WALS: A Patient-Scientist Lens on How and Why to Move Faster to First in Human

Who speaks in this episode?

• Sonia Valabh (Main speaker)
• Matt Hull (Host)

What is discussed, and when

1. 0:00 – 10:00: Prion Disease, Broad Institute, Harvard, Sonia Valabh
2. 10:00 – 20:00: Prion Disease
3. 20:00 – 30:00: Prion Disease, Oligonucleotides, Clinical Trial, NINDS
4. 40:00 – 50:00: FDA
5. 50:00 – 1:00:00: Prion Disease, Clinical Trial
6. 1:00:00 – 1:10:00: Prion Disease, Clinical Trial

Notable quotes from "WALS: A Patient-Scientist Lens on How and Why to Move Faster to First in Human"

• HER PRESENTATION IS MORE THAN THE RESULTS THAT YOU'RE GOING TO SEE. SONIA IS AN INSPIRATION TO EVERY PATIENT CAREGIVER AND FAMILY MEMBER OF SOMEONE WITH RARE DISEASE. BEFORE I INTRODUCE HER I NEED TO READ.

  about Sonia Valabh · at 0:21

• RAPID DEMENTIA LIKE ILLNESS, AUTOPSY SHOWED HER MOTHER DIED OF PRION DISEASE, FATAL FAMILIAL INSOMNIA. SOME SUFFERERS SEEM TO LOSE THE ABILITY TO SLEEP AND AS THE NAME SUGGESTS, TERRIBLE. SHE WENT THROUGH TESTING SHE.

  about Prion Disease · at 1:53

• OLIGONUCLEOTIDES ARRIVED ON THE SCENE AS TREATMENT STRATEGY FOR NEUROLOGIC CONDITIONS. SHE PITCHED A CHANGE OF PROJECT TO SUPERVISOR AND HE WENT ON BOARD.

  about Oligonucleotides · at 2:58

• WE HAVE BEEN HANDED. WE WERE SUPER LUCKY MANY THAT THOUGHT PROCESS TO MEET THE PEOPLE WHO TURNED INTO OUR LIFE LONG MENTORS AT THE BROAD INSTITUTE ERIC LANDERS STEWART SCHREIBER AND OTHERS WHO THOUGHT OR.

  about Broad Institute · at 9:22

• NINDS IGNITE FUNDED PROJECT TRANSITIONED TO A SORT OF LIKE IND ENABLING PHASE. WE WERE SUPER LUCKY TO BE ABLE TO WORK THROUGH THE URGENT MECHANISM TO DO THE THINGS THAT NORMALLY ONLY ACCOMPANY CAN -- A COMPANY CAN.

  about NIH · at 24:07

• IT'S BROUGHT TOGETHER. WE ARE ALL GETTING TO LEARN TOGETHER IN REAL TIME. SO THE VISION BEHIND CHARM IS IT'S SORT OF GOT SOME OPPOSING PROPERTIES. HERE WITH WE ARE TALKING AS OPPOSED TO OLIGO YOU DOSE EVERY THREE OR.

  about Gene Editing · at 27:26

• AND I THINK BASED ON THE DATA WE SEE, THE ANSWER IS YES. SCGE AS A MECHANISM WILL SUPPORT US TO TWO THROUGH IND ENABLING STUDIES. THAT'S THE TRANSITION WE ARE IN THE PROCESS OF MAKING.

  about SCGE Consortium · at 30:53

Who and what is mentioned in this episode?

People

• Sonia Valabh — Person · Main speaker · 1 mention · first at 0:14
  Central speaker describing her personal and scientific journey developing prion-disease therapeutics, including oligonucleotide and gene-editing approaches, and the regulatory/clinical-trial challenges.
• Matt Hull — Person · Host / introducer (event moderator) · 1 mention · first at 0:07
  Introduces Sonia Valabh, provides her background story, and frames the talk within NCATS/NIH translational-science context.
  ALL RIGHT, GOOD AFTERNOON, EVERYBODY, THANK YOU FOR COMING ALOK. I'M MATT HULL,K SCIENTIFIC DIRECTOR T AT NCATS. I'M DELIGHTED TO INTRODUCE DR. SONIA VALABH, DIRECTOR OF PREION SCIENCE AT THE BROAD INSTITUTE.
• Alok — Person · Audience member / attendee (greeted) · 1 mention · first at 0:06
  Mentioned only as someone present (“Thank you for coming Alok”); no additional identifying context in the transcript.
  ALL RIGHT, GOOD AFTERNOON, EVERYBODY, THANK YOU FOR COMING ALOK. I'M MATT HULL,K SCIENTIFIC DIRECTOR T AT NCATS. I'M DELIGHTED TO INTRODUCE DR. SONIA VALABH, DIRECTOR OF PREION.

Companies & orgs

• Broad Institute — Company · Business focus · 3 mentions · first at 0:19
  Where Dr. Sonia Valabh conducts her research and develops treatments for prion disease.
• NIH — Company · Funding source · 4 mentions
  Provides significant funding for the research and development of treatments for prion disease.
• Harvard — Company · Educational institution · 2 mentions · first at 1:33
  Where Dr. Valabh earned her Ph.D. and conducted initial research.
  EARN PREGNANT ENTRY INTO A Ph.D. PROGRAM AT HARVARD MEDICAL SCHOOL SHE DID IN SCHREIBER'S LAB, SHE WORKED SIDE BY SIDE WITH HER HUSBAND AND EVEN DEFENDING TO. THE SUREST DEFINITION OF TRUE LOVE I HAVE.
• National Institute of Health — Company · Funding source · 1 mention · first at 3:37
  Another name for NIH, providing funding for the research.
  ACHIEVE WITH SIGNIFICANT FUNDING FROM THE NATIONAL INSTITUTES OF HEALTH PARTICULARLY NINDS AND COMMON FUND WITH NCATS. TODAY SHE WILL TELL YOU ABOUT THE OPPORTUNITIES AND CHALLENGES THAT COME WITH CREATING A NEW.
• FDA — Company · Regulatory body · 1 mention · first at 46:09
  Involved in the approval process for the new therapeutics being developed.
  ACCOMPANY CAN -- A COMPANY CAN DO. SO WE DID GLP TOXICOLOGY IN TWO SPECIES. WE WENT TO FDA AND ASKED CAN WE DO SINGLE SPECIES TOX GIVEN THIS IS A UNLET MEEDCAL NEED THAT IS RAPIDLY FATAL WITH NO STANDARD OF CARE.
• NINDS — Company · Funding source · 2 mentions · first at 3:38
  Part of NIH, providing funding for the research.
  NINDS IGNITE FUNDED PROJECT TRANSITIONED TO A SORT OF LIKE IND ENABLING PHASE. WE WERE SUPER LUCKY TO BE ABLE TO WORK THROUGH THE URGENT MECHANISM TO DO THE THINGS THAT NORMALLY ONLY ACCOMPANY CAN -- A COMPANY CAN.
• SCGE Consortium — Company · Collaborative group · 1 mention · first at 27:09
  Supports the gene therapy program being developed for prion disease.

Concepts & topics

• Prion Disease — Concept · Core topic · 23 mentions · first at 1:58
  Central theme of the episode, discussing the rapid neurodegenerative disease and its impact on families.
• Oligonucleotides — Concept · Therapeutic modality · 2 mentions · first at 2:58
  One of the two therapeutic modalities being developed to treat prion disease.
• Gene Editing — Concept · Therapeutic modality · 1 mention · first at 3:20
  One of the two therapeutic modalities being developed to treat prion disease.
• Clinical Trial — Concept · Strategy · 7 mentions · first at 3:27
  Discussed as the next step in testing the developed therapeutics for prion disease.
  DEVELOPING PREVENTIVE TREATMENT FOR PRION DISEASE AS QUICK AS POSSIBLE. THE RESULT IS THAT SONIA AND HER TEAM SHORTLY WILL HAVE TWO SEPARATE THERAPEUTICS IN CLINICAL TRIALS. ONE OLIGONUCLEOTIDE AND OTHER GENE.
• Fatal Familial Insomnia — Concept · Specific condition · 1 mention · first at 1:58
  A specific type of prion disease that affected Dr. Valabh's mother.
  AUTOPSY SHOWED HER MOTHER DIED OF PRION DISEASE, FATAL FAMILIAL INSOMNIA. SOME SUFFERERS SEEM TO LOSE THE ABILITY TO SLEEP AND AS THE NAME SUGGESTS, TERRIBLE. SHE WENT THROUGH TESTING SHE INHERITED THE MUTATION IN THE.

Full transcript with timestamps

0:04 ALL RIGHT, GOOD AFTERNOON, EVERYBODY, THANK YOU FOR COMING ALOK. I'M MATT HULL,K SCIENTIFIC DIRECTOR T AT NCATS. I'M DELIGHTED TO INTRODUCE DR. SONIA VALABH, DIRECTOR OF PREION SCIENCE AT THE BROAD INSTITUTE. HER PRESENTATION IS MORE THAN THE RESULTS THAT YOU'RE GOING TO SEE. SONIA IS AN INSPIRATION TO EVERY PATIENT CAREGIVER AND FAMILY MEMBER OF SOMEONE WITH RARE DISEASE. BEFORE I INTRODUCE HER I NEED TO READ THESE SOME OTHER THINGS OUT SOME FORMAL NOTES OR THEY'LL GIVE ME ANOTHER DATA CAL CALL. THE CODER CONTINUING MEDICAL EDUCATION IS 66829. IT SAYS HERE I'LL REPEAT THAT SO I WILL. 66829. ALSO FOR THOSE. WATCHING REMOTELY AT VIDEOCAST, YOU CAN SUBMIT QUESTIONS TO THE SPEAKER ANY TIME FOR THIS LECTURE JUST LICK THE BUTTON THAT SAYS SEND LIVE FEEDBACK, BELOW THE WINDOW. THAT WITH VIDEO AND TYPE IN YOUR MESSAGE AND AT THE CONCLUSION OF THE PRESENTATION CHRIS WILL BE READING THOSE OUT TO SONIA. IF

1:10 YOU ARE NOT ROOM THERE'S TWO MICROPHONES DURING THE Q&A COMPONENT OF THIS PRESENTATION. THERE WILL BE A RECEPTION OUTSIDE AT THE END, WE WILL REMIND YOU AND PLEASE JOIN US. IF YOU ARE ON VIDEOCAST YOU MISS OUT. ALL RIGHT SO WE GET TO INTRODUCE OUR SPEAKER. DR. VALABH GREW UP IN A TOWN CALLED HERM DAMAGE WESTERN PENNSYLVANIA AND HER UNDERGRADUATE DEGREE AT (INAUDIBLE) COLLEGE AND JUS DOCTOR DEGREE AT HARVARD. SHE EMBARKED ON A PROMISING CAREER IN LAW AND CONSULTING AND MARRIED, HER HUSBAND ERIC WAS WORKING AS A CITY ENGINEER. THE TRANSPORTATION ENGINEER. THEN IN 2010 SONIA WATCHED HER MOTHER DIE FROM WHAT SEEMED A SUDDEN RAPID DEMENTIA LIKE ILLNESS, AUTOPSY SHOWED HER MOTHER DIED OF PRION DISEASE, FATAL FAMILIAL INSOMNIA. SOME SUFFERERS SEEM TO LOSE THE ABILITY TO SLEEP AND AS THE NAME SUGGESTS, TERRIBLE. SHE WENT THROUGH TESTING SHE INHERITED THE MUTATION IN THE PRION GREEN GENE. THEY DROPPED

2:13 LITERALLY EVERYTHING AND BEGAN TO DO WHAT SO MANY OTHER FAMILIES HAVE HAD TO DO BEFORE THEM, LEARN BIOLOGY AND MEDICINE AND PURSUE A TREATMENT AND CURE OR PREVENTION FOR A RARE DISEASE THAT IS NOT ON ANY RADAR AND VERY UNDERSTUDIED. THEY DID SO MUCH FOR THAN THAT. SONIA STARTED OFF BY WORKING AS A LAB TECH M LEARNING BIOLOGY AND HOW TO DO EXPERIMENTS IN THE LAB. WHILE GOING TONIGHT CLASSES. AND EARN PREGNANT ENTRY INTO A Ph.D. PROGRAM AT HARVARD MEDICAL SCHOOL SHE DID IN SCHREIBER'S LAB, SHE WORKED SIDE BY SIDE WITH HER HUSBAND AND EVEN DEFENDING TO. THE SUREST DEFINITION OF TRUE LOVE I HAVE HEARD OF. SHE STARTED Ph.D.

2:54 HOPING TO CREATE A SMALL MOLECULE FOR PRION DISEASE. OLIGONUCLEOTIDES ARRIVED ON THE SCENE AS TREATMENT STRATEGY FOR NEUROLOGIC CONDITIONS. SHE PITCHED A CHANGE OF PROJECT TO SUPERVISOR AND HE WENT ON BOARD ALL SUPERVISORS LOVE MEDIA PITCHES OF BRAND NEW PROJECTS FROM Ph.D. STUDENTS. SHE CERTAIN EARNED HER Ph.D. AND OPENED HER OWN LAB AT THE BROAD INSTITUTE WITH THE GOAL OF DEVELOPING PREVENTIVE TREATMENT FOR PRION DISEASE AS QUICK AS POSSIBLE. THE RESULT IS THAT SONIA AND HER TEAM SHORTLY WILL HAVE TWO SEPARATE THERAPEUTICS IN CLINICAL TRIALS. ONE OLIGONUCLEOTIDE AND OTHER GENE EDITING. THIS TRANSACTIONAL SCIENCE APPROACH CAN ONLY BE ACHIEVE WITH SIGNIFICANT FUNDING FROM THE NATIONAL INSTITUTES OF HEALTH PARTICULARLY NINDS AND COMMON FUND WITH NCATS. TODAY SHE WILL TELL YOU ABOUT THE OPPORTUNITIES AND CHALLENGES THAT COME WITH CREATING A NEW GENERATION OF MEDICINES AND SOME OF THE INSIGHTS WHEN SOMEONE

3:51 JUGGLES SCIENTIFIC CHALLENGES CLINICAL CHALLENGES AND REGULATORY CHALLENGES AT THE SAME TIME ONE DESK. THANK YOU FOR VISITING TODAY. YOU ARE ONE OF MY HEROES BUT EXCITED FOR YOU TO SHARE YOUR SCIENCE WITH EVERYBODY TODAY. THANK YOU FOR BEING WITH US.

4:13 >> THANK YOU, EVEN, IT IS A PLEASURE TO BE HERE. I'M EXCITED TO SHARE WITH YOU WHERE WE ARE ON THIS JOURNEY WHICH IS VERY FAR FROM THE BEGINNING. BUT STILL LIKE ALSO FAR FROM THE END, THERE'S STILL SO MUCH TO DO. SO I WILL GIVE YOU A LITTLE BIT OF INTRODUCTION TO US THOUGH YOU JUST HEARD THE IMPORTANT STORY BEATS, SO THE YEAR 2010 IS KIND OF WHERE THIS STORY BEGINS. ERIC AND I MARRIED FOR ABOUT SIX MONTHS WHEN THIS STARTED TO UNFOLDED IN MY FAMILY. THIS WAS MY MOM'S DISEASE COURSE, SHE WAS 51 AT THE TIME. AND ALL WE KNEW IS THAT WE WERE SEEING HER GO INTO COMPLETELY UNEXPLAINED NEUROLOGICAL TAIL SPIN. SO DAY TO DAY WEEK TO WEEK SHE WAS LOSING HER ABILITIES. AND NAIVELY I WOULD HAVE THOUGHT AT TIME THAT IF YOU ARE WATCHING SOMEONE UNDERGO SUCH DRAMATIC CHANGES SO FAST, RIGHT, LIKE LOSING HER MEMORY, HER ABILITY TO SPEAK, LOSING HER ABILITY TO BATHE HERSELF AND FEED HERSELF, THIS IS HAPPENING ON A TIME

5:27 SCALE OF WEEKS FROM BEING COMPLETELY HEALTHY. IT WAS SO DRAMATIC I THOUGHT YOU PUT HER IN FRONT OF A DOCTOR AND HE WOULD SAY IT'S X. BUT THAT'S NOT WHAT HAPPENED. INSTEAD WE TOOK HER AROUND WHY WOULD SHE CONTINUES TO DECLINE, TO SOME OF THE BEST HOSPITALS IN THE COUNTRY, AND WE WERE NOT ABLE TO GET A DIAGNOSIS IN HER LIFETIME. SHE WENT ON LIFE SUPPORT NEAR THE MIDDLE OF THAT YEAR. IT WAS A SUPER CONFUSING TIME, WE STILL HAD NO DIAGNOSIS. WE RECEIVED A PRELIMINARY DIAGNOSIS MAYBE THIS IS PRION DISEASE NEAR THE END OF THAT YEAR. WHICH WAS ENOUGH INFORMATION TO REACH FAMILY CONSENSUS TO TAKE HER OFF OF LIFE SUPPORT AND IT WAS ONLY FROM HER AUTOPSY THAT WE LEARNED THAT SHE DIED OF GENETIC PRION DISEASE. SO HERE IS LIKE A WHOLE NEW CHAPTER OF THIS THING THAT OPENS UP. WE HAD NO INKLING BEFORE THAT THAT THIS WAS GENETIC. THERE WAS NO FAMILY HISTORY, AND I NOW THINK OF IT AS EVERY GENETIC DISEASE EVEN IF

6:35 USUALLY INHERITED HAS TO START SOMEWHERE, MAYBE IT START WITH MY MOM. ANY RATE, WE ARE PRESENTED WITH THIS NEW PIECE OF INFORMATION, THIS IS AN AUTOSOMAL DOMINANT MUTATION AND THE PRION PROTEIN GENE, I'M 50/50 TO HAVE INHERITED IT FROM MY MOM. AND WENT INTO THE PROCESS OF TRYING TO GET PREDICTIVE GENETIC TESTING. AS A SIDE BAR, WE DON'T MAKE THIS EASY FOR PEOPLE. AND SO I JUMPED THROUGH ALL THE HOOPS AND DID EVERYTHING I COULD TO CONVINCE PEOPLE THAT I KNEW MYSELF BETTER THAN THEY KNEW ME. I WANTED THIS INFORMATION. AND I REALLY HAD TO KIND OF PUSH AGAINST A SENTIMENT THAT THIS IS A FATAL DISEASE, IT IS NOT TREATABLE, NOT PREVENTABLE, IF YOU HAVE MY MUTATION OR HANDFUL OF OTHERS, VERY, VERY LIKELY TO CAUSE SEES ADULTHOOD, ET CETERA, WHY WOULD YOU WANT TO KNOW THIS? AND GOT THROUGH ALL THE LINES OF DEFENSE SO THAT I COULD ACCESS THE INFORMATION THAT HAD ALREADY BEEN IN EVERY CELL OF MY BODY

7:43 SINCE I WAS CONCEIVED AND THAT'S HOW I CAME TO LEARN AT THE END OF 2011 THAT I DID INHERIT MY MOM'S MUTATION. SO IT'S REALLY NOT THE NEWS THAT ANYBODY HOPES FOR. BUT WHAT I WILL SAY IS, I TOTALLY STAND BY MY IMPULSE AND LIKE WHATEVER SELF-KNOWLEDGE IT WAS THAT DROVE ME TO GET TESTED. BECAUSE BEING IN LIMBO WAITING FOR THIS TEST WAS LIKE I THINK THE MOST ACUTE TORTURE I HAVE EVER UNDERGONE. AND YOU KNOW, ONCE I HAD IT I KNEW. AND REST OF MY LIFE COULD BEGIN. NOW I COULDN'T HAVE PREDICT HAD THAT REST OF MY LIFE WOULD LOOK LIKE AS IT TURNS OUT THIS CATALYZED A BIG CAREER CHANGE FOR ME AND FOR ERIC. THE INITIAL VISION WAS THIS IS A DISEASE THAT IS RARE ENOUGH THAT MY MOM WASN'T EFFECTIVELY DIAGNOSED IN HER LIFETIME. WE WANT COUNT ON THE MEDICAL ESTABLISHMENT TO SERVE AS A LINK BETWEEN US AND WHATEVER MIGHT BE LEARNED OVER TIME. SO WE IMMEDIATE TO BE SORT OF OUR OWN SAVVY ADVOCATES.

8:53 THAT WAS THE SPIRIT IN WHICH WE UNDERTOOK LEARNING WHAT WE COULD ON THE SIDE, CALLING PEOPLE, TRYING TO UNDERSTAND WHAT IS PRION DISEASE AND WHAT IS KNOWN. THAT'S THE KIND OF MOMENTUM OF ITS OWN AND WE ENDED UP LEAVING OUR CAREERS FOR ENTRY LEVEL JOBS IN SCIENCE, DID THAT FOR COUPLE OF YEARS, REGROUPED, TRIED TO FIGURE OUT IF WE CAN MAKE A GO OF THIS, HOW DO WE REFOCUS OUR EFFORTS ON EXACTLY THE PROBLEM WE HAVE BEEN HANDED. WE WERE SUPER LUCKY MANY THAT THOUGHT PROCESS TO MEET THE PEOPLE WHO TURNED INTO OUR LIFE LONG MENTORS AT THE BROAD INSTITUTE ERIC LANDERS STEWART SCHREIBER AND OTHERS WHO THOUGHT OR PROBLEM WAS INTERESTED AND BET ON US TO WORK ON IT. AND SO THAT'S WHERE WE DID HOUR Ph.D.s, WE HAVE BEEN THERE EVER SINCE, TODAY WE ARE LAB OF 17 PEOPLE. WHAT I FIND INTERESTING ABOUT OUR QUEST IS THAT THE NORTH STAR HAS NEVER CHANGED LIKE WE HAVE OUR PROBLEM. BUT WHAT IT ASKS OF US IS CONSTANTLY CHANGING. THAT'S

10:00 PARTLY A FUNCTION OF RAPIDLY EVOLVING TECHNOLOGICAL LANDSCAPE WE ARE SO LUCKY TO BE PART OF. IT IS PARTLY A PROBLEM OF OUR -- PARTLY A FUNCTION OF OUR UNDERSTANDING WHAT IT TAKES TO NOT JUST HAVE IS A SENSE OF BIOLOGY AND HOW TO GO AFTER IT BUT TO REALLY MAKE A MEDICINE AND I AM SUPER HUMBLED BY HOW THIS DIDN'T TURN OUT TO BE A PROCESS OF RETRAINING ONCE IN ORDER TO BECOME SCIENTISTS BUT HOW TO SORT OF A CONSTANT RETRAINING AS WE MOVE THROUGH THE ARC OF MAKING IDEAS INTO MEDICINES AND AS THE LANDSCAPE AROUND US CONTINUES TO CHANGE AND NOMINATE BETTER IDEAS. NEVER A BORING DAY. I WILL TELL YOU A LITTLE BIT ABOUT WHERE WE ARE AT IN ALL THIS. BUT FIRST JUST A BIT ABOUT THE DISEASE. SO RAPID NEURODEGENERATIVE DISEASE IS KIND OF LIKE TESTIFY PITHIEST EXPLANATION OF WHAT THIS IS. AND YOU SAW THE TIME LINE FOR MY MOM. IT REALLY IS ON AVERAGE LESS THAN HALF A YEAR FROM FIRST SYMPTOM TO DEATH. AS WE HAVE DUG

11:16 INTO THIS MORE OURSELVES, I THINK THE NATURAL HISTORY DATA ACTUALLY SUGGESTS SOMETHING MORE AGGRESSIVE. BECAUSE FIRST SYMPTOM AS RECORDED IN THE LITERATURE IS OFTEN RETROSPECTIVE. IT IS NOT SOMETHING THAT YOU MIGHT HAVE BEEN ABLE TO IDENTIFY AT THE TIME. IF WE COUNT FROM FIRST LUMBAR PUNCTURE, FIRST CSF DRAW, FIRST DIAGNOSTIC ASSAY RUN, IF WE COUNT TWO LIFE SUPPORT MEASURES AS OPPOSED TO DEATH IN THE FORMAL SENSE THAT WINDOW IS EVEN SMALLER, MAYBE THE MEDIAN THERE IS ON THE ODE OF 30, 40 -- ORDER OF 30, 40 DAYS SO WE CAN THINK OF THIS DISEASE DISEASE AS A LIGHTNING STRIKE, A PARADIGM@IC EXAMPLE WHAT IF A DISEASE JUST STRUCK LIKE THAT AND KILLED YOU ALMOST RIGHT AWAY. WE ARE RARE BUT NOT ULTRA RARE. SOMETIMES YOU HEAR ONE IN A MILLION. A WEIRD THING ABOUT PRION DISEASE AND HOW WE CONTINUE IT, ANY GIVEN TIME THERE AREN'T THAT MANY PEOPLE ALIVE WITH THE DISEASE BECAUSE IT KILLS YOU SO QUICKLY. IF WE

12:26 INTEGRATE OVER THE HUMAN LIFETIME PRION DISEASE WILL KILL ONE IN 6,000 PEOPLE. SO IF LIKE -- IT SEEMS WEIRD THERE ARE A FEW CASES IN THE SAME TOWN OR IN THE SAME HOSPITAL THAT IS PROBABLY NOT WEIRD, THAT IS PROBABLY THE STATISTICS AT WORK. ANY RATE, WHAT WE WERE SO LUCKY TO BE GIVEN, THE GENETIC TEST REPORT WAS NOT LUCKY, HOWEVER, IT REPRESENTS A KIND OF LIKE LUCKY THING WHICH IS THAT THE GENETICS OF PRION DISEASE HAVE BEEN SOLVED FOR A LONG TIME. AND WE ACTUALLY HAVE A REALLY CLEAR MOLECULAR MECHANISM THAT UNDERLIES EVERY SINGLE CASE. YOU HEARD THE TERM FFI FROM MATT, CJD IS MAYBE THE MOST COMMON CLINICAL TERM FOR PRION DISEASE, THERE ARE OTHERS. THIS IS ALSO A DISEASE OF MA MAILIA, NOT JUST PEOPLE. BUT ACROSS EVERY CASE OF PRION DISEASE, THERE'S THIS BLUEPRINT THAT DRIVES THE PATHOGENESIS. SO IT IS A SINGLE GENE PRNP THAT GIVES RISE TO A SINGLE RNA THAT GIVES RISE TO A SINGLE PROTEIN. PRION PROTEIN IN

13:38 ITS NATIVE STATE IS A PROTEIN WE HAVE AND THAT IS ACTUALLY UBIQUITOUSLY EXPRESSED IN OUR TISSUES MOST HIGHLY IN THE BRAIN AND NOT NORMALLY A PROBLEM. IT IS CAPABLE OF MISFOLDING. THIS IS THE EVENT THAT TURNS INTO A SO CALLED PRION, PROTEIN ONLY PATHOGEN THAT SPREADS ACROSS THE BRAIN AND KILLS NEURONS. THIS IS KIND OF LIKE A FAMOUS THIN THIN. THIS SEEMED TO CONTRA VACCINE THE CENTRAL DOGMA, THERE'S NOBEL PRIZES AWARDED FOR THIS, THIS IS A SURPRISING PIECE OF BIOLOGY WHICH I THINK ACTUALLY MEANS MORE ATTENTION HAS BEEN PAID TO PRION DISEASE THAN MIGHT HAVE BEEN OTHERWISE OR THAT MIGHT BE TOO COMPARABLY RARE DISEASES.

14:21 ANY RATE, WE ARE LUCKY TO HAVE CLARITY, IF YOU JUST LOOK AT THE EARLY SYMPTOM, IF YOU LOOK AT THE NEUROPATHOLOGY, IF YOU LOOK AT THE ALPHABET SOUP OF NAMES, YOU THINK PRION DISEASE IS VERY COMPLEX, THERE'S LIKE THIS WHOLE CONFUSING MIX OF THINGS BUT ACTUALLY WE HAVE GOT THIS ONE CAUSAL STORY. THE OTHER THING WE HAVE, WE INHERITED THIS, FROM THE PEOPLE WHO CAME BEFORE US, IS CLEAR EVIDENCE FROM GENETIC MANIPULATION OF PRP LEVELS IN ANIMALS, THAT IF YOU HAVE MORE PRP THAT DRIVES MORE AGGRESSIVE FORM OF PRION DISEASE. IF YOU HAVE LESS PRP DISEASE IS DELAYED AND HAPPENS MORE SLOWLY. IF YOU HAVE NO PRP THE DISEASE CAN'T HAPPEN AT ALL. SO WHAT YOU ARE LOOKING AT HERE THIS IS LIKE THE MODEL IN PRION DISEASE, BECAUSE IT IS TECHNICALLY TRANSMISSIBLE NOT INFECTIOUS NOT CASUALLY TRANSMISSIBLE BUT TECHNICALLY TRANSMISSIBLE UNDER THE RIGHT CIRCUMSTANCES YOU CAN INOCULATE WILD TYPE ANIMALS WITH PRIONS

15:29 AND THEY WILL DEVELOP FULL BLOWN TERMINAL PRION DISEASE. THIS IS THE MODEL. IF YOU LOOK AT A THE ONE ON X AXIS THAT'S ENDOGENOUS PRP EXPRESSION LEVELS. IF YOU DIAL UP FROM WILL YOU ARE OVEREXPRESSING, YOU DIAL DOWN YOU ARE UNDEREXPRESSING. IF YOU KNOCK OUT BOTH COPIES OF PRP, IT DOESN'T MATTER HOW MANY PRIONS YOU INOCULATE INTO THE BRAIN. THERE'S NO FUEL TO THE FIRE, THE DISEASE CAN'T TAKE OFF AND THE ANIMAL IS FINE. SO THIS IS REPLICATED MANY TIMES INCLUDING IN CONDITIONAL SYSTEMS. THE COMPANION QUESTION, IF THAT IS SORT OF A IS CENTRAL ORIENTING THERAPEUTIC HYPOTHESIS YOU MIGHT ASK IS IT SAFE TO REDUCE THE AMOUNT OF PRP IN THE BRAIN? I THINK WE HAVE A LOT OF DIFFERENT LINES OF EVIDENCE TO SUGGEST THAT IT IS. SO AT THIS POINT WE HAVE EIGHT KNOCK OUT MOUSE LINES, WE HAVE KNOCK OUT HAMSTERS AND RATS AND COWS AND GOATS, ALL THESE ANIMALS ARE HEALTHY. WE HAVE HUMAN GENETIC EVIDENCE FROM POPULATION SCALE

16:35 GENOMIC DATA SETS WHERE WE CAN LOOK HOW OFTEN PRP IS INACTIVATED BY CHANCE, HOW OFTEN IS LOSS OF FUNCTION ALLELE JUST CROP UP. THIS IS SOMETHING THAT WILL HAPPEN TO GENES AT SOME BASAL RATE THAT IS A FUNCTION OF THE SIZE OF THAT GENE. SOME RATE IN THE POPULATION UNLESS NATURAL SELECTION IS ACTING AGAINST THAT EVENT BECAUSE THE GENE IS ESSENTIAL OR VERY IMPORTANT. IN THE CASE OF PRNP, WE SEE AS MANY LOSS OF FUNCTION ALLELES IN THE POPULATION AS WE WOULD EXPECT IF NATURAL SELECTION DID NOT MIND IF THE GENE WAS KNOCKED OUT. SO FROM ALL OF THESE LINES OF EVIDENCE I THINK WHAT WE CAN SAY IS THERE WILL ALWAYS BE MORE BASIC BIOLOGY TO UNPACK. THERE IS A LOT WE DON'T KNOW ABOUT PRIONS. I DON'T FEEL I CAN TELL YOU HOW THEY KILL CELLS. WE ARE ONLY AT THE VERY BEGINNING OF UNDERSTANDING THE SET OF 3-D CONFIRMATIONS PRIONS CAN TAKE ON THAT ARE SELF-PROPAGATING AND NEUROTOXIC. THERE IS A LOT TO DO THERE ALWAYS WILL BE BUT SORT OF

17:46 LIEGE THE PREMISE OF MY CAREER PIVOT, MY HYPOTHESIS IS, WE KNOW ENOUGH TO DEVELOP MEANINGFUL THERAPIES. WE KNOW ENOUGH. WE CAN STAND ON THAT AND REACH FOR THE NEXT STEP. I THINK OF IT AS A QUESTION OF LIKE WE INVESTED A LOT IN UNDERSTANDING PRION BIOLOGY TO THE POINT WE DO TODAY. HOW DO WE MAKE GOOD ON THAT INVESTMENT? IT IS BY WE CONTINUE BASIC SCIENCE, ABSOLUTELY. BUT WE ALSO ENACT TRANSITION FROM BASIC BIOLOGY TO TARGETED TRANSLATION. SO I WANT TO SPEND TIME DESCRIBEING WHAT THAT LOOKS LIKE IN OUR LAB. WE HAVE TWO THERAPEUTIC MODALITIES WE ARE DEVELOPING AS ACT EPIDEMIC LAB, ONE IS OLIGO ONE IS GENE THERAPY. BOTH NOVEL MODALITIES HAVEN'T BEEN IN HUMANS YET. BUT WE HOPE TO CHANGE THAT. WE ARE QUARTERBACKING THE WHOLE PROCESS. SO WE DON'T HAVE A PHARMA PARTNER, WE TRYING TO TAKE ON EVERY STAGE OF DRUG DEVELOPMENT, JUST AMAZINGLY DIFFICULT BUT I'M ALSO GOING TO MAKE A CASE TO YOU I HOPE THAT

19:04 IT IS REALLY POWERFUL AND IMPORTANT THAT WE HAD THE OPPORTUNITY TO DEVELOP THESE DRUGS IN THIS WAY. I THINK WE HAVE A REAL PRIVILEGE AND OPPORTUNITY AS ACADEMIC DRUG DEVELOPERS TO SHARE EVERYTHING WE ARE LEARNING. TO MAKE A USUALLY VERY OPAQUE PROCESS MORE TRANSPARENT TO THE WORLD. AND TO MOVE QUICKLY, ASK AGGRESSIVE QUESTIONS, TRY TO DO RIGHT BY PATIENTS IN A TOTALLY DIFFERENT WAY AS POSSIBLE NORMAL CIRCUMSTANCES IN A COMPANY. SO I CAN'T SHARE ANYTHING ABOUT WHAT WE HAVE DONE WITHOUT RECOGNIZING THESE PEOPLE AND I SEE TIM RIGHT THERE. WAVE TO THE PEOPLE, TIM.

19:50 JOAN IS HERE SOMEWHERE TOO. I KNOW I. HI IT. HI. WE HAVE BEENO FORTUNATE TO WORK WITH THESE PEOPLE AND FUNDED BY THESE MECHANISMS. ABSOLUTELY NOTHING I SHOW YOU TODAY WOULD BE POSSIBLE WOULD THE VERY SPECIAL SPECIFIC THING THAT IS TARGETED TRANSLATIONAL MECHANISMS AT NIH BIVALENT EASY RNA. THIS IS AN OLIGO MODALITY DEVELOPED BY ANASTASIA AT UMAS. I REMEMBER IN 2019 WHEN SHE CAME TO BROAD AN PRESENTED HER DATA. SHE SHOWED THIS IMAGE AND SHE SAID WE THINK THAT THIS FORMAT OF EASY RNA IS ABLE TO GET -- SI RNA IS ABLE TO GET AROUND THE BRAIN. THOSE ARE MY MAGIC WORDS. PRION DISEASE IS A DISEASE OF EVERY NEURON, EVERY NEURON IS SUSCEPTIBLE. WE NEED TO GET AROUND THE WHOLE BRAIN.

20:50 SOMETIMES I THINK BUT FOR DELIVERY OUR PROBLEM WOULD BE SOLVED. THIS IS A TRIVIAL PROBLEM TO SOLVE IN A DISH TO ELIMINATE PRION PROTEIN FROM THOSE CELLS. GETTING AROUND THE BRAIN IS LIKE IT IS OUR CENTRAL CHALLENGE. WHAT SHE AND HER TEAM DID WAS THEY TOOK SI RNAs, TECHNOLOGY THAT HAD BEEN AROUND BUT HAD BEEN REALLY HARD TO DELIVER EFFECTIVELY TO THE CENTRAL NERVOUS SYSTEM AND FORMATTED THEM IN A DIFFERENT WAY BASICALLY TWO DUPLEXES WITH A LINKER. AND FOR WHATEVER REASON IN THIS DIFFERENT FORMAT THE DRUG HAD REALLY DIFFERENT BIODISTRIBUTION PROPERTIES FROM A SINGLE INJECTION COULD GET AROUND THE BRAIN PRETTY WELL, COULD LAST FOR SIX MONTHS, WE SAID WE HAVE TO TRY THIS. AND SO WE EMBARKED ON WHAT IS NOW GOING ON A FIVE, SIX YEAR COLLABORATION. INITIALLY SCREENING FOR POTENCY, BOTH SURVIVAL CURVES UP THERE GENERATED USING A MOUSE TOOL COMPOUND THAT IS NOT POTENT AS HUMAN COMPOUND BUT YOU CAN SEE

21:57 TWO DIFFERENT TREATMENT PARADIGMS. ON THE LEFT ARE RELATIVELY EARLIER TREATMENT. THIS IS STILL A PATHOLOGICAL TIME POINT. ON THE RIGHT A FRANKLY SYMPTOMATIC TIME POINT. SO YOU CAN SEE BOTH PARADIGMS WE HAVE A CLEAR SURVIVAL BENEFIT WITH THE PINK LINE. BUT I WILL RETURN TO THE FACT THE MAGNITUDE OF BENEFIT IS DIFFERENT DEPENDING WHEN YOU TREAT. ANY RATE WE HAVE THE OPPORTUNITY TO DO SCREENING FOR A CANDIDATE AND WE THINK OF PRION DISEASE AS A WHOLE BRAIN DISEASE SO POTENCY YOU ARE SEEING IN THAT TOP PLOT IS REALLY WHOLE BRAIN HEMISPHERE, NOT CHERRY PICKED AT ALL, RUN ON AN ELISA. SO TO SEE ON THE ORDER OF 70% KNOCK DOWN OF PRP ACROSS THE WHOLE BRAIN WAS PRETTY IMPRESSIVE TO US.

22:47 YOU CAN SEE IN THE REGIONAL DATA BELOW THAT, DOES POTENCY VARY BY REGION? SURE. BUT WE ARE ABLE TO ACHIEVE MEANINGFUL TARGET ENGAGEMENT ACROSS THE BRAIN IN MICE. DURABILITY TO SEE TARGET ENGAGEMENT I WOULD CALL MEANINGFUL AT FOR MAYBE EVEN -- AT FOUR MAYBE SIX MONTHS WAS IMPRESSIVE TO US. AT ANY RATE, WE WERE ABLE TO SCREEN OUR WAY THROUGH HUMAN LEAD, THAT'S THE MOLECULE RIGHT THERE. AND AS WE THINK ABOUT THE OLIGO SPACE IS EXPANDING ANTISENSE OLIGONUCLEOTIDES HAVE BEEN TESTED IN HUMANS FOR A VARIETY OF DIFFERENT CNS DISEASES. AS WE WERE LOOKING AT THE DATA FROM THIS MOLECULE, A LOT WE CAN ONLY REALLY LEARN FROM THE HUMAN EXPERIMENT BUT I SEE REASONS TO BE ENCOURAGED. I THINK WE HAVE SEEN REALLY CLEAN SAFETY RESULTS. WE HAVE SEEN NICE DURABILITY, NICE POTENT MAXIMAL KNOCKDOWN. THERE'S REASON TO HOPE THIS COULD BE A SUPERIOR CHEMISTRY. IT REMAINS TO BE TESTED BUT THIS ABSOLUTELY SEEMED WORTH ADVANCING. AND THIS

24:04 IS WHERE WORK THAT BEGAN AS AN NINDS IGNITE FUNDED PROJECT TRANSITIONED TO A SORT OF LIKE IND ENABLING PHASE. WE WERE SUPER LUCKY TO BE ABLE TO WORK THROUGH THE URGENT MECHANISM TO DO THE THINGS THAT NORMALLY ONLY ACCOMPANY CAN -- A COMPANY CAN DO. SO WE DID GLP TOXICOLOGY IN TWO SPECIES. WE WENT TO FDA AND ASKED CAN WE DO SINGLE SPECIES TOX GIVEN THIS IS A UNLET MEEDCAL NEED THAT IS RAPIDLY FATAL WITH NO STANDARD OF CARE. WE WERE TOLD DO RODENT DO LARGE MAMMAL ALSO WE WORKED OUT THE STUDY DESIGN TOGETHER WE DID THE STUDY, AND ALL OF THESE OTHER ACTIVITIES AS WELL. I WOULD HAVE TO SAY BEFORE WE GOT TO THIS STAGE, I CANNOT HAVE IMAGINED HOW MANY DIFFERENT ACTIVITIES WE WERE GOING TO END UP CONTRACTING OUT IN ORDER TO MAKE OUR DRUG PRODUCT.

25:12 NEVERTHELESS WE KIND OF LIKE PUSHED THROUGH ALL OF THESE DIFFERENT ACTIVITIES, FILED OUR IND IN FEBRUARY OF THIS YEAR, AND RECEIVED CLEARANCE TO DOSE SYMPTOMATIC PATIENTS IN MARCH. IT IS NOW THE CASE THAT WE ARE TRANSITIONING YET AGAIN TO A MECHANISM CALLED NEURONEXT THAT WILL BE FUNDING OUR FIRST IN HUMAN CLINICAL EXPERIENCE. AND SETUP IS UNDERWAY AT FIVE DIFFERENT CLINICAL TRIAL SITES. WE ARE CAUTIOUSLY HOPEFUL THAT MAYBE WE CAN DOSE A FIRST PATIENT EARLY IN THE NEW YEAR, MAYBE JANUARY OR FEBRUARY. IT IS A SMALL TRIAL. YOU CAN SEE 15 PATIENTS. WE WILL GET A DOSE -- WILL GET A DOSE OF THIS DRUG. IT IS AN ABSOLUTE LABOR OF LOVE TO GET THIS OFF THE GROUND AND TO COLLECT EVEN THAT SMALL AMOUNT OF INITIAL DATA. BUT I THINK THERE'S SOMETHING ABOUT GETTING A BRAND NEW MODALITY TO THE FIRST PEOPLE THAT THEN I THINK IS GOING TO BE NO MATTER WHAT WE SEE SUPER INFORMATIVE FOR US.

26:34 HOPEFULLY IF WHAT WE SEE IS POSITIVE, COULD OPEN THE DOOR FOR THIS MODALITY TO BE USEFUL FOR OTHER DISEASES. THIS STORY IS STILL MIDSTREAM AND KIND OF AT AN EXCITING INFLECTION POINT I THINK. I WILL RETURN TO THE THINGS WE STILL HAVE TO FIGHT FOR IN THIS PROGRAM SHORTLY BUT FIRST I WILL QUEUE UP THE COUNTERPOINT, GENE THERAPY PROGRAM WE ARE WORKING ON. SO THIS IS WORK WE ARE SO LUCKY TO BE DOING THROUGH THE SCGE CONSORTIUM. LUCKY NOT ONLY BECAUSE THAT PROGRAM IS ENABLING THIS LARGE SCALE DRUG DEVELOPMENT EFFORT BUT ALSO BECAUSE OF THE GROUP OF TEAMS IT'S BROUGHT TOGETHER. WE ARE ALL GETTING TO LEARN TOGETHER IN REAL TIME. SO THE VISION BEHIND CHARM IS IT'S SORT OF GOT SOME OPPOSING PROPERTIES. HERE WITH WE ARE TALKING AS OPPOSED TO OLIGO YOU DOSE EVERY THREE OR SIX MONTHS, A ONE TIME THERAPY.

27:45 SO WE ARE IMAGINING AN AAV DELIVERED EPIGENETIC EDITOR. AND THE WAY THE EDITOR WORKS IS THAT YOU HAVE A DNA TARGETING DOMAIN THAT DIRECT YOUR MOLECULAR MACHINE TO THE PRNP PROMOTER IN THIS CASE AN YOU HAVE RECRUITMENT DOMAINS THAT BRING ALONG ENDOGENOUS METHYLTRANSFERASE TO INSTALL METHYLATION MARKS AT THE PROMOTER AND SHUT DOWN THE GENE. WE HAVE REASON TO THINK DATA TO SUPPORT THE IDEA THAT THIS WOULD BE A PERMANENT CHANGE. YOU TURN OFF PRNP AND DEPENDING ON HOW GOOD YOUR DELIVERY IS, YOU CAN SEE IN THAT IMAGE WHERE THE YELLOW CELLS ARE PRNP POSITIVE NEURONS, REALLY UBIQUITOUS ACROSS THE BRAIN. AND WITH A SINGLE IV DOSE OF CHARM IN THE MOUSE SPECIFIC AAV VECTOR PHPEB, YOU CAN SEE HOW EFFECTIVELY WE ARE FLIPPING THE NEURONS PRP NEGATIVE. THE WHOLE PREMISE OF THIS AS A THERAPY IS BEING ABLE TO ACHIEVE THAT SAME KIND OF DELIVERY IN THE HUMAN BRAIN. AS RECENTLY AS THREE YEARS AGO I THINK I WOULDN'T HAVE BET ON IT

29:07 BECAUSE DELIVERING SOMETHING COMPLEX AS GENE THERAPY WHERE YOU ARE DELIVERING THE DNA, YOU NEED THE DELIVER IT IN SOMETHING, UNLIKE OUR OLIGOS WHICH ARE CHEMICALLY STABILIZED AND YOU CAN PUT THE OLIGO ITSELF INTO SPINAL FLUID WE NEED SOME SORT OF PACKAGE. AND WE JUST DIDN'T REALLY HAVE VECTORS CAPABLE OF REACHING THE WHOLE BRAIN. I THINK A KEY SEA CHANGE I SEE HAPPENING IN THE FIELD IS WE CAN IMAGINE WE AT LEAST HAVE VECTORS WORTH TRYING FOR THIS PURPOSE. SEW WE ARE SUPER LUCKY TO WORK WITH OUR BROAD NEIGHBOR BEN (INDISCERNIBLE) WHO DEVELOPED A TRANSPARENT RECEPTOR BINDING CAPSID SIMILAR TO THE HUMAN RECEPTOR AND YOU CAN SEE PHEB TOOL MOUSE CAPSID ON THE LEFT VERSUS THE TRANSPARENT RECEPTOR CAPSID IN DOSE RESPOND.

30:01 THE TRANSPARENT CAPSID, IN TRANSPARENT HUMANIZED MICE LOOKS BETTER. SO IN THIS PARADIGM, IN A DOSE DEPENDENT WAY, WE CAN SEE UPWARDS OF 80, 90% PRP REDUCTION ACROSS THE WHOLE BRAIN WHICH IS I THINK IMMENSELY EXCITING. THERE IS VERY MUCH LIKE A QUESTION OF TRANSLATION HERE. LIKE BIVALENT SI RNA CHARM IS SOMETHING THAT'S NOT BEEN TESTED IN HUMANS BEFORE AND THE TRANSPARENT CAPSID NOT TESTED IN IN HUMANS BEFORE. TRANSFERRIN. THERE IS A CERTAIN AMOUNT WE CAN DERISK IN OUR PRE-CLINICAL STUDIES AN IND ENABLING STUDIES BUT THERE IS A LOT WE WON'T KNOW UNTIL WE TEST IN HUMANS. THE QUESTION REALLY IS, LIKE IS THIS WORTHY OF PURSUING AND TESTING?

30:53 AND I THINK BASED ON THE DATA WE SEE, THE ANSWER IS YES. SCGE AS A MECHANISM WILL SUPPORT US TO TWO THROUGH IND ENABLING STUDIES. THAT'S THE TRANSITION WE ARE IN THE PROCESS OF MAKING RIGHT NOW. SO WE BASICALLY JUST DEFINED OUR HUMAN CANDIDATE AND WE ARE IN THE PROCESS OF WORKING WITH A MANUFACTURER TO SCALE UP FROM SMALL PREPS OF VIRUS TO RIGHT NOW TEN LITERS, THEN 50 LITTERS FOR A TOXICOLOGY STUDY ULTIMATELY 500 LITEDDERS PROBABLY FOR OUR CLINICAL BATCH. -- LITTERS FOR THAT CLINICAL BATCH. THAT PROCESS AND SCALEUP IS BEING QC ED, WE ARE GETTING THE PIECES IN PLACE TO RUN A PILOT TOXICOLOGY THAN FULL TOXICOLOGY STUDY NEXT YEAR.

31:44 THOSE STUDIES WILL BE IN HUMANIZED MICE. I WILL TELL YOU MORE ABOUT IT ACTUALLY. SO THIS CAPSID IS VERY, VERY SPECIFIC IN THE HUMAN TRANSFERRIN RECEPTOR. WE KNOW BEN HAS DONE THE WORK TO SHOW IF YOU PUT IT INTO OTHER MAMMAL WITH OTHER TRANSFERRIN RECEPTOR AMINO ACID SEQUENCES, YOU WON'T SEW THE SAME BIODISTRIBUTION, IT WON'T CROSS THE BLOOD BRAIN BARRIER AND GET INTO THE BRAIN. IN OUR INITIAL MEETING WITH CBER CENTER FOR BIOLOGICS EVALUATION RESEARCH TALKING ABOUT THIS PROGRAM WE SAID IT WOULDN'T BE RELEVANT TO DO SAFETY STUDIES WITH THIS CAPSID IN ANY ANIMAL WHERE WE ARE NOT GETTING BIODISTRIBUTION INTO THE BRAIN. SO WE PROPOSE THAT WE WILL DO OUR TOXICOLOGY IN HUMANIZED MICE. THAT WILL BE OUR DEFINITIVE STUDY. THEN WE WILL GO INTO HUMANS. WHAT WE GOT IN THAT EARLY INTERACTION WAS PRELIMINARY BUY IN. THE FEEDBACK WAS YOUR DATA MAKES SENSE LET'S KEEP TALKING BUT MAKES SENSE TO US. SO THAT IS

32:55 WHAT WE ARE PLANNING. I WILL JUST SAY ON THE SIDE, AND THIS IS KIND OF AN UNFUNDED MANDATE AT THE MOMENT, BUT I DO THINK THAT CHARM IS SUCH A BABY TECHNOLOGY THERE IS A LOT OF VALUE THAT WE ARE LEAVING ON THE TABLE. THIS HAS BEEN REALLY PAINFUL. FOR ME AND THE WHOLE TEAM. LOCKING A CLINICAL CANDIDATE KNOWING WE CAN KEEP IMPROVING IT. I HAVE A LOT MORE EMPATHY NOW FOR WHAT COMPANIES GO THROUGH AS THEY ARE MOVING THEIR PROGRAMS FORWARD. I THINK KEY WAYS WE CAN IMPROVE CHARM, WE HAVE REASON TO THINK IT IS LIKE VERY POTENT, ONCE IT REACHED A CELL AND WE HAVE ONLY TWO TARGETS PER CELL, YOU ARE TARGETING THE DNA. SO I THINK DIALING THE EXPRESSION SO IT IS THE MINIMUM YOU NEED PER CELL WOULD BE ONE DIRECTION FOR IMPROVEMENT. WE KNOW CHARM CAN BE ENGINEERED TO BE SELF-SILENCING. IT WILL TAKE TIME TO GET THE KINETICS OF THAT TUNED BUT I THINK THAT COULD BE A REALLY EXCITING DIRECTION FOR THERAPY WE THINK YOU DOPE NEED

34:01 TO EXPRESS CONTINUOUSLY FOR THE REST OF YOUR LIFE. I THINK THERE IS WORK WE CAN DO TO MAKE THE DNA TARGETING DOMAIN MORE SPECIFIC, THERE'S WORK WE CAN DO TO MAKE THE CAPSID DOSABLE INTO A LARGER PROPORTION OF OUR PATIENT POPULATION. ALL OF THIS IS SORT OF I'M WORKING IT MENTALLY INTO V 2 BECAUSE MANDATE TO PATIENTS IS TO MOVE FORWARD NOW TOWARDS V 1 FOR THE CLINIC. SO JUST TO REFLECT FOR A MOMENT ON THE FACT THAT I HAVE TOLD YOU AN OLIGO STORY AND ALSO A GENE THERAPY STORY. I THINK THESE ARE LIKE MEANINGFULLY DIVERSIFIED WAYS TO COME AT THE SAME PROBLEM. OLIGOS ARE REVERSIBLE FOR BETTER AND FOR WORSE, A GENE THERAPY IS NOT. WE ARE LOOKING AT DIFFERENT ROUTES OF ADMINISTRATION. A GENE THERAPY IS GOING TO CLAMP OUR TARGET, WE THINK OVER THE LONG TERM, AN OLIGO WILL GIVE US PEEKS AND TROUGHS BETWEEN DOSES.

35:06 THERE'S AN INTERESTING DIFFERENCE IN WHAT IT MEANS TO TURN PRP DOWN BY 50% IN THE WHOLE BRAIN. IN THE CONTEXT OF OLIGOWE THINK FROM SINGLE CELL DATA THAT MEANS WE ARE REDUCE PRP BY SOME DEGREE IN EVERY NEURON IN EVERY CELL. IN THE CONTEXT OF GENE THERAPY THAT PROBABLY MEANS WE ARE TURNING PRP DOWN OR OFF COMPLETELY, IN THE CELLS WE REACH, WE MIGHT NOT BE REACHING EVERY CELL. WHICH OF THOSE IS A BETTER WAY TO COME AT THE DISEASE BIOLOGY? WE DON'T KNOW. THESE ARE ALL THINGS WE HAVE TO TEST. I ALSO THINK OUTSIDE OF THE SCIENCE THERE ARE WAYS DIVERSIFICATION IS IMPORTANT. THE OLIGO CAN GET THERE FASTER. THE GENE THERAPY I THINK IF WE FILE AN IND IN 2027 I WILL BE SUPER PROUD. I THINK SOMETHING THAT I'M SENSITIVE TO ON BEHALF OF MY COMMUNITY IS WHAT ARE WE ASKING OF PEOPLE IF THEY GO ON THIS THERAPY? ONE AND DONE MEANS, THIS WILL SOUND CYNICAL BUT I HAVE HAD A LOT OF INTERFACE WITH HOSPITAL SYSTEMS

36:18 IN MY LIFE. ONE AND DONE MEANS NO ONE CAN TAKE IT AWAY FROM YOU. YOU ARE NOT CONSTANTLY FIGHTING FOR DOCTORS APPOINTMENTS, NOT FIGHTING YOUR INSURANCE COMPANY, YOU ARE NOT ON THE PHONE EVERY DAY WITH A SPECIALTY PHARMACY. IT IS DONE. IT IS DONE. YOU PROBABLY HAVE DOCTOR'S APPOINTMENTS TO MONITOR HOW YOU ARE DOING BUT THAT IS DIFFERENT. A LOT OF RARE DISEASE GENE THERAPY AND OLIGO PROGRAMS TAKEN ON BY COMPANIES AND WE ALL CELEBRATE AND THAT SEEMS AWESOME, A LOT GET SHELVED. NOT HERE TO TELL YOU ANYONE IS EVIL BUT WHEN THAT HAPPENS PEOPLE WHO HAD ACCESS TO A DRUG MIGHT LOSE ITS. SO THESE ARE THINGS I HAVE TO THINK ABOUT. TRILLION DOLLARS FINAL POINT HERE IS DOING THE RIGHT TRIALS. I WILL SAY MORE ABOUT THAT IN A MINUTE. I WANT TO RETURN TO THE POINT THIS IS NOT THE USUAL WAY DRUGS GET DEVELOPED. THIS IS EXTREMELY SPECIAL. HAVING THE LIBERTY TO SHARE WHAT WE ARE DOING HAS BEEN HUGE BECAUSE IT CREATES OUTSIZE

37:30 VALUE OUT OF OUR STRUGGLE AND I NEED THAT. BECAUSE THE STRUGGLE IS REAL. WE HAVE WE HAVE THE LIBERTY WHICH COMPANIES DON'T NECESSARILY TO PUT NOT JUST OUR DATA AND OUR RESULTS ON LINE IN A PUBLICLY ACCESSIBLE WAY BUT ALSO OUR IND ENABLING STUDIES TOXICOLOGY MANUFACTURING DETAILS, AND ALSO REGULATORY SUBMISSION AND FEEDBACK WE GOT FROM FDA. I ONLY KNOW LIKE A SINGLE DIGIT NUMBER OF EXAMPLES WHERE THAT INFORMATION IS AVAILABLE ONLINE. IT IS ACADEMIC DRUG DEVELOPERS DEVELOPERS LIKK IT IS IMPORTANT, ITS HELPS DEMYSTIFY THE PROCESS AND GIVES TOOLS TO OTHERS WHOP WANT TO DO THIS AND HAVE -- WHO WANT TO DO THIS AND HAVE NO IDEA WHERE TO START. IT SHINES A LIGHT ON WHETHER WE DOING, AND HOPEFULLY MAKES IT BETTER, IT GIVES PEOPLE THE OPPORTUNITY TO GIVE US ADVICE. I THINK THE WAY WE INTERACT WITH REGULATORS IS DIFFERENT. I THINK GOING IN AS PATIENT SCIENTISTS WE CAN HAVE A MORE FRANK CONVERSATION. WE

38:47 AREN'T STEWARDING LONG TERM CORPORATE REPUTATION. WE CAN ASK ABOUT HOW TO MOVE AS QUICKLY AS POSSIBLE AND WE ARE NOT AFRAID TO. THEN I THINK THESE PROGRAMS JUST HAVE MOVED QUICKLY. AND THE IDEA OF BEING ABLE TO DERISK BRAND NEW MODALITIES FOR THE BRAIN IN THE CONTEXT OF A RAPIDLY FATAL DISEASE WHERE RISK BENEFIT JUSTIFIES REALLY SWIFT DEVELOPMENT. I THINK THERE'S SOMETHING THERE. WE SPEND A LOT OF TIME WAITING TO GET TO THE FIRST HUMAN DOSE AND DOING DERISKING IN OTHER SYSTEMS THAT IS NEVER GOING TO BE PERFECT AND THAT IS NEVER GOING TO BE ABLE THE ANSWER OUR MOST IMPORTANT QUESTIONS. SO I THINK OFFERING A BALANCED PATH, A PATH THAT RECOGNIZES THE RISK BENEFIT OF THE DISEASE WHILE ALSO MOVING US TO OUR FIRST HUMAN LEARNINGS QUICKER, I THINK THIS IS ACTUALLY REALLY IMPORTANT PIECE OF THIS PUZZLE. SO ALL OF THIS BRINGS US KIND OF BACK TO THE SAME QUESTION WHICH IS LIKE THIS IS A LOT, THIS IS A LOT THAT NIH

40:02 HAS ENTRUSTED US WITH AND A LOT THAT WE HAVE INVESTED AND BRINGING THESE TWO MODALITIES TO THIS STAGE. BUT WE ARE NOT THERE YET. THE NEXT LEAP IS INTO THE CLINICAL SPACE. THIS IS WHERE OUR QUEST HAS AMAZED ME BECAUSE I COULD HAVE COME IN THINKING WHAT WE NEED IS THE MOLECULE AND TURNS OUT WHAT WE NEED IS A MOLECULE PLUS LIKE SO MANY OTHER PIECES OF INFRASTRUCTURE THAT WILL MAKE MEANINGFUL TRIALS POSSIBLE. THESE ARE -- THIS IS LIKE A SAMPLING OF HOE OF THE GENETICS AND NATURAL HISTORY AND PHARMACODYNAMIC BIOMARKER AND PATIENT REGISTRY, THERE'S SO MANY OTHER PIECES TO THE PUZZLE.

40:51 AND IN SOME WAYS I LOOK AT THIS, AND I THINK HERE IS A BASIS FOR OPTIMISM P. ANY GIVEN MOLECULE IS MORE LIKELY TO FAIL THAN SUCCEED. THAT IS OUR WORLD. THAT ACTUALLY IS DRUG DEVELOPMENT. THESE PIECES ARE I THINK ENDOWMENT FOR OUR FIELD THAT ANYONE CAN BUILD ON IN THE FUTURE. ANY NEXT MODALITY, ANY BETTER IDEA. AND I THEREFORE THINK IT IS REALLY IMPORTANT THAT WE HAVE DONE THIS AGAIN OUTSIDE OF A COMPANY. BECAUSE NOW IT IS EVERYONE'S. FOR COMMON DISEASE WOULD THIS BE DONE IN COMPANY? ABSOLUTELY. IT WOULD LIVE OR DIE FOR THE PURPOSES OF THAT COMPANY AND ONLY WHILE THAT PROGRAM IS ALIVE IN THAT COMPANY. SO I THINK I AM REALLY HAPPY TO HAVE BEEN ABLE TO DO THIS WORK. I THINK THESE ARE KIND OF THE THINGS EVERY RARE DISEASE NEEDS. THERE'S STILL ON THIS FRONT MORE TO DO. I WILL SAY IT IS NOT ALWAYS OBVIOUS HOW TO FUND THIS STAFF. QUITE A BIT WE HAVE DONE THROUGH WHAT I CALL BAKE SALE MONEY, LITERALLY

42:07 PATIENTS AND FAMILY DONATE TO OUR NON-PROFIT AND THAT HELPS POWER SOME OF THE FILLING OF THE GAPS THAT IS LESS OBVIOUS HOW TO FILL. BUT I JUST I LOOK AT THIS STUFF AND THINK THIS IS OUR FOUNDATION. THINKING ABOUT THE CLINICAL PIECE. I THINK IT IS ONLY COMMON SENSE THAT IN DISEASE DRIVEN BY IRREVERSIBLE LOSS OF NEURONS, THE EARLIER YOU TREAT THE MORE GOOD YOU CAN DO. WE HAVE SEEN THIS OVER AND OVER IN OUR PRE-CLINICAL DATA. EVERY SURVIVAL STUDY WE HAVE DONE IS TIME POINT DEPENDENT. PREVENTIVE TREATMENT YOU GET THE OUTSIZE BENEFIT UP TOP. EARLY SYMPTOMATIC MAYBE YOU CAN DO A BENEFIT FOR A SUBSET OF ANIMALS.

42:55 THERE IS SUCH A THING AS TOO LITTLE TOO LATE. AT THE ADVANCE SYMPTOMATIC STAGE OF DISEASE. WHEN I THINK HOW WE MAP THESE LEARNINGS ON TO THE HUMAN SITUATION, WE HAVE TWO PATIENT POPULATIONS. SYMPTOMATIC AND PRE-SYMPTOMATIC AT RISK. AND I THINK THEY OFFER THE POTENTIAL FOR COMPLIMENTARY HUMAN DATA SETS. THE PROSPECT FOR CLINICAL OBSERVABLE BENEFIT ON THE ONE HAND, THE PROSPECT FOR SORT OF MUCH LESS COMPLICATED LOOK AT SAFETY AND TARGET ENGAGEMENT. A PRE-RECRUITABLE POPULATION YOU CAN HAVE LINED UP AND READY TO GO. ON THE OTHER HAND, AND THE MAGNITUDE AND TYPE OF BENEFIT YOU CAN DO FOR THESE TWO POPULATIONS IS I THINK JUST REALLY DIFFERENT..

43:46 STABILIZATION KIND OF BE THE HIGHEST GOAL WE CAN EXPECT IN A SYMPTOMATIC POPULATION. VERSUS EXTENSIONS OF HEALTHY LIFE, DELAYING OR PREVENTING ONSET. IN HEALTHY POPULATION, THAT HASN'T SHOWN SYMPTOMS YET WE CAN MEASURE PRION PROTEIN LEVELS IN SPINAL FLUID AND KNOW IF YES REDUCING PEEPION PROTEIN LEVELS IN THE PAIN -- PRION PROTEIN LEVELS IN THE BRAIN AND YOU BUILD ON THAT BASIC UNDERSTANDING OF THE DISEASE AND YOU HAVE A TOOL, A BIOMARKER REASONABLY LIKELY TO PREDICT CLINICAL BENEFIT IN OUR AT RISK PEOPLE SO THIS IS HOW WE HAVE CONCEIVED A PREVENTION TRIALS AND I WILL JUST QUEUE UP WHERE THIS CONVERSATION IS FOR OUR TWO DIFFERENT DRUG DEVELOPMENT PATHS. I HAVE ALREADY TOLD YOU A LITTLE BIT ABOUT THE FEEDBACK FROM CBER, WHERE THEY SAID YES IT MAKES SENSE TO PROCEED IN BOTH POPULATIONS IN YOUR FIRST TRIAL. OBVIOUSLY WE WILL DO RISK MITIGATING THINGS THAT MAKE SENSE. MAYBE WE WILL HAVE A MINIMUM AGE FOR ENROLLMENT THAT

44:47 REFLECTS THE RISK DISTRIBUTION OVER THE LIFE SPAN. MAYBE AT EACH DOSE LEVEL WE WILL DOSE SYMPTOMATIC PATIENT BEFORE A PRESYMPTOMATIC PERSON. THESE THINGS MAKE SENSE. WE HAVE GOTTEN VERY DIFFERENT FEEDBACK FROM CDER, CENTER FOR DRUG EVALUATION AND RESEARCH WHICH IS OVERSEEING OUR OLIGO. I MENTION WE WERE CLEAR TO DOSE SYMPTOMATIC PATIENTS. WE ARE ON PARTIAL CLINICAL HOLD FOR PRE-SYMPTOMATIC BUT AT ISSUE HERE IS THE QUESTION OF WHETHER OUR SAFETY PACKAGE IS GOOD ENOUGH OR WHETHER WE NEED TO ADS A NON-HUMAN PRIMATE STUDY. IN THE SPECIES WE HAVE ALREADY DOSED RATS AND DOGS, WE HAVE BEEN ABLE TO EFFECTIVELY DERISK EVERYTHING EXCEPT ON TARGET PRP LOWERING BECAUSE THE SI RNA IS NOT TARGETING IN THOSE SPECIES.

45:41 ON THE OTHER HAND >> WE TALKED EARLIER ABOUT ALL THE DIFFERENT FORMS OF DATA THAT SUGGEST LOWERING PRP INCLUDING ALL THE WAY TO ZERO FOR ANY TIME INCLUDING THE WHOLE LIFE SPAN IS SAFE. I WOULD HAVE TO SAY I DON'T FIND THIS FEEDBACK RESPONSIVE TO THE RISK BENEFIT OF THE DISEASE AND IT IS A CONVERSATION ONGOING. WE HAVE SUBMITTED A RESPONSE TO THE CLINICAL HOLD KIND OF OUTLINING THAT ARGUMENT. AND WE ARE WAITING TO MARY BACK. I THINK AS I LOOK AT THE DISPARITY, ONE THING I NOTICE WE HAVE GOTTEN MORE CONSERVATIVE FEEDBACK IN THE CONTEXT OF THE DRUG THAT IS REVERSIBLE. I'M NOT HERE TO SUGGEST THE WORLD HAS TO ALWAYS MAKE SENSE BUT IF THIS MADE SLIGHTLY MORE SENSE I WOULD BE REALLY HAPPY. SO IT IS SOMETHING WE ARE WORKING ON. AND WE WILL JUST HAVE TO SEE. WOULD WE HAVE BEEN ABLE DO SOME OF THIS WORK WITHOUT THE SPECIAL NIH MECHANISMS I HAVE MENTIONED TO YOU? DEFINITELY NOT. THIS IS NOT RO1 FUNDABLE WORK. THIS IS

47:07 NOT ABOUT NOVEL HYPOTHESIS OR NOVEL TARGETS OR NODAL BIOLOGY, THIS IS EXECUTING THE TOOLS WE HAVE TO MAKE SOMETHING CONCRETE FOR PATIENTS USEFUL IN OUR LIFETIMES. I THINK IT IS SPECIAL GIVEN THAT OPPORTUNITY. I WANT TO DO EVERYTHING WE CAN WITH IT I THINK ONE THING THAT KEEPS ME UP AT NIGHT THESE DAYS IS THE THE IDEA OUR QUEST HAS TRANSITIONED FROM A PHASE WHERE THE JEOPARDY WAS LARGELY OR ENTIRELY SCIENTIFIC TO A PHASE WHERE THE SCIENTIFIC JEOPARDY ISN'T GONE, SOME AMOUNT WILL BE WITH US FOREVER. BUT WE ARE MUCH MORE IN A REGIME OF HUMAN SYSTEMS JEOPARDY. OUR ABILITY TO PROGRESS FROM HERE DEPENDS A LOT MORE ON BRINGING PEOPLE ON BOARD TO THINK ABOUT RISK BENEFIT AND WHAT MAKES SENSE NOT IN GENERAL BUT IN THE CONTEXT OF THIS EXACT BIOLOGY AND THIS EXACT DISEASE.

48:08 WE NEED TO ASK WHAT IS THIS BIOLOGY ASKING OF US? AND I THINK WHAT IT IS ASKING OF US IS TO MOVE QUICKLY. I THINK THE RECENT FDA COMMENTARY OR PLAUSIBLE MECHANISMS PATHWAY COULD HAVE A REALLY NICE INTERSECTION WITH WHAT MAKES SENSE HERE. WHERE WE HAVE SUCH HIGH CONFIDENCE IN A SINGLE GENETIC CAUSE OF DISEASE. CAN WE MOVE INTO A SMALL NUMBER OF PEOPLE MONITORING THAT GENE PRODUCT CLOSELY AND ASK ARE WE MOVING IN THE RIGHT DIRECTION. I ALSO THINK ANOTHER WAY HUMAN SYSTEMS ARE SHOWING UP FOR US AND MAYBE CHALLENGING US IS GETTING THE RIGHT HANDED AND LEFT HAND TO TALK TO EACH OTHER.

49:03 I THINK IT IS INTERESTING THAT WE HAVE GOTTEN SUCH LIKE DIFFERENCE FEEDBACK FROM DIFFERENT ARMS OF THE FDA. WE WERE ASKED FOR A MONKEY STUDY BY CENTER FOR DRUG EVALUATION AN RESEARCH, THEN WE WERE -- WE TOOK THAT FEEDBACK TO THE URGENT PROGRAM WHICH HAD FUNDED, RIGHT, OUR IND ENABLING STUDIES AND SAY HERE WITH WHAT WE ASKED OR AND IT WAS UNDER BUDGET. COULD A NEW MECHANISM BE FOUND? I DON'T KNOW BUT IT IS INTERESTING THAT IN PRINCIPLE AT LEAST, THIS IS ALL FEDERAL GOVERNMENT. GETTING THESE PIECES TO TALK TO EACH OTHER IN THE CONTEXT OF RARE DISEASE WHERE PEOPLE ARE WAITING ON US WOULD BE A TERRIFIC AMBITION. I THINK THAT WE HAVE BEEN GIVEN A REAL OPPORTUNITY HERE TO FIGHT FOR PRIMARY PREVENTION WHICH I HI IS THE RIGHT THING IN A LOT OF DEGENERATIVE DISEASES IN A LOT OF NEURODEGENERATIVE DISEASES, BUT WE HAVE AN ESPECIALLY BLACK AND WHITE CASE. WHERE ONCE YOU ARE SYMPTOMATIC A LOT IS GOING

50:25 WRONG AND GOING WRONG REALLY FAST. SO I THINK IT IS KIND OF OUR RESPONSIBILITY ON BEHALF OF THE COMMUNITY TO TRY THIS. AND WE HAVE SO MANY TOOLS LINED UP. IF WE CAN'T DO IT HERE I QUESTION WHERE WE CAN EVER DO IT. FINAL THOUGHTS. SO I'M 41. THAT IS A SURVIVAL CURVE OF PEOPLE WITH MY MUTATION. SO WE HAVE NOW BEEN AT THIS HOW LONG? GOING ON SAY CALL IT 12, 13 YEARS. WE HAVE SO MUCH NOW THAT I COULD NOT HAVE IMAGINED WHEN WE STARTED DOWN THIS ROAD. IT IS STILL THE CASE THAT WHEN A PATIENT REACHES OUT TO ME WHICH HAPPENS BASICALLY EVERY DAY, WHAT I HAVE TO SAY TO THEM IS THERE'S NOTHING. AND I TRY TO OFFER THEM WHAT RESOURCES I CAN BUT I CAN OFFER THEM A DRUG.

51:23 AND EVEN WHEN WE ARE ENROLLING SI RNA CLINICAL TRIAL YOU SAW THE NUMBERS, 15 PEOPLE. THE VAST MAJORITY OF PEOPLE WHO REACH OUT TO ME I WILL STILL BE SAYING THERE'S NOTHING. SO TO HAVE COME THIS FAR AND YET HAVE SO FAR TO GO IS I WOULDN'T HAVE IMAGINED IT THIS WAY. WE ARE IN A BUSINESS WHERE TIME LINES SLIP AND ONLY SLIP IN ONE DIRECTION. THAT'S HUMAN IN EVERY INDUSTRY AND ALSO TRUE IN DRUG DEVELOPMENT. THIS IS A TIME LINE THAT DOESN'T SLIP. SO I ACTUALLY KNOW ALL THESE FOLKS. AND I CAN TELL YOU AT ANY GIVEN TIME WHO IN MY COMMUNITY IS ACTIVELY DYING OF PRION DISEASE TODAY BECAUSE WE DIDN'T GET THERE FAST ENOUGH FOR THEM. SO THAT'S OUR MANDATE. FINAL THING I WILL SAY. SO THESE ARE MY KIDS.

52:17 KAVARI IS FIVE, (INDISCERNIBLE) IS EIGHT. SO I WAS REALLY LUCKY TO BE ABLE TO HAVE THESE KIDS THROUGH IVF PGD WHICH ISN'T BULLETPROOF, NOTHING IS BUT THEY WERE BIOPSIED AS EMBRYOS AND WE HAVE ALL THE REASONABLE CONFIDENCE WE COULD ASK FOR THAT THEY AR ARE MUTATION NEGATIVE. M GOING TO FIGHT FOR PREVENTION FOR THE PEOPLE WHO ARE LIVING AT RISK TODAY. AND I THINK THIS IS LIKE A REALLY COOL WAY SCIENCE HAS BROUGHT US AN EVEN MORE UPSTREAM FORM OF PREVENTION. THE KIDS KNOW WHAT WE DO FOR A LIVING AND THEY KNOW WHY. AND HOWEVER IT GOES I WANT THEM TO KNOW WE FOUGHT FOR THIS. SO WITH ALL OF THAT, I WILL JUST SAY THANK YOU.

53:17 >> WE HAVE TIME FOR QUESTIONS. AT THE MIC. I SEE SOMEONE MAKING A MOVE. EXCELLENT, PLEASE. >> I H. MY NAME IS (INAUDIBLE) I WORK IN NCATS. I HAVE ZERO EXPERIENCE IN CLINICAL TRIAL BUT YOU GOT ME THINK -- FIRST GREAT TALK. I NEED THE SAY THAT. VERY INTERESTING. YOU WERE TALKING ABOUT SYMPTOMATIC PATIENTS, ASYMPTOMATIC PATIENTS, ENROLLING THEM, AND I KEPT THINKING IF I AM A PERSON WHO IS A SYMPTOMATIC TODAY AND I DON'T KNOW WHEN I MAYBE BECAME SYMPTOMATIC AND PROBABLY NOT CONSIDERING ENROLLING, HOW DOES THAT WORK?

54:02 BECAUSE BY THE TIME YOU GET SYMPTOMS YOUR WINDOW OF CONSENTING TO A CLINICAL TRIAL IS EXTREMELY SMALL. SO HOW DOES THE INFORMED CONSENT HOW YOU DESIGN THAT TO HELP PEOPLE UNDERSTAND THEIR OPTIONS AND IS THERE ANY OTHER DISEASE THAT IT HAS REACHED THE CLINICAL TRIAL STAGE WHICH SIMILAR SITUATION HAPPENS IN WHICH THE SYMPTOMATIC WINDOW IS -- YOU CAN PREDICT LIKE YOU SAY SYMPTOMATIC PEOPLE IN GENERAL BUT YOU DON'T REALLY NOLO WHO THESE PEOPLE -- I DON'T UNDERSTAND VERY WELL, SEEMS LIKE THERE IS SOMETHING THAT IS DIFFICULT TO GET RIGHT AND I WILL LOVE IT IF YOU EXPLAIN THAT A LITTLE BIT MORE HOW YOU DEAL WITH THAT.

54:47 >> ABSOLUTELY. YEAH. SO MANY THINGS ARE DIFFICULT TO GET RIGHT INCLUDING YOU ARE CORRECT, WE CAN'T RECRUIT BOAR THE TRIAL NOW FOR SYMPTOMATIC PATIENTS. ANYONE WE RECRUIT TODAY IS LIKELY TO BE DEAD BY THE TIME WE CAN DOSE THEM. SO THAT IS SOMETHING THAT HAS TO HAPPEN IN REAL TIME. INFORMED CONSENT IS COMPLICATED. PRION DISEASE PATIENTS LOSE DIFFERENT THINGS EARLY IN THE PROCESS. I THINK WE HAVE TO BE REALLY STRICT AND THAT IS ALSO GOING TO BE VERY PAINFUL ABOUT TRYING TO ENROLL PEOPLE WHILE THEY STILL HAVE SOME MINIMAL FUNCTIONAL SCORE.

55:23 WE HAVE PREION DISEASE RATING SCALES WE CAN USE TO TRY TO ENROLL PEOPLE EARLY ENOUGH TO PRESERVE MEANINGFUL QUALITY OF LIFE. DOES MA MEAN THEY ARE ABLE TO GIVE INFORMED CONSENT? MAYBE IN SOME CASES BUT NOT OTHERS. AND IN THOSE OTHERS CASES IT IS NEXT OF KIN, THE SPOUSE OR FAMILY MEMBER WHO DRIVES THE ENROLLMENT PROCESS AND SIGNS ON THEIR BEHALF. >> OR MAYBE POSSIBLE SOMEBODY WILL SAY AS LONG AS I'M ASYMPTOMATIC I DON'T WANT TO DO ANYTHING BUT IF I WERE TO BE SYMPTOMATIC THEN BY ALL MEANS DEPLOY ANYTHING YOU CAN DO TO -- I WILL BE INTERESTED AT THAT POINT INTO THE SYMPTOMATIC ARM BUT NOT IN ASYMPTOMATIC.

56:06 CONSENTING ADVANCE IF THAT IS A THING. >> THESE ARE ALL CONVERSATIONS PEOPLE CAN HAVE WITH THEIR CLINICIANS AND THEIR FAMILIES. I GUESS WHAT I WOULD SAY IS EVERYBODY'S WAY OF EXPERIENCING THEIR RISK IS DIFFERENT. I DON'T NEED EVERY PERSON TO ENGAGE WITH THEIR RISK IN THE SAME WAY. THERE ARE LOTS OF PEOPLE IN THE CARRIER COMMUNITY WHO CARED FOR THEIR LOVED ONES AS THEY HAVE DIED OF PRION DISEASE MAYBE MANY TIMES OVER. I HAVE A FRIEND WHO FIVE GENERATIONS OF HER FAMILY ARE KNOWN TO HAVE DIED IN THIS WAY. THERE ARE PEOPLE WHO IF REASONABLE SAFETY HAS BEEN ESTABLISHED WILL TAKE THE OPPORTUNITY TO GO ON THERAPY AND EXPERIMENTAL THERAPY BEFORE THEY ARE SYMPTOMATIC. THERE ARE PEOPLE WHO WILL WANT TO WAIT UNTIL THEY ARE SYMPTOMATIC.

56:53 THERE ARE PEOPLE WHO EVEN WHEN THERE IS APPROVED DRUG WILL NOT WANT TO ENGAGE WITH THEIR RISK UNTIL THEY ARE SYMPTOMATIC. SO I THINK WE NEED A WORLD WHICH ALL OF THESE CHOICES ARE RESPECTED. >> SECOND PART OF THE QUESTION, IS THERE ANY OTHER DISEASE YOU KNOW ABOUT THAT HAS SIMILAR -- >> THIS EXACT CONSTELLATION OF PARAMETERS MAYBE NOT, THERE ARE CERTAINLY CANCERS THAT KILL PEEP AS RAPIDLY, THERE HAVE BEEN SECONDARY PREVENTION TRIALS IN SOME NEURODEGENERATIVE DISEASES. THERE IS A TRIAL RIGHT NOW OF SOD 1 TARGETING ASO THAT IS ENROLLING PEOPLE WHO ARE PRE-SYMPTOMATIC AND TRACKING THEIR NFL AND WHEN NFL RISES THAT TRIGGERS HEM TO RANDOMIZE THE DRUG. TO ME THAT IS CALLED SECONDARY PREVENTION. WE ARE STILL WAITING FOR SOMETHING TO GO WRONG. PRIMARY PREVENTION.

57:56 MEANS WE HAVE NO SIGNED MOLECULAR OR CLINICAL THAT ANYTHING IS WRONG EXCEPT CHANGE IN DNA. BUT THERE ARE CERTAINLY PIECE MEAL PRECEDENTS, YES. >> THANK YOU. >> SINCE YOUR BEING INDICTED HERE AND LEARNING A LITTLE BIT MORE ABOUT PRION DISEASE WE SPOKE THIS MORNING I HAVE NO PREVIOUS KNOWLEDGE OF; I HAVE TO ADMIT I'M REALLY CURIOUS ABOUT THEWISE CHEMICAL FUNCTION OF PRNPRNP. YOU YOU MENTIONED THISA LITTLE BIT HEY LISTEN WE ARE GOING TO MOVE PAST THAT BECAUSE WE CAN'T HAVE THESE THERAPEUTIC MODALITIES WHICH WILL BYPASS THAT. -- WE CAN HAVE THESE MODALITIES. THE UBIQUITOUS EXPRESSION CNS EXPRESSION BUT AT THE SAME TIME THE KNOCK OUT ANIMALS ARE VIABLE AND HEALTHY.

58:40 WHAT ARE YOU AND OTHERS LEARNING ABOUT THE NATIVE FUNCTION OF THIS? IS THERE A DEVELOPMENTAL ROLE? >> YEAH. IT IS A GREAT QUESTION WE HAVE A LITERATURE FULL OF IDEAS ABOUT PRP NATIVE FUNCTION MOST WHICH HAVEN'T CONVINCINGLY REPLICATED BUT THERE IS A FUNCTION THAT WE HAVE REPRODUCED IN THE LAB I'M FAIRLY CONFIDENT IS REAL WHICH IS THAT PRP APPEARS TO HELP MAINTAIN MYELIN ON PERIPHERAL NERVES SO IN OLDER ANIMALS, WE HAVE SEEN THIS IN MICE, IT IS REPORTED IN MICE, WE HAVE SEEN IT ALSO IN RATS AND HAMSTERS, IF YOU IMAGE THE SCIATIC NERVE OF AGED ANIMALS LIKE 60 WEEKS OLD YOU CAN SEE AN UNINVOLVED FORMATION IN THE MYELIN WHERE IT IS KIND OF DAMAGED REPAIRED DAMAGED REPAIRED. PULLING A BEHAVIORAL PHENOTYPE OUT OF THAT IS HARD SO WE HAVE NOT SEEN BEHAVIORAL IMPACT OF THAT. BUT I THINK THE HISTOLOGY IS REAL. AND I THINK IT TELLS US WE SHOULD MONITOR AND STANDARD NEUROLOGICAL BATTERY RUN IN A CNS CLINICAL

59:51 TRIAL LIKE PERIPHERAL NERVE RESPONSE WILL BE MONITORED. WE SEE THAT IN HOMOZYGOUS KNOCK OUTS NOT IN RATS. SO ANYTHING TAKING DOWN BUT NOT DOWN TO ZERO, EVEN IF WE HAD A BEHAVIORAL PHENOTYPE IN ANIMALS I QUESTION WHETHER WE WOULD SEE IT IN PEOPLE. ANY RATE, I THINK THAT'S ONE THING TO KEEP AN EYE ON. YEAH. >> IS THERE A PATHOLOGY IN THE MYELIN SHEATHE OR ANYWHERE THAT WOULD INDICATE AT THE OUTSET OF DISEASE THERE IS AN EXACERBATION OF THAT PARTICULAR BIOCHEMICAL ROLE THAT IS CONTRIBUTING TO DISEASE SYMPTOMS AND ULTIMATELY DEATH?

1:00:34 >> YEAH. I MEAN, THIS TIES TO A LARGER QUESTION WHICH IS TRIG TRIGGER. AND MY THOUGHTS ON THIS ARE PRETTY UNSATISFYING. I THINK SO PRION DISEASE WILL KILL ONE IN 6,000 PEOPLE THIS WILL THE GENERAL POPULATION ABSENT A MUTATION. THAT IS AS FAR AS WE CAN TELL VERY EQUAL OPPORTUNITY ACROSS THE WORLD, JUST DEPENDS HOW HARD YOU LOOK FOR IT. AND THEN WITHIN GENETIC FAMILIES, THE AGE OF ONSET, THIS IS TRUE WITHIN PEDIGREES OPINION SIB PAIRS AN EVEN MANY THE SMALL NUMBER OF REPORTED CASES OF IDENTICAL TWINS T AGE OF ON SENT VARIES BY YEARS OR DECADES. TO ME THAT SPEAKS TO A RANDOMNESS LIKE TRILLIONS OF COPIES OF THE NATIVE UNSTRUCTURED PROTEIN FLOPPING AROUND SAMPLING LOTS OF CON FIR MAYINGS IN A TIME DEPENDENT WAY. SOME NUMBER OF TIMES IT WILL HAPPEN TO SAMPLE UNLUCKY SELF-PROPAGATING CONFIRMATION. AND THAT IS MY WORKING MODEL FOR WHY PRION DISEASE CAN BE RANDOM ACROSS A POPULATION AND THEN IN HIGH RISK

1:01:44 SITUATIONS RANDOM ACROSS TIME. THERE ARE PEOPLE WHO LOOK FOR GENETIC MODIFIERS, NONE OF LARGE EFFECT SIZE OUTSIDE OF PRNP ITSELF SO FAR. THERE ARE ALSO PEOPLE WHO LOOK FOR AND THINK ABOUT ENVIRONMENTAL TRIGGERS. I THINK NOTHING HAS UNSEATED MY MODEL IN MY OWN HEAD SO FAR. >> I WOULDN'T EITHER. I'M GOING TO END THE WAY SHE STARTED, AMAZING TALK, TERRIFIC EVERYTHING AND I'M SURE LIKE EVERYBODY HERE, WISH YOU THE BEST GETTING THIS THROUGH. >> HI, I ENJOYED THE TALK AS WELL. MY QUESTION IS GIVEN HOW IMPORTANT TIME IS IN THIS ENTIRE ENDEAVOR WHY HAVE YOU CHOSEN TO GO ABOUT IT AS AN ACADEMIC DRUG DEVELOPER RATHER THAN TRYING TO BRING IN A COMPANY WHO MAY HAVE MORE MONEY, MORE PEOPLE TO THROW AT THE PROBLEM?

1:02:42 >> LOTS OF THOUGHTS ON THAT. I WOULD SAY SO I FOCUS TODAY ON THE STORY THAT I CONTROL. WE ALSO COLLABORATE WITH COMPANIES AND I THINK SOME OF MOST IMPORTANT THINGS I HAVE LEARNED ABOUT DRUG DEVELOPMENT HAVE BEEN LESSONS LEARNED FROM OUR COLLABORATORS. I THINK FOR ME THESE TWO PROGRAMS, AND HOPEFULLY GETTING THEM THROUGH FIRST IN HUMAN OURSELVES, THAT -- THOSE ARE MY LEVERS FOR LIKE I THINK ASKING THE RIGHT QUESTIONS AND PUSHING THE PARADIGMS THAT I THINK ARE REALLY GOING TO MOVE PRION DISEASE. I HAVE MET SUCH AMAZING INDIVIDUALS WHO DO DRUG DEVELOPMENT INSIDE OF COMPANIES AND LIKE CREATIVE SMART BRAVE AWESOME PEOPLE. AND I ALSO SEE THE WAYS THEY FIGHT THE SYSTEMS THEY ARE BUILT INTO. AND HOW PLANS GET GENERISIZED OVER TIME, THERE IS A REGRESSION OF MEAN THE WAY THINGS ARE DONE, MAYBE NOT A FULL REGRESSION BUT I SEE ALL THE DIFFERENT PRESSURES ON GETTING PROCESSES TO CONFORM WHEREAS BIOLOGY DOES NOT.

1:03:58 THAT'S JUST THE TENSION THEY ARE BRIDGING ALL THE TIME. WHEN I THINK ABOUT PARTNERSHIPS WITH COMPANIES, I THINK ABOUT IT IN TERMS OF RESOURCES THAT COME IN AND CONTROL THAT GOES OUT. THAT'S JUST A CONSTANT DIALOGUE AND I THINK WE LEARN SO MUCH FROM THEM. SO I'M SUPER GRATEFUL FOR ALL THOSE PARTNERSHIPS AND ALL THOSE LEARNINGS AND FOR ME HAVING A DIVERSIFIED PORTFOLIO IS ULTIMATELY THE THING THAT BRINGS ME CONFIDENCE. IT IS GOING TO TAKE ALL THE ABOVE. >> AWESOME, THANK YOU SO MUCH. >> THANK YOU FOR COMING AND DELIVERING THIS AWESOME TALK. MY QUESTION IS I DON'T KNOW, PROBABLY NOT THE ONLY ONE WONDERING THIS. WHAT -- I GUESS WHAT DO YOU SEE FOR YOURSELF AND -- IN YOUR OWN POSITION AS SOMEONE WITH THIS MUTATION?

1:05:03 THESE THERAPEUTICS YOU HAVE IN DEVELOPMENT, IS IF THE TIME COMES DO YOU SEE YOURSELF? LIKE ENDING UP USING THEM IN SOME WAY? >> I WOULD ABSOLUTELY LOVE TO BE ON A SAFE EFFECTIVE PRP LOWERING DRUG, YES. I WOULD BE REALLY HAPPY TO ENROLL IN A PREVENTIVE CLINICAL TRIAL WITH STRONG DATA TO SUPPORT IT. HERE IS WHAT ELSE I WILL SAY ABOUT OUR OWN DRUG DEVELOPMENT PROGRAMS, I GET TO SEE ALL DATA TO MAKE AN INFORMED DECISION ABOUT WHETHER I WANT SOME DAY TO ENROLL IN STUDY. AND THAT PIECE OF IT WON'T BE UP TO ME, I WON'T BE THE CLINICAL TRIAL SITE PI. I WON'T MAKE ELIGIBILITY DISCUSSION DECISIONS AND I WILL SHOW UP JUST LIKE ANYBODY ELSE. HOPING THAT I GET LUCKY AND GET ENROLLED IN THE STUDY. BUT YES, PEOPLE ASK ME SOMETIMES ABOUT COMBINATION THERAPIES AND THEY ASK ME SOMETIMES ABOUT WITH THERAPIES WOULD YOU CHOOSE. I THINK THAT IS LIKE -- IT IS SUCH A LOVELY QUESTION. THAT PRESUME AS BETTER WORLD THAN THE ONE WE

1:06:17 HAVE GOT. IN THE WORLD WE HAVE GOT, IF YOU HAVE ACCESS TO SOMETHING GO ON IT IMMEDIATELY IF THE DATA SUPPORT IT. IN THE WORLD WE HAVE GOT IT IS A VERY, VERY RARE PATIENT WHO IS ACTUALLY GOING TO BE IN A POSITION TEMPORALLY FINANCIALLY AN LOGISTICALLY TO HAVE A CHOICE ACTUALLY. WE ARE MANY YEARS AWAY FROM A WORLD WHERE WE HAVE MULTIPLE APPROVED THERAPIES THAT A PATIENT CAN GO TALK TO THEIR DOCTOR ABOUT AND SELECT FROM MENU STYLE. I WAS RECENTLY WITH THE OPS MEETING WHERE A SPINAL MUSCULAR ATROPHY PATIENT TYPE 3 ADULT PATIENT DESCRIBED EXACTLY THAT SITUATION. GOING TO HIS NEUROLOGIST AND BEING TOLD THERE ARE THREE APPROVED THERAPIES LIKE HERE THEY ARE. HERE ARE THE PROS AND CONS. HERE IS AN OVERVIEW OF THE DATA WHICH WOULD YOU LIKE? AND MY HEART JUST BROKE. THAT IS IMAGINABLE. BUT WE ARE NOT THERE YET SO MY IMMEDIATE ADVICE IS LIKE ANYONE IN THE PRION DISEASE COMMUNITY, IF YOU HAVE A CHANCE TO GO ON

1:07:23 THE DRUG AND YOU THINK THE DATA SUPPORT IT, DO IT. >> SOMETHING ELSE THAT JUST OCCURRED TO ME, I DON'T OF COURSE I DONE KNOW ANYTHING ABOUT PRION DISEASE AND LIKE THE STATUS OF RESEARCH IN THIS AREA. ARE THERE OTHERS RESEARCHING OTHER PRION DISEASES OUT THERE AND ARE THEY HOW CLOSE ARE THEY IN DEVELOPING THEIR OWN THERAPEUTICS? DO YOU HAVE ANY IDEA? >> SURE. YEAH. I WOULD SAY -- WELL, HOW THE WORLD PRION GETS USED CHANGES OVER TIME. I THINK ABOUT PRION DISEASE AS ARRAYAL UNIT BEING ALL DISEASE DRIVEN BY PRNP AND PRP. UNDER THAT UMBRELLA WE HAVE THINGS PREVIOUSLY THOUGHT AS DIFFERENT AND FOR THERAPEUTIC STANDPOINT WE CAN NOW UNIFY THEM. OUTSIDE OF THAT UMBRELLA PEOPLE USE THE TERM PRION LIKE TO DESCRIBE THE BEHAVIOR OF OTHER PROTEINS LIKE TAU AND ALPHA SYNUCLEIN. FOR ME IT IS ALWAYS A QUESTION LIKE AS A PERSON WHO THINKS IN A DRUG DEVELOPMENT LENS, IT IS ALWAYS A QUESTION OF LIKE WHERE IS THAT

1:08:42 ANALOGY USEFUL AND WHERE IS IT NOT USEFUL? I DON'T THINK ANY MOLECULE THAT I DEVELOP THAT TARGETS PRP IN PARTICULAR IS GOING TO BE USEFUL AGAINST THOSE DISEASES. BUT MAYBE THE WAY WE ARE THINKING COULD BE A USEFUL BLUEPRINT. LIKE A SUBSTRATE REDUCTION AND ENDS UP BEING A USEFUL STRATEGY FOR PRION DISEASE COULD IT BE FOR TAU? THERE'S CERTAINLY PEOPLE OUT THERE WHO THINK SO. AND ANY OF THE OTHER LEARNINGS, THE SORT OF STRAIN SPECIFICITY OR DETECTING SEEDS IN CSF OR THE SORT OF TEMPORAL SENSITIVITY OF WHAT TREATMENT CAN DO. I THINK THERE MAYBE ANALOGIES IN ALL OF THAT.

1:09:22 THERE'S CERTAINLY PEOPLE LOOKING TO APPELLEE MANY OF THE SAME TOOLS TO THOSE OTHER GAIN OF FUNCTION NEUROLOGICAL PROTEINS. >> THANK YOU. >> THANK YOU SO MUCH, SONIA. JOIN ME IN A ROUND OF APPLAUSE, THANK YOU FOR SHARING YOUR JOURNEY WITH US. >> I PROMISED YOU A RECEPTION AND SNACKS BUT THE CRACKERS AN CHEESE WERE NOT DELIVERED. CAN'T BELIEF I'M DOING THIS SO UNFORTUNATELY THE BE NEWS IS NO CHEESE AND CRACKER, GOOD NEWS SONIA Z MORE TIME FOR YOU TO MOB HER AND ASK OTHER QUESTIONS NOW THE FORMAL PART OF THE PRESENTATION IS OVER. THANK YOU FOR COMING, EVERYONE.

Questions about this episode

Who speaks in "WALS: A Patient-Scientist Lens on How and Why to Move Faster to First in Human"?

Sonia Valabh (Main speaker), Matt Hull (Host).

What is discussed in "WALS: A Patient-Scientist Lens on How and Why to Move Faster to First in Human"?

In order: 0:00 Prion Disease, Broad Institute, Harvard, Sonia Valabh; 10:00 Prion Disease; 20:00 Prion Disease, Oligonucleotides, Clinical Trial, NINDS; 40:00 FDA; 50:00 Prion Disease, Clinical Trial; 1:00:00 Prion Disease, Clinical Trial.

What is mentioned in this NIH VideoCast episode?

15 people, works and ideas are mentioned, including Prion Disease, Sonia Valabh, Broad Institute, Oligonucleotides, Gene Editing, Clinical Trial. Each one on this page links to its own page with every episode that mentions it.

How long is "WALS: A Patient-Scientist Lens on How and Why to Move Faster to First in Human"?

The episode runs 1 h 10 min; the transcript is about 9,772 words in 68 timestamped sections.

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