1 00:00:11,440 --> 00:00:13,640 Welcome to the Clinical Center Grand Rounds, 2 00:00:13,640 --> 00:00:17,440 a weekly series of educational lectures for physicians and 3 00:00:17,440 --> 00:00:20,080 health care professionals broadcast from the Clinical 4 00:00:20,080 --> 00:00:23,040 Center at the National Institutes of Health in 5 00:00:23,040 --> 00:00:24,840 Bethesda, MD. 6 00:00:24,840 --> 00:00:28,400 The NIH Clinical Center is the world's largest hospital totally 7 00:00:28,400 --> 00:00:32,080 dedicated to investigational research and leads the global 8 00:00:32,080 --> 00:00:35,040 effort in training today's investigators and discovering 9 00:00:35,040 --> 00:00:37,200 tomorrow's cures. 10 00:00:37,200 --> 00:00:45,840 Learn more by visiting us online at http://clinicalcenter.nih.gov 11 00:00:45,840 --> 00:00:48,040 TODAY WE ARE HONORED TO HAVE TWO 12 00:00:48,040 --> 00:00:49,240 SURGEON SCIENTISTS FROM THE 13 00:00:49,240 --> 00:00:50,440 NATIONAL INSTITUTE ON DEAFNESS 14 00:00:50,440 --> 00:00:53,840 AND OTHER COMMUNICATION 15 00:00:53,840 --> 00:00:54,600 DISORDERS. 16 00:00:54,600 --> 00:00:55,680 DR. MICHAEL HAO, PRINCIPAL 17 00:00:55,680 --> 00:00:57,200 INVESTIGATOR FOR THE AUDITORY 18 00:00:57,200 --> 00:00:58,600 DEVELOPMENT AND RESTORATION 19 00:00:58,600 --> 00:01:00,240 PROGRAM AND ASSOCIATE PROFESSOR 20 00:01:00,240 --> 00:01:04,000 IN THE DEPARTMENT OF 21 00:01:04,000 --> 00:01:05,440 OTOLARYNGOLOGY AT GEORGETOWN 22 00:01:05,440 --> 00:01:10,040 UNIVERSITY AND DR. WADE CHIEN, 23 00:01:10,040 --> 00:01:11,440 PROFESSOR IN THE DEPARTMENT OF 24 00:01:11,440 --> 00:01:13,920 OTOLARYNGOLOGY AT JOHNS HOPKINS. 25 00:01:13,920 --> 00:01:15,920 OUR FIRST SPEAKER IS DR. HAO. 26 00:01:15,920 --> 00:01:18,120 DR. HAO RECEIVED HIS BACHELOR'S 27 00:01:18,120 --> 00:01:19,400 AND MEDICAL DEGREE FROM BOSTON 28 00:01:19,400 --> 00:01:19,840 UNIVERSITY. 29 00:01:19,840 --> 00:01:22,240 HE THEN COMPLETED HIS 30 00:01:22,240 --> 00:01:23,680 OTOLARYNGOLOGY HEAD NECK SURGERY 31 00:01:23,680 --> 00:01:26,520 RESIDENCY TRAINING AT THE WAYNE 32 00:01:26,520 --> 00:01:28,920 STATE UNIVERSITY FOLLOWED BY A 33 00:01:28,920 --> 00:01:32,120 NEURON WILLING TO FELLOWSHIP IN 34 00:01:32,120 --> 00:01:33,720 LOS ANGELES. 35 00:01:33,720 --> 00:01:38,520 DR. HAO ALSO PURSUED A T32 36 00:01:38,520 --> 00:01:38,960 USC/HRI HEARING AND 37 00:01:38,960 --> 00:01:39,480 COMMUNICATIONS NEUROSCIENE 38 00:01:39,480 --> 00:01:40,080 POSTDOCTORAL RESEARCH TRAINING 39 00:01:40,080 --> 00:01:40,760 FELLOWSHIP PRIOR TO JOINING 40 00:01:40,760 --> 00:01:41,280 NIDCD. 41 00:01:41,280 --> 00:01:44,360 HE JOINED THE NIDCD'S 42 00:01:44,360 --> 00:01:45,560 OTOLARYNGOLOGY SURGEON SCIENTIST 43 00:01:45,560 --> 00:01:48,280 PROGRAM IN 2013. 44 00:01:48,280 --> 00:01:49,720 IN ADDITION TO HIS ROLE AS 45 00:01:49,720 --> 00:01:50,720 ASSOCIATE PROFESSOR THE A 46 00:01:50,720 --> 00:01:52,120 GEORGETOWN, DR. HAO ALSO SERVES 47 00:01:52,120 --> 00:01:57,040 AS MEDICAL DIRECTOR FOR THE 48 00:01:57,040 --> 00:01:58,160 MEDSTAR GEORGETOWN UNIVERSITY 49 00:01:58,160 --> 00:01:58,680 HOSPITAL COCHLEAR IMPLANT 50 00:01:58,680 --> 00:01:59,560 PROGRAM. 51 00:01:59,560 --> 00:02:01,000 DR. HAO'S LAB IDENTIFIES NEW 52 00:02:01,000 --> 00:02:02,760 TREATMENTS FOR HEARING 53 00:02:02,760 --> 00:02:03,800 INSTABILITY DISORDERS, WHICH 54 00:02:03,800 --> 00:02:06,880 INCLUDE MOST NOTABLY MENIERE'S 55 00:02:06,880 --> 00:02:08,440 DISEASE, IDEOPATHIC SUDDEN 56 00:02:08,440 --> 00:02:10,480 NEURAL CENTER HEARING LOSS AND 57 00:02:10,480 --> 00:02:11,680 AUTOIMMUNE EAR DISEASE. 58 00:02:11,680 --> 00:02:13,320 HIS LABORATORY USES A 59 00:02:13,320 --> 00:02:15,520 COMBINATION OF MICROBIOLOGY AND 60 00:02:15,520 --> 00:02:18,880 BIOINFORMATICS INCLUDING SINGLE 61 00:02:18,880 --> 00:02:23,160 KREM MRNA SEQUENCING UTILIZING 62 00:02:23,160 --> 00:02:25,280 ADULT MAMMALIAN SYSTEMS. 63 00:02:25,280 --> 00:02:27,240 DR. HAO HAS AUTHORED OR 64 00:02:27,240 --> 00:02:28,640 CO-AUTHORED OVER 60 PUBLICATIONS 65 00:02:28,640 --> 00:02:31,360 AND BOOK CHAPTERS. 66 00:02:31,360 --> 00:02:32,560 DR. HAO IS THE CHAIRMAN OF THE 67 00:02:32,560 --> 00:02:33,320 RESEARCH COMMITTEE FOR THE 68 00:02:33,320 --> 00:02:35,000 AMERICAN COCHLEAR IMPLANT 69 00:02:35,000 --> 00:02:37,960 ALLIANCE, AND IS A MEMBER OF 70 00:02:37,960 --> 00:02:39,800 NUMEROUS MEDICAL SOCIETIES 71 00:02:39,800 --> 00:02:42,520 INCLUDING THE AMERICAN 72 00:02:42,520 --> 00:02:44,120 NEUROONTOLOGY SOCIETY, THE 73 00:02:44,120 --> 00:02:45,280 AMERICAN ACADEMY OF 74 00:02:45,280 --> 00:02:46,600 OTOLARYNGOLOGY, HEAD NECK 75 00:02:46,600 --> 00:02:48,360 SURGERY, THE ASSOCIATION FOR 76 00:02:48,360 --> 00:02:51,760 RESEARCH IN OTOLARYNGOLOGY, THE 77 00:02:51,760 --> 00:02:52,480 NORTH AMERICAN SKULL BASE 78 00:02:52,480 --> 00:02:56,520 SOCIETY AND DR. HAO IS BOARD 79 00:02:56,520 --> 00:02:58,160 CERTIFIED IN OTOLARYNGOLOGY HEAD 80 00:02:58,160 --> 00:03:04,840 AND NECK SURGERY, OWE WILLING TD 81 00:03:04,840 --> 00:03:05,520 NEUROONTOLOGY. 82 00:03:05,520 --> 00:03:11,960 OUR SECOND SPEAKER IS DR. WADE 83 00:03:11,960 --> 00:03:19,040 CHIEN, NIDCD, AND DEPARTM PROVEE 84 00:03:19,040 --> 00:03:19,680 JOHNS HOPKINS SCHOOL OF 85 00:03:19,680 --> 00:03:20,240 MEDICINE. 86 00:03:20,240 --> 00:03:21,280 DR. CHIN RECEIVED HIS BACHELOR'S 87 00:03:21,280 --> 00:03:24,080 IN BIOLOGY AND MUSIC FROM 88 00:03:24,080 --> 00:03:24,680 BRANDEIS UNIVERSITY, AND THEN 89 00:03:24,680 --> 00:03:27,760 EARNED HIS MEDICAL DEGREE AT THE 90 00:03:27,760 --> 00:03:31,120 UNIVERSITY OF SOUTHERN 91 00:03:31,120 --> 00:03:31,680 CALIFORNIA, KECK SCHOOL OF 92 00:03:31,680 --> 00:03:32,080 MEDICINE. 93 00:03:32,080 --> 00:03:34,040 HE COMPLETED RESIDENCY TRAINING 94 00:03:34,040 --> 00:03:36,360 AT THE HARVARD COMBINED 95 00:03:36,360 --> 00:03:38,240 OTOLARYNGOLOGY TRAINING PROGRAM 96 00:03:38,240 --> 00:03:42,040 AND A NEUROONTOLOGY FELLOWSHIP 97 00:03:42,040 --> 00:03:43,680 AT JOHNS HOPKINS HOSPITAL. 98 00:03:43,680 --> 00:03:46,000 ALUMNUS OF THE HOWARD HUGHES 99 00:03:46,000 --> 00:03:46,840 MEDICAL INSTITUTE NIH RESEARCH 100 00:03:46,840 --> 00:03:47,960 SCHOLARS PROGRAM, DURING WHICH 101 00:03:47,960 --> 00:03:54,080 HE WORKED WITH DR. GERALD 102 00:03:54,080 --> 00:03:54,520 FISHBACH. 103 00:03:54,520 --> 00:03:57,600 ALSO RECIPIENT OF A T32 TRAINING 104 00:03:57,600 --> 00:03:58,800 GRANT IN RESIDENCY. 105 00:03:58,800 --> 00:04:02,600 DR. CHIEN JOINED NIDCD AS AN 106 00:04:02,600 --> 00:04:03,040 INVESTIGATOR IN THE 107 00:04:03,040 --> 00:04:04,480 OTOLARYNGOLOGY SURGEON SCIENTIST 108 00:04:04,480 --> 00:04:06,560 PROGRAM IN 2011 AND NOW HIS LAB 109 00:04:06,560 --> 00:04:08,400 STUDIES THE APPLICATION OF INNER 110 00:04:08,400 --> 00:04:10,480 EAR GENE THERAPY AS A TREATMENT 111 00:04:10,480 --> 00:04:12,760 FOR HEARING LOSS AND DIZZINESS. 112 00:04:12,760 --> 00:04:15,520 A NATIONALLY AND INTERNATIONALLY 113 00:04:15,520 --> 00:04:21,000 RECOGNIZED SPEAKER, DR. CHIEN IS 114 00:04:21,000 --> 00:04:23,040 A DIPLOMAT FOR THE AMERICAN 115 00:04:23,040 --> 00:04:25,200 BOARD OF OTOLARYNGOLOGY AND 116 00:04:25,200 --> 00:04:26,640 AMERICAN BOARD OF NEUROONTOLOGY 117 00:04:26,640 --> 00:04:27,560 SKULL BASE SURGERY. 118 00:04:27,560 --> 00:04:29,240 HE IS A MEMBER OF THE AMERICAN 119 00:04:29,240 --> 00:04:32,880 OAT LOGICAL SOCIETY AND A FELLOW 120 00:04:32,880 --> 00:04:34,120 OF THE -- AND SERVES ON THE 121 00:04:34,120 --> 00:04:37,440 COMMITTEES OF NUMEROUS NATIONAL 122 00:04:37,440 --> 00:04:38,200 PROFESSIONAL NEURON WILLING TO 123 00:04:38,200 --> 00:04:38,560 ORGANIZATIONS. 124 00:04:38,560 --> 00:04:40,000 SO NOW PLEASE WELCOME OUR 125 00:04:40,000 --> 00:04:42,400 SPEAKERS, DR. HAO AND DR. CHIEN, 126 00:04:42,400 --> 00:04:45,280 FOR THEIR TALKS ENTITLED HEARING 127 00:04:45,280 --> 00:04:47,640 INSTABILITY DISORDERS, MOUSE AND 128 00:04:47,640 --> 00:04:48,560 HUMAN CORRELATES, AND THE 129 00:04:48,560 --> 00:04:52,040 DEVELOPMENT OF GENE THERAPY -- 130 00:04:52,040 --> 00:04:53,560 INNER EAR GENE THERAPY FOR USHER 131 00:04:53,560 --> 00:04:54,680 SYNDROME. 132 00:04:54,680 --> 00:04:56,040 >>THANK YOU, EVERYONE, FOR 133 00:04:56,040 --> 00:05:09,360 YOUR ATTENTION TODAY. 134 00:05:09,360 --> 00:05:13,640 SO I HAVE NO DISCLOSURES. 135 00:05:13,640 --> 00:05:15,520 AND THESE ARE THE LEARNING 136 00:05:15,520 --> 00:05:16,400 OBJECTIVES FOR TODAY. 137 00:05:16,400 --> 00:05:18,000 I HOPE THAT I CAN LEAVE YOU WITH 138 00:05:18,000 --> 00:05:21,440 SOME SENSE FOR AN AWARENESS OF 139 00:05:21,440 --> 00:05:22,720 HEARING INSTABILITY DISORDERS 140 00:05:22,720 --> 00:05:24,920 INCLUDING MENIERE'S DISEASE, AND 141 00:05:24,920 --> 00:05:26,800 TO GIVE YOU A SENSE FOR THE 142 00:05:26,800 --> 00:05:30,480 DIAGNOSTIC UTILITY OF MRI IN 143 00:05:30,480 --> 00:05:33,440 DIAGNOSING ENDO LYMPHATIC 144 00:05:33,440 --> 00:05:35,880 HYDROPS, ONE OF THE HISTOLOGICAL 145 00:05:35,880 --> 00:05:36,920 HALLMARKS FOR THIS DISEASE. 146 00:05:36,920 --> 00:05:38,120 SO THIS IS A BRIEF OUTLINE OF 147 00:05:38,120 --> 00:05:39,160 WHAT I'M GOING TO BE TALKING 148 00:05:39,160 --> 00:05:41,760 ABOUT TODAY. 149 00:05:41,760 --> 00:05:45,800 AND I'LL GET RIGHT INTO IT. 150 00:05:45,800 --> 00:05:47,720 BUT TAKING A STEP BACK, HEARING 151 00:05:47,720 --> 00:05:49,200 INSTABILITY DISORDERS ARE 152 00:05:49,200 --> 00:05:52,240 DISEASES WHERE PATIENTS 153 00:05:52,240 --> 00:05:53,360 EXPERIENCE EITHER FLUCTUATION IN 154 00:05:53,360 --> 00:05:56,480 OR SUDDEN CHANGES IN THEIR 155 00:05:56,480 --> 00:06:00,040 HEARING, AND OPERATIONALLY, WE 156 00:06:00,040 --> 00:06:03,880 DEFINE THIS AS EITHER A 157 00:06:03,880 --> 00:06:05,920 20-DECIBEL CHANGE OVER ONE OR 158 00:06:05,920 --> 00:06:07,960 MORE FREQUENCIES OR A 15-DECIBEL 159 00:06:07,960 --> 00:06:09,000 CHANGE AT TWO OR MORE 160 00:06:09,000 --> 00:06:09,320 FREQUENCIES. 161 00:06:09,320 --> 00:06:12,480 THIS IS KIND OF BASED ON THE 162 00:06:12,480 --> 00:06:15,000 AMERICAN SPEECH AND HEARING 163 00:06:15,000 --> 00:06:15,680 ASSOCIATION'S DEFINITION OF 164 00:06:15,680 --> 00:06:19,160 SIGNIFICANT CHANGE IN HEARING. 165 00:06:19,160 --> 00:06:21,160 SO MY LAB'S MISSION IS TO FIND 166 00:06:21,160 --> 00:06:22,240 TREATMENTS FOR HEARING 167 00:06:22,240 --> 00:06:24,400 INSTABILITY DISORDERS, AND ONE 168 00:06:24,400 --> 00:06:27,680 OF THE MAIN HYPOTHESES OF MY LAB 169 00:06:27,680 --> 00:06:31,720 IS THAT ION HOMEOSTATIC 170 00:06:31,720 --> 00:06:34,280 DYSFUNCTION CONTRIBUTES TO 171 00:06:34,280 --> 00:06:34,680 HEARING INSTABILITY. 172 00:06:34,680 --> 00:06:35,880 WE'VE USED THE COMBINATION OF 173 00:06:35,880 --> 00:06:39,520 MOUSE MODELS AND TRANSCRIPTOME 174 00:06:39,520 --> 00:06:42,800 STUDIES OF THE STRIA VAST CHAIRS 175 00:06:42,800 --> 00:06:50,560 TVASCULARIS,AND WE'VE ALSO -- OT 176 00:06:50,560 --> 00:06:53,080 WORK INVOLVES BOTH AN EFFORT TO 177 00:06:53,080 --> 00:06:55,400 LINK ION HOMEOSTATIC DYSFUNCTION 178 00:06:55,400 --> 00:06:57,800 WITH HUMAN HEARING INSTABILITY, 179 00:06:57,800 --> 00:06:59,760 AND A DEEP PHENOTYPING CLINICAL 180 00:06:59,760 --> 00:07:05,880 PROTOCOL FOR THESE PATIENTS WITH 181 00:07:05,880 --> 00:07:07,720 AN AIM IN THE FUTURE TO IDENTIFY 182 00:07:07,720 --> 00:07:08,920 REPURPOSEFUL AND NOVEL 183 00:07:08,920 --> 00:07:12,880 THERAPEUTICS FOR THESE DISEASES. 184 00:07:12,880 --> 00:07:15,360 SO HEARING INSTABILITY 185 00:07:15,360 --> 00:07:17,680 DISORDERS, WHICH INCLUDE MOST 186 00:07:17,680 --> 00:07:19,760 COMMONLY MENIERE'S DISEASE AND 187 00:07:19,760 --> 00:07:22,360 IDEOPA TICK SUDDEN SENSORINEURAL 188 00:07:22,360 --> 00:07:23,560 HEARING LOSS AMONG OTHERS, 189 00:07:23,560 --> 00:07:25,200 REMAIN INCOMPLETELY UNDERSTOOD, 190 00:07:25,200 --> 00:07:27,840 AND REALLY HAVE FEW IF ANY 191 00:07:27,840 --> 00:07:29,920 EFFECTIVE TREATMENTS FOR HEARING 192 00:07:29,920 --> 00:07:31,120 LOSS. 193 00:07:31,120 --> 00:07:34,640 NOW, HERE YOU SEE AN EXAMPLE OF 194 00:07:34,640 --> 00:07:38,680 A PATIENT WITH MENIERE'S 195 00:07:38,680 --> 00:07:41,040 DISEASE, AND THEY HAVE A 196 00:07:41,040 --> 00:07:45,720 HISTOLOGICAL HALLMARK CALLED 197 00:07:45,720 --> 00:07:48,920 ENDO LYMPHATIC HYDROPS, THE ENDO 198 00:07:48,920 --> 00:07:50,120 LYMPH CONTAINING COMPARTMENT OF 199 00:07:50,120 --> 00:07:50,680 THE COCHLEA. 200 00:07:50,680 --> 00:07:52,960 THIS IS IN DISTINCTION TO WHAT A 201 00:07:52,960 --> 00:07:56,040 NORMAL COCHLEA WOULD LOOK LIKE 202 00:07:56,040 --> 00:07:57,680 IN TERMS OF THAT CENTRAL 203 00:07:57,680 --> 00:08:02,160 COMPARTMENT, WHICH IS CALLED THE 204 00:08:02,160 --> 00:08:04,640 SCALA MEDIA SO IT LOOKS MORE 205 00:08:04,640 --> 00:08:05,120 TRIANGULAR. 206 00:08:05,120 --> 00:08:06,760 WE DON'T KNOW WHETHER THIS IS -- 207 00:08:06,760 --> 00:08:09,240 IT REMAINS KIND OF A POINT OF 208 00:08:09,240 --> 00:08:09,920 ACTIVE DEBATE ABOUT WHETHER THIS 209 00:08:09,920 --> 00:08:10,920 IS AN ACTUAL CAUSE OF THE 210 00:08:10,920 --> 00:08:12,760 DISEASE OR WHETHER IT'S A 211 00:08:12,760 --> 00:08:14,880 REFLECTION OF SOME UNDERLYING 212 00:08:14,880 --> 00:08:16,680 PROCESS. 213 00:08:16,680 --> 00:08:18,520 REGARDLESS, IT'S THOUGHT THAT 214 00:08:18,520 --> 00:08:23,280 THERE'S SOME DYSFUNCTIONAL ENDO 215 00:08:23,280 --> 00:08:24,480 LYMPH HOMEOSTATIC PROCESS THAT'S 216 00:08:24,480 --> 00:08:26,000 OCCURRING IN THE COCHLEA THAT'S 217 00:08:26,000 --> 00:08:27,840 SOMEHOW CONNECTED WITH THESE 218 00:08:27,840 --> 00:08:28,800 DISEASES. 219 00:08:28,800 --> 00:08:33,000 AND FURTHERMORE, STRIA 220 00:08:33,000 --> 00:08:34,000 VASCULARIS PATHOLOGY HAS BEEN 221 00:08:34,000 --> 00:08:37,040 NOTED IN THESE DISEASES, AND 222 00:08:37,040 --> 00:08:38,680 HERE IS JUST AN EXAMPLE OF KIND 223 00:08:38,680 --> 00:08:46,320 OF THIS ABNORMALLY THIN STRIA 224 00:08:46,320 --> 00:08:49,720 VASCULARIS, YOU SEE A THICKER 225 00:08:49,720 --> 00:08:51,400 ONE IN AN AGE MATCHED NORMAL 226 00:08:51,400 --> 00:08:51,880 HEARING INDIVIDUAL. 227 00:08:51,880 --> 00:08:53,560 IT'S BEEN SHOWN THAT THE STRIA 228 00:08:53,560 --> 00:08:56,840 IN THESE DISEASES IS MORE 229 00:08:56,840 --> 00:08:59,360 ATROPHIED, IN PARTICULAR IN 230 00:08:59,360 --> 00:09:00,520 MENIERE'S DISEASE VERSUS KIND OF 231 00:09:00,520 --> 00:09:03,840 AGE MATCHED CONTROLS. 232 00:09:03,840 --> 00:09:06,160 SO MENIERE'S DISEASE, A MORE 233 00:09:06,160 --> 00:09:08,120 COMMON FORM OF HEARING 234 00:09:08,120 --> 00:09:09,640 INSTABILITY, IS BROADLY 235 00:09:09,640 --> 00:09:14,680 CHARACTERIZED BY E EPISODIC 236 00:09:14,680 --> 00:09:16,800 VERTIGO, SENSORINEURAL HEARING 237 00:09:16,800 --> 00:09:22,760 LOSS AND FLU FLUCTUATING SYMPTOS 238 00:09:22,760 --> 00:09:26,480 SUCH AS TINNITUS, FULLNESS, EAR 239 00:09:26,480 --> 00:09:28,760 PRESSURE OR HEARING LOSS. 240 00:09:28,760 --> 00:09:30,640 THE DIAGNOSTIC CRITERIA 241 00:09:30,640 --> 00:09:32,040 SEPARATES MENIERE'S DISEASE INTO 242 00:09:32,040 --> 00:09:34,440 TWO CATEGORIES: DEFINITE AND 243 00:09:34,440 --> 00:09:36,440 PROBABLE MENIERE'S DISEASE. 244 00:09:36,440 --> 00:09:39,960 THE PRIMARY DISTINCTION IS THAT 245 00:09:39,960 --> 00:09:41,520 IN DEFINITE MENIERE'S DISEASE, 246 00:09:41,520 --> 00:09:45,000 THERE'S AN AUDIOMETRICLY 247 00:09:45,000 --> 00:09:47,400 DOCUMENTED LOW TO MEDIUM 248 00:09:47,400 --> 00:09:48,800 FREQUENCY SENSORINEURAL HEARING 249 00:09:48,800 --> 00:09:51,080 LOSS IN AT LEAST ONE EAR ON AT 250 00:09:51,080 --> 00:09:52,880 LEAST ONE OCCASION BEFORE, 251 00:09:52,880 --> 00:09:55,880 DURING AND AFTER AN EPISODE OF 252 00:09:55,880 --> 00:09:56,360 VERTIGO. 253 00:09:56,360 --> 00:09:57,760 SO THIS DISEASE IN PARTICULAR 254 00:09:57,760 --> 00:10:01,920 REMAINS VERY MUCH A CLINICAL 255 00:10:01,920 --> 00:10:04,520 DIAGNOSIS, BUT THESE ARE 256 00:10:04,520 --> 00:10:11,960 DISEASES WITH KIND OF FAIRLY 257 00:10:11,960 --> 00:10:13,200 CHALLENGING -- THAT ARE FAIRLY 258 00:10:13,200 --> 00:10:14,960 CHALLENGING IN TERMS OF HEARING 259 00:10:14,960 --> 00:10:19,760 LOSS AND THE TREATMENT OF THAT. 260 00:10:19,760 --> 00:10:23,880 SO TO POINT YOU TO THE STRIA 261 00:10:23,880 --> 00:10:25,240 VASCULARIS FUNCTION, THE STRIA 262 00:10:25,240 --> 00:10:26,640 IS COMPOSED OF THREE MAIN LAYERS 263 00:10:26,640 --> 00:10:29,280 OF CELLS INCLUDING MARGINAL, 264 00:10:29,280 --> 00:10:31,800 INTERMEDIATE, AND BASAL CELLS, 265 00:10:31,800 --> 00:10:33,760 AS WELL AS RARER CELL TYPES. 266 00:10:33,760 --> 00:10:35,920 JUST TO TAKE A STEP BACK, THE 267 00:10:35,920 --> 00:10:37,320 STRIA VASCULARIS IS HOUSED IN 268 00:10:37,320 --> 00:10:39,960 THE LATERAL WALL OF THE COCHLEA, 269 00:10:39,960 --> 00:10:42,000 AND IT FUNCTIONS TO GENERATE 270 00:10:42,000 --> 00:10:44,760 WHAT'S CALLED THE ENDO COCHLEAR 271 00:10:44,760 --> 00:10:46,760 POTENTIAL AS WELL AS TO REGULATE 272 00:10:46,760 --> 00:10:50,440 ION CONCENTRATION HERE, AND 273 00:10:50,440 --> 00:10:52,000 WITHOUT IT, THE HAIR CELLS WOULD 274 00:10:52,000 --> 00:10:53,880 NOT BE CAPABLE OF FUNCTIONING 275 00:10:53,880 --> 00:10:57,480 AND IT ESSENTIALLY SERVES AS A 276 00:10:57,480 --> 00:10:58,360 BATTERY. 277 00:10:58,360 --> 00:11:00,040 SO THIS THREE-LAYERED STRUCTURE 278 00:11:00,040 --> 00:11:01,720 IS COMPOSED OF THESE MARGINAL 279 00:11:01,720 --> 00:11:06,120 CELLS WHICH FACE THE END LINTH H 280 00:11:06,120 --> 00:11:07,240 FOLLOWED BY THE INTERMEDIATE 281 00:11:07,240 --> 00:11:08,640 CELLS HERE IN GREEN FOLLOWED BY 282 00:11:08,640 --> 00:11:11,400 THE BASAL CELLS HERE IN BLUE. 283 00:11:11,400 --> 00:11:13,800 NOTICE IN THIS INTERMEDIATE CELL 284 00:11:13,800 --> 00:11:15,920 LAYER, THERE ARE ALSO 285 00:11:15,920 --> 00:11:19,400 ENDOTHELIAL CELLS, PERICYTES AND 286 00:11:19,400 --> 00:11:26,640 THERE ARE ALSO MACROPHAGES HERE. 287 00:11:26,640 --> 00:11:27,960 SO THESE THREE LAYERS WORK 288 00:11:27,960 --> 00:11:32,480 TOGETHER TO GENERATE THE 289 00:11:32,480 --> 00:11:33,440 ENDOCOCHLEAR POTENTIAL AND 290 00:11:33,440 --> 00:11:34,960 HOMEOSTEA TIS AND IT REALLY 291 00:11:34,960 --> 00:11:36,280 REMAINS TO BE DEFINED ABOUT 292 00:11:36,280 --> 00:11:40,360 WHETHER CHANGES IN THE STRUCTURE 293 00:11:40,360 --> 00:11:41,400 OR THE FUNCTION OF THIS TISSUE 294 00:11:41,400 --> 00:11:42,920 RESULTS IN HEARING INSTABILITY. 295 00:11:42,920 --> 00:11:44,680 BUT IT IS A GOOD PLACE TO START 296 00:11:44,680 --> 00:11:50,480 TO UNDERSTAND HOW ION 297 00:11:50,480 --> 00:11:51,680 HOMEOSTASIS OCCURS IN THE 298 00:11:51,680 --> 00:11:52,440 COCHLEA. 299 00:11:52,440 --> 00:11:54,680 SO WHILE ITS CAUSE REMAINS 300 00:11:54,680 --> 00:11:57,240 UNKNOWN, MENIERE'S DISEASE HAS 301 00:11:57,240 --> 00:12:02,680 BEEN ASSOCIATED WITH SEVERAL 302 00:12:02,680 --> 00:12:03,760 GENETIC VARIANTS OVER TIME, AND 303 00:12:03,760 --> 00:12:05,520 WITH THIS IN MIND, WE 304 00:12:05,520 --> 00:12:06,640 SYSTEMATICALLY REVIEWED THE 305 00:12:06,640 --> 00:12:08,120 LITERATURE ON GENETIC VARIANTS 306 00:12:08,120 --> 00:12:13,000 IN MENIERE'S DISEASE. 307 00:12:13,000 --> 00:12:16,040 AND CROSS-REFERENCED THESE WITH 308 00:12:16,040 --> 00:12:19,440 SINGLE CELL RNA SEQUENCING DATA 309 00:12:19,440 --> 00:12:20,640 GENERATED BY MY LAB. 310 00:12:20,640 --> 00:12:23,280 WHAT I SEE HERE IS A HEAT MAP OF 311 00:12:23,280 --> 00:12:26,360 THE MAJOR STRIAL CELL TYPES 312 00:12:26,360 --> 00:12:30,040 ARRAYED HORIZONTALLY, SO THE 313 00:12:30,040 --> 00:12:31,760 MARGINAL CELLS IN RED, 314 00:12:31,760 --> 00:12:32,880 INTERMEDIATE CELLS IN GREEN AND 315 00:12:32,880 --> 00:12:35,960 BASAL CELLS IN BLUE HERE. 316 00:12:35,960 --> 00:12:37,160 AND THE GENES ASSOCIATED WITH 317 00:12:37,160 --> 00:12:39,000 THE GENETIC VARIANTS CONNECTED 318 00:12:39,000 --> 00:12:41,080 TO MENIERE'S DISEASE ARE ALONG 319 00:12:41,080 --> 00:12:45,560 THE VERTICAL ACCESS. 320 00:12:45,560 --> 00:12:47,320 WHAT WE FOUND IS A SIGNIFICANT 321 00:12:47,320 --> 00:12:48,960 SUBSET ARE EXPRESSED BY MARGINAL 322 00:12:48,960 --> 00:12:50,080 AND INTERMEDIATE CELLS. 323 00:12:50,080 --> 00:12:54,880 NOW, THIS IS CIRCUMSTANTIAL 324 00:12:54,880 --> 00:12:56,360 EVIDENCE FOR A POTENTIAL ROLE OF 325 00:12:56,360 --> 00:12:59,880 THESE CELL TYPES IN MENIERE'S 326 00:12:59,880 --> 00:13:00,760 DISEASE. 327 00:13:00,760 --> 00:13:01,880 SO WITH THAT BACKGROUND, I'M 328 00:13:01,880 --> 00:13:03,040 GOING TO GO INTO THE FIRST 329 00:13:03,040 --> 00:13:03,880 PROJECT. 330 00:13:03,880 --> 00:13:07,000 WHICH IS THE CLINICAL PROTOCOL 331 00:13:07,000 --> 00:13:08,520 INVOLVING DEEP PHENOTYPING OF 332 00:13:08,520 --> 00:13:11,840 PATIENTS WITH THESE DISORDERS. 333 00:13:11,840 --> 00:13:16,080 SO THIS IS AN ACTIVELY 334 00:13:16,080 --> 00:13:17,400 RECRUITING PROTOCOL HERE, AND 335 00:13:17,400 --> 00:13:20,120 THE GOAL IS TO UTILIZE DEEP 336 00:13:20,120 --> 00:13:24,720 PHENOTYPING MEASURES TO 337 00:13:24,720 --> 00:13:25,800 EVENTUALLY IDENTIFY NOVEL 338 00:13:25,800 --> 00:13:29,320 THERAPIES FOR THESE PATIENTS. 339 00:13:29,320 --> 00:13:33,680 DEEP PHENOTYPING IN THIS CASE 340 00:13:33,680 --> 00:13:36,840 INVOLVES THE USE OF CONTRAST 341 00:13:36,840 --> 00:13:40,600 ENHANCED DELAYED FLAIR MRI, 342 00:13:40,600 --> 00:13:44,400 AUDIO NE TAUDIOMETRIC AND VESTIR 343 00:13:44,400 --> 00:13:46,600 MEASURES AND IMMUNOPHENOTYPING. 344 00:13:46,600 --> 00:13:48,240 THIS IS A LONGITUDINAL STUDY 345 00:13:48,240 --> 00:13:50,520 THAT IS DESIGNED TO TRY TO 346 00:13:50,520 --> 00:13:53,480 IDENTIFY GROUPS OF PATIENTS THAT 347 00:13:53,480 --> 00:13:55,920 MIGHT HAVE COMMON FEATURES. 348 00:13:55,920 --> 00:13:57,520 AND ONE OF OUR CHALLENGES IN 349 00:13:57,520 --> 00:14:01,120 THIS PATIENT POPULATION IS, IT'S 350 00:14:01,120 --> 00:14:03,000 THOUGHT THAT PATIENTS WITH THESE 351 00:14:03,000 --> 00:14:04,840 DISEASES PROBABLY CONSTITUTE 352 00:14:04,840 --> 00:14:06,800 SEVERAL DIFFERENT DISORDERS, SO 353 00:14:06,800 --> 00:14:09,240 THIS PROTOCOL IS DESIGNED TO TRY 354 00:14:09,240 --> 00:14:13,160 TO HELP SORT THAT OUT. 355 00:14:13,160 --> 00:14:15,880 SO AS I MENTIONED, ONE OF THE 356 00:14:15,880 --> 00:14:16,640 HALLMARKS OF THIS DISEASE IS 357 00:14:16,640 --> 00:14:19,200 SOMETHING CALLED END LYMPHATIC 358 00:14:19,200 --> 00:14:19,480 HYDROPS. 359 00:14:19,480 --> 00:14:22,800 IT'S REALLY AN EXPANSION OF THE 360 00:14:22,800 --> 00:14:23,680 ENDO LYMPH CONTAINING SPACES OF 361 00:14:23,680 --> 00:14:27,080 THE INNER EAR, SPECIFICALLY OF 362 00:14:27,080 --> 00:14:28,920 THE VESTIBULE HERE IN GREEN, AND 363 00:14:28,920 --> 00:14:30,240 THE COCHLEA HERE IN YELLOW. 364 00:14:30,240 --> 00:14:35,960 SO YOU CAN SEE THAT EXPANSION. 365 00:14:35,960 --> 00:14:37,160 PREVIOUSLY WE HAD REALLY ONLY 366 00:14:37,160 --> 00:14:39,600 BEEN ABLE TO DO THIS BY 367 00:14:39,600 --> 00:14:40,560 EXAMINING TEMPORAL BONES THAT 368 00:14:40,560 --> 00:14:44,200 HAD BEEN DONATED TO US AFTER 369 00:14:44,200 --> 00:14:49,400 PATIENTS HAD DIED. 370 00:14:49,400 --> 00:14:53,080 BUT NOW THE USE OF CON TRANS 371 00:14:53,080 --> 00:15:01,840 ENHANCED FLAIR MRI INVOLVES 372 00:15:01,840 --> 00:15:03,720 GADOLINIUM INJECTIONS AND 373 00:15:03,720 --> 00:15:09,600 WAITING FOR ABOUT 4 TO 8 HOURS 374 00:15:09,600 --> 00:15:10,800 AFTER THE INJECTION. 375 00:15:10,800 --> 00:15:12,560 THIS ALLOWS THE GADOLINIUM TO 376 00:15:12,560 --> 00:15:14,040 FILL AND THAT'S DEMONSTRATED BY 377 00:15:14,040 --> 00:15:16,800 THE WHITE SPACES ON THIS FLAIR 378 00:15:16,800 --> 00:15:17,160 MRI. 379 00:15:17,160 --> 00:15:22,720 THIS IS AN AXIAL FLAIR, DELAYED 380 00:15:22,720 --> 00:15:24,600 FLAIR IMAGE OF A PATIENT WITH 381 00:15:24,600 --> 00:15:26,640 RIGHT-SIDED MENIERE'S DISEASE, 382 00:15:26,640 --> 00:15:29,280 SO THE WHITE SPACES ARE THE 383 00:15:29,280 --> 00:15:30,400 PERILYMPH AND THE DARK SPACES 384 00:15:30,400 --> 00:15:32,520 WHAT YOU SEE WITH THE RED ARROWS 385 00:15:32,520 --> 00:15:34,760 ARE THE END LYMPH. 386 00:15:34,760 --> 00:15:36,400 NORMALLY THE ENDOLYMPH IS HARD 387 00:15:36,400 --> 00:15:37,920 TO SEE SO WHEN YOU ACTUALLY SEE 388 00:15:37,920 --> 00:15:41,880 THESE DARK SPACES, THAT'S AN 389 00:15:41,880 --> 00:15:43,360 INDICATOR OF ENDOLYMPHATIC 390 00:15:43,360 --> 00:15:43,600 HYDROPS. 391 00:15:43,600 --> 00:15:46,160 WE HAVE A VERY SKILLED 392 00:15:46,160 --> 00:15:46,800 NEURORADIOLOGIST HERE THAT WE 393 00:15:46,800 --> 00:15:50,960 WORK WITH, DR. JOHN BUCKMAN, WHO 394 00:15:50,960 --> 00:15:54,120 I'LL ACKNOWLEDGE AT THE END BUT 395 00:15:54,120 --> 00:15:55,320 HIS EXPERTISE HERE IS CRITICAL. 396 00:15:55,320 --> 00:15:58,720 SO CURRENT GRADING SCHEMES OR 397 00:15:58,720 --> 00:16:00,160 SYSTEMS FOR ENDOLYMPHATIC 398 00:16:00,160 --> 00:16:03,720 HYDROPS ARE HIGHLY SUBJECTIVE, 399 00:16:03,720 --> 00:16:06,720 AND YOU CAN SEE EXAMPLES OF A 400 00:16:06,720 --> 00:16:10,120 COCHLEAR GRADING SCHEME AND WHAT 401 00:16:10,120 --> 00:16:13,840 YOU'RE SEEING TO THE RIGHT ARE 402 00:16:13,840 --> 00:16:16,160 THE -- THE IMAGES ABOVE ARE 403 00:16:16,160 --> 00:16:18,120 IMAGES THAT SHOW TOTAL FLUID AND 404 00:16:18,120 --> 00:16:20,440 IMAGES BELOW ARE IMAGES THAT ARE 405 00:16:20,440 --> 00:16:23,000 THE FLAIR IMAGES THAT SHOW US 406 00:16:23,000 --> 00:16:28,240 BEING ABLE TO IDENTIFY HYDROPS. 407 00:16:28,240 --> 00:16:29,760 HERE IS AN EXAMPLE WHERE THERE'S 408 00:16:29,760 --> 00:16:31,040 NONE AND HERE IS AN EXAMPLE 409 00:16:31,040 --> 00:16:35,000 WHERE THERE IS A GRADE 410 00:16:35,000 --> 00:16:36,080 2 ENDOLYMPHATIC HYDROPS IN THE 411 00:16:36,080 --> 00:16:37,080 COCHLEA. 412 00:16:37,080 --> 00:16:40,320 SIMILARLY, THERE'S A SYSTEM, 413 00:16:40,320 --> 00:16:41,720 THIS IS AN EXAMPLE OF A SYSTEM 414 00:16:41,720 --> 00:16:43,720 THAT'S USED TO DIAGNOSE HYDROPS 415 00:16:43,720 --> 00:16:47,400 IN THE VESTIBULE, OR THE BALANCE 416 00:16:47,400 --> 00:16:53,440 PART OF THE INNER EAR. 417 00:16:53,440 --> 00:16:56,040 SO OUR GOAL REALLY, GIVEN THE 418 00:16:56,040 --> 00:16:57,400 SUBJECTIVITY OF THESE GRADING 419 00:16:57,400 --> 00:17:00,560 SYSTEMS, IS TO ACCURATELY 420 00:17:00,560 --> 00:17:03,400 QUANTIFY ENDOLYMPHATIC HYDROPS. 421 00:17:03,400 --> 00:17:05,520 AND BEING ABLE TO DO THIS COULD 422 00:17:05,520 --> 00:17:07,320 CHANGE THE UTILITY OF THIS 423 00:17:07,320 --> 00:17:09,400 IMAGING MODALITY, AS WELL AS OUR 424 00:17:09,400 --> 00:17:11,360 ABILITY TO ASSESS CHANGES IN THE 425 00:17:11,360 --> 00:17:12,080 INNER EAR. 426 00:17:12,080 --> 00:17:14,320 NOW, WE USE SEVERAL MRI 427 00:17:14,320 --> 00:17:15,200 SEQUENCES. 428 00:17:15,200 --> 00:17:18,080 THE FIRST ONE BEING SHORT TAU 429 00:17:18,080 --> 00:17:21,320 INVERSION RECOVERY OR STIR 430 00:17:21,320 --> 00:17:24,600 SEQUENCES ON MRI, WHICH GIVE US 431 00:17:24,600 --> 00:17:26,160 THE TOTAL FLUID IN THE INNER 432 00:17:26,160 --> 00:17:26,920 EAR. 433 00:17:26,920 --> 00:17:29,840 AND HERE YOU SEE AN EXAMPLE OF 434 00:17:29,840 --> 00:17:31,000 THAT. 435 00:17:31,000 --> 00:17:33,040 AND THEN FLUID ATTENUATED 436 00:17:33,040 --> 00:17:34,560 INVERSION RECOVERY SEQUENCES OR 437 00:17:34,560 --> 00:17:38,280 FLAIR SEQUENCES ON DELAYED 438 00:17:38,280 --> 00:17:42,160 SEQUENCING ALLOW US TO DETERMINE 439 00:17:42,160 --> 00:17:43,040 PERILYMPH SIGNAL, AND THAT'S 440 00:17:43,040 --> 00:17:45,160 WHAT YOU SEE HERE. 441 00:17:45,160 --> 00:17:50,200 THEN THOSE TWO IMAGES ARE 442 00:17:50,200 --> 00:17:52,800 UTILIZED TO SUBTRACT ONE FROM 443 00:17:52,800 --> 00:17:55,160 THE OTHER TO IDENTIFY THE 444 00:17:55,160 --> 00:17:56,960 ENDOLYMPH SPACE YOU SEE IN THIS 445 00:17:56,960 --> 00:17:58,320 DIFFERENCE IMAGE, AND THEN WE'RE 446 00:17:58,320 --> 00:18:03,200 OVERLAYING THE TWO MASKS OF THE 447 00:18:03,200 --> 00:18:05,400 DIFFERENT FLUIDS SO THE 448 00:18:05,400 --> 00:18:07,840 PERILYMPH IN GREEN AND THE 449 00:18:07,840 --> 00:18:12,400 ENDOLYMPH IN PINK, OR RED. 450 00:18:12,400 --> 00:18:14,400 SO USING THIS METHODOLOGY, WE'RE 451 00:18:14,400 --> 00:18:16,680 CAPABLE -- WE CAN IDENTIFY 452 00:18:16,680 --> 00:18:22,000 EVIDENCE OF HYDROPS AND IDENTIFY 453 00:18:22,000 --> 00:18:23,880 KIND OF THE ENDOLYMPH CONTAINING 454 00:18:23,880 --> 00:18:26,080 SPACES OF THE COCHLEA AND 455 00:18:26,080 --> 00:18:26,360 VESTIBULE. 456 00:18:26,360 --> 00:18:28,920 SO THIS IS A BRIEF OVERVIEW OF 457 00:18:28,920 --> 00:18:32,160 OUR CURRENT EFFORTS AT 458 00:18:32,160 --> 00:18:35,600 QUANTIFYING IN A PEOP PIPELINE 459 00:18:35,600 --> 00:18:38,080 FASHION BOTH ENDOLYMPH AND 460 00:18:38,080 --> 00:18:39,840 PERILYMPH FASHIONS. 461 00:18:39,840 --> 00:18:40,840 CURRENTLY IT'S SUPERVISED BUT 462 00:18:40,840 --> 00:18:42,040 THE CURRENT GOAL IS TO DEVELOP 463 00:18:42,040 --> 00:18:43,360 METHODS TO OUGHT MADE ALL THE 464 00:18:43,360 --> 00:18:45,000 STEPS INCLUDING SEGMENTATION, 465 00:18:45,000 --> 00:18:47,040 AND WE'RE ACTIVELY RECRUITING 466 00:18:47,040 --> 00:18:48,360 PATIENTS TO BUILD THE DATASETS 467 00:18:48,360 --> 00:18:50,120 TO TRAIN THE NECESSARY MODELS TO 468 00:18:50,120 --> 00:18:56,040 ACCOMPLISH THIS TASK 469 00:18:56,040 --> 00:18:57,920 SO NOW I KIND OF WANT TO TALK 470 00:18:57,920 --> 00:19:01,840 ABOUT A FEW EXAMPLES TO GIVE YOU 471 00:19:01,840 --> 00:19:03,040 A FLAVOR OF THIS KIND OF 472 00:19:03,040 --> 00:19:03,280 IMAGING. 473 00:19:03,280 --> 00:19:04,440 THIS IS ONE PATIENT WHOSE 474 00:19:04,440 --> 00:19:12,040 HEARING IN THIS CASE BECAME 475 00:19:12,040 --> 00:19:13,520 BETTER AND WORSE DURING TWO 476 00:19:13,520 --> 00:19:14,480 SEGMENTS OF THE PROTOCOL. 477 00:19:14,480 --> 00:19:15,600 THIS PATIENT HAD EXHIBITED 478 00:19:15,600 --> 00:19:17,120 EVIDENCE OF HEARING INSTABILITY 479 00:19:17,120 --> 00:19:20,960 PRIOR TO BEING RECRUITED TO THE 480 00:19:20,960 --> 00:19:23,800 CLINICAL CENTER HERE. 481 00:19:23,800 --> 00:19:27,720 SO HERE'S AN EXAMPLE OF THE 482 00:19:27,720 --> 00:19:31,120 KINDS OF RECONSTRUCTIONS WE'RE 483 00:19:31,120 --> 00:19:33,760 DOING IN TERMS OF IMAGING 484 00:19:33,760 --> 00:19:34,840 ENDOLYMPHATIC HYDROPS. 485 00:19:34,840 --> 00:19:37,040 THE PERILYMPH SIGNALS IN GREEN 486 00:19:37,040 --> 00:19:40,080 HERE AND THE ENDOLYMPH SIGNAL IS 487 00:19:40,080 --> 00:19:41,760 IN PINK. 488 00:19:41,760 --> 00:19:46,560 AND WE'RE QUANTIFYING THE RATIO 489 00:19:46,560 --> 00:19:49,040 OF ENDOLYMPH TO PERILYMPH 490 00:19:49,040 --> 00:19:51,560 VOLUMES, AND IN THIS CASE, THIS 491 00:19:51,560 --> 00:19:55,200 PATIENT'S VESTIBULAR VOLUME 492 00:19:55,200 --> 00:19:56,920 RIGHT HERE STARTED OUT LARGER 493 00:19:56,920 --> 00:19:59,680 AND THEN BECAME SMALLER, AND 494 00:19:59,680 --> 00:20:01,880 THIS APPEARS TO CORRELATE WITH 495 00:20:01,880 --> 00:20:03,160 THE PATIENT'S HEARING 496 00:20:03,160 --> 00:20:05,800 IMPROVEMENT. 497 00:20:05,800 --> 00:20:09,160 THE COCHLEA IS MORE DIFFICULT 498 00:20:09,160 --> 00:20:11,160 FOR US TO VISUALIZE AND 499 00:20:11,160 --> 00:20:12,920 QUANTIFY, BUT WE ARE WORKING ON 500 00:20:12,920 --> 00:20:17,800 THAT CURRENTLY TOO. 501 00:20:17,800 --> 00:20:19,160 SO THESE ARE ANOTHER COUPLE 502 00:20:19,160 --> 00:20:24,040 PATIENTS FROM THE PROTOCOL WHO 503 00:20:24,040 --> 00:20:26,800 HAVE COMPLETED THEIR ENTIRE 504 00:20:26,800 --> 00:20:27,320 PROTOCOL. 505 00:20:27,320 --> 00:20:29,520 WE'VE BEEN ABLE TO LOOK AT THEIR 506 00:20:29,520 --> 00:20:33,720 DATA OVER TIME, AND PATIENT 1 IS 507 00:20:33,720 --> 00:20:36,400 A PATIENT WITH HEARING 508 00:20:36,400 --> 00:20:39,160 INSTABILITY WHILE ON PROTOCOL. 509 00:20:39,160 --> 00:20:40,360 BOTH OF THESE PATIENTS HAVE A 510 00:20:40,360 --> 00:20:41,560 HISTORY OF HEARING INSTABILITY, 511 00:20:41,560 --> 00:20:44,600 BUT THE PATIENT, PATIENT 2, HAD 512 00:20:44,600 --> 00:20:46,040 RELATIVELY STABLE HEARING WHILE 513 00:20:46,040 --> 00:20:47,160 ON PROTOCOL. 514 00:20:47,160 --> 00:20:49,800 AND IN THIS CASE, PATIENT 1 HAD 515 00:20:49,800 --> 00:20:51,280 EVIDENCE OF ENDOLYMPHATIC 516 00:20:51,280 --> 00:20:52,840 HYDROPS AND PATIENT 2 DID NOT 517 00:20:52,840 --> 00:20:55,880 HAVE EVIDENCE OF ENDOLYMPHATIC 518 00:20:55,880 --> 00:20:58,240 HYDROPS AS KIND OF ASCERTAINED 519 00:20:58,240 --> 00:21:02,280 BY DR. BUCKMAN ON HIS READS OF 520 00:21:02,280 --> 00:21:03,680 THE SEQUENTIAL MRIs OF THESE 521 00:21:03,680 --> 00:21:05,080 PATIENTS OVER TIME. 522 00:21:05,080 --> 00:21:07,360 SO ONE OF THE THINGS THAT WE SEE 523 00:21:07,360 --> 00:21:12,720 USING SPECTRAL FLOW CYTOMETRY TO 524 00:21:12,720 --> 00:21:14,320 PERFORM CELLULAR IMMUNOPROFILING 525 00:21:14,320 --> 00:21:16,680 IS THAT PATIENT 1, WHO HAS 526 00:21:16,680 --> 00:21:19,200 EVIDENCE OF HEARING INSTABILITY, 527 00:21:19,200 --> 00:21:22,360 DEMONSTRATES A GREATER 528 00:21:22,360 --> 00:21:24,200 PROPORTION OF IMMUNE CELL 529 00:21:24,200 --> 00:21:25,760 POPULATIONS THAT ARE INVOLVED IN 530 00:21:25,760 --> 00:21:28,840 INNATE IMMUNITY. 531 00:21:28,840 --> 00:21:31,760 AND THOSE INCLUDE MONOCYTES, 532 00:21:31,760 --> 00:21:33,680 DENDRITIC CELLS AND NK CELLS. 533 00:21:33,680 --> 00:21:37,040 AND THE T-CELL POPULATIONS ARE 534 00:21:37,040 --> 00:21:44,680 NOT SIGNIFICANTLY CHANGED. 535 00:21:44,680 --> 00:21:46,880 SO FURTHERMORE, CYTOKINE 536 00:21:46,880 --> 00:21:47,960 PROFILING ON THESE TWO PATIENTS 537 00:21:47,960 --> 00:21:50,480 AS AN EXAMPLE SUGGESTS THE 538 00:21:50,480 --> 00:21:52,960 POSSIBILITY OF AN INCREASE IN 539 00:21:52,960 --> 00:21:56,040 PRO INFLAMMATORY CYTOKINES IN 540 00:21:56,040 --> 00:21:57,040 THE SETTING OF HEARING 541 00:21:57,040 --> 00:21:57,360 INSTABILITY. 542 00:21:57,360 --> 00:22:03,600 WHAT WE DID HERE WAS, WE 543 00:22:03,600 --> 00:22:07,200 PERFORMED -- STIMULATED THE 544 00:22:07,200 --> 00:22:07,800 PERIPHERAL BLOOD MONO NUCLEAR 545 00:22:07,800 --> 00:22:09,840 CELLS AND COMPARED THEM TO 546 00:22:09,840 --> 00:22:10,600 UNSTIMULATED CONTROLS, AND WHAT 547 00:22:10,600 --> 00:22:12,560 WE FOUND IS THAT THE PATIENT 548 00:22:12,560 --> 00:22:15,200 WITH HEARING INSTABILITY IN THIS 549 00:22:15,200 --> 00:22:22,520 CASE DEMONSTRATES A 550 00:22:22,520 --> 00:22:23,960 GREATER DEGREE OF PRO 551 00:22:23,960 --> 00:22:26,360 INFLAMMATORY CYTOKINES AFTER 552 00:22:26,360 --> 00:22:28,760 STIMULATION, COMPARED TO THE 553 00:22:28,760 --> 00:22:32,480 PATIENT WITH RELATIVELY STABLE 554 00:22:32,480 --> 00:22:38,480 HEARING IN ORANGE HERE. 555 00:22:38,480 --> 00:22:39,680 SO TO SUMMARIZE KIND OF WHAT 556 00:22:39,680 --> 00:22:44,160 WE'VE STARTED TO LEARN IN THIS 557 00:22:44,160 --> 00:22:47,040 PROTOCOL, CONTRAST ENHANCED 558 00:22:47,040 --> 00:22:50,160 DELAYED FLAIR MRI CAN DIAGNOSE 559 00:22:50,160 --> 00:22:50,720 ENDOLYMPHATIC HYDROPS IN 560 00:22:50,720 --> 00:22:52,160 PATIENTS WITH HEARING 561 00:22:52,160 --> 00:22:53,120 INSTABILITY. 562 00:22:53,120 --> 00:22:54,480 PRELIMINARY DATA FROM OUR GROUP 563 00:22:54,480 --> 00:22:55,680 SUGGESTS THAT SOME PATIENTS WITH 564 00:22:55,680 --> 00:22:58,360 HEARING INSTABILITY DEMONSTRATE 565 00:22:58,360 --> 00:22:59,920 ALTERATIONS IN INNATE IMMUNE 566 00:22:59,920 --> 00:23:02,560 CELL POPULATIONS AND AN 567 00:23:02,560 --> 00:23:03,600 UNDERLYING PREDISPOSITION 568 00:23:03,600 --> 00:23:06,240 TOWARDS THE PRODUCTION OF PRO 569 00:23:06,240 --> 00:23:07,920 INFLAMMATORY CYTOKINES. 570 00:23:07,920 --> 00:23:09,760 FUTURE WORK IS FOCUSING ON 571 00:23:09,760 --> 00:23:13,160 CREATING AN AI-BASED AUTOMATED 572 00:23:13,160 --> 00:23:16,880 METHOD TO OBJECTIVELY QUANTIFY 573 00:23:16,880 --> 00:23:20,040 ENDOLYMPHATIC HYDROPS AND WILL 574 00:23:20,040 --> 00:23:20,640 IDENTIFY POTENTIAL IMMUNOLOGIC 575 00:23:20,640 --> 00:23:22,560 AND NON-IMMUNOLOGIC BIOMARKERS 576 00:23:22,560 --> 00:23:24,960 THAT MAY SERVE AS THERAPEUTIC 577 00:23:24,960 --> 00:23:26,520 TARGETS. 578 00:23:26,520 --> 00:23:29,680 SO GOING ON TO OUR WORK WITH THE 579 00:23:29,680 --> 00:23:33,520 MOUSE MODELS, WE'VE BEEN 580 00:23:33,520 --> 00:23:34,800 INVESTIGATING THE MECHANISMS OF 581 00:23:34,800 --> 00:23:36,240 HEARING INSTABILITY IN THE 582 00:23:36,240 --> 00:23:38,480 SETTING OF STRIA VASCULARIS 583 00:23:38,480 --> 00:23:41,600 DYSFUNCTION USING A MOUSE MODEL 584 00:23:41,600 --> 00:23:47,280 DEVELOPED HERE AT THE NIDCD. 585 00:23:47,280 --> 00:23:48,480 IT'S THE INSUFFICIENCY MOUSE 586 00:23:48,480 --> 00:23:48,840 MODEL. 587 00:23:48,840 --> 00:23:52,640 WHILE I DON'T HAVE TIME TO 588 00:23:52,640 --> 00:23:53,720 DESCRIBE ALL THE DETAILS ABOUT 589 00:23:53,720 --> 00:23:55,160 OUR INVESTIGATIONS, I'M GOING TO 590 00:23:55,160 --> 00:23:56,880 DESCRIBE THIS MOUSE MODEL AND 591 00:23:56,880 --> 00:23:58,520 WHY I THINK IT'S A GOOD MOUSE 592 00:23:58,520 --> 00:24:04,760 MODEL TO STUDY THESE DISEASES. 593 00:24:04,760 --> 00:24:07,520 SO THIS MOUSE MODEL IS THE ONLY 594 00:24:07,520 --> 00:24:10,240 MOUSE MODEL THAT DOESN'T RELY ON 595 00:24:10,240 --> 00:24:13,840 A SURGICAL PROCEDURE OR 596 00:24:13,840 --> 00:24:17,160 PERSISTENT DRUG ADMINISTRATION 597 00:24:17,160 --> 00:24:20,760 TO PRODUCE PERSISTENT 598 00:24:20,760 --> 00:24:21,520 INTERMITTENTLY -- INTERMITTENT 599 00:24:21,520 --> 00:24:23,280 HEARING FLUCTUATION OVER TIME. 600 00:24:23,280 --> 00:24:25,480 AND AGAIN, THIS MOUSE MODEL WAS 601 00:24:25,480 --> 00:24:26,880 DEVELOPED HERE AS A 602 00:24:26,880 --> 00:24:28,320 COLLABORATION BETWEEN THE 603 00:24:28,320 --> 00:24:30,800 GRIFFITH AND FRIEDMAN LAB AT 604 00:24:30,800 --> 00:24:34,000 NIDCD, AND IT CONSISTS OF TWO 605 00:24:34,000 --> 00:24:35,840 TRANSGENIC MOUSE LINES, AN 606 00:24:35,840 --> 00:24:40,360 EFFECTOR AND RESPONDER MOUSE 607 00:24:40,360 --> 00:24:42,080 LINE BRED ON TO THE BACKGROUND 608 00:24:42,080 --> 00:24:44,400 OF A PENDRIN NULL MOUSE. 609 00:24:44,400 --> 00:24:47,240 NOW THE EFFECTOR AND RESPONDER 610 00:24:47,240 --> 00:24:50,280 TRANSGENIC LINES ALLOW US TO USE 611 00:24:50,280 --> 00:24:51,840 DOXYCYCLINE TO INDUCE THE 612 00:24:51,840 --> 00:24:54,880 EXPRESSION OF PENDRIN. 613 00:24:54,880 --> 00:24:59,240 AND WE DO THIS BETWEEN E0 AND 614 00:24:59,240 --> 00:25:02,440 E17.5 TO ALLOW FOR THE INNER EAR 615 00:25:02,440 --> 00:25:04,080 TO DEVELOP NORMALLY. 616 00:25:04,080 --> 00:25:07,680 AFTER THIS TIME, DOC DOXYCYCLINS 617 00:25:07,680 --> 00:25:10,160 STOPPED AND THESE MICE ARE 618 00:25:10,160 --> 00:25:13,600 TESTED BETWEEN P30 OR ONE MONTH 619 00:25:13,600 --> 00:25:15,360 AND TWO MONTHS, AND THESE 620 00:25:15,360 --> 00:25:16,760 PATIENTS -- OR THESE MICE 621 00:25:16,760 --> 00:25:20,160 EXHIBIT HEARING FLUCTUATION AS 622 00:25:20,160 --> 00:25:22,560 PREVIOUSLY DESCRIBED BY THE 623 00:25:22,560 --> 00:25:23,320 GRIFFITH LAB. 624 00:25:23,320 --> 00:25:26,480 AND THE EXPERIMENTAL MICE ARE 625 00:25:26,480 --> 00:25:28,240 CALLED -- WITH THE TWO TRANS 626 00:25:28,240 --> 00:25:29,880 GENES ON THE PENDRIN NULL 627 00:25:29,880 --> 00:25:35,000 BACKGROUND ARE CALLED DE17.5 628 00:25:35,000 --> 00:25:36,760 MICE AND THE MICE HETEROSIGH 629 00:25:36,760 --> 00:25:38,720 GUESS FOR PENDRIN SERVE AS AN 630 00:25:38,720 --> 00:25:39,160 ADDITIONAL CONTROL. 631 00:25:39,160 --> 00:25:44,760 SO YOU SEE THAT HERE. 632 00:25:44,760 --> 00:25:52,400 SO APPROXIMATELY 60% OF THE 633 00:25:52,400 --> 00:25:53,640 DE17.5 MICE DEMONSTRATE HEARING 634 00:25:53,640 --> 00:25:58,640 INSTABILITY AND YOU CAN SEE THAT 635 00:25:58,640 --> 00:25:59,240 HERE. 636 00:25:59,240 --> 00:26:01,160 AND OF THE MICE THAT 637 00:26:01,160 --> 00:26:09,800 FLUCTUATFLUCTUATE,THE DE17.5 MIN 638 00:26:09,800 --> 00:26:11,520 EXHIBIT GREATER CUMULATIVE 639 00:26:11,520 --> 00:26:13,520 THRESHOLD SHIFTS THAN THEIR 640 00:26:13,520 --> 00:26:17,840 NON-FLUCTUATING COUNTERPARTS. 641 00:26:17,840 --> 00:26:21,400 FURTHERMORE, THE DE17.5 MICE 642 00:26:21,400 --> 00:26:24,120 ALSO DEMONSTRATE STRIA 643 00:26:24,120 --> 00:26:24,800 VASCULARIS DYSFUNCTION IN THE 644 00:26:24,800 --> 00:26:28,280 FORM OF ENDOCOCHLEAR POTENTIAL 645 00:26:28,280 --> 00:26:30,440 REDUCTIONS, AND ALSO DEMONSTRATE 646 00:26:30,440 --> 00:26:32,640 EVIDENCE OF IMMUNE DYSFUNCTION 647 00:26:32,640 --> 00:26:36,040 OR DYSREGULATION, SPECIFICALLY 648 00:26:36,040 --> 00:26:39,280 MICE WITH FLUCTUATION 649 00:26:39,280 --> 00:26:43,040 DEMONSTRATE INCREASED NUMBERS OF 650 00:26:43,040 --> 00:26:45,680 LATERAL WALL AND STRIA 651 00:26:45,680 --> 00:26:48,520 VASCULARIS COCHLEAR MACROPHAGES. 652 00:26:48,520 --> 00:26:51,240 SO ONE OF OUR HYPOTHESES HERE IS 653 00:26:51,240 --> 00:26:53,320 THAT EITHER THE REDUCED ABILITY 654 00:26:53,320 --> 00:26:56,800 TO RESPOND TO INFLAMMATION 655 00:26:56,800 --> 00:26:59,440 AND/OR -- AND FORM OF IONIC 656 00:26:59,440 --> 00:27:00,240 HOMEOSTATIC DYSFUNCTION RESULTS 657 00:27:00,240 --> 00:27:02,720 IN THIS PREDISPOSITION TO 658 00:27:02,720 --> 00:27:04,680 HEARING INSTABILITY IN THE MOUSE 659 00:27:04,680 --> 00:27:05,240 MODEL. 660 00:27:05,240 --> 00:27:06,880 AND WE THINK THAT MIGHT BE 661 00:27:06,880 --> 00:27:13,320 TRANSLATABLE TO HUMANS TOO. 662 00:27:13,320 --> 00:27:14,640 FINALLY, THIS MOUSE MODEL 663 00:27:14,640 --> 00:27:17,160 DEMONSTRATES A HISTOLOGIC 664 00:27:17,160 --> 00:27:18,920 HALLMARK FOR HEARING INSTABILITY 665 00:27:18,920 --> 00:27:20,760 DISORDERS. 666 00:27:20,760 --> 00:27:21,880 NAMELY, ENDOLYMPHATIC HYDROPS. 667 00:27:21,880 --> 00:27:27,200 AND HERE YOU SEE PLASTIC 668 00:27:27,200 --> 00:27:28,400 SECTIONS FROM MICE WITH AND 669 00:27:28,400 --> 00:27:32,480 WITHOUT HEARING INSTABILITY OVER 670 00:27:32,480 --> 00:27:35,880 TIME, AND THE MICE WITH HEARING 671 00:27:35,880 --> 00:27:37,480 INSTABILITY SEEM TO DEMONSTRATE 672 00:27:37,480 --> 00:27:41,280 A GREATER EXTENT OF 673 00:27:41,280 --> 00:27:43,960 ENDOLYMPHATIC HYDROPS. 674 00:27:43,960 --> 00:27:46,360 OF GREATER DEGREE, THAT IS. 675 00:27:46,360 --> 00:27:48,440 THAT'S THAT EXPANSION OF THIS 676 00:27:48,440 --> 00:27:51,360 CENTRAL COMPARTMENT. 677 00:27:51,360 --> 00:27:57,760 SO IN SUMMARY, HERE, THE PENDRIN 678 00:27:57,760 --> 00:27:59,680 A INSUFFICIENCY MOUSE MODEL MAY 679 00:27:59,680 --> 00:28:01,120 SERVE AS A REASONABLE MODEL FOR 680 00:28:01,120 --> 00:28:02,800 HEARING INSTABILITY DISORDERS. 681 00:28:02,800 --> 00:28:04,600 CURRENTLY WE'RE UTILIZING SINGLE 682 00:28:04,600 --> 00:28:06,040 CELL AND SINGLE NUCLEAR 683 00:28:06,040 --> 00:28:07,400 TRANSCRIPTIONAL PROFILING TO 684 00:28:07,400 --> 00:28:09,040 INVESTIGATE THE UNDERLYING 685 00:28:09,040 --> 00:28:10,080 MECHANISMS OF HEARING 686 00:28:10,080 --> 00:28:11,440 INSTABILITY IN THIS MOUSE MODEL 687 00:28:11,440 --> 00:28:14,480 AND TO IDENTIFY POTENTIALLY 688 00:28:14,480 --> 00:28:16,000 REPURPOSABLE THERAPEUTICS FOR 689 00:28:16,000 --> 00:28:17,960 THESE DISEASES IN THE MOUSE 690 00:28:17,960 --> 00:28:18,960 MODEL. 691 00:28:18,960 --> 00:28:21,720 AND IN THE FUTURE, AND REALLY 692 00:28:21,720 --> 00:28:23,120 CURRENTLY, WE'RE FOCUSING ON 693 00:28:23,120 --> 00:28:25,320 UTILIZING THIS MOUSE MODEL TO 694 00:28:25,320 --> 00:28:27,720 DEVELOP PRELIMINARY DATA TO 695 00:28:27,720 --> 00:28:30,120 SUPPORT THE REPURPOSING OF 696 00:28:30,120 --> 00:28:31,200 FDA-APPROVED MEDICATIONS TO 697 00:28:31,200 --> 00:28:34,480 TREAT HEARING INSTABILITY. 698 00:28:34,480 --> 00:28:35,800 AND WITH THAT, I'D LIKE TO THANK 699 00:28:35,800 --> 00:28:38,120 YOU FOR YOUR ATTENTION, AND I'D 700 00:28:38,120 --> 00:28:40,000 LIKE TO ACKNOWLEDGE THE MEMBERS 701 00:28:40,000 --> 00:28:42,920 OF MY LAB, WHOSE WORK YOU'VE 702 00:28:42,920 --> 00:28:46,080 SEEN HERE TODAY, AND ALSO THE 703 00:28:46,080 --> 00:28:49,120 NIDCD CLINICAL RESEARCH TEAM AND 704 00:28:49,120 --> 00:28:50,560 THE AUDIOLOGY UNIT, WHO HAVE 705 00:28:50,560 --> 00:28:54,840 BEEN VERY SUPPORTIVE IN GETTING 706 00:28:54,840 --> 00:28:56,280 MY CLINICAL PROTOCOL UP AND 707 00:28:56,280 --> 00:28:57,120 RUNNING AND RECRUITING LIKE IT 708 00:28:57,120 --> 00:28:57,680 IS NOW. 709 00:28:57,680 --> 00:28:59,120 AND WITH THAT, THANK YOU AGAIN 710 00:28:59,120 --> 00:29:01,920 FOR YOUR ATTENTION. 711 00:29:01,920 --> 00:29:03,240 >>GOOD AFTERNOON, EVERYONE. 712 00:29:03,240 --> 00:29:06,040 I WANT TO THANK DR. BURKLOW FOR 713 00:29:06,040 --> 00:29:07,760 THE INVITATION TO PRESENT IN 714 00:29:07,760 --> 00:29:08,560 TODAY'S GRAND ROUNDS WITH 715 00:29:08,560 --> 00:29:09,200 DR. HAO. 716 00:29:09,200 --> 00:29:10,800 SO OVER THE NEXT 25 MINUTES OR 717 00:29:10,800 --> 00:29:11,680 SO, I'D LIKE TO TALK TO YOU 718 00:29:11,680 --> 00:29:12,040 ABOUT THE DEVELOPMENT OF INNER 719 00:29:12,040 --> 00:29:13,720 EAR GENE THERAPY AS THE 720 00:29:13,720 --> 00:29:15,120 TREATMENT FOR HEARING LOSS AND 721 00:29:15,120 --> 00:29:16,560 DIZZINESS, AND MORE 722 00:29:16,560 --> 00:29:17,320 SPECIFICALLY, I'D LIKE TO TALK 723 00:29:17,320 --> 00:29:18,200 ABOUT SOME OF THE WORK WE'RE 724 00:29:18,200 --> 00:29:20,160 DOING IN THE LAB TO TRY TO APPLY 725 00:29:20,160 --> 00:29:21,800 INNER EAR GENE THERAPY TO USHER 726 00:29:21,800 --> 00:29:22,720 SYNDROME. 727 00:29:22,720 --> 00:29:24,680 I HAVE NOTHING TO DISCLOSE. 728 00:29:24,680 --> 00:29:26,400 SO AS MANY OF YOU KNOW, HEARING 729 00:29:26,400 --> 00:29:28,080 LOSS IS A MAJOR DISABILITY 730 00:29:28,080 --> 00:29:29,240 AFFECTING THE WORLD'S POPULATION 731 00:29:29,240 --> 00:29:30,440 TODAY. 732 00:29:30,440 --> 00:29:33,640 WE KNOW THAT ABOUT HALF OF THE 733 00:29:33,640 --> 00:29:34,600 POPULATION 75 YEARS AND OLDER 734 00:29:34,600 --> 00:29:35,360 HAVE HEARING LOSS. 735 00:29:35,360 --> 00:29:37,360 HEARING LOSS IS NOT JUST A 736 00:29:37,360 --> 00:29:39,400 DISEASE PROCESS, IT AFFECTS THE 737 00:29:39,400 --> 00:29:41,160 ELDERLY POPULATION. 738 00:29:41,160 --> 00:29:43,480 IT ALSO AFFECTS MANY NEWBORNS AS 739 00:29:43,480 --> 00:29:44,000 WELL. 740 00:29:44,000 --> 00:29:46,680 WE KNOW THAT ABOUT 3 OUT OF 741 00:29:46,680 --> 00:29:47,600 1,000 LIVE BIRTHS ARE AFFECTED 742 00:29:47,600 --> 00:29:48,400 WITH HEARING LOSS. 743 00:29:48,400 --> 00:29:50,160 SO IT IS TRULY A DISEASE PROCESS 744 00:29:50,160 --> 00:29:52,240 THAT AFFECTS A WIDE RANGE OF 745 00:29:52,240 --> 00:29:54,600 POPULATION. 746 00:29:54,600 --> 00:29:55,400 CURRENTLY, PATIENTS WITH HEARING 747 00:29:55,400 --> 00:29:57,360 LOSS ARE TYPICALLY TREATED WITH 748 00:29:57,360 --> 00:29:58,800 HEARING AIDS IF THEIR HEARING 749 00:29:58,800 --> 00:30:00,640 LOSS IS MILD TO MODERATE IN 750 00:30:00,640 --> 00:30:02,080 SEVERITY, AND FOR THOSE THAT 751 00:30:02,080 --> 00:30:03,800 HAVE SEVERE TO PROFOUND HEARING 752 00:30:03,800 --> 00:30:05,120 LOSS, A COCHLEAR IMPLANT MAY BE 753 00:30:05,120 --> 00:30:09,080 AN OPTION. 754 00:30:09,080 --> 00:30:11,560 THE TECHNICAL ADVANCES OF 755 00:30:11,560 --> 00:30:13,880 HEARING AID AND COCHLEAR IMPLANT 756 00:30:13,880 --> 00:30:14,560 TECHNOLOGIES, SIGNIFICANT 757 00:30:14,560 --> 00:30:16,200 DRAWBACKS TO BOTH OF THESE 758 00:30:16,200 --> 00:30:18,160 THERAPEUTIC OPTIONS. 759 00:30:18,160 --> 00:30:21,440 SIMILARLY, DIZZINESS CAUSED BY 760 00:30:21,440 --> 00:30:22,200 VESTIBULAR DYSFUNCTION IS ALSO A 761 00:30:22,200 --> 00:30:24,360 MAIL JUROR CAUSE OF DISABILITY 762 00:30:24,360 --> 00:30:26,120 IN THE WORLD POPULATION TODAY 763 00:30:26,120 --> 00:30:27,520 FROM EPIDEMIOLOGIC STUDIES, WE 764 00:30:27,520 --> 00:30:28,920 KNOW THAT ABOUT 40% OF THE 765 00:30:28,920 --> 00:30:30,200 AMERICAN ADULTS SEEK MEDICAL 766 00:30:30,200 --> 00:30:34,840 HELP FOR DIZZINESS EVERY YEAR. 767 00:30:34,840 --> 00:30:36,720 VESTIBULAR DYSFUNCTION CAN ALSO 768 00:30:36,720 --> 00:30:37,360 AFFECT CHILDREN AND IN FACT 769 00:30:37,360 --> 00:30:39,760 CHILDREN WITH VESTIBULAR 770 00:30:39,760 --> 00:30:40,960 DYSFUNCTION CAN DEVELOP LEARNING 771 00:30:40,960 --> 00:30:42,160 DISABILITIES AND DELAYED MOTOR 772 00:30:42,160 --> 00:30:42,960 SCIELS SCILS. 773 00:30:42,960 --> 00:30:44,160 TREATMENT OPTIONS FOR THOSE 774 00:30:44,160 --> 00:30:46,080 PATIENTS WITH VESTIBULAR 775 00:30:46,080 --> 00:30:46,880 DYSFUNCTION ARE EVEN MORE 776 00:30:46,880 --> 00:30:48,600 LIMITED THAN THOSE AVAILABLE FOR 777 00:30:48,600 --> 00:30:50,400 PATIENTS WITH HEARING LOSS. 778 00:30:50,400 --> 00:30:52,040 AND IT IS BECAUSE OF THE LIMITED 779 00:30:52,040 --> 00:30:53,360 NUMBER OF EFFECTIVE TREATMENT 780 00:30:53,360 --> 00:30:55,560 OPTIONS FOR BOTH HEARING LOSS 781 00:30:55,560 --> 00:30:57,280 AND DIZZINESS THAT HAVE REALLY 782 00:30:57,280 --> 00:30:59,040 INSPIRED PEOPLE LIKE MYSELF AND 783 00:30:59,040 --> 00:31:00,800 MANY OTHERS IN THE FIELD TO TRY 784 00:31:00,800 --> 00:31:02,400 TO DEVELOP NEWER THERAPIES TO 785 00:31:02,400 --> 00:31:06,400 HELP THESE PATIENTS. 786 00:31:06,400 --> 00:31:08,720 OVER THE PAST FEW YEARS, OUR LAB 787 00:31:08,720 --> 00:31:12,120 HAS BEEN FOCUS ON INNER EAR GENE 788 00:31:12,120 --> 00:31:13,920 THERAPY AS WAY TO TREAT HEARING 789 00:31:13,920 --> 00:31:14,720 LOSS AND DIZZINESS. 790 00:31:14,720 --> 00:31:16,840 THE IDEA OF GENE THERAPY WAS 791 00:31:16,840 --> 00:31:21,720 FIRST PROPOSED IN THE 1970s BY 792 00:31:21,720 --> 00:31:24,120 ROBLIN AND FRIEDMANN AND AT THAT 793 00:31:24,120 --> 00:31:25,000 TIME THERE WAS VERY LITTLE KNOWN 794 00:31:25,000 --> 00:31:26,400 ABOUT THE HUMAN GENOME. 795 00:31:26,400 --> 00:31:27,960 DESPITE THERE WAS NOT A LOT 796 00:31:27,960 --> 00:31:28,840 KNOWN ABOUT THE HUMAN GENOME, 797 00:31:28,840 --> 00:31:30,680 THEY PROPOSED THE RADICAL IDEA 798 00:31:30,680 --> 00:31:32,560 THAT IF THE DISEASE PROCESS IS 799 00:31:32,560 --> 00:31:34,200 CAUSED BY A MUTATION OF A 800 00:31:34,200 --> 00:31:35,920 CERTAIN GENE OF INTEREST, FOR 801 00:31:35,920 --> 00:31:38,680 EXAMPLE, AND THE MUTATION CAUSES 802 00:31:38,680 --> 00:31:40,240 DYSFUNCTION IN AN ORGAN SYSTEM, 803 00:31:40,240 --> 00:31:41,880 COULD WE POTENTIALLY DELIVER 804 00:31:41,880 --> 00:31:44,120 NORMAL COPIES OF THE CDNA OF 805 00:31:44,120 --> 00:31:46,320 THAT PARTICULAR GENE OF INTEREST 806 00:31:46,320 --> 00:31:47,720 INTO THE DISEASE ORGAN SYSTEM TO 807 00:31:47,720 --> 00:31:49,840 TRY TO RESTORE FUNCTION. 808 00:31:49,840 --> 00:31:53,640 SO TO APPLY THIS TO THE INNER 809 00:31:53,640 --> 00:31:54,760 EAR, HEARING LOSS AND DIZZINESS 810 00:31:54,760 --> 00:31:56,640 IS CAUSE BID MUTATIONS AFFECTING 811 00:31:56,640 --> 00:31:59,040 A GENE THAT IS IMPORTANT FOR THE 812 00:31:59,040 --> 00:32:00,240 DEVELOPMENT OF THE 813 00:32:00,240 --> 00:32:03,400 MECHANOSENSORY HAIR CELLS, WHICH 814 00:32:03,400 --> 00:32:05,360 ARE THE VERY IMPORTANT CELL TYPE 815 00:32:05,360 --> 00:32:07,360 FOR SOME PERCEPTION, THEY ARE 816 00:32:07,360 --> 00:32:09,080 THE MAIN SENSORS FOR AUDITORY 817 00:32:09,080 --> 00:32:11,840 PERCEPTION IN THE INNER EAR, 818 00:32:11,840 --> 00:32:13,680 THEN COULD WE POTENTIALLY 819 00:32:13,680 --> 00:32:15,680 DELIVER NORMAL COPIES OF THIS 820 00:32:15,680 --> 00:32:17,080 PARTICULAR GENE CDNA INTO THE 821 00:32:17,080 --> 00:32:18,720 INNER EAR TO TRY TO RESTORE 822 00:32:18,720 --> 00:32:21,000 FUNCTION IN THE INNER EAR. 823 00:32:21,000 --> 00:32:25,600 OVER THE PAST FEW YEARS, WE HAVE 824 00:32:25,600 --> 00:32:28,000 FOCUSED ON USING PRIMARILY THE 825 00:32:28,000 --> 00:32:29,440 ADENOASSOCIATED VIRUS OR THE AAV 826 00:32:29,440 --> 00:32:31,520 AS THE VIRAL VECTOR OF CHOICE 827 00:32:31,520 --> 00:32:34,920 FOR GENE DELIVERY IN VARIOUS 828 00:32:34,920 --> 00:32:37,640 MOUSE MODELS WE'RE WORKING ON IN 829 00:32:37,640 --> 00:32:38,200 THE LAB. 830 00:32:38,200 --> 00:32:40,040 FIRST OF ALL, AAV IS 831 00:32:40,040 --> 00:32:41,000 NON-PATHOGENIC IN HUMANS AND 832 00:32:41,000 --> 00:32:42,320 ALSO IN MICE, THEREFORE, IT IS A 833 00:32:42,320 --> 00:32:43,560 VERY SAFE VIRUS TO USE. 834 00:32:43,560 --> 00:32:45,080 IT HAS BEEN SHOWN TO BE ABLE TO 835 00:32:45,080 --> 00:32:46,080 INFECT MULTIPLE CELL TYPES AND 836 00:32:46,080 --> 00:32:51,120 BY ENGINEERING THE -- WE CAN 837 00:32:51,120 --> 00:32:52,520 ACTUALLY ACHIEVE FAIRLY CELL 838 00:32:52,520 --> 00:32:53,400 TYPE SPECIFIC TRANSDUCTION. 839 00:32:53,400 --> 00:32:54,800 AND BECAUSE OF THESE FAVORABLE 840 00:32:54,800 --> 00:32:57,360 PROPERTIES, AAV IS ONE OF THE 841 00:32:57,360 --> 00:32:59,600 MOST COMMONLY USED VIRAL VECTORS 842 00:32:59,600 --> 00:33:01,120 IN HUMAN GENE THERAPY CLINICAL 843 00:33:01,120 --> 00:33:01,600 TRIALS TODAY. 844 00:33:01,600 --> 00:33:04,000 ONE DRAWBACK FOR AAV IS THE FACT 845 00:33:04,000 --> 00:33:06,960 THAT THE CARRYING CAPACITY OF 846 00:33:06,960 --> 00:33:09,360 THE SIZE THAT THE CDNA CAN CARRY 847 00:33:09,360 --> 00:33:11,880 IS ABOUT 4.5 KB AND THEREFORE, 848 00:33:11,880 --> 00:33:12,760 IF ONE IS INTERESTED IN 849 00:33:12,760 --> 00:33:15,280 DELIVERING A LARGER CDNA, THAT 850 00:33:15,280 --> 00:33:16,120 COULD POTENTIALLY BECOME 851 00:33:16,120 --> 00:33:17,120 CHALLENGING AND WE'LL TALK ABOUT 852 00:33:17,120 --> 00:33:19,960 THAT TODAY. 853 00:33:19,960 --> 00:33:24,240 SO ONE COMMON CAUSE OF 854 00:33:24,240 --> 00:33:25,440 HEREDITARY HEARING LOSS IS USHER 855 00:33:25,440 --> 00:33:26,880 SYNDROME. 856 00:33:26,880 --> 00:33:27,640 USHER SYNDROME IS THE MOST 857 00:33:27,640 --> 00:33:29,160 COMMON CAUSE OF DEAFNESS AND 858 00:33:29,160 --> 00:33:29,920 BLINDNESS IN THE WORLD. 859 00:33:29,920 --> 00:33:33,080 IT IS INHERITED IN AN AUTOSOMAL 860 00:33:33,080 --> 00:33:34,280 RECESSIVE MANNER. 861 00:33:34,280 --> 00:33:36,040 AND USHER SYNDROME CAN BE 862 00:33:36,040 --> 00:33:37,440 CLASSIFIED INTO THREE DIFFERENT 863 00:33:37,440 --> 00:33:39,800 TYPES, DEPENDING ON THE DISEASE 864 00:33:39,800 --> 00:33:41,960 PHENOTYPE, THE S SEVERITY OF THE 865 00:33:41,960 --> 00:33:43,080 PHENOTYPE AND ALSO THE ONSET OF 866 00:33:43,080 --> 00:33:43,920 THE SYMPTOMS. 867 00:33:43,920 --> 00:33:46,560 SO THE TIME 1 PATIENTS HAVE THE 868 00:33:46,560 --> 00:33:47,480 MOST SEVERE DISEASE PHENOTYPE, 869 00:33:47,480 --> 00:33:49,280 THEY ARE USUALLY BORN WITH 870 00:33:49,280 --> 00:33:50,280 PROFOUND HEARING LOSS AT BIRTH, 871 00:33:50,280 --> 00:33:52,560 THEY DEVELOP VISUAL LOSS AS A 872 00:33:52,560 --> 00:33:54,720 RESULT OF RETINITIS PIGMENTOSA 873 00:33:54,720 --> 00:33:56,520 AT AN EARLY AGE AND THEY ALSO 874 00:33:56,520 --> 00:33:57,720 HAVE VESTIBULAR DYSFUNCTION AS 875 00:33:57,720 --> 00:33:58,480 WELL. 876 00:33:58,480 --> 00:34:00,240 THE TYPE 2 PATIENTS ARE 877 00:34:00,240 --> 00:34:02,200 TYPICALLY BORN WITH MODERATE TO 878 00:34:02,200 --> 00:34:04,280 SEVERE HEARING LOSS AT BIRTH, 879 00:34:04,280 --> 00:34:05,720 AND THEIR VISUAL LOSS APPEARS A 880 00:34:05,720 --> 00:34:06,880 LITTLE LATER IN LIFE COMPARED TO 881 00:34:06,880 --> 00:34:08,560 THE TYPE 1 PATIENTS, AND THEY 882 00:34:08,560 --> 00:34:10,400 TYPICALLY HAVE FAIRLY NORMAL 883 00:34:10,400 --> 00:34:11,400 BALANCE FUNCTIONS. 884 00:34:11,400 --> 00:34:14,200 THE TYPE 3 PATIENTS, THEY 885 00:34:14,200 --> 00:34:15,640 DEVELOP PROGRESSIVE HEARING LOSS 886 00:34:15,640 --> 00:34:16,720 USUALLY DURING CHILDHOOD OR 887 00:34:16,720 --> 00:34:21,080 EARLY TEENS, AND THEY HAVE 888 00:34:21,080 --> 00:34:22,520 VARIABLE ONSET OF VISUAL LOSSES 889 00:34:22,520 --> 00:34:23,960 AND THEY TYPICALLY HAVE NORMAL 890 00:34:23,960 --> 00:34:25,680 TO NEAR NORMAL BALANCE FUNCTIONS 891 00:34:25,680 --> 00:34:29,120 DURING CHILDHOOD AND THEY MAY 892 00:34:29,120 --> 00:34:30,080 DEVELOP BALANCE FUNCTION ISSUES 893 00:34:30,080 --> 00:34:31,280 DOWN THE ROAD. 894 00:34:31,280 --> 00:34:34,120 AND OVER HERE ON THE LEFT-HAND 895 00:34:34,120 --> 00:34:36,200 SIDE IS A LIST OF THE GENES THAT 896 00:34:36,200 --> 00:34:40,040 ARE INVOLVED WITH -- THAT HAVE 897 00:34:40,040 --> 00:34:44,000 BEEN SHOWN TO CAUSE USHER SIM 898 00:34:44,000 --> 00:34:45,320 DROME LISTED RIGHT HERE. 899 00:34:45,320 --> 00:34:47,200 SO WE WANTED TO IDENTIFY A 900 00:34:47,200 --> 00:34:48,840 SUITABLE TYPE OF USHER SYNDROME 901 00:34:48,840 --> 00:34:50,240 TO APPLY INNER EAR GENE THERAPY 902 00:34:50,240 --> 00:34:51,120 TO. 903 00:34:51,120 --> 00:34:54,960 SO WE DECIDED TO TRY TO STUDY 904 00:34:54,960 --> 00:34:56,480 USHER SYNDROME TYPE 1B. 905 00:34:56,480 --> 00:34:58,280 THE USHER SYNDROME TYPE 1B IS 906 00:34:58,280 --> 00:34:59,880 ONE OF THE MORE COMMON CAUSES OF 907 00:34:59,880 --> 00:35:00,960 USHER SYNDROME. 908 00:35:00,960 --> 00:35:03,360 SO THIS FIGURE HERE WAS TAKEN 909 00:35:03,360 --> 00:35:05,760 FROM A META-ANALYSIS WHERE THEY 910 00:35:05,760 --> 00:35:07,720 ANALYZED THE GENETIC DATA FROM 911 00:35:07,720 --> 00:35:09,040 PATIENTS WITH USHER SYNDROME AND 912 00:35:09,040 --> 00:35:12,760 WHAT THEY FOUND WAS THAT IN 913 00:35:12,760 --> 00:35:16,280 ABOUT 21% OF PATIENTS, USHER 914 00:35:16,280 --> 00:35:18,240 SYNDROME IS ACTUALLY CAUSED BY 915 00:35:18,240 --> 00:35:20,760 MUTATIONS IN MYO7A, THE 916 00:35:20,760 --> 00:35:22,200 CAUSATIVE GENE FOR USHER 917 00:35:22,200 --> 00:35:23,160 SYNDROME TYPE 1B. 918 00:35:23,160 --> 00:35:26,240 THE SECOND REASON WE WANTED TO 919 00:35:26,240 --> 00:35:27,520 STUDY TYPE 1B IS THE FACT THAT 920 00:35:27,520 --> 00:35:28,880 THE TYPE 1 PATIENTS HAVE THE 921 00:35:28,880 --> 00:35:30,680 MOST SEVERE DISEASE PHENOTYPE 922 00:35:30,680 --> 00:35:33,000 AND, THEREFORE, WE FELT THE 923 00:35:33,000 --> 00:35:34,080 POTENTIAL TO DEVELOP AN 924 00:35:34,080 --> 00:35:35,400 EFFECTIVE TREATMENT OPTION FOR 925 00:35:35,400 --> 00:35:38,040 THEIR HEARING LOSS AND DIZZINESS 926 00:35:38,040 --> 00:35:39,240 WOULD POTENTIALLY HAVE THE 927 00:35:39,240 --> 00:35:40,120 BIGGEST IMPACT ON THEIR QUALITY 928 00:35:40,120 --> 00:35:40,760 OF LIFE. 929 00:35:40,760 --> 00:35:42,080 SO WE TURNED TO THE LITERATURE 930 00:35:42,080 --> 00:35:44,800 TO TRY TO IDENTIFY A SUITABLE 931 00:35:44,800 --> 00:35:49,760 ANIMAL MOUSE MODEL FOR STUDYING 932 00:35:49,760 --> 00:35:54,640 US H-1B AND WE DECIDED TO USE 933 00:35:54,640 --> 00:35:56,080 THE 4626SB MOUSE MUTANT. 934 00:35:56,080 --> 00:35:57,720 THE REASON IS THIS MOUSE 935 00:35:57,720 --> 00:35:59,360 ESSENTIALLY IS A NULL, HAS A 936 00:35:59,360 --> 00:36:03,280 NULL MUTATION, AND THIS MOUSE 937 00:36:03,280 --> 00:36:04,720 HAS PROFOUND HEARING LOSS 938 00:36:04,720 --> 00:36:06,480 THROUGHOUT LIFE SIMILAR TO 939 00:36:06,480 --> 00:36:08,120 PATIENTS WITH US H-1B. 940 00:36:08,120 --> 00:36:10,120 IN ADDITION, THIS PARTICULAR 941 00:36:10,120 --> 00:36:12,160 MUTANT MOUSE HAS SIGNIFICANT 942 00:36:12,160 --> 00:36:13,160 VESTIBULAR DYSFUNCTION AS WELL 943 00:36:13,160 --> 00:36:15,960 AS EVIDENCED BY THE CIRCLING 944 00:36:15,960 --> 00:36:19,720 BEHAVE ARE YO, HEAD BOBBING AND 945 00:36:19,720 --> 00:36:20,800 HYPERACTIVITIES, VERY SIMILAR TO 946 00:36:20,800 --> 00:36:23,200 THOSE PATIENTS WITH US H-1B. 947 00:36:23,200 --> 00:36:25,200 SO WE'LL CALL THIS MOUSE MODEL 948 00:36:25,200 --> 00:36:27,280 THE SHAKER1 MOUSE THROUGHOUT THE 949 00:36:27,280 --> 00:36:29,160 REST OF THE TALK. 950 00:36:29,160 --> 00:36:31,240 WHEN THE INVESTIGATORS ANALYZED 951 00:36:31,240 --> 00:36:33,960 THE INARE EAR TISSUES FROM THE 952 00:36:33,960 --> 00:36:35,360 SHAKER1 MICE, WHAT THEY FOUND 953 00:36:35,360 --> 00:36:37,800 WAS THAT THE HAIR CELLS IN THE 954 00:36:37,800 --> 00:36:39,080 COCHLEA AND THOSE IN THE 955 00:36:39,080 --> 00:36:43,520 VESTIBULAR ORGANS HAVE 956 00:36:43,520 --> 00:36:45,400 SIGNIFICANT STEREOCILIA BUNDLE, 957 00:36:45,400 --> 00:36:48,480 THESE HAIRLIKE PROJECTIONS ON 958 00:36:48,480 --> 00:36:49,360 THE MECHANOSENSORY HAIR CELLS 959 00:36:49,360 --> 00:36:50,400 CRITICAL FOR THE DETECTION OF 960 00:36:50,400 --> 00:36:51,400 SOUND INFORMATION COMING INTO 961 00:36:51,400 --> 00:36:54,840 THE INNER EAR. 962 00:36:54,840 --> 00:36:56,400 IN ADDITION THE COCHLEAR HAIR 963 00:36:56,400 --> 00:36:58,280 CELLS UNDERGO RAPID DEGENERATION 964 00:36:58,280 --> 00:37:04,760 AFTER BIRTH. 965 00:37:04,760 --> 00:37:06,200 SO ONE CHALLENGE OF DELIVERING 966 00:37:06,200 --> 00:37:09,680 THIS INTO THE MOUSE INNER EAR IS 967 00:37:09,680 --> 00:37:12,680 THAT THE MOUSE IS QUITE LARGE, 968 00:37:12,680 --> 00:37:15,600 ABOUT 6.7, 6.8KB IN SIZE, 969 00:37:15,600 --> 00:37:16,800 THEREFORE IT EXCEEDS THE 970 00:37:16,800 --> 00:37:18,800 CARRYING CAPACITY OF A SINGLE 971 00:37:18,800 --> 00:37:19,680 AAV. 972 00:37:19,680 --> 00:37:21,960 SO TO OVERCOME THIS CHALLENGE, 973 00:37:21,960 --> 00:37:23,080 INVESTIGATORS IN THE FIELD HAVE 974 00:37:23,080 --> 00:37:25,920 USED WHAT'S CALLED A DUO AAV 975 00:37:25,920 --> 00:37:28,000 APPROACH TO DELIVER LARGE 976 00:37:28,000 --> 00:37:29,200 CDNAs INTO THE CELL TYPES. 977 00:37:29,200 --> 00:37:30,520 SO THE WAY THIS WORKS IS ONE CAN 978 00:37:30,520 --> 00:37:33,160 ACTUALLY BREAK UP A LARGE CDNA 979 00:37:33,160 --> 00:37:35,600 IN TWO DIFFERENT FRAGMENTS, THE 980 00:37:35,600 --> 00:37:37,840 5 PRIME AND 3 PRIME FRAGMENT AND 981 00:37:37,840 --> 00:37:42,160 ONE CAN USE TWO AAV TO DELIVER 982 00:37:42,160 --> 00:37:45,720 THEM INTO THE CELL TYPES. 983 00:37:45,720 --> 00:37:51,200 AT THE END, THESE CDNA 984 00:37:51,200 --> 00:37:51,960 FRAGMENTS, THE SEQUENCES CAN 985 00:37:51,960 --> 00:37:53,840 ACTUALLY HELP THE TWO FRAGMENTS 986 00:37:53,840 --> 00:37:56,440 RECOMBINE TO PRODUCE A FULL 987 00:37:56,440 --> 00:37:58,960 LENGTH PROTEIN PRODUCT. 988 00:37:58,960 --> 00:38:05,800 SO THIS WORK WAS DONE BY 989 00:38:05,800 --> 00:38:06,760 DR. BOYE'S GROUP AT UNIVERSITY 990 00:38:06,760 --> 00:38:07,320 OF FLORIDA. 991 00:38:07,320 --> 00:38:10,240 THEY APPLIED THE DUAL-AAV 992 00:38:10,240 --> 00:38:16,640 TECHNIQUE TO DELIVER THE HUMAN 993 00:38:16,640 --> 00:38:19,480 MYO7A CDNA, AND THEY WERE ABLE 994 00:38:19,480 --> 00:38:24,920 TO FIND FOLDING PROTEIN IN THESE 995 00:38:24,920 --> 00:38:25,520 CELLS. 996 00:38:25,520 --> 00:38:27,800 THEY THEN INJECTED THE DUAL AAV 997 00:38:27,800 --> 00:38:32,840 VECTORS CARRYING THE HUMAN MOUSE 998 00:38:32,840 --> 00:38:33,960 RETINA AND THEY FOUND IN THE 999 00:38:33,960 --> 00:38:37,600 INJECTED MICE, HUMAN MYO7A 1000 00:38:37,600 --> 00:38:40,320 PROTEIN WAS EXPRESSED SHOWN IN 1001 00:38:40,320 --> 00:38:41,960 GREEN IN THE MOUSE RETINA. 1002 00:38:41,960 --> 00:38:43,840 IN A SEPARATE STUDY THAT WAS 1003 00:38:43,840 --> 00:38:45,360 PUBLISHED AROUND THE SAME TIME, 1004 00:38:45,360 --> 00:38:47,440 THEY ALSO APPLY THE SAME DUAL 1005 00:38:47,440 --> 00:38:49,320 AAV APPROACH TO TRY TO DELIVER 1006 00:38:49,320 --> 00:38:52,360 THE HUMAN MYO7A CDNA INTO FIRST 1007 00:38:52,360 --> 00:38:53,880 A CELL LINE SHOWN RIGHT HERE, 1008 00:38:53,880 --> 00:38:55,320 AND AGAIN ON THE WESTERN BLOT 1009 00:38:55,320 --> 00:38:58,720 ANAL SEIZE, THEY WERE ABLE TO 1010 00:38:58,720 --> 00:39:01,560 SHOW EXPRESSION OF THE FULL 1011 00:39:01,560 --> 00:39:02,760 LENGTH MYO7A PROTEIN. 1012 00:39:02,760 --> 00:39:05,200 AND WHAT THEY THEN DID IN THE 1013 00:39:05,200 --> 00:39:07,600 STUDY WAS THEY INJECTED THEIR 1014 00:39:07,600 --> 00:39:10,560 DUAL AAV VECTORS CARRYING THE 1015 00:39:10,560 --> 00:39:16,600 HUMAN MYO7A CDNA INTO THE 1016 00:39:16,600 --> 00:39:17,480 SHAKER1 MOUSE, THE SAME MOUSE 1017 00:39:17,480 --> 00:39:18,680 WE'RE USING IN OUR STUDY. 1018 00:39:18,680 --> 00:39:20,240 IN THE TREATED MICE, THEY WERE 1019 00:39:20,240 --> 00:39:23,080 ABLE TO INCREASE THE MYO7A 1020 00:39:23,080 --> 00:39:25,080 PRODUCTION UP TO ABOUT 20% OF 1021 00:39:25,080 --> 00:39:26,200 THE WILD TYPE LEVELS. 1022 00:39:26,200 --> 00:39:28,480 SO WE WANTED TO SEE IF WE COULD 1023 00:39:28,480 --> 00:39:30,040 POTENTIALLY ALSO APPLY THE DUAL 1024 00:39:30,040 --> 00:39:32,320 AAV APPROACH TO DELIVER THE 1025 00:39:32,320 --> 00:39:36,280 HUMAN MYO7A CDNA INTO THE 1026 00:39:36,280 --> 00:39:37,720 SHAKER1 MOUSE INNER EAR TO HELP 1027 00:39:37,720 --> 00:39:39,480 TO IMPROVE ITS AUDITORY AND 1028 00:39:39,480 --> 00:39:39,920 VESTIBULAR FUNCTION. 1029 00:39:39,920 --> 00:39:47,400 SO WE COLLABORATED WITH BOYE'S 1030 00:39:47,400 --> 00:39:48,000 GROUP. 1031 00:39:48,000 --> 00:39:49,600 WE THEN INJECTED THESE VECTORS 1032 00:39:49,600 --> 00:39:53,640 INTO THE NEONATAL SHAKER1 MICE 1033 00:39:53,640 --> 00:39:59,880 INNER EARS, WE THEN ASSESSED 1034 00:39:59,880 --> 00:40:02,920 THEIR AUDITORY AND VESTIBULAR 1035 00:40:02,920 --> 00:40:04,080 FUNCTION ABOUT ONE MONTH AFTER 1036 00:40:04,080 --> 00:40:04,720 INJECTION. 1037 00:40:04,720 --> 00:40:06,040 WE FIRST TURN OUR ATTENTION TO 1038 00:40:06,040 --> 00:40:06,320 THE COCHLEA. 1039 00:40:06,320 --> 00:40:09,120 IN THE WILD TYPE, WE CAN SEE THE 1040 00:40:09,120 --> 00:40:10,240 MYO7A SHOWN IN GREEN EXPRESSED 1041 00:40:10,240 --> 00:40:13,160 BY BOTH THE INNER AND OUTER HAIR 1042 00:40:13,160 --> 00:40:14,760 CELLS. 1043 00:40:14,760 --> 00:40:16,040 MYO7A IS A COMMONLY USED MARKER 1044 00:40:16,040 --> 00:40:17,240 FOR MARKING THE HAIR CELLS IN 1045 00:40:17,240 --> 00:40:18,320 THE INNER EAR. 1046 00:40:18,320 --> 00:40:21,280 IN THE SHAKER1 MOUSE THAT DIDN'T 1047 00:40:21,280 --> 00:40:23,560 UNDERGO GENE THERAPY TREATMENT, 1048 00:40:23,560 --> 00:40:25,040 THERE WAS NO EXPRESSION AT ALL, 1049 00:40:25,040 --> 00:40:25,560 ONLY HAIR CELLS. 1050 00:40:25,560 --> 00:40:27,640 WHEN WE INJECTED THE DUAL-AAV 1051 00:40:27,640 --> 00:40:29,280 VECTORS INTO THE SHAKER1 MICE 1052 00:40:29,280 --> 00:40:30,160 WHAT WE FOUND WAS THAT IN SOME 1053 00:40:30,160 --> 00:40:32,120 OF THE INNER HAIR CELLS AND 1054 00:40:32,120 --> 00:40:33,800 OUTER HAIR CELLS, THEY STARTED 1055 00:40:33,800 --> 00:40:37,520 TO EXPRESS MYO7A. 1056 00:40:37,520 --> 00:40:39,320 WE THEN QUANTIFIED THE 1057 00:40:39,320 --> 00:40:40,480 TRANSDUCTION EFFICIENCY OF THE 1058 00:40:40,480 --> 00:40:44,000 DUAL AAV VECTORS IN THE TREATED 1059 00:40:44,000 --> 00:40:46,200 SHAKER 1 MICE AND WHAT WE FOUND 1060 00:40:46,200 --> 00:40:48,040 WAS THAT THE TRANSDUCTION 1061 00:40:48,040 --> 00:40:49,240 EFFICIENCY WAS CLOSE TO 80% OF 1062 00:40:49,240 --> 00:40:51,600 THE COCHLEAR HAIR CELLS AT THE 1063 00:40:51,600 --> 00:40:53,880 APEX OF THE COCHLEA AND THIS 1064 00:40:53,880 --> 00:40:55,080 DECREASED TOWARDS THE BASE OF 1065 00:40:55,080 --> 00:40:56,640 THE COCHLEA DOWN TO ABOUT 40% 1066 00:40:56,640 --> 00:40:57,720 FOR THE INNER HAIR CELLS AND 1067 00:40:57,720 --> 00:41:00,440 DOWN TO ABOUT 20% FOR THE OUTER 1068 00:41:00,440 --> 00:41:01,240 HAIR CELLS. 1069 00:41:01,240 --> 00:41:02,880 THE TRANSDUCTION EFFICIENCY WAS 1070 00:41:02,880 --> 00:41:04,080 HIGHER AT THE APEX OF THE 1071 00:41:04,080 --> 00:41:05,280 COCHLEA THAN THE BASE OF THE 1072 00:41:05,280 --> 00:41:06,640 COCHLEA. 1073 00:41:06,640 --> 00:41:09,800 WE WANTED TO SEE IF THE 1074 00:41:09,800 --> 00:41:11,240 TREATMENT OF DUAL AAV GENE 1075 00:41:11,240 --> 00:41:12,720 THERAPY CAN POTENTIALLY IMPROVE 1076 00:41:12,720 --> 00:41:14,840 THE HAIR CELL SURVIVAL IN THE 1077 00:41:14,840 --> 00:41:15,320 SHAKER 1 MICE. 1078 00:41:15,320 --> 00:41:17,040 REMEMBER I MENTIONED EARLIER 1079 00:41:17,040 --> 00:41:20,440 THAT THESE -- IN THESE MUTANT 1080 00:41:20,440 --> 00:41:24,200 MICE, THE COCHLEAR HAIR CELLS 1081 00:41:24,200 --> 00:41:25,240 UNDERGO RAPID DEGENERATION AFTER 1082 00:41:25,240 --> 00:41:25,480 BIRTH. 1083 00:41:25,480 --> 00:41:31,080 WHAT WE FOUND IS IN THE TREATED 1084 00:41:31,080 --> 00:41:33,600 SHAKER1 MICE THERE WAS A 1085 00:41:33,600 --> 00:41:34,440 SIGNIFICANT INCREASE COMPARED TO 1086 00:41:34,440 --> 00:41:36,560 THE UNTREATED SHAKER1 MICE SHOWN 1087 00:41:36,560 --> 00:41:37,240 IN BLUE HERE. 1088 00:41:37,240 --> 00:41:38,320 AGAIN NOTICE THAT THE 1089 00:41:38,320 --> 00:41:39,440 IMPROVEMENT IN HAIR CELL 1090 00:41:39,440 --> 00:41:41,080 SURVIVAL WAS THE BEST AT THE 1091 00:41:41,080 --> 00:41:42,320 APEX OF THE COCHLEA COMPARED TO 1092 00:41:42,320 --> 00:41:43,920 THE BASE OF THE COCHLEA AND THIS 1093 00:41:43,920 --> 00:41:45,360 CORRELATED WITH THE TRANSDUCTION 1094 00:41:45,360 --> 00:41:48,200 EFFICIENCY PATTERN AS WELL. 1095 00:41:48,200 --> 00:41:50,080 AS I MENTIONED BEFORE, THESE 1096 00:41:50,080 --> 00:41:55,880 ANIMALS, THESE SHAKER1 MICE HAVE 1097 00:41:55,880 --> 00:41:57,000 THESE PROJECTIONS ON THE HAIR 1098 00:41:57,000 --> 00:41:57,200 CELLS. 1099 00:41:57,200 --> 00:42:00,600 THIS IS WHAT THE STEREOCILIA 1100 00:42:00,600 --> 00:42:01,600 BUNDLES LOOK LIKE. 1101 00:42:01,600 --> 00:42:04,560 THEY'RE FAIRLY ORGANIZED IN THE 1102 00:42:04,560 --> 00:42:06,440 INNER AND OUTER HAIR CELLS. 1103 00:42:06,440 --> 00:42:10,520 IN THE UNTREATED, YOU ACTUALLY 1104 00:42:10,520 --> 00:42:12,880 SEE A FAIR AMOUNT OF HAIR CELL 1105 00:42:12,880 --> 00:42:13,480 DEGENERATION, PARTICULARLY AT 1106 00:42:13,480 --> 00:42:14,880 THE OUTER HAIR CELLS. 1107 00:42:14,880 --> 00:42:16,520 IN A TREATED SHAKER1 MICE WE 1108 00:42:16,520 --> 00:42:18,160 DIDN'T SEE ANY IMPROVEMENT IN 1109 00:42:18,160 --> 00:42:19,280 THE STEREOCILIA BUNDLES. 1110 00:42:19,280 --> 00:42:20,520 YOU CAN SEE THE BUNDLES FOR THE 1111 00:42:20,520 --> 00:42:22,360 INNER AND OUTER HAIR CELLS WERE 1112 00:42:22,360 --> 00:42:26,400 STILL FAIRLY DISORGANIZED. 1113 00:42:26,400 --> 00:42:28,720 SO WE SENSE THAT WITH THE DUAL 1114 00:42:28,720 --> 00:42:31,480 AAV GENE THERAPY -- WE ARE GOING 1115 00:42:31,480 --> 00:42:34,960 TO SEE EXPRESSION OF MYO7A AND 1116 00:42:34,960 --> 00:42:38,240 ALSO IMPROVEMENT IN HAIR CELL 1117 00:42:38,240 --> 00:42:40,640 SURVIVAL OF STEREOCILIA BUNDLES 1118 00:42:40,640 --> 00:42:42,080 THAT ARE STILL FAIRLY 1119 00:42:42,080 --> 00:42:42,520 DISORGANIZED. 1120 00:42:42,520 --> 00:42:43,960 WE THEN TESTED THE AUDITORY 1121 00:42:43,960 --> 00:42:46,880 FUNCTION OF THESE ANIMALS USING 1122 00:42:46,880 --> 00:42:47,560 AUDITORY BRAINSTEM RESPONSE 1123 00:42:47,560 --> 00:42:48,520 TESTING AND WHAT WE FOUND IS 1124 00:42:48,520 --> 00:42:52,200 THAT IN THE TREATED SHAKER1 MICE 1125 00:42:52,200 --> 00:42:54,840 THERE WAS NO MEASURABLE AAV 1126 00:42:54,840 --> 00:42:57,680 WAVEFORMS EVEN AT THE MAXIMUM 1127 00:42:57,680 --> 00:42:58,800 LEVELS OF 90 DB. 1128 00:42:58,800 --> 00:43:00,320 SO WE THEN TURN OUR ATTENTION TO 1129 00:43:00,320 --> 00:43:01,760 THE VESTIBULAR ORGANS AND THESE 1130 00:43:01,760 --> 00:43:06,680 ARE IMAGES TAKEN FROM THE MOUSE 1131 00:43:06,680 --> 00:43:11,960 K --EXPRESSED BY THE VESTIBULARR 1132 00:43:11,960 --> 00:43:13,280 CELLS SHOWN IN GREEN RIGHT HERE. 1133 00:43:13,280 --> 00:43:18,000 WHEREAS IN THE UNTREATED SHAKERE 1134 00:43:18,000 --> 00:43:20,200 ANY MYO7A EXPRESSION AT ALL. 1135 00:43:20,200 --> 00:43:25,240 IN THE TREATED SHAKER 1 MICE -- 1136 00:43:25,240 --> 00:43:26,360 SHOWN IN GREEN RIGHT HERE. 1137 00:43:26,360 --> 00:43:28,200 WE WANTED TO SEE WHAT A 1138 00:43:28,200 --> 00:43:29,960 TRANSDUCTION EFFICIENCY OF THE 1139 00:43:29,960 --> 00:43:31,760 VESTIBULAR HAIR CELLS WERE SO WE 1140 00:43:31,760 --> 00:43:33,040 CALCULATED A NUMBER OF 1141 00:43:33,040 --> 00:43:34,040 VESTIBULAR HAIR CELLS THAT 1142 00:43:34,040 --> 00:43:36,720 EXPRESS MYO7A AND WHAT WE FOUND 1143 00:43:36,720 --> 00:43:37,920 WAS THAT TRANSDUCTION EFFICIENCY 1144 00:43:37,920 --> 00:43:40,840 WAS ABOUT 80% IN THE VESTIBULAR 1145 00:43:40,840 --> 00:43:42,000 ORGANS. 1146 00:43:42,000 --> 00:43:43,840 ONE INTERESTING THING THAT WE 1147 00:43:43,840 --> 00:43:45,600 FOUND WAS THAT AS OPPOSED TO THE 1148 00:43:45,600 --> 00:43:47,320 COCHLEA, WHERE THE HAIR CELLS 1149 00:43:47,320 --> 00:43:48,880 UNDERWENT RAPID DEGENERATION, 1150 00:43:48,880 --> 00:43:51,200 THE VESTIBULAR HAIR CELLS IN THE 1151 00:43:51,200 --> 00:43:55,240 SHAKER1 MICE SEEMED TO REMAIN 1152 00:43:55,240 --> 00:43:57,920 VIABLE FOR BOTH THE WILD TYPE 1153 00:43:57,920 --> 00:44:01,720 ANIMALS AND HETEROZYGOUS LITTER 1154 00:44:01,720 --> 00:44:04,960 MATES, AS YOU CAN SEE THE 1155 00:44:04,960 --> 00:44:06,920 VESTIBULAR HAIR CELL COUNT WERE 1156 00:44:06,920 --> 00:44:09,600 FAIRLY SIMILAR SO THE VESTIBULAR 1157 00:44:09,600 --> 00:44:12,440 HAIR CELLS IN SHAKER1 MICE DO 1158 00:44:12,440 --> 00:44:17,560 NOT -- THIS POTENTIALLY 1159 00:44:17,560 --> 00:44:21,240 INDICATES THEY'RE STILL VIABLE 1160 00:44:21,240 --> 00:44:22,480 TO POTENTIALLY BENEFIT FROM THE 1161 00:44:22,480 --> 00:44:24,880 DUAL AAV GENE THERAPY. 1162 00:44:24,880 --> 00:44:26,880 AS I MENTIONED BEFORE, THE HAIR 1163 00:44:26,880 --> 00:44:29,000 CELLS IN THE SHAKER 1 MICE HAD 1164 00:44:29,000 --> 00:44:34,000 HIGHLY DISORGANIZED STEREOCILIA 1165 00:44:34,000 --> 00:44:34,840 BUNDLES. 1166 00:44:34,840 --> 00:44:36,560 M THE BUNDLES IN THE HAIR CELLS 1167 00:44:36,560 --> 00:44:37,960 WERE VERY DISORGANIZED. 1168 00:44:37,960 --> 00:44:39,960 WHEN WE TREATED THE SHAKER1 MICE 1169 00:44:39,960 --> 00:44:42,280 WITH THE DUAL AAV GENE THERAPY, 1170 00:44:42,280 --> 00:44:46,400 WE SAW THE STER STEREOCILIA WERH 1171 00:44:46,400 --> 00:44:47,640 MORE ORGANIZED SIMILAR TO THE 1172 00:44:47,640 --> 00:44:49,520 WILD TYPE ANIMALS. 1173 00:44:49,520 --> 00:44:51,280 WE WANTED TO SEE IF THIS 1174 00:44:51,280 --> 00:44:52,800 IMPROVEMENT MORPHOLOGY 1175 00:44:52,800 --> 00:44:54,120 TRANSLATED INTO IMPROVEMENT IN 1176 00:44:54,120 --> 00:44:54,920 VESTIBULAR FUNCTION. 1177 00:44:54,920 --> 00:44:56,880 ONE SIMPLE WAY OF MEASURING 1178 00:44:56,880 --> 00:44:57,680 VESTIBULAR FUNCTION IN MICE IS 1179 00:44:57,680 --> 00:44:59,080 TO LOOK AT THEIR CIRCLING 1180 00:44:59,080 --> 00:45:00,120 BEHAVIOR. 1181 00:45:00,120 --> 00:45:02,080 AND WE HAVE A SET-UP IN THE LAB 1182 00:45:02,080 --> 00:45:03,800 WHERE WE HAVE A CAMERA THAT CAN 1183 00:45:03,800 --> 00:45:05,360 RECORD THE MOVEMENT OF THESE 1184 00:45:05,360 --> 00:45:07,120 ANIMALS AND WE HAVE A COMPUTER 1185 00:45:07,120 --> 00:45:08,720 SOFTWARE THAT CAN GENERATE -- 1186 00:45:08,720 --> 00:45:10,320 THAT I CAN TRACK THE MOVEMENT OF 1187 00:45:10,320 --> 00:45:11,560 THESE ANIMALS IN GENERALLY 1188 00:45:11,560 --> 00:45:13,160 WHAT'S CALLED A TRACK PLOT OF 1189 00:45:13,160 --> 00:45:13,960 THESE ANIMALS. 1190 00:45:13,960 --> 00:45:15,800 IN A WILD TYPE MOUSE, THEY TEND 1191 00:45:15,800 --> 00:45:17,160 TO WALK IN A STRAIGHT LINE MORE 1192 00:45:17,160 --> 00:45:19,640 OR LESS AND TENDS TO EXPLORE THE 1193 00:45:19,640 --> 00:45:20,640 PERIPHERY OF THE CAGE THAT IT IS 1194 00:45:20,640 --> 00:45:21,120 HOUSED IN. 1195 00:45:21,120 --> 00:45:23,120 IN THE UNTREATED SHAKER 1 MOUSE, 1196 00:45:23,120 --> 00:45:24,480 YOU CAN SEE THE TRACK PLOT IS 1197 00:45:24,480 --> 00:45:26,240 VERY MESSY BECAUSE THIS MOUSE 1198 00:45:26,240 --> 00:45:27,400 RAN AROUND QUITE A BIT IN 1199 00:45:27,400 --> 00:45:28,040 CIRCLES. 1200 00:45:28,040 --> 00:45:29,680 IN THE TREATED SHAKER 1 MICE, 1201 00:45:29,680 --> 00:45:33,640 WHAT WE FOUND WAS THAT THE TRACK 1202 00:45:33,640 --> 00:45:35,840 PLOT IS MUCH CLEANER SIMILAR TO 1203 00:45:35,840 --> 00:45:37,280 THAT OF A WILD TYPE MOUSE THAT 1204 00:45:37,280 --> 00:45:38,560 THE CIRCLING BEHAVIOR SEEMS TO 1205 00:45:38,560 --> 00:45:44,480 BE TREE DUED A ROOB D REDUCED AE 1206 00:45:44,480 --> 00:45:47,520 THERAPY TREATMENT. 1207 00:45:47,520 --> 00:45:52,440 A 2-MINUTE TIME INTERVAL IN THE 1208 00:45:52,440 --> 00:45:54,200 UNTREATED, THEY CIRCLED AROUND A 1209 00:45:54,200 --> 00:45:56,760 LITTLE BIT LESS THAN 10 CIRCLES 1210 00:45:56,760 --> 00:45:57,200 EVERY 2 MINUTES. 1211 00:45:57,200 --> 00:45:58,840 IN THE UNTREATED SHAKER 1 MICE 1212 00:45:58,840 --> 00:46:00,440 THEY CIRCLED ABOUT 35 ROTATIONS 1213 00:46:00,440 --> 00:46:01,320 IN ABOUT 2 MINUTES. 1214 00:46:01,320 --> 00:46:03,120 IN THE TREATED SHAKER 1 MICE, WE 1215 00:46:03,120 --> 00:46:07,400 SAW SIGNIFICANT REDUCTION IN IS 1216 00:46:07,400 --> 00:46:08,000 THE CIRCLING BEHAVIOR DOWN TO 1217 00:46:08,000 --> 00:46:08,880 ABOUT 15 ROTATIONS EVERY 1218 00:46:08,880 --> 00:46:12,560 2 MINUTES. 1219 00:46:12,560 --> 00:46:14,640 WE ALSO TREATED SOME OF THE 1220 00:46:14,640 --> 00:46:15,640 HETEROZYGOUS LITTER MATES WITH 1221 00:46:15,640 --> 00:46:16,880 THE GENE THERAPY AND WE DIDN'T 1222 00:46:16,880 --> 00:46:18,640 SEE ANY ELEVATION IN CIRCLING 1223 00:46:18,640 --> 00:46:18,920 BEHAVIOR. 1224 00:46:18,920 --> 00:46:22,120 IN ADDITION, AS ANOTHER CONTROL, 1225 00:46:22,120 --> 00:46:25,560 WE TREATED WITH JUST THE 5 PRIME 1226 00:46:25,560 --> 00:46:27,200 AAV VECTOR SO WITHOUT THE 1227 00:46:27,200 --> 00:46:28,480 3 PRIME VECTOR AND WHAT WE FOUND 1228 00:46:28,480 --> 00:46:29,760 WAS THAT THOSE ANIMALS TREATED 1229 00:46:29,760 --> 00:46:31,480 WITH JUST THE 5 PRIME VECTOR 1230 00:46:31,480 --> 00:46:34,800 STILL HAD SIGNIFICANTLY ELEVATED 1231 00:46:34,800 --> 00:46:37,240 CIRCLING, THAT OF THE UNTREATED 1232 00:46:37,240 --> 00:46:38,280 SHAKER 1 MOUSE. 1233 00:46:38,280 --> 00:46:39,720 NOW WHILE CIRCLING IS A GOOD 1234 00:46:39,720 --> 00:46:41,000 MEASURE OF VESTIBULAR FUNCTION 1235 00:46:41,000 --> 00:46:42,520 IT IS NOT VERY SPECIFIC FOR THE 1236 00:46:42,520 --> 00:46:43,240 VESTIBULAR SYSTEM AND THEREFORE 1237 00:46:43,240 --> 00:46:44,560 WE WANTED TO SEE IF WE CAN FIND 1238 00:46:44,560 --> 00:46:47,120 A DIFFERENT TEST THAT COULD 1239 00:46:47,120 --> 00:46:48,200 POTENTIALLY HELP US BETTER 1240 00:46:48,200 --> 00:46:50,520 ASSESS THE VESTIBULAR SYSTEM 1241 00:46:50,520 --> 00:46:50,960 SPECIFICALLY. 1242 00:46:50,960 --> 00:46:57,640 WE DECIDED TO USE THE VESTIBULAR 1243 00:46:57,640 --> 00:47:00,800 EVOKED POTENTIAL OR VSEP, 1244 00:47:00,800 --> 00:47:02,160 PLACING ELECTRODES ON THE SCAL 1245 00:47:02,160 --> 00:47:06,080 CH THESE ANIMALS' HEADS, TO 1246 00:47:06,080 --> 00:47:11,360 GENERATE A HEAD IMPULSE TO 1247 00:47:11,360 --> 00:47:13,880 STIMULATE, USING ELECTRODES TO 1248 00:47:13,880 --> 00:47:20,160 RECORD THE EE ELECTRICAL 1249 00:47:20,160 --> 00:47:20,520 RESPONSES. 1250 00:47:20,520 --> 00:47:21,720 IN THE WILD TYPE MOUSE WE CAN 1251 00:47:21,720 --> 00:47:24,560 SEE A NICE VSEP MEASURE OF 1252 00:47:24,560 --> 00:47:27,840 WAVEFORMS DOWN TO MINUS 90DB, 1253 00:47:27,840 --> 00:47:29,400 WHEREAS IN THE SHAKER 1 MICE, WE 1254 00:47:29,400 --> 00:47:36,320 DIDN'T SEE ANY MEASURABLE 1255 00:47:36,320 --> 00:47:36,680 WAVEFORMS. 1256 00:47:36,680 --> 00:47:38,640 IN THE SHAKER 1 MICE THAT WERE 1257 00:47:38,640 --> 00:47:41,840 TREATED WITH THE DUAL AAV GENE 1258 00:47:41,840 --> 00:47:44,080 THERAPY, THEY ACTUALLY HAD 1259 00:47:44,080 --> 00:47:45,760 MEASURABLE VSEP WAVEFORMS, SOME 1260 00:47:45,760 --> 00:47:46,840 OF THEIR THRESHOLDS ACTUALLY 1261 00:47:46,840 --> 00:47:48,720 DOWN TO THE LEVEL OF THE WILD 1262 00:47:48,720 --> 00:47:52,320 TYPE ANIMALS. 1263 00:47:52,320 --> 00:47:53,880 YOU CAN SEE THE THRESHOLDS ARE 1264 00:47:53,880 --> 00:47:54,640 LISTED RIGHT HERE. 1265 00:47:54,640 --> 00:47:57,960 AND AGAIN, IN THE WILD TYPE 1266 00:47:57,960 --> 00:48:00,680 ANIMALS, WILD TYPE LITTER MATES 1267 00:48:00,680 --> 00:48:02,200 AND HETEROZYGOUS LITTER MATES, 1268 00:48:02,200 --> 00:48:04,360 WE SEE THE VSEP THRESHOLDS ON 1269 00:48:04,360 --> 00:48:06,400 AVERAGE ABOUT MINUS 10DB WHEREAS 1270 00:48:06,400 --> 00:48:08,200 WE DIDN'T SEE ANY MEASURABLE 1271 00:48:08,200 --> 00:48:09,480 RESPONSES AT ALL WITH THE 1272 00:48:09,480 --> 00:48:11,800 UNTREATED SHAKER 1 MICE, WE 1273 00:48:11,800 --> 00:48:17,080 MARKED THIS ESSENTIALLY AS PLUS 1274 00:48:17,080 --> 00:48:18,280 7.5DB AS THE THRESHOLD. 1275 00:48:18,280 --> 00:48:21,240 MANY OF THE SHAKER 1 MICE WERE 1276 00:48:21,240 --> 00:48:22,920 TREATED WITH DUAL AAV GENE 1277 00:48:22,920 --> 00:48:25,440 THERAPY, WE CAN SEE MEASURABLE 1278 00:48:25,440 --> 00:48:26,120 VSEP WAVEFORMS. 1279 00:48:26,120 --> 00:48:27,320 WE ALSO TREATED SOME OF THE WILD 1280 00:48:27,320 --> 00:48:28,880 TYPE AND HETEROZYGOUS LITTER 1281 00:48:28,880 --> 00:48:30,720 MATES WITH THE DUAL AAV VECTORS, 1282 00:48:30,720 --> 00:48:32,160 AGAIN, WE DIDN'T SEE ANY 1283 00:48:32,160 --> 00:48:34,440 ELEVATION IN THE VSEP 1284 00:48:34,440 --> 00:48:34,760 THRESHOLDS. 1285 00:48:34,760 --> 00:48:36,440 WE AGAIN TREATED SOME OF THE 1286 00:48:36,440 --> 00:48:39,200 SHAKER 1 MICE WITH JUST A 1287 00:48:39,200 --> 00:48:40,400 5 PRIME VECTOR AND DIDN'T SEE 1288 00:48:40,400 --> 00:48:43,040 ANY IMPROVEMENT IN THE VSEP 1289 00:48:43,040 --> 00:48:44,440 THRESHOLDS AT ALL. 1290 00:48:44,440 --> 00:48:46,560 SO THESE DETAILS DEMONSTRATE 1291 00:48:46,560 --> 00:48:48,280 THAT WITH THE DUAL AAV GENE 1292 00:48:48,280 --> 00:48:50,160 THERAPY, WE SEEM TO BE ABLE TO 1293 00:48:50,160 --> 00:48:52,280 IMPROVE THE VESTIBULAR FUNCTION 1294 00:48:52,280 --> 00:48:55,920 IN THESE MUTANT MICE. SO TO 1295 00:48:55,920 --> 00:48:57,520 SUMMARIZE, OUR DUAL AAV GENE 1296 00:48:57,520 --> 00:49:00,040 THERAPY WAS ABLE TO -- WE WERE 1297 00:49:00,040 --> 00:49:01,920 ABLE TO USE THE DUAL AAV GENE 1298 00:49:01,920 --> 00:49:05,880 THERAPY TO DELIVER THE MYO7A 1299 00:49:05,880 --> 00:49:07,440 CDNA INTO THE SHAKER 1 MOUSE 1300 00:49:07,440 --> 00:49:09,200 INNER EAR AND TRANSDUCED HAIR 1301 00:49:09,200 --> 00:49:11,720 CELLS DID EXPRESS MYO7A. 1302 00:49:11,720 --> 00:49:13,080 IN THE COCHLEA, WE FOUND THAT 1303 00:49:13,080 --> 00:49:14,800 THE DUAL AAV GENE THERAPY WAS 1304 00:49:14,800 --> 00:49:16,920 ABLE TO IMPROVE THE HAIR CELL 1305 00:49:16,920 --> 00:49:18,160 SURVIVAL, BUT UNFORTUNATELY WE 1306 00:49:18,160 --> 00:49:20,560 DIDN'T SEE ANY IMPROVEMENT IN 1307 00:49:20,560 --> 00:49:22,960 THE STEREOCILIA BUNDLE 1308 00:49:22,960 --> 00:49:23,880 MORPHOLOGY AUDITORY FUNCTION. 1309 00:49:23,880 --> 00:49:27,720 IN THE VESTIBULAR ORGANS, WE SAW 1310 00:49:27,720 --> 00:49:29,920 THE THERAPY IMPROVED THE 1311 00:49:29,920 --> 00:49:31,440 STEREOCILIA MORPHOLOGY IN THE 1312 00:49:31,440 --> 00:49:34,600 SHAKER ONE VESTIBULAR HAIR CELLS 1313 00:49:34,600 --> 00:49:36,520 AND ALSO IMPROVED THE VESTIBULAR 1314 00:49:36,520 --> 00:49:38,160 FUNCTION IN THE SHAKER 1 MUTANT 1315 00:49:38,160 --> 00:49:38,360 MICE. 1316 00:49:38,360 --> 00:49:39,560 IT IS OUR HOPE THAT THESE DATA 1317 00:49:39,560 --> 00:49:44,520 WILL FORM A FOUNDATION TO 1318 00:49:44,520 --> 00:49:45,840 TRANSLATE GENE THERAPY AS A 1319 00:49:45,840 --> 00:49:46,800 TREATMENT FOR PATIENTS WITH 1320 00:49:46,800 --> 00:49:49,040 USHER SYNDROME TO IMPROVE THEIR 1321 00:49:49,040 --> 00:49:49,840 VESTIBULAR FUNCTION DOWN THE 1322 00:49:49,840 --> 00:49:50,040 ROAD. 1323 00:49:50,040 --> 00:49:52,440 SO I'D LIKE TO CONCLUDE BY 1324 00:49:52,440 --> 00:49:54,600 ACKNOWLEDGING THE LAB MEMBERS IN 1325 00:49:54,600 --> 00:49:58,200 MY LAB THAT DID ALL THIS WORK, 1326 00:49:58,200 --> 00:50:07,520 KEVIN ISGRIG, MHAMED, JIANLIANG, 1327 00:50:07,520 --> 00:50:11,120 YASUKO, ZAYNEP, MOAZ, SAMANTHA, 1328 00:50:11,120 --> 00:50:14,760 I WANT TO THANK TOM FRIEDMAN AT 1329 00:50:14,760 --> 00:50:18,680 NIDCD, TRACY FITZGERALD, TALAH 1330 00:50:18,680 --> 00:50:20,240 WAFA FOR THEIR EXPERT HELP IN 1331 00:50:20,240 --> 00:50:21,120 GETTING A LOT OF THIS DATA. 1332 00:50:21,120 --> 00:50:24,080 I WANT TO THANK SHANNON'S GROUP 1333 00:50:24,080 --> 00:50:25,040 AT UNIVERSITY OF FLORIDA FOR 1334 00:50:25,040 --> 00:50:28,400 HELPING US TO OBTAIN THESE DUAL 1335 00:50:28,400 --> 00:50:29,840 VECTORS, DUAL AAV VECTORS FOR 1336 00:50:29,840 --> 00:50:30,480 OUR STUDY. 1337 00:50:30,480 --> 00:50:32,480 SO WITH THAT, I'D LIKE TO 1338 00:50:32,480 --> 00:50:34,240 CONCLUDE MY TALK AND HAPPY TO 1339 00:50:34,240 --> 00:50:35,520 TAKE ANY QUESTIONS YOU MAY HAVE. 1340 00:50:35,520 --> 00:50:37,120 THANK YOU. 1341 00:50:37,120 --> 00:50:39,400 >>THANK YOU, DR. CHIEN, VERY 1342 00:50:39,400 --> 00:50:41,080 MUCH FOR YOUR PRESENTATION, AND 1343 00:50:41,080 --> 00:50:43,800 THANK YOU, DR. HAO AS WELL. 1344 00:50:43,800 --> 00:50:45,480 THANK YOU FOR SHARING YOUR VERY 1345 00:50:45,480 --> 00:50:50,840 IMPORTANT EXCITING WORK AND 1346 00:50:50,840 --> 00:50:51,720 UNDERSTANDING OF HEARING LOSS 1347 00:50:51,720 --> 00:50:53,360 AND AVENUES FOR IMPROVEMENT. 1348 00:50:53,360 --> 00:50:54,400 WHILE MANY OF US ARE NOT 1349 00:50:54,400 --> 00:50:55,600 DIRECTLY INVOFERLED WITH THE 1350 00:50:55,600 --> 00:50:56,800 MANAGEMENT AND TREATMENT OF 1351 00:50:56,800 --> 00:50:59,000 HEARING INSTABILITY AND HEARING 1352 00:50:59,000 --> 00:51:01,080 LOSS, MANY OF US, UP TO HALF 1353 00:51:01,080 --> 00:51:05,080 ACCORDING TO THE DATA SHARED BY 1354 00:51:05,080 --> 00:51:06,480 DR. CHIEN, CAN SEE THIS IN OUR 1355 00:51:06,480 --> 00:51:07,920 OWN FUTURE. 1356 00:51:07,920 --> 00:51:09,800 SO THIS TOPIC IS OF NOT JUST 1357 00:51:09,800 --> 00:51:11,000 SCIENTIFIC INTEREST BUT ALSO 1358 00:51:11,000 --> 00:51:13,200 PERSONAL INTEREST. 1359 00:51:13,200 --> 00:51:17,160 SO THANK YOU VERY MUCH. 1360 00:51:17,160 --> 00:51:18,800 A COUPLE QUESTIONS HAVE COME IN. 1361 00:51:18,800 --> 00:51:22,640 SO FIRST FOR DR. CHIEN, WITH 1362 00:51:22,640 --> 00:51:25,840 REGARDS TO GENE THERAPY IN 1363 00:51:25,840 --> 00:51:27,200 HUMANS, WHAT ARE THE CHALLENGES 1364 00:51:27,200 --> 00:51:32,960 IN TRANSLATING INNER GENE 1365 00:51:32,960 --> 00:51:34,760 THERAPY MOUSE MODELS TO 1366 00:51:34,760 --> 00:51:35,040 PATIENTS? 1367 00:51:35,040 --> 00:51:37,840 >>ABSOLUTELY. 1368 00:51:37,840 --> 00:51:39,800 SO I THINK WHILE WE HAVE MANY 1369 00:51:39,800 --> 00:51:41,000 WONDERFUL MOUSE MODELS THAT WE 1370 00:51:41,000 --> 00:51:44,160 CAN STUDY, DIFFERENT TYPES OF 1371 00:51:44,160 --> 00:51:45,240 HEARING LOSS, IT'S IMPORTANT TO 1372 00:51:45,240 --> 00:51:47,400 REMEMBER THAT THEY ARE -- THERE 1373 00:51:47,400 --> 00:51:48,720 ARE DIFFERENCES BETWEEN THE 1374 00:51:48,720 --> 00:51:50,080 MOUSE INNER EAR AND THE HUMAN 1375 00:51:50,080 --> 00:51:52,960 INNER EAR. 1376 00:51:52,960 --> 00:51:54,440 AND THERE ARE ALSO MANY 1377 00:51:54,440 --> 00:51:55,760 SIMILARITIES BUT THERE ARE ALSO 1378 00:51:55,760 --> 00:51:56,560 SOME SIGNIFICANT DIFFERENCES TO 1379 00:51:56,560 --> 00:51:56,960 THINK ABOUT. 1380 00:51:56,960 --> 00:51:58,080 ONE OF THE MAJOR DIFFERENCES IS 1381 00:51:58,080 --> 00:52:02,440 THE FACT THAT IN HUMANS, WE ARE 1382 00:52:02,440 --> 00:52:05,200 ACTUALLY BORN WITH LEARING HEARG 1383 00:52:05,200 --> 00:52:06,400 WHEREAS IN MICE, HEARING DOES 1384 00:52:06,400 --> 00:52:08,400 NOT DEVELOP FULLY UNTIL ABOUT 12 1385 00:52:08,400 --> 00:52:10,480 TO 14 DAYS AFTER BIRTH. 1386 00:52:10,480 --> 00:52:13,080 SO IN MOST OF THE GENE THERAPY 1387 00:52:13,080 --> 00:52:14,680 STUDIES THAT WE PUBLISH TO TRY 1388 00:52:14,680 --> 00:52:16,120 TO IMPROVE THE AUDITORY FUNCTION 1389 00:52:16,120 --> 00:52:17,800 IN VARIOUS MOUSE MODELS OF 1390 00:52:17,800 --> 00:52:19,640 HEARING LOSSES, MOST OF THE TIME 1391 00:52:19,640 --> 00:52:22,160 YOU HAVE TO DELIVER THE THERAPY 1392 00:52:22,160 --> 00:52:23,880 VERY EARLY ON, BETWEEN THE FIRST 1393 00:52:23,880 --> 00:52:25,000 COUPLE DAYS OF LIFE IN ORDER FOR 1394 00:52:25,000 --> 00:52:26,600 THE THERAPY TO BE EFFECTIVE. 1395 00:52:26,600 --> 00:52:28,560 SO IF YOU WERE TO TRANSLATE THIS 1396 00:52:28,560 --> 00:52:31,760 TIMELINE INTO HUMANS, THIS WOULD 1397 00:52:31,760 --> 00:52:32,760 POTENTIALLY INDICATE THAT WE MAY 1398 00:52:32,760 --> 00:52:34,960 HAVE TO DELIVER THE GENE THERAPY 1399 00:52:34,960 --> 00:52:36,920 BEFORE THE ONSET OF HEARING 1400 00:52:36,920 --> 00:52:38,840 OCCURS IN HUMANS, WHICH WOULD 1401 00:52:38,840 --> 00:52:40,800 BE -- THIS WILL HAVE TO BE DONE 1402 00:52:40,800 --> 00:52:42,680 IN UTERO, WHICH CERTAINLY HAS 1403 00:52:42,680 --> 00:52:45,560 MANY TECHNICAL AND POTENTIALLY 1404 00:52:45,560 --> 00:52:46,680 EVEN ETHICAL CHALLENGES AS WELL 1405 00:52:46,680 --> 00:52:50,560 SO I THINK THAT'S ONE MAJOR 1406 00:52:50,560 --> 00:52:51,920 HURDLE ONE HAS TO TRY TO 1407 00:52:51,920 --> 00:52:55,880 OVERCOME, IS TO TRY TO SEE IF -- 1408 00:52:55,880 --> 00:52:57,320 TO SHOW THAT GENE THERAPY IS 1409 00:52:57,320 --> 00:52:59,840 EFFECTIVE IN THE MATURE AND 1410 00:52:59,840 --> 00:53:04,800 DEVELOPED INNER EAR BEFORE 1411 00:53:04,800 --> 00:53:05,800 SUCCESSFULLY DONE IN HUMANS. 1412 00:53:05,800 --> 00:53:06,920 >>WHAT WAS THE AGE OF THE 1413 00:53:06,920 --> 00:53:09,320 TREATED MICE, AND CAN THE 1414 00:53:09,320 --> 00:53:12,240 TREATMENT BE USED IN ADULT MICE? 1415 00:53:12,240 --> 00:53:17,280 >>SO IN OUR STUDY, WE TREATED 1416 00:53:17,280 --> 00:53:21,600 THESE MICE BETWEEN T0 AND T5. 1417 00:53:21,600 --> 00:53:23,040 WE ARE CURRENTLY TESTING WHETHER 1418 00:53:23,040 --> 00:53:24,240 OUR THERAPY IS EFFECTIVE IN 1419 00:53:24,240 --> 00:53:26,320 ADULT MICE AND HOPEFULLY I'LL 1420 00:53:26,320 --> 00:53:28,440 HAVE SOME MORE DATA TO SHARE ON 1421 00:53:28,440 --> 00:53:31,760 THAT TOPIC NEXT TIME. 1422 00:53:31,760 --> 00:53:34,760 >>ONE MORE QUELL IN FOLLOW-UP. 1423 00:53:34,760 --> 00:53:36,800 IT WAS ENCOURAGING TO SEE THE 1424 00:53:36,800 --> 00:53:37,800 VESTIBULAR IMPROVEMENT IN THE 1425 00:53:37,800 --> 00:53:39,640 MOUSE MODEL THAT RECEIVED THE 1426 00:53:39,640 --> 00:53:42,200 DUAL AAV GENE THERAPY. 1427 00:53:42,200 --> 00:53:43,640 ARE THESE IMPROVEMENTS SUSTAINED 1428 00:53:43,640 --> 00:53:45,160 OR WAS THERE REGRESSION? 1429 00:53:45,160 --> 00:53:46,640 >>YES, THAT'S A GREAT QUESTION. 1430 00:53:46,640 --> 00:53:47,640 SO THAT'S SOMETHING THAT WE'RE 1431 00:53:47,640 --> 00:53:50,880 ALSO ASSESSING AS WELL. 1432 00:53:50,880 --> 00:53:52,680 SO WE ARE TRYING TO ASSESS THE 1433 00:53:52,680 --> 00:53:53,680 LONG TERM OUTCOME OF THESE 1434 00:53:53,680 --> 00:53:57,400 ANIMALS AND SEE IF WE CAN SEE 1435 00:53:57,400 --> 00:53:58,720 SUSTAINED VESTIBULAR IMPROVEMENT 1436 00:53:58,720 --> 00:54:00,520 OVER TIME. 1437 00:54:00,520 --> 00:54:02,840 >>AND THIS IS FOR DR. HAO. 1438 00:54:02,840 --> 00:54:05,920 SO WHAT EVIDENCE DO WE HAVE THAT 1439 00:54:05,920 --> 00:54:06,960 MENIERE'S DISEASE INVOLVES 1440 00:54:06,960 --> 00:54:09,000 PROBLEMS IN ION HOMEOSTASIS IN 1441 00:54:09,000 --> 00:54:14,960 HUMANS? 1442 00:54:14,960 --> 00:54:17,120 >>I THINK THE EVIDENCE THAT IT 1443 00:54:17,120 --> 00:54:27,320 DOES IS THAT WE CAN NOW IDENTIFY 1444 00:54:27,320 --> 00:54:28,760 HYDROPS IN HUMAN PATIENTS WHILE 1445 00:54:28,760 --> 00:54:30,400 THEY'RE LIVING, AND IN SOME 1446 00:54:30,400 --> 00:54:33,720 CASES, WE SEE CHANGES IN THEM. 1447 00:54:33,720 --> 00:54:34,520 SO THERE'S SOMETHING GOING ON IN 1448 00:54:34,520 --> 00:54:38,120 THE EAR THAT CONTROLS FLUID AND 1449 00:54:38,120 --> 00:54:40,520 LIKELY ION REGULATION. 1450 00:54:40,520 --> 00:54:42,960 IN MANY CASES, THESE PATIENTS 1451 00:54:42,960 --> 00:54:46,240 RESPOND TO MEDICATIONS THAT HAVE 1452 00:54:46,240 --> 00:54:50,040 A ROLE IN REGULATING ION 1453 00:54:50,040 --> 00:54:51,040 CHANNELS. 1454 00:54:51,040 --> 00:54:53,480 SO NOT JUST STEROIDS BUT OTHER 1455 00:54:53,480 --> 00:54:54,840 MEDICATIONS. 1456 00:54:54,840 --> 00:54:57,560 SO I THINK THOSE ARE THE PIECES 1457 00:54:57,560 --> 00:55:00,880 OF EVIDENCE THAT WE HAVE, I 1458 00:55:00,880 --> 00:55:02,720 THINK FOR EVIDENCE THAT, YOU 1459 00:55:02,720 --> 00:55:04,720 KNOW, ION HOMEOSTASIS IS 1460 00:55:04,720 --> 00:55:06,560 INVOLVED. 1461 00:55:06,560 --> 00:55:11,880 >>THANK YOU. 1462 00:55:11,880 --> 00:55:13,960 ARE YOU FINDING THAT THE FLAIR 1463 00:55:13,960 --> 00:55:17,800 MRI EVIDENCE OF THE 1464 00:55:17,800 --> 00:55:18,640 ENDOLYMPHATIC HYDROPS, IS THAT 1465 00:55:18,640 --> 00:55:19,920 AN EARLY FINDING OR LATE FINDING 1466 00:55:19,920 --> 00:55:21,920 WHEN COMPARED TO THE CLINICAL 1467 00:55:21,920 --> 00:55:22,800 SYMPTOMATOLOGY OF HEARING LOSS 1468 00:55:22,800 --> 00:55:25,400 AND OTHER FINDINGS? 1469 00:55:25,400 --> 00:55:27,720 >>THAT'S A VERY GOOD QUESTION. 1470 00:55:27,720 --> 00:55:29,680 I DON'T THINK WE TRULY KNOW THE 1471 00:55:29,680 --> 00:55:31,920 ANSWER TO THAT QUESTION YET. 1472 00:55:31,920 --> 00:55:35,680 ONE OF THE REASONS FOR US 1473 00:55:35,680 --> 00:55:37,200 WANTING TO FOLLOW ALL THESE 1474 00:55:37,200 --> 00:55:39,080 PATIENTS LONGITUDINALLY WAS TO 1475 00:55:39,080 --> 00:55:40,640 SEE HOW HYDROPS EVOLVES OVER 1476 00:55:40,640 --> 00:55:40,840 TIME. 1477 00:55:40,840 --> 00:55:43,280 AND IN SOME CASES, WE'VE SEEN 1478 00:55:43,280 --> 00:55:44,280 HYDROPS DECREASE WITH 1479 00:55:44,280 --> 00:55:46,040 IMPROVEMENT IN HEARING AND IN 1480 00:55:46,040 --> 00:55:47,480 SOME CASES WE'VE SEEN IT NOT 1481 00:55:47,480 --> 00:55:48,800 DECREASE. 1482 00:55:48,800 --> 00:55:52,520 SO I THINK THIS FORM OF IMAGING 1483 00:55:52,520 --> 00:55:54,480 MAY ALSO HELP US PHENOTYPE SOME 1484 00:55:54,480 --> 00:55:57,920 OF THESE PATIENTS INTO GROUPS, 1485 00:55:57,920 --> 00:55:59,240 INTO HOW THEIR HYDROPS MIGHT 1486 00:55:59,240 --> 00:56:02,880 CHANGE OVER TIME. 1487 00:56:02,880 --> 00:56:03,760 >>THANK YOU. 1488 00:56:03,760 --> 00:56:06,520 THIS QUESTION IS FOR DR. CHIEN. 1489 00:56:06,520 --> 00:56:09,200 DR. CHIEN, WHAT ARE THE THEORIES 1490 00:56:09,200 --> 00:56:10,920 ABOUT WHY THE DUAL AAV GENE 1491 00:56:10,920 --> 00:56:12,240 THERAPY IMPROVED VESTIBULAR 1492 00:56:12,240 --> 00:56:13,480 FUNCTION WHILE IT DID NOT 1493 00:56:13,480 --> 00:56:16,400 IMPROVE THE AUDITORY FUNCTION IN 1494 00:56:16,400 --> 00:56:17,320 THE SHAKER1 MUTANT MOUSE? 1495 00:56:17,320 --> 00:56:18,800 >>YEAH, AND THAT'S SOMETHING 1496 00:56:18,800 --> 00:56:20,760 THAT WE ARE THINKING QUITE A LOT 1497 00:56:20,760 --> 00:56:22,760 ABOUT, BUT I THINK ONE 1498 00:56:22,760 --> 00:56:24,200 POSSIBILITY AS I MENTIONED 1499 00:56:24,200 --> 00:56:27,680 BEFORE, THE COCHLEAR HAIR CELLS 1500 00:56:27,680 --> 00:56:29,400 ACTUALLY ON THE -- ACTUALLY THE 1501 00:56:29,400 --> 00:56:30,440 DEGENERATION HAS BEEN SHOWN TO 1502 00:56:30,440 --> 00:56:33,840 OCCUR EVEN IN UTERO, EVEN BY 1503 00:56:33,840 --> 00:56:37,680 EMBRYONIC DAY 17, 17.5 OR SO, SO 1504 00:56:37,680 --> 00:56:39,160 WHEREAS THE VESTIBULAR HAIR 1505 00:56:39,160 --> 00:56:42,240 CELLS ARE VIABLE AFTER BIRTH. 1506 00:56:42,240 --> 00:56:44,960 AND SO IT IS POSSIBLE THAT EVEN 1507 00:56:44,960 --> 00:56:52,040 THOUGH WE COULD RESTORE MYO7 -- 1508 00:56:52,040 --> 00:56:54,120 IN SOME OF THESE HAIR CELLS, 1509 00:56:54,120 --> 00:56:55,120 MANY ARE PROBABLY ON THE WAY TO 1510 00:56:55,120 --> 00:56:56,240 DYING AND IT'S TOO LATE TO 1511 00:56:56,240 --> 00:56:58,520 INTERVENE AND TRY TO REVERSE THE 1512 00:56:58,520 --> 00:56:58,760 COURSE. 1513 00:56:58,760 --> 00:57:00,200 WHEREAS WITH VESTIBULAR HAIR 1514 00:57:00,200 --> 00:57:01,560 CELLS, THEY'RE STILL VIABLE AND 1515 00:57:01,560 --> 00:57:04,040 ABLE TO RESPOND TO BENEFICIAL 1516 00:57:04,040 --> 00:57:05,600 EFFECTS OF GENE THERAPY. 1517 00:57:05,600 --> 00:57:07,080 SO THAT'S OUR BEST GUESS AS TO 1518 00:57:07,080 --> 00:57:08,720 WHY IT'S MORE EFFECTIVE IN THE 1519 00:57:08,720 --> 00:57:09,760 VESTIBULAR ORGANS THAN COMPARED 1520 00:57:09,760 --> 00:57:10,920 TO THE COCHLEA. 1521 00:57:10,920 --> 00:57:14,680 >>THANK YOU. 1522 00:57:14,680 --> 00:57:16,840 AND SO ONE QUESTION COMES IN, 1523 00:57:16,840 --> 00:57:18,760 ARE YOU EXPLORING ANY GENE 1524 00:57:18,760 --> 00:57:20,120 EDITING APPROACHES? 1525 00:57:20,120 --> 00:57:21,880 >>YES, NOT FOR THIS PARTICULAR 1526 00:57:21,880 --> 00:57:23,280 MOUSE MODEL, BUT FOR SOME OF THE 1527 00:57:23,280 --> 00:57:24,960 OTHER MOUSE MODELS, ESPECIALLY 1528 00:57:24,960 --> 00:57:28,040 THOSE THAT HAVE A -- LIKE A 1529 00:57:28,040 --> 00:57:29,360 DOMINANT NEGATIVE MUTATION, 1530 00:57:29,360 --> 00:57:34,200 WE'RE TRYING TO DO GENE EDITING 1531 00:57:34,200 --> 00:57:37,080 AS A WAY TO IMPROVE THE FUNCTION 1532 00:57:37,080 --> 00:57:42,320 IN THOSE ANIMALS. 1533 00:57:42,320 --> 00:57:44,120 >>LOOKS LIKE WE HAVE JUST ONE 1534 00:57:44,120 --> 00:57:45,880 LAST QUESTION, AND THIS AGAIN IS 1535 00:57:45,880 --> 00:57:49,920 DR. HAO GOING BACK TO MR. 1536 00:57:49,920 --> 00:57:51,520 DO THE FLAIR MR FINDINGS 1537 00:57:51,520 --> 00:57:53,440 CORRELATE WITH THE DEGREE OF 1538 00:57:53,440 --> 00:57:54,920 HEARING INSTABILITY IN ANY WAY? 1539 00:57:54,920 --> 00:57:57,760 >>SO SOME OF OUR PRELIMINARY 1540 00:57:57,760 --> 00:58:05,440 DATA SUGGESTS THAT THE AMOUNT OF 1541 00:58:05,440 --> 00:58:06,560 HYDROPS DOES CORRELATE 1542 00:58:06,560 --> 00:58:08,880 PARTICULARLY FROM THE VESTIBULAR 1543 00:58:08,880 --> 00:58:10,520 STANDPOINT, DOES CORRELATE WITH 1544 00:58:10,520 --> 00:58:14,520 PURE TONE THRESHOLDS, SO THE 1545 00:58:14,520 --> 00:58:15,840 WORSE A PATIENT'S HEARING IS, IN 1546 00:58:15,840 --> 00:58:19,640 SOME CASES, THE WORSE THEIR -- 1547 00:58:19,640 --> 00:58:25,200 OR GREATER THEIR HYDROPS IS. 1548 00:58:25,200 --> 00:58:28,480 >>THANK YOU VERY MUCH, 1549 00:58:28,480 --> 00:58:30,640 DR. CHIEN, DR. HAO, I THINK THAT 1550 00:58:30,640 --> 00:58:32,080 WAS THE LAST QUESTION RECEIVED. 1551 00:58:32,080 --> 00:58:33,200 THIS TAKES US UP TO THE TOP OF 1552 00:58:33,200 --> 00:58:33,680 THE HOUR. 1553 00:58:33,680 --> 00:58:35,640 AGAIN, I WANT TO THANK BOTH OF 1554 00:58:35,640 --> 00:58:39,320 YOU FOR SHARING YOUR WORK. 1555 00:58:39,320 --> 00:58:40,200 SINCERELY APPRECIATE THAT YOU'RE 1556 00:58:40,200 --> 00:58:42,440 PROVIDING SUCH HIGH QUALITY 1557 00:58:42,440 --> 00:58:43,800 PRESENTATIONS FOR OUR CLINICAL 1558 00:58:43,800 --> 00:58:45,240 CENTER GRAND ROUNDS, AND TO THE 1559 00:58:45,240 --> 00:58:48,120 NIH COMMUNITY AND BEYOND. 1560 00:58:48,120 --> 00:58:48,880 EVERYBODY, HAVE A GREAT DAY. 1561 00:58:48,880 --> 00:00:00,000 THANK YOU VERY MUCH.