Welcome to the Clinical Center Grand Rounds, a weekly series of educational lectures for physicians and health care professionals broadcast from the Clinical Center at the National Institutes of Health in Bethesda, MD. The NIH Clinical Center is the world's largest hospital totally dedicated to investigational research and leads the global effort in training today's investigators and discovering tomorrow's cures. Learn more by visiting us online at http://clinicalcenter.nih.gov TODAY WE'RE HONORED TO HEAR FROM 2 COLLEAGUES AT THE NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES. DR. DONALD C. LOWE AND DR. BROOKS WHO WILL PRESENT ON GENE THERAPY APPROACHES FOR MULTIPLE RARE DISEASES, THE PGGTC INITIATIVES. DR. LOWE, THE DIRECTOR OF THE THERAPEUTIC THERAPEUTIC BRANCH FOR PRECLINICAL INNOVATION AT NCATS IS OUR FIRST SPEAKER. DR. LOWE RECEIVED Ph.D. IN MOLECULAR AND CELLULAR PHYSIOLOGY IN YALE UNIVERSITY. THEN PURSUED POST DOCTORAL STUDIES AT THE LUDWIG INSTITUTE FOR CANCER RESEARCH AT UNIVERSITY OF COLLEGE LONDON. IN 1992 HE JOINED THE FACULTY OF THE NEWLY ESTABLISHED DEPARTMENT OF NEURAL BIOLOGY AT DUKE UNIVERSITY AND IN THE LATE 1990S, DR. LOWE CONFOUNDED A BIOTECH CHUSM STUDYING NEUROSCIENCE SERVING AS CHIEF SCIENTIFIC OFFICER UNTIL 2002, THEN RETURNED TO DUKE UNIVERSITY TO ESTABLISH DRUG DISCOVERY ON A COLLABORATION MODEL THAT PARTNERED WITH OVER A DECADE FOR 40 ACTIVE INSTITUTIONS AND MORE THAN 20 BIOTECH AND MAJOR FORM SUITICAL FIRMS. DR. LOWE'S WORK HELPED TO DEVELOP NEW DRUG AND DRUG TARGET CANDIDATES THAT FOR DISEASINGS THAT AFFECT THE CENTRAL NERVOUS SYSTEM, INCLUDING HUNTING TON'S DISEASE, ALZHEIMERS GLAUCOMA, ESCHEMIC STROKE AND BRAIN CANCER. DR. LOWE HOLDS 3 PATENTS AND A LEADERSHIP MEMBER OF TRANSLATION TOGETHER, A COLLABORATION OF TRANSLATIONAL RESEARCH ORGANIZATIONS FROM AROUND THE WORLD. HE IS CONFOUNDER OF HD REACH, A NONPROFIT ORGANIZATION DEDICATED TO BRINGING QUALITY HEALTHCARE, EDUCATION AND SOCIAL ASSISTANCE TO ALL PATIENTS AND FAMILIES AFFECTED BY HUNTING TON'S DISEASE ACROSS THE STATE OF NORTH CAROLINA. DR. LOWE HAS RECEIVED A NUMBER OF AWARDS TO INCLUDE THE [INDISCERNIBLE] RESEARCH FELLOWSHIP, [INDISCERNIBLE] FELLOWSHIP AWARD IN NEUROSCIENCE, AND THE BIG KNIGHT SCHOLAR AWARD AS WELL AS NUMEROUS NCATS DIRECTOR'S AWARDS AND 2 NIH DIRECTOR'S AWARDS. OUR SECOND PRESENTER IS DR. PJ BROOKS, ACTING DIRECTOR OF THE OFFICE OF RARE DISEASE AND RESEARCH AT NCATS. DR. BROOKS RECEIVED A MASTER'S DEGREE IN PSYCHOLOGY FROM THE UNIVERSITY OF TORONTO AND WENT ON TO EARN A Ph.D. IN NEUROBIOLOGY FROM UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL. FOLLOWING A POST DOCTORAL FELLOWSHIP AT ROCKEFELLER UNIVERSITY, DR. BROOKS BECAME AN INVESTIGATOR IN THE NATIONAL INSTITUTE ON CONTROL ABUSE AND ALCOHOLISM, WHERE HE DEVELOPED AN INTERNATIONALLY RECOGNIZED RESEARCH PROGRAM FOCUSED ON RARE [INDISCERNIBLE] DISEASES RESULT FREE RADICALS GENERATED DEFECTIVE DNA REPAIR INCLUDING 0 DERMA PIG MATOSEIN AND [INDISCERNIBLE]. IN 2010 DR. BROCKS JOINED THE OFFICE OF RARE DISEASE AND RESEARCH WHERE HE IS NOW DEVELOPING NOVEL APPROACHES FOR CLINICAL TRIALS AND RARE DISEASES BY MOVING BEYOND 1 DISEASE AT A TIME APPROACHES. EXAMPLES INCLUDE THERAPEUTICS AT SHARE MOLECULAR MECHANISMS UNDERLYING MULTIPLE RARE DISEASES AND PLATFORM TECHNOLOGIES FOR DELIVERY OF NUCLEIC ACID THERAPEUTICS INCLUDING PAVE-GT AND GBTC THAT WE WILL DISCUSS TODAY. HE HAS CO-AUTHORED BOOKS AND A LEADER IN RESEARCH AND ADMINISTRATION, SERVING AS A COORDINATOR FOR NIH COMMON--NIH COMMON FUND, SOMATIC CELL GENOME EDITING PROGRAM AND AS AN INTERDISCIPLINARY SCIENTIFIC COMMITTEE CHAIR FOR THE INTERNATIONAL RARE DISEASES RESEARCH CONSORTIUM. PLEASE WELCOME OUR FIRST SPEAKER DR. LO. >> THANK YOU AGAIN FOR THAT VERY GENEROUS INTRO. MY COLLEAGUE DR. BROOKS AND I ARE DELIGHTED AND HONORED TO BE INVITED TO SPEAK TODAY ON THE GENE THERAPY APPROACHES THAT WE'VE BEEN WORKING ON. I THINK THESE BIZARRE ACRONYMS PAVE GT AND BGTC WILL MAKE A LOT MORE SENSE DURING THE COURSE OF THE NEXT HOUR. TO TART WITH I HAVE NO FINANCIAL DISCLOSURES AND THE LEARNING OBJECTIVE FOR DR. BROOKS AND I TO LET YOU KNOW ABOUT THE STRATEGIES AND INITTIAIVE ITS WE'RE TAKING TO IMPROVE ACCESSIBILITY TO ALL PAIBTS, PARTICULARLY RARE DISEASE PATIENTS. SO I THOUGHT I WOULD START OFF WITH JUST A COUPLE OF WORDS ABOUT WHO WE ARE, THAT IS WHAT IS THE NATIONAL CENTER OF ADVANCING TRANSLATIONAL SCIENCES? AND WHAT HATTER OF IT IS WORKING ON THESE PROJECTS. SO NCATS AS I HOPED MOST ALL OF YOU KNOW IS THE YOUNGEST KID ON THE BLOCK AT NIH, WE'RE THE NEWEST OF THE 27 ICs JUST HITTING OUR FIRST DECADE. AND ON OUR EMBLEM, SEAL HERE, CAN YOU SEE THAT WE REALLY WORK ACROSS THE SPECTRUM OF TRANSLATIONAL SCIENCES WITH THE ACCEPTION OF BASIC RESEARCH. SO THAT'S IN CONTRAST TO MOST ALL OF THE OTHER INSTITUTES AT NIH AND IT'S BECAUSE THE AMAZING BASIC RESEARCH THAT HAS BEEN UNDERTAKEN BY NIH AND THE RESEARCH COMMUNITY OVER THE PAST DECADES AND HUNDRED YEARS IF NOT MORE, HAS GENERATED AMAZING KNOWLEDGE ABOUT THE CAUSES OF DISEASE. --NO, THAT WE KNOW OF TODAY. AND WITH IMPROVEMENTS IN GENE SEQUENCING AND IN MORE GERONTOLOGYSTS NME-CE CHARACTERIZATION AND ANALYSIS, THIS NUMBER KEEPS ON RISING. SO THAT'S THE GOOD NEWS ON THE BASIC RESEARCH SIDE, WE HAVE A MUCH BETTER UNDERSTANDING OF THE CAUSES OF DISEASE OF THOUSANDS AND PERHAPS OVER 10,000 DIFFERENT DISEASES BUT IF YOU LOOK AT HOW MANY DISEASES, HAVE FDA APPROVED TREATMENTS. THAT'S STILL LAGS BEHIND AND AROUND 500 OR SO. AND EACH YEAR, IF YOU FOLLOW, WHAT THE FDA APPROVES, IT'S REALLY ONLY A HANDFUL OF NEW TREATMENT THIS IS YEAR, EACH YEAR, SO AT THIS RATE WE WILL NOT CATCH UP ANYTIME SOON. THIS PROBLEM IS WORSENED BY THIS ANALYSIS THAT WAS DONE A FEW YEARS AGO, EROOM'S LAW IS FOR ALL YOU CHP FANS OUT THERE IS THE INVERSION OR BACKWARDS VERSION OF MOORE'S LAW WHERE THE COST OF MANUFACTURING MICROCHIPS GOES DOWN EXPONENTIALLY EACH YEAR. EROOM'S LAW SHOWS THAT IN THIS GRAPH, THE NUMBER OF DRUGS APPROVED BY FDA, PER MILLION DOLLARS IN R&D SPENDING IN IT COUNTRY, THE X-AXIS IS TIME, CAN YOU SEE IN THIS LOG SCALE, THE LOG GRAPH THAT IN FACT, THE COST OF DRUG DEVELOPMENT ARE GOING UP EACH YEAR SO THIS CAN'T BE GOOD. SO 1 WAY TO INCAPSULATE NCATS MISSION IN TERMS OF TRYING TO ADDRESS THIS PROBLEM, OF TRANSLATING BASIC RESEARCH STUDIES INTO NEW DRUG CANDIDATES, 1 WAY YOU CAN THINK OF NCATS MISSION IS THAT WE'RE HERE TO REALLY TRY TO IDENTIFY AND TACKLE THE COMMON BOTTLENECKS THAT KEEP NEW DRUG DEVELOPMENT FROM HAPPENING BETTER AND FASTER ACROSS ALL INDICATIONS AND REALLY FOR ALL PATIENTS AND ESPECIALLY RARE DISEASE PATIENTS AS THIS TALK AND THE NEXT TALK WILL TRY TO COMMUNICATE. SO THE PART OF NCATS THAT I WORK IS CALLED THE THERAPEUTIC DEVELOPMENT BRANCH AND WE WORK WITHIN THIS AREA BOUND BY THE RED CIRCLE SO MANY OF HAVE YOU SEEN THIS CHEVRON DIAGRAM MANY TIMES. OT LEFT YOU START WITH BASIC SCIENCES, THAT HAVE IDENTIFIED PERHAPS A NEW MOLECULAR TARGET THAT COULD BE USED TO TREAT A DISEASE INDICATION AND FROM THERE ON, THERE ARE A NUMBER OF STEPS BEFORE YOU CAN GET TO A POTENTIAL DRUG CANDIDATE, THAT'S THE B-COMPOUND THAT HAS TO BE OPTIMIZED TO HAVE THE RIGHT PHARMACEUTICAL PROPERTIES AND BE DEVELOPED FULL SKPE BAKUGAN ALL DAILY BASIS THEA SUBMITTED TO THE FDA BEFORE THE DATA WILL CLEAR FOR THE SAFETY AND POTENTIAL EFFICACY OF THE THIS DRUG CANDIDATE IN THE CLINICAL TRIALS FOR FIRST EVALUATION OF SAFETY AND THEN WHETHER OR NOT THE DRUG WORKS. SO IN THIS CIRCLE, IT'S USUALLY CALLED PRECLINICAL DEVELOPMENT. IT'S AIM IS TO DEVELOP NEW DRUG CANDIDATES FOR TIME DECLEARANCE ZONE, SO AN INVESTIGATION NEW DRUG FILING AND CLEARANCE WITH THE FDA AND THIS SEGMENT OF DRUG DEVELOPMENT USUALLY TAKES SEVERAL YEARS AND I PUT DOWN THERE ON THE SLIDE $4 MILLION BUT USUALLY A LOT MORE THAN THAT AND THERE'S A BUNCH OF PROBLEMS WITH THIS, IT'S VERY HARD SCIENCE BUT THERE ARE ALSO VERY FEW FUNDING MECHANISMS, IN THIS AREA, AND COMMERCIAL INVESTMENT IS VERY HARD TO FIND BECAUSE HISTORICALLY, THE FAILURE RATES DURING THIS PART OF THE DRUG [INDISCERNIBLE] CHAIN SEQUENCE IS EXTREMELY HIGH. SO MANY, MANY PEOPLE CALL THIS STAGE OF DRUG DEVELOPMENT THE VALLEY OF DEATH AND ACTUALLY, THAT'S WHAT WE'RE HERE TO DO. SO OUR BRANCH LIVES AND WE HOPE THRIVES WITH THAT. IT'S ADDITIONALLY CALLED THE VALLEY OF DEATH BECAUSE IF YOU LOOK AT THIS FROM A BUSINESS PERSPECTIVE AND IN THIS GRAPH, THE Y-AXIS IS THE VALUE OF THE DRUG CANDIDATE, THE MARKET VALUE COMPUTED,--MARKET VALUE OF THE DRUG CANDIDATE AND ON THE X-AXIS S&P TIME OR MONEY, HOW MUCH MONEY YOU INVEST INTO THE DEVELOPMENT OF THIS NEW DRUG CANDIDATE. SO ON THE LEFT IS THE STARTING THE BASIC SCIENCE SIDE, YOU HAVE THE IDEA, YOU START TO GENERATE POTENTIAL DRUG PRODUCTS AND DRUG CANDIDATES AND AS YOU WILL SEE, THE MORE MONEY YOU INVEST AND MORE TIME YOU PUT INTO THIS PROJECT, THE LESS, THE MARKET VALUE OF THIS DRUG CANDIDATE AND THAT'S BECAUSE THE MARKET YOU'RE PUTTING MORE AND MORE CAPITAL AT RISK AND REALLY AS YOU SEE FROM THE GRAPH, UNTIL YOU GET FDA CLEARANCE FOR FIRST IN HUMAN TESTING, SO IND STATE AND REALLY THROUGH PHASE 1 SAFETY TRIALS, THE VALUE OF THE DRUG CANDIDATE DOESN'T REALLY START TO INCREASE AND SO THIS VALLEY OF DEATH IS BOTH A SCIENTIFIC VALLEY OF DEATH BECAUSE FAILURE RATES ARE SO HIGH, IT'S ALSO AN ECONOMIC VALLEY OF DEATH BECAUSE THE MARKET VALUE OF THESE EARLY STAGE DRUG CANDIDATES ARE VERY WELL, VERY TENUOUS. SO, OUR GROUP, THE THERAPEUTICS DEVELOPMENT BRANCH HAS PUT TOGETHER TO TRY TO TACKLE THE GENERAL PROBLEMS THAT ARE ENCOUNTERED IN THE VALLEY OF DEATH, THIS STAGE OF THE VERY RISKY STAGE OF PRECLINICAL DRUG DEVELOPMENT. WE HAVE A NUMBER OF TEAMS, ABOUT 60 SCIENTISTS ALTOGETHER, AND WE USE A COLLABORATIVE MODEL TO PARTNER WITH OTHER INVESTIGATORS AT NIH, WITH ACADEMIC GROUPS, AND WITH SMALL BIOTECH COMPANIES, PERHAPS THAT HAVE JUST BEEN SPUN OUT OF ACADEMIC GROUPS AND THE IDEA IS TO PARTNER TOGETHER SO THAT ALL THE NECESSARY SKILLS CAN BE BROUGHT TOGETHER TO REALLY AGGRESSIVELY PUSH FORWARD AND TRY TO IDENTIFY AND SOLVE BOTTLENECKS THAT ARE COMMON IN THIS PRECLINICAL DEVELOPMENT SPACE. AND YOU CAN SEE WE'RE BROKEN UP INTO A NUMBER OF TEAMS, THESE ARE--THESE ARE COMMON, THE COMMON DIVISIONS, AND THE BIOTECH COMPANY OR FORM SUITICAL COMPANY THAT ARE REALLY NECESSARY TO ADDRESS ALL THE ISSUES THAT THE FDA WILL BE CONCERNED ABOUT. AND THAT STARTS WITH THE BIOLOGY AND CHEMISTRY OF A DRUG CANDIDATE THROUGH ITS CONNECTION WITH PHARMA CODE DMPK, SAFETY, TOXICOLOGY AND MANUFACTURING AND A HUGE PART OF THIS IS PROJECT MANAGEMENT BEING ABLE TO COORDINATE ALL THESE DIFFERENT PIECES THAT GO INTO PRECLINICAL DEVELOPMENT. IS IT POTENT ENOUGH, IS IT COLLECTIVE ENOUGH, DOES IT GET TO THE RIGHT PLACE IN THE RIGHT TYPES AND TISSUES AND SHOW THAT THIS EFFICACY IN THE ANIMAL DISEASE MODEL IF IT EXISTS AND VERY IMPORTANTLY ESPECIALLY IN THE INITIAL TRIALS IT'S CAN YOU SHOW EVIDENCE THAT THAT AT THE DRUG EXPOSURE LEVEL, YOU NEED FOR EFFICACY, WILL THAT DRUG BE SAFE AND NONTOXIC. THE LAST 2 ARE ESPECIALLY DIFFICULT AREAS TO FIND IN AN ACADEMIC STUDY OR BASIC RESEARCH SETTING AND THAT IS CAN YOU ACTUALLY MANUFACTURE THIS DRUG AND PURE ENOUGH FORM AND LARGE ENOUGH QUANTITIES FOR TESTING IN HUMANS BECAUSE IN THE LABORATORY OF COURSE YOU MAY ONLY NEED A FEW MILLIGRAMS BUT PEOPLE MAYBE ONLY NEED GRAMS OR KILOGRAMS MAYBE FOR SOME OF THESE STUDIES SO MANUFACTURING IS A HUGE QUESTION AND CAN THE DRUG BE FORMULATED INTO THE ROOTS OF FOR THE ROOT OF ADMINISTRATION THAT YOU NEED. SO MAYBE A PILL, INJECTABLE, MAYBE A SPRAY, ALL THESE PROBLEMS HAVE TO BE WORKED OUT AND DATA PACKAGED VERY NICELY FOR SUBMISSION TO THE FDA, AND INDs AND UNTIL FDA CLEARS THE IND, OF COURSE 1 CANNOT START TESTING THIS DRUG CANDIDATE IN PEOPLE. SO THAT'S WHAT WE DO. SO OUR GROUP OF 60 PEOPLE IN A WAY, YOU CAN THINK OF US AS A SWISS ARMY KNIFE OF BIOTECH COMPANIES, SO WE PARTNER ALMOST ALL OF OUR PROJECTS WITH OUTSIDE PARTIES AND WE ALLEVIATE THE OUTSIDE PARTY FROM THE NECESSITY TO START THEIR OWN BIOTECH COMPANY. SO WE WORK TOGETHER WITH PARTNERS FOR ALMOST ALL OUR PROJECTS, I THINK WE DO A PRETTY GOOD JOB, WE CLEARED, HOPED TO CLEAR OVER 40 NEW DRUG CANDIDATES, INTO THE PHASE 2 CLINICAL TRIALS OFFER THE LAST DECADE, AND AS YOU'LL SEE FROM THE--AS YOU WILL SEE FROM THE TABLE, UP TOP, MANY OF THESE DRUGS ARE PROGRESSING THROUGH THE SEQUENCE OF CLINICAL TRIALS, PHASE 1, PHASE 2, PHASE 3, AND WE'RE HOPING THIS YEAR AND NEXT, PERHAP THIS IS FIRST DRUG WILL BE RELEASED. SO IT'S IN THIS CONTEXT THAT WE CAME TO WORK WITH TJ AND OTHER COLLEAGUES ON THIS AGTG PROJECT WHICH I WILL TELL YOU A BIT MORE ABOUT, SO YOU SEE FROM THE SAMPLE WE WORK IN A LOT OF DIFFERENT AREAS, RARE DISEASES AND WORK AS PART OF THE HEAL INITIATIVE, WHEN COVID HIT US, WE TRIED TO MOBILIZE AND DO OUR BEST TO HELP ADDRESS TRANSLATIONAL BOTTLENECKS AND NEW COVID DRUG DEVELOPMENT, I WON'T HAVE TIME TO TELL YOU ABOUT ANOTHER PROGRAM WE HAVE ONGOING, WHICH LOOKSA THE A DIFFERENT KIND'VE GENE THERAPY, THAT ADDRESS YOU THINK CAN BE SENT TO THE OLIGO NUCLEOTIDE DRUGS WHEN THERE ARE PARTICULAR PROBLEMS WHEN THE DISEASES ARE EXTREMELY RARE, DOWN TO PERHAPS A DISEASE NOT ONLY A SINGLE PATIENT HAS. SO THEN WE STARTED THIS INITIATIVE, THE LINK IS UNDERNEATH AND THE CORE OF THIS PROJECT IS LOOKING AT THIS TYPE OF GENE THERAPY WHERE YOU ESSENTIALLY AS YOU ALL KNOW I'M SURE REPLACE PART OF A VIRAL GENOME, LIKE A THERAPEUTIC CONSTRUCT THAT YOU THINK WILL PROVIDE PATIENT BENEFIT AND YOU PUT THAT, SUBSTITUTE THAT INTO THE VIRAL GENOME, WITHIN THE VIRUS CAN BE ESSENTIALLY USEAISE VECTOR OR AS AN AGENT TO DELIVER THAT CHAIN TO THE DESIRED CELL TYPES AND TISSUES. THIS IS NOW AND INVENTED, THE IDEA INVENTED SOME DECADES AGO, THIS OLD JOURNAL COVER MAGAZINE COVER FROM TIME IS OVER 20 YEARS OLD, REALLY PROMISING GENE THERAPY, AS FUTURE OF MEDICINE. SO THE AV VECTORS HAVE BECOME THE MAIN STAY. AND IN FACT THIS FIELD IS MATURING VERY NICELY SO THE FIRST FEW FDA APPROVALS OF GENE THERAPY DRUGS BASED ON AAV, CAN YOU SEE A COUPLE FIRST 2 APPROVALSOT RIGHT AND SO WE'RE NOT LOOKING SO MUCH THE SCIENCE OF GENE THERAPY OR EVEN THE FUNDAMENTAL DRUG PROCESSES FOR GENE THERAPY, THOSE WELL ENOUGH TO HAVE APPROVED GENE THERAPY PRODUCTS AND MANY MORE IN LINE FOR WHAT WE'RE LOOKING FOR IS THE ISSUE OF ACCESSIBILITY. WHAT WILL IT TAKE FOR GENE THERAPY TO BE AVAILABLE FOR MANY MORE DISEASE, NOT A FEW AT A TIME. BUT TO REALLY MAKE A DENT AND THOUSANDS OF DISEASES THAT COULD BENEFIT FROM GENE THERAPY. SO THE PROBLEM STATEMENT REALLY IS WHAT CAN WE DO TO LOWER THE BARRIERS TO ACCESSIBILITY, ESPECIALLY TO RARE DISEASE PATIENTS AND THE MARKET COSTS FOR THESE GENE THERAPIES SUCH AS READ ON THE RIGHT GIVE YOU SOME CLUE AS THE PAIR BERNEA DEETS THAT YOU MIGHT ENCOUNTER AND THE FIRST 1 REALLY THE FIRST 1 IS AN ECONOMIC 1 SO THIS IS AN HISTOGRAPH SHOWING THE DISTRIBUTION OF THE PREVALENCE OF RARE DISEASES. SO THEY'RE--THERE ARE THOUSANDS AND THOUSANDS OF RARE DISEASES COLLECTIVELY AND IT CONSTITUTES SOMETHING LIKE 20 OR 30% OF ALL DISEASE BURDEN WHICH YOU WILL SEE IN THE HISTOGRAM WHERE THE X-AXIS, THIS HISTOGRAM IS AN ESTIMATED PREVALENCE OF RARE DISEASES AND THE Y-AXIS IS THE NUMBER OF RARE DECEASES OF THAT PREVALENCE. YOU CAN SEE THAT THE VAST MAJORITY OF THE RARE DISEASES HAVE VERY LOW PREVALENCE AND WHAT I'VE SHOWN IN RED, IS THAT FROM A COMMERCIAL PERSPECTIVE OF A PHARMACEUTICAL COMPANY OR BIOTECH COMPANY GENERALLY SPEAKING WOULD NOTED CONSIDER ANY ANY RARE DISEASE WITH PREVALENCE LOWER THAN A FEW THOUSAND PATIENTS TO BE COMMERCIALLY VIABLE. SO A MAIN STAY OF WHAT DRIVES THE DEVELOPMENT AND MARKETING DISTRIBUTION OF DRUGS IN OUR COUNTRY THAT IS THE PHARMACEUTICAL INDUSTRY, BIOPHARMACEUTICAL SECTOR IS REALLY UNABLE TO ADDRESS THE VAST MAJORITY OF DISEASES BECAUSE OF THIS COMMERCIAL LIMITATION, AND SO THAT'S AND THAT'S BECAUSE THE PREVALENCE CONSITUTE A VIABLE BUSINESS PROMULGATE CISION, THERE ISN'T A TYPICAL KIND OF COLLABORATION WITH INDUSTRY THAT WE CAN COUNT ON. SO THIS IN TURN DRIVES A SECOND CLASS OF PROBLEMS SO IF THESE DISEASES ARE NOT THAT COMMERCIAL VIABLE AND YOU CAN SEE THAT IS REFLECTED IN THE COST OF TREATMENT FOR THESE DISEASES, THERE ARE A BUNCH OF FOLLOW ON EFFECTS AND 1 OF THESE, SO SOME OF THESE ARE LISTED IN THE CENTER BOX, SO 1 THING THAT HAPPENS IS THAT INTELLECTUAL PROPERTY, THERE IT IS ARE VERY STRONGLY ENFORCED SO THAT IS PROPRIETARY KNOW HOW AND THESE ARE NOT GENERALLY SHARED BECAUSE OF COMMERCIAL MARKET IS SO TIGHT THAT MEANS IF YOU'RE AN RESEARCHER, NIH RESEARCHER, PATIENT, FOUNDATION WORK NOTHING A RARE DISEASE, YOU WILL HAVE VERY LITTLE ACCESS, PROBLEMATIC ACCESS TO THE KINDS OF EXPERTISE AND RESOURCES YOU NEED TO DEVELOP THE GENE THERAPY. CONSEQUENTLY BECAUSE OF THESE OF WHAT IT COSTS TO MANUFACTURE THIS, GENES CAN BE EXTREMELY HIGH TO GENERATE ENOUGH AV GENE VECTOR EVEN TO CONDUCT PHASE 1 CLINICAL TRIAL CURRENT MARKET COSTS ARE 5 MILLION OR MORE. AND EVEN IF YOU HAVE 5 MILLION OR MORE, IT'S TIGHTLY HELD AND IT'S DIFFICULT TO GET A MANUFACTURING SLOT THAT IS--MANUFACTURING FACILITIES ARE SO TIED UP IN COMMERCIAL PRODUCT, VERY HARD TO GET A NONCOMMERCIAL PRODUCT MADE EVEN IF YOU HAVE TO FUND IT. AND THEN THE THIRD PROBLEM IS BECAUSE OF THESE ISSUES IN ACCESSIBILITY IN THE GENERAL COMMUNITY THERE'S A LACK OF THESE IN MAKING GENE VECTORS AND CERTAINLY A LACK OF EXPERIENCE INTO THE PRECLINICAL DEMANDS IN TERMS OF GOING FROM THE AAV GENE CONSTRUCT THAT WORKS IN THE LAB THROUGH THE DEVELOPMENT PROCESS TO A POINT WHERE MAYBE GENE CANDIDATE, GENE THERAPY CANDIDATE CAN BE EVALUATED BY THE CLEARANCE AND THE TESTING SO IT'S A FOLLOW ON, SET OF PROBLEMS AND SO, WHAT WE'RE SEEKING TO ADDRESS IN THE AGT PROGRAM IS TO MAKE THAT AN OPEN BOOK, PROCESS INSTEAD SO INSTEAD OF HAVING THE ENTIRE METHODOLOGY AND ROADMAP THROUGH AAV GENE THERAPY IS A HELD TIGHT CLOSE SECRET, PUT IT TOGETHER AND MAKE A PUBLIC VERSION, OPEN BOOK, PUBLIC VERSION OF HOW TO CONSTRUCT AN AAV GENE THERAPY AND HOW TO THAT I CAN THAT GENE THERAPY CANDIDATE ALL THE WAY THROUGH PRECLINICAL DEVELOPMENT AND SUBMITTING THAT DATA PACKAGE TO FDA FOR THAT IND PACKAGE FOR CLEARANCE INTO PHASE 1 TRIALS. MORE OVER WE WILL TRY TO SHOW SOME ECONOMY OF SCALE. THE WHOLE PROMISE OF GENE THERAPY IS THAT IT'S A PLATFORM THAT IS THE VERY SAME OUTSIDE VECTOR, THE CAPSID, THE AAV VECTOR CAN BE THE SAME BUT CAN BE USED TO TREAT DIFFERENT DISEASES BY SWAPPING IN DIFFERENT GENE THERAPY PAY LOADS, DIFFERENT GENE CONSTRUCTS INTO THE PAY LEAD SIDE UP IN AAV GENE VECTOR SO WE CAN SHOW THAT BY DEVELOPING 4 THERAPIES AT ONCE. WE WILL USE THE SAME OUTSIDE GENE THERAPY VECTORS SO AAV 9, WHICH IS A CAP SID TYPE OF AAV THAT HAS VERY BROAD TROAPIC--SO THAT IS AAV 9 OR CAN BE USED TO TRANSDUCE SO IN THE CNS, IN THE PERIPHERY, WE WILL MAKE THESE VECTORS SO THAT CAN BE ADMINISTERED THROUGH THE SAME ROUTE OF AND ADMINISTRATION, AND IMPORTANTLY FOR THE FDA, AND FOR THE PRECLINICAL REGULATORY PROCESS, USE THE IDENTICAL PRODUCTION MANUFACTURING AND PURIFICATION METHODS SO THE ONLY THING THAT WILL BE DIFFERENT AS I WAS MENTIONING IN THE CONTEXT OF A PLATFORM IS THAT THESE 4 DRUGS WILL HAVE DIFFERENT GENE CONTRUCTS INSIDE OTHERWISE THEY WILL BE IDENTICAL AND THIS SHOULD SHOW THE ECONOMY OF SCALE USING IDENTICAL PRECLINICAL PLGHTS BUT USING THAT TO CARRY DIFFERENT PAY LOADS TO ADDRESS DIFFERENT DISEASES. SO, THE GOAL, NUMBER 1, IS TO MAKE THIS REALLY AN OPEN BOOK, A PUBLIC METHODOLOGY THAT CAN BE WIDELY DISSEMINATED AND ANYBODY COULD FOLLOW ALONG WITH THEIR OWN GENE THERAPY STRATEGIES WITHOUT ANY STRINGS ATTACHED SO IT'S PART OF THAT GOAL TO USE REAGENTS AND PROCESSES INCLUDING MANUFACTURING PROCESSES THAT ARE FREE INTELLECTUAL PROPERTY CONSTRAINTS, SO THEREFORE ON TOP OF SCIENCE, THERE PONENT BE ANY ISSUES ABOUT HAVING TO PAY VERY COSTLY LICENSING FEES WHICH CURRENTLY IS QUITE COMMON. AND SO IMPORTANTLY, AS I SAY, WE WILL MAKE ALL THE METHODS AND PROTOCOLS, THROUGH THE AAV PACKAGES AND SUBMIT TO THE FDA PUBLIC AND WE WILL BE POSTING ON OUR WEBSITE IN REALTIME AS WELL AS FDA FEEDBACK. THIS IS A REALLY IMPORTANT COMPONENT OF NEW DRUG DEVELOPMENT THAT IS GETTING FDA FEEDBACK ALONG THE WAY, AS YOU PRIMATES PAIR TO FILE AN IND PACKAGE WITH THE FDA AND THAT FEEDBACK AND VERY UNCOMMON TO HAVE THAT SHARE, AND WE ARE DELIGHT THAD FDA AGREED TO ALLOW US TO SHARE THEIR FEEDBACK TO OUR REGULATORY FILINGS ON OUR WEBSITE AS WELL. THAT'S THE GENERAL IDEA OF THE PAVE GT PROGRAM AND I COULDN'T RESIST THIS SLIDE, THIS JOKING SHOWS MY AGE, NO 1 YOUNGER THAN I WOULD KNOW WHAT THIS IS BUT IF THERE'S ANYONE AS OLD AS I AM THAT USED TO WORK ON CARS YOU WOULD RECOGNIZE THE CHILTON MANUEL OR MANUELS OF THIS SORT. SO IN THE OLD DAYS BEFORE CARS AND TRUCKS HAD MICROCHIPS AND SUCH, YOU BEING WORK ON YOUR OWN CAR AND SO--SO WE OFTEN THINK OF PAVE GT PROGRAM AS NOT OF THE MOST ADVANCED MOST AMAIDZING GENE THERAPY VECTOR GENOME OR BUT RATHER A GENE THERAPY VECTOR WILL THAT BE GOOD FOR EVERYTHING. SO OR FOR EVERYONE ARE, SO THAT THE GENE THERAPY VECTOR IS A DRUG THAT ALMOST EVERYONE CAN AFFORD, IT CAN TAKE ANY PAY LOAD TO ALMOST ANYWHERE AND YOU CAN GET ALL THE PARTS DOWN AT THE CORNER STORE, AND YOU WILL HAVE A MANUEL LIKE THE CHILTON MANUEL THAT SHOWS YOU EXACTLY HOW TO DEVELOP, MAKE AND REPAIR EVERY SINGLE ASPECT OF THIS GENE THERAPY VECTOR. SO AGAIN, REALLY THE WATCH WORD FOR AGT, IS ACCESSIBILITY PARTICULARLY TO THE COMMERCIAL SECTOR WOULD BE VERY UNLIKELY TO PLAY A MAJOR ROLE. SO I KNOW WE'RE RUNNING OUT OF TIME. JUST GIVE YOU A COUPLE MINUTES ABOUT THE SCIENCE AND MORE AND MORE OF THIS WILL COME OUT IN PUBLICATIONS AND OUR WEBSITE, BUT AS YOU IMAGINE, ALTHOUGH I TRIED TO CONVEY THE IDEA OF THE PAVE GT INITIATIVES, YOU KNOW AS THOUGH IT WAS A SIMPLE IDEA, IT'S ACTUALLY QUITE A COMPLICATED PROCESS AND QUITE A LARGE SCALE PROJECT SO AS I MENTIONED, WE'RE DEVELOPING 4 GENE THERAPIES AT THE SAME TIME IN PARALLEL, AND THESE ARE DIVIDED UP INTO 2 PAIRS. SO IT'S 2 PLUS 2 MODEL AND THE REASON IS THAT THERE ARE A NUMBER OF DISEASE STATES, INDICATION THAT ESSENTIALLY COULD COME TO BE, COULD ARISE FROM DIFFERENT KINDS OF MUTATIONS IN DIFFERENT GENES THAT GIVE YOU MORE OR LESS THE SAME DISEASE. SO THIS IS WHAT WE'RE TRYING TO ACHIEVE IN TERMS OF DEMONSTRATING THE ECONOMY OF SCALE AND DEVELOPING GENES FROM THE VERY INCEPTION THROUGH FREQUENT DEVELOPMENT ALL THE WAY INTO CLINICAL STUDIES. SO, WE'RE LOOKING AT 2 LIVER DISEASES AND 2 ORGANIC [INDISCERNIBLE], AND 2 CNSs, 2 CONGENITAL MY O SINNIAS, THOSE ARE IN COLLABORATIONS, THOSE ARE CLOS COLLABORATORS CHUCK VENDITTI, AT THE HUMAN GENOME AND CARSON BONNEMANN AT NINDS, SO THEY'RE WORKING WITH US AND DOING ALL THE HEAVY LIFTING FOR THE GENE THERAPY CONSTRUCTS FOR THESE 4 DISEASES, THE 2 MYASTHENIAS, AND THE 2 IND PACKAGES. SO DOING ALL THE CHARACTERIZATIONS FOR THE PHARMA CODE, KINETIC PROPERTIES AND PROPERTIES OF THE GENE VECTORS, SCALING THEM UP FOR MANUFACTURING AND SHOWING THAT THEY CAN BE MANUFACTURED HERE AND FORMULATED INTO THE PRODUCTS THAT THEY NEED TO BE AND IMPORTANTLY TO SHOW IN TOXICOLOGY STUDIES THAT THESE GENE VECTORS SHOULD BE SAFE AND ALONG THE WAY, BUILDING THE REGULATORY FILINGS THAT WILL BE NECESSARY FOR INITIAL DISCUSSIONS WITH THE IND AND THEN FOR A FINAL SUBMISSION OF THE IND PACKAGE TO THE FDA, SO IN OUR SHOP, [INDISCERNIBLE] SCIENTISTS AND PROJECT MANAGERS, IN OUR GROUP THAT ARE LEADING THIS PROJECT ALONG WITH THE OTHER 60 SCIENTISTS WE HAVE IN OUR GROUP AND ALONG WITH A NUMBER OF COMMERCIAL RESEARCH ORGANIZATIONS AND COMMERCIAL MANUFACTURING OPERATIONS, CROs AND CMOs THAT ARE DOING THE BULK OF THE LARGE SCALE MANUFACTURING WORK. AS THESE VECTORS ARE FINISHED, THEN WE GO BACK TO CHUCK AND CARSTEN, AND SO AS PART OF THE ECONOMY OF SKILL, THEY ARE GOING TO BE CONDUCTING UMBRELLA TRIALS THAT IS TO USE THE SAME CLINICAL PROTOCOL WITH THE SAME CLINICAL END POINTS TO EVALUATE BOTH PAIRS OF THESE VECTORS IN THE PC CA, AND MAAD, ARE DIFFERENT GENES AND DIFFERENT GENE MUTATIONS BUT THEY CAUSE DISEASES THAT MANIFEST SIMILAR FASHION. AND SO WE'RE HOPING THAT IN THE NEXT YEAR OR 2, TO START THOSE CLINICAL STUDIES EXPW WE'RE EXCITED ABOUT WHERE WE ARE, WHICH IS A LITTLE BIT ON THE EARLY END BUT REALLY HITTING OUR STRIDE. I ONLY SHOWED 4 PICTURES THERE, AND IN THIS SLIDE, STILL ONLY SHOWING A FRACTION OF ALL THE PEOPLE THAT ARE CONTRIBUTING VERY CRITICALLY, TO THIS WORK. OUR GROUP AT NCATS, OUR VARIOUS GROUPS ADDED NCATS, NOT ONLY OUR BRANCH THAT I TOLD YOU ABOUT BUT THE OFFICE OF RARE DISEASES RESEARCH, YOU CAN SEE PJ'S PHOTO IN THE MIDDLE OF THAT BOX IN THE UPPER CENTER, AND A LOT OF THIS AS I MENTIONED, OR HINTED AT HAS TO DO WITH LICENSING ISSUES, INTELLECTUAL PROPERTY, SO, THE ROLL OF OF OUR OFFICE OF STRATEGIC ALLIANCES AND THAT AND NHGRI AND NINDS HAVE BEEN QUITE CRITICAL, VERY CRITICAL AS WELL. THERE ARE CHUCK AND CARSTEN AND FOLKS FROM THEIR GROUP AS WELL AS OUR CLINICAL DIRECTOR AT NICHD. SO AGAIN, THIS IS JUST A SUBSET OF PLAYERS THAT HAVE TO COME TOGETHER TO MAKE THIS BIG PROJECT WORK AND WE'RE HOPING THAT IN THE END BY CONDUCTING ALL OF THIS, DEVELOPMENT OF 4 GENE THERAPY VECTORS IN THE PUBLIC DOMAIN, AND TO MAKE ALL THE FILINGS AND EVEN THE FDA FEEDBACK PUBLIC, THIS WILL REALLY SERVE TO FACILITATE A MUCH BROADER AND CHEAPER AND APPROACHABLE PROPOSITION FOR THE RARE DISEASE COMMUNITY SO THAT OVER TIME GENE THERAPY AND IN THIS PARTICULAR CASE WILL BE MUCH MORE ACCESSIBLE TO ACADEMIC SCALE WORK AND TO RARE DISEASES BUT LOW, LOW, NUMBERS OF PATIENTS AND IN THE END, OBVIOUSLY THE GOAL IS TO REALLY TRY TO MOVE THIS GRAPH A BIT, SO THAT THE 500 DRUGS THAT ARE APPROVED CURRENTLY THAT IS ALMOST CREEPING UP YEAR BY WREER THIS COULD BE 1 OF THE WAYS IN WHICH WE COULD MAKE A REAL DENT IN THE FRACTION OF DISEASES THAT HAVE FDA APPROVED TREATMENTS. SO THAT'S A THUMB NAIL SKETCH OF THE PAVE GT PROGRAM. I HAND IT OVER TO MY COLLEAGUE T. J. BROOKS NEXT AND HAPPY TO ANSWER ANY QUESTIONS AT THE END OF THE HOUR. THANK YOU DON THESE ARE LEARNING OBJECTIVES I WILL TALK ABOUT OR THE BGTC AND BRIEFLY AT THE END IS TALKING ABOUT OPPORTUNITIES FOR THE NIH AND THE SOMATIC CELL GENOME EDITING PROGRAM THEY THINK WILL BE OF INTEREST TO THIS SLIDE. SO THIS IS THE BGTC AND ORGANIZED BY THE FOWBDATION FOR THE NIH WHICH VERY IMPORTANTLY IS NOT PART OF THE NIH AND THAT HAS IMPLICATIONS FOR HOW WE CAN DO THIS THERE YOU CAN SEE THE GROUP, MIERS, PETER MARKS, AT FDA WHO WAS REALLY INVOLVED IN SPEARHEADING THIS PROGRAM AND GETTING IT OFF THE GROUND WITH GREAT MANAGEMENT AND PARTICIPATION FROM COURTNEY AND BRAD FROM THE NIH. NEXT SLIDE. SO THE GOALS OF THE BGTC ARE IN SOME WAYS SIMILAR TO THOSE OF PAVE GT WHICH IS TO AAV TECHNOLOGY MORE ACCESSIBLE PARTICULARLY FOR DISEASES OF NO COMMERCIAL INTEREST. ACCELERATE THE POTENTIAL OF THE STREAMLINE OF CLINICAL AND PREPRODUCT TESTING AND FACILITATE SCIENTIFIC AND REGULATORY ADVANCE THAT WILL BENEFIT THE WHOLE FIELD OF AAV GENE THERAPY AND ULTIMATELY BRING GENE THERAPIES TO INDIVIDUALS IN NEED SOONER. NEXT SLIDE. SO THERE'S BASICALLY 2 COMPONENTS TO THE BGTC AND WE ALL A BASIC BIOLOGY COMPONENT ON THE TOP WHICH IS FOCUSED ON NOT JUST A BASIC BIOLOGY OF AAV IN GENERAL, BUT MORE SPECIFICALLY TO ENHANCE VECTOR GENERATION AND ALSO ENHANCE THERAPEUTIC GENE EXPRESSION IN PEOPLE AND THERE'S ALSO A CLINICAL COMPONENT THAT IS FOCUSED ON WHAT WE CALL BESPOKE CLINICAL APPLICATIONS, IN THIS CASE, IT'S REALLY ANOTHER WAY OF SAYING DISEASE OF NO COMMERCIAL INTEREST, WE'RE TRYING TO STANDARDIZE VARIOUS ASPECTS OF THE PROJECT AND TO COME UP WITH A PATHWAY TO START UF AAV GENE THERAPY CLINICAL TRIALS MORE EFFICIENTLY. NEXT SLIDE. AND THESE 2 EFFORTS ARE RELATED TO EACH OTHER, ULTIMATELY WE ANTICIPATE THAT THEY ENHANCING VECTOR GENERATION WILL IMPACT VECTOR MANUFACTURING AND ANALYTICS IN THE CLINICAL COMOPPOSITE BEHAVIORIAL PHENOTYPE AND THEN THE SIMILARLY WE HOPE THAT ENHANCING GENE EXPRESSION IN PATIENTS CAN BE INCLUDED IN SOME OF OUR CLINICAL TRIALS. TO THE EXTENT THAT WE CAN IDENTIFY WAYS TO IMPROVE BOTH OF THOSE STEPS. NEXT SLIDE. SO AS WE'RE SETTING UP BCGT, WITH THIS, WE HAD A LOT OF PARTICIPANTS WITH INDUSTRY AND ACADEMIA INVOLVED AND SOME HICK UPS WITH COVID, BUT WE THOUGHT ABOUT A WAY TO,A PROVE AAV VECTOR PRODUCTION WOULD BE TO FOCUS ON THE INDIVIDUAL STEPS INVOLVED IN MAKING AAV GENE THERAPIES AND THAT WOULD INCLUDE THE STEPS INVOLVED FROM PUTTING THE THERAPEUTIC GENE CONSTRUCT AND THE HELPER VIRUSES AND THINGS INTO CELLS AND THEN WHAT HAPPENS TO THOSE CONSTRUCTS IN THE CELLS AND KIND OF IDENTIFY EACH INDIVIDUAL STEP AND SEE IF WE CAN OPTIMIZE EACH 1 OF THOSE INDIVIDUAL STEPS SEPARATELY. AND WE PUT OUT A REQUEST FOR PROPOSALS FOR APPLICATIONS IN THE COMMUNITY ON HOW TO DO THIS THAT REQUEST WAS CLOSED ON FEBRUARY 18th. NEXT SLIDE. AND WE THOUGHT OF DOING SOMETHING SIMILAR FOR IMPROVING AAV GENE EXPRESSION TO THINK OF ALL OF THE STEPS THAT HAPPEN AFTER TARGET CELL IS INFECTED WITH A THERAPEUTIC AAV CONSTRUCT ALL THE WAY THROUGH THE PROCESS OF PRODUCING THE THERAPEUTIC GENE WHICH OF COURSE IS WHAT IS NEEDED TO GET TO THERAPEUTIC EFFICACY, IF YOU LOOK AT EACH 1 OF THOSE STEPS INDIVIDUAL LEE, CAN WE OPTIMIZE EACH 1 OF THEM. AND HERE AGAIN, WE HAD FUNDING OPPORTUNITIES THAT WERE OPENED UP AND NEXT SLIDE. AND SO THE WHYED WE HAD IS TO ASK THE COMMUNITY FOR HIGH THROUGH PUT SCREENING COMPATIBLE ASSAYS TO OPTIMIZE EACH OF THOSE MECHANISTIC STEPS, WITH THE IDEA THAT ONCE WE'VE GOTTEN THOSE ASSAYS WE WOULD CARRY OUT HIGH THROUGH PUT SCREENING EFFORTS USING FOR EXAMPLE, WHOLE GENOME SCREENS TO IMPROVE AAV VECTOR GENERATION, OR SCREENING APPROVED DRUGS IN TARGET CELLS FOR THE CLINICAL TRIALS, FOR THE PROJECTS ON ENHANCING THERAPEUTIC GENE EXPRESSION AND WE PLAN TO DO THIS WORKING WITH THE NCATS INTRAMURAL HIGH THROUGH PUT SCREENING FACILITY BUT WE ALSO WROTE THESE FUNDING OPPORTUNITIES TO BE OPEN TO OTHER NOVEL APPROACHES AS WELL TO CAST A VERY WIDE NET TO THE COMMUNITY REALIZING THAT A GOAL TO THESE--THE ULTIMATE RESULTS OF THESE EFFORTS WERE ALL GOING TO BE PUT INTO THE PUBLIC DOMAIN AND THAT'S A VERY IMPORTANT ASPECT OF THIS PUBLIC PRIVATE PARTNERSHIP. WE TRIED TO MAKE THE WHOLE THING IN THE PRECOMPETITIVE SPACE SO WE COULD PUT ALL THE DATA AND ALL THE RESULTS INTO THE PUBLIC DOMAIN TO BENEFIT THE WHOLE COMMUNITY AND THAT OF COURSE IS OBVIOUSLY GOING TO LIMIT THE KIND OF APPLICATIONS WE GET TO THE EXTENT THAT PEOPLE ARE WORKING ON THINGS WHERE THEY'RE VERY CONCERNED ABOUT INTELLECTUAL PROPERTY AND THEY WOULD OBVIOUSLY NOT APPLY AND WE DID UNDERSTAND THAT AND DO UNDERSTAND THAT. NEXT SLIDE. SO THE APPLICATIONS WERE RECEIVED IN FEBRUARY AND WE'RE STARTING THE REVIEW PROCESS OF THEM. AS WE GO THROUGH THEM WE'RE IDENTIFYING YOU KNOW DIFFERENT PROJECTS AND PLAN TO HAVE A FORMAL REVIEW IN THE NEXT FEW WEEKS OR SO, I WOULD LIKE TO MENTION THERE IS A POSSIBILITY THAT WE MAY END UP RELEASING ADDITIONAL FUNDING OPPORTUNITIES. SO THOSE OF YOU WHO THINK YOU MIGHT HAVA AN INTEREST IN THIS AND MAY HAVE MISSED THE FIRST 1 THERE'S POSSIBILITY OF ADDITIONAL FUNDING OPPORTUNITIES IN THE FUTURE. NEXT SLIDE. SO 1 OF THE THINGS WE'RE DOING WITHIN THE MANUFACTURING WORK STREAM OF THE BGTC IS TO SEE IF YOU CAN DEVELOP A MINIMAL SET OF QUALITY ATTRIBUTES THAT WOULD BE USED TO DETERMINE IF A AN AV,'S MANUFACTURED IN PHASE, YOU MIGHT THINK THAT THE FACT THAT THE IDEA OF DIFFERENT SETS OF DATA, DEMONSTRATE SAFETY, OF SAFETY ATTRIBUTES, SO, WORKING WITH A GROUP OF INDIVIDUALS FROM BOTH PUBLIC AND PRIVATE ENTITIES AT THIS MINIMAL SET. MEETING EVERY OTHER WEEK NOW TO KIND OF NARROW IT DOWN, IT'S A SURPRISINGLY, COMPLICATED PROCESS BUT I THINK WE'RE MAKING GOOD PROGRESS ON IT, AND WE'RE REALLY FOCUSED ON THINGS THAT WOULD BE INDEPENDENT OF THE TYPE, SORT OF STANDARDIZED TYPES OF ASSAYS YOU DOA THAT WOULD BE RELEVANT ANY AAV THAT WOULD GO INTO HUMANS, THINGS LIKE FOR EXAMPLE, DETERMINING THAT IT'S STERILE. THE HOPE IS THAT WE CAN ULTIMATELY COME UP WITH THIS MINIMAL SET OF ATTRIBUTES AND THEN WE WILL HAVE A DISCUSSION WITH THE F, DIDA TO GET THEIR FEEDBACK, AND AGAIN WITH THE GOAL OF DEVELOPING SORT OF A STANDARD HERE THAT CAN BE USED BY OTHER INVESTIGATORS, NOT ONLY WITHIN THE UNITED STATES, BUT EVEN IN ON THE COUNTRIES AS WELL. AND THEN OF COURSE WE WILL USE THOSE ATTRIBUTES IN OUR OWN CLINICAL TRIALS WITHIN THE GGTC AND THIS IS 1 TIEWNLT WHERE I THINK WE CAN HAVE SOME ACTION WITH PAVE GT AS WELL. THE NEXT SLIDE. SO THE IDEA OF THE CLINICAL PROGRAM IS REALLY AGAIN SIMILAR TO PAVE GT IS TO NOT TRY TO DO ANYTHING NEW AND CUTTING EDGE WITH REGARD TO THE VECTORS, WE WANT TO SPECIFICALLY USE THE VECTORS THAT HAVE BEEN USED PREVIOUSLY FOR AAV GENE THERAPY TRIALS WHERE THERE'S APPROVED INDs, WE WANT TO WORK WITH MANUFACTURES WHO HAVE MADE VECTOR AND GOTTEN INDs AND BASICALLY TAKE THOSE SAME PROCESSES, AND PUT DIFFERENT THERAPEUTIC GENES IN AND ULTIMATELY COME UP WITH A THERAPEUTIC STREAMLINE PLATFORM TO GET TO CLINICAL TRIALS AND REALLY TO TRY TO ALSO TAKE ADVANTAGE OF MASTER FILES AND PREVIOUS DATA THAT THESE DIFFERENT MANUFACTURES WILL HAVE IN EXPERIENCE WITH THE FDA. AND SO WE ANTICIPATE THAT VECTOR MANUFACTURING WITHIN THE VTT WILL BE DONE BY SOME OF THE COMMERCIAL PARTNERS THAT ARE PARTICIPATING IN THE PROGRAM. AND WE ENVISION HAVING A LIMITED NUMBER OF AAV SEROTYPES, THESE WILL BE 1S THAT HAVE ALREADY BEEN USED IN CLINICAL TRIALS AND A LIMITED NUMBER OF DELIVERY MODALITIES TO TRY TO GET DIVERSITY OF TISSUES TO INSURE THAT THIS CLINICAL TRIAL PIPELINE IS AS BROAD AS WE CAN POSSIBLY MAKE IT. NEXT SLIDE. SO TO DO THE CLINICAL TRIAL WOULD BE LOOKING FOR PERHAPS 5 OR 6 DISEASES THAT HAVE A HIGH LIKELIHOOD OF CLINICAL SUCCESS FOR AAV GENE THERAPY TO BE SELECTED BY THE STEERING COMMITTEE AND SO, WE WOULD BE THINKING BASICALLY OF YOU KNOW SINGLE GENE DISORDERS, VERY IMPORTANTLY THESE HAVE TO BE DISEASE WHERE THERE'S NO COMMERCIAL INTEREST. WE WOULD LIKE TO HAVE DISEASES WITH THE CLINICAL OUTCOMES CAN BE ASSESSED IN A FAIRLY SHORT PERIOD OF TIME, ALREADY ASSEMBLED PATIENT GROUPS, CLINICAL INVESTIGATORS, ET CETERA. AND TO RUN THESE PROGRAMS AND BASED ON DEVELOPING THEM, ULTIMATELY COME UP WITH THE STANDARDIZED PROCESS FOR STARTING OFF CLINICAL TRIALS EMPLOY AND SO THE WAY WE'VE DONE THIS IS BASICALLY PUT OUT A FUNDING OPPORTUNITY AND ASK THE COMMUNITY TO SUBMIT THEIR PROPOSED DISEASES FOR CONSIDERATION. NEXT SLIDE. AND SO, YOU OPEN THAT PROCESS, WE'VE GOTTEN MULTIPLE SUBMISSIONS AND WE'RE NOT GOING TO BE TRYING TO DOWN SELECT TO GET TO A SMALLER NUMBER OF DISEASES AND ULTIMATELY CHOOSE THE 5 OR 6 OR SO THAT WE WILL ULTIMATELY STUDY AND IMPORTANTLY, THESE WILL HAVE TO BE PAIR WTD VECTOR MANUFACTURING FOR DOING THE FIRST IN HUMAN CLINICAL TRIALS. NEXT SLIDE. AND ULTIMATELY COME OUT OF THIS IS SOMETHING LIKE A MANUEL FOR AAV GENE THERAPY CLINICAL DEVELOPMENT, INSIGHTS AND LEARNINGS THAT FACILITATE THE SUCCESS OF FUTURE GENE THERAPYS, INCLUDING IMPROVEMENTS IN AAV TARGET GENE EXPRESSION, IMPROVEMENT NEGLIGENCE THE WAY WE MAKE CLINICAL AAV VECTORS THIS HARMONIZED AND VALIDATED SET OF CLINICAL QUALITY ATTRIBUTES AND STANDARDIZED REGULATORY SUBMISSION PACKAGE AND TEMPLATES, IN PARTICULARLY REALLY UTILIZING EXPLOITING VECTOR MASTER FILE SO THAT WHEN NEW DISEASES NEED TO BE ADDRESSED AND THERAPIES FOR NEW DISEASE NEED TO BE ADDRESSED MANUFACTURES CAN RELAY AS MUCH AS POSSIBLE ON PREVIOUSLY GENERATED DATA ON THE PRODUCTION OF THOSE AAV VECTORS. AGAIN, A VERY SIMILAR IDEA TO WHAT WE HAVE IN PAVE GT. NEXT SLIDE. SO THESE ARE THE PARTNERS WE HAVE IN THE BGTC, YOU CAN SEE WE HAVE PARTICIPATION IN MULTIPLE NIH INSTITUTES AND CENTERS, 11 DIFFERENT ENTITIES, VERY IMPORTANTLY, WE HAVE THE ACTIVE PARTICIPATION OF THE FTA CENTER FOR BIOLOGICS, AND AS I SAID, PETER MARK SYSTEM INTIMATELY INVOLVED IN INITIATING THIS PROGRAM WHICH WAS CRUCIAL FOR ITS SUCCESS ON THE RIGHT YOU CAN SEE OUR VARIOUS OTHER PARTNERS INCLUDING MULTIPLE FOR PROFIT ENTITIES AS WELL AS NONPROFITS AS WELL. SO OVERALL QUITE LARGE CONSORTIUM. NEXT SLIDE. SO THE WAY THE STRUCTURE THAT WORKS WE HAVE AN EXECUTIVE COMMITTEE THAT OVERSEES THE BGTC AND THIS COMMITTEE SEES A LOT OF OTHER FNIH ACCELERATED MEDICINES PARTNERSHIP, OUR STEERING COMMITTEE IS MADE UP OF 50% NIH AND 50% PRIVATE SECTOR INDIVIDUALS, AND WE'VE GOT DIFFERENT AND TRY TO ADDRESS ALL THE DIFFERENT ASPECTS THAT WE'RE TRYING TO ACHIEVE AND THEN THE BGTC. NEXT SLIDE. AND SO THIS KIND OF GOES THROUGH SOME OF THE DIFFERENT COMMITTEE ROLES AND I WON'T GO THROUGH THIS IN A LOT OF DETAIL, BUT YOU CAN SEE HOW WE'RE TRYING TO DEVELOP THE OVERSIGHT OF THE BGTC TO INCLUDE THE PERSPECTIVES AS BOTH THE DEFENDANT AND THE PRIVATE SECTOR, SINCE THIS IS OF COURSE A PRIVATE PUBLIC PRIVATE PARTNERSHIP, AND THERE ARE ASPECTS OF THIS THAT WILL--ULTIMATELY ALL OF THE DATA WILL COME OUT TO THE PUBLIC DOMAIN BUT WE ANTICIPATE HAVING ANNUAL MEETINGS AND INCLUDING SOME THAT WILL OPEN TO THE PUBLIC SO THE PUBLIC AND THE COMMUNITY CAN SEE THE PROGRESS THAT WE'VE BEEN MAKING. NEXT SLIDE. AND THESE ARE SOME OF THE SPECIFIC ROLES AGAIN, I WON'T DWELL ON THIS FOR THE SAKE OF TIME. BUT I WOULD ALSO NOTE DOWN THERE, WE'VE ALSO INCLUDED IN THE BGTC, GROUPS REPRESENTING PATIENTS INCLUDING THE NATIONAL ORGANIZATION FOR RARE DISEASES, AND WE'VE GOT A LOT OF THOUGHT TO THE COMMUNICATIONS INVOLVED IN THE BGTC SO THAT AS WE DO MAKE PROGRESS, WE COMMUNICATE THAT PROGRESS IN WAYS THAT MAKE SENSE TO THE DIFFERENT STAKEHOLDERS WHO WILL BE RECEIVING IT. NEXT SLIDE. SO IN TERMS OF THE TIMELINES, WE'RE NOW IN 2022 AS I SAID WE'VE GONE PAST, GOTTEN APPLICATIONS FOR THE DIFFERENT WORK ALREADY REVIEWING THOSE AND HOPE TO HAVE PROGRESS IN TERMS OF IDENTIFYING DISEASES WE WANT TO STUDY, BY THE END OF APRIL AS WELL AS MORE PROGRESS ON SOME OF THE OTHER INITIATIVES, TO ULTIMATELY GET TO THE POINT WE'RE STARTING TO SEE RESULTS AND OF COURSE, WE WILL BE KEEPING THE COMMUNITY UPDATED AS WE MOVE THROUGH THIS EFFORT. NEXT SLIDE. JUST TO KIND COMPARE THE BGTC AND PAVE GT BECAUSE THEY SOUND SIMILAR, THERE ARE CERTAIN SIMILARITIES BUT THERE ARE DIFFERENCES IN THE BGTC, WE CHOSE 4 DISEASES OF INTEREST AND THE NIH CLINICAL CENTER, AND THE BGTC AS WE'RE SING PROBABLY 5 OR 6 OR SO WE WILL HAVE A SINGLE MANUFACTURE OF MAKING ALL 4 VECTORS AND THE BGTC WILL HAVE A CONSORTIUM IN BOTH CASES WE PLAN TO MAKE THE INFORMATION AS PUBLIC ULTIMATELY WITH PAVE GT, WE PLAN TO DO THAT A LOT MORE, A LOT SOONER AND A LOT MORE EXPLICITLY, AND WE HOPE THAT THE BGTC WE'LL SEE HOW THE TIMING GOES ON THAT. AND PAVE GT WILL DO ALL THE WORK OF THE NIH CLINICAL CENTER, WHEREAS IN THE BGTC WE ANTICIPATE DIFFERENT CLINICAL SITES WHICH MAY IN FACT INCLUDE THE NIH CLINICAL CENTER, AND AGAIN THE PAVE GT IS A SINGLE SEROTYPE AND BGT IS MULTIPLE SEROTYPES. NEXT SLIDE. AND THEN JUST AT THE LAST FEW MINUTES HERE, I WANTED TO BRIEFLY MENTION SOME PROGRESS ON THE NIH SOMATIC CELL GENOME EDITING PROGRAM, THIS IS 1 THAT IS FUNDED THROUGH THE NIH COMMON FUND THAT NCATS IS INVOLVED IN, COORDINATE ALONG THAT WITH NINDS, AND MANY OTHER NIH INSTITUTES AND CENTERS PARTICIPATING AS WELL. SO THE PHASE 1 OF THE PROGRAM WAS DESIGNED TO LOWER THE BARRIERS FOR THE GENOME EDITING THERAPIES BY DEVELOPING BETTER ANIMAL MODELS FOR TESTING GENOME EDITING READS AND DELIVERY SYSTEMS. BETTER WAYS TO ASSESS THAN BIOLODGEICAL EFFECTS OF GENOME EDITING A BIG COMPONENT ON IMPROVING GENOME EDITING OF THE MACHINERY. EXPANDING THE HUMAN GENOME EDITING REPERER TWOAR AND COORDINATING AND DISSEMINATION FUNCTION THAT WOULD PUT UP INTO A PUBLIC TOOL KIT ALL OF THE DISCOVERIES THAT HAVE BEEN MADE UNDER THE SCG PHASE 1 PROGRAM. NEXT SLIDE. AND IF YOU JUST CLICK THROUGH THAT, YOU CAN CLICK IT AGAIN, WE'VE HAD MULTIPLE PUBLICATIONS THAT WE'VE SUPPORTED THROUGH THE SCG PHASE 1, MOST OF THEM FOCUSED ON DEVELOPING BETTER TOOLS AND INCLUDING THE PRIME EDITOR THAT WE PROVIDED SOME OF THE FUNDING FOR AND BETTER DELIVERY TECHNOLOGIES BUT, NEXT SLIDE. THERE IS AN OUTPATIENT SETTING FOR COMPLON FUND PROGRAMS TO HAVE MULTIPLE PHASES, UP TO 25-YEAR PHASES SO WE HAVE IN FACT PROPOSED THE SECOND PHASE WHICH WILL BE MORE FOCUSED ON GETTING INTO THE CLINIC WHERE PHASE 1 WAS REALLY ALL ABOUT TECHNOLOGY DEVELOPMENT AND 1 OF THE INITIATIVES WE PROPOSED IN PHASE 2, AND BETTER DEVELOPMENT OF BETTER GENOME EDITING ASSAYS THAT WOULD BE ESSENTIALLY QUALIFIED OR AT THE LEVEL OF PRECISION THAT WOULD BE ULTIMATELY REQUIRED FOR REGULATORY APPROVAL. WE WOULD LIKE TO THINK THAT SOME OF THESE WOULD ULTIMATELY BECOME PART OF THE STANDARD FDA APPROVAL PROCESS ALTHOUGH WE CAN'T KNOW THAT BUT THAT'S A GOAL. SO THESE WILL BE 3 YEAR AWARDS TO DEVELOP THESE NEW ASSAYS. NEXT SLIDE. INITIATIVE 2 WILL BE FOCUS SPECIFICALLY ON IND ENABLING STUDIES IN DIFFERENT DECS WITH DIFFERENT TARGET TISSUES. AND THE GOAL OF THESE AWARDS WILL BE TO DEVELOP PACKAGES OR BRING THINGS ALL THE WAY UP TO THE POINT OF GETTING AN IND WITHOUT GOING INTO THE CLINICAL TRIAL WITH THE HOPE THAT ONCE AN IND IS ATTAINED, THAT WILL MAKE IT MORE ATTRACTIVE FOR OTHER ENTITIES TO PICK UP THE IND AND ULTIMATELY SUPPORT THOSE CLINICAL TRIALS. THESE WILL BE 5 YEAR AWARDS. NEXT SLIDE. AS YOU TALKED A LOT ABOUT THERAPEUTIC PLATFORMS, GENOME EDITING IS BY DEFINITION ALMOST THERAPEUTIC PLATFORM, SO INITIATIVE 3 OF THE COMMON FUND THAT WE ENVISION WILL FOCUS ACTUALLY ON PLATFORM CLINICAL TRIALS AND THE IDEA OF BEING--THIS WILL BE A BI PHASIC PROGRAM, THE FIRST FACE WILL BE TO GET AN IND AND THE SECOND PHASE TO CARRY OUT A CLINICAL TRIAL WITH THE IMPORTANT REQUIREMENT THAT THESE CLINICAL TRIALS WILL HAVE TO INVOLVE MORE THAN 1 DISEASE, SO THE IDEA WOULD BE, YOU WOULD HAVE 1 EDITOR, ON 1 DELIVERY SYSTEM, BUT MORE THAN 1 DISEASE. AND TO REALLY SEE IF WE CAN ESTABLISH A CLINICAL TRIAL PLATFORM FOR GENOME EDITING. NEXT SLIDE. COORDINATION CENTER THROUGHOUT THE SCGE PROGRAM THAT WILL SUPPORT SEMIANNUAL MEETINGS BUT ALSO IMPORTANTLY DATA AND PROTOCOL SHARING AND ULTIMATELY ACROSS THE BROADER COMMUNITY SO THAT THE RESULTS OF THESE EFFORTS CAN BE EXTENDED THROUGH THE MUCH BROADER COMMUNITY FOCUSED ON DEVELOPING TREATMENTS FOR FOR SINGLE GENE DISORDERS, BOTH RARE AND COMMON IN FACT. œNEXT SLIDE. VERY LAST THING I WILL SAY IS I POINTED THIS OUT, BECAUSE WE ANTICIPATE--I CAN TALK ABOUT THIS BECAUSE WE PUBLISHED NOW THESE NOTICES OF INTENT TO PUBLIC FUNDING OPPORTUNITIES SO THESE ARE THESE FORMAL NOTICES TO,A LETTER THE COMMUNITY THAT WE WILL BE HAVING THESE FUNDING OPPORTUNITIES COMING UP AND I POINT OUT HERE BECAUSE IN THE PAST NIH INTRAMURAL INVESTIGATORS HAVE BEEN ABLE TO APPLY FOR A COMMON FUND PROGRAMS AND WE ANTICIPATE THAT WILL BE THE CASE FOR THESE 1S AS WELL, SO THESE ARE THE NOTICE OF INTENTS TO PUBLISH THAT PEOPLE CAN LOOK THROUGH IF THERE'S INTEREST. AND I THINK THAT'S MY LAST SLIDE. SO I WILL THANK YOU ALL FOR LISTENING ON BEHALF OF DON AND MYSELF. I THINK WE HAVE QUESTIONS SUBMITTED LATER WE CAN TRY TO ADDRESS THEM VIA E-MAIL BUT THANK YOU VERY MUCH. >> YEAH, THANK YOU DR. BROOKS AND DR. LO, FOR SHARING REALLY THOUGHT-PROVOKING PRESENTATIONS ON THE PAVE GT AND THE BGTC INITIATIVES, YOU KNOW TO ADVANCE THESE TECHNOLOGIES WITH THE GOAL OF PURSUING, THE GOAL OF YOU KNOW EXPANDING REACHING GENE THERAPIES FOR MANY MORE PATIENTS WITH RARE DISEASES, YOU ARE RIGHT WE HAVE SEVERAL QUESTIONS BECAUSE OF YOUR PRESENTATIONS, AND I WILL FORD THEM TO YOU SO I'M SORRY WE CAN'T ANSWER THEM HERE BUT I WANT TO THANK THE BOTH OF YOU AND THE NIH COMMUNITY FOR JOINING US TODAY AND I WISH EVERYONE A GREAT AFTERNOON. THANK YOU FOR JOINING US.