:53,720 BEFORE TWO VARIANTS PRODUCED BY 4135 03:03:53,720 --> 03:03:57,040 THE SAME MRNA, IN THE FIELD 4136 03:03:57,040 --> 03:03:59,560 DEBATED FOR A LONG TIME MICRO 4137 03:03:59,560 --> 03:04:02,200 NICHL OF ACTION FOR MUTATION A 4138 03:04:02,200 --> 03:04:02,960 LOSS OF FUNCTION OR FUNCTION 4139 03:04:02,960 --> 03:04:04,480 TYPE OF MUTATION THAT HAS 4140 03:04:04,480 --> 03:04:06,520 DIFFERENT IMPLICATIONS FOR THE 4141 03:04:06,520 --> 03:04:10,680 TYPE OF DESIGN THAT YOU USE IN 4142 03:04:10,680 --> 03:04:12,040 THE AV. 4143 03:04:12,040 --> 03:04:13,760 ONE THE QUESTIONS I ASKED MYSELF 4144 03:04:13,760 --> 03:04:16,200 DO WE REALLY UNDERSTAND WHAT THE 4145 03:04:16,200 --> 03:04:18,120 CELL TYPES OUR TARGET CELL TYPES 4146 03:04:18,120 --> 03:04:20,400 ARE? AND YOU KNOW THIS MORNING, 4147 03:04:20,400 --> 03:04:21,920 JUST FOR FUN POINTS I WENT 4148 03:04:21,920 --> 03:04:23,480 THROUGH QUITE A FEW DATABASES TO 4149 03:04:23,480 --> 03:04:25,200 TRY TO ANSWER THAT QUESTION. 4150 03:04:25,200 --> 03:04:29,000 AND AS PETER MENTIONED EARLIER 4151 03:04:29,000 --> 03:04:32,840 DURING THESE STUDIES EXPRESSION 4152 03:04:32,840 --> 03:04:34,400 WAS DISTRIBUTED QUITE WIDELY 4153 03:04:34,400 --> 03:04:37,880 THROUGHOUT THE BODY, BUT THERE 4154 03:04:37,880 --> 03:04:39,120 NO MEANS OF THE OHM PLACE IN THE 4155 03:04:39,120 --> 03:04:41,960 BODY EXPRESSED AT THOSE HIGH 4156 03:04:41,960 --> 03:04:45,200 LEVELS SEE HERE IN HEART MUSCLE 4157 03:04:45,200 --> 03:04:48,080 SKELETAL MUSCLE THE PROTEIN IS 4158 03:04:48,080 --> 03:04:49,720 EXPRESSED AT VERY HIGH LEVELS 4159 03:04:49,720 --> 03:04:52,960 EVEN HIGHER THAN ELSEWHERE IN 4160 03:04:52,960 --> 03:04:54,800 THE CEREBRAL CORTEX. KEEP IN 4161 03:04:54,800 --> 03:04:56,720 MIND THAT ASPECT IF YOU LOOK AT 4162 03:04:56,720 --> 03:04:59,520 THE TISSUE LEVEL THE RNA LEVELS 4163 03:04:59,520 --> 03:05:02,000 ACTUALLY BECOMES EVEN MORE 4164 03:05:02,000 --> 03:05:03,280 INTERESTING BECAUSE IN FACT IT 4165 03:05:03,280 --> 03:05:04,560 SEEMS LIKE THE HIGHEST 4166 03:05:04,560 --> 03:05:06,120 EXPRESSION LEVEL OF RNA OR 4167 03:05:06,120 --> 03:05:08,600 HIGHEST LEVELS OF R. NA ARE 4168 03:05:08,600 --> 03:05:09,880 WHITE MATTER OF COURSE NOT TOO 4169 03:05:09,880 --> 03:05:10,920 FAR IN THE AREAS CERTAINLY IN 4170 03:05:10,920 --> 03:05:15,200 THE BRAIN, AND AS YOU SEE HERE 4171 03:05:15,200 --> 03:05:16,280 THE EXPRESSION ARE THE PRIFL 4172 03:05:16,280 --> 03:05:17,600 TISSUES AS WELL. 4173 03:05:17,600 --> 03:05:19,800 SO INTERESTING TO THINK ABOUT 4174 03:05:19,800 --> 03:05:22,280 WHAT OTHER ASPECTS OF THE 4175 03:05:22,280 --> 03:05:24,680 DISEASE MAY WE BE MISSING, STILL 4176 03:05:24,680 --> 03:05:28,400 CLINICALLY, THAT MAY BE ALTERED 4177 03:05:28,400 --> 03:05:33,360 DUE TO THE THAT THESE PATIENTS 4178 03:05:33,360 --> 03:05:36,400 CARRY. EXPRESS SEEMINGLY M1 4179 03:05:36,400 --> 03:05:37,360 EXPRESSED IN THE SPINAL CORD 4180 03:05:37,360 --> 03:05:40,000 QUITE A BIT. AT THE SINGLE CELL 4181 03:05:40,000 --> 03:05:40,800 LEVEL AGAIN IT'S REALLY QUITE 4182 03:05:40,800 --> 03:05:43,360 INTERESTING TO SEE THAT IN THE 4183 03:05:43,360 --> 03:05:45,880 CENTRUM THE RESISTS THE HIGHEST 4184 03:05:45,880 --> 03:05:48,080 EXPRESSION IS ACTUALLY OBSERVED 4185 03:05:48,080 --> 03:05:52,200 IN THE DANGER SITES AND IT'S 4186 03:05:52,200 --> 03:05:54,160 IMPORTANT TO CONSIDER THAT EVEN 4187 03:05:54,160 --> 03:06:05,480 WHAT WE HEARD TOGETHERS ABOUT 4188 03:06:05,480 --> 03:06:07,080 AXONAL, WHITE MATTER DISEASES 4189 03:06:07,080 --> 03:06:09,160 THAT HAVE PROFOUND NEUROLOGICAL 4190 03:06:09,160 --> 03:06:11,080 IMPACTS AND WONDER IF DELIVERY 4191 03:06:11,080 --> 03:06:14,440 OF GENES OR ASOS TO NEURONS 4192 03:06:14,440 --> 03:06:16,400 ALONE WILL SUFFICE TO ACTUALLY 4193 03:06:16,400 --> 03:06:18,920 CORRECT A DISEASE PHENOTYPE. SO 4194 03:06:18,920 --> 03:06:20,000 ACTUALLY QUITE IMPORTANT TO 4195 03:06:20,000 --> 03:06:22,240 THINK ABOUT WHAT TYPES OF CELLS 4196 03:06:22,240 --> 03:06:24,280 DO WE NEED TO TARGET TO ACTUALLY 4197 03:06:24,280 --> 03:06:25,720 ACHIEVE A THERAPEUTIC TREND. 4198 03:06:25,720 --> 03:06:28,200 OF COURSE WE'RE NOT AT THE STAGE 4199 03:06:28,200 --> 03:06:30,680 WHERE WE ACTUALLY CAN DELIVER AT 4200 03:06:30,680 --> 03:06:32,280 WILL WITH EVERY SINGLE CELL PACK 4201 03:06:32,280 --> 03:06:35,320 THAT WE WANT. SO TO CERTAIN 4202 03:06:35,320 --> 03:06:37,880 EXTENT THE EXPERIMENTS WE'RE 4203 03:06:37,880 --> 03:06:40,080 DOING ARE EM POOERL PEESHG CAL 4204 03:06:40,080 --> 03:06:42,120 IN NATURE DESIGN FOR TESTING AND 4205 03:06:42,120 --> 03:06:43,720 ANIMAL MODEL. SO YOU CAN SEE 4206 03:06:43,720 --> 03:06:45,200 HERE SORT OF AGAIN AT THE TISSUE 4207 03:06:45,200 --> 03:06:47,840 LEVEL THAT THERE'S A LOT OF RNA 4208 03:06:47,840 --> 03:06:49,400 INFORMATION FOR MULTIPLE 4209 03:06:49,400 --> 03:06:53,200 TISSUES, AND ONCE AGAIN AT THE 4210 03:06:53,200 --> 03:06:56,240 RNA LEVEL THE CELL LEVEL HIGHEST 4211 03:06:56,240 --> 03:06:58,240 EXPRESSION LEVELS ARE IN THE 4212 03:06:58,240 --> 03:06:58,800 SITE LINEAGE. 4213 03:06:58,800 --> 03:07:00,200 SO AN INTERESTING ASPECT TO 4214 03:07:00,200 --> 03:07:03,440 CONSIDERMENT IF YOU LOOK AT 4215 03:07:03,440 --> 03:07:05,600 ANOTHER DATABASE TO DROP IS FROM 4216 03:07:05,600 --> 03:07:08,160 AT MIT YOU CAN LOOK IN HERE 4217 03:07:08,160 --> 03:07:09,760 LAYER FIVE NEURONS REALLY 4218 03:07:09,760 --> 03:07:12,160 EXPRESS THE HIGHEST LEVELS IN 4219 03:07:12,160 --> 03:07:15,600 THE FRONTAL CORTEX BUT FOLLOWED 4220 03:07:15,600 --> 03:07:17,000 IMMEDIATELY BY THE SITES AS WELL 4221 03:07:17,000 --> 03:07:19,000 AND IF YOU LOOK FOR INSTANCE IN 4222 03:07:19,000 --> 03:07:20,800 THE CEREBELLUM WHERE WE SAW 4223 03:07:20,800 --> 03:07:23,520 BEFORE THE HIGHEST LEVEL OF 4224 03:07:23,520 --> 03:07:25,160 EXPRESSION YOU CAN SEE AGAIN ALL 4225 03:07:25,160 --> 03:07:27,120 THE SITES AND NEURONS THEY ARE 4226 03:07:27,120 --> 03:07:29,680 ACTUALLY EXPRESSED AT VERY HIGH 4227 03:07:29,680 --> 03:07:30,160 LEVELS. 4228 03:07:30,160 --> 03:07:31,360 IF YOU LOOK YET AT ANOTHER 4229 03:07:31,360 --> 03:07:33,000 DATABASE AND EACH ONE OF THEM 4230 03:07:33,000 --> 03:07:35,920 HAS ADVENTURES ON ITS OWN FOR 4231 03:07:35,920 --> 03:07:37,000 INSTANCE SPINAL CORD WE DIDN'T 4232 03:07:37,000 --> 03:07:40,400 SEE ANYTHING FOR THE SPINAL CORD 4233 03:07:40,400 --> 03:07:43,840 BEFORE BUT HERE ON GTEX PORTAL 4234 03:07:43,840 --> 03:07:47,320 AT MIT YOU CAN SEE HERE THEY ARE 4235 03:07:47,320 --> 03:07:48,680 AGAIN IN THE SPINAL CORD NOT 4236 03:07:48,680 --> 03:07:50,200 TERRIBLY SURPRISING EVEN THE 4237 03:07:50,200 --> 03:07:51,600 PHENOTYPE OF THE DISEASE AND 4238 03:07:51,600 --> 03:07:52,920 THIS IS WHAT PROMPTED A QUESTION 4239 03:07:52,920 --> 03:07:56,520 FOR ME YESTERDAY, IN TERMS OF 4240 03:07:56,520 --> 03:08:01,400 THE DIFFERENT ISOFORMS AND IT 4241 03:08:01,400 --> 03:08:04,080 LOOKS LIKE THERE ARE TWO TYPES 4242 03:08:04,080 --> 03:08:07,600 OF MRNAS THAT ARE USED DIFFERENT 4243 03:08:07,600 --> 03:08:11,680 ISOFORMS THE PROTEIN THE ONES 4244 03:08:11,680 --> 03:08:15,440 MOSTLY USED IS ONE THAT SOME 4245 03:08:15,440 --> 03:08:19,080 EVIDENCE TO SUGGEST THAT MRNA 4246 03:08:19,080 --> 03:08:23,920 WITHOUT AXONAL FOUR AND SEE HERE 4247 03:08:23,920 --> 03:08:25,400 EXPRESSED IN THE BRAIN QUITE A 4248 03:08:25,400 --> 03:08:27,400 BIT. BECOMES MORE COMPLICATED 4249 03:08:27,400 --> 03:08:30,160 TO DEVELOP A GENE THERAPY WHERE 4250 03:08:30,160 --> 03:08:36,160 YOU CAN ALTERNATIVELY SPLICE A 4251 03:08:36,160 --> 03:08:37,000 PARTICULAR AXON NOT QUITE 4252 03:08:37,000 --> 03:08:38,760 IMPOSSIBLE BUT IS IT TRUE OR 4253 03:08:38,760 --> 03:08:40,040 NOT? I DON'T THINK THERE'S 4254 03:08:40,040 --> 03:08:41,200 ENOUGH INFORMATION ON THAT 4255 03:08:41,200 --> 03:08:42,120 FRONT. 4256 03:08:42,120 --> 03:08:46,320 SO JUST TO SUMMARIZE THE ASPECT 4257 03:08:46,320 --> 03:08:47,600 OF THE DESIGN AS I MENTIONED TO 4258 03:08:47,600 --> 03:08:49,400 YOU BEFORE THE SIZE OF THE GENE 4259 03:08:49,400 --> 03:08:52,600 MATTERS OR THE SIZE AT LEAST OF 4260 03:08:52,600 --> 03:08:57,000 THE CODING SEQUENCE DOES MATTER 4261 03:08:57,000 --> 03:09:02,240 1.85KB FOR SPASTIN AND 4262 03:09:02,240 --> 03:09:05,680 UNFORTUNATELY A SING GREL STRAND 4263 03:09:05,680 --> 03:09:07,680 10 HUNDRED FOLD AT LEAST FACT OF 4264 03:09:07,680 --> 03:09:10,520 THE MATTER IS IF WE USE A VECTOR 4265 03:09:10,520 --> 03:09:12,680 SOFT COMPLIMENTARY YOU HAVE TO 4266 03:09:12,680 --> 03:09:16,320 HAVE IVR AND SO YOU ARE LEFT 4267 03:09:16,320 --> 03:09:19,760 WITHOUT 250 PAIRS TO PUT IN 4268 03:09:19,760 --> 03:09:20,440 THERE PROMOTING, WHILE THAT'S 4269 03:09:20,440 --> 03:09:25,400 NOT A LOT OF SPACE FOR A 4270 03:09:25,400 --> 03:09:28,120 PROMOTER ONE COULD TAKE SOME 4271 03:09:28,120 --> 03:09:30,600 COMPROMISES DOING THAT BUT A 4272 03:09:30,600 --> 03:09:33,200 SINGLE STRAND AAV VECTOR 4273 03:09:33,200 --> 03:09:34,720 DESIGNED SO MORE SPACE TO 4274 03:09:34,720 --> 03:09:35,600 INCLUDE REGULATORY ELEMENTS. 4275 03:09:35,600 --> 03:09:38,600 THEN COMING BACK TO THAT IDEA OF 4276 03:09:38,600 --> 03:09:40,760 TOXICITY, THE QUESTION IS DO WE 4277 03:09:40,760 --> 03:09:42,120 USE THE SUPER STRONG YOU KNOW 4278 03:09:42,120 --> 03:09:46,200 MANY PROGRAMS BASED ON USING 4279 03:09:46,200 --> 03:09:49,160 PROMOTER, IN FACT THE XS AND 4280 03:09:49,160 --> 03:09:50,600 NOVARTIS DRUG FOR SMA IS 4281 03:09:50,600 --> 03:09:53,000 ACTUALLY BASED ON USING 4282 03:09:53,000 --> 03:09:54,640 PROMOTERS ACTUALLY ALWAYS A 4283 03:09:54,640 --> 03:09:58,600 SURPRISE TO ME NOT INCREDIBLY 4284 03:09:58,600 --> 03:10:01,400 TOXIC BUT IT DOES WORK PRETTY 4285 03:10:01,400 --> 03:10:05,000 WELL OTHERS ONE CAN CONSIDER. 4286 03:10:05,000 --> 03:10:06,800 NEURONAL DRIVEN. THE OTHER 4287 03:10:06,800 --> 03:10:08,160 APPROACH ONE THAT I ACTUALLY 4288 03:10:08,160 --> 03:10:10,280 FAVOR I THINK THERE'S A LOT OF 4289 03:10:10,280 --> 03:10:11,680 PEOPLE USING IT I THINK MAKES 4290 03:10:11,680 --> 03:10:13,840 SENSE USING WEAK PROMOTERS AND 4291 03:10:13,840 --> 03:10:16,120 WEAK PROMOTERS I PERSONALLY 4292 03:10:16,120 --> 03:10:18,040 THINK IN GENERAL CELLS CAN ADAPT 4293 03:10:18,040 --> 03:10:20,440 TO HAVING LOWER AMOUNTS OF A 4294 03:10:20,440 --> 03:10:22,640 PROTEIN PERHAPS BETTER THAN 4295 03:10:22,640 --> 03:10:24,800 HAVING A CONSTANT LEVEL 4296 03:10:24,800 --> 03:10:26,920 EXTREMELY HIGH WHERE YOU CAN 4297 03:10:26,920 --> 03:10:29,360 ENGAGE UNFOLDED RESPONSES, SO 4298 03:10:29,360 --> 03:10:31,520 THE NOTION OF ACTUALLY USING 4299 03:10:31,520 --> 03:10:33,720 WHEAT PROMOTERS QUITE A BIT OF 4300 03:10:33,720 --> 03:10:37,320 MERIT THE QUESTION ABOUT THESE 4301 03:10:37,320 --> 03:10:42,920 WEAK PROMOTERS DO THEY EXPRESS 4302 03:10:42,920 --> 03:10:45,560 EVERYTHING WE NEED. THE ANSWER 4303 03:10:45,560 --> 03:10:47,880 IS ABSOLUTELY NOT. WELL 4304 03:10:47,880 --> 03:10:48,800 ACTUALLY THAT'S NOT QUITE TRUE 4305 03:10:48,800 --> 03:10:50,440 IN FACT IF YOU CHANGE THE 4306 03:10:50,440 --> 03:10:55,840 PROMOTER FROM ONE OF THESE 4307 03:10:55,840 --> 03:10:59,840 UBIQUITOUS, BASIC PROTEIN 4308 03:10:59,840 --> 03:11:02,520 PROMOTER IN FACT LO AND BEHOLD 4309 03:11:02,520 --> 03:11:09,360 IT TRANS DO YOU SAYS, YOU CAN'T 4310 03:11:09,360 --> 03:11:11,320 HAVE GENE EXPRESS ON ALL VENDOR 4311 03:11:11,320 --> 03:11:12,400 SITES. THE GENE TRANSFER 4312 03:11:12,400 --> 03:11:14,080 PROPERTIES OF A VECTOR WITH AAV 4313 03:11:14,080 --> 03:11:17,360 ARE OBVIOUSLY DETERMINED BY THE 4314 03:11:17,360 --> 03:11:20,200 CAP SAID WE ALL UNDERSTAND THAT 4315 03:11:20,200 --> 03:11:22,120 INTRINSIC A PROPERTY TO BE ABLE 4316 03:11:22,120 --> 03:11:25,240 TO ENTER CELLS BUT OUR 4317 03:11:25,240 --> 03:11:30,800 PERCEPTION OF TROEPISM IS 4318 03:11:30,800 --> 03:11:36,080 DRIVEN BY WHAT WE USE THE TRUE 4319 03:11:36,080 --> 03:11:41,320 TROPISM ON AAV VECTORS, OTHER 4320 03:11:41,320 --> 03:11:43,080 POSSIBILITY ONE MORE POSSIBLE 4321 03:11:43,080 --> 03:11:47,800 BECAUSE SINGLE CELL APAC THE 4322 03:11:47,800 --> 03:11:50,120 EXPRESS SORE TRYING TO FINALED 4323 03:11:50,120 --> 03:11:51,120 PROMOTE TORE ELEMENT NECESSARY 4324 03:11:51,120 --> 03:11:53,160 TO DRIVE NORMAL ELEMENT 4325 03:11:53,160 --> 03:11:55,000 EXPRESSION AS YOU HEARD BEFORE 4326 03:11:55,000 --> 03:11:55,760 CHANGING CAPACITY IS PRETTY 4327 03:11:55,760 --> 03:11:57,400 SMALL SO YOU REALLY HAVE TO TRY 4328 03:11:57,400 --> 03:12:00,400 TO MINIMIZE A NUMBER OF ELEMENTS 4329 03:12:00,400 --> 03:12:04,480 THAT YOU USE TO DRIVE GENE 4330 03:12:04,480 --> 03:12:04,800 EXPRESSION. 4331 03:12:04,800 --> 03:12:06,080 IDEALLY WE WOULD DIVIDE 4332 03:12:06,080 --> 03:12:08,200 CASSETTES THAT USE THE MINIMUM 4333 03:12:08,200 --> 03:12:10,520 PROMOTERS THAT ARE NECESSARY TO 4334 03:12:10,520 --> 03:12:14,440 EXPRESS THE GENE IN ITS PROPER 4335 03:12:14,440 --> 03:12:16,640 LEVELS AND CERTAIN CELL TYPES. 4336 03:12:16,640 --> 03:12:20,040 NOW WHETHER THE AAV HAS THE 4337 03:12:20,040 --> 03:12:21,400 RIGHT SIZE OR THE TRANSIENT 4338 03:12:21,400 --> 03:12:22,600 CAPACITY TO INCLUDE ALL THE 4339 03:12:22,600 --> 03:12:23,880 ELEMENTS THAT REMAINS TO BE 4340 03:12:23,880 --> 03:12:24,120 SEEN. 4341 03:12:24,120 --> 03:12:31,800 IN TERMS OF REGULATORY ELEMENTS 4342 03:12:31,800 --> 03:12:34,200 POLYASE YOU CAN USE DIFFERENT 4343 03:12:34,200 --> 03:12:36,960 POLYASE AND DO YOU USE 4344 03:12:36,960 --> 03:12:39,560 UNTRANSLATED REGIONS, AS 3 4345 03:12:39,560 --> 03:12:44,520 PRIME? OFTEN THEY INCLUDE 4346 03:12:44,520 --> 03:12:45,120 MICRORNA TARGETS SO THAT'S 4347 03:12:45,120 --> 03:12:47,600 ANOTHER FACTOR TO TAKE INTO 4348 03:12:47,600 --> 03:12:48,600 ACCOUNT WHETHER THAT'S SOMETHING 4349 03:12:48,600 --> 03:12:50,320 THAT WE WOULD LIKE TO INCLUDE OR 4350 03:12:50,320 --> 03:12:52,200 NOT. AND OF COURSE ALL OF THIS 4351 03:12:52,200 --> 03:12:54,560 BOILS DOWN TO WHAT I SAID 4352 03:12:54,560 --> 03:12:58,400 EVERYTHING HAS TO FIT WITHIN 4353 03:12:58,400 --> 03:13:01,000 4.75KB A BIT OF AN EXERCISE IN 4354 03:13:01,000 --> 03:13:03,120 TRIAL AND ERROR AND INCLUDE MORE 4355 03:13:03,120 --> 03:13:04,440 ELEMENT THAT WE FIND A PROBLEM 4356 03:13:04,440 --> 03:13:07,400 IF THERE IS NO PROBLEM THAT WE 4357 03:13:07,400 --> 03:13:09,000 HOPE THINGS MOVE ON AND WORK 4358 03:13:09,000 --> 03:13:09,400 WELL. 4359 03:13:09,400 --> 03:13:11,800 THEN THE FINAL QUESTION IS, YOU 4360 03:13:11,800 --> 03:13:16,200 KNOW, WHAT IS THE GENE TRANSFER 4361 03:13:16,200 --> 03:13:18,160 CODE? THAT DEPENDS ON THE 4362 03:13:18,160 --> 03:13:20,160 MECHANISM IF IT'S A LOSS OF 4363 03:13:20,160 --> 03:13:22,760 FUNCTION TYPE OF DISEASE THAT 4364 03:13:22,760 --> 03:13:24,000 CAN MUTATIONS CAUSE LOSS OF 4365 03:13:24,000 --> 03:13:26,720 FUNCTION IN PROTEIN WE FIND 4366 03:13:26,720 --> 03:13:27,600 OURSELVES IN PURE 4367 03:13:27,600 --> 03:13:28,800 SUPPLEMENTATION TYPE OF 4368 03:13:28,800 --> 03:13:31,840 APPROACH, ON THE OTHER HAND, IF 4369 03:13:31,840 --> 03:13:34,000 YOU HAVE DISEASE THAT MUTATION 4370 03:13:34,000 --> 03:13:35,600 GAIN FUNCTION MUTATIONS, WELL 4371 03:13:35,600 --> 03:13:38,520 ACTUALLY JUST PUTTING IN THE 4372 03:13:38,520 --> 03:13:40,200 NORMAL COPY OF A GENE IS LIKELY 4373 03:13:40,200 --> 03:13:42,080 NOT GOING TO SOLVE THE PROBLEM 4374 03:13:42,080 --> 03:13:44,160 SO IDEALLY WHAT YOU WANT TO DO 4375 03:13:44,160 --> 03:13:46,800 IS COMBINE A SILENCING AND 4376 03:13:46,800 --> 03:13:47,840 REPLACEMENT APPROACH SO DUAL 4377 03:13:47,840 --> 03:13:50,080 FUNCTION TYPE OF DESIGN AND AS 4378 03:13:50,080 --> 03:13:53,320 YOU UNDERSTAND BECAUSE I DO WORK 4379 03:13:53,320 --> 03:13:55,800 WITH PETER USING HIS MOUSE MODEL 4380 03:13:55,800 --> 03:13:57,360 OBVIOUSLY WE SUBSCRIBE TO THAT 4381 03:13:57,360 --> 03:13:59,000 NOTION THAT IN FACT YOU NEED TO 4382 03:13:59,000 --> 03:14:01,640 DO BOTH TO ACHIEVE A THERAPEUTIC 4383 03:14:01,640 --> 03:14:02,160 EFFECT. 4384 03:14:02,160 --> 03:14:05,440 NOW ONE MAY POSIT THAT NOT EVERY 4385 03:14:05,440 --> 03:14:07,400 MUTATION IS NECESSARILY A 4386 03:14:07,400 --> 03:14:08,600 FUNCTION MUTATION THAT'S ONLY 4387 03:14:08,600 --> 03:14:10,080 SOME OF THEM MIGHT BE, AND THAT 4388 03:14:10,080 --> 03:14:13,400 IS POSSIBLE, BUT THERE AGAIN, 4389 03:14:13,400 --> 03:14:17,400 THE ISSUE IS IF YOU DESIGN 4390 03:14:17,400 --> 03:14:19,600 VECTORS THAT ARE ONLY USEFUL FOR 4391 03:14:19,600 --> 03:14:23,680 ONE SUBSET OF MUTATIONS, WELL 4392 03:14:23,680 --> 03:14:24,920 FOR DISEASE THAT IS ALREADY 4393 03:14:24,920 --> 03:14:26,400 ULTRA RARE AND NOW YOU CAN ONLY 4394 03:14:26,400 --> 03:14:28,640 TREAT A SLICE OF THAT 4395 03:14:28,640 --> 03:14:32,720 POPULATION, WELL EVENTUALLY YOU 4396 03:14:32,720 --> 03:14:33,800 CAN'T FIND PATIENTS OR YOU HAVE 4397 03:14:33,800 --> 03:14:35,360 A LOT OF DIFFICULTY FINDING 4398 03:14:35,360 --> 03:14:37,000 PATIENTS AND THEN STRUGGLE WITH 4399 03:14:37,000 --> 03:14:38,120 EVEN MORE COMPLICATED QUESTION 4400 03:14:38,120 --> 03:14:42,080 OF DO I KNOW EXACTLY WHAT EACH 4401 03:14:42,080 --> 03:14:43,880 MUTATION IS? FUNCTION OR LOSS 4402 03:14:43,880 --> 03:14:45,200 OF FUNCTION. SO PRAGMATIC 4403 03:14:45,200 --> 03:14:47,280 APPROACH THAT WE'RE TAKING IS 4404 03:14:47,280 --> 03:14:49,080 WELL LOOK, REGARDLESS OF THE 4405 03:14:49,080 --> 03:14:52,000 MECHANISM, IF WE SILENCING, 4406 03:14:52,000 --> 03:14:53,400 SILENCE THE ENDOGENOUS AND 4407 03:14:53,400 --> 03:14:54,800 REPLACE THEM WITH NORMAL 4408 03:14:54,800 --> 03:14:56,040 PROTEIN, WELL THAT WOULD BE 4409 03:14:56,040 --> 03:14:59,160 OKAY. AND THE RISK THERE IS 4410 03:14:59,160 --> 03:15:00,440 RELATIVELY SMALL BECAUSE IN 4411 03:15:00,440 --> 03:15:02,800 EVERY CELL WE CAN SILENCE THE 4412 03:15:02,800 --> 03:15:04,520 GENE WE'RE ALSO EXPRESSING THE 4413 03:15:04,520 --> 03:15:06,960 GENE. SO ON THE OTHER HAND, IF 4414 03:15:06,960 --> 03:15:09,400 THE TWO THINGS WILL YOU THINK 4415 03:15:09,400 --> 03:15:11,840 LINK FROM EACH OTHER THAT COULD 4416 03:15:11,840 --> 03:15:13,400 BECOME A PROBLEM BECAUSE AFTER 4417 03:15:13,400 --> 03:15:15,120 ALL EVOLUTION DID A FABULOUS JOB 4418 03:15:15,120 --> 03:15:17,920 OF HAVING THESE GENES AND 4419 03:15:17,920 --> 03:15:20,000 EXPRESSING THEM SO THE NOTION 4420 03:15:20,000 --> 03:15:23,400 THAT WE INCLUDE REALLY SILENCED 4421 03:15:23,400 --> 03:15:25,320 GENES LEFT AND RIGHT OF COURSE 4422 03:15:25,320 --> 03:15:26,040 PERSONALLY I THINK THAT'S 4423 03:15:26,040 --> 03:15:27,280 LAUGHING IN THE FACE OF 4424 03:15:27,280 --> 03:15:29,280 EVOLUTION BUT YOU KNOW WE'LL SEE 4425 03:15:29,280 --> 03:15:30,760 WHAT THAT BRINGS IN CLINICAL 4426 03:15:30,760 --> 03:15:31,320 TRIALS. 4427 03:15:31,320 --> 03:15:33,160 WHERE WE STAND TODAY IN THE 4428 03:15:33,160 --> 03:15:35,320 COLLABORATION WITH PETER AND 4429 03:15:35,320 --> 03:15:37,360 OSCAR CHANG'S LAB THAT GENERATE 4430 03:15:37,360 --> 03:15:42,120 THE DESIGN FIRST GENERATION OF 4431 03:15:42,120 --> 03:15:45,360 PASS SPASTIC VECTORS ONGOING AND 4432 03:15:45,360 --> 03:15:46,720 WE DESIGN NOW A SECOND 4433 03:15:46,720 --> 03:15:48,920 GENERATION OF VECTORS TO 4434 03:15:48,920 --> 03:15:51,000 INTRODUCE THEM TO TAKING SOME OF 4435 03:15:51,000 --> 03:15:53,400 THESE CONSIDERATIONS THAT I'VE 4436 03:15:53,400 --> 03:15:56,880 MADE ARE ON. 4437 03:15:56,880 --> 03:15:58,760 I THINK THAT'S IT. I TOOK A 4438 03:15:58,760 --> 03:16:01,200 LITTLE LONGER THAN I ANTICIPATED 4439 03:16:01,200 --> 03:16:02,080 I APOLOGIZE. 4440 03:16:02,080 --> 03:16:04,000 >> THAT'S WONDERFUL THANK YOU 4441 03:16:04,000 --> 03:16:07,280 VERY MUCH SO IMPORTANT FOR SHARE 4442 03:16:07,280 --> 03:16:10,000 YOURS EXPERTISE. SO WE HAVE ONE 4443 03:16:10,000 --> 03:16:12,160 LAST SPEAKER RUNNING A BIT OVER 4444 03:16:12,160 --> 03:16:13,840 TIME BUT I WANT TO MAKE SURE WE 4445 03:16:13,840 --> 03:16:16,280 HAVE GOOD TIME FOR Q AND A AND 4446 03:16:16,280 --> 03:16:18,160 DISCUSSIONS SO WE CAN REMAIN ON 4447 03:16:18,160 --> 03:16:22,840 THE ZOOM CALL A LITTLE PAST 2:00 4448 03:16:22,840 --> 03:16:23,360 FENDI 4449 03:16:23,360 --> 03:16:24,560 DEPENDING ON POOEMS 4450 03:16:24,560 --> 03:16:25,680 AVAILABILITY. WE WON'T GET CAN 4451 03:16:25,680 --> 03:16:30,120 YOU TELL OFF. FINAL SPEAKER IS 4452 03:16:30,120 --> 03:16:33,400 JAHANNAZ DASTGIR. THANK YOU SO 4453 03:16:33,400 --> 03:16:36,040 MU 4454 03:16:36,040 --> 03:16:36,240 MUCH. 4455 03:16:36,240 --> 03:16:37,160 >> JAHANNAZ DASTGIR: HI 4456 03:16:37,160 --> 03:16:38,360 EVERYBODY THANK YOU AIR REAN FOR 4457 03:16:38,360 --> 03:16:39,360 HAVING ME HERE TODAY AND THANK 4458 03:16:39,360 --> 03:16:40,960 YOU ALL FOR YOUR ATTENTION. 4459 03:16:40,960 --> 03:16:45,360 SO AS I HOPE YOU ALL CAN HEAR ME 4460 03:16:45,360 --> 03:16:47,760 OKAY. AS AIR REAN HAD MENTIONED 4461 03:16:47,760 --> 03:16:49,320 EARLIER MY BACKGROUND WAS PRETTY 4462 03:16:49,320 --> 03:16:53,000 MUCH SPENDING 10 YEARS IN 4463 03:16:53,000 --> 03:16:56,560 FELLOWSHIP AND THEN GOING ON TO 4464 03:16:56,560 --> 03:16:58,800 BE IN ACADEMIA, I CONTINUED TO 4465 03:16:58,800 --> 03:17:01,800 WORK AS A CLINICIAN PART TIME 4466 03:17:01,800 --> 03:17:03,680 AND JUST STARTED TO TAKE A 4467 03:17:03,680 --> 03:17:05,560 POSITION I TOOK A POSITION OVER 4468 03:17:05,560 --> 03:17:08,040 THE PAST YEAR IN A SMALL BIOTECH 4469 03:17:08,040 --> 03:17:11,440 COMPANY THAT'S BEEN DEVELOPING A 4470 03:17:11,440 --> 03:17:15,720 DRUG FOR SORE BIT TALL DEE HIGH 4471 03:17:15,720 --> 03:17:18,800 DRAUJ GENERAL NAYS DEFICIENCY 4472 03:17:18,800 --> 03:17:21,920 NEURO MUSCULAR SPECIALIST 4473 03:17:21,920 --> 03:17:24,000 PEDIATRIC BY TRAINING AND ALSO 4474 03:17:24,000 --> 03:17:27,160 HAVE A VERY STRONG INTEREST IN 4475 03:17:27,160 --> 03:17:30,120 NEURO GENETIC DISORDERS AS WELL 4476 03:17:30,120 --> 03:17:32,400 PROBABLY PLACED IN ME DURING MY 4477 03:17:32,400 --> 03:17:35,480 TIME AT NIH WHICH I'M GRATEFUL 4478 03:17:35,480 --> 03:17:36,120 FOR. 4479 03:17:36,120 --> 03:17:40,680 SO ARYAN HAD ASKED WHAT DO SMALL 4480 03:17:40,680 --> 03:17:41,920 STARTUP COMPANIES LOOK FOR SNO 4481 03:17:41,920 --> 03:17:43,480 SN SO WHAT I'VE LEARNED I'M 4482 03:17:43,480 --> 03:17:45,080 GOING TO SHARE WITH YOU TODAY. 4483 03:17:45,080 --> 03:17:47,720 SO FIRST OF ALL, IS THERE A 4484 03:17:47,720 --> 03:17:49,760 DRUG? SO I WAS SO GRATEFUL TO 4485 03:17:49,760 --> 03:17:50,640 SEE ALL OF THE EXCITING 4486 03:17:50,640 --> 03:17:53,000 INFORMATION HERE ON SPG4 4487 03:17:53,000 --> 03:17:54,400 PATIENTS I ACTUALLY HAVE TWO IN 4488 03:17:54,400 --> 03:17:57,120 MY OWN PRACTICE SO IT'S VERY 4489 03:17:57,120 --> 03:17:57,800 EXCITING FOR THEM. 4490 03:17:57,800 --> 03:17:59,520 SO YOU KNOW AS I THINK WAS 4491 03:17:59,520 --> 03:18:02,800 MENTIONED IN THE MODELIS TALK AS 4492 03:18:02,800 --> 03:18:06,120 WELL. SOME COMPANIES DO HAVE AN 4493 03:18:06,120 --> 03:18:08,400 INDICATOR -- THEY TRY TO 4494 03:18:08,400 --> 03:18:09,600 REPURPOSE DRUGS THAT HAVE BEEN 4495 03:18:09,600 --> 03:18:11,440 PURPOSELY USED FOR OTHER 4496 03:18:11,440 --> 03:18:14,480 INDICATIONS, THE EASIEST EXAMPLE 4497 03:18:14,480 --> 03:18:16,000 I'M FAMILIAR WITH A COMPANY 4498 03:18:16,000 --> 03:18:17,600 CALLED PHARM X FOR EXAMPLE THEY 4499 03:18:17,600 --> 03:18:20,080 DEVELOPED AICALLY OWE DRUG A 4500 03:18:20,080 --> 03:18:21,400 COMBINATION OF THREE DRUGS 4501 03:18:21,400 --> 03:18:23,000 TYPICALLY USED IN PRACTICE AND 4502 03:18:23,000 --> 03:18:27,600 SAFELY EVEN IN THE PEDIATRIC FOR 4503 03:18:27,600 --> 03:18:30,160 EXAMPLE. THROUGH SCREENINGS OF 4504 03:18:30,160 --> 03:18:31,520 CHEMICAL LIBRARIES THEY NOTICED 4505 03:18:31,520 --> 03:18:36,600 THIS WORKED FOR CM T1A, SHARK 4506 03:18:36,600 --> 03:18:39,480 MARINE TOOTH 1A. THEN YOU HAVE 4507 03:18:39,480 --> 03:18:44,440 ACADEMIC OR LAB DEVELOPED DRUGS 4508 03:18:44,440 --> 03:18:47,560 GENE THERAPY OR SMALL MOLECULES 4509 03:18:47,560 --> 03:18:49,320 PARTICULAR CULTURE OR PATHWAY. 4510 03:18:49,320 --> 03:18:51,680 AND THEN HOW DO YOU PEAK THEIR 4511 03:18:51,680 --> 03:18:53,400 INTEREST? SO IF A COMPANY IS 4512 03:18:53,400 --> 03:18:56,760 ALREADY DEVELOPING A DRUG WITH A 4513 03:18:56,760 --> 03:18:57,680 SPECIFIC THERAPEUTIC TARGET FOR 4514 03:18:57,680 --> 03:18:59,560 ONE DISORDER AND ANOTHER 4515 03:18:59,560 --> 03:19:00,960 DISORDER WITH THE SAME 4516 03:19:00,960 --> 03:19:02,000 THERAPEUTIC TARGET IS DISCOVERED 4517 03:19:02,000 --> 03:19:04,000 IN PUBLICATIONS THEY WILL GO 4518 03:19:04,000 --> 03:19:05,520 THROUGH IT. THAT'S HAPPENED 4519 03:19:05,520 --> 03:19:07,480 WITH THE CURRENTLY WORK FOR 4520 03:19:07,480 --> 03:19:08,640 APPLIED THERAPEUTICS. SO 4521 03:19:08,640 --> 03:19:12,360 BASICALLY THEY HAD A DRUG THAT'S 4522 03:19:12,360 --> 03:19:15,600 AN REDUCTASE INHIBITOR DEVELOPED 4523 03:19:15,600 --> 03:19:18,160 FOR DIABETIC CARDIOMYOPATHY 4524 03:19:18,160 --> 03:19:19,040 PRIMARILY. AND THEN THIS PAPER 4525 03:19:19,040 --> 03:19:22,680 WAB WAS PUBLISHED IN NATURE 4526 03:19:22,680 --> 03:19:25,400 GENETICS IN MAY OF 2020, THEY 4527 03:19:25,400 --> 03:19:28,080 SAID MUTATIONS COMMONLY 4528 03:19:28,080 --> 03:19:30,920 TREATABLE WITH IMPLICATIONS FOR 4529 03:19:30,920 --> 03:19:35,000 DIABETES OH, MY GOSH OUR DRUG 4530 03:19:35,000 --> 03:19:36,160 ACTUALLY INHIBITS PRU PRODUCTION 4531 03:19:36,160 --> 03:19:43,000 OF SORBITOL LET'S DO IT. THIS 4532 03:19:43,000 --> 03:19:44,800 BIOTECH COMPANY OPERATES AT A 4533 03:19:44,800 --> 03:19:46,600 FASTER PACE THAN BIG PHARMA 4534 03:19:46,600 --> 03:19:47,880 EXCITED TO GET THIS DRUG ON THE 4535 03:19:47,880 --> 03:19:49,520 PIPELINE AND HIRED ME TO DEVELOP 4536 03:19:49,520 --> 03:19:50,560 THE PROGRAM THERE. 4537 03:19:50,560 --> 03:19:53,080 SO IT'S IMPORTANT, YOUR 4538 03:19:53,080 --> 03:19:55,800 PUBLICATIONS ACTUALLY REALLY 4539 03:19:55,800 --> 03:19:56,560 MATTER, WHICH IS GREAT. 4540 03:19:56,560 --> 03:19:58,120 ANOTHER WAY TO PIQUE THEIR 4541 03:19:58,120 --> 03:19:59,080 INTEREST OKAY FINE YOU DON'T 4542 03:19:59,080 --> 03:20:01,400 HAVE ALL YOUR DATA YET TOGETHER 4543 03:20:01,400 --> 03:20:04,160 OR LONGITUDINAL DATA YET 4544 03:20:04,160 --> 03:20:05,960 TOGETHER PUT OUT A PAPER PRESENT 4545 03:20:05,960 --> 03:20:08,120 ABSTRACTS AND MEETINGS THESE 4546 03:20:08,120 --> 03:20:10,440 GUYS ARE ALL AT MEETINGS ALL THE 4547 03:20:10,440 --> 03:20:12,120 TIME EXCITED TO SEE ANY OTHER 4548 03:20:12,120 --> 03:20:15,120 IMPLICATIONS OF THE DRUGS THEY 4549 03:20:15,120 --> 03:20:16,400 MIGHT HAVE. 4550 03:20:16,400 --> 03:20:17,600 REACH OUT TO THE COMPANY 4551 03:20:17,600 --> 03:20:19,040 DIRECTLY. I'VE LEARNED IF 4552 03:20:19,040 --> 03:20:21,360 THERE'S AN E-MAIL ON THE WEBSITE 4553 03:20:21,360 --> 03:20:23,720 FOR A PROGRAM THAT E-MAIL 4554 03:20:23,720 --> 03:20:26,160 DOESN'T GO TO NOWHERE YOU MIGHT 4555 03:20:26,160 --> 03:20:28,120 THINK MOST PLACES YOU REACH OUT 4556 03:20:28,120 --> 03:20:29,600 NOT GET TO THE RIGHT PEOPLE. 4557 03:20:29,600 --> 03:20:30,720 USUALLY A PATIENT ADVOCACY 4558 03:20:30,720 --> 03:20:32,320 PERSON WHO IS PART OF THAT WHO 4559 03:20:32,320 --> 03:20:34,120 WILL FUNNEL IT TO A MEDICAL 4560 03:20:34,120 --> 03:20:35,480 DIRECTOR, AND THEN IF IT'S A 4561 03:20:35,480 --> 03:20:36,200 SMALLER COMPANY, FOR EXAMPLE IF 4562 03:20:36,200 --> 03:20:38,320 I GET IT, I GIVE IT DIRECTLY TO 4563 03:20:38,320 --> 03:20:42,160 THE CM O, OR THE CEO, IT'S A 4564 03:20:42,160 --> 03:20:44,240 VERY CLOSE KNIT RELATIONSHIP SO 4565 03:20:44,240 --> 03:20:45,400 NEVER UNDER ESTIMATE REACHING 4566 03:20:45,400 --> 03:20:47,560 OUT TO PEOPLE DIRECTLY, IN 4567 03:20:47,560 --> 03:20:49,040 SMALLER COMPANIES I IMAGINE BIG 4568 03:20:49,040 --> 03:20:50,000 PHARMA IT'S VERY DIFFERENT. 4569 03:20:50,000 --> 03:20:51,800 AND THEN THE NEXT THING IS ARE 4570 03:20:51,800 --> 03:20:53,520 THERE PATIENTS? SO THIS IS VERY 4571 03:20:53,520 --> 03:20:55,120 IMPORTANT. SO FOR EXAMPLE IF 4572 03:20:55,120 --> 03:20:57,200 YOU WANT TO MAKE SURE THAT THE 4573 03:20:57,200 --> 03:20:58,120 COMPANIES ARE INTERESTED YOU 4574 03:20:58,120 --> 03:21:00,000 NEED PATIENT NUMBERS RIGHT? SO 4575 03:21:00,000 --> 03:21:01,960 THE WAY FOR EXAMPLE I CAN USE 4576 03:21:01,960 --> 03:21:06,760 THE SEXAMPLES OF WHAT WE'VE BEEN 4577 03:21:06,760 --> 03:21:08,360 WORKING ON, WHEN THE GENE WAS 4578 03:21:08,360 --> 03:21:09,360 IDENTIFIED WHO WERE THE FIRST 4579 03:21:09,360 --> 03:21:11,880 PEOPLE WE WENT TO TRY TO TO FIND 4580 03:21:11,880 --> 03:21:14,800 PATIENTS ARE THE PEOPLE ON THE 4581 03:21:14,800 --> 03:21:15,480 PAPER. HOW MANY PATIENTS DO YOU 4582 03:21:15,480 --> 03:21:16,960 HAVE EXACTLY IS THAT ENOUGH FOR 4583 03:21:16,960 --> 03:21:19,200 US TO DO A TRIAL? THEN YOU DO 4584 03:21:19,200 --> 03:21:21,360 SOMETHING WHERE YOU REACH OUT TO 4585 03:21:21,360 --> 03:21:22,960 REGISTRIES I HIGHLIGHTED THIS 4586 03:21:22,960 --> 03:21:25,800 AFTER LISTENING TO SOME OF THE 4587 03:21:25,800 --> 03:21:28,200 TALKS HERE. SO DURING THE 4588 03:21:28,200 --> 03:21:30,120 SYMPOSIUM THAT YOU KNOW WHEN YOU 4589 03:21:30,120 --> 03:21:31,600 WERE TALKING ABOUT I THINK IT 4590 03:21:31,600 --> 03:21:34,120 WAS THAT ONE PHYSICIAN AT BOSTON 4591 03:21:34,120 --> 03:21:34,960 CHILDREN'S I THINK DR. TRAINER 4592 03:21:34,960 --> 03:21:36,080 WAS TALKING ABOUT THAT PHYSICIAN 4593 03:21:36,080 --> 03:21:39,280 I'M FOR GETTING HIS NAME NOW 4594 03:21:39,280 --> 03:21:40,640 APOLOGIZE, SAYING IT WAS 2 4595 03:21:40,640 --> 03:21:41,440 MILLION DOLLARS TO DO WHAT HE 4596 03:21:41,440 --> 03:21:43,160 WAS DOING AND IT WAS A LOT. 4597 03:21:43,160 --> 03:21:45,800 YOUR PERSPECTIVE ON MONEY 4598 03:21:45,800 --> 03:21:46,960 COMPLETELY CHANGES WHEN YOU 4599 03:21:46,960 --> 03:21:49,320 START WORKING FOR PHARMACEUTICAL 4600 03:21:49,320 --> 03:21:51,800 COMPANIES IN ALL HONESTY. AND 2 4601 03:21:51,800 --> 03:21:52,800 MILLION DOLLARS IS A LOT BUT NOT 4602 03:21:52,800 --> 03:21:55,080 A LOT. IF THAT MAKES ANY SENSE. 4603 03:21:55,080 --> 03:21:56,680 SO THESE COMPANIES HAVE MONEY. 4604 03:21:56,680 --> 03:21:58,320 SO IF YOU HAVE A SMALL 4605 03:21:58,320 --> 03:22:00,120 FOUNDATION, WHO HAS A REGISTRY 4606 03:22:00,120 --> 03:22:03,160 OF PATIENTS, FOR EXAMPLE IF A 4607 03:22:03,160 --> 03:22:05,000 STUDY IS TRYING TO FIND 4608 03:22:05,000 --> 03:22:08,240 PATIENTS, THERE'S OFTEN 4609 03:22:08,240 --> 03:22:11,040 RELATIONSHIPS BETWEEN THE 4610 03:22:11,040 --> 03:22:12,160 BIOTECH PHARMA -- PHARMA COMPANY 4611 03:22:12,160 --> 03:22:13,720 AND THE REGISTRY WHERE THEY WILL 4612 03:22:13,720 --> 03:22:15,000 GIVE YOU INFORMATION ON THE 4613 03:22:15,000 --> 03:22:18,880 PATIENT DATA. THEY MIGHT REACH 4614 03:22:18,880 --> 03:22:20,280 OUT TO THE PATIENT ON YOUR 4615 03:22:20,280 --> 03:22:22,160 BEHALF BUT YOU WILL GET NO 4616 03:22:22,160 --> 03:22:22,920 IDENTIFYING INFORMATION. WE 4617 03:22:22,920 --> 03:22:25,360 HAVE 20 PATIENTS WITH THIS, BLAH 4618 03:22:25,360 --> 03:22:27,080 BLAH BLAH BLAH, OKAY YOU HAVE TO 4619 03:22:27,080 --> 03:22:28,280 GIVE US A CERTAIN AMOUNT OF 4620 03:22:28,280 --> 03:22:30,320 MONEY TO GET ACCESS TO THIS 4621 03:22:30,320 --> 03:22:31,280 INFORMATION, FOR EXAMPLE. I WAS 4622 03:22:31,280 --> 03:22:33,080 SHOCKED TO LEARN THAT BUT IN THE 4623 03:22:33,080 --> 03:22:34,720 SAME TIME I WAS LIKE WOW THIS IS 4624 03:22:34,720 --> 03:22:36,800 GREAT BECAUSE ACTUALLY THE 4625 03:22:36,800 --> 03:22:38,040 BIOTECH OR PHARMA COMPANY IS 4626 03:22:38,040 --> 03:22:40,000 ACTUALLY GIVING MONEY TO THE 4627 03:22:40,000 --> 03:22:40,880 REGISTRIES WHICH IS GREAT 4628 03:22:40,880 --> 03:22:41,920 BECAUSE IN THE END WHAT IS THE 4629 03:22:41,920 --> 03:22:44,080 REGISTRY DOING WITH THAT MONEY. 4630 03:22:44,080 --> 03:22:45,360 THE REGISTRY IS USUALLY TRIED 4631 03:22:45,360 --> 03:22:48,080 TIED TO A FOUNDATION SUPPORTING 4632 03:22:48,080 --> 03:22:48,440 RESEARCH. 4633 03:22:48,440 --> 03:22:51,200 SO IT'S KIND OF A SELF FEEDING 4634 03:22:51,200 --> 03:22:53,200 MECHANISM IS IN SOME WAYS WHICH 4635 03:22:53,200 --> 03:22:55,000 I WAS EXCITED TO SEE. THAT IS 4636 03:22:55,000 --> 03:22:56,960 ONE WAY THERE IS ACTUALLY GREAT 4637 03:22:56,960 --> 03:22:58,520 UTILITY TO IDENTIFY PATIENTS AND 4638 03:22:58,520 --> 03:23:00,920 HAVE A GREAT REGISTRY WHICH I 4639 03:23:00,920 --> 03:23:02,800 BELIEVE SPG4 HAS, WHICH IS 4640 03:23:02,800 --> 03:23:04,160 GREAT. 4641 03:23:04,160 --> 03:23:05,320 SPONSORED GENETIC TESTING IS 4642 03:23:05,320 --> 03:23:07,000 ANOTHER WAY TO FIND PATIENTS. I 4643 03:23:07,000 --> 03:23:10,040 KNOW WE HAVE THE CP PANEL, FOR 4644 03:23:10,040 --> 03:23:12,000 EXAMPLE, THAT PICKS UP THE 4645 03:23:12,000 --> 03:23:14,040 MUTATION THROUGH IN VITAE I SENT 4646 03:23:14,040 --> 03:23:15,560 IT OUT MYSELF THIS IS EXCELLENT 4647 03:23:15,560 --> 03:23:17,200 AND ALSO JUST YOU KNOW LISTING 4648 03:23:17,200 --> 03:23:18,720 AT THE BOTTOM SO AND SO IS 4649 03:23:18,720 --> 03:23:22,160 WORKING ON THIS DISEASE, AND YOU 4650 03:23:22,160 --> 03:23:24,080 KNOW YOU CAN CONTACT THEM IF 4651 03:23:24,080 --> 03:23:25,160 YOU'RE INTERESTED ON ADDITIONAL 4652 03:23:25,160 --> 03:23:26,560 RESEARCH OR WHAT NOT. 4653 03:23:26,560 --> 03:23:29,360 THAT'S IMPORTANT. AND ALSO 4654 03:23:29,360 --> 03:23:32,160 PROMOTING AWARENESS AMONG CP 4655 03:23:32,160 --> 03:23:33,240 CLINICS, PHYSIATRISTS AND 4656 03:23:33,240 --> 03:23:35,840 NEUROLOGISTS SO JUST BASED ON MY 4657 03:23:35,840 --> 03:23:36,440 OWN CLINICAL BACKGROUND FOR 4658 03:23:36,440 --> 03:23:38,200 EXAMPLE I REMEMBER WORKING IN 4659 03:23:38,200 --> 03:23:40,760 SOME SPASTICITY CLINICS OUTSIDE 4660 03:23:40,760 --> 03:23:52,160 OF NIH AND THE WHOLE POINT OF 4661 03:23:52,160 --> 03:23:56,080 THESE PASPASTICITY WHAT IS THE 4662 03:23:56,080 --> 03:23:57,880 CAUSE OF THE SPASTICITY SOME HAD 4663 03:23:57,880 --> 03:24:01,240 KNOWN STROKES BUT A LOOT DIDN'T 4664 03:24:01,240 --> 03:24:02,400 HAS ANYBODY DONE GENETICS ON 4665 03:24:02,400 --> 03:24:04,480 THESE PATIENTS? YOU WOULD BE 4666 03:24:04,480 --> 03:24:05,320 SURPRISED I THINK THERE ARE A 4667 03:24:05,320 --> 03:24:09,120 LOT OF REALLY BIG NUMBERS MUCH 4668 03:24:09,120 --> 03:24:11,360 PATIENTS OUT THERE THAT HAVE 4669 03:24:11,360 --> 03:24:14,160 UNIDENTIFIED SPG, LET ALONE 4670 03:24:14,160 --> 03:24:16,360 SPG4, THE NEXT THING COMPANIES 4671 03:24:16,360 --> 03:24:17,960 OFTEN LOOK FOR IS IF THERE IS A 4672 03:24:17,960 --> 03:24:19,960 PROPER ANIMAL MODEL SO RAT, 4673 03:24:19,960 --> 03:24:23,640 MOUSE, FLY, COW, WORM, DOES THE 4674 03:24:23,640 --> 03:24:25,840 ANIMAL MODEL MATCH THE HUMAN 4675 03:24:25,840 --> 03:24:26,840 PHENOTYPE? AGAIN ANOTHER SOURCE 4676 03:24:26,840 --> 03:24:29,000 OF MONEY FOR RESEARCH IF YOU DO 4677 03:24:29,000 --> 03:24:30,040 DEVELOP SOMETHING TO PROMOTE 4678 03:24:30,040 --> 03:24:31,400 DEVELOPING THESE MODELS IS THAT 4679 03:24:31,400 --> 03:24:34,200 THESE MODELS CAN BE PURCHASED IN 4680 03:24:34,200 --> 03:24:37,360 ORDER TO -- LIKE YOU COULD BE 4681 03:24:37,360 --> 03:24:39,160 FINANCIALLY SUPPORTED TO HELP 4682 03:24:39,160 --> 03:24:42,120 TEST THE DRUG EFFICACY. A 4683 03:24:42,120 --> 03:24:44,160 SYMBIOTIC RELATIONSHIP BETWEEN 4684 03:24:44,160 --> 03:24:46,160 PHARMA AND ACADEMIA AND PHARMA 4685 03:24:46,160 --> 03:24:47,960 AND SCIENTISTS, FOR EXAMPLE, 4686 03:24:47,960 --> 03:24:49,280 USUALLY STARTS OUT WHERE YOU 4687 03:24:49,280 --> 03:24:52,440 HAVE IN VITRO TESTING CELL DATA 4688 03:24:52,440 --> 03:24:54,240 ANIMAL MODELS, HEALTHY 4689 03:24:54,240 --> 03:24:56,160 VOLUNTEERS PILOT STUDY IN PHASE 4690 03:24:56,160 --> 03:24:56,400 THREE. 4691 03:24:56,400 --> 03:24:58,400 ONCE YOU GET THE ANIMAL MODEL IN 4692 03:24:58,400 --> 03:25:00,200 PLACE AND YOU CAN TEST THE DRUG 4693 03:25:00,200 --> 03:25:03,520 ON THE ANIMAL MOWED MODEL YOU'RE 4694 03:25:03,520 --> 03:25:05,000 PRETTY MUCH DONE WITH THE MOST 4695 03:25:05,000 --> 03:25:05,960 IMPORTANT PART OF THE DRUG 4696 03:25:05,960 --> 03:25:07,520 DEVELOPMENT PHASE ASIDE FROM THE 4697 03:25:07,520 --> 03:25:09,400 CLINICAL OUTCOMES WHICH I'LL 4698 03:25:09,400 --> 03:25:11,600 TALK TO YOU LATER. 4699 03:25:11,600 --> 03:25:13,760 SO THIS IS ONE PART THAT I THINK 4700 03:25:13,760 --> 03:25:15,800 IS VERY IMPORTANT TO THINK ABOUT 4701 03:25:15,800 --> 03:25:20,240 AND I THINK IS OFTEN A RATE 4702 03:25:20,240 --> 03:25:22,120 LIMITING STEP AND VERY, VERY 4703 03:25:22,120 --> 03:25:23,160 IMPORTANT TO DRUG DEVELOPMENT. 4704 03:25:23,160 --> 03:25:24,880 SO IT IS THE HARDEST THING IS TO 4705 03:25:24,880 --> 03:25:26,960 HAVE A -- TO GET A DRUG THE 4706 03:25:26,960 --> 03:25:28,480 HARDEST ITEM THAT YOU NEED TO 4707 03:25:28,480 --> 03:25:30,600 FIND, IN ORDER TO GET A DRUG 4708 03:25:30,600 --> 03:25:32,160 APPROVED, IS A FUNCTIONAL 4709 03:25:32,160 --> 03:25:33,320 CLINICAL OUTCOME MEASURE. 4710 03:25:33,320 --> 03:25:35,680 SO THIS IS SOMETHING THAT NEEDS 4711 03:25:35,680 --> 03:25:39,280 TO BE RESPONSIVE TO CHANGE OVER 4712 03:25:39,280 --> 03:25:41,360 TIME. AND IT MEASURES PRIMARILY 4713 03:25:41,360 --> 03:25:43,400 WHAT IS SOUGHT AFTER BY THE FDA 4714 03:25:43,400 --> 03:25:45,160 TO PROVE THAT THE DRUG WORKS. 4715 03:25:45,160 --> 03:25:48,120 NOW WE DEFINITELY INVEST A LOT 4716 03:25:48,120 --> 03:25:51,600 IN BIOMARKERS SUCH AS 4717 03:25:51,600 --> 03:25:53,400 PHARMACODYNAMIC EFFECTS USING 4718 03:25:53,400 --> 03:25:55,440 THE EXAMPLE OF WHAT WE'RE 4719 03:25:55,440 --> 03:25:57,920 WORKING ON RIGHT NOW. SORBITOL 4720 03:25:57,920 --> 03:26:01,200 IS A BLOOD ASSAY WE CAN CHECK 4721 03:26:01,200 --> 03:26:02,480 THE SKY HIGH IN PATIENTS 4722 03:26:02,480 --> 03:26:04,680 RESPONDS TO DRUG USE BUT IS THAT 4723 03:26:04,680 --> 03:26:06,120 ENOUGH? IT'S USUALLY NOT ENOUGH 4724 03:26:06,120 --> 03:26:08,240 EVEN IF YOU HAVE A BLOOD 4725 03:26:08,240 --> 03:26:09,520 BIOMARKER YOU REALLY NEED A 4726 03:26:09,520 --> 03:26:11,000 FUNCTIONAL CLINICAL OUTCOME 4727 03:26:11,000 --> 03:26:11,960 MEASURE TO SUPPORT THE FACT THAT 4728 03:26:11,960 --> 03:26:14,160 EVEN IF -- LIKE SO WHAT DOES IT 4729 03:26:14,160 --> 03:26:16,840 EVEN MATTER IF THE SORBITOL 4730 03:26:16,840 --> 03:26:18,600 LEVELS DROP IS WHAT THE FDA IS 4731 03:26:18,600 --> 03:26:20,200 GOING TO SAY. DOES IT MATTER? 4732 03:26:20,200 --> 03:26:22,400 HOW DO YOU KNOW IT MATTERS IT'S 4733 03:26:22,400 --> 03:26:23,480 THE FUNCTIONAL CLINICAL OUTCOMES 4734 03:26:23,480 --> 03:26:25,800 THAT MATTER. THE WAY TO 4735 03:26:25,800 --> 03:26:28,760 IDENTIFY WHETHER OR NOT THE 4736 03:26:28,760 --> 03:26:29,400 FUNCTIONAL CLINICAL OUTCOME IS 4737 03:26:29,400 --> 03:26:30,520 GOING TO MATTER IS HAVING A 4738 03:26:30,520 --> 03:26:32,680 NATURAL HISTORY STUDY. 4739 03:26:32,680 --> 03:26:34,720 FOR EXAMPLE IN OUR DRUG GROUP, 4740 03:26:34,720 --> 03:26:37,400 FOR EXAMPLE IN OUR FOR OUR 4741 03:26:37,400 --> 03:26:39,360 DISEASE WE'RE WORKING ON THERE 4742 03:26:39,360 --> 03:26:43,200 WAS NO NATURAL HISTORY ON SORB, 4743 03:26:43,200 --> 03:26:45,360 ON CM T BUT NOT SPECIFIC TO SORB 4744 03:26:45,360 --> 03:26:47,040 AND CREATES A LOT OF STRESS IN 4745 03:26:47,040 --> 03:26:48,920 TERMS OF TRYING TO IDENTIFY 4746 03:26:48,920 --> 03:26:52,840 WHAT'S THE PRIMARY OUTCOME 4747 03:26:52,840 --> 03:26:53,640 MEASURE SECONDARY WHAT'S GOING 4748 03:26:53,640 --> 03:26:55,800 TO WORK FOR THE FDA WHAT WILL 4749 03:26:55,800 --> 03:26:57,400 THEY ACCEPT. IT LEADS TO A LOT 4750 03:26:57,400 --> 03:26:58,720 OF STRESS. 4751 03:26:58,720 --> 03:27:00,040 HAVING THAT INFORMATION ALREADY 4752 03:27:00,040 --> 03:27:02,880 AHEAD OF TIME IS INVALUABLE. SO 4753 03:27:02,880 --> 03:27:05,080 HAVING, LIKE, AT LEAST A 4754 03:27:05,080 --> 03:27:06,920 TWO-YEAR PERIOD OF A PROSPECTIVE 4755 03:27:06,920 --> 03:27:08,240 TRIAL ON A NATURAL HISTORY STUDY 4756 03:27:08,240 --> 03:27:09,320 THAT YOU CAN PUT TOGETHER AS A 4757 03:27:09,320 --> 03:27:12,920 GROUP AND I KNOW THERE ARE 4758 03:27:12,920 --> 03:27:16,600 TRIALS ALREADY IN SPASTIC 4759 03:27:16,600 --> 03:27:17,240 PARAPLEG 4760 03:27:17,240 --> 03:27:17,960 PARAPLEGIA, I DON'T KNOW IF IT'S 4761 03:27:17,960 --> 03:27:21,520 SPECIFICALLY TO SPG4, BUT HAVING 4762 03:27:21,520 --> 03:27:22,760 INVALUABLE AND MAKE THAT NEXT 4763 03:27:22,760 --> 03:27:25,040 STEP OF GOING FROM ANIMAL TO 4764 03:27:25,040 --> 03:27:26,920 HUMAN TRIALS VERY EASY. 4765 03:27:26,920 --> 03:27:28,600 THE OTHER THING I THINK IS VERY 4766 03:27:28,600 --> 03:27:30,800 IMPORTANT AND SO BEAUTIFUL TO 4767 03:27:30,800 --> 03:27:32,800 SEE ALL OF YOU HERE TOGETHERS, 4768 03:27:32,800 --> 03:27:35,240 IN THIS SYMPOSIA IS YOU NEED TO 4769 03:27:35,240 --> 03:27:37,080 HAVE A COHESIVE PHYSICIAN 4770 03:27:37,080 --> 03:27:38,080 SCIENTIST COLLABORATION ON HOW 4771 03:27:38,080 --> 03:27:41,400 TO MEASURE OUTCOMES IN THIS 4772 03:27:41,400 --> 03:27:44,440 PATIENT POPULATION. 4773 03:27:44,440 --> 03:27:45,840 SO MAKING SURE YOU ARE ALL ON 4774 03:27:45,840 --> 03:27:47,160 THE SAME PAGE MAKING SURE THERE 4775 03:27:47,160 --> 03:27:48,720 IS NO BACK AND FORTH ON WHICH IS 4776 03:27:48,720 --> 03:27:50,560 THE BEST OUTCOME MEASURE, HAVE 4777 03:27:50,560 --> 03:27:51,800 THAT DISCUSSION BEFORE YOU 4778 03:27:51,800 --> 03:27:53,400 PRESENT IT TO THE COMPANY, FOR 4779 03:27:53,400 --> 03:27:54,600 EXAMPLE, MAKE SURE THAT YOU 4780 03:27:54,600 --> 03:27:56,360 PRESENT AS A UNIFIED FRONT. I 4781 03:27:56,360 --> 03:27:57,720 THINK THIS IS HUGE. AND GIVES 4782 03:27:57,720 --> 03:28:00,120 YOU A LOT OF STRENGTH AND POWER 4783 03:28:00,120 --> 03:28:01,280 AS A COMMUNITY. 4784 03:28:01,280 --> 03:28:02,640 AND AGAIN, ONCE YOU HAVE THIS 4785 03:28:02,640 --> 03:28:04,040 NATURAL HISTORY DATA, THE WAY 4786 03:28:04,040 --> 03:28:06,040 THE MONEY CAN BE CYCLED BACK 4787 03:28:06,040 --> 03:28:07,600 TOWARDS RESEARCH AND SUPPORTING 4788 03:28:07,600 --> 03:28:09,160 RESEARCH IS THAT SOMETIMES THIS 4789 03:28:09,160 --> 03:28:10,560 NATURAL HISTORY DATA CAN 4790 03:28:10,560 --> 03:28:11,880 ACTUALLY BE PURCHASED AS WELL. 4791 03:28:11,880 --> 03:28:13,320 SO AGAIN, NO PATIENT IDENTIFYING 4792 03:28:13,320 --> 03:28:16,160 INFORMATION BUT YOU DO GET YOU 4793 03:28:16,160 --> 03:28:17,400 KNOW WHEN THE PHARMA COMPANY 4794 03:28:17,400 --> 03:28:18,800 WANTS TO KNOW WHAT DOES THE 4795 03:28:18,800 --> 03:28:20,240 NATURAL HISTORY STUDY SHOW YOU 4796 03:28:20,240 --> 03:28:21,800 CAN SAY I WILL GIVE YOU THIS 4797 03:28:21,800 --> 03:28:23,680 INFORMATION BUT IT COMES AT A 4798 03:28:23,680 --> 03:28:26,880 PRICE. IT'S FINE TO DO THAT 4799 03:28:26,880 --> 03:28:31,000 BECAUSE IT'S A WAY TO YOU KNOW 4800 03:28:31,000 --> 03:28:32,720 MAKE SURE ACADEMIA IS SUPPORTED 4801 03:28:32,720 --> 03:28:34,320 AND MONEY GOES TO GRANTS IN 4802 03:28:34,320 --> 03:28:36,160 TERMS OF RESEARCH AND SUPPORTS 4803 03:28:36,160 --> 03:28:38,400 THE CONSORTIUM AND MEETINGS THAT 4804 03:28:38,400 --> 03:28:39,720 YOU'RE HAVING AND WHAT NOT. 4805 03:28:39,720 --> 03:28:41,320 SO AFTER THAT, YOU -- SO IF YOU 4806 03:28:41,320 --> 03:28:44,960 DO ACTUALLY HAVE LIKE A DRUG, AN 4807 03:28:44,960 --> 03:28:46,600 ANIMAL MODEL AND NATURAL 4808 03:28:46,600 --> 03:28:48,120 HISTORY, YOU HAVE TO ASK 4809 03:28:48,120 --> 03:28:50,640 YOURSELF, IS THIS COMPOUND 4810 03:28:50,640 --> 03:28:53,800 DRUGABLE? SO CAN THE 4811 03:28:53,800 --> 03:28:54,680 PHARMACODYNAMIC EFFECTS OF THE 4812 03:28:54,680 --> 03:28:56,280 DRUG BE MONITORED? YOU KNOW YOU 4813 03:28:56,280 --> 03:28:57,560 NEED TO BE ABLE TO MONITOR THE 4814 03:28:57,560 --> 03:28:59,400 DRUG ACTION AND EFFICACY, YOU 4815 03:28:59,400 --> 03:29:04,000 NEED TO KNOW IF THERE'S A 4816 03:29:04,000 --> 03:29:04,600 BIOMARKER RELEVANT TO THE 4817 03:29:04,600 --> 03:29:06,120 DISEASE PROCESS THAT NEEDS TO BE 4818 03:29:06,120 --> 03:29:07,880 DEVELOPED AND THE OTHER THING 4819 03:29:07,880 --> 03:29:09,400 THAT GETS CHECKED WHEN DOING 4820 03:29:09,400 --> 03:29:11,400 DRUG DEVELOPMENT AND 4821 03:29:11,400 --> 03:29:15,000 PHARMACODYNAMICS I MEAN PHARMACO 4822 03:29:15,000 --> 03:29:19,080 PHARMACOKINETICS IMPORTANT TO 4823 03:29:19,080 --> 03:29:21,400 DETERMINE FOR ABSORPTION 4824 03:29:21,400 --> 03:29:24,160 DISTRIBUTION METABOLISM AND 4825 03:29:24,160 --> 03:29:25,440 EXECUTION. 4826 03:29:25,440 --> 03:29:27,720 IS THERE A POTENTIAL RISK OF 4827 03:29:27,720 --> 03:29:30,160 DRUG TOXICITY AND OTHER 4828 03:29:30,160 --> 03:29:33,080 COMPONENTS IN DRUG FORMULATION 4829 03:29:33,080 --> 03:29:35,480 AND MANUFACTURING ARE CHEMICAL 4830 03:29:35,480 --> 03:29:37,360 STABILIZERS AND THERE'S A 4831 03:29:37,360 --> 03:29:39,520 DRAMATIC EFFECT ON BIO 4832 03:29:39,520 --> 03:29:41,080 AVAILABILITY AND DRUG EFFICACY 4833 03:29:41,080 --> 03:29:42,480 SO ONCE YOU GET PAST THE PHASE 4834 03:29:42,480 --> 03:29:46,560 OF THIS DRUG IS SAFE WE CAN DO 4835 03:29:46,560 --> 03:29:48,120 PHARMACODYNAMIC AND 4836 03:29:48,120 --> 03:29:49,080 PHARMACOKINETIC STUDIES AFTER 4837 03:29:49,080 --> 03:29:51,440 THAT YOU HAVE TO START THINKING 4838 03:29:51,440 --> 03:29:52,920 HOW CAN THIS DRUG BE FORM 4839 03:29:52,920 --> 03:29:54,120 SCOMPLATD THE MANUFACTURING 4840 03:29:54,120 --> 03:29:56,560 COSTS, LIKE FOR EXAMPLE I KNOW 4841 03:29:56,560 --> 03:29:58,080 THERE HAVE BEEN STUDIES ON 4842 03:29:58,080 --> 03:29:58,880 CERTAIN CONDITIONS THAT THE 4843 03:29:58,880 --> 03:30:00,120 MANUFACTURING OF THE DRUGS 4844 03:30:00,120 --> 03:30:02,040 ESPECIALLY WHEN IT COMES TO GENE 4845 03:30:02,040 --> 03:30:03,800 THERAPY OR VECTOR DEVELOPMENT IS 4846 03:30:03,800 --> 03:30:05,400 INCREDIBLY EXPENSIVE YOU HAVE TO 4847 03:30:05,400 --> 03:30:07,280 THINK ABOUT HOW SUSTAINABLE IS 4848 03:30:07,280 --> 03:30:10,120 THAT HOW CAN YOU MAKE SURE THAT 4849 03:30:10,120 --> 03:30:11,080 DRUG GETS DISTRIBUTED 4850 03:30:11,080 --> 03:30:13,880 APPROPRIATELY EVEN AFTER YOU 4851 03:30:13,880 --> 03:30:17,240 DEVELOP IT. 4852 03:30:17,240 --> 03:30:19,120 AND THEN WHO TO APPROACH IF THEY 4853 03:30:19,120 --> 03:30:20,720 TONIGHT REACH OUT TO YOU FIRST? 4854 03:30:20,720 --> 03:30:22,160 ALWAYS KNOW FROM MY EXPERIENCE 4855 03:30:22,160 --> 03:30:24,480 ON A BIOTECH SIDE PHARMA SIDE 4856 03:30:24,480 --> 03:30:26,480 ALL LOOKING TO SIGH IF THERE'S 4857 03:30:26,480 --> 03:30:28,600 ANY NEW DATA COMING ABOUT ALL 4858 03:30:28,600 --> 03:30:30,800 INTERESTED IN FINDING OUT OTHER 4859 03:30:30,800 --> 03:30:33,240 APPLICATIONS OF THE DRUGS WE 4860 03:30:33,240 --> 03:30:34,520 MIGHT BE DEVELOPING. AGAIN 4861 03:30:34,520 --> 03:30:40,120 WORKING WITH BIOTECH ORTECH OR 4862 03:30:40,120 --> 03:30:43,160 SMALL PHARMA IS EASIER, YOU HAVE 4863 03:30:43,160 --> 03:30:45,240 EASIER ACCESS TO DECISION MAKERS 4864 03:30:45,240 --> 03:30:47,520 AND THESE DECISION MAKERS TEND 4865 03:30:47,520 --> 03:30:48,800 TO ACT VERY QUICKLY BECAUSE 4866 03:30:48,800 --> 03:30:50,960 AGAIN USING THE EXAMPLE OF 4867 03:30:50,960 --> 03:30:53,240 COMPANY THAT I WORK FOR THE CEO 4868 03:30:53,240 --> 03:30:54,120 FOR EXAMPLE PURCHASED THE PATENT 4869 03:30:54,120 --> 03:30:56,280 TO THE DRUG, AND SHE'S IN DRUG 4870 03:30:56,280 --> 03:30:57,560 DEVELOPMENT RIGHT NOW. AND 4871 03:30:57,560 --> 03:30:58,880 SHE'S BEEN DEVELOPING FOR QUITE 4872 03:30:58,880 --> 03:31:01,120 SOME TIME. AND THEY'RE ALWAYS 4873 03:31:01,120 --> 03:31:03,520 LOOKING FOR YOU KNOW ANY OTHER 4874 03:31:03,520 --> 03:31:04,400 APPLICATION OF THIS SPECIFIC 4875 03:31:04,400 --> 03:31:06,000 DRUG TO AGAIN GET THE ATTENTION 4876 03:31:06,000 --> 03:31:09,080 OF INVESTORS AND THEN SUPPORT 4877 03:31:09,080 --> 03:31:09,880 THE FURTHER DEVELOPMENT OF THE 4878 03:31:09,880 --> 03:31:12,080 DRUG AND KEEP THE COMPANY ALIVE. 4879 03:31:12,080 --> 03:31:14,080 SO ANY -- DON'T EVER THINK THAT 4880 03:31:14,080 --> 03:31:15,520 ANY QUESTION IS TOO SMALL REACH 4881 03:31:15,520 --> 03:31:17,360 OUT TO THEM AND REACH OUT ON THE 4882 03:31:17,360 --> 03:31:18,200 WEBSITES AS WELL. 4883 03:31:18,200 --> 03:31:20,120 AND THEN FINALLY, YOU CAN STILL 4884 03:31:20,120 --> 03:31:22,560 STAY INVOLVED ONCE BIOTECH OR 4885 03:31:22,560 --> 03:31:26,120 PHARMA IS INVOLVED, SO 4886 03:31:26,120 --> 03:31:28,760 OFTENTIMES YOU KNOW ONCE THE 4887 03:31:28,760 --> 03:31:29,400 COMPANY REACHES OUT TO FOR 4888 03:31:29,400 --> 03:31:32,000 EXAMPLE THE PERSON ON THE PAPER 4889 03:31:32,000 --> 03:31:32,680 HOW MANY PATIENTS DO YOU HAVE 4890 03:31:32,680 --> 03:31:34,280 THEY IDENTIFY YOU AS A KEY 4891 03:31:34,280 --> 03:31:38,120 OPINION LEADER OR KOL AND THEY 4892 03:31:38,120 --> 03:31:41,720 IDENTIFY THESE BASED ON WHO'S AN 4893 03:31:41,720 --> 03:31:43,920 AUTHOR A PAPER WHO HAS PATIENTS 4894 03:31:43,920 --> 03:31:45,600 IDENTIFIED AS CONSORTIUM OR PART 4895 03:31:45,600 --> 03:31:48,160 OF A CONSORTIUM YOU HAVE TO 4896 03:31:48,160 --> 03:31:50,280 REALIZE THEY WORK FAST SO FAST 4897 03:31:50,280 --> 03:31:55,680 IT'S UNNERVERING, IF YOU WORK IN 4898 03:31:55,680 --> 03:31:56,360 ACADEMIA OR COME TO AN ACADEMIC 4899 03:31:56,360 --> 03:31:57,840 BACKGROUND LIKE I DO IT'S 4900 03:31:57,840 --> 03:31:59,560 ALARMING OH, MY GOD THESE THINGS 4901 03:31:59,560 --> 03:32:02,320 ARE MOVING SO SO QUICKLY BUT IN 4902 03:32:02,320 --> 03:32:04,000 A WAY IT'S VERY GOOD BECAUSE IT 4903 03:32:04,000 --> 03:32:04,800 JUST FORCES THINGS ALONG. 4904 03:32:04,800 --> 03:32:06,920 BUT YOU DON'T HAVE TO GO AS FAST 4905 03:32:06,920 --> 03:32:09,920 AS THEY'RE GOING I THINK IT'S A 4906 03:32:09,920 --> 03:32:10,600 SYMBIOTIC RELATIONSHIP WHERE YOU 4907 03:32:10,600 --> 03:32:12,440 WORK TOGETHER AND GET TO A HAPPY 4908 03:32:12,440 --> 03:32:14,480 MEDIUM AND NOT GET STUCK IN THE 4909 03:32:14,480 --> 03:32:16,400 STAGNATION OF NEEDING MONEY TO 4910 03:32:16,400 --> 03:32:17,360 MAKE PROGRESS WITH YOUR WORK 4911 03:32:17,360 --> 03:32:19,720 THAT YOU WANT TO DO, HAVING A 4912 03:32:19,720 --> 03:32:21,040 COMPANY THAT'S READY TO SUPPLY 4913 03:32:21,040 --> 03:32:21,760 YOU FINANCIAL SUPPORT FOR THE 4914 03:32:21,760 --> 03:32:23,400 WORK YOU WANT TO DO, AND THEN 4915 03:32:23,400 --> 03:32:25,840 KIND OF WORKING TOGETHER AT THE 4916 03:32:25,840 --> 03:32:26,600 SAFE AND CORRECT SPEED TO 4917 03:32:26,600 --> 03:32:29,280 DEVELOP THE DRUG THAT YOU NEED 4918 03:32:29,280 --> 03:32:31,560 FOR -- FOR YOUR DRUG, FOR YOUR 4919 03:32:31,560 --> 03:32:32,920 CONDITIONS, SUCH AS SPG4. 4920 03:32:32,920 --> 03:32:35,680 SO I WOULD SAY YOU WANT TO LEARN 4921 03:32:35,680 --> 03:32:37,480 TO COMPLIMENT BIOTECH OR PHARMA 4922 03:32:37,480 --> 03:32:40,200 ALLOWS IF YOU HAVE A GOOD 4923 03:32:40,200 --> 03:32:41,720 WORKING RELATIONSHIP BETWEEN 4924 03:32:41,720 --> 03:32:43,680 KOLS AND CONSORTIA THIS LEADS TO 4925 03:32:43,680 --> 03:32:45,320 MORE MONITORING THE STUD TEE 4926 03:32:45,320 --> 03:32:48,080 THAT GETS DEVELOPED MORE OF THE 4927 03:32:48,080 --> 03:32:49,320 KOL INPUT INTO THE DRUG 4928 03:32:49,320 --> 03:32:50,640 DEVELOPMENT WHICH OVERALL MAKES 4929 03:32:50,640 --> 03:32:53,400 IT IT A BETTER STUDY I'M A BIG 4930 03:32:53,400 --> 03:32:56,400 PROPONENT OF HAVING ALL THE 4931 03:32:56,400 --> 03:32:57,080 PEOPLE INVOLVED EVERYBODY ON 4932 03:32:57,080 --> 03:32:59,000 THIS CALL FOR EXAMPLE IF A DRUG 4933 03:32:59,000 --> 03:33:00,920 IS GETTING DEVELOPED FOR SPG4 WE 4934 03:33:00,920 --> 03:33:02,720 NEED YOUR INPUT NOT EVEN JUST 4935 03:33:02,720 --> 03:33:06,120 SCIENTISTS OR CLINICIANS, EVEN 4936 03:33:06,120 --> 03:33:07,560 PATIENTS, PATIENTS REALLY 4937 03:33:07,560 --> 03:33:08,160 MATTER, PATIENT FAMILIES, 4938 03:33:08,160 --> 03:33:10,600 PATIENT ROUND TABLES, GETTING A 4939 03:33:10,600 --> 03:33:12,120 REALLY COMPLIMENTARY 4940 03:33:12,120 --> 03:33:14,600 RELATIONSHIP WITH A BIOTECH 4941 03:33:14,600 --> 03:33:15,840 PHARMA COMPANY IS IMPORTANT. 4942 03:33:15,840 --> 03:33:16,840 I WOULD ALSO RECOMMEND THAT IF 4943 03:33:16,840 --> 03:33:20,160 YOU HAVE FELLOWS THAT ARE IN 4944 03:33:20,160 --> 03:33:21,360 TRAINING, YOU KNOW WHEN I WAS 4945 03:33:21,360 --> 03:33:22,320 TRAINING PHARMA WAS ALWAYS 4946 03:33:22,320 --> 03:33:23,600 THOUGHT OF BEING THE DARK SIDE 4947 03:33:23,600 --> 03:33:27,240 AND IT WASN'T VERY ENCOURAGED, 4948 03:33:27,240 --> 03:33:28,240 BUT WHAT ENDS UP HAPPENING IS 4949 03:33:28,240 --> 03:33:30,120 YOU GET A LOT OF PEOPLE THAT 4950 03:33:30,120 --> 03:33:31,000 AREN'T NECESSARILY THE RIGHT 4951 03:33:31,000 --> 03:33:34,280 PEOPLE WHO ARE TRAINED TO 4952 03:33:34,280 --> 03:33:35,280 RECOGNIZE, TREAT AND MONITOR 4953 03:33:35,280 --> 03:33:38,360 THIS DISEASE WORKING ON THE 4954 03:33:38,360 --> 03:33:38,560 TRIAL. 4955 03:33:38,560 --> 03:33:40,720 SO IF YOU HAVE A COMPANY THAT 4956 03:33:40,720 --> 03:33:42,080 HIRES THE RIGHT PEOPLE THEN YOU 4957 03:33:42,080 --> 03:33:43,960 HAVE SOMEONE ON THE INSIDE 4958 03:33:43,960 --> 03:33:47,240 MAKING SURE WHATEVER YOU ON THE 4959 03:33:47,240 --> 03:33:49,040 OUT SIDE ARE RECOMMENDING GETS 4960 03:33:49,040 --> 03:33:49,760 TRANSLATED CORRECTLY TO THE 4961 03:33:49,760 --> 03:33:51,760 HIGHER UPS IN THE COMPANY AND 4962 03:33:51,760 --> 03:33:53,120 THAT THE STUDY IS DONE CORRECTLY 4963 03:33:53,120 --> 03:33:54,160 FROM THE INSIDE. 4964 03:33:54,160 --> 03:33:55,920 I DO SEE THERE IS EVOLUTION IN 4965 03:33:55,920 --> 03:33:57,400 PHYSICIANS AND A LOT MORE PEOPLE 4966 03:33:57,400 --> 03:33:59,400 HAVING AN INTEREST IN WORKING IN 4967 03:33:59,400 --> 03:34:00,800 PHARMA I THINK THERE'S A LOT OF 4968 03:34:00,800 --> 03:34:03,320 GOOD THAT A LOT OF PEOPLE WITH 4969 03:34:03,320 --> 03:34:04,640 EXTENSIVE TRAINING CAN PROVIDE 4970 03:34:04,640 --> 03:34:05,880 FROM WITHIN PHARMACEUTICAL 4971 03:34:05,880 --> 03:34:07,400 COMPANIES AND BIOTECH COMPANIES 4972 03:34:07,400 --> 03:34:09,040 JUST TO MAKE SURE WITHIN THE 4973 03:34:09,040 --> 03:34:11,800 INSIDE THAT THINGS GET DONE 4974 03:34:11,800 --> 03:34:12,040 CORRECTLY. 4975 03:34:12,040 --> 03:34:15,360 SO I HOPE YOU FIND THAT HELPFUL. 4976 03:34:15,360 --> 03:34:19,040 AND THANK YOU AGAIN TO ARIANNE 4977 03:34:19,040 --> 03:34:22,760 FOR THIS LOVELY OPPORTUNITY TO 4978 03:34:22,760 --> 03:34:23,120 SPEAK TODAY. 4979 03:34:23,120 --> 03:34:23,760 >> THANK YOU SO MUCH BEAUTIFUL 4980 03:34:23,760 --> 03:34:26,320 FOR A LOT OF US LIKE A BLACK BOX 4981 03:34:26,320 --> 03:34:28,720 ON HOW TO GET DRUGS FROM 4982 03:34:28,720 --> 03:34:30,120 ACADEMIA INTO TRIAL SO THANK YOU 4983 03:34:30,120 --> 03:34:32,040 SO MUCH FOR YOUR INSIGHTS AND 4984 03:34:32,040 --> 03:34:35,200 WE'LL NOW OPEN THE SESSION TO 4985 03:34:35,200 --> 03:34:35,600 QUESTIONS. 4986 03:34:35,600 --> 03:34:36,640 MAYBE PEOPLE COULD UNMUTE 4987 03:34:36,640 --> 03:34:37,400 THEMSELVES AND ASK THEIR 4988 03:34:37,400 --> 03:34:39,440 QUESTIONS AND WE'LL TRY TO -- 4989 03:34:39,440 --> 03:34:40,600 MAY AND I WILL TRY TO GOOD 4990 03:34:40,600 --> 03:34:41,720 EVENING GALLAUDET THROUGH THE 4991 03:34:41,720 --> 03:34:43,240 CHAT BUT MANY QUESTIONS 4992 03:34:43,240 --> 03:34:44,320 THROUGHOUT THE DAY IF YOU RECALL 4993 03:34:44,320 --> 03:34:45,680 YOUR QUESTION AND ASK IT 4994 03:34:45,680 --> 03:34:49,360 DIRECTLY THAT WILL MAKE OUR JOB 4995 03:34:49,360 --> 03:34:58,400 EASIER. THANK YOU SO MUCH. 4996 03:34:58,400 --> 03:35:01,400 >> CAN I ASK A QUESTION. 4997 03:35:01,400 --> 03:35:03,280 >> YES PLEASE GO AHEAD. 4998 03:35:03,280 --> 03:35:05,400 >> HELLO. I THANK ALL THE 4999 03:35:05,400 --> 03:35:07,880 SPEAKERS THIS HAS BEEN A 5000 03:35:07,880 --> 03:35:09,200 WONDERFUL SYMPOSIUM THANK YOU SO 5001 03:35:09,200 --> 03:35:11,000 MUCH FOR ORGANIZING THIS AND 5002 03:35:11,000 --> 03:35:12,160 THANK YOU SO MUCH FOR YOUR WORK 5003 03:35:12,160 --> 03:35:13,200 IN THIS FIELD WE WEREN'T ABLE TO 5004 03:35:13,200 --> 03:35:15,600 HAVE ALL THE SPEAKERS WE WANTED 5005 03:35:15,600 --> 03:35:17,360 BUT WE HOPE TO HEAR FROM YOU IN 5006 03:35:17,360 --> 03:35:19,600 AN UP COMING MEETING THANK YOU 5007 03:35:19,600 --> 03:35:19,920 FORJOINING. 5008 03:35:19,920 --> 03:35:22,600 >> OF COURSE NO PROBLEM. ONE OF 5009 03:35:22,600 --> 03:35:24,120 THE QUESTIONS I HAVE IS GENE -- 5010 03:35:24,120 --> 03:35:25,840 GENE THERAPY, ABOUT GENE 5011 03:35:25,840 --> 03:35:31,120 THERAPY, SO WE KNOW THAT AAV ARE 5012 03:35:31,120 --> 03:35:32,800 VERY, YOU KNOW THEY ARE VERY 5013 03:35:32,800 --> 03:35:35,000 GOOD BECAUSE NON TOXIC BUT 5014 03:35:35,000 --> 03:35:37,240 LIMITATION IS THE GENE SIZE BUT 5015 03:35:37,240 --> 03:35:38,960 IF WE'RE DEVELOPING PERSONALIZED 5016 03:35:38,960 --> 03:35:41,160 MEDICINE APPROACHES AND IN SOME 5017 03:35:41,160 --> 03:35:42,640 CASES THE GENE SIZE WILL BE VERY 5018 03:35:42,640 --> 03:35:46,560 LARGE AND WE WON'T BE ABLE TO 5019 03:35:46,560 --> 03:35:46,840 E 5020 03:35:46,840 --> 03:35:48,560 ACCOMMODATE WITHIN THE AAV, AND 5021 03:35:48,560 --> 03:35:50,240 FOR PROBLEMS LIKE THIS I WOULD 5022 03:35:50,240 --> 03:35:53,400 LIKE TO ASK MY COLLEAGUES, 5023 03:35:53,400 --> 03:35:55,360 WHAT'S THE POTENTIAL SOLUTION IN 5024 03:35:55,360 --> 03:35:59,720 THE FUTURE? HOW CAN WE 5025 03:35:59,720 --> 03:36:04,120 ACCOMMODATE PATIENTS WHOSE 5026 03:36:04,120 --> 03:36:04,880 JOOEGENES 5027 03:36:04,880 --> 03:36:06,600 ARE LARGER THAN THE SIZE WE CAN 5028 03:36:06,600 --> 03:36:09,960 ACCOMMODATE WITHIN THE AAV, 5029 03:36:09,960 --> 03:36:12,120 THANK YOU. SO MAYBE MIGUEL MAY 5030 03:36:12,120 --> 03:36:14,760 HAVE SOMETHING TO SAY, MAYBE 5031 03:36:14,760 --> 03:36:17,840 PETER MAY HAVE SOMETHING TO SAY, 5032 03:36:17,840 --> 03:36:18,720 MAYBE DARIOUSH MAY HAVE 5033 03:36:18,720 --> 03:36:21,400 SOMETHING TO SAY, I DON'T KNOW 5034 03:36:21,400 --> 03:36:23,920 WHO WOULD HAVE AN IDEA. 5035 03:36:23,920 --> 03:36:28,240 >> HI HANDE, NICE TO SEE YOU. 5036 03:36:28,240 --> 03:36:31,000 SO YEAH WELL WE DEAL WITH THAT, 5037 03:36:31,000 --> 03:36:36,840 WE HAVE A PROGRAM IN NF1, SO YOU 5038 03:36:36,840 --> 03:36:41,040 KNOW FOR VERY LARGE 8.8KB, YOU 5039 03:36:41,040 --> 03:36:44,800 KNOW THERE IS AAV DOES FUNNY 5040 03:36:44,800 --> 03:36:46,400 CONTRIBUTION IN THE NUCLEUS, AND 5041 03:36:46,400 --> 03:36:51,040 WHAT PEOPLE HAVE FOUND OUT, AND 5042 03:36:51,040 --> 03:36:53,960 WE'VE DEMONSTRATED FOR NF1 AS 5043 03:36:53,960 --> 03:36:54,920 WELL YOU CAN DEVELOP A TWO 5044 03:36:54,920 --> 03:36:58,400 VECTOR SYSTEM. IT BECOMES THE 5045 03:36:58,400 --> 03:37:00,760 GENOMES RECOMBINE IN THE NUCLEUS 5046 03:37:00,760 --> 03:37:02,440 AND YOU CAN USE DIFFERENT TRICKS 5047 03:37:02,440 --> 03:37:04,120 YOU CAN ACTUALLY EXPRESS THE 5048 03:37:04,120 --> 03:37:06,120 FULL LENGTH. THAT WORKS WELL. 5049 03:37:06,120 --> 03:37:08,600 SO THE DIFFICULTY THAT WAS 5050 03:37:08,600 --> 03:37:11,160 ACTUALLY EMPLOYED FIRST BECAUSE 5051 03:37:11,160 --> 03:37:13,040 VERY LOCALIZED AREA RELATIVELY 5052 03:37:13,040 --> 03:37:15,600 EASY (DEVELOPED IN THE EYE 5053 03:37:15,600 --> 03:37:17,360 FIRST) BRAIN A LITTLE MORE 5054 03:37:17,360 --> 03:37:18,600 COMPLICATED BECAUSE OF 5055 03:37:18,600 --> 03:37:20,120 DEFICIENCIES NOT TREMENDOUSLY 5056 03:37:20,120 --> 03:37:22,960 HIGH. SO I THINK FOR DISEASES 5057 03:37:22,960 --> 03:37:26,040 LIKE NF1, AND YOU KNOW OTHERS, 5058 03:37:26,040 --> 03:37:27,360 OBVIOUSLY, WHERE THE GENE IS TOO 5059 03:37:27,360 --> 03:37:29,280 LARGE WE'RE GOING TO HAVE TO 5060 03:37:29,280 --> 03:37:31,200 HAVE A LEAK IN EFFICIENCY TO 5061 03:37:31,200 --> 03:37:32,800 ACTUALLY BE ABLE TO DO IT 5062 03:37:32,800 --> 03:37:35,400 BECAUSE WE'RE HAVING THESE 5063 03:37:35,400 --> 03:37:36,520 CONVERSATIONS OVER THE CHAT WITH 5064 03:37:36,520 --> 03:37:38,600 DARIOUSH ABOUT YOU KNOW 5065 03:37:38,600 --> 03:37:39,800 TRANSACTION OF THE ESSENTIALLY 5066 03:37:39,800 --> 03:37:44,000 THE BRAIN FROM A CSF INFUSION A 5067 03:37:44,000 --> 03:37:46,760 SUPER REGION OF THE CNS AND I 5068 03:37:46,760 --> 03:37:49,000 MEAN IT'S LIMITED IT'S VERY, 5069 03:37:49,000 --> 03:37:50,800 VERY LIMITED FOR SURE. SO YOU 5070 03:37:50,800 --> 03:37:56,360 KNOW I THINK THE SUCCESS WITH 5071 03:37:56,360 --> 03:37:58,240 SPINAL MUSCULAR KIND OF LULLED 5072 03:37:58,240 --> 03:38:00,440 US INTO A SENSE WE'RE PRETTY 5073 03:38:00,440 --> 03:38:01,600 MUCH DONE WE CAN CURE ANYTHING. 5074 03:38:01,600 --> 03:38:03,880 I SUSPECT FOR DISEASE WHERE YOU 5075 03:38:03,880 --> 03:38:09,400 DON'T HAVE BY STANDER EFFECTS OR 5076 03:38:09,400 --> 03:38:15,960 YOU KNOW AN ENZYME SECRETED, 5077 03:38:15,960 --> 03:38:18,160 WHAT HAPPENED SO SMA PERFECT 5078 03:38:18,160 --> 03:38:21,400 VECTOR FOR PERFECT DISEASE 5079 03:38:21,400 --> 03:38:26,800 PERFECT TROPISM, HOPEFULLY NOT 5080 03:38:26,800 --> 03:38:28,160 TOXIC BUT EFFECT ARE YOU KNOW 5081 03:38:28,160 --> 03:38:31,680 SMALL, LET'S PUT IT THAT WAY. 5082 03:38:31,680 --> 03:38:32,960 >> DO YOU THINK WE SHALL FOCUS 5083 03:38:32,960 --> 03:38:36,520 ON THE ANTI VIRUS IN ADDITION TO 5084 03:38:36,520 --> 03:38:39,520 AVV? LANSY OFFERS A LARGER SIZE 5085 03:38:39,520 --> 03:38:46,280 AND MAYBE WE CAN HAVE LESS TALK 5086 03:38:46,280 --> 03:38:53,320 TAME THEM A B MIGUEL: YOU'RE 5087 03:38:53,320 --> 03:38:54,400 RIGHT. THE PROBLEM IS 5088 03:38:54,400 --> 03:38:54,760 MANUFACTURING. 5089 03:38:54,760 --> 03:38:56,880 MANUFACTURING LINKING IS 5090 03:38:56,880 --> 03:38:57,880 DIFFICULT. IT IS DIFFICULT. 5091 03:38:57,880 --> 03:38:59,360 ISSUES WITH STABILITY OF THE 5092 03:38:59,360 --> 03:39:02,280 PRODUCT. ONE THAT HAS TO BE 5093 03:39:02,280 --> 03:39:05,720 KEPT AT MINUS 80 AND THE 5094 03:39:05,720 --> 03:39:07,160 DEFICIENCY DISTRIBUTION ITSELF 5095 03:39:07,160 --> 03:39:09,440 IS MUCH, MUCH MORE LIMITED. SO 5096 03:39:09,440 --> 03:39:11,960 IT'S A VERY USEFUL PLATFORM FOR 5097 03:39:11,960 --> 03:39:14,000 SURE IT HAS THAT ADVANTAGE, 5098 03:39:14,000 --> 03:39:16,000 OBVIOUSLY CAN INTEGRATE NON 5099 03:39:16,000 --> 03:39:17,320 DIVIDES CELLS BUT DISTRIBUTION 5100 03:39:17,320 --> 03:39:19,680 WISE IS A BIT MORE CHALLENGING, 5101 03:39:19,680 --> 03:39:25,160 I THINK. AND MANUFACTURING AS 5102 03:39:25,160 --> 03:39:25,520 WE 5103 03:39:25,520 --> 03:39:28,000 WELL. 5104 03:39:28,000 --> 03:39:32,160 >> I SEE DR. CHIANG HAS RAISED 5105 03:39:32,160 --> 03:39:32,920 HIS HAND. 5106 03:39:32,920 --> 03:39:35,160 >> THAT'S GOOD TO SEE MIGUEL 5107 03:39:35,160 --> 03:39:36,880 AGAIN I HAVE A QUESTION MIGUEL 5108 03:39:36,880 --> 03:39:38,400 WE HAVEN'T TALKED ABOUT IT 5109 03:39:38,400 --> 03:39:40,400 DURING OUR CONVERSATION. YOU 5110 03:39:40,400 --> 03:39:42,640 KNOW INSTEAD OF HAVING THE WHOLE 5111 03:39:42,640 --> 03:39:44,520 GENOME LIKE THE GENINGS IN THERE 5112 03:39:44,520 --> 03:39:46,960 YOU KNOW TRY TO OVERCOME LIKE 5113 03:39:46,960 --> 03:39:48,280 YOU KNOW THE ENSUFFICIENCY OR 5114 03:39:48,280 --> 03:39:51,880 THE LOSS OF THE FUNCTION CAN WE 5115 03:39:51,880 --> 03:39:54,560 ACTUALLY RESTRATIFY THE APPROACH 5116 03:39:54,560 --> 03:39:59,840 TO TARGETING SOME MICRO RNA 5117 03:39:59,840 --> 03:40:01,200 USING ANTI ZEN BECAUSE YOU HAVE 5118 03:40:01,200 --> 03:40:03,960 KNOWN FOR OTHER DISEASES A LOT 5119 03:40:03,960 --> 03:40:06,480 OF MICRO RNA ARE REGULATED TO 5120 03:40:06,480 --> 03:40:07,720 REGULATE GENE EXPRESSION. 5121 03:40:07,720 --> 03:40:09,360 AND I BET WE CAN FIND A COUPLE 5122 03:40:09,360 --> 03:40:13,160 OF MICRO RNA THAT CAN 5123 03:40:13,160 --> 03:40:17,240 SPECIFICALLY REGULATE SPATANS 5124 03:40:17,240 --> 03:40:18,600 OVER EXPRESSION LEVEL. IF WE 5125 03:40:18,600 --> 03:40:23,000 TARGET MICRO RNA KIND OF PIGGY 5126 03:40:23,000 --> 03:40:26,680 BACK ON THE ANTI ZEN TECHNOLOGY 5127 03:40:26,680 --> 03:40:28,760 WE CAN INSTEAD OF HAVING GENOME 5128 03:40:28,760 --> 03:40:32,520 BUT TARGET MICRO RNA SO PROBABLY 5129 03:40:32,520 --> 03:40:35,080 YOU KNOW APPROACH TO THE SAME 5130 03:40:35,080 --> 03:40:36,520 KIND OF FILE PROJECT WHAT DO YOU 5131 03:40:36,520 --> 03:40:38,680 THINK WHAT'S YOUR TAKE ON THAT. 5132 03:40:38,680 --> 03:40:39,720 >> MIGUEL ESTEVES: OH, SO WE 5133 03:40:39,720 --> 03:40:44,400 DON'T HAVE -- WELL AT LEAST OUR 5134 03:40:44,400 --> 03:40:46,880 KNOWLEDGE OF MICRO ASE WE HAVE A 5135 03:40:46,880 --> 03:40:49,000 THOUSAND OF THEM? THEY DON'T 5136 03:40:49,000 --> 03:40:51,520 REGULATE A SINGLE GENE, RIGHT? 5137 03:40:51,520 --> 03:40:54,120 REGULATING A MICRO RNA IT'S 5138 03:40:54,120 --> 03:40:56,000 POSSIBLE YOU CERTAINLY CAN USE 5139 03:40:56,000 --> 03:40:58,280 SPONGES ESSENTIALLY WHAT'S 5140 03:40:58,280 --> 03:41:00,800 CALLED SPONGES FOR MICRO RNA. S 5141 03:41:00,800 --> 03:41:02,480 ON THE OTHER HAND I APOLOGIZE 5142 03:41:02,480 --> 03:41:05,000 FOR NOT REMEMBERING THE NAME OF 5143 03:41:05,000 --> 03:41:08,360 OUR FIRST SPEAKER, THAT IT 5144 03:41:08,360 --> 03:41:10,600 REALLY IS USE CORRECT LOTS OF 5145 03:41:10,600 --> 03:41:12,320 GENES DO HAVE THESE ANTI SENSE 5146 03:41:12,320 --> 03:41:17,360 NOT NON CODING RNAS INVOLVED IN 5147 03:41:17,360 --> 03:41:19,600 GENE EXPRESSION. 5148 03:41:19,600 --> 03:41:24,120 QUITE A FEW PROGRAMS USING THIS 5149 03:41:24,120 --> 03:41:25,520 TO TARGET THESE NON CODING 5150 03:41:25,520 --> 03:41:27,800 TRANSCRIPT THAT USUALLY OVERLAP 5151 03:41:27,800 --> 03:41:30,760 THE TRANSCRIPTIONAL START SITE. 5152 03:41:30,760 --> 03:41:33,360 YEAH YOU CAN ACTUALLY UP 5153 03:41:33,360 --> 03:41:38,360 REGULATE GENES THE QUESTION IS 5154 03:41:38,360 --> 03:41:41,760 FALLING BACK ON FUNCTION VERSUS 5155 03:41:41,760 --> 03:41:44,200 INSUFFICIENCY FOR INSTANCE WE 5156 03:41:44,200 --> 03:41:48,680 HAVE COW MODEL. SHE'S REJOINED 5157 03:41:48,680 --> 03:41:51,280 AND SHE IDENTIFIED A COW MODEL 5158 03:41:51,280 --> 03:41:54,160 THAT IS ACTUALLY I THINK A HAPPY 5159 03:41:54,160 --> 03:41:55,880 INSUFFICIENCY BECAUSE THE 5160 03:41:55,880 --> 03:41:58,200 ANIMALS NEED TO BE CURIOUS OF 5161 03:41:58,200 --> 03:42:00,120 THE MUTANTS OTHERWISE WE'LL HAVE 5162 03:42:00,120 --> 03:42:02,600 AN AGGRESSIVE PHENOTYPE. I 5163 03:42:02,600 --> 03:42:04,600 DON'T KNOW IF YOU REMEMBER HOW 5164 03:42:04,600 --> 03:42:07,080 LONG THEY LIVE IN A SITUATION 5165 03:42:07,080 --> 03:42:08,360 LIKE THAT IF YOU HAVE 5166 03:42:08,360 --> 03:42:09,760 INTERWHEELS THAT'S NOT GOING TO 5167 03:42:09,760 --> 03:42:11,320 HELP YOU BUT I DON'T THINK 5168 03:42:11,320 --> 03:42:13,080 THAT'S THE CASE FOR MOST 5169 03:42:13,080 --> 03:42:13,920 PATIENTS RIGHT. 5170 03:42:13,920 --> 03:42:15,680 >> RIGHT THE SECOND QUESTION I 5171 03:42:15,680 --> 03:42:21,360 HAVE IS TO THE PANEL I THINK 5172 03:42:21,360 --> 03:42:22,960 HANDE WHO IS EXPERT IN UPPER 5173 03:42:22,960 --> 03:42:25,000 MOTOR NEURON STUDIES AS A 5174 03:42:25,000 --> 03:42:30,120 SOCIETY TO STUDY SSP, FOCUS ON 5175 03:42:30,120 --> 03:42:31,800 UPPER NEURON OR IS THIS A 5176 03:42:31,800 --> 03:42:33,360 DISSEAT THAT AFFECTS OTHER TYPES 5177 03:42:33,360 --> 03:42:38,600 OF NEURONS I'M NOT 100 PERCENT 5178 03:42:38,600 --> 03:42:39,960 CONVINCED SPECIFICALLY CAUSED 5179 03:42:39,960 --> 03:42:42,080 MUTE TAGS ON JUST UPPER MOTOR 5180 03:42:42,080 --> 03:42:44,880 NEURON TO BE HONEST I KNOW HANDE 5181 03:42:44,880 --> 03:42:47,840 HAS A LOT OF DATA DEMONSTRATED A 5182 03:42:47,840 --> 03:42:49,320 PATHWAY BUT I'M WONDERING IF 5183 03:42:49,320 --> 03:42:52,240 THERE IS ANY YOU KNOW KIND OF 5184 03:42:52,240 --> 03:42:54,000 STUDY THAT CAN BE DONE CHECKING 5185 03:42:54,000 --> 03:43:04,320 ON EVEN LIKE INHIBITORY NEURONS, 5186 03:43:04,320 --> 03:43:08,080 CASES IN ALS LOSS EVER 5187 03:43:08,080 --> 03:43:10,200 INHIBITORY MOTOR NEURONS PROCEED 5188 03:43:10,200 --> 03:43:13,160 IN LOSS OF MOTOR NEURONS IN ALS 5189 03:43:13,160 --> 03:43:15,400 IF SOMEBODY CAN COMMENT ON THAT 5190 03:43:15,400 --> 03:43:17,360 THAT WOULD BE GREAT. 5191 03:43:17,360 --> 03:43:21,360 >> IN OUR PATIENTS WITH INFANT 5192 03:43:21,360 --> 03:43:24,120 TILE ONSET. THE ONE HAVE NEFB 5193 03:43:24,120 --> 03:43:26,200 CON STUKS DUKS STUDIES I HAVEN'T 5194 03:43:26,200 --> 03:43:28,520 FOUND NEUROPATHY IN UNLIKE OTHER 5195 03:43:28,520 --> 03:43:32,520 FORMS OF HSP WHERE NEUROPATHIES 5196 03:43:32,520 --> 03:43:36,560 TONED RUN CONCORD NATELY SUCH AS 5197 03:43:36,560 --> 03:43:37,800 PG11 I DON'T KNOW WHAT DARIOUSH 5198 03:43:37,800 --> 03:43:39,360 HAS FOUND IN HIS PATIENTS I WAS 5199 03:43:39,360 --> 03:43:41,440 TRYING TO LOOK AT THAT BEFORE 5200 03:43:41,440 --> 03:43:44,000 THIS CONFERENCE BUT I DO THINK 5201 03:43:44,000 --> 03:43:46,280 WE NEED TO BE CAREFUL AND GET 5202 03:43:46,280 --> 03:43:48,800 NERVE CON DUSHGS STUDIES ON 5203 03:43:48,800 --> 03:43:52,000 PATIENTS TO FORMALLY ANSWER THAT 5204 03:43:52,000 --> 03:43:52,360 QUESTION. 5205 03:43:52,360 --> 03:43:56,120 >> THIS IS KATHARINE ONE OF THE 5206 03:43:56,120 --> 03:43:59,360 OTHER ISSUES (INAUDIBLE) 5207 03:43:59,360 --> 03:44:01,920 SOMETIMES THESE PATIENTS HAVE 5208 03:44:01,920 --> 03:44:03,600 BONING AND CENTRAL CONDUCTION 5209 03:44:03,600 --> 03:44:06,160 TIMES SO WE HAVE TO LOOK MORE 5210 03:44:06,160 --> 03:44:08,760 PROXIMALLY THAN WE DO WHEN DOING 5211 03:44:08,760 --> 03:44:10,480 STANDARD NERVE CONDUCTION 5212 03:44:10,480 --> 03:44:13,400 TESTING OF THEM AND DOING SSEPS 5213 03:44:13,400 --> 03:44:15,920 TO LOOK FOR CONDUCTION TIME 5214 03:44:15,920 --> 03:44:18,880 CHANGES THAT MIGHT PROVIDE 5215 03:44:18,880 --> 03:44:23,000 INFORMATION THAT WE DON'T SEE 5216 03:44:23,000 --> 03:44:23,280 SOCIALLY. 5217 03:44:23,280 --> 03:44:24,520 >> THAT WOULD BE ANOTHER GREAT 5218 03:44:24,520 --> 03:44:26,040 STUDY I WOULD LIKE TO LOOK AT 5219 03:44:26,040 --> 03:44:27,800 TOGETHER. I HAVE MONITORING ON 5220 03:44:27,800 --> 03:44:29,760 SOME PATIENTS WHO HAVE HAD 5221 03:44:29,760 --> 03:44:30,800 SCOLIOSIS SURGERY SO MUCH I NEED 5222 03:44:30,800 --> 03:44:36,120 TO LOOK AT AND I AGREE WITH YOU. 5223 03:44:37,120 --> 03:44:37,280 OF. 5224 03:44:37,280 --> 03:44:39,280 >> IF I CAN JUST QUICKLY ADD TO 5225 03:44:39,280 --> 03:44:40,800 THAT FROM MY PERSPECTIVE? I 5226 03:44:40,800 --> 03:44:41,920 THINK IT'S A VERY IMPORTANT 5227 03:44:41,920 --> 03:44:44,520 QUESTION. I THINK THE 5228 03:44:44,520 --> 03:44:45,600 INVOLVEMENT OF YOU KNOW OF 5229 03:44:45,600 --> 03:44:47,400 PERIPHERAL NERVOUS SYSTEM IS ONE 5230 03:44:47,400 --> 03:44:48,600 QUESTION BUT I THINK WHEN WE 5231 03:44:48,600 --> 03:44:50,800 THINK ABOUT WHAT BRAIN REGIONS 5232 03:44:50,800 --> 03:44:53,080 TO TARGET WITH ANY THERAPY I DO 5233 03:44:53,080 --> 03:44:56,120 WORRY WE WOULD PROBABLY HAVE TO 5234 03:44:56,120 --> 03:44:59,160 TARGET WIDESPREAD SUPER TUTORIAL 5235 03:44:59,160 --> 03:45:01,400 BRAIN REGIONS TO REALLY -- TO 5236 03:45:01,400 --> 03:45:03,400 REALLY TACKLE THE UNDERLYING 5237 03:45:03,400 --> 03:45:04,800 DISEASE PROCESS. THE FOCUS HERE 5238 03:45:04,800 --> 03:45:07,920 IS ON CORTICAL SPINAL TRACKS 5239 03:45:07,920 --> 03:45:09,400 BECAUSE FRANKLY THAT'S WHAT WE 5240 03:45:09,400 --> 03:45:10,960 SEE PROGRESSING CLINICALLY. 5241 03:45:10,960 --> 03:45:12,640 BUT -- BUT IT'S MORE COMPLICATED 5242 03:45:12,640 --> 03:45:15,160 THAN THAT. AND WE'VE HAD A 5243 03:45:15,160 --> 03:45:16,120 LITTLE BIT OF DISCUSSION OVER 5244 03:45:16,120 --> 03:45:17,680 THE CHAT ABOUT HOW TO ACHIEVE 5245 03:45:17,680 --> 03:45:19,600 THAT WITH A CURRENT VECTORS, I 5246 03:45:19,600 --> 03:45:21,840 THINK IT'S -- IT'S A BIG 5247 03:45:21,840 --> 03:45:23,400 CHALLENGE FOR THE FIELD, AND I 5248 03:45:23,400 --> 03:45:25,280 THINK WE NEED VERY GOOD 5249 03:45:25,280 --> 03:45:27,320 COMPARATIVE STUDIES IN NON HUMAN 5250 03:45:27,320 --> 03:45:29,720 PRIMATES TO REALLY TELL WHAT THE 5251 03:45:29,720 --> 03:45:31,120 BEST APPROACH IS AND CERTAINLY 5252 03:45:31,120 --> 03:45:33,760 WE NEED A NEXT GENERATION OF CAP 5253 03:45:33,760 --> 03:45:36,960 SAID AT SOME POINT. BUT I THINK 5254 03:45:36,960 --> 03:45:39,240 THIS QUESTION OF SOW DO WE 5255 03:45:39,240 --> 03:45:41,360 DEFINE THE TARGET AND HOW GET 5256 03:45:41,360 --> 03:45:42,600 TRANSGENIC EXPRESSION WHERE WE 5257 03:45:42,600 --> 03:45:44,400 NEED TO GET IT IS A VERY GOOD 5258 03:45:44,400 --> 03:45:46,480 ONE AND ONE THAT IS NOT EASY TO 5259 03:45:46,480 --> 03:45:48,120 ANSWER, I'M AFRAID. 5260 03:45:48,120 --> 03:45:50,440 AND IT'S RELEVANT FOR ALL AGES, 5261 03:45:50,440 --> 03:45:52,400 NOT JUST FOR SPG4. 5262 03:45:52,400 --> 03:45:55,120 >> IF I COULD ADD A THOUGHT TO 5263 03:45:55,120 --> 03:45:58,480 THAT? ONE THE THINGS THAT 5264 03:45:58,480 --> 03:46:03,040 OCCURS TO ME IS WHY ARE CORTICAL 5265 03:46:03,040 --> 03:46:04,520 SPINAL TRACKS PARTICULARLY 5266 03:46:04,520 --> 03:46:07,960 VULNERABLE TO DEGENERATION IN 5267 03:46:07,960 --> 03:46:09,200 THIS DISEASE WHEN ALL OF THE 5268 03:46:09,200 --> 03:46:12,560 OTHER CELLS OF THE NERVOUS 5269 03:46:12,560 --> 03:46:18,160 SYSTEM ALSO EXPRESS SPASTIN AND 5270 03:46:18,160 --> 03:46:23,400 EVEN THOUGH THE LEVELS OF 5271 03:46:23,400 --> 03:46:26,480 M1SPASTIN ARE EXTREMELY LOW 5272 03:46:26,480 --> 03:46:28,280 BELOW THE LEVEL OF DETECTION 5273 03:46:28,280 --> 03:46:31,640 STILL TO HAVE A TOXIC EFFECT OUR 5274 03:46:31,640 --> 03:46:35,080 STUDIES ON SQUIDS FOR EXAMPLE 5275 03:46:35,080 --> 03:46:36,160 SHOW IT'S VANISHING LOW LEVELS 5276 03:46:36,160 --> 03:46:38,160 ARE REQUIRED TO HAVE A TOXIC 5277 03:46:38,160 --> 03:46:42,000 EFFECT. SO WHAT I'M WONDERING 5278 03:46:42,000 --> 03:46:43,000 IS PERHAPS WE SHOULD BE THINKING 5279 03:46:43,000 --> 03:46:45,600 ABOUT THE VULNERABILITIES OF THE 5280 03:46:45,600 --> 03:46:47,760 THE COURT YAL SPINAL TRACKS 5281 03:46:47,760 --> 03:46:49,680 THEY'RE PARTICULARLY LONG AXONS 5282 03:46:49,680 --> 03:46:51,920 COMPARED TO MANY OF THE AXONS OF 5283 03:46:51,920 --> 03:46:57,080 THE BODY, AND IT REALLY MAY BE A 5284 03:46:57,080 --> 03:47:00,560 FAILURE IN THEIR ABILITY TO 5285 03:47:00,560 --> 03:47:04,920 UNDERGO SUFFICIENT OTOPOGY TO 5286 03:47:04,920 --> 03:47:08,680 DEGREAT THESE MUTANTS, WHEREAS 5287 03:47:08,680 --> 03:47:10,600 OTHER CELLS OF THE NERVOUS 5288 03:47:10,600 --> 03:47:12,640 SYSTEM OTHER CELLS OF THE BODY 5289 03:47:12,640 --> 03:47:15,400 MAY HAVE SUFFICIENT OTOPOGY 5290 03:47:15,400 --> 03:47:18,160 SUFFICIENT EFFICIENCY TO DEGRADE 5291 03:47:18,160 --> 03:47:20,160 AND KEEP TOXIC EFFECTS AT BAY. 5292 03:47:20,160 --> 03:47:21,400 SO I THINK THAT'S ANOTHER AVENUE 5293 03:47:21,400 --> 03:47:24,160 THAT WE SHOULD PAY ATTENTION TO, 5294 03:47:24,160 --> 03:47:25,400 BECAUSE THERE CERTAINLY ARE 5295 03:47:25,400 --> 03:47:29,080 CASES COMPLICATED CASES, WHERE 5296 03:47:29,080 --> 03:47:31,160 PATIENTS WITH HSP DO SUFFER 5297 03:47:31,160 --> 03:47:34,160 COGNITIVE DIFFICULTIES, FOR 5298 03:47:34,160 --> 03:47:36,080 EXAMPLE, AND IT'S THE SAME GENE 5299 03:47:36,080 --> 03:47:36,360 MUTATION. 5300 03:47:36,360 --> 03:47:40,160 SO I'M THINKING IT'S A 5301 03:47:40,160 --> 03:47:40,800 VULNERABILITY ISSUE THAT 5302 03:47:40,800 --> 03:47:42,960 NORMALLY SAY THAT THE CENTERS 5303 03:47:42,960 --> 03:47:44,800 FOR THE BRAIN RESPONSIBLE FOR 5304 03:47:44,800 --> 03:47:48,120 COGNITION AND MEMORY THEY CAN 5305 03:47:48,120 --> 03:47:52,400 HANDLE THE LOAD OF A MUTANT 5306 03:47:52,400 --> 03:47:53,680 PROTEIN THEY CAN DEGRADE IT FAST 5307 03:47:53,680 --> 03:47:56,160 ENOUGH USUALLY BUT NOT ALWAYS. 5308 03:47:56,160 --> 03:47:59,000 FOR SOME REASON CORTICAL SPINAL 5309 03:47:59,000 --> 03:48:01,200 TRACKS CAN'T. AND IF YOU THINK 5310 03:48:01,200 --> 03:48:13,880 OF ALL THOSE 92 POTENTIALLY MORE 5311 03:48:13,880 --> 03:48:14,320 JOOE 5312 03:48:14,320 --> 03:48:14,720 JEA 5313 03:48:14,720 --> 03:48:15,880 GENES THAT CAN MUTATED ALL OF 5314 03:48:15,880 --> 03:48:17,400 WHICH GIVE A VERY COMPLICATED 5315 03:48:17,400 --> 03:48:19,320 DISEASE SYSTEM IS IT BECAUSE 5316 03:48:19,320 --> 03:48:21,400 THEY ALL TAP INTO THE SAME 5317 03:48:21,400 --> 03:48:23,840 PATHWAY OR BECAUSE CORTICAL 5318 03:48:23,840 --> 03:48:26,200 SPINAL TRACKS ARE JUST SO 5319 03:48:26,200 --> 03:48:27,200 VULNERABLE. SO I THINK THAT'S 5320 03:48:27,200 --> 03:48:31,360 ANOTHER WAY TO THINK ABOUT ALL. 5321 03:48:31,360 --> 03:48:35,520 >> HANDE: PETER I THINK YOU 5322 03:48:35,520 --> 03:48:37,400 NAILED IT THIS SHOWS VERY 5323 03:48:37,400 --> 03:48:39,920 IMPORTANT BECAUSE LIMITATION IS 5324 03:48:39,920 --> 03:48:41,880 EXPRESSED IN ALL CELLS 5325 03:48:41,880 --> 03:48:44,280 EVERYWHERE BUT SELECT NEURAL 5326 03:48:44,280 --> 03:48:46,160 POPULATIONS SHOW PRIMARY 5327 03:48:46,160 --> 03:48:48,480 VULNERABILITY THAT DOESN'T MEAN 5328 03:48:48,480 --> 03:48:50,000 OTHERS ARE NOT ALL AFFECTED THIS 5329 03:48:50,000 --> 03:48:51,560 MEANS THESE ARE MORE AFFECTED 5330 03:48:51,560 --> 03:48:53,400 AND THEY SHOW EARLY 5331 03:48:53,400 --> 03:48:55,160 VULNERABILITY AND PROGRESS OF 5332 03:48:55,160 --> 03:48:57,400 DEGENERATION THEY START THE RACE 5333 03:48:57,400 --> 03:48:59,240 EARLY. AND WE SEE THEIR -- WE 5334 03:48:59,240 --> 03:49:02,600 SEE THE OUTCOME AS CORTICAL 5335 03:49:02,600 --> 03:49:04,440 SPINAL TRACK DEGENERATION AND SO 5336 03:49:04,440 --> 03:49:05,080 FORTH. 5337 03:49:05,080 --> 03:49:07,280 AND COMING BACK TO THE INTER 5338 03:49:07,280 --> 03:49:10,400 NEAR RONS AND P OTHER CELLS 5339 03:49:10,400 --> 03:49:13,400 BEING EFFECTED I THINK INTERTER 5340 03:49:13,400 --> 03:49:14,520 NEURONS ALSO AFFECTED BUT I 5341 03:49:14,520 --> 03:49:16,920 THINK AS YOU SAY THEY MAY 5342 03:49:16,920 --> 03:49:19,400 COMPENSATION MAYBE NOT AS 5343 03:49:19,400 --> 03:49:25,120 VULNERABLE BUT CORTICAL SPIEM 5344 03:49:25,120 --> 03:49:27,920 NEURONS VERY VULNERABLE. IF 5345 03:49:27,920 --> 03:49:31,800 THERE'S ANY PER TER BANS OF 5346 03:49:31,800 --> 03:49:34,160 IMBALANCE THEY PAY THE PRICE NO 5347 03:49:34,160 --> 03:49:38,080 LUXURY OR LEG ROOM OR WIGGLE WAY 5348 03:49:38,080 --> 03:49:40,320 TO BE OKAY. EVERYTHING NEEDS TO 5349 03:49:40,320 --> 03:49:41,280 WORK PERFECTLY TO FUNCTION 5350 03:49:41,280 --> 03:49:42,720 PERFECT FOR THEM TO FUNCTION. 5351 03:49:42,720 --> 03:49:46,400 AND WE SEE COMING BACK TO 5352 03:49:46,400 --> 03:49:48,600 LEANNE'S QUESTION THAT BCD 5353 03:49:48,600 --> 03:49:52,560 CORTICAL SPINAL MULTI NEURONS 5354 03:49:52,560 --> 03:49:54,160 DISPLAY EARLY -- MUCH EARLIER 5355 03:49:54,160 --> 03:49:56,000 THAN ANY NEURONS IN THE BRAIN 5356 03:49:56,000 --> 03:49:57,400 AND WE CROSS THE MOUSE THAT 5357 03:49:57,400 --> 03:50:00,080 PETER ACTUALLY VERY GENEROUSLY 5358 03:50:00,080 --> 03:50:05,400 SHARED WITH US HIS SPATIN MODEL 5359 03:50:05,400 --> 03:50:10,400 SO THE FACTS VERIFY THEM DO 5360 03:50:10,400 --> 03:50:12,760 PROTOOMICS TOGETHER WITH ALL 5361 03:50:12,760 --> 03:50:13,880 MIXED CORTICAL CELLS SOMETHING 5362 03:50:13,880 --> 03:50:14,800 UNIQUE ABOUT THESE CELLS 5363 03:50:14,800 --> 03:50:16,320 SOMETHING INTRINSIC ABOUT THEM 5364 03:50:16,320 --> 03:50:24,440 THAT THIS MUTATION MAKES THEM OR 5365 03:50:24,440 --> 03:50:24,800 PU 5366 03:50:24,800 --> 03:50:29,040 PUSHES THEM TO MUCH EARLIER TO 5367 03:50:29,040 --> 03:50:29,400 VULNERABILITY. 5368 03:50:29,400 --> 03:50:34,520 COMING BACK DARIA'S QUESTION. 5369 03:50:34,520 --> 03:50:38,960 IF WE MOVE TO CLINICAL TRIALS 5370 03:50:38,960 --> 03:50:39,560 THERE'S THE SAYING IN TURKISH 5371 03:50:39,560 --> 03:50:40,800 THE MOMENT YOU WANT TO CURE THE 5372 03:50:40,800 --> 03:50:42,720 EYE, YOU ACTUALLY DESTROY THE 5373 03:50:42,720 --> 03:50:44,800 WHOLE THING, YOU KNOW? BECAUSE 5374 03:50:44,800 --> 03:50:48,080 YES WE WANT TO CURE THE UPPER 5375 03:50:48,080 --> 03:50:50,160 MOTOR NEURONS BUT IF WE'RE 5376 03:50:50,160 --> 03:50:51,440 UNSELECTIVE IN OUR EFFORT AND 5377 03:50:51,440 --> 03:50:52,800 START SHOOTING EVERYONE AND THEN 5378 03:50:52,800 --> 03:50:54,800 WE MAY ACTUALLY GIVE THE GENES 5379 03:50:54,800 --> 03:50:57,680 THAT ARE NOT NEEDED OR OVER 5380 03:50:57,680 --> 03:51:00,120 EXPRESSION MAY EVEN BE TOXIC TO 5381 03:51:00,120 --> 03:51:01,840 SOME UNRELATED CELLS OR GENES, 5382 03:51:01,840 --> 03:51:04,160 SO RATHER THAN HAVING AN IMPACT 5383 03:51:04,160 --> 03:51:08,600 OVERALL GOOD IMPACT WE MAY HAVE 5384 03:51:08,600 --> 03:51:10,080 SOME TOXICITY SOME SIDE EFFECTS 5385 03:51:10,080 --> 03:51:11,240 SOME UNWANTED EFFECTS FOR THE 5386 03:51:11,240 --> 03:51:13,120 PATIENTS ESPECIALLY THESE ARE 5387 03:51:13,120 --> 03:51:15,320 FOR GENE THERAPY ONE TIME AND 5388 03:51:15,320 --> 03:51:17,400 LIFELONG EFFECTS THIS WOULD BE 5389 03:51:17,400 --> 03:51:19,800 EXTREMELY DANGEROUS. I WOULD BE 5390 03:51:19,800 --> 03:51:22,400 VERY CONSCIOUS TO DELIVERING THE 5391 03:51:22,400 --> 03:51:24,080 GENES OF INTEREST ONLY TO THE 5392 03:51:24,080 --> 03:51:25,880 NEURONS IN NEED WITHOUT 5393 03:51:25,880 --> 03:51:28,000 AFFECTING OTHER CELLS AND 5394 03:51:28,000 --> 03:51:28,280 NEURONS. 5395 03:51:28,280 --> 03:51:29,360 >> RIGHT AND AS MIGUEL POINTED 5396 03:51:29,360 --> 03:51:31,400 OUT WE'RE TALKING ABOUT A MICRO 5397 03:51:31,400 --> 03:51:34,440 TUBE YAL PROTEIN THAT IF YOU 5398 03:51:34,440 --> 03:51:37,120 OVER EXPRESS AT THE CELLS YOU 5399 03:51:37,120 --> 03:51:40,400 OBLITERATE THE MICRO TUBULAR RAY 5400 03:51:40,400 --> 03:51:42,840 SO GOING FOR A SOMEWHAT LEVEL 5401 03:51:42,840 --> 03:51:44,280 EXPRESSION TO HAVE NO OVER 5402 03:51:44,280 --> 03:51:45,720 EXPRESSION IS REALLY IMPORTANT. 5403 03:51:45,720 --> 03:51:47,880 I THINK ANOTHER PIECE OF THIS 5404 03:51:47,880 --> 03:51:52,320 PUZZLE IS THE FACT THAT IN THE 5405 03:51:52,320 --> 03:51:53,400 SAME FAMILY ONE FAMILY MEMBER 5406 03:51:53,400 --> 03:51:56,000 MAY NOT SEE SYMPTOMS UNTIL HIS 5407 03:51:56,000 --> 03:51:58,520 OR HER 70S, ANOTHER FAMILY 5408 03:51:58,520 --> 03:52:05,000 MEMBER MAY SEE THE SYMPTOMS AT 5409 03:52:05,000 --> 03:52:06,680 CHILDHOOD. AND WHY IS IT? IS 5410 03:52:06,680 --> 03:52:10,000 IT BECAUSE THIS PERSON HAS A 5411 03:52:10,000 --> 03:52:13,880 MORE -- MORE ACTIVE OTOPAGY THAN 5412 03:52:13,880 --> 03:52:15,440 THIS PERSON OR WHAT? IF WE 5413 03:52:15,440 --> 03:52:17,320 COULD SOLVE THAT MYSTERY THEN IT 5414 03:52:17,320 --> 03:52:18,760 MIGHT ENABLE US TO BETTER 5415 03:52:18,760 --> 03:52:20,600 UNDERSTAND THE ISSUE OF 5416 03:52:20,600 --> 03:52:21,960 VULNERABILITY AND THEN TREAT THE 5417 03:52:21,960 --> 03:52:23,360 ISSUE OF VULNERABILITY IN ORDER 5418 03:52:23,360 --> 03:52:25,360 TO HELP PATIENTS OVERCOME. 5419 03:52:25,360 --> 03:52:27,160 I THINK ALSO, BEFORE WE CLOSE 5420 03:52:27,160 --> 03:52:29,000 THE -- THE SYMPOSIUM, WE NEED TO 5421 03:52:29,000 --> 03:52:33,360 GET BACK TO THE ISSUE OF 5422 03:52:33,360 --> 03:52:35,880 PEDIATRIC CASES AND INNOVEMBER 5423 03:52:35,880 --> 03:52:38,240 VOE CASES AND IS IT THAT THE 5424 03:52:38,240 --> 03:52:42,400 SAME MUTATION IN THESE DE NOVO 5425 03:52:42,400 --> 03:52:47,680 CASES IS CHILDHOOD ONSET? WHEN 5426 03:52:47,680 --> 03:52:50,240 IN HEREDITARY CASES IT'S ADULT 5427 03:52:50,240 --> 03:52:52,400 ONSET? AND I THINK IT MUST BE 5428 03:52:52,400 --> 03:52:55,760 TELLING US SOMETHING ABOUT THE 5429 03:52:55,760 --> 03:52:58,320 GENETIC BACKGROUND THAT A FAMILY 5430 03:52:58,320 --> 03:53:00,840 WHO HAS HAD THIS MUTATION FOR 5431 03:53:00,840 --> 03:53:02,840 GENERATION AFTER GENERATION 5432 03:53:02,840 --> 03:53:05,120 AFTER GENERATION, THEY'RE 5433 03:53:05,120 --> 03:53:06,760 OBVIOUSLY REPRODUCTIVELY CAPABLE 5434 03:53:06,760 --> 03:53:10,560 OF HANDLING THAT MUTATION WELL 5435 03:53:10,560 --> 03:53:12,120 ENOUGH TO GROW UP AND HAVE 5436 03:53:12,120 --> 03:53:14,800 CHILDREN AND PASS IT ON. 5437 03:53:14,800 --> 03:53:17,520 OTHER PEOPLE, WHOSE FAMILIES 5438 03:53:17,520 --> 03:53:21,280 DON'T HAVE THAT MUTATION IN 5439 03:53:21,280 --> 03:53:24,120 THEIR BACKGROUND, IT HITS THEM 5440 03:53:24,120 --> 03:53:25,320 MUCH HARDER AND THOSE CHILDREN 5441 03:53:25,320 --> 03:53:28,480 MAY NEVER GET TO REPRODUCTIVE 5442 03:53:28,480 --> 03:53:28,960 AGE. 5443 03:53:28,960 --> 03:53:32,320 SO I THINK IT'S TELLING US HOW 5444 03:53:32,320 --> 03:53:34,160 IMPORTANT GENETIC BACKGROUND IS. 5445 03:53:34,160 --> 03:53:38,000 AND THAT YOU CAN'T CONSIDER JUST 5446 03:53:38,000 --> 03:53:41,360 SPG4 IN ISOLATION OF EVERYTHING 5447 03:53:41,360 --> 03:53:44,600 ELSE THAT'S GOING ON. 5448 03:53:44,600 --> 03:53:48,400 >> I'M NOT SURE THAT'S A 5449 03:53:48,400 --> 03:53:48,720 QUESTION? 5450 03:53:48,720 --> 03:53:52,920 >> YES, SORRY, GUYS, I THINK 5451 03:53:52,920 --> 03:53:58,280 KIND OF GOING TO PETE BAAS'S 5452 03:53:58,280 --> 03:54:00,160 COMMENT BUT ALSO -- SORRY WE ALL 5453 03:54:00,160 --> 03:54:02,240 KNOW I HAVE A SICK CHILD -- SO 5454 03:54:02,240 --> 03:54:04,640 AS -- AS WE RELOOK AT OUR 5455 03:54:04,640 --> 03:54:07,240 PATIENT, WHAT IS A GOOD OUTCOME 5456 03:54:07,240 --> 03:54:08,840 MEASURE? BECAUSE AS I WATCHED 5457 03:54:08,840 --> 03:54:10,880 THE 10-YEAR VIDEOS, I THINK 5458 03:54:10,880 --> 03:54:12,720 IT'S -- IT'S GOING TO BE HARD. 5459 03:54:12,720 --> 03:54:15,280 I THINK IT'S GOING TO BE HARD TO 5460 03:54:15,280 --> 03:54:18,120 FIND WHAT IS A GOOD OUTCOME 5461 03:54:18,120 --> 03:54:20,280 MEASURE AND LIKE DR. ALTER 5462 03:54:20,280 --> 03:54:23,400 BROUGHT UP SOME OF THESE 5463 03:54:23,400 --> 03:54:24,960 PATIENTS NEED THEIR PASS SYS 5464 03:54:24,960 --> 03:54:29,160 CITY AND IT HELPS THEM WALK AND 5465 03:54:29,160 --> 03:54:30,080 AMBULATE I THINK THAT'S A 5466 03:54:30,080 --> 03:54:31,160 SEPARATE QUESTION WE NEED TO 5467 03:54:31,160 --> 03:54:31,400 ANSWER. 5468 03:54:31,400 --> 03:54:33,360 >> WELL RELATED TO THAT IS WHEN 5469 03:54:33,360 --> 03:54:37,880 WE APPLY THE GENE THERAPY ARE WE 5470 03:54:37,880 --> 03:54:39,480 TRYING TO STOP THE PROGRESSION 5471 03:54:39,480 --> 03:54:42,640 OF THE SYMPTOMS, STOP THE 5472 03:54:42,640 --> 03:54:44,200 SYMPTOMS FROM GETTING WORSE OR 5473 03:54:44,200 --> 03:54:47,800 DO WE REALLY HAVE A CHANCE OF 5474 03:54:47,800 --> 03:54:49,360 REVERSING THE SYMPTOMS, 5475 03:54:49,360 --> 03:54:51,840 REVERSING THE DEGENERATION 5476 03:54:51,840 --> 03:54:53,400 THAT'S ALREADY HAPPENED? IN 5477 03:54:53,400 --> 03:54:55,000 THIS SENSE I THINK THE PEDIATRIC 5478 03:54:55,000 --> 03:54:58,000 ONSET CASES ARE -- HAVE THE BEST 5479 03:54:58,000 --> 03:55:00,960 POSSIBILITY FOR SUCCESS. TO 5480 03:55:00,960 --> 03:55:04,440 TAKE AN ADULT PATIENT AND STOP 5481 03:55:04,440 --> 03:55:06,840 THE EXPRESSION OF THE GLUTEN 5482 03:55:06,840 --> 03:55:10,040 PROTEIN AND THEN HOPE THAT 5483 03:55:10,040 --> 03:55:12,040 CORTICAL SPINAL TRACKS ARE 5484 03:55:12,040 --> 03:55:16,440 SOMEHOW GOING TO REGENERATE 5485 03:55:16,440 --> 03:55:20,440 APPROPRIATELY, THAT'S A MUCH 5486 03:55:20,440 --> 03:55:22,640 GREATER CHALLENGE THAN A CHILD 5487 03:55:22,640 --> 03:55:24,880 WHO IS STILL DEVELOPING HIS OR 5488 03:55:24,880 --> 03:55:26,760 HER CORTICAL SPINAL TRACKS. SO 5489 03:55:26,760 --> 03:55:28,520 I THINK IT'S A VERY HOPEFUL 5490 03:55:28,520 --> 03:55:33,400 MESSAGE IN THE FACT THAT WE'RE 5491 03:55:33,400 --> 03:55:36,520 TALKING ABOUT CHILDREN. 5492 03:55:36,520 --> 03:55:38,960 >> MAY I MAKE A COMMENT? 5493 03:55:38,960 --> 03:55:39,880 >> YES GO AHEAD PLEASE. 5494 03:55:39,880 --> 03:55:41,800 >> FOR THE OUTCOME MEASURES, I 5495 03:55:41,800 --> 03:55:43,040 THINK THOSE ARE IMPORTANT FOR 5496 03:55:43,040 --> 03:55:45,600 CLINICAL TRIALS, AS WELL. AND I 5497 03:55:45,600 --> 03:55:49,160 THINK THE BEST OUTCOME MEASURE 5498 03:55:49,160 --> 03:55:52,720 WOULD BE PHARMACOKINETIC 5499 03:55:52,720 --> 03:55:55,440 BIOMARKERS THAT WOULD TELL US 5500 03:55:55,440 --> 03:55:57,160 THE TIMING OF MOTOR NEURAL LOSS 5501 03:55:57,160 --> 03:55:59,320 IN THESE PATIENTS SO WE CAN 5502 03:55:59,320 --> 03:56:01,600 TRACK INVESTIGATE WHETHER A DRUG 5503 03:56:01,600 --> 03:56:07,720 TREATMENT OR AAV MEDIATED GENE 5504 03:56:07,720 --> 03:56:09,200 DELIVERY TREATMENT OR ANY 5505 03:56:09,200 --> 03:56:10,000 THERAPEUTIC TREATMENT WOULD HAVE 5506 03:56:10,000 --> 03:56:12,400 AN IMPACT IN THE TIMING AND 5507 03:56:12,400 --> 03:56:16,760 EXTENT OF MOTOR NEURAL LOSS AND 5508 03:56:16,760 --> 03:56:18,680 THEIR CONNECTIVITY. 5509 03:56:18,680 --> 03:56:21,400 FOR KNOWS BIOMARKERS I THINK 5510 03:56:21,400 --> 03:56:23,160 REBECCA MADE A GOOD PRESENTATION 5511 03:56:23,160 --> 03:56:25,000 THEY HAD THE FAMILIES AVAILABLE 5512 03:56:25,000 --> 03:56:29,280 IN OUR SMALL COHORT WE PERFORM 5513 03:56:29,280 --> 03:56:31,800 LIP POE DOME MIX, MET THERE 5514 03:56:31,800 --> 03:56:34,800 SEEMS TO BE A SIGNATURE ACTUALLY 5515 03:56:34,800 --> 03:56:37,320 BASICALLY IN THE LIPIDS THAT 5516 03:56:37,320 --> 03:56:39,480 SHOWS THE UPPER MOTOR NEURAL 5517 03:56:39,480 --> 03:56:40,840 LOSS. SO OF COURSE MORE WORK 5518 03:56:40,840 --> 03:56:43,880 NEEDS TO BE DONE BUT I THINK 5519 03:56:43,880 --> 03:56:46,560 THERE IS -- THERE IS LIFE AT THE 5520 03:56:46,560 --> 03:56:47,200 END OF THE TUNNEL THAT WE WILL 5521 03:56:47,200 --> 03:56:52,960 HAVE BIOMARKERS WITHIN A COUPLE 5522 03:56:52,960 --> 03:56:53,160 YEARS. 5523 03:56:53,160 --> 03:56:55,840 >> THERE ARE ALSO CLINICAL 5524 03:56:55,840 --> 03:56:58,960 BIOMARKERS THAT ARE NECESSARY AS 5525 03:56:58,960 --> 03:57:01,000 WELL BECAUSE WE NEED TO MEASURE 5526 03:57:01,000 --> 03:57:02,200 FUNCTION AND FUNCTIONAL OUTCOMES 5527 03:57:02,200 --> 03:57:05,120 AS WELL, YOU KNOW, SO THAT WE 5528 03:57:05,120 --> 03:57:06,000 CORRECT SOMETHING 5529 03:57:06,000 --> 03:57:07,160 PHYSIOLOGICALLY WE WANT TO KNOW 5530 03:57:07,160 --> 03:57:08,480 THAT THAT HAS AN IMPACT ON 5531 03:57:08,480 --> 03:57:10,040 FUNCTION. SO THERE'S A NUMBER 5532 03:57:10,040 --> 03:57:14,000 OF THINGS THAT CAN BE USED AND 5533 03:57:14,000 --> 03:57:15,320 ARE BEING DEVELOPED THAT ARE, 5534 03:57:15,320 --> 03:57:18,880 YOU KNOW, AVAILABLE TO MULTIPLE 5535 03:57:18,880 --> 03:57:21,720 SITES LIKE THE USE OF A WEARABLE 5536 03:57:21,720 --> 03:57:24,080 SENSORS, RATHER THAN FOR 5537 03:57:24,080 --> 03:57:25,920 INSTANCE USING THE GATE LAB 5538 03:57:25,920 --> 03:57:29,400 USING WEARABLE SENSORS OR A GATE 5539 03:57:29,400 --> 03:57:32,560 MAP OR AN ULTRASOUND BIOMARKERS 5540 03:57:32,560 --> 03:57:33,640 OF MUSCLE WE HAVE A LOT OF 5541 03:57:33,640 --> 03:57:34,720 OPPORTUNITIES TO LOOK AT THINGS, 5542 03:57:34,720 --> 03:57:36,200 BUT I AGREE WITH YOU THAT WE 5543 03:57:36,200 --> 03:57:40,760 NEED BIOMARKERS IN BOTH ASPECTS 5544 03:57:40,760 --> 03:57:44,240 BOTH IN THE PHYSIO LOGIC AND 5545 03:57:44,240 --> 03:57:47,080 THEN THE FUNCTIONAL REALMS. 5546 03:57:47,080 --> 03:57:49,360 >> THIS IS ANOTHER ISSUE WITH 5547 03:57:49,360 --> 03:57:51,160 MOUSE MODELS THAT WE FACE MAYBE 5548 03:57:51,160 --> 03:57:53,000 ON ANOTHER OCCASION I WOULD LIKE 5549 03:57:53,000 --> 03:57:55,000 TO TALK MORE WITH CRAIG ABOUT 5550 03:57:55,000 --> 03:57:57,160 IT, BECAUSE WHEN WE PURSUE 5551 03:57:57,160 --> 03:57:58,800 THERAPIES ALL OF THE BEHAVIORAL 5552 03:57:58,800 --> 03:58:06,160 STUDIES AND THE HISTOLOGICAL AN 5553 03:58:06,160 --> 03:58:14,000 TOM TOM CAL STUDIES THEY /* /- 5554 03:58:14,000 --> 03:58:15,400 ANATOMICAL STUDIES THEY TAKE 5555 03:58:15,400 --> 03:58:18,760 MONTHS WE NEED MONTHS TO 5556 03:58:18,760 --> 03:58:19,760 ASCERTAIN WHETHER THESE 5557 03:58:19,760 --> 03:58:21,160 THERAPIES WITH WORKING OR NOT. 5558 03:58:21,160 --> 03:58:22,600 I'M OPEN TO SUGGESTIONS FROM THE 5559 03:58:22,600 --> 03:58:24,160 COMMUNITY ON WHAT WE CAN DO 5560 03:58:24,160 --> 03:58:27,680 OTHER THAN MONTHS AND MONTHS AND 5561 03:58:27,680 --> 03:58:32,560 MONTHS OF CAT WALK BEHAVIOR. 5562 03:58:32,560 --> 03:58:36,000 >> SO I HAVE A QUESTION FOR THE 5563 03:58:36,000 --> 03:58:38,440 MDS, YOU GUYS PRESENTED VERY 5564 03:58:38,440 --> 03:58:39,800 INTERESTING INFORMATION ON SOME 5565 03:58:39,800 --> 03:58:43,320 OF THESE PATIENTS. I WORK ON 5566 03:58:43,320 --> 03:58:45,160 DISEASES WHERE THERE'S ACTUALLY 5567 03:58:45,160 --> 03:58:49,720 NO QUESTION WHERE IT'S A NEURO 5568 03:58:49,720 --> 03:58:51,400 GENETIC PROCESS NO ONE QUESTIONS 5569 03:58:51,400 --> 03:58:53,160 THAT, ONE OF THE THINGS THAT WAS 5570 03:58:53,160 --> 03:58:55,360 STRIKING ABOUT THESE VIDEOS THAT 5571 03:58:55,360 --> 03:58:57,600 WERE SEPARATED BY ALMOST A 5572 03:58:57,600 --> 03:59:00,280 DECADE IN SOME CASES IS THAT IT 5573 03:59:00,280 --> 03:59:03,720 DIDN'T APPEAR TO GET WORSE. SO 5574 03:59:03,720 --> 03:59:05,120 I STRUGGLE A LITTLE BIT WITH THE 5575 03:59:05,120 --> 03:59:07,720 CONCEPT OF NEURO GENERATION IN 5576 03:59:07,720 --> 03:59:11,160 SPG4 IN A DISEASE THAT HAS AN 5577 03:59:11,160 --> 03:59:12,200 ONSET AND THEN SEEMS TO BE 5578 03:59:12,200 --> 03:59:14,400 STATIC FOR A LONG TIME. 5579 03:59:14,400 --> 03:59:16,920 SO IS THAT -- I JUST LIKE TO 5580 03:59:16,920 --> 03:59:18,160 HEAR A LITTLE BIT ABOUT THIS -- 5581 03:59:18,160 --> 03:59:22,000 THE CONCEPT OF NEURO DEN JEJ 5582 03:59:22,000 --> 03:59:23,440 RAGS VERSUS THIS FUNCTION WHICH 5583 03:59:23,440 --> 03:59:24,800 OBVIOUSLY IS VERY IMPORTANT TO 5584 03:59:24,800 --> 03:59:26,880 THAT QUESTION THAT PETER ASKED 5585 03:59:26,880 --> 03:59:28,240 ABOUT ESSENTIALLY REVERSE 5586 03:59:28,240 --> 03:59:31,040 ABILITY, RIGHT? SO YEAH, THANK 5587 03:59:31,040 --> 03:59:31,800 YOU. 5588 03:59:31,800 --> 03:59:32,720 >> I KNOW KATHARINE WANTS TO 5589 03:59:32,720 --> 03:59:34,160 ANSWER I WANT TO INTERJECT 5590 03:59:34,160 --> 03:59:35,640 BRIEFLY A LOT OF FAMILIES 5591 03:59:35,640 --> 03:59:37,000 WATCHING ONLINE HAVE E MAFLED 5592 03:59:37,000 --> 03:59:38,680 ABOUT THAT BECAUSE THE VIDEOS 5593 03:59:38,680 --> 03:59:40,520 DID SEEM MORE STATIC THAN A LOT 5594 03:59:40,520 --> 03:59:42,760 OF WHAT THEY EXPERIENCE FROM 5595 03:59:42,760 --> 03:59:43,920 THEIR CHILDREN KATHARINE HAS -- 5596 03:59:43,920 --> 03:59:45,920 >> I WOULD SAY FROM MY 5597 03:59:45,920 --> 03:59:49,400 PERSPECTIVE AS A MOTION 5598 03:59:49,400 --> 03:59:50,520 ANALYSIS/MOBILITY EXPERT, IS 5599 03:59:50,520 --> 03:59:53,600 THAT I DIDN'T THINK THAT THE 5600 03:59:53,600 --> 03:59:57,400 GATE WAS STATIC. THAT THEIR 5601 03:59:57,400 --> 04:00:00,600 FUNCTION CHANGED FROM MORE A C 5602 04:00:00,600 --> 04:00:03,640 MODEL OR SPASTICITY WAS WORSE TO 5603 04:00:03,640 --> 04:00:05,480 WEAKNESS WAS MORE PROMINENT 5604 04:00:05,480 --> 04:00:07,160 FEATURE IN KIDS AS THEY GOT 5605 04:00:07,160 --> 04:00:09,000 OLDER AND THAT'S ACTUALLY 5606 04:00:09,000 --> 04:00:11,680 TYPICAL WITH KIDS WITH CEREBRAL 5607 04:00:11,680 --> 04:00:13,000 PALSY AS WELL MOST KIDS OR MANY 5608 04:00:13,000 --> 04:00:15,080 KIDS THAT I SAW IN MICHELLE'S 5609 04:00:15,080 --> 04:00:20,760 VIDEOS THEY SORT OF WENT FROM AN 5610 04:00:20,760 --> 04:00:21,520 AQUINAS GATE TORE CROUCH GATE 5611 04:00:21,520 --> 04:00:24,000 THE GATE IS EVOLVING THAT'S WHY 5612 04:00:24,000 --> 04:00:26,280 I MEANT WE NEED BIOMARKERS 5613 04:00:26,280 --> 04:00:27,920 QUANTITATIVE BIOMARKERS IN WHAT 5614 04:00:27,920 --> 04:00:30,520 CHANGES IN GATES, AND YOU CAN 5615 04:00:30,520 --> 04:00:32,040 LOOK AT GATE SPEEDS THAT 5616 04:00:32,040 --> 04:00:34,120 VARIABILITY, WE CAN BE LOOKING 5617 04:00:34,120 --> 04:00:36,080 AT OXYGEN CONSUMPTION, METABOLIC 5618 04:00:36,080 --> 04:00:38,440 COST OF WALKING, BECAUSE THE 5619 04:00:38,440 --> 04:00:40,600 METABOLIC COST OF WALKING WHEN 5620 04:00:40,600 --> 04:00:43,000 YOU ARE WEAK ARE REALLY HIGH. 5621 04:00:43,000 --> 04:00:47,680 AND SAME THING WITH SPASTICITY 5622 04:00:47,680 --> 04:00:48,800 THESE KIDS ARE USING 10 TIMES 5623 04:00:48,800 --> 04:00:51,440 THE AMOUNT OF OXYGEN AND 5624 04:00:51,440 --> 04:00:53,320 METABOLIC COST THAN KIDS WALKING 5625 04:00:53,320 --> 04:00:55,560 WITHOUT THESE CONDITIONS. 5626 04:00:55,560 --> 04:00:56,800 GETTING QUANTITATIVE GATE 5627 04:00:56,800 --> 04:00:58,400 MEASURES OF SOME SORT I THINK 5628 04:00:58,400 --> 04:00:59,720 WILL HELP US DETERMINE HOW 5629 04:00:59,720 --> 04:01:00,680 STATIC ARE THESE CONDITIONS. 5630 04:01:00,680 --> 04:01:04,360 IT MAY BE MORE THAT THEY'RE 5631 04:01:04,360 --> 04:01:07,840 CHANGING, NOT STATIC BUT 5632 04:01:07,840 --> 04:01:08,120 CHANGING. 5633 04:01:08,120 --> 04:01:11,560 AND SO IT'S -- IT'S GOING TO 5634 04:01:11,560 --> 04:01:14,800 REQUIRE MEASUREMENT. 5635 04:01:14,800 --> 04:01:17,160 >> THANK YOU FOR SAYING THAT SO 5636 04:01:17,160 --> 04:01:18,560 ELOQUENTLY I DO WORK WITH THE 5637 04:01:18,560 --> 04:01:20,680 HEAD OF OUR GATE LAB WHO CAN 5638 04:01:20,680 --> 04:01:21,760 EXPLAIN THAT. THAT'S WHY I 5639 04:01:21,760 --> 04:01:24,000 WANTED TO SHOW THE VIDEOS, 5640 04:01:24,000 --> 04:01:27,000 ACTUALLY BECAUSE THERE ARE TWO 5641 04:01:27,000 --> 04:01:28,320 SUBSETS. WE DO SEE PATIENTS 5642 04:01:28,320 --> 04:01:34,800 WITH SPG4 WHO YOU KNOW I TALKED 5643 04:01:34,800 --> 04:01:36,360 WITH A FAMILY ABOUT A Q TUBE THE 5644 04:01:36,360 --> 04:01:39,160 OTHER DAY THAT WOULD BE A NEW 5645 04:01:39,160 --> 04:01:41,120 THING TO HER IT'S A CLEAR 5646 04:01:41,120 --> 04:01:43,600 INDICATION OF WORSENING HOWEVER 5647 04:01:43,600 --> 04:01:45,560 ANOTHER SUBSET REALLY HARD TO 5648 04:01:45,560 --> 04:01:46,560 MEASURE ALMOST SEEMS LIKE 5649 04:01:46,560 --> 04:01:49,240 DIFFICULTY IN MEASUREMENT IS 5650 04:01:49,240 --> 04:01:51,600 MORE OF THE PATIENTS THAT I SEE. 5651 04:01:51,600 --> 04:01:54,600 AND THAT'S WHAT I WANTED TO 5652 04:01:54,600 --> 04:01:57,120 HIGHLIGHT AND GET ALL OF OUR 5653 04:01:57,120 --> 04:01:58,800 SMART BRAINS TOGETHER ABOUT, 5654 04:01:58,800 --> 04:02:00,800 BECAUSE THE CURRENTS GENE 5655 04:02:00,800 --> 04:02:01,880 THERAPIES ARE LIKE THEY WERE 5656 04:02:01,880 --> 04:02:04,480 SAYING FOR PATIENTS WHO THERE'S 5657 04:02:04,480 --> 04:02:06,080 THIS VERY CLEAR DETERIORATION 5658 04:02:06,080 --> 04:02:09,160 WITHIN A VERY SHORT PERIOD OF 5659 04:02:09,160 --> 04:02:10,800 TIME. LIKE IN THESE NEEDS WE 5660 04:02:10,800 --> 04:02:14,320 SEE THEM CRASH VERY QUICKLY AND 5661 04:02:14,320 --> 04:02:18,840 YOU KNOW THAT'S I DIDN'T BROUGHT 5662 04:02:18,840 --> 04:02:20,600 UP THESE OTHER QUESTIONS, WHAT 5663 04:02:20,600 --> 04:02:23,880 IS THE BENEFIT RISK BENEFIT SIDE 5664 04:02:23,880 --> 04:02:26,160 EFFECTS IN OUR HEART WE WANT IT 5665 04:02:26,160 --> 04:02:26,840 MAKE THESE PATIENTS BETTER 5666 04:02:26,840 --> 04:02:28,400 SUPPORT THEM AND DO THE RIGHT 5667 04:02:28,400 --> 04:02:30,200 THINGS BY THE FAMILIES. 5668 04:02:30,200 --> 04:02:32,040 SO I THINK THESE ARE THE REALLY 5669 04:02:32,040 --> 04:02:34,120 HARD THOUGHTS WE GO THROUGH AS 5670 04:02:34,120 --> 04:02:36,960 WE TRY TO TREAT THEM AND DO 5671 04:02:36,960 --> 04:02:40,200 EVERYTHING WE CAN FOR THEM. 5672 04:02:40,200 --> 04:02:42,080 >> DARIOUSH GO AHEAD. 5673 04:02:42,080 --> 04:02:46,160 >> DARIUS: I HAVE A COUPLE 5674 04:02:46,160 --> 04:02:47,720 THOUGHTS I THINK THESE ARE ALL 5675 04:02:47,720 --> 04:02:50,120 GUED POINTS I THINK TO MIGUEL'S 5676 04:02:50,120 --> 04:02:52,040 POINT THE KEY QUESTION HERE IS 5677 04:02:52,040 --> 04:02:54,160 HOW MUCH OF THE SYMPTOMS OR 5678 04:02:54,160 --> 04:02:55,800 PHENOTYPE IF YOU WILL IS 5679 04:02:55,800 --> 04:03:00,560 EXPLAINED BY AN EFFECT ON NEURO 5680 04:03:00,560 --> 04:03:01,080 DEVELOPMENT? HOW MUCH IS 5681 04:03:01,080 --> 04:03:02,600 DYSFUNCTION HOW MUCH 5682 04:03:02,600 --> 04:03:03,240 DEGENERATIVE? I DON'T THINK 5683 04:03:03,240 --> 04:03:04,400 ANYONE HAS A GOOD SENSE OF THAT 5684 04:03:04,400 --> 04:03:06,040 YET. IT'S NOT JUST A PROBLEM 5685 04:03:06,040 --> 04:03:10,360 FOR -- FOR YOU KNOW EARLY ONSET 5686 04:03:10,360 --> 04:03:12,400 SPG4 BUT FOR MANY OTHER 5687 04:03:12,400 --> 04:03:14,360 DISORDERS THAT WE SORT OF GROUP 5688 04:03:14,360 --> 04:03:16,920 INTO THE HSP CATEGORY. 5689 04:03:16,920 --> 04:03:19,480 I THINK COMING BACK FROM THE 5690 04:03:19,480 --> 04:03:20,480 VIDEOS I'VE PRESENTED FROM THE 5691 04:03:20,480 --> 04:03:22,120 DATA FROM OUR EXPERIENCE IN 5692 04:03:22,120 --> 04:03:24,240 MEETING 17 CHILDREN WITH THIS 5693 04:03:24,240 --> 04:03:25,720 CONDITION, IT SEEMS THAT THERE 5694 04:03:25,720 --> 04:03:27,880 ARE DIFFERENT TRAJECTORIES AND I 5695 04:03:27,880 --> 04:03:29,480 THINK THERE ARE SOME THAT 5696 04:03:29,480 --> 04:03:30,480 CLEARLY PROGRESS VERY FAST I 5697 04:03:30,480 --> 04:03:33,040 THINK YOU'VE SEEN OUR DATA THE 5698 04:03:33,040 --> 04:03:35,600 MAJORITY OF THE PARROTS WE MEET 5699 04:03:35,600 --> 04:03:37,280 REQUIRE WHEELCHAIR VERY EARLY 5700 04:03:37,280 --> 04:03:37,440 ON. 5701 04:03:37,440 --> 04:03:38,800 I THINK THERE IS A LITTLE BIT OF 5702 04:03:38,800 --> 04:03:40,760 A MIXED POPULATION, I THINK THE 5703 04:03:40,760 --> 04:03:42,080 ONLY ANSWER TO -- THE ONLY WAY 5704 04:03:42,080 --> 04:03:44,280 TO EVEN THIS QUESTION IS WE NEED 5705 04:03:44,280 --> 04:03:45,760 TO BUILD A LARGER NATURAL 5706 04:03:45,760 --> 04:03:46,480 HISTORY STUDY. 5707 04:03:46,480 --> 04:03:48,400 I THINK WE JUST NEED THE 5708 04:03:48,400 --> 04:03:51,080 NUMBERS. THAT'S THE ONLY WAY TO 5709 04:03:51,080 --> 04:03:52,160 GET REALLY GET AT THIS QUESTION. 5710 04:03:52,160 --> 04:03:54,800 I WANT TO COME BACK TO MIGUEL'S 5711 04:03:54,800 --> 04:03:57,560 FIRST QUESTION, WHICH WAS HOW 5712 04:03:57,560 --> 04:04:00,120 MUCH IS PUT FORWARD OR PETA'S 5713 04:04:00,120 --> 04:04:01,920 QUESTION HOW MUCH IS REVERSIBLE. 5714 04:04:01,920 --> 04:04:03,840 I DON'T THINK ANYONE CAN ANSWER 5715 04:04:03,840 --> 04:04:05,320 THAT QUESTION WITH ANY CERTAINTY 5716 04:04:05,320 --> 04:04:06,600 BECAUSE NONE OF THE PRECLINICAL 5717 04:04:06,600 --> 04:04:09,720 MODELS PREDICT THAT. IT'S 5718 04:04:09,720 --> 04:04:13,000 FRANKLY NEVER BEEN DONE BEFORE. 5719 04:04:13,000 --> 04:04:14,600 SO I THINK IT'S VERY -- IT'S 5720 04:04:14,600 --> 04:04:16,440 VERY UNCLEAR TO ME HOW MUCH IS 5721 04:04:16,440 --> 04:04:18,600 REVERSIBLE. HOW MUCH IS 5722 04:04:18,600 --> 04:04:19,840 PREVENTIBLE. AND THAT GETS US 5723 04:04:19,840 --> 04:04:21,840 THE QUESTION OF THERAPEUTIC 5724 04:04:21,840 --> 04:04:24,400 WINDOW AND MAKES IT EVEN MORE 5725 04:04:24,400 --> 04:04:24,680 COMPLICATED. 5726 04:04:24,680 --> 04:04:27,040 BUT I WOULD JUST CAUTION AND SAY 5727 04:04:27,040 --> 04:04:31,480 I DON'T THINK WE REALLY KNOW HOW 5728 04:04:31,480 --> 04:04:33,680 MUCH IS INDEED ADDRESSABLE EVEN 5729 04:04:33,680 --> 04:04:36,040 IF YOU RESTORE PERFECT 5730 04:04:36,040 --> 04:04:40,960 EXPRESSION OF A NORMAL ALLELE I 5731 04:04:40,960 --> 04:04:42,480 THINK THAT'S JUST WE WON'T KNOW 5732 04:04:42,480 --> 04:04:46,960 UNTIL WE DO IT IS THE POINT. 5733 04:04:46,960 --> 04:04:49,720 >> AND MAYBE WE CAN TRY TO HAVE 5734 04:04:49,720 --> 04:04:51,760 ANOTHER FIVE-MINUTE DISCUSSION 5735 04:04:51,760 --> 04:04:53,440 AND CLOSE AROUND 2:30 BECAUSE I 5736 04:04:53,440 --> 04:04:54,800 KNOW PEOPLE HAVE OTHER THINGS TO 5737 04:04:54,800 --> 04:04:56,840 DO ON THEIR WEEKEND SO PLEASE 5738 04:04:56,840 --> 04:04:58,760 FEEL FREE IF YOU HAVE OTHER 5739 04:04:58,760 --> 04:04:59,480 ADDITIONAL QUESTIONS IN THE LAST 5740 04:04:59,480 --> 04:05:03,120 FIVE MINUTES I SEE DR. KIN KNEE 5741 04:05:03,120 --> 04:05:04,720 HAS RAISED HIS HAND. 5742 04:05:04,720 --> 04:05:06,920 >> WE WERE TALKING ABOUT WE CAN 5743 04:05:06,920 --> 04:05:09,200 SORT OF PIGGY BACK ON WHAT 5744 04:05:09,200 --> 04:05:10,560 SPINAL CORD INJURY GROUPS HAVE 5745 04:05:10,560 --> 04:05:13,000 DONE THE DEGENERATIVE, LIKE 5746 04:05:13,000 --> 04:05:15,840 THAT'S INJURY INDUCED SORT OF 5747 04:05:15,840 --> 04:05:16,680 DEGENERATION, I THINK IF WE 5748 04:05:16,680 --> 04:05:19,080 REALLY BELIEVE THIS DISEASE HAS 5749 04:05:19,080 --> 04:05:21,840 A NEURO DEGENERATIVE ELEMENTINGS 5750 04:05:21,840 --> 04:05:23,840 IN THERE THERE'S SOME THERAPIES 5751 04:05:23,840 --> 04:05:27,280 SHOWING SOME PROMISING RESULT ON 5752 04:05:27,280 --> 04:05:29,720 REGENERATE CNS NEURONS CAN BE 5753 04:05:29,720 --> 04:05:31,600 PROBABLY APPLIED TO WHAT WE'RE 5754 04:05:31,600 --> 04:05:33,400 STUDYING HERE. JUST A THOUGHT 5755 04:05:33,400 --> 04:05:35,360 NOT LIKE IT'S VERY MATURE AT THE 5756 04:05:35,360 --> 04:05:36,720 MOMENT BUT I THINK WE CAN THINK 5757 04:05:36,720 --> 04:05:39,360 ABOUT IT IN WE REALLY THINK 5758 04:05:39,360 --> 04:05:43,040 NEURO DEGENERATIVE COMPONENTS 5759 04:05:43,040 --> 04:05:48,520 WANT TO PROMOTE EITHER THE 5760 04:05:48,520 --> 04:05:51,040 REGENERATION REGROWTH. INCREASE 5761 04:05:51,040 --> 04:05:52,720 AND BRANCH INTO MAKE CONNECTIONS 5762 04:05:52,720 --> 04:05:55,040 I THINK THAT COULD BE SOMETHING 5763 04:05:55,040 --> 04:05:58,880 AT THE THERAPY YOU KNOW YOU CAN 5764 04:05:58,880 --> 04:06:03,160 SORT OF THINK ABOUT. 5765 04:06:03,160 --> 04:06:11,480 >> ANY OTHER LAST MINUTE BURNING 5766 04:06:11,480 --> 04:06:13,400 QUESTIONS OR COMMENTS? 5767 04:06:13,400 --> 04:06:14,280 >> MOST OF THE CHAT QUESTIONS 5768 04:06:14,280 --> 04:06:17,480 HAVE BEEN ANSWERED ON MY END. 5769 04:06:17,480 --> 04:06:19,480 >> MY ONLY LAST COMMENT OR 5770 04:06:19,480 --> 04:06:22,080 ACTUALLY WAS JUST TO THANKS TO 5771 04:06:22,080 --> 04:06:25,960 ARIANE TO ORGANIZE THIS AND 5772 04:06:25,960 --> 04:06:27,200 EVERYONE ELSE THAT WAS IN THE 5773 04:06:27,200 --> 04:06:30,840 BACKGROUND COLLEEN, EVERYBODY 5774 04:06:30,840 --> 04:06:33,400 THAT WAS HELPING MAKE THIS RUN 5775 04:06:33,400 --> 04:06:36,080 SMOOTHLY. SO ARIANE I WISH YOU 5776 04:06:36,080 --> 04:06:38,760 COULD HEAR US ALL APPLAUDING 5777 04:06:38,760 --> 04:06:38,960 YOU. 5778 04:06:38,960 --> 04:06:40,760 >> THANK YOU IT'S BEEN SUCH AN 5779 04:06:40,760 --> 04:06:42,120 HONOR I WAS INSPIRED BY THESE 5780 04:06:42,120 --> 04:06:44,120 CHILDREN WE SAW AND CHRIS WHO 5781 04:06:44,120 --> 04:06:46,280 WOULD CALL ME ON MY OFFICE LINE 5782 04:06:46,280 --> 04:06:48,120 WHAT ARE YOU AND THE NIH DOING 5783 04:06:48,120 --> 04:06:50,520 FOR MY CHILD. SO THE LEAST I 5784 04:06:50,520 --> 04:06:52,560 COULD DO IS PUT SCIENTIST WHO 5785 04:06:52,560 --> 04:06:53,720 KNOW ABOUT THIS TOPIC TOGETHER 5786 04:06:53,720 --> 04:06:55,920 SO I FEEL HONORED TO HAVE BEEN 5787 04:06:55,920 --> 04:06:57,480 ABLE TO DO THAT. THANK YOU 5788 04:06:57,480 --> 04:06:58,480 EVERYBODY FOR SPENDING YOUR 5789 04:06:58,480 --> 04:06:59,680 FRIDAY AND PART OF SATURDAY WITH 5790 04:06:59,680 --> 04:07:03,200 US. I KNOW IT'S GOING TO SPEAR 5791 04:07:03,200 --> 04:07:06,160 ALONG A LOT OF CLASH 5792 04:07:06,160 --> 04:07:07,080 COLLABORATIONS BETWEEN 5793 04:07:07,080 --> 04:07:09,840 SCIENTISTS PRESENT AND I KNOW 5794 04:07:09,840 --> 04:07:12,000 IT'S REASSURING FOR THE FAMILIES 5795 04:07:12,000 --> 04:07:14,480 THAT PEOPLE ARE THINKING A LOT 5796 04:07:14,480 --> 04:07:17,280 ABOUT THIS TOP SXIK A LOT OF 5797 04:07:17,280 --> 04:07:19,080 DISCUSSION GOING TO THIS. 5798 04:07:19,080 --> 04:07:20,480 >> THANK YOU FORJOINING. 5799 04:07:20,480 --> 04:07:21,840 >> THANK YOU ALL VERY MUCH. 5800 04:07:21,840 --> 04:07:24,400 IT'S SO MEANINGFUL TO SEE 5801 04:07:24,400 --> 04:07:26,000 EVERYBODY COLLABORATING WE HOPE 5802 04:07:26,000 --> 04:07:26,720 WE CAN FACILITATE MORE AND LEAD 5803 04:07:26,720 --> 04:07:29,040 KIND OF DISCUSSIONS IN THE 5804 04:07:29,040 --> 04:07:30,720 FUTURE AND I'M HERE TO ASSIST 5805 04:07:30,720 --> 04:07:33,280 FROM A PATIENT ADVOCACY 5806 04:07:33,280 --> 04:07:36,120 PERSPECTIVE AS MUCH AS POSSIBLE 5807 04:07:36,120 --> 04:07:37,000 THANK YOU ALL. 5808 04:07:37,000 --> 04:07:37,760 >> THANK YOU SO MUCH. 5809 04:07:37,760 --> 04:07:38,680 >> I WILL BE IN TOUCH WITH NEXT 5810 04:07:38,680 --> 04:13:12,960 STEPS. THANK YOU.