1 00:00:06,006 --> 00:00:07,841 WE'RE GOING TO GET STARTED. 2 00:00:07,841 --> 00:00:09,042 IT'S MY PLEASURE TO WELCOME ALL 3 00:00:09,042 --> 00:00:10,911 OF YOU TO OUR WORKSHOP ON 4 00:00:10,911 --> 00:00:12,880 GENETIC STRATEGIES TO TREAT THE 5 00:00:12,880 --> 00:00:20,120 EPILEPSIES. 6 00:00:20,120 --> 00:00:21,889 SO THE IDEA FOR THIS WORKSHOP 7 00:00:21,889 --> 00:00:26,026 STARTED A COUPLE OF YEARS AGO AT 8 00:00:26,026 --> 00:00:27,227 AES, WHERE I WENT TO SEVERAL OF 9 00:00:27,227 --> 00:00:29,763 THE PATIENT ADVOCACY SATELLITE 10 00:00:29,763 --> 00:00:31,365 MEETINGS, AND EVERYBODY WAS 11 00:00:31,365 --> 00:00:34,334 SAYING WE WANT GENE THERAPY FOR 12 00:00:34,334 --> 00:00:36,637 OUR GENETIC EPILEPSY. 13 00:00:36,637 --> 00:00:39,206 AND SO WE STARTED PLANNING THIS 14 00:00:39,206 --> 00:00:40,874 AND FINALLY WE'RE ALL HERE, SO 15 00:00:40,874 --> 00:00:42,976 THANKS TO EVERYONE FOR JOINING 16 00:00:42,976 --> 00:00:46,513 US HERE TODAY, BOTH ONLINE, WE 17 00:00:46,513 --> 00:00:47,915 HAVE QUITE A NUMBER OF PEOPLE 18 00:00:47,915 --> 00:00:50,117 ONLINE AND PEOPLE HERE IN THE 19 00:00:50,117 --> 00:00:51,285 ROOM. 20 00:00:51,285 --> 00:00:53,253 SO IT'S MY PLEASURE TO FIRST 21 00:00:53,253 --> 00:00:55,856 INTRODUCE DR. WALTER KOROSHETZ, 22 00:00:55,856 --> 00:00:56,990 DIRECTOR OF NINDS, WHO'S GOING 23 00:00:56,990 --> 00:01:00,794 TO OPEN THE WORKSHOP WITH SOME 24 00:01:00,794 --> 00:01:01,528 INTRODUCTORY COMMENTS. 25 00:01:01,528 --> 00:01:08,802 WALTER? 26 00:01:08,802 --> 00:01:10,571 >> GOOD MORNING, FOLKS. 27 00:01:10,571 --> 00:01:13,040 GOOD MORNING TO PEOPLE ONLINE. 28 00:01:13,040 --> 00:01:16,043 APPRECIATE EVERYONE'S COMING AND 29 00:01:16,043 --> 00:01:17,110 JOINING WITH THE GROUP, WHICH I 30 00:01:17,110 --> 00:01:20,047 THINK IS GOING TO BE TALKING 31 00:01:20,047 --> 00:01:21,448 ABOUT REALLY ONE OF THE MAIN 32 00:01:21,448 --> 00:01:23,317 CHALLENGES FOR THE FUTURE, BUT A 33 00:01:23,317 --> 00:01:25,319 LOT OF WORK HAS GONE IN TO 34 00:01:25,319 --> 00:01:29,690 GETTING OURSELVES IN PLACE TO 35 00:01:29,690 --> 00:01:32,392 KIND OF TAKE ON THIS CHALLENGE, 36 00:01:32,392 --> 00:01:35,729 AND THAT'S TRYING TO GET 37 00:01:35,729 --> 00:01:37,764 STRATEGIES TO TREAT THE GENETIC 38 00:01:37,764 --> 00:01:42,269 EPILEPSIES. 39 00:01:42,269 --> 00:01:52,779 SO SOME OF THIS MAY BRING BACK 40 00:02:04,091 --> 00:02:08,695 SOME PAINFUL MEMORIES TO PEOPLE 41 00:02:08,695 --> 00:02:10,430 ABOUT THE REALLY AMAZING 42 00:02:10,430 --> 00:02:13,500 PROJECTS THAT WENT ON TO 43 00:02:13,500 --> 00:02:16,837 IDENTIFY GENETIC CAUSES IN THE 44 00:02:16,837 --> 00:02:21,174 EPILEPSIES, AND THIS TOOK 45 00:02:21,174 --> 00:02:22,042 PROBABLY THOUSANDS OF PEOPLE 46 00:02:22,042 --> 00:02:25,212 WORKING ON PROJECT, INCLUDING 47 00:02:25,212 --> 00:02:26,947 TENS OF THOUSANDS OF SUBJECTS, 48 00:02:26,947 --> 00:02:29,783 PEOPLE WITH EPILEPSY WORKING 49 00:02:29,783 --> 00:02:31,651 TOGETHER TO COLLECT THE GENETIC 50 00:02:31,651 --> 00:02:34,388 INFORMATION TO PHENOTYPE THE 51 00:02:34,388 --> 00:02:37,124 PATIENT, AND THIS WAS DONE IN 52 00:02:37,124 --> 00:02:39,226 WHAT WAS OUR FIRST CENTER 53 00:02:39,226 --> 00:02:43,130 WITHOUT WALLS FOR EPILEPSY, 54 00:02:43,130 --> 00:02:44,164 WHICH IS A PROGRAM THAT WE FOUND 55 00:02:44,164 --> 00:02:46,400 TO BE SO SUCCESSFUL THAT WE 56 00:02:46,400 --> 00:02:48,068 CONTINUED IT NOT ONLY IN 57 00:02:48,068 --> 00:02:49,403 EPILEPSY, WE'RE TRYING TO MOVE 58 00:02:49,403 --> 00:02:51,238 IT INTO SOME OF OUR OTHER GRANT 59 00:02:51,238 --> 00:02:53,407 MECHANISMS AS WELL. 60 00:02:53,407 --> 00:02:59,246 WE ALSO HAD -- CWOW WAS LOOKING 61 00:02:59,246 --> 00:03:04,151 AT THE VERY TRAGIC PROBLEM OF 62 00:03:04,151 --> 00:03:08,321 SUDDEN UNEXPLAINED DEATH IN 63 00:03:08,321 --> 00:03:10,257 EPILEPSY, A PROJECT TRYING TO 64 00:03:10,257 --> 00:03:12,359 GET AT HOW WE MIGHT PREVENT 65 00:03:12,359 --> 00:03:16,096 EPILEPSY IN A CONDITION THAT MAY 66 00:03:16,096 --> 00:03:18,598 LEAD TO TRAUMATIC BRAIN INJURY 67 00:03:18,598 --> 00:03:20,167 THAT'S GOT A HIGH RISK FOR 68 00:03:20,167 --> 00:03:20,901 DEVELOPING EPILEPSY. 69 00:03:20,901 --> 00:03:22,002 CLEARLY THAT WOULD BE ONE OF THE 70 00:03:22,002 --> 00:03:25,605 HOLY GRAILS OF TRYING TO GET 71 00:03:25,605 --> 00:03:28,809 CONTROL OF THIS PROBLEM WOULD BE 72 00:03:28,809 --> 00:03:33,914 DEVELOP PREVENTIVE STRATEGIES. 73 00:03:33,914 --> 00:03:36,116 THEN IN TERMS OF WORKING UP THE 74 00:03:36,116 --> 00:03:38,085 GENE FINDINGS, WHICH ARE MANY, 75 00:03:38,085 --> 00:03:42,255 WE HAVE TWO CWOWs, ONE LOOKING 76 00:03:42,255 --> 00:03:43,590 AT THE ION CHANNEL EPILEPSIES 77 00:03:43,590 --> 00:03:46,293 AND THE OTHER LOOKING AT THE 78 00:03:46,293 --> 00:03:48,829 NON-ION CHANNEL VARIANTS THAT 79 00:03:48,829 --> 00:03:51,765 ARE RELATED TO EPILEPSY. 80 00:03:51,765 --> 00:03:53,834 AND SO CLEARLY ON THE GENETIC 81 00:03:53,834 --> 00:03:55,569 SIDE, THERE'S A CLEAR KIND OF 82 00:03:55,569 --> 00:03:59,873 LINEAR PATH FROM IDENTIFYING THE 83 00:03:59,873 --> 00:04:00,507 ABNORMALITIES, TRYING TO MATCH 84 00:04:00,507 --> 00:04:02,175 THEM UP WITH A PHENOTYPE, TRYING 85 00:04:02,175 --> 00:04:03,910 TO THEN GO DOWN AND UNDERSTAND 86 00:04:03,910 --> 00:04:07,747 WHAT THE MECHANISM OF THE 87 00:04:07,747 --> 00:04:09,015 DIFFERENT GENETIC FORMS AND THEN 88 00:04:09,015 --> 00:04:09,916 WHAT WE'LL BE TALKING ABOUT 89 00:04:09,916 --> 00:04:11,118 TODAY IS HOW DO YOU ACTUALLY 90 00:04:11,118 --> 00:04:13,620 TREAT THOSE. 91 00:04:13,620 --> 00:04:15,222 SO I THINK THE GOOD NEWS IS THAT 92 00:04:15,222 --> 00:04:17,224 WE'VE MADE A LOT OF PROGRESS. 93 00:04:17,224 --> 00:04:18,692 THE BAD NEWS IS THAT WE'VE GOT A 94 00:04:18,692 --> 00:04:22,829 LOT OF TARGETS TO PURSUE, AND IN 95 00:04:22,829 --> 00:04:26,333 SOME INSTANCES, THERE'S NO 96 00:04:26,333 --> 00:04:30,203 SUBSTITUTE FOR GOING REALLY IN 97 00:04:30,203 --> 00:04:32,205 DEPTH AND VERY SPECIFIC GO AFTER 98 00:04:32,205 --> 00:04:34,207 ONE MUTATION, WHAT DOES DO, WHAT 99 00:04:34,207 --> 00:04:36,610 IS THE BEST WAY TO AMELIORATE 100 00:04:36,610 --> 00:04:36,810 IT. 101 00:04:36,810 --> 00:04:38,578 IT WOULD BE NICE, HOWEVER, IF WE 102 00:04:38,578 --> 00:04:41,414 COULD KIND OF PARCEL THINGS 103 00:04:41,414 --> 00:04:43,150 TOGETHER AND UNDERSTAND A 104 00:04:43,150 --> 00:04:44,684 COUPLE -- SOME TREATMENTS THAT 105 00:04:44,684 --> 00:04:45,685 MIGHT AFFECT MULTIPLE DIFFERENT 106 00:04:45,685 --> 00:04:48,622 FORMS OF THESE EPILEPSIES, BUT 107 00:04:48,622 --> 00:04:51,091 THE SUCCESS OF THAT REMAINS TO 108 00:04:51,091 --> 00:04:52,692 BE SEEN, SUCCESS MEANING 109 00:04:52,692 --> 00:04:54,528 SOMETHING BETTER THAN WHAT'S 110 00:04:54,528 --> 00:04:55,962 ALREADY -- THAT'S HAPPENED WITH 111 00:04:55,962 --> 00:04:58,064 SMALL MOLECULES. 112 00:04:58,064 --> 00:04:59,466 AND THEN I THINK I'LL END UP 113 00:04:59,466 --> 00:05:04,604 WITH THE IDEA THAT AS FOLKS HERE 114 00:05:04,604 --> 00:05:06,339 HAVE BEEN LOOKING AT THE GENETIC 115 00:05:06,339 --> 00:05:09,442 MECHANISM OF EPILEPSY, SOME 116 00:05:09,442 --> 00:05:11,044 FOLKS IN THE EPILEPSIES, A LOT 117 00:05:11,044 --> 00:05:12,512 OF FOLKS OUTSIDE THE EPILEPSIES 118 00:05:12,512 --> 00:05:15,248 THAT HAVE BEEN TRYING TO DEVELOP 119 00:05:15,248 --> 00:05:18,185 WAYS OF TREATING GENETIC 120 00:05:18,185 --> 00:05:23,523 DISORDERS AND AGAIN, THEY FACE A 121 00:05:23,523 --> 00:05:26,159 SIMILAR PROBLEM IN TERMS OF 122 00:05:26,159 --> 00:05:27,127 SPECIFICITY AND ONE GOING RIGHT 123 00:05:27,127 --> 00:05:28,328 AFTER ANOTHER, BUT THAT SEEMS TO 124 00:05:28,328 --> 00:05:29,362 BE SOMETHING THAT WE'RE GOING TO 125 00:05:29,362 --> 00:05:32,365 HAVE TO FACE IN ALL THE RARE 126 00:05:32,365 --> 00:05:34,334 DISEASES, EPILEPSY IS A MODEL 127 00:05:34,334 --> 00:05:37,103 BUT YOU'RE JOINING IN A LARGER 128 00:05:37,103 --> 00:05:41,708 CROWD. 129 00:05:41,708 --> 00:05:42,776 SO A COUPLE THINGS ARE STILL 130 00:05:42,776 --> 00:05:43,243 GOING ON. 131 00:05:43,243 --> 00:05:45,078 SO THERE ARE STUDIES LOOKING AT 132 00:05:45,078 --> 00:05:48,014 THE GENETICS, LOOKING AT THE 133 00:05:48,014 --> 00:05:49,649 CONTRIBUTION OF COPY NUMBER 134 00:05:49,649 --> 00:05:52,419 VARIANTS AND GENETIC 135 00:05:52,419 --> 00:05:55,589 ARCHITECTURE OF EPILEPSY. 136 00:05:55,589 --> 00:05:57,324 THIS SLIDE IS A LITTLE OUT OF 137 00:05:57,324 --> 00:05:58,792 PLACE BUT THERE WAS ANOTHER 138 00:05:58,792 --> 00:06:02,462 RECENT STUDY PUBLISHED BY THE 139 00:06:02,462 --> 00:06:03,563 INTERNATIONAL LEAGUE AGAINST 140 00:06:03,563 --> 00:06:06,166 EPILEPSY CONSORTIUM FOR COMPLEX 141 00:06:06,166 --> 00:06:08,568 EPILEPSIES LOOKING AT THE 142 00:06:08,568 --> 00:06:10,770 GENETIC GENERALIZED EPILEPSIES 143 00:06:10,770 --> 00:06:17,544 AND IDENTIFYING 26 LOCI SPECIFIC 144 00:06:17,544 --> 00:06:20,981 FOR FAMILIAL GENETIC EPILEPSY, 145 00:06:20,981 --> 00:06:22,482 AND I THINK THE POINT OF THIS 146 00:06:22,482 --> 00:06:23,883 PAPER, WHICH I THOUGHT WAS 147 00:06:23,883 --> 00:06:25,652 IMPORTANT, IS THAT IF YOU TAKE 148 00:06:25,652 --> 00:06:26,953 ALL THE EPILEPSIES TOGETHER AND 149 00:06:26,953 --> 00:06:29,189 YOU LOOK, YOU HAVE SO MUCH NOISE 150 00:06:29,189 --> 00:06:30,824 THAT OFTENTIMES YOU MISS THINGS, 151 00:06:30,824 --> 00:06:33,093 BUT IF YOU CAN REALLY GET THE 152 00:06:33,093 --> 00:06:34,527 PHENOTYPING DOWN, THAT THINGS 153 00:06:34,527 --> 00:06:36,930 WILL POP UP THAT ARE SIGNIFICANT 154 00:06:36,930 --> 00:06:39,332 AND IMPORTANT TO FOLLOW UP ON. 155 00:06:39,332 --> 00:06:41,735 THIS PAPER ALSO LOOKED AT SOME 156 00:06:41,735 --> 00:06:44,804 OF THESE VARIANTS THAT THEY 157 00:06:44,804 --> 00:06:46,206 FOUND ARE IN PATHWAYS AND THEY 158 00:06:46,206 --> 00:06:48,375 TRIED TO MATCH THOSE PATHWAYS UP 159 00:06:48,375 --> 00:06:49,943 TO PARTICULAR DRUGS, SOME OF 160 00:06:49,943 --> 00:06:51,344 WHICH ARE USED IN EPILEPSIES, 161 00:06:51,344 --> 00:06:53,213 SOME OF WHICH ARE NOT. 162 00:06:53,213 --> 00:06:56,583 BUT AGAIN, IT'S ANOTHER THEME 163 00:06:56,583 --> 00:06:58,151 THAT WHEN -- AND THIS HAS 164 00:06:58,151 --> 00:07:00,120 HAPPENED CERTAINLY IN OTHER 165 00:07:00,120 --> 00:07:03,857 GENETIC -- I THINK I'LL MENTION 166 00:07:03,857 --> 00:07:06,059 ONE -- ONCE YOU HAVE A MECHANISM 167 00:07:06,059 --> 00:07:07,227 SOMETIMES YOU DO GET A CLUE AS 168 00:07:07,227 --> 00:07:08,428 TO WHAT DRUG IS GOING TO BE 169 00:07:08,428 --> 00:07:08,862 WORKING. 170 00:07:08,862 --> 00:07:10,597 SO IN TERMS OF TREATMENT, 171 00:07:10,597 --> 00:07:12,666 THERE'S KIND OF REALLY NOVEL 172 00:07:12,666 --> 00:07:14,000 TREATMENTS AND THEN THERE'S 173 00:07:14,000 --> 00:07:15,135 BETTER USE OF TREATMENTS THAT 174 00:07:15,135 --> 00:07:17,037 ARE AVAILABLE NOW, SOME OF WHICH 175 00:07:17,037 --> 00:07:18,938 IN THE EPILEPSY SPACE, SOME OF 176 00:07:18,938 --> 00:07:24,377 WHICH MAY NOT BE. 177 00:07:24,377 --> 00:07:27,113 SO THERE'S ANOTHER STUDY, I 178 00:07:27,113 --> 00:07:29,015 THINK THIS IS ONE WHERE THEY 179 00:07:29,015 --> 00:07:30,183 FIND PEOPLE WITH SEIZURES AND 180 00:07:30,183 --> 00:07:34,888 PEOPLE WITH KNOWN EPILEPSY GOING 181 00:07:34,888 --> 00:07:37,757 OUT AGAIN, PHENOME-WIDE-EYED FIX 182 00:07:37,757 --> 00:07:39,793 OF COPY NUMBER VARIANTS AND 183 00:07:39,793 --> 00:07:47,667 LOOKED AT THE NUMBERS HERE. 184 00:07:47,667 --> 00:07:49,869 THEN IN LOOKING AT THE 185 00:07:49,869 --> 00:07:52,839 PARTICULAR CHANNELS THAT CAUSE 186 00:07:52,839 --> 00:07:54,274 EPILEPSY, THIS IS ONE OF 187 00:07:54,274 --> 00:07:58,178 MULTIPLE EXAMPLES, A POTASSIUM 188 00:07:58,178 --> 00:07:59,746 CHANNEL, LOOKING AT PEOPLE WHO 189 00:07:59,746 --> 00:08:03,183 HAVE MUTATIONS IN THIS POTASSIUM 190 00:08:03,183 --> 00:08:05,151 CHANNEL AND THE TAKE-HOME POINT, 191 00:08:05,151 --> 00:08:07,487 OF COURSE, IS THAT THERE'S MANY 192 00:08:07,487 --> 00:08:09,122 DIFFERENT PHENOTYPES THAT YOU 193 00:08:09,122 --> 00:08:11,424 SEE WHERE PEOPLE HAVE THE SAME 194 00:08:11,424 --> 00:08:11,858 MUTATION. 195 00:08:11,858 --> 00:08:13,126 HERE THEY LOOK AT THE STRUCTURE 196 00:08:13,126 --> 00:08:16,029 OF THE CHANNEL AND IDENTIFY SOME 197 00:08:16,029 --> 00:08:19,199 KIND OF CLUSTERING OF PHENOTYPES 198 00:08:19,199 --> 00:08:20,266 ASSOCIATED WITH PARTICULAR 199 00:08:20,266 --> 00:08:22,402 MUTATIONS IN THE CHANNEL, SO THE 200 00:08:22,402 --> 00:08:23,670 ISSUE WITH THE CHANNELS, OF 201 00:08:23,670 --> 00:08:25,238 COURSE, IS THAT SOMETIMES 202 00:08:25,238 --> 00:08:26,840 THERE'S LOSS OF FUNCTION, 203 00:08:26,840 --> 00:08:27,607 SOMETIMES THERE'S GAIN OF 204 00:08:27,607 --> 00:08:29,576 FUNCTION MUTATIONS IN THE SAME 205 00:08:29,576 --> 00:08:32,011 CHANNEL, SOMETIMES THERE WILL BE 206 00:08:32,011 --> 00:08:33,213 MODIFICATIONS IN EITHER 207 00:08:33,213 --> 00:08:35,382 DIRECTION, AND THOSE MAY BE 208 00:08:35,382 --> 00:08:39,519 SPECIFIC FOR THE MUTATION, NOT 209 00:08:39,519 --> 00:08:40,954 JUST THE CHANNEL THAT'S 210 00:08:40,954 --> 00:08:41,821 AFFECTED. 211 00:08:41,821 --> 00:08:44,657 SO AGAIN, ANOTHER LEVEL OF 212 00:08:44,657 --> 00:08:47,093 SPECIFICITY ONCE YOU HAVE THE 213 00:08:47,093 --> 00:08:49,696 CHANNEL DOESN'T MEAN THAT YOU 214 00:08:49,696 --> 00:08:51,331 HAVE THE TREATMENT. 215 00:08:51,331 --> 00:08:52,766 YOU NEED TO KNOW WHAT THAT 216 00:08:52,766 --> 00:08:55,168 DEFECT IS DOING AND DIFFERENT 217 00:08:55,168 --> 00:08:57,370 DEFECTS IN THAT CHANNEL DO 218 00:08:57,370 --> 00:09:04,010 DIFFERENT THINGS. 219 00:09:04,010 --> 00:09:06,546 THEN AGAIN A WHOLE BUNCH OF 220 00:09:06,546 --> 00:09:07,647 REPORTS THAT HAVE COME UP FROM 221 00:09:07,647 --> 00:09:09,616 THE CWOWs LOOKING AT THE 222 00:09:09,616 --> 00:09:11,351 MUTATIONS THAT HAVE COME UP FROM 223 00:09:11,351 --> 00:09:14,087 THE BIG GWAS STUDIES AND THE BIG 224 00:09:14,087 --> 00:09:19,025 GENETIC STUDIES, AND THEN THE 225 00:09:19,025 --> 00:09:22,929 QUESTION IS A COUPLE OF IDEAS ON 226 00:09:22,929 --> 00:09:24,130 WHAT WE MIGHT BE THINKING OF 227 00:09:24,130 --> 00:09:26,533 GOING FORWARD, SO I WAS 228 00:09:26,533 --> 00:09:29,903 INTRIGUED BY HEARING THIS AT THE 229 00:09:29,903 --> 00:09:32,439 AMERICAN EPILEPSY SOCIETY A 230 00:09:32,439 --> 00:09:33,173 COUPLE YEARS AGO. 231 00:09:33,173 --> 00:09:35,708 THE IDEA HERE IS THAT THIS IS 232 00:09:35,708 --> 00:09:37,243 SOMETHING THAT WOULD CUT ACROSS 233 00:09:37,243 --> 00:09:39,112 ANY EPILEPSY CAUSED BY 234 00:09:39,112 --> 00:09:40,680 SYNCHRONOUS VERY ABNORMAL 235 00:09:40,680 --> 00:09:43,149 SYNCHRONOUS FIRING. 236 00:09:43,149 --> 00:09:46,453 THE BRAIN DOESN'T USUALLY IN ITS 237 00:09:46,453 --> 00:09:47,754 NORMAL ACTIVITY, IT DOESN'T 238 00:09:47,754 --> 00:09:49,189 USUALLY DO ANYTHING THAT LOOKS 239 00:09:49,189 --> 00:09:50,290 LIKE EPILEPSY. 240 00:09:50,290 --> 00:09:54,994 EPILEPSY IS A VERY PECULIAR 241 00:09:54,994 --> 00:09:56,529 STATE, CIRCUIT STATE, AND SO THE 242 00:09:56,529 --> 00:10:00,133 QUESTION IS, IS THERE A WAY TO 243 00:10:00,133 --> 00:10:02,168 KIND OF INTERFERE SO THAT STATE 244 00:10:02,168 --> 00:10:07,707 IS NEVER ENGAGED. 245 00:10:07,707 --> 00:10:10,844 AND THE STATE IS CHARACTERIZED 246 00:10:10,844 --> 00:10:12,846 BY JUST UNBELIEVABLY ROBUST 247 00:10:12,846 --> 00:10:13,913 SYNCHRONOUS FIRING, WHICH WILL 248 00:10:13,913 --> 00:10:15,114 BE ASSOCIATED WITH THINGS LIKE 249 00:10:15,114 --> 00:10:20,887 REALLY TREMENDOUS ACTIVATION 250 00:10:20,887 --> 00:10:28,127 OF -- NOTHING QUITE LIKE 251 00:10:28,127 --> 00:10:32,799 EPILEPSY, I DON'T THINK. 252 00:10:32,799 --> 00:10:34,000 ANYWAY, IN THIS PROJECT, WHAT 253 00:10:34,000 --> 00:10:36,135 THEY DO IS THEY HAVE A GENE 254 00:10:36,135 --> 00:10:38,071 THERAPY FOR POTASSIUM CHANNEL, 255 00:10:38,071 --> 00:10:41,808 AND THIS POTASSIUM CHANNEL WILL 256 00:10:41,808 --> 00:10:44,711 BE ACTIVATED BY CFOS SO THE 257 00:10:44,711 --> 00:10:46,246 CELLS THAT ARE ACTIVATING THE 258 00:10:46,246 --> 00:10:48,214 SEIZURE WILL TURN ON THIS 259 00:10:48,214 --> 00:10:49,582 CHANNEL AND THE POTASSIUM 260 00:10:49,582 --> 00:10:50,783 CHANNEL WILL SLOW DOWN THE 261 00:10:50,783 --> 00:10:51,751 FIRING RATE AND STOP THE 262 00:10:51,751 --> 00:10:56,756 SEIZURES. 263 00:10:56,756 --> 00:11:00,026 AND THEN IT BASE CLEAR PETERS 264 00:11:00,026 --> 00:11:01,461 OUT AND THE CHANNEL IS GOING 265 00:11:01,461 --> 00:11:03,863 NORMALLY, BUT THAT CHANNEL WILL 266 00:11:03,863 --> 00:11:06,699 BE ACTIVE FOR A WHILE SO IF A 267 00:11:06,699 --> 00:11:08,401 NEW SEIZURE STARTS TO BREW, IT 268 00:11:08,401 --> 00:11:09,469 WILL SHUT DOWN THAT SEIZURE. 269 00:11:09,469 --> 00:11:11,838 IF YOU GO FOR MONTHS WITHOUT 270 00:11:11,838 --> 00:11:15,041 HAVING ANY SEIZURES AND THE 271 00:11:15,041 --> 00:11:16,342 POTASSIUM CHANNEL IS QUIET BUT 272 00:11:16,342 --> 00:11:18,211 THE NEXT SEIZURE WILL ACTIVATE 273 00:11:18,211 --> 00:11:19,812 IT AGAIN AND YOU MIGHT GET 274 00:11:19,812 --> 00:11:22,549 ANOTHER THREE MONTHS OF 275 00:11:22,549 --> 00:11:23,883 ACTIVITY. 276 00:11:23,883 --> 00:11:27,921 BUT IT'S AN IDEA WHICH WOULD USE 277 00:11:27,921 --> 00:11:28,688 GENOMIC THERAPY THAT WOULD BE 278 00:11:28,688 --> 00:11:30,990 VERY POTENT AT BLOCKING THESE 279 00:11:30,990 --> 00:11:33,059 KIND OF REALLY ABNORMAL 280 00:11:33,059 --> 00:11:34,360 ACTIVITY, AND THIS IS IN A 281 00:11:34,360 --> 00:11:36,029 CLOSED LOOP SYSTEM. 282 00:11:36,029 --> 00:11:39,399 SO THIS IS NOT NECESSARILY 283 00:11:39,399 --> 00:11:40,066 GIVING A DRUG. 284 00:11:40,066 --> 00:11:42,302 THIS IS THE SEIZURE ITSELF 285 00:11:42,302 --> 00:11:43,436 ACTIVATES THE TREATMENT. 286 00:11:43,436 --> 00:11:45,004 SO THAT'S KIND OF THE DEFINITION 287 00:11:45,004 --> 00:11:45,872 OF CLOSED LOOP. 288 00:11:45,872 --> 00:11:47,507 OF COURSE WE'RE DOING CLOSED 289 00:11:47,507 --> 00:11:51,544 LOOP IN EPILEPSY WITH 290 00:11:51,544 --> 00:11:55,148 STIMULATION, THIS IS KIND OF A 291 00:11:55,148 --> 00:11:56,182 SIMILAR GENETIC TECHNIQUE. 292 00:11:56,182 --> 00:11:57,450 THERE ARE OTHER TECHNIQUES, AND 293 00:11:57,450 --> 00:12:05,091 THIS IS ONE THAT IS INTRODUCING 294 00:12:05,091 --> 00:12:07,460 AN ARTIFICIAL ACETYLCHOLINE 295 00:12:07,460 --> 00:12:09,162 RECEPTOR THAT IS ACTIVATED BY A 296 00:12:09,162 --> 00:12:15,068 DRUG THAT, AGAIN, WILL QUIET THE 297 00:12:15,068 --> 00:12:18,037 CELLS USING CHEMO GENETIC 298 00:12:18,037 --> 00:12:19,205 APPROACHES I THINK IS ALSO 299 00:12:19,205 --> 00:12:20,607 SOMETHING THAT COULD FOLLOW THAT 300 00:12:20,607 --> 00:12:24,377 SAME KIND OF PATH THAT WE TALKED 301 00:12:24,377 --> 00:12:25,478 ABOUT IN THE PREVIOUS SLIDE, BUT 302 00:12:25,478 --> 00:12:27,847 NOW IT'S A DRUG, WI BUT IT'S A G 303 00:12:27,847 --> 00:12:30,917 THAT HAS GOT MUCH MORE 304 00:12:30,917 --> 00:12:33,119 SPECIFICITY POTENTIALLY, MUCH 305 00:12:33,119 --> 00:12:36,189 MORE GREATER EFFECT SIZE ON 306 00:12:36,189 --> 00:12:37,657 ABNORMAL CELL FIRING WITH ANY 307 00:12:37,657 --> 00:12:38,825 THE SMALL MOLECULE IS GOING TO 308 00:12:38,825 --> 00:12:39,892 BE ABLE TO DO. 309 00:12:39,892 --> 00:12:43,162 THE PROBLEM WITH SMALL MOLECULES 310 00:12:43,162 --> 00:12:45,565 IS THAT YOU CAN STOP ANY SEIZURE 311 00:12:45,565 --> 00:12:47,800 YOU WANT BUT YOU'LL BE 312 00:12:47,800 --> 00:12:50,603 UNCONSCIOUS, ON RESPIRATOR, AND 313 00:12:50,603 --> 00:12:53,072 THAT MAY BE FACETIOUS BUT THE 314 00:12:53,072 --> 00:12:54,674 POINT IS THAT SMALL MOLECULES, 315 00:12:54,674 --> 00:12:55,908 YOU CAN'T GET THE EFFECT SIZE 316 00:12:55,908 --> 00:12:57,844 YOU NEED IN EPILEPSY BECAUSE THE 317 00:12:57,844 --> 00:12:58,845 SIDE EFFECTS HAVE COME FROM 318 00:12:58,845 --> 00:13:00,446 RAISING THE DOSES THAT ARE 319 00:13:00,446 --> 00:13:02,081 NECESSARY TO QUIET THE 320 00:13:02,081 --> 00:13:03,316 ELECTRICAL ACTIVITY THAT 321 00:13:03,316 --> 00:13:04,283 UNDERLIES THE SEIZURES. 322 00:13:04,283 --> 00:13:05,952 BUT THE GENOMIC THERAPIES ALLOW 323 00:13:05,952 --> 00:13:07,220 YOU TO GET AROUND THAT, EITHER 324 00:13:07,220 --> 00:13:08,788 BY TAILORING IT -- WELL, 325 00:13:08,788 --> 00:13:09,989 PARTICULARLY BY TAILORING IT 326 00:13:09,989 --> 00:13:13,259 JUST TO THE CELLS THAT YOU WANT, 327 00:13:13,259 --> 00:13:16,229 AND THEN POTENTIALLY BY 328 00:13:16,229 --> 00:13:18,831 CONTROLLING IT BY THE SEIZURE 329 00:13:18,831 --> 00:13:24,470 ACTIVITY ITSELF FOR A DRUG THAT 330 00:13:24,470 --> 00:13:25,638 ACTIVATES JUST THAT GENE AND 331 00:13:25,638 --> 00:13:26,873 JUST THE SPECIFIC CELL TYPES 332 00:13:26,873 --> 00:13:29,676 THAT YOU WANT. 333 00:13:29,676 --> 00:13:31,310 SO THESE KIND OF THINGS ARE, FOR 334 00:13:31,310 --> 00:13:34,047 US, A NEW OPPORTUNITY TO START 335 00:13:34,047 --> 00:13:36,349 THINKING ABOUT ANTISEIZURE 336 00:13:36,349 --> 00:13:46,526 MEDICATIONS FOR SURE. 337 00:13:46,526 --> 00:13:48,161 SORE THIS IS ANOTHER KIND OF 338 00:13:48,161 --> 00:13:49,128 THERAPY THAT AGAIN IS GOING TO 339 00:13:49,128 --> 00:13:50,463 BE MUCH MORE SPECIFIC THAN ANY 340 00:13:50,463 --> 00:13:56,169 KIND OF SMALL MOLECULE. 341 00:13:56,169 --> 00:13:57,770 THESE HAVE BEEN USED IN PEOPLE, 342 00:13:57,770 --> 00:13:59,639 GENE THERAPIES ARE USED IN 343 00:13:59,639 --> 00:14:01,274 PEOPLE, GENE EDITING IS GOING 344 00:14:01,274 --> 00:14:02,175 INTO PEOPLE SOON. 345 00:14:02,175 --> 00:14:06,312 SO I WOULD SAY THAT THESE KIND 346 00:14:06,312 --> 00:14:07,847 OF TECHNOLOGIES ARE THINGS I 347 00:14:07,847 --> 00:14:10,450 THINK WE SHOULD KEEP OUR EYE ON, 348 00:14:10,450 --> 00:14:11,451 PARTICULARLY FOR THE GENETIC 349 00:14:11,451 --> 00:14:16,689 FORMS OF EPILEPSY WHERE THEY'RE 350 00:14:16,689 --> 00:14:17,523 MOST SUITED FOR PEOPLE IN THE 351 00:14:17,523 --> 00:14:18,791 BEGINNING TO GET A HANDLE ON HOW 352 00:14:18,791 --> 00:14:20,093 WE CAN SAFELY USE THESE 353 00:14:20,093 --> 00:14:20,460 THERAPIES. 354 00:14:20,460 --> 00:14:22,795 WE DON'T KNOW WHAT THEIR EFFECTS 355 00:14:22,795 --> 00:14:23,496 ARE LONG TERM. 356 00:14:23,496 --> 00:14:24,697 THERE ARE CERTAINLY RISKS 357 00:14:24,697 --> 00:14:27,867 ASSOCIATED WITH USING THEM. 358 00:14:27,867 --> 00:14:30,203 SO THE CASES THAT WHERE YOU CAN 359 00:14:30,203 --> 00:14:36,409 ETHICALLY KIND OF UNDERSTAND THE 360 00:14:36,409 --> 00:14:37,376 RISK-BENEFIT RATIO AND HAVE A 361 00:14:37,376 --> 00:14:38,611 DISCUSSION WITH THE FAMILY, IT'S 362 00:14:38,611 --> 00:14:40,813 GOING TO BE IN CLEARLY THE MOST 363 00:14:40,813 --> 00:14:42,148 SEVERE CASES, BUT THESE ARE THE 364 00:14:42,148 --> 00:14:47,587 KIND OF THINGS THAT ARE -- TO 365 00:14:47,587 --> 00:14:50,289 THINK ABOUT IN EPILEPSY BUT 366 00:14:50,289 --> 00:14:51,491 OTHER GENETIC DISEASES THAT ARE 367 00:14:51,491 --> 00:14:52,492 ACTUALLY FURTHER OUT BECAUSE OF 368 00:14:52,492 --> 00:14:56,629 THE NATURE OF THE DISEASE FOR 369 00:14:56,629 --> 00:14:58,698 THINGS LIKE -- ATROPHY WHERE THE 370 00:14:58,698 --> 00:15:00,233 INFANTS ARE DEAD IN A YEAR, THAT 371 00:15:00,233 --> 00:15:02,535 WAS CLEARLY THE FIRST ONE TO 372 00:15:02,535 --> 00:15:03,803 COME TO FRUITION. 373 00:15:03,803 --> 00:15:06,506 THIS IS THE ONE I TALKED ABOUT 374 00:15:06,506 --> 00:15:07,340 WITH THE GWAS. 375 00:15:07,340 --> 00:15:08,875 I GUESS THE OTHER THING WE'RE 376 00:15:08,875 --> 00:15:10,743 LEARNING IS ABOUT THE SOMATIC 377 00:15:10,743 --> 00:15:15,348 MUTATIONS THAT ARE OCCURRING 378 00:15:15,348 --> 00:15:18,618 PARTICULARLY IN THE MESIAL 379 00:15:18,618 --> 00:15:20,052 TEMPORAL LOBE IN EPILEPSY. 380 00:15:20,052 --> 00:15:21,454 CERTAINLY FOLKS IN THIS ROOM 381 00:15:21,454 --> 00:15:24,524 WORKED ON SOMATIC MUTATION AND 382 00:15:24,524 --> 00:15:25,391 FOCAL EPILEPSIES. 383 00:15:25,391 --> 00:15:28,127 I THINK I WAS A LITTLE BIT 384 00:15:28,127 --> 00:15:29,428 SURPRISED ABOUT THE FREQUENCY IN 385 00:15:29,428 --> 00:15:35,301 WHICH THESE HAVE BEEN SEEN IN 386 00:15:35,301 --> 00:15:37,970 MEDIAL TEMPORAL LOBE EPILEPSY. 387 00:15:37,970 --> 00:15:41,240 THE QUESTION IS WHAT STARTED 388 00:15:41,240 --> 00:15:44,777 THEM, CAUSED A FEBRILE SEIZURE, 389 00:15:44,777 --> 00:15:49,248 AND THEN THEY ACTUALLY GIVE RISE 390 00:15:49,248 --> 00:15:50,783 TO EPILEPSY OVER TIME. 391 00:15:50,783 --> 00:15:54,287 BUT AGAIN ANOTHER POTENTIALLY 392 00:15:54,287 --> 00:15:55,588 GENETIC HANDLE THAT MADE ME 393 00:15:55,588 --> 00:15:57,657 THINK OF AS AN ACQUIRED FORM OF 394 00:15:57,657 --> 00:15:58,090 EPILEPSY. 395 00:15:58,090 --> 00:16:01,994 I GUESS ALSO OFFER POTENTIAL 396 00:16:01,994 --> 00:16:03,462 AVENUES FOR TREATMENT, THEY'RE 397 00:16:03,462 --> 00:16:05,331 PROBABLY GOING TO HAVE TO BE 398 00:16:05,331 --> 00:16:10,236 QUITE SPECIFIC, GIVEN THE -- 399 00:16:10,236 --> 00:16:12,104 THAT THESE PATHWAYS ARE USED FOR 400 00:16:12,104 --> 00:16:13,339 SO MANY DIFFERENT THINGS IN THE 401 00:16:13,339 --> 00:16:14,740 BRAIN AND THE REST OF THE BODY. 402 00:16:14,740 --> 00:16:18,578 SO NINDS HAS BEEN THINKING KIND 403 00:16:18,578 --> 00:16:22,815 OF FORWARD-WISE, HATS OFF TO 404 00:16:22,815 --> 00:16:27,186 NINA SCHOR AND ADAM HARTMAN IN 405 00:16:27,186 --> 00:16:28,521 TRYING TO THINK ABOUT GENE 406 00:16:28,521 --> 00:16:32,225 THERAPIES GOING FORWARD, SO 407 00:16:32,225 --> 00:16:34,093 WE'VE KIND OF BEEN LOOKING FOR 408 00:16:34,093 --> 00:16:35,494 ANY OPPORTUNITY TO EXPLORE THIS 409 00:16:35,494 --> 00:16:36,162 SPACE FOR NINDS. 410 00:16:36,162 --> 00:16:37,597 WE HAVE OUR OWN NETWORK, WHICH 411 00:16:37,597 --> 00:16:42,602 IS CALLED URGENT, WHICH IS FOR 412 00:16:42,602 --> 00:16:43,269 ULTRA-RARE GENE THERAPY. 413 00:16:43,269 --> 00:16:46,672 WE HAVE A NUMBER OF PROJECTS 414 00:16:46,672 --> 00:16:48,207 ONGOING, MOST OF THESE REALLY 415 00:16:48,207 --> 00:16:49,942 DEVASTATING DISEASES THAT AFFECT 416 00:16:49,942 --> 00:16:50,576 CHILDREN. 417 00:16:50,576 --> 00:16:52,144 THE INTRAMURAL PROGRAM HAS BEEN 418 00:16:52,144 --> 00:16:55,114 INVOLVED IN A GENE THERAPY 419 00:16:55,114 --> 00:16:58,918 PROJECT WITH THE NCATS. 420 00:16:58,918 --> 00:17:01,053 WE ARE ONE OF THE GROUPS THAT 421 00:17:01,053 --> 00:17:03,956 WORK IN A PUBLIC-PRIVATE 422 00:17:03,956 --> 00:17:05,324 PARTNERSHIP RUN BY THE 423 00:17:05,324 --> 00:17:12,698 FOUNDATION FOR NIH TO DEVELOP A 424 00:17:12,698 --> 00:17:13,866 PLATFORM WHERE YOU CAN PLUG IN 425 00:17:13,866 --> 00:17:15,535 THE GENE THAT YOU'RE INTERESTED 426 00:17:15,535 --> 00:17:17,203 IN FOR A BUNCH OF DIFFERENT RARE 427 00:17:17,203 --> 00:17:17,737 DISEASES. 428 00:17:17,737 --> 00:17:19,572 WE'VE GOT, AGAIN, A NUMBER OF 429 00:17:19,572 --> 00:17:21,774 PROJECTS ONGOING THERE. 430 00:17:21,774 --> 00:17:23,209 IN THE 431 00:17:23,209 --> 00:17:23,976 NEURO SPACE. 432 00:17:23,976 --> 00:17:27,914 THEN THE EC EXCITING THING IS 433 00:17:27,914 --> 00:17:29,782 THERE'S A COMMON FUND PROJECT 434 00:17:29,782 --> 00:17:31,384 CALLED SOMATIC CELL GENOME 435 00:17:31,384 --> 00:17:35,688 EDITING. 436 00:17:35,688 --> 00:17:37,423 SOME OF THESE REALLY 437 00:17:37,423 --> 00:17:38,391 FORWARD-LOOKING TREATMENTS 438 00:17:38,391 --> 00:17:40,026 PEOPLE ARE DOING THE WAY OF GENE 439 00:17:40,026 --> 00:17:43,863 EDITING, AND THIS IS REALLY 440 00:17:43,863 --> 00:17:45,665 COMING ALONG. 441 00:17:45,665 --> 00:17:46,933 I THINK IT'S TRICKY, THERE'S 442 00:17:46,933 --> 00:17:50,036 LOTS OF THINGS TO FIGURE OUT, 443 00:17:50,036 --> 00:17:52,305 BUT THE POTENCY OF THESE 444 00:17:52,305 --> 00:17:54,840 TECHNOLOGIES IS REALLY QUITE 445 00:17:54,840 --> 00:17:57,577 AMAZING, AND I THINK WE'RE 446 00:17:57,577 --> 00:17:59,378 SEEING SOME OF THEM COMING TO 447 00:17:59,378 --> 00:18:00,813 FRUITION NOW IN THE EYE, IN THE 448 00:18:00,813 --> 00:18:11,691 LIVER PROBABLY, PROJECTS IN THEO 449 00:18:12,491 --> 00:18:14,594 DELIVER SOMATIC GENE EDITING 450 00:18:14,594 --> 00:18:16,228 TOOL INTO THE BRAIN, $6 MILLION, 451 00:18:16,228 --> 00:18:22,068 IF ANYBODY IS INTERESTED. 452 00:18:22,068 --> 00:18:23,469 IT CAN'T BE A GENE, IT CAN'T BE 453 00:18:23,469 --> 00:18:26,806 A VIRUS, IT'S A NON-VIRAL -- 454 00:18:26,806 --> 00:18:28,741 LOTS OF THINGS TO TALK ABOUT IN 455 00:18:28,741 --> 00:18:33,079 TERMS OF THAT. 456 00:18:33,079 --> 00:18:34,513 AND URGENT, I MENTIONED THESE 457 00:18:34,513 --> 00:18:36,482 ARE THE PROJECTS WE HAVE ONGOING 458 00:18:36,482 --> 00:18:41,988 NOW, SO LI LYSOSOME STORAGE 459 00:18:41,988 --> 00:18:44,523 DISEASE, A NUMBER OF RARE 460 00:18:44,523 --> 00:18:49,528 GENETIC -- ALS, TRYING TO GET 11 461 00:18:49,528 --> 00:18:51,030 DIFFERENT -- FOR 11 DIFFERENT 462 00:18:51,030 --> 00:18:54,100 VARIANTS THAT CAUSE RARE ALS 463 00:18:54,100 --> 00:18:54,300 FORMS. 464 00:18:54,300 --> 00:18:56,402 SO IT'S A REALLY INTERESTING 465 00:18:56,402 --> 00:18:58,371 AREA THAT WE'RE, I THINK, 466 00:18:58,371 --> 00:19:02,742 TALKING ABOUT TODAY. 467 00:19:02,742 --> 00:19:04,343 REALLY EXCITED ABOUT THE FUTURE 468 00:19:04,343 --> 00:19:08,748 OF THESE GENETIC THERAPIES, AND 469 00:19:08,748 --> 00:19:12,818 CLEARLY IN THE EPILEPSY SPACE, 470 00:19:12,818 --> 00:19:15,521 GENETIC EPILEPSIES. 471 00:19:15,521 --> 00:19:17,590 SO I JUST WANTED TO MENTION 472 00:19:17,590 --> 00:19:22,962 WE'VE BEEN WORKING WITH THE 473 00:19:22,962 --> 00:19:24,630 COMMUNITY FOR MANY YEARS, WE 474 00:19:24,630 --> 00:19:26,565 FEEL REALLY GOOD THAT THERE'S A 475 00:19:26,565 --> 00:19:29,368 GREAT SPIRIT AND COMMUNITY 476 00:19:29,368 --> 00:19:31,303 EFFORT HERE SHARING, THINKING 477 00:19:31,303 --> 00:19:33,139 TOGETHER, WORKING ON THE 478 00:19:33,139 --> 00:19:34,106 BENCHMARKS TOGETHER AND REALLY 479 00:19:34,106 --> 00:19:36,175 APPRECIATE THE WORK THAT PEOPLE 480 00:19:36,175 --> 00:19:42,548 DO IN THE AUDIENCE HERE. 481 00:19:42,548 --> 00:19:44,016 SO WITH THAT I WANT TO THANK YOU 482 00:19:44,016 --> 00:19:45,151 ALL AGAIN FOR COMING AND HOPING 483 00:19:45,151 --> 00:19:47,019 THAT YOU CAN THINK REALLY HARD 484 00:19:47,019 --> 00:19:50,656 AND GIVE US -- GIVE YOURSELVES 485 00:19:50,656 --> 00:19:51,957 AND NINDS SOME GOOD IDEAS MOVING 486 00:19:51,957 --> 00:19:52,191 FORWARD. 487 00:19:52,191 --> 00:19:53,159 THANK YOU VERY MUCH. 488 00:19:53,159 --> 00:20:03,335 [APPLAUSE] 489 00:20:03,903 --> 00:20:14,313 >> THANK YOU, DR. KOROSHETZ. 490 00:20:15,548 --> 00:20:16,882 SO I JUST WANT TO SET THE STAGE 491 00:20:16,882 --> 00:20:27,326 QUICKLY FOR THE WORKSHOP. 492 00:20:46,812 --> 00:20:48,814 SO THE PURPOSE OF THIS WORKSHOP 493 00:20:48,814 --> 00:20:50,516 IS TO BRING INVESTIGATORS 494 00:20:50,516 --> 00:20:51,684 TOGETHER WHO HAVE DEVELOPED 495 00:20:51,684 --> 00:20:53,853 GENETIC STRATEGIES TO TREAT 496 00:20:53,853 --> 00:20:55,721 NEUROLOGICAL DISEASES, SO YOU 497 00:20:55,721 --> 00:20:57,223 WILL HEAR FROM SEVERAL SPEAKERS 498 00:20:57,223 --> 00:21:00,493 TODAY, MANY SPEAKERS TODAY AND 499 00:21:00,493 --> 00:21:01,827 TOMORROW WHO ARE NOT WORKING ON 500 00:21:01,827 --> 00:21:03,162 THE EPILEPSIES, BUT ARE WORKING 501 00:21:03,162 --> 00:21:05,231 ON OTHER NEUROLOGICAL DISORDERS, 502 00:21:05,231 --> 00:21:07,299 AND THIS IS ON PURPOSE, SO THAT 503 00:21:07,299 --> 00:21:12,338 WE CAN LEARN FROM THEM WHAT HAS 504 00:21:12,338 --> 00:21:14,240 WORKED, WHAT HAS NOT WORKED, 505 00:21:14,240 --> 00:21:15,074 WHAT THEIR EXPERIENCE HAS BEEN 506 00:21:15,074 --> 00:21:16,175 TO DEVELOP THESE GENETIC 507 00:21:16,175 --> 00:21:17,476 STRATEGIES. 508 00:21:17,476 --> 00:21:19,678 THE GOALS ARE REALLY TO EXPLORE 509 00:21:19,678 --> 00:21:21,747 STATE OF THE ART STRATEGIES FOR 510 00:21:21,747 --> 00:21:25,551 TREATING GENETIC DISEASES AND 511 00:21:25,551 --> 00:21:27,119 SPECIFICALLY FOR FUTURE 512 00:21:27,119 --> 00:21:28,287 DISCUSSIONS ON THE GENETIC 513 00:21:28,287 --> 00:21:29,388 EPILEPSIES. 514 00:21:29,388 --> 00:21:30,623 DISCUSS THE PROGRESS, PITFALLS 515 00:21:30,623 --> 00:21:32,124 AND LESSONS LEARNED FROM 516 00:21:32,124 --> 00:21:33,659 NEUROLOGICAL TRIALS AND 517 00:21:33,659 --> 00:21:34,226 TREATMENTS, IDENTIFY 518 00:21:34,226 --> 00:21:35,761 CONSIDERATIONS FOR DESIGNING AND 519 00:21:35,761 --> 00:21:37,062 IMPLEMENTING THERAPIES TO TREAT 520 00:21:37,062 --> 00:21:39,565 THE EPILEPSIES, AND DISCUSS THE 521 00:21:39,565 --> 00:21:42,201 CRUCIAL ISSUES BEYOND JUST 522 00:21:42,201 --> 00:21:43,602 DEVELOPING THE TREATMENT, AND 523 00:21:43,602 --> 00:21:45,404 THAT WILL BE DISCUSSION FOUR, 524 00:21:45,404 --> 00:21:47,106 WHERE WE'LL REALLY EXPLORE 525 00:21:47,106 --> 00:21:48,808 ETHICAL ISSUES, PERSPECTIVES 526 00:21:48,808 --> 00:21:50,876 FROM PARENTS AND INDIVIDUALS 527 00:21:50,876 --> 00:21:54,146 WHOSE CHILDREN HAVE PARTICIPATED 528 00:21:54,146 --> 00:21:55,414 IN GENETIC THERAPY CLINICAL 529 00:21:55,414 --> 00:21:59,518 TRIALS. 530 00:21:59,518 --> 00:22:01,086 SO I'D LIKE TO TAKE THIS 531 00:22:01,086 --> 00:22:04,089 OPPORTUNITY TO THANK THE 532 00:22:04,089 --> 00:22:05,825 ORGANIZING COMMITTEE. 533 00:22:05,825 --> 00:22:07,259 THE ORGANIZING COMMITTEE WAS 534 00:22:07,259 --> 00:22:08,994 COMPOSED OF MANY INDIVIDUALS 535 00:22:08,994 --> 00:22:10,629 FROM NINDS BUT A SPECIAL THANK 536 00:22:10,629 --> 00:22:15,334 YOU TO LAURIE, HEATHER, ANNE AND 537 00:22:15,334 --> 00:22:16,535 DAN, OUR EXTRAMURAL 538 00:22:16,535 --> 00:22:18,737 INVESTIGATORS WHO WERE PART OF 539 00:22:18,737 --> 00:22:20,506 THE ORGANIZING COMMITTEE AND WHO 540 00:22:20,506 --> 00:22:22,308 YOU WILL HEAR FROM AS MODERATORS 541 00:22:22,308 --> 00:22:23,108 OF THE SESSIONS TODAY AND 542 00:22:23,108 --> 00:22:24,710 TOMORROW. 543 00:22:24,710 --> 00:22:29,248 A SPECIAL THANKS TO ANDREW CHEN, 544 00:22:29,248 --> 00:22:31,050 WHO'S ON OUR NINDS STAFF, FOR 545 00:22:31,050 --> 00:22:32,718 HIS HELP THROUGHOUT THIS WHOLE 546 00:22:32,718 --> 00:22:34,053 PROCESS AS WELL AND A SPECIAL 547 00:22:34,053 --> 00:22:37,189 SHOUT OUT TO ROSE LI AND 548 00:22:37,189 --> 00:22:38,624 ASSOCIATES, THE RLA STAFF. 549 00:22:38,624 --> 00:22:40,159 THIS WORKSHOP WOULD NOT BE 550 00:22:40,159 --> 00:22:41,794 POSSIBLE WITHOUT ALL OF YOUR 551 00:22:41,794 --> 00:22:43,429 HELP TO WORK WITH US ON THE 552 00:22:43,429 --> 00:22:45,064 TRAVEL, THE LOGISTICS, 553 00:22:45,064 --> 00:22:46,098 EVERYTHING AROUND MAKING THIS 554 00:22:46,098 --> 00:22:52,438 WORKSHOP POSSIBLE. 555 00:22:52,438 --> 00:22:54,073 SO WITH THAT, I WOULD LIKE TO 556 00:22:54,073 --> 00:22:58,544 INTRODUCE OUR FIRST SPEAKER, OR 557 00:22:58,544 --> 00:22:59,845 SPEAKER THIS MORNING, SIMON 558 00:22:59,845 --> 00:23:00,279 FROST. 559 00:23:00,279 --> 00:23:02,715 SIMON IS PART OF THE TIBER 560 00:23:02,715 --> 00:23:04,116 CAPITAL GROUP HERE IN THE D.C. 561 00:23:04,116 --> 00:23:05,584 AREA, BUT HE'S NOT GOING TO BE 562 00:23:05,584 --> 00:23:06,619 TALKING ABOUT FINANCES TODAY, I 563 00:23:06,619 --> 00:23:08,487 DON'T THINK, OR MAYBE 564 00:23:08,487 --> 00:23:10,356 INDIRECTLY, BUT IT'S MY PLEASURE 565 00:23:10,356 --> 00:23:12,358 TO INTRODUCE SIMON TO TALK ABOUT 566 00:23:12,358 --> 00:23:13,859 ACTION POTENTIAL, AN EFFORT TO 567 00:23:13,859 --> 00:23:16,462 DEVELOP GENETIC STRATEGIES FOR A 568 00:23:16,462 --> 00:23:17,563 RARE NEUROLOGICAL DISEASE. 569 00:23:17,563 --> 00:23:27,840 WELCOME, SIMON. 570 00:23:28,140 --> 00:23:29,708 >> I THINK I MIGHT BE A LITTLE 571 00:23:29,708 --> 00:23:31,010 TALL FOR THE MICROPHONE. 572 00:23:31,010 --> 00:23:32,011 APOLOGIES. 573 00:23:32,011 --> 00:23:36,382 BUT I'M SIMON FROST. 574 00:23:36,382 --> 00:23:38,450 I KNOW YOU'VE HEARD ABOUT THE 575 00:23:38,450 --> 00:23:39,818 DIAGNOSTIC ODYSSEY IN RARE 576 00:23:39,818 --> 00:23:41,654 DISEASES MANY TIMES BEFORE, 577 00:23:41,654 --> 00:23:43,188 SO -- AND MY FAMILY'S STORY 578 00:23:43,188 --> 00:23:44,690 REALLY ISN'T THAT MUCH DIFFERENT 579 00:23:44,690 --> 00:23:45,791 FROM MANY OTHERS BUT I'M GOING 580 00:23:45,791 --> 00:23:47,860 TO TRY TO TELL THE STORY JUST A 581 00:23:47,860 --> 00:23:49,061 LITTLE BIT DIFFERENTLY TODAY. 582 00:23:49,061 --> 00:23:51,096 IN MY DAY JOB, I'M AN ECONOMIST. 583 00:23:51,096 --> 00:23:52,798 AND I LIKE TO TALK ABOUT 584 00:23:52,798 --> 00:23:53,032 NUMBERS. 585 00:23:53,032 --> 00:23:55,868 SO I'M GOING TO TALK ABOUT SOME 586 00:23:55,868 --> 00:23:57,469 ASTRONOMICAL NUMBERS. 587 00:23:57,469 --> 00:24:00,005 AND SOME QUANTUM PHYSICS. 588 00:24:00,005 --> 00:24:04,610 SURPRISE. 589 00:24:04,610 --> 00:24:06,478 SO ALL OF YOU KNOW THIS 590 00:24:06,478 --> 00:24:06,779 EQUATION. 591 00:24:06,779 --> 00:24:08,213 IT TELLS US AMONGST OTHER THINGS 592 00:24:08,213 --> 00:24:09,882 THAT THE POTENTIAL ENERGY IN THE 593 00:24:09,882 --> 00:24:12,151 UNIVERSE EQUALS THE MASS OF ALL 594 00:24:12,151 --> 00:24:13,452 OF THE COMPONENTS OF THE 595 00:24:13,452 --> 00:24:16,622 UNIVERSE MULTIPLIED BY AN 596 00:24:16,622 --> 00:24:18,157 ENORMOUS CONSTANT SQUARED. 597 00:24:18,157 --> 00:24:20,326 NOW, I DO WANT TO POINT OUT 598 00:24:20,326 --> 00:24:22,361 QUICKLY THAT EINSTEIN HAD NO 599 00:24:22,361 --> 00:24:24,396 BUSINESS SQUARING THAT CONSTANT. 600 00:24:24,396 --> 00:24:25,931 THAT'S KIND OF THE POINT OF THE 601 00:24:25,931 --> 00:24:26,365 CONSTANT. 602 00:24:26,365 --> 00:24:27,733 BUT I THINK HE WAS TRYING TO 603 00:24:27,733 --> 00:24:28,334 SCREW WITH OUR HEADS. 604 00:24:28,334 --> 00:24:30,202 I THINK HE WAS TRYING TO POINT 605 00:24:30,202 --> 00:24:32,705 OUT JUST HOW MIND-BLOWINGLY 606 00:24:32,705 --> 00:24:36,108 MASSIVE THESE NUMBERS ARE. 607 00:24:36,108 --> 00:24:39,912 NOW, AS YOU KNOW, E, THE 608 00:24:39,912 --> 00:24:40,646 CONSTANT, REPRESENTS THE SPEED 609 00:24:40,646 --> 00:24:43,982 OF LIGHT, AND THE SPEED OF LIGHT 610 00:24:43,982 --> 00:24:45,284 IS 670 MILLION MILES AN HOUR. 611 00:24:45,284 --> 00:24:48,687 WHEN YOU SQUARE THAT, YOU GET 612 00:24:48,687 --> 00:24:51,056 ALMOST 450 QUADRILLION MILES AN 613 00:24:51,056 --> 00:24:53,492 HOUR, WHICH IS OBVIOUSLY AN 614 00:24:53,492 --> 00:24:58,897 ASTRONOMICAL NUMBER. 615 00:24:58,897 --> 00:25:01,633 NOW IT DOESN'T STOP THERE. 616 00:25:01,633 --> 00:25:05,904 WE HAVE ONE SEPTRILLION STARS, 617 00:25:05,904 --> 00:25:08,307 THAT'S A TRILLION, TRILLION 618 00:25:08,307 --> 00:25:09,541 SOLAR SYSTEMS. 619 00:25:09,541 --> 00:25:11,477 THAT'S MORE SOLAR SYSTEMS THAN 620 00:25:11,477 --> 00:25:14,113 GRAINS OF SAND ON EARTH. 621 00:25:14,113 --> 00:25:15,647 IT'S 10 TRILLION SOLAR SYSTEMS 622 00:25:15,647 --> 00:25:17,850 FOR EVERY PERSON THAT HAS EVER 623 00:25:17,850 --> 00:25:19,485 LIVED. 624 00:25:19,485 --> 00:25:20,886 AND IF YOU TAKE ALL OF THOSE 625 00:25:20,886 --> 00:25:23,088 SOLAR SYSTEMS, THE MASS THAT 626 00:25:23,088 --> 00:25:24,623 MAKES UP ALL OF THOSE SOLAR 627 00:25:24,623 --> 00:25:26,291 SYSTEMS AND YOU MULTIPLY IT BY 628 00:25:26,291 --> 00:25:30,629 THAT ENORMOUS CONSTANT, SQUARED, 629 00:25:30,629 --> 00:25:32,931 YOU GET RATHER AN ASTRONOMICAL 630 00:25:32,931 --> 00:25:35,134 NUMBER THAT IS THE POTENTIAL 631 00:25:35,134 --> 00:25:40,973 ENERGY IN THE UNIVERSE. 632 00:25:40,973 --> 00:25:43,242 WE LIVE IN AN INCONCEIVABLY 633 00:25:43,242 --> 00:25:45,310 LARGE COSMOS AND WE'RE INFAN 634 00:25:45,310 --> 00:25:46,712 TESS MEDICALLY SMALL. 635 00:25:46,712 --> 00:25:49,848 WE HAVE ABOUT AS MUCH 636 00:25:49,848 --> 00:25:51,216 SIGNIFICANCE AS A SINGLE ATOM 637 00:25:51,216 --> 00:25:52,951 HAS IN THE ENTIRE HUMAN BODY. 638 00:25:52,951 --> 00:25:54,820 HOW DO WE POSSIBLY CONCEIVE OF 639 00:25:54,820 --> 00:25:55,554 SUCH NUMBERS? 640 00:25:55,554 --> 00:25:58,223 HOW DO WE FIND THE SIGNIFICANCE 641 00:25:58,223 --> 00:26:00,292 IN A UNIVERSE LIKE THAT? 642 00:26:00,292 --> 00:26:02,294 NOW I HAVE AN ANSWER, AND I'M 643 00:26:02,294 --> 00:26:03,796 GOING TO SHARE IT. 644 00:26:03,796 --> 00:26:05,431 AND I PROMISE IT'S NOT GOING TO 645 00:26:05,431 --> 00:26:06,832 INVOLVE ANY MORE QUANTUM 646 00:26:06,832 --> 00:26:07,499 PHYSICS. 647 00:26:07,499 --> 00:26:09,234 BUT IT IS GOING TO INVOLVE A 648 00:26:09,234 --> 00:26:11,236 LITTLE BIT OF HISTORY. 649 00:26:11,236 --> 00:26:12,871 SO IN CASE YOU DIDN'T KNOW, THE 650 00:26:12,871 --> 00:26:14,173 EARTH IS OLD. 651 00:26:14,173 --> 00:26:17,910 IN FACT, IT'S FOUR AND A HALF 652 00:26:17,910 --> 00:26:18,644 BILLION YEARS OLD. 653 00:26:18,644 --> 00:26:20,612 AND EVER SINCE THE BEGINNING OF 654 00:26:20,612 --> 00:26:22,681 TIME, NUCLEIC ACIDS AND AMINO 655 00:26:22,681 --> 00:26:24,116 ACIDS AND PEPTIDES HAVE BEEN 656 00:26:24,116 --> 00:26:29,488 LINING UP TO FORM HUMAN BEINGS, 657 00:26:29,488 --> 00:26:36,128 AND OVER THAT TIME, THEY HAVE 658 00:26:36,128 --> 00:26:40,365 LINED OF 3.2 BILLION NUCLEAR 659 00:26:40,365 --> 00:26:41,900 TILES TO FORM THE HUMAN GENOME 660 00:26:41,900 --> 00:26:44,403 AND MAYBE MORE IMPORTANTLY, 661 00:26:44,403 --> 00:26:47,439 30 MILLION NUCLEOTIDES TO FORM 662 00:26:47,439 --> 00:26:50,676 THE EXOME IN THE RIGHT ORDER AND 663 00:26:50,676 --> 00:26:51,743 24,000 PROTEIN CODING GENES. 664 00:26:51,743 --> 00:26:53,212 IF YOU'RE INTENSELY SHARP WITH 665 00:26:53,212 --> 00:26:54,379 IT, YOU WOULD HAVE NOTICED THAT 666 00:26:54,379 --> 00:26:55,614 THOSE NUMBERS ARE STARTING TO 667 00:26:55,614 --> 00:26:56,682 GET PROGRESSIVELY SMALLER. 668 00:26:56,682 --> 00:26:58,016 I THINK EINSTEIN MIGHT HAVE 669 00:26:58,016 --> 00:27:00,052 NOTICED THAT TOO. 670 00:27:00,052 --> 00:27:04,323 AND SINCE EINSTEIN WAS AROUND 671 00:27:04,323 --> 00:27:07,259 SINCE 1956 WE'VE SEEN A TRILLION 672 00:27:07,259 --> 00:27:08,260 FOLD INCREASE IN COMPUTING 673 00:27:08,260 --> 00:27:08,927 POWER. 674 00:27:08,927 --> 00:27:10,996 EINSTEIN CAME UP WITH THESE 675 00:27:10,996 --> 00:27:13,065 REALLY ELEGANT ASTRONOMICAL 676 00:27:13,065 --> 00:27:15,133 EQUATIONS USING A TRILLIONTH OF 677 00:27:15,133 --> 00:27:19,071 THE POWER THAT WE HAVE TODAY. 678 00:27:19,071 --> 00:27:26,211 THE COMPUTING POWER. 679 00:27:26,211 --> 00:27:28,380 NOW, WE LIVE IN THE AGE OF A.I. 680 00:27:28,380 --> 00:27:31,083 AND SUPERCOMPUTERS. 681 00:27:31,083 --> 00:27:35,487 IF YOU HAVE AS MUCH NEANDERTHAL 682 00:27:35,487 --> 00:27:42,160 DNA AS I DO, YOU STILL USE AN 683 00:27:42,160 --> 00:27:42,728 EXCEL SPREADSHEET. 684 00:27:42,728 --> 00:27:45,030 WHEN I LOOK AT MY FAVORITE EXCEL 685 00:27:45,030 --> 00:27:47,032 SPREADSHEET, I SEE THAT IT HAS 686 00:27:47,032 --> 00:27:49,134 MORE THAN A MILLION ROWS, MORE 687 00:27:49,134 --> 00:27:51,670 THAN 16,000 COLUMNS, IN OTHER 688 00:27:51,670 --> 00:27:54,973 WORDS, MORE THAN 60 BILLION 689 00:27:54,973 --> 00:27:55,207 CELLS. 690 00:27:55,207 --> 00:27:57,142 WHICH IF I PUT A SINGLE 691 00:27:57,142 --> 00:27:58,043 NUCLEOTIDE IN EACH OF THOSE 692 00:27:58,043 --> 00:28:00,212 CELLS I CAN FIT FIVE HUMAN 693 00:28:00,212 --> 00:28:03,916 GENOMES INTO A SINGLE -- OF AN 694 00:28:03,916 --> 00:28:05,017 EXCEL SPREADSHEET. 695 00:28:05,017 --> 00:28:07,886 2 1/2 GENOMES IF YOU HAPPEN TO 696 00:28:07,886 --> 00:28:11,390 BE DEPLOYED, EVEN -- JUST MADE 697 00:28:11,390 --> 00:28:13,225 UP KNOWS HOW TO FIDDLE AROUND 698 00:28:13,225 --> 00:28:19,565 WITH EXCEL SPREADSHEETS. 699 00:28:19,565 --> 00:28:20,232 FINALLY, SOME BIOLOGY. 700 00:28:20,232 --> 00:28:22,401 I WANT TO CONTRAST THE NUMBERS 701 00:28:22,401 --> 00:28:24,970 THAT WE SEE IN RARE DISEASES 702 00:28:24,970 --> 00:28:26,471 WITH THE ASTRONOMICAL NUMBERS 703 00:28:26,471 --> 00:28:30,175 THAT I JUST TALKED ABOUT. 704 00:28:30,175 --> 00:28:31,610 WE ONLY HAVE ABOUT 10,000 RARE 705 00:28:31,610 --> 00:28:32,077 DISEASES. 706 00:28:32,077 --> 00:28:33,912 THAT MEANS THAT IF YOU SPEND THE 707 00:28:33,912 --> 00:28:36,315 NEXT FOUR OR FIVE HOURS LISTING 708 00:28:36,315 --> 00:28:39,351 ALL OF THEM, YOU'LL GET RIGHT TO 709 00:28:39,351 --> 00:28:40,252 THE END OF THE LIST. 710 00:28:40,252 --> 00:28:46,792 AS LONG AS THEY'RE NOT ALL CAL 711 00:28:46,792 --> 00:28:48,126 CALLED HEMOPHILIA OF CHILDHOOD. 712 00:28:48,126 --> 00:28:51,196 THE GOOD NEWS IS THAT WE HAVE 713 00:28:51,196 --> 00:28:52,631 TSH 80% OF ALL OF THOSE RARE 714 00:28:52,631 --> 00:28:54,199 DISEASES ARE GENETIC AND MOST OF 715 00:28:54,199 --> 00:28:57,836 THOSE ARE MONO GENETIC. 716 00:28:57,836 --> 00:28:59,071 THAT'S A BEAUTIFUL THING BECAUSE 717 00:28:59,071 --> 00:29:01,673 IT GIVES US TARGETS. 718 00:29:01,673 --> 00:29:03,275 NOT JUST THE ROSETTA STONE OF 719 00:29:03,275 --> 00:29:04,643 RARE DISEASES BUT THE ROSETTA 720 00:29:04,643 --> 00:29:05,711 STONE OF HUMAN BIOLOGY. 721 00:29:05,711 --> 00:29:07,679 IT GIVES US A WAY AS A SOCIETY 722 00:29:07,679 --> 00:29:09,982 TO USE GENOTYPE DATA AS A 723 00:29:09,982 --> 00:29:11,817 FOUNDATIONAL DATASET, AND TO 724 00:29:11,817 --> 00:29:13,919 BUILD ON TOP OF THAT A DEEP 725 00:29:13,919 --> 00:29:15,120 PHENOTYPIC UNDERSTANDING OF 726 00:29:15,120 --> 00:29:19,725 HUMAN BIOLOGY. 727 00:29:19,725 --> 00:29:21,293 IT GIVES US A WAY TO BREAK 728 00:29:21,293 --> 00:29:23,462 GENETIC DISEASES DOWN TO THEIR 729 00:29:23,462 --> 00:29:24,229 UNDERLYING COMPONENTS, DOWN TO 730 00:29:24,229 --> 00:29:27,199 THEIR MOLECULAR BASIS, AND TO 731 00:29:27,199 --> 00:29:27,899 IDENTIFIED THE STRUCTURE 732 00:29:27,899 --> 00:29:28,700 FUNCTION PROBLEMS WITH HE FACE 733 00:29:28,700 --> 00:29:33,271 WITH OUR 24,000 OR SO PROTEIN 734 00:29:33,271 --> 00:29:33,939 ENCODING GENES. 735 00:29:33,939 --> 00:29:35,607 MOST IMPORTANTLY, IT GIVES US A 736 00:29:35,607 --> 00:29:37,242 WAY TO IDENTIFY THERAPEUTIC 737 00:29:37,242 --> 00:29:39,978 TARGETS. 738 00:29:39,978 --> 00:29:42,047 BUT WE PREFER TO DIAGNOSE OUR 739 00:29:42,047 --> 00:29:45,217 PATIENTS CLINICALLY. 740 00:29:45,217 --> 00:29:47,653 AND WE'RE REALLY BAD AT 741 00:29:47,653 --> 00:29:48,286 DIAGNOSING OUR PATIENTS 742 00:29:48,286 --> 00:29:49,154 CLINICALLY. 743 00:29:49,154 --> 00:29:52,424 IN FACT, IT TAKES US 6.3 YEARS 744 00:29:52,424 --> 00:29:55,193 ON AVERAGE TO DIAGNOSE A RARE 745 00:29:55,193 --> 00:29:56,395 DISEASE PATIENT IN THE UNITED 746 00:29:56,395 --> 00:29:58,130 STATES. 747 00:29:58,130 --> 00:29:59,564 CLINICAL DIAGNOSES ARE SIMPLY 748 00:29:59,564 --> 00:30:04,569 NOT WORKING FOR RARE DISEASES. 749 00:30:04,569 --> 00:30:06,471 YET EVEN THOUGH WE'RE 750 00:30:06,471 --> 00:30:07,205 STATISTICICALLY AWFUL AT 751 00:30:07,205 --> 00:30:09,274 DIAGNOSING RARE DISEASES IN THE 752 00:30:09,274 --> 00:30:11,376 U.S., THERE ARE STILL 1 IN 10 OF 753 00:30:11,376 --> 00:30:12,678 US THAT HAVE BEEN DIAGNOSED WITH 754 00:30:12,678 --> 00:30:13,745 A RARE DISEASE. 755 00:30:13,745 --> 00:30:16,815 AND I DON'T NEED EINSTEIN'S HELP 756 00:30:16,815 --> 00:30:20,318 TO CALCULATE WITH A RATIO OF 757 00:30:20,318 --> 00:30:26,124 1 IN 10 ACROSS 8 BILLION PEOPLE 758 00:30:26,124 --> 00:30:28,093 WORLDWIDE, THAT WE HAVE ABOUT 759 00:30:28,093 --> 00:30:28,860 800 MILLION PEOPLE THAT HAVE 760 00:30:28,860 --> 00:30:29,961 RARE DISEASES ON EARTH. 761 00:30:29,961 --> 00:30:32,564 YET THE REST OF THE WORLD IS 762 00:30:32,564 --> 00:30:34,099 EVEN WORSE THAN WE ARE AT 763 00:30:34,099 --> 00:30:35,934 DIAGNOSING RARE DISEASE PATIENTS 764 00:30:35,934 --> 00:30:41,540 AND THE OFFICIAL NUMBER OF 765 00:30:41,540 --> 00:30:43,075 350 MILLION PEOPLE WORLDWIDE, 766 00:30:43,075 --> 00:30:46,878 REFLECTING A PAINFUL GAP OF 767 00:30:46,878 --> 00:30:47,713 450 MILLION PEOPLE AROUND THE 768 00:30:47,713 --> 00:30:50,182 WORLD THAT ARE BEING LEFT 769 00:30:50,182 --> 00:30:50,949 UNDIAGNOSED OR BEING LEFT TO 770 00:30:50,949 --> 00:30:51,283 DIE. 771 00:30:51,283 --> 00:30:52,584 BUT THAT'S NOT ONE OF THE 772 00:30:52,584 --> 00:30:53,719 BIGGEST HUMAN CRIES SEES THAT WE 773 00:30:53,719 --> 00:30:59,825 HAVCRISES AT THEMOMENT, I'M NOT. 774 00:30:59,825 --> 00:31:03,395 NOW THAT GETS ME TO MY FAMILY'S 775 00:31:03,395 --> 00:31:04,463 STORY AND WHAT WE'RE TRYING TO 776 00:31:04,463 --> 00:31:08,333 DO TO TACKLE RARE DISEASES. 777 00:31:08,333 --> 00:31:11,036 THIS IS MY ANNABEL. 778 00:31:11,036 --> 00:31:14,706 WHEN ANNABEL WAS 2 MONTHS OLD 779 00:31:14,706 --> 00:31:16,942 SHE HAD WHAT LOOKED LIKE 780 00:31:16,942 --> 00:31:17,809 EPILEPTIC SEIZURES. 781 00:31:17,809 --> 00:31:20,879 DESPITE NO EEG FINDINGS, SHE WAS 782 00:31:20,879 --> 00:31:21,913 MISDIAGNOSED WITH EPILEPSY. 783 00:31:21,913 --> 00:31:28,854 SHE WAS PUT ON ANTICONVULSANTS, 784 00:31:28,854 --> 00:31:32,691 AND HER EPISODES DIDN'T CHANGE. 785 00:31:32,691 --> 00:31:34,259 EVERY THREE DAYS OR SO, SHE 786 00:31:34,259 --> 00:31:36,194 WOULD HAVE SPELLS OF SEVERELY 787 00:31:36,194 --> 00:31:37,729 REDUCED CONSCIOUSNESS. 788 00:31:37,729 --> 00:31:40,465 SHE WOULD HAVE BOUTS OF 789 00:31:40,465 --> 00:31:41,900 PARALYSIS THAT WOULD LAST FOR UP 790 00:31:41,900 --> 00:31:42,434 TO 10 DAYS. 791 00:31:42,434 --> 00:31:45,837 SHE WOULD HAVE PAINFUL DYSTONIA. 792 00:31:45,837 --> 00:31:49,107 ONE NIGHT, I MUST HAVE HEARD 793 00:31:49,107 --> 00:31:50,308 SOMETHING ON MY BABY MONITOR 794 00:31:50,308 --> 00:31:53,145 NEXT TO MY BED AND I RUSHED TO 795 00:31:53,145 --> 00:31:54,579 ANNABEL'S ROOM, SHE HAD VOMITED, 796 00:31:54,579 --> 00:31:55,981 SHE WAS CHOKING, AND SHE WASN'T 797 00:31:55,981 --> 00:31:59,251 BREATHING. 798 00:31:59,251 --> 00:32:00,552 I TRIED TO SCOOP OUT HER MOUTH 799 00:32:00,552 --> 00:32:01,887 WITH MY FINGERS. 800 00:32:01,887 --> 00:32:04,289 I TRIED TO GIVE HER BACK BLOWS, 801 00:32:04,289 --> 00:32:06,158 I EVEN TRIED THE HEIMLICH 802 00:32:06,158 --> 00:32:07,592 MANEUVER ON THIS TINY 803 00:32:07,592 --> 00:32:08,059 2-YEAR-OLD. 804 00:32:08,059 --> 00:32:09,995 IT MUST HAVE BEEN ABOUT A MINUTE 805 00:32:09,995 --> 00:32:11,763 BUT IT FELT LIKE AN ETERNITY 806 00:32:11,763 --> 00:32:13,932 BEFORE I MANAGED TO CLEAR HER 807 00:32:13,932 --> 00:32:17,202 AIRWAY AND GET HER TO BREATHE. 808 00:32:17,202 --> 00:32:19,504 THIS DIDN'T SEEM LIKE EPILEPSY. 809 00:32:19,504 --> 00:32:23,408 MY WIFE AND I TRAVELED THE 810 00:32:23,408 --> 00:32:24,743 COUNTRY, TALKING WITH EVERY 811 00:32:24,743 --> 00:32:25,644 NEUROLOGIST THAT WE COULD FIND, 812 00:32:25,644 --> 00:32:28,246 AND WE FOUND ONE OF THE BEST AT 813 00:32:28,246 --> 00:32:32,284 THE BOSTON CHILDREN'S HOSPITAL, 814 00:32:32,284 --> 00:32:33,151 DR. PHIL PEARL. 815 00:32:33,151 --> 00:32:35,921 BY SHEER LUCK, DR. PEARL HAD 816 00:32:35,921 --> 00:32:38,890 JUST AGAIN TO A CONFERENCE ON 817 00:32:38,890 --> 00:32:39,191 AHC. 818 00:32:39,191 --> 00:32:42,360 WHAT HE SAW IN ANNABEL WAS 819 00:32:42,360 --> 00:32:45,096 EERILY SIMILAR. 820 00:32:45,096 --> 00:32:47,065 THE ORDERED THE GENETIC TESTS 821 00:32:47,065 --> 00:32:48,133 AND LO AND BEHOLD, SHE CAME BACK 822 00:32:48,133 --> 00:32:53,972 WITH A DE NOVO MUTATION WITH THE 823 00:32:53,972 --> 00:32:57,042 GENE MOST ASSOCIATED WITH A HC. 824 00:32:57,042 --> 00:32:58,677 A DISEASE THAT ONLY HAS A 825 00:32:58,677 --> 00:33:02,180 THOUSAND PATIENTS WORLDWIDE. 826 00:33:02,180 --> 00:33:03,582 IF ANNABEL WERE A STATISTIC, 827 00:33:03,582 --> 00:33:11,590 SHE'D BE 1 IN A MILLION. 828 00:33:11,590 --> 00:33:13,191 SO WE SPENT TWO YEARS OF 829 00:33:13,191 --> 00:33:14,392 ANNABEL'S SHORT LIFE FUMBLING 830 00:33:14,392 --> 00:33:19,130 AROUND WITH GENETIC DIAGNOSES. 831 00:33:19,130 --> 00:33:20,432 NOW TWO YEARS IN NORMAL LIFE IS 832 00:33:20,432 --> 00:33:25,203 DWIGHT A LONGQUITE A LONG TIME U 833 00:33:25,203 --> 00:33:26,872 HAVE A CHILD SICK AS ANNABEL 834 00:33:26,872 --> 00:33:30,375 WAS, TWO YEARS FEELS LIKE AN 835 00:33:30,375 --> 00:33:31,443 ETERNITY, AND THIRDLY, IT COULD 836 00:33:31,443 --> 00:33:32,344 HAVE BEEN AVOIDED. 837 00:33:32,344 --> 00:33:37,048 WE COULD HAVE AVOIDED THE 838 00:33:37,048 --> 00:33:37,916 EXPENSIVE HOSPITAL VISITS, WE 839 00:33:37,916 --> 00:33:41,219 COULD HAVE AVOIDED GIVING HER 840 00:33:41,219 --> 00:33:42,854 THE ANTIEPILEPTICS THAT PROBABLY 841 00:33:42,854 --> 00:33:44,356 HURT HER MORE THAN HELPED HER, 842 00:33:44,356 --> 00:33:48,526 WE COULD HAVE DONE WHOLE GENOME 843 00:33:48,526 --> 00:33:51,263 SEQUENCING WHEN SHE WAS BORN OR 844 00:33:51,263 --> 00:33:54,266 AFTER HER FIRST MAJOR EPISODE 845 00:33:54,266 --> 00:33:56,301 AND WE COULD HAVE DIAGNOSED HER 846 00:33:56,301 --> 00:33:57,502 IN 6.1 DAYS LIKE THESE CHILDREN 847 00:33:57,502 --> 00:34:00,005 WERE, OR LIKE THESE CHILDREN 848 00:34:00,005 --> 00:34:00,772 WERE. 849 00:34:00,772 --> 00:34:02,107 SADLY, ANNABEL WAS ONE OF THE 850 00:34:02,107 --> 00:34:04,709 LUCKY ONES, IT TOOK US JUST 851 00:34:04,709 --> 00:34:05,810 2 YEARS, WHEREAS I SAID BEFORE, 852 00:34:05,810 --> 00:34:08,446 IT TAKES ALMOST 6.3 YEARS ON 853 00:34:08,446 --> 00:34:10,081 AVERAGE TO DIAGNOSE A RARE 854 00:34:10,081 --> 00:34:12,484 DISEASE PATIENT IN THE U.S. 855 00:34:12,484 --> 00:34:15,020 BUT THAT GENETIC DIAGNOSIS GAVE 856 00:34:15,020 --> 00:34:17,956 US REAL HOPE, AND IT GAVE US A 857 00:34:17,956 --> 00:34:23,094 DIRECTION TO POINT OUR RESEARCH 858 00:34:23,094 --> 00:34:25,597 EFFORTS TO IT, AND THAT'S ALL WE 859 00:34:25,597 --> 00:34:26,164 NEEDED. 860 00:34:26,164 --> 00:34:27,465 SO ON THE PLANE ON THE WAY HOME 861 00:34:27,465 --> 00:34:29,601 FROM BOSTON CHILDREN'S HOSPITAL, 862 00:34:29,601 --> 00:34:32,938 MY WIFE AND I STARTED TO READ 863 00:34:32,938 --> 00:34:34,239 RESEARCH PAPERS ABOUT AHC. 864 00:34:34,239 --> 00:34:36,808 WHEN WE GOT HOME, WE HIRED A 865 00:34:36,808 --> 00:34:40,045 SCIENTIST WHO IS AN INCREDIBLE 866 00:34:40,045 --> 00:34:41,947 PERSON WHO WORKED HERE AT THE 867 00:34:41,947 --> 00:34:45,417 NIH, STUDYING RARE NEUROLOGICAL 868 00:34:45,417 --> 00:34:47,052 DISEASES IN C. ELEGANS. 869 00:34:47,052 --> 00:34:48,553 BETWEEN THE THREE OF US, WE READ 870 00:34:48,553 --> 00:34:54,025 MANY HUNDREDS OF PAPERS. 871 00:34:54,025 --> 00:34:55,994 SO ONCE WE -- WHAT WE FOUND OUT 872 00:34:55,994 --> 00:35:00,865 VERY EARLY ON WAS THAT 873 00:35:00,865 --> 00:35:02,267 ATH1A3 CODES FOR THE ALPHA 874 00:35:02,267 --> 00:35:03,601 SUBUNIT OF THE SODIUM POTASSIUM 875 00:35:03,601 --> 00:35:03,902 PUMP. 876 00:35:03,902 --> 00:35:06,871 WE LOOKED AT ALL OF THE DISEASE 877 00:35:06,871 --> 00:35:07,973 ASSOCIATED VARIANTS, AND YOU CAN 878 00:35:07,973 --> 00:35:10,108 SEE THERE ARE 220 OF THEM. 879 00:35:10,108 --> 00:35:12,544 SUPER IMPOSED ON TO THE 3D 880 00:35:12,544 --> 00:35:13,678 PROTEIN. 881 00:35:13,678 --> 00:35:15,847 WE SAW AS DR. KOROSHETZ WAS 882 00:35:15,847 --> 00:35:17,349 SAYING THAT THERE WERE HOT SPOTS 883 00:35:17,349 --> 00:35:20,385 ASSOCIATED WITH THE PROTEIN 884 00:35:20,385 --> 00:35:21,620 WHERE MOLECULAR CHANGES COULDN'T 885 00:35:21,620 --> 00:35:24,489 BE TOLERATED. 886 00:35:24,489 --> 00:35:27,659 WE UNDERSTOOD QUICKLY THAT THE 887 00:35:27,659 --> 00:35:30,562 SODIUM POTASSIUM PUMP PUMPS OUT 888 00:35:30,562 --> 00:35:34,766 OF NEURONS THREE SODIUM IONS AND 889 00:35:34,766 --> 00:35:39,671 PUMPS IN EVERY CYCLE AGAINST THE 890 00:35:39,671 --> 00:35:40,638 CONCENTRATION GRADIENT TO CREATE 891 00:35:40,638 --> 00:35:42,607 AND MAINTAIN THE ELECTRICAL AND 892 00:35:42,607 --> 00:35:43,708 CHEMICAL IMBALANCES IN THE BRAIN 893 00:35:43,708 --> 00:35:45,110 THAT ALLOW NEURONS TO FIRE AND 894 00:35:45,110 --> 00:35:51,182 KEEP FIRING. 895 00:35:51,182 --> 00:35:53,318 WE ALSO UNDERSTOOD VERY QUICKLY 896 00:35:53,318 --> 00:35:56,821 THAT THIS PARTICULAR PROTEIN 897 00:35:56,821 --> 00:35:59,991 AFFECTS HIGH FREQUENCY NEURONS 898 00:35:59,991 --> 00:36:02,427 LIKE GABAMINERGIC NEURONS MORE 899 00:36:02,427 --> 00:36:03,695 THAN MOST OTHER NEURONS. 900 00:36:03,695 --> 00:36:06,698 IT DOES EXPRESS MOSTLY IN 901 00:36:06,698 --> 00:36:07,532 NEURONS. 902 00:36:07,532 --> 00:36:10,935 ANY CHANGES TO THE CYCLE RATES 903 00:36:10,935 --> 00:36:14,105 OF THESE PUMPS HAVE A REAL 904 00:36:14,105 --> 00:36:17,375 EFFECT ON SYMPTOMS IN PATIENTS. 905 00:36:17,375 --> 00:36:19,310 WE ALSO UNDERSTOOD VERY QUICKLY 906 00:36:19,310 --> 00:36:20,712 AND EARLY ON THAT THERE WERE 907 00:36:20,712 --> 00:36:23,982 SOME REAL OPPORTUNITIES TO LOOK 908 00:36:23,982 --> 00:36:26,317 AT OTHER PARTICULAR MUTATIONS IN 909 00:36:26,317 --> 00:36:27,018 OTHER GENES. 910 00:36:27,018 --> 00:36:29,988 IT WAS A SIGNIFICANT OVERLAP 911 00:36:29,988 --> 00:36:32,023 BETWEEN OUR DISEASE AND OTHER 912 00:36:32,023 --> 00:36:36,161 DISEASES ASSOCIATED WITH THESE 913 00:36:36,161 --> 00:36:39,731 GENES, SODIUM CHANNELS, 914 00:36:39,731 --> 00:36:41,166 POTASSIUM CHANNELS, A REAL 915 00:36:41,166 --> 00:36:43,501 OPPORTUNITY FOR A PLATFORM 916 00:36:43,501 --> 00:36:45,870 APPROACH TO THERAPY DEVELOPMENT 917 00:36:45,870 --> 00:36:47,372 AND RESEARCH. 918 00:36:47,372 --> 00:36:49,140 WE CREATED A STRATEGIC FRAMEWORK 919 00:36:49,140 --> 00:36:51,309 FOR RESEARCH, LOOKING AT 920 00:36:51,309 --> 00:36:53,178 RESEARCH PROJECTS BOTH 921 00:36:53,178 --> 00:36:54,679 SEQUENTIALLY AND IN PARALLEL. 922 00:36:54,679 --> 00:36:57,148 WE LOOKED FOR SHORTCUTS, WAYS 923 00:36:57,148 --> 00:36:59,751 THAT WE MIGHT BE ABLE TO FIGURE 924 00:36:59,751 --> 00:37:01,286 OUT WHETHER OR NOT A PARTICULAR 925 00:37:01,286 --> 00:37:02,053 THERAPEUTIC WOULD WORK WITHOUT 926 00:37:02,053 --> 00:37:05,190 HAVING TO UNDERSTAND THE FULL 927 00:37:05,190 --> 00:37:09,160 MECHANISTIC OPERATIONS OF THE 928 00:37:09,160 --> 00:37:09,961 PUMP. 929 00:37:09,961 --> 00:37:12,864 WE CREATED A CIRCULAR HYPOTHESIS 930 00:37:12,864 --> 00:37:13,998 TESTING METHODOLOGY WHERE WE 931 00:37:13,998 --> 00:37:17,502 WOULD LITERALLY TAKE THE TIES ON 932 00:37:17,502 --> 00:37:19,337 WELL DOCUMENTED REVISED 933 00:37:19,337 --> 00:37:20,105 HYPOTHESES EVERY STEP OF THE 934 00:37:20,105 --> 00:37:22,874 WAY. 935 00:37:22,874 --> 00:37:25,610 WE IDENTIFIED THERAPEUTIC 936 00:37:25,610 --> 00:37:29,080 OPTIONS, AND LIKE SO MANY OTHER 937 00:37:29,080 --> 00:37:30,815 DISEASES, THERE WERE ESSENTIALLY 938 00:37:30,815 --> 00:37:31,950 ONLY FOUR AVAILABLE TO US. 939 00:37:31,950 --> 00:37:35,420 GENE THERAPIES LIKE AAB MEDIATED 940 00:37:35,420 --> 00:37:37,155 GENE THERAPY, KNOCKDOWN OPTIONS 941 00:37:37,155 --> 00:37:40,125 LIKE ASOs, GENE EDITING, BASE 942 00:37:40,125 --> 00:37:41,793 EDITING, PRIME EDITING 943 00:37:41,793 --> 00:37:43,128 ESPECIALLY, AND DRUG SCREENS. 944 00:37:43,128 --> 00:37:44,763 WE PURSUED ALL OF THEM IN 945 00:37:44,763 --> 00:37:48,700 PARALLEL. 946 00:37:48,700 --> 00:37:50,435 WE ALSO IDENTIFIED THE 947 00:37:50,435 --> 00:37:51,636 PRE-CLINICAL TOOLS THAT WE HAD 948 00:37:51,636 --> 00:37:52,804 AVAILABLE, AND WE CENTRALIZED 949 00:37:52,804 --> 00:37:54,239 THEM. 950 00:37:54,239 --> 00:37:56,541 ADDING MANY MOUSE MODELS, CELL 951 00:37:56,541 --> 00:37:58,243 LINES, ASSAYS AND DATA ALONG THE 952 00:37:58,243 --> 00:37:59,711 WAY, AND MAKING SURE THAT THEY 953 00:37:59,711 --> 00:38:01,012 WERE AVAILABLE TO ALL 954 00:38:01,012 --> 00:38:02,046 RESEARCHERS WHO WANTED OR NEEDED 955 00:38:02,046 --> 00:38:04,015 THEM. 956 00:38:04,015 --> 00:38:06,818 WE WERE TRYING TO CATALYZE 957 00:38:06,818 --> 00:38:11,823 RESEARCH, AND IT WORKED BETTER 958 00:38:11,823 --> 00:38:12,757 THAN WE EVER COULD HAVE IMAGINE 959 00:38:12,757 --> 00:38:13,391 DOLLARS. 960 00:38:13,391 --> 00:38:15,360 WE WORKED WITH MANY STRATEGIC 961 00:38:15,360 --> 00:38:16,427 PARTNERS, ESPECIALLY THOSE FOLKS 962 00:38:16,427 --> 00:38:18,663 ON THE SCREEN. 963 00:38:18,663 --> 00:38:20,632 NOW, I SAY "WE" A LOT, BUT I 964 00:38:20,632 --> 00:38:22,367 THINK YOU KNOW THAT THE REAL 965 00:38:22,367 --> 00:38:24,135 FIREPOWER CAME FROM PEOPLE AT 966 00:38:24,135 --> 00:38:27,305 THESE INSTITUTIONS WITH ME, MY 967 00:38:27,305 --> 00:38:34,746 WIFE NINA AND DR. NATALIA MORSCH 968 00:38:34,746 --> 00:38:36,147 WORKING AS A HUB TO CONNECT THE 969 00:38:36,147 --> 00:38:36,814 DOTS. 970 00:38:36,814 --> 00:38:37,749 NOW I AM HERE TO TELL YOU 971 00:38:37,749 --> 00:38:38,583 SOMETHING REALLY IMPORTANT. 972 00:38:38,583 --> 00:38:40,318 NONE OF THIS WAS NOVEL. 973 00:38:40,318 --> 00:38:41,853 NONE OF THIS WAS 974 00:38:41,853 --> 00:38:42,821 GROUND-BREAKING. 975 00:38:42,821 --> 00:38:46,224 THIS WAS US REINVENTING THE 976 00:38:46,224 --> 00:38:47,559 WHEEL FOR YET ANOTHER RARE 977 00:38:47,559 --> 00:38:48,960 DISEASE, AND WE KNEW IT. 978 00:38:48,960 --> 00:38:50,395 BUT WE ALSO KNEW WE DIDN'T HAVE 979 00:38:50,395 --> 00:38:52,130 ANY OTHER OPTIONS. 980 00:38:52,130 --> 00:38:53,898 WE HAD TO DO IT OURSELVES. 981 00:38:53,898 --> 00:38:58,503 NOBODY WAS GOING TO HELP US. 982 00:38:58,503 --> 00:39:00,805 THIS IS THE CASE FOR MANY, MAYBE 983 00:39:00,805 --> 00:39:02,140 MOST, OF THE OTHER 10,000 RARE 984 00:39:02,140 --> 00:39:05,877 DISEASES. 985 00:39:05,877 --> 00:39:07,745 BUT EVEN REINVENTING THE WHEEL, 986 00:39:07,745 --> 00:39:09,881 EVEN FOLLOWING THOSE TRIED AND 987 00:39:09,881 --> 00:39:11,683 TESTED PARTS OF THERAPEUTIC 988 00:39:11,683 --> 00:39:14,252 DEVELOPMENT FOR OTHER SUCCESSFUL 989 00:39:14,252 --> 00:39:16,154 THERAPIES, LED US TO AMAZING 990 00:39:16,154 --> 00:39:17,322 RESULTS. 991 00:39:17,322 --> 00:39:19,958 WE'VE SEEN A RESCUE IN VITRO AND 992 00:39:19,958 --> 00:39:22,493 IN VIVO USING OUR AAV-MEDIATED 993 00:39:22,493 --> 00:39:24,262 GENE THERAPIES. 994 00:39:24,262 --> 00:39:25,763 WE'VE SEEN A COMPENSATING 995 00:39:25,763 --> 00:39:27,298 MECHANISM WHERE IF WE KNOCK OUT 996 00:39:27,298 --> 00:39:29,267 THE MUTANT ALLELE, WE SEE AN 997 00:39:29,267 --> 00:39:30,602 INCREASED NUMBER OF PROTEINS 998 00:39:30,602 --> 00:39:32,237 THAT ALMOST GETS TO WILDTYPE 999 00:39:32,237 --> 00:39:33,705 LEVELS. 1000 00:39:33,705 --> 00:39:36,074 WE'VE IDENTIFIED SEVERAL 1001 00:39:36,074 --> 00:39:38,243 CANDIDATE COMPOUNDS, TESTING 1002 00:39:38,243 --> 00:39:39,510 THOSE IN VIVO AND IN VITRO AT 1003 00:39:39,510 --> 00:39:41,546 THE MOMENT, AND PROBABLY MOST 1004 00:39:41,546 --> 00:39:43,214 EXCITINGLY AND MOST RECENTLY, 1005 00:39:43,214 --> 00:39:45,049 WE'VE SEEN SIGNIFICANT 1006 00:39:45,049 --> 00:39:47,685 ADVANCEMENTS IN GENE EDITING, 1007 00:39:47,685 --> 00:39:48,920 ESPECIALLY PRIME EDITING, WITH 1008 00:39:48,920 --> 00:39:53,524 OUR COLLABORATION WITH THE LU 1009 00:39:53,524 --> 00:39:58,229 LAB AT THE BROAD INSTITUTE. 1010 00:39:58,229 --> 00:40:00,198 SO WE SPENT THE LAST FIVE YEARS 1011 00:40:00,198 --> 00:40:02,500 SYSTEMATIZING OUR RESEARCH, 1012 00:40:02,500 --> 00:40:03,801 CENTRALIZING OUR TOOLS LIKE OUR 1013 00:40:03,801 --> 00:40:06,638 ANIMAL MODELS, OUR CELL LINES 1014 00:40:06,638 --> 00:40:08,339 AND OUR SAs, AND WE'VE BEEN 1015 00:40:08,339 --> 00:40:10,275 MAKING THEM FREELY AVAILABLE TO 1016 00:40:10,275 --> 00:40:14,579 ANYBODY WHO WANTS TO MEET THEM, 1017 00:40:14,579 --> 00:40:16,214 IN THE MEANTIME, CONNECTING 1018 00:40:16,214 --> 00:40:17,382 CRITICAL SCIENTISTS AND SCALING 1019 00:40:17,382 --> 00:40:17,949 OPERATIONS. 1020 00:40:17,949 --> 00:40:20,919 NOW SCALING OPERATIONS IS NOT 1021 00:40:20,919 --> 00:40:23,354 SOMETHING THAT MOST FOLKS IN THE 1022 00:40:23,354 --> 00:40:24,656 RARE DISEASE WORLD KNOW HOW TO 1023 00:40:24,656 --> 00:40:24,922 DO. 1024 00:40:24,922 --> 00:40:27,392 THESE FOLKS ARE ALL TRYING 1025 00:40:27,392 --> 00:40:28,960 DESPERATELY TO SAVE THEIR DYING 1026 00:40:28,960 --> 00:40:30,261 CHILDREN. 1027 00:40:30,261 --> 00:40:31,462 THEY DON'T HAVE THE EXPERIENCE, 1028 00:40:31,462 --> 00:40:34,098 THE MONEY, THE EXPERTISE TO BE 1029 00:40:34,098 --> 00:40:39,937 ABLE TO PUT TOGETHER SCIENTIFIC 1030 00:40:39,937 --> 00:40:41,973 PLANS THAT ARE SOPHISTICATED. 1031 00:40:41,973 --> 00:40:43,841 SO I'M TRYING TO FIGURE OUT A 1032 00:40:43,841 --> 00:40:45,576 WAY THAT WE CAN REINVENT THE 1033 00:40:45,576 --> 00:40:47,145 WHEEL TOGETHER FOR AS MANY RARE 1034 00:40:47,145 --> 00:40:48,446 DISEASES AS POSSIBLE IN 1035 00:40:48,446 --> 00:40:51,616 PARALLEL. 1036 00:40:51,616 --> 00:40:54,719 IN THE PROCESS OF THINKING ABOUT 1037 00:40:54,719 --> 00:40:57,455 SCALING, BACK TO CHRIS AUSTIN, 1038 00:40:57,455 --> 00:41:00,491 WHO I THINK A LOT OF YOU KNOW, 1039 00:41:00,491 --> 00:41:04,562 APPROACHED ME TO JOIN THE -- 1040 00:41:04,562 --> 00:41:05,430 ACCELERATION BOARD AT THE NIH 1041 00:41:05,430 --> 00:41:08,266 WHERE WE MIGHT BE ABLE TO THINK 1042 00:41:08,266 --> 00:41:09,367 ABOUT MORE APPROACHES TOGETHER. 1043 00:41:09,367 --> 00:41:10,802 AND I'VE BEEN TRYING EVER SINCE 1044 00:41:10,802 --> 00:41:12,537 TO FIGURE OUT WAYS TO ACCELERATE 1045 00:41:12,537 --> 00:41:14,172 THE PATH TOWARDS A MORE 1046 00:41:14,172 --> 00:41:15,106 WIDESPREAD PLATFORM-BASED 1047 00:41:15,106 --> 00:41:15,707 APPROACH. 1048 00:41:15,707 --> 00:41:17,809 TO ACCOMPLISH THIS, I'VE TRIED 1049 00:41:17,809 --> 00:41:21,279 TO PUT TOGETHER HIGH QUALITY 1050 00:41:21,279 --> 00:41:22,680 CENTRALIZED DATA FOR RARE 1051 00:41:22,680 --> 00:41:24,716 DISEASES AND MAKE THOSE DATA 1052 00:41:24,716 --> 00:41:26,451 AVAILABLE TO HIGH POWERED 1053 00:41:26,451 --> 00:41:30,088 ANALYTICS USING A.I. AND 1054 00:41:30,088 --> 00:41:39,063 SUPERVISOR COMPUTERSSUPERVISUPEL 1055 00:41:39,063 --> 00:41:39,397 SPREADSHEETS. 1056 00:41:39,397 --> 00:41:44,569 THE IDEA IS TO GATHER 1057 00:41:44,569 --> 00:41:45,636 CENTRALIZED GENOTYPE AND 1058 00:41:45,636 --> 00:41:46,771 PHENOTYPE DATA TO BREAK DISEASES 1059 00:41:46,771 --> 00:41:50,274 DOWN TO THEIR MOLECULAR BASIS. 1060 00:41:50,274 --> 00:41:51,242 TO CATEGORIZE DISEASES WITH 1061 00:41:51,242 --> 00:41:52,543 COMMON SYMPTOMS AND COMMON 1062 00:41:52,543 --> 00:41:56,114 PATHWAYS INTO LARGER CO-RESEARCH 1063 00:41:56,114 --> 00:41:58,149 UNITS AND TO BUILD THAT ROSETTA 1064 00:41:58,149 --> 00:41:59,884 STONE THAT I WAS TALKING ABOUT 1065 00:41:59,884 --> 00:42:01,619 BEFORE TO DECODE RARE DISEASES 1066 00:42:01,619 --> 00:42:04,589 IN HUMAN BUY OSM BIOLOGY. 1067 00:42:04,589 --> 00:42:05,823 RECENTLY I'VE HELPED TO LEAD THE 1068 00:42:05,823 --> 00:42:08,326 FORMATION OF A COALITION FOR THE 1069 00:42:08,326 --> 00:42:10,528 GENOMEIC ANSWERS FOR CHILDREN'S 1070 00:42:10,528 --> 00:42:14,465 HEALTH ALLIANCE, ALLOWING 1071 00:42:14,465 --> 00:42:16,434 MEDICAID TO PAY FOR WHOLE GENOME 1072 00:42:16,434 --> 00:42:17,902 SEQUENCING FOR ALL RARE DISEASES 1073 00:42:17,902 --> 00:42:20,838 FOR PATIENTS THAT NEED IT OR 1074 00:42:20,838 --> 00:42:22,173 PATIENTS WITH RESPECT TO GENETIC 1075 00:42:22,173 --> 00:42:22,473 DISEASES. 1076 00:42:22,473 --> 00:42:23,674 AND VERY IMPORTANTLY, TO 1077 00:42:23,674 --> 00:42:25,643 CENTRALIZE THOSE DATA TO BE ABLE 1078 00:42:25,643 --> 00:42:27,678 TO ACCESS THOSE AND USE THEM TO 1079 00:42:27,678 --> 00:42:34,519 CREATE THAT ROSETTA STONE. 1080 00:42:34,519 --> 00:42:35,686 NOW AS A RARE DISEASE COMMUNITY, 1081 00:42:35,686 --> 00:42:37,088 I THINK WE COULD VERY SOON HAVE 1082 00:42:37,088 --> 00:42:40,758 THE PUZZLE PIECES TOGETHER THAT 1083 00:42:40,758 --> 00:42:43,261 WE NEED TO CREATE A BLUEPRINT 1084 00:42:43,261 --> 00:42:46,898 FOR MANY O OTHER RARE DISEASES O 1085 00:42:46,898 --> 00:42:48,599 FOLLOW, TO REPLICATE, 1086 00:42:48,599 --> 00:42:49,967 EXTRAPOLATE THE SUCCESS WE'VE 1087 00:42:49,967 --> 00:42:51,736 SEEN BOTH JOINTLY AS SEPARATELY 1088 00:42:51,736 --> 00:42:55,239 IN THE RARE DISEASE WORLD UP TO 1089 00:42:55,239 --> 00:42:57,875 THIS POINT, TO CREATE THOSE 1090 00:42:57,875 --> 00:42:59,377 PLATFORMS FOR MANY OTHER 1091 00:42:59,377 --> 00:43:01,512 DISEASES TO BE STUDIED 1092 00:43:01,512 --> 00:43:02,380 SIMULTANEOUSLY, AND TO TREAT AS 1093 00:43:02,380 --> 00:43:03,448 MANY PATIENTS AS POSSIBLE 1094 00:43:03,448 --> 00:43:06,617 ULTIMATELY. 1095 00:43:06,617 --> 00:43:12,924 WITH THE ADVANCED AN Y ANALYTICL 1096 00:43:12,924 --> 00:43:15,760 TOOLS WE NOW HAVE AND GIVEN THE 1097 00:43:15,760 --> 00:43:16,561 ASTRONOMICAL MATHEMATICAL 1098 00:43:16,561 --> 00:43:18,396 PROBLEMS WE'VE ALREADY SOLVED AS 1099 00:43:18,396 --> 00:43:19,464 HUMANITY WITH COMPUTER POWER 1100 00:43:19,464 --> 00:43:21,732 THAT WAS A TRILLION OF WHAT WE 1101 00:43:21,732 --> 00:43:23,201 HAVE TODAY, I THINK THESE 1102 00:43:23,201 --> 00:43:24,836 NUMBERS SHOULDN'T BE 1103 00:43:24,836 --> 00:43:26,704 INTIMIDATING ANYMORE. 1104 00:43:26,704 --> 00:43:28,506 WE'RE TALKING ABOUT JUST 10,000 1105 00:43:28,506 --> 00:43:29,373 RARE DISEASES. 1106 00:43:29,373 --> 00:43:33,344 WE'RE TALKING ABOUT JUST 24,000 1107 00:43:33,344 --> 00:43:34,312 PROTEIN CODING GENES. 1108 00:43:34,312 --> 00:43:37,381 WE ARE NOT TALKING ABOUT A 1109 00:43:37,381 --> 00:43:40,351 TRILLION TRILLION SOLAR SYSTEMS, 1110 00:43:40,351 --> 00:43:41,285 WE'RE NOT TALKING ABOUT THE 1111 00:43:41,285 --> 00:43:42,420 SPEED OF LIGHT SQUARED. 1112 00:43:42,420 --> 00:43:46,924 THESE NUMBERS ARE ACHIEVABLE. 1113 00:43:46,924 --> 00:43:48,459 WE JUST NEED A COORDINATED PLAN. 1114 00:43:48,459 --> 00:43:50,695 WE CAN EITHER KEEP REINVENT 1115 00:43:50,695 --> 00:43:54,732 BEINVENTINGTHE WHEEL OR WE CAN A 1116 00:43:54,732 --> 00:43:56,267 SYSTEMATIZED CENTRALIZED 1117 00:43:56,267 --> 00:43:58,569 WHEEL-MAKING FACTORY THAT CAN 1118 00:43:58,569 --> 00:44:00,972 HELP UP TO 800 MILLION PEOPLE 1119 00:44:00,972 --> 00:44:02,940 TODAY, AND MAYBE AN ASTRONOMICAL 1120 00:44:02,940 --> 00:44:04,175 NUMBER TOMORROW. 1121 00:44:04,175 --> 00:44:07,311 AND WHILE WE DO LIVE IN AN 1122 00:44:07,311 --> 00:44:08,913 INCONCEIVABLY VAST COSMOS, AND 1123 00:44:08,913 --> 00:44:11,716 WHILE WE ARE INFAN TESS 1124 00:44:11,716 --> 00:44:13,050 MEDICALLY SMALL, I THINK THAT 1125 00:44:13,050 --> 00:44:15,286 ALL OF US IN THIS ROOM HAVE THE 1126 00:44:15,286 --> 00:44:16,787 OPPORTUNITY TO CHANGE THE FUTURE 1127 00:44:16,787 --> 00:44:20,958 FOR HUMANITY, AND I THINK THAT'S 1128 00:44:20,958 --> 00:44:24,896 PERHAPS WHE WHAT REALLY COUNTS. 1129 00:44:24,896 --> 00:44:25,296 THANK YOU. 1130 00:44:25,296 --> 00:44:35,473 [APPLAUSE] 1131 00:44:48,586 --> 00:44:50,254 >> THANK YOU VERY MUCH, SIMON. 1132 00:44:50,254 --> 00:44:51,289 BEFORE I INTRODUCE THE MODERATOR 1133 00:44:51,289 --> 00:44:54,025 OF THE FIRST SESSION, JUST SOME 1134 00:44:54,025 --> 00:44:55,560 LOGISTICS FOR HOW THE WORKSHOP 1135 00:44:55,560 --> 00:44:56,294 IS GOING TO RUN. 1136 00:44:56,294 --> 00:44:58,229 SO EACH SPEAKER WILL HAVE 20 1137 00:44:58,229 --> 00:44:59,964 MINUTES PLUS 5 MINUTES FOR 1138 00:44:59,964 --> 00:45:01,165 CLARIFYING QUESTIONS, AND THEN 1139 00:45:01,165 --> 00:45:02,500 THERE WILL BE A PANEL DISCUSSION 1140 00:45:02,500 --> 00:45:04,068 AT THE END. 1141 00:45:04,068 --> 00:45:06,537 FOR ALL OF THE MEMBERS -- 1142 00:45:06,537 --> 00:45:08,606 SPEAKERS WITHIN THAT SESSION. 1143 00:45:08,606 --> 00:45:12,109 SO HERE IN THE ROOM, I IF YOU HE 1144 00:45:12,109 --> 00:45:13,444 A QUESTION, PLEASE GO TO THE 1145 00:45:13,444 --> 00:45:13,744 MICROPHONE. 1146 00:45:13,744 --> 00:45:14,946 IT'S ON THE SIDE OF THE ROOM. 1147 00:45:14,946 --> 00:45:17,582 WE'LL ALSO HAVE A ROVING 1148 00:45:17,582 --> 00:45:18,482 MICROPHONE FOR PEOPLE WHO WANT 1149 00:45:18,482 --> 00:45:22,853 TO ASK QUESTIONS. 1150 00:45:22,853 --> 00:45:24,855 ONLINE, YOU CAN RAISE YOUR HAND, 1151 00:45:24,855 --> 00:45:27,458 AND WE WILL MAKE SURE THAT WE 1152 00:45:27,458 --> 00:45:29,160 CALL ON YOU AND YOU'LL BE ABLE 1153 00:45:29,160 --> 00:45:30,995 TO UNMUTE AND TURN ON YOUR 1154 00:45:30,995 --> 00:45:33,431 CAMERA SO THAT YOU CAN ASK YOUR 1155 00:45:33,431 --> 00:45:35,600 QUESTION AND INTERACT DIRECTLY. 1156 00:45:35,600 --> 00:45:37,335 THE CHAT IS OPEN FOR PEOPLE 1157 00:45:37,335 --> 00:45:41,205 ONLINE WHO WANT TO OPEN UP 1158 00:45:41,205 --> 00:45:43,474 DISCUSSION AND MAKE COMMENTS IN 1159 00:45:43,474 --> 00:45:44,175 THE CHAT. 1160 00:45:44,175 --> 00:45:45,476 WE WON'T BE TAKING QUESTIONS 1161 00:45:45,476 --> 00:45:48,713 FROM THERE, SO PLEASE JUST -- IF 1162 00:45:48,713 --> 00:45:49,847 YOU HAVE A QUESTION, RAISE YOUR 1163 00:45:49,847 --> 00:45:51,048 HAND. 1164 00:45:51,048 --> 00:45:52,550 JUST A COUPLE OF OTHER THINGS, 1165 00:45:52,550 --> 00:45:53,951 THE RESTROOMS ARE OUT THE DOOR 1166 00:45:53,951 --> 00:45:56,520 AND TO THE LEFT. 1167 00:45:56,520 --> 00:45:58,856 DURING THE BREAKS AND AT LUNCH, 1168 00:45:58,856 --> 00:46:00,424 PLEASE TAKE A LOOK AT THE 1169 00:46:00,424 --> 00:46:01,392 POSTERS ON THE TABLES AND 1170 00:46:01,392 --> 00:46:02,960 THERE'S ALSO A DEDICATED POSTER 1171 00:46:02,960 --> 00:46:04,929 SESSION FROM 1:00 TO 2:00. 1172 00:46:04,929 --> 00:46:07,965 THE ROOM ADJACENT TO THIS ROOM 1173 00:46:07,965 --> 00:46:09,233 IS AVAILABLE FOR ANYONE WHO MAY 1174 00:46:09,233 --> 00:46:12,703 NEED TO SKIP OUT AND DO A PHONE 1175 00:46:12,703 --> 00:46:14,372 CALL OR TAKE A ZOOM MEETING, 1176 00:46:14,372 --> 00:46:15,473 WHATEVER YOU NEED TO DO, BUT 1177 00:46:15,473 --> 00:46:16,574 THAT ROOM IS AVAILABLE. 1178 00:46:16,574 --> 00:46:18,676 JUST ASK AT THE FRONT DESK OR 1179 00:46:18,676 --> 00:46:20,745 JUST MOSEY OVER THAT WAY. 1180 00:46:20,745 --> 00:46:23,748 SO WITH THAT, IT'S MY PLEASURE 1181 00:46:23,748 --> 00:46:31,522 TO INTRODUCE DAN LOWENSTEIN FROM 1182 00:46:31,522 --> 00:46:32,423 THE UNIVERSITY OF CALIFORNIA, 1183 00:46:32,423 --> 00:46:33,724 SAN FRANCISCO WHO'S GOING TO 1184 00:46:33,724 --> 00:46:35,426 MODERATE THE FIRST DISCUSSION. 1185 00:46:35,426 --> 00:46:36,994 WELCOME, DAN. 1186 00:46:36,994 --> 00:46:40,097 >> THANK YOU, VICKY. 1187 00:46:40,097 --> 00:46:41,332 THANKS FOR ALL WHO ARE ATTENDING 1188 00:46:41,332 --> 00:46:42,667 HERE AND ARE JOINING US 1189 00:46:42,667 --> 00:46:45,136 VIRTUALLY ONLINE. 1190 00:46:45,136 --> 00:46:47,171 IT'S A PLEASURE TO BE PART OF 1191 00:46:47,171 --> 00:46:48,706 THE PLANNING GROUP THAT'S PUT 1192 00:46:48,706 --> 00:46:49,807 THIS TOGETHER, AND JUST TO GIVE 1193 00:46:49,807 --> 00:46:51,575 A LITTLE BIT OF CONTEXT BEFORE 1194 00:46:51,575 --> 00:46:55,846 THE SPECIFICS OF THIS FIRST 1195 00:46:55,846 --> 00:47:02,753 SESSION, THE ARC OF HISTORY, 1196 00:47:02,753 --> 00:47:04,155 SCIENCE, ANYTHING, CAN BE 1197 00:47:04,155 --> 00:47:05,056 DEFINED BY DIFFERENT POINTS 1198 00:47:05,056 --> 00:47:07,358 ALONG THAT PATH. 1199 00:47:07,358 --> 00:47:08,793 AND TO SEE FOLKS GATHERED HERE 1200 00:47:08,793 --> 00:47:10,094 AND THOSE OF YOU AGAIN WHO ARE 1201 00:47:10,094 --> 00:47:11,862 WITH US VIRTUALLY, CERTAINLY 1202 00:47:11,862 --> 00:47:16,667 REMINDS ME OF WHAT I'VE SEEN IN 1203 00:47:16,667 --> 00:47:19,103 MY LIFETIME, WHICH -- IT TRULY 1204 00:47:19,103 --> 00:47:22,139 IS EXTRAORDINARY. 1205 00:47:22,139 --> 00:47:24,642 WE CAN GO BACK WHEN IT COMES TO 1206 00:47:24,642 --> 00:47:26,777 THE PROGRESS THAT WE'VE MADE IN 1207 00:47:26,777 --> 00:47:31,582 EPILEPSY AND GENETICS TO 1989, 1208 00:47:31,582 --> 00:47:35,553 THE FIRST I' IDENTIFICATION OF A 1209 00:47:35,553 --> 00:47:37,021 LOCUS WAY BACK THEN CONNECTED TO 1210 00:47:37,021 --> 00:47:38,322 WHAT TURNED OUT TO BE A 1211 00:47:38,322 --> 00:47:41,158 POTASSIUM CHANNEL DISORDER. 1212 00:47:41,158 --> 00:47:44,462 1995 OR SO, OUR WONDERFUL 1213 00:47:44,462 --> 00:47:48,265 FRIENDS IN MELBOURNE AND 1214 00:47:48,265 --> 00:47:49,734 CONNECTED SCIENTISTS WERE ABLE 1215 00:47:49,734 --> 00:47:52,236 TO IDENTIFY THE FIRST TRUE 1216 00:47:52,236 --> 00:47:57,041 EPILEPSY GENE ASSOCIATED WITH AN 1217 00:47:57,041 --> 00:48:00,044 AUTOSOMAL DOMINANT FRONTAL LOBE 1218 00:48:00,044 --> 00:48:01,445 EPILEPSY, AND THIS PARTICULAR 1219 00:48:01,445 --> 00:48:03,748 WORKSHOP REMINDS ME OF THE 1220 00:48:03,748 --> 00:48:08,052 WORKSHOP THAT WAS -- I THINK IT 1221 00:48:08,052 --> 00:48:10,721 WAS 2009, WHICH WAS A FOCUS ON 1222 00:48:10,721 --> 00:48:12,089 TRYING TO UNDERSTAND WHERE WE 1223 00:48:12,089 --> 00:48:15,159 WERE WITH THE GENETICS OF 1224 00:48:15,159 --> 00:48:17,228 EPILEPSY. 1225 00:48:17,228 --> 00:48:18,662 YOU'VE ALREADY HEARD FROM 1226 00:48:18,662 --> 00:48:19,330 DR. KOROSHETZ, THIS THEN LED TO 1227 00:48:19,330 --> 00:48:20,564 THE RECOGNITION THAT WE WERE AT 1228 00:48:20,564 --> 00:48:24,869 A MOMENT IN TIME, A POINT IN 1229 00:48:24,869 --> 00:48:27,071 TIME WHERE WE COULD MAKE SOMELY 1230 00:48:27,071 --> 00:48:28,606 SIGNIFICANT PROGRESS IF WE CAME 1231 00:48:28,606 --> 00:48:30,741 TOGETHER AND CREATED THE KINDS 1232 00:48:30,741 --> 00:48:34,512 OF TEAMS TO FORM THE CENTERS 1233 00:48:34,512 --> 00:48:37,047 WITHOUT WALLS AND THAT THEN LED 1234 00:48:37,047 --> 00:48:41,519 TO EPI4K, EPI25 AND COUNTLESS 1235 00:48:41,519 --> 00:48:44,421 OTHER GROUPS OF, AGAIN, 1236 00:48:44,421 --> 00:48:45,589 MULTIDISCIPLINARY TEAMS 1237 00:48:45,589 --> 00:48:47,691 THAT HAVE MADE SPECTACULAR 1238 00:48:47,691 --> 00:48:48,759 ADVANCES IN THE GENETICS OF 1239 00:48:48,759 --> 00:48:49,527 EPILEPSY. 1240 00:48:49,527 --> 00:48:53,164 TO GO FROM 1989, WHERE THERE WAS 1241 00:48:53,164 --> 00:48:54,799 A LOCUS, TO NOW HAVING THE 1242 00:48:54,799 --> 00:48:57,234 IDENTIFICATION OF TARGETS AND 1243 00:48:57,234 --> 00:48:59,437 THE CLEARCUT IMPACT THAT IT'S 1244 00:48:59,437 --> 00:49:01,639 HAD ON THE PRACTICE OF MEDICINE, 1245 00:49:01,639 --> 00:49:06,110 ON THE CARE OF CHILDREN AND 1246 00:49:06,110 --> 00:49:07,311 OTHERS SUFFERING FROM EPILEPSY 1247 00:49:07,311 --> 00:49:09,013 HAS BEEN NOTHING SHORT OF 1248 00:49:09,013 --> 00:49:12,583 SPECTACULAR. 1249 00:49:12,583 --> 00:49:14,351 SO OUR GATHERING TODAY, I THINK, 1250 00:49:14,351 --> 00:49:16,453 HAS THE PROMISE OF ANOTHER ONE 1251 00:49:16,453 --> 00:49:17,788 OF THOSE IDENTIFIABLE POINTS IN 1252 00:49:17,788 --> 00:49:18,122 TIME. 1253 00:49:18,122 --> 00:49:19,657 BECAUSE WE ARE -- NO QUESTION, 1254 00:49:19,657 --> 00:49:21,725 WE ARE AT THE PLACE WHERE WE CAN 1255 00:49:21,725 --> 00:49:23,527 NOW DEVELOP MORE AND MORE 1256 00:49:23,527 --> 00:49:25,162 EFFECTIVE THERAPIES AND CURES 1257 00:49:25,162 --> 00:49:26,864 RELATED TO WHAT WE'VE UNDERSTOOD 1258 00:49:26,864 --> 00:49:28,132 IN THE GENETICS OF EPILEPSY. 1259 00:49:28,132 --> 00:49:32,403 SO IN THIS FIRST SESSION, THE 1260 00:49:32,403 --> 00:49:34,205 PLANNING COMMITTEE AS YOU'VE 1261 00:49:34,205 --> 00:49:35,606 ALREADY HEARD, IT WAS EASY TO 1262 00:49:35,606 --> 00:49:36,907 RECOGNIZE THAT WE NEED TO RELY 1263 00:49:36,907 --> 00:49:44,982 ON FOLKS OUTSIDE OF OUR FIELD TO 1264 00:49:44,982 --> 00:49:46,417 TRY TO UNDERSTAND WHAT WE'RE 1265 00:49:46,417 --> 00:49:47,785 TRYING TO DO IN A VERY 1266 00:49:47,785 --> 00:49:48,552 COMPLICATED, CHALLENGING 1267 00:49:48,552 --> 00:49:50,154 PROBLEM, AND THAT IS GENETIC 1268 00:49:50,154 --> 00:49:51,722 THERAPIES RELATED TO BRAIN 1269 00:49:51,722 --> 00:49:52,356 DISORDERS, SPECIFICALLY 1270 00:49:52,356 --> 00:49:53,490 EPILEPSY. 1271 00:49:53,490 --> 00:49:54,825 AND AS WE'VE BEEN THINKING ABOUT 1272 00:49:54,825 --> 00:49:59,930 THIS, I THINK THAT THERE ARE 1273 00:49:59,930 --> 00:50:01,866 THREE AREAS THAT WE NEED TO 1274 00:50:01,866 --> 00:50:03,167 CONTEND WITH THAT ALL OF US ARE 1275 00:50:03,167 --> 00:50:05,169 AWARE OF BUT I JUST WANT TO 1276 00:50:05,169 --> 00:50:05,870 EMPHASIZE THEM. 1277 00:50:05,870 --> 00:50:07,771 THREE ASPECTS OF GENE THERAPIES 1278 00:50:07,771 --> 00:50:08,839 FOR EPILEPSY THAT ARE 1279 00:50:08,839 --> 00:50:09,473 PARTICULARLY, PARTICULARLY 1280 00:50:09,473 --> 00:50:10,341 CHALLENGING. 1281 00:50:10,341 --> 00:50:13,344 THE FIRST ONE IS DEALING WITH 1282 00:50:13,344 --> 00:50:14,678 THE BLOOD BRAIN BARRIER. 1283 00:50:14,678 --> 00:50:17,615 A LOT OF THE MOST IMPORTANT 1284 00:50:17,615 --> 00:50:19,917 ADVANCES IN GENE THERAPY TO DATE 1285 00:50:19,917 --> 00:50:21,452 IN OTHER DISEASES HAVE NOT HAD 1286 00:50:21,452 --> 00:50:24,255 TO CONTEND WITH THAT. 1287 00:50:24,255 --> 00:50:26,290 ALTERING, FOR EXAMPLE, THE 1288 00:50:26,290 --> 00:50:28,058 HEMATOPOIETIC SYSTEM OR ALTERING 1289 00:50:28,058 --> 00:50:29,526 AN IDENTIFIABLE CANCER OUTSIDE 1290 00:50:29,526 --> 00:50:30,594 OF THE BRAIN. 1291 00:50:30,594 --> 00:50:31,996 WE'RE IN A WHOLE DIFFERENT 1292 00:50:31,996 --> 00:50:33,631 UNIVERSE WHEN IT COMES TO TRYING 1293 00:50:33,631 --> 00:50:36,767 TO GET GENE THERAPIES 1294 00:50:36,767 --> 00:50:37,868 EFFECTIVELY ACROSS THE BLOOD 1295 00:50:37,868 --> 00:50:38,469 BRAIN BARRIER. 1296 00:50:38,469 --> 00:50:42,106 THE SECOND IS THE NEED FOR EARLY 1297 00:50:42,106 --> 00:50:44,308 INTERVENTION FOR MANY OF THE 1298 00:50:44,308 --> 00:50:45,075 EPILEPSIES, BECAUSE IN THE 1299 00:50:45,075 --> 00:50:47,811 GENETIC DISORDERS, THEY MANIFEST 1300 00:50:47,811 --> 00:50:49,146 EARLY, THE NETWORK HAS ALREADY 1301 00:50:49,146 --> 00:50:51,448 BEEN SET UP TO A CERTAIN EXTENT, 1302 00:50:51,448 --> 00:50:53,150 AND WE NEED TO BE ABLE TO 1303 00:50:53,150 --> 00:50:54,285 INTERVENE EARLY ENOUGH AND AS 1304 00:50:54,285 --> 00:50:55,886 YOU'LL HEAR FROM ONE OF OUR 1305 00:50:55,886 --> 00:50:59,156 SPEAKERS, WE INVITED TIPPI 1306 00:50:59,156 --> 00:51:00,024 SPECIFICALLY BECAUSE SHE'S BEEN 1307 00:51:00,024 --> 00:51:01,225 THINKING ABOUT THAT. 1308 00:51:01,225 --> 00:51:04,328 AND THEN FINALLY, AND THIS ONE 1309 00:51:04,328 --> 00:51:05,863 VEXES ME PERHAPS THE MOST, AND 1310 00:51:05,863 --> 00:51:08,399 THAT IS, HOW DO WE COME UP WITH 1311 00:51:08,399 --> 00:51:12,236 HIGH FIDELITY TARGETING OF THE 1312 00:51:12,236 --> 00:51:17,474 VERY COMPLEX AND MESHED SYSTEM? 1313 00:51:17,474 --> 00:51:19,109 THE IMMUNE SYSTEM IS PROBABLY 1314 00:51:19,109 --> 00:51:22,479 THE EQUIVALENT COMPLEX SYSTEM 1315 00:51:22,479 --> 00:51:24,815 THAT EXISTS IN THE BODY COMPARED 1316 00:51:24,815 --> 00:51:27,084 TO THE NERVOUS SYSTEM, BUT IT'S 1317 00:51:27,084 --> 00:51:28,419 A LITTLE BIT DIFFERENT. 1318 00:51:28,419 --> 00:51:30,955 IT'S DISPERSED, IT CAN BE 1319 00:51:30,955 --> 00:51:33,057 SEPARABLE, AT LEAST OUTSIDE OF 1320 00:51:33,057 --> 00:51:34,458 THE BRAIN, WHEREAS WITHIN THE 1321 00:51:34,458 --> 00:51:35,759 BRAIN, THE CIRCUITRY IS A HECK 1322 00:51:35,759 --> 00:51:38,929 OF A LOT MORE NOT ONLY COMPLEX 1323 00:51:38,929 --> 00:51:42,633 BUT ALSO ENMESHED WITHIN OTHER 1324 00:51:42,633 --> 00:51:43,400 NEURONAL SUBTYPES AS WELL AS 1325 00:51:43,400 --> 00:51:50,474 OTHER CELL TYPES, AND SHE'S 1326 00:51:50,474 --> 00:51:51,408 GOING TO HELP US UNDERSTAND 1327 00:51:51,408 --> 00:51:51,642 THAT. 1328 00:51:51,642 --> 00:51:52,609 SO THAT'S THE CONTEXT. 1329 00:51:52,609 --> 00:51:54,211 I'M GOING TO DESCRIBE OUR THREE 1330 00:51:54,211 --> 00:51:54,478 SPEAKERS. 1331 00:51:54,478 --> 00:51:56,046 MANY OF YOU KNOW THEM BUT THESE 1332 00:51:56,046 --> 00:51:58,449 ARE SPECTACULAR FOLKS WHO WE'VE 1333 00:51:58,449 --> 00:52:00,351 CONVINCED NEED TO COME FROM FAR 1334 00:52:00,351 --> 00:52:06,924 AND WIDE TO JOIN US. 1335 00:52:06,924 --> 00:52:10,127 BEV DAVIDSON IS A WELL-KNOWN 1336 00:52:10,127 --> 00:52:11,795 RENOWNED GENETICIST AND 1337 00:52:11,795 --> 00:52:12,896 NEUROSCIENTIST WHO'S CURRENTLY 1338 00:52:12,896 --> 00:52:15,733 SERVING AS THE CHIEF SCIENTIFIC 1339 00:52:15,733 --> 00:52:17,601 OFFICER AT CHILDREN'S HOSPITAL 1340 00:52:17,601 --> 00:52:23,340 OF PHILLY AND PROFES PROFESSOR E 1341 00:52:23,340 --> 00:52:26,143 UNIVERSITY OF PENNSYLVANIA. 1342 00:52:26,143 --> 00:52:27,678 HER WORK HAS BEEN FOCUSING ON 1343 00:52:27,678 --> 00:52:29,246 MECHANISMS OF NEURODEGENERATIVE 1344 00:52:29,246 --> 00:52:30,347 DISEASES AND DEVELOPING GENE 1345 00:52:30,347 --> 00:52:31,615 THERAPY APPROACHES TO TREAT 1346 00:52:31,615 --> 00:52:33,784 CONDITIONS SUCH AS HUNTINGTON'S 1347 00:52:33,784 --> 00:52:34,985 DISEASE AND OTHER INHERITED 1348 00:52:34,985 --> 00:52:35,719 NEUROLOGICAL DISORDERS. 1349 00:52:35,719 --> 00:52:38,255 HER RESEARCH HAS REALLY BEEN 1350 00:52:38,255 --> 00:52:40,157 INSTRUMENTAL IN ADVANCING THE 1351 00:52:40,157 --> 00:52:43,327 USE OF RNA INTERFERENCE AND GENE 1352 00:52:43,327 --> 00:52:49,133 EDITING TECHNOLOGIES TO SILENCE 1353 00:52:49,133 --> 00:52:50,801 DISEASES AND COMING UP WITH NEW 1354 00:52:50,801 --> 00:52:51,902 THERAPEUTIC APPROACHES. 1355 00:52:51,902 --> 00:52:53,637 SHE'S A MEMBER OF THE NATIONAL 1356 00:52:53,637 --> 00:52:54,972 ACADEMY OF MEDICINE, WHICH AMONG 1357 00:52:54,972 --> 00:53:01,011 OTHER THINGS IS PART OF THE 1358 00:53:01,011 --> 00:53:02,212 RECOGNITION OF HER REMARKABLE 1359 00:53:02,212 --> 00:53:02,679 CONTRIBUTIONS. 1360 00:53:02,679 --> 00:53:05,582 WE'LL HEAR FROM TIPPI MCKENZIE 1361 00:53:05,582 --> 00:53:08,886 ON LINE, PROFESSOR OF SURGERY AT 1362 00:53:08,886 --> 00:53:09,553 THE UNIVERSITY OF CALIFORNIA 1363 00:53:09,553 --> 00:53:10,320 SAN FRANCISCO AND A LEADING 1364 00:53:10,320 --> 00:53:11,822 EXPERT IN THE FIELD OF FETAL 1365 00:53:11,822 --> 00:53:13,323 SURGERY AND MATERNAL FETAL 1366 00:53:13,323 --> 00:53:13,824 MEDICINE. 1367 00:53:13,824 --> 00:53:15,292 HER RESEARCH HAS BEEN AIMING TO 1368 00:53:15,292 --> 00:53:17,161 UNDERSTAND AND TREAT CONGENITAL 1369 00:53:17,161 --> 00:53:19,830 DISEASES THROUGH PRENATAL 1370 00:53:19,830 --> 00:53:22,132 INTERVENTIONS. 1371 00:53:22,132 --> 00:53:24,968 SHE'S REALLY ADVANCED THE FIELD 1372 00:53:24,968 --> 00:53:27,404 OF IN UTERO STEM CELL 1373 00:53:27,404 --> 00:53:28,172 TRANSPLANTATION AND GENE 1374 00:53:28,172 --> 00:53:28,939 THERAPY. 1375 00:53:28,939 --> 00:53:31,575 AND CO-DIRECTS A CENTER AT UCSF 1376 00:53:31,575 --> 00:53:33,444 ON MATERNAL FETAL PRECISION 1377 00:53:33,444 --> 00:53:35,746 MEDICINE. 1378 00:53:35,746 --> 00:53:38,582 AND THEN FINALLY, FYODOR URNOV, 1379 00:53:38,582 --> 00:53:39,917 WHO IS A PROFESSOR OF MOLECULAR 1380 00:53:39,917 --> 00:53:41,952 AND CELL BIOLOGY AT THE 1381 00:53:41,952 --> 00:53:42,486 UNIVERSITY OF CALIFORNIA, 1382 00:53:42,486 --> 00:53:42,753 BERKELEY. 1383 00:53:42,753 --> 00:53:44,988 AND A LEADING SCIENTIST IN THE 1384 00:53:44,988 --> 00:53:46,190 FIELD OF GENOME EDITING. 1385 00:53:46,190 --> 00:53:49,159 I HAPPEN TO KNOW FY ODOR QUITE 1386 00:53:49,159 --> 00:53:50,461 WELL BECAUSE I HAD THE 1387 00:53:50,461 --> 00:53:52,930 OPPORTUNITY TO SERVE AS A MEMBER 1388 00:53:52,930 --> 00:53:56,867 OF THE SCIENTIFIC ADVISORY BOARD 1389 00:53:56,867 --> 00:53:58,602 AT THE INNOVATIVE GENOMICS 1390 00:53:58,602 --> 00:54:02,639 INSTITUTE, THE IGI BASED AT 1391 00:54:02,639 --> 00:54:07,044 BERKELEY, AND FYODOR IS JUST A 1392 00:54:07,044 --> 00:54:07,611 REMARKABLE SCIENTIST WHO HAS 1393 00:54:07,611 --> 00:54:11,148 BEEN FOCUSING ON DEVELOPING AND 1394 00:54:11,148 --> 00:54:13,784 APPLYING CRISPR-BASED 1395 00:54:13,784 --> 00:54:14,318 TECHNOLOGIES FOR THERAPY 1396 00:54:14,318 --> 00:54:14,751 PURPOSES. 1397 00:54:14,751 --> 00:54:17,955 HIS RESEARCH HAS BEEN PIVOTAL IN 1398 00:54:17,955 --> 00:54:22,559 ADVANCING THE PRECISION AND 1399 00:54:22,559 --> 00:54:26,163 APPLICATION OF CRISPR TREATING 1400 00:54:26,163 --> 00:54:27,364 APPROACHES FOR TREATING GENETIC 1401 00:54:27,364 --> 00:54:27,898 DISORDERS. 1402 00:54:27,898 --> 00:54:29,500 HE'S ACTIVELY INVOLVED IN THE 1403 00:54:29,500 --> 00:54:30,467 ETHICAL CONSIDERATIONS AND 1404 00:54:30,467 --> 00:54:31,335 POLICY DISCUSSIONS SURROUNDING 1405 00:54:31,335 --> 00:54:33,203 THE USE OF GENOME EDITING AND 1406 00:54:33,203 --> 00:54:35,806 HAS HAD MANY, MANY RECOGNITIONS, 1407 00:54:35,806 --> 00:54:38,642 MOST RECENTLY BEING YOUR I THINK 1408 00:54:38,642 --> 00:54:45,382 PH.D. ALMA MATER AT BROWN, ONE 1409 00:54:45,382 --> 00:54:46,850 OF THE HIGHEST HONORS THAT THEY 1410 00:54:46,850 --> 00:54:48,919 GIVE TO THEIR ALUMNI AND THEIR 1411 00:54:48,919 --> 00:54:50,220 SCIENTISTS. 1412 00:54:50,220 --> 00:54:51,722 SO THOSE ARE THE THREE SPEAKERS 1413 00:54:51,722 --> 00:54:53,023 THIS MORNING. 1414 00:54:53,023 --> 00:54:55,392 YOU'LL HEAR FROM ANNE PODURI 1415 00:55:02,965 --> 00:55:04,600 THE NUMBER ONE RULE IN MY FIELD 1416 00:55:04,600 --> 00:55:06,235 WHICH IS CLINICAL GENE ID ITING 1417 00:55:06,235 --> 00:55:08,037 IS NEVER, EVER, EVERY GIVE 1418 00:55:08,037 --> 00:55:08,671 FAMILIES FALSE HOPE. 1419 00:55:08,671 --> 00:55:09,538 THERE ARE SEVERAL FAMILIES IN 1420 00:55:09,538 --> 00:55:11,440 THE ROOM, INCLUDING THE FAMILY 1421 00:55:11,440 --> 00:55:15,578 THAT JOINED ME ON THIS TRIP. 1422 00:55:15,578 --> 00:55:19,315 SO I SPENT A LOT OF TIME 1423 00:55:19,315 --> 00:55:22,685 THINKING ABOUT HOW TO -- SORRY, 1424 00:55:22,685 --> 00:55:24,120 ACTUALLY MY NORMAL LEVEL OF 1425 00:55:24,120 --> 00:55:25,654 SPEECH IS VERY LOUD. 1426 00:55:25,654 --> 00:55:27,423 I JUST DIDN'T WANT TO OVERWHELM. 1427 00:55:27,423 --> 00:55:28,591 HOW DOES THIS SOUND WHERE YOU 1428 00:55:28,591 --> 00:55:29,592 ARE? 1429 00:55:29,592 --> 00:55:30,359 ALL RIGHT. 1430 00:55:30,359 --> 00:55:32,027 I'M GOING TO FAIL THE 1431 00:55:32,027 --> 00:55:32,461 INTELLIGENCE TEST. 1432 00:55:32,461 --> 00:55:37,767 HOW DO I ADVANCE THE SLIDE? 1433 00:55:37,767 --> 00:55:39,835 AH-HA! 1434 00:55:39,835 --> 00:55:43,305 THE THINGIE WORKS. 1435 00:55:43,305 --> 00:55:47,476 SO LOOK, MY GOAL IS TO GIVE YOU 1436 00:55:47,476 --> 00:55:51,514 A JUNE 2024 DEFINITIVE REALITY 1437 00:55:51,514 --> 00:55:53,849 SNAPSHOT. 1438 00:55:53,849 --> 00:55:56,185 WE ARE SERIOUS PEOPLE GATHERED 1439 00:55:56,185 --> 00:55:58,554 TO TREAT A VERY SERIOUS DISEASE. 1440 00:55:58,554 --> 00:56:00,423 HERE ARE MY DISCLOSURES. 1441 00:56:00,423 --> 00:56:02,024 SOME OF THEM WILL BE RELEVANT AS 1442 00:56:02,024 --> 00:56:03,125 I SPEAK. 1443 00:56:03,125 --> 00:56:05,127 THE GENE EDITING FIELD HAS HAD A 1444 00:56:05,127 --> 00:56:05,561 LANDMARK MOMENT. 1445 00:56:05,561 --> 00:56:08,964 WE HAVE AN APPROVED MEDICINE. 1446 00:56:08,964 --> 00:56:12,435 FOR SICKLE CELL DISEASE, NO LE 1447 00:56:12,435 --> 00:56:12,635 LESS. 1448 00:56:12,635 --> 00:56:15,204 I HAD THE MO NOR OF INTRODUCING 1449 00:56:15,204 --> 00:56:16,672 GENE EDITING AT THE ADVISORY 1450 00:56:16,672 --> 00:56:17,740 COMMITTEE MEETING THAT APPROVED 1451 00:56:17,740 --> 00:56:20,042 THIS MEDICINE, AND I SHOWED THAT 1452 00:56:20,042 --> 00:56:24,413 VERSION OF THE SLIDE IN WHICH I 1453 00:56:24,413 --> 00:56:26,615 PUT OUT THE TRAJECTORY OF MY 1454 00:56:26,615 --> 00:56:29,785 FIELD THAT BEGAN WORK -- WITH A 1455 00:56:29,785 --> 00:56:30,786 NON-WORKING POINTER BECAUSE THIS 1456 00:56:30,786 --> 00:56:35,925 IS NOT A POINTER. 1457 00:56:35,925 --> 00:56:37,526 NO WORRIES, I'LL JUST WAVE. 1458 00:56:37,526 --> 00:56:40,896 AT THE VERY, VERY END IS WORK 1459 00:56:40,896 --> 00:56:42,932 DONE IN 1994 THAT STARTED GENE 1460 00:56:42,932 --> 00:56:44,467 EDITING. 1461 00:56:44,467 --> 00:56:45,468 MY COLLEAGUES ESTABLISHED THE 1462 00:56:45,468 --> 00:56:48,137 TREATMENTS OF CLINICAL GENE 1463 00:56:48,137 --> 00:56:50,606 EDITING IN 2005 AND NAMED THE 1464 00:56:50,606 --> 00:56:52,508 TECHNOLOGY, THE WORLD COMPLETELY 1465 00:56:52,508 --> 00:56:55,277 CHANGED, THEY COMPARE IT FROM 1466 00:56:55,277 --> 00:57:02,084 GOING FROM LPs TO SPOTIFY, 1467 00:57:02,084 --> 00:57:05,855 CRISPR GENOME MEDICINE AND NOW 1468 00:57:05,855 --> 00:57:08,557 WE HAVE AN APPROVED MEDICINE. 1469 00:57:08,557 --> 00:57:11,527 THAT'S VICTORIA GRAY, THE FIRST 1470 00:57:11,527 --> 00:57:16,031 SUBJECT TO BE -- SO I STAND 1471 00:57:16,031 --> 00:57:17,366 BEFORE YOU TO SAY THE NEXT 10 1472 00:57:17,366 --> 00:57:20,302 YEARS WILL NOT FEATURE A LINEAR 1473 00:57:20,302 --> 00:57:21,537 GROWTH OF THE FIELD BUT WILL 1474 00:57:21,537 --> 00:57:22,671 FEATURE AN EXPONENTIAL GROWTH OF 1475 00:57:22,671 --> 00:57:25,241 THE FIELD AND I WILL SUPPORT THE 1476 00:57:25,241 --> 00:57:27,009 STATEMENT THAT 100% OF MY FOCUS 1477 00:57:27,009 --> 00:57:29,545 TODAY IS TO WEAPONIZE THE 1478 00:57:29,545 --> 00:57:30,746 POSITIONS OF THE PHYSICIAN 1479 00:57:30,746 --> 00:57:32,982 SCIENTISTS AND SCIENTISTS ROOM 1480 00:57:32,982 --> 00:57:35,885 WITH HOW DO YOU DO A CRISPR JEAN 1481 00:57:35,885 --> 00:57:36,986 EDITING TRIAL FOR EPILEPSY IN 1482 00:57:36,986 --> 00:57:37,753 THE NEXT FIVE YEARS. 1483 00:57:37,753 --> 00:57:40,155 THE REASON FOR MY DATABASED 1484 00:57:40,155 --> 00:57:41,891 OPTIMISM COMES WITH A PARALLEL 1485 00:57:41,891 --> 00:57:44,093 TRACK MUTUALLY REINFORCING 1486 00:57:44,093 --> 00:57:47,196 INNOVATION IN THE TOOLBOX OF 1487 00:57:47,196 --> 00:57:48,364 CLINICAL TRACK RECORD OF EDITING 1488 00:57:48,364 --> 00:57:49,765 AND I WILL REVIEW THE FIRST TWO 1489 00:57:49,765 --> 00:57:51,333 AND I'M NOT GOING TO REVIEW THE 1490 00:57:51,333 --> 00:57:52,134 THIRD BECAUSE I KNEW I WAS GOING 1491 00:57:52,134 --> 00:57:54,937 TO IF AFTER BEV DAVIDSON SO I'M 1492 00:57:54,937 --> 00:58:00,242 NOT GOING TO TRY TO SHOOT THE 1493 00:58:00,242 --> 00:58:00,843 SHOT AFTER CAITLYN CLARKE. 1494 00:58:00,843 --> 00:58:04,580 THIS IS SOME DATA THAT ALSO JUST 1495 00:58:04,580 --> 00:58:06,348 CAME OUT AND THE BOTTOM LINE IS 1496 00:58:06,348 --> 00:58:08,517 AS BEV JUST SHOWED, THE BRAIN IS 1497 00:58:08,517 --> 00:58:09,718 TRANSDUCIBLE IN WAYS WE HAVE 1498 00:58:09,718 --> 00:58:11,253 NEVER DREAMT OF, AND I AGREE 1499 00:58:11,253 --> 00:58:13,022 WITH DR. KOROSHETZ, HOW DOES 1500 00:58:13,022 --> 00:58:15,858 THIS THING DO IT? 1501 00:58:15,858 --> 00:58:19,628 WELL, AS MY EX-INDUSTRY SELF IN 1502 00:58:19,628 --> 00:58:21,597 KIND OF AN AWKWARD WAY DOESN'T 1503 00:58:21,597 --> 00:58:22,731 CARE. 1504 00:58:22,731 --> 00:58:24,433 IN THE SENSE IF I CAN GET THE 1505 00:58:24,433 --> 00:58:25,868 PAYLOAD THERE AND IF I CAN SHOW 1506 00:58:25,868 --> 00:58:27,403 IT'S SAFE AND TOLERATED IN 1507 00:58:27,403 --> 00:58:28,504 NON-HUMAN PRIMATES, THEN I CAN 1508 00:58:28,504 --> 00:58:30,039 SPEAK WITH THE AGENCY. 1509 00:58:30,039 --> 00:58:31,273 BUT I AGREE THE QUESTION OF HOW 1510 00:58:31,273 --> 00:58:32,575 THIS HAPPENS IS A REALLY 1511 00:58:32,575 --> 00:58:34,376 IMPORTANT ONE. 1512 00:58:34,376 --> 00:58:36,779 SO MY JOB IS TO REVIEW WITH YOU 1513 00:58:36,779 --> 00:58:38,013 GENOME EDITING, AND I WANT TO 1514 00:58:38,013 --> 00:58:39,315 THANK DR. KOROSHETZ AND I WANT 1515 00:58:39,315 --> 00:58:44,720 TO THANK THE NIH, FOR HAVING 1516 00:58:44,720 --> 00:58:50,159 FUNDED A UNIQUE FIRST IN CLASS 1517 00:58:50,159 --> 00:58:51,026 FIVE-YEAR, $170 MILLION EFFORT 1518 00:58:51,026 --> 00:58:53,228 ON PUTTING CRISPR INTO PEOPLE. 1519 00:58:53,228 --> 00:58:58,634 IT'S CALL THE SOMATIC GENOME 1520 00:58:58,634 --> 00:59:00,469 EDITING CONSORTIUM. 1521 00:59:00,469 --> 00:59:02,237 THANK YOU, DR. KOROSHETZ, FOR 1522 00:59:02,237 --> 00:59:02,871 YOUR LEADERSHIP. 1523 00:59:02,871 --> 00:59:04,873 I'M NOT GOING TO REVIEW GENE 1524 00:59:04,873 --> 00:59:05,975 EDITING IN THE ABSTRACT. 1525 00:59:05,975 --> 00:59:07,643 I'M GOING TO REVIEW GENE EDITING 1526 00:59:07,643 --> 00:59:09,078 FOR THE BRAIN FUNDED BY THE NIH 1527 00:59:09,078 --> 00:59:10,379 BY PEOPLE IN THIS INSTITUTE AND 1528 00:59:10,379 --> 00:59:11,480 YOU CAN LEVERAGE EVERY SINGLE 1529 00:59:11,480 --> 00:59:13,182 SILL BOL OF EVERYTHING I'M ABOUT 1530 00:59:13,182 --> 00:59:14,216 TO DESCRIBE EVEN THOUGH NONE OF 1531 00:59:14,216 --> 00:59:16,418 THESE PROGRAMS ARE TREATING 1532 00:59:16,418 --> 00:59:17,886 EPILEPSY, BECAUSE FOUNDATIONALLY 1533 00:59:17,886 --> 00:59:19,288 AS I'M ABOUT TO EXPLAIN, CRISPR 1534 00:59:19,288 --> 00:59:20,055 IS A PLATFORM. 1535 00:59:20,055 --> 00:59:21,256 SO I'M GOING TO START FROM THE 1536 00:59:21,256 --> 00:59:23,158 TOP WHICH IS A PROJECT LED BY 1537 00:59:23,158 --> 00:59:26,328 JENNIFER DOUDNA AT MY IN INSTITE 1538 00:59:26,328 --> 00:59:28,230 AND I'M GOING TO INTRODUCE THE 1539 00:59:28,230 --> 00:59:29,732 WAY THE EDITING IS BEING DONE 1540 00:59:29,732 --> 00:59:30,966 THROUGH THE PRISSMM OF ONGOING 1541 00:59:30,966 --> 00:59:32,134 CLINICAL TRIALS FOR CRISPR. 1542 00:59:32,134 --> 00:59:34,670 SO YOU CAN UNDERSTAND HOW THIS 1543 00:59:34,670 --> 00:59:36,772 IS AN ITERATIVE PROGRESS, ONE 1544 00:59:36,772 --> 00:59:39,742 TRIAL BUILDS ON ANOTHER AND THEN 1545 00:59:39,742 --> 00:59:44,880 BUILDS ON THE NEXT. 1546 00:59:44,880 --> 00:59:48,083 SO THE IDEA OF GENE EDITING IS 1547 00:59:48,083 --> 00:59:49,485 YOU CREATE A DOUBLE STRAND 1548 00:59:49,485 --> 00:59:51,453 BREAK, NO, THEY DO NOT KILL 1549 00:59:51,453 --> 00:59:56,859 CELLS IF YOU DO THEM RIGHT,, SO 1550 00:59:56,859 --> 00:59:59,595 AT THIS POINT, WHAT DO YOU MEAN? 1551 00:59:59,595 --> 01:00:01,563 I READ IN THE POPULAR MEDIA THAT 1552 01:00:01,563 --> 01:00:03,565 TARGETS CAUSE CANCER AND KILL 1553 01:00:03,565 --> 01:00:04,533 PEOPLE. 1554 01:00:04,533 --> 01:00:05,634 IF YOU WORK WITH THE RIGHT 1555 01:00:05,634 --> 01:00:06,935 PEOPLE, WHETHER IN ACADEMIA OR 1556 01:00:06,935 --> 01:00:08,504 IN INDUSTRY, THEY WILL DELIVER 1557 01:00:08,504 --> 01:00:11,240 TO YOU A GENE EDITOR WITH SINGLE 1558 01:00:11,240 --> 01:00:13,709 LOCUS DEMONSTRABLE SPECIFICITY 1559 01:00:13,709 --> 01:00:19,581 IN IMD-GRADE MODELS WITH NO OFF 1560 01:00:19,581 --> 01:00:21,216 TARGETS ABOVE THE LIMIT OF 1561 01:00:21,216 --> 01:00:21,483 DETECTION. 1562 01:00:21,483 --> 01:00:24,820 IT IS A TECHNICALLY SOLVED 1563 01:00:24,820 --> 01:00:25,387 PROBLEM. 1564 01:00:25,387 --> 01:00:26,855 DOES THIS MEAN THE EDITOR WILL 1565 01:00:26,855 --> 01:00:28,357 BE SAFE IN HUMANS? 1566 01:00:28,357 --> 01:00:29,058 NOBODY KNOWS. 1567 01:00:29,058 --> 01:00:30,359 I WILL SAY AT THE VERY END, THE 1568 01:00:30,359 --> 01:00:32,461 ONLY WAY TO FIND OUT THAT 1569 01:00:32,461 --> 01:00:36,598 SOMETHING IS SAFE -- BUT I HEAR 1570 01:00:36,598 --> 01:00:37,833 THOSE OF YOU CURRENTLY SAYING 1571 01:00:37,833 --> 01:00:41,904 NOW IS NOT THE TIME FOR CRISPR 1572 01:00:41,904 --> 01:00:42,838 BECAUSE -- TARGET SOMETHING. 1573 01:00:42,838 --> 01:00:46,041 PERISH THE THOUGHT. 1574 01:00:46,041 --> 01:00:47,710 IN PHASE 3 WITH A DOUBLE STRANT 1575 01:00:47,710 --> 01:00:54,850 BREAK TO DO GENE DISRUPTION, 1576 01:00:54,850 --> 01:00:56,552 IN -- SUBJECTS. 1577 01:00:56,552 --> 01:00:58,220 THIS BRAND NEW TECHNOLOGY CALLED 1578 01:00:58,220 --> 01:00:59,555 CRISPR, WHICH ONE DAY MAY 1579 01:00:59,555 --> 01:01:03,258 HAVE -- ARE YOU JOKING? 1580 01:01:03,258 --> 01:01:05,527 765 SUBJECTS IN A PHASE 3 TRIAL. 1581 01:01:05,527 --> 01:01:06,562 HOW DID THEY GET THAT FAR? 1582 01:01:06,562 --> 01:01:08,897 THEY USED NON-VIRAL DELIVERY, 1583 01:01:08,897 --> 01:01:10,733 WITH A NANOPARTICLE, 1584 01:01:10,733 --> 01:01:12,935 SYSTEMICALLY ADMINISTERED 1585 01:01:12,935 --> 01:01:16,572 WITH -- TO DELIVER, IDENTIFIES 1586 01:01:16,572 --> 01:01:19,842 THE DTR GENE, A MU TAN FORM OF 1587 01:01:19,842 --> 01:01:22,578 WHICH CAUSE THE 1588 01:01:22,578 --> 01:01:23,712 NEURODEGENERATION AND HARD 1589 01:01:23,712 --> 01:01:25,881 DEGENERATION AND KNOCKS THE GENE 1590 01:01:25,881 --> 01:01:26,281 OUT. 1591 01:01:26,281 --> 01:01:28,050 WHAT'S REALLY IMPACTFUL IS THIS, 1592 01:01:28,050 --> 01:01:29,952 THERE'S A COMPLETE UNCOUPLING OF 1593 01:01:29,952 --> 01:01:31,353 THE PHARMACOKINETICS AND 1594 01:01:31,353 --> 01:01:32,955 PHARMACODYNAMICS. 1595 01:01:32,955 --> 01:01:34,890 THE EDITOR BY PHARMACOKINETIC 1596 01:01:34,890 --> 01:01:37,493 STUDIES LASTS FOR 72 HOURS. 1597 01:01:37,493 --> 01:01:38,694 THE PHARMACODYNAMICS ARE AS LONG 1598 01:01:38,694 --> 01:01:39,561 AS PEOPLE HAVE LOOKED. 1599 01:01:39,561 --> 01:01:40,829 SO WHAT YOU'RE LOOKING AT HERE 1600 01:01:40,829 --> 01:01:42,131 AT THE SUBJECTS FOR TWO 1601 01:01:42,131 --> 01:01:43,599 DIFFERENT COHORTS ARE DOSED AT 1602 01:01:43,599 --> 01:01:44,867 DAY ZERO, AND THEN YOU MONITOR 1603 01:01:44,867 --> 01:01:48,504 THE SERUM BIOMARKER IN THE 1604 01:01:48,504 --> 01:01:49,972 BLOODSTREAM OF THE TARGET GENE 1605 01:01:49,972 --> 01:01:53,008 BEING KNOCKED OUT, OUT TO 24 1606 01:01:53,008 --> 01:01:53,375 MONTHS. 1607 01:01:53,375 --> 01:02:00,516 THEY HAVE ACHIEVED 96% WHOLE 1608 01:02:00,516 --> 01:02:04,453 GENOME SINGLE GENE KNOCKOUT WITH 1609 01:02:04,453 --> 01:02:08,390 NO DETECTABLE OFF TARGET 1610 01:02:08,390 --> 01:02:09,057 EFFECTS. 1611 01:02:09,057 --> 01:02:12,194 SPRTLSEPARATELY, THEY HAVE KEPT 1612 01:02:12,194 --> 01:02:14,663 EVERYTHING THE SAME, THEY 1613 01:02:14,663 --> 01:02:17,633 CHANGED ONE THING, 20 1614 01:02:17,633 --> 01:02:18,834 NUCLEOTIDES IN THE GUIDE RNA, 1615 01:02:18,834 --> 01:02:22,104 THE TARGET OF DIFFERENT -- THE 1616 01:02:22,104 --> 01:02:22,905 ROUTE OF ADMINISTRATION IS THE 1617 01:02:22,905 --> 01:02:23,572 SAME. 1618 01:02:23,572 --> 01:02:25,874 THE BIOMARKER IS DIFFERENT. 1619 01:02:25,874 --> 01:02:27,176 BUT CRISPR IS A PLATFORM. 1620 01:02:27,176 --> 01:02:29,077 YOU GO FROM MEDICINE ONE TO 1621 01:02:29,077 --> 01:02:31,280 MEDICINE TWO BY SWAPPING OUT 20 1622 01:02:31,280 --> 01:02:31,814 NUCLEOTIDES OF THE GUIDE. 1623 01:02:31,814 --> 01:02:33,949 THE SAME IS TREUP TO DEVELOPING 1624 01:02:33,949 --> 01:02:38,420 EPIGENETIC STRATEGIES -- TO 1625 01:02:38,420 --> 01:02:38,821 CLINICAL PRACTICE. 1626 01:02:38,821 --> 01:02:41,723 AT THE HIGHEST DOSE COHORT, OUT 1627 01:02:41,723 --> 01:02:44,359 TO 88 WEEKS POST DOSING. 1628 01:02:44,359 --> 01:02:47,429 THEY SEE IDENTICAL LEVELS OF 1629 01:02:47,429 --> 01:02:48,897 ELIMINATION OF A DIFFERENT SERUM 1630 01:02:48,897 --> 01:02:49,264 MARKER. 1631 01:02:49,264 --> 01:02:50,999 THIS IS HOW FAR A KNOCKOUT BASED 1632 01:02:50,999 --> 01:02:53,335 APPROACH TO CRISPR GENE EDITING 1633 01:02:53,335 --> 01:02:54,503 HAS GONE INTO THE CLINIC. 1634 01:02:54,503 --> 01:02:58,674 THIS IS ALSO THE APPROACH THAT'S 1635 01:02:58,674 --> 01:03:00,375 THE BASIS FOR -- BRINGING US 1636 01:03:00,375 --> 01:03:01,677 CLOSER TO THE HEAD, AT LEAST, 1637 01:03:01,677 --> 01:03:04,246 HAS DOSED 15 SUBJECTS WITH AAV, 1638 01:03:04,246 --> 01:03:05,848 AND AGAIN I THANK BEV AND THE 1639 01:03:05,848 --> 01:03:07,950 FIELD OF AAV FOR HAVING GIVEN 1640 01:03:07,950 --> 01:03:09,551 THUS TOOL IN WHICH THEY'RE 1641 01:03:09,551 --> 01:03:10,219 CREATING TWO DOUBLE STRAND 1642 01:03:10,219 --> 01:03:11,687 BREAKS TO ELIMINATE THE 1643 01:03:11,687 --> 01:03:12,821 PATHOGENIC VARIANTS WHICH 1644 01:03:12,821 --> 01:03:13,722 CREATES LOSS OF VISION. 1645 01:03:13,722 --> 01:03:15,824 THE RESULT FROM THIS COHORT WERE 1646 01:03:15,824 --> 01:03:16,825 JUST PUBLISHED IN THE NEW 1647 01:03:16,825 --> 01:03:17,726 ENGLAND JOURNAL. 1648 01:03:17,726 --> 01:03:19,828 BY THE WAY, VICKY HAS MY SLIDES 1649 01:03:19,828 --> 01:03:21,430 SO ANYONE, PLEASE, YOU'RE 1650 01:03:21,430 --> 01:03:22,364 WELCOME TO MY SLIDES. 1651 01:03:22,364 --> 01:03:24,433 THE BOTTOM LINE S THERE IS CLEAR 1652 01:03:24,433 --> 01:03:26,401 PRELIMINARY EVIDENCE OF EFFICACY 1653 01:03:26,401 --> 01:03:29,438 AND -- UNFORTUNATELY THEY 1654 01:03:29,438 --> 01:03:30,606 DROPPED THE PROGRAM BECAUSE IT'S 1655 01:03:30,606 --> 01:03:31,773 NOT COMMERCIALLY VIABLE BECAUSE 1656 01:03:31,773 --> 01:03:33,408 THERE ARE ONLY 300 PATIENTS AND 1657 01:03:33,408 --> 01:03:35,477 EVEN IF THEY PRICE IT AT 1658 01:03:35,477 --> 01:03:36,411 $3.5 MILLION A PATIENT, THEY 1659 01:03:36,411 --> 01:03:37,946 WON'T BE ABLE TO MAKE MONEY. 1660 01:03:37,946 --> 01:03:39,581 I'M NOT TRYING TO BE -- BUT 1661 01:03:39,581 --> 01:03:46,822 THAT'S WHAT THEY JUST DID. 1662 01:03:46,822 --> 01:03:48,590 JENNIFER AND HER WONDERFUL TEAM 1663 01:03:48,590 --> 01:03:50,759 HAS NOW FUNDED THE CONSORTIUM TO 1664 01:03:50,759 --> 01:03:52,027 TAKE OVER THE NEXT FOUR YEARS TO 1665 01:03:52,027 --> 01:03:54,529 THE CLINIC THIS APPROACH OF A 1666 01:03:54,529 --> 01:03:57,599 DOUBLE CUT USING EITHER AAV OR 1667 01:03:57,599 --> 01:04:02,104 INNOVATIVE METHODS OF DELIVERY, 1668 01:04:02,104 --> 01:04:03,138 PROBABLY INTRAPARENCHYMAL AT 1669 01:04:03,138 --> 01:04:06,375 LEAST INITIALLY TO EXCISE 1670 01:04:06,375 --> 01:04:07,709 PATHOGENIC REPEATS IN THE BRAIN 1671 01:04:07,709 --> 01:04:11,446 OF SUBJECTS WITH EITHER HD OR 1672 01:04:11,446 --> 01:04:12,981 C9 -- OR ALS. 1673 01:04:12,981 --> 01:04:14,283 WHY AM I TELLING YOU THIS? 1674 01:04:14,283 --> 01:04:15,951 BECAUSE WE CAN ENGINEER A GENE 1675 01:04:15,951 --> 01:04:18,487 EDITOR THAT WILL ELIMINATE A 1676 01:04:18,487 --> 01:04:19,888 PATHOGENIC GAIN OF FUNCTION 1677 01:04:19,888 --> 01:04:23,358 VARIANT IN AN EPILEPSY CAUSING 1678 01:04:23,358 --> 01:04:30,866 GENE, ALEVE-SELECTIVELY. ALLELEH 1679 01:04:30,866 --> 01:04:32,701 HIGH EFFICIENCY AND SPECIFICITY, 1680 01:04:32,701 --> 01:04:34,303 100% OF THE REGULATORY INTO 1681 01:04:34,303 --> 01:04:35,203 MANUFACTURING LEARNINGS FROM OUR 1682 01:04:35,203 --> 01:04:36,038 PROJECTS ARE AVAILABLE TO 1683 01:04:36,038 --> 01:04:36,872 EVERYONE IN THIS ROOM. 1684 01:04:36,872 --> 01:04:38,607 THIS IS A FEDERALLY FUNDED 1685 01:04:38,607 --> 01:04:39,274 EFFORT. 1686 01:04:39,274 --> 01:04:42,811 WE ARE FUNDED TO BE THE RISING 1687 01:04:42,811 --> 01:04:43,879 TIDE. 1688 01:04:43,879 --> 01:04:46,315 BUT THEODORE, THIS IS HUNT TINGE 1689 01:04:46,315 --> 01:04:47,950 TONS AND HD AND ALS. 1690 01:04:47,950 --> 01:04:49,551 WHAT DOES THAT HAVE TO DO WITH 1691 01:04:49,551 --> 01:04:50,185 EPILEPSY? 1692 01:04:50,185 --> 01:04:50,852 EVERYTHING. 1693 01:04:50,852 --> 01:04:52,721 THE DISEASE END POINTS ARE 1694 01:04:52,721 --> 01:04:55,357 DIFFERENT BUT HOW YOU MAKE THE 1695 01:04:55,357 --> 01:04:57,326 VIRUS IS THE SAME, HOW YOU DO 1696 01:04:57,326 --> 01:04:58,527 THE SAFETY IS THE SAME, 1697 01:04:58,527 --> 01:04:59,528 EVERYTHING IS THE SAME EXCEPT 1698 01:04:59,528 --> 01:05:00,862 THE DISEASE-SPECIFIC MODEL. 1699 01:05:00,862 --> 01:05:04,800 SO YOU CAN TAKE 90% OF THE INK D 1700 01:05:04,800 --> 01:05:08,003 AND THE PATH TO IT AND DO A 1701 01:05:08,003 --> 01:05:08,537 GLOBAL SEARCH REPLACE. 1702 01:05:08,537 --> 01:05:19,081 THEY HAVE GONE FROM TGR -- NEXT. 1703 01:05:20,215 --> 01:05:21,583 THEY HAVE A REMARKABLE PROJECT 1704 01:05:21,583 --> 01:05:22,884 TO USE THE SECOND VERSION OF 1705 01:05:22,884 --> 01:05:24,653 GENE EDITING WHICH IS CALLED 1706 01:05:24,653 --> 01:05:29,024 BASE EDITING. 1707 01:05:29,024 --> 01:05:32,794 THEY ARE FUNDED TO DO BASE 1708 01:05:32,794 --> 01:05:37,165 EDITING FOR FIRST SPINAL 1709 01:05:37,165 --> 01:05:40,235 MUSCULAR ATROPHY -- I DON'T HAVE 1710 01:05:40,235 --> 01:05:41,670 TO TELL THIS AUDIENCE WHAT THE 1711 01:05:41,670 --> 01:05:43,038 SEIZURE SPECTRUM IS IN GIRLS AND 1712 01:05:43,038 --> 01:05:44,873 WOMEN WITH TOURETTE'S SYNDROME. 1713 01:05:44,873 --> 01:05:46,775 SO WHAT IS BASE EDITING? 1714 01:05:46,775 --> 01:05:48,310 I DON'T WANT TO GO THROUGH THIS 1715 01:05:48,310 --> 01:05:49,511 BECAUSE IT WILL JUST PUT 1716 01:05:49,511 --> 01:05:50,278 EVERYONE TO SLEEP. 1717 01:05:50,278 --> 01:05:53,148 BUT HERE IS WHAT I NEED YOU TO 1718 01:05:53,148 --> 01:05:54,349 UNDERSTAND. 1719 01:05:54,349 --> 01:05:57,652 IT IS A WAY TO REPAIR POINT 1720 01:05:57,652 --> 01:05:57,919 MUTATIONS. 1721 01:05:57,919 --> 01:05:59,721 IT IS ALSO A WAY TO CREATE POINT 1722 01:05:59,721 --> 01:06:00,856 MUTATIONS IF YOU WANT TO DO THAT 1723 01:06:00,856 --> 01:06:04,459 AND I IT DOES NOT INVOLVE A DOUE 1724 01:06:04,459 --> 01:06:04,893 STRAND BREAK. 1725 01:06:04,893 --> 01:06:07,029 IF YOU NEED TO REPAIR A 1726 01:06:07,029 --> 01:06:08,563 CAUSATIVE MUTATION, IT'S A 1727 01:06:08,563 --> 01:06:12,367 REALLY GOOD WAY TO DO THIS. 1728 01:06:12,367 --> 01:06:14,936 SO IT IS IN THE CLINIC, IT IS IN 1729 01:06:14,936 --> 01:06:16,338 THE CLINIC FOR HEART DISEASE NO 1730 01:06:16,338 --> 01:06:17,672 LESS. 1731 01:06:17,672 --> 01:06:20,342 VERVE HAS TAKEN A MESSENGER RNA 1732 01:06:20,342 --> 01:06:22,511 ENCODING BASE EDITOR AND GUIDE 1733 01:06:22,511 --> 01:06:26,114 RNA AND IT SOUNDS AWFULLY 1734 01:06:26,114 --> 01:06:27,315 LIKE -- BECAUSE CRISPR IS A 1735 01:06:27,315 --> 01:06:27,816 PLATFORM. 1736 01:06:27,816 --> 01:06:30,085 BUT INSTEAD OF TARGETING TTR, 1737 01:06:30,085 --> 01:06:35,390 THEY TARGETED PCS K-9, HARBORING 1738 01:06:35,390 --> 01:06:36,591 A BASE EDITOR. 1739 01:06:36,591 --> 01:06:38,593 AND SO THAT'S THE PRECISE CHANGE 1740 01:06:38,593 --> 01:06:40,962 ON THE RIGHT YOU SEE HERE, JUST 1741 01:06:40,962 --> 01:06:42,664 ONE BASE PAIR CHANGE WHICH 1742 01:06:42,664 --> 01:06:45,167 KNOCKS OUT PCS K-9. 1743 01:06:45,167 --> 01:06:46,701 THIS IS THE CLINICAL RELEVANCE, 1744 01:06:46,701 --> 01:06:48,703 FOLKS, THAT THE HIGHEST DOSE 1745 01:06:48,703 --> 01:06:50,138 COHORT SUBJECT EXPERIENCE IS 60% 1746 01:06:50,138 --> 01:06:52,107 REDUCTION IN SERUM CHOLESTEROL. 1747 01:06:52,107 --> 01:06:53,308 I EMPHASIZE, THIS IS NOT A 1748 01:06:53,308 --> 01:06:53,809 MOUSE. 1749 01:06:53,809 --> 01:06:55,343 THIS IS A NEW ZEALANDER. 1750 01:06:55,343 --> 01:06:56,211 THAT'S WHERE THEY'RE DOING THE 1751 01:06:56,211 --> 01:06:58,647 TRIAL. 1752 01:06:58,647 --> 01:07:00,649 THEY HAVE AN OPEN IND IN THE 1753 01:07:00,649 --> 01:07:03,218 UNITED STATES. 1754 01:07:03,218 --> 01:07:06,154 CRITICALLY TO THE POINT OF 1755 01:07:06,154 --> 01:07:08,824 UNCOUPLING PHARMACOKINETICS TO 1756 01:07:08,824 --> 01:07:09,224 PHARMACODYNAMICS. 1757 01:07:09,224 --> 01:07:10,592 THIS IS A DIFFERENT BIOTECH, 1758 01:07:10,592 --> 01:07:11,626 DIFFERENT EDITOR, COMPLETELY 1759 01:07:11,626 --> 01:07:13,228 DIFFERENT DISEASE BUT THE 1760 01:07:13,228 --> 01:07:14,162 PHENOMENON IS THE SAME. 1761 01:07:14,162 --> 01:07:16,231 THE DURABILITY OF THE 1762 01:07:16,231 --> 01:07:17,899 PHARMACODYNAMIC EFFECT OUT TO 1763 01:07:17,899 --> 01:07:18,967 180 DAYS POST DOSING IS 1764 01:07:18,967 --> 01:07:23,705 COMPLETELY UNCOUPLED FROM THE 7H 1765 01:07:23,705 --> 01:07:25,240 THE DRUG SUBSTANCE LIVES IN THE 1766 01:07:25,240 --> 01:07:30,679 BLOODSTREAM OF THE SUBJECT. 1767 01:07:30,679 --> 01:07:32,981 WHY AM I TELLING YOU THIS WITH 1768 01:07:32,981 --> 01:07:37,185 RESPECT TO NEUROLOGIC DISEASE? 1769 01:07:37,185 --> 01:07:39,955 BECAUSE THEY'RE FUNDED BY THE 1770 01:07:39,955 --> 01:07:43,792 SOMATIC CELL GENOME -- I CONSULT 1771 01:07:43,792 --> 01:07:45,327 FOR FRANK BENNETT AND I TRULY 1772 01:07:45,327 --> 01:07:46,128 WORSHIP HIM. 1773 01:07:46,128 --> 01:07:47,629 I KNOW MANY OF YOU KNOW WHAT THE 1774 01:07:47,629 --> 01:07:50,232 LIFETIME COSTS ARE OF TREATING A 1775 01:07:50,232 --> 01:07:54,870 SUBJECT WITH SMA WITH SPIN RAH 1776 01:07:54,870 --> 01:07:55,704 IS A. 1777 01:07:55,704 --> 01:07:56,304 I KNOW YOU KNOW. 1778 01:07:56,304 --> 01:07:57,038 NOT A JOKE. 1779 01:07:57,038 --> 01:07:59,074 SO WHILE IT HAS SAVED 14,000 1780 01:07:59,074 --> 01:07:59,975 CHILDREN, THE HEALTHCARE 1781 01:07:59,975 --> 01:08:00,942 ECONOMICS ARE DIFFICULT. 1782 01:08:00,942 --> 01:08:02,310 THIS AIMS TO BE A ONE AND DONE 1783 01:08:02,310 --> 01:08:05,180 AND THAT'S A BIG THEME FOR 1784 01:08:05,180 --> 01:08:06,281 CRISPR TOOLS. 1785 01:08:06,281 --> 01:08:09,050 SO THEY PUBLISHED NON-CLINICAL 1786 01:08:09,050 --> 01:08:10,986 EFFICACY IN SCIENCE SO I WON'T 1787 01:08:10,986 --> 01:08:12,988 GO THROUGH THIS, BUT I WANT TO 1788 01:08:12,988 --> 01:08:14,189 EMPHASIZE TO THIS COMMUNITY THAT 1789 01:08:14,189 --> 01:08:15,924 THE WAY IT'S CONFIGURED IS TO 1790 01:08:15,924 --> 01:08:17,492 LEVERAGE THE PLATFORM NATURE OF 1791 01:08:17,492 --> 01:08:19,728 CRISPR AS AN APPROACH AND TO 1792 01:08:19,728 --> 01:08:21,930 HAVE INVESTIGATORS FIRST TREAT 1793 01:08:21,930 --> 01:08:23,565 SUBJECTS ON ONE COHORT, IN THIS 1794 01:08:23,565 --> 01:08:26,468 CASE, THIS WOULD BE FOR SMA, AND 1795 01:08:26,468 --> 01:08:27,636 THEN REPURPOSE IT FOR A 1796 01:08:27,636 --> 01:08:28,537 DIFFERENT NEUROLOGIC DISEASE AND 1797 01:08:28,537 --> 01:08:33,275 IN THIS CASE, THEY'RE GOING TO 1798 01:08:33,275 --> 01:08:35,477 GO FOR -- I IMAGINE MANY OF YOU 1799 01:08:35,477 --> 01:08:40,749 HAVE SEEN THE STAGGERING REPORTS 1800 01:08:40,749 --> 01:08:41,816 SHOWING TWO SUBJECTS WITH 1801 01:08:41,816 --> 01:08:43,451 TOURETTE'S SYNDROME WHO WERE 1802 01:08:43,451 --> 01:08:45,620 DOSED WITH AAE CONTROLLABLE -- 1803 01:08:45,620 --> 01:08:47,322 THEY HAVE EXPERIENCED AN 1804 01:08:47,322 --> 01:08:48,757 IMPROVEMENT THAT NEUROLOGISTS 1805 01:08:48,757 --> 01:08:50,659 HAVE NEVER SEEN, LIZ I KNOW IS 1806 01:08:50,659 --> 01:08:52,127 IN THE AUDIENCE IS VERY PROUD OF 1807 01:08:52,127 --> 01:08:52,661 THIS. 1808 01:08:52,661 --> 01:08:56,398 I AM NOT GOING TO SAY A SINGLE 1809 01:08:56,398 --> 01:08:58,066 WORD ABOUT IT EXCEPT MY JAW WAS 1810 01:08:58,066 --> 01:09:02,904 ON THE FLOOR, I'M JUST A PH.D., 1811 01:09:02,904 --> 01:09:05,207 BUT YOU'RE IN THE GENES CLINIC, 1812 01:09:05,207 --> 01:09:06,308 THIS IS THE PLATFORM THIS 1813 01:09:06,308 --> 01:09:07,642 PLATFORM WILL STAND ON, AND THEY 1814 01:09:07,642 --> 01:09:11,313 WILL HAVE A SEIZURE END POINT IN 1815 01:09:11,313 --> 01:09:12,814 THEIR TARGET PROFILE, THEY WILL 1816 01:09:12,814 --> 01:09:15,784 HAVE A SE SEIZURE END POINT IN 1817 01:09:15,784 --> 01:09:16,985 THEIR CLINICAL TRIAL DESIGN. 1818 01:09:16,985 --> 01:09:21,856 THEY WILL HAVE BIODISTRIBUTION 1819 01:09:21,856 --> 01:09:27,562 DATA IN THE BRAIN. 1820 01:09:27,562 --> 01:09:29,297 YOU WILL BE ABLE TO LEVERAGE ALL 1821 01:09:29,297 --> 01:09:31,600 OF THAT FOR A CRISPR TRIAL FOR 1822 01:09:31,600 --> 01:09:32,067 EPILEPSY. 1823 01:09:32,067 --> 01:09:35,270 THERE'S ALSO PRIME EDITING. 1824 01:09:35,270 --> 01:09:36,805 IT'S IN PRINCIPLE, AND THIS 1825 01:09:36,805 --> 01:09:38,406 PERSON WHO GAVE THIS VERY MOVING 1826 01:09:38,406 --> 01:09:40,008 TALK AT THE BEGINNING MENTIONED 1827 01:09:40,008 --> 01:09:43,511 PRIME ET EDITING. 1828 01:09:43,511 --> 01:09:45,480 IN PRINCIPLE, IT'S A MORE 1829 01:09:45,480 --> 01:09:46,514 VERSATILE MUTATION REPAIR 1830 01:09:46,514 --> 01:09:46,982 METHOD. 1831 01:09:46,982 --> 01:09:49,050 IN PRACTICE, IT'S VERY FINICKY, 1832 01:09:49,050 --> 01:09:50,452 YOU HAVE TO APPROACH IT WITH 1833 01:09:50,452 --> 01:09:50,919 CARE. 1834 01:09:50,919 --> 01:09:52,787 IT IS ABOUT TO ENTER THE CLINIC 1835 01:09:52,787 --> 01:09:55,790 FOR A BLOOD DISEASE, CHRONIC 1836 01:09:55,790 --> 01:09:57,859 GRANULOSIS DISEASE, BY THE WAY, 1837 01:09:57,859 --> 01:10:00,161 HARRY MALEK AT THE NIH IS THE 1838 01:10:00,161 --> 01:10:01,162 WORLD'S LEADER ON THIS. 1839 01:10:01,162 --> 01:10:02,530 THE POINT I WANT TO MAKE IS THE 1840 01:10:02,530 --> 01:10:03,098 PAPER ON THE LEFT. 1841 01:10:03,098 --> 01:10:05,066 THIS IS FROM THE INVENTOR OF THE 1842 01:10:05,066 --> 01:10:08,670 PRIME EDITING, DAVID LU, HERE 1843 01:10:08,670 --> 01:10:12,340 THEY DID FAIRLY PLAIN VANILLA 1844 01:10:12,340 --> 01:10:13,541 DELIVERY OF PRIME EDITOR TO THE 1845 01:10:13,541 --> 01:10:15,310 MOUSE BRAIN. 1846 01:10:15,310 --> 01:10:16,177 THE BAR GRAPH ON THE RIGHT THAT 1847 01:10:16,177 --> 01:10:17,445 YOU CAN'T REALLY SEE, WHICH IS A 1848 01:10:17,445 --> 01:10:19,314 GOOD THING, BASICALLY MEASURES 1849 01:10:19,314 --> 01:10:20,915 BASE PRIME EDITING EFFICIENCY IN 1850 01:10:20,915 --> 01:10:22,717 VARIOUS TISSUES OF THE MOUSE 1851 01:10:22,717 --> 01:10:23,151 BRAIN. 1852 01:10:23,151 --> 01:10:26,021 THIS IS A 2023 STUDY DONE WITH 1853 01:10:26,021 --> 01:10:28,189 2021 TECHNOLOGY. 1854 01:10:28,189 --> 01:10:29,891 I CAN ASSURE YOU STANDING ON THE 1855 01:10:29,891 --> 01:10:31,126 SHOULDERS OF THE KIND OF DATA 1856 01:10:31,126 --> 01:10:32,160 THAT BEV DAVIDSON JUST SHOWED 1857 01:10:32,160 --> 01:10:34,129 YOU THAT WE'RE GOING TO GET TO 1858 01:10:34,129 --> 01:10:35,830 HIGH DOUBLE DIGITS PRIME EDITING 1859 01:10:35,830 --> 01:10:42,203 WITH SYSTEMIC ADMINISTRATION OF 1860 01:10:42,203 --> 01:10:44,306 NON-HUMAN PRIMATES VERY, VERY 1861 01:10:44,306 --> 01:10:46,508 SOON. 1862 01:10:46,508 --> 01:10:49,010 SO THIS WILL BE TREATED BY BASE 1863 01:10:49,010 --> 01:10:50,111 EDITING BECAUSE OF SOME 1864 01:10:50,111 --> 01:10:50,912 LIMITATIONS WE HAVE. 1865 01:10:50,912 --> 01:10:52,347 THERE IS PRIME EDITING 1866 01:10:52,347 --> 01:10:54,883 ACCELERATING VERY, VERY FAST. 1867 01:10:54,883 --> 01:11:00,055 FINALLY, SONIA VALLABH WHO NEEDS 1868 01:11:00,055 --> 01:11:01,156 NO INTRODUCTION TO THIS AUDIENCE 1869 01:11:01,156 --> 01:11:02,557 IS FUNDED TO DO SOMETHING ABOUT 1870 01:11:02,557 --> 01:11:04,893 THE PRION DISEASE THAT KILLED 1871 01:11:04,893 --> 01:11:06,561 HER MOTHER IN THIS DEVASTATING 1872 01:11:06,561 --> 01:11:08,229 WAY, MAY KILL HER BECAUSE SHE'S 1873 01:11:08,229 --> 01:11:09,364 40 YEARS OLD AND WE DON'T KNOW 1874 01:11:09,364 --> 01:11:10,332 HOW MUCH LONGER SHE HAS. 1875 01:11:10,332 --> 01:11:11,966 I HAD BREAKFAST WITH HER A FEW 1876 01:11:11,966 --> 01:11:13,702 WEEKS BAG. 1877 01:11:13,702 --> 01:11:14,202 BACK. 1878 01:11:14,202 --> 01:11:15,203 AND THE TECHNIQUE THEY'RE USING 1879 01:11:15,203 --> 01:11:16,738 IS YET ANOTHER ADDITION TO THE 1880 01:11:16,738 --> 01:11:18,740 CRISPR TOOLBOX, WHICH IS EPI 1881 01:11:18,740 --> 01:11:18,973 EDITING. 1882 01:11:18,973 --> 01:11:21,009 I NEED TO DISCLOSE A CONFLICT OF 1883 01:11:21,009 --> 01:11:23,545 INTEREST, I AM THE SCIENTIFIC 1884 01:11:23,545 --> 01:11:27,415 CO-FOUNDER, TECHNOLOGY COMPANY 1885 01:11:27,415 --> 01:11:29,718 THAT SEEKS TO MAKE COMMERCIAL 1886 01:11:29,718 --> 01:11:33,888 MEDICINES OFF EPI EDITING, BUT 1887 01:11:33,888 --> 01:11:34,789 MY EMOTIONAL CONFLICT OF 1888 01:11:34,789 --> 01:11:36,324 INTEREST IS EVEN LARGER. 1889 01:11:36,324 --> 01:11:38,626 BASICALLY NO DOUBLE STRAND 1890 01:11:38,626 --> 01:11:39,627 BREAKS, NO GENETIC CHANGES, IT'S 1891 01:11:39,627 --> 01:11:41,963 THE ABILITY TO INACTIVATE OR 1892 01:11:41,963 --> 01:11:42,597 ACTIVATE GENES AS WELL. 1893 01:11:42,597 --> 01:11:44,032 I'M NOT GOING TO GO THROUGH 1894 01:11:44,032 --> 01:11:45,166 TECHNICAL DETAILS EXCEPT TO SAY 1895 01:11:45,166 --> 01:11:47,402 THAT YOU CAN CUE THE DURATION OF 1896 01:11:47,402 --> 01:11:48,937 THE EFFECT SHORTER OR LONGER, 1897 01:11:48,937 --> 01:11:51,206 AND CRITICALLY, IT GIVES YOU THE 1898 01:11:51,206 --> 01:11:54,576 OPPORTUNITY FOR ALLELE-SELECTIVE 1899 01:11:54,576 --> 01:11:55,710 ACTIVATION OR INACTIVATION OF 1900 01:11:55,710 --> 01:11:56,311 GENE EXPRESSION. 1901 01:11:56,311 --> 01:11:58,213 AND I'M SURE THIS IS FINISHING 1902 01:11:58,213 --> 01:11:59,314 ALL SORTS OF PUZZLES IN YOUR 1903 01:11:59,314 --> 01:12:00,982 HEAD WITH RESPECT TO HOW THAT 1904 01:12:00,982 --> 01:12:03,084 CAN BE RELEVANT TO BOTH GAIN OF 1905 01:12:03,084 --> 01:12:04,419 FUNCTION AND LOSS OF FUNCTION 1906 01:12:04,419 --> 01:12:06,421 MUTATION IN EPILEPSY. 1907 01:12:06,421 --> 01:12:07,455 SO I'M GOING TO IN THE INTEREST 1908 01:12:07,455 --> 01:12:11,526 OF TIME SKIP THROUGH THIS AND 1909 01:12:11,526 --> 01:12:12,660 JUST GET STRAIGHT TO THIS. 1910 01:12:12,660 --> 01:12:13,661 THIS IS A PARTIAL LIST OF 1911 01:12:13,661 --> 01:12:15,764 COMPANIES THAT ARE 1912 01:12:15,764 --> 01:12:18,666 COMMERCIALIZING EPIGENOME 1913 01:12:18,666 --> 01:12:19,868 EDITING. 1914 01:12:19,868 --> 01:12:21,403 ONE OF THEM, ENCODED, HAS AN 1915 01:12:21,403 --> 01:12:27,642 OPEN IND FOR EPIGENOME EDITING, 1916 01:12:27,642 --> 01:12:29,110 AND THEIR NON-CLINICAL EFFICACY 1917 01:12:29,110 --> 01:12:30,979 IN MOUSE AND THEIR SAFETY AND 1918 01:12:30,979 --> 01:12:32,614 BIODISTRIBUTION IN NON-HUMAN 1919 01:12:32,614 --> 01:12:36,518 PRIMATE IS PUBLISHED. 1920 01:12:36,518 --> 01:12:40,221 BECAUSE I DON'T WORK ON 1921 01:12:40,221 --> 01:12:41,222 EPILEPSIES I'M NOT GOING TO 1922 01:12:41,222 --> 01:12:42,757 REVIEW A SINGLE PIECE OF THESE 1923 01:12:42,757 --> 01:12:43,792 DATA EXCEPT TO TELL YOU THAT 1924 01:12:43,792 --> 01:12:45,226 THEY'RE BUILDING AN ENGINEERED 1925 01:12:45,226 --> 01:12:46,194 TRANSCRIPTION FACTOR THAT AIMS 1926 01:12:46,194 --> 01:12:48,096 TO ACTIVATE THE REMAINING COPY 1927 01:12:48,096 --> 01:12:49,664 AND THEY'RE USING A PROMOTOR 1928 01:12:49,664 --> 01:12:52,367 THAT IS SPECIFIC TO INHIBITORY 1929 01:12:52,367 --> 01:12:52,700 INTERNEURONS. 1930 01:12:52,700 --> 01:12:54,736 I DON'T KNOW HOW TO SPELL IT SO 1931 01:12:54,736 --> 01:12:56,471 I'M NOT GOING TO EMBARRASS 1932 01:12:56,471 --> 01:12:57,472 MYSELF BUT I'M JUST SAYING TO 1933 01:12:57,472 --> 01:12:59,007 YOU WHAT THEY'RE DOING. 1934 01:12:59,007 --> 01:13:00,375 AND I DON'T KNOW ANYTHING ABOUT 1935 01:13:00,375 --> 01:13:01,709 MOUSE MODELS OF EPILEPSY BUT 1936 01:13:01,709 --> 01:13:02,777 MANY OF YOU DO. 1937 01:13:02,777 --> 01:13:04,979 SO IF YOU ARE INTERESTED IN HOW 1938 01:13:04,979 --> 01:13:06,848 AN EXISTING BIOTECHNOLOGY 1939 01:13:06,848 --> 01:13:13,087 COMPANY IS DEPLOYING EP GINO EPE 1940 01:13:13,087 --> 01:13:14,522 EDITING FOR A SPECIFIC 1941 01:13:14,522 --> 01:13:17,492 CONGENITAL SEIZURE DISORDER, 1942 01:13:17,492 --> 01:13:20,728 AGAIN THEY HAVE AN OPEN IND. 1943 01:13:20,728 --> 01:13:22,163 WHY AM I TELLING YOU THIS? 1944 01:13:22,163 --> 01:13:24,866 WELL, BECAUSE SONIA HAS A GRANT 1945 01:13:24,866 --> 01:13:26,768 TO DO THIS FOR PRION DISEASE. 1946 01:13:26,768 --> 01:13:28,570 THIS WOULD INVOLVE 1947 01:13:28,570 --> 01:13:30,738 ADMINISTRATION OF AN AAV THAT 1948 01:13:30,738 --> 01:13:32,674 HARBORS AN EPI EDITOR THAT WILL 1949 01:13:32,674 --> 01:13:34,843 SILENCE THE MUTANT ALLELE. 1950 01:13:34,843 --> 01:13:39,681 THAT KILLED HER MOM AND SO 1951 01:13:39,681 --> 01:13:41,049 EVERYTHING THAT THEY LEARN FROM 1952 01:13:41,049 --> 01:13:43,518 THIS EFFORT, YET AGAIN, WILL BE 1953 01:13:43,518 --> 01:13:45,687 UNDER THE RIGHT TERMS PUBLICLY 1954 01:13:45,687 --> 01:13:47,489 AVAILABLE INFORMATION, AND MOST 1955 01:13:47,489 --> 01:13:48,756 CERTAINLY AVAILABLE TO ANYONE IN 1956 01:13:48,756 --> 01:13:50,358 THIS ROOM WHO WISHES TO THINK 1957 01:13:50,358 --> 01:13:54,529 ABOUT EPI EDITING FOR THEIR 1958 01:13:54,529 --> 01:13:58,399 FLTHEIRLABOR OF EFFORTS. 1959 01:13:58,399 --> 01:14:00,935 I SAID TO HE BEGINNING THE 1960 01:14:00,935 --> 01:14:01,803 CLINICAL TRACK RECORD AND 1961 01:14:01,803 --> 01:14:03,538 DELIVERY WILL CONTINUE TO DRIVE 1962 01:14:03,538 --> 01:14:05,073 CRISPR PROGRESS. 1963 01:14:05,073 --> 01:14:06,140 SPECIFICALLY I TOLD YOU WE 1964 01:14:06,140 --> 01:14:10,278 STARTED WITH CLASSICAL EDITING, 1965 01:14:10,278 --> 01:14:14,115 AND THEN WE TRANSITIONED TO BASE 1966 01:14:14,115 --> 01:14:16,518 EDITING. 1967 01:14:16,518 --> 01:14:17,785 EPI EDITING. 1968 01:14:17,785 --> 01:14:18,653 IT CAN ONLY GROW. 1969 01:14:18,653 --> 01:14:22,390 I MENTIONED WE HAVE AN APPROVED 1970 01:14:22,390 --> 01:14:23,758 MEDICINE. 1971 01:14:23,758 --> 01:14:25,493 BUT I ALSO SAID THAT CRISPR IS A 1972 01:14:25,493 --> 01:14:27,328 PLATFORM THAT UNTIL YOU HAVE THE 1973 01:14:27,328 --> 01:14:30,698 PHASE 3 TRIAL WITH 765 SUBJECTS, 1974 01:14:30,698 --> 01:14:33,635 AND ALL THEY DID IS CHANGE 20 -- 1975 01:14:33,635 --> 01:14:36,471 I MENTIONED THAT PLATFO 1976 01:14:36,471 --> 01:14:37,138 PLATFORMABILITY -- THE FACT THAT 1977 01:14:37,138 --> 01:14:38,106 A DIFFERENT COMPANY USES THE 1978 01:14:38,106 --> 01:14:39,407 SAME DELIVERY TO TREAT A 1979 01:14:39,407 --> 01:14:40,375 COMPLETELY DIFFERENT DISEASE. 1980 01:14:40,375 --> 01:14:41,976 MOST IMPORTANTLY, I TOLD YOU 1981 01:14:41,976 --> 01:14:44,946 ABOUT THE PROGRAM THAT IS LED BY 1982 01:14:44,946 --> 01:14:46,781 THIS INSTITUTE, THE SOMATIC CELL 1983 01:14:46,781 --> 01:14:49,050 GENOME CONSORTIUM COLLABORATION, 1984 01:14:49,050 --> 01:14:51,085 WHICH HAS FUNDED THREE PROGRAMS 1985 01:14:51,085 --> 01:14:53,021 ALL THE WAY TO IND TO TARGET 1986 01:14:53,021 --> 01:14:58,226 MURLT MULTIPLE DISORTS OF THE CL 1987 01:14:58,226 --> 01:15:00,295 AND PERIPHERAL NERVOUS SYSTEM 1988 01:15:00,295 --> 01:15:01,930 AND EVERY SYLLABLE OF INNOVATION 1989 01:15:01,930 --> 01:15:03,631 THAT COMES OUT OF THAT WILL BE 1990 01:15:03,631 --> 01:15:05,600 AVAILABLE TO YOU. 1991 01:15:05,600 --> 01:15:07,902 INCLUDING -- IN CLOSING, DO YOU 1992 01:15:07,902 --> 01:15:11,139 MIND IF I TAKE ONE MORE MINUTE? 1993 01:15:11,139 --> 01:15:13,975 FOLKS, I DO NOT WANT TO BE A 1994 01:15:13,975 --> 01:15:15,843 DEBBIE DOWNER, I WANT TO BE 1995 01:15:15,843 --> 01:15:18,780 DEBBIE REALIST. 1996 01:15:18,780 --> 01:15:21,215 THERE IS ONE NEUROLOGIC DISEASE 1997 01:15:21,215 --> 01:15:25,420 IIN THE ENTIRE PORTFOLIO OF ALL 1998 01:15:25,420 --> 01:15:27,822 THE BIOTECH FOR-PROFIT CRISPR 1999 01:15:27,822 --> 01:15:29,290 COMPANIES IN THE WORLD. 2000 01:15:29,290 --> 01:15:31,159 ONE. 2001 01:15:31,159 --> 01:15:31,960 WHY IS THAT? 2002 01:15:31,960 --> 01:15:33,127 IS IT BECAUSE THEY'RE NOT GOOD 2003 01:15:33,127 --> 01:15:33,695 TARGETS? 2004 01:15:33,695 --> 01:15:34,495 NO. 2005 01:15:34,495 --> 01:15:36,331 IT'S BECAUSE CAPITALISM. 2006 01:15:36,331 --> 01:15:37,932 AGAIN, I'M NOT TRYING TO BE 2007 01:15:37,932 --> 01:15:38,866 ELIZABETH WARREN, I'M JUST 2008 01:15:38,866 --> 01:15:40,201 TELLING YOU WHAT IS REALLY 2009 01:15:40,201 --> 01:15:40,702 HAPPENING. 2010 01:15:40,702 --> 01:15:42,637 INVESTORS ARE INSISTING ON LATE 2011 01:15:42,637 --> 01:15:46,240 STAGE CLINICAL ASSETS I AND 2012 01:15:46,240 --> 01:15:46,975 NEUROLOGIC DISEASE TRIALS TAKE 2013 01:15:46,975 --> 01:15:47,408 LONG. 2014 01:15:47,408 --> 01:15:48,509 WHY ARE THEY DOING THAT? 2015 01:15:48,509 --> 01:15:50,478 I AM TOLD IT'S BECAUSE MONEY IS 2016 01:15:50,478 --> 01:15:51,746 EXPENSIVE RIGHT NOW. 2017 01:15:51,746 --> 01:15:54,616 NOW, THERE IS A SERIOUS ANSWER. 2018 01:15:54,616 --> 01:15:57,719 BUT WHY AM I TELLING YOU THIS? 2019 01:15:57,719 --> 01:15:59,120 I'M TELLING YOU THAT THAT I 2020 01:15:59,120 --> 01:16:00,321 BELIEVE THAT NOW IS A UNIQUE 2021 01:16:00,321 --> 01:16:02,256 MOMENT IN TIME FOR THE FEDERAL 2022 01:16:02,256 --> 01:16:03,491 ACADEMIC AND NON-PROFIT SECTOR 2023 01:16:03,491 --> 01:16:04,692 TO STEP UP. 2024 01:16:04,692 --> 01:16:07,095 THE FIRST THING YOU MUST 2025 01:16:07,095 --> 01:16:09,430 UNDERSTAND, FYODOR, LET'S DO 10 2026 01:16:09,430 --> 01:16:11,199 YEARS OF HUMAN PRIMATE STUDIES 2027 01:16:11,199 --> 01:16:12,734 BEFORE THINKING ABOUT EPILEPSY. 2028 01:16:12,734 --> 01:16:14,235 ABSOLUTELY NOT. 2029 01:16:14,235 --> 01:16:16,504 THE ONLY WAY TO FIND OUT HOW TO 2030 01:16:16,504 --> 01:16:18,306 SAFELY AND EFFECTIVELY GENE-EDIT 2031 01:16:18,306 --> 01:16:19,774 PEOPLE IS TO GENE-EDIT MORE 2032 01:16:19,774 --> 01:16:20,942 PEOPLE. 2033 01:16:20,942 --> 01:16:22,577 THAT APPLIES TO GENE THERAPY AS 2034 01:16:22,577 --> 01:16:24,212 WELL AND REMEMBER, GENE THERAPY 2035 01:16:24,212 --> 01:16:27,482 STARTED HERE, AT THE NIH, PETE 2036 01:16:27,482 --> 01:16:28,783 ROSENBERG IN 1989. 2037 01:16:28,783 --> 01:16:30,385 AND IN THAT 35-YEAR HISTORY OF 2038 01:16:30,385 --> 01:16:32,320 THE FIELD, NOT A SINGLE SEVERE 2039 01:16:32,320 --> 01:16:33,721 ADD DIVERSITY EVENT THAT WE SAW 2040 01:16:33,721 --> 01:16:35,523 ON TRIALS OF GENE THERAPY OR 2041 01:16:35,523 --> 01:16:37,492 GENE EDITING WERE PREDICTED FROM 2042 01:16:37,492 --> 01:16:39,627 ANY NON-CLINICAL STUDIES. 2043 01:16:39,627 --> 01:16:41,496 SO IF ANYONE IN THE ROOM THINKS, 2044 01:16:41,496 --> 01:16:44,165 LET'S DOSE A LOT MORE MONKEYS 2045 01:16:44,165 --> 01:16:46,801 BEFORE WE ARE COMFORTABLE DOSING 2046 01:16:46,801 --> 01:16:49,971 HUMANS, FOLKS, RESPECTFULLY, YOU 2047 01:16:49,971 --> 01:16:51,272 ARE DELUDING YOURSELF BY 2048 01:16:51,272 --> 01:16:52,573 THINKING YOU'RE MAKING THE 2049 01:16:52,573 --> 01:16:54,542 THERAPY SAFER BY DOSING MORE 2050 01:16:54,542 --> 01:16:54,876 MONKEYS. 2051 01:16:54,876 --> 01:16:56,511 I'M NOT SAYING YOU SHOULDN'T 2052 01:16:56,511 --> 01:16:57,345 DOSE MONKEYS. 2053 01:16:57,345 --> 01:17:00,515 I'M SAYING THE REAL -- THAT WILL 2054 01:17:00,515 --> 01:17:01,883 EMERGE WILL ONLY EMERGE IF YOU 2055 01:17:01,883 --> 01:17:05,486 DO THE CLINICAL TRIAL. 2056 01:17:05,486 --> 01:17:09,991 ANSO IF YOUR GOAL IS TO USE CRIR 2057 01:17:09,991 --> 01:17:11,726 TO TREAT EPILEPSIES, PROGRAMS 2058 01:17:11,726 --> 01:17:13,394 CAN BE BUILT -- AND THIS IS MY 2059 01:17:13,394 --> 01:17:14,996 MOST IMPORTANT STATEMENT OF THE 2060 01:17:14,996 --> 01:17:16,297 DAY -- RIGHT NOW. 2061 01:17:16,297 --> 01:17:16,931 NOT FOUR YEARS FROM NOW. 2062 01:17:16,931 --> 01:17:18,533 THAT TAKE ON SPECIFIC TARGETS IN 2063 01:17:18,533 --> 01:17:21,169 THE EPILEPSY SPACE, THAT GANTT 2064 01:17:21,169 --> 01:17:24,138 CHART THEM OUT WITH MILESTONES 2065 01:17:24,138 --> 01:17:27,675 AND GO/NO-GO GATES, AND 2066 01:17:27,675 --> 01:17:28,242 DR. KOROSHETZ, TIM AND CHRIS 2067 01:17:28,242 --> 01:17:30,344 WILL GLADLY SEND YOU THOSE GANTT 2068 01:17:30,344 --> 01:17:31,879 CHARTS FOR THE FIVE PROGRAMS 2069 01:17:31,879 --> 01:17:33,514 THAT THEY ARE CURRENTLY 2070 01:17:33,514 --> 01:17:35,016 MANAGING. 2071 01:17:35,016 --> 01:17:36,651 AND THEN YOU PUT THEM THROUGH 2072 01:17:36,651 --> 01:17:39,620 REGULATORY REVIEW, USING THE 2073 01:17:39,620 --> 01:17:41,022 FRAMEWORK THAT THE CONSORTIUM 2074 01:17:41,022 --> 01:17:43,391 HAS ESTABLISHED, TO ADVANCE TO 2075 01:17:43,391 --> 01:17:44,926 IND AND CLINICAL TRIALS. 2076 01:17:44,926 --> 01:17:47,061 LAST QUOTE, THIS IS THE QUOTE I 2077 01:17:47,061 --> 01:17:50,131 ALWAYS END MY TALKS ON, AMANDA 2078 01:17:50,131 --> 01:17:54,068 GOGORMAN SAID AT PRESIDENT BIDES 2079 01:17:54,068 --> 01:17:56,804 INAUGURATION, WHY SHOULD THE 2080 01:17:56,804 --> 01:17:58,740 FEDERAL GOVERNMENT DO THIS, WHY 2081 01:17:58,740 --> 01:18:00,408 SHOULD THE ACADEMICS AND 2082 01:18:00,408 --> 01:18:01,509 NON-PROFITS DO THIS? 2083 01:18:01,509 --> 01:18:02,310 WELL, BECAUSE WE'RE POWERFUL. 2084 01:18:02,310 --> 01:18:07,715 AND THE WAY TO LIVE MOST -- 2085 01:18:07,715 --> 01:18:08,182 THANK YOU. 2086 01:18:08,182 --> 01:18:12,420 [APPLAUSE] 2087 01:18:12,420 --> 01:18:14,589 >> WE'RE A LITTLE BIT OVER BUT 2088 01:18:14,589 --> 01:18:15,757 CAN WE TAKE TWO OR THREE 2089 01:18:15,757 --> 01:18:16,090 QUESTIONS? 2090 01:18:16,090 --> 01:18:18,593 WE'RE GOING TO THEN HAVE A 2091 01:18:18,593 --> 01:18:18,793 BREAK. 2092 01:18:18,793 --> 01:18:29,203 THE MICROPHONES WORKING? 2093 01:18:38,579 --> 01:18:39,247 WHILE YOU'RE READING THAT, I 2094 01:18:39,247 --> 01:18:40,114 HAVE A QUESTION FOR YOU. 2095 01:18:40,114 --> 01:18:42,583 WHAT EXPLAINS THE PROLONGED 2096 01:18:42,583 --> 01:18:43,818 PHARMACODYNAMIC EFFECT? 2097 01:18:43,818 --> 01:18:46,087 >> SO THE PROLONGED 2098 01:18:46,087 --> 01:18:46,988 PHARMACODYNAMIC EFFECT AS BEST 2099 01:18:46,988 --> 01:18:50,758 AS WE CAN TELL BY LITERALLY 2100 01:18:50,758 --> 01:18:52,126 GENOTYPING NON-HUMAN PRIMATES, 2101 01:18:52,126 --> 01:18:55,129 IS THAT THE EDITED ALLELES DO 2102 01:18:55,129 --> 01:18:57,198 NOT GENETICALLY REVERT. 2103 01:18:57,198 --> 01:18:58,699 SO -- AND FURTHERMORE, THE 2104 01:18:58,699 --> 01:19:03,004 EDITED CELLS DO NOT EPITOSE. 2105 01:19:03,004 --> 01:19:04,672 THAT WAS THE BIG FEAR. 2106 01:19:04,672 --> 01:19:07,809 BUT IF THE EDITED CELLS WOULD 2107 01:19:07,809 --> 01:19:09,443 EPITOSE AND WOULD BE OVERGROWN, 2108 01:19:09,443 --> 01:19:11,045 THEN THE PHARMACODYNAMICS WOULD 2109 01:19:11,045 --> 01:19:11,345 PLUMMET. 2110 01:19:11,345 --> 01:19:13,481 BUT STRIKINGLY, THE EDITED CELLS 2111 01:19:13,481 --> 01:19:15,316 PERSIST. 2112 01:19:15,316 --> 01:19:17,084 AND SO THE KNOCKOUT ALLELES JUST 2113 01:19:17,084 --> 01:19:17,952 HAVE NOWHERE TO GO. 2114 01:19:17,952 --> 01:19:19,654 BUT I WANT TO BE CLEAR, WE WERE 2115 01:19:19,654 --> 01:19:24,058 ALL AFRAID THAT YOU WOULD GET 2116 01:19:24,058 --> 01:19:26,360 80% EDITING AT TWO MONTHS AND 2117 01:19:26,360 --> 01:19:28,796 THEN 4% EDITING AT A YEAR, 2118 01:19:28,796 --> 01:19:30,464 BECAUSE YOU KNOW, EDITING IS 2119 01:19:30,464 --> 01:19:30,998 TOXIC. 2120 01:19:30,998 --> 01:19:32,466 THAT'S NOT WHAT WAS SEEN IN 2121 01:19:32,466 --> 01:19:32,834 CLINICAL TRIAL. 2122 01:19:32,834 --> 01:19:33,401 I'M GLAD YOU ASKED. 2123 01:19:33,401 --> 01:19:36,904 IT WAS A KEY CONCERN, FRANKLY. 2124 01:19:36,904 --> 01:19:38,239 VICKY, IS THERE A QUESTION 2125 01:19:38,239 --> 01:19:42,677 ONLINE? 2126 01:19:42,677 --> 01:19:46,747 JUST READ IT? 2127 01:19:46,747 --> 01:19:54,555 >> QUESTION FROM -- 2128 01:19:54,555 --> 01:19:56,557 >> AS I LIKE TO SAY IN SUCH 2129 01:19:56,557 --> 01:19:57,825 SITUATIONS, NO DISRESPECT TO 2130 01:19:57,825 --> 01:19:59,260 ANYONE, WE CAN CHANGE A SINGLE 2131 01:19:59,260 --> 01:20:00,461 BASE PAIR IN THE HUMAN GENOME 2132 01:20:00,461 --> 01:20:02,663 BUT CERTAINLY AT THE GENOMICS 2133 01:20:02,663 --> 01:20:05,233 INSTITUTE WHERE WE DO THAT, WE 2134 01:20:05,233 --> 01:20:10,504 STRUGGLE WITH AAGs ALL THE 2135 01:20:10,504 --> 01:20:11,005 TIME. 2136 01:20:11,005 --> 01:20:12,807 BEV DAVIDSON HAS IT FULLY UNDER 2137 01:20:12,807 --> 01:20:15,476 CONTROL. 2138 01:20:15,476 --> 01:20:18,179 I KNOW, I KNOW, DR. DAVIDSON IS 2139 01:20:18,179 --> 01:20:20,648 SAYING, GET YOUR STUFF -- LET'S 2140 01:20:20,648 --> 01:20:20,882 GO. 2141 01:20:20,882 --> 01:20:22,783 YES. 2142 01:20:22,783 --> 01:20:24,085 I MEAN, LOOK AT THE 2143 01:20:24,085 --> 01:20:25,686 BIODISTRIBUTION YOU SAW IN THE 2144 01:20:25,686 --> 01:20:29,590 NHP BEV JUST SHOWED. 2145 01:20:29,590 --> 01:20:36,264 GOT IT, VICKY? 2146 01:20:36,264 --> 01:20:37,798 >> WE'RE HAVING PROBLEMS 2147 01:20:37,798 --> 01:20:39,200 UNMUTING THE PERSON. 2148 01:20:39,200 --> 01:20:41,903 WE'RE INVITING HIM TO UNMUTE. 2149 01:20:41,903 --> 01:20:42,904 CAN YOU UNMUTE? 2150 01:20:42,904 --> 01:20:44,438 >> SO CAN THAT PERSON ASK DURING 2151 01:20:44,438 --> 01:20:45,506 THE PANEL? 2152 01:20:45,506 --> 01:20:47,541 >> YES, WE CAN COME BACK. 2153 01:20:47,541 --> 01:20:48,643 >> OKAY. 2154 01:20:48,643 --> 01:20:49,677 WITH NO DISRESPECT. 2155 01:20:49,677 --> 01:20:50,611 >> WHY DON'T WE DO THAT. 2156 01:20:50,611 --> 01:20:51,846 >> OKAY. 2157 01:20:51,846 --> 01:20:52,046 SORRY. 2158 01:20:52,046 --> 01:20:53,648 >> ANY OTHER QUESTIONS IN THE 2159 01:20:53,648 --> 01:20:54,081 ROOM? 2160 01:20:54,081 --> 01:20:54,548 NO? 2161 01:20:54,548 --> 01:20:55,616 SO WE'RE SCHEDULED TO NOW TAKE A 2162 01:20:55,616 --> 01:20:56,117 BREAK. 2163 01:20:56,117 --> 01:20:57,285 WE'LL BE BACK IN 11 MINUTES OR SO. 2164 01:20:57,285 --> 01:20:59,987 THANKS AGAIN. 2165 01:21:06,027 --> 01:21:09,430 >> OKAY, WE'RE GOING TO START 2166 01:21:09,430 --> 01:21:18,839 UP. 2167 01:21:18,839 --> 01:21:20,675 IF YOU COULD TAKE YOUR SEATS, 2168 01:21:20,675 --> 01:21:22,009 PLEASE, AND DR. TIPPI MACKENZIE 2169 01:21:22,009 --> 01:21:25,579 IS GOING TO PRESENT. 2170 01:21:25,579 --> 01:21:27,348 TIPPI -- I THINK SHE'S IN 2171 01:21:27,348 --> 01:21:29,583 EUROPE, SO SHE HAD TO -- BECAUSE 2172 01:21:29,583 --> 01:21:31,352 OF THE TIME ISSUE, SHE'S 2173 01:21:31,352 --> 01:21:33,888 RECORDED HER PRESENTATION, BUT 2174 01:21:33,888 --> 01:21:35,456 IS POTENTIALLY AVAILABLE FOR THE 2175 01:21:35,456 --> 01:21:35,656 Q & A. 2176 01:21:35,656 --> 01:21:36,724 SO IF YOU COULD ALL PLEASE TAKE 2177 01:21:36,724 --> 01:21:43,064 YOUR SEATS. 2178 01:21:43,064 --> 01:21:44,832 AND SHE'S ON ZOOM. 2179 01:21:44,832 --> 01:21:45,132 GREAT. 2180 01:21:45,132 --> 01:21:47,402 SO LET'S START THE RECORDED PART AND TIPPI IS LISTENING IN. 2181 01:21:50,908 --> 01:21:51,175 HI EVERYONE. 2182 01:21:51,175 --> 01:21:52,476 THANK YOU SO MUCH FOR THE 2183 01:21:52,476 --> 01:21:53,844 INVITATION TO PRESENT, AND I 2184 01:21:53,844 --> 01:21:55,112 APOLOGIZE FOR NOT BEING ABLE TO 2185 01:21:55,112 --> 01:21:56,480 BE THERE IN PERSON. 2186 01:21:56,480 --> 01:21:58,081 MY NAME IS TIPPI MACKENZIE. 2187 01:21:58,081 --> 01:22:00,184 I'M A PROFESSOR OF SURGERY AT 2188 01:22:00,184 --> 01:22:03,554 UCSF AND I DIRECT OUR STEM CELL 2189 01:22:03,554 --> 01:22:05,289 INSTITUTE, AS WELL AS 2190 01:22:05,289 --> 01:22:06,823 CO-DIRECTING OUR CENTER FOR 2191 01:22:06,823 --> 01:22:07,724 MATERNAL-FETAL PRECISION 2192 01:22:07,724 --> 01:22:08,892 MEDICINE, WHERE WE TRY TO 2193 01:22:08,892 --> 01:22:10,327 DEVELOP NEW THERAPIES FOR 2194 01:22:10,327 --> 01:22:13,931 FETUSES WITH GENETIC DISEASES. 2195 01:22:13,931 --> 01:22:18,302 THESE ARE MY DISCLOSURES. 2196 01:22:18,302 --> 01:22:20,804 SO I'M VERY EXCITED ABOUT 2197 01:22:20,804 --> 01:22:22,539 TELLING YOU ABOUT INNOVATIONS IN 2198 01:22:22,539 --> 01:22:24,174 FETAL THERAPY AND HOW THESE 2199 01:22:24,174 --> 01:22:26,677 COULD BE RELEVANT FOR TREATING 2200 01:22:26,677 --> 01:22:28,111 PATIENTS WITH GENETIC CAUSES OF 2201 01:22:28,111 --> 01:22:29,846 EPILEPSY. 2202 01:22:29,846 --> 01:22:31,715 SO FETAL SURGERY IS A FIELD THAT 2203 01:22:31,715 --> 01:22:34,351 WAS INVENTED AT UCSF IN THE 2204 01:22:34,351 --> 01:22:35,385 1980s, AND HAS BEEN 2205 01:22:35,385 --> 01:22:37,020 DISSEMINATED ALL OVER THE WORLD 2206 01:22:37,020 --> 01:22:39,856 NOW, WHERE PEOPLE CAN DO OPEN 2207 01:22:39,856 --> 01:22:41,525 FETAL SURGERY FOR CONDITIONS 2208 01:22:41,525 --> 01:22:43,260 SUCH AS SPINA BIFIDA, AND I'M 2209 01:22:43,260 --> 01:22:45,429 SHOWING YOU A SPINA BIFIDA 2210 01:22:45,429 --> 01:22:46,730 REPAIR HERE, AS WELL AS 2211 01:22:46,730 --> 01:22:48,799 LAPAROSCOPIC SURGERIES IN THE 2212 01:22:48,799 --> 01:22:52,769 FETUS, WHICH WE CALL FETOSCOPIC, 2213 01:22:52,769 --> 01:22:54,071 CATHETER BASED INTERVENTIONS TO 2214 01:22:54,071 --> 01:22:55,239 DRAIN FLUID COLLECTIONS, ET 2215 01:22:55,239 --> 01:22:57,407 CETERA, AND WE HAVE AN AMAZING 2216 01:22:57,407 --> 01:23:00,410 WAY OF GETTING INTO THE FETAL 2217 01:23:00,410 --> 01:23:01,478 UMBILICAL VEIN, USUALLY JUST 2218 01:23:01,478 --> 01:23:02,779 WITH ULTRASOUND GUIDANCE, AND 2219 01:23:02,779 --> 01:23:04,514 THIS ACTUALLY HAS BEEN AROUND 2220 01:23:04,514 --> 01:23:07,951 SINCE THE 1960s TO GIVE BLOOD 2221 01:23:07,951 --> 01:23:09,486 TRANSFUSIONS FOR PATIENTS WHO 2222 01:23:09,486 --> 01:23:10,821 HAVE RH INEXAT ABILITY BETWEEN 2223 01:23:10,821 --> 01:23:13,657 THE MOTHER AND THE FETUS. 2224 01:23:13,657 --> 01:23:17,127 AND THE ABILITY TO GIVE A 2225 01:23:17,127 --> 01:23:20,631 SYSTEMIC INVEUTION ALLOWS US TO 2226 01:23:20,631 --> 01:23:22,165 CONSIDER SEMI STILL 2227 01:23:22,165 --> 01:23:23,066 TRANSPLANTATION, ENZYME 2228 01:23:23,066 --> 01:23:25,135 REPLACEMENT THERAPY OR, IN THE 2229 01:23:25,135 --> 01:23:26,670 FUTURE, GENE THERAPY OR GENOME 2230 01:23:26,670 --> 01:23:27,838 EDITING AND COLLECTIVELY WE CAN 2231 01:23:27,838 --> 01:23:30,107 REFER TO THESE AS FETAL 2232 01:23:30,107 --> 01:23:30,841 MOLECULAR THERAPIES. 2233 01:23:30,841 --> 01:23:32,209 YOU MAY WONDER WHY NOT WAIT 2234 01:23:32,209 --> 01:23:32,576 UNTIL BIRTH. 2235 01:23:32,576 --> 01:23:35,112 OF COURSE WE'RE TRYING TO 2236 01:23:35,112 --> 01:23:36,313 PREVENT IRREVERSIBLE ORGAN 2237 01:23:36,313 --> 01:23:37,014 DAMAGE. 2238 01:23:37,014 --> 01:23:38,382 BUT IN ADDITION TO THAT, THE 2239 01:23:38,382 --> 01:23:39,683 FETAL ENVIRONMENT OFFERS 2240 01:23:39,683 --> 01:23:42,185 NUMEROUS ADVANTAGES BIOLOGICALLY 2241 01:23:42,185 --> 01:23:43,954 FOR THE SUCCESS OF SUCH 2242 01:23:43,954 --> 01:23:46,123 THERAPIES, SUCH AS HAVING A MORE 2243 01:23:46,123 --> 01:23:48,759 PERMEABLE BLOOD BRAIN BARRIER 2244 01:23:48,759 --> 01:23:51,461 LIKELY UP UNTIL THE END OF THE 2245 01:23:51,461 --> 01:23:52,362 SECOND TRIMESTER, A UNIQUE 2246 01:23:52,362 --> 01:23:54,331 IMMUNE SYSTEM THAT ALLOWS US TO 2247 01:23:54,331 --> 01:23:57,067 TOLERIZE TO NEW ANTIGENS SUCH AS 2248 01:23:57,067 --> 01:23:58,502 TRANSGENE ENCODED PROTEINS, 2249 01:23:58,502 --> 01:24:00,470 ACCESSIBLE STEM CELL 2250 01:24:00,470 --> 01:24:01,872 POPULATIONS, AS WELL AS A SMALL 2251 01:24:01,872 --> 01:24:03,707 SIZE THAT ALLOWS US TO REALLY 2252 01:24:03,707 --> 01:24:05,676 DECREASE THE MANUFACTURING COST 2253 01:24:05,676 --> 01:24:08,245 OF A NEW THERAPY. 2254 01:24:08,245 --> 01:24:10,380 WE USUALLY DOSE AROUND 400 OR 2255 01:24:10,380 --> 01:24:14,885 500 GRAMS OF FETAL WEIGHT. 2256 01:24:14,885 --> 01:24:17,387 THERE ARE RATIONALE FOR TREATING 2257 01:24:17,387 --> 01:24:18,822 CONDITIONS IN ALL OF THESE 2258 01:24:18,822 --> 01:24:21,558 DIFFERENT SYSTEMS. 2259 01:24:21,558 --> 01:24:22,993 FOR THE CNS SPECIFICALLY, WE 2260 01:24:22,993 --> 01:24:31,101 THINK A LOT ABOUT SMA OR 2261 01:24:31,101 --> 01:24:32,069 ANGELMAN, OF COURSE THEY MUST 2262 01:24:32,069 --> 01:24:33,337 ALL BE SEVERE AND EARLY ONSET 2263 01:24:33,337 --> 01:24:35,539 AND HAVE A GOOD GENOTYPE 2264 01:24:35,539 --> 01:24:36,406 PHENOTYPE CORRELATION BECAUSE BY 2265 01:24:36,406 --> 01:24:38,041 DEFINITION WE'RE TREATING A 2266 01:24:38,041 --> 01:24:38,775 GENOTYPE THAT WE'VE DETECTED ON 2267 01:24:38,775 --> 01:24:40,877 THE FETUS WITHOUT HOPEFULLY -- 2268 01:24:40,877 --> 01:24:41,111 YES. 2269 01:24:41,111 --> 01:24:44,281 SO THIS IS THE TOOLKIT FOR 2270 01:24:44,281 --> 01:24:46,950 PRENATAL THERAPY OF CNS 2271 01:24:46,950 --> 01:24:47,851 DISEASES. 2272 01:24:47,851 --> 01:24:51,054 SO WE CAN HAVE PRETEENS OR SMALL 2273 01:24:51,054 --> 01:24:53,557 MOLECULES, GENE REPLACEMENT 2274 01:24:53,557 --> 01:24:54,691 THERAPY OR GENOME EDITING. 2275 01:24:54,691 --> 01:24:56,293 IN THE CURRENT REALM WE'RE 2276 01:24:56,293 --> 01:24:58,362 CURRENTLY FOCUSING ON THERAPIES 2277 01:24:58,362 --> 01:24:59,563 FDA-APPROVED FOR CHILDREN FOR 2278 01:24:59,563 --> 01:25:00,530 APPLICATIONS FOR PRENATAL 2279 01:25:00,530 --> 01:25:01,198 THERAPY. 2280 01:25:01,198 --> 01:25:02,966 SO IN TERMS OF THE PIPELINE OF 2281 01:25:02,966 --> 01:25:08,438 PLEK RAR FMOLECULAR THERAPIES AE 2282 01:25:08,438 --> 01:25:10,073 HAVE EXPERIENCE WITH SOME STEM 2283 01:25:10,073 --> 01:25:11,942 CELL TRANSPLANTATION THAT'S LESS 2284 01:25:11,942 --> 01:25:12,943 RELEVANT FOR TODAY SO I WON'T 2285 01:25:12,943 --> 01:25:13,910 REALLY TALK ABOUT THAT. 2286 01:25:13,910 --> 01:25:15,412 WE HAVE AN ONGOING CLINICAL 2287 01:25:15,412 --> 01:25:17,381 TRIAL FOR IN UTERO ENZYME 2288 01:25:17,381 --> 01:25:19,383 REPLACEMENT THERAPY IN LYSOSOMAL 2289 01:25:19,383 --> 01:25:20,517 STORAGE DISEASES. 2290 01:25:20,517 --> 01:25:22,052 I THINK THAT IS LIKELY RELEVANT 2291 01:25:22,052 --> 01:25:23,954 SO I WILL TALK A LITTLE BIT 2292 01:25:23,954 --> 01:25:26,223 ABOUT OUR EXPERIENCE, AND THEN 2293 01:25:26,223 --> 01:25:28,158 WE AND OTHERS ARE REALLY WORKING 2294 01:25:28,158 --> 01:25:30,360 ON PRE-CLINICAL MODELS FOR 2295 01:25:30,360 --> 01:25:34,598 PRENATAL GENE THERAPY, USING 2296 01:25:34,598 --> 01:25:37,033 ASOs, AAV GENE REPLACEMENT OR 2297 01:25:37,033 --> 01:25:38,001 GENOME EDITING. 2298 01:25:38,001 --> 01:25:39,202 AND I'LL PAUSE AND SAY THAT THIS 2299 01:25:39,202 --> 01:25:42,472 FIELD IS NOT AT ALL ABOUT 2300 01:25:42,472 --> 01:25:44,641 EDITING IVF EMBRYOS. 2301 01:25:44,641 --> 01:25:46,176 WE'RE REALLY THINKING ONLY ABOUT 2302 01:25:46,176 --> 01:25:47,844 EDITING SOMATIC CELLS IN A 2303 01:25:47,844 --> 01:25:52,849 SECOND TRIMESTER FETUS. 2304 01:25:52,849 --> 01:25:54,384 SO LYSOSOMAL STORAGE DISEASES, 2305 01:25:54,384 --> 01:25:56,353 AS YOU ALL KNOW, ARE GENETIC 2306 01:25:56,353 --> 01:25:58,321 DISEASES CAUSING DEFICIENCIES IN 2307 01:25:58,321 --> 01:26:00,056 CRITICAL LYSOSOMAL ENZYMES, AND 2308 01:26:00,056 --> 01:26:01,158 WE FIRST GOT INTERESTED IN THEM 2309 01:26:01,158 --> 01:26:02,559 BECAUSE SOME OF THEM CAN PRESENT 2310 01:26:02,559 --> 01:26:06,730 WITH HYDROPS, FOR EXAMPLE, ON 2311 01:26:06,730 --> 01:26:09,533 MPS7 AND HAVE IN UTERO DEMISE. 2312 01:26:09,533 --> 01:26:11,234 ALTHOUGH THERE ARE SOME 2313 01:26:11,234 --> 01:26:13,403 POSTNATAL THERAPIES SUCH AS 2314 01:26:13,403 --> 01:26:14,704 RECOMBINANT ENZYME REPLACEMENT 2315 01:26:14,704 --> 01:26:15,906 THERAPY OR STEM CELL TRANSPLANT, 2316 01:26:15,906 --> 01:26:17,207 THERE IS STILL RATIONALE IN THAT 2317 01:26:17,207 --> 01:26:19,176 YOU CAN POTENTIALLY PREERCHT IN 2318 01:26:19,176 --> 01:26:20,844 UTERO DEMISE, INDUCE TOLERANCE 2319 01:26:20,844 --> 01:26:26,450 TO THE MISSING ENZYME, IN WHICH 2320 01:26:26,450 --> 01:26:27,584 IMMUNE REACTIONS CAN BE LIMITED 2321 01:26:27,584 --> 01:26:29,052 IN SOME CONDITIONS SUCH AS POM 2322 01:26:29,052 --> 01:26:30,353 PAY DISEASE, YOU CAN DELIVER 2323 01:26:30,353 --> 01:26:31,721 ENZYME TO THE BRAIN AT LEAST 2324 01:26:31,721 --> 01:26:33,123 DURING THE PERIOD THAT THE BLOOD 2325 01:26:33,123 --> 01:26:35,058 BRAIN BARRIER IS PERMEABLE AND 2326 01:26:35,058 --> 01:26:36,726 PREVENT ONGOING ORGAN DAMAGE. 2327 01:26:36,726 --> 01:26:38,795 SO WE FIRST DID THIS IN MICE, OF 2328 01:26:38,795 --> 01:26:42,098 COURSE, AS YOU DO, SO IN 2329 01:26:42,098 --> 01:26:44,234 MPS7 MICE, WE SAW THAT IN UTERO 2330 01:26:44,234 --> 01:26:46,770 INFUSIONS OF THE ENZYME IMPROVE 2331 01:26:46,770 --> 01:26:47,537 SURVIVAL, DECREASE STORAGE. 2332 01:26:47,537 --> 01:26:49,272 THEY DID PENETRATE INTO 2333 01:26:49,272 --> 01:26:51,441 MICROGLIA IN THE CNS, IMPROVE 2334 01:26:51,441 --> 01:26:52,976 BONE LENGTH AND IMPORTANTLY, 2335 01:26:52,976 --> 01:26:55,278 INDUCE TOLERANCE TO THEIR COME 2336 01:26:55,278 --> 01:26:56,179 NENT PROTEIN. 2337 01:26:56,179 --> 01:26:57,047 THAT'S PUBLISHED SO I WON'T GET 2338 01:26:57,047 --> 01:26:57,781 INTO IT. 2339 01:26:57,781 --> 01:27:00,417 PRIOR TO AEMPLOYING FOR AN IND, 2340 01:27:00,417 --> 01:27:01,852 WE ALSO STARTED PERFORMING A 2341 01:27:01,852 --> 01:27:04,754 SURVEY OF PATIENT GROUPS WITH -- 2342 01:27:04,754 --> 01:27:06,957 WE'VE HEARD AN OVERWHELMING YES 2343 01:27:06,957 --> 01:27:08,825 TO FETAL THERAPY AND WE'VE HAD 2344 01:27:08,825 --> 01:27:11,561 AN IND SINCE 2020. 2345 01:27:11,561 --> 01:27:12,996 AND THE CLINICAL TRIAL WAS 2346 01:27:12,996 --> 01:27:15,031 LAUNCHED A FEW YEARS AGO. 2347 01:27:15,031 --> 01:27:17,334 SO IT'S THE PEARL TRIAL. 2348 01:27:17,334 --> 01:27:19,202 WE WERE ABLE TO GET A PLATFORM 2349 01:27:19,202 --> 01:27:21,738 IND TO TREAT PATIENTS WITH EIGHT 2350 01:27:21,738 --> 01:27:22,806 DIFFERENT CONDITIONS, ALL OF 2351 01:27:22,806 --> 01:27:24,908 THESE HAVE AN FDA-APPROVED IV 2352 01:27:24,908 --> 01:27:26,309 FORMULATION OF THE ENZYME. 2353 01:27:26,309 --> 01:27:28,411 AND THE WAY IT WORKS IS USUALLY 2354 01:27:28,411 --> 01:27:30,146 THE DIAGNOSIS IN A FETUS IS MADE 2355 01:27:30,146 --> 01:27:33,884 IN FAMILIES WHERE THEY ALREADY 2356 01:27:33,884 --> 01:27:34,851 KNOW THEY'RE CARRIERS, THEY 2357 01:27:34,851 --> 01:27:36,720 MIGHT HAVE HAD A PREESKT 2358 01:27:36,720 --> 01:27:37,954 AFFECTED PREGNANCY OR A CHILD, 2359 01:27:37,954 --> 01:27:39,256 AND ONCE THE DIAGNOSIS IS 2360 01:27:39,256 --> 01:27:42,292 CONFIRMED AND THE PATIENT MEETS 2361 01:27:42,292 --> 01:27:44,361 ENROLLMENT CRITERIA, WE DO THE 2362 01:27:44,361 --> 01:27:46,329 ENZYME INFUSIONS EVERY TWO TO 2363 01:27:46,329 --> 01:27:47,397 FOUR WEEKS BECAUSE THAT'S THE 2364 01:27:47,397 --> 01:27:48,832 HALF-LIFE OF THE ENZYME THROUGH 2365 01:27:48,832 --> 01:27:50,500 THE UMBILICAL VEIN, AND THEN 2366 01:27:50,500 --> 01:27:52,569 AFTER BIRTH, WE DO STANDARD OF 2367 01:27:52,569 --> 01:27:54,237 CARE ENZYME REPLACEMENT THERAPY, 2368 01:27:54,237 --> 01:27:57,240 OF COURSE, BUT THEY'RE ELIGIBLE 2369 01:27:57,240 --> 01:27:58,375 FOR OTHER CLINICAL TRIALS OF 2370 01:27:58,375 --> 01:28:00,443 GENE THERAPIES OR STEM CELLS, 2371 01:28:00,443 --> 01:28:02,045 AND THEN WE'RE DOING A FIVE-YEAR 2372 01:28:02,045 --> 01:28:04,714 FOLLOW-UP. 2373 01:28:04,714 --> 01:28:06,650 IT'S A PHASE ONE TRIAL SO OUR 2374 01:28:06,650 --> 01:28:07,350 PRIMARY OBJECTIVES ARE SAFETY 2375 01:28:07,350 --> 01:28:09,386 AND FEASIBILITY, BUT THE 2376 01:28:09,386 --> 01:28:10,720 SECONDARY OBJECTIVES, OF COURSE, 2377 01:28:10,720 --> 01:28:12,589 ARE EFFICACY, SO ARE WE 2378 01:28:12,589 --> 01:28:15,091 DECREASING THE METABOLIC 2379 01:28:15,091 --> 01:28:16,927 BYPRODUCTS, THE GAGS, ARE WE 2380 01:28:16,927 --> 01:28:17,594 INDUCING TOLERANCE TO THE 2381 01:28:17,594 --> 01:28:19,462 PROTEIN AND ALSO LOOKING AT 2382 01:28:19,462 --> 01:28:20,997 LONG-TERM OUTCOMES. 2383 01:28:20,997 --> 01:28:24,034 SO THE WAY WE DO THIS ULTRASOUND 2384 01:28:24,034 --> 01:28:29,105 GUIDED INJECTION IS -- WELL, DRG 2385 01:28:29,105 --> 01:28:30,140 MFM WHO DOES ALL OF THESE IN 2386 01:28:30,140 --> 01:28:32,375 ADDITION TO THE IN UTERO 2387 01:28:32,375 --> 01:28:32,809 TRANSFUSIONS. 2388 01:28:32,809 --> 01:28:35,745 AND SO AT THE POINT OF ENTRY OF 2389 01:28:35,745 --> 01:28:37,547 THE NEEDLE INTO THE UMBILICAL 2390 01:28:37,547 --> 01:28:38,615 VEIN, YOU CAN DRAW BACK A LITTLE 2391 01:28:38,615 --> 01:28:40,183 BIT OF BLOOD AND THAT'S REALLY 2392 01:28:40,183 --> 01:28:41,785 USEFUL FOR CHECKING TROUGH 2393 01:28:41,785 --> 01:28:44,421 LEVELS AND SUBSEQUENT INFUSIONS, 2394 01:28:44,421 --> 01:28:46,957 CHECKING AP ANTI-DRUG ANTIBODIES 2395 01:28:46,957 --> 01:28:48,158 WELL AS UNDERSTANDING WHETHER 2396 01:28:48,158 --> 01:28:50,093 WE'RE MAKING A DIFFERENCE IN 2397 01:28:50,093 --> 01:28:51,428 DISEASE-SPECIFIC BIOMARKERS. 2398 01:28:51,428 --> 01:28:52,629 IT'S OF COURSE A TECHNICALLY 2399 01:28:52,629 --> 01:28:55,265 DELL CAN'T PROCEDURE, SO WE 2400 01:28:55,265 --> 01:28:56,066 ALWAYS COUNSEL FAMILIES THAT 2401 01:28:56,066 --> 01:28:58,868 THERE IS A RISK OF PRETERM 2402 01:28:58,868 --> 01:29:01,271 DELIVERY, OR EVEN IN UTERO 2403 01:29:01,271 --> 01:29:01,504 DEMISE. 2404 01:29:01,504 --> 01:29:05,742 WE THINK THE RISK IS LESS THAN E 2405 01:29:05,742 --> 01:29:11,014 LESS THAN 1% SIDE OF IT. 2406 01:29:11,014 --> 01:29:12,415 SO OUR FIRST EXPERIENCE WAS WITH 2407 01:29:12,415 --> 01:29:16,252 A FAMILY WHOSE THIRD FETUS WAS 2408 01:29:16,252 --> 01:29:18,755 DIAGNOSED WITH INFANTILE ONSET 2409 01:29:18,755 --> 01:29:19,656 POMPE DISEASE. 2410 01:29:19,656 --> 01:29:22,392 THE CRIM NEGATIVE IOPD, WHICH IS 2411 01:29:22,392 --> 01:29:24,694 THE MORE SEVERE VERSION, AND THE 2412 01:29:24,694 --> 01:29:26,529 SIBLING 1 HAD BEEN DIAGNOSED AT 2413 01:29:26,529 --> 01:29:27,664 8 MONTHS, SUFFERED FROM IMMUNE 2414 01:29:27,664 --> 01:29:30,700 REACTIONS TO THE ENZYME AND DIED 2415 01:29:30,700 --> 01:29:32,469 AT 29 MONTHS. 2416 01:29:32,469 --> 01:29:33,870 SIBLING TWO WAS PRENATALLY 2417 01:29:33,870 --> 01:29:35,972 DIAGNOSED AND HAD PALLIATIVE 2418 01:29:35,972 --> 01:29:37,407 CARE, SO THE PATIENTS WERE VERY 2419 01:29:37,407 --> 01:29:39,175 MOTIVATED TO SEEK KIND OF A 2420 01:29:39,175 --> 01:29:41,378 DIFFERENT TREATMENT PLAN FOR THE 2421 01:29:41,378 --> 01:29:42,545 THIRD PREGNANCY. 2422 01:29:42,545 --> 01:29:44,848 THE RATIONALE FOR THE IN UTERO 2423 01:29:44,848 --> 01:29:46,449 THERAPY WAS THE NON-SEVERE 2424 01:29:46,449 --> 01:29:47,684 PHENOTYPE IN THIS FAMILY. 2425 01:29:47,684 --> 01:29:50,320 THEY'D HAD EARLY ONSET 2426 01:29:50,320 --> 01:29:50,820 CARDIOMYOPATHY AS WELL. 2427 01:29:50,820 --> 01:29:52,188 THIS WAS AN INNATIONAL 2428 01:29:52,188 --> 01:29:53,657 COLLABORATION KIND OF IN THE 2429 01:29:53,657 --> 01:29:54,824 HEAT OF THE PANDEMIC WITH 2430 01:29:54,824 --> 01:29:56,993 COLLEAGUES AT CHILDREN'S 2431 01:29:56,993 --> 01:29:58,428 HOSPITAL OF EASTERN ONTARIO AND 2432 01:29:58,428 --> 01:30:00,597 DUKE, WHERE WE DID NON-DIRECTIVE 2433 01:30:00,597 --> 01:30:02,065 COUNSELING, THE PATIENT RECEIVED 2434 01:30:02,065 --> 01:30:05,935 SIX DOSES OF THE ENZYME INFUSION 2435 01:30:05,935 --> 01:30:07,537 AND HAD A TERM DELIVERY AND IS 2436 01:30:07,537 --> 01:30:08,638 NOW TWO YEARS OLD AND DOING 2437 01:30:08,638 --> 01:30:10,874 WELL. 2438 01:30:10,874 --> 01:30:12,942 WE DID SEE A BENEFIT IN THE 2439 01:30:12,942 --> 01:30:13,677 CARDIOMYOPATHY. 2440 01:30:13,677 --> 01:30:16,846 SO I'M SHOWING YOU HERE PRENATAL 2441 01:30:16,846 --> 01:30:18,048 ECHOCARDIOGRAMS FROM SIBLING 2, 2442 01:30:18,048 --> 01:30:19,716 THE AFFECTED FETUS WHO WAS NOT 2443 01:30:19,716 --> 01:30:20,717 TREATED, AND YOU SEE THAT 2444 01:30:20,717 --> 01:30:22,118 THERE'S A THICKENING OF THE 2445 01:30:22,118 --> 01:30:23,553 SEPTUM BETWEEN THE RIGHT AND 2446 01:30:23,553 --> 01:30:26,189 LEFT VENTRICLE HERE, THE Z SCORE 2447 01:30:26,189 --> 01:30:26,823 WAS 7. 2448 01:30:26,823 --> 01:30:29,492 WHEREAS IN THE IP UTERO-TREATED 2449 01:30:29,492 --> 01:30:30,994 PATIENT, THE SEPTAL THICKNESS 2450 01:30:30,994 --> 01:30:33,530 WAS NORMAL. 2451 01:30:33,530 --> 01:30:35,565 AT BIRTH THE PATIENT HAD NORMAL 2452 01:30:35,565 --> 01:30:38,234 CK LEVELS, COMPARING THEM TO A 2453 01:30:38,234 --> 01:30:41,171 NEWBORN SCREENING, A COHORT OF 2454 01:30:41,171 --> 01:30:44,340 CRIM NEGATIVE IOPD PATIENTS, YOU 2455 01:30:44,340 --> 01:30:45,775 CAN SEE THAT THEY ALL START WITH 2456 01:30:45,775 --> 01:30:47,644 HIGHER THAN NORMAL CK LEVELS. 2457 01:30:47,644 --> 01:30:49,979 AND CONSISTENT WITH THAT, WE DID 2458 01:30:49,979 --> 01:30:50,914 SEE A MOTOR BENEFIT IN OUR 2459 01:30:50,914 --> 01:30:53,316 PATIENT WHO HAD NORMAL 2460 01:30:53,316 --> 01:30:55,652 MILESTONES AS OPPOSED TO TWO OUT 2461 01:30:55,652 --> 01:30:57,120 OF THE FOUR OF THE NEWBORN 2462 01:30:57,120 --> 01:30:58,888 DIAGNOSED PATIENTS WHO HAD MOTOR 2463 01:30:58,888 --> 01:31:00,457 DELAYS. 2464 01:31:00,457 --> 01:31:02,058 AND OUR PATIENT WALKED AT 11 2465 01:31:02,058 --> 01:31:03,693 MONTHS. 2466 01:31:03,693 --> 01:31:06,896 SO WE'VE SINCE TREATED THREE 2467 01:31:06,896 --> 01:31:08,631 PATIENTS, AND THERE ARE ALSO TWO 2468 01:31:08,631 --> 01:31:09,833 MORE IN UTERO RIGHT NOW. 2469 01:31:09,833 --> 01:31:12,035 WE HAVEN'T HAD, THANK GOODNESS, 2470 01:31:12,035 --> 01:31:13,136 ANY SAFETY EVENTS. 2471 01:31:13,136 --> 01:31:15,138 EACH PATIENT RECEIVED THREE TO 2472 01:31:15,138 --> 01:31:15,972 SIX IN UTERO INFUSIONS. 2473 01:31:15,972 --> 01:31:18,174 THEY WERE ALL BORN AT TERM AND 2474 01:31:18,174 --> 01:31:19,809 THEY'RE ALL RECEIVING POSTNATAL 2475 01:31:19,809 --> 01:31:20,376 ENZYME THERAPY. 2476 01:31:20,376 --> 01:31:22,979 AND WE ARE SEEING MARKERS OF 2477 01:31:22,979 --> 01:31:24,280 EFFICACY IN ADDITION TO THE 2478 01:31:24,280 --> 01:31:26,249 RESCUED PREDICTED ORGAN 2479 01:31:26,249 --> 01:31:28,218 DYSFUNCTION, WE'RE SEEING NORMAL 2480 01:31:28,218 --> 01:31:29,619 BIOMARKERS IN NEWBORN SCREENING, 2481 01:31:29,619 --> 01:31:31,955 AND A DECREASE EVEN IN THE FETAL 2482 01:31:31,955 --> 01:31:33,656 BLOOD GAGs OVER TIME AND 2483 01:31:33,656 --> 01:31:35,792 RESCUE OF PLACENTAL STORAGE. 2484 01:31:35,792 --> 01:31:37,293 THE NEUROLOGICAL TESTING IS 2485 01:31:37,293 --> 01:31:38,461 ONGOING. 2486 01:31:38,461 --> 01:31:39,963 AND WE'RE CONTINUING TO ENROLL 2487 01:31:39,963 --> 01:31:42,265 PATIENTS. 2488 01:31:42,265 --> 01:31:43,833 SO ENZYME REPLACEMENT THERAPY, 2489 01:31:43,833 --> 01:31:46,102 OF COURSE, MAY BE PROMISING BUT 2490 01:31:46,102 --> 01:31:48,304 IT'S NOT A DEFINITIVE CURE, SO 2491 01:31:48,304 --> 01:31:50,039 MARCHING SLOWLY INTO MORE 2492 01:31:50,039 --> 01:31:52,342 DEFINITIVE THERAPIES, MOVING ON 2493 01:31:52,342 --> 01:31:54,210 TO THE GENE THERAPY PORTION OF 2494 01:31:54,210 --> 01:31:55,378 THE TALK. 2495 01:31:55,378 --> 01:31:59,983 SO FIRST GENE THERAPY LIGHT, 2496 01:31:59,983 --> 01:32:01,284 ANTISENSE OLIGONUCLEOTIDES. 2497 01:32:01,284 --> 01:32:04,254 WE'VE DONE SOME STUDIES IN 2498 01:32:04,254 --> 01:32:06,923 ANGELMAN SYNDROME IN MICE. 2499 01:32:06,923 --> 01:32:08,558 ANGELMAN SYNDROME AS YOU ALL 2500 01:32:08,558 --> 01:32:11,427 KNOW IS A SEVERE GENETIC DISEASE 2501 01:32:11,427 --> 01:32:12,061 CHARACTERIZED BY DELAY AS WELL 2502 01:32:12,061 --> 01:32:13,062 AS SEIZURES. 2503 01:32:13,062 --> 01:32:15,999 AND THE GENETICS OF IT IS REALLY 2504 01:32:15,999 --> 01:32:16,533 INTERESTING. 2505 01:32:16,533 --> 01:32:19,469 SO IN THE UBE3A GENE, IN 2506 01:32:19,469 --> 01:32:21,204 NEURONS, THE PATERNAL ALLELE IS 2507 01:32:21,204 --> 01:32:22,572 SILENCED, SO YOU CAN PRESENT 2508 01:32:22,572 --> 01:32:23,873 WITH ANGELMAN'S SYNDROME IF 2509 01:32:23,873 --> 01:32:27,710 THERE'S A MA TERN LOSS OF MATERF 2510 01:32:27,710 --> 01:32:28,411 FUNCTION. 2511 01:32:28,411 --> 01:32:32,081 THE SILENCING OF THE PARENTAL 2512 01:32:32,081 --> 01:32:35,051 ALLELE -- THE UB3 A ANTISENSE. 2513 01:32:35,051 --> 01:32:37,220 PEOPLE HAVE DESIGNED ANTISENSE 2514 01:32:37,220 --> 01:32:39,556 OLIGOS TO INHIBIT THE 2515 01:32:39,556 --> 01:32:41,491 UBA3 ANTISENSE AND REINSTATE THE 2516 01:32:41,491 --> 01:32:42,826 PATERNAL ALLELE EXPRESSION. 2517 01:32:42,826 --> 01:32:44,794 SO YOU CAN STUDY THIS REALLY 2518 01:32:44,794 --> 01:32:46,563 NICELY IN A MOUSE MODEL WHERE 2519 01:32:46,563 --> 01:32:50,266 THERE'S A UB3AYFP, SO WE DID 2520 01:32:50,266 --> 01:32:52,902 EXPERIMENTS WHERE WE BRED THE 2521 01:32:52,902 --> 01:32:56,506 YFP ON THE PATERNAL SIDE AND TO 2522 01:32:56,506 --> 01:32:59,242 THE RESULTANT PUPS WE DELIVERED 2523 01:32:59,242 --> 01:33:02,212 AN ANTISENSE OLIGOTO SEE HOW 2524 01:33:02,212 --> 01:33:05,281 WELL WE COULD REINSTATE PATERNAL 2525 01:33:05,281 --> 01:33:06,049 ALLELE EXPRESSION, SO WAKING UP 2526 01:33:06,049 --> 01:33:08,985 OF THAT ALLELE CAN BE READ OUT 2527 01:33:08,985 --> 01:33:13,189 AS YFP POS TIFL POSITIVITY OF TS 2528 01:33:13,189 --> 01:33:14,390 IN ALL THE SUBSEQUENT PLOTS I'M 2529 01:33:14,390 --> 01:33:15,124 GOING TO SHOW YOU. 2530 01:33:15,124 --> 01:33:17,527 SO THESE ARE THE BRAINS OF IN 2531 01:33:17,527 --> 01:33:18,528 UTERO INJECTED ANIMALS. 2532 01:33:18,528 --> 01:33:23,666 HERE WE'VE DONE AN INTRACRANAL L 2533 01:33:23,666 --> 01:33:25,134 INJECTION, WE INJECTED THE LEFT 2534 01:33:25,134 --> 01:33:26,202 VENTRICLE, YOU CAN SEE THEM ALL 2535 01:33:26,202 --> 01:33:27,770 LIGHT UP WITH THE METHYLENE BLUE 2536 01:33:27,770 --> 01:33:28,304 HERE. 2537 01:33:28,304 --> 01:33:30,840 NEGATIVE CONTROLS, NOTHING IS 2538 01:33:30,840 --> 01:33:33,042 GREEN AND MATERNAL ALLELE 2539 01:33:33,042 --> 01:33:34,210 POSITIVE CONTROLS, ALL THE CELLS 2540 01:33:34,210 --> 01:33:38,715 ARE GREEN AND INTRACRANIAL 2541 01:33:38,715 --> 01:33:41,684 INJECTION AT BOTH A 1 AND 2542 01:33:41,684 --> 01:33:42,585 2.5-MICROGRAM DOSE DOES RESULT 2543 01:33:42,585 --> 01:33:44,554 IN YFP EXPRESSION IN BOTH 2544 01:33:44,554 --> 01:33:45,855 CORTICAL AND HIPPO CAM PAL 2545 01:33:45,855 --> 01:33:47,056 NEURONS AND THAT'S QUANTIFIED 2546 01:33:47,056 --> 01:33:48,725 HERE. 2547 01:33:48,725 --> 01:33:50,793 WE ALSO DID SIMILAR EXPRESSIONS 2548 01:33:50,793 --> 01:33:53,496 NOW IN ANGELMAN KNOCKOUT MICE 2549 01:33:53,496 --> 01:33:57,533 WHERE WE'VE BREAD BRED THE KNON 2550 01:33:57,533 --> 01:33:59,669 THE MATERNAL SIDE AND INJECTED 2551 01:33:59,669 --> 01:34:00,036 INTRACRANIALLY. 2552 01:34:00,036 --> 01:34:01,404 YOU CAN SEE WITH ANGELMAN, WE 2553 01:34:01,404 --> 01:34:04,173 CAN SEE LOOKING AT UB3A PROTEIN 2554 01:34:04,173 --> 01:34:08,311 EXPRESSION, WE CAN SEE THE 2555 01:34:08,311 --> 01:34:10,280 EXPRESSION RESTORED IN THE 2556 01:34:10,280 --> 01:34:11,414 CORTEX ON THE HIPPOCAMPUS. 2557 01:34:11,414 --> 01:34:13,049 THIS DID TRANSLATE INTO SOME 2558 01:34:13,049 --> 01:34:17,120 IMPROVEMENTS, ALTHOUGH SUBTLE 2559 01:34:17,120 --> 01:34:19,722 ELEMENT IN FEAR CONDITIONING AS 2560 01:34:19,722 --> 01:34:22,258 WELL AS -- TRAINING IN ANGELMEN 2561 01:34:22,258 --> 01:34:29,866 MICE THAT WERE TREATED WITH ASO. 2562 01:34:29,866 --> 01:34:31,000 WE ALSO THEN WANTED TO SEE, 2563 01:34:31,000 --> 01:34:31,968 INTRACRANIAL INJECTIONS SOUND 2564 01:34:31,968 --> 01:34:34,504 PRETTY SCARY, ALTHOUGH WE CAN 2565 01:34:34,504 --> 01:34:41,844 DPO TDOTHE SPINA BIFIDA REPAIRSR 2566 01:34:41,844 --> 01:34:43,513 NEUROSURGEON HAS REASSURED US IT 2567 01:34:43,513 --> 01:34:45,048 SHOULD BE REASONABLY SAFE TO 2568 01:34:45,048 --> 01:34:46,349 OFFER IN HUMANS, WE WANTED TO 2569 01:34:46,349 --> 01:34:49,018 SEE IF AN AMNIOTIC FLUID 2570 01:34:49,018 --> 01:34:49,986 INJECTION CAN ACTUALLY DO THE 2571 01:34:49,986 --> 01:34:50,853 SAME THING IN THE PERIOD BEFORE 2572 01:34:50,853 --> 01:34:52,055 THE BLOOD BRAIN BARRIER HAS 2573 01:34:52,055 --> 01:34:52,722 CLOSED. 2574 01:34:52,722 --> 01:34:54,157 SO HERE WE'RE INJECTING IN FETAL 2575 01:34:54,157 --> 01:34:56,225 MICE IN THE AMNIOTIC FLUID, AND 2576 01:34:56,225 --> 01:34:58,428 YOU CAN SEE WE CAN GIVE A MUCH 2577 01:34:58,428 --> 01:34:59,963 HIGHER DOSE, SO HERE THEY COULD 2578 01:34:59,963 --> 01:35:02,398 TOLERATE A 20-MICROGRAM DOSE. 2579 01:35:02,398 --> 01:35:04,934 AND WHEN YOU COMPARE THE 2580 01:35:04,934 --> 01:35:06,135 INTRAAMNIOTIC HERE TO THE 2581 01:35:06,135 --> 01:35:07,470 INTRACRANIAL, THERE'S A LOT MORE 2582 01:35:07,470 --> 01:35:10,506 GREEN IN BOTH THE CORTEX AND THE 2583 01:35:10,506 --> 01:35:12,175 HIPPOCAMPUS, AND THAT IS 2584 01:35:12,175 --> 01:35:14,043 QUANTIFIED HERE, THE 2585 01:35:14,043 --> 01:35:15,345 INTRAAMNIOTIC COMPARED TO THE 2586 01:35:15,345 --> 01:35:17,847 INTRACRANIAL. 2587 01:35:17,847 --> 01:35:19,082 WE DID SOME WORK TO TRY TO 2588 01:35:19,082 --> 01:35:21,918 FIGURE OUT HOW DOES THE ASO 2589 01:35:21,918 --> 01:35:23,453 ACTUALLY ENTER THE CNS. 2590 01:35:23,453 --> 01:35:26,089 SO HERE WE'VE DONE RNA IN SITU 2591 01:35:26,089 --> 01:35:28,191 HYBRIDIZATION USING A PROBE 2592 01:35:28,191 --> 01:35:29,492 AGAINST THE BACKBONE OF THAT 2593 01:35:29,492 --> 01:35:30,660 ASO, AND YOU CAN SEE ALL THE 2594 01:35:30,660 --> 01:35:31,995 PINK IS THE INJECTED CELLS THAT 2595 01:35:31,995 --> 01:35:34,297 HAVE TAKEN UP ASO. 2596 01:35:34,297 --> 01:35:43,306 WE SEE A LOT IN THE DORSAL 2597 01:35:43,306 --> 01:35:45,575 PALLIDUM -- AND WE DETECTED ASOO 2598 01:35:45,575 --> 01:35:47,677 POSITIVITY IN THE RESPIRATORY 2599 01:35:47,677 --> 01:35:48,478 EPITHELIUM. 2600 01:35:48,478 --> 01:35:50,313 THE OLFACTORY EPITHELIUM 2601 01:35:50,313 --> 01:35:52,615 POTENTIALLY GOING THROUGH THE 2602 01:35:52,615 --> 01:35:54,050 CRIBRIFORM PLATE AS WELL AS THE 2603 01:35:54,050 --> 01:35:56,252 CORE YOID PLEXUS SO POTENTIAL 2604 01:35:56,252 --> 01:36:01,724 ROUTES OF ENTRY INTO THE CNS OF 2605 01:36:01,724 --> 01:36:03,559 THE ASO. 2606 01:36:03,559 --> 01:36:05,361 SO WHEN WE LOOK AT THE FETUS AS 2607 01:36:05,361 --> 01:36:07,096 A WHOLE, RED IS HOT, BLUE IS 2608 01:36:07,096 --> 01:36:08,898 COLD, WE WERE EXCITED ABOUT THE 2609 01:36:08,898 --> 01:36:09,632 GREEN NEURONS IN THE BRAIN, BUT 2610 01:36:09,632 --> 01:36:11,167 YOU CAN SEE THE BRAIN IS KIND OF 2611 01:36:11,167 --> 01:36:12,502 THE LEAST OF IT. 2612 01:36:12,502 --> 01:36:15,905 AND THERE'S A LOT OF ASO 2613 01:36:15,905 --> 01:36:17,440 PENETRATION INTO THE LUNG, THE 2614 01:36:17,440 --> 01:36:18,674 HEART, THE LIVER AND THE GI 2615 01:36:18,674 --> 01:36:20,843 TRACT. 2616 01:36:20,843 --> 01:36:22,178 AND THAT'S QUANTIFIED HERE. 2617 01:36:22,178 --> 01:36:25,014 SO WE'RE REALLY EXCITED ABOUT 2618 01:36:25,014 --> 01:36:28,651 USING THE INTRAAMNIOTIC ROUTE TO 2619 01:36:28,651 --> 01:36:29,752 DELIVER THERAPEUTIC RNAs 2620 01:36:29,752 --> 01:36:32,255 INCLUDING ASOs, NOT JUST FOR 2621 01:36:32,255 --> 01:36:34,357 CNS DISEASES BUT POTENTIALLY FOR 2622 01:36:34,357 --> 01:36:35,625 SOME OTHER SYSTEMIC DISEASES AS 2623 01:36:35,625 --> 01:36:37,760 WELL. 2624 01:36:37,760 --> 01:36:39,962 AND SO OUR USUAL PROTOCOL FOR 2625 01:36:39,962 --> 01:36:41,831 TRYING TO FIGURE OUT IF 2626 01:36:41,831 --> 01:36:42,465 SOMETHING WORKS CLINICALLY, OF 2627 01:36:42,465 --> 01:36:43,800 COURSE, IS TO DO A MOUSE STUDY 2628 01:36:43,800 --> 01:36:45,802 AND THEN A SHEEP STUDY. 2629 01:36:45,802 --> 01:36:48,971 SO WE'VE BEEN CL COLLABORATING W 2630 01:36:48,971 --> 01:36:53,509 WITH BIOGENERA BIOGEN TO USE ANO 2631 01:36:53,509 --> 01:36:57,113 SIMILAR TO NUSINERSEN USED IN 2632 01:36:57,113 --> 01:36:58,948 PATIENTS WITH SPINAL ATROPHY IN 2633 01:36:58,948 --> 01:37:01,751 SHEEP, AND THIS IS -- WE'VE DONE 2634 01:37:01,751 --> 01:37:03,352 BOTH INTRAAMNIOTIC INJECTIONS, 2635 01:37:03,352 --> 01:37:06,322 AS WELL AS SOME INTERCYST SISTER 2636 01:37:06,322 --> 01:37:08,991 MA MAGNA INJECTIONS WITH OUR 2637 01:37:08,991 --> 01:37:10,393 FETAL NEUROSURGEON DR. GUPTA AND 2638 01:37:10,393 --> 01:37:11,227 THAT'S SHOWN HERE. 2639 01:37:11,227 --> 01:37:13,029 SHEEP HAVE VERY SMALL 2640 01:37:13,029 --> 01:37:16,632 VENTRICLES, SO WE HAD TO DO 2641 01:37:16,632 --> 01:37:21,504 CHRCISTERNA MAGNA INJECTIONS. 2642 01:37:21,504 --> 01:37:22,939 YOU CAN SEE WHEN WE LOOK IN THE 2643 01:37:22,939 --> 01:37:24,440 SPINAL CORD FOR THE ASO, AND 2644 01:37:24,440 --> 01:37:33,816 THIS IS NOW IN ELI E ELISA FORE 2645 01:37:33,816 --> 01:37:35,585 ASO, AT THE MEDIUM AND HIGH 2646 01:37:35,585 --> 01:37:38,988 DOSE, WE'RE SEEING WHAT WE'VE 2647 01:37:38,988 --> 01:37:40,857 BEEN TOLD LEVELS OF 1 TO 10 ARE 2648 01:37:40,857 --> 01:37:42,291 SORT OF IN THE THERAPEUTIC 2649 01:37:42,291 --> 01:37:42,959 RANGE. 2650 01:37:42,959 --> 01:37:46,295 SO THIS IS ENCOURAGING. 2651 01:37:46,295 --> 01:37:48,231 OF COURSE WHEN YOU DO THE 2652 01:37:48,231 --> 01:37:49,198 INTRACRANIAL INJECTION, WHICH IS 2653 01:37:49,198 --> 01:37:50,266 SORT OF OUR POSITIVE CONTROL IN 2654 01:37:50,266 --> 01:37:51,434 THIS EXPERIMENT, YOU GET MUCH 2655 01:37:51,434 --> 01:37:52,935 HIGHER LEVELS. 2656 01:37:52,935 --> 01:37:54,170 AND JUST LIKE IN THE MOUSE 2657 01:37:54,170 --> 01:37:57,607 STUDY, ALTHOUGH WE'RE SEEING 2658 01:37:57,607 --> 01:37:58,508 SOME DISTRIBUTION INTO THE 2659 01:37:58,508 --> 01:38:00,443 SPINAL CORD, A LOT OF THE 2660 01:38:00,443 --> 01:38:01,410 DISTRIBUTION SEEMS TO BE IN SOME 2661 01:38:01,410 --> 01:38:04,614 OF THE OTHER ORGANS AS WELL. 2662 01:38:04,614 --> 01:38:06,549 SO WE THINK THIS IS ENCOURAGING 2663 01:38:06,549 --> 01:38:08,651 BUT OBVIOUSLY WE NEED SOME MORE 2664 01:38:08,651 --> 01:38:10,520 WORK, ESPECIALLY BECAUSE THIS 2665 01:38:10,520 --> 01:38:12,421 TOOL COMPOUND HAS NOT BEEN USED 2666 01:38:12,421 --> 01:38:14,891 IN HUMANS AT THIS POINT. 2667 01:38:14,891 --> 01:38:18,194 WE'RE ALSO THINKING VERY 2668 01:38:18,194 --> 01:38:20,496 CRITICALLY ABOUT CAN YOU DO GENE 2669 01:38:20,496 --> 01:38:22,031 REPLACEMENT THERAPY JUST GIVEN 2670 01:38:22,031 --> 01:38:24,000 THAT MANY PATIENTS ARE NOT GOING 2671 01:38:24,000 --> 01:38:26,302 TO HAVE DISEASES OR SPECIFIC 2672 01:38:26,302 --> 01:38:28,404 MUTATIONS THAT ARE AMENABLE TO 2673 01:38:28,404 --> 01:38:29,405 ASO THERAPY. 2674 01:38:29,405 --> 01:38:31,240 SO WE'VE COLLABORATED WITH 2675 01:38:31,240 --> 01:38:35,645 NOVARTIS IN OBTAINING AN 2676 01:38:35,645 --> 01:38:38,080 AAV9-GFP VECTOR THAT'S SIMILAR 2677 01:38:38,080 --> 01:38:40,983 TO ZOLGENSMA USED IN CHILDREN 2678 01:38:40,983 --> 01:38:41,918 WITH SMA. 2679 01:38:41,918 --> 01:38:45,388 THIS TIME USING UMBILICAL VEIN 2680 01:38:45,388 --> 01:38:47,123 INJECTIONS IN FETAL LAMBS. 2681 01:38:47,123 --> 01:38:50,493 AND AS YOU CAN IMAGINE, THIS 2682 01:38:50,493 --> 01:38:53,229 WORKED REALLY WELL USING THE 2683 01:38:53,229 --> 01:38:54,664 DOSE-ADJUSTED FOR WHAT INFANTS 2684 01:38:54,664 --> 01:38:56,132 WITH SMA WOULD BE GIVEN. 2685 01:38:56,132 --> 01:38:57,867 WE SAW WIDESPREAD 2686 01:38:57,867 --> 01:38:59,068 BIODISTRIBUTION IN THE CNS, SO 2687 01:38:59,068 --> 01:39:03,005 HERE I'M SHOWING YOU GFP AND NEW 2688 01:39:03,005 --> 01:39:04,440 END STAINING IN THE CERVICAL, 2689 01:39:04,440 --> 01:39:06,342 THORACIC AND LUMBAR SPINAL 2690 01:39:06,342 --> 01:39:07,843 CORDS, AND WE'RE EXCITED BY THIS 2691 01:39:07,843 --> 01:39:10,479 BECAUSE IN ADDITION TO SMA, OF 2692 01:39:10,479 --> 01:39:13,015 COURSE, OTHER NUMEROUS POTENTIAL 2693 01:39:13,015 --> 01:39:14,317 INDICATIONS FOR DISEASES THAT 2694 01:39:14,317 --> 01:39:17,320 WOULD MAKE SENSE POTENTIALLY TO 2695 01:39:17,320 --> 01:39:19,488 TREAT IN UTERO, INCLUDING 2696 01:39:19,488 --> 01:39:21,591 POTENTIALLY GENOME ONE, GENOME 2697 01:39:21,591 --> 01:39:23,125 TWO, NEUROPATHIC GAUCHER JUST TO 2698 01:39:23,125 --> 01:39:24,560 NAME A FEW. 2699 01:39:24,560 --> 01:39:27,496 AAV9, OF COURSE, ALSO TRANSDUCES 2700 01:39:27,496 --> 01:39:28,397 THE MUSCLE CELLS REALLY WELL, 2701 01:39:28,397 --> 01:39:30,800 AND WE SAW THAT HERE, AND SO 2702 01:39:30,800 --> 01:39:32,435 POTENTIALLY THIS COULD BE 2703 01:39:32,435 --> 01:39:34,337 CONSIDERED AS A STRATEGY FOR 2704 01:39:34,337 --> 01:39:35,671 MUSCULAR DISPROPHYS AS WELL. 2705 01:39:35,671 --> 01:39:38,608 AND THIS PAPER IS RECENTLY OUT. 2706 01:39:38,608 --> 01:39:40,776 SO THAT BROAD BIODISTRIBUTION, 2707 01:39:40,776 --> 01:39:42,778 THOUGH, IS A TWO-EDGED SWORD, 2708 01:39:42,778 --> 01:39:46,449 AND WITH ANY FIELD, BUT 2709 01:39:46,449 --> 01:39:47,984 ESPECIALLY WITH FETAL THERAPY WE 2710 01:39:47,984 --> 01:39:49,051 REALLY HAVE TO THINK ABOUT THE 2711 01:39:49,051 --> 01:39:51,287 RISKS AND THE BENEFITS AND AS I 2712 01:39:51,287 --> 01:39:52,255 MENTIONED WE'RE ABSOLUTELY NOT 2713 01:39:52,255 --> 01:39:53,556 INTERESTED IN DOING ANY 2714 01:39:53,556 --> 01:39:54,123 HERITABLE EDITING. 2715 01:39:54,123 --> 01:39:55,591 SO WE HAVE LOOKED TO SEE WHETHER 2716 01:39:55,591 --> 01:39:59,095 THIS AAV9-GFP GETS INTO GERM 2717 01:39:59,095 --> 01:40:01,297 CELLS IN COLLABORATION WITH 2718 01:40:01,297 --> 01:40:04,367 DIANA LAIRD, AMAZING GERM CELL 2719 01:40:04,367 --> 01:40:07,103 BIOLOGIST AT UCSF. 2720 01:40:07,103 --> 01:40:08,437 INTERESTINGLY AND UNFORTUNATELY 2721 01:40:08,437 --> 01:40:10,139 IN THE OVARIES OF THESE FETAL 2722 01:40:10,139 --> 01:40:13,476 LAMBS INJECTED WITH AAV9-GFP, WE 2723 01:40:13,476 --> 01:40:16,112 ARE SEEING GFP EXPRESSION. 2724 01:40:16,112 --> 01:40:17,346 INTERESTINGLY WE SEE ONLY IN THE 2725 01:40:17,346 --> 01:40:19,181 OVARIES AND NOT IN THE TESTES, 2726 01:40:19,181 --> 01:40:23,619 SO IT ONLY HAPPENS TO THE FEMALE 2727 01:40:23,619 --> 01:40:25,688 LAMBS. 2728 01:40:25,688 --> 01:40:26,756 THEN LOOKING AT THE LITERATURE, 2729 01:40:26,756 --> 01:40:28,557 THERE IS AN AUTOPSY STUDY OF TWO 2730 01:40:28,557 --> 01:40:32,962 INFANTS WHO HAD RECEIVED 2731 01:40:32,962 --> 01:40:34,797 ZOLGENSMA AND THERE IS PCR 2732 01:40:34,797 --> 01:40:36,032 POSITIVITY FOR VECTOR IN THE GOA 2733 01:40:36,032 --> 01:40:41,971 FLADGONADS, SO WE THINK THIS ISN 2734 01:40:41,971 --> 01:40:42,672 IMPORTANT CONSIDERATION. 2735 01:40:42,672 --> 01:40:45,908 OF COURSE THE AAV SHOULD REMAIN 2736 01:40:45,908 --> 01:40:47,109 EPISOMAL SO THIS ISN'T A 2737 01:40:47,109 --> 01:40:48,210 HERITABLE GENE PER SE BUT I 2738 01:40:48,210 --> 01:40:50,046 THINK THIS WOULD BE CONCERNED IF 2739 01:40:50,046 --> 01:40:51,480 AAV WERE USED AS A DELIVERY 2740 01:40:51,480 --> 01:40:52,748 VEHICLE FOR A GENOME EDITOR 2741 01:40:52,748 --> 01:40:54,417 BECAUSE IN THAT CASE, EVEN IF 2742 01:40:54,417 --> 01:40:55,084 THE VECTOR DOESN'T INTEGRATE, 2743 01:40:55,084 --> 01:40:57,019 YOU WOULD POTENTIALLY HAVE A 2744 01:40:57,019 --> 01:40:59,288 HERITABLE EDITING BECAUSE YOU'VE 2745 01:40:59,288 --> 01:41:01,257 DELIVERED A GENOME EDITOR. 2746 01:41:01,257 --> 01:41:03,426 AND SO THAT BRINGS US TO WHAT I 2747 01:41:03,426 --> 01:41:05,661 THINK IS REALLY THE FUTURE, OF 2748 01:41:05,661 --> 01:41:07,229 COURSE, IN VIVO GENOME EDITING, 2749 01:41:07,229 --> 01:41:09,165 LIKELY USING LIPID 2750 01:41:09,165 --> 01:41:10,366 NANOPARTICLES, ALTHOUGH THE 2751 01:41:10,366 --> 01:41:11,133 DELIVERY VEHICLES CONTINUE TO 2752 01:41:11,133 --> 01:41:12,902 EVOLVE SO QUICKLY, RIGHT? 2753 01:41:12,902 --> 01:41:17,173 AND SO THIS IN OUR LAB IS JUST 2754 01:41:17,173 --> 01:41:19,308 IN MICE SO FAR USING THESE CRE 2755 01:41:19,308 --> 01:41:22,445 REPORTER MICE TO DELIVER LNPs 2756 01:41:22,445 --> 01:41:24,180 DELIVERING CRE MRNA. 2757 01:41:24,180 --> 01:41:25,581 WE'RE COLLABORATING WITH A 2758 01:41:25,581 --> 01:41:31,921 NUMBER OF LNP EXPERTS INCLUD ANN 2759 01:41:31,921 --> 01:41:33,422 USING OUR MOUSE MODEL TO INJECT 2760 01:41:33,422 --> 01:41:36,826 THESE LNP-CRE INTO THE FETAL 2761 01:41:36,826 --> 01:41:38,627 MOUSE. 2762 01:41:38,627 --> 01:41:39,495 WHERE RECOMBINATION EVENTS 2763 01:41:39,495 --> 01:41:41,464 BECAUSE OF THE CRE CAN BE READ 2764 01:41:41,464 --> 01:41:44,367 OUT AS RED CELLS TURNING GFP 2765 01:41:44,367 --> 01:41:44,700 POSITIVE. 2766 01:41:44,700 --> 01:41:46,669 SO YOU GET REALLY BROAD 2767 01:41:46,669 --> 01:41:48,537 BIODISTRIBUTION AS YOU CAN SEE 2768 01:41:48,537 --> 01:41:50,706 HERE, THIS IS A STAINING ABOUT 2769 01:41:50,706 --> 01:41:52,241 FOUR DAYS AFTER WE'VE DONE THE 2770 01:41:52,241 --> 01:41:53,676 IN UTERO INJECTION. 2771 01:41:53,676 --> 01:41:55,344 A LOT OF STAINING IN THE LIVER 2772 01:41:55,344 --> 01:41:56,712 AND THE HEART, OF COURSE. 2773 01:41:56,712 --> 01:41:58,047 WE'RE REALLY INTERESTED IN 2774 01:41:58,047 --> 01:41:59,348 WHETHER THIS CAN BE USED TO 2775 01:41:59,348 --> 01:42:01,050 DELIVER A THERAPEUTIC TO 2776 01:42:01,050 --> 01:42:02,151 HEMATOPOIETIC STEM CELLS, WHICH 2777 01:42:02,151 --> 01:42:03,853 ARE IN THE FETAL LIVER AT THAT 2778 01:42:03,853 --> 01:42:04,854 GESTATIONAL AGE AND WE ARE 2779 01:42:04,854 --> 01:42:08,190 SEEING SOME HINTS WHEN WE LOOK 2780 01:42:08,190 --> 01:42:09,825 AT HSCs FROM THOSE INJECTED 2781 01:42:09,825 --> 01:42:12,228 MICE THAT THERE IS SOME 2782 01:42:12,228 --> 01:42:12,795 RECOMBINATION EVENTS. 2783 01:42:12,795 --> 01:42:14,663 SO WE THINK THAT THIS COULD BE A 2784 01:42:14,663 --> 01:42:16,632 PROMISING METHOD FOR SHORT TERM 2785 01:42:16,632 --> 01:42:18,501 DELIVERY OF THE GENOME EDITORS 2786 01:42:18,501 --> 01:42:21,237 FOR SELECT SOMATIC TISSUES. 2787 01:42:21,237 --> 01:42:24,106 THE CNS DELIVERY IS OF COURSE 2788 01:42:24,106 --> 01:42:26,942 MORE CHALLENGING AS MANY OF YOU 2789 01:42:26,942 --> 01:42:29,078 ARE EXPERTS IN, BUT OF COURSE 2790 01:42:29,078 --> 01:42:30,613 THERE ARE NUMEROUS METHODS IN 2791 01:42:30,613 --> 01:42:34,116 DEVELOPMENT. 2792 01:42:34,116 --> 01:42:35,451 AND THE VISION FOR ALL OF THIS 2793 01:42:35,451 --> 01:42:36,585 HONESTLY IS TO DEVELOP A PROGRAM 2794 01:42:36,585 --> 01:42:37,720 WHERE WE CAN HAVE A PRENATAL 2795 01:42:37,720 --> 01:42:38,954 DIAGNOSIS AND THERAPY FOR 2796 01:42:38,954 --> 01:42:41,357 PATIENT WITH SEVERE EARLY ONSET 2797 01:42:41,357 --> 01:42:43,159 DISEASES. 2798 01:42:43,159 --> 01:42:44,860 SO WOULD HE WOULD BE PERFORMING 2799 01:42:44,860 --> 01:42:45,394 EARLY GENETIC DIAGNOSIS. 2800 01:42:45,394 --> 01:42:46,996 WE ALREADY HAVE A DIAGNOSTIC ARM 2801 01:42:46,996 --> 01:42:49,432 OF OUR GROUP WHO'S DOING WHOLE 2802 01:42:49,432 --> 01:42:52,435 EXOME AND WHOLE GENOME 2803 01:42:52,435 --> 01:42:53,903 SEQUENCING, FIRST STARTED OUT IN 2804 01:42:53,903 --> 01:42:55,237 PATIENTS WITH ULTRASOUND 2805 01:42:55,237 --> 01:42:56,172 DETECTED ANOMALIES BUT REALLY 2806 01:42:56,172 --> 01:42:59,942 ALSO MOVING INTO PHENOTYPICALLY 2807 01:42:59,942 --> 01:43:01,310 NORMAL FETUSES. 2808 01:43:01,310 --> 01:43:03,212 ONCE WE CONFIRM THE DISEASE, YOU 2809 01:43:03,212 --> 01:43:05,648 OF COURSE DO NON-DIRECTIVE 2810 01:43:05,648 --> 01:43:07,283 COUNSELING, WHICH IS REALLY THE 2811 01:43:07,283 --> 01:43:09,952 CORNER STONE OF THIS ENTERPRISE, 2812 01:43:09,952 --> 01:43:10,886 REALLY PRESENTING THE OPTIONS OF 2813 01:43:10,886 --> 01:43:14,423 NOT CONTINUING THE PREGNANCY, 2814 01:43:14,423 --> 01:43:15,191 NOT DOING ANYTHING DIFFERENT IN 2815 01:43:15,191 --> 01:43:17,259 THE PREGNANCY OR ENROLLING IN A 2816 01:43:17,259 --> 01:43:20,396 CLINICAL TRIAL. 2817 01:43:20,396 --> 01:43:21,697 AND THEN YOU WOULD MANUFACTURE 2818 01:43:21,697 --> 01:43:22,865 THE DELIVERY WITH THE IDEAL 2819 01:43:22,865 --> 01:43:24,433 DELIVERY VEHICLE, THE EDITOR 2820 01:43:24,433 --> 01:43:25,301 THAT'S OPTIMIZED FOR THE 2821 01:43:25,301 --> 01:43:27,269 RELEVANT TISSUE, AND THAT'S 2822 01:43:27,269 --> 01:43:28,671 IDEALLY BEEN INACTIVATED FOR 2823 01:43:28,671 --> 01:43:30,272 GERM CELLS AND OTHER NON-TARGET 2824 01:43:30,272 --> 01:43:31,907 ORGANS. 2825 01:43:31,907 --> 01:43:33,075 AND THEN THE INJECTION WOULD BE 2826 01:43:33,075 --> 01:43:36,212 INTO THE UMBILICAL VEIN AS WE'VE 2827 01:43:36,212 --> 01:43:36,679 REVIEWED. 2828 01:43:36,679 --> 01:43:39,048 THIS PROCEDURE IS UNDER LOCAL 2829 01:43:39,048 --> 01:43:39,715 ANESTHESIA AND TAKES ABOUT 30 2830 01:43:39,715 --> 01:43:42,084 MINUTES. 2831 01:43:42,084 --> 01:43:43,385 AND THEN YOU WOULD NEED TO DO 2832 01:43:43,385 --> 01:43:45,654 MONITORING OF ON AND OFF TARGET 2833 01:43:45,654 --> 01:43:47,756 EDITS, PROBABLY USING CELL-FREE 2834 01:43:47,756 --> 01:43:51,160 DNA AND RNA IN MATERNAL AND CORD 2835 01:43:51,160 --> 01:43:52,461 BLOOD. AND IN THE FUTURE, IF 2836 01:43:52,461 --> 01:43:54,396 THERE'S A NEW MUTATION, YOU 2837 01:43:54,396 --> 01:43:55,698 COULD POTENTIALLY DESIGN THE 2838 01:43:55,698 --> 01:43:58,234 GUIDE RNAs AND TEST ON PATIENT 2839 01:43:58,234 --> 01:44:00,002 CELLS, ALTHOUGH THE TIMELINE OF 2840 01:44:00,002 --> 01:44:01,337 THAT FOR PRENATAL APPLICATIONS 2841 01:44:01,337 --> 01:44:04,406 IS STILL NOT FAST ENOUGH. 2842 01:44:04,406 --> 01:44:05,808 SO IN CONCLUSION FOR ALL OF 2843 01:44:05,808 --> 01:44:09,144 THESE DIFFERENT POTENTIAL 2844 01:44:09,144 --> 01:44:10,346 THERAPEUTICS, SO IN TERMS OF 2845 01:44:10,346 --> 01:44:12,882 PROTEINS OR SMALL MOLECULES, IN 2846 01:44:12,882 --> 01:44:15,117 TERMS OF THE ENZYME REPLACEMENT, 2847 01:44:15,117 --> 01:44:16,619 THE PROTEIN REPLACEMENT DATA, 2848 01:44:16,619 --> 01:44:17,953 DEFINITELY ENCOURAGING BUT EACH 2849 01:44:17,953 --> 01:44:20,689 PATIENT NEEDS MULTIPLE INFUSIONS 2850 01:44:20,689 --> 01:44:26,328 SO FAR AND IT'S NOT PERMANENT. 2851 01:44:26,328 --> 01:44:27,796 ANTISENSE OLIGOS, THE TIMELINE 2852 01:44:27,796 --> 01:44:29,498 WOULD PROBABLY BE A SINGLE IN 2853 01:44:29,498 --> 01:44:30,733 UTERO INFUSION AND WE'RE VERY 2854 01:44:30,733 --> 01:44:32,268 ENCOURAGED TO SEE CNS 2855 01:44:32,268 --> 01:44:33,502 PENETRATION EVEN WITH THE 2856 01:44:33,502 --> 01:44:34,937 AMNIOTIC FLUID DELIVERY, BUT 2857 01:44:34,937 --> 01:44:36,372 THIS NEEDS A LITTLE BIT MORE 2858 01:44:36,372 --> 01:44:38,774 WORK BEFORE CLINICAL 2859 01:44:38,774 --> 01:44:39,408 APPLICATIONS. 2860 01:44:39,408 --> 01:44:41,877 GENE REPLACEMENT THERAPY WITH 2861 01:44:41,877 --> 01:44:43,946 AAV, WE ARE, OF COURSE, EXCITED 2862 01:44:43,946 --> 01:44:45,915 BY THE EXCELLENT CNS 2863 01:44:45,915 --> 01:44:46,949 DISTRIBUTION, BUT AT LEAST FOR 2864 01:44:46,949 --> 01:44:51,086 THE AAV9 CAPSID, WE HAVE SOME 2865 01:44:51,086 --> 01:44:53,289 CAUTIONARY DATA FOR USE TO 2866 01:44:53,289 --> 01:44:57,426 DELIVER GENOME EDITORS. 2867 01:44:57,426 --> 01:44:58,761 AND FOR GENOME EDITING, I THINK 2868 01:44:58,761 --> 01:45:00,429 IT'S REALLY PROMISING BUT OF 2869 01:45:00,429 --> 01:45:01,830 COURSE WE NEED EFFECTIVE 2870 01:45:01,830 --> 01:45:03,532 DELIVERY METHODS FOR THE CNS AND 2871 01:45:03,532 --> 01:45:05,267 THE MUTATION-SPECIFIC METHODS 2872 01:45:05,267 --> 01:45:07,069 MAY BE CHALLENGING FOR THE 2873 01:45:07,069 --> 01:45:08,737 PRENATAL TIMELINE. 2874 01:45:08,737 --> 01:45:09,939 SO THANK YOU AGAIN SO MUCH. 2875 01:45:09,939 --> 01:45:12,241 I'D LOVE TO ACKNOWLEDGE THE 2876 01:45:12,241 --> 01:45:14,310 PEOPLE IN MY LAB WHO REALLY MAKE 2877 01:45:14,310 --> 01:45:16,979 IT ALL HAPPEN, THE CLINICAL 2878 01:45:16,979 --> 01:45:18,280 TRIAL TEAM FOR THE IN UTERO 2879 01:45:18,280 --> 01:45:20,382 ENZYME REPLACEMENT THERAPY. 2880 01:45:20,382 --> 01:45:22,217 ON ALL OF OUR COLLABORATORS, 2881 01:45:22,217 --> 01:45:25,454 BOTH AT UCSF AND AT OTHER 2882 01:45:25,454 --> 01:45:26,989 INSTITUTIONS FOR THE THREE 2883 01:45:26,989 --> 01:45:30,225 STUDIES THAT ARE PRESENTED, AND 2884 01:45:30,225 --> 01:45:30,726 OUR FUNDING SOURCES. 2885 01:45:30,726 --> 01:45:31,961 THANK YOU SO MUCH, AND I'LL BE 2886 01:45:31,961 --> 01:45:41,804 HAPPY TO TAKE ANY QUESTIONS. 2887 01:45:41,804 --> 01:45:42,071 [APPLAUSE] 2888 01:45:42,071 --> 01:45:44,707 >> OKAY, THANK YOU SO MUCH, 2889 01:45:44,707 --> 01:45:46,141 TIPPI, AND I BELIEVE YOU'RE 2890 01:45:46,141 --> 01:45:47,610 ONLINE AND YOU CAN HEAR US? 2891 01:45:47,610 --> 01:45:48,677 >> YES, YES, I'M HERE. 2892 01:45:48,677 --> 01:45:50,312 THANK YOU SO MUCH, DAN. 2893 01:45:50,312 --> 01:45:50,646 >> BEAUTIFUL. 2894 01:45:50,646 --> 01:45:52,848 GREAT. 2895 01:45:52,848 --> 01:45:55,818 SO MAYBE BEV AND FYODOR, IF YOU 2896 01:45:55,818 --> 01:45:57,453 DON'T MIND CAN YOU COME UP HERE? 2897 01:45:57,453 --> 01:45:58,787 THIS IS NOW OPEN Q & A FOR 2898 01:45:58,787 --> 01:46:04,159 EVERYBODY. 2899 01:46:04,159 --> 01:46:05,694 IS FYODOR HERE? 2900 01:46:05,694 --> 01:46:07,696 HE'S COMING? 2901 01:46:07,696 --> 01:46:10,633 OKAY. 2902 01:46:10,633 --> 01:46:12,468 QUESTIONS FOR TIPPI DIRECTLY BUT 2903 01:46:12,468 --> 01:46:13,702 ALSO OUR OTHER SPEAKERS. 2904 01:46:13,702 --> 01:46:14,470 OKAY. 2905 01:46:14,470 --> 01:46:24,546 ANN? 2906 01:46:26,281 --> 01:46:27,583 >> HI, TIPPI. 2907 01:46:27,583 --> 01:46:35,457 HELLO? 2908 01:46:35,457 --> 01:46:37,793 THANKS SO MUCH. 2909 01:46:37,793 --> 01:46:38,594 IT'S ANN PODURI. 2910 01:46:38,594 --> 01:46:39,361 THIS IS FASCINATING. 2911 01:46:39,361 --> 01:46:40,562 I JUST WONDERED IF YOU COULD 2912 01:46:40,562 --> 01:46:41,897 TALK US THROUGH A LITTLE BIT 2913 01:46:41,897 --> 01:46:43,332 ABOUT WHY YOU'RE TRYING TO AVOID 2914 01:46:43,332 --> 01:46:47,369 THE GERM CELLS IN TERMS OF ON 2915 01:46:47,369 --> 01:46:49,538 TARGET, OFF TARGET VERSUS NEXT 2916 01:46:49,538 --> 01:46:50,673 GENERATION, CHOICE-MAKING AND SO 2917 01:46:50,673 --> 01:46:52,408 ON, I'M THINKING IN TEXTING WITH 2918 01:46:52,408 --> 01:46:54,143 A NUMBER OF PEOPLE WHO ARE WATCH 2919 01:46:54,143 --> 01:46:54,843 ONLINE TOO IN TERMS OF THE 2920 01:46:54,843 --> 01:46:56,011 VARIOUS REASONS FOR THAT, BUT IF 2921 01:46:56,011 --> 01:46:57,112 YOU COULD TALK US THROUGH THAT, 2922 01:46:57,112 --> 01:46:58,280 THAT WOULD BE GREAT. 2923 01:46:58,280 --> 01:46:58,714 >> SURE. 2924 01:46:58,714 --> 01:46:58,914 YEAH. 2925 01:46:58,914 --> 01:47:00,683 I MEAN, I THINK YOU BASICALLY 2926 01:47:00,683 --> 01:47:01,016 NAMED THEM. 2927 01:47:01,016 --> 01:47:04,086 YOU KNOW, WE DON'T WANT TO MESS 2928 01:47:04,086 --> 01:47:04,987 WITH EVOLUTION PRIMARILY. 2929 01:47:04,987 --> 01:47:07,456 I FEEL LIKE THERE'S DEFINITELY A 2930 01:47:07,456 --> 01:47:09,024 RED LINE AGAINST GOING IN THE 2931 01:47:09,024 --> 01:47:10,059 GERMLINE, AND THERE'S A LOT YOU 2932 01:47:10,059 --> 01:47:11,994 CAN DO WITH TREATING SOMATIC 2933 01:47:11,994 --> 01:47:13,762 CELLS IN THE CURRENT GENERATION, 2934 01:47:13,762 --> 01:47:15,831 AND I THINK WE ALSO DON'T KNOW 2935 01:47:15,831 --> 01:47:17,833 ENOUGH ABOUT OFF-TARGET EFFECTS, 2936 01:47:17,833 --> 01:47:19,902 AND SO HAVING AN OFF-TARGET 2937 01:47:19,902 --> 01:47:21,203 EFFECT THAT HAS BEEN CONTINUED 2938 01:47:21,203 --> 01:47:23,072 THROUGH THE GERMLINE SUCH THAT 2939 01:47:23,072 --> 01:47:25,074 THERE MIGHT BE A CANCER RISK IN 2940 01:47:25,074 --> 01:47:26,375 SUBSEQUENT GENERATIONS, ET 2941 01:47:26,375 --> 01:47:28,243 CETERA, I THINK I JUST DON'T 2942 01:47:28,243 --> 01:47:31,046 THINK IT'S SAFE AND ETHICAL. 2943 01:47:31,046 --> 01:47:34,950 >> CAN I JUST ADD ONE THING, 2944 01:47:34,950 --> 01:47:36,852 LEGALLY, PETER MARKS, HEAD OF 2945 01:47:36,852 --> 01:47:39,988 THE CBER, HE SEES THAT GERMLINE 2946 01:47:39,988 --> 01:47:41,457 MODIFICATION AS A NON-STARTER, 2947 01:47:41,457 --> 01:47:42,524 JUST BASED ON THE CLIMATE. 2948 01:47:42,524 --> 01:47:43,992 IN OTHER WORDS, WE SHOULD JUST 2949 01:47:43,992 --> 01:47:44,860 STOP THINKING ABOUT THAT BEING 2950 01:47:44,860 --> 01:47:47,096 AN OPTION. 2951 01:47:47,096 --> 01:47:47,663 >> [INAUDIBLE] 2952 01:47:47,663 --> 01:47:50,566 >> WELL, OKAY. 2953 01:47:50,566 --> 01:47:51,467 PEOPLE ASK ME ALL THE TIME, 2954 01:47:51,467 --> 01:47:54,503 RIGHT, LIKE IF I COULD GET RID 2955 01:47:54,503 --> 01:47:55,504 OF APOE4. 2956 01:47:55,504 --> 01:47:57,306 BUP WE CAN TALK ABOUT THAT AT 2957 01:47:57,306 --> 01:47:58,507 GREAT LENGTH, BUT THE BOTTOM 2958 01:47:58,507 --> 01:47:59,908 LINE IS, IT IS A NON-STARTER 2959 01:47:59,908 --> 01:48:00,242 TODAY. 2960 01:48:00,242 --> 01:48:01,777 WE CAN TALK ABOUT THE ETHICS, 2961 01:48:01,777 --> 01:48:03,879 THE SCIENCE, BUT POLITICALLY AND 2962 01:48:03,879 --> 01:48:06,582 LEGALLY, THERE'S A RIDER TO AN 2963 01:48:06,582 --> 01:48:07,816 APPROPRIATION BILL, IT A 2964 01:48:07,816 --> 01:48:08,617 POLITICAL NON-STARTER. 2965 01:48:08,617 --> 01:48:10,319 IT WILL NOT HAPPEN IN THE NEXT 2966 01:48:10,319 --> 01:48:11,286 FIVE YEARS IN THIS COUNTRY. 2967 01:48:11,286 --> 01:48:15,991 >> CAN I ADD TO THAT TOO, AND I 2968 01:48:15,991 --> 01:48:16,959 THINK ONE OF THE BEAUTIFUL 2969 01:48:16,959 --> 01:48:18,494 THINGS ABOUT THE CRISPR 2970 01:48:18,494 --> 01:48:19,628 TECHNOLOGIES IS THE SPECIFICITY, 2971 01:48:19,628 --> 01:48:22,464 SO WHAT WE'RE TALKING ABOUT HERE 2972 01:48:22,464 --> 01:48:27,269 IS PASSING ON ON-TARGET EDITING. 2973 01:48:27,269 --> 01:48:29,138 TIPPI MENTIONED, YOU KNOW, THE 2974 01:48:29,138 --> 01:48:30,806 RISKS OF OFF-TARGET EDITING AND 2975 01:48:30,806 --> 01:48:33,475 I THINK, YOU KNOW, AS FYODOR 2976 01:48:33,475 --> 01:48:34,977 AMPLIFIED DURING HIS TALK, 2977 01:48:34,977 --> 01:48:36,311 THERE'S A LOT OF SAFETY DATA OUT 2978 01:48:36,311 --> 01:48:38,147 THERE NOW THAT'S ACCRUING, BUT 2979 01:48:38,147 --> 01:48:41,350 WHEN WE LOOK FOR ALL THE OFF 2980 01:48:41,350 --> 01:48:43,986 TARGETS EVEN WITH AN ACTIVE 2981 01:48:43,986 --> 01:48:47,723 NUCLEASE, IT'S PRETTY RARE. 2982 01:48:47,723 --> 01:48:49,191 >> THERE'S A COUPLE QUESTIONS 2983 01:48:49,191 --> 01:48:51,560 ONLINE. 2984 01:48:51,560 --> 01:48:54,196 SO QUESTIONS FROM JEFF NOABLES, 2985 01:48:54,196 --> 01:48:57,499 HAS SPECIFICITY BEEN TESTED IN 2986 01:48:57,499 --> 01:48:58,734 IMMATURE DEVELOPING BRAIN? 2987 01:48:58,734 --> 01:49:05,140 >> WE HAVE GIVEN OUR VECTORS TO 2988 01:49:05,140 --> 01:49:07,509 BILL PORONTO, WHO IS A COLLEAGUE 2989 01:49:07,509 --> 01:49:09,778 OF TIPPIS, AND HE HAS PUT THESE 2990 01:49:09,778 --> 01:49:11,647 INTO HIS FETAL MODEL SYSTEMS, 2991 01:49:11,647 --> 01:49:13,649 AND SO FAR THINGS LOOK PRETTY 2992 01:49:13,649 --> 01:49:14,183 GOOD. 2993 01:49:14,183 --> 01:49:18,253 IT'S EARLY DAYS, THOSE, BECAUSE 2994 01:49:18,253 --> 01:49:20,556 IT'S VERY PRELIMINARY, VERY FEW 2995 01:49:20,556 --> 01:49:21,890 ANIMALS, BUT SO FAR WE HAVEN'T 2996 01:49:21,890 --> 01:49:23,759 FOUND A SYSTEM IN WHICH THEY'RE 2997 01:49:23,759 --> 01:49:24,493 REFRACTORY. 2998 01:49:24,493 --> 01:49:25,494 >> ALTHOUGH THE PARADOX, IF I 2999 01:49:25,494 --> 01:49:27,062 MAY STEP IN, FROM THE CRISPR 3000 01:49:27,062 --> 01:49:29,898 ANGLE IS THE AGENCY DOESN'T LIKE 3001 01:49:29,898 --> 01:49:31,867 NONSPECIFIC BIODISTRIBUTION. 3002 01:49:31,867 --> 01:49:37,039 SO VERVE, THE COMPANY THAT DID 3003 01:49:37,039 --> 01:49:38,340 THE -- DISEASE -- THEY WERE ON 3004 01:49:38,340 --> 01:49:40,475 CLINICAL HOLD IN THE U.S. FOR A 3005 01:49:40,475 --> 01:49:42,311 YEAR BECAUSE THEY WERE CONCERNED 3006 01:49:42,311 --> 01:49:44,046 ABOUT OFF TARGET AND OFF TARGET 3007 01:49:44,046 --> 01:49:44,847 TISSUES. 3008 01:49:44,847 --> 01:49:47,449 SO STRATEGICALLY FOR THE FIELD 3009 01:49:47,449 --> 01:49:49,117 TO KIND OF THE WORK THAT BEV 3010 01:49:49,117 --> 01:49:51,019 ALLUDED TO, REALLY IS THE DRIVER 3011 01:49:51,019 --> 01:49:53,822 OF ULTIMATE PROGRESS BECAUSE OFF 3012 01:49:53,822 --> 01:49:55,057 TISSUE BY DISTRIBUTION WHATEVER 3013 01:49:55,057 --> 01:49:56,158 YOUR PAYLOAD IS, THE EASIER A 3014 01:49:56,158 --> 01:49:57,926 PATH YOU WILL HAVE THROUGH 3015 01:49:57,926 --> 01:49:58,794 REGULATORY REVIEW IN THE U.S. 3016 01:49:58,794 --> 01:49:59,995 THAT'S JUST PRACTICALLY A TRUTH 3017 01:49:59,995 --> 01:50:01,663 RIGHT NOW. 3018 01:50:01,663 --> 01:50:04,166 >> ANOTHER QUESTION FROM BRANDY 3019 01:50:04,166 --> 01:50:05,367 THAT SORT OF TIES INTO THIS, HOW 3020 01:50:05,367 --> 01:50:06,935 DO YOU ANTICIPATE HANDLING 3021 01:50:06,935 --> 01:50:08,403 DISORDERS THAT HAVE MULTISYSTEM 3022 01:50:08,403 --> 01:50:11,473 IMPACTS WHERE YOU T DO WANT TO 3023 01:50:11,473 --> 01:50:13,442 TARGET MORE THAN THE BRAIN, LIKE 3024 01:50:13,442 --> 01:50:18,146 SUPER SCLEROSIS COMPLEX, SURGE 3025 01:50:18,146 --> 01:50:18,747 WEBER, ET CETERA? 3026 01:50:18,747 --> 01:50:20,682 >> YOU KNOW, WE'VE TALKED ABOUT 3027 01:50:20,682 --> 01:50:21,550 THIS AT LENGTH EVEN WITH 3028 01:50:21,550 --> 01:50:22,851 INDIVIDUALS IN MY LAB INCLUDED 3029 01:50:22,851 --> 01:50:24,353 THAT WORKS IN VARIOUS DISORDERS 3030 01:50:24,353 --> 01:50:27,522 KNOWN AS THE LYSOSOMAL STORAGE 3031 01:50:27,522 --> 01:50:28,924 DISEASES WHERE THERE'S MANY THAT 3032 01:50:28,924 --> 01:50:30,492 ARE BRAIN-CENTRIC BUT THERE'S A 3033 01:50:30,492 --> 01:50:33,095 LOT OF THEM THAT TIPPI MENTIONED 3034 01:50:33,095 --> 01:50:35,430 ALSO THAT HAVE INVOLVED THE 3035 01:50:35,430 --> 01:50:36,832 BONE, INVOLVED THE LIVER, 3036 01:50:36,832 --> 01:50:38,834 INVOLVED THE SPLEEN AND INVOLVED 3037 01:50:38,834 --> 01:50:39,101 THE BRAIN. 3038 01:50:39,101 --> 01:50:40,402 SO THERE, I ACTUALLY THINK THE 3039 01:50:40,402 --> 01:50:43,038 PATH FORWARD IS LIKELY GOING TO 3040 01:50:43,038 --> 01:50:45,674 BE AN LNP DELIVERY FOR THE PRIF 3041 01:50:45,674 --> 01:50:47,976 LAL SYSTEMS AND PROBABLY A MORE 3042 01:50:47,976 --> 01:50:50,612 TARGETED AAV FOR THE -- OR YOU 3043 01:50:50,612 --> 01:50:53,949 USE SOMETHING THAT, YOU KNOW, 3044 01:50:53,949 --> 01:50:58,520 FYODOR SHOWED WITH THE RECEPTOR 3045 01:50:58,520 --> 01:50:59,955 TARGETED AAVs BECAUSE THAT 3046 01:50:59,955 --> 01:51:03,091 GETS INTO EVERY ORGAN, EVERY 3047 01:51:03,091 --> 01:51:04,927 ENDOTHELIAL CELL EXPRESSES THOSE 3048 01:51:04,927 --> 01:51:05,193 RECEPTORS. 3049 01:51:05,193 --> 01:51:06,662 AS LONG AS YOU CAN MAKE THEM 3050 01:51:06,662 --> 01:51:08,096 EFFICIENT ENOUGH TO DO LOW 3051 01:51:08,096 --> 01:51:09,231 ENOUGH DOSE WHERE YOU DON'T 3052 01:51:09,231 --> 01:51:11,033 DESTROY ALL THE TRANSDUCED 3053 01:51:11,033 --> 01:51:12,701 CELLS, I THINK IT BECOMES 3054 01:51:12,701 --> 01:51:14,603 SOMEWHAT PRACTICAL BUT WE'LL 3055 01:51:14,603 --> 01:51:18,807 HAVE TO SEE. 3056 01:51:18,807 --> 01:51:22,511 >> IT'S IMPORTANT TO UNDERSTAND, 3057 01:51:22,511 --> 01:51:23,879 PEOPLE SAY FUNCTIONAL CURE FOR 3058 01:51:23,879 --> 01:51:25,614 SICKLE CELL DISEASE, BUT I SPEAK 3059 01:51:25,614 --> 01:51:26,381 WITH PHYSICIANS WHO TREAT 3060 01:51:26,381 --> 01:51:27,482 INDIVIDUALS LIVING WITH SICKLE 3061 01:51:27,482 --> 01:51:29,851 CELL DISEASE QUITE A BIT, 3062 01:51:29,851 --> 01:51:31,153 INCLUDING JOHN TISDALE HERE, 3063 01:51:31,153 --> 01:51:33,121 MARK WALTERS AT CHILDREN'S 3064 01:51:33,121 --> 01:51:35,624 OAKLAND, BUT PEOPLE WHO HAVE 3065 01:51:35,624 --> 01:51:40,329 RECEIVED THEM FOR SICKLE CELL 3066 01:51:40,329 --> 01:51:44,633 DISEASE, THEY STILL HAVE 3067 01:51:44,633 --> 01:51:45,834 NECROSIS AND SEVERE PAIN. 3068 01:51:45,834 --> 01:51:47,269 IN FACT THEY STILL RECEIVE 3069 01:51:47,269 --> 01:51:48,370 PAINKILLERS FOR THEIR PAIN 3070 01:51:48,370 --> 01:51:52,207 EPISODES EVEN THOUGH -- THIS IS 3071 01:51:52,207 --> 01:51:54,409 ALL GOING TO SAY THAT THE AGENCY 3072 01:51:54,409 --> 01:51:55,844 IS COMFORTABLE WITH THE CONCEPT 3073 01:51:55,844 --> 01:52:01,917 OF HAVING THE APPROVABLE END 3074 01:52:01,917 --> 01:52:04,119 POINT BE NOT AT 100% CURE. 3075 01:52:04,119 --> 01:52:05,253 I'M NOT SAYING THAT'S WHAT WE 3076 01:52:05,253 --> 01:52:06,955 STRIVE FOR, BUT LET'S FIX ONE 3077 01:52:06,955 --> 01:52:07,622 PART OF THE BODY. 3078 01:52:07,622 --> 01:52:08,857 BUT I'M JUST SAYING THAT TODAY, 3079 01:52:08,857 --> 01:52:11,259 AT THE STAGE WHERE THAT FIELD 3080 01:52:11,259 --> 01:52:13,328 IS, SOMETHING THAT POSITIVELY 3081 01:52:13,328 --> 01:52:14,429 IMPACTS THE PATIENT'S LIVED 3082 01:52:14,429 --> 01:52:15,897 EXPERIENCE IS SOMETHING THAT THE 3083 01:52:15,897 --> 01:52:19,501 AGENCY IS COMFORTABLE WITH HAV 3084 01:52:19,501 --> 01:52:19,801 HAVING. 3085 01:52:19,801 --> 01:52:20,902 >> AND IT ALSO SPEAKS TO THE 3086 01:52:20,902 --> 01:52:21,803 IMPORTANCE OF EARLY 3087 01:52:21,803 --> 01:52:24,072 INTERVENTION. 3088 01:52:24,072 --> 01:52:25,907 >> IF I CAN JUST AMPLIFY BOTH OF 3089 01:52:25,907 --> 01:52:28,410 THOSE POINTS, I THINK LYSOSOMAL 3090 01:52:28,410 --> 01:52:29,845 STORAGE DISEASES ARE A GREAT 3091 01:52:29,845 --> 01:52:31,046 TARGET BECAUSE OF THE CONCEPT OF 3092 01:52:31,046 --> 01:52:31,513 CROSS-CORRECTION. 3093 01:52:31,513 --> 01:52:34,116 SO IF YOU GET YOUR LNP IN THE 3094 01:52:34,116 --> 01:52:36,718 LIVER AND THE HEPATOCYTES ARE 3095 01:52:36,718 --> 01:52:38,220 TURNING UP A NORMAL ENZYME, THEN 3096 01:52:38,220 --> 01:52:39,521 IT CAN CROSS-CORRECT THE MANY 3097 01:52:39,521 --> 01:52:41,523 OTHER CELLS IN THE BODY. 3098 01:52:41,523 --> 01:52:43,225 OF COURSE EXCEPT FOR THE CNS. 3099 01:52:43,225 --> 01:52:45,827 SO BEV, I REALLY LIKED WHAT YOU 3100 01:52:45,827 --> 01:52:46,928 SAID ABOUT SOMETHING SEPARATE 3101 01:52:46,928 --> 01:52:48,930 FOR THE CNS, AND I DEFINITELY 3102 01:52:48,930 --> 01:52:51,099 AGREE THAT WE DON'T HAVE TO AIM 3103 01:52:51,099 --> 01:52:53,568 FOR A 100% CURE AS WE'RE GETTING 3104 01:52:53,568 --> 01:52:57,506 STARTED IN THIS FIELD. 3105 01:52:57,506 --> 01:52:58,740 >> LAURIE? 3106 01:52:58,740 --> 01:53:02,244 >> BEV -- 3107 01:53:02,244 --> 01:53:03,145 >> I THINK IT'S ON. 3108 01:53:03,145 --> 01:53:06,648 >> OKAY. 3109 01:53:06,648 --> 01:53:09,017 BEV, I'M WONDERING IF YOU CAN 3110 01:53:09,017 --> 01:53:10,886 POSTULATE ON WHAT YOU THINK THE 3111 01:53:10,886 --> 01:53:12,454 MECHANISM IS FOR YOUR 3112 01:53:12,454 --> 01:53:12,988 CELL-SPECIFIC TARGETING. 3113 01:53:12,988 --> 01:53:16,491 BECAUSE I'M THINKING ABOUT 3114 01:53:16,491 --> 01:53:19,961 DRAVET SYNDROME, AND IT'S JUST 3115 01:53:19,961 --> 01:53:21,563 NOT -- A THAT'S 3116 01:53:21,563 --> 01:53:22,731 HAPLOINSUFFICIENT BUT A LOT OF 3117 01:53:22,731 --> 01:53:24,466 GENES ARE DIFFERENT IN RESPONSE 3118 01:53:24,466 --> 01:53:27,903 TO THAT. 3119 01:53:27,903 --> 01:53:31,006 SO WOULD WE GET THERE TARGETING 3120 01:53:31,006 --> 01:53:32,107 NEURONS THE WAY YOU'RE THINKING 3121 01:53:32,107 --> 01:53:34,643 ABOUT IT IN A DISEASE MODEL? 3122 01:53:34,643 --> 01:53:35,811 DO WE KNOW? 3123 01:53:35,811 --> 01:53:38,180 >> SO THE QUESTION FOR THOSE IN 3124 01:53:38,180 --> 01:53:39,714 THE ROOM THAT PROBABLY HEARD YOU 3125 01:53:39,714 --> 01:53:40,882 ONLINE WAS, YOU KNOW, CAN 3126 01:53:40,882 --> 01:53:43,118 SOMETHING LIKE I DESCRIBED WORK 3127 01:53:43,118 --> 01:53:48,390 FOR DRAVET AND OTHER DISORDERS, 3128 01:53:48,390 --> 01:53:49,891 OTHER EPILEPSY DISORDERS 3129 01:53:49,891 --> 01:53:50,892 AFFECTING VERY SPECIFIC CLASSES 3130 01:53:50,892 --> 01:53:51,693 OF NEURONS. 3131 01:53:51,693 --> 01:53:54,563 AND I DO THINK SO. 3132 01:53:54,563 --> 01:53:57,933 WE'VE BUILT IN, AS I MENTIONED, 3133 01:53:57,933 --> 01:54:02,404 THIS SINGLE CELL APPROACH THAT 3134 01:54:02,404 --> 01:54:03,905 THEN CAN IDENTIFY WHAT CAPSIDS 3135 01:54:03,905 --> 01:54:04,973 ARE GOING TO WHAT CELLS. 3136 01:54:04,973 --> 01:54:07,476 FIRST WE CAN GET THE REGIONAL 3137 01:54:07,476 --> 01:54:09,077 SPECIFICITY, YOU KNOW, HERE WE 3138 01:54:09,077 --> 01:54:10,846 WANT TO HIT MAYBE THE ENTIRE 3139 01:54:10,846 --> 01:54:12,914 TEMPORAL CORTEX OR THE ENTIRE 3140 01:54:12,914 --> 01:54:16,051 HIPPOCAMPUS OR BOTH, AND THEN 3141 01:54:16,051 --> 01:54:19,421 YOU BEGIN TO IMPLEMENT THE 3142 01:54:19,421 --> 01:54:21,590 SINGLE CELL TRANSDUCTION 3143 01:54:21,590 --> 01:54:22,457 INFORMATION AND LAYER THAT ON 3144 01:54:22,457 --> 01:54:23,425 TOP OF IT. 3145 01:54:23,425 --> 01:54:25,060 AND THEN YOU CAN GET THAT 3146 01:54:25,060 --> 01:54:25,360 SPECIFICITY. 3147 01:54:25,360 --> 01:54:28,396 THE OTHER WAY IS TO GET YOU TO 3148 01:54:28,396 --> 01:54:31,700 BASICALLY ALL THE REGIONAL AREAS 3149 01:54:31,700 --> 01:54:34,169 THAT YOU WANT TO HIT IN MOST OF 3150 01:54:34,169 --> 01:54:35,904 THE NEURONS AND THEN YOU USE THE 3151 01:54:35,904 --> 01:54:37,472 PAYLOAD, YOU KNOW, SOME OF THE 3152 01:54:37,472 --> 01:54:40,208 BEAUTIFUL WORK COMING OUT OF THE 3153 01:54:40,208 --> 01:54:41,977 ALLAN BRAIN ATLAS, FOR EXAMPLE 3154 01:54:41,977 --> 01:54:43,912 THAT HAS IDENTIFIED VERY 3155 01:54:43,912 --> 01:54:44,946 RESTRICTIVE ENHANCERS THAT CAN 3156 01:54:44,946 --> 01:54:46,281 ALLOW FOR EXPRESSION IN SPECIFIC 3157 01:54:46,281 --> 01:54:47,048 CLASSES OF NEURONS. 3158 01:54:47,048 --> 01:54:50,018 SO I THINK THERE'S WAYS TO 3159 01:54:50,018 --> 01:54:51,486 ENGINEER NOT JUST THE CAPSIDS 3160 01:54:51,486 --> 01:54:52,988 THAT I'VE DONE BUT ALSO THE 3161 01:54:52,988 --> 01:54:54,589 PAYLOADS IN A WAY THAT PROVIDES 3162 01:54:54,589 --> 01:54:56,124 THAT LEVEL OF SPECIFICITY AND I 3163 01:54:56,124 --> 01:54:57,359 DON'T WANT TO UNDERMINE THOSE 3164 01:54:57,359 --> 01:55:00,529 THAT ARE WORKING ON PAYLOAD 3165 01:55:00,529 --> 01:55:01,062 ENGINEERING. 3166 01:55:01,062 --> 01:55:02,831 I'M ONE OF THEM TOO. 3167 01:55:02,831 --> 01:55:06,801 BECAUSE I THINK THERE'S TIMES 3168 01:55:06,801 --> 01:55:11,373 WHERE YOU NEED BOTH. 3169 01:55:11,373 --> 01:55:14,376 AND MAYBE FOR EDITING, IT'S A 3170 01:55:14,376 --> 01:55:15,944 SIMILAR THING, YOU MAY NOT NEED 3171 01:55:15,944 --> 01:55:17,245 TO EDIT ALL THESE OTHER CELLS, 3172 01:55:17,245 --> 01:55:19,514 ALTHOUGH IT WOULDN'T REALLY 3173 01:55:19,514 --> 01:55:21,683 MATTER IF THE GENE'S NOT 3174 01:55:21,683 --> 01:55:22,450 EXPRESSED ANYWAY. 3175 01:55:22,450 --> 01:55:24,619 BUT FOR GENE REPLACEMENT-TYPE 3176 01:55:24,619 --> 01:55:26,855 THERAPIES OR TAKING OUR VECTORS 3177 01:55:26,855 --> 01:55:31,560 TO THE LIVER, VECTORIZED 3178 01:55:31,560 --> 01:55:32,994 ANTISENSE TECHNOLOGY OR SOME 3179 01:55:32,994 --> 01:55:34,529 OTHER WAY TO KNOCK DOWN, I THINK 3180 01:55:34,529 --> 01:55:34,896 IT'S IMPORTANT. 3181 01:55:34,896 --> 01:55:36,398 >> JUST REALLY QUICKLY, AS I 3182 01:55:36,398 --> 01:55:38,400 MENTIONED, I DON'T KNOW HOW TO 3183 01:55:38,400 --> 01:55:39,868 SPELL INHIBITORY INTERNEURON, 3184 01:55:39,868 --> 01:55:42,470 BUT IF YOU LOOK AT -- PLEASE. 3185 01:55:42,470 --> 01:55:42,904 I'M SERIOUS. 3186 01:55:42,904 --> 01:55:44,773 I HAVE WIKIPEDIA LEVEL KNOWLEDGE 3187 01:55:44,773 --> 01:55:45,941 THAT THEY EXIST. 3188 01:55:45,941 --> 01:55:47,108 BUT ENCODED IN THEIR PAPER, 3189 01:55:47,108 --> 01:55:49,511 WHICH I MENTIONED, AND ON THEIR 3190 01:55:49,511 --> 01:55:51,680 WEBSITE GO ON AND ON FOR PAGES 3191 01:55:51,680 --> 01:55:53,515 ABOUT HOW THEY DID ALL OF THESE 3192 01:55:53,515 --> 01:55:57,185 SCREENS FOR PROMOTERS THAT DRIVE 3193 01:55:57,185 --> 01:55:59,020 PAYLOAD CONTROL, AND THEN THEY 3194 01:55:59,020 --> 01:55:59,988 ACTUALLY TALK ACTIVELY ABOUT HOW 3195 01:55:59,988 --> 01:56:01,790 THAT IS THE ONLY WAY TO DO THIS 3196 01:56:01,790 --> 01:56:05,727 BECAUSE, AGAIN, I'M NOT A -- 3197 01:56:05,727 --> 01:56:06,428 BIOLOGIST BUT WHERE I'M GOING 3198 01:56:06,428 --> 01:56:08,263 WITH THIS IS EXACTLY TO BEV'S 3199 01:56:08,263 --> 01:56:08,997 POINT. 3200 01:56:08,997 --> 01:56:10,899 SPECIFICITY OF PAYLOAD 3201 01:56:10,899 --> 01:56:12,200 EXPRESSION IS A MAJOR DIRECTION 3202 01:56:12,200 --> 01:56:13,902 FOR THE FIELD, AND IT SOUNDS 3203 01:56:13,902 --> 01:56:15,103 LIKE FROM PEOPLE WHO ACTUALLY 3204 01:56:15,103 --> 01:56:17,105 WORK WITH DRAVET, THAT IS 3205 01:56:17,105 --> 01:56:17,472 SOMETHING TO DO. 3206 01:56:17,472 --> 01:56:19,074 >> AND THEN REMOVING THAT 3207 01:56:19,074 --> 01:56:21,409 OFF-TARGET EXPOSURE, AS BOTH 3208 01:56:21,409 --> 01:56:23,411 FYODOR AND I ARE TALKING ABOUT 3209 01:56:23,411 --> 01:56:24,846 WHERE MOST OF YOUR PAYLOAD GOES 3210 01:56:24,846 --> 01:56:26,681 TO YOUR TARGET AND IS EXPRESSING 3211 01:56:26,681 --> 01:56:27,782 YOUR TARGET, THERE'S NO REASON 3212 01:56:27,782 --> 01:56:30,018 TO TREAT THE SPLEEN, THE KIDNEY 3213 01:56:30,018 --> 01:56:33,088 AND THE LIVER WITH YOUR DEAD 3214 01:56:33,088 --> 01:56:34,723 CAPSID THAT DOESN'T EXPRESS. 3215 01:56:34,723 --> 01:56:36,091 OKAY, IT DOESN'T EXPRESS BUT 3216 01:56:36,091 --> 01:56:36,958 IT'S STILL GOING THERE AND 3217 01:56:36,958 --> 01:56:37,993 THAT'S NOT GOOD. 3218 01:56:37,993 --> 01:56:40,929 >> YES? 3219 01:56:40,929 --> 01:56:43,498 >> I HAVE A QUESTION FOR 3220 01:56:43,498 --> 01:56:43,832 DR. DAVIDSON. 3221 01:56:43,832 --> 01:56:45,800 SO YOU TALK ABOUT YOUR CIRCUITRY 3222 01:56:45,800 --> 01:56:47,269 MANIPULATION OF THE AAV, SO WE 3223 01:56:47,269 --> 01:56:51,973 KNOW IF YOU HAVE LIKE -- IS THAT 3224 01:56:51,973 --> 01:56:53,775 A POSSIBILITY -- SPOT OF 3225 01:56:53,775 --> 01:56:55,443 INJECTION THAT IT WILL KEEP -- 3226 01:56:55,443 --> 01:56:58,713 THAT GOES THROUGH THE -- AND -- 3227 01:56:58,713 --> 01:57:04,586 THEN GOES TO ALL THESE -- 3228 01:57:04,586 --> 01:57:04,853 DISEASE -- 3229 01:57:04,853 --> 01:57:06,321 >> THAT'S WHAT WE THINK IS 3230 01:57:06,321 --> 01:57:06,655 HAPPENING. 3231 01:57:06,655 --> 01:57:08,256 WE'RE DOING CRISPR SCREENS RIGHT 3232 01:57:08,256 --> 01:57:12,694 NOW TO IDENTIFY THE RECEPTOR, 3233 01:57:12,694 --> 01:57:14,763 WHICH IT STILL USES THE AAV 3234 01:57:14,763 --> 01:57:16,765 RECEPTOR SO WE HAVEN'T KNOCKED 3235 01:57:16,765 --> 01:57:18,233 OUT ITS NATIVE BINDING BUT WHAT 3236 01:57:18,233 --> 01:57:19,534 WE'VE DONE IS ADD A COMPLEMENT 3237 01:57:19,534 --> 01:57:24,205 OF DIFFERENT CO-RECEPTOR, THAT 3238 01:57:24,205 --> 01:57:25,874 IS BASICALLY INTRACELLULAR, THAT 3239 01:57:25,874 --> 01:57:27,442 IS ALLOWING THESE THINGS TO MOVE 3240 01:57:27,442 --> 01:57:28,543 AS THEY ARE. 3241 01:57:28,543 --> 01:57:32,213 I WISH I COULD SAY MORE, BUT WE 3242 01:57:32,213 --> 01:57:33,882 HAVE 100 CANDIDATE GENES TO 3243 01:57:33,882 --> 01:57:40,255 TEST, SO STAY TUNED. 3244 01:57:40,255 --> 01:57:43,258 >> A QUESTION ONLINE AND THEN IN 3245 01:57:43,258 --> 01:57:43,658 THE ROOM. 3246 01:57:43,658 --> 01:57:45,760 >> ANOTHER QUESTION FROM JEFF. 3247 01:57:45,760 --> 01:57:54,903 IN ION CHANNELLOPATHY EPILEPSY, 3248 01:57:54,903 --> 01:57:55,403 EXCITATION TRANSCRIPTION 3249 01:57:55,403 --> 01:57:57,405 COUPLING IS A KEY FEATURE FOR 3250 01:57:57,405 --> 01:58:00,275 HEALTHY NEURAL SIGNALING, WHICH 3251 01:58:00,275 --> 01:58:02,010 STRATEGY CAN PRESERVE THIS 3252 01:58:02,010 --> 01:58:02,610 REGULATION? 3253 01:58:02,610 --> 01:58:04,045 WHI 3254 01:58:04,045 --> 01:58:06,448 >> YOU MEAN GENE REPLACEMENT 3255 01:58:06,448 --> 01:58:08,750 VERSUS GENE YOCKDOWN VERSUS ALL 3256 01:58:08,750 --> 01:58:09,417 OF THESE? 3257 01:58:09,417 --> 01:58:11,086 I THINK YOU HAVE TO LOOK AT EACH 3258 01:58:11,086 --> 01:58:12,587 INDIVIDUAL DISEASE, YOU KNOW, IN 3259 01:58:12,587 --> 01:58:13,021 ISOLATION. 3260 01:58:13,021 --> 01:58:15,690 FOR EXAMPLE, I WORK WITH 3261 01:58:15,690 --> 01:58:18,193 COLLEAGUES AT CHOP WITH 3262 01:58:18,193 --> 01:58:19,427 HAPLOINSUFFICIENCY DISORDERS 3263 01:58:19,427 --> 01:58:22,063 WHERE GENE REPLACEMENT MAY NOT 3264 01:58:22,063 --> 01:58:29,003 MAKE SENSE, BUT WE'RE DEVELOPING 3265 01:58:29,003 --> 01:58:34,042 ANTISENT BLOCKING 3266 01:58:34,042 --> 01:58:35,377 OLIGONUCLEOTIDES THAT CAN 3267 01:58:35,377 --> 01:58:38,079 ESSENTIALLY BLOCK A MIKE -- 3268 01:58:38,079 --> 01:58:40,615 BINDING SITE, REDUCING MODESTLY 3269 01:58:40,615 --> 01:58:41,916 THE LEVEL OF EXPRESSION, THEN 3270 01:58:41,916 --> 01:58:43,118 YOU GET TWICE THE EXPRESSION. 3271 01:58:43,118 --> 01:58:45,420 SO IN MY OPINION IT DOESN'T MAKE 3272 01:58:45,420 --> 01:58:49,257 SENSE FOR GENE THERAPY. 3273 01:58:49,257 --> 01:58:50,358 THERE ARE OTHER METHODS YOU 3274 01:58:50,358 --> 01:58:52,861 COULD USE AND I THINK THE PRIME 3275 01:58:52,861 --> 01:58:53,628 EDITING OF BLOCKING THAT SITE 3276 01:58:53,628 --> 01:58:56,664 WITH THE VECTORS THAT I DELIVER 3277 01:58:56,664 --> 01:59:02,570 IS A TOTALLY COOL NEW WAY THAT I 3278 01:59:02,570 --> 01:59:04,172 ACTUALLY JUST THOUGHT OF AS 3279 01:59:04,172 --> 01:59:05,707 FYODOR WAS TALKING AND I WANT TO 3280 01:59:05,707 --> 01:59:06,975 WORK WITH HIM TO DEVELOP THAT. 3281 01:59:06,975 --> 01:59:08,343 >> THERE YOU GO. 3282 01:59:08,343 --> 01:59:09,944 >> JUST QUICKLY, I ALSO WANT TO 3283 01:59:09,944 --> 01:59:12,180 TOUCH ON THIS CONCEPT OF EDITING 3284 01:59:12,180 --> 01:59:15,450 AS A TOOL TO MAKE ALLELES. 3285 01:59:15,450 --> 01:59:17,118 THE SIMPLEST THING FOR US TO DO 3286 01:59:17,118 --> 01:59:18,720 IS KNOCK SOMETHING OUT. 3287 01:59:18,720 --> 01:59:22,657 IF GETTING RID OF SOMETHING IS 3288 01:59:22,657 --> 01:59:23,892 USEFUL FOR EXACTLY THE BIOLOGY 3289 01:59:23,892 --> 01:59:25,560 THAT WAS JUST DESCRIBED, BRING 3290 01:59:25,560 --> 01:59:29,731 IT ON. 3291 01:59:29,731 --> 01:59:31,466 ACTIVATING SOMETHING OR 3292 01:59:31,466 --> 01:59:32,467 SILENCING SOMETHING AT THE 3293 01:59:32,467 --> 01:59:33,668 ENDOGENOUS LEVEL IS ALSO QUITE 3294 01:59:33,668 --> 01:59:35,937 FEASIBLE. 3295 01:59:35,937 --> 01:59:37,806 REPAIR OF POINT MUTATION, AGAIN, 3296 01:59:37,806 --> 01:59:42,143 I KNOW THERE'S LUNCH AHEAD, THE 3297 01:59:42,143 --> 01:59:43,378 CHALLENGE AT THE REGULATORY 3298 01:59:43,378 --> 01:59:45,113 LEVEL, PLEASE BEAR WITH ME, IS 3299 01:59:45,113 --> 01:59:47,382 IF YOU CHANGE THE GUIDE RNA OF 3300 01:59:47,382 --> 01:59:49,150 THE MUTATION THAT AFFECTS CHILD 3301 01:59:49,150 --> 01:59:49,717 NUMBER ONE TO A DIFFERENT 3302 01:59:49,717 --> 01:59:51,486 MUTATION THAT AFFECTS CHILD 3303 01:59:51,486 --> 01:59:53,721 NUMBER TWO, AS OF TODAY, IN THE 3304 01:59:53,721 --> 01:59:54,823 FOOD AND DRUG ADMINISTRATION'S 3305 01:59:54,823 --> 01:59:56,724 MINDSET, IT'S A DIFFERENT 3306 01:59:56,724 --> 01:59:56,958 PRODUCT. 3307 01:59:56,958 --> 01:59:58,726 SO YOU HAVE TO REDO A 3308 01:59:58,726 --> 02:00:00,094 SUBSTANTIAL NUMBER OF THE 3309 02:00:00,094 --> 02:00:01,229 EXPENSIVE NON-CLINICAL STUDIES 3310 02:00:01,229 --> 02:00:02,864 EVEN THOUGH IT'S THE SAME 3311 02:00:02,864 --> 02:00:04,833 DISEASE, CRISPR IS A PLATFORM, 3312 02:00:04,833 --> 02:00:06,000 BLAH, BLAH, BLAH. 3313 02:00:06,000 --> 02:00:08,937 WHICH IS WHY FOR ME, AGAIN, I'M 3314 02:00:08,937 --> 02:00:10,572 A GENE EDITOR, I WILL BE THE 3315 02:00:10,572 --> 02:00:12,707 FIRST ONE TO SAY IF GENE THERAPY 3316 02:00:12,707 --> 02:00:13,708 WITH AAV WORKS, USE IT. 3317 02:00:13,708 --> 02:00:15,677 FOR ALL THE REASONS THAT I'VE 3318 02:00:15,677 --> 02:00:17,545 JUST -- HAVING SAID THAT, THAT 3319 02:00:17,545 --> 02:00:18,813 DOESN'T MEAN WE SHOULDN'T BE 3320 02:00:18,813 --> 02:00:19,881 TAKING ONSETTINGS WHERE WE NEED 3321 02:00:19,881 --> 02:00:21,349 TO REPAIR THE MUTATION ONE BY 3322 02:00:21,349 --> 02:00:21,516 ONE. 3323 02:00:21,516 --> 02:00:23,151 THE REASON I SAY THIS IS, WE ARE 3324 02:00:23,151 --> 02:00:26,087 ACTIVELY WORKING WITH THE FDA, 3325 02:00:26,087 --> 02:00:27,455 AGAIN, I KNOW THERE ARE 3326 02:00:27,455 --> 02:00:31,192 CLINICIANS IN THE ROOM -- IS TO 3327 02:00:31,192 --> 02:00:34,028 START GETTING INDs WOULD BE 3328 02:00:34,028 --> 02:00:38,199 BASKETS AND THE BASKET WOULD 3329 02:00:38,199 --> 02:00:40,301 HOLD A SYNDROME -- SO WHAT THAT 3330 02:00:40,301 --> 02:00:42,537 MEANS IN ENGLISH IS YOU HAVE A 3331 02:00:42,537 --> 02:00:44,005 CONSTELLATION OF GENETIC 3332 02:00:44,005 --> 02:00:46,407 CONDITIONS WHICH PRESENT VERY 3333 02:00:46,407 --> 02:00:47,208 SIMILARLY, DIFFERENT GENES, 3334 02:00:47,208 --> 02:00:48,276 DIFFERENT MUTATIONS, BUT THEN 3335 02:00:48,276 --> 02:00:51,746 YOU COULD HAVE A BASKET IND 3336 02:00:51,746 --> 02:00:53,081 WHERE DIFFERENT GENE EDITORS ARE 3337 02:00:53,081 --> 02:00:55,016 PUT INTO THE SAME IND, AND ALLOW 3338 02:00:55,016 --> 02:00:57,852 YOU TO TREAT THE PATIENTS AS 3339 02:00:57,852 --> 02:00:58,920 THEY COME IN BASIS. 3340 02:00:58,920 --> 02:01:00,788 THIS IS NOT YET REALITY, THIS 3341 02:01:00,788 --> 02:01:02,323 HAS NEVER BEEN DONE BEFORE, BUT 3342 02:01:02,323 --> 02:01:05,159 I JUST WANT TO NUANCE THIS 3343 02:01:05,159 --> 02:01:06,561 QUESTION ABOUT HOW YOU RESTORE 3344 02:01:06,561 --> 02:01:08,162 THE BIOLOGY. 3345 02:01:08,162 --> 02:01:10,999 IN TERMS OF, LIKE, THE LOGISTICS 3346 02:01:10,999 --> 02:01:15,270 OF DEPLOYING A MOLECULAR OUTC 3347 02:01:15,270 --> 02:01:16,771 OUTCOME, VARYING CHALLENGE AND 3348 02:01:16,771 --> 02:01:18,072 REGULATORY BARRIER, DEPENDING ON 3349 02:01:18,072 --> 02:01:24,178 WHAT EXACTLY YOU'RE RESEARCHING. 3350 02:01:24,178 --> 02:01:26,347 >> OTHER COUNTRIES ARE DOING 3351 02:01:26,347 --> 02:01:27,682 THIS, SO SOMEWHAT TIME WE FOLLOW 3352 02:01:27,682 --> 02:01:28,182 SUIT. 3353 02:01:28,182 --> 02:01:29,050 BASKET TRIAL. 3354 02:01:29,050 --> 02:01:30,318 >> YES, BASKET TRIAL, YES. 3355 02:01:30,318 --> 02:01:31,786 >> I THINK IT'S BEEN A GREAT 3356 02:01:31,786 --> 02:01:32,520 MORNING, A GREAT DISCUSSION. 3357 02:01:32,520 --> 02:01:34,389 I HAVE A QUESTION ABOUT GENE 3358 02:01:34,389 --> 02:01:37,125 EDITING, AND WHAT PROPORTION OF 3359 02:01:37,125 --> 02:01:40,762 NEURONS CAN BE IMPACTED BY GENE 3360 02:01:40,762 --> 02:01:44,732 EDITING, WHICH PERCENTAGE OF 3361 02:01:44,732 --> 02:01:47,001 CELLS YOU'RE AFFECTING, AND THEN 3362 02:01:47,001 --> 02:01:48,202 FOR DIFFERENT DISORDERS, WHAT 3363 02:01:48,202 --> 02:01:50,905 PROPORTION OF NEURONS YOU'RE 3364 02:01:50,905 --> 02:01:51,773 AFFECTING. 3365 02:01:51,773 --> 02:01:53,308 ENS MATIC DEFECTS WHERE YOU NEED 3366 02:01:53,308 --> 02:01:55,043 SOME SMALL AMOUNT OF RESIDUAL 3367 02:01:55,043 --> 02:01:57,979 ENZYME ACTIVITY MIGHT BE MUCH 3368 02:01:57,979 --> 02:02:04,919 EASIER TO ADDRESS, GE 3369 02:02:04,919 --> 02:02:06,020 GUILLAIN-BARRE DROME -- 3370 02:02:06,020 --> 02:02:08,222 >> I'LL START AND THEN I'LL PASS 3371 02:02:08,222 --> 02:02:12,927 TO MY COLLEAGUES, BUT FOR 3372 02:02:12,927 --> 02:02:14,762 LYSOSOMAL STORAGE DISEASES, 3373 02:02:14,762 --> 02:02:16,998 POSTNATALLY AT LEAST, YOU REALLY 3374 02:02:16,998 --> 02:02:20,435 NEED MORE THAN 100% EXPRESSION 3375 02:02:20,435 --> 02:02:24,272 IN THOSE CORRECTED CELLS IN THE 3376 02:02:24,272 --> 02:02:27,475 BRAIN TO ALLOW FOR SUFFICIENT 3377 02:02:27,475 --> 02:02:31,446 SECRETION AND A PENUMBRA OF 3378 02:02:31,446 --> 02:02:33,047 ENZYME TO BE SECRETED. 3379 02:02:33,047 --> 02:02:34,382 IF YOU'RE JUST EXPRESSING WILD 3380 02:02:34,382 --> 02:02:36,217 TYPE AMOUNTS, IT WILL JUST 3381 02:02:36,217 --> 02:02:39,153 IMPACT A FEW CELLS. 3382 02:02:39,153 --> 02:02:42,256 SO I THINK THE GOAL FOR 3383 02:02:42,256 --> 02:02:43,524 SOMETHING LIKE A LYSOSOMAL 3384 02:02:43,524 --> 02:02:44,125 STORAGE DISEASE IS THAT YOU 3385 02:02:44,125 --> 02:02:47,462 WOULD HAVE TO CORRECT A LOT OF 3386 02:02:47,462 --> 02:02:49,631 CELLS TO HAVE AN IMPACT ON THOSE 3387 02:02:49,631 --> 02:02:50,498 SURROUNDING CELLS AROUND THEM, 3388 02:02:50,498 --> 02:02:51,599 BECAUSE YOU WOULDN'T SECRETE 3389 02:02:51,599 --> 02:02:53,134 ENOUGH ENZYME TO MAKE MUCH OF A 3390 02:02:53,134 --> 02:02:53,735 DIFFERENCE, AT LEAST IN THE 3391 02:02:53,735 --> 02:02:55,603 BRAIN. 3392 02:02:55,603 --> 02:02:59,641 MOST OF THESE ENZYMES FI BIND V, 3393 02:02:59,641 --> 02:03:01,442 VERY BEAUTIFULLY TO THE 3394 02:03:01,442 --> 02:03:02,310 EXTRACELLULAR MATRIX, SO IT 3395 02:03:02,310 --> 02:03:03,745 TAKES A LOT MORE THAN NORMAL TO 3396 02:03:03,745 --> 02:03:07,548 MOVE THEM AROUND. 3397 02:03:07,548 --> 02:03:09,283 FOR SOMETHING LIKE HUNTINGTON'S 3398 02:03:09,283 --> 02:03:10,051 DISEASE, I THINK EVERY DISEASE, 3399 02:03:10,051 --> 02:03:11,919 YOU HAVE TO ASK THIS QUESTION. 3400 02:03:11,919 --> 02:03:12,487 IT'S A BEAUTIFUL QUESTION 3401 02:03:12,487 --> 02:03:14,188 BECAUSE I THINK AS YOU DEVELOP A 3402 02:03:14,188 --> 02:03:17,125 THERAPY FOR A DISORDER, THIS IS 3403 02:03:17,125 --> 02:03:18,159 A CRITICAL THING TO KNOW, HOW 3404 02:03:18,159 --> 02:03:20,795 MUCH DO I NEED TO CORRECT TO 3405 02:03:20,795 --> 02:03:24,432 IMPACT A CHANGE, A MEANINGFUL 3406 02:03:24,432 --> 02:03:25,533 CHANGE IN A PATIENT, AND MAYBE 3407 02:03:25,533 --> 02:03:27,001 YOU CAN GET SOME INDICATION OF 3408 02:03:27,001 --> 02:03:32,840 THAT FROM MODEL SYSTEMS, AND FOR 3409 02:03:32,840 --> 02:03:34,042 HUNTINGTONS, I THINK WE NEED TO 3410 02:03:34,042 --> 02:03:38,579 CORRECT ABOUT 50% OF THE MEDIUM 3411 02:03:38,579 --> 02:03:44,152 SPINY NEURONS IN THE -- THOSE 3412 02:03:44,152 --> 02:03:46,254 CELLS ARE MOST IMPACTED BY WHAT 3413 02:03:46,254 --> 02:03:48,823 WE NOW KNOW IS SOMATIC REPEAT 3414 02:03:48,823 --> 02:03:50,224 EXPANSION WHERE -- THEY START 3415 02:03:50,224 --> 02:03:51,559 OFF -- OVER TIME, OVER DECADES, 3416 02:03:51,559 --> 02:03:54,162 SOME OF THOSE CELLS END UP WITH 3417 02:03:54,162 --> 02:03:55,430 OVER A HUNDRED REPEATS, SO YOU 3418 02:03:55,430 --> 02:03:56,998 WOULD WANT TO -- AND YOU'D HAVE 3419 02:03:56,998 --> 02:04:00,401 TO GO IN EARLY ENOUGH TO MAKE A 3420 02:04:00,401 --> 02:04:01,235 DIFFERENCE, AND THEN THE CELLS 3421 02:04:01,235 --> 02:04:04,605 CAN NO LONGER TOLERATE THAT. 3422 02:04:04,605 --> 02:04:06,841 SO WE REALLY THINK -- I THINK 3423 02:04:06,841 --> 02:04:07,975 THIS IS, AGAIN, SIMILAR TO SOME 3424 02:04:07,975 --> 02:04:10,378 OF THE OTHER QUESTIONS, A VERY 3425 02:04:10,378 --> 02:04:11,279 SPECIFIC QUESTION. 3426 02:04:11,279 --> 02:04:12,780 >> TIPPI, DO YOU WANT TO SAY 3427 02:04:12,780 --> 02:04:13,848 SOMETHING ABOUT HOW YOU'RE 3428 02:04:13,848 --> 02:04:16,050 THINKING ABOUT THE SORT OF THE 3429 02:04:16,050 --> 02:04:18,186 EFFICACY VERSUS CLINICAL BIN 3430 02:04:18,186 --> 02:04:21,389 FETS,BENEFITS, AND THEN I'LL SAY 3431 02:04:21,389 --> 02:04:22,090 SOMETHING. 3432 02:04:22,090 --> 02:04:23,224 >> I AGREE WITH ALL OF THAT, AND 3433 02:04:23,224 --> 02:04:24,625 JUST TO ADD THAT THE OTHER 3434 02:04:24,625 --> 02:04:28,329 KNOWLEDGE GAP I SEE IS WHEN IN 3435 02:04:28,329 --> 02:04:30,064 DEVELOPMENT DO YOU ACTUALLY NEED 3436 02:04:30,064 --> 02:04:32,233 THE EXPRESSION THE MOST. 3437 02:04:32,233 --> 02:04:36,738 SO FOR EXAMPLE, FOR SMA, 3438 02:04:36,738 --> 02:04:38,639 CHARLOTTE SUMNER'S WORK SHOWS 3439 02:04:38,639 --> 02:04:40,508 THE SMN EXPRESSION IN NEURONS IS 3440 02:04:40,508 --> 02:04:42,610 HIGHEST PRENATALLY, SUGGESTING 3441 02:04:42,610 --> 02:04:45,113 THAT PERHAPS THE PRENATAL 3442 02:04:45,113 --> 02:04:47,815 CORRECTION IS REALLY THE MOST 3443 02:04:47,815 --> 02:04:49,150 IMPORTANT, SO HAVING A TREATMENT 3444 02:04:49,150 --> 02:04:51,652 WHERE YOU RESTORE EXPRESSION IN 3445 02:04:51,652 --> 02:04:53,254 A CERTAIN CRITICAL DEVELOPMENTAL 3446 02:04:53,254 --> 02:04:55,656 TIME WINDOW MAY BE JUST AS 3447 02:04:55,656 --> 02:04:57,024 IMPORTANT AS HAVING THE RIGHT 3448 02:04:57,024 --> 02:05:00,461 LEVEL OF EXPRESSION, SO I THINK 3449 02:05:00,461 --> 02:05:01,429 WE NEED TO THINK REALLY 3450 02:05:01,429 --> 02:05:05,600 CAREFULLY THERE. 3451 02:05:05,600 --> 02:05:10,171 >> YOUR QUESTION LET'S ME RE-GET 3452 02:05:10,171 --> 02:05:11,906 ON MY FAVORITE HIGH HORSE. 3453 02:05:11,906 --> 02:05:13,341 AS BEST AS I CAN TELL, THE ONLY 3454 02:05:13,341 --> 02:05:14,642 WAY TO ANSWER THIS QUESTION 3455 02:05:14,642 --> 02:05:16,077 DEFINITIVELY IS DO THE CLINICAL 3456 02:05:16,077 --> 02:05:17,044 TRIALS. 3457 02:05:17,044 --> 02:05:19,447 AND I MEAN, NOBODY WANTS TO DO 3458 02:05:19,447 --> 02:05:20,648 UNPRODUCTIVE EXPERIMENTS ON 3459 02:05:20,648 --> 02:05:23,117 SUFFERING HUMAN BEINGS. 3460 02:05:23,117 --> 02:05:24,752 BUT A GREAT EXAMPLE IS SICKLE. 3461 02:05:24,752 --> 02:05:27,789 THE WAY WE KNOW THAT 10 TO 20% 3462 02:05:27,789 --> 02:05:29,557 REPAIR IS ENOUGH TO REMEDY THE 3463 02:05:29,557 --> 02:05:30,625 SICKLE PHENOTYPE IS NOT BECAUSE 3464 02:05:30,625 --> 02:05:32,293 WE HAVE SOME DEEP INSIGHT FROM A 3465 02:05:32,293 --> 02:05:34,028 MOUSE. 3466 02:05:34,028 --> 02:05:35,863 THAT'S A HUMAN EXPERIMENT, WHICH 3467 02:05:35,863 --> 02:05:37,732 WAS INADVERTENT. 3468 02:05:37,732 --> 02:05:39,600 IT WAS ALLOGENEIC BONE 3469 02:05:39,600 --> 02:05:39,967 TRANSPLANTATION. 3470 02:05:39,967 --> 02:05:42,603 I LEARNED THAT FROM MARK WALTERS 3471 02:05:42,603 --> 02:05:43,371 AND JOHN TISDALE HERE. 3472 02:05:43,371 --> 02:05:46,207 WHEN YOU DO AN ALLOGENEIC BONE 3473 02:05:46,207 --> 02:05:47,308 TRANSPLANT, IT IS CURATIVE, EVEN 3474 02:05:47,308 --> 02:05:49,577 WHEN A SUBJECT IS ONLY 10% 3475 02:05:49,577 --> 02:05:51,879 CHIMERIC FOR THE DONOR MARROW. 3476 02:05:51,879 --> 02:05:53,281 SO NOW WE'RE NOT GOING TO DO 3477 02:05:53,281 --> 02:05:55,249 BRAIN TRANSPLANTS, I'M SORRY, 3478 02:05:55,249 --> 02:05:57,752 BUT -- NOT TO -- BUT IN BRASS 3479 02:05:57,752 --> 02:06:04,492 TAX TERTACKS TERMS, TO ME, IT IS 3480 02:06:04,492 --> 02:06:06,260 AMAZING TO HAVE SOME BIOMARKER 3481 02:06:06,260 --> 02:06:07,228 OF TARGET ENGAGEMENT. 3482 02:06:07,228 --> 02:06:08,529 I DON'T KNOW WHETHER YOU HAVE 3483 02:06:08,529 --> 02:06:10,798 SUCH A BIOMARKER IN EPILEPSIES. 3484 02:06:10,798 --> 02:06:13,401 SO IN OTHER WORDS, IF YOU CAN 3485 02:06:13,401 --> 02:06:15,903 DOSE A SUBJECT, TYPICALLY YOU GO 3486 02:06:15,903 --> 02:06:16,571 IN WITH A LOW DOSE. 3487 02:06:16,571 --> 02:06:18,639 IF YOU CAN EVALUATE THE 3488 02:06:18,639 --> 02:06:21,175 PERCENTAGE ON TARGET ENGAGEMENT 3489 02:06:21,175 --> 02:06:23,411 RELATIVE TO AFFECT ON SYMPTOMS, 3490 02:06:23,411 --> 02:06:25,813 THIS IS PURE GOLD, BECAUSE YOU 3491 02:06:25,813 --> 02:06:28,649 CAN THEN DERIVE A 3492 02:06:28,649 --> 02:06:29,650 RELATIONSHIP -- THE ANSWER TO 3493 02:06:29,650 --> 02:06:30,718 YOUR QUESTION, AND YES, THAT'S 3494 02:06:30,718 --> 02:06:32,420 CLINICAL RESEARCH, SO YES, YOU 3495 02:06:32,420 --> 02:06:34,288 SORT OF HOLD -- YOU SORT OF 3496 02:06:34,288 --> 02:06:36,924 CLOSE YOUR EYES IN AN EMOTIONAL 3497 02:06:36,924 --> 02:06:38,926 WAY, BUT I DON'T KNOW OF IT ANY 3498 02:06:38,926 --> 02:06:41,095 OTHER WAY. 3499 02:06:41,095 --> 02:06:42,530 >> JUST TO COMMENT ALSO, WE 3500 02:06:42,530 --> 02:06:44,866 DON'T HAVE THE BIOMARKER YET. 3501 02:06:44,866 --> 02:06:47,001 AS FAR AS I KNOW. 3502 02:06:47,001 --> 02:06:50,338 BUT YOUR QUESTION I REALLY GETST 3503 02:06:50,338 --> 02:06:51,305 THE COMPLEXITY OF THE SYSTEMS 3504 02:06:51,305 --> 02:06:52,940 THAT WE'RE WORKING ON IN THE 3505 02:06:52,940 --> 02:06:54,008 EPILEPSIES BECAUSE I DON'T THINK 3506 02:06:54,008 --> 02:06:55,009 WE KNOW THE ANSWER. 3507 02:06:55,009 --> 02:06:57,545 I MEAN, EVERY HUMAN BRAIN IS 3508 02:06:57,545 --> 02:06:59,280 QUITE CAPABLE OF HAVING A FULL 3509 02:06:59,280 --> 02:07:10,191 BLOWN GENERALIZED TAXIC TONIC KC 3510 02:07:11,993 --> 02:07:13,294 SEIZURE. 3511 02:07:13,294 --> 02:07:14,862 EACH EPILEPSY TYPE HAS ITS OWN 3512 02:07:14,862 --> 02:07:15,196 BALANCE POINT. 3513 02:07:15,196 --> 02:07:16,530 EVEN IF WE KNEW -- WELL, IF WE 3514 02:07:16,530 --> 02:07:17,732 KNEW THE BALANCE POINT, WE'D 3515 02:07:17,732 --> 02:07:20,167 HAVE A BETTER SENSE OF JUST 3516 02:07:20,167 --> 02:07:21,869 EXACTLY HOW MUCH OF IT NEEDS TO 3517 02:07:21,869 --> 02:07:24,805 BE IMPACTED, WHETHER IT'S 3518 02:07:24,805 --> 02:07:28,676 DECREASING ECK EYE TAI EXCITATIR 3519 02:07:28,676 --> 02:07:30,011 INCREASING INHIBITION. 3520 02:07:30,011 --> 02:07:32,246 >> CATHY IS GOING TO BE HERE IN 3521 02:07:32,246 --> 02:07:34,415 A BIT, I CERTAINLY PLAN TO FALL 3522 02:07:34,415 --> 02:07:36,684 DOWN ON THOSE KNEES WHEN SHE 3523 02:07:36,684 --> 02:07:38,219 GETS HERE. 3524 02:07:38,219 --> 02:07:40,655 SHE GOT THE FIRST AAV THERAPY 3525 02:07:40,655 --> 02:07:43,457 FOR GENETIC DISEASE APPROVED AND 3526 02:07:43,457 --> 02:07:44,992 PFIZER JUST GOT APPROVAL FOR HER 3527 02:07:44,992 --> 02:07:45,559 HEMOPHILIA DRUG. 3528 02:07:45,559 --> 02:07:46,627 I DON'T KNOW OF ANYBODY ELSE. 3529 02:07:46,627 --> 02:07:48,396 BUT SO THE REASON I BROUGHT HER 3530 02:07:48,396 --> 02:07:49,830 UP, SHE CAN SPEAK AT GREAT 3531 02:07:49,830 --> 02:07:51,499 LENGTH ABOUT THE UTILITY OF 3532 02:07:51,499 --> 02:07:55,136 LARGER ANIMAL MODELS. 3533 02:07:55,136 --> 02:07:57,271 THERE ARE THESE KING CHARLES 3534 02:07:57,271 --> 02:07:58,472 SPANIELS WITH THIS OR THIS OTHER 3535 02:07:58,472 --> 02:08:00,341 KIND OF DOG WITH THAT, AND YOU 3536 02:08:00,341 --> 02:08:07,415 CAN DO DOSE-RESPONSES. 3537 02:08:07,415 --> 02:08:07,949 BUT IS THERE A DOG -- 3538 02:08:07,949 --> 02:08:08,816 >> THERE IS. 3539 02:08:08,816 --> 02:08:10,918 DOGS ARE PROBABLY ONE OF THE 3540 02:08:10,918 --> 02:08:12,887 BEST MAMMALIAN SPECIES TO STUDY 3541 02:08:12,887 --> 02:08:16,157 WHEN IT COMES TO EPILEPSY. 3542 02:08:16,157 --> 02:08:16,958 ABSOLUTELY. 3543 02:08:16,958 --> 02:08:18,225 >> POODLES. 3544 02:08:18,225 --> 02:08:21,228 >> WE CAN DISCUSS OVER LUNCH 3545 02:08:21,228 --> 02:08:24,665 JUST HOW MUCH PRE-CLINICAL 3546 02:08:24,665 --> 02:08:26,500 OPPORTUNITY WE HAVE HERE, BUT 3547 02:08:26,500 --> 02:08:30,004 YEAH, YEP. 3548 02:08:30,004 --> 02:08:31,272 >> I'LL JUST ECHO THAT. 3549 02:08:31,272 --> 02:08:34,108 I DON'T KNOW ANYONE ELSE THAT'S 3550 02:08:34,108 --> 02:08:34,875 DEVELOPED TWO OUT OF SIX 3551 02:08:34,875 --> 02:08:36,277 APPROVED DRUGS IN THE WORLD 3552 02:08:36,277 --> 02:08:38,913 OTHER THAN KATHY. 3553 02:08:38,913 --> 02:08:42,049 >> KATHY WAS MEANT TO BE THE 3554 02:08:42,049 --> 02:08:45,353 FOURTH SPEAKER OF THIS SESSION 3555 02:08:45,353 --> 02:08:47,221 BUT BECAUSE SHE'S TRAVELING, SHE 3556 02:08:47,221 --> 02:08:48,289 WILL BE HERE THIS AFTERNOON AND 3557 02:08:48,289 --> 02:08:49,724 ANN WILL BE DOING THE 3558 02:08:49,724 --> 02:08:50,057 INTRODUCTION. 3559 02:08:50,057 --> 02:08:51,325 WITH THAT, WE ARE AT THE TOP OF 3560 02:08:51,325 --> 02:08:52,526 THE HOUR, IT'S TIME FOR LUNCH 3561 02:08:52,526 --> 02:08:53,728 AND POSTER SESSION. 3562 02:08:53,728 --> 02:08:58,265 AND THANK YOU TO OUR THREE OF 3563 02:08:58,265 --> 02:08:58,866 FOUR SPEAKERS WHO YOU REALLY 3564 02:08:58,866 --> 02:09:00,067 HAVE ACCOMPLISHED WHAT WE HOPED 3565 02:09:00,067 --> 02:09:01,802 FOR, WHICH IS THE OUTSIDE 3566 02:09:01,802 --> 02:09:04,005 PERSPECTIVE AND THE INTERSECTION 3567 02:09:04,005 --> 02:09:05,706 WITH THE EPILEPSY, SO A HAND FOR 3568 02:09:05,706 --> 02:09:06,640 OUR SPEAKERS, PLEASE. 3569 02:09:06,640 --> 02:09:12,813 [APPLAUSE] 3570 02:09:13,047 --> 02:09:14,949 >> IT'S MY PLEASURE TO INTRODUCE 3571 02:09:14,949 --> 02:09:17,351 THE MODERATOR OF OUR NEXT 3572 02:09:17,351 --> 02:09:20,354 SESSION, DR. ANN -- EXCUSE ME, 3573 02:09:20,354 --> 02:09:22,490 CAN I GET EVERYONE'S ATTENTION. 3574 02:09:22,490 --> 02:09:22,890 THANK YOU. 3575 02:09:22,890 --> 02:09:24,492 IT'S MY PLEASURE TO INTRODUCE 3576 02:09:24,492 --> 02:09:26,727 THE MODERATOR FOR THE NEXT 3577 02:09:26,727 --> 02:09:30,965 SESSION, DR. ANN PODURI A 3578 02:09:30,965 --> 02:09:34,402 PROFESSOR AT BOSTON CHILDREN'S 3579 02:09:34,402 --> 02:09:36,670 HOSPITAL AND HARVARD AND WE 3580 02:09:36,670 --> 02:09:38,506 CHAIRED A COMMITTEE TOGETHER AND 3581 02:09:38,506 --> 02:09:42,410 I HAVE KNOWN ANN FOR QUITE SOME 3582 02:09:42,410 --> 02:09:43,044 TIME. 3583 02:09:43,044 --> 02:09:44,779 TAKE IT AWAY, ANN. 3584 02:09:44,779 --> 02:09:46,280 >> ABOUT AFTERNOON, EVERYONE. 3585 02:09:46,280 --> 02:09:49,583 THANKS FOR BEING HERE AND THANKS 3586 02:09:49,583 --> 02:09:50,951 EVERYONE ONLINE. 3587 02:09:50,951 --> 02:09:52,753 WE HAD A GOOD FIRST SESSION TO 3588 02:09:52,753 --> 02:09:54,121 SET THE STAGE FOR THIS ONE. 3589 02:09:54,121 --> 02:09:56,991 BEFORE I START TO INTRODUCE THIS 3590 02:09:56,991 --> 02:09:59,026 ONE I WANT TO THANK VICKY FOR 3591 02:09:59,026 --> 02:10:02,129 BRINGING US TOGETHER AND HELPING 3592 02:10:02,129 --> 02:10:06,033 US THINK WHAT WOULD BE NOT JUST 3593 02:10:06,033 --> 02:10:07,568 HELPFUL BUT FORWARD LOOKING 3594 02:10:07,568 --> 02:10:08,469 EFFORTS TO HAVE THE 3595 02:10:08,469 --> 02:10:08,803 CONVERSATION. 3596 02:10:08,803 --> 02:10:10,337 I'M EXCITED TO BRING A WONDERFUL 3597 02:10:10,337 --> 02:10:18,479 LINE UP OF SPEAKERS ON THE PATH 3598 02:10:18,479 --> 02:10:19,747 PROGRESS, PITFALLS AND LESSONS 3599 02:10:19,747 --> 02:10:22,883 FROM NEUROLOGICAL AND 3600 02:10:22,883 --> 02:10:23,818 NON-NEUROLOGICAL TRAILS AND 3601 02:10:23,818 --> 02:10:25,052 TREATMENTS AND WE KNOW WHAT 3602 02:10:25,052 --> 02:10:27,021 GENES AND CELLS WE WANT TO 3603 02:10:27,021 --> 02:10:29,790 TARGET AND STARTING TO LEARN 3604 02:10:29,790 --> 02:10:33,828 NATURAL HISTORY AND WE HEARD 3605 02:10:33,828 --> 02:10:35,062 FLOUED AND -- LOUD AND CLEAR 3606 02:10:35,062 --> 02:10:36,797 THE TOOLBOX THERE AND IT'S A 3607 02:10:36,797 --> 02:10:40,301 GREAT CALL TO ACTION FOR ALL OFS 3608 02:10:40,301 --> 02:10:42,203 TO THINK ABOUT THAT AND WE HAVE 3609 02:10:42,203 --> 02:10:43,571 WORK THAT GOES IN BETWEEN THE 3610 02:10:43,571 --> 02:10:46,874 IDEAS AND TOOLBOXES AND GETTING 3611 02:10:46,874 --> 02:10:49,076 DRUGS AND S TO PATIENTS AND 3612 02:10:49,076 --> 02:10:50,444 WE'RE DELIGHTED TO HAVE SEVERAL 3613 02:10:50,444 --> 02:10:52,446 EXAMPLES NOW WHERE THAT HAS 3614 02:10:52,446 --> 02:10:55,483 HAPPENED ALL THE WAY TO TRIALS. 3615 02:10:55,483 --> 02:10:58,152 AS WITH SESSION 1, SESSION 2 WE 3616 02:10:58,152 --> 02:11:01,722 WANTED TO BRING YOU SOME 3617 02:11:01,722 --> 02:11:02,456 EXAMPLES THAT AREN'T IN THE 3618 02:11:02,456 --> 02:11:03,524 SPACE AND THINK WE CAN LEARN 3619 02:11:03,524 --> 02:11:07,027 FROM THE OTHER EXAMPLES AND THE 3620 02:11:07,027 --> 02:11:09,330 BASIC FOUNDATIONS FOR PLATFORMS 3621 02:11:09,330 --> 02:11:10,965 IN EPILEPSIES AND DELIGHTED WE 3622 02:11:10,965 --> 02:11:13,667 HAVE SOME NEUROLOGICAL AND SOME 3623 02:11:13,667 --> 02:11:14,401 NON-NEUROLOGICAL AND SOME 3624 02:11:14,401 --> 02:11:19,073 EPILEPSY AND EPILEPSY ADJACENT 3625 02:11:19,073 --> 02:11:19,640 DISORDERS WE'LL HEAR ABOUT. 3626 02:11:19,640 --> 02:11:21,308 THE OTHER ASPECT IS LOOKING AT 3627 02:11:21,308 --> 02:11:22,743 OUR FIELD AND BEYOND HOW ARE WE 3628 02:11:22,743 --> 02:11:24,411 GOING TO NOT JUST GET THE TRIALS 3629 02:11:24,411 --> 02:11:25,913 TO HAPPEN BUT HOW ARE WE GOING 3630 02:11:25,913 --> 02:11:31,051 TO GET THE TRIALS TO HAPPEN FOR 3631 02:11:31,051 --> 02:11:31,552 EVERY PATIENT. 3632 02:11:31,552 --> 02:11:33,087 YOU'LL HEAR SOME EXAMPLES AND 3633 02:11:33,087 --> 02:11:35,923 IDEAS LOOKING TO THE FUTURE. 3634 02:11:35,923 --> 02:11:39,026 HOPEFULLY NOT TOO DISTANT WHERE 3635 02:11:39,026 --> 02:11:40,227 WE CAN DIAGNOSE EVERYBODY WITH 3636 02:11:40,227 --> 02:11:40,561 THE DISORDER. 3637 02:11:40,561 --> 02:11:42,463 SO THEY'RE NOT HIDING IN THE 3638 02:11:42,463 --> 02:11:43,664 SHADOWS AS MENTIONED THIS 3639 02:11:43,664 --> 02:11:47,034 MORNING BUT REALLY KNOWN AND 3640 02:11:47,034 --> 02:11:49,803 PRESENTING AND PREVENTING EARLY 3641 02:11:49,803 --> 02:11:51,038 MAYBE PRENATAL APPROACH CAN BE 3642 02:11:51,038 --> 02:11:54,642 USED. 3643 02:11:54,642 --> 02:11:59,046 WITH THAT I'LL GIVE A QUICK RUN 3644 02:11:59,046 --> 02:12:07,221 DOWN OF OUR SPEAKERS. 3645 02:12:07,221 --> 02:12:07,922 ALL RIGHT. 3646 02:12:07,922 --> 02:12:12,626 WE'LL START WITH CARSTEN 3647 02:12:12,626 --> 02:12:14,828 BONNEMAN AND I'VE KNOWN HIM 3648 02:12:14,828 --> 02:12:17,498 SINCE HE WAS RUNNING A MUSCULAR 3649 02:12:17,498 --> 02:12:19,266 CLINIC AT CHOC AND IN ADDITION 3650 02:12:19,266 --> 02:12:20,868 TO THE FANTASTIC THINGS YOU'LL 3651 02:12:20,868 --> 02:12:27,174 HEAR ABOUT GENE THERAPY AS A 3652 02:12:27,174 --> 02:12:29,410 PLATFORM, HE'S BEEN INVOLVED 3653 02:12:29,410 --> 02:12:30,945 FROM PATIENT DESCRIPTION TO GENE 3654 02:12:30,945 --> 02:12:33,480 AND NOW THERAPIES. 3655 02:12:33,480 --> 02:12:36,617 A LOVELY ARC HE'LL TELL US ABOUT 3656 02:12:36,617 --> 02:12:41,755 AND LIZ BERRY KRAVITZ AND WILL 3657 02:12:41,755 --> 02:12:49,597 TALK TO US ABOUT ANGEL SYNDROME 3658 02:12:49,597 --> 02:12:55,769 AND THERAPIES AND BROUGHT MANY 3659 02:12:55,769 --> 02:12:57,738 PEOPLE TOGETHER WITH HER HARD 3660 02:12:57,738 --> 02:13:00,507 WORK AND LOOKING TO THE 3661 02:13:00,507 --> 02:13:01,675 REGULATORY ENVIRONMENT AND 3662 02:13:01,675 --> 02:13:05,246 FLORIAN EICHLER TALKING ABOUT 3663 02:13:05,246 --> 02:13:07,214 RISK AND TREATMENT CHOICES AND 3664 02:13:07,214 --> 02:13:11,785 NEUROLOGICAL DISEASES AND IS A 3665 02:13:11,785 --> 02:13:14,355 PROFESSOR IN THE MUSCULAR 3666 02:13:14,355 --> 02:13:16,290 DYSTROPHY PROGRAM AND HAS DONE 3667 02:13:16,290 --> 02:13:20,094 EXCITING WORK AND WE HAVE KATHY 3668 02:13:20,094 --> 02:13:24,031 HIGH TO TALK ABOUT THE NEW PATHS 3669 02:13:24,031 --> 02:13:30,638 OF WATERFALL LETTONS LEARN FROM 3670 02:13:30,638 --> 02:13:32,339 AAV AND FROM ROCKEFELLER AND 3671 02:13:32,339 --> 02:13:35,042 HE'S TALKED ABOUT FOUNDATIONAL 3672 02:13:35,042 --> 02:13:38,445 WORK ALREADY AND HAS DONE 3673 02:13:38,445 --> 02:13:41,782 FOUNDATIONAL WORK WITH 3674 02:13:41,782 --> 02:13:45,653 TREATMENTS YOU'LL NOW HEAR ABOUT 3675 02:13:45,653 --> 02:13:48,122 AND WENDY CHUNG FROM BOSTON 3676 02:13:48,122 --> 02:13:49,957 CHILDREN'S HOSPITAL AND TALK 3677 02:13:49,957 --> 02:13:52,059 ABOUT FROM N OF 1 TO POPULATION 3678 02:13:52,059 --> 02:13:53,794 HEALTH TO TREAT GENETIC 3679 02:13:53,794 --> 02:13:55,362 EPILEPSIES AND IS PASSIONATE 3680 02:13:55,362 --> 02:13:56,830 ABOUT EARLY DIAGNOSIS IN 3681 02:13:56,830 --> 02:14:00,334 PATIENTS AND HOW CAN WE REALLY 3682 02:14:00,334 --> 02:14:02,870 THINK ABOUT NOT JUST DISORDERS 3683 02:14:02,870 --> 02:14:04,004 BUT THE BROAD POPULATION OF 3684 02:14:04,004 --> 02:14:05,739 CHILDREN WITH NEUROLOGICAL 3685 02:14:05,739 --> 02:14:07,374 DISORDERS AND ALL THE STRATEGIES 3686 02:14:07,374 --> 02:14:08,809 CAN APPLY TO THEM IN THE FUTURE. 3687 02:14:08,809 --> 02:14:14,682 WITH THAT I'LL TURN IT OVER TO 3688 02:14:14,682 --> 02:14:25,025 CARSTEN WHO IS HERE. 3689 02:14:43,110 --> 02:14:44,511 >> THANK YOU VERY MUCH. 3690 02:14:44,511 --> 02:14:46,146 CAN YOU HEAR ME OR SHOULD I SIT 3691 02:14:46,146 --> 02:14:47,981 CLOSER TO THE MICROPHONE? 3692 02:14:47,981 --> 02:14:49,616 YEAH? 3693 02:14:49,616 --> 02:14:55,055 OKAY. 3694 02:14:55,055 --> 02:14:56,056 THANK YOU FOR HAVING ME. 3695 02:14:56,056 --> 02:14:58,959 MY LAB IS UPSTAIRS IN THIS 3696 02:14:58,959 --> 02:14:59,560 BUILDING SO IT'S HOMETOWN FOR 3697 02:14:59,560 --> 02:15:01,328 ME. 3698 02:15:01,328 --> 02:15:05,099 I'M GOING TO TRY TO DO AND IN 3699 02:15:05,099 --> 02:15:07,935 THE NEXT HALF HOUR IS GET YOU 3700 02:15:07,935 --> 02:15:09,937 REAL WORLD EXPERIENCE OF GENE 3701 02:15:09,937 --> 02:15:16,243 THERAPY INTO PATIENTS WITH A 3702 02:15:16,243 --> 02:15:22,116 NEURODEGENERATIVE DISEASE AND 3703 02:15:22,116 --> 02:15:23,384 THOUGHTS AND WHAT THAT ACTUALLY 3704 02:15:23,384 --> 02:15:24,852 IS AND WHAT WE SHOULD THINK 3705 02:15:24,852 --> 02:15:25,853 ABOUT. 3706 02:15:25,853 --> 02:15:29,590 THIS IS NO NEWS TO YOU OR IN THE 3707 02:15:29,590 --> 02:15:31,425 ROOM WHETHER COLLECTIVELY WE'RE 3708 02:15:31,425 --> 02:15:33,927 AWARE THEY'RE MOSTLY GENETIC AND 3709 02:15:33,927 --> 02:15:37,498 MOSTLY AFFECT CHILDREN AND WHEN 3710 02:15:37,498 --> 02:15:39,166 THEY AFFECT CHILDREN THERE'S A 3711 02:15:39,166 --> 02:15:44,972 LARGE UNMET NEED THAT RARE 3712 02:15:44,972 --> 02:15:50,744 DISEASES COLLECTIVELY GET 3713 02:15:50,744 --> 02:15:51,378 DISORDERS IN THE RARE DISEASE 3714 02:15:51,378 --> 02:15:52,312 SPACE. 3715 02:15:52,312 --> 02:15:55,048 AND WITH MANY GENETIC DISEASES 3716 02:15:55,048 --> 02:15:57,317 THAT MAKE UP RARE DISEASE AND 3717 02:15:57,317 --> 02:15:59,052 PREPARED BY NEXT GENERATION 3718 02:15:59,052 --> 02:16:00,988 SEQUENCING WE'RE DISCOVERING 3719 02:16:00,988 --> 02:16:01,755 MORE AND MORE DISEASE CHANGE 3720 02:16:01,755 --> 02:16:05,692 THAN JUST ONE FAMILY OR A FEW 3721 02:16:05,692 --> 02:16:07,027 PATIENTS AND HALF THE DISEASES 3722 02:16:07,027 --> 02:16:13,000 HAVE A RARE GENETIC TARGET AND 3723 02:16:13,000 --> 02:16:14,234 THINK ABOUT THE TREATMENT AND IN 3724 02:16:14,234 --> 02:16:17,604 FRONT OF YOU IS SOMETHING YOU 3725 02:16:17,604 --> 02:16:20,407 UNDERSTAND GENETICALLY AND THE 3726 02:16:20,407 --> 02:16:28,315 WORK -- ROOT TO GOT THERE AND 3727 02:16:28,315 --> 02:16:31,919 THEY ENCOMPASS ANYTHING WITH THE 3728 02:16:31,919 --> 02:16:35,022 GENETIC THERAPIES AND THEY'RE 3729 02:16:35,022 --> 02:16:36,757 ATTRACTIVE BECAUSE THEY'RE ROOT 3730 02:16:36,757 --> 02:16:39,393 CAUSAL AND GENETIC DISORDERS THE 3731 02:16:39,393 --> 02:16:43,230 ROOT IS THE GENETIC MUTATION AND 3732 02:16:43,230 --> 02:16:44,598 THE CLOSER WE GET THE HIGHER WE 3733 02:16:44,598 --> 02:16:48,335 CAN EXPECT THE IMPACT TO BE. 3734 02:16:48,335 --> 02:16:51,572 AND SO IT'S A NEED AND OFTEN 3735 02:16:51,572 --> 02:16:54,675 OPPORTUNITY TO DEVELOP PLATFORM 3736 02:16:54,675 --> 02:16:55,943 GENETIC THERAPIES AND THERAPIES 3737 02:16:55,943 --> 02:16:58,479 A TOOL BOX THAT ALLOWS US TO 3738 02:16:58,479 --> 02:16:59,646 APPLY LEARNING FROM ONE DISEASE 3739 02:16:59,646 --> 02:17:02,716 TO A SIMILAR DISEASE WITH A MUCH 3740 02:17:02,716 --> 02:17:06,520 SHORTER DEVELOPMENTAL PIPELINE 3741 02:17:06,520 --> 02:17:07,321 TO GET THERE. 3742 02:17:07,321 --> 02:17:08,689 THAT'S WHERE MOST IN THE ROOM 3743 02:17:08,689 --> 02:17:10,224 TRIED TO LEARN THIS. 3744 02:17:10,224 --> 02:17:16,630 BUT YOU HAVE TO START WITH 3745 02:17:16,630 --> 02:17:23,036 DISEASES AND IN MY TALK I'LL BE 3746 02:17:23,036 --> 02:17:25,172 TALKING ABOUT THE WORKHORSE OF 3747 02:17:25,172 --> 02:17:26,240 GENE THERAPY AND GENE 3748 02:17:26,240 --> 02:17:28,208 REPLACEMENT THERAPY. 3749 02:17:28,208 --> 02:17:31,612 YOU HEARD ABOUT THERAPEUTIC 3750 02:17:31,612 --> 02:17:36,316 APPROACHES THIS MORNING AND THIS 3751 02:17:36,316 --> 02:17:40,687 IS HAPPENING AT THE SIMPLISTIC 3752 02:17:40,687 --> 02:17:42,523 GENE REPLACEMENT AND YOU'LL SEE 3753 02:17:42,523 --> 02:17:44,758 THE APPROACH THAT WILL INFORM 3754 02:17:44,758 --> 02:17:47,427 ALL OTHER APPROACH AT THE SAME 3755 02:17:47,427 --> 02:17:50,264 TIME SO AAV AS YOU HEARD THIS 3756 02:17:50,264 --> 02:17:53,400 MORNING IS A SMALL VIRUS THAT 3757 02:17:53,400 --> 02:17:56,537 COMES ALONG FOR THE RIDE FOR 3758 02:17:56,537 --> 02:18:01,341 LARGER ADENOVIRUSES AND COMES 3759 02:18:01,341 --> 02:18:06,446 ALONG BECAUSE IT HAS AN 3760 02:18:06,446 --> 02:18:16,890 INCOMPLETE GENE AND IT'S 3761 02:18:22,696 --> 02:18:25,499 PROBABLY NOT PATHOGENIC AT ALL 3762 02:18:25,499 --> 02:18:31,038 MAYBE SOME HEPATITIS THAT COULD 3763 02:18:31,038 --> 02:18:37,744 HAVE BEEN CAUGHT IT'S A 3764 02:18:37,744 --> 02:18:39,046 NON-PATHOGENIC VIRUS SIMPLE IN 3765 02:18:39,046 --> 02:18:41,615 ITS GENOME YOU CAN SEE AND 3766 02:18:41,615 --> 02:18:46,053 THAT'S NOT A COMPLETE GENOME. 3767 02:18:46,053 --> 02:18:48,822 IT NEEDS VIRUSES TO HELP IT 3768 02:18:48,822 --> 02:18:49,022 ALONG. 3769 02:18:49,022 --> 02:18:52,326 IT'S A SINGLE-STRANDED DNA 3770 02:18:52,326 --> 02:18:52,559 VIRUS. 3771 02:18:52,559 --> 02:18:58,332 IT PACKAGES A SINGLE STRAND OF 3772 02:18:58,332 --> 02:19:03,870 DNA IN THE CAPSID AND THE 3773 02:19:03,870 --> 02:19:06,239 INCOMPLETE GENOME HAS THE 3774 02:19:06,239 --> 02:19:11,011 CAPACITY FOR 4.6KB AND MANY 3775 02:19:11,011 --> 02:19:12,079 NATURALLY OCCURRING PHENOTYPES 3776 02:19:12,079 --> 02:19:13,614 WHETHER IT'S OUT IN NATURAL AND 3777 02:19:13,614 --> 02:19:14,815 ANIMAL SPECIES AND THOSE ARE THE 3778 02:19:14,815 --> 02:19:18,185 ONES THAT HAVE BEEN USED IN GENE 3779 02:19:18,185 --> 02:19:21,488 THERAPIES TO DATE BUT AS YOU 3780 02:19:21,488 --> 02:19:22,422 HEARD THIS MORNING THERE'S NEW 3781 02:19:22,422 --> 02:19:24,358 TYPE DEVELOPING ALL THE TIME AND 3782 02:19:24,358 --> 02:19:27,160 VERY IMPORTANT BECAUSE THEY CAN 3783 02:19:27,160 --> 02:19:29,329 IMPROVE THE TARGET INTO CELL 3784 02:19:29,329 --> 02:19:31,598 MUTATION AND YOU WANT TO GO BY 3785 02:19:31,598 --> 02:19:33,834 NOT GOING AT THE SAME TIME AND 3786 02:19:33,834 --> 02:19:37,037 DO NOT WANT TO GO AND THAT 3787 02:19:37,037 --> 02:19:41,408 ENHANCED TARGET BEING TROPISM 3788 02:19:41,408 --> 02:19:43,610 AND THE FUTURE IS HAPPENING IN 3789 02:19:43,610 --> 02:19:48,215 SOME TRIALS BUT WHAT I TELL YOU 3790 02:19:48,215 --> 02:19:49,082 ABOUT TODAY ARE TRADITIONAL 3791 02:19:49,082 --> 02:19:49,516 PHENOTYPES. 3792 02:19:49,516 --> 02:19:55,455 WHAT YOU PACKAGE INTO AN AAV IS 3793 02:19:55,455 --> 02:19:56,957 THE GENE OF THE AAV ARE REPLACED 3794 02:19:56,957 --> 02:20:03,563 WITH WHAT YOU WANT TO DELIVER IN 3795 02:20:03,563 --> 02:20:11,104 BETWEEN THE TWO LEFT OVER AND 3796 02:20:11,104 --> 02:20:15,442 IT'S DRIVEN BY A PROMOTER OR 3797 02:20:15,442 --> 02:20:17,144 ANOTHER GOOD MORNING ELEMENT 3798 02:20:17,144 --> 02:20:19,680 THAT IS VERY IMPORTANT AND YOU 3799 02:20:19,680 --> 02:20:20,714 CAN PUT ANYTHING THAT FITS IN 3800 02:20:20,714 --> 02:20:25,686 THE MUTATION YOU CAN FIT IN 3801 02:20:25,686 --> 02:20:28,789 THERE AND EDITING TOOLS AND 3802 02:20:28,789 --> 02:20:35,562 ANYTHING THAT FITS CAN BE 3803 02:20:35,562 --> 02:20:35,829 DELIVERED. 3804 02:20:35,829 --> 02:20:37,664 THE DELIVERY AND TROPISM IS 3805 02:20:37,664 --> 02:20:39,866 DEPENDENT ON THE CAPSID. 3806 02:20:39,866 --> 02:20:42,836 THERE'S THINGS YOU CAN DO IN THE 3807 02:20:42,836 --> 02:20:45,472 TRANS GENE AVAILABLE IF YOU WANT 3808 02:20:45,472 --> 02:20:49,276 TO DELIVER DOUBLE STRANDED DNA 3809 02:20:49,276 --> 02:20:50,744 RIGHT AWAY FOR THE EXPRESSION OF 3810 02:20:50,744 --> 02:20:58,018 THE VIRUS YOU CAN DO THAT AS 3811 02:20:58,018 --> 02:21:00,687 COMPLIMENTARY CONSTRUCT AND 3812 02:21:00,687 --> 02:21:03,490 THEY'RE DOUBLE STRANDED AND WHAT 3813 02:21:03,490 --> 02:21:04,691 WE HAVE HERE IN A TRIAL I'LL 3814 02:21:04,691 --> 02:21:05,358 TELL YOU ABOUT. 3815 02:21:05,358 --> 02:21:12,566 BUT A SINGLE STRANDED AAV IS 3816 02:21:12,566 --> 02:21:14,334 IMPORTANT TO AAV AND FOR THE 3817 02:21:14,334 --> 02:21:17,370 MOST PART DOES NOT INTEGRATE 3818 02:21:17,370 --> 02:21:19,673 INTO THE GENE AND THE NUCLEAR 3819 02:21:19,673 --> 02:21:22,876 DELIVERS THE MESSAGE THERE WHICH 3820 02:21:22,876 --> 02:21:32,285 IS GOOD FOR POST MITOTIC CELLS 3821 02:21:32,285 --> 02:21:35,422 AND HIGH TURNOVER AND CAN BE A 3822 02:21:35,422 --> 02:21:36,490 PROBLEM WHEN THE CELLS TURN OVER 3823 02:21:36,490 --> 02:21:39,025 BECAUSE IT'S NOT INHERITED WITH 3824 02:21:39,025 --> 02:21:40,894 THE CHROMOSOMES. 3825 02:21:40,894 --> 02:21:43,029 AND THIS IS JUST A VERY BRIEFLY 3826 02:21:43,029 --> 02:21:44,598 HOW YOU PUT THIS TOGETHER. 3827 02:21:44,598 --> 02:21:50,637 I JUST WANT TO SHOW YOU THAT 3828 02:21:50,637 --> 02:21:55,575 WHAT WE HAVE PUT TOGETHER WITH 3829 02:21:55,575 --> 02:22:00,347 THE HELP OF THE VIRUSES AND THE 3830 02:22:00,347 --> 02:22:02,949 HELPER GENES TOGETHER IN A DISH 3831 02:22:02,949 --> 02:22:03,550 AND MAKE AAV. 3832 02:22:03,550 --> 02:22:06,553 THAT IS TRUE BUT IN REAL LIFE 3833 02:22:06,553 --> 02:22:09,956 IT'S MUCH MORE COMPLICATED 3834 02:22:09,956 --> 02:22:11,358 PROCESS THAT REQUIRES MANY STEPS 3835 02:22:11,358 --> 02:22:16,897 OF PURIFICATION AND ANALYTICS. 3836 02:22:16,897 --> 02:22:23,036 AND THAT'S WHAT MAKES AAV 3837 02:22:23,036 --> 02:22:23,670 EXPENSIVE IN THE PROCESS. 3838 02:22:23,670 --> 02:22:29,843 WHAT COUNTS AS QUANTITATIVE AND 3839 02:22:29,843 --> 02:22:31,111 POTENCY AND TECHNICAL TERMS WITH 3840 02:22:31,111 --> 02:22:32,946 REAL MEANING YOU NEED TO HAVE 3841 02:22:32,946 --> 02:22:34,514 FULL VIRUS PARTICLES THAT 3842 02:22:34,514 --> 02:22:35,282 DELIVER THE GOODS TO BE 3843 02:22:35,282 --> 02:22:38,351 EFFICACIOUS. 3844 02:22:38,351 --> 02:22:42,789 AND THIS IS TO SHOW THAT THIS IS 3845 02:22:42,789 --> 02:22:44,958 ALREADY MANY MANY CLINICAL 3846 02:22:44,958 --> 02:22:47,127 TRIALS HAPPENING IN PEDIATRIC 3847 02:22:47,127 --> 02:22:48,795 NEUROLOGICAL DISEASES. 3848 02:22:48,795 --> 02:22:55,035 WE HAVE FDA APPROVED MEDIATED 3849 02:22:55,035 --> 02:22:59,272 GENES AND THEY LEAD THE PACK 3850 02:22:59,272 --> 02:23:01,107 HERE AND THE OTHER TWO ARE IN 3851 02:23:01,107 --> 02:23:03,910 DISEASES AND NEUROLOGICAL 3852 02:23:03,910 --> 02:23:11,051 DISEASES AND NEUROMUSCULAR 3853 02:23:11,051 --> 02:23:13,687 DISEASE AROUND AND DUCHENNE'S 3854 02:23:13,687 --> 02:23:16,590 MUSCULAR DYSTROPHY AND THESE ARE 3855 02:23:16,590 --> 02:23:19,059 APPROVED FOR THESE DISORDERS 3856 02:23:19,059 --> 02:23:27,033 COMMON AMONG THESE STEEZS -- 3857 02:23:27,033 --> 02:23:33,773 DISEASES AND I HAVE TO SAY WE 3858 02:23:33,773 --> 02:23:35,876 WOULD HAVE IT APPRESSED FOR 3859 02:23:35,876 --> 02:23:39,045 CERTAIN DISEASE AND NOW YOU GET 3860 02:23:39,045 --> 02:23:39,980 CHILDREN WALKING WITH THE 3861 02:23:39,980 --> 02:23:42,782 DISEASE WITH THE CAVEAT YOU HAVE 3862 02:23:42,782 --> 02:23:43,817 TO DO IT EARLY. 3863 02:23:43,817 --> 02:23:49,256 YOU HAVE A NARROW WINDOW OF 3864 02:23:49,256 --> 02:23:51,458 OPPORTUNITIES AND WE'LL COME 3865 02:23:51,458 --> 02:23:51,758 BACK. 3866 02:23:51,758 --> 02:23:54,728 THAT'S AN IMPORTANT TOPIC TO 3867 02:23:54,728 --> 02:23:54,961 DISCUSS. 3868 02:23:54,961 --> 02:23:59,966 REALLY THIS HAS OPENED THE DOORS 3869 02:23:59,966 --> 02:24:02,269 AND GENE THERAPY WITH THE CAVEAT 3870 02:24:02,269 --> 02:24:07,674 THAT NOT EVERYTHING IS AS GOOD 3871 02:24:07,674 --> 02:24:15,382 TO BE EXPECTED AS GOOD AS THE 3872 02:24:15,382 --> 02:24:15,649 OUTCOMES. 3873 02:24:15,649 --> 02:24:19,085 WE THINK HOW CAN WE MAKE THIS 3874 02:24:19,085 --> 02:24:23,924 APPROACH OF AAV GENE THERAPY 3875 02:24:23,924 --> 02:24:28,561 PARTICULARLY TO 3876 02:24:28,561 --> 02:24:31,665 NEURODEGENERATIVE DISORDER AND 3877 02:24:31,665 --> 02:24:34,567 IT STARTED WITH PATIENT ADVOCACY 3878 02:24:34,567 --> 02:24:42,075 AND MADE A VECTOR THAT WAS 3879 02:24:42,075 --> 02:24:43,610 CAPABLE OF THE GENE AND THEY 3880 02:24:43,610 --> 02:24:45,345 CAME TO US AND SAID CAN YOU MAKE 3881 02:24:45,345 --> 02:24:45,845 A CLINICAL TRIAL. 3882 02:24:45,845 --> 02:24:48,248 HOW DO WE DO THIS AND PUT THIS 3883 02:24:48,248 --> 02:24:49,382 INTO PATIENTS? 3884 02:24:49,382 --> 02:24:52,118 IT WAS DESIGN TO BE PUT 3885 02:24:52,118 --> 02:24:55,188 INTRAFECALLY INTO THE FLUID OF 3886 02:24:55,188 --> 02:24:55,655 THE CHILDREN. 3887 02:24:55,655 --> 02:24:59,793 THAT LED TO THE FIRST IN HUMAN 3888 02:24:59,793 --> 02:25:00,627 INTRAFECAL GENE THERAPY TRIAL 3889 02:25:00,627 --> 02:25:05,265 AND THE FIRST TIME IT WAS PUT IN 3890 02:25:05,265 --> 02:25:10,570 THIS SPACE FOR GENE -- 3891 02:25:10,570 --> 02:25:11,638 INTRATHECAL SPACE FOR CHILDREN 5 3892 02:25:11,638 --> 02:25:19,079 YEARS AND OLDER. 3893 02:25:19,079 --> 02:25:28,388 AND GIANT AX OM YOU WILL 3894 02:25:28,388 --> 02:25:33,994 NEUROPATHY AND IF YOU UBIQUINATE 3895 02:25:33,994 --> 02:25:37,497 WITH THE TISSUES AND NEURONS YOU 3896 02:25:37,497 --> 02:25:43,036 SEE FILL AMOUNT THAT RESPONDS 3897 02:25:43,036 --> 02:25:50,276 THE AXONS FROM THE DISEASE. 3898 02:25:50,276 --> 02:25:53,279 AND IT'S ALSO IN THE HAIR 3899 02:25:53,279 --> 02:25:56,683 CHILDREN WITH CURLY HAIR BECAUSE 3900 02:25:56,683 --> 02:26:01,621 OF KERATIN IN THE DISEASE. 3901 02:26:01,621 --> 02:26:05,658 BUT IT STARTS AT THE ATRAVELIA 3902 02:26:06,326 --> 02:26:06,326 3903 02:26:14,868 --> 02:26:18,238 ATRAXIA AND AFFECTS MORE AND 3904 02:26:18,238 --> 02:26:21,941 AFFECTS THE OPTIC NERVE. 3905 02:26:21,941 --> 02:26:23,410 IT'S ONE OF THE MORE PROGRESSIVE 3906 02:26:23,410 --> 02:26:26,946 DISORDERS I KNOW IN CHILDHOOD. 3907 02:26:26,946 --> 02:26:31,651 BUT IT'S A SMALL GENE AND 3908 02:26:31,651 --> 02:26:34,687 RECESSIVE AND WE THINK OF GENE 3909 02:26:34,687 --> 02:26:35,255 REPLACEMENT. 3910 02:26:35,255 --> 02:26:40,994 PUT THE MISSING GENE IN WITH THE 3911 02:26:40,994 --> 02:26:45,365 GENE DELIVERY AND HOW DO YOU GET 3912 02:26:45,365 --> 02:26:48,535 TO THE CNS? 3913 02:26:48,535 --> 02:26:51,104 YOU CAN GO INTRAVENOUS. 3914 02:26:51,104 --> 02:26:53,740 THAT DELIVERS BECAUSE OF THE 3915 02:26:53,740 --> 02:26:59,913 BLOOD BRAIN BARRIER AND IT'S 3916 02:26:59,913 --> 02:27:02,148 QUITE PERMEABLE AND HOPEFULLY 3917 02:27:02,148 --> 02:27:04,818 WE'LL HAVE NEWER TYPES LATER TO 3918 02:27:04,818 --> 02:27:05,318 OVERCOME THAT. 3919 02:27:05,318 --> 02:27:07,287 YOU CAN'T GO DIRECTORY TO THE 3920 02:27:07,287 --> 02:27:11,024 SPACE AND WE HAVE CHOSEN THE 3921 02:27:11,024 --> 02:27:15,895 INTRATHECAL WAY TO GET THERE BUT 3922 02:27:15,895 --> 02:27:18,064 THERE ARE OTHER WAYS IN WHICH WE 3923 02:27:18,064 --> 02:27:19,666 CAN DISCUSS LATER IF YOU THINK 3924 02:27:19,666 --> 02:27:23,503 OF BRAIN OCCUPATION OF AAV. 3925 02:27:23,503 --> 02:27:26,372 YOU DON'T HAVE TO GO AND READ 3926 02:27:26,372 --> 02:27:28,875 THIS BUT TO SAY AT THIS POINT 3927 02:27:28,875 --> 02:27:31,511 THERE'S 14 PATIENTS 6 TO 14 AT 3928 02:27:31,511 --> 02:27:34,481 FOUR DIFFERENT DOSE LEVELS. 3929 02:27:34,481 --> 02:27:40,386 THIS IS THE CONSTRUCT AND A 3930 02:27:40,386 --> 02:27:41,254 COMPLEMENTARY CONSTRUCT AND A 3931 02:27:41,254 --> 02:27:42,922 RELATIVELY WEEK PROMOTER AND THE 3932 02:27:42,922 --> 02:27:47,026 WEAK PROMOTER IS AN IMPORTANT 3933 02:27:47,026 --> 02:27:49,529 ACCESS IN THE SPACE OF THE 3934 02:27:49,529 --> 02:28:00,039 TRIALS IT'S STRONG ENOUGH BUT 3935 02:28:00,039 --> 02:28:02,509 NOT STRONG ENOUGH TO DRIVE 3936 02:28:02,509 --> 02:28:05,311 SPECIFICITY FROM THE TRIAL AND 3937 02:28:05,311 --> 02:28:08,515 PACKAGED INTO AAV 9. 3938 02:28:08,515 --> 02:28:10,049 AND THIS IS THE ESCALATION. 3939 02:28:10,049 --> 02:28:13,653 WE STARTED ONE WILL A LOW DOSE 3940 02:28:13,653 --> 02:28:19,058 INITIALLY AGAIN THE FIRST 3941 02:28:19,058 --> 02:28:21,294 APPLICATION AND CURRENTLY HIGHER 3942 02:28:21,294 --> 02:28:31,437 DOSE AND INTRATHECAL DELIVERY 3943 02:28:31,437 --> 02:28:33,940 AND THE INTRODUCTION LITERALLY 3944 02:28:33,940 --> 02:28:43,016 ROTATED DURING THE TIME TO ALLOW 3945 02:28:43,016 --> 02:28:46,686 HOPING TO HIT OUR TARGETS AND 3946 02:28:46,686 --> 02:28:49,656 HIGHLIGHTING THE OPTIC NERVE AND 3947 02:28:49,656 --> 02:28:51,624 THE BONE. 3948 02:28:51,624 --> 02:28:56,262 WE HAVE TO DO THIS PART OF THE 3949 02:28:56,262 --> 02:28:56,629 TRIAL. 3950 02:28:56,629 --> 02:29:01,234 YOU SEE THE BIOPSY AND INFUSION 3951 02:29:01,234 --> 02:29:04,170 OF THE AAV INTO THIS SPACE AND 3952 02:29:04,170 --> 02:29:04,737 WE CAN SEE THE TREND AFTER 3953 02:29:04,737 --> 02:29:14,914 DELIVERY. 3954 02:29:16,783 --> 02:29:20,053 WE SAW ANY OPPORTUNITY OF THE 3955 02:29:20,053 --> 02:29:22,288 MODULATION OF THE AAV AND NOT 3956 02:29:22,288 --> 02:29:24,991 WAITING FOR THINGS TO HAPPEN. 3957 02:29:24,991 --> 02:29:30,430 WE DID THE VIRUS IN THE SPACE 3958 02:29:30,430 --> 02:29:32,665 AND YOU KNOW WE SEE THAT IN A 3959 02:29:32,665 --> 02:29:35,702 LITTLE BIT AND ALSO TO ALLOW US 3960 02:29:35,702 --> 02:29:43,042 TO GET THE TRANS GENE PATIENTS 3961 02:29:43,042 --> 02:29:44,244 WHO HAVE FUNCTION WITH NO 3962 02:29:44,244 --> 02:29:45,345 PROTEIN PRODUCTION AND HAVE 3963 02:29:45,345 --> 02:29:46,479 NEVER SEEN THIS PROTEIN AND WHEN 3964 02:29:46,479 --> 02:29:51,050 YOU GIVE THEM THE AAV YOU DO A 3965 02:29:51,050 --> 02:29:55,655 LITTLE BIT OF TRANSPLANTATION 3966 02:29:55,655 --> 02:29:59,125 AND WANT TO MAKE SURE THEY DON'T 3967 02:29:59,125 --> 02:30:05,131 REJECT IT. 3968 02:30:05,131 --> 02:30:09,335 AND YOU HAVE TRIALS THAT CAN BE 3969 02:30:09,335 --> 02:30:09,602 REJECTED. 3970 02:30:09,602 --> 02:30:20,113 WE DID THIS WITH A PROTOCOL 3971 02:30:25,318 --> 02:30:29,088 RAPAMYCIN IS NOT LOST IN THE 3972 02:30:29,088 --> 02:30:37,597 SPACE AND THIS WAS A CASE OF THE 3973 02:30:37,597 --> 02:30:44,203 AFBD AND IT HAD NO EVIDENCE OF 3974 02:30:44,203 --> 02:30:49,676 THE AAV RELATED TOXICITY WHICH 3975 02:30:49,676 --> 02:30:57,317 IS WHEN WE IDENTIFY TOXICITY OF 3976 02:30:57,317 --> 02:30:59,052 THE PATIENT. 3977 02:30:59,052 --> 02:31:01,654 THE PROMOTER WAS SUFFICIENTLY 3978 02:31:01,654 --> 02:31:07,293 LOW REACTIVE AND DIDN'T 3979 02:31:07,293 --> 02:31:09,662 OVERPRODUCE THE GENE INTRODUCING 3980 02:31:09,662 --> 02:31:13,666 THE TOXICITY INDEPENDENTLY. 3981 02:31:13,666 --> 02:31:16,069 SO WHAT IS SOME AFFIRMATION IN 3982 02:31:16,069 --> 02:31:20,239 THE SPACE IN THREE MONTHS 3983 02:31:20,239 --> 02:31:25,311 ASYMPTOMATIC AND PROTEIN 3984 02:31:25,311 --> 02:31:27,080 INNERVATION AND 3985 02:31:27,080 --> 02:31:37,657 REPRESENTATIVESIVE AND THERE WAS 3986 02:31:37,657 --> 02:31:45,565 NO INFLAMMATION AND WE SAW 3987 02:31:45,565 --> 02:31:48,701 MENINGITIS THAT COULD BE MANAGED 3988 02:31:48,701 --> 02:31:51,037 WITH THES REGIMENT. 3989 02:31:51,037 --> 02:31:53,773 AND ANOTHER LESSON FROM THIS 3990 02:31:53,773 --> 02:31:56,976 TRIAL IS THAT WE DID NOT EXCLUDE 3991 02:31:56,976 --> 02:31:59,846 PATIENTS WHO WERE ZERO POSITIVE 3992 02:31:59,846 --> 02:32:03,049 AT BASELINE. 3993 02:32:03,049 --> 02:32:05,651 MANY SUSPENDED GENE THERAPY 3994 02:32:05,651 --> 02:32:07,520 TRIALS YOU HAVE ANTIBODIES YOU 3995 02:32:07,520 --> 02:32:10,556 WANT TO GIVE BUT WE IGNORED THAT 3996 02:32:10,556 --> 02:32:12,692 IN THIS TRIAL TO SUGGEST THAT 3997 02:32:12,692 --> 02:32:17,463 THAT WOULD NOT EXTEND TO THE 3998 02:32:17,463 --> 02:32:22,535 SPACE AND AT BASELINE NONE OF 3999 02:32:22,535 --> 02:32:26,706 OUR PATIENTS HAVE ANTIBODIES IN 4000 02:32:26,706 --> 02:32:30,042 THE CNS SPACE WITH DOSING 4001 02:32:30,042 --> 02:32:33,846 HOWEVER, ONCE YOU INTRODUCE 4002 02:32:33,846 --> 02:32:35,047 INTRATHECALLY THE SYSTEM WAKES 4003 02:32:35,047 --> 02:32:43,589 UP MAKING ANTIBODIES IN THE 4004 02:32:43,589 --> 02:32:46,359 PERIPHERY AND PATIENTS RESPOND 4005 02:32:46,359 --> 02:32:49,462 YOU CAN SEE HERE WE HAVE 4006 02:32:49,462 --> 02:32:50,129 NEUTRALIZING ANTIBODY ACROSS THE 4007 02:32:50,129 --> 02:32:55,701 BOARD DOABLE OVER A YEAR AND 4008 02:32:55,701 --> 02:32:59,071 PROBABLY MORE. 4009 02:32:59,071 --> 02:33:01,140 HOPEFULLY THIS WOULD HELP IN 4010 02:33:01,140 --> 02:33:02,575 DOSING. 4011 02:33:02,575 --> 02:33:05,445 WHAT ABOUT EFFICACY ANALYSIS 4012 02:33:05,445 --> 02:33:06,379 HERE? 4013 02:33:06,379 --> 02:33:08,381 THIS WAS A PRIMARY. 4014 02:33:08,381 --> 02:33:12,285 BAYESIAN ANALYSIS AND WE 4015 02:33:12,285 --> 02:33:13,686 GENERATED INDEPENDENT AND MOST 4016 02:33:13,686 --> 02:33:16,322 IMPORTANTLY THE PATIENT'S OWN 4017 02:33:16,322 --> 02:33:18,324 HISTORY WITH THE MOTOR FUNCTION 4018 02:33:18,324 --> 02:33:22,161 MEASURE WHICH YOU CAN SEE IS 4019 02:33:22,161 --> 02:33:25,531 DEEPLY BEFORE WE DOSE WITH IT 4020 02:33:25,531 --> 02:33:27,800 AND WE HAVE ABSOLUTE 4021 02:33:27,800 --> 02:33:32,171 CONFIRMATION IN OUR INDEPENDENT 4022 02:33:32,171 --> 02:33:34,740 NATURAL HISTORY STUDY AND WHAT 4023 02:33:34,740 --> 02:33:37,109 YOU CAN SEE IS THE POSSIBILITY 4024 02:33:37,109 --> 02:33:41,047 OF SLOWING THE MOTOR FUNCTION. 4025 02:33:41,047 --> 02:33:51,824 THIS IS A MAITHE MAIN APPROACH 4026 02:33:55,761 --> 02:34:06,239 SO THERE'S AN END POINT AND HAVE 4027 02:34:11,110 --> 02:34:12,278 19%. 4028 02:34:12,278 --> 02:34:17,517 SIGNIFICANT IN THE ANALYSIS AND 4029 02:34:17,517 --> 02:34:21,854 YOU CAN SEE THESE CHILDREN HAVE 4030 02:34:21,854 --> 02:34:26,292 A PROGRESSION BUT IT'S A SLOW 4031 02:34:26,292 --> 02:34:27,026 PROGRESSION. 4032 02:34:27,026 --> 02:34:33,966 IT HAS TO DO WITH WHEN WE 4033 02:34:33,966 --> 02:34:35,034 ININ AND 4034 02:34:35,034 --> 02:34:43,476 HOW WE INTERVENE AND WHEN YOU 4035 02:34:43,476 --> 02:34:46,379 LOOK WHERE THE DISEASE STARTS 4036 02:34:46,379 --> 02:34:49,415 YOU CAN SEE THESE ARE ACTION 4037 02:34:49,415 --> 02:34:55,021 POTENTIALS AND MEASUREMENT AND 4038 02:34:55,021 --> 02:34:59,025 NO CHILD EVER RECORDED THIS 4039 02:34:59,025 --> 02:35:01,727 ANYWHERE AND YOU CAN SEE AFTER 4040 02:35:01,727 --> 02:35:05,731 DOSES IN PARTICULAR THE NERVES 4041 02:35:05,731 --> 02:35:11,037 AT ENTRY IN THE ARM WE HAVE NOT 4042 02:35:11,037 --> 02:35:17,710 ONLY IMPROVEMENT IN THE ACTION 4043 02:35:17,710 --> 02:35:19,512 BUT AFTER DOSING SOMETIMES 4 4044 02:35:19,512 --> 02:35:20,613 YEARS OLD. 4045 02:35:20,613 --> 02:35:22,982 IT TAKES PATIENTS TIME FOR A 4046 02:35:22,982 --> 02:35:25,184 NERVE TO REPAIR IF THE NERVE IS 4047 02:35:25,184 --> 02:35:28,187 STILL VIABLE. 4048 02:35:28,187 --> 02:35:30,890 THAT MAY BE AN ADVANTAGE AND 4049 02:35:30,890 --> 02:35:35,294 THERE MAY BE MORE CAPABLE OF 4050 02:35:35,294 --> 02:35:37,897 GOING TO THAT DISEASE AND WE 4051 02:35:37,897 --> 02:35:43,736 ALSO HAVE EVIDENCE OF 4052 02:35:43,736 --> 02:35:44,437 REGENERATIVE CAPABILITY IN THE 4053 02:35:44,437 --> 02:35:47,373 CENTRAL NERVE AFTER DOSING. 4054 02:35:47,373 --> 02:35:52,778 BUT LOOK AT THIS PROBLEM. 4055 02:35:52,778 --> 02:35:57,483 THIS IS A PERIPHERAL NERVE AND I 4056 02:35:57,483 --> 02:36:02,088 WANT TO CLEAR THIS ENTIRE AXON 4057 02:36:02,088 --> 02:36:07,026 FOR PATHOLOGY AND FILAMENT AND 4058 02:36:07,026 --> 02:36:13,799 IT'S GOING TO TAKE TIME AND WHEN 4059 02:36:13,799 --> 02:36:21,107 YOU START THERAPY. 4060 02:36:21,107 --> 02:36:25,077 THIS IS WHAT WE HAVE TO DOSE AND 4061 02:36:25,077 --> 02:36:26,545 ENDING THE GENETIC DISEASE AND 4062 02:36:26,545 --> 02:36:29,115 WE HAVE A WINDOW OF OPPORTUNITY 4063 02:36:29,115 --> 02:36:29,982 AND SOMETIMES SLOWLY. 4064 02:36:29,982 --> 02:36:34,587 BUT IN OUR PATIENTS IT CLOSES IN 4065 02:36:34,587 --> 02:36:36,055 DIFFERENT TIMES FROM LONG NERVES 4066 02:36:36,055 --> 02:36:39,558 TO THE LEGS ARE MORE INFECTED 4067 02:36:39,558 --> 02:36:44,764 AND THE SHORT TERM IN THE ARM 4068 02:36:44,764 --> 02:36:45,431 ARE SHOWN AFTER ADMINISTRATION 4069 02:36:45,431 --> 02:36:48,167 THEREFORE EVIDENCE OF 4070 02:36:48,167 --> 02:36:49,201 REGENERATIVE CAPABILITY AND 4071 02:36:49,201 --> 02:36:50,336 EVIDENCE OF SLOWING OF THE 4072 02:36:50,336 --> 02:36:55,041 DISEASE BUT THE FULL IMPACT I 4073 02:36:55,041 --> 02:36:59,045 THINK WILL BE FOR YOUNG CHILDREN 4074 02:36:59,045 --> 02:37:05,451 EARLY IN THE DISEASE. 4075 02:37:05,451 --> 02:37:08,954 AND THIS IS RELATIONSHIP TO 4076 02:37:08,954 --> 02:37:10,022 COMPLICATIONS YOU HAVE THE 4077 02:37:10,022 --> 02:37:11,557 DISEASE ONLY 9 MONTHS LATER. 4078 02:37:11,557 --> 02:37:17,863 SHE WAS DOSED AT THE LOWEST DOSE 4079 02:37:17,863 --> 02:37:22,735 AND THIS CHILD DNA AND THEY SAID 4080 02:37:22,735 --> 02:37:24,370 YOU CAN'T DOSE YOUNG CHILDREN 4081 02:37:24,370 --> 02:37:30,342 YOU HAVE TO GO TO OLDER PATIENTS 4082 02:37:30,342 --> 02:37:33,713 AND THE MEDICAL PEOPLE HAD US GO 4083 02:37:33,713 --> 02:37:35,948 TO PATIENTS MORE ADVANCED IN THE 4084 02:37:35,948 --> 02:37:37,650 DISEASE AND THEREFORE HAD MORE 4085 02:37:37,650 --> 02:37:39,585 MEDICAL COMPLICATIONS AND LO AND 4086 02:37:39,585 --> 02:37:43,556 BEHOLD WE LOST TWO PATIENTS TO 4087 02:37:43,556 --> 02:37:47,727 THE DISEASE EARLY ON WITH THE 4088 02:37:47,727 --> 02:37:48,794 OLDER CHILDREN. 4089 02:37:48,794 --> 02:37:54,800 AND I SHOWED YOU AT THE LOWER 4090 02:37:54,800 --> 02:37:58,237 DOSE YOU CAN SEE WE LOOKED AT 4091 02:37:58,237 --> 02:38:02,374 THE BRAIN AND OPTIC NERVE AND 4092 02:38:02,374 --> 02:38:05,444 THAT'S SOMETHING TO CONSIDER AND 4093 02:38:05,444 --> 02:38:08,748 THINK ABOUT CHILDREN'S CNS 4094 02:38:08,748 --> 02:38:09,515 DISEASE AND MAYBE DIFFERENT 4095 02:38:09,515 --> 02:38:12,618 LEVELS WOULD BE A GOOD ENTRY 4096 02:38:12,618 --> 02:38:16,288 POINT AND GET GOOD DISTRIBUTION 4097 02:38:16,288 --> 02:38:19,058 FROM THE INTRATHECAL 4098 02:38:19,058 --> 02:38:29,335 ADMINISTRATION. 4099 02:38:34,039 --> 02:38:37,743 THERE'S A HUMAN GENOME BUT 4100 02:38:37,743 --> 02:38:38,944 DIFFERENT. 4101 02:38:38,944 --> 02:38:44,884 [OFF-MIC] 4102 02:38:44,884 --> 02:38:47,820 >> NO, IT DOESN'T. 4103 02:38:47,820 --> 02:38:50,589 A LOT OF IT GOES TO THE SPLEEN 4104 02:38:50,589 --> 02:38:53,726 AND, YEAH. 4105 02:38:53,726 --> 02:38:59,031 A LOT OF IT GOES TO THE SPLEEN. 4106 02:38:59,031 --> 02:39:09,141 YOU LOOK AT THE SPLEEN. 4107 02:39:09,141 --> 02:39:12,978 THIS PROVIDES INSIGHT. 4108 02:39:12,978 --> 02:39:15,114 I THINK A COLLABORATIVE MODEL OF 4109 02:39:15,114 --> 02:39:19,084 EFFICACY AND ACADEMIA AND 4110 02:39:19,084 --> 02:39:24,523 INTRAMURAL, NIH AND INDUSTRY CAN 4111 02:39:24,523 --> 02:39:31,430 COME TOGETHER. 4112 02:39:31,430 --> 02:39:35,034 INDUSTRY HAS DROPPED OUT 4113 02:39:35,034 --> 02:39:37,970 MEANWHILE WE HAVE THIS IN THE 4114 02:39:37,970 --> 02:39:41,907 END AND YOU CAN DISCUSS THIS. 4115 02:39:41,907 --> 02:39:45,744 AND THE FIRST INTRATHECAL TRIAL 4116 02:39:45,744 --> 02:39:51,050 THAT ESTABLISH THOSE AND SAFETY 4117 02:39:51,050 --> 02:39:53,252 AND ESTABLISHED A PLATFORM FOR 4118 02:39:53,252 --> 02:39:54,787 THE DISEASE NOT BEING CARRIED 4119 02:39:54,787 --> 02:39:55,054 FORWARD. 4120 02:39:55,054 --> 02:39:58,057 I'M RUNNING OUT OF TIME BUT WANT 4121 02:39:58,057 --> 02:39:59,658 TO GIVE YOU THE LESSONS EMERGING 4122 02:39:59,658 --> 02:40:06,832 FROM THIS AND MAYBE I CAN PICK 4123 02:40:06,832 --> 02:40:11,003 THE PLATFORM. 4124 02:40:11,003 --> 02:40:15,541 AND THESE ARE INTRAFECAL DOSING. 4125 02:40:15,541 --> 02:40:20,779 IN NEURAL MODULATION IT'S VERY 4126 02:40:20,779 --> 02:40:23,048 IMPORTANT TO REALIZE FROM THE 4127 02:40:23,048 --> 02:40:26,051 ASPECT OF GENE THERAPY INHERENT 4128 02:40:26,051 --> 02:40:28,087 FROM THE APPROACH AND WHAT YOU 4129 02:40:28,087 --> 02:40:30,890 DO AND DELIVER. 4130 02:40:30,890 --> 02:40:34,460 AND INTRATHECAL DOSING HAS 4131 02:40:34,460 --> 02:40:37,229 EFFECTIVE TARGETING OF THE 4132 02:40:37,229 --> 02:40:39,531 CAPSID AND SO WHAT YOU CAN DO TO 4133 02:40:39,531 --> 02:40:49,675 IMPROVE THAT WILL BE HELPFUL AND 4134 02:40:49,675 --> 02:41:00,119 THE TIME BEING IMPORTANT. 4135 02:41:06,258 --> 02:41:07,026 LET ME JUST ACKNOWLEDGE MANY 4136 02:41:07,026 --> 02:41:15,801 PEOPLE. 4137 02:41:15,801 --> 02:41:26,145 THANK YOU VERY MUCH. 4138 02:41:39,258 --> 02:41:43,095 >> THANK YOU. 4139 02:41:43,095 --> 02:41:46,999 ANY QUESTIONS? 4140 02:41:46,999 --> 02:41:49,101 THAT'S A GOOD PROBLEM THIS IS A 4141 02:41:49,101 --> 02:41:50,736 DISEASE SO IN FAMILIES WHERE 4142 02:41:50,736 --> 02:41:52,071 THERE'S BEEN ONE CHILD AFFECTED, 4143 02:41:52,071 --> 02:41:55,808 FAMILY MEMBERS WILL KNOW BECAUSE 4144 02:41:55,808 --> 02:42:00,112 OF THE PHENOTYPE AND SO WE HAD 4145 02:42:00,112 --> 02:42:01,480 THE OPPORTUNITY TO EXAMINE 1 4146 02:42:01,480 --> 02:42:07,653 YEAR OF AGE AND THERE'S A 4147 02:42:07,653 --> 02:42:14,626 NEUROLOGICAL PHENOTYPE. 4148 02:42:14,626 --> 02:42:17,930 MOST OF THE TRACING IS NOT EXOME 4149 02:42:17,930 --> 02:42:19,732 BASED THE GENE CANDIDATE SO IF 4150 02:42:19,732 --> 02:42:23,035 THERE'S NO SUSPICION OF THE 4151 02:42:23,035 --> 02:42:25,738 DISEASE AND WE GET THE WHOLE 4152 02:42:25,738 --> 02:42:30,009 EXOME SEQUENCING TO FIND IT AND 4153 02:42:30,009 --> 02:42:35,114 THE DIAGNOSIS IS MADE WITHOUT 4154 02:42:35,114 --> 02:42:39,051 SUSPECT 4155 02:42:39,051 --> 02:42:45,424 SUSPECTING IT AND HOPE ANY WITH 4156 02:42:45,424 --> 02:42:49,094 PATIENTS EARLY ON AND PHENOTYPES 4157 02:42:49,094 --> 02:42:56,935 MAKE MORE LIKE THE NEUROPATHY 4158 02:42:56,935 --> 02:43:05,911 AND THOSE SEE PRODUCTION LATER. 4159 02:43:05,911 --> 02:43:16,088 THANK YOU. 4160 02:43:44,083 --> 02:43:45,484 >> HI, EVERYONE. 4161 02:43:45,484 --> 02:43:49,354 I WAS PRIVILEGED AND HAPPY TO BE 4162 02:43:49,354 --> 02:43:50,789 INVITED TO SPEAK HERE. 4163 02:43:50,789 --> 02:43:53,192 THANKS TO ANN AND THE 4164 02:43:53,192 --> 02:43:53,492 ORGANIZERS. 4165 02:43:53,492 --> 02:43:54,426 I'M GOING TO TALK ABOUT -- I 4166 02:43:54,426 --> 02:43:57,129 HAVE A GENERAL TITLE BUT I'M 4167 02:43:57,129 --> 02:44:00,132 GOING TO TALK ABOUT ANGELMAN 4168 02:44:00,132 --> 02:44:00,999 SYNDROME BECAUSE I THINK IT'S 4169 02:44:00,999 --> 02:44:02,901 GOING FORWARD FOR WHAT WE CAN 4170 02:44:02,901 --> 02:44:05,170 EXPECT WHEN WE BRING ALL THESE 4171 02:44:05,170 --> 02:44:05,938 GREAT BASIC SCIENCE ADVANCES 4172 02:44:05,938 --> 02:44:07,739 WE'VE BEEN TALKING ABOUT INTO 4173 02:44:07,739 --> 02:44:10,042 THE CLINIC AND TREAT PATIENTS 4174 02:44:10,042 --> 02:44:10,776 AFTER THEY'VE ALREADY UNDER GONE 4175 02:44:10,776 --> 02:44:17,883 SOME LEVEL OF DEVELOPMENT. 4176 02:44:17,883 --> 02:44:21,687 YOU HAVE A LOT OF DISCLOSURES 4177 02:44:21,687 --> 02:44:24,723 AND WORK WITH A LOT OF COMPANIES 4178 02:44:24,723 --> 02:44:26,391 WORKING ON REQUIREDS AND THE 4179 02:44:26,391 --> 02:44:28,794 USPI FOR THE ANGELMAN SYNDROME 4180 02:44:28,794 --> 02:44:30,696 TRIALS THEREFORE I HAVE NO BIAS. 4181 02:44:30,696 --> 02:44:31,330 I'M INTERESTED IN ALL OF THEM 4182 02:44:31,330 --> 02:44:35,400 WORKING. 4183 02:44:35,400 --> 02:44:38,504 SO UNFORTUNATELY THIS MORNING WE 4184 02:44:38,504 --> 02:44:40,205 HAD INTRODUCTION TO ANGELMAN 4185 02:44:40,205 --> 02:44:40,472 SYNDROME. 4186 02:44:40,472 --> 02:44:42,374 I'M GOING TO RUN OVER THIS 4187 02:44:42,374 --> 02:44:42,608 QUICKLY. 4188 02:44:42,608 --> 02:44:45,544 IT'S A SEVERE DEVELOPMENTAL 4189 02:44:45,544 --> 02:44:49,314 DISORDER WITH SEVERELY PROFOUND 4190 02:44:49,314 --> 02:44:50,249 INTELLECTUAL DISABILITY AND MOST 4191 02:44:50,249 --> 02:44:53,085 PATIENTS DON'T TALK AT ALL. 4192 02:44:53,085 --> 02:44:55,220 MOTOR SKILL AND SLEEP AND 4193 02:44:55,220 --> 02:44:57,556 SEIZURE AND THEY HAVE A LOT OF 4194 02:44:57,556 --> 02:44:59,224 BEHAVIOR PROBLEMS, VERY 4195 02:44:59,224 --> 02:45:01,727 IMPULSIVE AND ANXIOUS AND 4196 02:45:01,727 --> 02:45:05,297 DIFFICULT AND ATTENTION SEEKING 4197 02:45:05,297 --> 02:45:07,733 AND EXCESSIVE SOCIABILITY IN 4198 02:45:07,733 --> 02:45:12,771 PUBLIC AND SOME DYSMORPHIC 4199 02:45:12,771 --> 02:45:19,077 FEATURES AND SOME HAVE 4200 02:45:19,077 --> 02:45:24,550 MICROSELFCEPHALY -- MICROCEPHALY 4201 02:45:24,550 --> 02:45:28,854 AND THIS GENE INTRINSIC IN 4202 02:45:28,854 --> 02:45:30,489 NEURONS BUT NOT IN ANY OTHER 4203 02:45:30,489 --> 02:45:33,525 CELLS AND ALL OF US ARE RUNNING 4204 02:45:33,525 --> 02:45:35,327 ON OUR MATERNAL GENE AND THE 4205 02:45:35,327 --> 02:45:36,662 PATERNAL GENE IS SHUT DOWN. 4206 02:45:36,662 --> 02:45:38,697 THERE'S VARIOUS ASPECTS OF THE 4207 02:45:38,697 --> 02:45:40,532 MATERNAL GENE THAT CAUSE 4208 02:45:40,532 --> 02:45:41,600 ANGELMAN SYNDROME INCLUDING A 4209 02:45:41,600 --> 02:45:43,335 DELETION WHICH IS COMMON AND GET 4210 02:45:43,335 --> 02:45:51,777 TWO CHROMOSOMES 15 FROM YOUR 4211 02:45:51,777 --> 02:45:55,747 FATHER AND MAKE IT LOOK LIKE A 4212 02:45:55,747 --> 02:45:58,450 PATERNAL GENE AND A MUTATION IN 4213 02:45:58,450 --> 02:46:00,552 THE MATERNALLY DERIVED GENE AND 4214 02:46:00,552 --> 02:46:02,154 THE NON-DELETION FORMS ARE 4215 02:46:02,154 --> 02:46:03,622 HIGHER FUNCTIONING MEAN THEY MAY 4216 02:46:03,622 --> 02:46:05,824 HAVE A FEW WORDS. 4217 02:46:05,824 --> 02:46:16,268 THEY HAVE LESSEE -- LESS 4218 02:46:19,805 --> 02:46:20,005 SEIZURES. 4219 02:46:20,005 --> 02:46:23,041 THE ANGELMAN SYNDROME COMMUNITY 4220 02:46:23,041 --> 02:46:24,977 HAS BEEN VERY PROACTIVE IN HOW 4221 02:46:24,977 --> 02:46:27,446 TO GET SET UP FOR CLINICAL 4222 02:46:27,446 --> 02:46:28,280 TRIALS. 4223 02:46:28,280 --> 02:46:30,015 THEY WATCHED OUT FAIL AND 4224 02:46:30,015 --> 02:46:31,750 LEARNED ALL THE LESSONS WE HAD 4225 02:46:31,750 --> 02:46:32,918 TO TEACH THEM. 4226 02:46:32,918 --> 02:46:35,454 THEY DID A DISEASE CONCEPT 4227 02:46:35,454 --> 02:46:37,656 KNOWING THEY'D NEED THAT FOR THE 4228 02:46:37,656 --> 02:46:38,090 FDA. 4229 02:46:38,090 --> 02:46:39,691 THIS MEANS INTERVIEWING 4230 02:46:39,691 --> 02:46:40,592 CAREGIVERS ABOUT WHAT'S MOST 4231 02:46:40,592 --> 02:46:44,062 IMPORTANT TO THEM AND GUESS WHAT 4232 02:46:44,062 --> 02:46:45,330 COMES UP ON TOP? 4233 02:46:45,330 --> 02:46:46,765 I'M NOT SURE WHERE MY POINTER 4234 02:46:46,765 --> 02:46:47,065 IS. 4235 02:46:47,065 --> 02:46:53,572 OH, THERE IS NO POINTER. 4236 02:46:53,572 --> 02:46:54,606 SO COMMUNICATION IS NUMBER ONE. 4237 02:46:54,606 --> 02:46:57,876 I THINK IF YOU TOOK ANY 4238 02:46:57,876 --> 02:46:59,878 DEVELOPMENTAL DISORDER WITH THE 4239 02:46:59,878 --> 02:47:03,048 LEVEL OF ANGELMAN SYNDROME THIS 4240 02:47:03,048 --> 02:47:11,023 WOULD COME UP NUMBER ONE AND 4241 02:47:11,023 --> 02:47:16,561 SESURES AND COGNITIVE FUNCTION 4242 02:47:16,561 --> 02:47:21,266 IS WHAT THEY WANT TREATED 4243 02:47:21,266 --> 02:47:24,970 DOCUMENTED FOR THE FDA AND THIS 4244 02:47:24,970 --> 02:47:27,039 IS ON THE BAILEY SCALES OF 4245 02:47:27,039 --> 02:47:29,641 INFANT DEVELOPMENT AND USE THAT 4246 02:47:29,641 --> 02:47:31,410 IN ANGELMAN SYNDROME PATIENTS OF 4247 02:47:31,410 --> 02:47:34,112 ALL AGE THOUGH THE MEASURE IS 4248 02:47:34,112 --> 02:47:38,817 FROM 0 TO 3 BECAUSE NO ANGELMAN 4249 02:47:38,817 --> 02:47:42,321 SYNDROME PATIENT GETS ABOVE 3. 4250 02:47:42,321 --> 02:47:45,190 THIS IS THE SCALE AND ONCE THEY 4251 02:47:45,190 --> 02:47:49,461 GET TO 4 IT'S FLAT THEY DON'T 4252 02:47:49,461 --> 02:47:50,228 MAKE PROGRESS. 4253 02:47:50,228 --> 02:47:53,832 THEY MAYBE MAKE SOME IN GROSS 4254 02:47:53,832 --> 02:47:55,233 MOTOR SKILLS AND FOR THE 4255 02:47:55,233 --> 02:47:56,568 DELETION PATIENTS THEY'RE MORE 4256 02:47:56,568 --> 02:47:59,037 IMPAIRED THAN THE NON-DELETION 4257 02:47:59,037 --> 02:48:01,907 PATIENTS. 4258 02:48:01,907 --> 02:48:04,209 THEY ALSO THOUGHT WE NEED A 4259 02:48:04,209 --> 02:48:06,178 BIOMARKER BECAUSE MAYBE WE DON'T 4260 02:48:06,178 --> 02:48:07,946 WANT TO DO CLINICAL TRIALS FOR 4261 02:48:07,946 --> 02:48:10,882 YEARS AND YEAR AND THERE'S A 4262 02:48:10,882 --> 02:48:15,053 NICE BIOMEDICAL OF INCREASED 4263 02:48:15,053 --> 02:48:19,057 DELTA POWER IN BLUE AND THAT 4264 02:48:19,057 --> 02:48:20,392 CORRELATES NICELY WITH THE 4265 02:48:20,392 --> 02:48:25,564 COGNITIVE SCORE ON THE BAY 4266 02:48:25,564 --> 02:48:27,332 BAYLEY AND IF YOU PREDICT THE 4267 02:48:27,332 --> 02:48:29,835 SCORE YOU GET A NICE CORRELATION 4268 02:48:29,835 --> 02:48:32,871 WITH THE ACTUAL BAYLEY COGNITIVE 4269 02:48:32,871 --> 02:48:34,473 SCORE SHOWING A NICE CORRELATION 4270 02:48:34,473 --> 02:48:37,743 OF A BIOMEDICAL WITH FUNCTIONAL 4271 02:48:37,743 --> 02:48:38,543 LEVEL IN ANGELMAN SYNDROME. 4272 02:48:38,543 --> 02:48:40,312 AND THEN IT TURNS OUT ANGELMAN 4273 02:48:40,312 --> 02:48:42,614 SYNDROME IS ACTUALLY SOMEWHAT 4274 02:48:42,614 --> 02:48:46,284 LOW-HANGING FRUIT GENETICALLY IN 4275 02:48:46,284 --> 02:48:48,687 TERMS OF A TREATMENT. 4276 02:48:48,687 --> 02:48:51,056 THIS IS A NORMAL PERSON MAKING 4277 02:48:51,056 --> 02:48:53,525 THE CHROMOSOME AND ALL THE 4278 02:48:53,525 --> 02:48:57,629 ASSOCIATED GENES INCLUDING THIS 4279 02:48:57,629 --> 02:49:00,132 ANTI-TRANSCRIPT THAT IS SHUT 4280 02:49:00,132 --> 02:49:03,034 DOWN AND THE PATERNAL CHROMOSOME 4281 02:49:03,034 --> 02:49:05,504 AND IT HIT RUNS INTO UB3A AND 4282 02:49:05,504 --> 02:49:10,375 SHUTS IT DOWN. 4283 02:49:10,375 --> 02:49:12,444 IN ANGELMAN SYNDROME WE SHUT IT 4284 02:49:12,444 --> 02:49:15,881 DOWN IN UB3A AND IF WE THROW INI 4285 02:49:15,881 --> 02:49:19,084 SO AND ALLOW IS TO BLOCK THIS 4286 02:49:19,084 --> 02:49:20,786 TRANSCRIPT, NOW WE CAN GET 4287 02:49:20,786 --> 02:49:23,088 TRANSCRIPTION OF UBE3 OFF THE 4288 02:49:23,088 --> 02:49:26,324 PATERNAL WHEEL. 4289 02:49:26,324 --> 02:49:28,660 IT TURNS OUT THIS WAS VERY 4290 02:49:28,660 --> 02:49:31,730 SUCCESSFUL IN MOUSE AND THIS IS 4291 02:49:31,730 --> 02:49:34,800 WORK IN A PAPER WHERE THE 4292 02:49:34,800 --> 02:49:36,067 TRANSCRIPT COULD BE SHOWN TO 4293 02:49:36,067 --> 02:49:40,472 COME DOWN AND THE UBE3A GOES UP 4294 02:49:40,472 --> 02:49:42,174 AND SEE IN THE WESTERN BLOT AND 4295 02:49:42,174 --> 02:49:47,045 NEURONS WE'RE MAKING UBE3A WHEN 4296 02:49:47,045 --> 02:49:50,649 EXPOSED TO THE ASO. 4297 02:49:50,649 --> 02:49:53,985 SO AS A RESULT OF THAT WORK 4298 02:49:53,985 --> 02:49:54,653 THREE CLINICAL DEVELOPMENT 4299 02:49:54,653 --> 02:49:56,388 EFFORTS WERE CITED. 4300 02:49:56,388 --> 02:50:01,259 ONE WAS GENETICS A COMPANY SET 4301 02:50:01,259 --> 02:50:03,829 UP BY THE ANGELMAN SYNDROME 4302 02:50:03,829 --> 02:50:07,532 SYNDROME AND THERAPEUTICS WHICH 4303 02:50:07,532 --> 02:50:09,301 THEY FELT THEY WERE MOVING 4304 02:50:09,301 --> 02:50:10,836 SLOWLY AND WANTED TO SPEED THEM 4305 02:50:10,836 --> 02:50:19,044 UP AND ULTIMATELY PARTNERED WITH 4306 02:50:19,044 --> 02:50:26,017 ULTRA INFORM GENYX AND A -- SOME 4307 02:50:26,017 --> 02:50:29,321 COULD BE A PLATFORM TRIAL BUT 4308 02:50:29,321 --> 02:50:30,288 WEREN'T BECAUSE THEY WERE WITH 4309 02:50:30,288 --> 02:50:31,756 DIFFERENT COMPANIES. 4310 02:50:31,756 --> 02:50:35,026 SIMILAR OBJECTIVES, SAFETY, 4311 02:50:35,026 --> 02:50:37,762 PHARMACO KINETICS OF THE DRUG 4312 02:50:37,762 --> 02:50:42,901 AND ANY OF THE DRUGS AND 4313 02:50:42,901 --> 02:50:46,705 CLINICAL ACTIVITY AND USING THE 4314 02:50:46,705 --> 02:50:48,206 OUTCOMES MEASURES THE BAYLEY 3 4315 02:50:48,206 --> 02:50:52,410 AND THE MOTOR MONITOR AND THIS 4316 02:50:52,410 --> 02:50:55,747 WAS THE VIDEOS OTHERWISE THEY'RE 4317 02:50:55,747 --> 02:50:57,949 ALL USING THE SAME GROUP OF 4318 02:50:57,949 --> 02:51:00,352 OUTCOME MEASURES BECAUSE THEY'RE 4319 02:51:00,352 --> 02:51:02,087 OUGHT MATCHED IN ANGELMAN 4320 02:51:02,087 --> 02:51:04,389 SYNDROME. 4321 02:51:04,389 --> 02:51:05,957 I'LL SHOW YOU WHAT'S GONE ON 4322 02:51:05,957 --> 02:51:08,193 WITH ALL THREE OF THE TRIALS. 4323 02:51:08,193 --> 02:51:10,028 THIS IS A ROCHE TRIAL. 4324 02:51:10,028 --> 02:51:12,364 THEY HAD DIFFERENT COHORTS AND 4325 02:51:12,364 --> 02:51:16,034 THE STARTED WITH OLDER PATIENTS 4326 02:51:16,034 --> 02:51:22,007 DOWN TO 1 TO 4-YEAR-OLDS AND HAD 4327 02:51:22,007 --> 02:51:25,777 A PAUSE AND HAD TWO TO THREE 4328 02:51:25,777 --> 02:51:29,381 DOSES AND THEN A PAUSE AND THEN 4329 02:51:29,381 --> 02:51:31,049 A LONG-TERM EXTENSION AND THIS 4330 02:51:31,049 --> 02:51:34,119 IS PROBLEMATIC BECAUSE THE 4331 02:51:34,119 --> 02:51:35,253 PATIENTS WERE UNDER DOSED AND 4332 02:51:35,253 --> 02:51:37,289 THE DOSING WAS TOO LONG AND 4333 02:51:37,289 --> 02:51:38,590 PEOPLE STARTED COMING OFF THE 4334 02:51:38,590 --> 02:51:40,325 DRUGS BEFORE THE NEXT DOSE. 4335 02:51:40,325 --> 02:51:42,260 THE SIDE EFFECTS WERE LIMITING 4336 02:51:42,260 --> 02:51:43,361 AND COULDN'T GO TO THE PLANS 4337 02:51:43,361 --> 02:51:45,230 HALF DOSE AND LAST SUMMER THEY 4338 02:51:45,230 --> 02:51:47,799 OBSERVED THE LEVEL OF EFFICACY 4339 02:51:47,799 --> 02:51:49,768 WAS NOT SUFFICIENT TO MEET THE 4340 02:51:49,768 --> 02:51:51,036 INTERNAL CRITERIA TO MOVE 4341 02:51:51,036 --> 02:51:51,903 FORWARD. 4342 02:51:51,903 --> 02:51:54,606 IT TURNED OUT ROCHE HAD A CHANGE 4343 02:51:54,606 --> 02:51:57,142 AND WASN'T TOO INTERESTED IN 4344 02:51:57,142 --> 02:51:58,944 RARE DISEASES AND THEY DID ADMIT 4345 02:51:58,944 --> 02:52:03,014 THEY HAD AN EFFECT ON THE EEG 4346 02:52:03,014 --> 02:52:05,016 ENCOURAGING AND HAD TO FIND A 4347 02:52:05,016 --> 02:52:06,651 PARTNER TO SALVAGE IT EVERY 4348 02:52:06,651 --> 02:52:06,851 SINCE. 4349 02:52:06,851 --> 02:52:09,054 THAT'S WHAT WE KNOW ABOUT ROCHE. 4350 02:52:09,054 --> 02:52:11,690 THEY'LL PRESENT MORE DATA IN 4351 02:52:11,690 --> 02:52:15,560 ABOUT A BOTH. 4352 02:52:15,560 --> 02:52:17,729 THIS IS ANOTHER TRIAL AND THEY 4353 02:52:17,729 --> 02:52:23,034 INCREASED THE TRIAL BETWEEN 4354 02:52:23,034 --> 02:52:25,737 COHORTS AND LOW, MEDIUM AND 4355 02:52:25,737 --> 02:52:27,238 HIGHEST AND YOUNG KIDS 2-5 AND 4356 02:52:27,238 --> 02:52:28,173 TREATED ADULTS. 4357 02:52:28,173 --> 02:52:29,474 THEY'RE THE ONLY ONES TO DO THAT 4358 02:52:29,474 --> 02:52:30,408 SO FAR. 4359 02:52:30,408 --> 02:52:35,046 THE FIRST COUPLE COHORTS HAD A 4360 02:52:35,046 --> 02:52:37,382 LONG WEIGHTING FOR LONG-TERM 4361 02:52:37,382 --> 02:52:38,383 EXTENSION AND THEN THOSE 4362 02:52:38,383 --> 02:52:41,786 PATIENTS ALL WENT TO AN EXTENDED 4363 02:52:41,786 --> 02:52:43,688 LONG-TERM EXTENSION. 4364 02:52:43,688 --> 02:52:45,323 THIS WAS ALSO SAFE AND WELL 4365 02:52:45,323 --> 02:52:45,724 TOLERATED. 4366 02:52:45,724 --> 02:52:47,659 THEY DID SEEM TO SHOW 4367 02:52:47,659 --> 02:52:52,764 IMPROVEMENT ACROSS MULTIPLE OF 4368 02:52:52,764 --> 02:52:57,168 THESE MEASURES SO AT SIX MONTHS 4369 02:52:57,168 --> 02:52:59,070 AND THESE ARE OFFICIAL 4370 02:52:59,070 --> 02:53:00,805 STATEMENTS. 4371 02:53:00,805 --> 02:53:02,474 TWO-THIRDS ACHIEVED IMPROVEMENT 4372 02:53:02,474 --> 02:53:04,409 IN COGNITION AND LANGUAGE AND 4373 02:53:04,409 --> 02:53:05,477 GROSS MOTOR SKILLS SAID TO BE 4374 02:53:05,477 --> 02:53:07,145 BETTER THAN WHAT YOU WOULD SEE 4375 02:53:07,145 --> 02:53:11,616 IN NATURAL HISTORY. 4376 02:53:11,616 --> 02:53:14,486 THE MAJORITY ALSO SHOWED IN 4377 02:53:14,486 --> 02:53:15,887 IMPROVEMENT IN EEG ACTIVITY 4378 02:53:15,887 --> 02:53:18,323 CORRELATING WITH POSITIVE 4379 02:53:18,323 --> 02:53:20,191 CHANGES IN THE DEVELOPMENTAL 4380 02:53:20,191 --> 02:53:20,592 SKILL. 4381 02:53:20,592 --> 02:53:23,061 THEY HAVEN'T PRESENTED PUBLIC 4382 02:53:23,061 --> 02:53:30,335 DATA. 4383 02:53:30,335 --> 02:53:37,776 ULT 4384 02:53:37,776 --> 02:53:39,477 ULTRAGENYX HAS A DIFFERENT 4385 02:53:39,477 --> 02:53:40,545 DISCLOSURE AND IT'S THERE BUT 4386 02:53:40,545 --> 02:53:43,048 NOT IN THE PUBLIC DOMAIN HAVING 4387 02:53:43,048 --> 02:53:46,718 SEEN A LOT OF THE PATIENTS. 4388 02:53:46,718 --> 02:53:50,155 SO THE STUDY INCREASED AS YOU 4389 02:53:50,155 --> 02:53:52,991 WENT FROM DOSE 1 TO DOSE 4. 4390 02:53:52,991 --> 02:53:56,561 THEY HAD FOUR MONTHLY DOSES AND 4391 02:53:56,561 --> 02:54:00,331 THEN WENT INTO MAINTENANCE 4392 02:54:00,331 --> 02:54:02,934 DOSING EVERY THREE MONTHS AND 4393 02:54:02,934 --> 02:54:04,969 HAD VARIOUS CIRCUITOUS ROUTE 4394 02:54:04,969 --> 02:54:05,270 ACTUALLY. 4395 02:54:05,270 --> 02:54:06,771 SO THE FIRST FIVE PARTICIPANTS 4396 02:54:06,771 --> 02:54:09,407 WHO WERE ALL DOSED AT OUR SITE 4397 02:54:09,407 --> 02:54:11,042 DURING THE PANDEMIC IT TURNS OUT 4398 02:54:11,042 --> 02:54:14,779 ALL DEVELOPED A SEVERE ADVERSE 4399 02:54:14,779 --> 02:54:17,916 EVENT WHICH WAS LEG WEAKNESS. 4400 02:54:17,916 --> 02:54:18,516 OTHERWISE THERE WERE MINOR 4401 02:54:18,516 --> 02:54:19,818 THINGS BUT ESSENTIALLY IT WAS A 4402 02:54:19,818 --> 02:54:21,219 SHOW STOPPER. 4403 02:54:21,219 --> 02:54:23,421 THE PATIENTS GOT INFLAMMATION, 4404 02:54:23,421 --> 02:54:26,725 YOU SEE THE INCREASED SIGNAL 4405 02:54:26,725 --> 02:54:31,029 AROUND THE NERVES AND HAD THIS 4406 02:54:31,029 --> 02:54:34,299 WAS CLEARLY AN ISSUE THAT WAS 4407 02:54:34,299 --> 02:54:34,566 TOXICITY. 4408 02:54:34,566 --> 02:54:38,236 THEY THOUGHT IT MAY BE AN AUTO 4409 02:54:38,236 --> 02:54:40,939 IMMUNE REACTION BUT SPENT TIME 4410 02:54:40,939 --> 02:54:44,476 PROVING THAT WASN'T TRUE AND THE 4411 02:54:44,476 --> 02:54:46,277 PATIENTS RESOLVED WITHIN A FEW 4412 02:54:46,277 --> 02:54:49,414 MONTHS AND THE CORTICAL 4413 02:54:49,414 --> 02:54:51,049 IMPROVEMENTS LASTED LONGER THAN 4414 02:54:51,049 --> 02:54:53,785 THE ADVERSE EVENTS. 4415 02:54:53,785 --> 02:54:55,754 THESE PATIENTS SHOWED 4416 02:54:55,754 --> 02:54:58,289 IMPROVEMENT IN THE CGI AND EEG. 4417 02:54:58,289 --> 02:54:59,524 THIS IS A LIST OF SOME OF THE 4418 02:54:59,524 --> 02:55:02,861 KINDS OF IMPROVEMENTS THAT WE'RE 4419 02:55:02,861 --> 02:55:03,094 SEEING. 4420 02:55:03,094 --> 02:55:05,530 THE FDA HAS PUT THE STUDY ON 4421 02:55:05,530 --> 02:55:08,533 HOLD FOR A LONG TIME AND GENETIC 4422 02:55:08,533 --> 02:55:17,809 AND ULTRAGENYX WENT TO LOWER 4423 02:55:17,809 --> 02:55:28,319 DOSES AND MOVED TO CANADA AND 4424 02:55:30,688 --> 02:55:38,596 U.K. AND SOME PATIENTS HAD LOST 4425 02:55:38,596 --> 02:55:41,099 GAINS AND ONE GOT AN EXTENDED 4426 02:55:41,099 --> 02:55:43,768 ACCESS FOR BECAUSE HE WAS HAVING 4427 02:55:43,768 --> 02:55:46,905 FREQUENT EPISODES AND FINALLY 4428 02:55:46,905 --> 02:55:49,107 THE FDA ALLOWED THE STUDY TO 4429 02:55:49,107 --> 02:55:51,042 RESTART AFTER THEY PRESENTED 4430 02:55:51,042 --> 02:55:53,178 THEIR U.S. DATA AFTER TWO YEARS 4431 02:55:53,178 --> 02:55:56,214 AND NOW THE STUDY IS GOING AGAIN 4432 02:55:56,214 --> 02:55:59,417 IN THE USA AT THE DOSES BEING 4433 02:55:59,417 --> 02:56:00,885 USED OUTSIDE THE USA. 4434 02:56:00,885 --> 02:56:02,353 TO GIVE YOU A FLAVOR FOR WHAT WE 4435 02:56:02,353 --> 02:56:04,255 FOUND IN THE FIRST FIVE PATIENTS 4436 02:56:04,255 --> 02:56:06,224 AND ONE OF THE FAMILIES SAID I'D 4437 02:56:06,224 --> 02:56:08,860 RATHER HAVE HIM IN A WHEELCHAIR 4438 02:56:08,860 --> 02:56:11,029 WITH THE GAINS HE'S MADE THAN 4439 02:56:11,029 --> 02:56:14,032 COME OFF THIS ASO. 4440 02:56:14,032 --> 02:56:16,968 THIS IS THE AMOUNT OF CHANGE IN 4441 02:56:16,968 --> 02:56:20,605 A YEAR THAT A PATIENT WITH 4442 02:56:20,605 --> 02:56:23,274 ANGELMAN SYNDROME MAKES AFTER 4443 02:56:23,274 --> 02:56:24,375 AGE 4. 4444 02:56:24,375 --> 02:56:27,212 THE DOTS ARE THE AMOUNT OF 4445 02:56:27,212 --> 02:56:27,979 CHANGE THE PATIENTS MADE IN LESS 4446 02:56:27,979 --> 02:56:31,749 THAN A YEAR. 4447 02:56:31,749 --> 02:56:33,184 SO THE CHANGE WAS VERY DIFFERENT 4448 02:56:33,184 --> 02:56:35,053 FROM WHAT WE SEE IN NATURAL 4449 02:56:35,053 --> 02:56:40,058 HISTORY. 4450 02:56:40,058 --> 02:56:49,934 SO WHEN THEY RE-YERE-NEAINITIAT 4451 02:56:49,934 --> 02:56:52,937 TRIAL AND HAD COHORTS 4-7 TO 4452 02:56:52,937 --> 02:56:55,039 PROVE SAFETY AND GOT 34 IN 4453 02:56:55,039 --> 02:57:00,478 COHORT A OUTSIDE THE USA AND 4454 02:57:00,478 --> 02:57:01,779 HAVEN'T BEEN GOING ALONG ENOUGH 4455 02:57:01,779 --> 02:57:03,248 IN THE USA TO HAVE THE DATA CUT. 4456 02:57:03,248 --> 02:57:06,050 WHAT HAVE THEY SEEN? 4457 02:57:06,050 --> 02:57:08,419 THE KIND OF STANDARDS THINGS YOU 4458 02:57:08,419 --> 02:57:09,721 MIGHT SEE. 4459 02:57:09,721 --> 02:57:11,055 THERE HAVEN'T BEEN EXTENSIVE 4460 02:57:11,055 --> 02:57:12,557 SIDE EFFECTS. 4461 02:57:12,557 --> 02:57:15,460 A COUPLE FAMILIES DISCONTINUED 4462 02:57:15,460 --> 02:57:19,063 BECAUSE OF TRAVEL AND EFFORT. 4463 02:57:19,063 --> 02:57:20,698 THREE PARTICIPANTS DID DEVELOP 4464 02:57:20,698 --> 02:57:26,504 MILD SYMPTOMS AND THEY ALL 4465 02:57:26,504 --> 02:57:31,776 RESOLVED AND GETTING DOSE AGAIN 4466 02:57:31,776 --> 02:57:42,320 AFTER RADICULOPATHY AND WE HAVE 4467 02:57:45,156 --> 02:57:45,990 SHARING THE NATURAL HISTORY DATA 4468 02:57:45,990 --> 02:57:48,426 WITH ALL INDUSTRY PARTNERS. 4469 02:57:48,426 --> 02:57:51,529 THERE'S TWO BATCHES. 4470 02:57:51,529 --> 02:57:53,898 ONE IS 2006 TO 2014 DOING THE 4471 02:57:53,898 --> 02:57:59,037 BAYLEY 3 AND THE VALUES AND THE 4472 02:57:59,037 --> 02:58:01,439 VALUES WERE CONVERTED AND 4473 02:58:01,439 --> 02:58:03,441 THERE'S A WAY TO DO THAT IN THE 4474 02:58:03,441 --> 02:58:07,045 MANUAL AND THE RECENT HISTORY OF 4475 02:58:07,045 --> 02:58:10,348 THE BAYLEY 4 WAS TESTED AND QUE 4476 02:58:10,348 --> 02:58:20,692 HAVE GSBs FROM THEM. 4477 02:58:25,830 --> 02:58:28,299 THE SECOND DOTTED LINE WOULD BE 4478 02:58:28,299 --> 02:58:29,434 STATISTICALLY SIGNIFICANT YOU 4479 02:58:29,434 --> 02:58:30,234 WOULDN'T SEE JUST FROM TEST 4480 02:58:30,234 --> 02:58:31,836 ADMINISTRATION AND SO AS YOU CAN 4481 02:58:31,836 --> 02:58:34,038 SEE COGNITION IS DOING MUCH 4482 02:58:34,038 --> 02:58:35,873 BETTER THAN NATURAL HISTORY OVER 4483 02:58:35,873 --> 02:58:38,242 THE COURSE OF THE TIME AND MOST 4484 02:58:38,242 --> 02:58:40,611 OF THIS IS COHORT 4-7 BUT 4485 02:58:40,611 --> 02:58:42,780 THEY'RE FOLLOWING THE SAME PATH 4486 02:58:42,780 --> 02:58:45,483 IN ALL THESE GRAPHS AND THIS IS 4487 02:58:45,483 --> 02:58:47,051 RECEPTIVE COMMUNICATION, SAME 4488 02:58:47,051 --> 02:58:49,354 RESULT. 4489 02:58:49,354 --> 02:58:51,923 THIS IS GROSS MOTOR SKILLS AND 4490 02:58:51,923 --> 02:58:53,424 NATURAL HISTORY AND ON THE ASO 4491 02:58:53,424 --> 02:58:56,928 AND WHEN THEY ONLY HAD DATA FROM 4492 02:58:56,928 --> 02:59:01,766 4-7 AND THIS IS THE ASA THE 4493 02:59:01,766 --> 02:59:04,535 ANGELMAN SYNDROME SYNDROME SO 4494 02:59:04,535 --> 02:59:07,739 YOU GET CONSISTENCY ACROSS SITES 4495 02:59:07,739 --> 02:59:10,008 AND SLEEP SEVERITY IMPROVED AND 4496 02:59:10,008 --> 02:59:11,342 BEHAVIORAL SEVERITY IMPROVED A 4497 02:59:11,342 --> 02:59:12,777 GREAT DEAL. 4498 02:59:12,777 --> 02:59:15,046 WHETHER YOU LOOK AT IT AS MEANS 4499 02:59:15,046 --> 02:59:18,349 OR IN A RESPONDER ANALYSIS IN 4500 02:59:18,349 --> 02:59:20,718 OTHER WORDS PATIENTS THAT HAD 4501 02:59:20,718 --> 02:59:22,120 IMPROVEMENTS VERSUS THOSE THAT 4502 02:59:22,120 --> 02:59:22,353 DIDN'T. 4503 02:59:22,353 --> 02:59:25,490 AND THIS IS WHAT ULTRA GENICS 4504 02:59:25,490 --> 02:59:28,726 HAD TO DO TO LOOK ACROSS THE 4505 02:59:28,726 --> 02:59:29,327 DOMAINS IN ANGELMAN SYNDROME 4506 02:59:29,327 --> 02:59:30,161 BECAUSE DIFFERENT THINGS AND YOU 4507 02:59:30,161 --> 02:59:31,763 CAN SEE FROM THE CHART IMPROVE 4508 02:59:31,763 --> 02:59:33,664 IN DIFFERENT PATIENTS AND 4509 02:59:33,664 --> 02:59:36,167 THEY'RE MORE SEVERE IN DIFFERENT 4510 02:59:36,167 --> 02:59:36,367 AREAS. 4511 02:59:36,367 --> 02:59:39,037 THE GREEN IS SOMETHING THAT 4512 02:59:39,037 --> 02:59:40,805 IMPROVED MORE THAN WOULD BE AND 4513 02:59:40,805 --> 02:59:42,673 IN THE CASE OF BEHAVIOR AND 4514 02:59:42,673 --> 02:59:44,208 SLEEP IN A CLINICAL AND 4515 02:59:44,208 --> 02:59:45,143 MEANINGFUL AMOUNT AND IN THE 4516 02:59:45,143 --> 02:59:50,848 CASE OF THE OTHER DOMAINS IS THE 4517 02:59:50,848 --> 02:59:54,318 BAYLEY AMOUNT MORE THAN WHAT 4518 02:59:54,318 --> 02:59:56,154 WOULD BE STATISTICALLY PREDICTED 4519 02:59:56,154 --> 02:59:56,854 OF VARIATION FROM ONE 4520 02:59:56,854 --> 02:59:58,923 ADMINISTRATION TO THE OTHER. 4521 02:59:58,923 --> 03:00:00,491 YOU CAN SEE MOST HAVE IMPROVED 4522 03:00:00,491 --> 03:00:02,026 IN ONE DOMAIN AND SOME HAVE 4523 03:00:02,026 --> 03:00:03,795 IMPROVED IN MANY DOMAINS AND 4524 03:00:03,795 --> 03:00:05,463 THIS IS EARLIER. 4525 03:00:05,463 --> 03:00:07,698 THESE ARE PATIENTS AT DAY 170 4526 03:00:07,698 --> 03:00:10,334 AND COHORT A AND B AND MANY 4527 03:00:10,334 --> 03:00:10,668 IMPROVED ALSO. 4528 03:00:10,668 --> 03:00:12,437 SO THIS IS THE KIND OF MEASURE 4529 03:00:12,437 --> 03:00:15,039 ONE COULD USE TO LOOK ACROSS THE 4530 03:00:15,039 --> 03:00:15,440 DISEASE. 4531 03:00:15,440 --> 03:00:19,410 THIS LOOKS ACROSS DISEASE AS THE 4532 03:00:19,410 --> 03:00:20,078 OVER ALL ANGELMAN SYNDROME 4533 03:00:20,078 --> 03:00:21,746 SEVERITY SCALE THE LOWER THE 4534 03:00:21,746 --> 03:00:23,047 BETTER. 4535 03:00:23,047 --> 03:00:30,788 THAT IS SHOWS IMPROVEMENT. 4536 03:00:30,788 --> 03:00:32,356 AND THIS GOES WITH THE COGNITIVE 4537 03:00:32,356 --> 03:00:35,026 AND LANGUAGE IMPROVEMENTS AND 4538 03:00:35,026 --> 03:00:38,029 THE SLEEP SYNDROME WHICH ARE 4539 03:00:38,029 --> 03:00:39,030 IMPROVING TO GO WITH THOSE 4540 03:00:39,030 --> 03:00:48,573 IMPROVEMENTS. 4541 03:00:48,573 --> 03:00:51,042 AND THESE IS TREATMENT AND THE 4542 03:00:51,042 --> 03:00:52,643 GREEN ARE THINGS THEY GAINED 4543 03:00:52,643 --> 03:00:53,344 DURING THE FIRST PART OF THE 4544 03:00:53,344 --> 03:00:55,813 TRIAL WHEN THEY WERE ON THE ASO 4545 03:00:55,813 --> 03:00:58,749 EARLY ON BEFORE THEY GOT THE 4546 03:00:58,749 --> 03:01:09,160 POLY RAH -- ROO -- 4547 03:01:18,769 --> 03:01:21,339 RADICULOPATHY AND THIS WAS GARND 4548 03:01:21,339 --> 03:01:21,973 AND LOST IN ASSOCIATION WITH THE 4549 03:01:21,973 --> 03:01:22,573 TREATMENT OF THE DRUG. 4550 03:01:22,573 --> 03:01:25,843 AND THEN A VIDEO WAS ALWAYS 4551 03:01:25,843 --> 03:01:28,079 WORTH A THOUSAND PLOTS. 4552 03:01:28,079 --> 03:01:32,250 SO I'M GOING TO SEE IF THESE 4553 03:01:32,250 --> 03:01:32,617 WORK. 4554 03:01:32,617 --> 03:01:35,987 THIS IS OUR ANGELMAN PATIENT 4555 03:01:35,987 --> 03:01:37,855 SITTING ON THE TRAMPOLINE AND 4556 03:01:37,855 --> 03:01:41,459 HAS TROUBLE GETTING ON HER FEET 4557 03:01:41,459 --> 03:01:44,328 TO JUMP WITH HER SISTERS AND 4558 03:01:44,328 --> 03:01:46,497 JUST SITS ON THE TRAMPOLINE TO 4559 03:01:46,497 --> 03:01:48,032 BE TOGETHER WITH THEM AND CAN 4560 03:01:48,032 --> 03:01:49,634 STAND UP. 4561 03:01:49,634 --> 03:01:51,169 SHE'S ACTUALLY PRETTY WELL 4562 03:01:51,169 --> 03:01:53,538 COORDINATED FOR ANGELMAN BUT 4563 03:01:53,538 --> 03:01:55,773 CAN'T REALLY JUMP AND HAS 4564 03:01:55,773 --> 03:01:56,974 TROUBLE MAINTAINING HER BALANCE. 4565 03:01:56,974 --> 03:01:58,709 THIS IS HER CHILD AFTER FIVE 4566 03:01:58,709 --> 03:02:02,980 DOSES OF AN ASO. 4567 03:02:02,980 --> 03:02:05,082 THESE WERE MAYBE SIX MONTHS 4568 03:02:05,082 --> 03:02:07,151 AFTER GOING ON THE ASO. 4569 03:02:07,151 --> 03:02:09,487 AND THERE SHE IS HAVING NO 4570 03:02:09,487 --> 03:02:10,588 TROUBLE JUMPING ON THE 4571 03:02:10,588 --> 03:02:12,757 TRAMPOLINE WITH HER SISTERS. 4572 03:02:12,757 --> 03:02:15,126 REMEMBER AFTER AGE 4 THESE KIDS 4573 03:02:15,126 --> 03:02:16,761 MAKE BASICALLY NO PROGRESS AND 4574 03:02:16,761 --> 03:02:22,066 SHE CAN JUMP ON TO HER AND SIT 4575 03:02:22,066 --> 03:02:23,768 AND JUMP BACK AND JUMP. 4576 03:02:23,768 --> 03:02:25,770 SO THAT'S REALLY A SUBSTANTIAL 4577 03:02:25,770 --> 03:02:30,274 CHANGE IN MOTOR FUNCTIONING. 4578 03:02:30,274 --> 03:02:32,710 HERE IS ONE OF OUR YOUNGEST 4579 03:02:32,710 --> 03:02:34,579 PATIENTS WHO IS GOING TO BE OVER 4580 03:02:34,579 --> 03:02:34,779 HERE. 4581 03:02:34,779 --> 03:02:36,013 AND HER MOTHER'S TRYING TO GET 4582 03:02:36,013 --> 03:02:37,114 HER TO WALK. 4583 03:02:37,114 --> 03:02:39,383 SO WHEN SHE CAME IN THE TRIAL 4584 03:02:39,383 --> 03:02:41,652 SHE WAS NOT AMBULATORY. 4585 03:02:41,652 --> 03:02:43,221 SHE COULD TAKE A FEW STEPS 4586 03:02:43,221 --> 03:02:53,664 BEFORE FALLING. 4587 03:02:53,664 --> 03:02:55,032 GETS UP AND THEN FALLS DOWN AND 4588 03:02:55,032 --> 03:02:57,335 HIS IS HER STATUS AT THE TRIAL 4589 03:02:57,335 --> 03:02:58,569 THEN AFTER ABOUT SIX TREATMENTS 4590 03:02:58,569 --> 03:03:03,040 THIS IS HER ON AN ANGELMAN 4591 03:03:03,040 --> 03:03:04,909 SYNDROME WALK WHERE SHE JUST 4592 03:03:04,909 --> 03:03:07,979 WALKED ALMOST A MILE AND HERE 4593 03:03:07,979 --> 03:03:10,314 SHE COMES RIGHT THROUGH THE 4594 03:03:10,314 --> 03:03:10,915 GATE. 4595 03:03:10,915 --> 03:03:14,752 SHE HAS HER ARMS UP AS IS 4596 03:03:14,752 --> 03:03:15,853 TYPICAL OF ANGELMAN SYNDROME BUT 4597 03:03:15,853 --> 03:03:18,155 THEY'LL COME DOWN WITH TIME. 4598 03:03:18,155 --> 03:03:20,224 THE PATIENTS GET MORE STABLE AND 4599 03:03:20,224 --> 03:03:24,161 THEY STOP HOLDING THEIR ARMS UP. 4600 03:03:24,161 --> 03:03:28,332 SO IN CONCLUSION, THE ASO IS IN 4601 03:03:28,332 --> 03:03:32,069 ALL STUDIES THAT HAVE SHOWN 4602 03:03:32,069 --> 03:03:32,336 BENEFITS. 4603 03:03:32,336 --> 03:03:34,939 I HAVE A PHONE FULL OF VIDEO 4604 03:03:34,939 --> 03:03:36,107 THAT COULD KNOCK YOU OFF YOUR 4605 03:03:36,107 --> 03:03:37,375 SOCKS BUT WE HAVE TO COLLECT 4606 03:03:37,375 --> 03:03:38,709 DATA IN A STANDARD FASHION. 4607 03:03:38,709 --> 03:03:41,245 SO SAFETY HAS BEEN ACCESSIBLE 4608 03:03:41,245 --> 03:03:42,446 FOR ALL THREE DRUGS. 4609 03:03:42,446 --> 03:03:43,781 UNDER DOSING HAS BEEN A PROBLEM 4610 03:03:43,781 --> 03:03:45,783 IN ALL THE TRIALS. 4611 03:03:45,783 --> 03:03:48,686 EVEN WITH 3 MONTHS THE DOSE 4612 03:03:48,686 --> 03:03:50,554 WEARS OFF AND THEN THEY HAVE 4613 03:03:50,554 --> 03:03:53,557 BEHAVIOR AND SLEEP REGRESSION 4614 03:03:53,557 --> 03:03:55,026 WHICH ARE THE MOST COMMON 4615 03:03:55,026 --> 03:03:56,460 SYMPTOMS AND THE DATA IS ALL 4616 03:03:56,460 --> 03:03:59,030 COLLECTED WHEN THEY COME BACK 4617 03:03:59,030 --> 03:04:01,299 FOR THE NEXT INFUSION AND SO 4618 03:04:01,299 --> 03:04:02,633 IT'S PROBABLY AN UNDER ESTIMATE 4619 03:04:02,633 --> 03:04:05,503 OF WHAT THEY'RE DOING AT PEAK. 4620 03:04:05,503 --> 03:04:07,805 THESE ARE EXTREMELY EXCITING 4621 03:04:07,805 --> 03:04:09,740 LIFE CHANGING THERAPIES AND THE 4622 03:04:09,740 --> 03:04:13,644 DATA IS GOING IN FOR PHASE III 4623 03:04:13,644 --> 03:04:14,779 AND WE'LL GO INTO THE PHASE III 4624 03:04:14,779 --> 03:04:16,881 BY THE END OF THE YEAR WITH TWO 4625 03:04:16,881 --> 03:04:19,784 COMPANIES AND THESE ARE 4626 03:04:19,784 --> 03:04:21,319 QUESTIONS FOR THE WORKSHOP THERE 4627 03:04:21,319 --> 03:04:22,687 ARE STILL ALL THESE QUESTIONS. 4628 03:04:22,687 --> 03:04:26,090 AT WHAT AGE DO WE NEED TO 4629 03:04:26,090 --> 03:04:26,324 CORRECT? 4630 03:04:26,324 --> 03:04:29,694 SO FAR WE'VE SEEN CHANGES BUT 4631 03:04:29,694 --> 03:04:31,762 ARE WE GOING TO A LOW ENOUGH 4632 03:04:31,762 --> 03:04:32,163 AGE. 4633 03:04:32,163 --> 03:04:34,298 WE HAVE FEW UNDER 4 WHO HAVE 4634 03:04:34,298 --> 03:04:36,000 BEEN TREATED. 4635 03:04:36,000 --> 03:04:37,234 HOW MUCH CORRECTION IS POSSIBLE 4636 03:04:37,234 --> 03:04:39,503 AT DIFFERENT AGES? 4637 03:04:39,503 --> 03:04:42,707 WHAT IF WE GOT IN AT NEWBORN 4638 03:04:42,707 --> 03:04:43,040 TIME? 4639 03:04:43,040 --> 03:04:46,177 COULD WE FIX LANGUAGE AND SOME 4640 03:04:46,177 --> 03:04:49,647 PATIENT HAVE DEVELOPED WORDS AND 4641 03:04:49,647 --> 03:04:50,781 TWO-WORD STATEMENTS BUT MANY 4642 03:04:50,781 --> 03:04:51,916 HAVEN'T DEVELOPED EXCESSIVE 4643 03:04:51,916 --> 03:04:52,183 LANGUAGE. 4644 03:04:52,183 --> 03:04:54,585 WHAT ARE THE TIME RANGES FOR 4645 03:04:54,585 --> 03:04:54,985 CLINICAL CHANGES? 4646 03:04:54,985 --> 03:04:58,322 THIS IS NOT A BABY WE'RE 4647 03:04:58,322 --> 03:04:59,223 TREATING. 4648 03:04:59,223 --> 03:05:00,958 BABIES HAVE A BRAIN WIRED TO 4649 03:05:00,958 --> 03:05:02,326 HAVE RAPID EXPANSION OF 4650 03:05:02,326 --> 03:05:02,626 DEVELOPMENT. 4651 03:05:02,626 --> 03:05:03,928 WE DON'T HAVE THAT ANYMORE IN 4652 03:05:03,928 --> 03:05:04,462 THESE KIDS. 4653 03:05:04,462 --> 03:05:05,363 SO THEY'RE GOING TO DEVELOP BUT 4654 03:05:05,363 --> 03:05:07,832 THERE'S NO SIGN IN OUR 4655 03:05:07,832 --> 03:05:11,035 PATIENTS -- 4656 03:05:11,035 --> 03:05:21,212 [NO AUDIO] 4657 03:05:59,116 --> 03:06:00,985 -- HOW WE MEASURE ONE DOMAIN AND 4658 03:06:00,985 --> 03:06:02,486 THE FDA STILL WANTS US TO PICK 4659 03:06:02,486 --> 03:06:05,289 THE ONE DOMAIN IN A GENETIC WAY 4660 03:06:05,289 --> 03:06:12,229 WITH MANY MANIFESTATIONS BUT IT 4661 03:06:12,229 --> 03:06:13,998 DIDN'T MAKE SENSE TO US BUT 4662 03:06:13,998 --> 03:06:14,999 THAT'S WHERE WE ARE WITH THE 4663 03:06:14,999 --> 03:06:17,601 FDA. 4664 03:06:17,601 --> 03:06:20,438 WITH THAT I'M GOING TO THANK MY 4665 03:06:20,438 --> 03:06:21,906 ANGELMAN TEAM AND OUR FUNDING 4666 03:06:21,906 --> 03:06:24,275 FROM THE ANGELMAN FOUNDATIONS 4667 03:06:24,275 --> 03:06:26,777 AND THE COMPANIES AND FROM THE 4668 03:06:26,777 --> 03:06:28,612 FDA AND NATURAL HISTORY STUDY 4669 03:06:28,612 --> 03:06:28,946 RECENTLY DOVE DEF 4670 03:06:30,881 --> 03:06:33,484 AND OUR FAMILIES WHO ARE OUR 4671 03:06:33,484 --> 03:06:34,518 PARTNERS IN MAKING THIS HAPPEN. 4672 03:06:34,518 --> 03:06:44,695 [APPLAUSE] 4673 03:06:59,677 --> 03:07:03,647 >> DO I HAVE ANY IDEA WHAT THE 4674 03:07:03,647 --> 03:07:04,682 PHASE III TRIAL STRUCTURE WILL 4675 03:07:04,682 --> 03:07:07,017 LOOK LIKE? 4676 03:07:07,017 --> 03:07:08,819 ACCORDING TO THE FDA, YES, IT'S 4677 03:07:08,819 --> 03:07:11,956 GOING TO BE A RANDOMIZED PLACEBO 4678 03:07:11,956 --> 03:07:13,657 CONTROL AND TRYING TO GET AWAY 4679 03:07:13,657 --> 03:07:15,926 FROM SHAM CONTROLS BECAUSE IT 4680 03:07:15,926 --> 03:07:17,862 WILL BE VERY DIFFICULT TO BLIND 4681 03:07:17,862 --> 03:07:19,830 THOSE BECAUSE IT'S A BIG RISK 4682 03:07:19,830 --> 03:07:24,768 WITH THE ANESTHESIA FOR THE LP. 4683 03:07:24,768 --> 03:07:27,037 WE HAVE GREAT NATURAL HISTORY, 4684 03:07:27,037 --> 03:07:28,639 NOT GOOD ENOUGH. 4685 03:07:28,639 --> 03:07:30,608 WE'LL BE DOING A CONTROL TRIAL. 4686 03:07:30,608 --> 03:07:32,743 WE WANT TO DO PLACEBO CONTROLLED 4687 03:07:32,743 --> 03:07:35,179 BECAUSE WE CAN GET CSS FOR 4688 03:07:35,179 --> 03:07:36,914 BIOMARKERS IN THE UNTREATED 4689 03:07:36,914 --> 03:07:41,652 GROUP AND WE HAVE TO DO 4690 03:07:41,652 --> 03:07:42,987 ANESTHESIA FOR THE SHAM OR 4691 03:07:42,987 --> 03:07:44,188 EVERYONE WILL BE UNBLINDED AND I 4692 03:07:44,188 --> 03:07:49,727 THINK IT WILL BE RANDOMIZED 2-1 4693 03:07:49,727 --> 03:07:51,295 AND THAT'S WHAT HAS BEEN BANDIED 4694 03:07:51,295 --> 03:07:52,963 ABOUT THOUGH NONE OF THIS IS 4695 03:07:52,963 --> 03:07:57,401 FINAL AND MAYBE FOR A YEAR AND 4696 03:07:57,401 --> 03:07:58,402 EVERYBODY WHO GETS A PLACEBO 4697 03:07:58,402 --> 03:08:05,709 WILL GO ON DRUG AT THE END. 4698 03:08:05,709 --> 03:08:07,811 >> I'M SURPRISED THE FDA WITH 4699 03:08:07,811 --> 03:08:10,915 THE ON, OFF, ON EFFECT. 4700 03:08:10,915 --> 03:08:14,818 BUT IN THE PHASE III TRIAL WILL 4701 03:08:14,818 --> 03:08:19,056 YOU REDUCE THE TIME SPAN OR STAY 4702 03:08:19,056 --> 03:08:28,699 GIVEN WHAT YOU SAID? 4703 03:08:28,699 --> 03:08:30,901 >> AND WHAT THE INTERVAL WILL BE 4704 03:08:30,901 --> 03:08:33,070 AFTER THAT IS STILL UP IN THE 4705 03:08:33,070 --> 03:08:33,504 AIR. 4706 03:08:33,504 --> 03:08:36,674 I MEAN, IF I HAD MY WAY IT WOULD 4707 03:08:36,674 --> 03:08:39,043 BE EVERY TWO MONTHS. 4708 03:08:39,043 --> 03:08:39,710 WHY? 4709 03:08:39,710 --> 03:08:42,646 IF THEY DON'T HAVE A TWO-MONTH 4710 03:08:42,646 --> 03:08:44,014 OPTION WE'LL NEVER GET INSURANCE 4711 03:08:44,014 --> 03:08:46,951 TO COVER IT EVERY TWO MONTHS AND 4712 03:08:46,951 --> 03:08:49,019 WILL HAVE PATIENTS ON THIS 4713 03:08:49,019 --> 03:08:51,021 ROLLER COSTAR OF IT'S WEARING 4714 03:08:51,021 --> 03:08:52,389 OFF AND WE'RE NOT SLEEPING 4715 03:08:52,389 --> 03:08:53,524 ANYMORE AT NIGHT AGAIN. 4716 03:08:53,524 --> 03:08:55,025 I'M A STRONG VOICE AT THE 4717 03:08:55,025 --> 03:08:56,594 INDUSTRY MEETINGS AND TRYING TO 4718 03:08:56,594 --> 03:08:59,029 CONVINCE THEM TO AT LEAST HAVE A 4719 03:08:59,029 --> 03:09:01,165 TWO-MONTH OPTION. 4720 03:09:01,165 --> 03:09:01,799 >> THIS EXTRAORDINARY. 4721 03:09:01,799 --> 03:09:02,499 THANK YOU. 4722 03:09:02,499 --> 03:09:04,234 I KNOW THERE'S ONLY SO MUCH YOU 4723 03:09:04,234 --> 03:09:05,369 CAN SAY SINCE YOU'RE AN 4724 03:09:05,369 --> 03:09:07,471 INVESTIGATOR IN ALL THREE TRIALS 4725 03:09:07,471 --> 03:09:11,041 BUT I'M CURIOUS ABOUT THE METCAM 4726 03:09:11,041 --> 03:09:13,978 OF THE ALLEGEDLY FAILED ROCHE 4727 03:09:13,978 --> 03:09:14,378 DRUG. 4728 03:09:14,378 --> 03:09:17,848 IS ANY COMPONENT ATTRIBUTABLE TO 4729 03:09:17,848 --> 03:09:20,384 THE CHEMISTRY TO THIS TARGET OR 4730 03:09:20,384 --> 03:09:21,885 YOU CAN'T SAY? 4731 03:09:21,885 --> 03:09:24,388 >> OKAY, WHAT WOULD ROCHE LET ME 4732 03:09:24,388 --> 03:09:24,788 SAY? 4733 03:09:24,788 --> 03:09:26,490 IT HAS NOTHING TO DO WITH THE 4734 03:09:26,490 --> 03:09:26,757 CHEMISTRY. 4735 03:09:26,757 --> 03:09:28,359 IT HAS NOTHING TO DO WITH 4736 03:09:28,359 --> 03:09:29,960 ANYTHING WRONG WITH THE 4737 03:09:29,960 --> 03:09:30,227 MOLECULE. 4738 03:09:30,227 --> 03:09:32,162 WHAT I WOULD SAY IS THAT IT HAS 4739 03:09:32,162 --> 03:09:35,065 FAR MORE TO DO WITH THE CHANGE 4740 03:09:35,065 --> 03:09:36,700 IN ROCHE'S PRIORITIES ABOUT WHAT 4741 03:09:36,700 --> 03:09:42,673 THEY'RE GOING TO DEVELOP. 4742 03:09:42,673 --> 03:09:44,141 WE KNOW IT'S ALSO BECAUSE THEY 4743 03:09:44,141 --> 03:09:45,342 STOPPED IT IN THE MIDDLE OF THE 4744 03:09:45,342 --> 03:09:46,944 TRIAL FOR NO GOOD REASON. 4745 03:09:46,944 --> 03:09:51,949 THAT WAS NO PROBLEMATIC SAFETY 4746 03:09:51,949 --> 03:09:56,186 DATA OR EFFICACY TRIAL AND SAID 4747 03:09:56,186 --> 03:09:57,254 WE'RE NOT INTERESTED ANYMORE AND 4748 03:09:57,254 --> 03:09:58,322 NOT GOING TO RUN THE TRIAL. 4749 03:09:58,322 --> 03:10:00,524 THAT'S A BIG PART OF THE REASON 4750 03:10:00,524 --> 03:10:01,859 FOR THE ANGELMAN SYNDROME 4751 03:10:01,859 --> 03:10:12,369 PROGRAM BEING DROPPED AS WELL. 4752 03:10:32,790 --> 03:10:34,725 >> EXCELLENT. 4753 03:10:34,725 --> 03:10:42,266 I'M DELIGHTED TO BE HERE AND IN 4754 03:10:42,266 --> 03:10:46,537 ILLUSTRIOUS COMPANY AND FORWARD 4755 03:10:46,537 --> 03:10:48,605 THINKING AGENDA ON THERAPY FOR 4756 03:10:48,605 --> 03:10:49,173 EPILEPSY. 4757 03:10:49,173 --> 03:10:54,311 YOU HEARD A LOT THIS MORNING 4758 03:10:54,311 --> 03:11:04,788 THAT WILL MAKE MYS WORK AND 4759 03:11:09,093 --> 03:11:10,094 CHALLENGES IN THE GENE THERAPY 4760 03:11:10,094 --> 03:11:13,063 TRIALS ARE HERE TO STAY AND I 4761 03:11:13,063 --> 03:11:14,765 HOPE THERE'LL BE LESSONS 4762 03:11:14,765 --> 03:11:15,032 LEARNED. 4763 03:11:15,032 --> 03:11:19,803 I WILL FOCUS MOSTLY ON 4764 03:11:19,803 --> 03:11:24,007 PROGRESSIVE DISORDERS THE WHITE 4765 03:11:24,007 --> 03:11:26,243 MATTER OF THE BRAIN AND MY 4766 03:11:26,243 --> 03:11:28,112 MESSAGE IN SHORT IS DISEASE 4767 03:11:28,112 --> 03:11:28,779 CONTEXT MATTERS AND DISEASE 4768 03:11:28,779 --> 03:11:30,781 COURSE AND VULNERABILITY OF 4769 03:11:30,781 --> 03:11:34,084 PATIENTS AND THAT IS REALLY WHAT 4770 03:11:34,084 --> 03:11:38,322 DRIVES TRIALS AS WE THINK ABOUT 4771 03:11:38,322 --> 03:11:42,493 VULNERABILITY IN RELATIONSHIP TO 4772 03:11:42,493 --> 03:11:45,596 DISEASE AND THE PLATFORM THAT 4773 03:11:45,596 --> 03:11:49,466 WILL BE WITH INVESTIGATORS AND 4774 03:11:49,466 --> 03:11:49,800 NAVIGATE. 4775 03:11:49,800 --> 03:12:00,210 BRIEFLY MY DISCLOSURES. 4776 03:12:02,713 --> 03:12:04,548 YOU'VE HEARD A LOT ABOUT AAV 4777 03:12:04,548 --> 03:12:07,584 GENE THERAPY AND EX VIVO THERAPY 4778 03:12:07,584 --> 03:12:10,354 AND I'LL PRESENT THE IN VIVO 4779 03:12:10,354 --> 03:12:12,589 APPROACHES USING AAV AND EX VIVO 4780 03:12:12,589 --> 03:12:16,660 GENE THERAPY AND SHOW HOW WE 4781 03:12:16,660 --> 03:12:18,028 APPLIED THIS IN VARIOUS 4782 03:12:18,028 --> 03:12:23,233 DYSTROPHIES DISORDERS AFFECTING 4783 03:12:23,233 --> 03:12:30,407 THE WHITE MATTER OF THE BRAIN I 4784 03:12:30,407 --> 03:12:31,809 CAN SEE THE BIOMARKER FOR THE 4785 03:12:31,809 --> 03:12:33,443 PATHOLOGY AND IMAGE WHAT IS 4786 03:12:33,443 --> 03:12:35,979 HAPPENING IN THE BRAIN AND SEE 4787 03:12:35,979 --> 03:12:39,783 THE RESOLUTION THERE. 4788 03:12:39,783 --> 03:12:43,287 SO IN VIVO GENE DELIVERY IS 4789 03:12:43,287 --> 03:12:45,589 DIRECT TO THE ORGAN AND WITH THE 4790 03:12:45,589 --> 03:12:47,991 EX VIVO IT DELIVERS THE 4791 03:12:47,991 --> 03:12:49,326 CORRECTED GENE. 4792 03:12:49,326 --> 03:12:58,902 FIRST I'LL PRESENT CANAVAN 4793 03:12:58,902 --> 03:13:01,405 DISEASE DISORDER AND THIS LEADS 4794 03:13:01,405 --> 03:13:07,044 TO THE ACCUMULATION OF A 4795 03:13:07,044 --> 03:13:10,848 PLEASURE OF URINE AS WELL AS IN 4796 03:13:10,848 --> 03:13:12,549 LEADING TO THE DISORDER WHERE 4797 03:13:12,549 --> 03:13:14,017 CHILDREN HAVE A HEAD SIZE AND 4798 03:13:14,017 --> 03:13:17,054 NEVER SIT UP ON THEIR OWN. 4799 03:13:17,054 --> 03:13:19,923 SOME CAN REACH SEIZURES AND THE 4800 03:13:19,923 --> 03:13:22,292 MRI IS WHITE MATTER EFFECTED AND 4801 03:13:22,292 --> 03:13:32,836 THE BRAIN STEM THAT IS USUALLY 4802 03:13:37,875 --> 03:13:42,246 MYELINATED EARLY NEVER MYELI 4803 03:13:42,246 --> 03:13:43,380 MYELINMYELIN 4804 03:13:43,380 --> 03:13:49,119 MYELINATES AND EVEN WITH A LIVER 4805 03:13:49,119 --> 03:13:49,820 DIRECTED DISORDER WAS SHOWN 4806 03:13:49,820 --> 03:13:58,495 IMPROVEMENT IN THE MICE SHOWING 4807 03:13:58,495 --> 03:14:02,399 SYSTEMIC CORRECTION WITH AN 4808 03:14:02,399 --> 03:14:02,666 ADDITION. 4809 03:14:02,666 --> 03:14:09,506 HERE THE FIRST PATIENT BEING 4810 03:14:09,506 --> 03:14:12,910 TREATED WAS AAV 9 AN OPEN LABEL 4811 03:14:12,910 --> 03:14:13,977 TRIAL FOR CHILDREN UP TO 30 4812 03:14:13,977 --> 03:14:14,745 MONTHS OF AGE. 4813 03:14:14,745 --> 03:14:17,748 AS MENTIONED OFTEN TODAY WE WANT 4814 03:14:17,748 --> 03:14:22,719 TO GET TO CHILDREN AS QUICKLY 4815 03:14:22,719 --> 03:14:24,421 AND AS EARLY AS AND POSSIBLE AND 4816 03:14:24,421 --> 03:14:29,559 FINISHED THE LOW DOSE COHORT AND 4817 03:14:29,559 --> 03:14:32,729 THEY'VE TREATED NOW TWO PATIENTS 4818 03:14:32,729 --> 03:14:37,234 AND THE HIGHER DOSE AS WELL. 4819 03:14:37,234 --> 03:14:43,040 SO ONE OF THE FIRST THINGS WE 4820 03:14:43,040 --> 03:14:49,680 NOTICED IS IMMUNE RESPONSES 4821 03:14:49,680 --> 03:14:51,048 AFTER THE ADMINISTRATION WAS 4822 03:14:51,048 --> 03:14:54,584 SOMETHING FOUND AND WE SEE DROPS 4823 03:14:54,584 --> 03:14:56,954 IN PLATELETS IN THE FIRST FEW 4824 03:14:56,954 --> 03:14:58,855 DAYS THAT USUALLY RESPONDS 4825 03:14:58,855 --> 03:15:00,223 SPONTANEOUSLY AFTER THE FIRST 4826 03:15:00,223 --> 03:15:03,126 WEEK BUT THEN ALSO ARISES IN AST 4827 03:15:03,126 --> 03:15:04,928 AND ALT AND TO THE LIVER 4828 03:15:04,928 --> 03:15:07,030 FUNCTIONS THAT NEED TO BE 4829 03:15:07,030 --> 03:15:12,502 MANAGED WITH GLUCCOCORTICOID 4830 03:15:12,502 --> 03:15:14,404 DOSE ADJUSTMENT. 4831 03:15:14,404 --> 03:15:15,572 THIS REQUIRED LEARNING IN THE 4832 03:15:15,572 --> 03:15:17,174 BEGINNING AND WE HAD TO LEARN 4833 03:15:17,174 --> 03:15:18,442 HOW TO DO THIS. 4834 03:15:18,442 --> 03:15:22,746 NEVERTHELESS WE SEE DRAMATIC 4835 03:15:22,746 --> 03:15:24,348 REDUCTIONS HERE IN URINE FROM 4836 03:15:24,348 --> 03:15:27,384 THE CLASSIC HIGH LEVELS THAT YOU 4837 03:15:27,384 --> 03:15:30,420 FIND IN THE DISEASE STATE DOWN 4838 03:15:30,420 --> 03:15:34,291 TO THE OTHER RANGE ASSOCIATED 4839 03:15:34,291 --> 03:15:36,593 WITH MILD DISEASE AND THIS 4840 03:15:36,593 --> 03:15:42,833 HAPPENS NOT ONLY HERE BUT IN CSF 4841 03:15:42,833 --> 03:15:45,502 AND SPECTROSCOPY IN THE BRAIN 4842 03:15:45,502 --> 03:15:47,437 AND WE DID NOT EXPECT TOGETHER 4843 03:15:47,437 --> 03:15:51,041 WE SAW SHRINKAGE OF THE BRAIN 4844 03:15:51,041 --> 03:15:56,747 SWELLING THAT USUALLY OCCURS AND 4845 03:15:56,747 --> 03:16:04,154 WE SAW. 4846 03:16:04,154 --> 03:16:07,024 WE LOOKED AT THE FIRST TWO AND 4847 03:16:07,024 --> 03:16:09,059 THOUGHT LUMBER PUNCTURES WERE 4848 03:16:09,059 --> 03:16:11,028 DOING AT 3 MONTHS BUT SINCE HAVE 4849 03:16:11,028 --> 03:16:13,830 NOT SEEN THAT AND IT SHOWS YOU 4850 03:16:13,830 --> 03:16:18,969 HERE THE AFFECT HERE OF THE GENE 4851 03:16:18,969 --> 03:16:22,606 THERAPY ON THE UNEXPECTED TURN. 4852 03:16:22,606 --> 03:16:25,709 AND NEVERTHELESS WE SAW 4853 03:16:25,709 --> 03:16:29,980 IMPROVEMENT IN MYELINATION WITH 4854 03:16:29,980 --> 03:16:33,183 EVER PATIENT TREATED AND YOU SEE 4855 03:16:33,183 --> 03:16:36,820 NICE MYELINATION OCCURRING ON T2 4856 03:16:36,820 --> 03:16:41,691 AND EVERY TIME YOU SEE MYELIN 4857 03:16:41,691 --> 03:16:44,561 BEING PUT DOWN IN THE WEIGHTED 4858 03:16:44,561 --> 03:16:45,595 IMAGE AND SOMETHING WE NEVER SEE 4859 03:16:45,595 --> 03:16:47,531 IN THE UNTREATED CONDITION. 4860 03:16:47,531 --> 03:16:48,698 MORE IMPORTANTLY WE SAW THESE 4861 03:16:48,698 --> 03:16:52,035 CHILDREN THAT NEVER LEARNED TO 4862 03:16:52,035 --> 03:16:55,038 SIT UP ON THEIR OWN AND NOW 4863 03:16:55,038 --> 03:16:58,408 BRINGING HAND TO MOUTH AND STILL 4864 03:16:58,408 --> 03:17:01,111 QUITE UNSTABLE HERE AFTER 4865 03:17:01,111 --> 03:17:03,046 TREATMENT BUT THEN STARTING TO 4866 03:17:03,046 --> 03:17:06,183 TAKE STEPS ON THEIR OWN AND THIS 4867 03:17:06,183 --> 03:17:08,718 LITTLE GIRL NOW ENTERING 4868 03:17:08,718 --> 03:17:11,054 KINDERGARTEN AND ABLE TO 4869 03:17:11,054 --> 03:17:13,423 AMBULATE INDEPENDENTLY. 4870 03:17:13,423 --> 03:17:17,727 SOMETHING THAT GIVES MUCH 4871 03:17:17,727 --> 03:17:18,061 SATISFACTION. 4872 03:17:18,061 --> 03:17:27,938 SO TO SUMMARIZE HERE, SPONGIFORM 4873 03:17:27,938 --> 03:17:37,814 EN ENCEPHALOPATHY AND WE TALK 4874 03:17:37,814 --> 03:17:42,052 ABOUT PERMISSIVE BLOOD BRAIN 4875 03:17:42,052 --> 03:17:44,154 BARRIER IN YOUNG CHILDREN ALLOWS 4876 03:17:44,154 --> 03:17:48,692 FOR SYSTEMIC AAV 9 AND GENE 4877 03:17:48,692 --> 03:17:50,227 DELIVER DELIVERY AND WE STEPPED 4878 03:17:50,227 --> 03:17:53,530 BACK AND HAVE BEEN ABLE TO 4879 03:17:53,530 --> 03:17:57,033 MANAGE AND AVOID EARLY 4880 03:17:57,033 --> 03:17:57,567 ADDITIONAL TURNING TURE. 4881 03:17:57,567 --> 03:18:01,238 TO HIGHLIGHT ANOTHER DISEASE WE 4882 03:18:01,238 --> 03:18:07,844 MADE PROGRESS IN IN INFANTILE 4883 03:18:07,844 --> 03:18:11,648 TAY SACHS AND SANDHOFF DISEASE 4884 03:18:11,648 --> 03:18:17,187 LEADS TO DEVASTATING COURSE WITH 4885 03:18:17,187 --> 03:18:19,256 HALF THESE CHILDREN IN THE FIRST 4886 03:18:19,256 --> 03:18:20,557 YEARS OF LIFE AND HALF THE 4887 03:18:20,557 --> 03:18:21,958 CHILDREN LEARN TO SIT UP ON 4888 03:18:21,958 --> 03:18:27,030 THEIR OWN TOGETHER AND NEVER DO 4889 03:18:27,030 --> 03:18:28,465 LEARN TO SIT UP ON THEIR OWN AND 4890 03:18:28,465 --> 03:18:32,002 YOU SEE THE PATHOLOGY HERE. 4891 03:18:32,002 --> 03:18:35,038 THE SOLUTION AROUND THE NEURONS 4892 03:18:35,038 --> 03:18:41,778 IS VERY WIDESPREAD IN THE BRAIN 4893 03:18:41,778 --> 03:18:47,017 AND THE RATIONALE HERE FOR GENE 4894 03:18:47,017 --> 03:18:51,021 THERAPY SHOWED THALAMIC 4895 03:18:51,021 --> 03:18:54,991 INJECTION OF AAV GM2 COULD LEAD 4896 03:18:54,991 --> 03:19:00,564 TO WIDESPREAD DELIVERY ACROSS 4897 03:19:00,564 --> 03:19:04,267 THE BRAIN BASED ON THE THALAMUS 4898 03:19:04,267 --> 03:19:07,971 AND THE FUNCTIONAL HUB FOR THE 4899 03:19:07,971 --> 03:19:12,309 TRANSPORTER AS WELL AS NOW YOU 4900 03:19:12,309 --> 03:19:16,146 HAVE NEIGHBORING CELLS AND SO WE 4901 03:19:16,146 --> 03:19:19,082 EMBARKED ON A WORLDWIDE TRIAL 4902 03:19:19,082 --> 03:19:23,954 RECRUITING PATIENTS AROUND THE 4903 03:19:23,954 --> 03:19:26,122 WORLD AND WORKING WITH A 4904 03:19:26,122 --> 03:19:28,892 NEUROSURGEON YOU CAN SEE THE 4905 03:19:28,892 --> 03:19:36,333 DELIVERY TO THE THALAMUS WE SEE 4906 03:19:36,333 --> 03:19:40,170 THE INJECTION HERE AND WE'VE 4907 03:19:40,170 --> 03:19:42,606 JUST COMPLETED THE DOSE 4908 03:19:42,606 --> 03:19:43,773 ESCALATION HERE. 4909 03:19:43,773 --> 03:19:49,579 THIS IS BILATERAL INTRATHALAMUS 4910 03:19:49,579 --> 03:19:53,483 AND AS WELL AS INTRATHECAL 4911 03:19:53,483 --> 03:19:57,687 DELIVERY AND WE THOUGHT WE COULD 4912 03:19:57,687 --> 03:19:59,122 HAVE LESS OF AN IMMUNE RESPONSE 4913 03:19:59,122 --> 03:20:02,392 AND WE DO SEE SYSTEMIC LEAKAGE 4914 03:20:02,392 --> 03:20:07,030 AND TOGETHER WE HAVE SEEN 4915 03:20:07,030 --> 03:20:12,736 ELEVATIONS IN LIVER ENZYMES AND 4916 03:20:12,736 --> 03:20:15,038 CORRESPONDS TO SEEING SOME T 4917 03:20:15,038 --> 03:20:16,673 CELL REACTIVITY. 4918 03:20:16,673 --> 03:20:21,711 NEVERTHELESS WE SEE INCREASES IN 4919 03:20:21,711 --> 03:20:25,248 CSF HEX AENZYME ACTIVITY AND 4920 03:20:25,248 --> 03:20:26,783 MEASURE THIS IN PATIENTS WITH 4921 03:20:26,783 --> 03:20:28,551 DETAILS I WON'T GO INTO HERE BUT 4922 03:20:28,551 --> 03:20:33,690 THIS ALSO CORRESPONDS TO THE 4923 03:20:33,690 --> 03:20:35,425 DROP WE HAVE SEEN REDUCING THE 4924 03:20:35,425 --> 03:20:37,861 SUBSTRATE THAT IS USUALLY 4925 03:20:37,861 --> 03:20:41,197 BUILDING UP AND CAUSING THOSE 4926 03:20:41,197 --> 03:20:43,133 INTRUSIONS THAT ARE A PROBLEM. 4927 03:20:43,133 --> 03:20:45,702 SO THIS WAS INITIALLY HOPEFUL 4928 03:20:45,702 --> 03:20:48,672 BUT WE DID SEE SETBACKS IN THE 4929 03:20:48,672 --> 03:20:50,473 JUVENILE COHORT OF OUR TRIAL. 4930 03:20:50,473 --> 03:20:53,977 WE WERE TREATING JUVENILE 4931 03:20:53,977 --> 03:20:57,514 PATIENTS AND THEY OFTEN PRESENT 4932 03:20:57,514 --> 03:21:01,084 WITH MOVEMENT DISORDERS AND THEN 4933 03:21:01,084 --> 03:21:04,154 DYSTONIA AND SEVERAL PATIENTS WE 4934 03:21:04,154 --> 03:21:09,426 SAW WORSENING THEREOF AFTER AAV 4935 03:21:09,426 --> 03:21:10,927 DELIVERY LEADING TO GENERALIZED 4936 03:21:10,927 --> 03:21:15,832 DISTONIA IN -- DYSTONIA AND 4937 03:21:15,832 --> 03:21:18,134 WONDERED WHETHER IT WAS DUE TO 4938 03:21:18,134 --> 03:21:20,804 INJECTION OR SAFETY WAS IMPACT 4939 03:21:20,804 --> 03:21:25,842 AND IN ANALYZING THE MRIs WE 4940 03:21:25,842 --> 03:21:33,850 FOUND THEY ALL HAD SOME EDEMA 4941 03:21:33,850 --> 03:21:37,854 RESOLVED WITH NO LASTING 4942 03:21:37,854 --> 03:21:48,031 REACTION. 4943 03:21:50,433 --> 03:22:00,910 AND WE SEE THE POOR MYELINATION 4944 03:22:06,182 --> 03:22:07,384 AND SEE IT'S INCOMPLETE NOW 4945 03:22:07,384 --> 03:22:11,788 IMPROVED OVER TIME. 4946 03:22:11,788 --> 03:22:13,390 SO STILL EARLY DAYS AND CLINICAL 4947 03:22:13,390 --> 03:22:15,725 READOUTS OF THE TRIAL. 4948 03:22:15,725 --> 03:22:18,762 WE'VE SEEN FROM PATIENTS THAT 4949 03:22:18,762 --> 03:22:21,531 HAVE CONTROL AND EVEN PULLING TO 4950 03:22:21,531 --> 03:22:23,366 STAND IT'S PRESERVED AND THAT IS 4951 03:22:23,366 --> 03:22:26,002 SOMETHING THAT WE WOULD NOT HAVE 4952 03:22:26,002 --> 03:22:27,337 EXPECTED IN THE NATURAL HISTORY 4953 03:22:27,337 --> 03:22:28,671 OF DISEASE. 4954 03:22:28,671 --> 03:22:30,940 SO JUST TO SUMMARIZE HERE WE'VE 4955 03:22:30,940 --> 03:22:34,177 SEEN THAT WE HAVE PROOF OF 4956 03:22:34,177 --> 03:22:37,580 CONCEPT OF ENZYME ACTIVITY 4957 03:22:37,580 --> 03:22:39,048 INCREASED WITHIN THE PATIENTS 4958 03:22:39,048 --> 03:22:42,952 MRI SHOWED EARLY SIGNALS 4959 03:22:42,952 --> 03:22:53,463 IMPROVED MYELINATION AND MADE 4960 03:22:54,697 --> 03:22:57,734 GAINS AND SOME JUVENILE 4961 03:22:57,734 --> 03:22:58,701 EXPERIENCED DYSTONIA AND IS NOT 4962 03:22:58,701 --> 03:23:00,904 THE RIGHT TREATMENT FOR THEM AND 4963 03:23:00,904 --> 03:23:06,342 THE LAST DISORDER I'LL TOUCH ON 4964 03:23:06,342 --> 03:23:14,017 IS X ALD ADRENOLEUKODYSTROPHY 4965 03:23:14,017 --> 03:23:16,453 AND THE SAME GENE, TWO 4966 03:23:16,453 --> 03:23:20,089 APPROACHES I'LL OUTLINE. 4967 03:23:20,089 --> 03:23:21,658 THIS IS A DEVASTATING DISORDER. 4968 03:23:21,658 --> 03:23:24,561 A YOUNG BOY COMES TO ME AND IS 4969 03:23:24,561 --> 03:23:28,698 SIX MONTHS BEFORE HE SEES ME IN 4970 03:23:28,698 --> 03:23:29,098 KARATE CLASS. 4971 03:23:29,098 --> 03:23:32,368 VERY PRECOCIOUS BOY AND THEN 4972 03:23:32,368 --> 03:23:37,207 ONCE AFFECTED HE COULD HARDLY 4973 03:23:37,207 --> 03:23:43,446 WALK AND HAS LOST HIS VISUAL 4974 03:23:43,446 --> 03:23:45,582 CHARACTERISTICS AND DEVASTATING 4975 03:23:45,582 --> 03:23:48,751 DISORDER THAT STRIKES BOYS IN 4976 03:23:48,751 --> 03:23:49,486 THEIR PRIME. 4977 03:23:49,486 --> 03:23:52,722 WE BUILT ON TWO DECADES OF 4978 03:23:52,722 --> 03:23:57,393 EXPERIENCE IN PATIENTS KNOWING 4979 03:23:57,393 --> 03:24:00,029 TREATED EARLY THESE BOYS COULD 4980 03:24:00,029 --> 03:24:01,698 BENEFIT FROM A WELL MATCHED BONE 4981 03:24:01,698 --> 03:24:04,767 MARROW TRANSPLANTATION. 4982 03:24:04,767 --> 03:24:07,670 WE THINK BECAUSE THE MICROGLIAL 4983 03:24:07,670 --> 03:24:09,172 CHANGES AROUND THE END AND WHEN 4984 03:24:09,172 --> 03:24:14,811 YOU BRING IN BONE MARROW DERIVED 4985 03:24:14,811 --> 03:24:17,847 MONOCYTES THEY DIFFERENTIATE TO 4986 03:24:17,847 --> 03:24:19,883 MICROGLIA AND CELLS EXPRESSING 4987 03:24:19,883 --> 03:24:21,217 PROTEIN. 4988 03:24:21,217 --> 03:24:27,023 WE EXPANDED THIS BECAUSE OF THE 4989 03:24:27,023 --> 03:24:29,526 ENGRAFTMENT PROBLEMS AND DECIDED 4990 03:24:29,526 --> 03:24:33,830 TO EMBARK ON THE APPROACH WHERE 4991 03:24:33,830 --> 03:24:35,431 WE HARVESTED BETWEEN THE BOYS 4992 03:24:35,431 --> 03:24:45,675 THEMSELVES AND TRANSVECTED THEM 4993 03:24:45,675 --> 03:24:47,977 AND DELIVERED TRANSITIONING AND 4994 03:24:47,977 --> 03:24:49,345 WATCHED THESE BOYS FOR A 4995 03:24:49,345 --> 03:24:51,014 TWO-YEAR PERIOD. 4996 03:24:51,014 --> 03:24:53,516 JUST TO KEEP IN MIND IT'S 4997 03:24:53,516 --> 03:24:55,018 IDENTICAL TO CONVENTIONAL BONE 4998 03:24:55,018 --> 03:24:58,221 MARROW TRANSPLANTATION AND CELLS 4999 03:24:58,221 --> 03:25:01,858 FROM THE BOYS THEMSELVES BUT NOT 5000 03:25:01,858 --> 03:25:02,659 FROM ALLOGENEIC DONOR. 5001 03:25:02,659 --> 03:25:06,029 I'LL CUT A LONG STORY SHORT HERE 5002 03:25:06,029 --> 03:25:11,034 TO SAY WE DROPPED ALL THE WAY TO 5003 03:25:11,034 --> 03:25:12,735 AN APPROVED FIRST GENE THERAPY 5004 03:25:12,735 --> 03:25:13,236 BY FDA. 5005 03:25:13,236 --> 03:25:13,903 LOTS OF UPS AROUND DOWNS OVER 5006 03:25:13,903 --> 03:25:19,876 THE YEARS. 5007 03:25:19,876 --> 03:25:24,981 SETBACKS THAT OCCURRED BOTH IN 5008 03:25:24,981 --> 03:25:28,084 TERMS OF THE COMMERCIAL PROCESS 5009 03:25:28,084 --> 03:25:32,989 AND THEN ALSO RECENT CASES OF 5010 03:25:32,989 --> 03:25:36,793 THE SYNDROME THAT NEVERTHELESS 5011 03:25:36,793 --> 03:25:39,762 WE GOT UNANIMOUS ADVISORY 5012 03:25:39,762 --> 03:25:42,966 APPROVAL AND STILL IN FAVOR OF 5013 03:25:42,966 --> 03:25:47,036 OUR GENE THERAPY APPROACH FOR 5014 03:25:47,036 --> 03:25:48,037 THESE BOYS. 5015 03:25:48,037 --> 03:25:52,308 I WANT TO HIGHLIGHT MOST OF OUR 5016 03:25:52,308 --> 03:25:59,048 CASES OF MYELODYSPLASTIC THERAPY 5017 03:25:59,048 --> 03:26:00,450 WE ARE WORKING ON HOW TO FIGURE 5018 03:26:00,450 --> 03:26:03,019 THIS OUT IN THE COMMERCIAL 5019 03:26:03,019 --> 03:26:03,386 SPACE. 5020 03:26:03,386 --> 03:26:06,789 WE'RE GOING BACK TO THE REGIMENT 5021 03:26:06,789 --> 03:26:09,659 WE HAD AND THERE MAY BE OTHER 5022 03:26:09,659 --> 03:26:11,461 COMPONENTS WE HAVE TO UNDERSTAND 5023 03:26:11,461 --> 03:26:15,031 AROUND MUTAGENESIS. 5024 03:26:15,031 --> 03:26:22,639 JUST TO HIGHLIGHT HERE 5025 03:26:22,639 --> 03:26:25,775 MICROGLIAL CELL LOSS AND OPEN 5026 03:26:25,775 --> 03:26:26,976 BLOOD BRAIN BARRIER ALLOW GENE 5027 03:26:26,976 --> 03:26:31,881 DELIVERY THROUGH HEMATOPOIETIC 5028 03:26:31,881 --> 03:26:34,651 STEM CELLS AND 94% ACHIEVED 5029 03:26:34,651 --> 03:26:38,388 STABLE NEUROLOGIC FUNCTION BUT 5030 03:26:38,388 --> 03:26:39,322 THERE'S STILL CHALLENGES IN THE 5031 03:26:39,322 --> 03:26:43,893 SYNDROME WE NEED TO FIGURE OUT. 5032 03:26:43,893 --> 03:26:45,561 SO GIST TO BRIEFLY HIGHLIGHT WE 5033 03:26:45,561 --> 03:26:47,664 ARE ALSO TREATING THE SPINAL 5034 03:26:47,664 --> 03:26:48,598 CORD DISEASE. 5035 03:26:48,598 --> 03:26:50,400 I WANT TO JUST EMPHASIZE THIS 5036 03:26:50,400 --> 03:26:53,269 WORK WOULD NOT HAVE BEEN 5037 03:26:53,269 --> 03:26:55,872 POSSIBLE WITHOUT BUILDING ON 5038 03:26:55,872 --> 03:26:57,073 EVERYTHING THAT WAS ACCOMPLISHED 5039 03:26:57,073 --> 03:27:05,882 BY BRIAN KASPAR AND JERRY 5040 03:27:05,882 --> 03:27:16,392 MENDELL AND WE LOOKED AT THE 5041 03:27:18,294 --> 03:27:23,800 ADRENOMYELOPATHY AND PACKAGED IT 5042 03:27:23,800 --> 03:27:31,040 TO A PROMOTER AND I WILL NOT GO 5043 03:27:31,040 --> 03:27:35,044 INTO DETAILS BECAUSE YOU HEARD 5044 03:27:35,044 --> 03:27:35,878 SIMILAR STORIES. 5045 03:27:35,878 --> 03:27:41,250 WE USED INTRATHECAL SOURCES TO 5046 03:27:41,250 --> 03:27:43,853 SLOW DELIVERY TO AVOID AS MUCH 5047 03:27:43,853 --> 03:27:44,887 SYSTEMIC LEAKAGE AS POSSIBLE AND 5048 03:27:44,887 --> 03:27:47,690 SHOW PROOF OF CONCEPT IN OUR ALD 5049 03:27:47,690 --> 03:27:50,293 MOUSE MODEL AND THIS IS 5050 03:27:50,293 --> 03:27:54,530 CURRENTLY IN TRIAL AT U MASS AND 5051 03:27:54,530 --> 03:28:01,938 AMSTERDAM WHERE WE NOW TREAT FOR 5052 03:28:01,938 --> 03:28:02,572 PATIENTS. 5053 03:28:02,572 --> 03:28:06,075 TO SUMMARIZE BRIEFLY, THE 5054 03:28:06,075 --> 03:28:07,543 MESSAGE I'M TRYING TO -- THE 5055 03:28:07,543 --> 03:28:11,280 PICTURE I'M TRYING TO PAINT IS 5056 03:28:11,280 --> 03:28:13,182 EVERY DISEASE MAY REQUIRE 5057 03:28:13,182 --> 03:28:15,017 DIFFERENT GENE THERAPY DEPENDS 5058 03:28:15,017 --> 03:28:19,055 ON WHAT CELL TYPES ARE AFFECTED 5059 03:28:19,055 --> 03:28:22,024 AND WHAT STAGE YOU ARE IN. 5060 03:28:22,024 --> 03:28:23,593 COULD USE AN AAV IN VIVO 5061 03:28:23,593 --> 03:28:25,528 APPROACH TO DIRECTLY TARGET 5062 03:28:25,528 --> 03:28:27,029 CERTAIN CELLS IN THE BRAIN IF 5063 03:28:27,029 --> 03:28:29,599 YOU DON'T WANT TO GO THROUGH 5064 03:28:29,599 --> 03:28:31,167 CONDITIONING AND THE CHE 5065 03:28:31,167 --> 03:28:33,369 CHEMOTHERAPY MAY NOT BE 5066 03:28:33,369 --> 03:28:34,904 TOLERATED IN A MORE FRAGILE 5067 03:28:34,904 --> 03:28:35,338 PATIENT POPULATION. 5068 03:28:35,338 --> 03:28:37,206 ON THE OTHER HAND YOU WANT TO 5069 03:28:37,206 --> 03:28:47,650 GET TO THE MICROGLIA AND 5070 03:28:55,725 --> 03:28:56,826 HEMATOPOINTETIC APPROACH AND 5071 03:28:56,826 --> 03:28:57,894 WE'RE MANAGING TREATMENT 5072 03:28:57,894 --> 03:29:00,463 COMPLICATIONS IS KEY. 5073 03:29:00,463 --> 03:29:02,832 I THINK WE HAVE SEEN TOXICITY 5074 03:29:02,832 --> 03:29:04,000 BUT WE'VE ALSO SEEN TOXICITY AT 5075 03:29:04,000 --> 03:29:07,036 THE SITE OF ENGAGEMENT OF THE 5076 03:29:07,036 --> 03:29:09,438 GENE THERAPY SO I DON'T TAKE 5077 03:29:09,438 --> 03:29:10,239 THIS ALL NEGATIVE. 5078 03:29:10,239 --> 03:29:18,815 I ACTUALLY TAKE THIS AS A SIGN 5079 03:29:18,815 --> 03:29:19,882 THAT WE ARE REACHING THERAPEUTIC 5080 03:29:19,882 --> 03:29:25,855 LEVELS AT THE SAME TIME WE 5081 03:29:25,855 --> 03:29:30,726 MANAGE WHERE KNOWING HOW TO 5082 03:29:30,726 --> 03:29:34,997 MONITOR AND FOLLOW MUTAGENESIS 5083 03:29:34,997 --> 03:29:41,537 AND YOU SEE THE SYNDROME AND 5084 03:29:41,537 --> 03:29:43,039 MIC 5085 03:29:43,039 --> 03:29:49,145 MICROANGIOPATHY AND LIVER 5086 03:29:49,145 --> 03:29:51,047 INFLAMMATION AND WE HAVE A 5087 03:29:51,047 --> 03:29:51,681 FELLOWSHIP AND THIS REQUIRES 5088 03:29:51,681 --> 03:29:54,383 BROAD TRAINING AND NEED A WHOLE 5089 03:29:54,383 --> 03:29:58,421 GENERATION OF INVESTIGATORS 5090 03:29:58,421 --> 03:29:59,722 FAMILIAR WITH THIS. 5091 03:29:59,722 --> 03:30:01,858 NEW GENETIC MEDICINES TO ALLOW 5092 03:30:01,858 --> 03:30:03,893 PRECISE TARGETING OF GENES AND 5093 03:30:03,893 --> 03:30:06,062 ADVERSE EVENTS CAN RESULT FROM 5094 03:30:06,062 --> 03:30:06,963 UNIQUE INTERPLAY OF TECHNOLOGY 5095 03:30:06,963 --> 03:30:07,430 AND DISEASE BIOLOGY. 5096 03:30:07,430 --> 03:30:09,498 I PERSONALLY THINK WE HAVE TO 5097 03:30:09,498 --> 03:30:11,267 MOVE AWAY FROM THINKING ABOUT 5098 03:30:11,267 --> 03:30:16,305 TECHNOLOGY PLATFORMS ALONE AND 5099 03:30:16,305 --> 03:30:20,409 CONSIDER SPECIFIC BIOLOGY IN THE 5100 03:30:20,409 --> 03:30:22,745 CONTEXT OF TECHNOLOGY BEING USED 5101 03:30:22,745 --> 03:30:25,514 WITH EVERY DISEASE DIFFERS AND 5102 03:30:25,514 --> 03:30:27,483 THE DISEASE STAGE IS CRITICAL IN 5103 03:30:27,483 --> 03:30:28,985 DIFFERENT DISEASE STAGES YOU 5104 03:30:28,985 --> 03:30:33,956 MIGHT SEE REALLY A CHANGE IN 5105 03:30:33,956 --> 03:30:35,124 TARGET CELLS AND THE EXPRESSION 5106 03:30:35,124 --> 03:30:41,530 AND THE VULNERABILITY OF THE 5107 03:30:41,530 --> 03:30:42,131 PATIENTS WITH STRATIFICATION. 5108 03:30:42,131 --> 03:30:44,500 WITH THAT I WANT TO ACKNOWLEDGE 5109 03:30:44,500 --> 03:30:46,702 FIRST AND FOREMOST ALL THE 5110 03:30:46,702 --> 03:30:48,070 PATIENTS THAT HAVE BEEN 5111 03:30:48,070 --> 03:30:49,839 COURAGEOUS AND PARTICIPATE IN 5112 03:30:49,839 --> 03:30:52,341 THE EXPERIMENTAL TRIALS WITH 5113 03:30:52,341 --> 03:30:53,609 WHOM WE COULDN'T HAVE DONE THIS. 5114 03:30:53,609 --> 03:30:55,044 THANK YOU AND I'M HAPPY TO 5115 03:30:55,044 --> 03:31:05,354 ANSWER QUESTIONS. 5116 03:31:08,291 --> 03:31:15,031 >> I CAN REPEAT THE QUESTION. 5117 03:31:15,031 --> 03:31:25,207 [OFF-MIC] 5118 03:31:30,546 --> 03:31:32,682 SO JUST TO BE CLEAR THE 5119 03:31:32,682 --> 03:31:35,051 QUESTION WAS TIMING FOR THOSE 5120 03:31:35,051 --> 03:31:37,954 THAT COULDN'T HEAR DO WE WAIT 5121 03:31:37,954 --> 03:31:41,757 UNTIL PATIENTS DEVELOP SYMPTOMS. 5122 03:31:41,757 --> 03:31:43,559 WE HAVE NEVER TREATED BEFORE 5123 03:31:43,559 --> 03:31:44,827 WE'VE SEEN CLEAR EVIDENCE OF 5124 03:31:44,827 --> 03:31:45,828 DISEASE. 5125 03:31:45,828 --> 03:31:47,396 THE ADVANTAGE WE HAVE WITH MRI 5126 03:31:47,396 --> 03:31:50,933 IS THAT WE HAVE THE SURROGATE 5127 03:31:50,933 --> 03:31:52,635 MARKER HERE AND WE KNOW WHEN A 5128 03:31:52,635 --> 03:31:54,270 LESION IS OCCURRING AND WHEN 5129 03:31:54,270 --> 03:31:56,939 THERE IS CONTRAST ENHANCEMENT 5130 03:31:56,939 --> 03:31:57,606 AND A FIRE BURNING. 5131 03:31:57,606 --> 03:31:59,642 SO WE CAN GET TO PATIENTS BEFORE 5132 03:31:59,642 --> 03:32:01,344 THEY HAVE SYMPTOMS BUT KNOWING 5133 03:32:01,344 --> 03:32:03,713 WELL THAT THERE IS ALREADY 5134 03:32:03,713 --> 03:32:04,146 PATHOLOGY EMERGING. 5135 03:32:04,146 --> 03:32:06,349 WE ARE STILL DOING THAT BUT WE 5136 03:32:06,349 --> 03:32:10,286 ARE BEING MORE CAUTIOUS AND 5137 03:32:10,286 --> 03:32:12,288 LOOKING FOR MATCH SIBLING DONORS 5138 03:32:12,288 --> 03:32:14,090 AND WILL BE GOING FOR 5139 03:32:14,090 --> 03:32:17,760 CONVENTIONAL BONE MARROW 5140 03:32:17,760 --> 03:32:19,061 TRANSPLANTATION KNOWING THAT 5141 03:32:19,061 --> 03:32:23,032 THEY MIGHT DO JUST AS WELL WITH 5142 03:32:23,032 --> 03:32:25,868 A 5143 03:32:25,868 --> 03:32:28,037 AN ALGENEIC TRANSPLANT AND 5144 03:32:28,037 --> 03:32:29,071 MAKING SMALL CHANGES AROUND THE 5145 03:32:29,071 --> 03:32:35,678 CONDITIONING REGIMENT. 5146 03:32:35,678 --> 03:32:40,983 WE'RE HOPING IT WILL IMPROVE 5147 03:32:40,983 --> 03:32:51,460 MOVING INTO THE FIRST TRIAL 5148 03:32:52,294 --> 03:32:54,930 ACROSS THE COUNTRY ALL PATIENTS 5149 03:32:54,930 --> 03:32:56,432 GETS MONITORED WITH MRI AND DO 5150 03:32:56,432 --> 03:32:57,933 WE SEE A LESION EMERGE, THAT IS 5151 03:32:57,933 --> 03:33:00,903 THEN THE TRIGGER. 5152 03:33:00,903 --> 03:33:03,706 SO IT'S NOT DIRECTLY FOR NEWBORN 5153 03:33:03,706 --> 03:33:03,973 SCREENING. 5154 03:33:03,973 --> 03:33:06,375 >> THAT'S INTERESTING. 5155 03:33:06,375 --> 03:33:09,445 THE QUESTION I HAD WAS ABOUT 5156 03:33:09,445 --> 03:33:11,580 YOUR CONDITIONING REGIMENT AND 5157 03:33:11,580 --> 03:33:13,883 IS IT DIFFERENT THAN WHAT'S 5158 03:33:13,883 --> 03:33:15,885 BEING USED FROM OTHER GROUPS FOR 5159 03:33:15,885 --> 03:33:18,521 THE MLD PATIENTS. 5160 03:33:18,521 --> 03:33:23,726 ARE YOU SEEING MORE OR LESS 5161 03:33:23,726 --> 03:33:24,026 DYSPLASIA? 5162 03:33:24,026 --> 03:33:30,199 >> SO WE'RE ENVIOUS OF THE MLD 5163 03:33:30,199 --> 03:33:33,035 BECAUSE THEY'VE NOT SEEN 5164 03:33:33,035 --> 03:33:43,913 INSERTIONAL MUTE MO-- MUTAGENE 5165 03:33:44,613 --> 03:33:46,749 AND WHAT WAS TAKEN OVER DECADES 5166 03:33:46,749 --> 03:33:49,652 WILL CHANGE ONLY ONE THING AT A 5167 03:33:49,652 --> 03:33:50,853 TIME KNOWING WE HAVE TO BUILD ON 5168 03:33:50,853 --> 03:33:56,292 THE SAFETY DATA OF THE PAST. 5169 03:33:59,095 --> 03:34:03,599 SO WE TOOK OVER FROM THE FIRST 5170 03:34:03,599 --> 03:34:05,401 EXPERIMENT IN PARIS AND WHERE 5171 03:34:05,401 --> 03:34:11,040 WE'VE SEEN MOST CASES EMERGE. 5172 03:34:11,040 --> 03:34:15,211 WE'RE HOPING THAT WILL BE IT. 5173 03:34:15,211 --> 03:34:18,881 >> HI, HOW ARE YOU. 5174 03:34:18,881 --> 03:34:22,685 I'M FROM CURE EPILEPSY. 5175 03:34:22,685 --> 03:34:29,091 A QUESTION ON YOUR ALG AND AS 5176 03:34:29,091 --> 03:34:34,864 YOU LOOK AT THE SERUM LEVELS FOR 5177 03:34:34,864 --> 03:34:37,867 CSF14 AND DOES THAT HAVE 5178 03:34:37,867 --> 03:34:38,934 CORRELATION WITH YOUR ALD? 5179 03:34:38,934 --> 03:34:49,478 >> SORRY, YOU WERE ASKING ABOUT? 5180 03:34:51,347 --> 03:34:55,217 >> THE MICROGLIAL MYOPATHY. 5181 03:34:55,217 --> 03:34:59,522 >> WE DON'T LOOK AT CSF1R 5182 03:34:59,522 --> 03:35:00,089 SPECIFICALLY. 5183 03:35:00,089 --> 03:35:09,365 I THINK IT'S VERY RELEVANT FOR 5184 03:35:09,365 --> 03:35:10,266 AXONAL STEROIDS. 5185 03:35:10,266 --> 03:35:19,074 I THINK IT WILL BE AN IMPORTANT 5186 03:35:19,074 --> 03:35:26,549 MARKER WE MIGHT LOOK AT THOSE AS 5187 03:35:26,549 --> 03:35:27,049 WELL. 5188 03:35:27,049 --> 03:35:34,123 [APPLAUSE] 5189 03:35:34,123 --> 03:35:38,561 >> WE'LL HAVE A PANEL DISCUSSION 5190 03:35:38,561 --> 03:35:40,930 AT THE END BUT WE HAVE A BREAK 5191 03:35:40,930 --> 03:35:42,798 NOW FOR ALMOST 20 MINUTES SO 5192 03:35:42,798 --> 03:35:45,334 PLEASE COME BACK BY 3:45 AND 5193 03:35:45,334 --> 03:35:49,338 CERTAINLY ENGAGE WITH THE 5194 03:35:49,338 --> 03:35:52,041 SPEAKERS ON THE BREAK AND AFTER THE PANEL DISCUSSION IT'D BE 5195 03:35:52,041 --> 03:35:52,640 GREAT TO HAVE A GROUP DISCUSSION AT THE END. 5196 03:35:54,238 --> 03:35:54,672 >> ALL RIGHT. 5197 03:35:54,672 --> 03:35:57,726 WE'RE GOING TO GET STARTED AGAIN. 5198 03:35:57,726 --> 03:36:00,128 WE'RE PLEASED SESSION 2 WAS ABLE 5199 03:36:00,128 --> 03:36:07,469 TO ATTRACT THIS SESSION AND NEW 5200 03:36:07,469 --> 03:36:10,372 PATHS TO WATERFALL AND LESSONS 5201 03:36:10,372 --> 03:36:12,908 FROM AAV PRODUCT DEVELOPMENT AND 5202 03:36:12,908 --> 03:36:15,143 GENETIC BLINDNESS AND HEMOPHILIA 5203 03:36:15,143 --> 03:36:16,711 AND THANK YOU FOR BEING HERE. 5204 03:36:16,711 --> 03:36:19,181 >> I'M ONLY SORRY ANOTHER 5205 03:36:19,181 --> 03:36:20,015 OBLIGATION KEPT ME FROM BEING 5206 03:36:20,015 --> 03:36:23,552 THIS MORNING BECAUSE I WOULD 5207 03:36:23,552 --> 03:36:25,387 HAVE LEARNED A LOT OF ABOUT 5208 03:36:25,387 --> 03:36:27,556 GENETIC EPILEPSY SUCH AN 5209 03:36:27,556 --> 03:36:37,866 IMPORTANT PROBLEM. 5210 03:36:42,904 --> 03:36:45,974 I'M GOING TO TALK WITH TWO AAV 5211 03:36:45,974 --> 03:36:50,011 PRODUCTS ONE FOR THE CONGENITAL 5212 03:36:50,011 --> 03:36:55,350 FORM OF BLINDNESS AND HEMOPLOID 5213 03:36:55,350 --> 03:36:58,320 B AND FIRST THESE ARE MY 5214 03:36:58,320 --> 03:37:00,722 DISCLOSURES. 5215 03:37:00,722 --> 03:37:03,658 THESE EXEMPLIFY TWO PROBLEMS AND 5216 03:37:03,658 --> 03:37:05,127 MAY BE OF INTEREST TO THE GROUP. 5217 03:37:05,127 --> 03:37:08,363 IN HEMOPHILIA WE HAD A 5218 03:37:08,363 --> 03:37:11,600 SIGNIFICANT ADVERSE EVENT NOT 5219 03:37:11,600 --> 03:37:13,768 PREDICTED BY STUDIES IN MICE, 5220 03:37:13,768 --> 03:37:24,212 RATS, RABBITS, HEMOPHILIC 5221 03:37:26,748 --> 03:37:29,651 ANIMALS AND THE OTHER FOR 5222 03:37:29,651 --> 03:37:32,454 CONGENITAL BLINDNESS THE MAJOR 5223 03:37:32,454 --> 03:37:35,557 HURDLE TURNED OUT TO BE NO 5224 03:37:35,557 --> 03:37:37,325 PHARMACOLOGIC PRODUCTS FOR 5225 03:37:37,325 --> 03:37:38,760 INHERITED RETINAL DISEASE AND NO 5226 03:37:38,760 --> 03:37:39,828 CONSENSUS FOR A PRIMARY END 5227 03:37:39,828 --> 03:37:43,598 POINT AND WE HAD TO DEVELOP ONE 5228 03:37:43,598 --> 03:37:45,367 AND THEN VALIDATE IT AND ADDS 5229 03:37:45,367 --> 03:37:50,639 YOU MAY KNOW IT CAN BE DIFFICULT 5230 03:37:50,639 --> 03:38:01,183 TO GET THE REGULATORY DEVELOPERS 5231 03:38:04,686 --> 03:38:09,558 AND COMPARE THEM AS GENE DRUG 5232 03:38:09,558 --> 03:38:10,425 DELIVERY PROBLEMS AND SHARE 5233 03:38:10,425 --> 03:38:12,327 PROBLEMS I ALWAYS THINK IT'S 5234 03:38:12,327 --> 03:38:14,129 IMPORTANT FOR THE DRUG DEVELOP 5235 03:38:14,129 --> 03:38:14,429 TO CONSULT. 5236 03:38:14,429 --> 03:38:17,966 LET ME START BY TALKING ABOUT 5237 03:38:17,966 --> 03:38:18,333 HEMOPHILIA B. 5238 03:38:18,333 --> 03:38:23,838 I'M A HEMATOLOGIST. 5239 03:38:23,838 --> 03:38:27,075 YOU'LL REMEMBER A KEY REACTION 5240 03:38:27,075 --> 03:38:29,411 IS THE ACTIVATION OF FACTOR 10 5241 03:38:29,411 --> 03:38:33,215 AND THAT TAKES PLACE UNDER THE 5242 03:38:33,215 --> 03:38:36,785 ACTION OF THE ENZYME AND THE 5243 03:38:36,785 --> 03:38:37,185 CO-FACTOR 8. 5244 03:38:37,185 --> 03:38:41,356 BOTH ARE INCLUDED IN THE X 5245 03:38:41,356 --> 03:38:46,161 CHROMOSOME AND SO HEMOPHILIA A 5246 03:38:46,161 --> 03:38:56,705 AND B OR FACTOR 9 DEFICIENCIES 5247 03:38:59,641 --> 03:39:02,577 IN MALES AND THOSE BORN WITH 5248 03:39:02,577 --> 03:39:05,013 THESE LEVELS OF FACTOR A OR 9 5249 03:39:05,013 --> 03:39:09,017 AND WE HAVE DEVELOPED TREATMENTS 5250 03:39:09,017 --> 03:39:12,420 AND FIRST A CLOTTING 5251 03:39:12,420 --> 03:39:15,557 CONCENTRATION AND CLOTTING 5252 03:39:15,557 --> 03:39:19,928 FACTOR CONCENTRATE WHICH INFUSED 5253 03:39:19,928 --> 03:39:20,996 INTRAVENOUSLY AND CAN PREVENT 5254 03:39:20,996 --> 03:39:25,500 AND IN THE LAST FIVE YEARS OR SO 5255 03:39:25,500 --> 03:39:28,637 FOR FACTOR 8 DEFICIENCY AN 5256 03:39:28,637 --> 03:39:31,573 ANTIBODY WAS DEVELOPED BY ROCHE 5257 03:39:31,573 --> 03:39:37,712 AND HOLDS FACTOR 9 AND 10 AND 5258 03:39:37,712 --> 03:39:40,282 SUBINJECTION IS A POSSIBILITY 5259 03:39:40,282 --> 03:39:45,420 WITH PEOPLE WITH HEMOPHILIA A. 5260 03:39:45,420 --> 03:39:49,391 THE WORK WE DID WAS BASED ON THE 5261 03:39:49,391 --> 03:39:52,060 GENE IN THE 1990s AND BEGAN WITH 5262 03:39:52,060 --> 03:39:57,699 A VARIETY OF VECTORS AND THE ONE 5263 03:39:57,699 --> 03:40:00,902 THAT WORKED BEST WAS AAB AND 5264 03:40:00,902 --> 03:40:02,370 STARTED WITH THE HEMOPHILIA B 5265 03:40:02,370 --> 03:40:04,039 MODEL BECAUSE THERE'S SHORTER 5266 03:40:04,039 --> 03:40:05,907 THAN THE FACTOR A GENE AND 5267 03:40:05,907 --> 03:40:10,178 EASILY FIT INTO AN AAV VECTOR. 5268 03:40:10,178 --> 03:40:11,946 WE SHOULD WE COULD INTRODUCE 5269 03:40:11,946 --> 03:40:13,615 THEM BY DIRECT INTRAMUSCULAR 5270 03:40:13,615 --> 03:40:18,420 INJECTION INTO THE MUSCLES OF A 5271 03:40:18,420 --> 03:40:22,157 DOG OR IN TO THE LIVER AND GET 5272 03:40:22,157 --> 03:40:23,658 LONG-TERM EXPRESSION IN THE DOG 5273 03:40:23,658 --> 03:40:25,226 OF CLOTTING FACTOR LEVELS AS YOU 5274 03:40:25,226 --> 03:40:29,464 CAN SEE IN THE BOTTOM FOR 5275 03:40:29,464 --> 03:40:30,398 INTRAMUSCULAR INJECTION WERE 5276 03:40:30,398 --> 03:40:32,701 BARELY ABOVE THE BASELINE WHICH 5277 03:40:32,701 --> 03:40:34,936 WAS NUL BUT STILL 5278 03:40:34,936 --> 03:40:36,438 DISTINGUISHABLE FROM THAT OR 5279 03:40:36,438 --> 03:40:38,873 GOING TO THE LIVER WITH A TEN 5280 03:40:38,873 --> 03:40:44,579 FOLD LOWER DOSE YOU CAN DELIVER. 5281 03:40:44,579 --> 03:40:47,549 WHEN WE GOT READY TO BEGIN THE 5282 03:40:47,549 --> 03:40:49,784 CLINICAL TRIALS THERE WAS NO 5283 03:40:49,784 --> 03:40:53,488 EXPERIENCE GIVING AAV INTRAM 5284 03:40:53,488 --> 03:40:56,157 INTRAMUSCULARLY OR LIVER IN 5285 03:40:56,157 --> 03:40:59,361 HUMANS AND BEGAN WITH THE 5286 03:40:59,361 --> 03:41:00,795 INTRAMUSCULAR INJECTION 5287 03:41:00,795 --> 03:41:02,397 REASONING IF SOMETHING TERRIBLE 5288 03:41:02,397 --> 03:41:05,967 WENT WRONG AND WE INJECTED THE 5289 03:41:05,967 --> 03:41:11,639 VECTOR INTO THE QUADRICEP IF WE 5290 03:41:11,639 --> 03:41:15,276 HAD TO RESECT IT AND REVERSIBLE 5291 03:41:15,276 --> 03:41:19,247 IN THE SENSE GOING TO THE LIVER 5292 03:41:19,247 --> 03:41:19,914 WOULD NOT BE. 5293 03:41:19,914 --> 03:41:22,384 THIS IS OUR WORK AT CHILDREN'S 5294 03:41:22,384 --> 03:41:24,219 HOSPITAL IN PHILADELPHIA WITH 5295 03:41:24,219 --> 03:41:25,854 THE INTRAMUSCULAR INJECTIONS AND 5296 03:41:25,854 --> 03:41:28,323 WHAT YOU SEE IN THE SECOND PANEL 5297 03:41:28,323 --> 03:41:33,862 IS AN IMMUNOHISTO CHEMISTRY FROM 5298 03:41:33,862 --> 03:41:38,032 THE BIOPSY AND IT SHOWS HE'S 5299 03:41:38,032 --> 03:41:40,101 MAKING FACTOR 9 AND TWITCH FIBE 5300 03:41:40,101 --> 03:41:41,536 ARE BETTER THAN FAST TWITCH 5301 03:41:41,536 --> 03:41:42,437 FIBERS AND WHAT YOU SEE IN THE 5302 03:41:42,437 --> 03:41:44,639 PATTERN THERE. 5303 03:41:44,639 --> 03:41:46,708 THE CIRCULATING LEVELS IN HUMANS 5304 03:41:46,708 --> 03:41:53,882 WERE NOT GOOD ENOUGH TO 5305 03:41:53,882 --> 03:41:55,383 AMELIORATE THE DISEASE AND 5306 03:41:55,383 --> 03:41:57,285 THOUGHT WE COULD DO PREFERENTIAL 5307 03:41:57,285 --> 03:41:58,586 ADMINISTRATION IN A PERSON AND 5308 03:41:58,586 --> 03:42:00,955 LETS MOVE ON TO THE LIVER. 5309 03:42:00,955 --> 03:42:02,824 WE DID THE INITIAL INFUSIONS IN 5310 03:42:02,824 --> 03:42:06,161 THE LIVER IN THE INTERVENTIONAL 5311 03:42:06,161 --> 03:42:07,262 RADIOLOGY SUITE THROUGH THE 5312 03:42:07,262 --> 03:42:09,230 HEPATIC ARTERY AND NOW AS YOU 5313 03:42:09,230 --> 03:42:10,231 HEARD FROM SEVERAL SPEAKERS WE 5314 03:42:10,231 --> 03:42:12,233 KNOW IF YOU GIVE IT 5315 03:42:12,233 --> 03:42:12,867 INTRAVENOUSLY MOST WILL GO TO 5316 03:42:12,867 --> 03:42:13,835 THE LIVER. 5317 03:42:13,835 --> 03:42:18,773 WE DIDN'T KNOW THAT THEN. 5318 03:42:18,773 --> 03:42:20,909 BUT ANYWAY, WHEN WE DID THIS WE 5319 03:42:20,909 --> 03:42:22,710 HAD TO START AT A LOW DOSE AND 5320 03:42:22,710 --> 03:42:24,312 NO PREVIOUS EXPERIENCE WITH 5321 03:42:24,312 --> 03:42:26,481 TRANSDUCING TO THE HUMAN LIVER 5322 03:42:26,481 --> 03:42:29,484 WITH AAV BUT BY THE TIME WE GOT 5323 03:42:29,484 --> 03:42:32,020 TO THE DOSE PREDICTED TO BE 5324 03:42:32,020 --> 03:42:36,758 THERAPEUTIC FROM THE STUDY AND 5325 03:42:36,758 --> 03:42:38,760 ANIMAL MODEL WE SAW FACTOR 9 5326 03:42:38,760 --> 03:42:39,994 EXPRESSION AND YOU CAN SEE FOR 5327 03:42:39,994 --> 03:42:43,565 THE FIRST FOUR WEEKS WE WERE 5328 03:42:43,565 --> 03:42:50,839 GETTING LEVELS OF 10 TO 12%. 5329 03:42:50,839 --> 03:42:53,808 HOWEVER, THE LEVELS STARTED TO 5330 03:42:53,808 --> 03:42:55,777 SLOWLY DECLINE AT THE SAME TIME 5331 03:42:55,777 --> 03:43:01,549 HE DELIVERED A RISE IN HIS LIVER 5332 03:43:01,549 --> 03:43:04,619 ENZYM 5333 03:43:04,619 --> 03:43:06,254 ENZYMES SO THE TRIAL WAS PLACED 5334 03:43:06,254 --> 03:43:09,090 ON HOLD AND WERE NOT EAGER TO DO 5335 03:43:09,090 --> 03:43:12,727 THIS IN OTHERS AND THIS IS AFTER 5336 03:43:12,727 --> 03:43:15,563 ONE PATIENT HAD DIED FROM 5337 03:43:15,563 --> 03:43:18,399 INTRODUCTION INTO THE ADENO 5338 03:43:18,399 --> 03:43:20,068 VECTOR AND WANTED TO UNDERSTAND 5339 03:43:20,068 --> 03:43:21,636 BEFORE WE WENT FORWARD. 5340 03:43:21,636 --> 03:43:23,838 THE TIME COURSE DID SUGGEST TO 5341 03:43:23,838 --> 03:43:25,507 US THIS WAS NOT DIRECT TOXICITY 5342 03:43:25,507 --> 03:43:26,040 FROM OUR VECTOR. 5343 03:43:26,040 --> 03:43:31,412 IT TOOK FOUR WEEKS TO DEVELOP 5344 03:43:31,412 --> 03:43:34,749 AND WE THOUGHT THIS MIGHT VERY 5345 03:43:34,749 --> 03:43:37,552 WELL BE IMMUNE RESPONSE TO A 5346 03:43:37,552 --> 03:43:41,623 CAPSID OR A TRANS VECTOR WHICH 5347 03:43:41,623 --> 03:43:43,925 MAY LOOK LIKE A FOREIGN VECTOR 5348 03:43:43,925 --> 03:43:48,997 FOR A PERSON WITH HEMOPHILIA AND 5349 03:43:48,997 --> 03:43:53,434 HAD NO TRANSIENT CAUSE FOR 5350 03:43:53,434 --> 03:43:54,602 RISING LIVER ENZYMES AND AFTER A 5351 03:43:54,602 --> 03:43:56,037 NUMBER OF STUDIES I DONT HAVE 5352 03:43:56,037 --> 03:43:57,872 TIME TO TELL YOU ABOUT WE SPENT 5353 03:43:57,872 --> 03:43:59,541 YEARS WORKING ON THIS THANKS TO 5354 03:43:59,541 --> 03:44:05,246 OUR FUNDING FROM HOWARD HUGHES 5355 03:44:05,246 --> 03:44:08,750 AND THE NIH AND TOOK YEARS AND 5356 03:44:08,750 --> 03:44:11,686 35 PUBLICATIONS AND THE MODEL WE 5357 03:44:11,686 --> 03:44:17,125 CAME UP WITH AND RED CIRCLES ARE 5358 03:44:17,125 --> 03:44:19,561 AAV AND HEPATOCYTES AND SOME OF 5359 03:44:19,561 --> 03:44:22,430 THE VECTOR GOES TO THE NUCLEUS 5360 03:44:22,430 --> 03:44:30,405 AND STARTS MAKING VECTOR 9. 5361 03:44:30,405 --> 03:44:34,542 A LOT REMAINS AND WE KNOW CAPSID 5362 03:44:34,542 --> 03:44:37,278 UNDER GOES PROTEASOMAL 5363 03:44:37,278 --> 03:44:40,949 PROCESSING AND EVENTUALLY GETS 5364 03:44:40,949 --> 03:44:43,117 TRANSMITTED TO THE ENDOPLASMIC 5365 03:44:43,117 --> 03:44:44,986 RETICULUM AND PLACED ON THE 5366 03:44:44,986 --> 03:44:47,555 TRANSDUCED CELL WHERE IT THEN 5367 03:44:47,555 --> 03:44:52,327 MAKES THE HEPATOCYTE TARGET FOR 5368 03:44:52,327 --> 03:44:55,129 CIRCULATING THE CD 8 T CELLS 5369 03:44:55,129 --> 03:44:56,297 BECAUSE IT THINKS IT'S VIRALLY 5370 03:44:56,297 --> 03:44:56,631 INFECTED. 5371 03:44:56,631 --> 03:45:00,034 WE DID A NUMBER OF THINGS. 5372 03:45:00,034 --> 03:45:03,771 WE IDENTIFIED THE PEPTIDE 5373 03:45:03,771 --> 03:45:06,341 COMPLEX WE DOING TYPING ON A 5374 03:45:06,341 --> 03:45:08,376 PATIENT AND THEN USING 5375 03:45:08,376 --> 03:45:10,411 INFORMATICS PROGRAMS TO PREDICT 5376 03:45:10,411 --> 03:45:12,714 WHICH PEPTIDES FROM THE CAPSID 5377 03:45:12,714 --> 03:45:15,750 WERE THE PREFERRED BINDERS TO 5378 03:45:15,750 --> 03:45:17,218 THOSE. 5379 03:45:17,218 --> 03:45:20,855 AND THEN WE USED THAT PENTAMER 5380 03:45:20,855 --> 03:45:23,625 OF THE PEPTIDE AND MOLECULE TO 5381 03:45:23,625 --> 03:45:26,995 ISOLATE A POPULATION OF CAPSID 5382 03:45:26,995 --> 03:45:28,296 SPECIFIC CD 8 T CELLS AND CLONED 5383 03:45:28,296 --> 03:45:32,734 THE T CELL RECEPTOR AND WERE 5384 03:45:32,734 --> 03:45:34,802 ABLE TO SET UP AN IN VITRO 5385 03:45:34,802 --> 03:45:38,806 SYSTEM AND WHAT IT CONVINCED US 5386 03:45:38,806 --> 03:45:40,241 OF WAS THIS WAS A DOSE DEPENDENT 5387 03:45:40,241 --> 03:45:47,081 PHENOMENON. 5388 03:45:47,081 --> 03:45:50,251 WE DIDN'T SEE IT IN THE DOSE 5389 03:45:50,251 --> 03:45:51,419 ESCALATION AND WOULD SOLVE 5390 03:45:51,419 --> 03:45:51,686 PROBLEMS. 5391 03:45:51,686 --> 03:45:53,988 AND SO WE WERE SPENDING A LOT OF 5392 03:45:53,988 --> 03:45:57,925 TIME TRYING TO WORK ON MORE 5393 03:45:57,925 --> 03:45:59,927 LIVER TROPIC CAPSIDS, A STRONGER 5394 03:45:59,927 --> 03:46:03,297 PROMOTER AND SO FORTH BUT THE 5395 03:46:03,297 --> 03:46:03,798 REAL ANSWER FOR US FOR 5396 03:46:03,798 --> 03:46:09,871 HEMOPHILIA CAME FROM WORK DONE 5397 03:46:09,871 --> 03:46:10,905 BY A COLLEGIATE CHILDREN'S 5398 03:46:10,905 --> 03:46:12,273 HOSPITAL HEMATOLOGY AND 5399 03:46:12,273 --> 03:46:14,509 COLLABORATED WITH A GROUP IN 5400 03:46:14,509 --> 03:46:18,246 ITALY TO DESCRIBE A HIGH 5401 03:46:18,246 --> 03:46:20,715 SPECIFIC ACTIVITY FACTOR 9 5402 03:46:20,715 --> 03:46:26,921 VARIANT IN A KINDRED THAT 5403 03:46:26,921 --> 03:46:30,425 PRESENTED WITH COAGULATABILITY 5404 03:46:30,425 --> 03:46:34,495 AND INCREASED THE ENZYME 5405 03:46:34,495 --> 03:46:34,729 TENFOLD. 5406 03:46:34,729 --> 03:46:38,599 WE REMADE OUR VECTORS WITH THIS 5407 03:46:38,599 --> 03:46:40,535 MORE SPECIFIC FACTOR 9. 5408 03:46:40,535 --> 03:46:50,211 WE USED THE BETTER HEPATOTROPIC 5409 03:46:50,211 --> 03:46:51,979 CAPSID AND WERE ABLE TO DROP OUR 5410 03:46:51,979 --> 03:46:53,581 DOSE FOURFOLD FROM THE DOSE 5411 03:46:53,581 --> 03:46:59,287 WHERE WE SAW THE IMMUNE 5412 03:46:59,287 --> 03:47:01,856 RESPONSES BEFORE AND LO AND 5413 03:47:01,856 --> 03:47:05,026 BEHOLD WE GOT A 3-FOLD HIGHER 5414 03:47:05,026 --> 03:47:08,663 CIRCULATING LEVEL OF FACTOR 9 5415 03:47:08,663 --> 03:47:14,368 AND NO PROBLEMS WITH IMMUNE 5416 03:47:14,368 --> 03:47:16,104 RESPONSES. 5417 03:47:16,104 --> 03:47:17,271 IS THAT PATIENT WENT FROM AND 5418 03:47:17,271 --> 03:47:20,975 WERE ABLE TO REPEAT THAT FOR 5419 03:47:20,975 --> 03:47:22,944 MOST OF THE REMAINING 10 5420 03:47:22,944 --> 03:47:23,211 PATIENTS. 5421 03:47:23,211 --> 03:47:24,178 TWO DEVELOPED THE IMMUNE 5422 03:47:24,178 --> 03:47:25,813 RESPONSES BUT THEY WERE EASILY 5423 03:47:25,813 --> 03:47:27,548 AND QUICKLY CONTROLLED WITH THE 5424 03:47:27,548 --> 03:47:29,183 COURSE OF STEROIDS AND YOU HEARD 5425 03:47:29,183 --> 03:47:30,852 THEM TALKING ABOUT FEATURES 5426 03:47:30,852 --> 03:47:32,754 STILL USED TO CONTROL THOSE 5427 03:47:32,754 --> 03:47:37,825 IMMUNE RESPONSES IN THE LIVER. 5428 03:47:37,825 --> 03:47:40,328 SO THE LEVELS OF CIRCULATING 5429 03:47:40,328 --> 03:47:42,163 FACTOR 9 THOSE PEOPLE HAD WERE 5430 03:47:42,163 --> 03:47:45,500 SUFFICIENT TO MARKEDLY REDUCE 5431 03:47:45,500 --> 03:47:46,667 THE FREQUENCY OF BLEEDING ON THE 5432 03:47:46,667 --> 03:47:48,136 LEFT SIDE OF THE CHART YOU SEE 5433 03:47:48,136 --> 03:47:49,937 THE NUMBER OF BLEEDS EACH OF THE 5434 03:47:49,937 --> 03:47:52,974 10 PEOPLE HAD IN THE YEAR BEFORE 5435 03:47:52,974 --> 03:47:55,176 VECTOR INFUSION AND THEN IN A 5436 03:47:55,176 --> 03:47:56,944 YEAR AFTER VECTOR INFUSION ON 5437 03:47:56,944 --> 03:47:57,211 THE RIGHT. 5438 03:47:57,211 --> 03:48:04,452 SO A MARK REDUCTION IN THE USE 5439 03:48:04,452 --> 03:48:05,386 OF FACTOR AS WELL AS REDUCTION 5440 03:48:05,386 --> 03:48:06,187 IN BLEEDING. 5441 03:48:06,187 --> 03:48:09,791 SO 30% LEVELS ARE GREAT AND 5442 03:48:09,791 --> 03:48:14,061 THEIR ADEQUATE TO PREVENT THE 5443 03:48:14,061 --> 03:48:16,130 BLEEDING EVEN IN PEOPLE WHO HAVE 5444 03:48:16,130 --> 03:48:17,799 HAD HEMOPHILIA MANY YEARS. 5445 03:48:17,799 --> 03:48:19,734 THESE PATIENTS WERE ALL ADULTS. 5446 03:48:19,734 --> 03:48:24,338 AS A GENE THERAPY DRUG 5447 03:48:24,338 --> 03:48:25,773 DEVELOPMENT PROBLEM IT STARTED 5448 03:48:25,773 --> 03:48:27,608 WITH A CLEAR PROOF OF CONCEPT IN 5449 03:48:27,608 --> 03:48:29,143 AN ANIMAL MODEL. 5450 03:48:29,143 --> 03:48:29,744 THAT'S IMPORTANT. 5451 03:48:29,744 --> 03:48:31,479 BUT THERE WAS NO CLINICAL 5452 03:48:31,479 --> 03:48:33,414 EXPERIENCE WITH EITHER ROUTES OF 5453 03:48:33,414 --> 03:48:34,115 ADMINISTRATION WE USED EITHER IN 5454 03:48:34,115 --> 03:48:37,652 THE MUSCLE OR LIVER. 5455 03:48:37,652 --> 03:48:39,554 THE CHOICE OF ENDS POINTS WAS 5456 03:48:39,554 --> 03:48:41,489 CLEAR BASED ON 50 YEARS OF DRUG 5457 03:48:41,489 --> 03:48:44,525 DEVELOPMENT FOR HEMOPHILIA AND 5458 03:48:44,525 --> 03:48:46,961 THE TEST ADVANTAGE CLEAR 5459 03:48:46,961 --> 03:48:47,662 QUANTITATIVE END POINTS. 5460 03:48:47,662 --> 03:48:50,064 THE BLEEDING FREQUENCY AND 5461 03:48:50,064 --> 03:48:51,666 CIRCULATING LEVEL OF CLOTTING 5462 03:48:51,666 --> 03:48:52,033 FACTOR. 5463 03:48:52,033 --> 03:48:54,602 HOWEVER, ALL THESE ISSUES 5464 03:48:54,602 --> 03:48:57,371 RELATED TO THE IMMUNE RESPONSE 5465 03:48:57,371 --> 03:48:59,574 TO INTRAVENOUSLY INFUSE AAV HAD 5466 03:48:59,574 --> 03:49:01,809 NOT BEEN PREDICTED BY ANIMAL 5467 03:49:01,809 --> 03:49:02,043 MODELS. 5468 03:49:02,043 --> 03:49:05,313 I THINK THE REASON IS WE'RE ONE 5469 03:49:05,313 --> 03:49:11,686 OF THE FEW SPECIES THAT ARE 5470 03:49:11,686 --> 03:49:15,122 NATURAL HOSTS FOR AAV AND A LOT 5471 03:49:15,122 --> 03:49:18,960 HAS NO DO WITH MEMORY T CELLS. 5472 03:49:18,960 --> 03:49:21,295 WE HAD TO WORK THAT OUT BECAUSE 5473 03:49:21,295 --> 03:49:23,397 THERE WERE NO GOOD ANIMAL MODELS 5474 03:49:23,397 --> 03:49:28,102 FOR IT. 5475 03:49:28,102 --> 03:49:32,740 I'LL MOVE ON TO THE PROBLEMS WE 5476 03:49:32,740 --> 03:49:34,308 HAD WITH LUXTERNA. 5477 03:49:34,308 --> 03:49:39,547 THIS IS AN ULTRA RARE RETINAL 5478 03:49:39,547 --> 03:49:43,117 DYSTROPHY CAUSED BY MUTATIONS BY 5479 03:49:43,117 --> 03:49:51,058 A PROTEIN RPE65 AND NIGHT 5480 03:49:51,058 --> 03:49:53,561 BLINDNESS IS ONE OF THE EARLIEST 5481 03:49:53,561 --> 03:49:54,061 SYMPTOMS. 5482 03:49:54,061 --> 03:49:56,264 SOME CHILDREN ARE BORN WITH 5483 03:49:56,264 --> 03:49:59,567 LITTLE VISION AND THE PARENT 5484 03:49:59,567 --> 03:50:02,003 MAKE THE DIAGNOSIS BECAUSE THEY 5485 03:50:02,003 --> 03:50:05,006 SEE THE CHILD IS NOT TRACKING 5486 03:50:05,006 --> 03:50:07,842 VISUALLY AND THEY ALL HAVE 5487 03:50:07,842 --> 03:50:13,014 SEVERE VISUAL IMPAIRMENT THAT 5488 03:50:13,014 --> 03:50:16,384 CONTINUES TO PROGRESS. 5489 03:50:16,384 --> 03:50:17,985 AND THERE'S NO RETINAL DYSTROPHY 5490 03:50:17,985 --> 03:50:19,553 BEFORE THE GENE WAS DEVELOPED 5491 03:50:19,553 --> 03:50:24,258 BUT THERE WAS AN NATIONALLY 5492 03:50:24,258 --> 03:50:34,168 OCCURRING DOG MODEL. 5493 03:50:34,168 --> 03:50:39,206 AND A COLLEAGUE RESTORED VISION 5494 03:50:39,206 --> 03:50:40,207 IN THE DOG. 5495 03:50:40,207 --> 03:50:50,751 IN YOU SEE THE RETINA WITH THE 5496 03:50:51,619 --> 03:50:53,354 RODS AND CONES INTERMIXED AND 5497 03:50:53,354 --> 03:50:55,623 THIS IS BASICALLY A ROD BASED 5498 03:50:55,623 --> 03:50:58,192 DISEASE BUT UP IN THE TOP THE 5499 03:50:58,192 --> 03:50:59,560 GRAY CELLS ARE THE RETINAL 5500 03:50:59,560 --> 03:51:00,528 PIGMENT EPITHELIAL CELLS. 5501 03:51:00,528 --> 03:51:03,164 THE PHOTO RECEPTORS DO NOT 5502 03:51:03,164 --> 03:51:04,265 COMPLETE ALL THEIR OWN 5503 03:51:04,265 --> 03:51:04,899 METABOLISM. 5504 03:51:04,899 --> 03:51:07,234 THEY'RE SOME OF THE MOST 5505 03:51:07,234 --> 03:51:11,772 METABOLICALLY ACTIVE CELLS IN 5506 03:51:11,772 --> 03:51:21,949 THE BODY. 5507 03:51:22,817 --> 03:51:23,918 INNING BLUE ARE ACTIVITIES IN 5508 03:51:23,918 --> 03:51:25,553 THE PHOTO RECEPTORS AND IN GREEN 5509 03:51:25,553 --> 03:51:28,055 THE ONES THAT TAKE PLACE IN THE 5510 03:51:28,055 --> 03:51:29,357 RETINAL PIGMENT EPITHELIAL 5511 03:51:29,357 --> 03:51:30,157 CELLS. 5512 03:51:30,157 --> 03:51:34,295 THE POINT IS EVENTUALLY WHEN 5513 03:51:34,295 --> 03:51:38,332 LIGHT STARTS YOU CHANGE TO A 5514 03:51:38,332 --> 03:51:40,368 TRANSFORM BUT THEN THE TRANS RET 5515 03:51:40,368 --> 03:51:42,803 NOL HAS TO BE TRANSPORTED BACK 5516 03:51:42,803 --> 03:51:45,706 TO THE RPE CELLS WHERE UNDER THE 5517 03:51:45,706 --> 03:51:55,383 ACTIVITY OF RPE65 THE RETINAL IS 5518 03:51:55,383 --> 03:51:59,687 REGENERATED AND WITHOUT THIS THE 5519 03:51:59,687 --> 03:52:02,990 CYCLE IS BROKEN AND THE ANATOMY 5520 03:52:02,990 --> 03:52:05,192 IS PRESERVED FOR A RELATIVELY 5521 03:52:05,192 --> 03:52:07,328 LONG TIME THOUGH THE BIO 5522 03:52:07,328 --> 03:52:09,130 CHEMISTRY IS BROKEN FROM THE 5523 03:52:09,130 --> 03:52:11,332 OUTSET AND WHAT GIVES US THE 5524 03:52:11,332 --> 03:52:15,569 OPPORTUNITY TO CORRECT THE 5525 03:52:15,569 --> 03:52:18,239 GENETIC DEFECT BECAUSE THE 5526 03:52:18,239 --> 03:52:19,373 ANATOMY IS STILL THERE AND IN 5527 03:52:19,373 --> 03:52:20,207 FACT. 5528 03:52:20,207 --> 03:52:23,544 THIS IS THE TOTAL PROGRAM TO GO 5529 03:52:23,544 --> 03:52:25,079 THROUGH IT QUICKLY. 5530 03:52:25,079 --> 03:52:26,881 THE FIRST WITH A STUDY IN THE 5531 03:52:26,881 --> 03:52:33,254 WORSE OF THE TWO EYES OF 5532 03:52:33,254 --> 03:52:35,489 AFFECTED INDIVIDUALS. 5533 03:52:35,489 --> 03:52:36,891 THE ORANGE BLOCK. 5534 03:52:36,891 --> 03:52:38,492 ALL DOSES WERE SAFE AND IT HIT 5535 03:52:38,492 --> 03:52:39,660 COVERS MORE OF THE RETINA. 5536 03:52:39,660 --> 03:52:41,362 IT HAD A LARGER VOLUME AND 5537 03:52:41,362 --> 03:52:43,597 DECIDED WE'D TAKE THAT FORWARD 5538 03:52:43,597 --> 03:52:45,800 INTO PHASE III. 5539 03:52:45,800 --> 03:52:47,468 HOWEVER, BEFORE WE STARTED PHASE 5540 03:52:47,468 --> 03:52:51,539 III WE HAD TO DO A SECOND PHASE 5541 03:52:51,539 --> 03:52:57,144 I STUDY WHERE WE INJECT WILL THE 5542 03:52:57,144 --> 03:52:58,946 CONTRALATERAL EYE WITH THE DOSE 5543 03:52:58,946 --> 03:53:00,948 INTENDED FOR PHASE III TO SHOW 5544 03:53:00,948 --> 03:53:04,051 IT WOULD BE SAFE AND WON'T HAVE 5545 03:53:04,051 --> 03:53:05,553 AN IMMUNE RESPONSE AND HAVE ONE 5546 03:53:05,553 --> 03:53:06,454 EYE INJECTED AND THEN THE OTHER 5547 03:53:06,454 --> 03:53:07,354 EYE INJECTED. 5548 03:53:07,354 --> 03:53:11,292 IT WAS ALL SAFE AND WE WERE ABLE 5549 03:53:11,292 --> 03:53:13,194 TO START PHASE III. 5550 03:53:13,194 --> 03:53:15,396 I'LL SAY A LITTLE BIT ABOUT THE 5551 03:53:15,396 --> 03:53:18,065 PHASE 3 TRIAL DESIGN AND ENDED 5552 03:53:18,065 --> 03:53:20,568 UP USING RANDOMIZED CONTROL 5553 03:53:20,568 --> 03:53:22,369 CROSSOVER DESIGN, OPEN LABEL. 5554 03:53:22,369 --> 03:53:24,438 WE ENROLLED CHILDREN AS WELL AS 5555 03:53:24,438 --> 03:53:28,843 ADULTS IN ALL OF THESE STUDIES, 5556 03:53:28,843 --> 03:53:31,545 PHASE I AND PHASE III. 5557 03:53:31,545 --> 03:53:33,180 I MENTIONED BEFORE BECAUSE THERE 5558 03:53:33,180 --> 03:53:35,149 WAS NO TREATMENT FOR THIS 5559 03:53:35,149 --> 03:53:37,518 DISEASE, WE HAD TO DEVELOP AND 5560 03:53:37,518 --> 03:53:38,686 VALIDATE A NOVEL END POINT. 5561 03:53:38,686 --> 03:53:41,622 THAT'S ON THE RIGHT THERE. 5562 03:53:41,622 --> 03:53:44,925 THE MULTI-LUMINOUS MOBILITY TEST 5563 03:53:44,925 --> 03:53:46,227 VALIDATION STUDY DONE IN OTHER 5564 03:53:46,227 --> 03:53:48,429 INDIVIDUALS WITH NORMAL VISION 5565 03:53:48,429 --> 03:53:51,031 OR WITHIN INHERITED RETINAL 5566 03:53:51,031 --> 03:53:53,634 DYSTROPHY AND I'LL SAY A LITTLE 5567 03:53:53,634 --> 03:53:55,169 BIT ABOUT THAT AND THE NATURAL 5568 03:53:55,169 --> 03:53:57,004 HISTORY DATA IN THE DISEASE WERE 5569 03:53:57,004 --> 03:53:57,204 SCANT. 5570 03:53:57,204 --> 03:54:00,341 THEY WERE MOSTLY SINGLE 5571 03:54:00,341 --> 03:54:01,642 INSTITUTION CASE REPORTS AND SO 5572 03:54:01,642 --> 03:54:03,210 AS PART OF THE CLINICAL 5573 03:54:03,210 --> 03:54:05,112 DEVELOPMENT PROGRAM WE CARRIED 5574 03:54:05,112 --> 03:54:06,780 OUT THE LARGEST NATURAL HISTORY 5575 03:54:06,780 --> 03:54:08,082 STUDY ON THIS THOUGH WE DID NOT 5576 03:54:08,082 --> 03:54:11,585 HAVE THE DATA WHEN WE STARTED 5577 03:54:11,585 --> 03:54:13,254 PHASE 3. 5578 03:54:13,254 --> 03:54:15,556 -- PHASE III. 5579 03:54:15,556 --> 03:54:16,624 WE WERE CARRYING IT OUT 5580 03:54:16,624 --> 03:54:17,791 SIMULTANEOUSLY AND I WON'T TALK 5581 03:54:17,791 --> 03:54:19,326 ABOUT THE MOST DIFFICULT PART OF 5582 03:54:19,326 --> 03:54:20,528 ALL THIS. 5583 03:54:20,528 --> 03:54:22,663 ANYWAY THE PRIMARY END POINT WAS 5584 03:54:22,663 --> 03:54:23,197 A MOBILITY TEST. 5585 03:54:23,197 --> 03:54:25,866 ALL THE REGULATORS ONLY BOTH 5586 03:54:25,866 --> 03:54:28,769 SIDES OF THE ATLANTIC WERE 5587 03:54:28,769 --> 03:54:29,470 NEE 5588 03:54:29,470 --> 03:54:32,006 NEEDED FOR THE PRIMARY END POINT 5589 03:54:32,006 --> 03:54:33,374 NOT A MEASURE OF VISUAL FUNCTION 5590 03:54:33,374 --> 03:54:34,708 BUT FUNCTIONAL VISION. 5591 03:54:34,708 --> 03:54:38,212 WHAT IS A VISUALLY DEPENDENT 5592 03:54:38,212 --> 03:54:39,547 ACTIVITY OF DAILY LIVING THE 5593 03:54:39,547 --> 03:54:41,081 PERSON COULDN'T DO BEFORE THIS 5594 03:54:41,081 --> 03:54:43,417 AND WAS ABLE TO DO AFTER THE 5595 03:54:43,417 --> 03:54:43,717 TREATMENT. 5596 03:54:43,717 --> 03:54:45,753 THAT WAS THE END POINT THEY WERE 5597 03:54:45,753 --> 03:54:46,453 LOOKING FOR. 5598 03:54:46,453 --> 03:54:48,455 AND IF YOU TAKE ABOUT VISUALLY 5599 03:54:48,455 --> 03:54:50,124 DEPENDENT ACTIVITIES OF DAILY 5600 03:54:50,124 --> 03:54:52,560 LIVING THAT WOULD BE RESTORED IN 5601 03:54:52,560 --> 03:54:54,795 THIS SITUATION IT COULD BE THE 5602 03:54:54,795 --> 03:54:57,398 ABILITY TO READ, IT COULD BE THE 5603 03:54:57,398 --> 03:54:59,266 ABILITY TO NAVIGATE. 5604 03:54:59,266 --> 03:55:00,434 BECAUSE WE WERE ENROLLING 5605 03:55:00,434 --> 03:55:03,537 CHILDREN TOO WE WANTED TO USE 5606 03:55:03,537 --> 03:55:05,072 SOMETHING THAT YOU COULD DO EVEN 5607 03:55:05,072 --> 03:55:07,107 IF YOU COULDN'T READ AND SO WE 5608 03:55:07,107 --> 03:55:09,076 DID FALL BACK ON A MOBILITY TEST 5609 03:55:09,076 --> 03:55:14,014 AND THE STRUCTURE OF THIS TEST 5610 03:55:14,014 --> 03:55:17,117 IS SHOWN HERE BASICALLY THE 5611 03:55:17,117 --> 03:55:19,553 MOBILITY TEST THAT WE USE IS A 5612 03:55:19,553 --> 03:55:22,323 SERIES OF ARROWS SILK SCREENED 5613 03:55:22,323 --> 03:55:25,826 ON TO A MAT AND INTRASPERSED 5614 03:55:25,826 --> 03:55:27,394 AMONG THOSE ARE OPTICAL THE 5615 03:55:27,394 --> 03:55:30,464 PATIENT IS INSTRUCTED TO AVOID. 5616 03:55:30,464 --> 03:55:32,533 WE CARRIED THIS OUT AT SEVEN 5617 03:55:32,533 --> 03:55:35,769 DIFFERENT LIGHT LEVELS RANGING 5618 03:55:35,769 --> 03:55:40,274 FROM THE VERY BRIGHT LEVEL OF AN 5619 03:55:40,274 --> 03:55:44,578 OFFICE TO THE VERY DIM LEVEL OF 5620 03:55:44,578 --> 03:55:49,216 A NIGHT LIGHT AND THERE WERE 5621 03:55:49,216 --> 03:55:53,554 STEPS IN BETWEEN THOSE. 5622 03:55:53,554 --> 03:55:56,523 THE WAY IT WAS USED AT THE 5623 03:55:56,523 --> 03:55:58,792 BASELINE IT WAS DETERMINED THE 5624 03:55:58,792 --> 03:56:00,628 LOWEST LIGHT FOR THE PATIENT AND 5625 03:56:00,628 --> 03:56:04,031 EXECUTE THE COURSE WITHIN THE 5626 03:56:04,031 --> 03:56:06,467 DEFINED TIME PERIOD AND WITHIN 5627 03:56:06,467 --> 03:56:08,168 MAKING ONLY A CERTAIN NUMBER OF 5628 03:56:08,168 --> 03:56:10,304 ERRORS AND I CAN'T MAKE MORE 5629 03:56:10,304 --> 03:56:12,473 ERRORS THAN THAT BY COLLIDING 5630 03:56:12,473 --> 03:56:14,141 WITH OBSTACLES BECAUSE THEY'LL 5631 03:56:14,141 --> 03:56:14,408 FAIL. 5632 03:56:14,408 --> 03:56:17,177 AND THEN YOU DO THE 5633 03:56:17,177 --> 03:56:18,746 INTERVENTION, WHICH IN THIS CASE 5634 03:56:18,746 --> 03:56:20,414 WAS BOTH EYES BEING INJECTED AND 5635 03:56:20,414 --> 03:56:22,716 THEN AT THE END OF ONE YEAR YOU 5636 03:56:22,716 --> 03:56:24,785 COMPARE THE PEOPLE WHO GOT THE 5637 03:56:24,785 --> 03:56:27,087 INTERVENTION TO A CONTROL GROUP 5638 03:56:27,087 --> 03:56:28,756 WHO MET ALL THE ELIGIBLE 5639 03:56:28,756 --> 03:56:30,291 CRITERIA BUT DID NOT GET 5640 03:56:30,291 --> 03:56:32,960 INJECTIONS AND THEN THAT'S THE 5641 03:56:32,960 --> 03:56:33,360 PRIMARY END POINT. 5642 03:56:33,360 --> 03:56:35,462 THE DIFFERENCE AND THE ABILITY 5643 03:56:35,462 --> 03:56:36,463 AT THE BASELINE VERSUS THE 5644 03:56:36,463 --> 03:56:40,934 INTERVENTION AT ONE YEAR. 5645 03:56:40,934 --> 03:56:43,170 SO WE DEVELOPED THE END POINT IN 5646 03:56:43,170 --> 03:56:44,605 DIALOGUE WITH THE FDA AND THEY 5647 03:56:44,605 --> 03:56:46,907 MADE A NUMBER OF SUGGESTIONS 5648 03:56:46,907 --> 03:56:48,976 THAT MADE IT MORE DIFFICULT TO 5649 03:56:48,976 --> 03:56:51,412 DO BUT MORE RIGOROUS AND 5650 03:56:51,412 --> 03:56:53,547 CONVINCING AND FOR THAT I THANK 5651 03:56:53,547 --> 03:56:54,848 THEM. 5652 03:56:54,848 --> 03:56:59,353 SO ONE OF THESE WAS WE HAD 12 5653 03:56:59,353 --> 03:57:01,255 COURSES IN RANDOM ORDER. 5654 03:57:01,255 --> 03:57:04,258 AND WE WERE ALREADY TESTING EACH 5655 03:57:04,258 --> 03:57:08,195 INDIVIDUALLY AND THE BILATERAL 5656 03:57:08,195 --> 03:57:08,595 TESTING CONDITION. 5657 03:57:08,595 --> 03:57:10,597 EVERYWHERE ONE OF THE COURSE WAS 5658 03:57:10,597 --> 03:57:14,001 VIDEO TAPED AND THE VIDEOTAPES 5659 03:57:14,001 --> 03:57:17,371 WERE SENT UP SHUFFLED ORDER TO 5660 03:57:17,371 --> 03:57:19,707 AN INDEPENDENT READING CENTER 5661 03:57:19,707 --> 03:57:22,376 WHO GRADED FOR TIME AND ERRORS 5662 03:57:22,376 --> 03:57:23,444 BASED ON A DETAILED RUBRIC WE 5663 03:57:23,444 --> 03:57:29,717 HAD GIVEN THEM. 5664 03:57:29,717 --> 03:57:32,453 THE PHASE III TRIAL DESIGN WAS 5665 03:57:32,453 --> 03:57:33,587 AS FOLLOWS. 5666 03:57:33,587 --> 03:57:36,190 WE COULDN'T USE NATURAL HISTORY 5667 03:57:36,190 --> 03:57:36,457 DATA. 5668 03:57:36,457 --> 03:57:37,991 IT WASN'T ENOUGH. 5669 03:57:37,991 --> 03:57:40,094 IT WASN'T ROBUST ENOUGH SO WE 5670 03:57:40,094 --> 03:57:40,694 COULDN'T DO THAT. 5671 03:57:40,694 --> 03:57:42,463 THE PERFECT SCIENTIFIC CONTROL 5672 03:57:42,463 --> 03:57:45,632 IS TO INJECT ONE EYE, LEAVE THE 5673 03:57:45,632 --> 03:57:47,167 OTHER ONE UNINJECTED AND COMPARE 5674 03:57:47,167 --> 03:57:55,542 THE TWO PERFORMSANCE AND HAS TH 5675 03:57:55,542 --> 03:57:57,945 SAME MUTATION AND DETERIORATION 5676 03:57:57,945 --> 03:58:00,180 BUT THE FDA POINTED OUT NO ONE 5677 03:58:00,180 --> 03:58:02,149 WOULD USE THE PRODUCT THAT WAY 5678 03:58:02,149 --> 03:58:03,951 AND WOULDN'T LET US DO IT THAT 5679 03:58:03,951 --> 03:58:06,887 WAY AND INSTEAD ENDED UP IN A 5680 03:58:06,887 --> 03:58:11,592 RANDOMIZED COSOVER DESIGN. 5681 03:58:11,592 --> 03:58:17,131 IT WAS OPEN LABEL SO PEOPLE WHO 5682 03:58:17,131 --> 03:58:19,199 MET THE ELIGIBILITY CRITERIA 5683 03:58:19,199 --> 03:58:20,467 WERE RANDOMIZED 2-1 TO EITHER 5684 03:58:20,467 --> 03:58:21,502 THE INTERVENTION GROUP TO GET 5685 03:58:21,502 --> 03:58:23,904 ONE EYE INJECTED AND A WEEK 5686 03:58:23,904 --> 03:58:27,207 LATER THE OTHER EYE INJECTED OR 5687 03:58:27,207 --> 03:58:29,376 TO THE CONTROL GROUP AND AFTER 5688 03:58:29,376 --> 03:58:32,679 TESTING AT BASELINE ASSESSED AT 5689 03:58:32,679 --> 03:58:37,818 30 DAYS, 90 DAYS, 165 DAYS AND 5690 03:58:37,818 --> 03:58:48,295 OTHER VISUAL FUNCTION 2E69S. 5691 03:58:49,696 --> 03:58:51,565 THE TEST WE HAD TO DO WAS 5692 03:58:51,565 --> 03:58:52,366 OUTLINED HERE. 5693 03:58:52,366 --> 03:58:55,569 PEOPLE CAME IN AND HAD THEIR 5694 03:58:55,569 --> 03:58:56,603 VISUAL ACUITY AND FUNCTION 5695 03:58:56,603 --> 03:59:00,841 MEASURED AND EXECUTED THE COURSE 5696 03:59:00,841 --> 03:59:02,709 TWICE ONE MONTH APART AND GAVE 5697 03:59:02,709 --> 03:59:04,411 US THE RELIABILITY DATA AND DID 5698 03:59:04,411 --> 03:59:06,447 THEY HAVE REPRODUCIBLE SCORES 5699 03:59:06,447 --> 03:59:07,748 AND THEN DID IT ONE YEAR LATER. 5700 03:59:07,748 --> 03:59:09,616 WE LEARNED SOMETHING VERY 5701 03:59:09,616 --> 03:59:09,883 IMPORTANT. 5702 03:59:09,883 --> 03:59:12,286 WE WERE DOING THIS ACTUALLY 5703 03:59:12,286 --> 03:59:15,322 WHILE WE WERE DOING PHASE III OF 5704 03:59:15,322 --> 03:59:20,994 THE INHERITED RETINAL DISEASE 5705 03:59:20,994 --> 03:59:22,296 SUBJECTS 28% GOT WORSE OVER THE 5706 03:59:22,296 --> 03:59:23,363 COURSE OF ONE YEAR. 5707 03:59:23,363 --> 03:59:24,198 WHY IS THAT IMPORTANT? 5708 03:59:24,198 --> 03:59:29,803 WHEN WE PROPOSED OUR TRIAL 5709 03:59:29,803 --> 03:59:36,610 DESIGN TO THE FDA AND WE ASKED 5710 03:59:36,610 --> 03:59:39,546 TO DO THE CROSSOVER AND SAID WE 5711 03:59:39,546 --> 03:59:41,682 NEEDED A YEAR IF WE WERE ABLE TO 5712 03:59:41,682 --> 03:59:43,717 SHOW THE CHANGE LEVELS IN NORMAL 5713 03:59:43,717 --> 03:59:45,352 PEOPLE WERE ZERO AND THEY COULD 5714 03:59:45,352 --> 03:59:47,554 PAST AT THE LOWEST LEVEL AND 5715 03:59:47,554 --> 03:59:49,256 THEN A YEAR LATER COULD PASS AT 5716 03:59:49,256 --> 03:59:54,461 THE SAME AND THOSE IN BLUE FIVE 5717 03:59:54,461 --> 03:59:58,565 GOT WORSE IN ONE YEAR AND TWO 5718 03:59:58,565 --> 04:00:00,767 GOT WORSE AND IF WE HAD THE DATA 5719 04:00:00,767 --> 04:00:03,370 IT WOULD HELP US CROSS OVER MORE 5720 04:00:03,370 --> 04:00:05,372 QUICKLY BUT DID SHOW THE TEST 5721 04:00:05,372 --> 04:00:06,440 COULD TRACK PERFORMANCE IN 5722 04:00:06,440 --> 04:00:12,546 PEOPLE WITH AN INHERITED RETINAL 5723 04:00:12,546 --> 04:00:14,414 DYSTROPHY OVER TIME. 5724 04:00:14,414 --> 04:00:15,616 AS I SAID THE GROUPS WERE 5725 04:00:15,616 --> 04:00:20,821 STRATIFIED FOR PERFORMANCE AT 5726 04:00:20,821 --> 04:00:28,495 THE BASELINE AND THE PEOPLE 5727 04:00:28,495 --> 04:00:31,532 WOULD GOT THE INTERVENTION 5728 04:00:31,532 --> 04:00:32,299 IMPROVED BY SEVERAL HEIGHT LEVEL 5729 04:00:32,299 --> 04:00:34,201 WHEREAS THE PEOPLE IN THE 5730 04:00:34,201 --> 04:00:38,138 CONTROL GROUP MAY BE APPROVED A 5731 04:00:38,138 --> 04:00:40,274 LITTLE BIT MAYBE HAD LEARNING 5732 04:00:40,274 --> 04:00:40,774 EFFECT BUT DIDN'T IMPROVE MY 5733 04:00:42,509 --> 04:00:43,844 MUCH AND MOST WERE ABLE TO 5734 04:00:43,844 --> 04:00:45,379 CROSSOVER AT THE END OF THE YEAR 5735 04:00:45,379 --> 04:00:47,247 AND RECAPITULATED THE DATA FROM 5736 04:00:47,247 --> 04:00:51,151 THE ORIGINAL INTERVENTION GROUP 5737 04:00:51,151 --> 04:00:51,552 AND ALL IMPROVED. 5738 04:00:51,552 --> 04:00:53,687 I'LL JUST SAY -- I'M OVER TIME. 5739 04:00:53,687 --> 04:00:58,792 WE DID HAVE OVER 4,000 VID 5740 04:00:58,792 --> 04:01:01,929 VIDEOTAPES BY THE TIME THE 5741 04:01:01,929 --> 04:01:03,430 PROGRAM WAS DONE THOUGH THERE 5742 04:01:03,430 --> 04:01:05,265 WERE ONLY 43 PATIENTS IN THE 5743 04:01:05,265 --> 04:01:07,000 PHASE III STUDY. 5744 04:01:07,000 --> 04:01:10,003 THE FDA CONTINUOUSLY EMPHASIZED 5745 04:01:10,003 --> 04:01:12,439 WE NEEDED TO EXPLAIN THE 5746 04:01:12,439 --> 04:01:13,473 MEANINGFULNESS ON IMPROVING ON 5747 04:01:13,473 --> 04:01:14,207 THE NOVEL END POINT. 5748 04:01:14,207 --> 04:01:16,510 WE CONTENDED THAT IF YOU 5749 04:01:16,510 --> 04:01:18,145 IMPROVED BY ONE LIGHT LEVEL IT 5750 04:01:18,145 --> 04:01:19,179 WOULD MAKE A DIFFERENCE. 5751 04:01:19,179 --> 04:01:21,381 THE FDA WANTED TO SEE AT LEAST 5752 04:01:21,381 --> 04:01:24,084 TWO LIGHT LEVELS AND AS I SHOWED 5753 04:01:24,084 --> 04:01:26,219 YOU FORTUNATELY THE AVERAGE 5754 04:01:26,219 --> 04:01:27,988 IMPROVEMENT WAS TO LIGHT LEVELS. 5755 04:01:27,988 --> 04:01:30,691 NOTE THIS TEST HAS A CEILING 5756 04:01:30,691 --> 04:01:30,991 EFFECT. 5757 04:01:30,991 --> 04:01:35,262 YOU CAN'T GET BETTER THAN ONE 5758 04:01:35,262 --> 04:01:36,997 LOOK AND IF YOU ANSWER AS MANY 5759 04:01:36,997 --> 04:01:38,899 AS THE CHILDREN DID ABLE TO PASS 5760 04:01:38,899 --> 04:01:42,536 AT 10 AND 4 IF THEY ENTERED AT 4 5761 04:01:42,536 --> 04:01:43,570 LUX WE'D ONLY SEE ONE LIGHT 5762 04:01:43,570 --> 04:01:53,880 LEVEL IMPROVEMENT. 5763 04:01:56,149 --> 04:01:59,553 OKAY IF WE COMPARE THEM THE 5764 04:01:59,553 --> 04:02:00,787 UNDERLYING PATHOPHYSIOLOGY WAS 5765 04:02:00,787 --> 04:02:02,923 EXQUISITELY WELL UNDERSTOOD. 5766 04:02:02,923 --> 04:02:05,292 WE HAD PROOF OF CONCEPT IN A 5767 04:02:05,292 --> 04:02:08,095 LARGE ANIMAL MODEL AND I THINK 5768 04:02:08,095 --> 04:02:08,795 THAT'S IMPORTANT. 5769 04:02:08,795 --> 04:02:11,231 THESE ARE OUTBRED STRENGTHS OF 5770 04:02:11,231 --> 04:02:15,469 ANIMALS NOT INBRED MICE. 5771 04:02:15,469 --> 04:02:16,903 FOR BOTH THERE WAS EITHER ZERO 5772 04:02:16,903 --> 04:02:18,472 EXPERIENCE WITH THAT ROUTE OF 5773 04:02:18,472 --> 04:02:19,539 ADMINISTRATION OF AAV OR IN THE 5774 04:02:19,539 --> 04:02:21,241 CASE OF SUBRETINAL 5775 04:02:21,241 --> 04:02:22,909 ADMINISTRATION ONE ADULT IN THE 5776 04:02:22,909 --> 04:02:26,046 U.K. WHEN WE STARTED THIS WORK. 5777 04:02:26,046 --> 04:02:32,653 AFTER THAT THEY DIVERGED 5778 04:02:32,653 --> 04:02:36,123 PROBLEMS FOR THE CHOICE OF END 5779 04:02:36,123 --> 04:02:43,563 POINTS WAS CLEAR FOR HEMOPHILIA 5780 04:02:43,563 --> 04:02:45,666 AND HAD TO BE IN THE 5781 04:02:45,666 --> 04:02:47,100 IMMUNOTHERAPY AND RESPONSES WERE 5782 04:02:47,100 --> 04:02:50,470 NOT PREDICTED WITH SYSTEMIC 5783 04:02:50,470 --> 04:02:52,673 ADMINISTRATION OF AAV BUT WITH 5784 04:02:52,673 --> 04:02:55,175 INHERITED RETINAL DYSTROPHY AND 5785 04:02:55,175 --> 04:02:58,011 GO IN WITH A SMALL DOSE IN A 5786 04:02:58,011 --> 04:03:00,447 PRIVILEGED SITE YOU GET A FREE 5787 04:03:00,447 --> 04:03:02,716 PASS AS LONG AS YOU DON'T GO TOO 5788 04:03:02,716 --> 04:03:03,884 HIGH ON THE DOSE. 5789 04:03:03,884 --> 04:03:04,284 OKAY. 5790 04:03:04,284 --> 04:03:07,554 I THINK I'M GOING TO HAVE TO 5791 04:03:07,554 --> 04:03:09,423 CONCLUDE HERE BY ACKNOWLEDGING 5792 04:03:09,423 --> 04:03:11,391 THE MANY PEOPLE BECAUSE I'M OVER 5793 04:03:11,391 --> 04:03:11,591 TIME. 5794 04:03:11,591 --> 04:03:13,927 THE MANY PEOPLE WHO WERE 5795 04:03:13,927 --> 04:03:15,929 INVOLVED BOTH IN THE HEMOPHILIA 5796 04:03:15,929 --> 04:03:22,002 B STUDY DONE AT CHOP AND THEN 5797 04:03:22,002 --> 04:03:25,872 PFIZER AND IN THE TRIAL STUDIES 5798 04:03:25,872 --> 04:03:29,776 DONE AT CHOC AND UNIVERSITY OF 5799 04:03:29,776 --> 04:03:31,078 IOWA AND SPARTAN. 5800 04:03:31,078 --> 04:03:32,079 THANK YOU FOR YOUR ATTENTION. 5801 04:03:32,079 --> 04:03:42,589 I'M SORRY FOR GOING OVER TIME. 5802 04:04:04,244 --> 04:04:12,452 >> THAT WAS A LOT OF WORK. 5803 04:04:12,452 --> 04:04:14,087 MY QUESTION IS IN TERMS OF WHAT 5804 04:04:14,087 --> 04:04:15,322 YOU KNOW ABOUT THE IMMUNE 5805 04:04:15,322 --> 04:04:16,523 RESPONSE IN AAV AND WHAT YOU 5806 04:04:16,523 --> 04:04:18,125 LEARNED DO YOU THINK IT'S FEW 5807 04:04:18,125 --> 04:04:24,197 TILE TO THINK ABOUT REDOSING? 5808 04:04:24,197 --> 04:04:33,707 >> NO, I DON'T THINK IT'S FUTILE 5809 04:04:33,707 --> 04:04:36,042 TO THINK RE-DOSING. 5810 04:04:36,042 --> 04:04:39,446 WE HAVE SUCCESSFULLY RE-DOSED 5811 04:04:39,446 --> 04:04:40,614 UNNON-HUMAN PRIMATES. 5812 04:04:40,614 --> 04:04:42,482 THAT'S A POSSIBILITY. 5813 04:04:42,482 --> 04:04:47,554 FOR SYSTEMIC ADMINISTRATION YOU 5814 04:04:47,554 --> 04:04:50,157 DO HAVE THESE HIGH TIDER 5815 04:04:50,157 --> 04:04:51,458 ANTIBODIES BUT THERE'S PROMISING 5816 04:04:51,458 --> 04:04:54,461 DATA TO TRY TO GET RID OF THAT 5817 04:04:54,461 --> 04:04:56,596 AND THEN YOU'LL HAVE TO QUELL 5818 04:04:56,596 --> 04:04:59,766 THE T CELL RESPONSE WHICH IS 5819 04:04:59,766 --> 04:05:02,302 GOING TO BE BRISKER THAN WHAT 5820 04:05:02,302 --> 04:05:03,570 WE'VE SEEN FROM NATURAL EXPOSURE 5821 04:05:03,570 --> 04:05:10,310 TO AAV. 5822 04:05:10,310 --> 04:05:12,212 >> KATHY, I WONDER IF YOU CAN 5823 04:05:12,212 --> 04:05:15,549 STEP BACK AND THINK OF YOUR 5824 04:05:15,549 --> 04:05:21,154 INTERACTIONS WITH THE FDA. 5825 04:05:21,154 --> 04:05:22,255 AND WHAT THEY'D BE TODAY IF YOU 5826 04:05:22,255 --> 04:05:24,257 BROUGHT THE TWO PROGRAMS 5827 04:05:24,257 --> 04:05:24,491 FORWARD. 5828 04:05:24,491 --> 04:05:27,494 DO YOU THINK THERE WOULD BE THE 5829 04:05:27,494 --> 04:05:30,463 SAME NUMBERS OF GROUPS IN 5830 04:05:30,463 --> 04:05:34,267 CONCERNS GIVEN SAY SOMEBODY ELSE 5831 04:05:34,267 --> 04:05:34,835 ALREADY DEVELOPED TWO DRUGS. 5832 04:05:34,835 --> 04:05:35,335 >> NO. 5833 04:05:35,335 --> 04:05:37,404 THE EARLY BIRD GETS THE WORM AND 5834 04:05:37,404 --> 04:05:38,638 THE SECOND MOUSE GETS THE 5835 04:05:38,638 --> 04:05:39,506 CHEESE. 5836 04:05:39,506 --> 04:05:43,510 WE WERE THE FIRST MOUSE AND OUR 5837 04:05:43,510 --> 04:05:45,111 NECK KEPT GETTING SNAPPED IN THE 5838 04:05:45,111 --> 04:05:47,747 TRAP AND YOU UNCOVER THE PROBLEM 5839 04:05:47,747 --> 04:05:49,349 AND YOU'RE ON HOLD UNTIL IT'S 5840 04:05:49,349 --> 04:05:49,616 SOLVED. 5841 04:05:49,616 --> 04:05:51,051 THANKS FOR ASKING THE QUESTION. 5842 04:05:51,051 --> 04:05:52,485 OF COURSE THERE WERE NO GUIDANCE 5843 04:05:52,485 --> 04:05:54,054 DOCUMENTS WHEN WE WERE DOING 5844 04:05:54,054 --> 04:05:54,721 THIS WORK. 5845 04:05:54,721 --> 04:05:59,893 NOW, THERE'S GUIDANCE DOCUMENTS 5846 04:05:59,893 --> 04:06:03,563 SOMETIMES EVERY MISTAKE TRICK TO 5847 04:06:03,563 --> 04:06:11,371 DEVELOP THE PROGRAM. 5848 04:06:11,371 --> 04:06:18,511 AS ALL OF US GAIN EXPERIENCE 5849 04:06:18,511 --> 04:06:19,012 EVERYTHING BECOMES MORE 5850 04:06:19,012 --> 04:06:28,221 RESOURCEFUL. 5851 04:06:28,221 --> 04:06:30,991 >> NOW FOR OUR FINAL SPEAKER 5852 04:06:30,991 --> 04:06:32,259 DR. WENDY CHUNG JOINING US 5853 04:06:32,259 --> 04:06:32,592 ONLINE. 5854 04:06:32,592 --> 04:06:39,566 WE CAN SEE YOU NOW. 5855 04:06:39,566 --> 04:06:48,508 WE'LL HEAR ABOUT ADVANCES IN 5856 04:06:48,508 --> 04:06:51,544 GENOMIC MEDICINE. 5857 04:06:51,544 --> 04:06:53,079 >> I'LL THINK ABOUT THIS WITH 5858 04:06:53,079 --> 04:06:54,781 EPILEPSY IN MIND AND START WITH 5859 04:06:54,781 --> 04:06:57,450 AUTISM THOUGH IT WAS FREQUENTLY 5860 04:06:57,450 --> 04:06:58,885 ASSOCIATED WITH EPILEPSY AND 5861 04:06:58,885 --> 04:07:01,721 SAME IS TRUE WHEN I THINK OF 5862 04:07:01,721 --> 04:07:04,457 AUTISM BE AN UMBRELLA DIAGNOSIS 5863 04:07:04,457 --> 04:07:06,393 WITH FEATURES DEPENDING ON THE 5864 04:07:06,393 --> 04:07:06,893 UNDERLYING ETIOLOGY. 5865 04:07:06,893 --> 04:07:10,563 MANY KNOW ME AS SOMEONE WHO'S 5866 04:07:10,563 --> 04:07:14,200 THOUGHT ABOUT THIS FOR A WHILE 5867 04:07:14,200 --> 04:07:17,270 AND WITHIN AUTISM THERE'S 5868 04:07:17,270 --> 04:07:19,572 EXTREME HETEROGENEITY AND HARD 5869 04:07:19,572 --> 04:07:21,241 TO UNDERSTAND THAT PROGNOSIS 5870 04:07:21,241 --> 04:07:23,143 SUPPORT WHAT CAN BE TAILORED FOR 5871 04:07:23,143 --> 04:07:24,511 THE INDIVIDUAL REQUIRED 5872 04:07:24,511 --> 04:07:25,879 STRATIFICATION ESPECIALLY FOR 5873 04:07:25,879 --> 04:07:27,180 YOUNG CHILDREN WHERE THE 5874 04:07:27,180 --> 04:07:32,218 PROGNOSIS IS NOT CLEAR. 5875 04:07:32,218 --> 04:07:39,859 IN DOING THAT, I WILL TALK ABOUT 5876 04:07:39,859 --> 04:07:40,994 STARK A NATIONAL AUTISM RESEARCH 5877 04:07:40,994 --> 04:07:44,898 COHORT AND THIS HAS INDIVIDUALS 5878 04:07:44,898 --> 04:07:46,399 WITH AUTISM AND OFFERED BUT NOT 5879 04:07:46,399 --> 04:07:48,501 REQUIRED TO PARTICIPATE IN THE 5880 04:07:48,501 --> 04:07:49,769 GENOMIC STUDIES NOW INCLUDING 5881 04:07:49,769 --> 04:07:52,372 WHOLE GENOME SEQUENCES WITH DATA 5882 04:07:52,372 --> 04:07:53,673 FREELY AVAILABLE FOR ANY WHO 5883 04:07:53,673 --> 04:07:56,176 WOULD LIKE TO USE IT WITH THE 5884 04:07:56,176 --> 04:07:59,546 STRATIFICATION BY UNDERLYING 5885 04:07:59,546 --> 04:08:02,749 GENETIC ETIOLOGY. 5886 04:08:02,749 --> 04:08:13,259 WITH THAT WE'RE STUDYING THE 5887 04:08:20,567 --> 04:08:22,869 PHENOTYPES AND WHAT'S IMPORTANT 5888 04:08:22,869 --> 04:08:25,005 IT TO RETURN GOOD MORNING 5889 04:08:25,005 --> 04:08:30,510 RESULTS WHEN WE IDENTIFY A 5890 04:08:30,510 --> 04:08:32,779 MONOGENIC ETIOLOGY WITH 10% OF 5891 04:08:32,779 --> 04:08:33,880 THE COHORTS AND HAVE A 5892 04:08:33,880 --> 04:08:35,081 CONTINUATION ON THE JOURNEY FOR 5893 04:08:35,081 --> 04:08:38,385 INDIVIDUALS WITH A SISTER STUDY 5894 04:08:38,385 --> 04:08:40,086 CALLED SIMON SEARCH LIGHT. 5895 04:08:40,086 --> 04:08:42,555 I SHOULD SAY SPARK IS DEFINED BY 5896 04:08:42,555 --> 04:08:45,992 THE PHENOTYPE DRIVEN WITH A 5897 04:08:45,992 --> 04:08:47,127 PROFESSION DIAGNOSIS OF AUTISM 5898 04:08:47,127 --> 04:08:48,428 WE CONFIRMED BY RECORD REVIEW TO 5899 04:08:48,428 --> 04:08:51,598 BE VALIDATED IN TERMS OF WHAT IS 5900 04:08:51,598 --> 04:08:59,205 SELF-REPORTED. 5901 04:08:59,205 --> 04:09:01,674 SIMON SEARCH LIGHT IS DEFINED BY 5902 04:09:01,674 --> 04:09:03,009 GENE OR COPY NUMBER VARIANT. 5903 04:09:03,009 --> 04:09:04,911 AS WE INCLUDED THIS FOR SPARK 5904 04:09:04,911 --> 04:09:07,547 IT'S A U.S.-BASED COHORT 5905 04:09:07,547 --> 04:09:11,584 ANCHORED ACROSS 31 CLINICAL 5906 04:09:11,584 --> 04:09:12,786 SITES MANY OF WHICH MAY 5907 04:09:12,786 --> 04:09:17,757 REPRESENT YOUR SITES. 5908 04:09:17,757 --> 04:09:24,030 THE DATA IS FREELY ABLE AND USE 5909 04:09:24,030 --> 04:09:25,131 PARTICIPANTS IN THEIR RESEARCH 5910 04:09:25,131 --> 04:09:25,999 STUDIES. 5911 04:09:25,999 --> 04:09:26,766 AS WE'VE BEEN RETURNING THE 5912 04:09:26,766 --> 04:09:30,303 INFORMATION THESE ARE GENETIC 5913 04:09:30,303 --> 04:09:31,371 RESULTS BY MONTH WE'VE BEEN 5914 04:09:31,371 --> 04:09:32,172 RETURNING OVER TIME. 5915 04:09:32,172 --> 04:09:35,542 SEE A LARGE NUMBER OF 5916 04:09:35,542 --> 04:09:36,242 INDIVIDUALS ESPECIALLY RECENTLY 5917 04:09:36,242 --> 04:09:37,310 GETTING GENETIC DIAGNOSES WITH 5918 04:09:37,310 --> 04:09:39,546 THIS AND STARTED TO AS A 5919 04:09:39,546 --> 04:09:43,183 COMMUNITY UNDERSTAND BETTER THE 5920 04:09:43,183 --> 04:09:44,717 GENES INVOLVED AND I'LL 5921 04:09:44,717 --> 04:09:45,618 HIGHLIGHT THERE ARE PARTICULAR 5922 04:09:45,618 --> 04:09:48,221 GENES PROBABLY BOTH MORE RELATED 5923 04:09:48,221 --> 04:09:50,290 TO EPILEPSY SPECIFICALLY THOSE 5924 04:09:50,290 --> 04:09:53,226 INVOLVED IN NEUROTRANSMISSION, 5925 04:09:53,226 --> 04:09:55,562 CHANNELOPATHIIES I'LL COME BACK 5926 04:09:55,562 --> 04:09:57,330 TO IN A SECOND AND SOME EASIER 5927 04:09:57,330 --> 04:09:59,799 THAN OTHERS TO THINK ABOUT 5928 04:09:59,799 --> 04:10:02,035 THERAPEUTIC TREATMENT. 5929 04:10:02,035 --> 04:10:04,170 MANY OF THESE WE RECOGNIZE RIGHT 5930 04:10:04,170 --> 04:10:05,872 NOW DUE TO MUTATIONS IN SOME 5931 04:10:05,872 --> 04:10:07,540 CASES AND I SAY THIS BASED ON 5932 04:10:07,540 --> 04:10:10,043 THE THERAPY IN SOME CASES LOSS 5933 04:10:10,043 --> 04:10:13,913 OF FUNCTIONAL ALLELES WITH 5934 04:10:13,913 --> 04:10:15,548 INSUFFICIENCY AND OTHERS WITH 5935 04:10:15,548 --> 04:10:20,153 MISSENT ALLELES WHY MAY 5936 04:10:20,153 --> 04:10:21,521 REPRESENT MISFUNCTION BUT NOT 5937 04:10:21,521 --> 04:10:24,524 LOSS OF FUNCTION AND THE WINDOW 5938 04:10:24,524 --> 04:10:25,458 OF OPPORTUNITY FOR TREATMENT 5939 04:10:25,458 --> 04:10:27,026 BECOMES NOT ONLY GENE SPECIFIC 5940 04:10:27,026 --> 04:10:31,131 BUT IN SOME CASES SUB GENE 5941 04:10:31,131 --> 04:10:32,132 SPECIFIC WITH DIFFERENT 5942 04:10:32,132 --> 04:10:33,900 MOLECULAR MECHANISMS BASED ON 5943 04:10:33,900 --> 04:10:34,534 THE UNDERLYING ALLELE. 5944 04:10:34,534 --> 04:10:43,276 AS I ALLUDED TO, INDIVIDUALS 5945 04:10:43,276 --> 04:10:44,344 GENETICALLY DIAGNOSED ARE 5946 04:10:44,344 --> 04:10:48,515 INVITED TO SIMONS SEARCH LIGHT 5947 04:10:48,515 --> 04:10:50,583 AND SOME BASED ON GENETIC 5948 04:10:50,583 --> 04:10:54,521 DIAGNOSIS LARGELY FROM CLINICAL 5949 04:10:54,521 --> 04:10:57,891 TESTING AND IT'S AN 5950 04:10:57,891 --> 04:11:00,527 INTERNATIONAL ONLINE REGISTRY TO 5951 04:11:00,527 --> 04:11:05,031 ANY QUALIFIED INVESTIGATOR. 5952 04:11:05,031 --> 04:11:07,800 FOR THOSE IN SIMONS SEARCH LIGHT 5953 04:11:07,800 --> 04:11:09,269 THERE'S APPROXIMATELY 170 5954 04:11:09,269 --> 04:11:10,870 CONDITIONS MORE NOW AND FOR 5955 04:11:10,870 --> 04:11:13,439 THOSE I KNOW THIS IS SMALL BUT 5956 04:11:13,439 --> 04:11:14,240 YOU MAY RECOGNIZE YOUR FAVORITE 5957 04:11:14,240 --> 04:11:17,644 GENE WITHIN THIS AND MANY OF 5958 04:11:17,644 --> 04:11:19,546 THESE GENES ARE GENES THAT 5959 04:11:19,546 --> 04:11:20,346 REPRESENT EPILEPSY CONDITIONS AS 5960 04:11:20,346 --> 04:11:21,981 WELL SO QUITE A BIT OF OVERLAP. 5961 04:11:21,981 --> 04:11:24,918 WE TRADE TO MAKE THIS AS 5962 04:11:24,918 --> 04:11:25,652 ACCESSIBLE AS POSSIBLE BY 5963 04:11:25,652 --> 04:11:27,587 INCLUDING MULTIPLE LANGUAGES AND 5964 04:11:27,587 --> 04:11:33,226 HAVE THE ABILITY TO SPEAK WITH A 5965 04:11:33,226 --> 04:11:38,198 GENETIC COUNSELORS AND 5966 04:11:38,198 --> 04:11:39,165 COLLECTION INFORMATION AND WHEN 5967 04:11:39,165 --> 04:11:43,236 POSSIBLE BIO SPECIMENS IN SOME 5968 04:11:43,236 --> 04:11:45,171 CASES IPS LINES FREELY ABLE TO 5969 04:11:45,171 --> 04:11:47,540 RESEARCHERS TO POWER SOME 5970 04:11:47,540 --> 04:11:57,884 PRECLINICAL STUDIES. 5971 04:12:01,020 --> 04:12:02,522 I'LL SHIFT NOW TO THIS CONDITION 5972 04:12:02,522 --> 04:12:04,490 I'VE STUDIED A WHILE IT'S LIKE 5973 04:12:04,490 --> 04:12:06,960 OTHERS ALSO ASSOCIATED WITH 5974 04:12:06,960 --> 04:12:14,133 EPILEPSY IN ABOUT 42% 5975 04:12:14,133 --> 04:12:15,435 DEVELOPMENT AND DELAY AND AUTISM 5976 04:12:15,435 --> 04:12:18,805 AND IN A QUARTER AND MORE 5977 04:12:18,805 --> 04:12:23,543 COMPLICATED IN THAT IT'S 5978 04:12:23,543 --> 04:12:25,111 NEURODEGENERATIVE. 5979 04:12:25,111 --> 04:12:29,716 WITH THAT WE ALSO HAVE VISUAL 5980 04:12:29,716 --> 04:12:31,217 IMPAIRMENT AND ADDITIONAL 5981 04:12:31,217 --> 04:12:33,519 FACTORS INCLUDE STRABISMUS AND 5982 04:12:33,519 --> 04:12:33,786 CATARACT. 5983 04:12:33,786 --> 04:12:39,559 THIS IS ALSO ASSOCIATED WITH 5984 04:12:39,559 --> 04:12:49,502 PERIPHERAL NEUROPATHY AND 5985 04:12:49,502 --> 04:12:53,239 SPASTICITY AND AMBULATION AND AS 5986 04:12:53,239 --> 04:12:57,243 THE CHALLENGING BECAUSE IT CAN 5987 04:12:57,243 --> 04:13:00,146 BE LETHAL BEFORE 5 YEARS OF AGE 5988 04:13:00,146 --> 04:13:03,182 IN SEVERELY IMPAIRED 5989 04:13:03,182 --> 04:13:03,583 INDIVIDUALS. 5990 04:13:03,583 --> 04:13:06,219 IT'S NEURODEGENERATIVE AND IF 5991 04:13:06,219 --> 04:13:07,887 YOU FOCUS ON THE CEREBELLUM 5992 04:13:07,887 --> 04:13:09,889 THOUGH WE CAN SEE THIS FOR 5993 04:13:09,889 --> 04:13:11,591 MULTIPLE PARTS OF THE BRAIN THE 5994 04:13:11,591 --> 04:13:14,727 REMARKABLE ATROPHY OVER A 2 YEAR 5995 04:13:14,727 --> 04:13:16,996 PERIOD IN THE CEREBELLUM AND 5996 04:13:16,996 --> 04:13:22,602 WE'VE DONE AUTOPSIES IN A FEW 5997 04:13:22,602 --> 04:13:24,704 INDIVIDU 5998 04:13:24,704 --> 04:13:28,207 INDIVIDUALS BEING ABLE TO SEE 5999 04:13:28,207 --> 04:13:32,912 NEURONAL CELL TYPES AND THE 6000 04:13:32,912 --> 04:13:34,480 CEREBELLUM MOST SEVERELY 6001 04:13:34,480 --> 04:13:36,182 IMPAIRED. 6002 04:13:36,182 --> 04:13:39,118 THE GENE IS A MOLECULAR 6003 04:13:39,118 --> 04:13:40,887 MECHANISM AND IT'S A MOLECULAR 6004 04:13:40,887 --> 04:13:50,196 MOTOR A HOMODIMER AND THE FEET 6005 04:13:50,196 --> 04:13:55,535 ARE THE MOTOR DOMAIN. 6006 04:13:55,535 --> 04:13:59,539 THIS IS THE END TERMINUS AND 6007 04:13:59,539 --> 04:14:02,875 IT'S TRANSPORTING CARGO ALONG 6008 04:14:02,875 --> 04:14:03,242 THE MICROTUBULE. 6009 04:14:03,242 --> 04:14:06,946 THIS HOMO DIMER IS IMPORTANT IN 6010 04:14:06,946 --> 04:14:10,583 THE SENSE THAT MOST MUTATION 6011 04:14:10,583 --> 04:14:12,518 HETEROZYGOUS AND ACT THROUGH A 6012 04:14:12,518 --> 04:14:13,353 DOMINANT NEGATIVE EFFECT. 6013 04:14:13,353 --> 04:14:18,191 THAT IS MUTATIONS LARGELY MISSED 6014 04:14:18,191 --> 04:14:19,292 SENSED MUTATIONS LARGELY IN THE 6015 04:14:19,292 --> 04:14:24,530 FEET OR THE MOTOR DOMAIN EITHER 6016 04:14:24,530 --> 04:14:35,074 MAKING CONTACT WITH THE MICROAND 6017 04:14:40,313 --> 04:14:42,115 THEY ACT TO POISON THE TOTALITY 6018 04:14:42,115 --> 04:14:43,483 OF THAT PROTEIN. 6019 04:14:43,483 --> 04:14:47,420 IN THEORY THERE'S AGAIN A SENSE 6020 04:14:47,420 --> 04:14:49,355 OF URGENCY MORE SO FOR ME FOR 6021 04:14:49,355 --> 04:14:50,690 THIS CONDITION THAN OTHERS I 6022 04:14:50,690 --> 04:14:53,292 WORK ON DUE TO THE DEGENERATIVE 6023 04:14:53,292 --> 04:14:54,327 NATURE AND FATALITIES ASSOCIATED 6024 04:14:54,327 --> 04:14:55,228 WITH THIS. 6025 04:14:55,228 --> 04:14:57,697 SO THIS WAS A CONDITION WE 6026 04:14:57,697 --> 04:14:59,632 DECIDED TO BE SLIGHTLY MORE 6027 04:14:59,632 --> 04:15:01,701 AGGRESSIVE WITH IN TERMS OF THE 6028 04:15:01,701 --> 04:15:02,802 HANDOFF TREATMENT. 6029 04:15:02,802 --> 04:15:07,106 HERE'S ONE OF THE CHALLENGES. 6030 04:15:07,106 --> 04:15:08,775 AND THIS IS A MUTATION IN THE 6031 04:15:08,775 --> 04:15:10,777 GENE AND STICK ON THE TOP WITH 6032 04:15:10,777 --> 04:15:12,345 THE LEFT PART THE GRAY NOW BLOWN 6033 04:15:12,345 --> 04:15:14,847 UP HERE OF THE MOTOR DOMAIN AND 6034 04:15:14,847 --> 04:15:18,518 EACH OF THE CIRCLES REPRESENTS A 6035 04:15:18,518 --> 04:15:21,320 DIFFERENT PATIENT. 6036 04:15:21,320 --> 04:15:24,457 AND HAVE RECURRENT MUTATIONS AND 6037 04:15:24,457 --> 04:15:24,957 CERTAIN POSITIONS. 6038 04:15:24,957 --> 04:15:27,260 THESE ARE UNRELATED INDIVIDUALS 6039 04:15:27,260 --> 04:15:30,029 AND THESE ARE MOSTLY DE NOVO 6040 04:15:30,029 --> 04:15:31,497 MUTATIONS AND YOU CAN SEE THE 6041 04:15:31,497 --> 04:15:33,199 LAUNCH NUMBER OF INDIVIDUALS SO 6042 04:15:33,199 --> 04:15:35,568 FAR ARE SINGLE INDIVIDUALS WITH 6043 04:15:35,568 --> 04:15:39,338 THE INDIVIDUAL ALLELES. 6044 04:15:39,338 --> 04:15:41,007 I'VE ALSO SHOWN THOUGH I HAVEN'T 6045 04:15:41,007 --> 04:15:42,975 TALKED ABOUT IT THERE'S FEW 6046 04:15:42,975 --> 04:15:43,910 RECESSIVE CASES AND I'M NOT 6047 04:15:43,910 --> 04:15:47,547 GOING TO SPEAK ABOUT IN A FEW 6048 04:15:47,547 --> 04:15:49,015 HETEROZYGOUS CASES ASSOCIATED 6049 04:15:49,015 --> 04:15:49,849 WITH A MILDER PHENOTYPE. 6050 04:15:49,849 --> 04:15:52,752 THE CHALLENGE AS WE WERE 6051 04:15:52,752 --> 04:15:54,020 THINKING ABOUT BOTH PROGNOSIS 6052 04:15:54,020 --> 04:15:56,322 FOR FAMILIES WHO GET THE NEW 6053 04:15:56,322 --> 04:15:56,856 DIAGNOSIS AS WELL AS HOW 6054 04:15:56,856 --> 04:15:58,357 AGGRESSIVE TO BE WITH TREATMENT 6055 04:15:58,357 --> 04:16:00,593 IS THAT THERE'S SUCH 6056 04:16:00,593 --> 04:16:03,196 HETEROGENEITY AND IN PARTICULAR 6057 04:16:03,196 --> 04:16:05,531 FOR A PEDIATRIC CONDITION 6058 04:16:05,531 --> 04:16:06,566 ASSOCIATED BOTH WITH A 6059 04:16:06,566 --> 04:16:07,533 DEVELOPMENT ASPECT ON THE UP 6060 04:16:07,533 --> 04:16:09,802 SLOPE AND DEGENERATIVE ASPECT ON 6061 04:16:09,802 --> 04:16:11,604 THE DOWN SLOPE AND THE EARLY 6062 04:16:11,604 --> 04:16:14,207 DAYS WHEN YOU'RE LARGELY GETTING 6063 04:16:14,207 --> 04:16:16,075 ACROSS SECTIONAL DATA UNTIL YOU 6064 04:16:16,075 --> 04:16:18,077 HAVE ENOUGH TIME TO GET 6065 04:16:18,077 --> 04:16:19,545 LONGITUDINAL DATA IT'S VERY 6066 04:16:19,545 --> 04:16:20,680 CHALLENGING TO UNDERSTAND THE 6067 04:16:20,680 --> 04:16:22,748 SEVERITY OF EACH OF THE ALLELES 6068 04:16:22,748 --> 04:16:24,951 AND WITH THE HETEROGENEITY TO 6069 04:16:24,951 --> 04:16:26,018 THINK ABOUT PROGNOSIS. 6070 04:16:26,018 --> 04:16:28,788 IT'S BEEN QUITE CHALLENGING IN 6071 04:16:28,788 --> 04:16:29,088 THAT WAY. 6072 04:16:29,088 --> 04:16:32,758 WE HAVE BEEN ABLE TO HAVE AN IN 6073 04:16:32,758 --> 04:16:34,460 VITRO MOLECULAR PHENOTYPE TO 6074 04:16:34,460 --> 04:16:38,164 BEING ABLE TO LOOK AT THE BIO 6075 04:16:38,164 --> 04:16:40,199 PHYSICAL PROPERTIES OF THE 6076 04:16:40,199 --> 04:16:41,534 MOTOR. 6077 04:16:41,534 --> 04:16:43,002 WHEN IT GETS STALLED AND FALLS 6078 04:16:43,002 --> 04:16:44,971 OFF THE MICROTUBULE AND HOW MUCH 6079 04:16:44,971 --> 04:16:46,873 IT CAN CARRY IN THE AXON AND 6080 04:16:46,873 --> 04:16:51,911 BEING ABLE TO USE THIS AS A 6081 04:16:51,911 --> 04:16:53,346 QUANTITATIVE PHENOTYPE WHERE WE 6082 04:16:53,346 --> 04:16:54,881 CAN MAKE A CORRELATION BETWEEN 6083 04:16:54,881 --> 04:16:56,349 MOLECULAR PHENOTYPE AND CLINICAL 6084 04:16:56,349 --> 04:16:56,849 PHENOTYPE. 6085 04:16:56,849 --> 04:16:58,050 THOUGH IT'S AGAIN NOT PERFECT 6086 04:16:58,050 --> 04:16:59,652 FOR ALL THE REASONS I SAID WITH 6087 04:16:59,652 --> 04:17:02,588 THE CLINICAL PHENOTYPE, THAT HAS 6088 04:17:02,588 --> 04:17:04,457 HELPED US IN TERMS OF SEVERITY 6089 04:17:04,457 --> 04:17:06,559 ESPECIALLY WITH THE EXTREMES WE 6090 04:17:06,559 --> 04:17:06,726 SEE. 6091 04:17:06,726 --> 04:17:10,196 WITH THAT WE'VE BEEN ABLE TO 6092 04:17:10,196 --> 04:17:11,063 DEVELOP HEURISTIC SEVERITY SCORE 6093 04:17:11,063 --> 04:17:15,568 AND NOW THAT WE HAVE IN SOME 6094 04:17:15,568 --> 04:17:18,638 INDIVIDUALS NOW THREE YEARS OF 6095 04:17:18,638 --> 04:17:20,072 LONGITUDINAL DATA STILL LIMITED 6096 04:17:20,072 --> 04:17:22,275 BUT ABLE TO MAKE THE 6097 04:17:22,275 --> 04:17:22,608 CORRELATIONS. 6098 04:17:22,608 --> 04:17:24,544 IN DOING SO TRYING TO THINK 6099 04:17:24,544 --> 04:17:26,078 ABOUT TARGETS FOR A TREATMENT 6100 04:17:26,078 --> 04:17:29,882 AND THIS WORK IS NOW IN 6101 04:17:29,882 --> 04:17:30,716 COLLABORATION WITH STAN COOK AND 6102 04:17:30,716 --> 04:17:32,318 THE TEAM AND THE STRATEGY IN 6103 04:17:32,318 --> 04:17:36,389 THIS CASE IS TO USE AN ALLELE 6104 04:17:36,389 --> 04:17:46,499 SPECIFIC ASO FOR RNA H1 6105 04:17:46,499 --> 04:17:54,073 DEGRADATION AND TRYING TO LEAVE 6106 04:17:54,073 --> 04:17:55,474 A SITUATION OF A PROTEIN THAT IS 6107 04:17:55,474 --> 04:17:55,775 FUNCTIONAL. 6108 04:17:55,775 --> 04:17:57,076 THE STRATEGY IN THIS CASE IS NOT 6109 04:17:57,076 --> 04:18:00,279 TO TARGET THE MUTANTS ALLELE PER 6110 04:18:00,279 --> 04:18:02,481 SE IN THE SENSE OF THE ACTUAL 6111 04:18:02,481 --> 04:18:04,483 MUTATION OR THE NUCLEOTIDE THAT 6112 04:18:04,483 --> 04:18:06,552 IS PROBLEMATIC BUT INSTEAD TO 6113 04:18:06,552 --> 04:18:11,390 TAKE UP POLYMORPHISM THAT IS 6114 04:18:11,390 --> 04:18:14,427 STILL WITHIN THE GENE AND INSIST 6115 04:18:14,427 --> 04:18:16,696 ON THE SAME STRAND AS THE 6116 04:18:16,696 --> 04:18:19,465 TRANSCRIPT BUT USE IT, I CALL A 6117 04:18:19,465 --> 04:18:21,567 HANDLE, BUT USE IT TO GRAB THE 6118 04:18:21,567 --> 04:18:24,570 GENE AND LEAD TO ALLELE SPECIFIC 6119 04:18:24,570 --> 04:18:25,338 DEGRADATION. 6120 04:18:25,338 --> 04:18:28,207 SO FAR WE'VE TREATED -- I'VE 6121 04:18:28,207 --> 04:18:30,543 TREATED ONE PATIENT. 6122 04:18:30,543 --> 04:18:34,146 THE STARTED AT 9 -- 8 YEARS OLD 6123 04:18:34,146 --> 04:18:36,282 AND WHILE THE TREATMENT HAS HAD 6124 04:18:36,282 --> 04:18:37,550 SUCCESS IT'S HAD SOME 6125 04:18:37,550 --> 04:18:38,651 LIMITATIONS AS WELL. 6126 04:18:38,651 --> 04:18:40,319 THIS IS SHOWING HER LONGITUDINAL 6127 04:18:40,319 --> 04:18:42,288 DATA OVER TIME AND THIS IS 6128 04:18:42,288 --> 04:18:46,559 INTRATHECAL INJECTION OF THE 6129 04:18:46,559 --> 04:18:46,892 ASO. 6130 04:18:46,892 --> 04:18:47,994 WE'VE HAD SEVERAL OUTCOME 6131 04:18:47,994 --> 04:18:49,996 MEASURES AND KNOWING THIS WAS 6132 04:18:49,996 --> 04:18:52,298 ASSOCIATED WITH EPILEPSY IN HER 6133 04:18:52,298 --> 04:18:54,433 CASE WE'VE LOOKED AT THE SEIZURE 6134 04:18:54,433 --> 04:18:58,471 DIARY FROM HER PARENTS AND 6135 04:18:58,471 --> 04:19:00,339 THERE'S BEEN EEGs BEING ABLE TO 6136 04:19:00,339 --> 04:19:06,946 LOOK AT THE NUMBER OF REPORTED 6137 04:19:06,946 --> 04:19:09,882 SEIZURES, THE LENGTH AND NUMBER 6138 04:19:09,882 --> 04:19:15,187 OF SEIZURES AND BECAUSE OF THE 6139 04:19:15,187 --> 04:19:16,255 SPASTICITY CAN BE ASSOCIATED 6140 04:19:16,255 --> 04:19:18,924 WITH FALLS AND BONE FRACTURES. 6141 04:19:18,924 --> 04:19:22,495 SO LOOKING AT THIS AND WITH THE 6142 04:19:22,495 --> 04:19:23,562 DIARIES HER PARENTS AND 6143 04:19:23,562 --> 04:19:24,563 CAREGIVERS LOOK LOOKING AT THE 6144 04:19:24,563 --> 04:19:26,999 BASELINE DATA WITH THE RUN IN 6145 04:19:26,999 --> 04:19:28,034 AND WITH INCREASING DOSE 6146 04:19:28,034 --> 04:19:29,301 ADMINISTRATION BEING ABLE TO SEE 6147 04:19:29,301 --> 04:19:30,636 THE ADDITIONAL TIME POINTS THEN 6148 04:19:30,636 --> 04:19:33,239 YOU CAN SEE A DECREASE IN THE 6149 04:19:33,239 --> 04:19:34,607 NUMBER OF SEIZURES. 6150 04:19:34,607 --> 04:19:45,051 THE LONGEST SEIZURES AND 6151 04:19:47,153 --> 04:19:48,054 PROGRESS INCREASED HER MOBILITY. 6152 04:19:48,054 --> 04:19:52,291 I WON'T GO IN MORE DETAIL BUT 6153 04:19:52,291 --> 04:19:54,593 ALSO LEARNING AND THIS WAS AN N 6154 04:19:54,593 --> 04:19:55,394 OF 1 TREATMENT. 6155 04:19:55,394 --> 04:19:57,296 ALSO THIS WERE MANY THINGS WE 6156 04:19:57,296 --> 04:19:58,898 LEARNED THAT DIDN'T NECESSARY 6157 04:19:58,898 --> 04:19:59,198 MOVE. 6158 04:19:59,198 --> 04:20:01,667 WE HAD INCLUDED A SIX-MINUTE 6159 04:20:01,667 --> 04:20:05,738 WALK TEST WHICH DESPITE 6160 04:20:05,738 --> 04:20:07,306 INCREASED AMBULATION DIDN'T 6161 04:20:07,306 --> 04:20:08,140 SIGNIFICANTLY CHANGE BUT THERE 6162 04:20:08,140 --> 04:20:11,977 WERE OTHER THINGS I DIDN'T KNOW 6163 04:20:11,977 --> 04:20:13,612 WOULD CHANGE LIKE COMPLEXITY OF 6164 04:20:13,612 --> 04:20:15,081 SPEECH, FINE MOTOR SKILLS AND 6165 04:20:15,081 --> 04:20:18,584 OTHER FACTORS BY VIDEO REVIEW 6166 04:20:18,584 --> 04:20:19,552 CLEARLY HAVE IMPROVED OVER TIME. 6167 04:20:19,552 --> 04:20:21,721 AND WITH THIS NOW A SECOND 6168 04:20:21,721 --> 04:20:23,055 PATIENT IS ACTUALLY BEING DOSED 6169 04:20:23,055 --> 04:20:27,193 WITH THE SAME ASO. 6170 04:20:27,193 --> 04:20:30,062 SO WITH THIS AND THIS IS THE 6171 04:20:30,062 --> 04:20:32,364 FINAL CHAPTER, KNOWING WHAT WE 6172 04:20:32,364 --> 04:20:33,165 KNOW ABOUT THESE RARE CONDITIONS 6173 04:20:33,165 --> 04:20:35,101 AND THAT AS THE A WINDOW OF 6174 04:20:35,101 --> 04:20:40,573 TREATABILITY IN THAT WINDOW IS 6175 04:20:40,573 --> 04:20:44,543 PROBABLY BEST IF EARLY BUT 6176 04:20:44,543 --> 04:20:46,178 IMPORTANT TO DISTINGUISH WHO 6177 04:20:46,178 --> 04:20:47,480 DOES AND DOESN'T NEED TREATMENT 6178 04:20:47,480 --> 04:20:50,850 WE STARTED IN NEW YORK CITY A 6179 04:20:50,850 --> 04:20:52,284 GENOMIC NEWBORN SCREENING 6180 04:20:52,284 --> 04:20:57,456 PROGRAM CALLED GUARDIAN GENOMIC 6181 04:20:57,456 --> 04:20:58,891 SCREENING AGAINST ALL DISEASES 6182 04:20:58,891 --> 04:21:01,961 AND FROM THE EXPERIENCE IN 6183 04:21:01,961 --> 04:21:03,129 SPINAL MUSCULAR ATROPHY AND A 6184 04:21:03,129 --> 04:21:05,698 PILOT STUDY IN NEW YORK WITH 6185 04:21:05,698 --> 04:21:06,565 NEWBORN SCREENING QUITE 6186 04:21:06,565 --> 04:21:08,400 SUCCESSFUL AND HAS NOW BEEN THE 6187 04:21:08,400 --> 04:21:10,002 BASIS FOR WHICH WE ADDED THAT TO 6188 04:21:10,002 --> 04:21:12,104 THE UNIVERSAL SCREENING PANEL. 6189 04:21:12,104 --> 04:21:16,408 SINCE THEN, WE'VE DONE PILOT 6190 04:21:16,408 --> 04:21:18,677 STUDIES WITH DUCHENNE MUSCULAR 6191 04:21:18,677 --> 04:21:22,681 DYSTROPHY AND SOME ARGUE THE 6192 04:21:22,681 --> 04:21:24,717 MOST AMBITIOUS AND DOING WHOLE 6193 04:21:24,717 --> 04:21:28,120 GENOME SEQUENCING ON THE NEWBORN 6194 04:21:28,120 --> 04:21:29,388 BLOOD SPOT IN COLLABORATION WITH 6195 04:21:29,388 --> 04:21:30,556 THE NEW YORK STATE DEPARTMENT OF 6196 04:21:30,556 --> 04:21:30,790 HEALTH. 6197 04:21:30,790 --> 04:21:32,424 WHILE WE DO SEQUENCING ON THE 6198 04:21:32,424 --> 04:21:38,264 WHOLE GENOME WE ONLY LOOK AT A 6199 04:21:38,264 --> 04:21:40,966 TARGETED SET OF GENES THIS IS 6200 04:21:40,966 --> 04:21:44,570 ALL A RESEARCH INCENTED STUDY IN 6201 04:21:44,570 --> 04:21:46,539 THE NEW YORK PRESBYTERIAN SYSTEM 6202 04:21:46,539 --> 04:21:48,407 FOCUSSED ON 238 GENES. 6203 04:21:48,407 --> 04:21:49,975 MOST OF WHICH ARE EITHER 6204 04:21:49,975 --> 04:21:52,244 OVERLAPPING FOR A QUALITY 6205 04:21:52,244 --> 04:21:54,580 CONTROL POINT OF VIEW WITH 6206 04:21:54,580 --> 04:21:56,282 TRADITIONAL NEWBORN SCREENING 6207 04:21:56,282 --> 04:21:59,118 GENES OR WITH GENES THERE'S 6208 04:21:59,118 --> 04:22:03,556 IMMEDIATELY FDA APPROVED 6209 04:22:03,556 --> 04:22:03,823 TREATMENT. 6210 04:22:03,823 --> 04:22:05,524 WITHIN THIS I WON'T GO TOO MUCH 6211 04:22:05,524 --> 04:22:07,560 IN THE DETAIL BUT FOCUS ON THE 6212 04:22:07,560 --> 04:22:08,861 GROUP 2 CONDITION. 6213 04:22:08,861 --> 04:22:11,964 I DESCRIBED THE CORE CONDITIONS 6214 04:22:11,964 --> 04:22:12,998 AND EVERYBODY WHO AGREES THE 6215 04:22:12,998 --> 04:22:14,500 STUDY DOES THAT AND AT THE GROUP 6216 04:22:14,500 --> 04:22:16,468 2 WERE AT THE REQUEST OF PARENTS 6217 04:22:16,468 --> 04:22:18,437 SAYING WE'RE ALSO INTERESTED IN 6218 04:22:18,437 --> 04:22:19,238 CONDITIONS RELATED TO EPILEPSY 6219 04:22:19,238 --> 04:22:20,773 OR SEIZURES BECAUSE THERE'S 6220 04:22:20,773 --> 04:22:24,577 SOMETHING WE MIGHT BE ABLE TO DO 6221 04:22:24,577 --> 04:22:25,444 WITH EARLY RECOGNITION AND 6222 04:22:25,444 --> 04:22:27,279 TREATMENT OF THE SEIZURES AND 6223 04:22:27,279 --> 04:22:31,483 THOSE CONDITIONS MAY STILL HAVE 6224 04:22:31,483 --> 04:22:34,653 RESIDUAL NEURAL DEVELOPMENT OR 6225 04:22:34,653 --> 04:22:36,055 COGNITIVE ISSUES AND THERE WAS 6226 04:22:36,055 --> 04:22:38,657 NOT 100% ANONYMITY IN THE 6227 04:22:38,657 --> 04:22:41,327 INTEREST IN WANTING THAT 6228 04:22:41,327 --> 04:22:44,830 INFORMATION SO WE THAT AN 6229 04:22:44,830 --> 04:22:47,566 OPTIO 6230 04:22:47,566 --> 04:22:48,567 OPTIO 6231 04:22:48,567 --> 04:22:51,537 OPTIO 6232 04:22:51,537 --> 04:22:53,205 OPTIONAL MODULE IN THE STUDY AND 6233 04:22:53,205 --> 04:22:56,141 WHEN APPROACHED APPROXIMATELY 6234 04:22:56,141 --> 04:22:58,677 75% OF PARENTS DESIRE AND 6235 04:22:58,677 --> 04:23:00,579 CONSENT TO DOING THE STUDY AND 6236 04:23:00,579 --> 04:23:02,615 IMPORTANTLY FOR THE GROUP 2 6237 04:23:02,615 --> 04:23:04,283 CONDITIONS OPTIONAL OVER ALL 92% 6238 04:23:04,283 --> 04:23:09,188 OF PARENTS OF THE VAST MAJORITY 6239 04:23:09,188 --> 04:23:10,656 OPT FOR CONDITIONS THOUGH THE 6240 04:23:10,656 --> 04:23:12,391 PERCENTAGE IS SLIGHTLY LESS FOR 6241 04:23:12,391 --> 04:23:14,126 THOSE WHO SPEAK SPANISH AND 6242 04:23:14,126 --> 04:23:16,061 CONSENT TO THE STUDY IN SPANISH. 6243 04:23:16,061 --> 04:23:23,569 THE STUDY IS INCREDIBLY HET 6244 04:23:23,569 --> 04:23:27,539 HETEROGENOUS FROM AN ETHNICITY 6245 04:23:27,539 --> 04:23:30,643 POINT OF VIEW AND WE DON'T HAVE 6246 04:23:30,643 --> 04:23:32,478 MUCH BIAS IN THE ENROLLMENT. 6247 04:23:32,478 --> 04:23:34,947 THESE ARE THE RESULTS OF WHAT 6248 04:23:34,947 --> 04:23:36,181 WAS RETURNED. 6249 04:23:36,181 --> 04:23:38,817 I POINT OUT THE GROUP 2 ARE LESS 6250 04:23:38,817 --> 04:23:40,953 FREQUENT THAN THE GROUP 1. 6251 04:23:40,953 --> 04:23:43,489 THERE ARE FALSE POSITIVES I'LL 6252 04:23:43,489 --> 04:23:46,525 HIGHLIGHT ON THE NEXT SLIDE AND 6253 04:23:46,525 --> 04:23:48,260 TRUE POSITIVES AND SOME 6254 04:23:48,260 --> 04:23:50,129 PRESUMPTIVE POSITIVES BECAUSE 6255 04:23:50,129 --> 04:23:52,998 THE CHILDREN HAVE NOT YET HAD 6256 04:23:52,998 --> 04:23:53,866 SYMPTOMS SO STILL RELATIVELY 6257 04:23:53,866 --> 04:23:54,400 EARLY DAYS. 6258 04:23:54,400 --> 04:23:58,504 FOR THIS GROUP I'LL POINT OUT 6259 04:23:58,504 --> 04:23:59,338 THIS ASCERTAINMENT IS 6260 04:23:59,338 --> 04:24:01,173 POPULATION-BASED ASCERTAINMENT 6261 04:24:01,173 --> 04:24:02,408 AND WHAT IS INTERESTING IN 6262 04:24:02,408 --> 04:24:03,542 NEWBORN SCREENING WHEN WE DO 6263 04:24:03,542 --> 04:24:04,643 THIS IS REALIZE THE FREQUENCY OF 6264 04:24:04,643 --> 04:24:06,578 THE CONDITIONS MAY NOT BE WHAT 6265 04:24:06,578 --> 04:24:12,351 WE CLINICALLY ASCERTAIN. 6266 04:24:12,351 --> 04:24:16,689 THE TOP ROW IS THE MOST COMMON 6267 04:24:16,689 --> 04:24:19,825 WE SEE WITHIN GROUP 2 FOR SCN1A 6268 04:24:19,825 --> 04:24:21,927 AND ONLY SEQUENCE THE BABY TO 6269 04:24:21,927 --> 04:24:24,530 START AND WHEN WE SEQUENCE THE 6270 04:24:24,530 --> 04:24:28,467 PARENTS IN THE CONNATE TRY WE 6271 04:24:28,467 --> 04:24:30,569 FIND THEY'RE OFTEN INHERITED 6272 04:24:30,569 --> 04:24:34,273 FROM ASYMPTOMATIC PARENTS AND 6273 04:24:34,273 --> 04:24:36,275 MANY OF WHAT I CALL FALSE 6274 04:24:36,275 --> 04:24:38,911 POSITIVES ARE INHERITED WITH 6275 04:24:38,911 --> 04:24:40,279 ASYMPTOMATIC PARENTS WITH NO 6276 04:24:40,279 --> 04:24:42,481 FAMILY HISTORY OF EPILEPSY. 6277 04:24:42,481 --> 04:24:44,883 AND SCN1A IS ASSOCIATED WITH A 6278 04:24:44,883 --> 04:24:46,518 BROAD PHENOTYPE AND THAT COULD 6279 04:24:46,518 --> 04:24:48,320 EXPLAIN WHY IT IS BUT DOES GET 6280 04:24:48,320 --> 04:24:48,620 COMPLICATED. 6281 04:24:48,620 --> 04:24:49,355 YOU CAN IMAGINE WHEN TRYING TO 6282 04:24:49,355 --> 04:24:53,025 EXPLAIN THIS TO PARENTS. 6283 04:24:53,025 --> 04:25:01,200 ALSO NOTABLY IN TERMS OF 6284 04:25:01,200 --> 04:25:02,534 TREATMENT, THIS IS MORE COMMON 6285 04:25:02,534 --> 04:25:04,837 AND FOR THIS GROUP I'LL POINT 6286 04:25:04,837 --> 04:25:09,008 OUT WE NOW IDENTIFIED EVEN TO 6287 04:25:09,008 --> 04:25:11,010 GROUP UPDATE THREE LITTLE GIRLS 6288 04:25:11,010 --> 04:25:13,579 WHAT ARE EXPECTED TO BE RETT 6289 04:25:13,579 --> 04:25:15,381 SYNDROME AND PRE OR ASYMPTOMATIC 6290 04:25:15,381 --> 04:25:16,815 AT THIS STAGE THOUGH BY 6291 04:25:16,815 --> 04:25:17,716 FOLLOWING CLOSELY WE CAN ALREADY 6292 04:25:17,716 --> 04:25:21,620 START TO SEE DECLINES OVER TIME. 6293 04:25:21,620 --> 04:25:26,892 SO WITH THIS WE IDENTIFIED 6294 04:25:26,892 --> 04:25:27,993 INDIVIDU 6295 04:25:27,993 --> 04:25:34,099 INDIVIDUALS AND THIS IS CDKL5 6296 04:25:34,099 --> 04:25:34,800 DIAGNOSED THROUGH GUARDIAN AND 6297 04:25:34,800 --> 04:25:35,334 USING THE INFORMATION FOR 6298 04:25:35,334 --> 04:25:37,336 TREATMENT. 6299 04:25:37,336 --> 04:25:39,171 AND THE REASON I EMPHASIZE ALL 6300 04:25:39,171 --> 04:25:40,706 THIS IS THIS COULD AND WAS 6301 04:25:40,706 --> 04:25:42,141 INTENDED TO OPEN UP THE 6302 04:25:42,141 --> 04:25:44,076 POSSIBILITY OF EARLY DIAGNOSIS 6303 04:25:44,076 --> 04:25:46,912 AND POTENTIALLY THERAPIES WE'RE 6304 04:25:46,912 --> 04:25:47,546 TALKING ABOUT AT THE CONFERENCE. 6305 04:25:47,546 --> 04:25:48,580 WITH THIS WE'RE TRYING TO BUILD 6306 04:25:48,580 --> 04:25:49,348 THE WHOLE INFRASTRUCTURE. 6307 04:25:49,348 --> 04:25:51,417 I WON'T GO INTO THIS GIVEN THE 6308 04:25:51,417 --> 04:25:56,855 INTEREST OF TIME AND SIMPLY TO 6309 04:25:56,855 --> 04:26:00,592 SAY WE HOPE WE'RE IMPROVING 6310 04:26:00,592 --> 04:26:02,428 EQUITY IN A POPULATION BASED WAY 6311 04:26:02,428 --> 04:26:04,696 IMPROVING ACCESS TO THE 6312 04:26:04,696 --> 04:26:07,232 DIAGNOSIS WHICH HOPEFULLY OPENS 6313 04:26:07,232 --> 04:26:09,334 OPPORTUNITIES FOR TREATMENT AND 6314 04:26:09,334 --> 04:26:11,437 THANK EVERYONE WHO HAS BEEN A 6315 04:26:11,437 --> 04:26:13,072 PART OF THIS AND LEAVE TIME FOR 6316 04:26:13,072 --> 04:26:20,479 QUESTIONS IN THE PANEL. 6317 04:26:20,479 --> 04:26:22,748 >> THANKS, SO MUCH, WENDY. 6318 04:26:22,748 --> 04:26:23,682 DOES ANYBODY HAVE QUESTIONS TO 6319 04:26:23,682 --> 04:26:26,118 START FOR WENDY IF YOU CAN USE 6320 04:26:26,118 --> 04:26:29,721 THE MIC THAT WOULD BE GREAT. 6321 04:26:29,721 --> 04:26:35,494 LIZ AND FLORIAN AND KATHY, 6322 04:26:35,494 --> 04:26:35,861 THAT'D BE GREAT. 6323 04:26:35,861 --> 04:26:37,496 >> HI, WENDY. 6324 04:26:37,496 --> 04:26:38,497 CAN YOU HEAR ME? 6325 04:26:38,497 --> 04:26:39,531 >> I CAN. 6326 04:26:39,531 --> 04:26:39,998 >> GREAT. 6327 04:26:39,998 --> 04:26:42,134 I WAS CURIOUS ABOUT YOUR 6328 04:26:42,134 --> 04:26:44,636 APPROACH FOR KIP 1A USING A 6329 04:26:44,636 --> 04:26:46,638 COMMON SNIP OR A SNAP RATHER 6330 04:26:46,638 --> 04:26:48,107 THAN THE ACTUAL MUTANT ALLELE 6331 04:26:48,107 --> 04:26:50,109 WHICH WHICH I THINK IS A GREAT 6332 04:26:50,109 --> 04:26:50,509 APPROACH. 6333 04:26:50,509 --> 04:26:55,514 I'M CURIOUS HOW COMMON IS THAT 6334 04:26:55,514 --> 04:26:57,149 SNIP AND WHAT PROPORTION OF 6335 04:26:57,149 --> 04:27:00,519 PATIENTS COULD YOU USE IT FOR DO 6336 04:27:00,519 --> 04:27:03,322 YOU THINK WITH KIP 1A WITHOUT 6337 04:27:03,322 --> 04:27:05,057 DEVELOP THERAPY FOR EVERY 6338 04:27:05,057 --> 04:27:05,491 PATIENT? 6339 04:27:05,491 --> 04:27:08,393 >> THE BOTTOM LINE IS ABOUT 10%. 6340 04:27:08,393 --> 04:27:10,295 IN TERMS OF LOOKING AT THE 6341 04:27:10,295 --> 04:27:15,968 VARIATION WITH THE GENE ASSUMING 6342 04:27:15,968 --> 04:27:18,570 ENOUGH VARIANCE COULD BE 6343 04:27:18,570 --> 04:27:22,274 TARGETED A LIBRARY BETWEEN 5 AND 6344 04:27:22,274 --> 04:27:23,575 10ASOs BUT DON'T THINK IT WILL 6345 04:27:23,575 --> 04:27:25,577 BE LESS THAN FIVE BUT COULD BE 6346 04:27:25,577 --> 04:27:27,279 SLIGHTLY MORE THAN 10. 6347 04:27:27,279 --> 04:27:30,149 I'M NOT SURE HOW TARGETABLE THE 6348 04:27:30,149 --> 04:27:33,986 COMMON ASOs WILL BE AND WE HAVE 6349 04:27:33,986 --> 04:27:35,554 SOME EVIDENCE THE ONES WE'D LIKE 6350 04:27:35,554 --> 04:27:46,031 TO TAR GET WON'T BE ENOUGH. 6351 04:27:47,799 --> 04:27:49,334 >> WAS THE STRATEGY TO TREAT A 6352 04:27:49,334 --> 04:27:50,869 GREATER NUMBER OF PATIENTS? 6353 04:27:50,869 --> 04:27:56,241 >> A LITTLE BIT OF BOTH. 6354 04:27:56,241 --> 04:28:06,585 THE PROCESS FROM THE SCREENING 6355 04:28:06,585 --> 04:28:09,021 WHICH ONES ARE MOST SELECTIVE 6356 04:28:09,021 --> 04:28:10,756 AND THIS IS THE CLEAR WINNER IN 6357 04:28:10,756 --> 04:28:12,991 HER PARTICULAR CASE AND AS A 6358 04:28:12,991 --> 04:28:14,993 DEMONSTRATION WITH FIRST IN WE 6359 04:28:14,993 --> 04:28:15,961 DIDN'T WORRY NEARLY AS MUCH 6360 04:28:15,961 --> 04:28:17,563 ABOUT THE ABILITY TO TARGET 6361 04:28:17,563 --> 04:28:17,896 EVERYONE. 6362 04:28:17,896 --> 04:28:19,231 WE WERE FIRST TRYING TO FIGURE 6363 04:28:19,231 --> 04:28:22,868 OUT COULD WE GET THIS TO WORK 6364 04:28:22,868 --> 04:28:23,702 AND DID IT BASED ON ALLELE 6365 04:28:23,702 --> 04:28:26,605 SPECIFICITY. 6366 04:28:26,605 --> 04:28:28,941 >> AS WE KICK OFF OUR PANEL 6367 04:28:28,941 --> 04:28:30,509 DISCUSSION WITH OUR SPEAKERS I 6368 04:28:30,509 --> 04:28:33,612 WANTED TO THANK OUR SPEAKERS FOR 6369 04:28:33,612 --> 04:28:35,547 THEIR WONDERFUL ILLUSTRATIVE 6370 04:28:35,547 --> 04:28:36,748 EXAMPLE AND FOR HIGHLIGHTING HOW 6371 04:28:36,748 --> 04:28:38,150 MUCH IS THERE TO SHARE AND HOW 6372 04:28:38,150 --> 04:28:40,686 MUCH YOU HAVE SHARED BOTH IN 6373 04:28:40,686 --> 04:28:42,221 TERMS OF POTENTIAL RISKS OF 6374 04:28:42,221 --> 04:28:45,023 THERAPIES WHICH CAN BE SHARED 6375 04:28:45,023 --> 04:28:47,292 WITHIN PLATFORMS BUT EVEN ACROSS 6376 04:28:47,292 --> 04:28:49,828 PLATFORMS AND ALSO POTENTIAL 6377 04:28:49,828 --> 04:28:52,297 BENEFITS IN HOW WE MEASURE THEM 6378 04:28:52,297 --> 04:28:54,099 AND TO GET TO THE CRUX OF ALL 6379 04:28:54,099 --> 04:28:59,738 YOUR TALKS, EVERYTHING IS A RISK 6380 04:28:59,738 --> 04:29:01,306 WHETHER FOR A TRIAL YOU'VE ALL 6381 04:29:01,306 --> 04:29:03,308 OUTLINED HOW TO LOOK FORWARD AND 6382 04:29:03,308 --> 04:29:05,477 DEAL WITH THE RISKS AS THEY 6383 04:29:05,477 --> 04:29:07,546 UNFOLD UNEXPECTEDLY AND ALSO HOW 6384 04:29:07,546 --> 04:29:08,480 TO THINK ABOUT POTENTIAL 6385 04:29:08,480 --> 04:29:10,582 BENEFITS AND WHAT OUTCOMES ARE 6386 04:29:10,582 --> 04:29:11,783 MOST IMPORTANT. 6387 04:29:11,783 --> 04:29:16,855 SO, I WON'T TAKE MORE TIME AND 6388 04:29:16,855 --> 04:29:18,490 LEAVE IT FOR MORE QUESTIONS BUT 6389 04:29:18,490 --> 04:29:19,825 I WANT TO ACKNOWLEDGE HOW 6390 04:29:19,825 --> 04:29:22,861 POWERFUL IT WAS TO HEAR EXAMPLES 6391 04:29:22,861 --> 04:29:23,562 AND THE BASIC POINTS WERE SO 6392 04:29:23,562 --> 04:29:28,567 WELL COVERED. 6393 04:29:28,567 --> 04:29:35,574 >> LET ME ECHO TO THE ORGANIZERS 6394 04:29:35,574 --> 04:29:39,044 WHAT AN AVENGER LEVEL OF 6395 04:29:39,044 --> 04:29:39,344 ACHIEVEMENT. 6396 04:29:39,344 --> 04:29:43,482 I'M GOING TO FOLLOW UP ON WHAT 6397 04:29:43,482 --> 04:29:45,751 YOU SAID YOU SPOKE ABOUT THE 6398 04:29:45,751 --> 04:29:50,455 ANTICIPATED IMMUNE RESPONSE. 6399 04:29:50,455 --> 04:29:51,823 THE CONDITION REGIMENT DEPENDENT 6400 04:29:51,823 --> 04:29:55,560 AND YOU MENTIONED LEG WEAKNESS 6401 04:29:55,560 --> 04:29:58,597 THAT ULTIMATELY CREATED A 6402 04:29:58,597 --> 04:30:00,565 TWO-YEAR CLINICAL HOLD. 6403 04:30:00,565 --> 04:30:06,571 AS ONE THINK ABOUT CHILDHOOD 6404 04:30:06,571 --> 04:30:10,275 EPILEPSIES AN BENEFIT RISK, A 6405 04:30:10,275 --> 04:30:12,878 HOW DO WE DEAL WITH THE FACT AS 6406 04:30:12,878 --> 04:30:16,915 BEST I CAN TELL THEY WERE NOT 6407 04:30:16,915 --> 04:30:18,817 PREDICTIVE OF LONG LEVEL 6408 04:30:18,817 --> 04:30:19,117 EXPERIMENT. 6409 04:30:19,117 --> 04:30:21,153 WHAT ADVISE WOULD YOU GIVE TO 6410 04:30:21,153 --> 04:30:24,489 THE GENETICISTS OR THOSE WRITING 6411 04:30:24,489 --> 04:30:27,459 THE PROFILE, HOW SHOULD WE DEAL 6412 04:30:27,459 --> 04:30:29,661 WITH THE FACT THERE MAY BE AN 6413 04:30:29,661 --> 04:30:31,863 ASE BUT WE DON'T KNOW WHAT 6414 04:30:31,863 --> 04:30:34,666 THEY'RE GOING TO BE? 6415 04:30:34,666 --> 04:30:37,536 >> WELL, I THINK EVERYONE IN THE 6416 04:30:37,536 --> 04:30:40,739 ROOM UNDERSTANDS THE FDA DOESN'T 6417 04:30:40,739 --> 04:30:42,574 LICENSE DRUGS BASED ON ANIMAL 6418 04:30:42,574 --> 04:30:45,977 STUDY ALONE BECAUSE IN CLINICAL 6419 04:30:45,977 --> 04:30:47,546 INVESTIGATION YOU FIND ASSAYS 6420 04:30:47,546 --> 04:30:50,949 THAT WERE NOT PREDICTED BY 6421 04:30:50,949 --> 04:30:55,420 ANIMAL STUDY AND I THINK THE 6422 04:30:55,420 --> 04:30:57,889 NUMBER IS SOMETHING LIKE ANIMAL 6423 04:30:57,889 --> 04:31:01,827 STUDIES ACCURATELY PREDICT ABOUT 6424 04:31:01,827 --> 04:31:03,028 70% OF ADVERSE EVENTS SEEN IN 6425 04:31:03,028 --> 04:31:04,529 HUMANS. 6426 04:31:04,529 --> 04:31:10,736 SO, WHAT CAN YOU DO OTHER THAN 6427 04:31:10,736 --> 04:31:13,071 ACKNOWLEDGE THAT IN THE INFORMED 6428 04:31:13,071 --> 04:31:15,140 CONSENT AND THEN IT BECOMES A 6429 04:31:15,140 --> 04:31:16,541 CHOICE OF THE FAMILIES IF 6430 04:31:16,541 --> 04:31:18,577 THEY'RE WILLING TO TAKE THE 6431 04:31:18,577 --> 04:31:21,079 RISK. 6432 04:31:21,079 --> 04:31:23,382 >> LET ME ADD TO THAT. 6433 04:31:23,382 --> 04:31:25,984 I DO THINK IT REQUIRES A LOT OF 6434 04:31:25,984 --> 04:31:30,956 COMMUNICATION WITH FAMILIES UP 6435 04:31:30,956 --> 04:31:31,323 FRONT. 6436 04:31:31,323 --> 04:31:32,858 AND THERE'S A REASON THERE'S 6437 04:31:32,858 --> 04:31:33,759 STAGGERED ENROLLMENT AND THIS IS 6438 04:31:33,759 --> 04:31:36,228 A HUGE PART OF THAT AND IT'S 6439 04:31:36,228 --> 04:31:38,530 VERY HARD FOR FAMILIES TO WRAP 6440 04:31:38,530 --> 04:31:41,867 THEIR HEAD AROUND WHY IS IT WE 6441 04:31:41,867 --> 04:31:45,237 HAVE TO WAIT UNTIL THE DSMB 6442 04:31:45,237 --> 04:31:47,539 MEETS AND IT'S AN INTEGRAL PART 6443 04:31:47,539 --> 04:31:53,378 OF OUR LANDSCAPE AND TO BE UP 6444 04:31:53,378 --> 04:31:54,546 FRONT COMMUNICATING ABOUT THIS 6445 04:31:54,546 --> 04:31:56,815 AND EXPLAIN THIS IS HOW WE LEARN 6446 04:31:56,815 --> 04:31:59,885 TOGETHER AND I THINK WE'RE IN A 6447 04:31:59,885 --> 04:32:00,585 DIFFERENT STAGE WHERE WE HAVE 6448 04:32:00,585 --> 04:32:03,555 MUCH MORE AWARENESS OF THE 6449 04:32:03,555 --> 04:32:06,558 IMMUNE RESPONSES COMPARED TO 6450 04:32:06,558 --> 04:32:09,327 PIONEERING WORK KATHY DID. 6451 04:32:09,327 --> 04:32:13,165 I THINK WE ARE IN A BETTER 6452 04:32:13,165 --> 04:32:14,766 POSITION TO REACT AND TRAIN AND 6453 04:32:14,766 --> 04:32:17,402 EDUCATE THE NEXT GENERATION OF 6454 04:32:17,402 --> 04:32:18,603 PHYSICIANS SO I THINK IT'S QUITE 6455 04:32:18,603 --> 04:32:20,405 ENCOURAGING. 6456 04:32:20,405 --> 04:32:23,341 >> YEAH, I THINK FOR THE ASOs WE 6457 04:32:23,341 --> 04:32:23,842 DON'T KNOW. 6458 04:32:23,842 --> 04:32:27,712 THERE ARE SOME THINGS BUT THE 6459 04:32:27,712 --> 04:32:31,383 ASO THAT PREDICTED WHAT WAS 10 6460 04:32:31,383 --> 04:32:33,718 TIMES THE DOSE IN THE MONKEY AND 6461 04:32:33,718 --> 04:32:38,023 THERE WAS NO SIGN OF IT. 6462 04:32:38,023 --> 04:32:39,224 IT'S CLEARLY A HUMAN AFFECT AND 6463 04:32:39,224 --> 04:32:41,660 YOU'RE NOT GOING TO BE ABLE TO 6464 04:32:41,660 --> 04:32:43,361 DO THAT WITHOUT GOING TO CLINIC. 6465 04:32:43,361 --> 04:32:46,765 ONE THING WE DID AT THE SITE AT 6466 04:32:46,765 --> 04:32:48,600 THE REQUEST OF THE FDA WAS THEY 6467 04:32:48,600 --> 04:32:49,201 WANTED TO MAKE SURE EVERYBODY 6468 04:32:49,201 --> 04:32:51,536 HAD A CHANCE TO BENEFIT AND SO 6469 04:32:51,536 --> 04:32:54,272 THE DOSE ACCELERATION WAS 6470 04:32:54,272 --> 04:32:55,574 PROBABLY TOO FAST AND IF THEY 6471 04:32:55,574 --> 04:32:58,376 HAD DONE IT AS AN EXTENDING DOSE 6472 04:32:58,376 --> 04:33:00,579 IN COHORT OPPOSED TO WITHIN 6473 04:33:00,579 --> 04:33:01,780 PATIENTS PROBABLY THEY WOULD 6474 04:33:01,780 --> 04:33:04,783 HAVE AVOIDED AND STARTED TO SEE 6475 04:33:04,783 --> 04:33:06,585 IT BUT START TO ELEVATE THE 6476 04:33:06,585 --> 04:33:07,919 PROTEINS AND WOULD HAVE HAD TO 6477 04:33:07,919 --> 04:33:08,987 BACK OFF. 6478 04:33:08,987 --> 04:33:13,325 I THINK IT'S A WARNING FOR ASOs 6479 04:33:13,325 --> 04:33:24,169 WE SHOULD DO AN ACRENDS -- AS 6480 04:33:38,683 --> 04:33:42,587 ASCENDING DOSE PROTOCOL. 6481 04:33:42,587 --> 04:33:52,797 ONE HAD IT. 6482 04:33:55,600 --> 04:34:00,138 THEY ABOUT BEEN GETTING 6483 04:34:00,138 --> 04:34:01,239 INCREASED DOSE AND DIDN'T 6484 04:34:01,239 --> 04:34:04,309 UNDERSTAND IT WAS A TIME RELATED 6485 04:34:04,309 --> 04:34:06,578 EVENT BUT NOW IN THE END WE 6486 04:34:06,578 --> 04:34:12,817 UNDERSTAND IT'S A DOSE RELATED 6487 04:34:12,817 --> 04:34:13,018 EVENT. 6488 04:34:13,018 --> 04:34:20,191 >> SO WHAT I'M OBSERVING WITH 6489 04:34:20,191 --> 04:34:22,160 THE CLINICAL TRIALS AND THERE'S 6490 04:34:22,160 --> 04:34:23,895 DATA COLLECTED WHICH IS 6491 04:34:23,895 --> 04:34:24,796 UNMATCHED COMPARED TO WHAT IS IN 6492 04:34:24,796 --> 04:34:29,601 RESEARCH. 6493 04:34:29,601 --> 04:34:36,608 AND THE PROBLEM IS THE DATA IS 6494 04:34:36,608 --> 04:34:38,510 NOT ACCESSIBLE BEYOND THE 6495 04:34:38,510 --> 04:34:39,544 CLINICAL TRIALS AND MANY WOULD 6496 04:34:39,544 --> 04:34:40,745 LOVE TO LEARN MORE ABOUT THE 6497 04:34:40,745 --> 04:34:44,182 DISEASE AND AS MENTIONED YOU 6498 04:34:44,182 --> 04:34:45,951 LEARN THROUGHOUT THE CLINICAL 6499 04:34:45,951 --> 04:34:50,889 TRIALS SOMETHING ABOUT THE 6500 04:34:50,889 --> 04:34:53,959 DISEASE. 6501 04:34:53,959 --> 04:34:56,861 WE'VE ALSO LOOKED BACK ON THE 6502 04:34:56,861 --> 04:34:59,030 TRIAL TO WHICH DEGREE THE DATA 6503 04:34:59,030 --> 04:35:02,200 WAS PUB LUCKILY ACCESSIBLE FOR 6504 04:35:02,200 --> 04:35:08,006 RESEARCH AND SECONDARILY WHICH 6505 04:35:08,006 --> 04:35:11,309 DEGREE WHERE AFTER THE TRIAL 6506 04:35:11,309 --> 04:35:12,544 LONG-TERM THERE WAS A 6507 04:35:12,544 --> 04:35:15,714 STANDARDIZED WAY FOR MORE 6508 04:35:15,714 --> 04:35:22,954 BENEFITS. 6509 04:35:22,954 --> 04:35:24,489 >> OKAY. 6510 04:35:24,489 --> 04:35:29,194 SO I THINK FOR MOST THE EARLY 6511 04:35:29,194 --> 04:35:31,563 GENE THERAPY TRIALS THE 6512 04:35:31,563 --> 04:35:35,567 REGULATORY AGENCIES HAVE 6513 04:35:35,567 --> 04:35:37,102 RECOMMENDED LONG-TERM FOLLOW-UP. 6514 04:35:37,102 --> 04:35:39,537 THERE'S A GUIDANCE FOR AAV 6515 04:35:39,537 --> 04:35:41,006 VECTORS IT SHOULD BE FIVE YEARS 6516 04:35:41,006 --> 04:35:44,909 FOR INTEGRATING VECTORS IT'S 6517 04:35:44,909 --> 04:35:54,919 LONGER THAN THAT. 6518 04:35:54,919 --> 04:35:55,520 BUT DESPITE THAT WELL DEFINED 6519 04:35:55,520 --> 04:35:56,221 GUIDANCE DOCUMENT THAT WHEN IT'S 6520 04:35:56,221 --> 04:36:06,798 APPROVED THEY ASK US TO KEEP A 6521 04:36:06,798 --> 04:36:07,432 SAFETY REGISTRY OF THE FIRST 500 6522 04:36:07,432 --> 04:36:08,066 PATIENTS WHO GOT THE TREATMENT 6523 04:36:08,066 --> 04:36:11,102 TO FOLLOW OUR PHASE III PATIENTS 6524 04:36:11,102 --> 04:36:12,871 FOR 10 YEARS. 6525 04:36:12,871 --> 04:36:15,573 WE HAVE PERIODICALLY PUBLISHED 6526 04:36:15,573 --> 04:36:16,675 THAT OVER TIME. 6527 04:36:16,675 --> 04:36:18,376 I THINK THE LAST PUBLICATION WAS 6528 04:36:18,376 --> 04:36:23,548 FIVE YEARS AND THERE'S AN 6529 04:36:23,548 --> 04:36:25,216 ABSTRACT NOW THAT GIVES DATA OUT 6530 04:36:25,216 --> 04:36:27,452 TO EIGHT YEARS BUT I MEAN I 6531 04:36:27,452 --> 04:36:29,187 THINK IT'S GOOD FOR THE FIELD TO 6532 04:36:29,187 --> 04:36:35,326 THE EXTENT THAT THIS DATA CAN BE 6533 04:36:35,326 --> 04:36:36,594 PUBLISHED IN THE MEDICAL 6534 04:36:36,594 --> 04:36:40,498 LITERATURE IT'S A GOOD THING 6535 04:36:40,498 --> 04:36:41,933 UNTIL THERE'S MORE CONFIDENCE 6536 04:36:41,933 --> 04:36:44,135 ABOUT THE SAFETY OF GENE 6537 04:36:44,135 --> 04:36:44,369 THERAPY. 6538 04:36:44,369 --> 04:36:47,038 I THINK THE RISK BENEFIT RATIO 6539 04:36:47,038 --> 04:36:50,842 WILL REMAIN A CHALLENGING TOPIC. 6540 04:36:50,842 --> 04:36:53,945 >> AND TO ADD TO THIS I THINK 6541 04:36:53,945 --> 04:36:58,416 IT'S RIGHT YOU BROUGHT UP THE 6542 04:36:58,416 --> 04:37:01,886 PATIENT'S PERSPECTIVE BECAUSE 6543 04:37:01,886 --> 04:37:03,855 IT'S QUITE POWERFUL IN THE RARE 6544 04:37:03,855 --> 04:37:04,422 DISEASE FIELD. 6545 04:37:04,422 --> 04:37:08,727 COMPANIES, INVESTIGATORS, ALL OF 6546 04:37:08,727 --> 04:37:11,463 US ARE ASKED TO MANAGE 6547 04:37:11,463 --> 04:37:15,533 RELATIONSHIPS TO MAINTAIN TRUST 6548 04:37:15,533 --> 04:37:17,235 AND PART IS BEING AS TRANSPARENT 6549 04:37:17,235 --> 04:37:19,070 AS YOU CAN BE ABOUT WHAT YOU 6550 04:37:19,070 --> 04:37:22,340 KNOW AND DON'T KNOW WHICH IS 6551 04:37:22,340 --> 04:37:26,077 OFTEN MORE PROMINENT THAN 6552 04:37:26,077 --> 04:37:27,545 PATIENTS MIGHT RECOGNIZE HOW TO 6553 04:37:27,545 --> 04:37:30,348 COME FORWARD WITH THAT AND THEN 6554 04:37:30,348 --> 04:37:34,219 SAY WARE NOT WITHHOLDING 6555 04:37:34,219 --> 04:37:37,722 ANYTHING WE JUST DON'T KNOW. 6556 04:37:37,722 --> 04:37:39,023 THERE'S TENSION IN THE PROCESS. 6557 04:37:39,023 --> 04:37:41,326 WE BUILT THINGS LIKE ADVISORY 6558 04:37:41,326 --> 04:37:48,600 COUNCILS WHERE WE BRING TOGETHER 6559 04:37:48,600 --> 04:37:53,004 MULTIPLE FACES AND COMMUNICATE 6560 04:37:53,004 --> 04:37:56,641 TO THE ADVOCACY GROUPS WE'RE 6561 04:37:56,641 --> 04:37:57,542 SHARING AS MUCH AS WE CAN 6562 04:37:57,542 --> 04:37:59,711 BECAUSE THE BENEFIT OF PATIENTS 6563 04:37:59,711 --> 04:38:01,379 IS FIRST AND FOREMOST. 6564 04:38:01,379 --> 04:38:03,214 >> YEAH, I THINK YOU RAISED A 6565 04:38:03,214 --> 04:38:03,848 COUPLE POINTS. 6566 04:38:03,848 --> 04:38:06,551 ONE IS DATA COLLECTION ACROSS 6567 04:38:06,551 --> 04:38:09,420 ONE DISEASE BUT ACROSS MULTIPLE 6568 04:38:09,420 --> 04:38:10,522 DISEASES AND IN ANGELMAN 6569 04:38:10,522 --> 04:38:11,823 SYNDROME THEY HAVE THE DATABASE 6570 04:38:11,823 --> 04:38:14,058 AND THERE'S HEAVY PRESSURE ON 6571 04:38:14,058 --> 04:38:15,260 COMPANIES THAT HAVE A FAILED 6572 04:38:15,260 --> 04:38:18,630 TRIAL AND ARE GETTING OUT OR 6573 04:38:18,630 --> 04:38:21,933 HAVE A COMPLETED TRIAL OR ROCHE 6574 04:38:21,933 --> 04:38:23,501 IS LEADING THE FIELD WITH THE 6575 04:38:23,501 --> 04:38:25,103 BASELINE DATA GOES INTO THE 6576 04:38:25,103 --> 04:38:26,304 REGISTRY TO COLLECT ALL OF IT. 6577 04:38:26,304 --> 04:38:31,943 I THINK WE'D LIKE TO HAVE ALL 6578 04:38:31,943 --> 04:38:35,046 THE TRIAL DATA AND THEY CAN WORK 6579 04:38:35,046 --> 04:38:37,148 WITH FDA AND PULL A CONTROL 6580 04:38:37,148 --> 04:38:43,521 GROUP OUT IF YOU HAVE DATA 6581 04:38:43,521 --> 04:38:48,626 COLLECTED FOR YOUR DISEASE AND 6582 04:38:48,626 --> 04:38:49,828 THE GENETIC TREATMENTS ARE 6583 04:38:49,828 --> 04:38:50,461 INCREDIBLY IMPORTANT AND ONCE 6584 04:38:50,461 --> 04:38:53,665 YOU HAVE ASO APPROVED WE'RE 6585 04:38:53,665 --> 04:38:56,134 GOING TO GET THAT APPROVED AND 6586 04:38:56,134 --> 04:38:56,734 HAVE A DIFFERENCE IN TREATED 6587 04:38:56,734 --> 04:39:02,607 VERSUS UNTREATED PATIENTS IN ONE 6588 04:39:02,607 --> 04:39:05,577 YEAR. 6589 04:39:05,577 --> 04:39:06,978 WE HAVE NO IDEA WHAT THE 6590 04:39:06,978 --> 04:39:09,814 LONG-TERM OUTCOME WILL BE UNLESS 6591 04:39:09,814 --> 04:39:14,485 WE HAVE A COLLECTION AND SAME 6592 04:39:14,485 --> 04:39:17,522 TRUE OF OTHERS APPROVED BUT THE 6593 04:39:17,522 --> 04:39:18,623 FDA REQUIRED A STUDY BE 6594 04:39:18,623 --> 04:39:22,393 CONDUCTED BUT THE TRUE QUESTIONS 6595 04:39:22,393 --> 04:39:24,629 WERE HOW LONG DID THE PATIENT 6596 04:39:24,629 --> 04:39:27,632 STABILIZE AND WHAT GOT WORSE? 6597 04:39:27,632 --> 04:39:30,635 NONE OF THAT DATA WAS COLLECTED 6598 04:39:30,635 --> 04:39:32,370 AND IT'S A GREAT OPPORTUNITY 6599 04:39:32,370 --> 04:39:32,570 LOST. 6600 04:39:32,570 --> 04:39:35,573 SAFETY DATA IS YES, IMPORTANT, 6601 04:39:35,573 --> 04:39:38,543 BUT FOR SOME LONG-TERM OUTCOMES 6602 04:39:38,543 --> 04:39:40,578 COLLECTING EFFICACY DATA IS 6603 04:39:40,578 --> 04:39:41,446 TREMENDOUSLY IMPORTANT BECAUSE 6604 04:39:41,446 --> 04:39:42,780 OTHERWISE WHEN WE TRY TO ADD THE 6605 04:39:42,780 --> 04:39:47,585 NEXT THERAPY HOW WILL WE KNOW 6606 04:39:47,585 --> 04:39:57,829 WHERE WE ARE? 6607 04:40:00,198 --> 04:40:02,600 >> WE LOOK FOR LIKE ONE THERAPY 6608 04:40:02,600 --> 04:40:03,468 FOR ALL THE PATIENT POPULATION 6609 04:40:03,468 --> 04:40:07,472 BUT EVENTUALLY WHEN WE MOVE TO 6610 04:40:07,472 --> 04:40:11,643 THE DOMAIN WE'LL HAVE ONE 6611 04:40:11,643 --> 04:40:14,512 PATIENT AND SEVERAL DIFFERENT. 6612 04:40:14,512 --> 04:40:23,755 IN THAT USING FDA APPROVAL AND 6613 04:40:23,755 --> 04:40:28,626 COMPARE WITH THE NATURAL HISTORY 6614 04:40:28,626 --> 04:40:37,535 OF CARRIER AND HOW DO THEY 6615 04:40:37,535 --> 04:40:39,570 IMPROVE? 6616 04:40:39,570 --> 04:40:49,747 THANK YOU. 6617 04:40:54,085 --> 04:40:55,553 >> YOU HAVE TO KNOW ENOUGH OF 6618 04:40:55,553 --> 04:40:57,322 THE RISK YOU'RE TAKING. 6619 04:40:57,322 --> 04:40:59,490 WE KNOW IN RARE DISEASES NATURAL 6620 04:40:59,490 --> 04:41:01,659 HISTORY IS SPARSE. 6621 04:41:01,659 --> 04:41:03,561 HOW MUCH CAN YOU KNOW AND HOW 6622 04:41:03,561 --> 04:41:06,664 CAN YOU STEP IN FRONT OF FDA TO 6623 04:41:06,664 --> 04:41:09,167 SAY GIVEN WHAT I KNOW AND WHAT I 6624 04:41:09,167 --> 04:41:14,405 DON'T KNOW I THINK THIS 6625 04:41:14,405 --> 04:41:14,672 WARRANTED. 6626 04:41:14,672 --> 04:41:17,542 SO I THINK THERE'S NO QUESTION 6627 04:41:17,542 --> 04:41:18,977 NATURAL HISTORY IS IMPORTANT BUT 6628 04:41:18,977 --> 04:41:21,045 IT'S HUGELY CHALLENGING AND RARE 6629 04:41:21,045 --> 04:41:27,185 CONDITION AND NOTE THE CHANGES 6630 04:41:27,185 --> 04:41:30,655 ON THEIR INTERVENTION AND THE 6631 04:41:30,655 --> 04:41:34,559 EFFECT YOU SEE OFTEN ARE IN PART 6632 04:41:34,559 --> 04:41:37,261 DUE TO THE PLATFORM AND THE 6633 04:41:37,261 --> 04:41:39,697 CONTEXT OF THE DISEASE. 6634 04:41:39,697 --> 04:41:45,470 I THINK ONE HAS TO CONTEX 6635 04:41:45,470 --> 04:41:45,803 CONTEXTUALIZE. 6636 04:41:45,803 --> 04:41:48,373 >> I THINK WHEN YOU DEAL WITH 6637 04:41:48,373 --> 04:41:48,940 THE END OF 1 TREATMENT AND 6638 04:41:48,940 --> 04:41:51,542 CLEARLY SEE A CLINICAL AFFECT 6639 04:41:51,542 --> 04:41:53,344 THAT SEEMS TO BE INCONSISTENT 6640 04:41:53,344 --> 04:41:53,811 WITH NATURAL HISTORY. 6641 04:41:53,811 --> 04:41:59,550 I DON'T KNOW THAT'S EVER AN 6642 04:41:59,550 --> 04:42:03,721 APPROVABLE OUTCOME AND HAVE A 6643 04:42:03,721 --> 04:42:06,657 SPECIFIC TARGET THAT MAY BE A 6644 04:42:06,657 --> 04:42:09,360 POLYMORPHISM BUT MAYBE A NUMBER 6645 04:42:09,360 --> 04:42:12,663 OF PATIENTS OR ONE PATIENT IS 6646 04:42:12,663 --> 04:42:14,932 THAT EVER AN APPROVABLE THING AT 6647 04:42:14,932 --> 04:42:17,502 FDA AND I THINK WE'LL SEE MORE 6648 04:42:17,502 --> 04:42:20,805 AND MORE WHEN WE EDIT SPECIFIC 6649 04:42:20,805 --> 04:42:21,072 MUTATIONS. 6650 04:42:21,072 --> 04:42:22,807 I DON'T KNOW WHERE THAT LEADS US 6651 04:42:22,807 --> 04:42:24,642 AND I THOUGHT ABOUT THAT A LOT 6652 04:42:24,642 --> 04:42:26,144 BECAUSE THE FDA COULD HAVE A 6653 04:42:26,144 --> 04:42:26,744 POLITICAL ONAPPLICATIONS AND 6654 04:42:26,744 --> 04:42:29,947 WHAT WILL WE DO AND WHAT IS THE 6655 04:42:29,947 --> 04:42:32,950 PLATFORM AND THEIR ROLE? 6656 04:42:32,950 --> 04:42:33,551 IF THE FAMILY UNDERSTAND THE 6657 04:42:33,551 --> 04:42:43,628 RISK AND THE CLINICIAN EXPLAINED 6658 04:42:43,628 --> 04:42:44,262 THEM WELL AND THE ETHICS BOARD 6659 04:42:44,262 --> 04:42:44,896 HAS INCREASED THERAPY AND YOU'LL 6660 04:42:44,896 --> 04:42:45,563 TREAT ONE PATIENT, I AM CONFUSED 6661 04:42:45,563 --> 04:42:50,435 WHERE THE FDA ROLE IS IN THAT 6662 04:42:50,435 --> 04:42:53,237 PROCESS AND WHETHER THEY CAN 6663 04:42:53,237 --> 04:42:56,374 KEEP UP WITH IT AND THINK THEY 6664 04:42:56,374 --> 04:42:58,042 CAN'T KEEP UP IN THE FUTURE. 6665 04:42:58,042 --> 04:43:05,316 >> ONE WAY TO MADE AVAILABLE IF 6666 04:43:05,316 --> 04:43:05,950 ANOTHER PATIENT IS FOUND THROUGH 6667 04:43:05,950 --> 04:43:09,187 PERPETUAL IMB AND THE 6668 04:43:09,187 --> 04:43:11,022 INVESTIGATIONAL PRODUCT IS 6669 04:43:11,022 --> 04:43:12,623 AVAILABLE AND OVER TIME MAYBE 6670 04:43:12,623 --> 04:43:14,826 ENOUGH PATIENTS ARE ACCUMULATED 6671 04:43:14,826 --> 04:43:16,961 AND IT COULD BE FOUND AS AN 6672 04:43:16,961 --> 04:43:18,663 APPROVALABLE PRODUCT BUT IT 6673 04:43:18,663 --> 04:43:23,568 DOESN'T HAVE TO HAPPEN. 6674 04:43:23,568 --> 04:43:28,005 >> DON'T THINK IT'S A FORMAL 6675 04:43:28,005 --> 04:43:28,773 APPROVAL WITH ONE PATIENT. 6676 04:43:28,773 --> 04:43:33,878 >> I HAD A DIFFERENT QUESTION 6677 04:43:33,878 --> 04:43:36,647 ALL ABOUT THE OPEN IND AND WE 6678 04:43:36,647 --> 04:43:39,016 HAD DISCUSSIONS AT MY 6679 04:43:39,016 --> 04:43:41,352 INSTITUTION ABOUT SPENDING 6680 04:43:41,352 --> 04:43:45,056 MILLIONS TO MAKE TO THE DRUG WHY 6681 04:43:45,056 --> 04:43:49,127 NOT JUST KEEP THE OPEN IND AND 6682 04:43:49,127 --> 04:43:50,495 THE COMMENT FROM PHYSICIANS IS 6683 04:43:50,495 --> 04:43:52,597 WHO WILL PAY FOR THEIR CLINICAL 6684 04:43:52,597 --> 04:43:54,532 CARE AND HOW WILL WE BUILD THIS 6685 04:43:54,532 --> 04:43:57,301 CARE FOR NON-APPROVED PRODUCTS? 6686 04:43:57,301 --> 04:44:01,205 THAT'S ONE THING TO PUT ON THE 6687 04:44:01,205 --> 04:44:01,405 SHELF. 6688 04:44:01,405 --> 04:44:03,274 THE OTHER QUESTION I ORIGINALLY 6689 04:44:03,274 --> 04:44:04,575 HAD BECAUSE I THINK IT'S A 6690 04:44:04,575 --> 04:44:08,312 POWERFUL DISCUSSION WAS I THINK 6691 04:44:08,312 --> 04:44:10,014 ALL OF YOU IN THE PANEL IN YOUR 6692 04:44:10,014 --> 04:44:14,519 PRESENTATIONS TODAY AND IT'S 6693 04:44:14,519 --> 04:44:15,553 AROUND THE EARLIER QUESTION 6694 04:44:15,553 --> 04:44:18,656 ABOUT THINKING CRITICALLY ABOUT 6695 04:44:18,656 --> 04:44:25,296 PROSPECTIVE STUDIES AND CREATING 6696 04:44:25,296 --> 04:44:29,967 BIO BANKS TO GO BACK TO LATER 10 6697 04:44:29,967 --> 04:44:32,036 YEARS LATER AFTER INDIVIDUALS 6698 04:44:32,036 --> 04:44:33,671 HAVE RECEIVED LIFE-CHANGING 6699 04:44:33,671 --> 04:44:34,272 THERAPIES AND THEN DEVELOP 6700 04:44:34,272 --> 04:44:35,540 SOMETHING WEIRD OR HAVE A 6701 04:44:35,540 --> 04:44:43,114 CLINICAL COURSE NEVER EXPECTED. 6702 04:44:43,114 --> 04:44:45,550 SO ENCOURAGING THE NIH OR OTHERS 6703 04:44:45,550 --> 04:44:49,387 TO THINK ABOUT HOW WE THINK OF 6704 04:44:49,387 --> 04:44:52,623 GOING BACK AND THEN ADDRESS 6705 04:44:52,623 --> 04:44:55,560 CLINICALLY RELEVANT QUESTIONS OF 6706 04:44:55,560 --> 04:45:04,936 PATIENTS THAT RECEIVE THESE. 6707 04:45:04,936 --> 04:45:05,937 >> YEAH, WE SHOULD DO EVERYTHING 6708 04:45:05,937 --> 04:45:06,470 WE CAN. 6709 04:45:06,470 --> 04:45:09,507 I THINK THE VALUE OF 6710 04:45:09,507 --> 04:45:11,576 PRETREATMENT NATURAL HISTORY OF 6711 04:45:11,576 --> 04:45:15,313 THE END OF 1 OR A FEW PATIENTS 6712 04:45:15,313 --> 04:45:17,915 CAN'T BE UNDERESTIMATED AND IT'S 6713 04:45:17,915 --> 04:45:21,319 IMPORTANT TO FOLLOW THEM AND 6714 04:45:21,319 --> 04:45:22,186 LOOK AT THE MEASURES AFTER THE 6715 04:45:22,186 --> 04:45:22,987 TREATMENT STARTS. 6716 04:45:22,987 --> 04:45:25,456 >> I THINK THIS IS THE LIFE 6717 04:45:25,456 --> 04:45:26,490 CYCLE. 6718 04:45:26,490 --> 04:45:27,558 YOU'RE CONSTANTLY TRYING TO 6719 04:45:27,558 --> 04:45:30,428 IMPROVE BECAUSE YOU DON'T HAVE 6720 04:45:30,428 --> 04:45:31,562 ENOUGH SHOULDN'T STOP YOU FROM 6721 04:45:31,562 --> 04:45:33,664 MOVING BUT YOU ACCUMULATE OVER 6722 04:45:33,664 --> 04:45:42,673 TIME IN PARALLEL AND BUILD. 6723 04:45:42,673 --> 04:45:47,845 SO 6724 04:45:48,946 --> 04:45:59,056 [OFF-MIC] 6725 04:46:14,305 --> 04:46:17,074 >> WELL, WE CONVINCE THEM THIS 6726 04:46:17,074 --> 04:46:18,643 IS WHAT THEY SHOULD PAY FOR. 6727 04:46:18,643 --> 04:46:19,677 SO FAR IT'S WORKED. 6728 04:46:19,677 --> 04:46:22,179 I THINK IT CREATES A DOUBLE 6729 04:46:22,179 --> 04:46:24,482 STANDARD BECAUSE IT'S HARD TO 6730 04:46:24,482 --> 04:46:25,716 GET PUBLIC INSURANCE I.E., 6731 04:46:25,716 --> 04:46:27,551 MEDICAID TO PAY FOR THAT KIND OF 6732 04:46:27,551 --> 04:46:32,456 THING SO IT CREATES A DIVIDE 6733 04:46:32,456 --> 04:46:43,801 BETWEEN HAVES AND HAVE-NOTES -- 6734 04:46:49,607 --> 04:46:49,907 HAVE-NOTS. 6735 04:46:49,907 --> 04:46:51,542 >> THE CLASS OF THERAPY MATTERS 6736 04:46:51,542 --> 04:47:01,652 HERE. 6737 04:47:03,521 --> 04:47:06,424 AND THERE'S EARLY DIRECT ACCESS 6738 04:47:06,424 --> 04:47:11,862 AND HARDER TO DO THAT FOR AN 6739 04:47:11,862 --> 04:47:12,663 EXTRA BASE MODALITY UNLESS 6740 04:47:12,663 --> 04:47:15,566 YOU'VE TAKEN IT ALL THE WAY TO 6741 04:47:15,566 --> 04:47:25,910 COMMERCIAL APPROVAL. 6742 04:47:44,962 --> 04:47:46,163 >> DID YOU HAVE A COMMENT BEFORE 6743 04:47:46,163 --> 04:47:48,165 THE NEXT QUESTION? 6744 04:47:48,165 --> 04:47:50,234 >> MAINLY ONE OF THE POINTS 6745 04:47:50,234 --> 04:47:52,403 DIFFERENCE IN SIMONS SEARCH 6746 04:47:52,403 --> 04:47:54,839 LIGHT IS TO AGGREGATE NATURAL 6747 04:47:54,839 --> 04:47:56,507 HISTORY DATA ON AS MANY PEOPLE 6748 04:47:56,507 --> 04:47:58,442 AS POSSIBLE AND WE'RE ADDING THE 6749 04:47:58,442 --> 04:48:02,480 IN-PERSON ASSESSMENTS AS WELL TO 6750 04:48:02,480 --> 04:48:02,813 P 6751 04:48:02,813 --> 04:48:04,415 PREPARE FOR THE FUTURE STATE AND 6752 04:48:04,415 --> 04:48:06,050 UNDERSTAND BEST CLINICAL 6753 04:48:06,050 --> 04:48:06,951 PRACTICES AND IF THERE ARE 6754 04:48:06,951 --> 04:48:09,086 EITHER TREATMENTS, THERAPIES 6755 04:48:09,086 --> 04:48:10,254 THAT MAY BE MORE OR LESS 6756 04:48:10,254 --> 04:48:11,856 EFFECTIVE UNTIL WE GET TO 6757 04:48:11,856 --> 04:48:12,556 CLINICAL TRIALS. 6758 04:48:12,556 --> 04:48:13,557 I THINK THREES WAY TO PREPARE 6759 04:48:13,557 --> 04:48:22,233 FOR THE FUTURE STATE NOW. 6760 04:48:22,233 --> 04:48:23,334 >> THANKS. 6761 04:48:23,334 --> 04:48:25,569 >> I REALIZE IT'S 4:58 IN THE 6762 04:48:25,569 --> 04:48:27,738 AFTERNOON SO I'LL SAY SOMETHING 6763 04:48:27,738 --> 04:48:34,011 PROVOCATIVE. 6764 04:48:34,011 --> 04:48:36,213 TAKE THIS TO SERIOUS PEOPLE AT 6765 04:48:36,213 --> 04:48:39,250 CMS AND PEOPLE WHO THINK HARD OF 6766 04:48:39,250 --> 04:48:39,583 REIMBURSEMENT. 6767 04:48:39,583 --> 04:48:41,085 THE PATH WE GEN EDITORS ARE 6768 04:48:41,085 --> 04:48:45,456 TAKING TO GET IN COMMERCIAL 6769 04:48:45,456 --> 04:48:50,895 REIMBURSEMENT FOR N OF 1 GUIDE 6770 04:48:50,895 --> 04:48:54,532 RNAs IS FIRST, WE HAVE TO BASKET 6771 04:48:54,532 --> 04:48:55,566 INDIVIDUALS BIASED ON A 6772 04:48:55,566 --> 04:48:59,236 BIOMARKER OR ACCELERATED 6773 04:48:59,236 --> 04:48:59,503 APPROVAL. 6774 04:48:59,503 --> 04:49:02,239 FOR IMMUNE DEFICIENCIES THIS 6775 04:49:02,239 --> 04:49:06,110 WOULD BE CDC COUNT IN SIX MONTHS 6776 04:49:06,110 --> 04:49:09,447 AND NORMALIZATION OF SERUM 6777 04:49:09,447 --> 04:49:09,880 AMMONIUM. 6778 04:49:09,880 --> 04:49:14,752 I DON'T KNOW WHAT THAT IS. 6779 04:49:14,752 --> 04:49:16,020 THAT'S IT. 6780 04:49:16,020 --> 04:49:18,322 IF THERE'S A HARMONIZABLE 6781 04:49:18,322 --> 04:49:19,523 BIOMEDICAL WHATEVER THAT IS, IT 6782 04:49:19,523 --> 04:49:21,025 DOESN'T HAVE TO BE FOR ALL OF 6783 04:49:21,025 --> 04:49:21,992 THEM JUST SUBSET. 6784 04:49:21,992 --> 04:49:24,662 THAT IS HOW WE STRUCTURE THE 6785 04:49:24,662 --> 04:49:27,064 CLINICAL DEVELOPMENT. 6786 04:49:27,064 --> 04:49:28,132 THAT'S COMPONENT NUMBER ONE. 6787 04:49:28,132 --> 04:49:30,601 COMPONENT NUMBER TWO, YOU KEEP 6788 04:49:30,601 --> 04:49:34,572 AS MUCH AS THE PROCESS AS YOU 6789 04:49:34,572 --> 04:49:36,807 CAN THE SAME. 6790 04:49:36,807 --> 04:49:44,081 THE EXCIPIENT AND CROSS OVER IN 6791 04:49:44,081 --> 04:49:44,949 WHICH YOU MAKE THE PATIENT 6792 04:49:44,949 --> 04:49:47,551 SPECIFIC COMPONENT. 6793 04:49:47,551 --> 04:49:52,690 WHAT I HEARD FROM PETER 6794 04:49:52,690 --> 04:49:56,160 PERSONALLY THEY THERE ARE 3.3 6795 04:49:56,160 --> 04:49:57,795 BILLION BASE PAIRS IN THE HUMAN 6796 04:49:57,795 --> 04:49:58,028 GENOME. 6797 04:49:58,028 --> 04:50:04,368 I DON'T WANT 3.3 REVIEW CRITERIA 6798 04:50:04,368 --> 04:50:06,103 FOR REGULATORS. 6799 04:50:06,103 --> 04:50:07,838 SO STRATEGICALLY IN THE NEXT 6800 04:50:07,838 --> 04:50:10,241 THREE, FOUR YEARS IS TO GET 6801 04:50:10,241 --> 04:50:13,177 PHYSICIANS WHO TREAT SPECIFIC 6802 04:50:13,177 --> 04:50:15,079 SYNDROMES TO AGREE AND WE GEN 6803 04:50:15,079 --> 04:50:16,480 EDITORS AND THE DELIVERY PEOPLE 6804 04:50:16,480 --> 04:50:18,549 HAVE TO AGREE HOW TO BUILD A 6805 04:50:18,549 --> 04:50:23,554 PLATFORM UNDER WHICH WE CAN 6806 04:50:23,554 --> 04:50:27,558 CHANGE A VERY TINY THING AND 6807 04:50:27,558 --> 04:50:32,496 THEN AFTER WE BUILT UP OUR 6808 04:50:32,496 --> 04:50:35,132 SUBJECTS THE HOPE IS THE AGENCY 6809 04:50:35,132 --> 04:50:38,035 WILL APPROVE THE PROCESS UNDER 6810 04:50:38,035 --> 04:50:40,771 WHICH YOU MAY DELIVER. 6811 04:50:40,771 --> 04:50:41,105 THAT'S ALL. 6812 04:50:41,105 --> 04:50:43,274 >> I THINK YOU CAN GO BEYOND 6813 04:50:43,274 --> 04:50:47,912 THAT NOT JUST UP TERMS OF SHARED 6814 04:50:47,912 --> 04:50:49,213 BIOMARKERS WHICH OF YET WE DON'T 6815 04:50:49,213 --> 04:50:50,881 HAVE AND HOW TO OVERCOME. 6816 04:50:50,881 --> 04:50:52,349 DO WE NEED A GENE SPECIFIC 6817 04:50:52,349 --> 04:50:54,685 OUTCOME FOR EVERY SINGLE ONE OF 6818 04:50:54,685 --> 04:50:58,522 THE HUNDREDS OF GENES WHERE THE 6819 04:50:58,522 --> 04:51:00,124 COMMON CORE FEATURES ARE SHARED 6820 04:51:00,124 --> 04:51:00,858 OR HAVE A PLATFORM? 6821 04:51:00,858 --> 04:51:02,893 >> OR NUMBERS OF SEIZURES OR 6822 04:51:02,893 --> 04:51:04,161 DURATION OF SEIZURES. 6823 04:51:04,161 --> 04:51:07,031 YOU DON'T HAVE TO USE A 6824 04:51:07,031 --> 04:51:08,165 BIOMARKER IN THAT SITUATION IF 6825 04:51:08,165 --> 04:51:11,602 YOU HAVE A GOOD CLINICAL END 6826 04:51:11,602 --> 04:51:14,905 POINT. 6827 04:51:14,905 --> 04:51:19,376 >> DR. BER TTAGNOLLI AND I MET 6828 04:51:19,376 --> 04:51:21,378 WITH THE FDA ON RARE DISEASES 6829 04:51:21,378 --> 04:51:24,648 AND HOW TO APPROACH THEM AND THE 6830 04:51:24,648 --> 04:51:26,083 CONVERSATIONS HERE ARE SIMILAR 6831 04:51:26,083 --> 04:51:27,117 TO WHAT OCCURRED THERE. 6832 04:51:27,117 --> 04:51:28,485 AND I'LL THROW OUT INFORMATION 6833 04:51:28,485 --> 04:51:36,060 THAT WHAT THE FDA SAYS IS THAT 6834 04:51:36,060 --> 04:51:37,695 THEY ARE BEING DELUGED WITH 50% 6835 04:51:37,695 --> 04:51:39,563 OF THEIR APPLICATIONS WITH RARE 6836 04:51:39,563 --> 04:51:43,801 DISEASE, 8,000 APPLICATIONS WENT 6837 04:51:43,801 --> 04:51:44,935 A COUPLE YEARS AND THEY'RE 6838 04:51:44,935 --> 04:51:49,206 LOOKING FOR GUIDANCE. 6839 04:51:49,206 --> 04:51:54,378 THEY SAID WHAT STYMIED THEM MOST 6840 04:51:54,378 --> 04:51:59,917 IS THE BIOMARKERS WERE VALIDATED 6841 04:51:59,917 --> 04:52:08,158 AND I THINK WHAT YOU SAID HERE 6842 04:52:08,158 --> 04:52:11,595 AND THEY CAN USE COMPASSIONATE 6843 04:52:11,595 --> 04:52:15,566 USE IS EASY TO DO ON THEIR END 6844 04:52:15,566 --> 04:52:19,703 BUT DIDN'T HELP YOU GET PAID. 6845 04:52:19,703 --> 04:52:24,675 I THINK WE'RE ALL IN THIS 6846 04:52:24,675 --> 04:52:25,309 TOGETHER IN SYSTEMATIZING AND 6847 04:52:25,309 --> 04:52:27,444 WITH THAT WE'RE TRYING TO 6848 04:52:27,444 --> 04:52:33,183 CONVINCE DR. BERTAGNOLLI TO DO 6849 04:52:33,183 --> 04:52:43,727 THAT AT NIH AND HOPEFULLY THINGS 6850 04:52:47,064 --> 04:52:48,198 WILL TURN AROUND. 6851 04:52:48,198 --> 04:52:49,166 SEEMED INTERESTING. 6852 04:52:49,166 --> 04:52:50,834 ANYWAY, I HAVE TO RUN BUT SEE 6853 04:52:50,834 --> 04:52:51,402 YOU TOMORROW. 6854 04:52:51,402 --> 04:52:56,640 >> THANKS, WALTER. 6855 04:52:56,640 --> 04:53:01,812 >> I WANT TO SAY ONE LAST THING 6856 04:53:01,812 --> 04:53:02,813 ABOUT GENETIC EPILEPSY AND 6857 04:53:02,813 --> 04:53:05,049 MEASURING SEIZURES IS A GREAT 6858 04:53:05,049 --> 04:53:07,284 OUTCOME BECAUSE FDA BELIEVES IN 6859 04:53:07,284 --> 04:53:09,420 IT AND IT'S MEASURABLE. 6860 04:53:09,420 --> 04:53:10,954 FOR OTHERS THEY HAVE EPILEPSY 6861 04:53:10,954 --> 04:53:14,224 BUT IT'S NOT THE MAIN AND WIN 6862 04:53:14,224 --> 04:53:17,194 ANGELMAN SYNDROME THOUGH 6863 04:53:17,194 --> 04:53:18,662 SEIZURES WAS ONE THING AND FOR 6864 04:53:18,662 --> 04:53:24,001 MOST THE FAMILIES IN THE TRIALS 6865 04:53:24,001 --> 04:53:25,402 COMMUNICATION ARE MORE IMPORTANT 6866 04:53:25,402 --> 04:53:29,506 AND WHEN WE WILL HAVE THE 6867 04:53:29,506 --> 04:53:31,542 PATIENTS IN TRIAL AND SAY OH, 6868 04:53:31,542 --> 04:53:36,146 THEY HAVEN'T HAD SEIZURES IN A 6869 04:53:36,146 --> 04:53:37,614 YEAR AND THEY ONLY HAD SEIZURES 6870 04:53:37,614 --> 04:53:38,148 EVERY PUBLIC HEALTH OR 6871 04:53:38,148 --> 04:53:38,415 SOMETHING. 6872 04:53:38,415 --> 04:53:40,417 I THINK WE'RE CHANGING THE 6873 04:53:40,417 --> 04:53:42,653 SEIZURES BUT GOES TO ILLUSTRATE 6874 04:53:42,653 --> 04:53:46,090 FOR A LOT OF THE GENETIC 6875 04:53:46,090 --> 04:53:47,558 EPILEPSIES, THE EPILEPSY IS NOT 6876 04:53:47,558 --> 04:53:48,425 THE BIGGEST PROBLEM. 6877 04:53:48,425 --> 04:53:50,561 IN THINKING ABOUT BIOMARKERS AND 6878 04:53:50,561 --> 04:53:52,496 CLINICAL OUTCOMES WE HAVE TO 6879 04:53:52,496 --> 04:53:54,665 FIGURE OUT WAYS OF THINKING OF 6880 04:53:54,665 --> 04:54:00,671 THE PARTS THAT AREN'T EPILEPSY 6881 04:54:00,671 --> 04:54:03,841 AND WE DID TALK ABOUT THAT 6882 04:54:03,841 --> 04:54:07,711 PROBLEM. 6883 04:54:07,711 --> 04:54:10,380 >> LAST QUICK FROM 6884 04:54:10,380 --> 04:54:14,518 DR. SCHREIBER. 6885 04:54:14,518 --> 04:54:22,760 >> I'LL BE BRIEF. 6886 04:54:22,760 --> 04:54:24,695 AND LOOKING AT BIO BANKING AND 6887 04:54:24,695 --> 04:54:26,663 IT STRUCK ME AS THE DISCUSSION 6888 04:54:26,663 --> 04:54:28,966 OF FAEs AND THINGS WE DIDN'T 6889 04:54:28,966 --> 04:54:29,199 EXPECT. 6890 04:54:29,199 --> 04:54:30,968 IS THERE ANYTHING ELSE WE SHOULD 6891 04:54:30,968 --> 04:54:33,070 COLLECT AT BASELINE THAT WE'RE 6892 04:54:33,070 --> 04:54:34,738 NOT GETTING NOW THAT WE MIGHT 6893 04:54:34,738 --> 04:54:35,539 WANT TO KNOW LATER? 6894 04:54:35,539 --> 04:54:39,543 I THINK A CASE OF AN MRI THE 6895 04:54:39,543 --> 04:54:44,615 PATIENT HAS ENCEPHALOPATHY AND 6896 04:54:44,615 --> 04:54:46,183 HADN'T HAD ONE IN 15 YEARS. 6897 04:54:46,183 --> 04:54:47,551 IS THERE SOMETHING LIKE THAT 6898 04:54:47,551 --> 04:54:49,453 WE'LL WANT TO HAVE AT BASELINE 6899 04:54:49,453 --> 04:54:52,656 TO THEN GO BACK AND LOOK IF 6900 04:54:52,656 --> 04:54:54,792 SOMETHING CHANGED? 6901 04:54:54,792 --> 04:55:04,968 YES OR NO. 6902 04:55:05,502 --> 04:55:06,670 >> THE DIFFICULTY IS RECOGNIZING 6903 04:55:06,670 --> 04:55:09,606 NOW WHAT YOU WILL NEED IN THE 6904 04:55:09,606 --> 04:55:09,907 FUTURE. 6905 04:55:09,907 --> 04:55:14,311 I THINK TO ADD TO WHAT WALTER 6906 04:55:14,311 --> 04:55:19,550 SAID, FDA WANTING BETTER DATA IS 6907 04:55:19,550 --> 04:55:24,354 ALWAYS PERTINENT WHETHER MRI, 6908 04:55:24,354 --> 04:55:27,291 BIOMARKERS, OTHER MEASURES. 6909 04:55:27,291 --> 04:55:29,793 IT HAS TO BE AROUND THE 6910 04:55:29,793 --> 04:55:30,961 CLINICALLY MEANINGFUL UNMET NEED 6911 04:55:30,961 --> 04:55:32,729 THAT'S WHAT WE MISS WE DON'T 6912 04:55:32,729 --> 04:55:35,065 DEFINE WELL WHAT WE'RE TRYING TO 6913 04:55:35,065 --> 04:55:35,299 CHANGE. 6914 04:55:35,299 --> 04:55:38,669 WE FOCUS IN ON THAT INSTEAD OF 6915 04:55:38,669 --> 04:55:41,405 GATHERING ALL DATA WILLY-NILLY 6916 04:55:41,405 --> 04:55:43,540 ACROSS THE DISEASE, THEN WE WILL 6917 04:55:43,540 --> 04:55:45,542 BE ABLE TO ACCELERATE FASTER. 6918 04:55:45,542 --> 04:55:49,012 I KNOW IT'S NOT A GOOD ANSWER 6919 04:55:49,012 --> 04:55:52,649 BUT I THINK PLATFORM SPECIFIC, 6920 04:55:52,649 --> 04:55:55,853 YES, THERE ARE NEW THINGS WE 6921 04:55:55,853 --> 04:55:57,287 WANT TO KNOW AND UNDERSTAND 6922 04:55:57,287 --> 04:55:58,288 WHAT'S HAPPENING IN THE BONE 6923 04:55:58,288 --> 04:56:03,861 MARROW OF SOME OF THESE CHILDREN 6924 04:56:03,861 --> 04:56:13,403 BEFORE WE START 6925 04:56:13,403 --> 04:56:14,638 >> WE'RE ALWAYS TRYING TO 6926 04:56:14,638 --> 04:56:15,205 BREAKING NEWS COST WITH 6927 04:56:15,205 --> 04:56:18,141 INFORMATION AND CAN'T DO EVERY 6928 04:56:18,141 --> 04:56:21,712 COST AND -- BALANCE COST WITH 6929 04:56:21,712 --> 04:56:26,783 INFORMATION AND YOU CAN'T DO 6930 04:56:26,783 --> 04:56:28,986 EVERY COST AND WE HAD NO REASON 6931 04:56:28,986 --> 04:56:30,153 SOME WOULD HAVE AN IMMUNE 6932 04:56:30,153 --> 04:56:31,388 RESPONSE BASED ON THE LIMITED 6933 04:56:31,388 --> 04:56:32,890 AMOUNT OF PREVIOUS EXPERIENCE. 6934 04:56:32,890 --> 04:56:34,892 SO WE HAD TO MODIFY THE TRIAL 6935 04:56:34,892 --> 04:56:40,931 AFTER WE SAW IT TO ADD THE 6936 04:56:40,931 --> 04:56:42,666 COLLECTION OF LYMPHOCYTES TO 6937 04:56:42,666 --> 04:56:43,767 STUDY IT MORE CAREFULLY. 6938 04:56:43,767 --> 04:56:46,336 I THINK ALREADY A NUMBER OF 6939 04:56:46,336 --> 04:56:47,537 THESE TRIALS ARE EXHAUSTING FOR 6940 04:56:47,537 --> 04:56:49,973 THE PATIENT AND THE FAMILY IN 6941 04:56:49,973 --> 04:56:51,541 TERMS OF THE NUMBER OF END 6942 04:56:51,541 --> 04:56:53,310 POINTS COLLECTED. 6943 04:56:53,310 --> 04:56:58,315 AND SO I THINK TO ADD THINGS IN 6944 04:56:58,315 --> 04:57:00,651 ADVANCE WHEN YOU DON'T 6945 04:57:00,651 --> 04:57:03,553 ANTICIPATE THEM IS PROBABLY NOT 6946 04:57:03,553 --> 04:57:09,893 PRACTICAL. 6947 04:57:09,893 --> 04:57:15,365 >> IT'S HARD TO PREDICT. 6948 04:57:15,365 --> 04:57:21,505 WE REALIZED THERE WAS A PREVIOUS 6949 04:57:21,505 --> 04:57:24,675 HISTORY NOT JUST OUR PATIENTS. 6950 04:57:24,675 --> 04:57:28,278 SO WE NOW KNOW WHAT IT'S LIKE 6951 04:57:28,278 --> 04:57:29,146 WITH THE ANGELMAN SYNDROME ONLY 6952 04:57:29,146 --> 04:57:30,380 BECAUSE IT OCCURRED BUT WE WOULD 6953 04:57:30,380 --> 04:57:32,082 NEVER HAVE BEEN ABLE TO PREDICT 6954 04:57:32,082 --> 04:57:35,052 WE WOULD NEED THAT SO IT'S HARD 6955 04:57:35,052 --> 04:57:35,352 TO COLLECT. 6956 04:57:35,352 --> 04:57:38,956 I THINK MRIs ARE OBVIOUS AND 6957 04:57:38,956 --> 04:57:39,723 MOST THE PROTOCOL DO COLLECT 6958 04:57:39,723 --> 04:57:42,793 MRIs AT THIS BEGINNING OF THE 6959 04:57:42,793 --> 04:57:43,727 STUDY. 6960 04:57:43,727 --> 04:57:45,629 BUT I MEAN DATA COLLECTION TO 6961 04:57:45,629 --> 04:57:51,134 INFORM US IN THE FUTURE WHAT WE 6962 04:57:51,134 --> 04:57:58,075 SHOULD COLLECT POOLING THAT IN 6963 04:57:58,075 --> 04:58:03,213 THE POT AND THE FUTURE IS 6964 04:58:03,213 --> 04:58:04,848 COLLECTING NOW FOR WHAT WE'LL 6965 04:58:04,848 --> 04:58:05,215 NEED LATER. 6966 04:58:05,215 --> 04:58:07,284 >> ON THAT NOTE I THINK WE'LL 6967 04:58:07,284 --> 04:58:08,785 CLOSE OUR SESSION, VICKY. 6968 04:58:08,785 --> 04:58:10,187 DID YOU WANT TO SAY A COUPLE 6969 04:58:10,187 --> 04:58:10,554 THINGS? 6970 04:58:10,554 --> 04:58:12,155 WHILE VICKY'S COMING UP I WANT 6971 04:58:12,155 --> 04:58:13,056 TO REFLECT. 6972 04:58:13,056 --> 04:58:16,259 WE HAD SUCH A POWERFUL SESSION 1 6973 04:58:16,259 --> 04:58:17,060 OF THE PROMISE AND SO MUCH 6974 04:58:17,060 --> 04:58:18,128 KNOWLEDGE HAS BEEN INVOLVED OF 6975 04:58:18,128 --> 04:58:20,797 THE PLATFORMS AND VECTORS AND 6976 04:58:20,797 --> 04:58:23,133 WAYS TO DELIVER. 6977 04:58:23,133 --> 04:58:24,301 AND ENERGIZING OUR COMMUNITY 6978 04:58:24,301 --> 04:58:26,703 WITH ALL THE GENETICS WE KNOW 6979 04:58:26,703 --> 04:58:28,338 AND THE LESSONS WE LEARNED WERE 6980 04:58:28,338 --> 04:58:29,806 SOMEWHAT SOBERING BUT I THINK 6981 04:58:29,806 --> 04:58:33,243 THEY'RE INSPIRING AND PAVES THE 6982 04:58:33,243 --> 04:58:33,577 WAY FORWARD. 6983 04:58:33,577 --> 04:58:37,614 WE DON'T NEED TO MAKE THE SAME 6984 04:58:37,614 --> 04:58:39,549 MISTAKES BUT CAN LEARN AND 6985 04:58:39,549 --> 04:58:41,051 COMPOUND AND ENERGIZED BY BOTH 6986 04:58:41,051 --> 04:58:41,385 SESSIONS. 6987 04:58:41,385 --> 04:58:42,552 THANK YOU SO MUCH AND THE 6988 04:58:42,552 --> 04:58:43,553 MORNING SPEAKERS AS WELL. 6989 04:58:43,553 --> 04:58:51,661 I LOOK FORWARD TO TOMORROW. 6990 04:58:51,661 --> 04:58:53,497 >> SO THANK YOU TO ALL THE 6991 04:58:53,497 --> 04:58:54,664 SPEAKERS TODAY. 6992 04:58:54,664 --> 04:58:57,167 IT'S BEEN A FANTASTIC DAY. 6993 04:58:57,167 --> 04:58:57,968 IT'S BEEN REALLY VERY 6994 04:58:57,968 --> 04:59:00,370 INTERESTING AND AMAZING SO THANK 6995 04:59:00,370 --> 04:59:00,704 YOU ALL. 6996 04:59:00,704 --> 04:59:02,439 WE'LL START AGAIN TOMORROW 6997 04:59:02,439 --> 04:59:05,008 MORNING AT 9:00 a.m. 6998 04:59:05,008 --> 04:59:06,810 SO, WE DO HAVE TO GO THROUGH 6999 04:59:06,810 --> 04:59:10,213 SECURITY AGAIN FOR THOSE WHO ARE 7000 04:59:10,213 --> 04:59:14,184 NOT NIH EMPLOYEES. 7001 04:59:14,184 --> 04:59:18,088 SORRY ABOUT THAT BUT THOSE ARE 7002 04:59:18,088 --> 04:59:19,022 SECURITY MEASURES AND THERE'S 7003 04:59:19,022 --> 04:59:20,323 LOTS OF PLACES TO EAT AND HAVE A 7004 04:59:20,323 --> 04:59:20,991 GOOD EVENING AND SEE YOU 7005 04:59:20,991 --> 04:59:21,258 TOMORROW. 7006 04:59:21,258 --> 04:59:21,324 6: 7007 04:59:22,392 --> 04:59:23,493 ABOUT