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>> ALL RIGHT.

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WELL, GREETINGS AND SALUTATIONS.

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I'M DAN KASTNER.

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I'M THE SCIENTIFIC DIRECTOR 

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EMERITUS AND STILL ACTIVE 

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PHYSICIAN SCIENTIST IN THE 

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INTRAMURAL RESEARCH PROGRAM OF 

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THE NATIONAL HUMAN GENOME 

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INSTITUTE AND IT IS MY ENORMOUS 

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PLEASURE TO WELCOME YOU TO THIS 

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THE 13th INSTALLMENT OF 

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DEMYSTIFYING MEDICINE, 2025.

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A SERIES OF PRESENTATIONS THAT 

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BRIDGE THE EXCITING DEVELOPMENTS

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IN BIOLOGY, ENGINEERING AND 

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COMPUTER SCIENCE WITH MEDICINE.

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AND OF COURSE YOU SEE THAT 

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ICONIC PHOTO UP IN THE UPPER 

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RIGHT HAND CORNER OF THE 

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CONSTRUCTION OF THE BROOKLYN 

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BRIDGE BACK IN THE LATE 1800s.

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AND YOU SEE THOSE TWO GUYS IS UP

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THERE ON THE CATWALK.

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ONE PROBABLY A PHYSICIAN FROM 

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MANHATTAN OR MAYBE A BASIC 

26
00:01:05,546 --> 00:01:06,580
SCIENTIST FROM BROOKLYN OR 

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OPPOSITE, I DON'T KNOW.

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MAYBE THEY COULD HAVE BEEN 

29
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DISCUSSING COAST POSULATES AND 

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WE'LL HAVE A BONANZA DISCUSSION 

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OF MUSCULOSKELETAL DISEASE AND 

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WE'LL HAVE A GREAT DEAL OF FUN 

33
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WITH TODAY'S SPEAKERS.

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THE SERIES, DEMYSTIFYING 

35
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MEDICINE OCCURS TUESDAY 

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AFTERNOONS FROM 3:00 TO 5:00 

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EASTERN TIME FROM JANUARY 

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THROUGH MAY OF 2025.

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YOU CAN WATCH IT ON THE LINK 

40
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SHOWN HERE ON THE SCREEN, CME 

41
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CREDIT IS AVAILABLE IF YOU 

42
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SIGNED UP AND THE CME CODE IS 

43
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SHOWN HERE, 58792.

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FOR THOSE WHO HAVE QUESTIONS 

45
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DURING THE TALKS, THERE ARE 

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GOING TO BE TWO TALKS, WHILE THE

47
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TALKS ARE GOING ON, YOU CAN 

48
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SUBMIT YOUR QUESTIONS SO THAT WE

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CAN DISCUSS THEM AT THE END OF 

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THE SESSION USING THE SEND LIVE 

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FEEDBACK BUTTON ON THE VIDEOCAST

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DISPLAY.

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ALL THE PREVIOUS SESSIONS ARE 

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ARCHIVED SHOWN AT THE LINK THERE

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ON THE SCREEN.

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AND FOR ADDITIONAL INFORMATION 

57
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YOU CAN GO TO DEMYSTIFYING 

58
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MED@NIH.gov.

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THIS IS A SERIES BRIDGING SILOS 

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AT THE NIH SINCE 2003.

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LET'S GET RIGHT ON TO IT.

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SO AS I MENTIONED, WE HAVE TWO 

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WONDERFUL SPEAKERS TODAY.

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THE FIRST IS GOING TO BE TALKING

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TO US ABOUT A VERY DIABOLICAL 

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THEME INFILTRATERS HOW THEY 

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DISRUPT MUSCLE CELLS FROM 

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WITHIN.

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LIKE A TROJAN HORSE, I GUESS.

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HE'S A SENIOR INVESTIGATOR AND 

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CHIEF OF THE MUSCLE DISEASE 

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SECTION OF THE LABORATORY OF 

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MUSCLE STEM CELLS AND GENE 

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REGULATION IN THE NATIONAL 

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INSTITUTE OF ARTHRITIS AND 

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MUSCULOSKELETAL AND SKIN 

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DISEASES.

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AND THE ADJUNCT PROFESSOR AT 

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JOHNS HOPKINS AND GOT HIS 

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MEDICAL DEGREE AT JOHNS HOPKINS 

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AND Ph.D. IN NEUROSCIENCE ALSO 

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FROM JOHNS HOPKINS AND DID HIS 

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RESIDENCY NEURO MUMUSCULAR 

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FELLOWSHIP AT JOHN HOPKINS AND 

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THE CO-FOUNDER MYOCYTIS AND THE 

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RECIPIENT OF MANY AWARDS AND ON 

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AND ON.

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HIS RESEARCH LABORATORY FOCUSES 

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ON DEFINING SUB TYPES OF 

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AUTOIMMUNE DISEASE AND 

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ELUCIDATING THE ROLE OF MIOSITIS

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AND UNDERSTANDING HOW 

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ENVIRONMENTAL EXPOSURES TRIGGER 

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AUTOIMMUNE MUSCLE DISEASE AND 

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DEVELOPING TARGETED THERAPIES.

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AND IT THE SECOND SPEAKER WILL 

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TALK TO US ABOUT ADENO MEDIATED 

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GENE THERAPY AND OPPORTUNITIES 

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AND CHALLENGES.

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DR. BONNEMAN IS CHIEF OF THE 

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NEUROMUSCULAR SECTION AT THE 

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NEUROGENETICS BRANCH OF THE 

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NATIONAL INSTITUTE FOR 

104
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NEUROLOGIC DISEASES AND STROKE.

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HE'S ALSO THE ADJUNCT FULL 

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PROFESSOR OF NEUROLOGY AT THE 

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UNIVERSITY OF PENNSYLVANIA.

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HE GOT HIS MEDICAL DEGREE SUMMA 

109
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CUM LAUDE AND DID CLINICAL AND 

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RESEARCH FELLOWSHIPS AT THE MASS

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GENERAL AND BOSTON CHILDREN'S 

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HOSPITAL AT HARVARD.

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HE'S AN ELECTED MEMBER OF THE 

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ASSOCIATION OF AMERICAN 

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PHYSICIANS, RECIPIENT OF THE 

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GEORGE CA JOBY AWARD OF THE NERN

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NEUROLOGICAL ASSOCIATION AND 

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RECIPIENT OF THE HONORARY AWARD 

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OF THE GERMAN NEUROPEDIATRIC 

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SOCIETY.

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HIS RESEARCH GROUP STUDIES THE 

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GENETICS AND PATHOGENESIS OF 

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EARLY ONSET NEUROMUSCULAR 

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DISORDERS OF CHILDHOOD.

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HIS GROUP WORKS ON GENE EDITING 

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AND RNA DIRECTED THERAPEUTICS 

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FOR ALLELE SPECIFIC KNOCK DOWN 

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OF SOME KIND OF ACTING MUTATIONS

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THERE, DOMINANTLY ACTING 

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MUTATIONS AND STUDIES OUTCOME 

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MEASURES IN AAV9 MEDIATED GENE 

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TRANS FOREGIANT AXONAL 

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NEUROPATHY.

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WITH THAT HAVING BEEN SAID I 

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THINK THAT'S IT FOR MEF FOREGIA 

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NEUROPATHY.

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WITH THAT HAVING BEEN SAID I 

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THINK THAT'S IT FOR MEER FOREGI 

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NEUROPATHY.

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WITH THAT HAVING BEEN SAID I 

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THINK THAT'S IT FOR ME FOREGIAN 

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NEUROPATHY.

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WITH THAT HAVING BEEN SAID I 

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THINK THAT'S ITOF FOREGIANT AXO 

145
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NEUROPATHY.

146
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WITH THAT HAVING BEEN SAID I 

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THINK THAT'S IT FOREGIANT AXONA 

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NEUROPATHY.

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WITH THAT HAVING BEEN SAID I 

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THINK THAT'S ITA FOREGIANT AXON 

151
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NEUROPATHY.

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WITH THAT HAVING BEEN SAID I 

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THINK THAT'S IT FOR MEOREGIANT  

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NEUROPATHY.

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WITH THAT HAVING BEEN SAID I 

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THINK THAT'S ITREGIANT AXONAL 

157
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NEUROPATHY.

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WITH THAT HAVING BEEN SAID I 

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THINK THAT'S IT FOR MEGIANT AXO 

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NEUROPATHY.

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WITH THAT HAVING BEEN SAID I 

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THINK THAT'S IT FOR MEIANT AXON 

163
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NEUROPATHY.

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WITH THAT HAVING BEEN SAID I 

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THINK THAT'S ITNT AXONAL 

166
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NEUROPATHY.

167
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WITH THAT HAVING BEEN SAID I 

168
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THINK THAT'S ITT AXONAL 

169
00:07:02,569 --> 00:07:02,870
NEUROPATHY.

170
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WITH THAT HAVING BEEN SAID I 

171
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THINK THAT'S IT AXONAL NEUROPAT.

172
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WITH THAT HAVING BEEN SAID I 

173
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THINK THAT'S ITAXONAL NEUROPATH.

174
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WITH THAT HAVING BEEN SAID I 

175
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THINK THAT'S IT FOR MEXONAL NEU.

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WITH THAT HAVING BEEN SAID I 

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THINK THAT'S IT FOR ME 

178
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>> THE TOPIC OF MY TALK IS
GOING

179
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TO BE INTRACELLULAR INFILTRATERS

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HOW ANTIBODIES DISRUPT FROM 

181
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WITHIN.

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DESIGN TO BE A PROVOCATIVE 

183
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TITLE.

184
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AND I HAVE A COUPLE DISCLOSURES.

185
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THE FIRST IS I AM ON A PATENT 

186
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FOR AN AUTOANTIBODY TO DEFECT 

187
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ANTIBODIES BUT HAVE RECEIVED 

188
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COMPENSATION FOR THAT.

189
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AND HAVE TREATMENTS FOR 

190
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MYOSITIS.

191
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AN OVERVIEW OF MY TALK IS TO 

192
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TELL YOU ABOUT MYOSITIS A 

193
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HETEROGENEOUS FAMILY OF RARE 

194
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AUTOIMMUNE DISEASES.

195
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I WANT TO TELL YOU ABOUT THE 

196
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FACT THERE'S MYOCYSITIS SPECIFI 

197
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DISTINCT CLINICAL PHENOTYPE.

198
00:07:49,716 --> 00:07:51,518
EACH MUCH THESE ANTIBODIES 

199
00:07:51,518 --> 00:07:53,087
RECOGNIZES A PROTEIN TARGET THAT

200
00:07:53,087 --> 00:07:56,457
IS INTRACELLULAR, NOT ON THE 

201
00:07:56,457 --> 00:07:57,024
SURFACE OF CELLS.

202
00:07:57,024 --> 00:08:00,761
THEN I'M GOING TO MOVE ON TO 

203
00:08:00,761 --> 00:08:04,031
PRESENT EVIDENCE WE NOW HAVE THE

204
00:08:04,031 --> 00:08:07,734
MYOSITIS SPECIFIC ANTIBODIES AND

205
00:08:07,734 --> 00:08:10,838
ASSOCIATED ANTIBODIES ARE 

206
00:08:10,838 --> 00:08:11,839
INTERNALIZED INTO MUSCLE CELLS 

207
00:08:11,839 --> 00:08:13,707
AND DISRUPT THE FUNCTION OF 

208
00:08:13,707 --> 00:08:17,344
THEIR TARGET PROTEINS AND WE 

209
00:08:17,344 --> 00:08:19,746
THINK IT'S A POTENTIALLY 

210
00:08:19,746 --> 00:08:23,550
IMPORTANT PART OF THE DISEASE 

211
00:08:23,550 --> 00:08:24,685
PATHOGENESIS.

212
00:08:24,685 --> 00:08:29,022
I'LL TOUCH ON THE FOUR.

213
00:08:29,022 --> 00:08:35,496
ONE IS DEFINED BY AUTOANTIBODIES

214
00:08:35,496 --> 00:08:39,133
AND THERE'S IMMUNE-MEDIATED 

215
00:08:39,133 --> 00:08:43,270
NECROTIZING MYOSITIS AND OVERLAP

216
00:08:43,270 --> 00:08:46,540
WHERE PATIENTS HAVE ANOTHER 

217
00:08:46,540 --> 00:08:50,344
DEFINED CONNECTIVE TISSUE 

218
00:08:50,344 --> 00:09:00,854
DISEASE WITH AN INFLAMMATORY 

219
00:09:02,055 --> 00:09:05,492
DISEASE.

220
00:09:05,492 --> 00:09:09,530
DERMATOMYOSITIS IS THEY HAVE 

221
00:09:09,530 --> 00:09:17,538
BOTH DERMO LOGIC FEATURES AND 

222
00:09:17,538 --> 00:09:21,141
GET RASHES ONE YOU CAN SEE.

223
00:09:21,141 --> 00:09:29,983
THE EMETHRITIS LESIONS AND THE 

224
00:09:29,983 --> 00:09:31,785
KNUCKLES HAVE A RED SCALY 

225
00:09:31,785 --> 00:09:35,389
LESION, THAT'S THE GOTRIN SIGN.

226
00:09:35,389 --> 00:09:37,090
HERE'S MY PICTORIAL 

227
00:09:37,090 --> 00:09:37,991
REPRESENTATION OF PROXIMAL 

228
00:09:37,991 --> 00:09:39,960
MUSCLE WEAKNESS THAT OCCURS IN 

229
00:09:39,960 --> 00:09:46,266
MOST IF NOT ALL PATIENTS WITH 

230
00:09:46,266 --> 00:09:47,901
DERMATOMYOSITIS AND ABOUT 70% TO

231
00:09:47,901 --> 00:09:52,239
80% OF THESE PATIENTS WILL HAVE 

232
00:09:52,239 --> 00:09:57,544
ONE OF SEVERAL KNOWN DERMATO 

233
00:09:57,544 --> 00:10:00,314
MYOCYSITIS ANTIBODIES AND TAY 

234
00:10:00,314 --> 00:10:01,882
TARGET INTRACELLULAR PROTEINS.

235
00:10:01,882 --> 00:10:02,449
THERE ARE FOUR I'M GOING TO 

236
00:10:02,449 --> 00:10:10,991
MENTION.

237
00:10:10,991 --> 00:10:16,797
THEY ARE RECOGNIZE TIP 1 GAMMA 

238
00:10:16,797 --> 00:10:18,999
AND KNOWN WITH CHROMATIN 

239
00:10:18,999 --> 00:10:21,501
REMODELLING AND BOTH HAVE 

240
00:10:21,501 --> 00:10:25,973
PREDOMINANTLY NUCLEAR 

241
00:10:25,973 --> 00:10:36,216
LOCALIZATION.

242
00:10:38,418 --> 00:10:41,555
AND THERE'S MI2 WITH A NUCLEAR 

243
00:10:41,555 --> 00:10:41,888
LOCALIZATION.

244
00:10:41,888 --> 00:10:45,525
THERE ARE OTHER PATIENTS WHO 

245
00:10:45,525 --> 00:10:49,997
HAVE AUTOANTIBODIES THAT 

246
00:10:49,997 --> 00:10:54,001
RECOGNIZE CYTOPLASMIC AND 

247
00:10:54,001 --> 00:11:00,507
USUALLY MDA5 THAT SITS IN THE 

248
00:11:00,507 --> 00:11:01,575
CYTOPLASM TO RECOGNIZE DOUBLE 

249
00:11:01,575 --> 00:11:04,645
STRANDED RNA AND TRIGGERS THE 

250
00:11:04,645 --> 00:11:06,480
INNATE IMMUNE RESPONSE AND AGAIN

251
00:11:06,480 --> 00:11:08,815
MDA5 IS A CYTOPLASMIC ROW TEEN.

252
00:11:08,815 --> 00:11:13,153
I WANT TO SPEND A FEW MINUTES 

253
00:11:13,153 --> 00:11:14,521
SPENDING A FEW MINUTES THAT 

254
00:11:14,521 --> 00:11:17,190
THOUGH THEY'RE ALL FOUND IN 

255
00:11:17,190 --> 00:11:19,192
PATIENTS THEY DEFINE UNIQUE 

256
00:11:19,192 --> 00:11:19,826
CLINICAL PHENOTYPES AND 

257
00:11:19,826 --> 00:11:22,929
IMPORTANT TO RECOGNIZE THAT 

258
00:11:22,929 --> 00:11:25,699
ALMOST ALL JUST HAVE ONE OF EACH

259
00:11:25,699 --> 00:11:30,037
OF THESE FOUR DIFFERENT MYOSITIS

260
00:11:30,037 --> 00:11:31,605
SPECIFIC ANTIBODIES.

261
00:11:31,605 --> 00:11:33,573
THE FIRST ARE FOUR WITH 

262
00:11:33,573 --> 00:11:35,208
ANTIBODIES AGAINST THE PROTEIN 

263
00:11:35,208 --> 00:11:39,379
CALLED TIP 1 GAMMA.

264
00:11:39,379 --> 00:11:41,415
THIS IS THE MOST COMMON ANTIBODY

265
00:11:41,415 --> 00:11:49,990
AND THE CLASSIC -- THEY HAVE THE

266
00:11:49,990 --> 00:11:51,558
CLASSIC FEATURES AND THE 

267
00:11:51,558 --> 00:11:53,560
ADDITIONAL THING IS THEY HAVE AN

268
00:11:53,560 --> 00:11:57,397
INCREASED RISK OF CO-EXISTING 

269
00:11:57,397 --> 00:12:01,968
MALIGNANCY COMPARED TO OTHER 

270
00:12:01,968 --> 00:12:03,303
DERMATOCYTIS PATIENTS AND 

271
00:12:03,303 --> 00:12:04,905
HEALTHY CONTROLS.

272
00:12:04,905 --> 00:12:09,976
THAT'S ASSOCIATED WITH THE TIF1 

273
00:12:09,976 --> 00:12:11,878
GAMMA ANTIBODIES.

274
00:12:11,878 --> 00:12:13,747
AND THE SECOND MOST COMMON IS 

275
00:12:13,747 --> 00:12:16,249
THE RECOGNITION OF THE PROTEIN 

276
00:12:16,249 --> 00:12:17,684
NXP2.

277
00:12:17,684 --> 00:12:19,353
IN CONTRAST TO OTHER PATIENTS, 

278
00:12:19,353 --> 00:12:23,890
THEY'RE MORE LIKELY TO HAVE SUB 

279
00:12:23,890 --> 00:12:24,291
CUTANEOUS EDEMA.

280
00:12:24,291 --> 00:12:28,762
THE FOREARM OF THE PATIENT WITH 

281
00:12:28,762 --> 00:12:29,096
PITTING EDEMA.

282
00:12:29,096 --> 00:12:29,830
NOTHING IN THE LEGS.

283
00:12:29,830 --> 00:12:34,701
THIS IS A FEATURE OF THE 

284
00:12:34,701 --> 00:12:35,302
DERMATOMYOSITIS.

285
00:12:35,302 --> 00:12:38,438
IT'S NOT BECAUSE OF HEART 

286
00:12:38,438 --> 00:12:39,573
FAILURE OR ANYTHING.

287
00:12:39,573 --> 00:12:50,117
MOST DERMATOMYOSITIS PATIENTS IS

288
00:12:54,388 --> 00:12:57,257
TRYING TO FULLY EXTEND THEIR 

289
00:12:57,257 --> 00:12:58,191
FINGERS AND THEY'RE WEAK AND 

290
00:12:58,191 --> 00:12:59,526
THAT'S AS FAR AS THEY CAN GO.

291
00:12:59,526 --> 00:13:02,696
THEY CAN DEVELOP A DREADED 

292
00:13:02,696 --> 00:13:05,866
COMPLICATION WHICH IS SUB 

293
00:13:05,866 --> 00:13:09,569
CUTANE

294
00:13:09,569 --> 00:13:12,038
CUTANE

295
00:13:12,038 --> 00:13:20,147
CUTANEOUS KAL -- CALCINOSIS AND 

296
00:13:20,147 --> 00:13:22,716
YOU CAN SEE THE RADIO DENSE 

297
00:13:22,716 --> 00:13:25,986
CALCIUM DEPOSITION THAT OCCURS 

298
00:13:25,986 --> 00:13:32,626
IN THE PATIENT.

299
00:13:32,626 --> 00:13:34,361
AND THEY'LL HAVE DIFFICULTY 

300
00:13:34,361 --> 00:13:35,195
SWALLOWING WHERE WE ONLY SEE 

301
00:13:35,195 --> 00:13:36,997
THIS IN A QUARTER OF THE 

302
00:13:36,997 --> 00:13:39,566
PATIENTS AND THE ONLY 

303
00:13:39,566 --> 00:13:41,935
DERMATOMYOSITIS PATIENTS I'VE 

304
00:13:41,935 --> 00:13:44,771
HAD TO HAVE A FEEDING TUBE HAVE 

305
00:13:44,771 --> 00:13:47,774
THE ANTRI-NXP2 DERMATOMYOSITIS.

306
00:13:47,774 --> 00:13:48,942
SOME PATIENTS WITH 

307
00:13:48,942 --> 00:13:49,976
DERMATOMYOSITIS HAVE ANTIBODIES 

308
00:13:49,976 --> 00:13:57,551
AGAINST THE PROTEIN MI2 PART OF 

309
00:13:57,551 --> 00:14:00,020
THE NUCLEOSOME ACETYLATION AND 

310
00:14:00,020 --> 00:14:03,156
HAVE THE MOST SEVERE WEAKNESS 

311
00:14:03,156 --> 00:14:05,592
AND HIGHEST MUSCLE ENZYME 

312
00:14:05,592 --> 00:14:05,859
VALUES.

313
00:14:05,859 --> 00:14:11,198
THE CK200 OR LOWER IN THE 

314
00:14:11,198 --> 00:14:14,167
ANTI-MI2 DERMATOMYOSITIS THE 

315
00:14:14,167 --> 00:14:15,936
MEAN REACHES 4,000 WHEREAS IN 

316
00:14:15,936 --> 00:14:18,972
OUR OTHER DERMATOMYOSITIS 

317
00:14:18,972 --> 00:14:20,841
PATIENTS WITH OTHER AUTOIMMUNE 

318
00:14:20,841 --> 00:14:22,709
PATIENTS THE MEAN IS IN THE 200 

319
00:14:22,709 --> 00:14:24,344
THOUGH IT CAN GET HIGHER IN SOME

320
00:14:24,344 --> 00:14:26,112
PATIENTS.

321
00:14:26,112 --> 00:14:28,515
AGAIN, THESE PATIENTS HAVE NOT 

322
00:14:28,515 --> 00:14:30,517
JUST MORE SEVERE WEAKNESS AND 

323
00:14:30,517 --> 00:14:32,586
HIGHER MUSCLE ENZYMES, WHEN YOU 

324
00:14:32,586 --> 00:14:36,556
LOOK HISTOLOGICALLY AT THEIR 

325
00:14:36,556 --> 00:14:38,792
MUSCLE TISSUE AND THE MOST 

326
00:14:38,792 --> 00:14:41,761
NECROSIS AND INFLAMMATION IN THE

327
00:14:41,761 --> 00:14:42,195
MUSCLE BIOPSY.

328
00:14:42,195 --> 00:14:43,864
THE LAST ANTIBODY I WANT TO TELL

329
00:14:43,864 --> 00:14:46,900
YOU ABOUT RECOGNIZES MDA5 WHICH 

330
00:14:46,900 --> 00:14:50,971
AGAIN IS A CYTOPLASMIC 

331
00:14:50,971 --> 00:14:52,873
DOUBLE-STRANDED RNA SENSOR.

332
00:14:52,873 --> 00:14:56,276
THESE PATIENTS HAVE UNIQUE 

333
00:14:56,276 --> 00:14:58,512
CUTANEOUS FEATURES.

334
00:14:58,512 --> 00:15:04,384
THEY GET THE CLASSIC GOTRIN SIGN

335
00:15:04,384 --> 00:15:09,556
OVER THEIR FINGERS AND 

336
00:15:09,556 --> 00:15:11,758
ULTERATING LESIONS ON THE 

337
00:15:11,758 --> 00:15:18,231
SURFACE OF THEIR PALMS AND -- 

338
00:15:18,231 --> 00:15:18,798
ULCERATING.

339
00:15:18,798 --> 00:15:22,836
AND THESE OFTEN DEVELOP 

340
00:15:22,836 --> 00:15:24,838
INTERSTITIAL LUNG DISEASE AND A 

341
00:15:24,838 --> 00:15:26,506
RAPID FORM THAT UNFORTUNATELY 

342
00:15:26,506 --> 00:15:37,050
HAS A VERY HIGH MORTALITY RATE.

343
00:15:47,561 --> 00:15:50,297
AND THE MUSCLE BIOPSIES CAN BE 

344
00:15:50,297 --> 00:15:52,232
RELATIVELY BLAND COMPARED TO 

345
00:15:52,232 --> 00:15:53,333
PATIENTS WITH OTHER TIMES OF 

346
00:15:53,333 --> 00:15:53,700
DERMATOMYOSITIS.

347
00:15:53,700 --> 00:15:55,502
HOPEFULLY I CONVINCED YOU THOUGH

348
00:15:55,502 --> 00:15:57,571
ALL THESE PATIENTS ARE SAID TO 

349
00:15:57,571 --> 00:15:59,873
HAVE DRAMATIC DERMATOMYOSITIS, 

350
00:15:59,873 --> 00:16:01,975
IN SOME WAYS EACH IS A UNIQUE 

351
00:16:01,975 --> 00:16:09,683
DISEASE DEFINED BY THE TYPE OF  

352
00:16:09,683 --> 00:16:09,983
RECOGNIZED.

353
00:16:09,983 --> 00:16:12,919
THE SECOND IS THE ANTISNTHETASE.

354
00:16:12,919 --> 00:16:16,423
IT'S DEFINED BY THE PRESENCE OF 

355
00:16:16,423 --> 00:16:24,831
AUTOBEYONDSS -- ANTIBODIES AND 

356
00:16:24,831 --> 00:16:26,232
THEY CORRECT TO THE APPROPRIATE 

357
00:16:26,232 --> 00:16:26,633
TRNA.

358
00:16:26,633 --> 00:16:30,804
YOU HAVE A BUNCH OF DIFFERENT 

359
00:16:30,804 --> 00:16:41,247
TRN As AND SYNTHETASE AND 

360
00:16:46,453 --> 00:16:50,156
THEY'RE REFERRED TO AS ANTI-JO-1

361
00:16:50,156 --> 00:17:00,667
AND OTHERS ARE RECOGNIZED AND 

362
00:17:01,101 --> 00:17:02,636
THESE PATIENTS HAVE A UNIQUE 

363
00:17:02,636 --> 00:17:03,970
SYNDROME THAT INCLUDES SOME OF 

364
00:17:03,970 --> 00:17:06,172
FEATURES I ALREADY TOLD YOU 

365
00:17:06,172 --> 00:17:09,976
ABOUT LIKE MYOSITIS AND 

366
00:17:09,976 --> 00:17:13,313
INTERSTITIAL LUNG DISEASE AND A 

367
00:17:13,313 --> 00:17:13,980
CLASSIC DERMATOMYOSITIS LIKE 

368
00:17:13,980 --> 00:17:16,282
RASH AND THESE PATIENTS WILL 

369
00:17:16,282 --> 00:17:17,283
OFTEN DEVELOP ARTHRITIS.

370
00:17:17,283 --> 00:17:21,588
THEY HAVE UNIQUE MANIFESTATIONS.

371
00:17:21,588 --> 00:17:32,132
THE HYPERCARE  -- FEATURES AND 

372
00:17:33,633 --> 00:17:37,404
THEY'LL HAVE SOME COMBENGS.

373
00:17:37,404 --> 00:17:41,107
AND THE LAST TYPE BEFORE WE MOVE

374
00:17:41,107 --> 00:17:49,683
ON IS THE TYPE OF MYOSITIS 

375
00:17:49,683 --> 00:17:51,351
CALLED NECROTIZING MYOSITIS.

376
00:17:51,351 --> 00:17:53,753
I HAVEN'T TOLD YOU TOO MUCH 

377
00:17:53,753 --> 00:17:56,289
ABOUT MUSCLE BIOPSIES SO FAR BUT

378
00:17:56,289 --> 00:17:57,991
WHETHER THEY'RE DERMATOMYOSITIS 

379
00:17:57,991 --> 00:18:00,427
OR ANTISNTHETASE HAVE A 

380
00:18:00,427 --> 00:18:01,961
SIGNIFICANT AMOUNT OF 

381
00:18:01,961 --> 00:18:03,496
INFLAMMATORY CELLS IN THEIR 

382
00:18:03,496 --> 00:18:03,730
TISSUE.

383
00:18:03,730 --> 00:18:07,100
IN CONTRAST THESE PATIENTS WITH 

384
00:18:07,100 --> 00:18:11,438
NECROTIZING HAVE MINIMAL 

385
00:18:11,438 --> 00:18:13,973
INFILTRATION BUT HAVE MYOFIBER 

386
00:18:13,973 --> 00:18:23,550
NECROSIS.

387
00:18:23,550 --> 00:18:25,518
THIS IS THE EARLY STAGE OF 

388
00:18:25,518 --> 00:18:27,987
NECROSIS AND THESE PATIENTS HAVE

389
00:18:27,987 --> 00:18:30,056
ONE OF TWO AUTOANTIBODIES.

390
00:18:30,056 --> 00:18:33,560
THEY CAN RECOGNIZE THE SIGNAL 

391
00:18:33,560 --> 00:18:36,963
RECOGNITION PART OR THEY CAN 

392
00:18:36,963 --> 00:18:42,635
RECOGNIZE THE PHARMACOLOGIC 

393
00:18:42,635 --> 00:18:42,936
STATINS.

394
00:18:42,936 --> 00:18:53,313
ONE OF THE FASCINATING THINGS 

395
00:18:53,313 --> 00:18:55,582
ABOUT ANTI-HMGCR IS THEY'RE AN 

396
00:18:55,582 --> 00:18:57,350
IMPORTANT PART OF MYOSITIS.

397
00:18:57,350 --> 00:19:00,653
IT OCCURS IN THE CONTEXT OF 

398
00:19:00,653 --> 00:19:01,988
ANOTHER RHEUMATOLOGIC DISEASE 

399
00:19:01,988 --> 00:19:03,690
LIKE LUPUS OR RHEUMATOID 

400
00:19:03,690 --> 00:19:03,957
ARTHRITIS.

401
00:19:03,957 --> 00:19:09,462
THESE PATIENTS DON'T HAVE THE 

402
00:19:09,462 --> 00:19:10,396
MYOSITIS SPECIFIC ANTIBODIES BUT

403
00:19:10,396 --> 00:19:11,698
HAVE ASSOCIATED ANTIBODIES.

404
00:19:11,698 --> 00:19:14,868
THEY'RE FOUND IN PATIENTS WITH 

405
00:19:14,868 --> 00:19:18,605
MYOSITIS AND OTHER RHEUMATOLOGIC

406
00:19:18,605 --> 00:19:18,905
CONDITIONS.

407
00:19:18,905 --> 00:19:21,574
THE ONE I'M GOING TO TALK ABOUT 

408
00:19:21,574 --> 00:19:23,510
IS ANTIBODIES RECOGNIZING A 

409
00:19:23,510 --> 00:19:25,612
PROTEIN COMPLEX CALLED PMSCL 

410
00:19:25,612 --> 00:19:30,583
OFTEN FOUND IN PATIENTS WITH A 

411
00:19:30,583 --> 00:19:32,952
SCLERO DERMAPHENOTYPE.

412
00:19:32,952 --> 00:19:36,389
ALL THESE ANTIBODIES I'VE TOLD 

413
00:19:36,389 --> 00:19:37,190
YOU ABOUT RECOGNIZE 

414
00:19:37,190 --> 00:19:39,392
INTRACELLULAR PROTEINS AND HAVE 

415
00:19:39,392 --> 00:19:41,728
BEEN THOUGHT OF FOR THE MOST 

416
00:19:41,728 --> 00:19:43,863
PART AS BIO MARKERS OF THESE 

417
00:19:43,863 --> 00:19:46,399
PHENOTYPES RATHER THAN PLAYING A

418
00:19:46,399 --> 00:19:47,433
PATHOGENIC ROLE.

419
00:19:47,433 --> 00:19:49,769
THAT'S MOSTLY BECAUSE THE 

420
00:19:49,769 --> 00:19:51,604
ANTIBODIES HAVE THOUGHT -- IT'S 

421
00:19:51,604 --> 00:19:53,940
BEEN THOUGHT THEY CAN'T REACH 

422
00:19:53,940 --> 00:19:55,008
THEIR INTRACELLULAR TARGETS.

423
00:19:55,008 --> 00:19:57,610
ONE THING WE'LL TRY TO CONVINCE 

424
00:19:57,610 --> 00:19:59,379
YOU OF TODAY IS THEY DO AND ARE 

425
00:19:59,379 --> 00:20:01,748
LIKELY TO HAVE A PATHOGENIC 

426
00:20:01,748 --> 00:20:02,015
ROLE.

427
00:20:02,015 --> 00:20:06,286
IT WAS REALLY A DIFFERENT 

428
00:20:06,286 --> 00:20:08,655
RESEARCH QUESTION THAT LED US TO

429
00:20:08,655 --> 00:20:10,657
CONSIDER WHETHER AUTOANTIBODIES 

430
00:20:10,657 --> 00:20:11,758
CAN ENTER MUSCLE CELLS.

431
00:20:11,758 --> 00:20:14,127
WE CAME AT IT FROM A DIFFERENT 

432
00:20:14,127 --> 00:20:16,963
DIRECTION WHICH IS TRYING TO 

433
00:20:16,963 --> 00:20:20,166
UNDERSTAND WHETHER SOME GENES 

434
00:20:20,166 --> 00:20:22,101
ARE UNIQUELY EXPRESSED IN THE 

435
00:20:22,101 --> 00:20:25,238
MUSCLE TISSUE OF PATIENTS WHO 

436
00:20:25,238 --> 00:20:33,580
HAVE A PARTICULAR TYPE OF 

437
00:20:33,580 --> 00:20:43,656
AUTOANTIBODY MYOSITIS.

438
00:20:43,656 --> 00:20:49,095
WE HAD 49 PATIENTS WITH 

439
00:20:49,095 --> 00:20:51,531
NECROTIZING MYOSITIS AND SOME 

440
00:20:51,531 --> 00:20:55,168
HAD SRP AND SOME HAD 

441
00:20:55,168 --> 00:21:00,874
DERMATOMYOSITIS AND EACH WITH A 

442
00:21:00,874 --> 00:21:08,681
DEFINED ANTIBODY AND 18 MUSCLE 

443
00:21:08,681 --> 00:21:12,218
BIOPSIES AND ONE FROM A DISEASE 

444
00:21:12,218 --> 00:21:15,021
CALLED INCLUSION BODY MYOSITIS 

445
00:21:15,021 --> 00:21:17,056
AND 20 MUSCLE BODY SPECIMENS 

446
00:21:17,056 --> 00:21:19,659
FROM HEALTHY NORMAL SUBJECTS.

447
00:21:19,659 --> 00:21:21,895
WE DID BULK RNA SEQ.

448
00:21:21,895 --> 00:21:25,431
THE QUESTION WE ASKED ARE THERE 

449
00:21:25,431 --> 00:21:27,867
GENES UNIQUELY EXPRESSED IN ONE 

450
00:21:27,867 --> 00:21:30,203
TYPE OF ANTIBODY DEFINED 

451
00:21:30,203 --> 00:21:30,470
MYOSITIS.

452
00:21:30,470 --> 00:21:32,705
THE REASON WE ASKED THAT TO WHAT

453
00:21:32,705 --> 00:21:34,240
IS UP OR DOWN REGULATED COMPARED

454
00:21:34,240 --> 00:21:37,277
TO NORMAL, WE RECOGNIZED MANY 

455
00:21:37,277 --> 00:21:40,246
GENES DYSREGULATED IN MYOSITIS 

456
00:21:40,246 --> 00:21:41,981
ARE GOING TO BE DYSREGULATED 

457
00:21:41,981 --> 00:21:43,082
BECAUSE THERE'S MUSCLE 

458
00:21:43,082 --> 00:21:44,884
RESTRICTION OR REGENERATION 

459
00:21:44,884 --> 00:21:46,920
GOING ON AND TELL US ABOUT 

460
00:21:46,920 --> 00:21:47,287
PATHOGENESIS.

461
00:21:47,287 --> 00:21:50,690
WE FIGURED IF WE FOCUSSED ON 

462
00:21:50,690 --> 00:21:53,993
THOSE UNIQUE TO A PARTICULAR 

463
00:21:53,993 --> 00:21:57,597
TYPE OF MYOSITIS WE MIGHT GET 

464
00:21:57,597 --> 00:21:58,665
SOME CLUES.

465
00:21:58,665 --> 00:22:01,701
FOR THIS STUDY ONE OF THE KEY 

466
00:22:01,701 --> 00:22:09,609
THINGS THAT STOOD OUT TO US FOR 

467
00:22:09,609 --> 00:22:10,343
THOSE WITH POSITIVE MYOSITIS 

468
00:22:10,343 --> 00:22:13,880
THEY HAD A UNIQUE SET OF 135 

469
00:22:13,880 --> 00:22:15,615
GENES NOT UPREGULATED IN OTHER 

470
00:22:15,615 --> 00:22:18,284
TYPES OF MYOSITIS OR NORMAL 

471
00:22:18,284 --> 00:22:18,651
TISSUE.

472
00:22:18,651 --> 00:22:23,156
SO 135 GENES THAT DEFINED 

473
00:22:23,156 --> 00:22:25,091
SOMETHING UNIQUE ABOUT THE 

474
00:22:25,091 --> 00:22:27,994
MUSCLE TISSUE MUCH PATIENTS WITH

475
00:22:27,994 --> 00:22:36,302
THE MYOSITIS.

476
00:22:36,302 --> 00:22:39,005
AND HERE'S AN UPREGULATED GENE 

477
00:22:39,005 --> 00:22:40,907
AND IT'S A TRANSCRIPTOMIC 

478
00:22:40,907 --> 00:22:44,377
REPRESSOR AND HERE YOU GOT THE 

479
00:22:44,377 --> 00:22:48,681
VALUES OF EXPRESSION OF SER21 IN

480
00:22:48,681 --> 00:22:50,650
NORMAL TISSUE AND THE MUSCLE 

481
00:22:50,650 --> 00:22:52,952
BIOPSIES WITH EACH DOT 

482
00:22:52,952 --> 00:22:55,154
REPRESENTING THE EXPRESSION AND 

483
00:22:55,154 --> 00:23:01,961
MUSCLE BIOPSY AND PATIENTS WITH 

484
00:23:01,961 --> 00:23:06,399
OTHER AUTOANTIBODIES AT THE GENE

485
00:23:06,399 --> 00:23:08,601
EXPRESSION LEVEL IT'S ONLY 

486
00:23:08,601 --> 00:23:12,138
EXPRESSED IN THE ANTI-MI2 

487
00:23:12,138 --> 00:23:13,106
SPECIFIC MUSCLE BIOPSIES.

488
00:23:13,106 --> 00:23:15,174
WE WANTED TO SEE IF IT WAS 

489
00:23:15,174 --> 00:23:17,844
TRANSLATED TO PROTEINS AND IT 

490
00:23:17,844 --> 00:23:18,111
IS.

491
00:23:18,111 --> 00:23:21,614
THE STAINING BY 

492
00:23:21,614 --> 00:23:23,082
IMMUNOFLUORESCENCE SHOWED IT'S 

493
00:23:23,082 --> 00:23:25,985
ONLY FOUND IN ANTI-MI2 POSITIVE 

494
00:23:25,985 --> 00:23:29,856
MUSCLE TISSUE AND HAS A NUCLEAR 

495
00:23:29,856 --> 00:23:32,458
LOCALIZATION PREDOMINANTLY AS WE

496
00:23:32,458 --> 00:23:33,393
WOULD EXPECT.

497
00:23:33,393 --> 00:23:37,163
SO WE ALSO LOOKED TO SEE IF 

498
00:23:37,163 --> 00:23:38,498
THERE WAS CORRELATION BETWEEN 

499
00:23:38,498 --> 00:23:44,037
THE EXPRESSION OF SRT1 AND 

500
00:23:44,037 --> 00:23:44,837
MUSCLE BIOPSIES.

501
00:23:44,837 --> 00:23:47,840
YOU SEE A RELATIVELY NORMAL 

502
00:23:47,840 --> 00:23:49,542
MUSCLE BIOPSY MORE NORMAL THAN 

503
00:23:49,542 --> 00:23:54,781
THE REST WITH VERY LITTLE SER21 

504
00:23:54,781 --> 00:23:56,582
EXPRESSION AND 0.0.

505
00:23:56,582 --> 00:24:01,587
MOVING RIGHT TO LEVEL AND HERE 

506
00:24:01,587 --> 00:24:03,423
YOU SEE INCREASING EXPRESSION 

507
00:24:03,423 --> 00:24:05,758
LEVELS OF SER21.

508
00:24:05,758 --> 00:24:09,162
AS THE EXPRESSION LEVELS OF SEV 

509
00:24:09,162 --> 00:24:11,497
ERT1 INCREASED YOU GET MORE AND 

510
00:24:11,497 --> 00:24:12,098
MORE MUSCLE DAMAGE.

511
00:24:12,098 --> 00:24:13,066
THERE'S A CORRELATION BETWEEN 

512
00:24:13,066 --> 00:24:14,534
THE AMOUNT OF DAMAGE AND THE 

513
00:24:14,534 --> 00:24:15,735
EXPRESSION OF THIS GENE.

514
00:24:15,735 --> 00:24:19,205
THE OTHER THING WE FOUND IS THAT

515
00:24:19,205 --> 00:24:21,974
THE SER T1 EXPRESSION LEVELS IN 

516
00:24:21,974 --> 00:24:23,376
AN INDIVIDUAL MUSCLE BIOPSIES 

517
00:24:23,376 --> 00:24:26,446
ARE CORRELATED WITH THE ANTI-MI2

518
00:24:26,446 --> 00:24:27,880
ANTIBODY LEVELS IN THE SERUM OF 

519
00:24:27,880 --> 00:24:29,882
THE PATIENTS THAT THE MUSCLE 

520
00:24:29,882 --> 00:24:31,050
BIOPSIES CAME FROM.

521
00:24:31,050 --> 00:24:34,821
THERE'S A LINK THERE AS WELL.

522
00:24:34,821 --> 00:24:37,790
SO THE NEXT THING WE DID WAS 

523
00:24:37,790 --> 00:24:40,626
THINK WELL, WHAT IS IT SRT1 AND 

524
00:24:40,626 --> 00:24:43,229
THE OTHER GENES INCLUDED IN THE 

525
00:24:43,229 --> 00:24:44,931
MIT2 POSITIVE IS SPECIFIC GENE 

526
00:24:44,931 --> 00:24:48,568
SET WHAT DO THEY HAVE IN COMMON?

527
00:24:48,568 --> 00:24:50,436
AND WE STARTED THINKING ABOUT, 

528
00:24:50,436 --> 00:24:53,739
WELL, WHAT IS THE FUNCTION OF 

529
00:24:53,739 --> 00:25:00,580
MIT AND WHAT DO THE ANTI-MI2 

530
00:25:00,580 --> 00:25:02,648
ANTIBODIES RECOGNIZE?

531
00:25:02,648 --> 00:25:05,551
THEY RECOGNIZE MI2 ALPHA AND 

532
00:25:05,551 --> 00:25:07,854
BETA BOTH IN THE NUCLEUS AND 

533
00:25:07,854 --> 00:25:09,388
BOTH ARE COMPONENTS OF THE 

534
00:25:09,388 --> 00:25:19,866
NUCLEOSOME REMODELLING AND

535
00:25:30,042 --> 00:25:30,610
DECEYTLATION AND WE LOOKED HOW 

536
00:25:30,610 --> 00:25:31,244
IT'S EXPRESSED IN MUSCLE TISSUE.

537
00:25:31,244 --> 00:25:39,619
WE FOUND THE AND IT'S ENRICHED 

538
00:25:39,619 --> 00:25:40,686
FOR GENES KNOWN TO BE REPRESSED 

539
00:25:40,686 --> 00:25:41,420
BY THE COMPLEX.

540
00:25:41,420 --> 00:25:44,157
WE GOT THE IDEA MAYBE THE 

541
00:25:44,157 --> 00:25:45,625
ANTIBODIES ARE SOMEHOW 

542
00:25:45,625 --> 00:25:48,561
DISRUPTING THE FUNCTION OF MI2 

543
00:25:48,561 --> 00:25:51,631
COMPLEX AND ALLOWING THE GENES 

544
00:25:51,631 --> 00:25:52,398
TO BE EXPRESSED WHICH ARE NORM 

545
00:25:52,398 --> 00:26:01,407
HI REPRESSED BY THE COMPLEX.

546
00:26:01,407 --> 00:26:02,942
THIS ONLY WORKS IF THEY GET IN 

547
00:26:02,942 --> 00:26:06,779
THE MUSCLE CELLS AND WE ALL KNEW

548
00:26:06,779 --> 00:26:11,050
THAT DOESN'T HAPPEN.

549
00:26:11,050 --> 00:26:12,318
IMMUNOGLOBULIN IS A LARGE CELL 

550
00:26:12,318 --> 00:26:14,787
AND CAN'T GET IN MUSCLE CELLS.

551
00:26:14,787 --> 00:26:17,957
WE DECIDED TO LOOK ANYWAY TO SEE

552
00:26:17,957 --> 00:26:19,659
WHAT WE CAN SEE.

553
00:26:19,659 --> 00:26:22,495
WE WOUND UP DOING DIRECT 

554
00:26:22,495 --> 00:26:26,832
IMMUNOFLUORESCENCE AND USED AN 

555
00:26:26,832 --> 00:26:28,367
ANTI-IMMUNOGLOBULIN AGAINST IGG 

556
00:26:28,367 --> 00:26:30,036
LABELLED GREEN AND LOOKED TO SEE

557
00:26:30,036 --> 00:26:33,673
WHAT THE DISTRIBUTION OF 

558
00:26:33,673 --> 00:26:36,409
IMMUNOGLOBULIN WAS IN PATIENTS 

559
00:26:36,409 --> 00:26:46,819
WITH THE MI-2 POSITIVE 

560
00:26:57,597 --> 00:26:58,631
DERMATOMYOSITIS AND HERE YOU SEE

561
00:26:58,631 --> 00:27:03,669
THE IMMUNOGLOBULIN AND THIS IS 

562
00:27:03,669 --> 00:27:05,538
THE NUCLEUS.

563
00:27:05,538 --> 00:27:09,008
THE IMMUNOGLOBULIN IS 

564
00:27:09,008 --> 00:27:11,510
ACCUMULATING IN THE MUSCLES AND 

565
00:27:11,510 --> 00:27:17,250
THIS IS REPRODUCIBLE AND ROBUST.

566
00:27:17,250 --> 00:27:21,654
YOU SEE IT JUST IN THE NUCLEI IN

567
00:27:21,654 --> 00:27:23,889
THE PATIENTS BUT NOT HEALTHY 

568
00:27:23,889 --> 00:27:24,156
CONTROLS.

569
00:27:24,156 --> 00:27:25,658
THAT WAS INTRIGUING.

570
00:27:25,658 --> 00:27:28,961
WE WANTED TO PROVE THE 

571
00:27:28,961 --> 00:27:31,564
ANTIBODIES CAN CAUSE THIS 

572
00:27:31,564 --> 00:27:32,231
DYSREGULATED EXPRESSION OF THE 

573
00:27:32,231 --> 00:27:33,966
GENE SET WE SEE IN THE PATIENTS 

574
00:27:33,966 --> 00:27:37,270
WITH ANTI-MI2 POSITIVE 

575
00:27:37,270 --> 00:27:37,637
DERMATOMYOSITIS.

576
00:27:37,637 --> 00:27:42,108
HOW CAN WE DO THAT?

577
00:27:42,108 --> 00:27:45,378
WE FOUND UP GROWING HUMAN 

578
00:27:45,378 --> 00:27:47,680
MYOBLASTS IN CULTURE AND BATHING

579
00:27:47,680 --> 00:27:51,017
THEM IN THE IMMUNOGLOBULIN FROM 

580
00:27:51,017 --> 00:27:52,285
AN INDIVIDUAL PATIENT AND THEN 

581
00:27:52,285 --> 00:27:54,587
MAKE SURE IT GOT IN THE CELLS.

582
00:27:54,587 --> 00:28:02,194
TO DO THAT WE ELECTROPOREATED 

583
00:28:02,194 --> 00:28:04,797
THE CELLS AND GOT IN THE FIBERS 

584
00:28:04,797 --> 00:28:07,533
AND THE CELLS SEAL UP AND THEN 

585
00:28:07,533 --> 00:28:10,403
DO BULK RNA SEQ ON THE CELLS 

586
00:28:10,403 --> 00:28:13,306
GROWING IN CULTURE WITH 

587
00:28:13,306 --> 00:28:14,907
INTERNALIZED ANTIBODIES AND SEE 

588
00:28:14,907 --> 00:28:17,343
THE FULL SET AND SEE IF THERE'S 

589
00:28:17,343 --> 00:28:20,546
DYSREGULATED GENE EXPRESSION AS 

590
00:28:20,546 --> 00:28:22,415
A CONSEQUENCE OF INTERNALIZING 

591
00:28:22,415 --> 00:28:23,549
THE ANTIBODY.

592
00:28:23,549 --> 00:28:27,653
WE DID THIS USING THE 

593
00:28:27,653 --> 00:28:28,354
IMMUNOGLOBULIN AND EACH COLUMN 

594
00:28:28,354 --> 00:28:30,756
IS THE EXPRESSION OF A GENE SET 

595
00:28:30,756 --> 00:28:31,691
FROM AN INDIVIDUAL PATIENT.

596
00:28:31,691 --> 00:28:39,398
THE GENE SET WE'RE LOOKING AT IS

597
00:28:39,398 --> 00:28:43,202
ALL THE GENES OVER EXPRESSED IN 

598
00:28:43,202 --> 00:28:45,938
THE PATIENTS AND SER21 AND THE 

599
00:28:45,938 --> 00:28:49,208
NEXT TOP 19 OR 20 OF THE 135 

600
00:28:49,208 --> 00:28:49,742
GENE SET.

601
00:28:49,742 --> 00:28:54,146
HERE WE HAVE INDIVIDUAL CONTROLS

602
00:28:54,146 --> 00:28:55,181
INTERNALIZED AND THEN FIVE 

603
00:28:55,181 --> 00:29:01,954
DIFFERENT IMMUNOGLOBULIN FROM 

604
00:29:01,954 --> 00:29:09,295
PATIENTS AND IMMUNOGLOBULIN FROM

605
00:29:09,295 --> 00:29:16,402
OTHER ANTIBODIES AND 

606
00:29:16,402 --> 00:29:17,370
ANTISNTHETASE AND THOSE 

607
00:29:17,370 --> 00:29:19,805
OVEREXPRESSED THE SAME GENE SET 

608
00:29:19,805 --> 00:29:21,640
THAT IS FOUND IN THE MUSCLE 

609
00:29:21,640 --> 00:29:32,118
TISSUE FROM THOSE PATIENTS.

610
00:29:41,894 --> 00:29:44,330
WE WANTED TO SEE WHAT PART IS 

611
00:29:44,330 --> 00:29:45,297
RECOGNIZED BY THE ANTIBODIES.

612
00:29:45,297 --> 00:29:48,768
THIS IS WORK WE DID WITH BEN 

613
00:29:48,768 --> 00:29:52,138
LARMON AT JOHNS HOPKINS AND DOES

614
00:29:52,138 --> 00:29:57,143
PHAGE IMMUNOPRECIPITATION 

615
00:29:57,143 --> 00:30:00,379
SEQUENCING AND SUFFICE TO SAY IS

616
00:30:00,379 --> 00:30:08,154
YOU CREATE A LIBRARY WHERE EACH 

617
00:30:08,154 --> 00:30:10,956
IS DISPLAYED IN THE HUMAN 

618
00:30:10,956 --> 00:30:19,665
SEGMENT OF ALL THE PROTEOMES AND

619
00:30:19,665 --> 00:30:20,599
THEY'RE STAGGERED WITH 

620
00:30:20,599 --> 00:30:23,636
OVERLAPPING PEP SIDES.

621
00:30:23,636 --> 00:30:27,440
YOU ADD YOUR MIXTURE AND SINCE 

622
00:30:27,440 --> 00:30:33,078
YOU DON'T HAVE AUTOANTIBODIES 

623
00:30:33,078 --> 00:30:33,979
AND THEY'LL RECOGNIZE A 

624
00:30:33,979 --> 00:30:36,782
PARTICULAR FAITH YOU CAN 

625
00:30:36,782 --> 00:30:38,284
PRECIPITATE IT AND DO DNA 

626
00:30:38,284 --> 00:30:41,153
SEQUENCING AND IDENTIFY THE 

627
00:30:41,153 --> 00:30:43,722
REGION OF THE FULL LENGTH 

628
00:30:43,722 --> 00:30:44,990
PROTEIN RECOGNIZED BY THE 

629
00:30:44,990 --> 00:30:45,491
AUTOANTIBODIES.

630
00:30:45,491 --> 00:30:48,794
WHAT WE FOUND WITH PATIENTS WITH

631
00:30:48,794 --> 00:30:51,664
ANTI-MI2 IS THERE'S AN 

632
00:30:51,664 --> 00:30:53,432
IMMUNODOMINANT EPITOPE THAT 

633
00:30:53,432 --> 00:31:00,940
RECOGNIZE BOTH MIT ALMA  -- 

634
00:31:00,940 --> 00:31:06,178
ALPHA AND BETA A.

635
00:31:06,178 --> 00:31:09,448
AND WHAT IS INTERESTING ABOUT 

636
00:31:09,448 --> 00:31:19,825
THIS IS AND THIS LINE TO THE PH1

637
00:31:19,825 --> 00:31:22,394
ONE DOMAIN AND THE REGION IS 

638
00:31:22,394 --> 00:31:25,498
CRITICAL FOR ENABLING IT TO 

639
00:31:25,498 --> 00:31:29,134
RECOGNIZE HISTOMODIFICATIONS AND

640
00:31:29,134 --> 00:31:32,705
REGULATION THE TARGET GENE 

641
00:31:32,705 --> 00:31:33,005
EXPRESSION.

642
00:31:33,005 --> 00:31:41,313
Ph.D  -- PHD1 ALLOWS IT TO 

643
00:31:41,313 --> 00:31:41,814
REGULATE THE GENE SET.

644
00:31:41,814 --> 00:31:44,517
BASED ON THIS WE HAVE A MODEL 

645
00:31:44,517 --> 00:31:47,553
FOR HOW WE THINK AUTOANTIBODIES 

646
00:31:47,553 --> 00:31:50,189
AGAINST MIT MAY BE PATHOGENIC.

647
00:31:50,189 --> 00:31:59,565
THIS IS MY RUDE UMENT RYUMENTRY 

648
00:31:59,565 --> 00:32:01,967
RUDIMENTARY AND THE GENOME 

649
00:32:01,967 --> 00:32:06,672
INCLUDES GENES INCLUDING SERT1 

650
00:32:06,672 --> 00:32:12,278
AND THE TRANSCRIPTION IS 

651
00:32:12,278 --> 00:32:14,013
REPRESSED BY THE NURD COMPLEX.

652
00:32:14,013 --> 00:32:17,950
AND FOR REASONS NOT WELL KNOWN, 

653
00:32:17,950 --> 00:32:20,119
SOME PATIENTS DEVELOP 

654
00:32:20,119 --> 00:32:21,153
AUTOANTIBODIES AND WE'VE SHOWN 

655
00:32:21,153 --> 00:32:23,122
THEY CAN GET INTO THE NUCLEUS 

656
00:32:23,122 --> 00:32:25,224
AND OUR MODEL IS THEY BIND TO 

657
00:32:25,224 --> 00:32:32,097
THE MIT COMPLEX PROBABLY AT THE 

658
00:32:32,097 --> 00:32:35,234
PHD DOMAIN AND THAT ALLOWS FOR 

659
00:32:35,234 --> 00:32:38,237
THE TRANSCRIPTION OF THE GENE 

660
00:32:38,237 --> 00:32:41,407
AND THE EXPRESSION OF SERT T1 

661
00:32:41,407 --> 00:32:43,809
PROTEIN AND OUR HYPOTHESIS IS 

662
00:32:43,809 --> 00:32:45,377
THAT IS CAUSING DAMAGE TO THE 

663
00:32:45,377 --> 00:32:47,513
MUSCLE FIBERS AND CONTRIBUTING 

664
00:32:47,513 --> 00:32:50,816
TO THE PATHOGENESIS OF THE 

665
00:32:50,816 --> 00:32:51,517
DISEASE.

666
00:32:51,517 --> 00:32:54,053
THOUGH WE STILL HAVE TO DO A 

667
00:32:54,053 --> 00:32:57,523
BETTER JOB DEMONSTRATING THE 

668
00:32:57,523 --> 00:32:57,790
CASE.

669
00:32:57,790 --> 00:33:01,026
ARE THERE OTHER MYOSITIS 

670
00:33:01,026 --> 00:33:03,295
ANTIBODIES THAN CAN GET IN CELLS

671
00:33:03,295 --> 00:33:05,965
AND DISRUPT THEIR FUNCTION 

672
00:33:05,965 --> 00:33:06,231
PROTEINS.

673
00:33:06,231 --> 00:33:08,400
WHEN WE DID IMMUNOFLUORESCENCE 

674
00:33:08,400 --> 00:33:11,203
FROM THE PATIENTS WITH THE 

675
00:33:11,203 --> 00:33:12,905
DIFFERENT TYPES OF MYOSITIS 

676
00:33:12,905 --> 00:33:15,040
ANTIBODIES WE FOUND 

677
00:33:15,040 --> 00:33:16,442
IMMUNOGLOBULIN ALWAYS GETS 

678
00:33:16,442 --> 00:33:19,144
CO-LOCALIZED WITH THE TARGET 

679
00:33:19,144 --> 00:33:19,411
PROTEINS.

680
00:33:19,411 --> 00:33:25,551
I SHOWED YOU THIS THE NUCLEUS IS

681
00:33:25,551 --> 00:33:32,925
WHERE IMMUNOGLOBULIN FOR THOSE 

682
00:33:32,925 --> 00:33:37,696
WHO HAVE IT LOCALIZE AND 

683
00:33:37,696 --> 00:33:40,132
PATIENTS WITH ANTIBODIES AGAINST

684
00:33:40,132 --> 00:33:45,671
INTRACELLULAR TARGETS FROM 

685
00:33:45,671 --> 00:33:49,975
IMMUNOGLOBULIN -- IF THEY'RE 

686
00:33:49,975 --> 00:33:59,084
CYTOPLASMIC NOT NUCLEAR, THE  

687
00:33:59,084 --> 00:34:00,386
IMMUNOGLOBULIN GOES TO WHERE THE

688
00:34:00,386 --> 00:34:02,187
TARGET ANTIGEN IS.

689
00:34:02,187 --> 00:34:05,924
I WANT TO SHOW YOU ONE MORE 

690
00:34:05,924 --> 00:34:08,027
EXAMPLE OF HOW THE 

691
00:34:08,027 --> 00:34:10,963
AUTOANTIBODIES CAN DISRUPT THE 

692
00:34:10,963 --> 00:34:11,330
FUNCTION.

693
00:34:11,330 --> 00:34:14,366
THESE ARE ANTIANTIBODIES FOR 

694
00:34:14,366 --> 00:34:17,603
PEOPLE WITH SCLERO DERMA-AND 

695
00:34:17,603 --> 00:34:19,705
MIXED CONNECTED TISSUE DISEASE 

696
00:34:19,705 --> 00:34:21,573
AND THEY'RE UNIQUE IN THAT THEY 

697
00:34:21,573 --> 00:34:23,709
HAVE MORE SEVERE WEAKNESS IN 

698
00:34:23,709 --> 00:34:24,810
THEIR ARMS THAN LEGS.

699
00:34:24,810 --> 00:34:29,281
THAT'S THE OPPOSITE OF OTHER 

700
00:34:29,281 --> 00:34:29,548
PATIENTS.

701
00:34:29,548 --> 00:34:32,151
THEY HAVE MANY MORE EXTRA MUSS 

702
00:34:32,151 --> 00:34:33,118
LAR MANIFESTATIONS COMPARED TO 

703
00:34:33,118 --> 00:34:36,121
OTHER PATIENTS I TOLD YOU ABOUT 

704
00:34:36,121 --> 00:34:40,159
INCLUDING THEY OFTEN HAVE SKIN 

705
00:34:40,159 --> 00:34:40,492
MANIFESTATION.

706
00:34:40,492 --> 00:34:42,528
WHAT DO ANTIBIOTICEDS RECOGNIZE?

707
00:34:42,528 --> 00:34:47,833
THEY RECOGNIZE TWO SUB UNITS.

708
00:34:47,833 --> 00:34:51,203
EXO C9 AND 10 OF THE NUCLEAR RNA

709
00:34:51,203 --> 00:34:52,404
EXPOSOME COMPLEX AND WHAT'S IT 

710
00:34:52,404 --> 00:34:52,638
DO?

711
00:34:52,638 --> 00:34:59,611
THE NORMAL DPUNG  AL FUNCTION I 

712
00:34:59,611 --> 00:35:01,480
DEGRADE LONG CODING RNAs.

713
00:35:01,480 --> 00:35:04,349
THAT'S A MAJOR FUNCTION.

714
00:35:04,349 --> 00:35:11,256
WE SAW THE IMMUNOGLOBULIN 

715
00:35:11,256 --> 00:35:14,259
ACCUMULATES IN THE NUCLEI.

716
00:35:14,259 --> 00:35:19,131
EACH HAVE IMMUNOGLOBULIN 

717
00:35:19,131 --> 00:35:24,269
DEPOSITION AND APPEARS TO HAVE A

718
00:35:24,269 --> 00:35:24,670
NUCLEAR POWER.

719
00:35:24,670 --> 00:35:27,706
WE DID A SIMILAR STUDY AS 

720
00:35:27,706 --> 00:35:33,512
PRESENTED ALREADY FOR MI2 AND 

721
00:35:33,512 --> 00:35:35,047
INCLUDE 669 MUSCLE ANTIBODIES 

722
00:35:35,047 --> 00:35:36,815
AND WE'RE NOW ASKING THE 

723
00:35:36,815 --> 00:35:39,685
QUESTION ARE THERE GENES THAT 

724
00:35:39,685 --> 00:35:43,589
ARE ONLY DYSREGULATED IN MUSCLE 

725
00:35:43,589 --> 00:35:46,525
BIOPSIES IN PATIENTS WITH THIS 

726
00:35:46,525 --> 00:35:47,626
AND THERE ARE 236 GENES.

727
00:35:47,626 --> 00:35:51,163
THERE ARE ONLY UPREGULATED IN 

728
00:35:51,163 --> 00:35:52,931
ANTI-PMSCL NOT THE OTHER TYPES 

729
00:35:52,931 --> 00:35:54,833
OF MYOSITIS OR HEALTHY CONTROLS.

730
00:35:54,833 --> 00:35:58,704
I'LL SHOW A LIST OF THE TOP 20 

731
00:35:58,704 --> 00:36:01,974
OR SO AND YOU PROBABLY DON'T 

732
00:36:01,974 --> 00:36:03,542
RECOGNIZE THE NAMES BECAUSE 

733
00:36:03,542 --> 00:36:06,845
THEY'RE ALL NUMBERS BECAUSE THE 

734
00:36:06,845 --> 00:36:10,582
TOP 20 AND GOING DOWN THE LIST 

735
00:36:10,582 --> 00:36:15,754
INTO THE 200s IS ALMOST 

736
00:36:15,754 --> 00:36:17,122
EXCLUSIVELY NOT LONG ENCODING 

737
00:36:17,122 --> 00:36:19,825
RNAs AND NON-DIVERGENT 

738
00:36:19,825 --> 00:36:21,460
TRANSCRIPTS AND THESE ARE THE 

739
00:36:21,460 --> 00:36:27,766
GENES NORMALLY DEGRADED BY 

740
00:36:27,766 --> 00:36:27,966
PMSCL.

741
00:36:27,966 --> 00:36:32,137
OUR HYPOTHESIS WAS BINDING TO 

742
00:36:32,137 --> 00:36:36,141
THE NUCLEAR EXPOSOME AND LEAD TO

743
00:36:36,141 --> 00:36:38,577
THE SURVIVAL OF LONG CODING RNAs

744
00:36:38,577 --> 00:36:40,612
AND DIVERGENT TRANSCRIPTS.

745
00:36:40,612 --> 00:36:41,980
AGAIN WE WANTED TO PROVE THE 

746
00:36:41,980 --> 00:36:43,682
ANTIBODIES CAN HAVE THE EFFECT 

747
00:36:43,682 --> 00:36:45,684
IN CULTURED MYOBLASTS.

748
00:36:45,684 --> 00:36:47,519
THIS IS BASICALLY THE SAME 

749
00:36:47,519 --> 00:36:48,120
EXPERIMENT.

750
00:36:48,120 --> 00:36:54,059
WE TAKE THE HUMAN MYOBLAST AND 

751
00:36:54,059 --> 00:36:55,627
BATHE THEM AND CREATE PORES AND 

752
00:36:55,627 --> 00:36:59,731
LET THE ANTIBODIES GET IN AND DO

753
00:36:59,731 --> 00:37:00,933
BULK RNA SEQ.

754
00:37:00,933 --> 00:37:03,001
THIS BASICALLY THE SAME 

755
00:37:03,001 --> 00:37:03,769
EXPERIMENT AS BEFORE ONLY NOW 

756
00:37:03,769 --> 00:37:07,206
THE GENES LISTED ON THE RIGHT 

757
00:37:07,206 --> 00:37:10,475
ARE THE TOP 20 GENES ONLY FOUND 

758
00:37:10,475 --> 00:37:13,979
IN MUSCLE BIOPSIES FROM PATIENTS

759
00:37:13,979 --> 00:37:18,617
WITH ANTI-PMSCL AND NOT LONG 

760
00:37:18,617 --> 00:37:22,821
ENCODING RNAs AND DIVERGENT 

761
00:37:22,821 --> 00:37:23,922
TRANSCRIPTS.

762
00:37:23,922 --> 00:37:26,225
WHEN WE INTERNALIZE THE 

763
00:37:26,225 --> 00:37:29,294
ANTIBODIES INTO THE MYOBLASTS WE

764
00:37:29,294 --> 00:37:32,264
GET HIGH LEVELS OF EXPRESSION OF

765
00:37:32,264 --> 00:37:34,800
THAT PMSCL SPECIFIC GENE SET AND

766
00:37:34,800 --> 00:37:38,670
DON'T SOO THE SAME WHEN WE 

767
00:37:38,670 --> 00:37:39,504
INTERNALIZE FROM OTHER MYOSITIS 

768
00:37:39,504 --> 00:37:41,306
OR HEALTHY CONTROLS.

769
00:37:41,306 --> 00:37:45,777
IT'S A VERY SPECIFIC EFFECT %F 

770
00:37:45,777 --> 00:37:48,280
THE ANTIBODIES AND THE 

771
00:37:48,280 --> 00:37:52,251
EXPRESSION OF THESE GENES IN 

772
00:37:52,251 --> 00:37:54,987
CULTURED CELL AND TISSUES.

773
00:37:54,987 --> 00:37:58,423
WE HAVE A MYOSITIS WHERE 

774
00:37:58,423 --> 00:38:00,826
PATIENTS DEVELOP THE 

775
00:38:00,826 --> 00:38:02,594
AUTOANTIBODIES.

776
00:38:02,594 --> 00:38:07,165
NORMALLY THE EXOSOME DEGRADES 

777
00:38:07,165 --> 00:38:09,835
THE LONG-ENCODING RNAs.

778
00:38:09,835 --> 00:38:12,437
SOMEHOW THEY GET IN AND CAN SEE 

779
00:38:12,437 --> 00:38:13,372
THEM IN THE MUSCLE TISSUE.

780
00:38:13,372 --> 00:38:15,741
OUR HYPOTHESIS IS THEY DISRUPT 

781
00:38:15,741 --> 00:38:19,244
THE ABILITY OF THE NUCLEAR 

782
00:38:19,244 --> 00:38:21,947
COMPLEX TO DEGRADE THESE LONG 

783
00:38:21,947 --> 00:38:24,182
ENCODING RNAs AND THAT RESULTS 

784
00:38:24,182 --> 00:38:26,718
IN THEIR OVER EXPRESSION.

785
00:38:26,718 --> 00:38:33,525
AGAIN, WE HYPOTHESIZE THAT IS AN

786
00:38:33,525 --> 00:38:35,861
IMPORTANT PART OF THE 

787
00:38:35,861 --> 00:38:36,461
PATHOGENESIS AND ACCOUNTS FOR 

788
00:38:36,461 --> 00:38:40,966
WHY PATIENTS HAVE A UNIQUE 

789
00:38:40,966 --> 00:38:41,466
PHENOTYPE.

790
00:38:41,466 --> 00:38:43,669
THE QUESTION CAN THEY GET TO 

791
00:38:43,669 --> 00:38:44,569
OTHER CELL TYPES.

792
00:38:44,569 --> 00:38:48,373
WE STARTED EXPLORING THIS AND 

793
00:38:48,373 --> 00:38:49,975
HAPPEN TO HAVE SKIN BIOPSY 

794
00:38:49,975 --> 00:38:59,051
TISSUE FROM AN PATIENT.

795
00:38:59,051 --> 00:39:01,186
IMMUNOGLOBULIN IS STAINED AND 

796
00:39:01,186 --> 00:39:04,589
YOU SEE IT'S ACCUMULATING IN THE

797
00:39:04,589 --> 00:39:04,823
NUCLEI.

798
00:39:04,823 --> 00:39:07,826
WE THINK IT'S THE SAME AS IN 

799
00:39:07,826 --> 00:39:10,295
MUSCLE TISSUE WHERE THE 

800
00:39:10,295 --> 00:39:11,730
IMMUNOGLOBULIN IS ACCUMULATING 

801
00:39:11,730 --> 00:39:12,898
IN THE NUCLEI.

802
00:39:12,898 --> 00:39:14,566
NOT JUST IN THE MUSCLE BUT IN 

803
00:39:14,566 --> 00:39:15,767
THE SKIN AND WE'RE DOING FURTHER

804
00:39:15,767 --> 00:39:19,771
WORK ON THAT.

805
00:39:19,771 --> 00:39:21,773
HOPEFULLY I'VE CONVINCED YOU AT 

806
00:39:21,773 --> 00:39:24,376
LEAST IN MYOSITIS FOR THE 

807
00:39:24,376 --> 00:39:25,677
SAMPLES I'VE SHOWN YOU AND CAN 

808
00:39:25,677 --> 00:39:27,612
SHOW YOU SAMPLES FROM OTHER 

809
00:39:27,612 --> 00:39:29,348
ANTIBODIES AS WELL, HOPEFULLY 

810
00:39:29,348 --> 00:39:30,682
I'VE CONVINCED YOU THE 

811
00:39:30,682 --> 00:39:32,617
ANTIBODIES GET INTO CELLS, REACH

812
00:39:32,617 --> 00:39:34,653
THEIR INTRACELLULAR TARGETS AND 

813
00:39:34,653 --> 00:39:35,354
DISRUPT THEIR FUNCTION.

814
00:39:35,354 --> 00:39:38,824
WHAT I ALSO WANT TO MENTION IS 

815
00:39:38,824 --> 00:39:44,429
THAT WHEN WE LOOKED AT THE 

816
00:39:44,429 --> 00:39:49,968
HISTORY OF THIS TURNS OUT 

817
00:39:49,968 --> 00:39:51,770
THEY'RE INTERNALIZED HAS BEEN 

818
00:39:51,770 --> 00:40:00,345
AROUND FOR THE LUPUS FIELD AND 

819
00:40:00,345 --> 00:40:03,081
THERE'S NUMEROUS EXAMPLES AND 

820
00:40:03,081 --> 00:40:08,587
LUPUS ANTIBODIES SUCH AS THOSE 

821
00:40:08,587 --> 00:40:10,922
AGAINST DOUBLE STRANDED DNA ALL 

822
00:40:10,922 --> 00:40:16,094
CAN PENETRATE CELLS AND LOCALIZE

823
00:40:16,094 --> 00:40:16,461
INTRACELLULARLY.

824
00:40:16,461 --> 00:40:17,462
THOUGH IT'S BEEN LESS CLEAR WHAT

825
00:40:17,462 --> 00:40:20,399
THE RESULT OF THAT IS.

826
00:40:20,399 --> 00:40:29,941
HOUR ANTIRIBOSOMAL ANTIBODIES 

827
00:40:29,941 --> 00:40:34,646
COULD DISRUPT PROTEIN SYNTHESIS 

828
00:40:34,646 --> 00:40:37,049
AND THEY CAN ACTIVATE IMMUNE 

829
00:40:37,049 --> 00:40:44,089
CELLS AND ACTUALLY INDUCE A P

830
00:40:44,089 --> 00:40:47,559
POPTOSIS AND IT'S BEEN KNOWN HOW

831
00:40:47,559 --> 00:40:50,062
IT OCCURS FOR SOME LUPUS 

832
00:40:50,062 --> 00:40:50,862
ANTIBODIES.

833
00:40:50,862 --> 00:40:57,235
THERE'S A MOUSE MODEL OF LUPUS 

834
00:40:57,235 --> 00:41:01,840
AND IT THEY'RE A DOUBLE STRANDED

835
00:41:01,840 --> 00:41:05,544
DNA MONOCLONAL ANTIBODY HAS BEEN

836
00:41:05,544 --> 00:41:11,550
STUDIED CAREFULLY AND THIS MOUSE

837
00:41:11,550 --> 00:41:12,184
DOUBLE-STRANDED DNA ANTIBODY 

838
00:41:12,184 --> 00:41:14,286
BINDS EXTRA CELLULAR DNA AND 

839
00:41:14,286 --> 00:41:17,522
THEN IT IS TRANSPORTED ACROSS 

840
00:41:17,522 --> 00:41:21,693
THE CELL MEMBRANE BY A PROTEIN 

841
00:41:21,693 --> 00:41:25,964
AND ACTIVELY TRANSPORTED IN AND 

842
00:41:25,964 --> 00:41:29,367
ONCE INSIDE THE CELL DOUBLE 

843
00:41:29,367 --> 00:41:30,569
STRANDED DNA ANTIBODIES CAN BIND

844
00:41:30,569 --> 00:41:34,539
AND GET IN THE NUCLEUS, BIND THE

845
00:41:34,539 --> 00:41:36,541
CHROMATIN WHERE THEY INHIBIT DNA

846
00:41:36,541 --> 00:41:36,975
REPAIR.

847
00:41:36,975 --> 00:41:39,344
SO THIS IDEA IN SOME OF THE 

848
00:41:39,344 --> 00:41:41,446
MECHANISMS FOR HOW ANTIBODIES 

849
00:41:41,446 --> 00:41:44,349
ENTER CELLS HAS BEEN WORKED OUT 

850
00:41:44,349 --> 00:41:45,951
FOR SOME OF THESE LUPUS 

851
00:41:45,951 --> 00:41:46,651
ANTIBODIES.

852
00:41:46,651 --> 00:41:48,954
SO WHAT ARE THE THERAPEUTIC 

853
00:41:48,954 --> 00:41:50,655
IMPLICATIONS FOR THIS?

854
00:41:50,655 --> 00:41:53,091
THE OBVIOUS ONE IS IF 

855
00:41:53,091 --> 00:41:55,994
AUTOANTIBODIES ARE PLAYING AN 

856
00:41:55,994 --> 00:42:01,266
IMPORTANT ROLE IN THE 

857
00:42:01,266 --> 00:42:02,367
PATHOGENESIS OF THESE AND 

858
00:42:02,367 --> 00:42:05,971
GETTING RID OF B CELLS SHOULD BE

859
00:42:05,971 --> 00:42:16,314
HELPFUL FOR THERAPY.

860
00:42:18,617 --> 00:42:21,953
CORTICOSTEROIDS REDUCE THE 

861
00:42:21,953 --> 00:42:32,497
LEVELS AND AND MYCOPHENOLATE AND

862
00:42:42,974 --> 00:42:44,009
RET

863
00:42:44,009 --> 00:42:46,745
RETUXOMAB CAN REDUCE IT IN THE 

864
00:42:46,745 --> 00:42:48,313
LYMPH NODES BUT THEY'RE WELL 

865
00:42:48,313 --> 00:42:49,281
ESTABLISHED TREATMENTS FOR 

866
00:42:49,281 --> 00:42:49,548
MYOSITIS.

867
00:42:49,548 --> 00:42:51,783
WHAT'S REALLY EXCITING IS WHAT 

868
00:42:51,783 --> 00:42:57,455
WE HEARD ABOUT RECENTLY WITH 

869
00:42:57,455 --> 00:43:01,960
REGARD TO USING CAR THERAPY FOR 

870
00:43:01,960 --> 00:43:08,433
OTHER AUTOIMMUNE CELLS AND 

871
00:43:08,433 --> 00:43:11,903
THEY'RE THE PATIENT'S OWN CELLS 

872
00:43:11,903 --> 00:43:15,941
TO REPLICATE A CHIMERIC RECEPTOR

873
00:43:15,941 --> 00:43:19,678
AND WHEN THESE ARE INFUSED AND 

874
00:43:19,678 --> 00:43:23,114
INFUSED BACK IN THE PATIENT THE 

875
00:43:23,114 --> 00:43:26,218
CAR-T CELLS BIND TO THE TARGET 

876
00:43:26,218 --> 00:43:28,019
AND THAT TRIGGERS THE T CELLS TO

877
00:43:28,019 --> 00:43:31,156
KILL THE TARGET CELL.

878
00:43:31,156 --> 00:43:35,727
SO THESE ACTIVATED CAR-T CELLS 

879
00:43:35,727 --> 00:43:38,897
ORIGINALLY DESIGN TO GET RID OF 

880
00:43:38,897 --> 00:43:41,600
B CELL LYMPHOMA CAN GET RID OF 

881
00:43:41,600 --> 00:43:45,237
NORMAL B CELLS THAT EXPRESS THE 

882
00:43:45,237 --> 00:43:45,470
TARGET.

883
00:43:45,470 --> 00:43:50,375
THE CD-19 CAR-T CELLS HAVE BEEN 

884
00:43:50,375 --> 00:43:57,082
USED TO TREAT MALICE  -- 

885
00:43:57,082 --> 00:43:58,083
MALIGNANCIES INCLUDING MYOSITIS.

886
00:43:58,083 --> 00:44:01,720
THIS IS ONE OF THE FIRST CASE 

887
00:44:01,720 --> 00:44:07,592
REPORTS OF A PATIENT AND ON THE 

888
00:44:07,592 --> 00:44:10,729
Y AXIS WE HAVE THE CK LEVEL AND 

889
00:44:10,729 --> 00:44:13,465
THEY GET TREATED AND THEN BOUNCE

890
00:44:13,465 --> 00:44:16,801
BACK UP AND EVENTUALLY THE 

891
00:44:16,801 --> 00:44:20,705
PATIENT BECOMES REFRACTORY TO 

892
00:44:20,705 --> 00:44:22,207
MULTIPLE TREATMENTS AND TREATED 

893
00:44:22,207 --> 00:44:27,812
WITH CAR-T THERAPY AND CAUSES 

894
00:44:27,812 --> 00:44:29,914
THE PATIENT TO GO TO LONG-TERM 

895
00:44:29,914 --> 00:44:31,182
DRUG-FREE REMISSION.

896
00:44:31,182 --> 00:44:33,251
THIS IS KIND OF THE PROMISE OR 

897
00:44:33,251 --> 00:44:41,526
THE HOPE FOR CD 19 AND OTHER 

898
00:44:41,526 --> 00:44:45,163
CELLULAR B CELL THERAPIES BEEN 

899
00:44:45,163 --> 00:44:50,402
NUMEROUS CASE REPORTS OF THOSE 

900
00:44:50,402 --> 00:44:53,204
CAR-T CELLS TO PUT PATIENTS WITH

901
00:44:53,204 --> 00:44:55,407
DIFFERENT TYPES OF MYOSITIS INTO

902
00:44:55,407 --> 00:44:56,875
DRUG-FREE WHAT APPEARS TO BE 

903
00:44:56,875 --> 00:45:03,148
DURABLE REMISSION.

904
00:45:03,148 --> 00:45:08,720
I SHOWED YOU ONE WAY 

905
00:45:08,720 --> 00:45:09,788
AUTOANTIBODIES CAN ENTER LIVE 

906
00:45:09,788 --> 00:45:15,560
CELLS.

907
00:45:15,560 --> 00:45:18,763
WE'RE INTERESTED IN FEATURES OF 

908
00:45:18,763 --> 00:45:21,566
ANTIBODIES THAT ALLOW THEM TO 

909
00:45:21,566 --> 00:45:22,567
ENTER LIVE CELLS.

910
00:45:22,567 --> 00:45:24,803
IN MUSCLE AND SKIN TISSUE, 

911
00:45:24,803 --> 00:45:27,539
ANTIBODIES CAN GAIN ACCESS TO 

912
00:45:27,539 --> 00:45:38,083
THE NUCLEI FOR WE'D LIKE TO SHOW

913
00:45:40,618 --> 00:45:42,687
WHICH WE HAVEN'T DONE AS WELL AS

914
00:45:42,687 --> 00:45:44,923
WE'D LIKE THE RESULTS IN THE 

915
00:45:44,923 --> 00:45:45,957
DYSFUNCTION OF THOSE CELLS AND 

916
00:45:45,957 --> 00:45:47,992
CONTRIBUTE TO THE SIGNIFICANT 

917
00:45:47,992 --> 00:45:49,527
WAY TO THE PATHOGENESIS DISEASE 

918
00:45:49,527 --> 00:45:56,234
AND IN ADDITION TO LUPUS AND 

919
00:45:56,234 --> 00:45:57,802
MYOSITIS WE'RE INTERESTED IN 

920
00:45:57,802 --> 00:45:59,003
WHETHER AUTOANTIBODY 

921
00:45:59,003 --> 00:45:59,971
INTERNALIZATION PLAYS A ROLE OR 

922
00:45:59,971 --> 00:46:03,441
OCCURS IN PATIENTS WITH OTHER 

923
00:46:03,441 --> 00:46:09,414
TYPES OF AUTOIMMUNE DISEASES 

924
00:46:09,414 --> 00:46:13,952
CHARACTERIZED BY SCLERODERMA AS 

925
00:46:13,952 --> 00:46:18,056
ANOTHER RHEUMATIC DISEASE.

926
00:46:18,056 --> 00:46:20,325
THE WORK WAS DONE BY A TEAM OF 

927
00:46:20,325 --> 00:46:20,625
PEOPLE.

928
00:46:20,625 --> 00:46:31,169
I WANT TO ESPECIALLY HIGHLIGHT 

929
00:46:32,437 --> 00:46:42,914
THE ROLE AND WILL IAGO FERNANDEZ

930
00:46:46,551 --> 00:46:56,628
SPEARHEAD THE WORK AND WE HAVE A

931
00:46:56,628 --> 00:46:58,963
STAFF SCIENTIST.

932
00:46:58,963 --> 00:47:03,134
AND WE HAVE A BIOLOGIST AND HAS 

933
00:47:03,134 --> 00:47:04,335
DONE A LOT OF WORK.

934
00:47:04,335 --> 00:47:12,777
AND TALENT ED POST-BAC DOING WOK

935
00:47:12,777 --> 00:47:15,980
ON AUTOANTIBODY INTERNALIZATION 

936
00:47:15,980 --> 00:47:17,682
AND THERE WERE PROGRAMS 

937
00:47:17,682 --> 00:47:20,485
INCLUDING STANFORD AND DUKE AND 

938
00:47:20,485 --> 00:47:25,957
UNIVERSITY OF MICHIGAN AND JOSÉ 

939
00:47:25,957 --> 00:47:27,826
MILISENDA WORKED IN OUR LAB AND 

940
00:47:27,826 --> 00:47:33,198
BACK IN BARCELONA AND CENTER IS 

941
00:47:33,198 --> 00:47:34,732
UM SAMPLES FROM THE PATIENTS 

942
00:47:34,732 --> 00:47:35,900
THAT'S MADE THE WORK POSSIBLE.

943
00:47:35,900 --> 00:47:38,369
I'LL END MY PRESENTATION THERE 

944
00:47:38,369 --> 00:47:40,138
AND IF I LEFT MYSELF TIME I'D BE

945
00:47:40,138 --> 00:47:42,640
HAPPY TO TAKE QUESTIONS.

946
00:47:42,640 --> 00:47:44,242
IF NOW'S THE APPROPRIATE TIME TO

947
00:47:44,242 --> 00:47:45,176
DO THAT.

948
00:47:45,176 --> 00:47:46,978
>> NO, IT'S NOT.

949
00:47:46,978 --> 00:47:49,948
>> OKAY.

950
00:47:49,948 --> 00:48:00,225
>> WRONG AGAIN.

951
00:48:08,566 --> 00:48:09,901
>> THANK YOU VERY MUCH.

952
00:48:09,901 --> 00:48:13,972
FOR GIVING ME THE OPPORTUNITY TO

953
00:48:13,972 --> 00:48:14,939
PRESENT TODAY.

954
00:48:14,939 --> 00:48:19,978
EQUAL SWITCH TO GENETIC MUSCLE 

955
00:48:19,978 --> 00:48:20,211
DISEASE.

956
00:48:20,211 --> 00:48:24,115
AND HOPEFULLY YOU'LL SEE AT THE 

957
00:48:24,115 --> 00:48:26,351
END OF THE PRESENTATION THERE IS

958
00:48:26,351 --> 00:48:29,988
AN IMPORTANT INTERFACE AND THE 

959
00:48:29,988 --> 00:48:39,163
IMMUNOLOGY OF THE MUSCLES.

960
00:48:39,163 --> 00:48:41,132
DISCLOSURES AND I'M THE P.I. ON 

961
00:48:41,132 --> 00:48:43,101
THE TRIALS I'LL DESCRIBE BRIEFLY

962
00:48:43,101 --> 00:48:44,903
IN THIS PRESENTATION AND WANT TO

963
00:48:44,903 --> 00:48:50,241
TALK TO A LOT OF GENE THERAPIES 

964
00:48:50,241 --> 00:48:53,978
AND PROVIDE SCIENTIFIC ADVICE 

965
00:48:53,978 --> 00:48:56,548
AND I HAVEN'T RECEIVED 

966
00:48:56,548 --> 00:48:57,148
COMPENSATION FOR ANYTHING IN 

967
00:48:57,148 --> 00:49:01,819
THIS SPACE.

968
00:49:01,819 --> 00:49:05,156
I'LL START AT A HIGH LEVEL BY 

969
00:49:05,156 --> 00:49:07,458
INTRODUCING A SIM MYSTIC CONCEPT

970
00:49:07,458 --> 00:49:09,661
WHICH IS THE PROMISE OF GENETIC 

971
00:49:09,661 --> 00:49:12,030
THERAPIES FOR GENETIC DISEASE.

972
00:49:12,030 --> 00:49:14,866
THIS IS A SUPER SIMPLE DIAGRAM 

973
00:49:14,866 --> 00:49:17,402
OF THE FLOW OF GENETIC 

974
00:49:17,402 --> 00:49:19,971
INFORMATION FROM DNA TO 

975
00:49:19,971 --> 00:49:25,043
TRANSCRIPT TO PATIENT WHEN YOU 

976
00:49:25,043 --> 00:49:28,780
HAVE A MUTATION IT'S ENCODED IN 

977
00:49:28,780 --> 00:49:31,149
THE DNA AND TRANSCRIBED AND 

978
00:49:31,149 --> 00:49:34,285
CAUSES IT TO FORM THE PROTEIN IN

979
00:49:34,285 --> 00:49:35,119
THE AFFECTED PATIENT.

980
00:49:35,119 --> 00:49:37,488
THE PROMISE OF GENE THERAPY IS 

981
00:49:37,488 --> 00:49:37,722
SIMPLE.

982
00:49:37,722 --> 00:49:40,525
THE CLOSER YOU GO TO THE GENETIC

983
00:49:40,525 --> 00:49:42,727
ORIGIN OF THE DISEASE, THE 

984
00:49:42,727 --> 00:49:44,329
HIGHER YOU EXPECT THE 

985
00:49:44,329 --> 00:49:44,963
THERAPEUTIC IMPACT TO BE BECAUSE

986
00:49:44,963 --> 00:49:47,632
YOU GO TO THE SOURCE OF IT.

987
00:49:47,632 --> 00:49:51,836
THAT'S BEEN THE BASIS OF 

988
00:49:51,836 --> 00:49:54,005
DEVELOPING TECHNOLOGIES TO 

989
00:49:54,005 --> 00:49:57,241
DIRECT THERAPIES TO THE 

990
00:49:57,241 --> 00:49:58,376
GENE-DIRECTED THERAPIES 

991
00:49:58,376 --> 00:49:59,811
INCLUDING GENE REPLACEMENT I'LL 

992
00:49:59,811 --> 00:50:03,848
TALK ABOUT TODAY AND ALSO 

993
00:50:03,848 --> 00:50:05,984
UPCOMING GENOMIC EDITING AND 

994
00:50:05,984 --> 00:50:08,286
TRANSCRIPT DIRECTED THERAPIES 

995
00:50:08,286 --> 00:50:11,122
THAT'S MAINLY THE SPACE OF THE 

996
00:50:11,122 --> 00:50:15,326
NUCLEOTIDES TO MODULATE SPLICING

997
00:50:15,326 --> 00:50:16,761
AND REGULATE GENES AND 

998
00:50:16,761 --> 00:50:17,061
TRANSCRIPTS.

999
00:50:17,061 --> 00:50:20,698
AND THE BEAUTY OF THIS IF YOU 

1000
00:50:20,698 --> 00:50:21,833
WILL IS THESE TOOLS ARE DISEASE 

1001
00:50:21,833 --> 00:50:29,641
OG -- AGNOSTIC AT WHAT THE 

1002
00:50:29,641 --> 00:50:32,310
MECHANISM MIGHT BE AND PERFECT 

1003
00:50:32,310 --> 00:50:37,448
TO PROVIDE A GENETIC TOOLBOX TO 

1004
00:50:37,448 --> 00:50:39,384
ADDRESS GENETIC DISORDERS AND 

1005
00:50:39,384 --> 00:50:41,786
PART OF THE TOPIC OF TODAY'S 

1006
00:50:41,786 --> 00:50:47,392
TALK AND ANOTHER INPET  -- 

1007
00:50:47,392 --> 00:50:50,028
IMPETUS OF DEVELOPING THE 

1008
00:50:50,028 --> 00:50:50,294
THERAPIES.

1009
00:50:50,294 --> 00:50:52,530
THE AV MEDIATED GENE REPLACEMENT

1010
00:50:52,530 --> 00:50:55,667
IS THE TOPIC OF WHAT I'LL TODAY 

1011
00:50:55,667 --> 00:50:56,968
AND YOU PROVIDE A PIECE OF DNA 

1012
00:50:56,968 --> 00:51:03,841
THAT ENCODES A GENE THAT MAY BE 

1013
00:51:03,841 --> 00:51:07,278
MISSING AND THE DNA WILL BE 

1014
00:51:07,278 --> 00:51:12,784
UPLOADED INTO THE NUCLEUS AND 

1015
00:51:12,784 --> 00:51:13,851
DOES NOT INTEGRATE INTO THE 

1016
00:51:13,851 --> 00:51:23,561
CHROMOSOMES AND HOPEFUL HAVE A 

1017
00:51:23,561 --> 00:51:26,497
THERAPEUTIC EFFECT ON THE 

1018
00:51:26,497 --> 00:51:26,731
PATIENT.

1019
00:51:26,731 --> 00:51:32,837
THE AND I'LL BE SPENDING A FEW 

1020
00:51:32,837 --> 00:51:36,708
WORDS ON WHAT THAT IS AND WHAT'S

1021
00:51:36,708 --> 00:51:37,809
IMPORTANT TO SUCCEED IS YOU 

1022
00:51:37,809 --> 00:51:40,678
TARGET WHERE YOU WANT TO GO AND 

1023
00:51:40,678 --> 00:51:42,747
HAVE SUFFICIENT EXPRESSION OF 

1024
00:51:42,747 --> 00:51:45,883
WHY YOU ARE DESIRED PRODUCT AND 

1025
00:51:45,883 --> 00:51:48,419
THE EXPRESSION IS DURABLE AND 

1026
00:51:48,419 --> 00:51:52,924
THERE'S NO TOXICITY TO THIS 

1027
00:51:52,924 --> 00:51:53,191
APPROACH.

1028
00:51:53,191 --> 00:51:59,564
THIS LITTLE GUY HERE STARTS WITH

1029
00:51:59,564 --> 00:52:02,600
A SINGLE-STRANDED DNA VIRUS THAT

1030
00:52:02,600 --> 00:52:06,637
CANNOT EXIST ON ITS OWN.

1031
00:52:06,637 --> 00:52:12,543
IT NEEDS BIG GUYS LIKE TO 

1032
00:52:12,543 --> 00:52:14,612
COMPLEMENT THE GENOME.

1033
00:52:14,612 --> 00:52:18,816
AND IT HAS HELPER GENES FROM THE

1034
00:52:18,816 --> 00:52:25,890
CO-EFFECTING VIRES TO BE ABLE TO

1035
00:52:25,890 --> 00:52:28,025
CAUSE THE INFECTION.

1036
00:52:28,025 --> 00:52:32,530
IT'S NON-PATHOGENIC.

1037
00:52:32,530 --> 00:52:37,135
IT COMES ALONG WITH THE RIDE FOR

1038
00:52:37,135 --> 00:52:38,936
BIGGER VIRUS ARE PATHOGENIC.

1039
00:52:38,936 --> 00:52:40,738
THAT'S A GREAT FEATURE TO THINK 

1040
00:52:40,738 --> 00:52:43,174
ABOUT GENE THERAPY.

1041
00:52:43,174 --> 00:52:45,843
AND THE CONCEPT OF GENE THERAPY 

1042
00:52:45,843 --> 00:52:49,714
IS TO USE THIS VIRUS TO DELIVER 

1043
00:52:49,714 --> 00:52:52,283
THINGS TO CELLS.

1044
00:52:52,283 --> 00:52:56,821
IT'S ABLE TO USE DIVIDING AS 

1045
00:52:56,821 --> 00:52:59,290
WELL AS NON-DIVIDING CELLS AND 

1046
00:52:59,290 --> 00:52:59,857
GENE EXPRESSION AND WE SEE 

1047
00:52:59,857 --> 00:53:05,730
LIMITATIONS TO THAT.

1048
00:53:05,730 --> 00:53:07,431
BECAUSE IT'S SO SMALL AND GENOME

1049
00:53:07,431 --> 00:53:10,301
IS SO SMALL, IF YOU USE IT TO 

1050
00:53:10,301 --> 00:53:13,838
DELIVER OTHER THINGS, THE 

1051
00:53:13,838 --> 00:53:16,274
PACKAGING CAPACITY IS LIMITED 

1052
00:53:16,274 --> 00:53:18,142
COMPARED TO THE NATURAL CAPACITY

1053
00:53:18,142 --> 00:53:22,180
OF THE VIRUS AND THAT'S 4.5KG 

1054
00:53:22,180 --> 00:53:23,314
RELEVANT IN THERAPEUTIC 

1055
00:53:23,314 --> 00:53:23,681
APPLICATIONS.

1056
00:53:23,681 --> 00:53:27,852
IT'S USED IN CLINICAL 

1057
00:53:27,852 --> 00:53:29,654
APPLICATIONS IN NATIONALLY 

1058
00:53:29,654 --> 00:53:32,323
OCCURRING STEREOTYPES AND OTHERS

1059
00:53:32,323 --> 00:53:33,324
THAT WE'LL TOUCH ON.

1060
00:53:33,324 --> 00:53:36,494
THIS IS WHAT IT LOOKS LIKE.

1061
00:53:36,494 --> 00:53:39,597
AND IN GENE THERAPY YOU REPLACE 

1062
00:53:39,597 --> 00:53:41,699
THE GENOME WITH WHAT YOU WANT TO

1063
00:53:41,699 --> 00:53:44,368
DELIVER AND THE ONLY THING LEFT 

1064
00:53:44,368 --> 00:53:47,271
OVER FROM THE GENOME ARE THE 

1065
00:53:47,271 --> 00:53:49,106
ITRs HERE AND THERE'S SOMETHING 

1066
00:53:49,106 --> 00:53:51,843
YOU WANT TO DELIVER IN BETWEEN 

1067
00:53:51,843 --> 00:53:55,813
AND PROMOTER AND TRANS GENE YOU 

1068
00:53:55,813 --> 00:54:00,384
WANT TO EXPRESS AND GENETIC 

1069
00:54:00,384 --> 00:54:03,855
ELEMEN

1070
00:54:03,855 --> 00:54:04,121
ELEMENTS.

1071
00:54:04,121 --> 00:54:08,226
THE WAY YOU DO THAT IS IN 

1072
00:54:08,226 --> 00:54:10,895
TRANSFECTION AND THAT'S ONE 

1073
00:54:10,895 --> 00:54:13,164
PLASMID AND THEY CONTAIN THE 

1074
00:54:13,164 --> 00:54:17,935
ORIGINAL AAV GENES AND THE THIRD

1075
00:54:17,935 --> 00:54:22,640
PLASMID THAT IS PACKAGED AND NOW

1076
00:54:22,640 --> 00:54:25,243
BECAUSE OF THE FEATURE, THIS IS 

1077
00:54:25,243 --> 00:54:26,611
WHAT ENDS UP IN THIS CAPSID.

1078
00:54:26,611 --> 00:54:28,312
SO NOW YOU HAVE A CAPSID THAT 

1079
00:54:28,312 --> 00:54:33,851
LOOKS FROM THE OUTSIDE LIKE A 

1080
00:54:33,851 --> 00:54:38,522
VIRUS AND WE HAVE REPLICATION 

1081
00:54:38,522 --> 00:54:40,057
AND IT'S A ONE-TIME INFECTION 

1082
00:54:40,057 --> 00:54:42,526
THAT DELIVERS TO THE CELLS.

1083
00:54:42,526 --> 00:54:45,863
AND THAT LOOKS LIKE THIS BINDS 

1084
00:54:45,863 --> 00:54:47,798
TO A SURFACE AND TAKEN UP BY THE

1085
00:54:47,798 --> 00:54:50,668
CELL AND BROUGHT TO THE NUCLEUS 

1086
00:54:50,668 --> 00:54:52,837
AND ENCODES IN THE NUCLEUS AND 

1087
00:54:52,837 --> 00:54:56,540
THEN YOU HAVE A SINGLE STRANDED 

1088
00:54:56,540 --> 00:55:01,178
GENE AND IT'S DOUBLE-STRANDED.

1089
00:55:01,178 --> 00:55:03,681
YOU MAKE IT AS A DOUBLE-STRANDED

1090
00:55:03,681 --> 00:55:05,016
CONSTRUCT AND WE CALL IT 

1091
00:55:05,016 --> 00:55:05,349
COMPLEMENTARY.

1092
00:55:05,349 --> 00:55:08,219
BUT THEN YOU ONLY HAVE HALF THE 

1093
00:55:08,219 --> 00:55:12,356
LOADING CAPACITY OF THE ORIGINAL

1094
00:55:12,356 --> 00:55:12,790
SIN

1095
00:55:12,790 --> 00:55:14,892
SINGLE-STRANDED ONE.

1096
00:55:14,892 --> 00:55:16,928
IT LIVES IN THE NUCLEUS THAT DO 

1097
00:55:16,928 --> 00:55:19,397
NOT FOR THE MOST PART INTEGRATE 

1098
00:55:19,397 --> 00:55:20,097
IN THE HOST GENOME.

1099
00:55:20,097 --> 00:55:27,738
A LITTLE BIT OF THAT HAPPENS BUT

1100
00:55:27,738 --> 00:55:28,139
MOST DOES NOT.

1101
00:55:28,139 --> 00:55:29,941
WHEN THE CELLS DIVIDES THEY 

1102
00:55:29,941 --> 00:55:34,545
DON'T GET REPLICATED.

1103
00:55:34,545 --> 00:55:38,683
THE HEAVILY DIVIDING CELL GETS 

1104
00:55:38,683 --> 00:55:38,883
LOST.

1105
00:55:38,883 --> 00:55:40,785
LET'S SWITCH GEARS AND TALK 

1106
00:55:40,785 --> 00:55:42,553
ABOUT MUSCLE DISEASE.

1107
00:55:42,553 --> 00:55:48,459
LET'S START WITH MUSCULAR 

1108
00:55:48,459 --> 00:55:51,228
DYSTROPHY AND MYOPATHIES.

1109
00:55:51,228 --> 00:55:53,130
IT'S DEGENERATIVE DISORDER OF 

1110
00:55:53,130 --> 00:55:53,431
MUSCLE.

1111
00:55:53,431 --> 00:55:55,700
IT'S A GROUP OF DISORDERS WHERE 

1112
00:55:55,700 --> 00:55:57,435
THE MUSCLE UNDER GOES 

1113
00:55:57,435 --> 00:55:59,570
DEGENERATION FOR VARIOUS REASONS

1114
00:55:59,570 --> 00:56:02,974
THAT WE'LL TOUCH UPON AND 

1115
00:56:02,974 --> 00:56:03,841
ATTEMP

1116
00:56:03,841 --> 00:56:06,577
ATTEMPTS AS LONG AS IT CAN AND 

1117
00:56:06,577 --> 00:56:09,613
AT THE END REGENERATION IS NO 

1118
00:56:09,613 --> 00:56:10,748
LONGER SFRNT.

1119
00:56:10,748 --> 00:56:13,718
THERE'S A NORMAL MUSCLE BYPASS 

1120
00:56:13,718 --> 00:56:19,757
AND SEE THE MYOFIBERS AND YOU 

1121
00:56:19,757 --> 00:56:21,459
SEE THE PERIPHERY OF THE FIBER.

1122
00:56:21,459 --> 00:56:25,930
YOU GET DEGENERATIVE FEATURES 

1123
00:56:25,930 --> 00:56:27,865
AND MACROPHAGES MOVING AND 

1124
00:56:27,865 --> 00:56:28,599
INFLAMMATORY RESPONSE AND IT 

1125
00:56:28,599 --> 00:56:31,602
TRIES TO REGENERATE AND GETS 

1126
00:56:31,602 --> 00:56:33,871
REPLACED BY CONNECTIVE TISSUE 

1127
00:56:33,871 --> 00:56:36,841
AND LOOKS SOMETHING LIKE THIS 

1128
00:56:36,841 --> 00:56:37,942
WHICH IS REALLY TOUGH TO 

1129
00:56:37,942 --> 00:56:45,316
ENVISION TO REPAIR.

1130
00:56:45,316 --> 00:56:50,688
YOU CAN SEE THAT IN THE MRI THE 

1131
00:56:50,688 --> 00:56:53,958
DARK MUSCLE IS THIS IS ADVANCED 

1132
00:56:53,958 --> 00:56:59,397
MUSCULAR DYSTROPHY AND IT'S 

1133
00:56:59,397 --> 00:57:03,300
TRANSFORMED AND JUST ANOTHER 

1134
00:57:03,300 --> 00:57:08,506
VIEW OF THIS AND NORMAL LOOKING 

1135
00:57:08,506 --> 00:57:13,344
MUSCLE AND TWO BIOPSIES YOU SEE 

1136
00:57:13,344 --> 00:57:17,114
THE PROCESS AND THE MUSCLE 

1137
00:57:17,114 --> 00:57:24,021
TIGERS DEGENERATE BEING 

1138
00:57:24,021 --> 00:57:25,322
FIBROC

1139
00:57:25,322 --> 00:57:28,426
FIBROCYTOSED.

1140
00:57:28,426 --> 00:57:33,531
AND THAT IS THE CYCLE AND 

1141
00:57:33,531 --> 00:57:34,799
INCREASING FIBROSIS IN THE 

1142
00:57:34,799 --> 00:57:35,066
MUSCLE.

1143
00:57:35,066 --> 00:57:37,201
THE MUSCULAR DYSTROPHY IS 

1144
00:57:37,201 --> 00:57:37,701
DIVERSE.

1145
00:57:37,701 --> 00:57:41,672
MANY THINGS CAN CAUSE THE 

1146
00:57:41,672 --> 00:57:47,178
DEGENERATIVE MUSCLE DISEASE AND 

1147
00:57:47,178 --> 00:57:47,878
THERE'S DISTRIBUTION OF WEAKNESS

1148
00:57:47,878 --> 00:57:58,255
OF A SYSTEM INVOLVED.

1149
00:57:58,556 --> 00:58:01,992
WE'LL TOUCH ON TWO AND FOCUS ON 

1150
00:58:01,992 --> 00:58:04,762
THE MOST COMMON, DUCHENNE 

1151
00:58:04,762 --> 00:58:05,596
MUSCULAR DYSTROPHY.

1152
00:58:05,596 --> 00:58:08,099
THIS IS THE FOCAL POINT WHICH IS

1153
00:58:08,099 --> 00:58:12,503
THE INTERFACE BETWEEN THE MUSCLE

1154
00:58:12,503 --> 00:58:16,107
FIBER AND THE EXTRA CELLULAR 

1155
00:58:16,107 --> 00:58:20,244
PLAY TRIX AND IT'S DISASSOCIATED

1156
00:58:20,244 --> 00:58:22,179
AND I'LL HIGHLIGHT THIS HERE AND

1157
00:58:22,179 --> 00:58:24,415
THIS IS THE PLASMA MEMBRANE.

1158
00:58:24,415 --> 00:58:27,751
THIS IS THE EXTRA CELLULAR 

1159
00:58:27,751 --> 00:58:30,654
MATRIX AND THIS IS WITHIN THE 

1160
00:58:30,654 --> 00:58:32,656
MUSCLE FIBER AND THERE'S A 

1161
00:58:32,656 --> 00:58:35,092
PROTEIN CALLED DYSTROPHY THAT 

1162
00:58:35,092 --> 00:58:37,461
LINKS TO A COMPLEX OF PROTEINS 

1163
00:58:37,461 --> 00:58:39,029
ACROSS THE PLASMA MEMBRANE THAT 

1164
00:58:39,029 --> 00:58:43,400
FORM A RECEPTOR FOR THE EXTRA 

1165
00:58:43,400 --> 00:58:49,573
CELLULAR MATRIX AND THE 

1166
00:58:49,573 --> 00:58:51,909
CHROMATIN TYPE 6 AND THIS IS 

1167
00:58:51,909 --> 00:58:56,280
LINKED AND MUSCLE BEING A 

1168
00:58:56,280 --> 00:58:58,382
CONTRACTILE TISSUE THE BOLD 

1169
00:58:58,382 --> 00:59:01,552
BETWEEN THE INTRACELLULAR AND 

1170
00:59:01,552 --> 00:59:03,821
EXTRA CELLULAR WERE IMPORTANT 

1171
00:59:03,821 --> 00:59:04,355
FOR THE TISSUE.

1172
00:59:04,355 --> 00:59:07,491
IT'S INTERESTING IF YOU HAVE 

1173
00:59:07,491 --> 00:59:09,960
MUTATIONS UP HERE IN THE EXTRA 

1174
00:59:09,960 --> 00:59:13,831
CELLULAR MATRIX YOU GET 

1175
00:59:13,831 --> 00:59:16,901
CONGENITAL MUSCULAR DYSTROPHY 

1176
00:59:16,901 --> 00:59:20,905
AND AT BIRTH AFFECTING THE 

1177
00:59:20,905 --> 00:59:23,707
COLLAGEN AND GLYCAN HERE.

1178
00:59:23,707 --> 00:59:27,378
YOU CAN SEE HOW STRIKING IT CAN 

1179
00:59:27,378 --> 00:59:29,213
BE.

1180
00:59:29,213 --> 00:59:32,750
THIS IS THE RECEPTOR AND NOT 

1181
00:59:32,750 --> 00:59:33,217
ONLY MUSCLE BUT BRAIN 

1182
00:59:33,217 --> 00:59:38,289
DEVELOPMENT INVOLVEMENT.

1183
00:59:38,289 --> 00:59:44,795
IT'S A DEFICIENCY WITH STRIKING 

1184
00:59:44,795 --> 00:59:45,930
WEAKNESS AT BIRTH AND 

1185
00:59:45,930 --> 00:59:47,932
DESTRUCTIVE LOOKING MUSCLE.

1186
00:59:47,932 --> 00:59:49,934
THESE ARE CHILDREN WITH COLLAGEN

1187
00:59:49,934 --> 00:59:53,137
TYPE 6 DISORDERS WHERE THERE'S A

1188
00:59:53,137 --> 00:59:57,007
PROMINENT CONNECTIVE TISSUE 

1189
00:59:57,007 --> 00:59:57,408
COMPONENT AS WELL.

1190
00:59:57,408 --> 01:00:01,979
ALL AT PRESENT HAVE EARLY ONSET 

1191
01:00:01,979 --> 01:00:04,181
MUSCULAR DYSTROPHIES.

1192
01:00:04,181 --> 01:00:14,725
THE COMPLEX CAUSES DYSTROPHIES 

1193
01:00:16,460 --> 01:00:23,400
AND THAT'S WHERE MUTATIONS CAUSE

1194
01:00:23,400 --> 01:00:27,871
DUCHENNE MUSCULAR DYSTROPHY AND 

1195
01:00:27,871 --> 01:00:32,710
THE MOST COMMON AFBT BOYS AND 

1196
01:00:32,710 --> 01:00:36,146
THERE'S STRIKING IMAGES HERE AND

1197
01:00:36,146 --> 01:00:39,183
YOU CAN SEE A BOY WHO LOOKS LIKE

1198
01:00:39,183 --> 01:00:43,587
HE HAS BIG MUSCLES BUT IT'S WHAT

1199
01:00:43,587 --> 01:00:47,558
WE CALL MUSCLE ALREADY REPLACED 

1200
01:00:47,558 --> 01:00:51,395
BY CONNECTIVE TISSUE GIVEN THE 

1201
01:00:51,395 --> 01:00:53,564
APPEARANCE OF HYPERTROPHY OF THE

1202
01:00:53,564 --> 01:00:55,899
MUSCLE A CHARACTERISTIC FEATURE 

1203
01:00:55,899 --> 01:00:56,400
OF THIS DISEASE.

1204
01:00:56,400 --> 01:01:00,571
IT'S QUITE COMMON AS YOU CAN 

1205
01:01:00,571 --> 01:01:03,073
SEE.

1206
01:01:03,073 --> 01:01:08,412
1 IN 3,500 TO 5,000 MALE BIRTHS.

1207
01:01:08,412 --> 01:01:18,155
IT LEARNINGS TO THE COMPLEX OF 

1208
01:01:18,155 --> 01:01:19,990
GLYCOPROTEINS AND THIS IS ONE 

1209
01:01:19,990 --> 01:01:30,668
THAT WAS IDENTIFIED AT THE TIME.

1210
01:01:30,668 --> 01:01:34,705
THIS IS A YOUNG BOY WITH 

1211
01:01:34,705 --> 01:01:41,912
DUCHENNE MUSCULAR DYSTROPHY AND 

1212
01:01:41,912 --> 01:01:45,716
LATER IN LIFE HERE HE'S 10 OR 

1213
01:01:45,716 --> 01:01:45,883
11.

1214
01:01:45,883 --> 01:01:48,218
HE'S WALKING BUT NOT ABLE TO GET

1215
01:01:48,218 --> 01:01:51,055
UP FROM THE FLOOR AND THREE OR 

1216
01:01:51,055 --> 01:01:54,525
FOUR MONTHS LATER HE LOSES 

1217
01:01:54,525 --> 01:01:56,193
AMBULATION AND THERE'S A PHASE 

1218
01:01:56,193 --> 01:02:01,965
OF WHEELCHAIR USE AND LOSS OF 

1219
01:02:01,965 --> 01:02:06,437
AMBULATION AND THE MYOPATHY AND 

1220
01:02:06,437 --> 01:02:06,704
SCOLIOSIS.

1221
01:02:06,704 --> 01:02:11,542
THIS HAS TO BE MANAGED TO AVOID 

1222
01:02:11,542 --> 01:02:13,844
THE SITUATION WHERE YOU HAVE 

1223
01:02:13,844 --> 01:02:17,981
UNTREATED SCOLIOSIS IN THIS BOY 

1224
01:02:17,981 --> 01:02:27,591
AND WHAT CAUSES THE DISEASE IS 

1225
01:02:27,591 --> 01:02:29,960
MOSTLY DELETIONS IN THE LARGE 

1226
01:02:29,960 --> 01:02:40,204
GENOMIC LOCUS.

1227
01:02:44,375 --> 01:02:49,646
IT'S PRONE TO DELETIONS IN THE 

1228
01:02:49,646 --> 01:02:52,015
GENE AND THEY'RE TO THE MISTAKE 

1229
01:02:52,015 --> 01:03:02,526
COMMON THESE ARE 75 EXONS AND 

1230
01:03:05,696 --> 01:03:08,399
HOW THEY BOUNDARY IN THE 

1231
01:03:08,399 --> 01:03:09,333
TRANSCRIPT.

1232
01:03:09,333 --> 01:03:12,936
THEY DEFINE WHERE IN THE READING

1233
01:03:12,936 --> 01:03:17,307
FRAME AN EXON WOULD START AND 

1234
01:03:17,307 --> 01:03:21,945
THE NEXT WOULD STOP.

1235
01:03:21,945 --> 01:03:25,215
THERE'S A DELETION AND THE 

1236
01:03:25,215 --> 01:03:31,655
FRAMEWORK IS PRESERVED BECAUSE 

1237
01:03:31,655 --> 01:03:35,759
BUT IF YOU HAVE IT HERE THEN 

1238
01:03:35,759 --> 01:03:46,069
IT'S INTERRUPTED.

1239
01:03:50,340 --> 01:04:00,818
AND THEY CLONED THE GENE A BOY 

1240
01:04:02,586 --> 01:04:05,689
HAD A DELETION LARGE ENOUGH TO 

1241
01:04:05,689 --> 01:04:16,233
BE SEEN AND THEY PUT THIS NEXT 

1242
01:04:22,706 --> 01:04:24,508
TO THE OTHER IN PAINSTAKING WORK

1243
01:04:24,508 --> 01:04:35,052
AND THIS IS ORIGINAL SLIDE AND 

1244
01:04:37,554 --> 01:04:41,959
SAW THE DELETIONS HAVE THE 

1245
01:04:41,959 --> 01:04:52,469
PROTEIN TRUNCATED AND ABSENT.

1246
01:04:59,276 --> 01:05:09,753
AND THEY HAD MODULATION LONGER.

1247
01:05:12,122 --> 01:05:19,563
THE OXIDATION SLIDE MOVED THE 

1248
01:05:19,563 --> 01:05:23,400
THERAPEUTICS FIELD YOU HAVE THE 

1249
01:05:23,400 --> 01:05:26,904
PROTEIN IN THE SCHEMATIC.

1250
01:05:26,904 --> 01:05:31,008
THIS WAS A FAMILY OF PATIENTS 

1251
01:05:31,008 --> 01:05:37,981
OBSERVED AND 45% OF THE PROTEIN 

1252
01:05:37,981 --> 01:05:48,125
WAS 

1253
01:05:50,827 --> 01:05:51,862
WASS

1254
01:05:51,862 --> 01:05:52,362
WASS

1255
01:05:52,362 --> 01:05:56,099
WASSING  AND THEY -- AND THEY 

1256
01:05:56,099 --> 01:05:59,403
ALLOWED FOR A LONGER FUNCTION 

1257
01:05:59,403 --> 01:06:01,038
THAN YOU WOULD IN THE DUCHENNE 

1258
01:06:01,038 --> 01:06:05,075
MUSCULAR DYSTROPHY.

1259
01:06:05,075 --> 01:06:15,586
S  AND THERE'S WORK THAT ARE 

1260
01:06:20,457 --> 01:06:25,395
INTERNALLY DELETED AND MUCH OF 

1261
01:06:25,395 --> 01:06:29,600
THE REPEAT DOMAIN STRUCTURE IS 

1262
01:06:29,600 --> 01:06:31,201
DELETED BUT THE BUSINESS ENDS 

1263
01:06:31,201 --> 01:06:40,611
ARE PRESERVED.

1264
01:06:40,611 --> 01:06:45,983
THESE ARE IN CLINICAL TRIAL OR 

1265
01:06:45,983 --> 01:06:49,052
APPROVED AND THEY WERE DESIGN 

1266
01:06:49,052 --> 01:06:53,156
THIS WAY.

1267
01:06:53,156 --> 01:07:00,063
S AND THERE'S VARIOUS GENOTYPES.

1268
01:07:00,063 --> 01:07:09,272
S AND THIS WAS A CLINICAL TRIAL 

1269
01:07:09,272 --> 01:07:13,977
AND GO THE WORK AND GO RIGHT TO 

1270
01:07:13,977 --> 01:07:18,548
THE PHASE III TRIALS AND A MIXED

1271
01:07:18,548 --> 01:07:18,815
PICTURE.

1272
01:07:18,815 --> 01:07:27,290
FOR THE PFIZER OUTCOME SHOWN 

1273
01:07:27,290 --> 01:07:30,694
HERE, THIS WAS UNAFFECTED.

1274
01:07:30,694 --> 01:07:35,098
IN A PHASE III TRIAL AT THE END 

1275
01:07:35,098 --> 01:07:36,900
USING AN ASSESSMENT CALLED THE 

1276
01:07:36,900 --> 01:07:39,703
NORTH STAR AMBULATORY ASSESSMENT

1277
01:07:39,703 --> 01:07:40,837
WAS NO DIFFERENCE BETWEEN THE 

1278
01:07:40,837 --> 01:07:41,972
PLACEBO GROUP AND TREATMENT 

1279
01:07:41,972 --> 01:07:47,944
GROUP.

1280
01:07:47,944 --> 01:07:50,681
ANOTHER CONSTRUCT USED THINGS 

1281
01:07:50,681 --> 01:07:51,915
LOOKED A LITTLE BIT MORE 

1282
01:07:51,915 --> 01:07:53,617
PROMISING AND THE PRIMARY END 

1283
01:07:53,617 --> 01:07:55,952
POINT WAS NOT MET HERE BUT 

1284
01:07:55,952 --> 01:07:57,988
SECONDARY END POINT IN THE 

1285
01:07:57,988 --> 01:08:01,958
COMPOSITE ANALYSIS DID REACH A 

1286
01:08:01,958 --> 01:08:04,261
SIGNIFICANT WHEN THEY SAW YOUNG 

1287
01:08:04,261 --> 01:08:07,731
PATIENTS TREATED WITH THIS HAD 

1288
01:08:07,731 --> 01:08:14,371
BETTER SCORES AND THE EXPRESSION

1289
01:08:14,371 --> 01:08:19,776
HAD BETTER OUTCOMES AND HERE IN 

1290
01:08:19,776 --> 01:08:20,744
THE BLOT AS WELL BEING 

1291
01:08:20,744 --> 01:08:21,011
EXPRESSED.

1292
01:08:21,011 --> 01:08:24,247
THAT LED TO APPROVAL OF THIS IN 

1293
01:08:24,247 --> 01:08:27,317
THE UNITED STATES AS GENE 

1294
01:08:27,317 --> 01:08:30,053
THERAPY FOR DUCHENNE MUSCULAR 

1295
01:08:30,053 --> 01:08:30,454
DYSTROPHY.

1296
01:08:30,454 --> 01:08:34,124
THE TWO OBSERVATIONS WERE SHOWN 

1297
01:08:34,124 --> 01:08:37,894
AND YOU CAN SEE HERE AFTER TWO 

1298
01:08:37,894 --> 01:08:40,630
YEARS THE SHIFT OF BENEFICIAL 

1299
01:08:40,630 --> 01:08:41,798
CHANGES IS MAINTAINED IN THE 

1300
01:08:41,798 --> 01:08:46,570
MEASURES IT'S NO LONGER PLACEBO 

1301
01:08:46,570 --> 01:08:47,170
CONTROLLED.

1302
01:08:47,170 --> 01:08:49,973
IT'S OPEN LABEL BUT STILL 

1303
01:08:49,973 --> 01:08:53,977
SHOWING SOME BENEFIT SHIFTING 

1304
01:08:53,977 --> 01:09:02,652
DISEASE.

1305
01:09:02,652 --> 01:09:04,254
ONE REASON IS THIS IS NOT IN THE

1306
01:09:04,254 --> 01:09:06,490
GENOME OF THE PATIENT GIVEN 

1307
01:09:06,490 --> 01:09:09,025
LATER IN THE PROGRESSION OF THE 

1308
01:09:09,025 --> 01:09:09,559
DISEASE.

1309
01:09:09,559 --> 01:09:12,195
THESE BOYS WERE TREATED BETWEEN 

1310
01:09:12,195 --> 01:09:16,666
5 AND 7 YEARS OF AGE.

1311
01:09:16,666 --> 01:09:19,970
IT'S INCOMPLETE RESTORATION 

1312
01:09:19,970 --> 01:09:20,737
COMPARED TO A GENOTYPE YOU'RE 

1313
01:09:20,737 --> 01:09:25,976
BORN WITH AND THERE'S A 

1314
01:09:25,976 --> 01:09:28,712
DIFFERENCE AND HAVING IT IS 

1315
01:09:28,712 --> 01:09:30,814
BETTER AND THAT'S UNDER 

1316
01:09:30,814 --> 01:09:32,082
DEVELOPMENT KNOW AS WELL.

1317
01:09:32,082 --> 01:09:36,319
WORK BY JEFF CHAMBERLAIN WHERE 

1318
01:09:36,319 --> 01:09:40,624
HE GIVES FRAGMENTS AND ABLE TO 

1319
01:09:40,624 --> 01:09:43,727
TRANS SPLICE ON TO THE PROTEIN 

1320
01:09:43,727 --> 01:09:47,264
LEVEL TO FORM FULL LENGTH 

1321
01:09:47,264 --> 01:09:49,299
DYSTROPHY AND IN THE PRECLINICAL

1322
01:09:49,299 --> 01:09:53,303
DEVELOPMENT AT THE MOMENT.

1323
01:09:53,303 --> 01:09:57,741
LET'S SWITCH GEARS TO CONGENITAL

1324
01:09:57,741 --> 01:09:58,241
MYOPATHIES.

1325
01:09:58,241 --> 01:10:03,213
THEY'RE LARGELY NON-DYSTROPIC.

1326
01:10:03,213 --> 01:10:05,982
HERE'S THE PATHOPHYSIOLOGY IS 

1327
01:10:05,982 --> 01:10:09,753
PLAYING OUT MOSTLY IN THE 

1328
01:10:09,753 --> 01:10:13,490
INTRACELLULAR COMPARTMENT BUT 

1329
01:10:13,490 --> 01:10:15,792
ALSO WHERE EXCITATION 

1330
01:10:15,792 --> 01:10:17,894
CONTRACTION HAPPENS DEEP IN THE 

1331
01:10:17,894 --> 01:10:23,266
MUSCLE FIBERS.

1332
01:10:23,266 --> 01:10:27,003
THEY'RE CHARACTERIZED BY THE 

1333
01:10:27,003 --> 01:10:29,973
PATHOLOGY AND YOU CAN SEE EARLY 

1334
01:10:29,973 --> 01:10:32,776
ONSET WEAKNESS AND STABILITY 

1335
01:10:32,776 --> 01:10:33,977
OVER THE YEARS HOWEVER, ARE MUCH

1336
01:10:33,977 --> 01:10:37,981
MORE SEVERE AT BIRTH BUT STILL 

1337
01:10:37,981 --> 01:10:40,817
WITH STABILITY.

1338
01:10:40,817 --> 01:10:45,255
THE DISEASE NAME ARRIVES FROM 

1339
01:10:45,255 --> 01:10:49,492
THE HISTOLOGICAL APPEARANCE AND 

1340
01:10:49,492 --> 01:10:51,895
THAT'S CHARACTERISTIC.

1341
01:10:51,895 --> 01:10:52,495
THIS I

1342
01:10:52,495 --> 01:10:56,867
THIS IS A PROTO TYPICAL 

1343
01:10:56,867 --> 01:10:57,968
APPEARANCE AND THIS IS MORE 

1344
01:10:57,968 --> 01:11:01,905
STABLE HISTOLOGICALLY OVER THE 

1345
01:11:01,905 --> 01:11:02,939
YEARS.

1346
01:11:02,939 --> 01:11:09,179
THESE ARE THE CORE MYOPATHY.

1347
01:11:09,179 --> 01:11:15,518
AND THIS IS THE ONE I'M GOING TO

1348
01:11:15,518 --> 01:11:19,489
FOCUS ON NOW BECAUSE OF GENE 

1349
01:11:19,489 --> 01:11:19,890
THERAPY DEVELOPED.

1350
01:11:19,890 --> 01:11:24,227
THE MYOPATHY IS THE MOST SEVERE 

1351
01:11:24,227 --> 01:11:28,365
IN THAT IT'S AN EXCELLENT 

1352
01:11:28,365 --> 01:11:28,732
DISEASE.

1353
01:11:28,732 --> 01:11:32,302
BOYS ARE SEVERELY WEAK FROM 

1354
01:11:32,302 --> 01:11:39,042
BIRTH AND THEY NEVER ---IBLE AND

1355
01:11:39,042 --> 01:11:44,681
THEY ARE DO NOT WALK BUT THEY'RE

1356
01:11:44,681 --> 01:11:48,852
DEPENDENT ON SUPPORT FOR THE 

1357
01:11:48,852 --> 01:11:49,419
LIFE TIME.

1358
01:11:49,419 --> 01:11:52,222
A LOT OF THEM, 50% DO NOT 

1359
01:11:52,222 --> 01:11:53,990
SURVIVE PAST 18 MONTHS BECAUSE 

1360
01:11:53,990 --> 01:11:57,394
OF COMPLICATIONS OF THE 

1361
01:11:57,394 --> 01:11:58,662
RESPIRATORY INSUFFICIENCY.

1362
01:11:58,662 --> 01:12:07,904
AND HERE THE GENE PRODUCT IS A 

1363
01:12:07,904 --> 01:12:13,243
PHOSPHOTASE AN ENZYMATIC 

1364
01:12:13,243 --> 01:12:16,780
ACTIVITY INVOLVED IN MARKERS.

1365
01:12:16,780 --> 01:12:21,952
THEY'RE MARKERS OF MEMBRANES 

1366
01:12:21,952 --> 01:12:25,755
THAT ALLOW MEMBRANES TO BE 

1367
01:12:25,755 --> 01:12:28,892
SORTED AND HAVE STRUCTURES SUCH 

1368
01:12:28,892 --> 01:12:33,396
AS THE CYTOPLASTIC RETICULUM AND

1369
01:12:33,396 --> 01:12:37,968
GIVE THE NAME TO THE DISEASE.

1370
01:12:37,968 --> 01:12:46,810
HERE GENE THERAPY WAS DEVELOPED 

1371
01:12:46,810 --> 01:12:51,214
AND THE PROMOTER THAT IS CALLED 

1372
01:12:51,214 --> 01:13:01,257
AAV8 AND THIS WAS TRIED AND THE 

1373
01:13:01,257 --> 01:13:03,727
NATURAL HISTORY OF THE DISEASE.

1374
01:13:03,727 --> 01:13:08,465
YOU CAN SEE A FEW IN THE NATURAL

1375
01:13:08,465 --> 01:13:17,640
HISTORY AND THOSE WICK THE LOWER

1376
01:13:17,640 --> 01:13:18,441
DOZE ARE VERY DIFFERENT.

1377
01:13:18,441 --> 01:13:26,583
THEY GOT TO STANDING OR WALKING 

1378
01:13:26,583 --> 01:13:29,185
IN THE YOUNG GROUP AND THE 

1379
01:13:29,185 --> 01:13:35,125
SUPPORT DROPPED OFF AND GOT OFF 

1380
01:13:35,125 --> 01:13:37,260
THE RESPIRATORY SUPPORT IN THAT 

1381
01:13:37,260 --> 01:13:37,560
TRIAL.

1382
01:13:37,560 --> 01:13:41,531
THE TRIAL IS ON HOLD BECAUSE OF 

1383
01:13:41,531 --> 01:13:46,536
LIVER TOXICITY THAT DEVELOPED 

1384
01:13:46,536 --> 01:13:49,372
AND I'LL COME BACK TO THAT IN A 

1385
01:13:49,372 --> 01:13:49,973
SECOND.

1386
01:13:49,973 --> 01:13:52,108
THERE'S A CLEAR EFFECT ON THE 

1387
01:13:52,108 --> 01:13:55,545
HISTOLOGY OF THE BIOPSIES.

1388
01:13:55,545 --> 01:13:57,981
THESE ARE BIOPSIES TAKEN AT 

1389
01:13:57,981 --> 01:13:59,983
BASELINE AND THEN 48 WEEKS 

1390
01:13:59,983 --> 01:14:01,351
LATER.

1391
01:14:01,351 --> 01:14:07,924
AND YOU CAN SEE THAT A NUMBER OF

1392
01:14:07,924 --> 01:14:12,262
THE FEATURES NORMALIZED WITH THE

1393
01:14:12,262 --> 01:14:12,495
THERAPY.

1394
01:14:12,495 --> 01:14:15,498
IN PARTICULAR THE APPEARANCE AND

1395
01:14:15,498 --> 01:14:17,033
THE MUSCLE FIBERS GREW.

1396
01:14:17,033 --> 01:14:20,837
THE NUCLEAR PLACEMENT DID NOT 

1397
01:14:20,837 --> 01:14:21,905
CHANGE.

1398
01:14:21,905 --> 01:14:25,208
IT REMAINS IN THE MIDDLE OF THE 

1399
01:14:25,208 --> 01:14:25,975
FIBER.

1400
01:14:25,975 --> 01:14:30,146
THERE WAS CLEARLY A HISTOLOGICAL

1401
01:14:30,146 --> 01:14:35,852
RESPONSE AS WELL.

1402
01:14:35,852 --> 01:14:40,123
THE MUSCLE IS A LARGE ORGAN.

1403
01:14:40,123 --> 01:14:42,826
40% OF BODY MASS IS DEPENDENT ON

1404
01:14:42,826 --> 01:14:45,195
THE BODY MASS INDEX AND FITNESS 

1405
01:14:45,195 --> 01:14:46,362
AND SO ON BUT IT IS A LARGE 

1406
01:14:46,362 --> 01:14:52,135
ORGAN.

1407
01:14:52,135 --> 01:14:55,105
CRUCIAL MUSCLES AND THE AXON 

1408
01:14:55,105 --> 01:15:00,510
MUSCLES FOR PREVENTING SCOLIOSIS

1409
01:15:00,510 --> 01:15:03,480
AND SOME MUSCULAR DYSTROPHIES 

1410
01:15:03,480 --> 01:15:05,215
AND ORGANS MAY BE AFFECTED AND 

1411
01:15:05,215 --> 01:15:05,748
NEED TO BE CONSIDERED.

1412
01:15:05,748 --> 01:15:09,652
AND THE OTHER IS OF COURSE THE 

1413
01:15:09,652 --> 01:15:12,655
MUSCLE IS NOT JUST ONE BUT 

1414
01:15:12,655 --> 01:15:16,126
CONTAINED DIFFERENT TYPES THAT 

1415
01:15:16,126 --> 01:15:20,497
MAY BE OF IMPORTANCE.

1416
01:15:20,497 --> 01:15:29,405
THERE'S THE MYONUCLEAR  AND 

1417
01:15:29,405 --> 01:15:31,407
SATELLITE CELLS MAY BE IMPORTANT

1418
01:15:31,407 --> 01:15:37,947
IN THE THERAPY AS IMMUNE CELL 

1419
01:15:37,947 --> 01:15:43,253
PRESENT THERE'S IMPORTANT CELLS 

1420
01:15:43,253 --> 01:15:49,893
FOR THE COLLAGEN 6 DYSTROPHY AND

1421
01:15:49,893 --> 01:15:53,396
TARGET THE CELLS THAT DRIVE THE 

1422
01:15:53,396 --> 01:15:55,465
DISEASE EFFECTIVELY.

1423
01:15:55,465 --> 01:16:01,437
AND SOME CELLS ARE DIVIDING OR 

1424
01:16:01,437 --> 01:16:05,675
TURNING OVER AND YOU HAVE AN AAV

1425
01:16:05,675 --> 01:16:06,309
CORRECTION YOU WOULD LOSE IT ALL

1426
01:16:06,309 --> 01:16:13,383
THE TIME.

1427
01:16:13,383 --> 01:16:17,587
IN ADDITION, ONE MUSCLE FIBER IS

1428
01:16:17,587 --> 01:16:22,125
A NUCLEATED STRUCTURE.

1429
01:16:22,125 --> 01:16:25,261
WHEN WE THINK OF GENE THERAPY 

1430
01:16:25,261 --> 01:16:28,198
CORRECTING THESE, IF YOU THINK 

1431
01:16:28,198 --> 01:16:33,203
OF MUSCULAR DYSTROPHY AND YOU 

1432
01:16:33,203 --> 01:16:35,672
HAVE THIS HERE BUT THEN YOU HAVE

1433
01:16:35,672 --> 01:16:39,809
GAPS, THIS IS A POINT OF OUR 

1434
01:16:39,809 --> 01:16:43,546
ABILITY TO CONSIDER.

1435
01:16:43,546 --> 01:16:48,885
ONE IS THE BRIGHT WINDOW.

1436
01:16:48,885 --> 01:16:52,455
IS IT EARLY STAGES OF THE 

1437
01:16:52,455 --> 01:16:54,290
DISEASE.

1438
01:16:54,290 --> 01:16:57,560
WHAT CAN YOU ESTABLISH AND WHAT 

1439
01:16:57,560 --> 01:16:58,228
IT IS THE OPPORTUNITY WINDOW OF 

1440
01:16:58,228 --> 01:17:04,434
TREATMENT.

1441
01:17:04,434 --> 01:17:07,203
 THAT MUST DEPEND ON THE NATURE 

1442
01:17:07,203 --> 01:17:07,971
OF THE DISEASE.

1443
01:17:07,971 --> 01:17:14,310
AND IT DECLINED OVER TIME AND 

1444
01:17:14,310 --> 01:17:16,579
YOU CAN ADDRESS THE GENE THERAPY

1445
01:17:16,579 --> 01:17:20,516
AND DEGENERATIVE DISEASE 

1446
01:17:20,516 --> 01:17:24,988
PROGRESSES IF YOU HAVE A MORE 

1447
01:17:24,988 --> 01:17:27,390
STABLE DISEASE WITH LESS 

1448
01:17:27,390 --> 01:17:33,963
DEGENERATION YOUR OPPORTUNITY IS

1449
01:17:33,963 --> 01:17:44,107
LONGER.

1450
01:17:44,474 --> 01:17:48,177
IN DUCHENNE DISEASE THE MUSCLE 

1451
01:17:48,177 --> 01:17:49,946
BIOPSY SHOWS THE DEGENERATIVE 

1452
01:17:49,946 --> 01:17:51,247
NATURE OF THE DISEASE.

1453
01:17:51,247 --> 01:17:52,815
YOU'RE DOSING INTO SOMETHING 

1454
01:17:52,815 --> 01:17:55,018
THAT IS ALREADY ACTIVE AND 

1455
01:17:55,018 --> 01:18:05,261
DEGENERATIVE.

1456
01:18:05,662 --> 01:18:07,363
IT'S DIVIDING AND ACTIVE COULD 

1457
01:18:07,363 --> 01:18:08,931
BE LOST OVER TIME IS DIFFERENT 

1458
01:18:08,931 --> 01:18:11,901
FROM GENE THERAPY IN A TISSUE 

1459
01:18:11,901 --> 01:18:19,509
THAT IS POST-MYTOTIC AND UNIQUE 

1460
01:18:19,509 --> 01:18:29,819
TO MUSCLE DISEASE.

1461
01:18:33,923 --> 01:18:37,160
THERE WILL BE MUSCLE COMBROEJ 

1462
01:18:37,160 --> 01:18:39,062
DRIVEN BY SATELLITE CELLS TO 

1463
01:18:39,062 --> 01:18:43,966
CREATE ADDITIONAL NUCLEI TO 

1464
01:18:43,966 --> 01:18:44,300
CREATE THIS.

1465
01:18:44,300 --> 01:18:47,970
YOU CAN IMAGINE IF A GENE 

1466
01:18:47,970 --> 01:18:50,173
THERAPY IS GIVEN EARLY ADD TO 

1467
01:18:50,173 --> 01:18:53,976
THAT THE MUSCULAR DYSTROPHY AND 

1468
01:18:53,976 --> 01:18:55,745
YOU COULD ENVISION THERE'S A 

1469
01:18:55,745 --> 01:18:57,980
DURABILITY PROBLEM WITH THIS 

1470
01:18:57,980 --> 01:19:08,157
APPROACH.

1471
01:19:20,770 --> 01:19:28,978
AND WE'VE HAD A MYOTROPIC AAD 

1472
01:19:28,978 --> 01:19:30,880
AND BETTER AT THE SATURATION OF 

1473
01:19:30,880 --> 01:19:33,983
THE TARGET TISSUE IS EXPECTED TO

1474
01:19:33,983 --> 01:19:38,955
BE BETTER.

1475
01:19:38,955 --> 01:19:40,189
THEY ARE BIND TO THE MOTIVE 

1476
01:19:40,189 --> 01:19:43,192
HERE.

1477
01:19:43,192 --> 01:19:48,164
THESE ARE THE COMMON 

1478
01:19:48,164 --> 01:19:52,201
DETERMINATES AND THE TISSUE OF 

1479
01:19:52,201 --> 01:19:56,372
THE FIBERS TIMES AND DURABILITY 

1480
01:19:56,372 --> 01:19:56,906
OF EXPRESSION.

1481
01:19:56,906 --> 01:19:58,241
ONE IS SUBSTRATE YOU'RE TRYING 

1482
01:19:58,241 --> 01:20:01,644
TO RESCUE HAS TO BE IN A STATE 

1483
01:20:01,644 --> 01:20:02,111
THAT STILL ALLOWS FOR 

1484
01:20:02,111 --> 01:20:10,186
REVERSIBILITY.

1485
01:20:10,186 --> 01:20:17,960
I WANT TO RAISE THE IMMUNOLOGY 

1486
01:20:17,960 --> 01:20:21,731
IN THE CONTEXT OF MUSCLE DISEASE

1487
01:20:21,731 --> 01:20:25,401
AND IT'S SOMETHING WE HAVE TO 

1488
01:20:25,401 --> 01:20:25,835
PHASE.

1489
01:20:25,835 --> 01:20:30,840
HERE ARE THE IMMUNOLOGICAL 

1490
01:20:30,840 --> 01:20:33,409
EVENTS THAT HAPPEN BEFORE AND 

1491
01:20:33,409 --> 01:20:36,512
AFTER GENE THERAPY.

1492
01:20:36,512 --> 01:20:41,184
AAV IS A NATURAL OCCURRING VIRUS

1493
01:20:41,184 --> 01:20:47,757
AND AS THE A PERCENTAGE OF 

1494
01:20:47,757 --> 01:20:50,693
PEOPLE ALREADY HAVE ANTIBODIES 

1495
01:20:50,693 --> 01:20:53,863
AND AFTER TRANSFER THERE'S 

1496
01:20:53,863 --> 01:20:58,534
INMATE IMMUNITY.

1497
01:20:58,534 --> 01:21:04,173
IT REACT TO THE HIGH VIRUS LOAD 

1498
01:21:04,173 --> 01:21:06,776
AND THERE'S IMMUNITY WHERE IT 

1499
01:21:06,776 --> 01:21:08,511
HAS AN ADAPTIVE IMMUNE RESPONSE 

1500
01:21:08,511 --> 01:21:11,214
AGAINST THE CAPSID BUT THEN ALSO

1501
01:21:11,214 --> 01:21:13,015
AS A TRANS GENE THAT'S EXPRESSED

1502
01:21:13,015 --> 01:21:20,323
AGAINST THE TRANS GENE ITSELF.

1503
01:21:20,323 --> 01:21:22,225
THERE'S DISEASE FACTORS AND 

1504
01:21:22,225 --> 01:21:25,394
STAGES BECAUSE OF THE INDIVIDUAL

1505
01:21:25,394 --> 01:21:26,028
ENVIRONMENT OF THE DISEASE AND 

1506
01:21:26,028 --> 01:21:33,135
THE HOST.

1507
01:21:33,135 --> 01:21:34,837
THESE SHOW THE DIFFERENT PHASES 

1508
01:21:34,837 --> 01:21:35,805
OF IMMUNE REACTION.

1509
01:21:35,805 --> 01:21:42,378
I'M GOING TO HIGHLIGHT A FEW.

1510
01:21:42,378 --> 01:21:46,182
ONE IS INNATE IMMUNE ACTIVATION.

1511
01:21:46,182 --> 01:21:49,085
THERE'S AN IMMEDIATE REACTION TO

1512
01:21:49,085 --> 01:21:52,188
THE HIGH LOWS OF VIRUSES AND 

1513
01:21:52,188 --> 01:21:54,557
THAT'S SOMETHING THAT CAN HELP 

1514
01:21:54,557 --> 01:21:56,292
EVEN WITH INFECTION.

1515
01:21:56,292 --> 01:21:58,761
IT'S AN ACTIVATION OF THE 

1516
01:21:58,761 --> 01:22:01,831
COMPLEMENT SYSTEM THAT THEN GOES

1517
01:22:01,831 --> 01:22:05,868
OUT OF CONTROL AND CAUSES THE 

1518
01:22:05,868 --> 01:22:09,972
DAMAGES AND CYTO PENA AND 

1519
01:22:09,972 --> 01:22:12,608
HEMOLYSIS AND ORGAN DAMAGE.

1520
01:22:12,608 --> 01:22:14,544
THERE'S HIGH DOZE TRIALS 

1521
01:22:14,544 --> 01:22:17,647
PARTICULARLY THOSE USING AAV9 

1522
01:22:17,647 --> 01:22:18,214
SEEMS TO BE A PARTICULAR 

1523
01:22:18,214 --> 01:22:28,658
VIABILITY OF THAT CAPSID.

1524
01:22:36,399 --> 01:22:39,201
THIS SEEN IN THE EARLY TRIALS 

1525
01:22:39,201 --> 01:22:40,603
AND CYTOTOXIC TRIALS WERE 

1526
01:22:40,603 --> 01:22:42,505
ATTACKING THE LIVER TRYING TO 

1527
01:22:42,505 --> 01:22:46,809
MAKE THE PROTEIN FACTOR AND THAT

1528
01:22:46,809 --> 01:22:51,414
LED TO DECREASING EFFICACY AND 

1529
01:22:51,414 --> 01:22:53,115
IN THE TRIAL WHERE THE LIVER IS 

1530
01:22:53,115 --> 01:23:03,526
A BYSTANDER IF YOU WILL.

1531
01:23:04,460 --> 01:23:06,829
SOMETIMES DRAMATICALLY SO AND 

1532
01:23:06,829 --> 01:23:09,966
CONTROLLED BY IMMUNE MODULATION 

1533
01:23:09,966 --> 01:23:16,105
SUCH AS STEROIDS.

1534
01:23:16,105 --> 01:23:18,441
THERE'S ONE SPECIFIC LIVER 

1535
01:23:18,441 --> 01:23:20,409
TOXICITY THAT BRINGS THE TRIAL 

1536
01:23:20,409 --> 01:23:22,211
AND M1 TRIAL AND FOUR PATIENTS 

1537
01:23:22,211 --> 01:23:27,917
IN THAT TRIAL DIED OF SEVERE 

1538
01:23:27,917 --> 01:23:29,352
LIVER FAILURE.

1539
01:23:29,352 --> 01:23:32,755
DIFFERENT FROM THE TOXIC EVENT 

1540
01:23:32,755 --> 01:23:36,425
IN THE OTHER HEMOPHILIA AND 

1541
01:23:36,425 --> 01:23:37,960
DUCHENNE TRIALS AND A DIFFERENT 

1542
01:23:37,960 --> 01:23:41,897
TYPE THAT HAPPENED IN THE BOYS.

1543
01:23:41,897 --> 01:23:44,967
THAT LED TO THE RECOGNITION THIS

1544
01:23:44,967 --> 01:23:55,478
NOT A PURE DISEASE BUT A CHO

1545
01:23:58,714 --> 01:24:01,951
CHOLESTATIC LIVER DISEASE AND 

1546
01:24:01,951 --> 01:24:09,558
AND HAS PROPENSITY TO 

1547
01:24:09,558 --> 01:24:11,060
CHOLESTASIS AND THEY'RE 

1548
01:24:11,060 --> 01:24:13,963
SOMETIMES PART OF VIRAL 

1549
01:24:13,963 --> 01:24:20,970
INFECTIONS.

1550
01:24:20,970 --> 01:24:25,341
THEY WERE ABLE TO SHOW TUBULAR 

1551
01:24:25,341 --> 01:24:28,177
MYOPATHY HAS A CHOLESTATIC 

1552
01:24:28,177 --> 01:24:32,148
DELIVER PHENOTYPE DUE TO DEFECT 

1553
01:24:32,148 --> 01:24:42,925
IN MEMBRANE TRAFFIC IKING WITH E

1554
01:24:43,392 --> 01:24:45,294
TRANSPORTER NOT IN PLACE AND IT 

1555
01:24:45,294 --> 01:24:47,530
GETS OVERLOADED AND THE SYSTEM 

1556
01:24:47,530 --> 01:24:49,832
GETS STRESSED TO A POINT IT GOES

1557
01:24:49,832 --> 01:24:53,803
INTO CHOLESTATIC FAILURE.

1558
01:24:53,803 --> 01:24:57,973
THE GENE PRODUCT IS UNDER A 

1559
01:24:57,973 --> 01:25:02,278
PROMOT

1560
01:25:02,278 --> 01:25:07,149
PROMOTER THAT LEAVES IT TO THIS 

1561
01:25:07,149 --> 01:25:07,983
PARTICULAR COMBINATION OF THE 

1562
01:25:07,983 --> 01:25:09,618
VIRAL LOAD AND THE DISEASE 

1563
01:25:09,618 --> 01:25:12,722
SPECIFIC SUSCEPTIBILITY.

1564
01:25:12,722 --> 01:25:14,990
WE CAN DISCUSS POSSIBLE 

1565
01:25:14,990 --> 01:25:15,691
SOLUTIONS TO THIS PROBLEM IN THE

1566
01:25:15,691 --> 01:25:16,092
DISCUSSION PHASE.

1567
01:25:16,092 --> 01:25:16,158
 

1568
01:25:21,597 --> 01:25:23,466
LASTLY I WANT TO MENTION GENE 

1569
01:25:23,466 --> 01:25:27,937
THERAPY IS A TRANSPLANTATION OF 

1570
01:25:27,937 --> 01:25:33,175
A PROTEIN INTO A HOST WHO MAY 

1571
01:25:33,175 --> 01:25:36,145
NOT HAVE SEEN THIS PEPTIDE EVER 

1572
01:25:36,145 --> 01:25:40,049
AND REACTING WITH ANTI-TRANS 

1573
01:25:40,049 --> 01:25:40,316
IMMUNITY.

1574
01:25:40,316 --> 01:25:49,391
IT COMES BACK TO ANDY'S TALK AND

1575
01:25:49,391 --> 01:25:51,393
WHEN YOU TRANSFECT THE MUSCLE 

1576
01:25:51,393 --> 01:25:53,929
GIVING IT A NEW PROTEIN TO 

1577
01:25:53,929 --> 01:25:55,531
EXPRESS IT WILL BE PRESENTED TO 

1578
01:25:55,531 --> 01:25:57,366
THE IMMUNE SYSTEM.

1579
01:25:57,366 --> 01:26:00,870
WHEN THE IMMUNE SYSTEM IT WILL 

1580
01:26:00,870 --> 01:26:04,573
TAKE NOTICE.

1581
01:26:04,573 --> 01:26:06,442
IN THE DUCHENNE MUSCULAR 

1582
01:26:06,442 --> 01:26:09,779
DYSTROPHY TRIALS IT WAS CLEAR 

1583
01:26:09,779 --> 01:26:11,647
SOME PATIENTS DEVELOPED ALL OF A

1584
01:26:11,647 --> 01:26:16,352
SUDDEN A VERY SEVERE MYOSITIS 

1585
01:26:16,352 --> 01:26:26,729
AND EVEN MYOCARDITIS.

1586
01:26:26,729 --> 01:26:32,668
THERE WAS A GROUP OF AND COME 

1587
01:26:32,668 --> 01:26:34,003
TOGETHER VERY RAPIDLY AND TRY TO

1588
01:26:34,003 --> 01:26:36,605
FIGURE OUT WHAT WAS GOING ON.

1589
01:26:36,605 --> 01:26:38,541
ALL THAT'S GOING ON IS THE 

1590
01:26:38,541 --> 01:26:40,509
PATIENTS HAD GENOMIC DELETIONS 

1591
01:26:40,509 --> 01:26:43,746
AS PART OF THEIR GENOTYPE FOR 

1592
01:26:43,746 --> 01:26:47,116
THE MUSCULAR DYSTROPHY AND 

1593
01:26:47,116 --> 01:26:49,518
OVERLAPPED THE PEPTIDE SEQUENCE 

1594
01:26:49,518 --> 01:26:51,887
DELIVERED BY THE TRANS GENES.

1595
01:26:51,887 --> 01:26:54,924
IN THESE PARTS ARE PATIENTS 

1596
01:26:54,924 --> 01:26:57,193
WHERE THEY'RE IMMUNE NAIVE.

1597
01:26:57,193 --> 01:26:59,128
THEY HAVEN'T SEEN THE EPITOPES 

1598
01:26:59,128 --> 01:27:02,097
AND THE IMMUNE SYSTEM WAS TRYING

1599
01:27:02,097 --> 01:27:07,069
TO REJECT IT.

1600
01:27:07,069 --> 01:27:11,407
AND THIS WAS HIGHLY EXPOSED AND 

1601
01:27:11,407 --> 01:27:13,909
MORE RECENT CASE WITH A DELETION

1602
01:27:13,909 --> 01:27:17,947
WAS ENOUGH TO CAUSE SEVERE 

1603
01:27:17,947 --> 01:27:21,383
MYOSITIS AND THEY WERE ABLE TO 

1604
01:27:21,383 --> 01:27:28,224
SHOW THIS WAS RECOGNIZED BY CYTO

1605
01:27:28,224 --> 01:27:34,230
TOXIC T CELLS AND THAT ALLOWS US

1606
01:27:34,230 --> 01:27:39,535
TO UNDERSTAND DEVELOP RISK 

1607
01:27:39,535 --> 01:27:41,203
PROFILES AND I CAN'T EMPHASIZE 

1608
01:27:41,203 --> 01:27:45,174
THE SHARING AROUND THIS IS KEY 

1609
01:27:45,174 --> 01:27:46,308
TO RECOGNIZE THIS AND DEVELOP 

1610
01:27:46,308 --> 01:27:56,685
MITIGATING STRATEGIES.

1611
01:27:57,386 --> 01:27:58,854
HERE THE LIVER COMES TO THE 

1612
01:27:58,854 --> 01:28:03,392
RESCUE AS A BY-STANDER AND 

1613
01:28:03,392 --> 01:28:07,696
INDUCING ORGAN NOW INVOLVED IN 

1614
01:28:07,696 --> 01:28:09,965
THE RESEARCH AND WE NEED TO 

1615
01:28:09,965 --> 01:28:15,104
UNDERSTAND THE RISKS BETTER.

1616
01:28:15,104 --> 01:28:16,906
I'LL LEAVE YOU WITH THESE 

1617
01:28:16,906 --> 01:28:20,242
THOUGHTS AND THANK THE 

1618
01:28:20,242 --> 01:28:24,546
COLLABORATORS AND MY TEAM AND 

1619
01:28:24,546 --> 01:28:25,948
THOSE INSTRUCTIONAL IN THE 

1620
01:28:25,948 --> 01:28:26,615
MUSCULAR DYSTROPHY TRIAL AND 

1621
01:28:26,615 --> 01:28:27,683
MOVE ON TO QUESTIONS.

1622
01:28:27,683 --> 01:28:30,252
THANK YOU VERY MUCH.

1623
01:28:30,252 --> 01:28:31,754
>> ALL RIGHT.

1624
01:28:31,754 --> 01:28:35,224
THANK YOU VERY MUCH FOR THAT 

1625
01:28:35,224 --> 01:28:37,960
REALLY ANFANTASTIC SET OF 

1626
01:28:37,960 --> 01:28:38,294
PRESENTATIONS.

1627
01:28:38,294 --> 01:28:48,537
IT'S AMAZING.

1628
01:28:49,305 --> 01:28:59,281
IT'S A TEST  -- TESTIMONY OF THE

1629
01:28:59,281 --> 01:29:02,484
HARD WORK INTO THIS AND HOW 

1630
01:29:02,484 --> 01:29:03,652
IMPORTANT MUSCLE IS AT ALL 

1631
01:29:03,652 --> 01:29:07,156
STAGES OF LIFE AND DOES MAKE UP 

1632
01:29:07,156 --> 01:29:16,231
A MAJOR PART OF OUR BODIES AND 

1633
01:29:16,231 --> 01:29:19,401
PHYSIOLOGY.

1634
01:29:19,401 --> 01:29:22,638
WE HAVE A GREAT GROUP OF 

1635
01:29:22,638 --> 01:29:24,006
QUESTIONERS IN THE AUDIENCE WITH

1636
01:29:24,006 --> 01:29:25,307
INTERESTING THOUGHTS AND 

1637
01:29:25,307 --> 01:29:25,908
PROBABLY ONE OF THE MOST 

1638
01:29:25,908 --> 01:29:28,310
IMPORTANT THINGS WE CAN TRY TO 

1639
01:29:28,310 --> 01:29:31,747
DO IS TIE TOGETHER THE THOUGHTS 

1640
01:29:31,747 --> 01:29:37,920
OF THESE TWO PRESENTATIONS.

1641
01:29:37,920 --> 01:29:41,957
ONE LINE OF QUESTIONS HAS TO DO 

1642
01:29:41,957 --> 01:29:53,035
WITH WHERE THE AUTOBEYOANTIBOY  

1643
01:29:54,536 --> 01:29:55,771
COMING FROM AND WHAT'S 

1644
01:29:55,771 --> 01:29:56,839
STIMULATING THEM AND THEN 

1645
01:29:56,839 --> 01:29:58,007
CONSIDER THE ISSUES WITH REGARD 

1646
01:29:58,007 --> 01:30:05,280
TO THE DYSTROPHIES AND 

1647
01:30:05,280 --> 01:30:05,647
MYOPATHIES.

1648
01:30:05,647 --> 01:30:10,919
I'LL PUT THE GOOD DR. MAMMEN IN 

1649
01:30:10,919 --> 01:30:21,163
THE HOT SEAT.

1650
01:30:25,267 --> 01:30:29,371
ONE POSSIBLE SOURCE, AND WHAT IS

1651
01:30:29,371 --> 01:30:32,274
STIMULATING THEM IS THE 

1652
01:30:32,274 --> 01:30:32,541
QUESTION?

1653
01:30:32,541 --> 01:30:34,743
>> THAT'S A HOLY GRAIL TO
TRY TO

1654
01:30:34,743 --> 01:30:35,177
UNDERSTAND THAT.

1655
01:30:35,177 --> 01:30:38,747
WE KNEW A COUPLE THINGS.

1656
01:30:38,747 --> 01:30:41,517
ONE IS NOT EVERYBODY HAS THE 

1657
01:30:41,517 --> 01:30:44,620
SAME RISK FOR DEVELOPING A 

1658
01:30:44,620 --> 01:30:46,722
PARTICULAR TYPE OF AUTOIMMUNITY.

1659
01:30:46,722 --> 01:30:49,558
THERE'S IMMUNOGENETIC RISK 

1660
01:30:49,558 --> 01:30:50,392
FACTORSES THAT PREDISPOSE 

1661
01:30:50,392 --> 01:30:52,861
PATIENT TO DEVELOPING DISEASE.

1662
01:30:52,861 --> 01:30:55,564
MANY SHARE THE RISK FACTORS BUT 

1663
01:30:55,564 --> 01:30:59,134
ONLY A RELATIVELY SMALL SUBSET 

1664
01:30:59,134 --> 01:31:03,138
WILL DEVELOP AUTOIMMUNITY.

1665
01:31:03,138 --> 01:31:05,808
WE THINK THERE'S ENVIRONMENTAL 

1666
01:31:05,808 --> 01:31:06,208
TRIGGERS.

1667
01:31:06,208 --> 01:31:07,409
AN ENVIRONMENT TRIGGER OR 

1668
01:31:07,409 --> 01:31:10,779
TRIGGERS THAT OCCUR TO A PATIENT

1669
01:31:10,779 --> 01:31:18,387
WHO HAS THE 2346R9  -- DEVELOP 

1670
01:31:18,387 --> 01:31:20,355
THE RISK FACTORS AND I'LL GIVE 

1671
01:31:20,355 --> 01:31:23,492
AN EXAMPLE OF WHAT IS PROBABLY 

1672
01:31:23,492 --> 01:31:27,162
THE BEST UNDERSTOOD ONE.

1673
01:31:27,162 --> 01:31:30,365
SOME WHO DEVELOP NECROTIZING 

1674
01:31:30,365 --> 01:31:34,837
MYOSITIS AND HAVE THE 

1675
01:31:34,837 --> 01:31:37,539
PHARMACOLOGIC TARGET OF STATINS.

1676
01:31:37,539 --> 01:31:40,909
THERE'S A POTENT IMMUNOGENETIC 

1677
01:31:40,909 --> 01:31:45,948
RISK FACTOR FOR DEVELOPING THIS 

1678
01:31:45,948 --> 01:31:52,287
FORM AND ABOUT 70% OF PATIENTS 

1679
01:31:52,287 --> 01:31:56,191
WITH THESE ANTIBODIES HAVE THE 

1680
01:31:56,191 --> 01:32:01,964
CLASS 2HLA ALLELE WHERE WE ONLY 

1681
01:32:01,964 --> 01:32:05,067
FOUND IT IN 15% OF THE HEALTHY 

1682
01:32:05,067 --> 01:32:05,367
POPULATIONS.

1683
01:32:05,367 --> 01:32:07,336
IT'S ONE OF THE STRONGEST 

1684
01:32:07,336 --> 01:32:11,306
IMMUNOGENETIC RISK FACTORS FOR 

1685
01:32:11,306 --> 01:32:13,742
AN AUTOIMMUNE DISEASE.

1686
01:32:13,742 --> 01:32:21,083
AND WE ALSO KNOW WHAT THE 

1687
01:32:21,083 --> 01:32:22,918
ENVIRONMENTAL RISK FACTOR IS AND

1688
01:32:22,918 --> 01:32:26,455
IT'S EXPOSURE TO STATIN 

1689
01:32:26,455 --> 01:32:27,156
MEDICATIONS.

1690
01:32:27,156 --> 01:32:33,061
AS I'M SURE THE AUDIENCE KNOW, 

1691
01:32:33,061 --> 01:32:36,098
THEY LOWER CHOLESTEROL LEVELS BY

1692
01:32:36,098 --> 01:32:39,201
INHIBITING THE FUNCTION SO 

1693
01:32:39,201 --> 01:32:41,203
THERE'S LESS BILE SYNTHESIS AND 

1694
01:32:41,203 --> 01:32:42,804
THERE'S A DIRECT LINK BETWEEN 

1695
01:32:42,804 --> 01:32:43,872
THE TARGET OF THE IMMUNE 

1696
01:32:43,872 --> 01:32:45,240
RESPONSE AND THE THING 

1697
01:32:45,240 --> 01:32:46,408
PREDISPOSING IT.

1698
01:32:46,408 --> 01:32:48,710
WHAT WE HYPOTHESIZE BUT DON'T 

1699
01:32:48,710 --> 01:32:52,581
KNOW FOR SURE IS THAT BINDING OF

1700
01:32:52,581 --> 01:33:02,224
THE STATIN TO HMGCR MAY GENERATE

1701
01:33:02,224 --> 01:33:06,562
NOVEL EPITOPES AND YOU 

1702
01:33:06,562 --> 01:33:07,362
SUBSEQUENTLY DEVELOP 

1703
01:33:07,362 --> 01:33:08,664
AUTOIMMUNITY AGAINST THESE 

1704
01:33:08,664 --> 01:33:12,167
SLIGHTLY DIFFERENT FRAGMENTS OF 

1705
01:33:12,167 --> 01:33:14,102
HMGCR THE SYSTEM HASN'T SEEN 

1706
01:33:14,102 --> 01:33:17,005
BEFORE AND THAT ANTIBODY 

1707
01:33:17,005 --> 01:33:21,243
RESPONSE SPREAD TO ALSO 

1708
01:33:21,243 --> 01:33:22,477
RECOGNIZE THE NATIVE WILD TYPE 

1709
01:33:22,477 --> 01:33:22,878
PROTEINS.

1710
01:33:22,878 --> 01:33:26,949
SO THAT'S AN EXAMPLE WHERE WHERE

1711
01:33:26,949 --> 01:33:29,351
TWO THINGS HAVE TO COME 

1712
01:33:29,351 --> 01:33:29,685
TOGETHER.

1713
01:33:29,685 --> 01:33:31,720
THE IMMUNOGENETIC RISK FACTOR 

1714
01:33:31,720 --> 01:33:33,255
AND THE STATIN EXPOSURE.

1715
01:33:33,255 --> 01:33:34,823
BUT IT'S NOT THAT SIMPLE BECAUSE

1716
01:33:34,823 --> 01:33:37,960
THE MAJORITY OF PATIENTS WHO 

1717
01:33:37,960 --> 01:33:39,695
HAVE BOTH THE IMMUNOGENETIC RISK

1718
01:33:39,695 --> 01:33:42,998
FACTOR AND EXPOSURE TO STATINS 

1719
01:33:42,998 --> 01:33:45,968
NEVER DEVELOP THAT AUTOIMMUNITY 

1720
01:33:45,968 --> 01:33:48,637
SO THERE HAVE BEEN ADDITIONAL 

1721
01:33:48,637 --> 01:33:49,938
FACTORS OR ENVIRONMENTAL FACTORS

1722
01:33:49,938 --> 01:33:56,311
WE DON'T KNOW.

1723
01:33:56,311 --> 01:34:00,315
TO THROW IN A TIDBIT, THE RISK 

1724
01:34:00,315 --> 01:34:01,950
FOR DEVELOPING THE DISEASE 

1725
01:34:01,950 --> 01:34:03,418
VARIES WIDELY ACROSS ETHNIC 

1726
01:34:03,418 --> 01:34:03,652
GROUPS.

1727
01:34:03,652 --> 01:34:06,922
IN THE UNITED STATES AMONG BLACK

1728
01:34:06,922 --> 01:34:12,327
AND WHITE AMERICANS 1 IN 30,000 

1729
01:34:12,327 --> 01:34:14,830
PATIENTS DEVELOP WITH A STATIN 

1730
01:34:14,830 --> 01:34:17,499
WILL DEVELOP THIS AND AMONG THE 

1731
01:34:17,499 --> 01:34:22,604
NAVAJO IN NEW MEXICO IS 1 IN 

1732
01:34:22,604 --> 01:34:22,804
300.

1733
01:34:22,804 --> 01:34:29,945
THEY HAVE ANOTHER FACTOR I 

1734
01:34:29,945 --> 01:34:32,414
PRESUME IT'S GENETIC AND THAT'S 

1735
01:34:32,414 --> 01:34:33,548
MY LONG WINDED EXAMPLE.

1736
01:34:33,548 --> 01:34:37,386
IT'S NOT JUST ONE THING.

1737
01:34:37,386 --> 01:34:39,988
MULTIPLE THINGS HAVE TO BE WITH 

1738
01:34:39,988 --> 01:34:44,259
THE RIGHT IMMUNOGENETICS AND THE

1739
01:34:44,259 --> 01:34:45,327
RIGHT ENVIRONMENTAL EXPOSURES TO

1740
01:34:45,327 --> 01:34:47,863
DEVELOP IT AND ONE FURTHER THING

1741
01:34:47,863 --> 01:34:52,034
ABOUT THE CLASS 2HLA ALLELE WE 

1742
01:34:52,034 --> 01:34:54,303
THINK IT'S PRE DISPOSING BECAUSE

1743
01:34:54,303 --> 01:34:57,572
THOSE ARE VERY INVOLVED IN 

1744
01:34:57,572 --> 01:35:00,042
PRESENT

1745
01:35:00,042 --> 01:35:00,709
PRESENTING ANTIGENS LEADING TO 

1746
01:35:00,709 --> 01:35:08,717
THE DEVELOPMENT OF ANTIBODIES.

1747
01:35:08,717 --> 01:35:12,954
FOR MOST FORMS OF AUTOIMMUNITIES

1748
01:35:12,954 --> 01:35:15,023
AND ANTIBODIES WE DON'T 

1749
01:35:15,023 --> 01:35:15,824
UNDERSTAND IT NEARLY AS WELL.

1750
01:35:15,824 --> 01:35:19,294
>> THAT'S VERY HELPFUL AND

1751
01:35:19,294 --> 01:35:26,601
THAT'S A GREAT EXAMPLE IN TERMS 

1752
01:35:26,601 --> 01:35:32,774
OF AN EXOGENOUS ANTIGEN IN A 

1753
01:35:32,774 --> 01:35:33,775
MEDICATION ORDINARILY AN 

1754
01:35:33,775 --> 01:35:35,610
INDIVIDUAL WOULDN'T ENCOUNTER IN

1755
01:35:35,610 --> 01:35:37,946
NATURAL LIFE THAT MIGHT THEN 

1756
01:35:37,946 --> 01:35:40,415
CREATE THIS KIND OF SITUATION IN

1757
01:35:40,415 --> 01:35:43,685
WHICH THE IMMUNE SYSTEM GETS 

1758
01:35:43,685 --> 01:35:54,096
SORT OF HOOKWINKED  -- 

1759
01:35:54,830 --> 01:36:00,469
HOOKWINKED AND BEFORE I BRING IT

1760
01:36:00,469 --> 01:36:04,272
OVER, WHAT ABOUT RATHER THAN IT 

1761
01:36:04,272 --> 01:36:09,945
BEING A MEDICATION IT BE AN 

1762
01:36:09,945 --> 01:36:20,255
INFECTIOUS AGENT.

1763
01:36:33,001 --> 01:36:35,537
COULD YOU LOOK AT THE 

1764
01:36:35,537 --> 01:36:37,105
SPECIFICITY OF THE ANTIBODIES.

1765
01:36:37,105 --> 01:36:40,308
THERE'S ANTIBODIES AGAINST THE 

1766
01:36:40,308 --> 01:36:42,611
INTRACELLULAR MOLECULES.

1767
01:36:42,611 --> 01:36:49,117
USING SEQ COULD YOU DEDUCE THE 

1768
01:36:49,117 --> 01:36:50,919
SMALL PIECE OF ANTIGEN AND THEN 

1769
01:36:50,919 --> 01:36:56,425
TRY TO LOOK AT THE DATABASE OF 

1770
01:36:56,425 --> 01:37:01,530
PATHOGENIC SEQUENCES TO DEDUCE 

1771
01:37:01,530 --> 01:37:03,932
WHAT MIGHT IT BE THAT MAY BE 

1772
01:37:03,932 --> 01:37:05,934
STIMULATING THAT IF YOU WANT TO 

1773
01:37:05,934 --> 01:37:08,503
BUY INTO THAT MODEL?

1774
01:37:08,503 --> 01:37:11,840
>> THAT INSTEAD OF
EXPRESSING 

1775
01:37:11,840 --> 01:37:17,979
THE WHOLE HUMAN PROTEOME YOU 

1776
01:37:17,979 --> 01:37:19,347
EXPRESS THE VIRUSES AND THE 

1777
01:37:19,347 --> 01:37:23,084
IMMUNE RESPONSE AND LOOK TO SEE 

1778
01:37:23,084 --> 01:37:25,954
IF PATIENTS WITH THE AUTOIMMUNE 

1779
01:37:25,954 --> 01:37:30,992
DISEASES HAVE BEEN EXPOSED TO A 

1780
01:37:30,992 --> 01:37:35,530
VIRUS IN GREATER FLRMZ.

1781
01:37:35,530 --> 01:37:38,467
SOME VIRUSES MAY HAVE SOME ROLE 

1782
01:37:38,467 --> 01:37:43,872
BUT IT'S NOT A SLAM DUNK.

1783
01:37:43,872 --> 01:37:54,416
MAYBE THE BEST MODEL IS GILLAN 

1784
01:37:57,319 --> 01:37:57,953
BU

1785
01:37:57,953 --> 01:38:00,755
BARRE -- GUILLAIN-BARRE.

1786
01:38:00,755 --> 01:38:02,557
I'M SPACING ON THE NAME.

1787
01:38:02,557 --> 01:38:04,159
THERE'S EXAMPLES OF THAT AND 

1788
01:38:04,159 --> 01:38:06,161
IT'S A MOLECULAR MIMICRY.

1789
01:38:06,161 --> 01:38:09,965
WE SO FAR HAVEN'T NAILED THAT 

1790
01:38:09,965 --> 01:38:13,435
DOWN FOR MOST THE RHEUMATIC 

1791
01:38:13,435 --> 01:38:13,702
DISEASES.

1792
01:38:13,702 --> 01:38:20,375
>> TO TRY TO TAKE IT OVER
THEN, 

1793
01:38:20,375 --> 01:38:24,980
YOU MIGHT THINK PATIENTS WITH 

1794
01:38:24,980 --> 01:38:35,724
SOME OF THE DYSTROPHIES OR MY N

1795
01:38:39,394 --> 01:38:46,968
 -- MYOPATHIES AND LIKE THE ONE 

1796
01:38:46,968 --> 01:38:48,904
ANDY TALKS ABOUT HIS PATIENTS 

1797
01:38:48,904 --> 01:38:50,672
GET ANTIBODIES AGAINST, IS THERE

1798
01:38:50,672 --> 01:38:52,307
EVIDENCE THOSE PATIENTS OR HAS 

1799
01:38:52,307 --> 01:38:55,744
ANYBODY LOOKED TO SEE WHETHER 

1800
01:38:55,744 --> 01:38:59,347
THOSE PATIENTS GET 

1801
01:38:59,347 --> 01:39:01,950
AUTOANTIBODIES AGAINST PROTEINS 

1802
01:39:01,950 --> 01:39:05,587
THAT ARE INSIDE MUSCLE CELLS?

1803
01:39:05,587 --> 01:39:12,794
>> WE DID LOOK AND IT'S
NOT SO 

1804
01:39:12,794 --> 01:39:13,562
STRAIGHTFORWARD.

1805
01:39:13,562 --> 01:39:17,866
WE LOOKED AT GENETIC DISEASE OF 

1806
01:39:17,866 --> 01:39:18,233
HMGCR.

1807
01:39:18,233 --> 01:39:21,703
THE GENETIC MUTATION OCCURRED IN

1808
01:39:21,703 --> 01:39:28,777
THE PROTEIN AND WE LOOKED TO SEE

1809
01:39:28,777 --> 01:39:30,912
IF THEY'D BE PART OF THE DISEASE

1810
01:39:30,912 --> 01:39:32,714
DRIVER.

1811
01:39:32,714 --> 01:39:39,487
THAT'S NOT THE CASE.

1812
01:39:39,487 --> 01:39:42,891
THERE'S BIG INCLUSIONS OF THE 

1813
01:39:42,891 --> 01:39:44,059
PROTEIN AND THERE'S ANTIBODIES 

1814
01:39:44,059 --> 01:39:47,329
KNOWN AGAINST THE PROTEIN TO SEE

1815
01:39:47,329 --> 01:39:49,931
IF IT WOULD TRIGGER AN 

1816
01:39:49,931 --> 01:39:52,200
ADDITIONAL ANTIBODY RESPONSE.

1817
01:39:52,200 --> 01:39:55,737
IT'S KNOWN ON THE NERVE SIDE 

1818
01:39:55,737 --> 01:40:06,147
IT'S KNOWN SOME OF THE FORMS ITS

1819
01:40:06,147 --> 01:40:09,551
LOOKS LIKE THEY HAVE A HIGHER 

1820
01:40:09,551 --> 01:40:11,886
PROPENSITY OF DEVELOPING 

1821
01:40:11,886 --> 01:40:13,588
AUTOINFLAMMATORY RESPONSE CALLED

1822
01:40:13,588 --> 01:40:14,422
CIDP.

1823
01:40:14,422 --> 01:40:16,625
THE QUESTION IS THAT AN EXAMPLE 

1824
01:40:16,625 --> 01:40:19,995
WHERE WHAT YOU DESCRIBED IS 

1825
01:40:19,995 --> 01:40:22,030
HAPPENING.

1826
01:40:22,030 --> 01:40:25,934
AND IT'S PRESENTED TO THE 

1827
01:40:25,934 --> 01:40:27,969
AUTOIMMUNE SYSTEM AND THE 

1828
01:40:27,969 --> 01:40:31,640
PROBLEM WITH GENE THERAPY IN 

1829
01:40:31,640 --> 01:40:35,510
DYSTROPHY IS THE DEGENERATIVE 

1830
01:40:35,510 --> 01:40:38,680
DISEASE CAUSES ITS OWN 

1831
01:40:38,680 --> 01:40:38,980
ENVIRONMENT.

1832
01:40:38,980 --> 01:40:43,852
THERE'S CELLULAR INFILTRATION 

1833
01:40:43,852 --> 01:40:54,396
AND INFLAMMATION HAPPENING AND 

1834
01:40:56,731 --> 01:41:01,936
THAT CAUSES THE HYPER 

1835
01:41:01,936 --> 01:41:03,738
INFLAMMATORY ENVIRONMENT AND IS 

1836
01:41:03,738 --> 01:41:05,940
THE POTENTIAL EXAMPLE OF THAT 

1837
01:41:05,940 --> 01:41:13,682
ONE A PATIENT MORE ADVANCED IN 

1838
01:41:13,682 --> 01:41:19,154
THE MUSCULAR DYSTROPHY TREATMENT

1839
01:41:19,154 --> 01:41:22,390
AND IT WAS PUBLISHED IN THE NEW 

1840
01:41:22,390 --> 01:41:25,593
ENGLAND JOURNAL OF MEDICINE.

1841
01:41:25,593 --> 01:41:28,697
THAT PATIENT HAD UNFORTUNATELY A

1842
01:41:28,697 --> 01:41:31,933
FATAL RESPONSE TO THE GENE 

1843
01:41:31,933 --> 01:41:36,304
THERAPY WHERE HE GOT INTO A 

1844
01:41:36,304 --> 01:41:37,839
HYPER INFLAMMATORY STATE AND 

1845
01:41:37,839 --> 01:41:40,608
CALLED MULTI-ORGAN DAMAGE THAT 

1846
01:41:40,608 --> 01:41:42,877
PROBABLY WAS A COMBINATION OF 

1847
01:41:42,877 --> 01:41:44,512
THE DISEASE STAGE AND THE 

1848
01:41:44,512 --> 01:41:45,880
ADDITIONAL STRESS FROM THE HIGH 

1849
01:41:45,880 --> 01:41:51,920
DOSE OF THE AAV GOING INTO HIS 

1850
01:41:51,920 --> 01:41:52,420
BODY.

1851
01:41:52,420 --> 01:41:55,390
SO THERE IS THAT INTERPLAY 

1852
01:41:55,390 --> 01:41:57,959
BETWEEN HEIGHTENED IMMUNITY FROM

1853
01:41:57,959 --> 01:42:00,729
THE UNDERLYING DISEASE AND THE 

1854
01:42:00,729 --> 01:42:01,963
ADDITIONAL CHALLENGE, 

1855
01:42:01,963 --> 01:42:03,098
THERAPEUTIC CHALLENGE OF THE 

1856
01:42:03,098 --> 01:42:04,966
GENE THERAPY THAT CAN OCCUR.

1857
01:42:04,966 --> 01:42:07,435
>> TO EXPAND ON THAT A
LITTLE 

1858
01:42:07,435 --> 01:42:09,337
BIT, WE HAVE SEEN SEVERAL 

1859
01:42:09,337 --> 01:42:13,374
PATIENTS WHO HAVE BOTH PRETTY 

1860
01:42:13,374 --> 01:42:15,410
WELL DEFINED AUTOIMMUNE MYOSITIS

1861
01:42:15,410 --> 01:42:16,444
AND ALSO A KNOWN GENETIC 

1862
01:42:16,444 --> 01:42:16,678
DISEASE.

1863
01:42:16,678 --> 01:42:24,052
I HAVE A PATIENT WHO HAS BOTH 

1864
01:42:24,052 --> 01:42:25,687
ANTI-MI2 POSITIVE 

1865
01:42:25,687 --> 01:42:28,056
DERMATOMYOSITIS AND MUSCULAR 

1866
01:42:28,056 --> 01:42:31,426
DYSTROPHY AND ONE HAS A 

1867
01:42:31,426 --> 01:42:33,261
DYSTROPHY WHO HAS THE 

1868
01:42:33,261 --> 01:42:35,330
ANTISYNTHETASE SYNDROME AND 

1869
01:42:35,330 --> 01:42:36,498
THERE'S OTHER EXAMPLES IN THE 

1870
01:42:36,498 --> 01:42:37,799
LITERATURE OF PEOPLE HAVING 

1871
01:42:37,799 --> 01:42:37,999
BOTH.

1872
01:42:37,999 --> 01:42:40,301
I DON'T THINK WE'VE DONE A GOOD 

1873
01:42:40,301 --> 01:42:44,139
JOB OF PINNING DOWN WHETHER 

1874
01:42:44,139 --> 01:42:45,540
THEY'RE AT RISK OR NOT.

1875
01:42:45,540 --> 01:42:48,009
CERTAINLY WHEN YOU SEE THE 

1876
01:42:48,009 --> 01:42:50,111
PATIENTS -- I ALSO HAVE A 

1877
01:42:50,111 --> 01:42:57,952
PATIENT WHO'S A CARRIER FOR 

1878
01:42:57,952 --> 01:43:00,622
DUCHENNE MUSCULAR DYSTROPHY AND 

1879
01:43:00,622 --> 01:43:00,989
HAVE MYOSITIS.

1880
01:43:00,989 --> 01:43:03,892
MAYBE PATIENTS WHO HAVE A 

1881
01:43:03,892 --> 01:43:07,295
GENETIC MUSCLE DISEASE MAY ALSO 

1882
01:43:07,295 --> 01:43:08,863
DEVELOP AUTOIMMUNITY TARGETING 

1883
01:43:08,863 --> 01:43:12,100
THE MUSCLE BUT IT'S NOT SUPER 

1884
01:43:12,100 --> 01:43:13,935
WELL STUDIED BUT SUPER 

1885
01:43:13,935 --> 01:43:24,145
INTERESTING.

1886
01:43:26,014 --> 01:43:28,750
>> THE IDEA THE MOLECULES
INSIDE

1887
01:43:28,750 --> 01:43:30,418
THE CELL WHETHER IT'S MUSCLE 

1888
01:43:30,418 --> 01:43:34,088
CELLS OR OTHER KIND OF CELL.

1889
01:43:34,088 --> 01:43:36,724
THOSE MOLECULES COULD UNDER SOME

1890
01:43:36,724 --> 01:43:38,927
CIRCUMSTANCES STIMULATE THE 

1891
01:43:38,927 --> 01:43:49,237
IMMUNE SYSTEM IS REALLY I THINK 

1892
01:43:49,237 --> 01:43:51,339
EYE OPENING AND WE THOUGHT THAT 

1893
01:43:51,339 --> 01:43:54,542
WERE A PHENOMENON AGAINST THE 

1894
01:43:54,542 --> 01:43:55,343
PROTEINS AND MAY HAVE AN 

1895
01:43:55,343 --> 01:43:58,713
IMPORTANT BIOLOGICAL ROLE.

1896
01:43:58,713 --> 01:44:09,157
THAT IS QUITE CONSIDERING.

1897
01:44:15,129 --> 01:44:17,932
WHAT'S GOING ON AND MAYBE YOU 

1898
01:44:17,932 --> 01:44:21,402
SAID IT BUT MAYBE I MISSED IT, 

1899
01:44:21,402 --> 01:44:23,037
SHOULD THE STANDARD OF TREATMENT

1900
01:44:23,037 --> 01:44:26,608
BE AN IMMUNE EXPRESSIVE THERAPY 

1901
01:44:26,608 --> 01:44:28,376
TO TAMP DOWN THAT INFLAMMATORY 

1902
01:44:28,376 --> 01:44:38,820
MILIEU YOU'RE MENTIONING?

1903
01:44:43,024 --> 01:44:44,425
>> BEYOND STEROID
ADMINISTRATION

1904
01:44:44,425 --> 01:44:47,262
IS NOW DOWN IN I THINK ALL THE 

1905
01:44:47,262 --> 01:44:47,795
GENE THERAPIES THAT I WAS 

1906
01:44:47,795 --> 01:44:53,868
INVOLVED IN.

1907
01:44:53,868 --> 01:44:58,106
COULD YOU REFINE IT AND I THINK 

1908
01:44:58,106 --> 01:45:04,279
THE ANSWER IS INTEREST.

1909
01:45:04,279 --> 01:45:06,581
WE HAVE TO UNDERSTAND MORE TO DO

1910
01:45:06,581 --> 01:45:10,018
RESPONSES INNATE AND ADAPTIVE TO

1911
01:45:10,018 --> 01:45:20,428
UNDERSTAND THIS BETTER.

1912
01:45:21,596 --> 01:45:23,998
AND YOU CAN COMBINE THE STEROID 

1913
01:45:23,998 --> 01:45:31,940
REGIMENT WITH ANTI-T CELL DRUGS 

1914
01:45:31,940 --> 01:45:33,808
TO PREVENT AGAINST THE CAPSID 

1915
01:45:33,808 --> 01:45:36,844
AND THE GENE TO AVOID REJECTIONS

1916
01:45:36,844 --> 01:45:38,780
LIKE I DESCRIBED IN THE DUCHENNE

1917
01:45:38,780 --> 01:45:40,381
TRIAL PUTTING THE GENE THERAPY 

1918
01:45:40,381 --> 01:45:50,525
AT RISK.

1919
01:45:58,132 --> 01:46:02,170
I THINK WE HAVE DONE SO MANY 

1920
01:46:02,170 --> 01:46:07,308
PROTOCOLS OUT THERE AND THERE'S 

1921
01:46:07,308 --> 01:46:08,743
NO COMPARATIVE ANALYSIS IN THE 

1922
01:46:08,743 --> 01:46:09,477
GENE THERAPY CONTEXT.

1923
01:46:09,477 --> 01:46:10,378
WE NEED TO COME TOGETHER AS A 

1924
01:46:10,378 --> 01:46:17,552
FIELD.

1925
01:46:17,552 --> 01:46:19,487
WE'RE DOING THAT TO LOOK AT THE 

1926
01:46:19,487 --> 01:46:24,425
LENS AND COMPARE THAT WITH THE 

1927
01:46:24,425 --> 01:46:33,401
REGIMENTS AND THERE'S A GENOTYPE

1928
01:46:33,401 --> 01:46:35,536
MENTIONED AND IT'S PROBABLY 

1929
01:46:35,536 --> 01:46:37,939
SOMETHING WE NEED TO TAKE NOTE 

1930
01:46:37,939 --> 01:46:43,578
OF IN GENE THERAPY TO TAILOR 

1931
01:46:43,578 --> 01:46:45,179
THERAPIES FOR PATIENTS AND 

1932
01:46:45,179 --> 01:46:46,614
INDIVIDUAL MAKE UP.

1933
01:46:46,614 --> 01:46:49,117
THAT HOPEFULLY IS THE PRECISION 

1934
01:46:49,117 --> 01:46:50,551
MEDICINE ASPECT OF GENE THERAPY 

1935
01:46:50,551 --> 01:46:51,719
COMING IN THE FUTURE.

1936
01:46:51,719 --> 01:46:53,955
>> YOU KNOW, THAT'S WHAT
YOU'RE 

1937
01:46:53,955 --> 01:46:55,723
SAYING IS REALLY IMPORTANT WITH 

1938
01:46:55,723 --> 01:46:57,558
REGARD TO GENE THERAPY BUT YOU 

1939
01:46:57,558 --> 01:47:00,561
CAN EVEN IMAGINE FOR A PATIENT 

1940
01:47:00,561 --> 01:47:02,163
THAT ISN'T UNDERGOING GENE 

1941
01:47:02,163 --> 01:47:04,432
THERAPY, IF THEY'RE HAVING THIS 

1942
01:47:04,432 --> 01:47:05,867
INFLAMMATORY PROCESS GOING ON 

1943
01:47:05,867 --> 01:47:08,469
THAT MAYBE IS EXACERBATING 

1944
01:47:08,469 --> 01:47:11,372
THINGS THAT MAYBE THEY SHOULD BE

1945
01:47:11,372 --> 01:47:13,975
ON SOME SORT OF 

1946
01:47:13,975 --> 01:47:16,677
IMMUNOSUPPRESSIVE AGENT AS WELL.

1947
01:47:16,677 --> 01:47:27,055
>> THAT'S COMMON WITH 

1948
01:47:28,122 --> 01:47:32,493
DEGENERATIVE DISORDERS.

1949
01:47:32,493 --> 01:47:36,798
>> MAYBE COMMENT ON THE
LONG 

1950
01:47:36,798 --> 01:47:39,300
STANDING TRADITION OF TREATING 

1951
01:47:39,300 --> 01:47:49,110
BOYS WITH DYSTROEPENOPATHY WITH 

1952
01:47:49,110 --> 01:47:50,344
STEROIDS.

1953
01:47:50,344 --> 01:47:54,682
>> THERE'S PROBABLY A
MEMBRANE 

1954
01:47:54,682 --> 01:47:57,318
HEALING ASPECT AND IMMUNOLOGICAL

1955
01:47:57,318 --> 01:48:01,956
AND BIOLOGICAL EFFECT OF THE 

1956
01:48:01,956 --> 01:48:07,728
STEROID.

1957
01:48:07,728 --> 01:48:16,070
>> ANOTHER  ASPECT YOU
RAISED IN

1958
01:48:16,070 --> 01:48:19,173
YOUR TALK LIKE THE $64 MILLION 

1959
01:48:19,173 --> 01:48:21,509
QUESTION NOW, I GUESS, THE WHOLE

1960
01:48:21,509 --> 01:48:24,278
QUESTION OF WHAT IS THE RIGHT 

1961
01:48:24,278 --> 01:48:34,822
TIME TO DO GENE THERAPY ON ANY 

1962
01:48:36,858 --> 01:48:39,227
OF THESE PARTICULAR THERAPIES 

1963
01:48:39,227 --> 01:48:41,796
AND COMES DOWN TO THE 

1964
01:48:41,796 --> 01:48:43,197
COMBINATION OR MORE.

1965
01:48:43,197 --> 01:48:53,608
>> THAT'S THE QUESTION.

1966
01:48:57,044 --> 01:48:58,946
AS SOON AS YOU IDENTITY THIS YOU

1967
01:48:58,946 --> 01:49:03,050
CAN TREAT THIS BUT PARTICULARLY 

1968
01:49:03,050 --> 01:49:04,418
IN MUSCLE DISEASE IS WHAT 

1969
01:49:04,418 --> 01:49:11,659
HAPPENS AND THE DISEASE HAD 

1970
01:49:11,659 --> 01:49:13,528
DURABILITY IF IT'S TREATED EARLY

1971
01:49:13,528 --> 01:49:17,965
ON IN THE IMPACT OF THE DISEASE 

1972
01:49:17,965 --> 01:49:20,501
AND IF ANYTHING WERE TO STAY THE

1973
01:49:20,501 --> 01:49:30,978
SAME BUT IN A POST-MYCROTIC 

1974
01:49:33,080 --> 01:49:36,450
TISSUE HAS NEURONS AND IF YOU 

1975
01:49:36,450 --> 01:49:39,820
CAN TREAT THEM ALL EFFECTIVELY, 

1976
01:49:39,820 --> 01:49:47,995
THAT IS PROBABLY FOR YEARS NOT 

1977
01:49:47,995 --> 01:49:50,898
DECADES BECAUSE THERE'S NO 

1978
01:49:50,898 --> 01:49:57,538
TURNOVER AND HERE YOU HAVE 

1979
01:49:57,538 --> 01:50:01,042
NUCLEI AND THEY'RE DIVIDING AND 

1980
01:50:01,042 --> 01:50:01,876
LOSING THE GENE THERAPY IN THE 

1981
01:50:01,876 --> 01:50:10,785
CASE OF AAD.

1982
01:50:10,785 --> 01:50:13,654
THE DURABILITY IS STILL 

1983
01:50:13,654 --> 01:50:16,557
PROMISING EVEN IN MUSCULAR 

1984
01:50:16,557 --> 01:50:17,024
DYSTROPHY.

1985
01:50:17,024 --> 01:50:21,629
THE EFFECT IS QUITE DURABLE 

1986
01:50:21,629 --> 01:50:30,137
HOPEFULLY BUT WE CANNOT REDOSE.

1987
01:50:30,137 --> 01:50:32,173
YOU CAN'T REDOSE CURRENTLY 

1988
01:50:32,173 --> 01:50:34,041
UNLESS YOU DO INTERVENTIONS THAT

1989
01:50:34,041 --> 01:50:36,844
ALLOW YOU TO CREATE AN IMMUNE 

1990
01:50:36,844 --> 01:50:37,979
WINDOW TO OVERCOME THE 

1991
01:50:37,979 --> 01:50:38,779
ANTIBODIES AND REDOSE.

1992
01:50:38,779 --> 01:50:39,747
IT'S NOT TRIVIAL.

1993
01:50:39,747 --> 01:50:46,654
IT'S NOT GOING TO BE EASY.

1994
01:50:46,654 --> 01:50:48,689
IF WE LOOKED TO THE FUTURE THAT 

1995
01:50:48,689 --> 01:50:51,058
WOULD BE A PUSH TO GENOME 

1996
01:50:51,058 --> 01:50:51,292
EDITING.

1997
01:50:51,292 --> 01:50:53,995
IF WERE ABLE TO CORRECT THE 

1998
01:50:53,995 --> 01:50:57,064
GENETIC MUTATION IN THE GAIN OME

1999
01:50:57,064 --> 01:51:00,434
ITSELF THEN IT COMES AS A 

2000
01:51:00,434 --> 01:51:02,770
BENEFIT AND YOU'RE PROLIFERATING

2001
01:51:02,770 --> 01:51:05,973
THE CORRECTION AND AMPLIFYING 

2002
01:51:05,973 --> 01:51:08,309
THE CORRECTION OF THE CELLS THAT

2003
01:51:08,309 --> 01:51:12,513
ARE CORRECT AND PROLIFERATING 

2004
01:51:12,513 --> 01:51:14,915
AND HEALING THE TISSUE.

2005
01:51:14,915 --> 01:51:17,118
THEN OF COURSE TREATING EARLY IS

2006
01:51:17,118 --> 01:51:20,054
NO QUESTION THAT THAT SHOULD BE 

2007
01:51:20,054 --> 01:51:21,989
DONE THEN YOU HAVE THE 

2008
01:51:21,989 --> 01:51:22,390
INTERACTION.

2009
01:51:22,390 --> 01:51:24,792
>> YEAH.

2010
01:51:24,792 --> 01:51:29,230
IT DOES SOUND LIKE THE EDITING 

2011
01:51:29,230 --> 01:51:32,667
OPTION IS SOMETHING THAT MAKES A

2012
01:51:32,667 --> 01:51:35,603
LOT OF SENSE FROM THE CONCEPTUAL

2013
01:51:35,603 --> 01:51:38,439
POINT OF VIEW YOU OUTLINED.

2014
01:51:38,439 --> 01:51:40,141
THE EARLY TREATMENT IS DESTINED 

2015
01:51:40,141 --> 01:51:43,944
IF YOU'RE USING AN AAV APPROACH 

2016
01:51:43,944 --> 01:51:44,979
IT'S DESTINED TO EVENTUALLY 

2017
01:51:44,979 --> 01:51:49,984
WEARING OFF BECAUSE MUCH THE 

2018
01:51:49,984 --> 01:51:53,988
FACT YOU'RE DEALING WITH A 

2019
01:51:53,988 --> 01:52:00,728
MITOTIC TISSUE.

2020
01:52:00,728 --> 01:52:04,632
WHAT IF YOU GAVE THE AAV AS AN 

2021
01:52:04,632 --> 01:52:06,434
INFUSION TO TOLERATING THEM.

2022
01:52:06,434 --> 01:52:08,269
THEY NEED IT ANYWAY BECAUSE 

2023
01:52:08,269 --> 01:52:08,502
THEY'RE.

2024
01:52:08,502 --> 01:52:10,971
YOU HAVE IT SO THEY'RE 

2025
01:52:10,971 --> 01:52:12,640
CONSTANTLY BEING DOSED?

2026
01:52:12,640 --> 01:52:23,017
HAS ANYONE TRIED THAT?

2027
01:52:26,354 --> 01:52:29,557
>> WHAT YOU INDUCED IS
HIGHER 

2028
01:52:29,557 --> 01:52:32,326
ORDERS OF MAGNITUDE.

2029
01:52:32,326 --> 01:52:34,528
SO YOU'RE CREATING A 

2030
01:52:34,528 --> 01:52:35,496
NEUTRALIZING ANTIBODY AND THE 

2031
01:52:35,496 --> 01:52:37,965
FIRST EXPOSURE OF THE EDITED 

2032
01:52:37,965 --> 01:52:41,602
GENE THERAPY THAT IS STILL THERE

2033
01:52:41,602 --> 01:52:45,072
DECADES OUT.

2034
01:52:45,072 --> 01:52:48,409
AND YOU CAN CREATE ANTIBODIES 

2035
01:52:48,409 --> 01:52:49,543
THAT PREVENT YOU FROM 

2036
01:52:49,543 --> 01:52:50,211
READMINISTER.

2037
01:52:50,211 --> 01:53:00,755
THE QUESTION IS CAN YOU BUILD 

2038
01:53:00,755 --> 01:53:01,822
TOLERATION PERMANENTLY IS TO BE 

2039
01:53:01,822 --> 01:53:02,123
CONSIDERED.

2040
01:53:02,123 --> 01:53:03,858
>> HERE'S OTHER QUESTIONS
COMING

2041
01:53:03,858 --> 01:53:14,235
IN FROM THE AUDIENCE.

2042
01:53:20,908 --> 01:53:23,677
DO THEY HAVE TO BE 

2043
01:53:23,677 --> 01:53:25,980
AUTOANTIBODIES OR DO THEY IN 

2044
01:53:25,980 --> 01:53:28,048
GENERAL ENTER CELLS?

2045
01:53:28,048 --> 01:53:29,850
IS THIS SOMETHING HAPPENING ALL 

2046
01:53:29,850 --> 01:53:32,253
THE TIME AND WE HAPPEN TO LOOK 

2047
01:53:32,253 --> 01:53:35,055
AT THE ONES THAT ARE 

2048
01:53:35,055 --> 01:53:35,489
AUTOANTIBODIES.

2049
01:53:35,489 --> 01:53:41,962
THERE'S A LOW LEVEL OF 

2050
01:53:41,962 --> 01:53:51,071
IMMUNOGLOBULIN IN THE CYTOPLASM.

2051
01:53:51,071 --> 01:53:54,041
WHAT WE FIND THAT'S UNIQUE ABOUT

2052
01:53:54,041 --> 01:53:57,812
MYOSITIS IS THE IMMUNOGLOBULIN 

2053
01:53:57,812 --> 01:53:58,479
CONCENTRATING WHERE THE TARGET 

2054
01:53:58,479 --> 01:54:07,588
ANTIGEN IS.

2055
01:54:07,588 --> 01:54:09,857
THE OTHER THING I'D MENTION IS 

2056
01:54:09,857 --> 01:54:12,460
THERE'S A WHOLE INTRACELLULAR 

2057
01:54:12,460 --> 01:54:14,662
SYSTEM THAT SEEMS TO EXIST FOR 

2058
01:54:14,662 --> 01:54:18,699
THE PURPOSE OF DEGRADING 

2059
01:54:18,699 --> 01:54:21,569
INTRACELLULAR IMMUNOGLOBULIN AND

2060
01:54:21,569 --> 01:54:24,905
THAT'S ROW 52 OR TRIM 21 WITH AN

2061
01:54:24,905 --> 01:54:28,542
FC BINDING DOMAIN THAT'S 

2062
01:54:28,542 --> 01:54:31,078
CYTOPLASMIC AND BIND TO 

2063
01:54:31,078 --> 01:54:33,614
INTRACELLULAR IMMUNOGLOBULIN AND

2064
01:54:33,614 --> 01:54:35,449
THAT'S TO A VIRUS OR SOMETHING 

2065
01:54:35,449 --> 01:54:37,985
AND WILL DEGRADE THE 

2066
01:54:37,985 --> 01:54:40,054
IMMUNOGLOBULIN AND WHATEVER 

2067
01:54:40,054 --> 01:54:42,423
ANTIGEN IS BOUND TO THE 

2068
01:54:42,423 --> 01:54:42,790
IMMUNOGLOBULIN.

2069
01:54:42,790 --> 01:54:45,960
THERE'S EVIDENCE WE'VE EVOLVED 

2070
01:54:45,960 --> 01:54:50,297
TO COPE WITH INTRACELLULAR 

2071
01:54:50,297 --> 01:54:50,664
IMMUNOGLOBULIN.

2072
01:54:50,664 --> 01:54:54,735
>> NOW THAT YOU BROUGHT UP
ROW 

2073
01:54:54,735 --> 01:54:58,539
52, WE HAVE TO MENTION THE FACT 

2074
01:54:58,539 --> 01:55:01,242
THAT IN SOME AUTOIMMUNE 

2075
01:55:01,242 --> 01:55:04,411
DISEASES, PATIENTS HAVE 

2076
01:55:04,411 --> 01:55:05,779
ANTIBODIES AGAINST R52 AND MAYBE

2077
01:55:05,779 --> 01:55:09,650
THAT'S SUBVERTING THE PROCESS 

2078
01:55:09,650 --> 01:55:13,454
AND ALLOWING INTRACELLULAR 

2079
01:55:13,454 --> 01:55:14,755
ANTIBODIES TO DO THE SAME THING.

2080
01:55:14,755 --> 01:55:17,124
>> THAT'S OUR HYPOTHESIS.

2081
01:55:17,124 --> 01:55:23,130
WE HAVE PRELIMINARY DATA THAT IF

2082
01:55:23,130 --> 01:55:26,367
YOU TAKE AN ANTIBODY IN THE CASE

2083
01:55:26,367 --> 01:55:32,506
WHERE WE DID IT AGAINST MDA5 AND

2084
01:55:32,506 --> 01:55:36,210
YOU CAN GET A SIGNIFICANT AMOUNT

2085
01:55:36,210 --> 01:55:43,817
OF INTERFERON EXPRESSION IF YOU 

2086
01:55:43,817 --> 01:55:48,322
JUST INTRODUCE MDA5 ANTIBODIES 

2087
01:55:48,322 --> 01:55:50,457
IF YOU INTRODUCE THE ROW 5 

2088
01:55:50,457 --> 01:55:51,959
ANTIBODIES YOU DON'T SEE 

2089
01:55:51,959 --> 01:55:54,995
ANYTHING BUT IF YOU PUT THEM 

2090
01:55:54,995 --> 01:55:57,398
TOGETHER THERE'S A MASSIVE 

2091
01:55:57,398 --> 01:56:00,701
INCREASE OF INTERFERON THAT GETS

2092
01:56:00,701 --> 01:56:04,538
PRODUCED AND THE ANTIBODIES 

2093
01:56:04,538 --> 01:56:13,581
POTENTIATE THE AFFECT AND 

2094
01:56:13,581 --> 01:56:15,749
PATIENTS WHO HAVE THIS WITH THE 

2095
01:56:15,749 --> 01:56:16,951
AUTOSPECIFIC ANTIBODIES HAVE 

2096
01:56:16,951 --> 01:56:18,919
MORE SEVERE DISEASE 

2097
01:56:18,919 --> 01:56:19,286
MANIFESTATIONS.

2098
01:56:19,286 --> 01:56:21,255
WE THINK THAT'S PROBABLY THE 

2099
01:56:21,255 --> 01:56:23,357
MECHANISM FOR WHY THEY HAVE MORE

2100
01:56:23,357 --> 01:56:24,858
SEVERE DISEASE MANIFESTATION.

2101
01:56:24,858 --> 01:56:27,428
THEY'RE BLOCKING THE DEGRADATION

2102
01:56:27,428 --> 01:56:29,897
OF THE AUTOANTIBODIES.

2103
01:56:29,897 --> 01:56:32,633
>> THAT'S REALLY
INTERESTING.

2104
01:56:32,633 --> 01:56:35,436
SO ANOTHER MEMBER OF OUR 

2105
01:56:35,436 --> 01:56:36,403
AUDIENCE IS A LITTLE BIT FAR OUT

2106
01:56:36,403 --> 01:56:38,005
IN TERMS OF THEIR THINKING BUT 

2107
01:56:38,005 --> 01:56:39,506
WHAT THE HECK.

2108
01:56:39,506 --> 01:56:43,510
I'LL ASK THE QUESTION ANYWAY.

2109
01:56:43,510 --> 01:56:46,947
DO PETS GETS MYOSITIS AND IF SO,

2110
01:56:46,947 --> 01:56:49,917
CAN THEIR OWNERS CATCH IT FROM 

2111
01:56:49,917 --> 01:56:50,250
THEIR PETS?

2112
01:56:50,250 --> 01:56:52,653
>> WELL, THE ANSWER TO THE
FIRST

2113
01:56:52,653 --> 01:56:56,557
QUESTION IS YES.

2114
01:56:56,557 --> 01:57:00,027
THERE'S A BREED OF DOGS THAT GET

2115
01:57:00,027 --> 01:57:00,461
DERMATOMYOSITIS.

2116
01:57:00,461 --> 01:57:02,696
I SHOULD KNOW WHICH ONE IT IS.

2117
01:57:02,696 --> 01:57:03,998
I HAVEN'T THOUGHT ABOUT IT FOR A

2118
01:57:03,998 --> 01:57:06,667
WHILE BUT THERE'S A BREED OF 

2119
01:57:06,667 --> 01:57:09,803
DOGS SUSCEPTIBLE TO IT.

2120
01:57:09,803 --> 01:57:16,543
AS THERE ARE DOGS THAT GET THESE

2121
01:57:16,543 --> 01:57:18,979
AUTOIMMUNE DISEASES.

2122
01:57:18,979 --> 01:57:20,047
NO, TO THE BEST OF MY KNOWLEDGE 

2123
01:57:20,047 --> 01:57:23,017
THERE'S NO EVIDENCE OR REASON TO

2124
01:57:23,017 --> 01:57:24,284
BELIEVE THE AUTOIMMUNITY WOULD 

2125
01:57:24,284 --> 01:57:26,654
BE TRANSFERRED TO THEIR OWNERS.

2126
01:57:26,654 --> 01:57:28,455
LIKE WE DON'T SEE IT TRANSFERRED

2127
01:57:28,455 --> 01:57:30,224
FROM ONE PERSON TO ANOTHER BY 

2128
01:57:30,224 --> 01:57:30,491
PROXIMITY.

2129
01:57:30,491 --> 01:57:34,595
WE WOULDN'T EXPECT IT TO OCCUR 

2130
01:57:34,595 --> 01:57:38,165
BUT YES, THERE'S A DOG MODEL OF 

2131
01:57:38,165 --> 01:57:38,999
DERMATOMYOSITIS SOME PEOPLE 

2132
01:57:38,999 --> 01:57:39,533
STUDY.

2133
01:57:39,533 --> 01:57:39,900
>> WOW.

2134
01:57:39,900 --> 01:57:45,506
WELL, THERE YOU GO.

2135
01:57:45,506 --> 01:57:49,977
I NEVER WOULD HAVE THOUGHT THE 

2136
01:57:49,977 --> 01:57:53,113
ANSWER IS YES.

2137
01:57:53,113 --> 01:57:55,282
ANYWAY, WE'RE UP AT 4:58 P.M. 

2138
01:57:55,282 --> 01:58:02,623
AND LESS THAN TWO MINUTES AWAY.

2139
01:58:02,623 --> 01:58:07,327
AT THIS POINT I THINK I NEED TO 

2140
01:58:07,327 --> 01:58:09,596
THANK BOTH OF YOU FOR YOUR 

2141
01:58:09,596 --> 01:58:10,764
PRESENTATIONS.

2142
01:58:10,764 --> 01:58:11,598
BREATHTAKING THE PROGRESS 

2143
01:58:11,598 --> 01:58:12,966
MEDICAL RESEARCH HAS TAKEN IN 

2144
01:58:12,966 --> 01:58:14,134
THE LAST FEW YEARS AND OUR LIFE 

2145
01:58:14,134 --> 01:58:16,003
TIMES.

2146
01:58:16,003 --> 01:58:18,272
AND IT'S REALLY GREAT TO SEE.

2147
01:58:18,272 --> 01:58:24,578
CONGRATULATIONS TO BOTH OF YOU 

2148
01:58:24,578 --> 01:58:25,879
AND YOUR RESPECTIVE FIELDS.

2149
01:58:25,879 --> 01:58:28,582
IT'S CLEAR THERE'S A LOT OF 

2150
01:58:28,582 --> 01:58:29,983
REALLY EXCITING THINGS YET TO 

2151
01:58:29,983 --> 01:58:32,019
COME.

2152
01:58:32,019 --> 01:58:35,956
ANYWAY, I THINK WITH THAT, WE'LL

2153
01:58:35,956 --> 01:58:39,793
SIGN OFF MAYBE A MINUTE EARLY 

2154
01:58:39,793 --> 01:58:41,862
AND LOOK FORWARD TO SEEING YOU 

2155
01:58:41,862 --> 01:58:43,964
AGAIN NEXT YEAR OR THE YEAR 

2156
01:58:43,964 --> 01:58:47,301
AFTER, WHATEVER, TO GIVE US A 

2157
01:58:47,301 --> 01:58:48,402
PROGRESS REPORT ON HOW THINGS 

2158
01:58:48,402 --> 01:58:49,103
ARE DEVELOPING THEN.

2159
01:58:49,103 --> 01:58:50,170
>> THANKS, DAN.

2160
01:58:50,170 --> 01:58:51,438
THANKS FOR THE STIMULATING 

2161
01:58:51,438 --> 01:58:55,442
CONVERSATION AND THE INVITE.

2162
01:58:55,442 --> 01:58:57,478
>> YES, THANKS FOR COMING.

2163
01:58:57,478 --> 01:58:57,978
BYE-BYE, EVERYONE.

2164
01:58:57,978 --> 01:58:58,045