>> NON-PROFIT FORUM, WE HAVE BEEN DOING THE NON-PROFIT FORUM SINCE 2005. THIS IS OUR 13th, WE KEEP GETTING BETTER AND BIGGER AND WE HAVE IMAGE NOW, WE HAVE BRANDING, A WEB PAGE ON THE NINDS SITE AND WE HAVE ANOTHER GREAT PROGRAM FOR YOU THE NEXT COUPLE OF DAYS. I HAVE A COUPLE OF ANNOUNCEMENTS. THE RESTROOMS ARE JUST OFF THE MAIN LOBBY. KAREN KELLEHER IS SITTING BY REGISTRATION LOOKING FOR VOLUNTEERS FOR FEEDBACK ON THE WEBSITE. PLEASE USE MICROPHONES, BECAUSE WE ARE VIDEOCASTING ALL THE SESSIONS IN THIS ROOM. AND NOW I WOULD LIKE TO WELCOME YOU TO THE ORIENTATION SESSION. WE STARTED THIS FEW YEARS AGO, I THINK WE HAVE ALWAYS HAD NIH 101 WHICH IS VERY POPULAR BUT LAST FEW YEARS WE HAVE ADDED THE ROLE OF THE PROGRAM DIRECTORS. LYNN JAKEMAN WILL TAKE THIS OVER, I WANT TO INTRODUCE HER, DIRECTOR OF DIVISION OF NEUROSCIENCE, HER DIVISION RECEIVES ALL THE GRANTS IN BASIC SCIENCE DISCOVERY AND NEUROLOGICAL DISEASE RESEARCH. LYNN IS A FORMER NINDS PROGRAM DIRECTOR WHO HELD THE PORTFOLIO IN SPINAL CORD INJURY, PERIPHERAL NERVE INJURY AND AXONAL REGENERATION. BEFORE THAT, LYNN WAS AT THE OHIO STATE UNIVERSITY FOR 13 YEARS IN THE DEPARTMENT OF CELL BIOLOGY. THANK YOU. HOPE YOU HAVE A GREAT DAY. >> THANK YOU, WELCOME EVERYONE. I WANT TO REITERATE, THANK YOU TO ALL OF YOU FOR COMING ATTENDING. THIS IS A LOT OF FUN FOR US TO DO. WE GET A CHANCE TO MEET WITH A LOT OF YOU AND YOUR ORGANIZATIONS, ONE ON ONE IN VARIOUS SETTINGS AROUND COUNTRY BUT THIS IS A CHANCE FOR YOU TO COME TO OUR HOME BASE SO WE'RE THRILLED THAT YOU ARE IN OUR BUILDING, A LOT OF EXTRAMURAL STAFF HAVE THEIR OFFICES. THIS IS AWESOME FOR US BECAUSE IF YOU HAVE A QUESTION WE DON'T HAVE THE ANSWER RIGHT ON HAND WE CAN RUN UPSTAIRS AND GET IT AND SO AND PARKING IS GOOD FOR US SO WE LIKE THIS. ANYWAY, THANK YOU FOR COMING. I WANT TO LET YOU KNOW WHAT'S GOING ON WITH THE FIRST SEX -- SESSION, WHICH IS NINDS 101. AS MARGO EXPLAINED, THIS IS AN OPPORTUNITY TO START OFF THE GROUND RUNNING WITH HOW THE NINDS RUNS, HOW WE DO THINGS THAT WE DO. SO FOR THOSE WHO ARE ALUMNI OF THE PROGRAM, HOW MANY ARE HERE WHO HAVE BEEN HERE BEFORE? SO FOR YOU, THIS WILL BE PROBABLY REITERATION OF THINGS YOU HEARD BEFORE BUT MAYBE IF YOU PAY ATTENTION YOU'LL PICK UP ON ONE OR TWO THINGS YOU HAVEN'T HEARD BEFORE. HOW MANY OF YOU ARE BRAND NEW? CONGRATULATIONS AND THANK YOU FOR COMING. THIS WILL BE NEW IF IT COMES FAST AND FURIOUS AND YOU WANT A LITTLE ADDITIONAL INFORMATION YOU CAN CONTACT ANY OF US OVER THE NEXT TWO DAYS, WE ARE HERE TO HELP YOU. I WANT TO INTRODUCE NOW OUR FIRST SPEAKER, DAVID OWENS IS GOING TO SPEAK AND PROVIDE MOST BACKGROUND HOW WE RUN THINGS IN NINDS 101, AND HE WILL ALSO BE WORKING WITH ERNIE LYONS. K ACTING DEPUTY DIRECTOR OF EXTRAMURAL ACTIVITIES AT NINDS SINCE OCTOBER 2014. BEFORE THAT HE WAS PROGRAM DIRECTOR IN REPAIR AND PLASTICITY CLUSTER. BY TOMORROW YOU'LL KNOW WHAT CLUSTERS ARE AND MANAGES THE STEM CELL PORTFOLIO THERE AND THEN HE'S BEEN INVOLVED IN A VARIETY OF NINDS AND TRANSNINDS ACTIVITIES COVERING TOPICS INCLUDING REGENERATIVE MEDICINE, CELL LINE AUTHENTICATION, PROMOTING BASIC NEUROSENSORY SEARCH AND FDA INTERACTIONS WITH THE NIH. HE GOT HIS Ph.D. IN NEUROBIOLOGY FROM COLUMBIA AND POST-DOCTORAL WORK IN DEVELOPMENTAL NEUROBIOLOGY AT THE NINDS INTRAMURAL PROGRAM. SO THAT'S DAVE OWENS, HE WILL BE WORKING WITH ERNIE LYONS CHIEF OF THE NINDS SCIENTIFIC REVIEW BRANCH. HE GOT HIS Ph.D. FROM JOHNS HOPKINS, HE WORKED AS A SCIENTIST ASSOCIATE AT NCI, NATIONAL CANCER INSTITUTE IN FREDERICK, MARYLAND. THEN MOVE TO THE DIVISION OF NEUROPATHOLOGY AT JOHNS HOPKINS AND JOINED NINDS AS A SCIENTIFIC REVIEW OFFICER WORKING HIS WAY TO BECOME CHIEF OF THAT OFFICE. HIS RESEARCH EXPERTISE IS IN NEUROTROPIC FACTORS NERVE INJURY AND REGENERATION, CELL DEATH MECHANISMS AND NEUROTOXICOLOGY. SO TAKE IT AWAY, DAVID. >> THANKS FOR COMING, I WANT TO POINT OUT THIS IS ERNIE, RAISE YOUR HAND. VERY GOOD. MY GOAL IS TO -- MY FIRST GOAL IS TO FIND THE SLIDES. FAILING AT MY FIRST GOAL. >> THANK YOU VERY MUCH. SO MY GOAL IS TO DO A VERY BRIEF RUN THROUGH OUR PROCESSES, I'M ALMOST EXCLUSIVELY GOING TO FOCUS ON WHAT I CALL GRANT MAKING. I WILL EXPLAIN MORE WHY I'M FOCUSING ON THAT. BUT TO START OUT, IT'S ALWAYS GOOD TO MENTION THAT THE NIH, THE NATIONAL INSTITUTES OF HEALTH IS ACTUALLY 27 DIFFERENT INSTITUTES AND CENTERS AND 24 OF THESE AWARD GRANTS. EACH OF THESE INSTITUTES HAVE DIFFERENT MISSIONS, FUNDING PRIORITIES, BUDGETS, WAY OF DOING THINGS, ET CETERA. SO IF YOU HEAR FROM US NINDS HOW WE DO THIS, IT DOESN'T NECESSARILY APPLY TO THE OTHER 27 MOSTLY THE OTHER 24 GRANT MAKING INSTITUTIONS. NOW, THE KEY THING HERE IS THIS MISSION. WE HAVE A MISSION AND OUR MISSION AT THE NINDS IS TO SEEK FUNDAMENTAL KNOWLEDGE ABOUT THE BRAIN AND THE NERVOUS SYSTEM AND TO USE THAT KNOWLEDGE TO REDUCE THE BURDEN OF NEUROLOGICAL DISEASE. THE WAY WE SUPPORT THIS MISSION IS WE FUND RESEARCH, THAT WILL BE THIS GRANT MAKING PROCESS OR PROCEDURE, WHATEVER WE WANT TO CALL IT, THAT I'M MOSTLY GOING TALK ABOUT BUT ALSO IN THE INTRAMURAL PROGRAM WE CONDUCT RESEARCH OURSELVES. SO NINDS IS BROKEN TO EXTRAMURAL PROGRAM WHERE I THINK 80% OF THE BUDGET IS USED AND THE INTRAMURAL PROGRAM ON THE CAMPUS WHERE THEY HAVE LABORATORIES THAT CONDUCT RESEARCH. SO WE SUPPORT RESEARCH IN BASIC TRANSLATIONAL AND CLINICAL NEUROSCIENCE, THROUGH GRANTS CONTRACTS WE SUPPORT MEETINGS, WE ALSO SUPPORT RESEARCH TRAINING, ANOTHER WAY WE ACCOMPLISH OUR MISSION AND IN THE EXTRAMURAL PROGRAM WE FUND RESEARCH TRAINING IN INTRAMURAL WE ACTUALLY TRAIN PEOPLE. THEN FINALLY, THIS COULD ACROSS THE ENTIRE INSTITUTE WE REALLY ARE AN INFORMATIONAL RESOURCE. SO WE CAN DISSEMINATE SCIENTIFIC DISCOVERIES AND WE CAN INFORM CONGRESS, THINGS LIKE A, HAVE MEETINGS SUCH AS WE ARE HAVING NOW INTERACTING WITH THE COMMUNITY, EXCHANGING IDEAS COMING UP WITH NEW IDEAS. KNOWING THE MISSION DRIVES US I'M GOING TO FOCUS AS I SAID, PROBABLY -- I'M GOING TO TRY TO REPEAT MYSELF A NUMBER OF TIMES. IN THE KEY THING HERE IS THIS GRANT CYCLE. A LARGE PART OF OUR -- THE EXTRAMURAL PROGRAM ACTIVITIES ARE IN THE FUNDING OF GRANTS, IT'S REALLY WE RUN THROUGH THREE -- THREE CYCLES A YEAR, EACH GRANT CYCLE ROUGHLY IS NINE MONTHS. YOU CAN BREAK DOWN THE GRANT CYCLE IN THREE MAJOR COMPONENTS, THE FIRST BEING THE PLANNING PHASE AND THIS IS WHERE SCIENTISTS AND WE CALL THEM PI OR PRINCIPLE INVESTIGATORS, THEY HAVE IDEAS, DEVELOP IDEAS AND PUT TOGETHER RESEARCH PROPOSALS OR GRANT APPLICATIONS. THESE APPLICATIONS ARE SUBMITTED FROM AN INSTITUTION AND ORGANIZATION AND THIS SOMETHING THAT MANY PEOPLE DON'T KNOW. WE DON'T AWARD GRANTS TO INDIVIDUALS. WE AWARD THEM TO ORGANIZATIONS. I WON'T DELVE IN THE REASON FOR THAT BUT PI HAS THEIR RESEARCH PROPOSAL SUBMITTED ON BEHALF OF THE BUYER INSTITUTION FOR EXAMPLE, OR MEDICAL CENTER AND THESE SUBMITTED APPLICATIONS COME IN TO DIVISION OF RECEIPT AND REFERRAL CSR. I WILL SAY A LITTLE BIT ABOUT CSR IN MINUTE. THIS IS A PROCESSING STATION. THESE APPLICATION COME IN, CSR ASSIGNS THE APPLICATION TO REVIEW GROUP, BECAUSE WE ARE MOVING IN NOW INTO THE REVIEW STAGE, BUT THEY ALSO SIGNED TO AN INSTITUTE. ONE OF THOSE 24 GRANT MAKING INSTITUTIONS. THEN ESSENTIALLY WE HAVE EXPERTS REVIEW THESE APPLICATIONS AND THEY WILL SCORE THEM AND THEY WILL ALSO PROVIDE A WRITTEN SUMMARY OF THE REVIEW FOR THE APPLICANT AND FOR US ACTUALLY. SO WE CAN SEE WHAT ESSENTIALLY THE STRENGTH AND WEAKNESSES ARE WITH WRITTE WORD OPPOSED TO A NUMERICAL VALUE. ONCE THE REVIEW PROCESS IS OVER, WE MOVE THEN TO THE FUNDING ASPECTS OF THE CYCLE, THIS IS WHERE THE STAFF HERE, WE DEVELOP PAY PLANS. WE HAVE ALL APPLICATIONS SUBMITTED IN REVIEW, THEY COME IN, WE DECIDE WHICH TO PAY, IT'S NOT A BIG LIST, THERE'S MANY PROGRAMS EVALUATING SO WE PUT TOGETHER A CONFERENCE HENSIVE PAY PLAN AND GO TO ADVISORY COUNCIL WITH THE PAY PLAN, THE COUNCIL CAN MAKE FURTHER RECOMMENDATIONS, AND THEN ESSENTIALLY IT GOES TO THE INSTITUTE DIRECTOR, THE DIRECTOR WILL MAKE A FUNDING DECISION AND THE AWARD IS FINALLY MADE. I WILL GO THROUGH EACH OF THESE IN MORE DETAIL, THAT'S WHY I'M RUNNING THROUGH THEM QUICKLY NOW. AGAIN I WILL REPEAT MYSELF TIME AND AGAIN. SO THE FIRST ASPECT IN THE FIRST ARM OF PRODUCING AN APPLICATION, IT SHOULD BE KNOWN ALL APPLICATIONS ARE SUBMITTED VIA FOA. FUNDING OPPORTUNITY ANNOUNCEMENT. I'M SURE MANY OF YOU HAVE BEEN AROUND HERE KNOWS NIH LIKES ACRONYMS AND I'LL SAY A LOT OF ACRONYMS BUT I WILL TRY TO SPELL THEM TOO. SO FOA OR FUNDING OPPORTUNITY ANNOUNCEMENT IS A GENERAL THING, ANYTHING SUBMITTED TO NIH HAS TO COME IN VIA FOA YET THERE'S DIFFERENT FLAVORS OF FOAs. SO FOR EXAMPLE, WE CAN HAVE AN FOA THAT SOLICITS RESEARCH IN A VERY SPECIFIC AREA, AND IT CAN COME IN VIA RFA OR REQUEST FOR APPLICATIONS. BUT THERE'S ALSO A WAY TO SUBMIT APPLICATIONS THAT ARE NOT BEING SPECIFICALLY ASKED FOR, THESE CAN COME IN UNDER WHAT THEY CALL A PARENT FOA. THIS WOULD BE A GENERAL CALL FOR ANY RESEARCH THAT WOULD FALL WITHIN THE MISSION OF THE ORGANIZATION YOU ARE APPLYING TO. THEN THERE'S ADDITIONAL FLAVORS OF THESE FOAs SO FOR EXAMPLE, -- GOT TO SAY ONE THING FIRST BEFORE THE EXAMPLE. ONE WAY TO FIND CURRENT FOAs, BOTH PARENT AS WELL AS SPECIFIC ONES IS THE NIH GUIDE FOR GRANTS AND CONTRACTS, THIS COMES OUT WEEKLY, THEY UPDATE IT WEEKLY. IT'S AN ELECTRONIC SITE. AND IT WILL INCLUDE ALL NIH FUNDING OPPORTUNITIES AND POLICY NOTICES. SO WHAT YOU CAN ACTUALLY DO IS YOU CAN GO INTO THE NIH GUIDE AND YOU CAN SEARCH, IT HAS SEARCH FEATURES. IF YOU ARE INTERESTED IN PARKINSON'S DISEASE RESEARCH, I BELIEVE IN THE YEAR 2016, YOU WOULD HAVE COME UP WITH MAYBE THIS LIST. WHAT YOU SEE HERE IS THE FIRST ACTIVE FOA AT THAT TIME IS THE MORRIS K UDALL CENTERS FOR EXCELLENCE IN PARKINSON DISEASE RESEARCH. THE FOA IS LISTED AS AN RFA, A SPECIFIC REQUEST FOR TYPE OF ARE RESEARCH THAT HAS NUMBERS THAT ARE IMPORTANT BUT IT HAS THIS THING P 50. THAT'S WHAT WE CALL AN ACTIVITY CODE OR A MECHANISM, IT'S THE TYPE OF GRANT. WHAT A P 50 IS ACTUALLY A CENTER GRANT. AS YOU LOOK DOWN THE LIST THERE'S VARIOUS OTHER TYPES, THERE'S THIS THING, A K-22, A CAREER TYPE AWARD AND A KO 1, ANOTHER CAREER AWARD, ET CETERA. THE ACTIVITY CODES AS WE CALL THEM MOST THINK OF THAT'S THE GRANT. THE FOA THE WAY YOU SUBMIT THE GRANT, THEN THE TOPIC AND THE TITLES THERE. ONCE -- ACTUALLY I THINK I'M GOING TO JUMP BACK. ACTUALLY A SLIDE WAS MISSING. I HAD ANOTHER SLIDE WHICH LISTED THE PARENT ANNOUNCEMENTS WHERE I WAS GOING TO GIVE ANOTHER SPIEL ON THESE ACTIVITY CODES BECAUSE THERE'S DIFFERENT ONES, SUCH AS AN RO1 WHICH IS THE MEAT AND POTATOES TYPE OF GRANT WHICH IS A LARGER RESEARCH GRANT GENERALLY FOUR TO FIVE YEARS, ABOUT OVER THE COURSE OF THOSE YEARS ABOUT A 2 MILLION TOTAL COST. THAT'S A SUBSTANTIAL RESEARCH AWARD. BUT THERE'S MANY DIFFERENT ACTIVITY CODES THAT CAN ACCOMPLISH MANY DIFFERENT TYPES OF RESEARCH, WE HAVE SMALL GRANTS, BIG GRANTS, TRAINING GRANTS, ET CETERA. NONETHELESS YOU CAN FIND ALL THESE, IF YOU SEARCH THE GUIDE, MOST KNOW OF THESE ALREADY BUT THE GUIDE WILL -- THE GUIDE IS USEFUL BECAUSE OF NEW TARGETED PROGRAMS OR SPECIFIC SOLICITATIONS THAT ARE COMING OUT IF YOU LOOK AT THE GUIDANCE AND SEARCH IT YOU CAN SEE THE NEW PROGRAMS AS THEY ROLL OUT. ONCE AN ORGANIZATION HAS SUBMITTED THEIR APPLICATION, IT WILL NOW GO BACK TO THE -- IT WILL GO INTO THE SECOND COMPONENT OF THE CYCLE, AND AS I MENTIONED IT WILL BE SET INITIALLY TO CSR IN THIS DIVISION OF RECEIPT AND REFERRAL. THEN IT WILL MOVE THROUGH THE REVIEW CYCLE THE NIH PEER REVIEW HAS A MISSION ITSELF, THAT IS TO SEE NIH APPLICATION RECEIVED FAIR INDEPENDENT EXPERT AND TIMELY REVIEWS FREE FROM INAPPROPRIATE INFLUENCES SO THAT NIH CAN FUND MOST PROMISING RESEARCH. AS YOU CAN SEE THIS WAS MAYBE THE FIRST NIH STUDY SECTION, PRETTY HOMOGENOUS LOOKING GROUP OF GUYS, THEN IT'S CHANGED OVER TIME. IT IS A LITTLE MORE DIVERSE WHICH IS PROBABLY A GOOD THING. NONETHELESS, THESE GROUPS GET TOGETHER AND THEY REVIEW OUR APPLICATIONS. NOW, THE CENTER FOR SCIENTIFIC REVIEW, REVIEWS MOST APPLICATIONS AT NIH. IT HAS 25 SETS OF STUDY SECTIONS CALLED INTEGRATED REVIEW GROUPS OR IRGs THESE ARE LARGER THEMATIC GROUPS. WITHIN EACH IRG IS GENERALLY ABOUT 8 TO 10 INDIVIDUAL STUDY SECTIONS. SO YOU CAN HAVE AN IRG THAT IS FOCUSED ON BRAIN DISORDERS AND WE THEN THAT IRG YOU CAN HAVE A STUDY SECTION THAT FOCUSES ON SAY NEURODEGENERATION AND CELL DEATH. SO OF THE 25 IRGs THAT CAN COVER THE FULL GAMUT OF NIH RESEARCH, YOU CAN FIND OUT WHO SITS ON THESE INDIVIDUAL PANELS GO TO CSR, THEY LIST WHO MEMBERS ARE, THEY LISTED THEM IN ADVANCE. I WILL DEFER TO MY REVIEW EXPERT. SO BEFORE REVIEW MEETING 30 DAYS BEFORE REVIEW MEET YOU CAN SEE WHO PANEL OF EXPERTS ARE WHO REVIEW APPLICATION. RIGHT. AFICIONADOS WE DON'T NEED THE GET INTO YET. IT'S PUBLICLY AVAILABLE. THAT'S MY POINT. YOU CAN SIGH WHO IS REVIEWING THE APPLICATIONS FOR US. AND THEN WE ALSO HAVE AND IN HOUSE REVIEW BRANCH. THIS IS RUN BY ERNIE, AS WE POINTED OUT. YOU CAN ASK WHY IN HOUSE REVIEW BRANCH. THERE'S APPLICATIONS MAYBE MORE HEAVILY MISSION FOCUSED OR HAVE CERTAIN THINGS SUCH AS INSTITUTE SPECIFIC, WHERE THEY HAVE REVIEW CRITERIA THAT ARE INSTITUTE-SPECIFIC. WE TEND TO REVIEW BIG GRANTS, I WILL CALL THEM THAT, IN HOUSE. SO CENTER GRANTS, PROGRAM PROJECT GRANTS, LARGE CLINICAL TRIALS, TRAINING GRANTS, THOSE AREN'T NECESSARILY BIG BUT WE ARE VERY INVESTED IN THE TRAINING OF THE NEXT GENERATION SO WE REALLY WANT TO HAVE A LITTLE MORE -- I DON'T WANT TO SAY HANDS ON BUT MORE INVOLVEMENT IN SETTING UP REVIEW PROCESS. SOME VARIOUS OTHER ONES, CONTRACTS AS WELL. SO IT'S ACTUALLY I THINK SERVED US WELL TO HAVE OUR OWN REVIEW BRANCH OVER THE YEARS. NOW, ONE COULD ASK WHAT DO THESE REVIEWERS DO? THE KEY THING, THERE'S THREE BIG THINGS REVIEW IS LOOKING FOR. THEY ARE LOOKING AT WHAT IS THE BIG PICTURE BEING PROPOSED? IS IT IMPORTANT? WHY IS IT IMPORTANT? AND CAN THE PERSON PROPOSING IT ACTUALLY DO IT? THAT'S A BIG PICTURE THING. BUT THERE'S ACTUALLY A VERY MORE SPECIFIC FORMAL CRITERIA WHICH THE REVIEWERS LOOK AT. SO THEY GIVE AN APPLICATION AN OVERALL IMPACT SCORE. NOW, THEY ALSO SCORE ON WHAT WE CALL THE CORE CRITERIA WHICH ARE FIVE CRITERIA OF SIGNIFICANCE INVESTIGATOR INNOVATION, APPROACH ENVIRONMENT. BUT IT'S IMPORTANT TO KNOW THAT THESE DON'T SIMPLY ADD UP IN AVERAGE, THAT'S WHAT THEY GIVE IMPACT SO EACH CRITERIA CAN CARRY DIFFERENT WEIGHT. YOU CAN HAVE A VERY GOOD IMPACT SCORE BUT HAVE A POOR SCORE ON SAY ENVIRONMENT. FROM YEARS OF EXPERIENCE I CAN SAY THIS APPROACH SCORE, IS THE ONE CORRELATES MOST WITH OVERALL IMPACT. IT IS FOLLOWED BY SIGNIFICANCE AND I CAN'T TELL YOU WHAT THREE, FOUR AND FIVE IS. BUT NONETHELESS, IT CONFUSES PEOPLE SOMETIMES WHEN THEY GET A REALLY GOOD SCORE IN THREE BUT APPROACHES ARE POOR SCORE WHY THEIR OVERALL IMPACT IS NOT SO HOT, IT'S GENERALLY THIS APPROACH IS THE PEER REVIEW TENDS TO WEIGH THAT MOST HEAVILY. THE NUTS AND BOLTS OF REVIEW PROCESS IS, THE PERSON WHO RUNS THE REVIEW, WE CALL SRO OR SCIENTIFIC REVIEW OFFICER, THEY ASSIGN ONE APPLICATION TO THREE REVIEWERSES. THE PANEL IS MADE UP OF DEPENDS HOW MANY APPLICATIONS BUT ON AVERAGE 15, 20 REVIEWERS. SO FOR EACH INDIVIDUAL APPLICATION, GENERALLY THREE REVIEWERS WILL LOOK AT IT THE MOST CLOSELY. SO YOU ASSIGN 'PRIMARY, SECONDARY AND TERTIARY REVIEWER, THEY WILL READ IT, POST A PRELIMINARY SCORE AND A WRITTEN CRITIQUE TO THIS ELECTRONIC SYSTEM, THE ERA OR ELECTRON UK RESEARCH ADMINISTRATOR. WHERE THE OTHER REVIEWERS CAN THEN GO IN AND LOOK AT THIS. ONCE THE ASSIGNMENTS ARE MADE AND PRELIMINARY REVIEWS DONE AND OTHER REVIEWERS WHO WEREN'T ASSIGNED APPLICATION LOOK VERY CLOSELY AT THE PRELIMINARY SCORES AND WRITE UPS, THEY GET TOGETHER USUALLY WITH A FACE TO FACE MEETING WHERE THEY GO THROUGH ALL THE APPLICATIONS AND THE GOAL IS THE PRIMARY REVIEWER WOULD PRESENT THE APPLICATION AND THEN THE SECONDRY AND TERTIARY CAN WEIGH IN ON THINGS NOT BROUGHT UP. THEN IT'S OPENED UP FOR DISCUSSION WITH THE PANEL, WHERE IN AN IDEAL WORLD THEY WOULD REACH A CONSENSUS, DOESN'T ALWAYS WORK THAT WAY BUT THE POINT IS TO HAVE THE PANEL VET APPLICATION. THEN THEY'LL MAKE A FINAL SCORE AND THEY ALL PUBLICLY STATE THE FINAL SCORE FROM THE PRIMARY SECONDARY TERTIARY BUT OTHER REVIEWERS WILL SCORE TOO. THEY PUT IT TOGETHER, THEY PUT IT IN A BIG PACKAGE AND SEND US THE SCORES. THIS THEN LEADS US TO THE FINAL PHASE OF THE CYCLE WHERE FUNDING PLANS ARE DEVELOPED. REVIEWERS SHIP THE SCORES AND SUMMARY STATEMENTS TO US. THIS IS A VERY IMPORTANT POINT TO BRING UP, WE DON'T JUST LOOK AT THE NUMBER, WE ARE READING THE TEXT AS WELL OF THE SUMMARY STATEMENTS WHEN WE DEVELOPING THE FUNDING PLANS, IT IS VERY IMPORTANT WHAT REVIEWERS ARE TELLING US AS WELL AS WHAT THEY ARE SHOWING US IN NUMBERS. SO HERE WE ARE NOW, WE ARE GETTING CLOSE TO THE END. SO THE MERIT REVIEW OR THE PEER REVIEW AS WE CALL IT, IS ALL KIND OF WE GET ACCESS HERE IN THE INSTITUTE STAFF STARTS TO DEVELOP WHAT WE CALL THE FUNDING PLAN. THE FUNDING PLAN AS I SAID, IT COMES IN VARIOUS FLAVORS, SOMETIMES THERE'S A SPECIFIC RFA AS I MENTIONED AND THAT WOULD HAVE ALL THE APPLICATIONS AND THE SCORES AND THE PERSON WHO IS THE LEAD ON THAT RFA WOULD LOOK AT IT AND DEVELOP A FUNDING PLAN, THEN WE HAVE THE PARENT ANNOUNCEMENTS, REALLY DON'T GENERALLY DEVELOPF . CXFCKER FUNDING PLAN FOR BUT MAKE THE SCORES AVAILABLE TO COUNCIL, ET CETERA, ET CETERA, SO THE COUNCIL MEETING WILL MEET. THE COUNCIL WILL MEET AT A MEETING WHICH IS IN TWO DAYS. WHEN WE DEVELOP THE PAY PLAN WHAT DETERMININGS WHETHER AWARDS WE'RE FROM POSING TO MAKE? A KEY ASPECT AS I MENTIONED IS PEER REVIEW, BOTH THE SCORE AND THE WRITTEN WORD. AND THEN ALSO THERE'S PROGRAMMATIC CONSIDERATIONS, THAT WOULD BE US MORE IN HOUSE AND NOW STAFF, FOR EXAMPLE, IF THERE WAS AN AREA OF RESEARCH WHICH WE HAVE -- SO MAYBE PRIORITIZE SOMETHING LIKE THAT OR IF THERE'S AREAS WE HAVE A LOT IN, THAT MAY GET A DIFFERENT PROGRAMMATIC CONSIDERATION. A VERY KEY THING DRIVING EVERYTHING IS HOW MUCH MONEY WE HAVE AVAILABLE FOR MAKING NEW AWARDS. THIS LEADS TO THIS IDEA WHERE CALLED A PAY LINE. THIS IS WHERE THE DIFFERENT NIH INSTITUTES FUNCTION SOMEWHAT DIFFERENTLY. WE'RE CONSIDERED A HARD PAY LINE INSTITUTE. WHAT A PAY LINE CAN BE LOOKED AT IS SIMPLY A FUNDING LINE. WE KNOW HOW MUCH MONEY WE HAVE AVAILABLE FOR NEW STUFF, AND WE ARE ABLE TO DETERMINE ROUGHLY HOW MUCH MORE NEW STUFF CAN WE PAY. IF YOU ARE ABOVE THE CERTAIN FUNDING LINE IN SCORE WE WILL PAY YOUR APPLICATION. THERE'S REALLY LITTLE CONSIDERATION, YOU JUST HAVE TO MAKE OUR PAY LINE. WE ACCEPTED THE APPLICATION SO THAT SHOULD SUGGEST THAT IT'S IN OUR MISSION AND WE ARE OKAY WITH IT. SO IF YOU MAKE OUR PAY LINE, PRETTY MUCH PAY IT. WE HAVE THE ABILITY TO PAY BEYOND PEA LINE FOR CERTAIN PRIORITY AREAS. I WILL MENTION ESI, EARLY STAGE INVESTIGATORS, WE MADE A DECISION, WE THINK THE NEXT GENERATION OF NEUROSCIENTISTS OR NEW PEOPLE STARTING IN THE LABORATORIES IS VERY EXTEND TECHNICAL, DERIVED TEN YEARS POST MOST YOUR TERMINAL DEGREE. I THINK SO THAT IS A HIGH PRIORITY. SO WE CAN PAY YOU BEYOND THE PAY LINE THERE. WHEN WE DETERMINE THE PAY LINE WE HAVE TO SOMEWHAT TAKE INTO ACCOUNT WHAT WE HAVE THERE CERTAIN PROGRAMS WE HAVE SET ASIDE A CERTAIN AMOUNT OF MONEY JUST FOR THAT PROGRAM. WE HAVE TO SUBTRACT THAT FROM THE AVAILABLE FUNDS WHEN SETTING THE PAY LINE. THE NEXT GETS TO HOW WE SET PAY LINE. THE WAY WE SET THE PAY LINE IS WE'LL GET MONEY FROM CONGRESS OR AN APPROPRIATION. THE KEY THING IS COMMITMENT BASE VERSUS EXEATING DOLLARS. WE MAKE AWARDS THAT ARE GENERALLY FOUR OR FIVE YEARS LONG YET WE GET MONEY BY THE YEAR. SO MOST OF OUR MONEY IS ACTUALLY CAUGHT UP IN OUR COMMITMENT OUR BILLS IF YOU WANT CALL THEM THAT. SO WE HAVE THE TAKE INTO ACCOUNT HOW MUCH WE COMMITTED, AND OUR APPROPRIATION AND THAT WILL TELL US WHAT WE HAVE -- WHAT WE CALL COMPETING DOLLARS. THAT IS AVAILABLE MONEY TO MAKE A NEW AWARDS. ANOTHER THING WE DO TO STRETCH OUR DOLLARS IS WE CUT GRANTS. THIS MAY NOT BE THE MOST POPULAR THING BUT WE MAKE ACROSS THE BOARD ADMINISTRATIVE CUT TO NEARLY EVERY GRANT WE AWARD. IT'S KIND OF NON-NEGOTIABLE, WE CUT YOUR GRANTS. WHAT THAT DOES, IS ESSENTIALLY GIVES US ABILITY TO EXTEND PAY LINE BECAUSE IT FREES MONEY TO PAY MORE GRANTS. THEN THE OTHER THING ABOUT SETTING THE PAY LINE IS AS I MENTION, WE HAVE TO SUBTRACT OUT THE FUNDS THAT ARE EARMARKED FOR CERTAIN PROGRAMS. SOME ARE HARD WE COULDN'T MESS WITH, SOME WE HAVE DONE IT MORE INSTITUTIONALLY AND DEPENDING WHAT WE HAVE AVAILABLE TO PAY WE COULD BE MORE FLEXIBLE. BUT FOR EXAMPLE, LIKE THE BRAIN INITIATIVE. I BELIEVE THE MONEY IS HARD SET FOR THE BRAIN INITIATIVE. WE COULDN'T QUOTE REPROGRAM THAT MONEY TO PAY OTHER THINGS. WE DO HAVE SOME PROGRAMS THAT IT'S REALLY NOT AS DIFFICULT, WE DON'T HAVE TO REPROGRAM IT, IT'S NOT CONGRESSIONALLY MANDATED MONEY, IT'S WITHIN OUR BASE. ONCE WITH DETERMINE THE PAY LINE WE HAVE GONE THROUGH APPLICATION CYCLE, WE HAVE PAY PLAN THEN GO TO COUNSEL. WHAT IS THIS COUNCIL I MENTIONED? SECOND LEVEL OF REVIEW THEY CALL IT. YOU COULD SAY ONE WAY IT LOOKS REVIEWS THE REVIEW, IT REVIEWS OUR PAY PLANS, IT'S REVIEWING OUR OVERALL THE BROAD IN A SENSE, WE HAVE COUNCIL THREE TIMES A YEAR SO WE MAKE AWARDS THREE TIMES A YEAR. WHAT COUNCIL ALSO DOES BEYOND LOOKING AT OUR FUNDING RECOMMENDATIONS IS THEY WILL PERFORM CONCEPT CLEARANCE ON NEW IDEAS. IF WE ARE GOING TO PROPOSE A NEW PROGRAM, MOSTLY IF IT HAS MONEY ATTACHED TO IT, IF WE WANT TO SET ASIDE MONEY, NOT ALWAYS, WE GENERALLY WILL PRESENT THIS AS COUNCIL AND I THINK THINGS HAVE CHANGED NOW, ALMOST LIKE EVERY CONCEPT WE NEED NOW TO PRESENT TO COUNCIL. WE TELL THEM WHAT IT'S FOR WHY DO IT, WHY IT'S IMPORTANT AND THEY CAN WEIGH IN AND GIVE US FEEDBACK, HELP US IMPROVE THE CONCEPT, WHAT NOT. AND THEN ANOTHER THING ADVISORY COUNCIL DOES IS IT WILL ADVISE US, ADVISORY COUNCIL, ADVISE ON OUR OVERALL GOALS. IF WE HAD A STRATEGIC PLANNING EFFORT WE WOULD HEAVILY INVOLVE OUR ADVISORY COUNCIL. BUT WE HAVE HAD MANY PROJECT OVER THE YEARS GETTING COUNCIL INVOLVED. SOME OF THE NEW PROGRAMS WE WILL DO ARE COMPLICATED, THEY COULD BE CONTROVERSIAL SO WE WANT TO ENGAGE OUR COUNCIL IN THE DEVELOPMENT OF THOSE PROGRAMS. SO THE COUNCIL IS MADE UP OF A CHAIRPERSON, USUALLY THE IC DIRECTOR, INSTITUTE OR CENTER DIRECTOR. AND IT'S ABOUT 12 TO 18 MEMBERS, THIRD ARE BASIC SCIENTISTS, A THIRD ARE MEDICAL SCIENTISTS, OR DOCTORS, AND THEN A THIRD ARE PUBLIC MEMBERS. JUST TO JUMP DOWN THE LAST BULLET, WE WANT EXPERTISE IN PUBLIC POLICY LAW ECONOMICS. PEOPLE FROM NON-PROFIT ORGANIZATIONS OFTENLY SERVE ON OUR COUNCIL. THEN IT HAS TO BE BALANCED FOR ETHNIC RACIAL GENDER DISABILITY AND GEOGRAPHICAL LOCATION. SO WE NEED THE FOUR PARTS OF THE COUNTRY THEY DETERMINED. WE HAVE EX-OFFICIO MEMBERS, PEOPLE FROM THE VA, THE DOD. WE HAVE AN EXECUTIVE SECRETARY WHO IS MY BOSS, BOB FINKLESTEEN WHO RUNS THE COUNCIL MEETING. EACH MEMBER WILL SERVE A FOUR YEAR TERM BUT WE KIND OF -- THERE'S STAGGERED SO A QUARTER OF THE COUNCIL MEMBERS ROTATE EACH YEAR OFF AND WE GET NEW ONES. SO IS IT'S A CONSTANT PROCESS OF REINVIGORATING COUNCIL. THEY ARE APPOINTED BY THE SECRETARY OF THE DEPARTMENT OF HEALTH AND HUMAN SERVICES YET WE MAKE THE NOMINATIONS. WE WILL SEND THEM IN NOMINATION SLATE AS WE CALL IT. THEY CAN APPROVE IT BUT WE CAN GET RECOMMENDATIONS FROM ANYWHERE. FROM INTERNALLY INSTITUTE GUYS LIKE YOU, FROM CONGRESS MEMBERS, THE PUBLIC ANYONE CAN SOLICIT A NOMINATION TO US. SO WHAT ARE THE ACTUAL FORMAL OPTIONS OF COUNCIL? COUNCIL CAN CONCUR WITH THE PROPOSED FUNDING PAY PLANS, THEY CAN MODIFY THEM. SO FOR EXAMPLE, IF WE WERE DOING AN RFA AND WE PUT FORWARD A PAY PLAN, AND THEY ACTUALLY OPPOSED TO ONE OF THE APPLICATIONS WE WANTED TO PAY, THEY COULD RECOMMEND NOT PAYING THAT. THEY COULD DISAPPROVE FUNDING PLAN OR INDIVIDUAL APPLICATION OR WHAT NOT BUT ULTIMATELY COUNCIL IS ADVISORY TO DIRECTOR. SO THEY -- WE HAVE OUR MEETING, THEY ADVISE US ON OUR PAY PLANS, AND THEN WE -- IT ALL FUNNELS DOWN TO DIRECTOR OF THE INSTITUTE WHO MAKES THE FINAL DECISION, AND WHEN ALL GOES WELL AN AWARD IS MADE. THE MAKING OF AN AWARD IS A WHOLE 'NOTHER -- I COULD HAVE ANOTHER SERIES OF THINGS HERE, THAT'S WHY OUR GRANTS MANAGEMENT DIVISION WHERE THEY WORK OUT KIND OF THE NUTS AND BULLETS OF AWARD, THERE'S POLICIES PROCEDURES LAWS WHEN WE SHIP FEDERAL MONEY OUT TO INDIVIDUALS. SO THAT'S ESSENTIALLY VERY QUICKLY OUR PROCESS, WE ARE CONSTANTLY GOING THROUGH IT, THREE TIMES A YEAR. EVERYTHING ELSE WE DO IN OUR WORKING LIFE FITS AROUND THESE THREE TIMES A YEAR. SO I WANT TO END MAYBE MAKE A FEW SUGGESTIONS HOW YOUR ORGANIZATIONS ARE INTEGRATED IN THIS PROCESS AN WORK WITH US IN THIS PROCESS. I HAVE THE LITTLE CHART HERE AGAIN OR WHATEVER THE FLOWCHART, FOR EXAMPLE, NON-PROFIT ORGANIZATIONS SOME OF THEM OBVIOUSLY SOME ARE SCIENTISTS MAYBE SOME ACTIVE RESEARCH SCIENTISTS TO DEVELOP RESEARCH PROPOSALS THEMSELVES OR A SCIENTIST WORK WITH A NON-PROFIT ORGANIZATION TO DEVELOP A RESEARCH PROPOSAL, AND NON-PROFITS SERVE AS INSTITUTIONAL ORGANIZATIONS, AS I SAID WE ACTUALLY HAVE TO HAVE AN OFFICIAL ORGANIZATION OR INSTITUTION THAT WILL SUBMIT THE AWARD APPLICATION. HOPEFULLY AWARD, TO US. YOUR ORGANIZATIONS CAN SERVE IN THAT ROYAL, THEY CAN RECOMMEND& PEER REVIEWERS OR SERVE ON PEER REVIEW PANELS. FINALLY OUR ORGANIZATION RECOMMENDS COUNCIL MEMBERS OR BE COUNCIL MEMBERS YOURSELVES. A LITTLE -- ONE FINAL POINT, WE ALSO THERE'S A FORMAL WAY THAT WE REQUEST INFORMATION. THESE ARE VIA RFI, REQUEST FOR INFORMATION, AND THIS IS WHEN WE RELEASE THEM TO THE COMMUNITY, AND WE WILL ASK FOR SPECIFIC TYPE OF FEEDBACK WHEN DEVELOPING A PROGRAM, WAY TO ENGAGE THE ENTIRE COMMUNITY, SO FOR EXAMPLE, BACK IN 2015 WE WERE LOOKING FOR INFORMATION ON INPUT AND DEVELOPMENT OF FEDERAL PAYING RESEARCH STRATEGY. WE HAVE GOTTEN FEEDBACK AND THIS IS REALLY DEVELOPED INTO A FAIRLY LARGE PROGRAM AT THIS POINT. THEN JUST TO REPEAT MYSELF, ONCE AGAIN, YOUR ORGANIZATIONS CAN WORK WITH INVESTIGATORS TO DEVELOP RESEARCH PROPOSALS AND SERVE AS THE APPLICANT ORGANIZATION. AND FROM THIS PART AS YOU SEE ELIGIBLE INSTITUTIONS. IS THAT WHAT IT SAYS? INFORMATION. ELIGIBILITY INFORMATION. SORRY ABOUT THAT. SO AS YOU CAN SEE DOWN HERE, NON-PROFITS ELIGIBLE TO BE THE ORGANIZATION FINALLY SOMETHING WE KNOW THAT'S VERY FRUITFUL OF THE INTERACTION BETWEEN RESEARCHERS AND KNOP PROFITS IS TO HELP PATIENT RECRUITMENT IN CLINICAL STUDIES BECAUSE YOU GUYS MANY TIMES HAVE ACCESS TO PATIENTS AT THE INDIVIDUAL RESEARCHERS MAY NOT SO YOU CAN COLLABORATE THERE AND WE HAVE HEARD THAT THAT'S BEEN A VERY SUCCESSFUL COLLABORATION IN MANY, MANY AREAS OVER THE YEARS. THEN IN TERMS OF REVIEWERS AND REVIEW MEMBERS OF STUDY SECTIONS AND COUNCIL MEMBERS YOU CAN SUBMIT NAMES TO US, ERNIE'S NAME IS HERE, I HAVE BOB'S NAME, MY BOSS WHO RUNS THE EXECUTIVE SECRETARY OF COUNCIL AND ME DOWN HERE, OR SEND US EMAILS, YOU CAN INDIVIDUALLY TELL US, WE CAN DO IT ANYWAYS. WE AS I MENTIONED THE COUNCIL MEMBERS ARE ROTATING OFF EACH YEAR SO WE ARE ALWAYS EVERY YEAR LOOKING FOR NEW COUNCIL MEMBERS OR RECOMMENDATIONS TO ADD TO OUR SLATE TO SAY WE DON'T MAKE FINAL DECISIONS. I THINK THIS IS THE FINAL SLIDE. WHAT I REALLY JUST WANTED -- THIS IS THE CSR WEBSITE. IF YOU DID WANT TO LEARN MORE ABOUT PEER REVIEW, CSR'S WEBSITE IS USEFUL. YOU CAN LOOK THROUGH THERE, FOR EXAMPLE, INTERESTED IN ROSTERS WHO ARE THESE PEOPLE THAT NIH GET TO REVIEW? YOU CAN FIND ALL THAT INFORMATION ON THE CSA WEBSITE. I BELIEVE THAT WAS MY FINAL SLIDE. YES. HAPPY TO TAKE QUESTIONS OR DISCUSSIONS OR LYNN, DO YOU WANT TO JUST DO IT ALL AT THE END? TWO QUESTIONS. OR ZERO QUESTIONS. ZERO TO TWO QUESTIONS. ZERO IT IS. THANKS A LOT. I THINK WHAT -- OH. SORRY. >> HAVING READ A FEW SUMMARY STATEMENTS, CURIOUS CAN YOU TELL US A LITTLE BIT MORE ABOUT HOW THE STUDY SECTION DEVELOP AND HOW REVIEWERS ARE CHOSEN TO SERVE. I LOOK HOW THEY'RE ORGANIZED THROUGH THE WEBSITE YOU MENTIONED. I'M WONDERING WHY CERTAIN PEOPLE ARE ASSIGNED TO CERTAIN STUDY SECTIONS AND WHO MAKES THOSE DECISIONS ABOUT WHERE REVIEWERS WILL SERVE? >> I WILL DEFER TO YOU. >> THANK YOU FOR THAT, GOOD QUESTION. EACH STUDY SECTION IS MANAGED BY AN SRO, SCIENTIFIC REVIEW OFFICER WHICH SERVES AS THE DESIGNATED FEDERAL OFFICIAL. AND MANAGES REVIEW ACCORDING TO NIH PUBLIC POLICY AND MAKE SURE REVIEWERS ARE FOLLOWING THE RULES AND WE TRY TO MAINTAIN A LEVEL PLAYING FIELD SO THAT THE APPLICATION IS OBJECTIVE AND FAIR. IT'S REALLY ULTIMATELY THE RESPONSIBILITY OF THE SRO TO SELECT THE MEMBERS. THEY SELECT THE REGULAR MEMBERS FOR STANDING STUDY SECTION, HOWEVER THEY OFTEN VET THOSE MEMBERS THROUGH OUR PROGRAM STAFF HERE AND ULTIMATELY THEY ARE APPOINTED BY OUR INSTITUTE DIRECTOR. OR C SR. TECHNICALLY CSR DIRECTOR. AND THEN FOR EACH STUDY SECTION WE ALSO TYPICALLY RECRUIT BASED ON THE APPLICATIONS THAT WE RECEIVE MAYBE HALF STUDY SECTION EACH ROUND WILL CONSIST OF AD HOC OR TEMPORARY MEMBERS. THAT WE SELECT BASED ON EXPERTISE THAT WE NEED FOR THE MEETING AND THE APPLICATIONS ARE ASSIGN THE THE STUDY SECTIONS BASED ON THE SCIENTIFIC TOPICS AND STUDY SECTIONS AS MENTIONED ARE ORGANIZED AND INTEGRATED REVIEW GROUPS BASED ON THE SCIENTIFIC AREAS REALLY. >> THANK YOU FOR YOUR PRESENTATION. THAT WAS ILLUMINATING. I THINK NINDS COVERS BUT I MIGHT BE MAKING THIS UP, SOMEWHAT LIKE 500 RARE NEUROLOGICAL CONDITIONS, GIVE OR TAKE, FOUR OR 500, DEPENDING WHO YOU SPLIT. I'M CURIOUS IF YOU TRACK THE NUMBER OF ORGANIZATIONS LIKE OURS THAT ARE MAKING APPLICATIONS FOR ANY TYPE OF GRANTS, WHETHER IT'S CONFERENCE GRANTS OR RESEARCH GRANTS AND SUCCESS PARTICULARLY OF THOSE ON THE RARER SIDE OF THE SPECTRUM. IF THAT'S PUBLICLY AVAILABLE. >> OFFHAND, I CAN'T SAY THIS WOULD BE, I WOULD MOVE -- WE'LL MOVE TO THE NEXT SECTION WHICH IS PROGRAMMATIC. I DON'T KNOW IF WE DO IT IN -- AND PLEASE CORRECT ME IF I'M WRONG PROGRAMMATIC PEOPLE. I DON'T THINK WE DO IT IN AN ORGANIZE ODE IF WE HAD A QUESTION WE WOULD BE ABLE TO DO THAT. WE DO A LOT OF ANALYSIS. WE CAN SPEND ALL OR TIME DOING ANALYSIS. SO WE TEND TO HAVE A QUESTION WE WANT TO ANSWER BEFORE WE DO AN ANALYSIS. BUT WE DEFINITELY CAN GET THE DATA YOU ARE MENTIONING. IF THAT WAS A QUESTION, WE ARE INTERESTED IN GETTING WE DEFINITELY CAN DO THAT. >> I CAN ALSO JUST ADD, IF OTHERS WILL TALK ABOUT IT, THERE IS A PUBLIC WEBSITE THAT NIH REPORTER, WHICH IF YOU'RE FAMILIAR WITH IT, YOU CAN GO ON AND SEE ALL THE APPLICATIONS WE FUND AND SEARCH BY MANY DIFFERENT VARIABLES TO FUND WHAT WE ARE FUNDING ACROSS. >> IT'S USEFUL BECAUSE YOU CAN DOWNLOAD ALL THE DATA IN XL SPREADSHEET AND YOUR OWN ANALYSIS AND THERE'S ALSO OVER THE YEARS, NIH HAS GOTTEN BETTER DEVELOPING TOOLS THAT PEOPLE CAN USE ON THE PUBLIC DATA WHERE THEY CAN MAKE -- YOU CAN DO EVERYTHING YOU WANT TO DO. IN THE PRIVACY OF YOUR OWN HOME. [APPLAUSE] >> THANKS, KEEP IN MIND THESE GUYS ARE AVAILABLE, THEY WILL BE AVAILABLE OFF AN ON THANK YOU THE DAY SO REACH OUT IF YOU HAVE ADDITIONAL QUESTIONS HOW WE MANAGE GRANTS COMING IN AND GOING OUT. SO I WANT TO INTRODUCE THEN THE NEXT SECTION WHICH IS A DISCUSSION OF WHAT PROGRAMS DIRECTORS DO PRIMARILY BUT OUR PROGRAM STAFF IN GENERAL. SO I'M GOING TO INTRODUCE JILL MORRIS, A PROGRAM DIRECTOR, AND JILL WILL DIVE DOWN A LITTLE BIT DEEPER INTO THE SAME CYCLE THAT DAVE OWENS PRESENTED TO YOU BUT ACTUALLY SHOW YOU WHERE THE PROGRAM DIRECTORS PLAY A ROLE THERE BECAUSE WE'RE HOPING THAT PART OF WHAT WILL BE THE HIGHLIGHT TODAY AND TOMORROW IS MEETING WITH SOME OF THOSE PROGRAM DIRECTORS. SO JILL, LET ME TELL YOU ABOUT HER. HER DISEASE RESEARCH PORTFOLIO, HER AREA OF SCIENTIFIC EXPERTISE INCLUDES MULTIPLE NEUROLOGICAL DISORDERS INCLUDING MANY OF THE RARE DISEASES, THE LEUKODYSTROPHIES IN BORN ERRORS OF METABOLISM, SPINA BIFIDA, HYDROCEPHALUS AND RARE GENETIC DISORDERS AND RESPONSIBLE FOR METHODOLOGY GRANTS REGARDING GENE THERAPY DELIVERY AND RNAi TECHNOLOGY AND WE SHE WILL DESCRIBE ABOUT THOSE AREAS. BEFORE SHE JOINED NIH SHE WAS ASSISTANT PROFESSOR IN THE DEPARTMENT OF PEDIATRICS IN THE FINEBERG SCHOOL OF MEDICINE NORTHWESTERN UNIVERSITY AND CHILDREN'S MEMORIAL RESEARCH CENTER. SHE WAS ALSO A SENIOR RESEARCH BIOLOGIST IN DEPARTMENT OF NEUROSCIENCE AT MERCK RESEARCH LABORATORIES AND SHE WAS SENIOR STAFF FELLOW IN THE UNIT OF MOLECULAR NEUROGENETICS AT NIH AND THERE SHE HELPED IDENTIFY THE GENE RESPONSIBLE FOR KNEE -- NEIMAN PIC DISEASE TYPE C. JILL, TAKE IT AWAY. >> I WILL TALK TO YOU ABOUT A DAY IN THE LIFE OF THE PROGRAM DIRECTOR. AND AT NINDS THE WAY -- SO EVERY IC INSTITUTE IS VERY DIFFERENT ON HOW THEY RUN THEIR -- ORGANIZE THEIR INSTITUTES, THEIR EXTRAMURAL INSTITUTES. AT NINDS WHAT WE DO WHICH I REALLY LIKE, IS WE ASSIGN ONE PROGRAM DIRECTOR IN CHARGE OF SPECIFIC DISEASE AREAS. SO YOU AS A COMMUNITY HAVE ONE POINT OF CONTACT. AS THIS POINT OF CONTACT THEN, I CAN EITHER BE ABLE TO ANSWER THE QUESTION YOURSELF OR FIND THE PERSON THAT WOULD BE ABLE TO ANSWER YOUR QUESTION. SO I'M GOING TO TALK ABOUT WHAT I DO ON A DAILY BASIS. WHAT I REALLY LIKE ABOUT MY JOB IS EVERY DAY IS DIFFERENT. WE HAVE DIFFERENT TYPES OF ACTIVITIES THAT WE'RE RESPONSIBLE FOR. FIRST I WANT TO THANK YOU THE REASON IS THAT WE VALUE THE CONTRIBUTIONS THAT ADVOCACY GROUPS MAKE IN RESEARCH. I WAS WRITING DOWN A COUPLE OF IDEAS OF WORK THAT I HAVE DONE WITH ADVOCACY GROUPS. ADVOCACY GROUPS ARE ESSENTIAL AT IDENTIFYING PATIENT NEEDS. SO OFTEN WE GET SO INTO THE RESEARCH THAT QUALITY OF LIFE ISSUES LIKE SLEEP, I OFTEN HERE PEDIATRIC DISORDERS WHERE PARENTS DON'T GET A DECENT NIGHT'S SLEEP BECAUSE OF TYPE OF DISORDER THEIR CHILD HAS, THEY'RE UNABLE TO SLEEP ALL NIGHT. THEY ALSO HELP US WITH IDENTIFYING GAPS IN THE RESEARCH. THEY BRING TOGETHER THE PATIENT COMMUNITIES, OFTEN WHICH IS ESSENTIAL FOR RECRUITMENT INTO STUDIES LIKE BIOMARKER DEVELOPMENT, CLINICAL TRIALS, DEVELOPING REGISTRIES. THEY PROVIDE FUNDING OPPORTUNITIES, YOU PROVIDE FUNDING OPPORTUNITIES TO JUNIOR INVESTIGATORS TO SENIOR INVESTIGATORS THAT ALLOW THEM TO GET THE DATA NECESSARY TO APPLY FOR AN NIH GRANT. YOU ALSO BRING TOGETHER THE RESEARCHERS SO MANY OF YOU HAVE ANNUAL MEETINGS WHERE YOU BRING TOGETHER RESEARCHERS WHO NOT ONLY BRAINSTORM NEW IDEAS BUT ALSO ESTABLISH COLLABORATION WITH EACH OTHER TO MOVE THE RESEARCH FORWARD. I PUT THIS UP, LYNN WENT THROUGH MY BACKGROUND, THE REASON I PUT THIS UP IS I WANT TO REASSURE ASSIGNED TO THE DISEASE AREA, THERE ARE MORE THAN JUST A PERSON SITTING AT THE COMPUTER, THEY HAVE A SCIENTIFIC BACKGROUND, MANY OF US HAVE RUN OUR RESEARCH LABS, I'M FAMILIAR WITH STRUGGLES RESEARCHERS GO THROUGH WITH APPLYING FOR A GRANT. MANY OF US HAVE BEEN IN INDUSTRY SO WE KNOW WHAT IT TAKES TO GET A DRUG INTO A CLINICAL TRIAL. SO YOU CAN BE REASSURED THE PERSON YOU ARE WORKING WITH, I HATE TO SEE IS NOT A GOVERNMENT BUREAUCRAT BUT ACTUALLY A SCIENTIST. YOU WILL BE WORKING WITH SOMEONE THAT HAS A BACK GROUND IN YOUR DISEASE AREA AND THAT IS ABLE -- GOING TO BE ABLE TO WORK WITH YOU TO MOVE THAT RESEARCH FORWARD. SO WHERE DO I FIT IN THE ORGANIZATION OF NINDS? THIS IS NINDS AS A WHOLE. NINDS OVERALL IS DIVIDED INTO THREE AREAS. THE DIVISION OF INTRAMURAL, I'LL TALK ABOUT IN A SECOND, OFFICE OF DIRECTOR WHICH INCLUDES THE OFFICE OF SCIENCE POLICY AND PLANNING, OFFICE OF COMMUNICATION AND PUBLIC LIAISON, THE BUDGETS OFFICE, OBVIOUSLY CRITICAL. AND THE DIVISION OF EXTRAMURAL RESEARCH, WHICH IS WHERE I WORK. OFFICE OF DIRECTOR WORKS BOTH WITH INTRAMURAL AND EXTRAMURAL DIVISIONS. THE DIVISION OF INTRAMURAL RESEARCH IS THE NIH RESEARCHERS ON CAMPUS. SO THERE ARE LIKE ANY OTHER SO THEY HAVE THEIR OWN RESEARCH LAB, THEY HAVE THEIR OWN BUDGETS. THEY ARE KEPT VERY SEPARATE FROM US. BECAUSE THEY ARE DOING THEIR OWN UNIQUE RESEARCH AND THEY ARE REPRESENTED BY NIH OVERALL. BUT WE REPRESENT EVERYBODY ELSE. SO EXTRAMURAL REMITS ALL THE UNIVERSITIES ACROSS THE COUNTRY THAT ARE DOING RESEARCH, ALL THE SMALL BUSINESSES, AS WELL AS SOME FOREIGN SITES. SO WE'RE RESPONSIBLE FOR FACILITATING THEIR RESEARCH AND THEIR FUNDING. SO WITHIN DIVISION OF EXTRAMURAL RESEARCH WE'RE DIVIDED TO FOUR AREAS. DIVISION OF CLINICAL RESEARCH, WHICH IS HEAD BY -- WRIGHT, BACK IN THE BACK, THIS IS WHERE ALL THE CLINICAL TRIALS ARE DONE, CLINICAL RESEARCH PROPOSALS THE DIVISION OF TRANSLATIONAL RESEARCH IS WHERE ALL TRANSLATIONAL RESEARCH COME THROUGH, WE HAVE SPECIFIC INITIATIVES FOR THE DEVELOPMENT OF SMALL MOLECULES AS WELL AS GENE THERAPY AND -- IS IN CHARGE OF THAT, DIVISION OF NEUROSCIENCE IS WHERE I AM. THIS IS WHERE THE PROGRAM DIRECTORS ARE. THAT ARE RESPONSIBLE FOR SPECIFIC DISEASE AREAS LOCATED AND THEN JAKE -- LYNN JAKEMAN IS MY BOSS. THEN DIVISION OF EXTRAMURAL ACTIVITY AND BOB IS HEAD OF THAT DIVISION, WHERE COUNCIL ACTIVITIES OCCUR, THE SCIENTIFIC REVIEW BRANCH, THAT ERNIE IS IN CHARGE OF. THE GRANTS MANAGEMENT GRANT AND ADMINISTRATIVE OFFICES. ALL OF US WORK TOGETHER SO WE ARE LOCATED IN THESE DIVISIONS, BUT WE ALL COLLABORATE. SO OBVIOUSLY I WORK WITH GRANTS MANAGEMENT ALL THE TIME ON MAKING SURE AWARDS ARE GETTING OUT. I TALK TO THE DIVISION OF TRANSLATIONAL RESEARCH ALL THE TIME ABOUT INVESTIGATORS WHO ARE APPLYING FOR TRANSLATIONAL GRANTS SO IT'S A COLLABORATIVE PROCESS. SO LYNN WILL TALK ABOUT THIS IN MORE DETAIL BUT IN THE DIVISION OF NEUROSCIENCE WE ARE ORGANIZED INTO CLUSTERS. AND I'M IN THE NEUROGENETICS WHICH YOU SAY CLUSTER, IT OOH E NOT THE BEST CLUSTER BUT IT'S UP THERE. THIS IS A TYPICAL PORTFOLIO. SO ANY PROGRAM DIRECTOR COULD GET UP HERE AND TELL YOU WHAT THEIR PORTFOLIO OF DISEASE AREAS ARE. MOST OF US HAVE A COMBINATION OF A DISEASE AREAS THAT THEY COVER. AS WELL AS BASIC RESEARCH. I HAVE BASIC RESEARCH REGARDING GLIA AND GENE THERAPY AS WELL AS DISEASE AREAS. SO WHAT IS MY ROLE? AS PROGRAM DIRECTOR? I HAVE VARIOUS ROLES AND WILL GO INTO MORE DETAIL BUT THE FIRST ONE IS MY ROLE INTERACTING WITH INVESTIGATORS AND FACILITATING FUNDING. THIS IS A GRANT CYCLE THEY SHOWED YOU. I PLAYED A ROLE THROUGHOUT THIS WHOLE PROCESS. SO YOU BEGIN WITH, A RESEARCHER CONTACTS YOU BECAUSE THEY HAVE COME UP WITH AN IDEA OF A GRANT THEY WANT TO SUBMIT. THE PERSON WILL SEND ME THEIR SPECIFIC AIMS AND HAVE A CALL WITH THEM, WE WILL TALK ABOUT THOSE SPECIFIC AIMS AND THE FIRST THING WE DETERMINE IF IT'S MISSION RELEVANT. SO IF IT'S A SHARED AREA, SO WE HAVE SHARED AREAS FOR EXAMPLE I'M IN CHARGE OF THE TERRET PORTFOLIO, IT'S SHAREDD WITH THE NATIONAL INSTITUTES OF MENTAL HEALTH. AND WE HAVE SPECIFIC CRITERIA WHERE A GRANT FOR EXAMPLE IF IT WAS FOCUSED THAT OCD OR ADHD IT WOULD LIKELY GO TO NIMH. IF THAT WAS THEIR GRANT I WOULD CONTACT PROGRAM DIRECTOR THERE AND HAVE THEM CONTACT NIMH FOR THAT FUNDING MECHANISM. IF IT'S WITHIN OUR MIX THAT'S GREAT OMISSION, THAT'S GREAT AND WE CAN TALK ABOUT WHAT POTENTIAL MECHANISM IS APPROPRIATE FOR THEM TO APPLY TO AND HELP THEM SELECT STUDY SECTIONS SO WE SPEND TIME LISTENING TO STUDY SECTION AND IT'S PRETTY RELATIVELY EASY UNLESS IT'S A UNIQUE GRANT FOR US TO BE LIKE OKAY MAJORITY OF GRANTS FOR EXAMPLE THE MAJORITY OF BASIC GRANTS AND GLIA GO TO THE STUDY SECTION CALLED CMBG. THAT'S KNOWN AS A GLIA STUDY SECTION. AS DAVE MENTIONED WE HAVE MANY FUNDING OPPORTUNITIES THE VAST MAJORITY COME THROUGH THE INVESTIGATOR INITIATED WHICH IS LIKE THE PARENT RO1. WE ALSO HAVE PROGRAM PROJECT GRANTS, EXPLORATORY GRANTS, TRAINING AWARDS, INVESTIGATORS THAT ARE JUST STARTING OUT IN YOUR PARTICULAR DISEASE AREA MAY BE APPLYING FOR A K AWARD OR FELLOWSHIPS. WE HAVE OUR TRANSLATIONAL PROGRAMS. I WANTED TO NOTE, WE HAVE SMALL BUSINESS AWARDS, THIS IS A CONGRESSIONALLY MANDATED SET ASIDE SO INVESTIGATORS AREN'T COMPETING FOR THESE DOLLARS, CONGRESS SET ASIDE A CERTAIN AMOUNT OF MONEY EVERY YEAR AND THIS IS SUPPOSED TO BOOST JOBS IN THE U.S.. BUT I HAVE HAD MANY ADVOCACY GROUPS THAT STARTED THEIR OWN SMALL BUSINESSES AND THEY END UP COLLABORATING WITH INVESTIGATORS AND THEY ESTABLISH A SMALL BUSINESS -- SMALL COMPANY AND THEY BEGIN DOING TRANSLATIONAL WORK. THEN WE HAVE OUR CLINICAL RESEARCH MECHANISMS LIKE THE RARE DISEASE CLINICAL RESEARCH NETWORK AND THE TRIALS. THE NEXT THING THAT HAPPENS IS APPLICANT SCHMITZ APPLICATION AND SUBMITTED THROUGH INSTITUTION TO REVIEW. I'M ON THE PHONE. LISTENING. WE CAN GO TO STUDY SECTION IF WE WANT BUT MOST LISTEN ON THE PHONE. WE ARE MUTED, THEY DON'T ALLOW US TO SAY A WORD. BUT WE ARE WILL BEING AND IT'S VALUABLE TO LISTEN TO STUDY SECTION FOR REVIEW OF APPLICANT BECAUSE YOU CAN GET A FEEL FOR WHAT I CALL THE FEEL FOR THE ROOM. SOMETIMES APPLICATION WILL HAVE ONE SET OF REVIEWERS THAT ARE DEAD SET THIS GROUP NEEDS THIS ANIMAL MODEL BEFORE THEY GET GRANT FUNDED. ANOTHER SET OF VIEWERS ARE LIKE I'M COMPETENT THIS GROUP CAN GET IT SO YOU CAN HEAR DISCUSSIONS AND IT HELPS YOU WHEN U THINK ABOUT ADVISING THE APPLICANT, YOU CAN SEE THERE WAS DISCUSSION ABOUT THE ANIMAL MODELS, I HI YOU NEED TO GET THIS ANIMAL MODEL BEFORE YOU RESUBMIT SO IT GIVES YOU A FEELING, YOU ALSO CAN HAIR OF THINGS WERE MAYBE INAPPROPRIATELY SAID OR SUMMARY STATEMENT COMES OUT IF THE SRO INADVERTENTLY MISSED A COMMENT THAT YOU FEEL NEEDS TO BE RELAYED TO THE APPLICANT. SO THOSE ARE ALL IMPORTANT ASPECTS. AFTER TE SRO PUTS TOGETHER SUMMARY STATEMENT, A PERSON IN CHARGE OF THE STUDY SECTION, THEY RELEASE A SUMMARY STATEMENT SO IT CONTAININGS A SUMMARY OF DISCUSSION, THAT'S WHAT I LISTEN TO AND THE COMMENTS FROM EACH INDIVIDUAL REVIEWER. SO I HAVE PHONE CALLS WITH WHAT THE PRIMARY CONCERNS WERE, WHAT THEY SHOULD DO, IF THERE WAS A FATAL FLAW, IT MAYBE THEY NED TO TAKE A STEP BACK AND APPLY FOR A DIFFERENT MECHANISM TO GET MORE PRELIMINARY DATA. MAYBE JUST ONE SMALL THING, MAYBE IT WAS GRANTSMANSHIP. A LOT OF TIMES WITH EARLY STAGE INVESTIGATORS, IT'S THEY DIDN'T TALK ABOUT THE RIGOR OF THE SCIENCE OR THEY DIDN'T TALK ABOUT THE PREMISE. AND JUST GETTING THAT EXTRA GRANTSMANSHIP. SO WE TALK ABOUT PATH FORWARD. SO NEXT WHAT HAPPENS IS THE COUNCIL CYCLE. SO WE HAVE FOUR PRE-COUNCIL MEETINGS, MOST INVESTIGATORS DON'T REALIZE WE HAVE FOUR MEETINGS, AND WHERE WE DISCUSS WHAT IS FUNDED WHAT MECHANISMS DIFFERENT MECHANISMS SO WE HAVE ONE THAT FOCUSES ON TRAINING GRANTS, ONE THAT FOCUSES ON TRANSLATIONAL GRANTS. WE HAVE TWO THAT DO ALL THE INITIATIVES, CLINICAL TRIALS, THESE ARE VERY IN DEPTH DISCUSSIONS, LEADERSHIP HAD THE SUMMARY STATEMENTS, AND WE DISCUSS WHAT'S GOING TO HAPPEN AND WHAT'S THE BEST PLAN FOR FUNDING. WE ALSO DISCUSS MERIT AWARDS. THINGS LIKE THE JAVITS AWARDS. POTENTIAL FUNDING OF THOSE APPLICANTS. SO THEN WE PRESENT THESE TO COUNCIL. ALWAYS A LITTLE NERVE WRACKING BUT WE PRESENTED THE COUNCIL AND HOPEFULLY THINGS GO SMOOTHLY AND THEY APPROVE OF THE FUNDING PLAN. AND THEN AFTER EVERYTHING IS DONE, STILL HAVE TO DO ADMINISTRATIVE VERY VIEW, WE HAVE TO MAKE SURE THEY DON'T HAVE ANOTHER GRANT FROM THE DEPARTMENT OF DEFENSE THAT COMPLETELY OVERLAPS. SO THEY DON'T HAVE A GRANT FROM YOU THAT OVERLAPSE AND WE WANT TO I CAN MAKE SURE WE ARE USING FEDERAL DOLLARS THE BEST WAY POSSIBLE. SO IT'S A VERY COLLABORATIVE PROCESS. WHEN WE ARE DOING ALL OF THIS, FOR EXAMPLE, I HAVE NUMEROUS TRANSLATIONAL GRANTS, I WILL HAVE MANY MEETINGS WITH THE TRANSLATIONAL GROUP ABOUT APPLICATION THAT'S BEEN REVIEWED, OR PRIOR TO REVIEW WE HAVE MANY PHONE CALLS WITH THE APPLICANT, WE HAVE CALLS WITH APPLICANT AS A TEAM TO DISCUSS A SUMMARY STATEMENT RECOMMENDATIONS FOR FUNDING. ADMINISTRATIVE FUNDING AND WE HAVE MANY INTERACTIONS WITH OTHER ICs AS WELL. SO THE NEXT ONE IS INTERACTING WITH ADVOCACY. THIS IS CRITICAL IN OUR ROLE SO WE PLAY A ROLE WITH WEBSITE INFORMATION, SO NINDS HAS A WEBSITE, WE OFTEN ASK ADVOCACY GROUPS TO REVIEW WHAT IS ON OUR WEBSITE TO WORK WITH US TO MAKE SURE IT'S THE MOST UP TO DATE INFORMATION. WE GET THE PATIENT PERSPECTIVE. WITH WORK WITH YOU ON COORDINATING CONFERENCES SO IF YOU ARE DOING A CONFERENCE WE CAN PROVIDE INSIGHT ON WHO WE THINK MIGHT BE A GOOD PERSON TO INVITE THEY WILL INDICATE YOU PROVIDE A LETTER SAYING WE WILL BE FUNDING THAT PATIENT REGISTRY FOR THIS APPLICATION. OR SOMETHING ON THAT LEVEL. WE HAVE PROGRAMS WHERE ADVOCACY GROUPS PICK UP GRANTS THAT MISS THE PAY LINE. THE ABILITY TO FUND APPLICATIONS THAT DID NOT MEET OUR PAY LINE. WE WORK WITH YOU TO IDENTIFY GAPS WITHIN THE RESEARCH. WE AS WHOLE WORKSHOPS AT TIMES. OVERALL AS PROGRAM DIRECTORS WE DEVELOP INITIATIVES. SO AN EXAMPLE WOULD BE BIOMARKERS. WITH ALL THE WORK THAT WE DO, WE REALIZE WE HAVE ALL OF THESE THERAPIES COMING FORWARD BUT WE DIDN'T -- FOR SOME OF THE DISORDERS WE DIDN'T HAVE STRONG BIOMARKERS VALIDATED TO SHOW WHETHER OR NOT A PARTICULAR TREATMENT WAS EFFICACIOUS. SO WHEN WE DO THESE INITIATIVES WE TRY TO PICK THINGS THAT CUT ACROSS ALL DISEASES AS WAS MENTIONED WE HAVE FOUR OR FIVE HUNDRED DISEASES WITHIN NINDS. SO WE TRY TO DO INITIATIVES THAT ANYONE WITHIN THE RESEARCH COMMUNITY OF NEUROLOGIC DISEASE APPLY FOR. ALSO WE HAVE ADMINISTRATIVE ROLES SO WE DO PROGRESS REPORTS, TO MAKE SURE PEOPLE ARE MAKING PROGRESS ON APPLICATIONS, ADMINISTRATIVE SUPPLEMENTS SO SOMEBODY CALLS AND THEIR MINUS 70 FREEZER BROKE DOWN WE CAN PROVIDE EXTRA FUNDS TO MAKE SURE THOSE SAMPLES AREN'T LOSS. DIVERSITY SUPPLEMENTS SO IF SOMEONE HAS A TRAINEE IN THEIR LAB FROM UNDER-REPRESENTED GROUP, THEY CAN PROVIDE FUNDING TO SUPPORT THAT PERSON. THEN WE HAVE COOPERATIVE GRANTS, U GRANTS, MONTHLY PHONE CALLS, MILESTONES WE REVIEW THE MILESTONES ON AN ANNUAL BASIS, THESE ARE THE TYPE OF ACTIVITIES WE HAVE. WE WORK CLOSELY WITH OFFICE OF COMMUNICATIONS AN PUBLIC LIAISONS. ON RECENT PUBLICATIONS WORTH HIGHLIGHTING AND THAT YOU MAY BE SUBMITTING A PRESS RELEASE ON THAT INSTITUTION MAY BE RECEIVING PRESS RELEASE ON AND ON IF WE FUNDED MAYBE THE HEEL INITIATIVE WOULD HAVE A PRESS RELEASE ON FUNDED APPLICATIONS. WE ALSO ARE RESPONSIBLE FOR RESPONDING TO CONGRESSIONAL LANGUAGE. WE ARE NOT ALLOWED TO LOBBY WE WORK WITH OFFICE OF SCIENCE POLICY AND PLANNING. THEY SEND US ON AWOKELY BASIS WHAT'S HAPPENING IN CONGRESS. I HAVE TO SAY BEFORE I HAVE HAD A JOB I DIDN'T KNOW WHAT WAS HAPPENING IN CONGRESS. THEY TELL US WE HAVE LANGUAGE ON THIS, WE NEED TO KNOW WHAT RESEARCH IS HAPPENING HERE. WE HAVE TRANSNINDS ACTIVITIES SO WE WORK TOGETHER A TEAM AND INTERACT ACROSS NIH AS A WHOLE I AM INVOLVED IN THE RARE DISEASE CLINICAL RESEARCH NETWORK RESPONSIBLE FOR FUNDING CLINICAL RESEARCH FOR THINGS LIKE BIOMARKER DISCOVERY AND CLINICAL OUTCOME MEASURE DISCOVERY. THERE'S ALSO BRAIN INITIATIVE AND COMMON FUND. ONE THING I DIDN'T ADD IS WE ALSO INTERACT ACROSS FUNDING FEDERAL AGENCIES. SO WE HAVE A LOT OF INTERACTIONSES WITH THE FDA -- INTERACTIONS WITH THE FA. WE WANT TO KNOW WHAT THEY'RE REQUIRING FOR INDs AND WHAT THEY THINK IS ESSENTIAL LIKE NATURAL HISTORY STUDIES. MANY OF US INTERACT WITH THE DEPARTMENT OF DEFENSE BECAUSE THEY HAVE THEIR OWN RESEARCH ACTIVITIES. WHEN YOU MEET WITH PROGRAM DIRECTORS TOMORROW THESE ARE THE QUESTIONS YOU CAN ASK BUT ENGAGE, ASK THEM ANYTHING YOU WANT THEY ARE THERE TO ANSWER YOUR QUESTIONS AND GIVE INSIGHT ON WHAT WE ARE DOING ON A DAILY BASIS. THANK YOU. [APPLAUSE] >> ANYBODY HAVE A QUICK QUESTION FOR JILL? LOTS OF TIME TO TALK SO I HAVE TWO MORE SLIDES TO ADD TO THE BACK OF JILL'S PRESENTATION. I THINK THIS -- YES. SO THIS IS JILL, IF YOU WANT TO CONTACT HER, THAT'S HER CONTACT INFORMATION. AND THEN I JUST WANT TO ADD THAT YOU'RE GOING TO HAVE TWO FORMAL OPPORTUNITIES TODAY AND TOMORROW, TO ACTUALLY MEET THE PROGRAM DIRECTORS. ONE IS GOING TO BE THIS AFTERNOON FROM 4 TO 5:30 IF YOU LOOK AT YOUR SCHEDULE, THIS IS A POSTER SESSION AND OUR POSTER SESSION THANKS TO THE GENEROUS DONATION OF SOME OF OUR GROUPS WHO ARE HERE, WE'RE GOING TO BE ABLE TO ENJOY SOME TREATS BUT ALSO ENJOY THE OPPORTUNITY TO MEET PROGRAM DIRECTORS AT THE POSTER SESSION. EACH OF THE ADMINISTRATIVE CLUSTERS THAT JILL TALKED ABOUT IN RED HERE, THE CHANNELS SYNAPSES AND CIRCUITS CLUSTER, THIS IS A GROUP OF PROGRAM DIRECTORS AND PROGRAM SPECIALISTS WHO OVERSEE THOSE GRANTS AND NEURAL ENVIRONMENT CLUSTER NEURAL GENETIC CLUSTER, NEURODEGENERATION CLUSTER REPAIR AND PLASTICITY SYSTEMS AND COGNITIVE NEUROSCIENCE CLUSTER. THIS IS THE SCAVENGER HUNT AT THE POSTER SESSION. SEE IF YOU CAN IDENTIFY THOSE POSTERS, IDENTIFY PROGRAM DIRECTORS AND FIGURE OUT WHAT THE TITLES OF THEIR CLUSTERS MEAN AND HOW IT TIES TO THE DIFFERENT AREAS OF RESEARCH THAT ARE COVERED BY THEM. SO I THINK THAT WILL BE A LOT OF FUN. WE ALSO HAVE POSTERS FOR THE DIVISION OF CLINICAL RESEARCH AND DIVISION OF TRANSLATIONAL RESEARCH. SO THOSE PROGRAMS DIRECTORS THAT WORK IN THOSE DIVISIONS HAVE ALSO CREATED POSTERS FOR YOU TO FIND IN YOUR SCAVENGER HUNT. YOU CAN CHECK OUT PROGRAMS AND OPPORTUNITIES THEY HAVE RUN OUT OF THOSE TWO DIVISIONS. THE SECOND CHANCE THE MEET PROGRAM DIRECTORS ARE IN SMALL GROUP MEETINGS. THIS WILL HAPPEN TOMORROW MORNING. WE HAVE A LITTLE OVER AN HOUR. WE WILL PROVIDE INFORMATION ABOUT THE SMALL GROUP MEETINGS BEFORE THEY HAPPEN. SO RIGHT AFTER THE BIG DATA PANEL SESSION WE'LL HAVE AN OPPORTUNITY TO TELL YOU ABOUT WHERE YOU FIND SPECIFIC PROGRAM DIRECTORS, IN THIS TIME FRAME SO YOU CAN HAVE SMALL GROUP MEETINGS AND YOU CAN GET ONE ON ONE AND PUT SOME FACES ON SOME NAMES AND ASK SOME VERY SPECIFIC QUESTIONS. SO THAT WRAPS UP THE SESSION ON NINDS 101 AND WHAT PROGRAM DIRECTORS DO. AND I'M GOING TO TURN IT OVER TO MARGEAUX FOR THE NEXT STEP. THANK YOU. [APPLAUSE] >> I FORGOT TO TELL YOU WHO I AM. I'M MARGEAUX WARREN, ACTING COMMUNICATIONS DIRECTOR FOR NINDS AND OUR OFFICE PUTS THIS MEETING TOGETHER EVERY YEAR. I WOULD LIKE TO INTRODUCE DR. NINA SHORE, M.D. Ph.D., OUR ACTING DIRECTOR TODAY. AND SHE WILL BE TELLING YOU MORE ABOUT THAT. >> BY NOW ALL OF YOU FIGURED OUT I'M NOT WALTER KOROSHETZ. TO GIVE YOU A LITTLE BIT OF AN UPDATE, WALTER -- I KNOW IS INCREDIBLY DISAPPOINTED NOT TO BE HERE WITH YOU TODAY BECAUSE I KNOW THIS IS ONE OF HIS VERY, VERY FAVORITE MEETINGS OF THE YEAR. YOU MAY HAVE ALREADY HEARD HE HAD A BICYCLING ACCIDENT ON SUNDAY, HE UNDERWENT ORTHOPEDIC SURGERY AND IS ALREADY DOING INCREDIBLY WELL, SITTING UP IN HIS CHAIR, SENDING EMAILS TO US, AND IS EXPECTED TO MAKE A COMPLETE RECOVERY BUT NOT AT THE POINT HE'S ABLE TO COME AND TALK WITH YOU TODAY. SO AGAIN, I'M NINA SHORE, I WAS UNTIL VERY SHORT WHILE AGO THE DEPUTY DIRECTOR OF THE NINDS. IT REALLY IS MY PLEASURE BOTH TO WELCOME YOU AND TO GET TO TALK TO YOU A LITTLE BIT TODAY BY WAY OF BACKGROUND I'M A CHILD NEUROLOGIST BY TRAINING. MY Ph.D. IS IN BIOCHEMISTRY AND PHARMACOLOGY. SO THE NOTION OF WORKING BOTH WITH ADVOCACY GROUPS AND WITH PATIENTS AND FAMILIES IS NOT AT ALL FOREIGN TO ME, IT IS REALLY PART OF WHAT THE FABRIC OF WHAT I HAVE DONE THROUGH MY ENTIRE CAREER. MANY OF THE DISEASES ON WHICH YOUR ORGANIZATIONS ARE FOCUSED ARE THE VERY DISEASES THAT MY PATIENTS CAME TO THE CLINIC WITH AND THAT MY LABORATORY FOCUSED ON FOR MANY YEARS. AGAIN, IT'S A SPECIAL PLEASURE, REALLY, FOR ME TO ADDRESS YOU TODAY. SO SOME OF WHAT I'M GOING TO SAY IS A LITTLE BIT REDUNDANT WITH WHAT YOU HEARD IN THE INTRODUCTION. THAT'S BY DESIGN. I THINK REPETITION IN VERY DIFFERENT FORMS OFTEN REINFORCES INFORMATION AND MAY RAISE QUESTIONS IN YOUR MINDS. I WANT TO REITERATE THAT YOU SHOULD FEEL FREE TO ASK QUESTIONS, NOT ONLY DURING THESE SESSIONS BUT DURING THE POSTER SESSION AND THE SMALL GROUP SESSIONS AS WELL. SO THIS YEAR WE HAVE A SLEW OF SESSIONS THAT WERE DRIVEN PARTLY BY WHAT WAS SO SUCCESSFUL LAST YEAR AND PARTLY BY SUGGESTIONS THAT CAME FROM PEOPLE LIKE YOU IN THE AUDIENCE AND FROM OUR WONDERFUL COMMITTEE. I WANT TO TAKE THIS OPPORTUNITY TO THANK THE COMMITTEE MEMBERS WHO TRULY WORKED INCREDIBLY HARD TO PUT THIS TOGETHER. THIS IS ANY OF YOU WHO PUT TOGETHER MEETINGS THAT I KNOW MANY OF YOUR ORGANIZATIONS DO, THERE ARE MANY, MANY, MANY MOVING PARTS IN ALL THESE ENTERPRISES. I'M TOLD WE HAVE 162 PEOPLE AND 52 ORGANIZATIONS REPRESENTED OVER THE NEXT COUPLE OF DAYS. NO MEAN FEAT TO PUT THIS TOGETHER. THANK YOU VERY, VERY MUCH. YOU HAVE ALREADY HEARD NIH 101. I'M GOING TO GIVE YOU THE CLIFF NOTES VERSION OF THIS SO THAT WE CATCH EVERYBODY UP ON THE SAME PAGE. NIH REALLY MUCH MORE OF A CONSORTIUM THAN LIKE A SINGLE ORGANIZATION. IT IS A GROUP OF INSTITUTES AND CENTERS WE CALL THEM ICs, THEY ARE ALL FOCUSED ON SEEKING FUNDAMENTAL KNOWLEDGE ABOUT THE NATURE AND BEHAVIOR OF LIVING SYSTEMS AND APPLYING THAT KNOWLEDGE TO IMPROVING THE LIVES OF PEOPLE SUFFERING WITH THOSE DISEASES. AND ULTIMATELY IN PREVENTING MANY OF THOSE DISEASES. IT HAS A $39.2 BILLION BUDGET IN 2019. THE INTERESTING THING IS THAT 80 TO 85% AT NIH AS A WHOLE AND IN ANY OF THE INSTITUTES OF THAT BUDGET GOES TO FUNDING INDIVIDUALS THAT ARE NOT ON THE NIH CAMPUS. INDIVIDUALS AND ORGANIZATIONS THAT ARE OUT IN THE REAL WORLD WORKING WITH PATIENTS, FAMILIES, LABORATORIES, DAY IN AND DAY OUT. EACH OF THE INSTITUTES HAS DIFFERENT OFTEN ORGAN SYSTEM OR AGE OR DISEASE TYPE FOCUSED MISSION. BECAUSE OF THAT THEY EACH ARE AT LIBERTY TO PRODUCE THEIR OWN FUNDING PRIORITIES, BUDGETS, THEY ARE GIVEN DIFFERENTCATIONS FROM CONGRESS IN ACCORDANCE WITH -- DIFFERENT ALLOCATIONS FROM CONGRESS IN ACCORDANCE WITH NEED AND SIZE AND IMPORTANCE OF THEIR MISSION TO THE UNITED STATES AS A WHOLE. THEY HAVE DIFFERENT WAYS OF DECIDING HOW TO SET FUNDING PRIORITIES I MUST SAY AS AN INVESTIGATOR FOR MANY, MANY, MANY YEARS, I SPENT 20 YEARS AT THE UNIVERSITY OF PITTSBURG AND IN THE DIVISION OF CHILD NEUROLOGY AND THEN THE LAST 12 YEARS BEFORE I CAME HERE, A YEAR AND A HALF AGO AS THE CHAIR OF PEDIATRICS AT THE UNIVERSITY OF ROCHESTER. SO I'M VERY WELL ACQUAINTED WITH WHAT IT'S LIKE ON THE OTHER SIDE OF THIS GRANT RECEIVING COIN. AND IT WAS A SURPRISE TO ME HOW DIFFERENT THE PRIORITIES AND THE WAYS OF SETTING THEM ARE FROM INSTITUTE TO INSTITUTE. WHEN I GOT HERE. THE NINDS HAS A MISSION THAT BY NOW IS FAMILIAR TO MOTION OR ALL OF YOU IN THE ROOM AGAIN TO SEEK FUNDAMENTAL KNOWLEDGE BUT IN OUR CASE TO USE THIS TO IMPROVE THE LIVES OF INDIVIDUALS WITH DISORDERS OF THE BRAIN AND NERVOUS SYSTEM IN GENERAL. WE INVEST AS YOU HAVE HEARD IN BASIC TRANSLATIONAL AND CLINICAL RESEARCH, WE ARE INVESTED AS WELL IN TRAINING THE NEXT GENERATION OF RESEARCHERS, WE ARE NOTHING IF WE DON'T LEAVE A LEGACY FOR FUTURE GENERATIONS. TO SUPPORT THE DEVELOPMENT OF TOOLS THAT SCIENTISTS WILL USE AS THEY DO THEIR RESEARCH, TO COMMUNICATE WITH ALL OF OUR STAKEHOLDERS AND WE SPEND A VERY LARGE FRACTION OF OUR TIME COMMUNICATING WITH BOTH THE LAY AND THE SCIENTIFIC PUBLIC. AND ALWAYS EVALUATING WHAT WE DO IN ASKING IF IT COULD BE BETTER. IN FACT, WE ARE SMACK IN THE MIDDLE OF A STRATEGIC PLANNING PROCESS THAT IS REALLY AIMED AT DOING EXACTLY THAT, TO SAY WHERE ARE WE NOW AND WHERE DO WE WANT TO BE FIVE YEARS FROM NOW. I DON'T HAVE TO TELL THIS AUDIENCE THE CHALLENGES FOR US ARE MANY. YOU HAVE ALREADY HEARD 500 OR SO DISEASES DEPENDING ON HOW YOU DIVIDE THE LANDSCAPE UP. AND EACH IF YOU BELIEF IN THE CONCEPT AS MS OF US DO OF PERSONALIZED MEDICINE, IT NOT ONLY SAYS THAT WE HAVE TO COME UP WITH PERSONALIZED SOLUTIONS BUT IT ALSO SAYS LOUD AND CLEAR THAT A POPULATION THAT HAS A DISEASE CONSISTS OF INDIVIDUALS THAT HAVE THEIR OWN VARIATION ON THAT THEME AND WHAT WORKS FOR ONE PERSON DOESN'T NECESSARILY WORK FOR EVERYONE. BECAUSE THE CHALLENGES ARE VARIED WE INVEST IN THE VERY BEST SCIENCE. IT DOESN'T MATTER TO US WHETHER THE SCIENCE THAT COMES IN IS BASIC TRANSLATIONAL OR CLINICAL, WHETHER IT FITS IN THE DIVISION OF NEUROSCIENCE OR DIVISION OF CLINICAL RESEARCH OR THE DIVISION OF TRANSLATIONAL RESEARCH, THE IDEA IS TO LOOK FOR THE VERY BEST SCIENCE, THE SCIENCE THAT HAS THE APPROPRIATE CONTROLS, THAT ADDRESSES A SIGNIFICANT PROBLEM, THAT STANDS A GOOD CHANCE OF MAKING A DENT IN SOME VERY, VERY MESSY AND DIFFICULT PROBLEMS. WE INVEST ACROSS THE AGE SPECTRUM. MILE WE WORK ON PARKINSON'S, OTHER DEGENERATIVE DISORDERS ASSOCIATED WITH AGING, WE ALSO WORK ON NEURO-DEVELOPMENTAL DISORDERS. AND DISEASES THAT BEGIN BEFORE& THE BEGINNING OF UP PENDENT LIFE. I WILL SAY MY OWN BIAS THOUGH I'M A PEDIATRIC NEUROLOGIST AND DEVELOPMENTAL BIOLOGIST, MY BIAS, I DON'T KNOW IF ANYBODY IN THIS AUDIENCE FEELS LIKE THEY HAVE BEEN STOPPED DEVELOPING BUT I KNOW I HAPPENED SO I DON'T KNOW WHY WE CALL DISEASE WHEN YOU'RE YOUNG DEVELOPMENTAL THEN DISEASE WHEN YOU GET OLDER SENESCENCE, DEGENERATION. I'M NOT DEGENERATING. THIS IS THE OTHER SIDE OF DEVELOPMENT. I WOULDN'T BE SURPRISED IF 10, 15 YEARS WE ARE TALKING ABOUT THE SEEDS THAT BECOME ALZHEIMER'S DISEASE OR PARKINSON DISEASE IN ADULTHOOD BUT THERE UNBEKNOWNST TO US AT THE VERY BEGINNING OF LIFE. SO I THINK THE NOTION THAT THIS SPECTRUM IS VERY BLURRY AND THEY'RE NOT DISCREET ETHIC AND YOU SWITCH FROM DEVELOPMENT TO SENESCENCE AT 18 OR 21, SEEMS LIKE FOREVER AGO, IT DOESN'T MAKE BIOLOGICAL SENSE. WE ARE ALL IN THIS TOGETHER, BECAUSE WE ARE ALL FIGHTING THE SAME FOE. WE SUPPORT HUNDREDS AND HUNDREDS OF DISEASES, IF YOUR PARTICULAR INTEREST IS NOT REPRESENTED HERE IT DIDN'T FIT INTO THE ARRAY THAT MADE THIS BRAIN LINE IMAGE. IF IT IS NERVOUS SYSTEM WE WORK ON IT. THAT IS THE TAKE HOME FOR THE WHOLE COUPLE OF DAYS. WE ALSO SUPPORT TRAINEES AND WE FEEL VERY, VERY STRONGLY THAT THEY NEED TO BE SUPPORTED AT EVERY STEP IN THEIR CAREER. AND THEY NEED TO BE SUPPORTED IN WAYS THAT ENCOURAGE DEVELOPMENT OF DIVERSE WORK FORCE. THE MORE OUR SCIENTIFIC WORK FORCE LOOKS LIKE THE PEOPLE THAT ARE AFLICKED WITH THE DISORDERS WE TREAT, THE BETTER OUR CHANCES OF MAKING A DENT IN THESE PROBLEMS. SO WE ARE VERY MUCH COMMITTED TO TRAINING. WE HAVE GRANT MECHANISMS THAT ARE AIMED SPECIFICALLY AT EARLY STAGE INVESTIGATORS, GRANT MECHANISMSES THAT ARE AIMED AT MID PHASE INVESTIGATORS, GRANT MECHANISMS THAT REWARD PEOPLE THAT HAVE BEEN SUCCESSFUL FOR AN ENTIRE CAREER AND KEEP THEIR ENTERPRISE GOING AND AWARD MECHANISMS THAT ENCOURAGE DIVERSITY IN THE WORK FORCE. WHAT WE ARE HERE ABOUT IS TO PARTNER WITH YOU. THIS IS A TEAM SUPPORT THAT WE ARE ENGAGED IN -- TEAM SPORT, THIS IS NOT SOMETHING A SINGLE INDIVIDUAL GOES HOME AND DOES IN HIS GARAGE. THIS IS SOMETHING THAT REQUIRES NETWORKING, THAT REQUIRES INPUT, THAT REQUIRES INVOLVEMENT OF PEOPLE WITH MANY DIFFERENT SKILL SETS AND WAYS OF LOOKING AT THE UNIVERSE. SO I'M GOING TO TALK BRIEFLY ABOUT WHY THESE SYNERGIES ARE IMPORTANT. I SAT DOWN FOR A TALK I GAVE RECENTLY AND ASKED MYSELF WHAT IS THE EVIDENCE OF THE IMPORTANCE OF SYNERGY IN THIS ENTERPRISE? AND I CAME UP WITH A LIST. I WILL TALK A LITTLE BIT ABOUT EACH OF THESE, OF SOME EXAMPLES OF SITUATIONS IN WHICH THE NIH AMONG OTHER ORGANIZATIONS MADE A DENT IN THE DISEASE OR IN OUR UNDERSTANDING OF A DISEASE. BUT COULD NOT HAVE DONE THAT WITHOUT THE ENGAGEMENT OF ADVOCACY GROUPS, OF ACADEMIC INSTITUTIONS, AND INDUSTRY AS WELL. I ASK MYSELF WHY IS IT THAT FOR SUCH A LONG TIME THIS HAS BEEN CRITICALLY IMPORTANT. IS IT JUST THE SHEER NUMBER OF PEOPLE IN WHICH CASE YOU COULD DO IT IN ONE OF THOSE AGENCIES IN JUST JUST ACCRUE ENOUGH INVESTIGATORS TO SIT IN A ROOM TOGETHER THAT WOULDN'T WORK EVEN CLOSE TO AS WELL. I THINK THE REASON FOR THAT IS DEPICTED IN THIS TABLE. THIS IS NOT MEANT FOR YOU TO RAY EVERY WORD IN IT. THE POINT OF THIS TABLE IS TO ILLUSTRATE HOW EACH FACTION, ACADEMIA, INDUSTRY, THE NON-PROFIT SECTOR, AND GOVERNMENT, BRING SOMETHING COMPLETELY DIFFERENT TO THE SAME TABLE. SO THAT IF YOU TALK FOR EXAMPLE ABOUT WHAT DOES IT MEAN IF YOU GET A NEGATIVE RESULT IN A STUDY? IN ACADEMIA, HAVING BEEN AN ACADEMICIAN FOR MANY YEARS, A NEGATIVE RESULT WAS NOT A BAD THING. IN MY LABORATORY. I EXPECTED ONE THING AND I GOT SOMETHING ELSE. I DID THE EXPERIMENT BECAUSE I EXPECTED A POSITIVE RESULT AND IT CAME OUT NEGATIVE. TO ME AS AN ACADEMICIAN, THAT SAID THAT THE WAY I UNDERSTOOD THAT SYSTEM OR THOUGHT THAT I UNDERSTOOD THAT SYSTEM, WAS NOT CORRECT. AND MAYBE IN UNDERSTANDING THE REASONS THE RESULT CAME OUT NEGATIVE WHEN I EXPECTED IT TO BE POSITIVE ALLOWINGS ME TO UNDERSTAND THAT BIOLOGICAL SYSTEM BETTER. SO IT REALLY IS THE IMPETUS FOR MECHANISTIC STUDIES. IN INDUSTRY, OFTEN A NEGATIVE RESULT IS THE REASON TO DROP THAT PROJECT AND TAKE A NEW APPROACH. IT'S NOT GOING TO RESULT IN A MARKETABLE PRODUCT. IN THE NON-PROFIT SECTOR FOR THE PEOPLE THAT YOU SERVE, FOR THE POPULATIONS AND FAMILIES THAT ARE DEALING WITH THE DISORDERS THAT YOU FOCUS ON, IT CAN MEAN DISAPPOINTMENT BUT IT CAN ALSO MEAN REDIRECTION. IT CAN MEAN OUR NON-PROFIT INVESTED IN THIS STRATEGY, IT'S A DISAPPOINTMENT IT'S NOT PANNING OUT BUT AN OPPORTUNITY TO REDIRECT AND FOCUS IN A DIFFERENT WAY. AND FOR GOVERNMENT, FOR US AT THE NIH, IT MEANS BOTH MECHANISTIC STUDIES IN OUR INTRAMURAL GROUP THAT FOCUSES ON BASIC RESEARCH, AND IT MEANS REDIRECTION IN THE PEOPLE THAT WE FUND. IN THE OUTSIDE. EACH SECTOR BRINGS SOMETHING VERY DIFFERENT BECAUSE WE LOOK VERY DIFFERENTLY UPON THE KINDS OF STUDIES WE DO. ADVOCACY IS YOUR PRIMARY MISSION. ACADEMIA, IT'S A SECONDARY MISSION. WE ALWAYS SAID IT WAS THE FORTH LEG ON THE THREE LEGGED STOOL. MANY ACADEMIC INSTITUTIONS SITS SMACK DAB IN THE MIDDLE OF COMMUNITIES THAT ARE TROUBLED AND CAN USE HELP OF ACADEMIC ENGINE. FOR INDUSTRY ADVOCACY IS NOT OFTEN A PRIMARY MISSION. I THINK INDUSTRY IS GETTING MORE INTERESTED AND BETTER AT DOING ADVOCACY OR WORKING WITH ADVOCACY GROUPS TO GET A SENSE OF WHAT IT IS THEY OUGHT TO BE ADDRESSING. BUT IT ISN'T A PRIMARY MISSION FOR THEM. FOR GOVERNMENT WE ARE NOT ALLOWED AS YOU HEARD BY FEDERAL LAW, TO BE ADVOCATES IN TRADITIONAL WAY OF LOBBYING CONGRESS BUT THROUGH YOU AND THROUGH EMPOWERING YOU, AND ARMING BUT YOU WITH THE INFORMATION AND BACKGROUND THAT YOU NEED, YOU ARE THE ADVOCATES FOR WHAT IT IS WE THINK IS BEST FOR HEALTH AND YOU ARE OUR INFORMANTS IN TERMS OF WHAT IT IS WE WORK ON. THIS IS AN EXAMPLE WHY THIS PARTNERSHIP WORKS SO WELL. PROBABLY ONE OF THE MOST RECENT SPECTACULAR IMPACTS OF THIS PARTNERSHIP HAS BEEN THE CHANGE IN THE LANDSCAPE FOR SPINAL MUSCULAR ATROPHY. AS A CHILD NEUROLOGIST, NOTHING TO ME IS MORE MIRACULOUS THAN TO SEE POTENTIAL TREATMENT AND MAYBE CURE OF SMA. THIS TO ME, I HAD THE RIVETING HORRIBLE EXPERIENCE HAVING TO TELL MANY FAMILIES WHAT THE PROGNOSIS WAS OFTEN FOR THEIR VERY, VERY YOUNG INFANT. TO REALLY HAVE EVEN THE PROMISE THAT WE MAY NOT HAVE TO TELL A FAMILY THOSE AWFUL THING ANY MORE IS TRULY MIRACULOUS. YOU CAN SEE ON THIS TIME LINE THAT THE BLUE DOTS HERE WHERE NIH WAS INVOLVED BUT BEFORE NIH CAME ADVOCACY GROUPS AND PATIENT GROUPS THAT FUNDED VERY, VERY EARLY STUDIES BEFORE STUDY SECTION AND CRITICAL REVIEW PROCESS, NIH CAME THROUGH LATER AND INDUSTRY HAS PICKED UP THIS IS SO POWERFUL FOR PATIENT AND FAMILIES. OUR EPILEPSY THERAPY SCREENING PROGRAM YOU SEE ARROWS WE MADE A MAJOR DENT WITH INDUSTRY IN DEVELOPING THE USE OF SOME ANTI-CONVULSANTS FOR EPILEPSY AND SEIZURE THERE ARE DOTS WE PLAYED A ROLE BUT A SECONDARY ROLE TO FOUNDATIONS AND TO INDUSTRY IN THIS PROCESS. ARE FAMILIAR WITH THE AMP PROGRAM FOR PARKINSON'S AND ALZHEIMER'S DISEASE, YOU CAN SEE IN THE MONTAGE ON THE RIGHT SIDE OF THE SCREEN THE FACT THAT MANY ADVOCACY GROUPS, INDUSTRY PART INERS, OTHER FEDERAL AGENCIES INVOLVE IN THIS PROCESS. ONE OF MOST RECENT EFFORTS IS THE HEEL INITIATIVE, THE HELPING TO END ADDICTION OVER THE LONG TERM INITIATIVE. AND IT INVOLVES TWO ARMS AIMED AT ADDICTION ITSELF AND TRYING TO PREVENT AND TREAT ADDICTION THE OTHER INVOLVED IN TRYING TO COME UP WITH NON-ADDICTIVE ALTERNATIVES TO TREATMENT OF PAIN AND I KNOW MANY DISORDERS WITH WHICH YOU FOCUS INVOLVE PAIN IN ONE FORM OR ANOTHER AND OFTEN CHRONIC PAIN WHICH IS SO DIFFICULT TO TREAT. THIS IS A PARTNERSHIP WITHIN NIH LARGELY BETWEEN NINDS AND NIDA, THE DRUG AWE BEUS INSTITUTE BUT ALSO INVOLVES ADVOCACY AND INDUSTRY PARTNERS AND THE BRAIN INITIATIVE. REALLY A SPECTACULAR DEVELOPMENT OF TECHNOLOGIES THAT WILL BOTH TELL US MORE FUNCTION OF THE BRAIN AND ALLOW US TO UNDERSTAND WHY IT GOES AWRY IN DISEASE. YOU CAN SEE IN THIS BOTTOM OF THE MONTAGE, SEVERAL I YENISEIS, A FEW FOUNDATIONS AND ULTIMATELY INDUSTRY BECAUSE OF DEVICE DEVELOPMENT IN THIS SPACE ARE INVOLVED IN THIS INITIATIVE. AGAIN, A VERY, VERY POWERFUL PARTNERSHIP, GROW HEARD A LITTLE BIT FROM JILL ABOUT THE OFFICE OF RARE DISEASE RESEARCH WITHIN NCATS, OUR PARTNER INSTITUTE. MANY OF YOU DEAL WITH RARE DISEASES AND WITH SMALL POPULATIONS THAT HAVE DEVASTATING DISORDERS. THIS IS AN EFFORT TRANS-NIH TO ACTUALLY MAKE A DENT IN THAT PROBLEM AND TO LEARN FROM THAT, I CANNOT TELL YOU HOW MUCH ABOUT COMMON DISORDERS IS LEARNED THROUGH THE UNDERSTANDING OF MANY OF THESE RARE DISORDERS. IT IS NOT AN ACE IS ISOLATED ENTERPRISE TO STUDY A GROUP WITH A RARE DISORDER, IT'S AN ENTERPRISE THAT INFORMS EVERYTHING WE KNOW ABOUT THE FUNCTION OF NERVOUS SYSTEM. WHAT ARE WE DOING IN THE FUTURE? THIS IS SOMETHING THAT'S VERY EXCITING FOR ME TO TALK ABOUT. NOT ONLY BECAUSE IT'S THE FUTURE BUT BECAUSE MUCH OF WHAT I'M GOING TO SAY GREW OUT OF THIS PARTNERSHIP AND MEETINGS SMALL GROUP DISCUSSION SECTION. THE BEST EXAMPLE OF THAT IS OUR NEW REQUEST FOR APPLICATIONS ON COMPARATIVE EFFECTIVENESS RESEARCH. MANY OF YOU AND MANY OF YOUR COLLEAGUES OUT IN THE COMMUNITIES CAME TO US AND SAID, YOU KNOW, IT'S GREAT YOU DO THESE CLINICAL RESEARCH STUDIES AND YOU DO THEM IN RAREFIED ATMOSPHERES, RESEARCH CLINICS. YOU DO THEM IN HOSPITAL SETTINGS. BUT OUR PATIENTS, OUR FAMILIES, THEY ARE OUT IN THE REAL WORLD. THEY HAVE PROBLEMS THAT YOU CAN'T REPLICATE IN YOUR RESEARCH ENVIRONMENT. IN IN ADDITION TO WHICH FOR MANY THERAPIES THERE'S A STANDARD OF CARE RIGHT NOW WHICH MAY BE ISN'T AS GOOD AS IT CAN BE BUT YOU CAN'T DO A REAL CONTROL ETHICALLY IN THAT POPULATION. YOU CAN COMPARE STANDARD OF CARE WHICH IS TREATMENT, NOT PLACEBO, NOT CONTROL, NOT NO TREATMENT, IT'S A TREATMENT YOU CAN COMPARE CURRENT TREATMENT WITH FUTURE PROPOSED TREATMENT. THOSE KINDS OF STUDIES ARE CALLED COMPARATIVE EFFECTIVENESS STUDIES. IT WAS PEOPLE LIKE YOU THAT CAME TO US AND SAID UNLESS YOU ADD THIS TO YOUR PORTFOLIO, YOU ARE NOT ADDRESSING THE EVERY DAY COMMON IN THE FIELD REAL PEOPLE PROBLEMS THAT OUR PATIENTS FACE. SO WE ARE JUST NOW STARTING TO GET IN THE FIRST APPLICTIONS FOR LOOKING IN A REAL WORLD WAY, AT NEW THERAPIES, NOT RELATIVE TO THE NULL HYPOTHESIS WHICH IS WHAT WE DO IN SCIENCE MOST OF THE TIME. BUT RELATIVE TO WHAT PATIENTS REALLY DO NOW IN THE REAL WORLD. AND SO THIS IS AN ADVANCE THAT GREW OUT OF MEETINGS LIKE THIS. YOU ARE GOING TO HEAR TOMORROW ABOUT THE ALL OF US INITIATIVE. THE ALL OF US INITIATIVE PARTICULARLY FOR RARE DISORDERS IS AN INTERESTING, INTERESTING OPPORTUNITY. IT IS THE EFFORT OF NIH TO RECRUIT A MILLION FAMILIES THAT ARE A CROSS SECTION OF THE POPULATION OF THE UNITED STATES AND TO ACTUALLY EXPAND THAT THEN ULTIMATELY BEYOND THE UNITED STATES. TO ACTUALLY CAPTURE SORT OF A SNAP SHOT IN VARIOUS POINTS OF TIME OF THE HEALTH AND THE PRACTICES AND THE REAL WORLD EXPERIENCES OF THESE POPULATIONS. AND TO CORRELATE THAT WITH THINGS LIKE GENOTYPING AND BLOOD CHEMISTRY AND TISSUE COMPOSITION WHERE SURGERY IS INVOLVED IN THEIR HEALTH COURSE, SO FORTH. YOU CAN READ ABOUT IT AT THIS WEBSITE BUT IT IS TRULY A MAMMOTH INFORMATION GATHERING EXERCISE. YOU CAN BE SURE IN THAT POPULATION OF A MILLION ARE GOING TO BE REPRESENTED ALL OF THE DISEASES FOR WHICH ADVOCACY GROUPS ARE SITTING IN THIS ROOM NOW. I WOULD BE REMISS IF I DIDN'T TELL YOU NEW THINGS OR PEOPLE IN CONGRESS AND THAT REPRESENTS AN OPPORTUNITY FOR US AS WELL. WE HAVE MANY LONG STANDING ADVOCATES, WE HAVE NEW FACES IN CONGRESS THAT REPRESENT A MUCH MORE DIVERSE THAN WE POPULATION THAN WE HAVE EVER HAD BEFORE. WE ALSO HAVE SOME PEOPLE THAT ARE LONG STANDING CONGRESS PEOPLE BUT IN NEW ROLES THAT WILL IMPACT IN NEW I AM SURE -- YOU I AM SURE WILL GET TO KNOW THEM AS YOUR HONOR ORGANIZATIONS GO OUT AND -- YOUR ORGANIZATIONS TALK TO HE WILL THIS ON CAPITOL HILL. IMPORTANT RESOURCES, WE AS A RESEARCH COMMUNITY OFTEN PUT THE RESOURCES UP THAT INVOLVE GETTING INFORMATION TO INVESTIGATORS, HOW DO WE GET THEM TO UNDERSTAND WHAT WE DO, HOW WE DO IT, WHAT THEY NEED TO DO TO TAP INTO IT. BUT THERE ARE SOME NEW RESOURCES FOR THE LAY COMMUNITY. THE FIRST URL, THE BRAIN LIFE URL IS ONE WITH WHICH I SUSPECT MANY OF YOU ARE FAMILIAR. IT REALLY IS ONE STOP SHOPPING FOR INFORMATION ON DISEASES THAT'S WRITTEN IN LAY FRIENDLY LANGUAGE. INFORMATION ON TWITTER, ON FACEBOOK, DR. KOROSHETZ IS ON THEM ALL U.S. JUST BOGGLES MY MIND HE TWEETS WITH REGULARITY AND HE'S PROBABLY DOING THAT AS WE SPEAK. AND THERE IS A NEW ONE I'M GOING TO DO A SHAMELESS PERSONAL PLUG. THERE IS NOW A DR. KOROSHETZ HAS LONG HAD A BLOG FOR THE SCIENTIFIC COMMUNITY. WHERE HE PROFILES VARIOUS ARTICLES THAT HAVE APPEARED IN THE PRESS THAT WERE FUNDED BY NIH OR NEW INITIATIVES. I DECIDED WHEN I GOT HERE YEAR AND A HALF AGO THIS SHOULD BE ANALOG OF THIS FOR THE LAY COMMUNITY, WE SHOULD ALLOW THE PUBLIC TO COME IN A BETTER WAY THAN BEFORE. I'M NINA SHORE, THIS IS THE SHORELINE. I DID NOT MAKE THAT NAME UP. WE HAVE COME OUT IN THE SECOND COLUMN AND FEEL FREE TO ENCOURAGE YOUR CONSTITUENCIES TO TAKE A LOOK AT IT. THIS IS HOW TO GET IN TOUCH WITH ME. I PUT DR. KOROSHETZ' TWITTER HANDLE DOWN THERE AS WELL. I DO NOT TWEET. I DID WHEN I HEADED GALISANO CHILDREN'S HOSPITAL ROCHESTER BUT THAT WAS ANOTHER STORY. I'M HAPPY TO HANG AROUND FOR THE REST OF THE TWO DAYS AND ANSWER QUESTIONS AS THEY COME UP. I THANK YOU AGAIN FOR BEING HERE WITH US AND BEING OUR PARTNERS. [APPLAUSE] >> OKAY. >> WE WILL NOW HAVE A SESSION ON CELL THERAPY THAT INVOLVES A PANEL. I WILL JUST INTRODUCE THE LEADERS THE MODERATORS OF THIS ENTERPRISE. YOU SEE THEM IN FRONT OF YOU. CYNTHIA OVIATE AND TIMOTHY LEVOTE. SHE'S A SCIENCE CARED COORDINATOR FOR THE, AT CHILDREN'S PROJECT, A NON-PROFIT ORGANIZATION THAT FUNDS BIOMEDICAL RESEARCH THAT'S AIMED AT FINDING THERAPIES AND A CURE FOR ATAXIA TL INJECT ASIA. HER PRIORITIES HAVE INCLUDED ACCELERATING INFORMATION OR GUIDANCE ON AT RESEARCH. ENCOURAGING NEW INVESTIGATORS TO LOOK AT OUTCOMES IN CLINICAL TRIALS. DR. LEVOTE IS A PROGRAM DIRECTOR HERE AT NINDS. IN THE DIVISION OF NEUROSCIENCE, HIS PORTFOLIO INCLUDES BASIC TRANSLATIONAL RESEARCH IN NEUROGENESIS, NEURAL STEM CELLS, HUMAN BRAIN ORGANOIDS. HE SERVED ON SEVERAL COMMITTEES AND INITIATIVES INCLUDING THE REGENERATIVE MEDICINE INNOVATION PROJECT THE TISSUE CHIP PROGRAM AND SOMATOCELL GENOME EDITING PROGRAM CUTTING EDGE INITIATIVES OF THE NIH THAT TRANSCEND VARIOUS INSTITUTES. HE RECEIVED HIS Ph.D. IN NEUROSCIENCE FROM THE UNIVERSITY OF WISCONSIN MADISON, HE DEVELOPED A MODEL OF NEURAL DEVELOPMENT USING EMBRYONIC STEM CELLS. PLEASE WELCOME OUR MODERATORS. >> THANK YOU. THE FIRST THING I WANT TO DO IS THANK YOU. I WANT TO THANK DR. KOROSHETZ, WALLER, STAFF FOR ORGANIZING THIS WONDERFUL FORUM, THANK YOU FOR BRINGING THIS TOGETHER. WE HAVE A GREAT PANEL TODAY. I THINK FOR THIS FIRST SESSION ON CELL THERAPY. BUT WE ONLY HAVE ONE HOUR. SO WE ASKED EACH PANELIST TO SPEAK FOR FIVE TO EIGHT MINUTES THEN I WILL ASK THAT YOU HOLE YOUR QUESTIONS OR WRITE YOUR QUESTIONS DOWN TO THE END WE CAN HAVE LARGER QUESTION AN ANSWER DISCUSSION SESSION. WE WILL LET THEM GO PRESENT FIRST. TO KICK OFF THE SESSION I WILL HAND IT OVER TO DR. LEVOTE WHO WILL DO A LITTLE MORE INTRODUCTION FOR THIS CELL THERAPY SESSION. >> HELLO, AGAIN. JUST TO REITERATE WHAT NINA SAID, I'M PROGRAM DIRECTOR AT NINDS AND MY PORTFOLIO COVERS STEM CELL RESEARCH. I THOUGHT I WOULD PROVIDE A LITTLE PUBLIC SERVICE ANNOUNCEMENT FIRST. AS WE HAVE HEARD ABOUT OUR EXCELLENT PANEL TODAY, THIS IS THE FIRST SLIDE IS IN STARK CONTRAST TO EFFORTS AND DEDICATION THAT THEY HAVE BROUGHT TO STEM CELL RESEARCH AND DEVELOPING THERAPIES FOR PATIENTS. THAT IS WHAT'S COVERED IN POPULAR PRINT RECENTLY AND THESE THREE NEW YORK TIMES HEADLINES WITHIN THE LAST MONTH, A PLETHORA OF EXAMPLES COVERING THIS TOPIC OF ROGUE AND DUBIOUS STEM CELL THERAPY CLINICS POPPING UP I CROSS THE NATION. TAKING ADVANTAGE OF PATIENTS SOMETIMES IN DESPERATE STRAIGHTS LOOKING FOR TREATMENTS. PROVIDING TREATMENTS UNPROVEN AND SOMETIMES DANGEROUS. THIS WAS A GOOD OPPORTUNITY FOR THIS AUDIENCE TO BE REMINDEDD OF THE DIFFERENCE THAT WORK THE NIH AND NINDS IS SUPPORTING AND WHAT YOU ARE READENING THE PRESS. SO IN CONTRAST, WE ARE GOING TO HEAR FROM FOUR SPEAKERS TODAY. ONE THING I WANT TO HIGHLIGHT IS THAT NOT ALL STEM CELLS ARE EQUIVALENT. WE WILL HEAR EXAMPLES OF USING VARIOUS TYPES OF STEM CELLS IN VARIOUS METHODS AND REMIND EVERYBODY THERE'S LOTS OF TOOLS IN THE STEM CELL THERAPY BOX THAT PEOPLE CAN TAKE ADVANTAGE OF SO DR. STUDER WILL DESCRIBE TREATMENTS HE'S DEVELOPING USING THE MOST PLURIPOTENT CELLS, EMBRYONIC STEM CELLS OR INDUCED PLURIPOTENT STEM CELLS WHICH REPLACEMENT CELL THERAPIES. ANOTHER EXAMPLE IS SOMETHING THAT IS A LITTLE LESS POTENT BUT CAN BE UTILIZED FOR EFFECTIVE TREATMENT AS WELL. FETALLY DERIVED STEM CELLS. DR. SPENTER WILL PROVIDE AN EXAMPLE OF THIS, HE'S IN THE NECESSARILY TRYING TO REPLACE CELLS BUT ENGENIUSLY COAXED STEM CELLS TO PROVIDE NEUROTROPIC FACTORS EXPRESSED BY STEM CELLS TO CELLS IN DISEASE STATES. TRYING TO REVIVE THEM OR IMPROVE THEIR ENVIRONMENT THEY ARE IN TO PROVIDE RECOVERY FOR PATIENTS. AND THEN -- WILL DESCRIBE A THERAPY HE'S DEVELOPING. AGAIN HE'S NOT TRYING TO REPLACE THE CELLS THAT ARE LOST AFTER STROKE, BUT HE'S TRYING TO PROVIDE NEUROTROPIC FACTORS AND IMMUNE MODULATORY FACTORS TO SITE OF INJURY TO HEALTH STRUCK PATIENTS. FINALLY FOR SOMETHING A LITTLE DIFFERENT, -- FROM OUR INTRAMURAL PROGRAM WILL DESCRIBE AN IMMUNOMODULATORY -- IMMUNOTHERAPY SHE'S DEVELOPED FOR A DEADLY BRAIN INFECTION. JUST A REMINDER NOT ALL THEM IS CELLS ARE THE SAME AND CAN BE USED IN LOTS OF DIFFERENT WAYS. I GUESS THE LAST THING THAT THE PANEL WOULD LIKE TO REMIND EVERYBODY, THIS IS LONG AND HARD WORK, THIS IS -- THEY HAVE DEDICATED THEIR LIVES, THESE DEVELOPING THESE TREATMENTS TAKES DECADES AND THE HIGHLIGHT VARIOUS MILESTONES OR HALLMARKS IN DEVELOPMENT OF THESE TREATMENTS ALONG DEVELOP MENTAL PATHWAY, AND MODERATOR TEMPER ENTHUSIASM AND HOPE, KNOW THERE IS HOPE USING THESE THERAPIES BUT IT TAKES TIME. BACK TO CYNTHIA NOW. >> THANK YOU. AS HE MENTIONED WE ARE FIRST GOING TO HEAR FROM DR. LOREN STUDER. THE DIRECT TO OF SLOAN-KETTERING CENTER FOR CANCER BIOLOGY, HE LED EARLY STUDIES ON GENETICALLY MODIFIED HUMAN EMBRYONIC STEM CELLS AND HIS LABORATORY WAS FIRST TO DEMONSTRATE THERAPEUTIC CLONENING A MOUSE MODEL OF A CENTRAL NERVOUS SYSTEM DISORDER AND HE WILL TALK TO US AS ADS MENTIONED POWER OF INDUCED PLURIPOTENT STEM CELLS. >> REAL PLEASURE TO BE HERE AND HOPEFULLY HAVE A DISCUSSION WITH YOU WHERE WE ARE WITH IMPLEMENTING CELL THERAPY. AS MENTIONED BEFORE PLURIPOTENT CELLS ARE POWERFUL BUT MAYBE STILL AT THE BEGINNING OF CLINICAL TRANSLATION. JUST A LITTLE FLAVOR HOW WE ARE TRYING TO CURRENTLY DO THAT IN THE CONTEXT OF PARKINSON'S DISEASE. -- NINDS OBVIOUSLY WHAT WE DID WERE TO LAST 10 TO 15 YEARS IS BUILDING THESE TREES OF DIFFERENCES, PLURIPOTENT STEM CELLS AT THE VERY BOTTOM AND LIKE A TREE THEY CAN GIVE RISE TO MANY LEAVES AND BRANCHES AND THOSE CELL TYPES ARE NOW VERY, VERY POWERFUL TOOLS YOU CAN LITERALLY MAKE THEM IN A DISH, YOU CAN MAKE THEM IN MILLIONS AND YOU CAN USE THEM TO STUDY A DISEASE OR IN SOME CASES MAYBE TO TREAT A DISEASE. THAT'S A PARTICULAR POWER OF THIS TECHNOLOGY NEARLY -- TECHNOLOGY THAT CAN INDUSTRIALIZE IN THE FUTURE IF U WHERE KNOW HOW TO DO IT. AND YOU HAVE TO UNDERSTAND DEVELOPMENTAL BIOLOGY MIND IT TO MAKE CELLS BEHAVE, IF YOU DON'T GIVE TOO MANY INSTRUCTIONS IT MIGHT MAKE THOSE CELLS BUT ALL AT THE SAME TIME. YOU GET KARYOTIC TISSUE, THE CHALLENGE IS HOW TO DO IT SYSTEMATIC ACCESS TO PRECISE CELL TYPES. DOPAMINE CELL THAT SITS DEEP IN THE BRAIN, AND ONLY HALF A MILLION OF THOSE CELLS ON EITHER SIDE OF YOUR BRAIN, SO RARE CELL TYPE. SYMPTOMS OF PARKINSON DISEASE SO THEREFORE MANY YEARS PEOPLE TRIED TO GET REPLACEMENT CELL TYPE, NOT SO MANUFACTURE TO PRODUCE, CAN YOU MAKE NEW ONES? SPARING THE DETAILS OVER THE DECADES BUT MOSTLY THAT SPECIFIC TO PLACE SPECIFIC DOPAMINENERGIC CELLS PLURIPOTENT STEM CELLS MOST POWERFUL EMBRYONIC OR INDUCED PLURIPOTENT STEM CELL PATIENT DIRECTOR. IT TOOK US NEARLY A DECADE TO FIGURE OUT HOW TO MAKE THOSE IN A DISH, NOT ONLY THEY LOOK LIKE DOPAMINE CELLS BUT FUNCTION IN A MOUSE IN A RAT OR IN A MONKEY MODEL OF DISEASE. WHAT WE MEAN BY THAT IS BEHAVIORAL IMPROVEMENT OF THE MOTOR SYSTEMS MIMIC THAT DISEASE. THIS IS CASE WE SEEM TO UNDERSTAND HOW DO CELLS WORK BECAUSE YOU CAN PUT CELLS IN THE BRAIN, THE ANIMAL STARTS IMPROVING, USE THOSE COOL TECHNIQUES SUPPORTED BY NINDS TO SHUT OFF ACTIVITY OF THE NERVE CELLS, THE GRAFTED CELLS ONLY BUT YOU SEE THE BENEFIT THE CELLS ARE GOES AWAY. SO WHAT THAT MEANS IS ACTUALLY THE CELLS HAVE TO INTEGRATE INTO THE BRAIN, ACTIVE TO FUNCTION. WE HAVE TO HAVE BASIC UNDERSTANDING HOW THAT WORKS BUT THE NEXT FIVE OR TEN YEARS YOU MAKE AN ACTUAL PRODUCT LIKE A DRUG PRODUCT SO WE HAVE NOW MANUFACTURED 10 BILLION CELLS, ABOUT 500,000 IN YOUR BRAIN, TEN BILLIONS THOSE AND CORRESPOND TO # THOUSAND HUMAN DOSES. WE PI GURRED HOW WE CAN CRYOPRESERVE THEM AND CHARACTERIZE TO GET ALWAYS CONSISTENTLY THE SAME CELLS AND DOING THAT AGAIN IN A CLEAN ROOM YOU HAVE TO HAVE APPROPRIATE SAFETY AND CLEANLINESS TO MAKE A DRUG LIKE PRODUCT. I DON'T HAVE TIME TO GO INTO MUCH DEEPNESS OF DETAIL BUT THE TIME LINES THESE ARE NOT QUICK STUDIES. TOOK US TEN YEARS TO GET THE NATURE PAPER TO FIGURE HOW TO MAKE THE RIGHT CELLS. NEARLY TEN YEARS OUT AND YOU JUST ABOUT GETTING TO THE STAGE OF HOPEFULLY THIS YEAR STARTING OFF FIRST PATIENT. AS YOU CAN SEE THERE ARE MANY STEPS ON THE ROAD EARLY FUNDING PROBABILITY THE FIRST TEN YEARS TO PART OF ANYONE AND LUCKY THAT -- NINDS AND STATE OF NEW YORK FUNDED THIS BATTERY OF TESTS WE NEED MONEY TO SHOW THAT WE CAN MAKE THEM DO DRUG LIKE PRODUCT. THEN ACTUALLY GET PARTNERSHIP AS A COMPANY, IN THIS CASE -- STARTED AT THE TIME. WHICH ALSO MY DISCLAIMER ACTUALLY CO-FOUNDED THIS COMPANY AND HAVE INTERESTING IN THIS COMPANY TO SUCCEED BUT PARTICULAR INTEREST IN HAVING ONE OF THE FIRST EXAMPLE, OF A PLURIPOTENT BASED NERVE CELL TO GO INTO THE BRAIN AND TO FUNCTION IN THE FUTURE. JUST NOW AT THE STAGE SUBMITTED OUR DOCUMENT TO THE FDA. IF EVERYTHING LOOKS GOOD THEY SHOULD KNOW SEPTEMBER OR AUGUST TO FIRST FIRST OF TEN PATIENTS WHAT IS NEXT YEAR. EXCITING NOW HAVING GONE THROUGH THAT LENGTHY PROCESS BUT LEARNED A LOT, AND COMING BACK TO THIS TREE, WE HOPE THAT IN THE FUTURE, WE CAN MAYBE MAYBE MAKE STEPS FASTER. YOU ALREADY HAVE ACCESS TO MANY CELLS AND WE LEARNED THOSE STEPS BUT IT'S CLEARLY DELIBERATE PROCESS TO ULTIMATELY GET THERE AND TEST FULL POTENTIAL OF THOSE CELLS. LET ME JUST PUT IN THE PEOPLE OF THE FUNDING ORGANIZATIONS THAT SUPPORTED THIS WORK. [APPLAUSE] >> THANK YOU DR. STUDER, NOW WE'LL HEAR FROM DR. WEXLER IN THE FIELD OF VASCULAR NEUROLOGY, HE'S DONE CLINICAL OUTCOMES, HIS PIVOTAL STUDY ON STROKE TREATMENT AND PREVENTION IS NEUROPROTECTIVE AGENTS ADS WELL AS STEM CELL THERAPIES AND HE WILL TALK WITH US ABOUT THE ADMINISTRATION, P THE BENEFITS OF CELL THERAPY FOR STROKE. >> GOOD AFTERNOON, EVERYONE. THANK YOU FOR INCLUDING ME IN THIS SESSION, HAPPY TO BE HER TO TELL YOU A LITTLE BIT OF WHAT WE HAVE BEEN DOING WITH STEM CELL THERAPY FOR STROKE. I'M A VASCULAR NEUROLOGIST, I HAVE BEEN INVOLVED WITH VARIOUS TYPES OF STROKE THERAPY FOR 30 YEARS. OVER THAT PERIOD OF TIME WE HAVE MADE REALLY GREAT ADVANCES IN TERMS OF PREVENTION OF STROKE AND EVEN MORE RECENTLY IN TERMS OF ACUTE THERAPY INTERVENING STROKE TO PREVENT DAMAGE THAT WOULD HAVE OCCURRED, THE AREA WE HAVE BEEN SOMEWHAT DEFICIENT IS IN RECOVERY PART SO ONCE SOMEONE HAS A STROKE AND THEY ARE LEFT WITH SIGNIFICANT NEUROLOGICAL DEFICITS WE HAVE LITTLE TO OFFER THEM. AS SOME OF YOU MAY KNOW STROKE IS FAIRLY COMMON, THERE'S 800,000 NEW STROKES EVER YEAR IN THE UNITED STATES. ALMOST HALF ARE LEFT WITH SOME DEGREE OF NEUROLOGICAL DEFICIT. ANYTHING WE CAN DO TO IMPROVE THAT SITUATION AND MAKE PEOPLE BETTER AND FUNCTION BETTER, MONTHS AND SOMETIMES YEARS AFTER THE STROKE WOULD CERTAINLY BE A WELCOME CHANGE. LET ME GET THIS UP. SO WHY DO WE THINK STEM CELLS CELL THERAPY IS GOING TO HELP? YOU U HEARD ABOUT THIS FROM THE INTRODUCTION. THESE CELLS ACT AS SMALL PARACRINE FACTORIES. THEY SECRETE A NUMBER OF FACTOR HELPFUL IN SETTING OF STROKE TO ENHANCE RECOVERY. THAT ARE DEPICTED HERE. SO WE KNOW THAT THESE CELLS GIVE FACTORS THAT PROMOTE NEUROGENESIS, THE FORMATION OF NERVE CELLS. THEY CAN ENHANCE ANGIOGENESIS, NEW VESSELS THAT GROW INTO THE AREA OF THE STROKE, THE DAMAGED BRAIN. THEY CAN HAVE NEGATIVE EFFECT ON THINGS HARMFUL SUCH AS INFLAMMATION. SO BUT SUPPRESSING INFLAMMATION, WE CAN IMPROVE RECOVERY AND REDUCE THE AMOUNT OF DAMAGE DONE FROM A STROKE. IN THE LATER STAGES THERE'S A FORMATION OF SCAR AT THE SITE OF A STROKE AND SOME OF THESE FACTORS GIVEN OFTEN BY STEM CELLS PERHAPS DELAY OR PREVENT FORMATION OF THIS SCAR TISSUE WHICH CAN ALSO IMPEDE RECOVERY PROCESS. SO THERE'S MULTIPLE FACTORS, MULTIPLE ROLLS FOR THESE CELLS, SOMEWHAT A SHOTGUN APPROACH, WE DON'T KNOW WHICH FACTORS ARE MOST IMPORTANT TO RECOVERY, THAT'S ONE OF THE FUTURE AREAS OF INVESTIGATION. BUT BY GIVING THIS BROAD SPECTRUM OF ACTIVITIES WE THINK WE CAN INDUCE THE BRAIN TO RECOVER TO A GREATER EXTENT. NOW IN APPLYING CELLS FOR STROKE RECOVERY, THERE'S A COUPLE OF IMPORTANT QUESTIONS WE HAVE TO ANSWER, FIRST IS WHAT TYPE OF CELLS, YOU HER ABOUT THE DIFFERENT TYPES OF CELLS THAT CAN BE USED. I WILL SHOW YOU SOME OF THE WORK THAT'S BEEN DONE ALREADY AND DIFFERENT TYPES OF CELLS USED FOR STROKE THERAPY. BUT THE OTHER QUESTIONS ARE HOW TO GIVE THE CELLS AND NUMBER OF DIFFERENT WAYS TO GIVE THEM. YOU CAN GIVE CELLS INTRAVENOUSLY OBVIOUSLY, THAT'S THE EASIEST, BUT IT'S UNCLEAR WHETHER ENOUGH CELLS REACH THE BRAIN FOR THE BLOOD BRAIN BARRIER TO BE EFFECTIVE. YOU CAN GIVE DIRECTLY INTO AN ARTERY WITH A CATHETER, BUT AGAIN, THERE COULD BE ISSUES WITH CROSSING THE BLOOD BRAIN BARRIER AND THESE CELLS ARE LARGE AN THEY CAN BLOCK UP THE SMALL CAPILLARIES AND POTENTIALLY CAUSE PROBLEMS IN THAT WAY. YOU CAN GIVE CELLS INTRATHECALLY IN THE SPINAL CELLS OF THE CANAL, HOW MUCH THAT GETS INTO THE BRAIN IS UNCLEAR, ONE WAY TO DELIVER IS THROUGH STEREOTACTIC TECHNIQUES WITH A SMALL BURR HOLE INJECTING THE CELLS DIRECTLY INTO THE AREA OF THE STROKE AND I WILL SHOW YOU SOME EXAMPLES OF STUDIES THAT USE THAT PARTICULAR APPROACH. WHICH ONE OF THIS IS APPROACHES WE USE HAS SOMETHING TO DO WITH THE TIMING AFTER STROKE. SO DIFFERENT TIMES AFTER STROKE WE APPLY DIFFERENT METHODS FOR DELIVERING THE CELLS. VERY EARLY ON WITHIN THE FIRST FEW HOURS WE PROBABLY ARE LOOKING AT A NEUROPROTECTIVE EFFECT AND INTRAVENOUS CELL TYPE MIGHT BE VERY APPROPRIATE AND IN THE FIRST FEW WEEKS MAYBE UP TO A MONTH. THERE'S A VERY ACTIVE REMODELING PROCESS GOING ON IN THE BRAIN IN THE SETTING OF ISCHEMIC INJURY INTO THE BRAIN. AND DURING THIS TIME IN FACT THE BRAIN GIVES OFF A CHEMOTACTIC SIGNAL THAT CAN ATTRACT THESE KINDS OF CELLS, SO YOU CAN GIVE THE CELLS INTRAVENOUSLY AND ARTERIALLY AND GET TO SITE OF INJURY. AT LATER STAGES, BEYOND A MONTH MAYBE UP TO YEARS LATER, THAT CHEMOTACTIC SIGNAL IS GONE. IT'S MORE DIFFICULT TO GET THE CELLS TO WHERE THEY ARE NEEDED. AND IN THAT CASE WE ARE MORE LIKELY TO GIVE THE CELLS DIRECTLY INTRACEREBRALLY INJECTING THEM INTO AREA OF THE STROKE ITSELF SO THEY CAN ENHANCE THE RECOVERY PROCESS WITH THE CELLS THAT ARE SURVIVING. SO LET ME JUST BRIEFLY SUMMARIZE IN THE LAST MINUTE OR SO SOME OF THE RECENT TRIALS JUST TO GIVE YOU AN IDEA OF WHERE WE ARE IN THE FIELD WITH CELL THERAPY FOR STROKE. WHAT IS NOT ON THIS SHIED ARE IN, -- SLIDE ARE MANY ANIMAL STUDIES OF STROKE, MODELS OF STROKE, IN ANIMALS THAT HAVE SHOWN VERY PROMISING BENEFITS IN TERMS OF REDUCING INFARCT SIZE, AND ENHANCING FUNCTIONAL RECOVERY. THEN THERE'S A SLEW OF EARLY PHASE SAFETY TRIALS THAT AGAIN SHOW ADEQUATE SAFETY FOR VARIOUS CELL TYPES AND HINTS OF IMPROVEMENT CLINICALLY. THERE'S STUDIES REALLY ALL OVER THE WORLD, MANY STUDIES IN EUROPE AND ASIA, THAT ARE ONGOING WITH CELLS THAT I DON'T HAVE ON THIS SLIDE SO WHAT I HAVE DONE HERE IS JUST PUT SOME OF THE MAJOR TRIALS PRIMARILY BEING PERFORMED AT THE UNITED STATES. THE FIRST FOUR OF THESE ARE COMPLETED TRIALS, THE MASTERS TRIAL WAS A STUDY USING ALLOGENEIC MSCs, MESENCHYMAL STEM CELLS APPLIED EARLY ON WITHIN THE FIRST DAY OR TWO OF ONSET STROKE WITH APPROPRIATE CONTROLS IN A BLINDED STUDY, THEY WERE GIVEN INTRAVENOUSLY AT THE EARLY PHASE. THIS STUDY DID NOT SHOW A SIGNIFICANT BENEFIT BASED UPON THE DESIGN OF THE STUDY, WHEN THEY LOOKED AT THE EARLY TREATED PATIENTS WITHIN THE FIRST UP TO 36 HOURS THERE WAS ACTUALLY A FAIRLY DRAMATIC DIFFERENCE BETWEEN THE TREATMENT GROUP AND THE CONTROLS AND I'LL TELL YOU A LITTLE BIT ABOUT THE NEXT TRIAL, THE MASTERS TWO TRIAL WHICH IS USING THIS EARLIER TIME WINDOW. THE TRIAL IS A CHRONIC STROKE TRIAL OPPOSED TO THE PREVIOUS ONE WHICH IS MORE ACUTE STROKES AND THESE WERE PATIENTS AGAIN SIX MONTHS UP TO SEVEN YEARS OUT FROM THEIR STROKE WHO HAD RESIDUAL DEFICITS TREATED WITH INTRACEREBRAL INJECTION OF THESE CELLS, AGAIN, ALLOGENEIC MSCs, THE CELLS WERE INJECT TO THE SUBCORTICAL REGION, A FAIRLY LARGE STUDY WITH SHAM CONTROLS SIMILAR TO PARKINSON'S STUDIES DONE PREVIOUSLY SO THEY WERE SHAM OPERATED PATIENTS, COMPARED TO THE TREATMENTED PATIENTS. AGAIN NO DIFFERENCE SO THIS IS SOMEWHAT DISAPPOINTING TO US THAT THERE WAS NO DIFFERENCE FOUND IN THIS SHAM CONTROL TRIAL. THE PISCES TWO TRIAL WAS SINGLE ARM PHASE 2 TRIAL OF NEURAL STEM CELLS, VERY SMALL STUDY THAT SHOWED SOME IMPROVEMENT BUT WITHOUT CONTROLS AND RECOVER TRIAL WAS INTERARTERIAL STUDY DIDN'T SHOW SIGNIFICANT BENEFIT BUT DID SHOW SOME PROMISING RESULTS THAT ARE GOING TO LEAD TO FURTHER TRIALS. FINALLY THERE'S A FEW ONGOING STUDIES, LISTED HERE THE MASTERS TWO TRIAL USING THE SAME ALLOGENEIC MSCs AS IN THE MASTERS TRIAL, IN EARLIER TIME WINDOW, LARGER GROUP OF PATIENTS, IN A DOUBLE BLIND RANDOMIZED CONTROL TRIAL, THIS IS IN A PHASE 3 STATE THE PISCES 3 TRIAL, CHRONIC STUDY FOLLOWING UP ON PISCES 2 WITH CELLS INTRACEREBRALLY INTO THE AREA OF THE STROKE, IS THAT STUDY GETTING UNDERWAY AND THIS IS A STUDY WITH UMBILICAL CORD BLOOD CELLS IN A NUMBER OF CENTERS AROUND THE COUNTRY PLANNING TO ENTER A HUNDRED PATIENTS IN DOUBLE BLIND RANDOMIZE TRIAL FOR MORE ACUTE STROKE WITHIN A FEW DAYS OF ONSET. SO THIS GIVES YOU AN IDEA WHERE WE ARE, WE HAVE PROGRESSED FROM THE EARLY STAGES FROM THE SAFETY TRIALS TO THE EARLY PHASE 2 TRIALS, NOW WE'RE IN THE LATE PHASE 2 TRIALS WITH APPROPRIATE CONTROLS, ONE PHASE 3 TRIAL, WE ARE NOT TO THE FINISH LINE YET, WE HAVEN'T FOUND ANY CELL THERAPY THAT IS READY FOR FDA APPROVAL. I THINK WE ARE GETTING THERE. IF THESE MORE RECENT STUDIES SHOW POSITIVE RESULTS AND PROMISING RESULTS, WE WILL BE CLOSER TO HAVING A GOOD CELL THERAPY FOR ENHANCING RECOVERY AFTER STROKE. I WOULD FINALLY MENTION THIS IS ONLY ONE OF SEVERAL THINGS BEING LOOKED AT TO ENHANCE STROKE RECOVERY, TRANSCRANIAL MAGNETIC STIMULATION, TRANSCRANE YAM DIRECT CURRENT STIMULATION, COMPUTER FACE ADVANCES SO THIS IS A VERY ACTIVE FIELD, CELL THERAPY IS A PROMISING PART OF WHAT WE'RE GOING TO SEE WITH AREA OF STROKE RECOVERY. THANKS. >> THANK YOU, DR. WEXLER. NEXT WE'LL HEAR FROM DR. CLIVE BENEFITSON, HE DIRECT IT IS CEDARS SIGH ANY REGENERATIVE CENTER AND USES WAYS TO REPURPOSE BRAIN CELLS FROM PATIENTS TO MODELS OF HUMAN DISEASE. HE LED THE FIRST GROUP TO SUCCESSFULLY MODEL SPINAL MUSCULAR ATROPHY IN HUNTINGTON DISEASE USING THIS TECHNOLOGY. HE'S GOING TO TELL US ABOUT SOME INTERESTING CLINICAL TRIALS AND IMPORTANCE OF MANAGING EXPECTATIONS FOR THIS FIELD THERAPY. >> THANKS VERY MUCH. NICE TO BE HERE. I'LL MOVE TO THE CLINICAL ARENA FURTHER FROM THE STROKE TRIAL AND SPECIALIZED TRIAL FOR THE DISEASE, YOU DON'T WANT TO BE DIAGNOSED WITH LOU GEHRIG'S DISEASE OR ALS BASED ON THE FAMOUS BASEBALL PLAYER, THIS STARTS WITH TWITCHING IN THE MUSCLE, THEN IN VERY RAPID ORDER, WITHIN THREE YEARS USUALLY YOU'RE COMPLETELY PARALYZED. THERE'S NO KNOWN EFFECTIVE DRUG, THE BEST IS -- WHICH GIVES YOU A THREE MONTH EXPANSION IN LIFE SPAN, THE DEAF ROW IS A NEW ONE STILL ONLY THREE TO FOUR MONTHS LIFE SPAN, AND THERE'S NOTHINGER FOR THIS DISEASE. LOSS OF MOTOR NEURONS DEGENERATIVE MOTOR NEURONS IN THE CORTEX, AND IN THE SPINAL CORD. SO THE APPROACH ONE CARTOON SLIDE LIKE LOREN WE USED THIS IN 2005 AND WE GOT INTO CLINIC IN 2017. THAT'S THE LAWRENCE AND I BEING PARALLEL UNIVERSES, WORK IN PARKINSONS AND ALS AND SAME PLACE SAME TIME. THE IDEA HERE IS ALSO WE HAD A LOT OF FUNDING FROM THE ALS ASSOCIATION, IF ANYONE IS HERE TODAY, REGENERATIVE MEDICINE, WITH THE $3 BILLION FOR STEM CELL STATE IN CALIFORNIA. AND OF COURSE NIH WAS HELPED AND OTHER FOUNDATIONS ALONG THE WAY WITH EARLY WORK FOUNDATION WORK FOR THIS CAME FROM NIH. WHAT ARE WE DOING? WE USE FETAL DERIVED NEURAL PROGENITORS. HUMAN FETAL TISSUE, WE ISOLATE THE BRAIN AND EXPAND IT IN THE PETRI DISH, WE FOUND WHEN WE PUT THE CELLS INTO THE SPINAL CORD A RAT MODEL OF ALS, THEY SURVIVED AND MADE NEW ASTROCYTES SO THEY PERFORM A FUNCTION, THE ASTROCYTES IN THIS DISEASE AS WELL HOWEVER THEY DIDN'T STOP MOTOR NEURONS FROM DYING. IF WE ENGINEER THEM TO MAKE A DRUG OR GROWTH FACTOR CALLED GBNF, WE FOUND THAT THESE CELLS THEN WOULD PROTECT MOTOR NEURON FROM DYING. THIS WAS QUITE A CHALLENGE TO MAKE THE CELLS ENGINEER A DRUG BUT NOW USING THE STEM CELL TO DELIVER THE DRUG, LIKE A TROJAN HORSE, THE STEM CELLS GOES IN MAKES AN ASTROCYTES, IT RELEASES THE DRUG. TO GET THESE CELLS INTO THE NERVOUS SYSTEM AS QUICK AS SPINAL CORD THERE WAS REALLY INEFFICIENT WAY SO WE DEVELOPED A DEVICE SO THIS OPENED UP ANOTHER PART OF FDA, CDRH, WE HAD TO APPLY TO. WE DESIGNED THIS DEVICE OVER PERIOD OF COUPLE OF YEARS. ANIMAL MODEL 17: WE FILED IN 2016 FILED AN IND WHICH MEANS INVESTIGATOR NEW DRUG TO PUT INTO PATIENTS. THE FINAL PART OF THIS, THIS WAS A UNIQUE DESIGN. STEM CELLS ALLOW YOU TO DO VERY CREATIVE THINGS IN CLINICAL TRIALS. SO WE DECIDED WE DIDN'T WANT TO DO A SHAM PROCEDURE, THE FDA SAID WE HAD TO GO LUMBAR FIRST TO TREAT LEGS. SO SPINAL CORD, HAS DIFFERENT SECTIONS THE LUMBAR SECTION CONTROLS LEG MOVEMENT SO IF WE PUT THE CELLS IN THE LUMBAR REGION OF THE SPINAL CORD WE ONLY EXPECT TO PROTECT YOUR LEG FUNCTION. THISES THE UNIQUE THING WITH STEM CELLS IF YOU CAN TARGET TO A PARTICULAR PART OF THE CNS YOU DON'T EXPECT EFFECTS THERE. WE DID A UNILATERAL APPROACH, WE PUT THE CELLS ON ONE SIDE OF THE SPINAL CORD AND FOLLOW THE PROGRESSION IN BOTH LEGS. SO YOU ONLY EXPECT TO SEE A EFFECT ON THE LEG THAT NEEDS THE CELLS AND THE OTHER SEARCH Z AS CONTROL AS PATIENT DIDN'T KNOW WHICH SIDE NEED THE CELLS NOR NEUROLOGISTS. IT'S NOT PA SHAM STUDY. IT'S AN INTERESTING DESIGN. THAT TOOK ABOUT FOUR YEARS TO GET THROUGH OF THIS PROCESS. THIS IS THE APPLICATION BY THE WAY. THERE ARE FOUR COPIES HERE TO BE FOUND BUT THERE'S FOUR AND A HALF THOUSANDS PAGES, I SEE WILSON BACK THERE, IT WENT OFF TO THE FDA, YOU WILL HEAR FROM WILSON LATER ON. WE HAVE TO SAY ALONG WAY THE FDA HAVE BEEN REMARKABLY RESPONSIVE BEFORE WE SUBMITTED THIS AND AFTER. THIS GOES BACK TO TIM'S FIRST SLIGHTED, WHAT THEY ARE TRYING TO DO IS SORT OUT THE SHALL TONS OUTS THERE, FOR $4,000 U OOH EEL FIX ANYTHING, BONE, BRAIN ANYTHING FROM THESE TRIALS GO AED H AND SOMEWHERE MIDDLE GROUND WE MOVE TOWARDS A MORE RAPID PROCESS. I THINK WILSON AND TEAM AND FDA ARE DOING A REMARKABLE JOB BALANCING SHUTTING DOWN BAD GROUPS AND LETTING THE GOD GROUPS IF YOU LIKE -- GOOD GROUPS WITH APPROVAL GO FORWARD. IT WAS A GREAT EXPERIENCE, WE WERE APPROVED, I WON'T TELL YOU ABOUT THE TRIAL PEP TO SAY IT WAS A TEAM EFFORT. THIS IS MY ACKNOWLEDGMENT SLIDE. TO PULL THIS TOGETHER WE REALLY NEEDED PEOPLE FROM NEUROLOGY AND IT WAS LED BY DR. ROBERT BAILOR AND NEUROSURGERY, AMAZING NEUROSURGEON PAT JOHNSON, A SPINE SURGEON. AND THESE TWO TOGETHER WITH THESE TEAMS STAFF AND OPERATING THEATER AND ANESTHETICS PHARMACY, WE HAD TO DOSE THESE PATIENTS WITH IMMUNOSUPPRESSION AS IF THEY WERE GETTING A HEART TRANSPLANT. THIS WAS AN ALLOGENEIC PRODUCT INTO CNS. I WILL TELL YOU IN A MINUTE WHAT HAPPENED. WE ALSO HAVE NURSING AND RECRUITMENT OF PATIENTS SO THOSE ARE BIG OPERATION AND RATHER EXPENSIVE, WE WERE FORTUNATE TO HAVE FUNDING FROM THE PROPOSALS. $6 MILLION PROPOSAL TO DO 18 PATIENTS. THIS WAS A SURGERY DAY, THIS IS THE TEAM IN SURGERY IN ORDER TO APPLY THE APPARATUS TO INJECTION THE CELLS, NOT GOING TO TELL YOU ABOUT GMP MANUFACTURING BUT LIKE LOUR RENTS WE HAD A THOUSAND TUBES OF PRODUCT FROZEN DOWN, SHIPPED TO OUR PHARMACY ON THE DAY OF SURGERY, HELD SHIPPED OVER TO SURGEONS T GET THE CELLS OUT PUT THEM IN THE CANNELLA. AND THE NEUROSURGEON INJECT THEM WITH DEVICE WE DEVELOP AND THE WHOLE PROCEDURE TOOK THREE HOURS. ACTUALLY TOOK FIVE HOURS THE FIRST TIME. ACTUALLY HAVE A CLOCK. SO THIS IS LAST COUPLE OF SLIDES, THIS IS A TEAM AFTER THE FIRST SURGERY, ON MAY 3RD. MY BIRTHDAY 2017. YOU CAN SEE PAT JOHNSON LOOKS STRESSED. THIS IS ON RESEARCH. HE'S NEVER -- NEUROSURGEONS TAKE THINGS OUT, THEY DON'T NORMALLY PUT THINGS BACK SO SIT OOHs A NEW THING FOR THEM. SO IT WAS STRESSFUL THE FIRST COUPLE OF SURGERIES, THIS IS THE LAST SURGERY, A LOT MORE RELAXED. ONCE NEUROSURGEONS GET USED TO SOMETHING IT BECOME AS ROUTINE. THE LAST SURGERY TOOK THREE HOURS AND THE FIRST WAS MORE LIKE FIVE AND A HALF. BY 18th PATIENT WE WERE GETTING PRETTY GOOD SURGERY TECHNIQUE, WE HAVE NO COMPLICATIONS GETTING THE CELLS DELIVERED TO PATIENTS. AND IT'S QUITE REMARKABLE BRAIN SURGERY WAS FAIRLY STRAIGHT FORWARD IF YOU HAVE A GOOD PROTOCOL AND WE CAN PUT CELLS BACK INTO THE NERVOUS SYSTEM. WE BLIND THE STUDY, THE PATIENTS -- NOT RELEASING RESULTS THE LAST PATIENT WILL REACH END OF PROTOCOL IN OCTOBER 2019. WE ARE FOLLOWING UP LEG STRENGTH AND ALL THAT INFORMATION WILL BECOME AVAILABLE WILL RELEASE THIS. WE DID A TWO DOSE STUDY STEM CELL TRANSPLANTS, DIFFERENT DOSES TO SEW A DOSE EFFECT. THE LOW DOSE GROUP IS COMPLETE. THE HIGH DOSE IS STILL MONITORING PROGRESSION OF THE DISEASE. WE HAD A FULL READ OUT IN OCTOBER. BUT CAN'T TELL YOU WE COMPLETED THE STUDY AND PRIMARY SAFETY LOOKS GOOD. THE LESSONS FIRST LEAVE YOU WITH BASED ON LAST FOUR POINTS, IT'S A MARATHON, NOT A SPRINT. YOU DON'T ENTER THESE THINGS RAPIDLY. UNLESS YOU ARE PAYING $4,000 FOR A QUICK STEM CELL TREATMENT, MEANS IT'S NOT GOING TO WORK. LAWN PROJECTS BUT I THINK WE ARE SETTING UP RATHER LIKE HEART TRANSPLANTS, FUTURE, THE KIND OF THING LORENS IS DOING IS SETTING THE FUTURE SO WE CAN GET THERAPY INTO CLINICS OVER THE NEXT TEN YEARS. YOU NEED SOLID FUNDING AND YOU NEED A LARGE TEAM AND I HATE TO SAY IT BUT SOME OF THE NIH FUNDING MECHANISMS DON'T ALLOW YOU REALLY TO DO THIS PROJECT. THIS TYPE OF PROJECT. THE BUDGET IS OVER 6 OR 7 MILLION. OF COURSE YOU CAN BECOME INTRAMURAL HERE TO NIH OR PROPER GENE THERAPY. THERE'S OTHER MECHANISMS TO DO IT. WE HAVE FUNDING TO DO IT IN STATE OF CALIFORNIA. YOU HAVE TO HAVE A GOOD RATIONALE. THE THING THAT HAS SOLD PEOPLE ON THIS IS REPLACE THE ASTROCYTE OF ENGINEERING AND PRE-CLINICAL STUDIES SUPPORTED THE FACT THAT THAT PROTECTED THESE NEURONS IN A RAT MODEL. SO WE HAD THAT RATIONALE FOR GOING FORWARD AND ALS HAS NO ANIMAL MODEL FOR SPORADIC ALS T. WE USE A GENETIC MODEL DOES NOT PREDICT OUTCOMES VERY WELL. WE HAVE AT LEAST A RATIONALE I THINK THE LAST IS YOU HAVE TO LEARN FROM THIS STUDY. WE DESIGNED IT SO IF WE GET A NEGATIVE RESULT WE KNOW IT'S NEGATIVE. AND PATIENT DESCRIBED THIS TO ME, I DON'T KNOW IF THIS IS GOING TO WORK. BUT I SEE THIS AS ANOTHER DOOR AD WHAT WE NEED TO DO, THERE ARE TEN DOORS OPEN TO ME WHEN PATIENT SELECTING A TRIAL. I WOULD LIKE TO GO THROUGH THE DOOR AND SEE IF IT'S THE ONE IF NOT I WOULD LIKE TO CLOSE IT SO THE NEXT PATIENT DOESN'T HAVE TO GO THROUGH THE SAME DOOR. WE CAN'T CLOSE THE DOOR UNLESS THE TRIALS GIVE YOU AN OUTCOME YOU CAN SAY YES IT WORKED NOR IT DIDN'T. SO TO BE NONNEST, I'M -- HONEST, IMI'M A SCIENTIST SO EITHER WAY I'M HAPPY. IF WE PROVE IT DOESN'T WORK WE'LL MOVE ON. IF WE PROVE IT DOES, THAT'S GREAT. SO THE OUTCOMES HAVE TO BE IN A WHEY GIVES AN ANSWER. I'LL STOP THERE. THANK YOU VERY MUCH. [APPLAUSE] >> THANK YOU, DR. SIMPSON. LAST AS MENTIONED WE WILL HEAR FROM DR. CORTEZ ON A LITTLE DIFFERENT TAKE. HE DIRECTS THE NEUROIMMUNOLOGY CLINIC AT NINDS, THERE SHE COLLABORATES WITH SEVERAL BASIC SCIENCE LABORATORIES TO CONDUCT PHASE 1 STUDIES IN NEUROINFLAMMATORY DISEASE OF THE CENTRAL NERVOUS SYSTEM. SHE'S GOING TO TALK TO US ABOUT A DIFFERENT APPROACH FOR CELL THERAPY. >> THANK YOU FOR INCLUDING ME ON THIS PANEL. WHAT I HAVE BEEN DOING IS A LITTLE BIT DIFFERENT AND PERHAPS SIMPLER, BUT ANOTHER GROWING APPLICATION OF CELL THERAPIES ISN'T THE PREVENTION AND HOPEFULLY THE ERADICATION OF REFRACTORY TREATMENT RESISTANT INFECTIONS. WHICH OCCUR IN VULNERABLE PATIENTS, IMMUNOCOMPROMISED PATIENTS OR CRITICALLY ILL INDIVIDUALS. DIFFERENTLY THAN DESCRIBED BY THE OTHER PANEL MEMBERS, THIS STRATEGY ISN'T USING STEM CELLS AT ALL BUT RATHER LEVERAGING EXISTING COMPARATIVELY MORE MATURE IMMUNE CELLS THAT ARE ABLE TO ATTACK AN INFECTIOUS AGENT THAT ARE HARVESTED FROM THE BLOOD OF HEALTHY DONORS. AND CAN BE VARIABLY SELECTED FROM THE BLOOD. AND THEN EXPANDED AND ENRICHED IN CULTURE. AGAINST EITHER MICROBE ITSELF OR PEPTIDES OF IMMUNODOMINANT ANTIGENS ON THE SURFACE OF MICROBES. IN ORDER TO GENERATE A CELL PRODUCT THAT IS A -- HAS ROBUST ANTI-TRIAL ACTIVITY WHICH CAN BE DELIVERED TO THE PATIENT JUST BY AN IV INFUSION. HOPEFULLY MANAGE TO CURE THAT INFECTION. IN THE LAST FEW YEARS, THIS STRATEGY IS COMMONLY AND ALSO SUCCESSFULLY USED IN THE SETTING OF PATIENTS WHO HAVE UNDERGONE BONE MARROW TRANSPLANT, WHO ARE PARTICULARLY SUSCEPTIBLE TO NUMBER OF VERY SERIOUS VIRAL INFECTIONS THAT CONTRIBUTE GREATLY TO MORTALITY IN THIS CLINICAL SETTING. CELLS EXPAN AND ENRICHED ARE NOT ENGINEERED IN ANYWAY AND MIGHT OFFER FUTURE OPPORTUNITIES TO ACTUALLY ENGINEER THESE CELLS IN SOME FASHION IN ORDER TO GENERATE MORE ROBUST ANTIVIRAL PRODUCT. AT NIH WE HAVE ADOPTED A SIMILAR STRATEGY AND TO LARGE EXTENT THIS IS POSSIBLE BECAUSE OF THE STREAMLINING OF THIS ENRICHMENT AND EXPANSION PHASE WHICH IS NOW TRIMMED DOWN TO 14 DAYS. WHICH MAKES IT A VIABLE OPTION OR WE CAN BEGIN TO EXPLORE THE VIABILITY OF THIS OPTION FOR TREATMENT OF ACUTE VIRAL INFECTIONS OUTSIDE BONE MARROW TRANSPLANTATION SETTINGS. INTRAMURAL NIH WHAT WE HAVE DONE IS APPLIED THIS TO SERIOUS DEVASTATING OPPORTUNISTIC INFECTION OF THE BRAIN. CALLED BY THE JC VIRUS CALLED PML WHICH ARE THERE IS NO AVAILABLE TREATMENT AND TYPICALLY PATIENTS DIE WITHIN A FEW MONTHS. WE HAVE JUST COMPLETED A SMALL STUDY, A PILOT STUDY, EXPANDING CELLS AGAINST THE JC VIRUS OBTAINED FROM FIRST DEGREE RELATIVES OF PATIENTS WITH PML AND TREATED TOTAL OF 12 PATIENTS. AND THE FIRST THING THAT WE CAN SAY IS THAT THIS TREATMENT WAS VERY SAFE AND TOLERATED BY OUR PATIENTS. AND ON TOP OF THAT WE ALSO HAD PRETTY ENCOURAGING RESULTS IN THAT OF THE 12 PATIENTS WHO WERE TREATED, SEVEN OF THESE SURVIVED THEIR PML WHILE FIVE WENT ON TO DIE. IDEALLY WE WOULD GET BETTER NUMBERS THAN THESE BUT IN PML WHICH IS AS DEADLY AS IT IS, THIS IS AN INCREDIBLY ENCOURAGING RESULT AND IT PROVIDES US AT LEAST PROOF OF PRINCIPLE THAT THIS TYPE OF CELL THERAPY STRATEGY MIGHT BE A VIABLE OPTION FOR THE FUTURE. AND MIGHT BE APPLIED TO OTHER INFECTIONS, REFRACTORY INFECTIONS. I AM A CLINICIAN. SO FOR ME PICTURES OF INDIVIDUAL PATIENTS MEAN A LOT. THIS IS ONE OF OUR TRIAL PARTICIPANTS A 40-YEAR-OLD WOMAN WITH PML. THIS IS HER PRE-TREATMENT BASELINE MRI WHICH SHOWS JERRY TO THE BRAIN WHICH IS ESSENTIALLY ACTIVE INFECTION. BY THE TIME SHE RECEIVED THREE VIRAL INFUSIONS SIX MONTHS POST TREATMENT THE AREA OF DISEASE BRAIN WAS FAR TRUNKED DOWN, THERE WAS A FAIR AMOUNT OF AD TROPHY ASSOCIATED WITH THAT, THE EXPECTED OUTCOME FOLLOWING INRECEIVELITIS. THERE ARE NO MORE SITE OF ACTIVE INFECTION AND RESIDUAL IN HER BRAIN IS SCARRING THAT WILL REMAIN. SHE ALSO CLINICALLY IMPROVED GREATLY. OUR EXPERIENCE WITH THIS STUDY HELPED TO IDENTIFY NUMBER OF OBSTACLES THAT HAVE TO BE OVERCOME. IF WE WANT TO BRING TYPES OF TREATMENT STRATEGIES TO GENERAL CLINICAL USE, THE MAJOR ISSUES FOR US ARE FIRST TIME TO TREATMENT. THE PROCESS FOR GENERATING THE PRODUCTS ARE GREATLY STREAMLINED AND TIMES OF SHORTENED SIGNIFICANTLY, THE TIME TO IDENTIFY SUITABLE DONOR AND DEVELOP A PERSONALIZED CELL PRODUCT TO GIVE TO PATIENT CAN TAKE FOUR TO SIX WEEKS, THIS IS INCREDIBLY VALUABLE TIME IN ACUTE AND POTENTIALLY DEADLY INFECTION. THIS WILL NEED TO BE SPED UP IN A FASHION OR FINDING ALTERNATIVE WAYS NORTHED TO BRING TREATMENT MORE QUICKLY TO ACUTELY ILL PATIENT AND TO HAWAII HOW IMPORTANT THIS IS, IN OUR STUDY FIVE PATIENTS WHO HAD BEEN SCREEN AND ELIGIBLE FOR PARTICIPATION DIED WHILE WAITING FOR A CELL PRODUCT TO BE MADE FOR THEM SPECIFICALLY. THIS IS CRITICAL. A SECOND ISSUE WE HAVE TO ADDRESS RELATES TO THE VARIABILITY OF THE QUALITY OF CELL PRODUCT THAT CAN BE MANUFACTURED. SO WHAT WE HAVE SEEN IS THAT BLOOD CELL PRODUCTS DERIVED FROM DIFFERENT DONORS DO HAVE VARIABLE QUALITY PROBABLY RELATED TO INFANT CHARACTERISTICS OF INDIVIDUAL DONORS SOME CAN MOUNT ROBUST ANTIVIRAL RESPONSE AND SOME LESS SO. OF THE PATIENTS WHO SURVIVE PML WE SEE CLEARLY THEY HAD ALL RECEIVED VERY ROBUST ANTIVIRAL PRODUCTS. SO THIS HIGHLIGHTS THE IMPORTANCE OF SUITABLE DONORS, STRONG DONORS FROM WHICH WE'RE MAKING OUR CELL PRODUCTS. THIS WILL REQUIRE BOTH MANUFACTURING CHANGES AND ALSO BAYS TO IDENTIFY SUITABLE DONORS. ANOTHER ISSUE CLEARLY IS THAT THE TYPE OF EXPERTISE REQUIRED TO GENERATE MANUFACTURE OF CELL PRODUCTS SUCH AS THESE IS LIMITED TO ACADEMIC CENTERS WHICH WILL LIMIT PATIENT ACCESS. THE GOAL ULTIMATELY WILL BE TO BROADEN ACCESS AND WE THINK THAT ONE WAY ALL THESE DIFFERENT OBSTACLES MIGHT BE MET IN THE FUTURE LOOKING FORWARD IS TO HAVE COMMERCIALLY AVAILABLE READY TO USE OFF THE SHELF ANTIVIRAL BLOOD BANK PRODUCT THAT WILL ALLOW IMMEDIATE ACCESS TO THE BLOOD PRODUCT AND HOPEFULLY GUARANTEE REPRODUCIBILITY OF THE QUALITY OF THE PRODUCT AS WELL. THANK YOU. [APPLAUSE] >> THANK YOU, DR. CORTEZ. NOW WE CAN OPEN IT UP TO QUESTIONS, IF YOU HAVE A QUESTION PLEASE REMEMBER COME UP TO THE MIC. DON'T BE SHY. WHOLE YOU ARE THINKING, I WILL ASK A QUESTION TO DR. STUDER OR WHOEVER ON THE PANEL TO ANSWER IT. THE AREA MOST EFFECTED IN THE AREA OF DISEASE IS THE SR. BELL ALMOST, THEY'RE LIKE PURR KINK CELL NEURONS. SO I KNOW PROTOCOLS ARE PUBLISHED TO MAKE COMPLEX PURKINJE CELLS FROM INDUCED PLURIPOTENT STEM CELLS, ARE THOSE REALLY ROBUST PROTOCOLS RIGHT NOW? REPRODUCIBLE CAN WE MAKE ENOUGH TO STUDY AS A DISEASE MODEL IN A DISH OR IS THERE POTENTIAL TO USE THEM FOR THERAPY? >> THIS IS DEFINITELY BEAUTIFUL SPECIAL TYPE OF NEURON PURKINGE CELL. NUMBER OF PEOPLE WORKED ON IT, A PIONEER IN THE TECHNOLOGY. DID NICE STUDY SHOWING IT COULD GET PURKINGE LIKE CELLS, TOOK 200 DAYS TO DIFFERENTIATE THEM TO LOOKING SIMILAR TO PURKINGE CELL, AND IT WAS A VERY COMPLEX PROCESS SO IT'S NOT SOMETHING THAT WE CAN PRODUCE AS EASILY AS DOPAMINE NEURON. SO I WOULDN'T -- CONTEXT OF DISEASE MODELING BUT IT NEEDS ADDITIONAL WORK TO MAKE THAT ROUTINE. I KNOW A NUMBER OF GROUPS TRYING TO DO THAT, TRYING TO REPRODUCE, IT'S A BIG CHALLENGE. EXPERIMENTAL MARKERS FOR PURKINGE HAS TRANSPLANTATION STUDIES BUT VERY FEW EARLY STAGE. SO I THINK THAT MIGHT BE MORE CHALLENGING EFFORT TO GET DOWN TO INTERESTING WORK ACTUALLY BY NUMBER OF GROUPS THAT TRY TO TAKE RESIDENT NEONATAL STAGE IN MOUSE, THE PROGENITOR SHOWN EVEN AT STAGE PURKINJE CELLS NORMAL IN DEVELOPMENT BUT IN PURKINGE MODELS -- THAT'S ANOTHER WAY THERAPEUTIC ANALYST CAN WORK BUT FOR THERAPEUTIC TRANSPLANTATION, IT CAN BE A VERY TOUGH ONE. >> TO ADD ONE OF THE CHALLENGES FOR CELLS LIKE PURKINGE CELLS IS GETTING THE CONNECTIONS BACK IN AN ADULT BRAIN IN THE COMPLEX CIRCUITRY. I THINK YOU MIGHT WANT TO TUCK -- THE GOOD THING ABOUT PARKINSON YOU PUT THE DOPAMINE NEURONS IN THE STRIATUM, THEY LOOK IN THE BRAIN STEM. THE WAY DOPAMINE WORKS IS OIL AND SIMPLE WAY NEEDS TO BE RELEASED TO MAKE A MINI CIRCUIT AND YOU GET RECOVERY. IN OTHER CIRCUITS IT MIGHT NOT BE AS SIMPLE SO FOR CEREBELLUM IT'S PROTECTIVE WAY TO STOP FROM DYING MAYBE WOULD BE MORE REALISTIC THAN REPLACE CEREBELLAR NEURON IN ADULT BRAIN. >> ANY OTHER QUESTIONS FOR THE PANEL? >> I A QUESTION IN REGARDS TO NEGATIVE TEST RESULTS. IT WAS MENTIONED HOW IMPORTANT THOSE ARE IN SUABLYCATIONS DON'T ALWAYS WANT TO REPORT THOSE, HARD TO GET THOSE, IS THERE A PLACE THAT ORGANIZATIONS THAT WE CAN GO TO FIND THESE NEGATIVE TEST RESULTS TO MAKE SURE THEY'RE NOT BEING TESTED AGAIN AND AGAIN? >> THERE'S NO -- THE BIGGEST JOURNAL OF IRREPRODUCIBLE DATA THEY CLOSED THAT DOWN. THERE WAS A JOURNAL OF NEGATIVE RESULTS, I THINK FOR CLINICAL TRIALS, TO BE FAIR THE CLINICAL TRIALS GENERALLY GET PUBLISHED BECAUSE IT'S A HUMAN TRIAL, SO LIKE SOME OF THE TRIALS YOU MENTIONED ARE ACTUALLY OUT THERE, SO GENERALLY THE CLINICAL TRIALS DO GET PUBLISHED AND I THINK WE HEAR ABOUT MOST STEM CELL TRIALS EVEN IF NEGATIVE. FAIR TO SAY. >> I WOULD SAY THOUGH THERE IS DEFINITELY A PUBLICATION BIAS THAT POSITIVE TRIALS ARE MORE LIKELY TO GET PUBLISHED THAN NEGATIVE TRIALS FIRST NEGATIVE TRIALS MAY NOT BE SUBMITTED. THOUGH WE ENCOURAGE THAT. BUT ALSO REVIEWERS AND JOURNAL EDITORS SEEM TO -- THEY OBVIOUSLY THEY WOULD PREFER TO REPORT POSITIVE THINGS AND NEGATIVE THINGS DON'T LOOK AS GOOD IN THEIR JOURNALS AND TO REVIEWERS. SO THAT BIAS DEFINITELY EXISTS. WE ALL TRY TO OVERCOME THAT BY FORCING OURSELVES TO SUBMIT NEGATIVE RESULTS AS WELL AS POSITIVE RESULTS AND HOPEFULLY GET THEM PUBLISHED. THAT IS DEFINITELY A PHENOMENON. >> WE HAVE A TABLE OF NEGATIVE. I WONDER HOW MANY ARE MISSING THAT HAVEN'T BEEN PUBLISHED THAT YOU KNOW ABOUT? >> NOT MANY. WHEN YOU GET TO PHASE 2 DEFINITELY PHASE 2 TRIALS, AND PHASE 2B TRIALS VIRTUALLY ALL OF THEM WILL GET PUBLISHED BUT IT'S THE EARLIER PHASE TRIALS THAT MIGHT GET PUSHED ASIDE. >> THANK YOU FOR A GREAT SESSION. I WAS CURIOUS IN TERMS OF WHAT'S THE BEST KNOWN DATA RIGHT NOW FOR DURATION OF THESE CELLS OR MANY KINDS OF CELLS BEING EXPLORED SURVIVORRING WITHIN THE NERVOUS SYSTEM. >> IT DEPEND ON WHICH KIND OF CELL STEM CELL YOU ARE USING. THE DOPAMINE NEURONS WE HAVEN'T START AD TRIAL YET, WE DON'T KNOW FOR SURE, IN ANIMAL MODELS THEY SURVIVED ONE AND A HALF YEAR, WE HAVE A SPECIAL SITUATION THERE BECAUSE WE HAVE EXPERIENCE FROM FETAL GRAFTING THAT WAS DONE IN THE LATE 80s EARLY 90s, WE HAVE PATIENTS TODAY THAT WHATEVER IT IS GET THE BRAIN AND CAN LOOK. THERE'S NOW GOOD EVIDENCE THAT DOPAMINE CELLS SURVIVE AT LEAST TO 24 YEARS IN DISEASED BRAIN. SOP THEY ACTUALLY PROBABLY SURVIVE NEARLY FOR THE REST OF LACK OF PATIENT, BUT THEN AGAIN VARY MESENCHYMAL STEM CELLS, THEY ARE TRANSIENT BUT NEURAL STEM CELLS UNDER CERTAIN CONDITION CAN BE TRANSIENT AND OTHER CONDITIONS THERE LONGER SO IT SOMETHING HAS TO BE CAREFULLY LOOKED AT AND SAFETY RISK OF THE CELLS AND FDA WANTS TO KNOW, CORRELATES WITH EFFICACY AND THIS IS AN IMPORTANT ISSUE. THEY KNOW AT LEAST SOME CELLS THEY ONLY REPLACE TISSUES THAT IT'S POSSIBLE THEY ARE ONE TIME TREATMENT TO TAKE OVER FUNCTION. >> U AGREE WITH EVERYTHING, IF YOU THINK ABOUT IT FETAL OR EMBRYONIC STEM CELL IN A 606-YEAR-OLD PATIENT THEY SHOULD OUTLIVE THE PATIENT. THEY MAY KEEP LIVING AFTER YOU PASS AWAY. AND THE SECOND, I DIDN'T MENTION IN OUR TRIAL, WE HAD FOUR PATIENTS COME TO POSTMORTEM AND ALL PART OF CLOSED DATA THAT I CAN -- I CAN SAY THAT THERE'S SURVIVING TRANSPLANTS, THAT WAS A YEAR AND A HALF AFTER THE TRANSPLANT WE GAVE IMMUNOSUPPRESSION FOR ONE YEAR AND IT WAS WITHDRAWN AS PER PROTOCOL. SO THE OTHER BIG QUESTION DO YOU NEED IMMUNOSUPPRESSION, HOW MUCH DO WE HAVE TO GIVE FETAL TRANSPLANTS ARE INTERESTING BECAUSE SOME DAYSES THEY GAVE NO IMMUNOSUPPRESION WHATSOEVER AND DID ALLOGENEIC TRANSPLANT AND OTHER CASES IT WAS 14 YEARS, HAS SURVIVING CELLS SO FOR PRIMARY FETAL TISSUE, YOU DON'T NEED IMMUNE SUPPRESSION IF IT'S A NEURAL TRANSPLANT. WE DON'T KNOW ABOUT STEM CELLS BECAUSE WHEN YOU GROW THEM THEY EXPRESS A RANGE OF ANTIGENS SO FOR OUR TRIAL AT LEAST ONE YEAR SUPPRESSION AND 15 MONTHS AFTER 15 MONTHS PATIENT PASS AND WE SEE PATIENT TRANSPLANT SURVIVAL. >> FROM ADVOCACY PERSPECTIVE, THAT'S GOLD. YOU HAVE THE IDEA OF THIS ONE TREATMENT AND IT WILL LAST FOR THE PATIENT'S LIFE SPAN. >> CORRECT. >> FROM A PRACTICALITIES OF WILL THESE THINGS, HOW LIKE THE COMMERCIAL MODELS WE HAVE WERE INDUSTRY INVEST IN DEVELOPMENT OF NEW THERAPEUTICS HAVE ANY CONVERSATIONS HAPPENED ABOUT -- IS INDUSTRY INVESTING IN THESE WHEN GIVEN ONE TREATMENT AND NEVER PAID AGAIN? >> I CAN ANSWER FROM MY SIDE, AMGEN HELD THE PATENT, GAVE A TALK TEN YEARS AGO ABOUT HOW TO MAKE MONEY BECAUSE YOU PUT THE CELLS IN. WHAT THEY ARE DOING IS THE GENE THERAPY, YOU WILL HEAR ABOUT THIS AFTERNOON THEY CHARGE THE INSURANCE WILL BE CHARGED IF YOU MAKING THE PRODUCT AND IT'S A BIOMARKER AND YOU CAN SEE IT'S STILL BEING MADE BY THE GENE OR BY THE CELL. SO YOU HAVE AN ANNUAL CHARGE FOR THAT PRODUCT. >> I WOULD SAY IN FOR STROKE, UNFORTUNATELY THERE'S A YEARLY SUPPLY OF NEW STROKES COMING ALONG ELIGIBLE FOR TREATMENT. WE TALK ABOUT 800,000 STROKES PER HERE, HALF WHOM ARE DISABLED AND WORLDWIDE IT'S SEVERAL TIMES THAT. EVEN IF IT'S A ONE TIME TREATMENT, THERE'S QUITE A BIG MARKET. >> MAYBE, TRUE IN THE PAST IS DIFFICULT TO GET FUNDING FOR THIS EFFORT BUT FOR THAT REASON BUT I THINK THAT CHANGED IN PART BECAUSE OF SUCCESS OF CELL THERAPY IN CANCER, HAS THE COSO CALLED CAR T-CELLS INTRODUCED SOME INDICATION OF ACUTE PATIENTS WHICH IS UNHEARD OF, THEN IT COMES TO CHALLENGE, IN THIS CASE YOU HAVE ONE TIME CHARGE, IT CAN BE HALF A MILLION, IT GETS EXSPENTTIVE, WHEN A ONE TRIAL TREATMENT BUT EXPENSIVE SO THAT'S AGAIN BIG DISCUSSION HOW THAT WILL BE HANDED WITH CELL BASED PRODUCTS IN THE FUTURE. >> YOU HEARD OF EARLIER $300,000 TREATMENT AND THAT'S HITTING THE INSURERS HARD. TWO DIFFERENT PRODUCTS GENE THERAPY PRODUCT WHICH WILL BE AT ONE TIME. AND THERE'S THE (INDISCERNIBLE) THAT IS CONTINUALLY YOU HAVE TO COME BACK FOR MORE INFUSIONS. IT'S A COMPLEXION MODEL YOU WILL SEE HOW IT PLAYS OUT. Q. WHEN IT COMES THE VALUE AND COST THE IMPORTANT THING FOR AUDIENCE TO REALIZE IS YOUR VOICE IS VERY IMPORTANT SO AS ADVOCATES DON'T GET LOST IN THE FIELD OF VALUE ASSESSMENT FOR THE PRODUCTS OF INTEREST FOR YOUR DISORDER T BE SURE YOUR VOICE IS HEARD. INSERT YOURSELF IF YOU HAVE TO. >> >> THE COST WILL COME DOWN, THAT'S THE WAY NATURE IS. SO MIGHT BE EXPENSIVE AT THE BEGINNING BUT ONCE VOLUME GOES UP WE FIND OUT WAYS TO MAKE IT TREATABLE. >> ANY OTHER QUESTIONS? Q. TRYING TO FORMULATE THIS QUESTION, HOW FOR A SMALL ADVOCACY ORGANIZATION DO YOU -- WOULD YOU -- WHAT WOULD BE SIGNS OF SUCCESS OR HOW SMALL ADVOCACY ORGANIZATION CAN CURATE AN EFFORT IN THIS EFFORT. THE EFFORT IS SO LARGE, IF YOU THINK TRYING TO EXPLORE IF THERE IS AN OPPORTUNITY FOR STEM CELLS IN CELL THERAPY IN A GIVEN DISEASE AREA I JUST TRY TO FIGURE HOW, IT'S A HARD THING TO ENVISION IF YOU ARE SITTING IN THIS AUDIENCE LOOK AT THE SCALE OF THESE AND YOU SAY THERE'S THAT DIAGRAM WITHIN A MIRACLE HAPPENS HOW DO YOU SCALE THIS EFFORT AND HOW COULD YOU CURATE THAT BECAUSE THERE AREN'T ENOUGH OF YOU BRILLIANT TYPES TO GO AROUND AND ADVISE EVERYONE, I DON'T KNOW IF YOU HAVE THOUGHTS. >> DEPENDS ON SPECIFIC FOUNDATION THAT GOES FOUNDATION BUT I THINK ONE AREA, LONG TIME LINE IN THE BEGINNING, THE BEGINNING WHEN OUR ID WAS CONSIDERED CRAZY, COULDN'T GET FUNDING FROM STUDY SECTION BECAUSE THERE'S NO GUARANTEE OF BIRTH, VERY HIGH RISK, MAYBE NINE OF TEN TIMES IT DOESN'T WORK. IF YOU HAVE FUNDING SOURCES, SOMETIMES URN CERTAINTIES LIKE (INDISCERNIBLE) THERE'S NOT ENOUGH PATIENT PATIENTS. THERE'S SO FEW PATIENTS AND PRIVATE FOUNDATIONS ARE VERY IMPORTANT, IT DEPENDS ON THE PARTICULARLY TRYING TO DO SOMETHING DIFFERENT FOR HIGHER RISK CAN BE REALLY VERY, VERY HELPFUL FOR YOUNG PEOPLE, OTHERWISE NOT BE TO GET THEM EXCITED ABOUT THE BIOLOGY BECAUSE THE 20 YEARS AFTER IS A LOT OF HARD WORK, THERE'S SOME BIOLOGY BUT MOST IS MORE BECOMING ENGINEERING TRANSLATING IT AND IT'S IMPORTANT. BUT IT -- IF YOU CAN GETS ENOUGH YOUNG INTELLIGENT PEOPLE WITH GREAT -- EVEN IF IT'S MORE FUN GETTING THEM EXCITING IS THE MAIN THING. >> I'LL CONFIRM YOUNG PEOPLE IS GREAT ENERGY. YOU HAVE TO BELIEVE IT'S -- YOU HAVE TO BELIEVE YOU CAN GET ON SPACE WITH A TEST. SO YOU HAVE TO THINK BIG BUT SEED WITH FOUNDATION MONEY ALSO GOT US GOING, WE DIDN'T GET A BIG GRAPH, THE HUNDREDK, THE WHOLE THING OFF THE GROUND, WISCONSIN, WE NEVER GOT TO THE NEXT STAGE, SO EVEN TIME WE REACHED A MILESTONE THOUGH IT WAS SMALL, BUILD A LARGER GRANT AND YOU END UP WITH BIGGER GRANTS TO DO THE TRIAL. FOUNDATIONS PAY A KEY ROLE, YOU HAVE TO DECIDE WHICH AREAS TO INVEST IN AND GOOD PRE-CLINICAL DATA OR GOOD RATIONALE SENSIBLE RATIONALE, NOT JUST STEM CELLS WILL KILL YOU OR RARE DISEASE DON'T WORRY WE'LL SORT IT OUT. A GOOD RATIONALE IS SOMETHING TO GO BY. >> THE OTHER ROLE FOR ADVOCACY HERE IS EDUCATING PATIENTS ABOUT THE HYPE OF STEM CELLS AND KEEPING THEM AWAY FROM PLACES WHERE THEY ARE WAISTING THEIR MONEY AND DIRECTING THEM, AS WE GET INTO MORE CLINICAL TRIALS WE NEED PEOPLE TO PARTICIPATE IN THOSE TRIALS. THAT'S KEY. THE -- CAN HELP MAYBE THEMSELVES BECAUSE WE DON'T KNOW WHETHER THE TREATMENTS WORK OR NOT BUT THEY CAN ALSO HELP FUTURE PEOPLE BY -- WITH THE SAME PROBLEM BY PARTICIPATING IN THESE TRIALS ALLOWING US TO FIND ANSWERS WHETHER OR NOT THE TREATMENT IS HELPFUL, THAT'S ANOTHER ROLE ADVOCACY ORGANIZATIONS WHERE THEY CAN CONTRIBUTE. SO WITH THAT I THINK WE ARE ALMOST AT OUR TIME T. I WOULD LIKE TO TOSS OUT TWO RESOURCES YOU MIGHT FIND INTERESTING TO LEARN MORE ABOUT STEM CELLS AND POTENTIAL FOR YOUR DISEASE, ONE IS THE AMERICAN SOCIETY FOR GENE AN CELL THERAPY, CHECK OUT THEIR WEBSITE. THE OTHER IS THE INTERNATIONAL SOCIETY FOR STEM CELL RESEARCH, THEY HAVE GOOD INFORMATION, THE PANEL -- OKAY. [APPLAUSE] IT'S A PLEASURE TO START OUR SECOND SYMPOSIUM AN PANEL DISCUSSION. THIS IS ON GENE THERAPY AND GENE EDITING. IT WAS NOT THAT LONG AGO THAT I WOULD HAVE SAID THIS WAS SPACE AGE MEDICINE AND WAY IN THE FUTURE, HERE IT IS NOT TOMORROW BUT ACTUALLY RIGHT NOW. SO VERY EXCITING. I'M GOING TO INTRODUCE OUR TWO MODERATORS. RONALD BARTEK AND JILL MORRIS, HE'S FROM THE ATAXIA RESEARCH ALLIANCE, ON THE BOARD OF DIRECTORS AND IS A PAST CHAIRMAN OF THE NATIONAL ORGANIZATION FOR RARE DISORDERS, NORD. RON SERVES ON BOARD OF DIRECTORS FOR THE ALLIANCE FOR A STRONGER FOOD AND DRUG ADMINISTRATION. AND ALLIANCE FOR REGION RA TICK MEDICINE. HE'S BEEN ON THE ADVISORY COUNCIL FOR NINDS AND THE NATIONAL CENTER FOR ADVANCE TRANSLATIONAL SCIENCES. HE'S THE FORMER PARTNER AND PRESIDENT OF BUSINESS GOVERNMENT DEVELOPMENT AFFAIRS FIRM, HIS PROFESSIONAL EXPERIENCE INCLUDES 20 YEARS OF FEDERAL EXECUTIVE AND LEGISLATIVE BRANCH SERVICE. HE HAS A DEGREE FROM WEST POINT AND MASTERS DEGREE WITH RUSSIAN AREA STUDIES FROM GEORGETOWN UNIVERSITY. HE'S NO STRANGER TO PARTS AROUND US. DR. JILL MORRIS, YOU HAVE MET ALREADY, ONE OF OUR PROGRAM DIRECTORS HERE AT NINDS. HER PORTFOLIO INCLUDES MULTIPLE NEUROLOGIC DISORDERS INCLUDING THE LEUKODYSTROPHIES INBORN ERRORS OF METABOLISM, SPINA BIFIDA, HYDROCEPHALUS AND RARE GENETIC DISORDERS. I THINK OF HER AS A DEVELOPMENTAL NEUROBIOLOGIST. I DON'T THINK IF SHE THINKS THAT'S GOOD OR BAD BUT IT'S GOOD FOR ME. SHE WAS A SENIOR RESEARCH BIOLOGIST DEPARTMENT OF NEUROSCIENCE RESEARCH LABORATORY, SHE'S A SENIOR STAFF FELLOW IN THE UNIT OF NEUROMOLECULAR GENETICS AT NIH AND HELP IDENTIFY GENE RESPONSIBLE FOR NIEMANN PICK TYPE C. WELCOME OUR PANEL AND OUR MODERATORS WILL INTRODUCE THE PANEL MEMBERS. >> THANK YOU, DR. SHORE. I'LL TAKE THE FIRST CRACK. AND WOULD LAKE TO JOIN CYNTHIA AND WHAT SHE DID EARLIER AND THANKING THE INSTITUTE FOR ONCE AGAIN CONVENING THE WONDERFUL FORUM AS IT HAS, THIS IS THE 11th YEAR. 13th. WOW. I MUST HAVE MISSED THE FIRST TWO. BUT NEVER SINCE. THANK YOU BOTH YOU ON THE ROOM AND ON LINE FOR PARTICIPATING TODAY. I WANT THE ASK FIRST BEFORE INTRODUCE THE OTHER PANELNISTS HOW MANY IN THE ROOM CURRENTLY HAVE GENE THERAPY CLINICAL TRIALS ONGOING? TWO HANDS. HOW MANY IN THE ROOM HAVE ACTIVE PRE-CLINICAL PROGRAM IN GENE THERAPY. FIVE HANDS. HOW MANY IN THE ROOM WOULD LIKE TO HAVE ACTIVE GENE THERAPY PROGRAM? ALL HANDS WOULD GO UP. OUR OBJECTIVE IN THIS PANEL IS TO ANSWER YOUR QUESTIONS, WE LIKE THAT IN TWO WAYS ONE, WE HAVE COLLECTIVELY IDENTIFIED 11 QUESTIONS WE ANTICIPATE YOU WOULD WANT TO ASK. WHAT WE WOULD LIKE TO DO FIRST IS GET THROUGH THOSE 11 QUESTIONS AND GIVE YOU AMPLE OPPORTUNITY TO ASK ADDITIONAL QUESTIONS OR TO EXPAND UPON QUESTIONS WE HAVE ASKED AND ANSWERED. FIRST LET ME INTRODUCE THE OTHER FOUR PANELISTS. FIRST, DR. BARRY BURN WHO IS PEDIATRIC CARDIOLOGIST AND SERVES AS DIRECTOR OF THE UNIVERSITY OF FLORIDA PAL GENE THERAPY CENTER. HIS RESEARCH TEAM HOPES TO USE GENE THERAPY TO RESTORE MUSCLE FUNCTION IN INHERITED NEUROMUSCULAR DISEASE, PARTICULARLY THOSE DISEASES THAT LEAD TO SKELETAL MUSCLE WEAKNESS. AND ABNORMALITIES IN MANY HEART AND RESPIRATORY FUNCTION. DR. WILSON BRIAN IS BOARD CERTIFIED IN NEUROLOGY AND IS DIRECTOR OF OFFICE OF TISSUES ADVANCED THERAPIES AT FDA CENTER FOR BOY LOGISTICS EVALUATION AND RESEARCH. THAT OFFICE MISSION IS TO ENSURE THE SAFETY AND EFFECTIVENESS OF BOY LOGICAL PRODUCTS INCLUDING GENE THERAPIES FOR HUMAN DISEASE. DR. BRIAN IS AN INVESTIGATOR IN CLINICAL TRIALS IN CEREBRAL VASCULAR DISEASE AND NEUROMUSCULAR DISORDERS. THEN WE HAVE LATE BREAKING NEWS. WE HAVE ADDITION OF TWO EXCELLENT NINDS SCIENTISTS THAT WORK WITH DR. DONOVAN AND DR. REGAIN FOLEY AND DECIDED OR AGREED TO JOIN OUR PANEL FIRST DR. DEMOS SADE, FAR LEFT MY FAR LEFT AND DR. SARA NEWHOUSE BOTH PEDIATRIC NEUROLOGISTS AT NINDS INTRAMURAL PROGRAM. THAT IS OUR PANEL, THAT IS OUR OBJECTIVE, WE WANT TO ANSWER YOUR QUESTIONS, LET'S GET STARTED WITH THE QUESTIONS WE ANTICIPATED. JILL WILL TAKE FIRST CUP. >> EXTRAMURALLY WE HAVE A VERY ACTIVE PROGRAM WITH A LOT OF ACTIVITY WITH GENE THERAPY APPLICATIONS COMING IN. FROM NEUROLOGIC DISEASES SO THIS IS A HIGH AREA FOR US BECAUSE OF INCREASING INTEREST IN TREATING NEUROLOGIC DISEASE WITH GENE THERAPY. SO WHAT I'M GOING TO FIRST ASK PANELISTS FOR A DESCRIPTION OF WHAT IS GENE THERAPY AND HOW IT DID YOU EVERS FROM FROM GENE DATING. >> WE ALL NEED TO TAKE A SHOT? >> YES. >> FOLLOW THE PROPER DEFINITIONS. FROM CODE OF FEDERAL REGULATION. I HAVE BEEN WORKING IN THIS FIELD FOR 20 YEARS. CONCEPT OF MEDICINES FIRST BECAME AN IDEA THAT EXISTED IN ONLY THE LABORATORY. WE KNEW WE CAN TRANSFER GENES INTO BACTERIA, WITH ALL THE WORK TO UNDERSTAND HOW BACTERIA PHAGOS WORK. WE MOVED TO MAMMALIAN VIRUSES. BORDERLINE POST-DOCTORAL TRAINING. THE WHOLE IDEA IS HOW TO TRANSFER GENETIC MATERIAL FROM ONE SOURCE TO ORGANISM, IN THIS CASE IN VIVO GENE THERAPY IS THE TRANSFER OF DNA IN THIS CASE FOR THE PURPOSE OF TREATING HUMAN DISEASE, DISEASE GENE TO INFECTED CELL HOPEFULLY AFFECTED CELL AND HOPEFULLY THAT WOULD CON FIR A NEW PHENOTYPE WHEN WE LONG TIME AFTER I STARTED IN THIS FIELD CONQUERED THE HUMAN GENOME PROJECT, WE AT LEAST KNEW THAT IN MANY CASES THERE WAS ONE GENE RESPONSIBLE PARTICULARLY IN RECESSIVE CONDITIONS FOR ONE DISEASE. THAT'S THE CONCEPT THAT WE ARE OPERATING UNDER, NOW WE HAVE THE TOOLS BASED ON A DIFFERENT VIRUS TO TRANSFER GENES INTO CELLS. AND INTERESTINGLY THAT SAME VIRUS WITH WORK BEGAN AT FLORIDA 30 YEARS AGO TO DEFINE AAV AS GENE THERAPY VECTOR, THIS IS A FORM OF PARVOVIRUS FAMILY. THE SAME VIRUS IS USED TO EFFECT GENE EDITING SO SOME SENSE GENE EDITING IS A FORM OF GENE THERAPY, AND IN EVEN RELATIVE TO LAST SESSION, CELL THERAPY IS FORM OF GENE THERAPY EXCEPT THE ENTIRE GENOME IS TRANSFERRED IN A CELL PACKAGE INTO ANOTHER A HOST. SO THAT'S A BIG MY VIEW OF IT SO WILSON CAN FROM A REGULATORY PERSPECTIVE. >> I THINK I AGREE WITH THAT. FOR THE FDA WE THINK GENE THERAPY. THIS IS NOT THE ONLY DEFINITION OF GENE THERAPY, DIFFERENT ORGANIZES HAVE DIFFERENT DEFINITIONS. THAT DETERMINES WHAT IS INCLUDED AND NOT INCLUDED. WE THINK GENE THERAPY AS BEING PRODUCTS THAT HAVE THE AFFECT BY TRANSCRIPTION OR TRANSLATION OF TRANSFERRED GENETIC MATERIAL. IN MOST CASES THAT MEANS SOMEONE IS PUTTING DNA INTO A VIRUS BEING TRANSFERRED INTO ANOTHER CELL. THE OTHER FORM OF GENE THERAPY, IS GENE EDITING THAT IS ONE FORM OF GENE THERAPY WHERE YOU HAVE GOT A PATIENT WHO HAS A DNA SEQUENCE THAT IS ABNORMAL IN SOME WAY AND WE HAVE TOOLS WE THINK WILL BE ABLE TO EDIT THAT SEQUENCE AND PERHAPS CORRECT IT. SO GENE EDITING WE THINK OF IS ONE FORM OF GENE THERAPY. >> I THINK IN OUR GROUP AND IN OUR LINE OF WORK, MOST TIME WORKING WITH GENE THERAPY IT'S MORE SIMPLY GENE REPLACEMENT SO RECESSIVE DISORDER WHERE THE GENE IS SMALL ENOUGH IT CAN BE PACKAGED INTO A VECTOR TARGETED TO THE TARGET TISSUE OF INTEREST THEY ARE GENE REPLACEMENT. THAT'S THE FORM OF GENE THERAPY WE ARE MOST CLOSELY INVOLVED WITH. >> SO THE NEXT QUESTION IS WHAT IS A GENERAL STATE OF PLAY IN GENE THERAPY IN THE UNITED STATES AROUND ELSEWHERE? Q. I THINK THERE ARE MORE RECENTLY ONE OR TWO GENES THERAPEUTIC AGENTS APPROVED IN THE U.S. AND THE EUROPEAN UNION BUT MOSTLY MOST OF GENE THERAPY OR GENE REPLACEMENT RIGHT NOW IS CLINICAL TRIALS OR PRE-CLINICAL STUDIES. AND WE, AGAIN, WE ARE INVOLVED IN GENE THERAPY AFFECTING THE NEUROMUSCULAR CENTRAL NERVOUS SYSTEM SO IN OUR GROUP WE DEAL WITH INTRATHECAL GENE THERAPY FOR AXONAL NEUROPATHY AND SYSTEMIC FOR MTM 1. WE ARE ACTIVELY ENROLLING PATIENTS BUT THERE'S MORE GOING ON. WITH MOTIVE OF DELIVERY TOO. >> I THINK WE KNOW'S EXCITEMENT ABOUT GENE THERAPY THESE DAYS. IN EARLY 2000s, THE HUMAN GENOME PROJECT SEQUENCED HUMAN GENOME AND SINCE THEN THEY HAVE BEEN THOUSANDS OF SCIENTISTS AROUND THE COUNTRY WHO ARE WORKING IN THESE LABS AND ISOLATING SPECIFIC GENES AND TRYING TO FIGURE OUT WHAT THEY DO AND WHAT DISEASES THEY ARE IMPORTANT IN AND THEN TRYING TO FIGURE OUT HOW TO FIX THEM THAT HAVE WORK THAT STARTED 15 YEARS AGO OR LONGER IS NOW GONE TO ANIMAL MODELS THE VECTORS, THE SCIENCE, THE TECHNOLOGY OF DELIVERING GENE THERAPIES HAD ADVANCED RAPIDLY. AND WE -- WE AT FDA LOOK HAT WHAT WE CALL INVESTIGATIONAL NEW DRUG APPLICATIONS, INDs. AND THESE ARE APPLICATIONS TO DO CLINICAL RESEARCH WITH GENE THERAPIES. THE NUMBER OF IND IN GENE THERAPY WENT UP BY OVER 90% FROM 2017 TO 2018. THAT'S IN ONE YEAR. I DON'T KNOW IF WE CAN SUSTAIN THAT BUT MOMENT UM IS INCREDIBLE. WE -- MOMENTUM IS INCREDIBLE. WE APPROVED THE FIRST THREE GENE THERAPIES IN 2017 AND WE DIDN'T APPROVE ANY IN 2018 BUT WE DO THINK THIS WILL BE A HUGE PART OF MEDICINE IN THE DECADES TO. COME. >> I THINK THAT'S A GREAT PERSPECTIVE. POINT THE SPEAR IN WAYS OF SEEING THE PROGRAMS COMING FORWARD UNTIL THEIR RELEASED TO THE PUBLIC. WE DON'T KNOW WHAT'S UNDER WATER IN TERMS OF MOMENTUM TO BRING STUDIES OFTEN FOUNDATION BASE AND DRIVEN EARLY STAGE BY SPECIFIC INDIVIDUAL PATIENT ENTITIES. SO THAT'S REALLY TRUE IN THE NEUROPATHY STUDY THAT CAME TO THE NIH INTRAMURAL PROGRAM AS A CREDA PROGRAM FUNDED PROGRAM. SO MANY PROGRAMS ARE BORNE OUT IN ACADEMIC RESEARCH LAB AS PART OF ACADEMIC HEALTH CENTERS WITH SOME FEDERAL OR FOUNDATION SUPPORT AND TO MAKE THEM SUSTAINABLE THEY GO THROUGH THIS PROCESS OF CONFIRMING SAFETY AND EFFICACY THAT ARE THE UNDERLYING PRINCIPLES THAT THE REGULATORY AGENCIES BRING AND THEN ONCE CONDITIONS ARE MET, THEY ARE MADE AVAILABLE ON A WIDER SCALE WE HOPE BOTTOM LINE SCALE TO THE PUBLIC. IT IS REALLY BURDENING BECAUSE AS WILSON SAID, IN EVERY CASE WHERE THERE'S A WELL KNOWN DISEASE PATHOPHYSIOLOGY THE DRUG IN THIS CASE GENE PRODUCT NOT JUST GENE BUT GENE PRODUCT IS WELL KNOWN TO HAVE A VERY SPECIFIC MECHANISM OF ACTION THAT INFLUENCE IT IS CONDITION, ESPECIALLY IN RECESSIVE DISEASES WHERE WE KNOW MOST OF THE TIME A PARENT CARRIER IS UNAFFECTED AND ONLY EARLIER IN LIFE WHEN YOU HAVE PARTIAL EXPRESSION OF THIS GENE, IF YOU CAN GET TO THAT LEVEL YOU MAY E MEAL YOUR RATE DISEASE SYMPTOMS SO THIS CREATES EXCITEMENT -- AMELIORATE DISEASE SYMPTOMS. BECAUSE OF THE LIKELIHOOD OF DURABILITY IN THOSE TISSUES BECAUSE THEY ARE FULLY DIFFERENTIATED. SO THAT'S -- IT'S AN EXCITING TIME. >> NEXT QUESTION REALLY SPIN OFF DR. BURNS. ON BEHALF OF EVERYBODY IN THE ROOM AND ONLINE, DO YOU BELIEVE ALL NEURO-- FOR ALL NEUROLOGICAL CONDITIONS, GENE THERAPY IS A REASONABLE STRATEGY REASONABLE APPROACH? AND IF SO, WHAT DO EACH DISEASE GROUPS NEED TO DO TO PREPARE THE PATH FORWARD? >> THE GOOD AND BAD OF INTERNALLY DIFFERENTIATED TISSUES IS THAT LIKELY TO BE DURABLE IF INTERVENTION IS SOON ENOUGH BUT IF WE TAKE THE VERY CURRENT CASE THAT WAS MENTIONED EARLIER OF SMA, ONCE NEURONS ARE GONE, THEY ARE NOT REPLACED BY PUTTING BACK THE MISSING GENE. SO THERE IS SOME DEGREE OF IRREVERSIBILITY AND SOME NEUROLOGICAL CONDITIONS. THERE ARE SOME WHICH ARE VERY AMENABLE TO WHICH THERE'S NOT NEURODEGENERATION. THAT MAY BE VERY AMENABLE THROUGHOUT LIFE THE LIFE COURSE TO INTERVENE BUT SOME ARE EITHER DEVELOPMENTAL CHANGES THAT ARE PROGRAMMED TO FOLLOW A CERTAIN PATTERN. WHEN THAT PATTERN IS DISRUPTED, IT MAY CREATE A PERMANENT PROBLEM. I WOULDN'T SAY EVERY CONDITION BUT CERTAINLY THE MAJORITY ONE HOPEFUL FOR, AS DANA POINTED OUT LOSS OF FUNCTION CHANGES ARE -- HAVE BEEN MORE INITIAL TARGETS BECAUSE WE KNOW WHAT LEVEL IS LIKELY TO LEAD TO MILDER SYMPTOM S. DOMINANT MUTATIONS ARE MORE CHALLENGING BUT MAYBE THROUGH EDITING TECHNOLOGIES OR RNA MEDIATED GENE THERAPY APPROACHES THAT THOSE ARE ALSO CONSIDERED TRACTABLE. >> KNOWING RIGHT ALONG AND EVERYBODY SHOULD FEEL FREE TO ANSWER, BECAUSE THESE GENE THERAPIES COULD BE CURATIVE, IF THOSE CRITERIA ARE MET YOU JUST DESCRIBED, SHOULD THESE PARTICULAR DISEASE GROUPS FOCUS ENTIRELY ON GENE THERAPY AT THE DISMISSAL OF OTHER THERAPEUTIC APPROACHES. >> I THINK FIRST AND FOREMOST, MOST OF THOSE CONDITIONS SHOULD FOLLOW OPTIMAL STANDARDS OF CARE AND NOT NEGLECT OTHER THINGS SUCH AS UNCERTAIN NEURODEGENERATIVE OR NEUROMUSCULAR DISORDERS, THE CARDIAC FUNCTION ARE AFFECTED. AND SOMETIMES NOT VERY EVIDENTLY AFFECTED AND SO THEY MIGHT BE DISMISSED AND ONE MIGHT THINK LET'S TWO FOR A GENE THERAPY BUT AT THE SAME TIME AESSENTIAL LIFE SAVING MANIFESTATIONS OF THE DISEASE ARE DISMISSED SO THAT SHOULD BE GOOD MEDICAL PRACTICE, SHOULD BE CONTINUED AND NOT DISMISSED FIRST AND FOREMOST AS THE BASELINE. DO YOU WANT TO COMMENT? >> IN ADDITION TO CARDIO PULMONARY OPTIMIZATION, WE TALK A LOT ABOUT NUTRITION AND WE TALK ABOUT SUPPORTING GROWTH AND DEVELOPMENT SO I THINK ONE OF THE THINGS WE WILL LEARN WITH THE MTM TRIAL AS WELL AS SMA EXPERIENCE IS THAT I'M VERY CAUTIOUS AS A PHYSICIAN TO USE THE C WORD. I THINK THAT WE WILL BE AFFECTING AND CHANGING THESE CONDITIONS BUT I THINK THEY ARE GOING TO IN THE YEARS TO COME AS CHILDREN GROW AND EXPRESS AND TREATED IN DIFFERENT WAYS WE WILL BE DEALING WITH CHILDREN THAT HAVE A DIFFERENT TYPE OF DISORDER BUT WILL SOME WAY HAVE A NEUROLOGICAL IMPACT SO I THINK WE WILL BE LEARNING HOW TO MANAGE AND TREAT DIFFERENT CONDITIONS THAT ARE HOPEFULLY HAVE A MUCH LONGER LIFE SPAN BUT I THINK OTHER SUPPORTIVE AREAS SHOULD BE -- I GUESS IGNORED OR PUT TO THE SIDE. EASY TO GET EXCITED ABOUT IT. >> I'M AN OPTIMIST. I THINK THAT WE HAVE TO DISTINGUISH WHETHER WE ARE TALKING ABOUT NEUROLOGIC DISEASES THAT ARE DEFINED BY SPECIFIC GENETIC MUTATION, MANY OF THESE RARE DISEASES. I THINK WE ARE GOING TO CURE THESE DISEASES, IT'S JUST A QUESTION OF TIME. SO I'M AN OPTIMIST ABOUT THAT. THEN THERE ARE MANY NEUROLOGICAL DISEASES WHERE THE GENETIC DEFINITION IS NOT SO CLEAR. WE HEARD DR. WEXLER TALK EARLIER ABOUT PATIENTS, THE HUNDREDS OF THOUSANDS OF PATIENTS WHO HAVE RESIDUAL DEFICITS FROM STROKE. I ACTUALLY THINK THAT GENE THERAPY WILL LIKELY HAVE A ROLE THERE TOO ONCE WE FIGURE OUT THE FACTORS THAT ARE IMPORTANT RECOVERY OF CELLS SO THAT WE CAN GENETICALLY ENGINEER CELLS TO BE MORE EFFECTIVE AND THAT WE WILL CREATE GENETICALLY ENGINEERED CELLS THAT WILL HELP MANY DIFFERENT DISEASES EVEN THOSE THAT ARE NOT GENETICALLY DEFINED BUT THAT'S PROBABLY MUCH FURTHER IN THE FUTURE. >> I'LL COMMENT SO I DON'T HAVE TO SIT BETWEEN WILSON AND SARA, THERE ARE TWO HOLES HERE BUT I'M MORE A SEN TRYST THERE ARE PROBABLY SOME ASPECT. WE TAKE FOR EXAMPLE, THE MUSCULOSKELETAL DISEASES THAT LEAD TO ALSO APPEARS TO BE ORTHOPEDIC DEFORMITY, SCOLIOSIS S HIP CONTRACTURES, OTHER THINGS THAT MAY WITH EARLY INTERVENTION MAY HAVE BEEN PREVENTED. SOME OF THOSE THINGS IF WE WERE TO WRAP THOSE INTO THE DEFINITION OF THE DISEASE FOR A LATE A BOY WITH DUCHENNE FOR EXAMPLE A TEENAGER MAY HAVE SUFFICIENT LOSS OF MUSCLE MASS OR DEPLETION OF THEIR STEM CELL POPULATION THAT EVEN THOUGH AT EARLIER AGE THAT MAY HAVE BEEN MORE IMPACTFUL THERAPY, NOT GOING TO BE CURED SO IT'S REALLY IMPORTANT TO MATCH EXPECTATION WITH REALITY. IN MOST OF THE CASES WHERE THERE'S LATE INTERVENTIONS. THIS WILL BE THE ADVENT, THE OTHER ADVENT OF HAVING IMPACTFUL THERAPIES WILL DRIVE THE -- US TO USE NEWBORN SCREEN MORE FREQUENTLY AND IN THOSE SETTINGS I COMPLETELY AGREE WITH WILSON THAT THERE ARE BETTER OPPORTUNITIES PARTICULARLY IN NEUROLOGICAL DISEASE TO HAVE VERY LONG LIVED IMPACTFUL THERAPIES. SO DEPENDS ON THE STAGE YOU COME IN AND THERE'S A LARGE BURDEN OF EXISTING PATIENTS WHICH THERE WAS ABSOLUTELY NOTHING NOT PAST AND CREATES A GROUND SWELL OF INTEREST IN THIS AREA. WHERE WE WILL HAVE MIXED THE OPPORTUNITY, THAT'S UP FORTUNATE BUT AS BARRY MENTIONED WITH NEWBORN SCREENING WITH ARE TREATING EARLIER AND EARLIER AND AS A MATTER OF FACT THERE ARE FOLKS VERY INTERESTED IN TREATING SOME DISORDERS IN IN UTERO BEFORE THE CHILD IS BORN. OBVIOUSLY THERE ARE ISSUES AROUND THOSE SORTS OF THINGS. >> ONE LAST THING TO ADD IS BEFORE REACHING A CURE, I THINK TO STAY IN THE CENTER WE WILL FIND OURSELVES IN A PLACE OF MODIFIED NATURAL HISTORY BECAUSE IN MENDELIAN DISORDERS THAT HAVE BEEN CHARACTERIZED FOR YEARS, I DON'T KNOW THAT WE FULLY UNDERSTAND THE DISEASE IN ALL OF ITS SYSTEM MANIFESTATIONS. I'M THINKING IN YOUR EXAMPLE OF MTM 1, THIS DISORDER IS CURRENT -- THERE IS A GENE REPLACEMENT THERAPY FOR THIS DISORDER TO REPAIR THE DEFICITS IN MUSCLES, WE DO KNOW THE GENE IS ALSO EXPRESSED HAS WIDE EXPRESSION IN LIVER GALLBLADDER AND OTHER ORGANS THAT WE ARE NOT ADDRESSING WITH THAT GENE, WITH THE SPECIFIC GENE THERAPY. I THINK WE WILL LEARN MORE ABOUT THE EFFECT OF THAT DISEASE ON THOSE OTHER ORGANS WHEN WE FIX OUR TARGET ORGAN SYSTEMS THAT WE ARE TARGETING WITH OUR GENE THERAPY. >> ONE OTHER POINT, RELATED TO THE EARLIER QUESTION, IN TERMS OF THE OTHER OPPORTUNITIES AND AS WAS POINTED OUT, IT'S IMPORTANT TO FOLLOW THE STANDARD OF CARE, THERE HAVE BEEN -- BEEN SAID BY ONE OF WILSON'S COLLEAGUES ACTUALLY THAT THESE THERAPIES MAY HAVE THEIR GREATEST IMPACT IN COMMUNITIES THE STANDARD OF CARE IS NOT AVAILABLE. BECAUSE THEY ARE SO DURABLE THAT IT WOULD ENABLE -- WE NEED TO KEEP THAT IN MIND AND IN RARE DISEASE COMMUNITY NOT REALLY SPEAKING ONLY TO THE U.S. POPULATION. SO THIS WOULD BE A REALLY IMPORTANT CHALLENGE GOING FORWARD ON OUR -- ON THE COMMERCIAL COMMUNITY TO MAKE SURE THAT TREATMENTS ARE BROADLY AVAILABLE. >> I WAS THINKING ABOUT THE INITIAL APPROVAL PERIOD TO START WITH A HOMOGENOUS LINE BUT IF WE HAVE THAT EVIDENCE WE CAN APPLY IT. >> SO THE ADVOCACY GROUPS THAT HAVE WORKING ON PEDIATRIC DISORDERS, SO TO GET NEWBORN SCREENING THERE HAS TO BE SOME TYPE OF POTENTIAL TREATMENT TO DO NEWBORN SCREENING AND NINDS WE DO HAVE A FUNDING OPPORTUNITY -- APPLICATION FUNDING OPPORTUNITY FOR APPLICATIONS DEVELOPING THERAPIES FOR DISORDERS THAT COULD EVENTUALLY LEAD TO NEWBORN SCREENING. AND ASK THE HOPE IS THAT IF THESE THERAPIES ARE DEVELOPED, THERE COULD BE AN INCREASE IN NUMBER OF PATIENTS WHOSE ARE READILY DIAGNOSED WITH THESE DISORDERS AND CAN BE TREATED AT EARLIER AGE BEFORE DEVASTATING EFFECTS OF THE DISEASE. SO WITH AAV MOST HAVE GENE THERAPIES WITH AAV ADENOASSOCIATED VIRUS, AND THAT IN MANY OF US WHO ALREADY HAVE IMMUNE RESPONSE TO AAV, SO HOW CONCERNED SHOULD WE BE ABOUT IMMUNE RESPONSE TO THE VIRUS AS WELL ADS POTENTIALLY THE GENE PRODUCT? -- AS WELL AS GENE PRODUCT? >> I CAN START ON THAT ONE. IN ONE OF THE CONDITIONS WE WORK ON, THERE IS NEWBORN SCREENING IN A NUMBER OF STATES NOW ABOUT A THIRD OF THE U.S. NEW IMPORTANT POPULATION IS SCREENED FOR ACTIVITY OR POMPEII DISEASE. WE KNOW IF THE -- BECAUSE OF SOMATIC GROWTH AND THE LIKELY LOSS OF EFFECT IN MUSCLE CELLS OVER THE LIFE SPAN, WE NEED TO FOCUS ON ABILITY TO READ MONEYSER THESE AGENTS. AND RIGHT NOW, IT'S AN IMPORTANT ASPECT OF ALL CURRENT TRIALS. ANY ENVIRONMENTAL OR PRIOR EXPOSURE TO GENE THERAPY AGENT EXCLUDES PATIENTS FROM CURRENT CLINICAL STUDIES AND IS LIKELY TO BE A PRACTICAL LIMITATION TO EVEN REPEAT COMMERCIAL USE WITHOUT SOME STRATEGIES TO EITHER GIVE PREVENTATIVE THERAPY OR SPECIFICALLY ELIMINATE ANTIBODY RESPONSES THAT LOCK -- THAT ARE SO AFFECTED WHY WE'RE IMMUNIZED AGAINST MANY COMMON PATHOGENS IS PROTECT US FROM EXPOSURE AND THAT IS WHAT HAPPENS IN THE CONTEXT OF GENE THERAPY. WE ARE EFFECTIVELY IMMUNIZED AGAINST SUBSEQUENT EXPOSURE TO VIRUS VERY READILY ELIMINATEED FROM THE CIRCULATION BY CIRCULATING ANTIBODIES. I THINK IT'S A VERY IMPORTANT PROBLEM ESPECIALLY IN CONTEXT OF NEWBORN SCREENING. AND IT'S NOT REALLY POSSIBLE, I THINK Y'ALL LEARN VERY WELL FROM THE TRIAL TO SIMPLY ISOLATE THE BRAIN WITH THESE VECTORS THAT ARE DESIGNED TO GO IN THE BRAIN FROM THE PERIPHERY CAN DO THE REVERSE EVEN IF YOU DEEM HAS DONE A LOT OF WORK IN THOSE AREAS IF YOU WANT TO COMMENT. >> SO I THINK WHAT BARRY IS REFERRING TO IS EVEN IF WE GO ABIDE BY THE DOGMA THAT THIS CNS IS HAS IMMUNE PRIVILEGE, IN THE GIANT AXONAL NEUROPATHY TRIAL WE HAVE INJECTED PATIENTS WITH SCREENED ANTIBODY POSITIVE WHO ARE SERO POSITIVE FOR AAV 9 AND PATIENTS WHO ARE SERO NEGATIVE AS WELL. BUT EVEN IN SERO NEGATIVE PATIENTS THAT ARE DOSED INTRATHECALLY, THERE IS VIRUS LEAKING THROUGH BACK OUT WARDS. AND ANTIBODIES CIRCULATING ANTIBODY RESPONSES ANTIBODY RESPONSE. >> ANOTHER QUESTION RIGHT OUT OF THAT, THANK YOU ALL VERY MUCH FOR THAT INTERJECTION. HOW LONG WOULD WE ANTICIPATE THAT THESE SINGLE GENE THERAPIES WILL LAST AND GIVEN THAT BUILD UP OF ANTIBODIES, CAN WE ANTICIPATE THE POSSIBILITY OF SECOND DOSE? AT LATER STAGE IN? >> WE KNOW IN A GIVEN NEURON THEY WILL PROBABLY LAST FOR THE LIFE OF THAT NEURON. THOUGH IN THE RETINA, THERE'S EVIDENCE FROM THE LCA WORK DONE BOTH FLORIDA AND SUBSEQUENTLY, THERE'S SOME WANING OF THE EFFECT BECAUSE NOT ALL CELLS ARE HAVE THAT LIFE LONG. SO THAT'S A CONCERN THAT THEY CUMULATIVE EFFECT IS NOT LIFE LONG BUT ANY GIVEN CELL, THEY SHOULD SUSTAIN THAT COPY INDEFINITELY, NOT TO SAY THAT THE OTHER ASPECTS OF VECTOR BEING THERE, GENE WON'T BE SILENCED OR INFLUENCED BY CHRONIC INFLAMMATION. RECESSIVE DISEASE, THERE IS ALSO THE POSSIBILITY OF LOSS OF TRANSGENE PRODUCT FROM INFLAMMATION BECAUSE IT'S NOVEL IN THE SETTING OF THAT WHEN THERE'S COMPLETE ABSENCE. THIS IS A FAVORABLE THING ABOUT SMA IS THAT THOSE THAT HAVE TRULY NO SMN, HAVE EMBRYONIC LETHALITY SO YOU NEVER SEE CHILDREN HAVE ZERO SMN, THAT'S BEEN FAVORABLE FOR THOSE STUDIES, IN OTHER CONDITIONS. WE IDENTIFY PATIENT WHOSE ARE TRUE NONSENSE MUTATIONS. PARTICULARLY IN AXONAL DISEASE. >> TO THE QUESTION WHETHER WE CAN ANTICIPATE A SECOND DOSE? >> I -- BAILEY WILSON CAN COMMENT, OBVIOUSLY WE HAVE TO ENSURE SAFETY IN EARLY STUDIES SO THE STANDARD THAT'S BEEN ADOPTED IS THAT -- AT THE MOMENT IS PATIENTS OTHER THAN UNIQUE CIRCUMSTANCES LIKE -- WE HAVE TO WEIGH RISK BENEFIT. BUT FOR THE MOST PART, IN IF SYSTEMIC ADMINISTRATION OF HIGHER DOSES OF VECTOR, THE STUDIES REQUIRE PATIENTS HAVE THE ABSOLUTELY NEGATIVE FOR EXPOSURE. WE HAVE A LOT TO LEARN ABOUT WHETHER -- WHAT EXPOSURE MEANS AND HOW TO DETECT IT. BECAUSE THE SERO POSITIVITY STATUS IS NOT THE ONLY MEASURE. WE KNOW CASES OF COLLEGE AGE KIDS WHO BECOME SUSCEPTIBLE TO MEASLES THOUGH THEY WERE VACCINATED EARLY IN LIFE. 'S ON THE NEWS. THAT MAY HAPPEN IN CONTEXT OF GENE THERAPY AS WELCH IT MAYBE THERE'S APPEARANCE OF BEING SUSCEPTIBLE BUT YET COULD HAVE SECONDARY IMMUNE RESPONSE FROM REMOTE PRIOR EXPOSURE SO THERE'S A LOT TO LEARN. THERE'S TOOLS AT OUR DISPOSAL TO MANIPULATE THE IMMUNE SYSTEM AND I REALLY MY EARLY WORK A LOT IN TRANSPLANT AND I DO NOW THINK THERE'S A LOT OF FEATURES OF ALLO GRAPH ORGAN TRANSPLANTATION IN GENE TRANSPLANTATION IS WHAT WE'RE ACCOMPLISHING IN A SIMPLER WAY ACTUALLY SO IT SHOULD BE ACHIEVABLE TO GET STABLE LONG TERM EXPRESSION. >> A QUESTION SEVERAL WRESTLED WITH IN THE PAST HOW SURE CAN WE BE FIRST DOSE IN A CLINICAL TRIAL WILL BE POTENTIALLY THERAPEUTIC? IT'S A QUESTION ON ALL OUR MINDS I THINK. >> FROM THE MTM TRIAL WE ARE WORK ON, DECISIONS WERE BASED ON PRE-CLINICAL ANIMAL MODELS AND ON ASSESSING ESPECIALLY LARGER ANIMAL MODELS AND SEEING THE LOWEST SAFEST MOST EFFICACIOUS DOSE IN AN ANIMAL MODEL THAT COULD HAVE AN AFFECT ON A HUMAN SO I THINK A LOT OF DECISIONS ARE BASED ON TOXICOLOGY, SAFETY TOLERABILITY AND WHERE WE'RE ABLE TO SEE A SIZABLE CHANGE IN A WAY IN ANIMAL MODEL BEYOND CELLULAR CHANGE FOR PATHOLOGY CHANGE OR SOMETHING LAB VALUE OR UNDER A MICROSCOPE WHERE WE'RE ABLE TO SEE A CHANGE IN THE ENTIRE ORGANISM WE COULD APPLY THAT TO THE TRIAL. THAT IS WHAT WE DID IN MTM TRIAL. >> THE AIM IS TO GIVE CLINICALLY SIGNIFICANT DOSE AND NOT JUST IMMUNIZE PARTICIPANT WITH NO PROSPECTIVE BENEFIT. BUT THERE IS NO WAY TO KNOW FOR SURE FROM THE OUTSET THAT THIS IS THE APPROPRIATE DOSE. SO IN THE GAN TRIAL WE HAVE GONE THROUGH SEVERAL DOSEs ASKLATIONS. AS A TRIAL HAS MOVED ON. >> I KNOW YOU HAVE A STRONG CONVICTION IN THIS REGARD. >> WE TRY TO AIM FOR SOMETHING BENEFICIAL BUT AS MENTIONED, WE EXTRAPOLATE FROM ANIMAL MODELS AN THOSE MODELS ARE NOT ALWAYS RELIABLE IN TELLING US ABOUT DOSE ESCALATION IN HUMANS SO WE MAKE OUR BEST EFFORT TO START WITH SOMETHING POTENTIALLY THERAPEUTIC. BUT IT CAN'T BE A GUARANTEE. >> HOW DO YOU DO A PLACEBO CONTROL GENE THERAPY TRIAL? >> I CAN SPEAK TO THIS. I THINK IT'S PUBLIC KNOWLEDGE NOW. THE TRIAL THAT WE HAVE BEEN INVOLVED IN ACTUALLY FDA AND WE FLIPPED TO SECON PHASE. A FEW THINGS TO CONSIDER IN THESE CONDITIONS ARE -- I THINK WE SKIPPED OVER A REALLY IMPORTANT QUESTION WE HAD IN THE BEGINNING, HOW DOES MY COMMUNITY PREPARE FOR THE PATH FORWARD IN A GENE THERAPY TRIAL. THIS WILL TIE IN. SO ONE OF THE BIGGEST IMPORTANT FEATURES IS RELIABLE AGE MATCH NATURAL HISTORY DATA. IN OUR RARE DISEASE COMMUNITY WE OFTEN RELY ON THIS NATURAL HISTORY DATA AS SOMETHING TO USE AS A SUBSTITUTE CONTROL GROUP IN A WAY TO SAY WE LOOK AT THE POPULATION OF THESE RARE CONDITIONS AND WHAT THE CHILDREN LOOK LIKE WITH THESE CONDITIONS OVER TIME. ARE WE ABLE TO BENEFIT FROM THAT HISTORICAL EXPERIENCE MOVE FORWARD AND SAY CAN WE LOOK AT THAT OVER A FEW HUNDRED YEARS OF STUDYING ONE OF THE MODELS AND WAYS WE CAN DO THAT IS NATURAL HISTORY DATA WHICH IS AT TIMES VARIABLE BUT AT TIMES MORE CONSISTENT. SOME OF THE THINGS WE ATTEMPTED TO DO IS HAVE SMALL GROUPS WITH ONE PATIENT SET ASIDE ADS A CONTROL, MONITOR FOR A CERTAIN PERIOD OF TIME, AND WHEN SAFETY AND EFFICACY IS DETERMINED TO A CERTAIN EXTENT BASED ON CRITERIA, TREAT CONTROL PATIENTS HANGING ON. IN SOME CONDITIONS THAT'S CHALLENGING BECAUSE THE TRIALS CAN GO ON PERHAPS LONGER THAN ANTICIPATED AND CONTROL PATIENTS ARE ILL AND VULNERABLE AND WE LOST PATIENTS AND CONTROL GROUPS WHILE WAITING FOR TREATMENT. ANOTHER APPROACH IS HAVING TWO PATIENTS OF SIMILAR AGE AND STAGE AT AGE OUTSET, HAVE A PRE-DETERMINED END POINT OBSERVE OVER END POINT OBSERVE PRIMARY OUTCOME MEASURES AND TREAT THE CHILD WHO HASN'T BEEN TREATED. FEW WAYS TO APPROACH IT, I' DISEASE DEPENDENT, IT'S TISSUE DEPENDENT, AGE DEPENDENT, DISEASE DEPENDENT, STATISTICS PLAY A BIG PART WHERE CAN WE SEE OUR GOAL IS WHERE CAN WE SEE A FUNCTIONAL MEANINGFUL OUTCOME IN SHORT AMOUNT OF TIME WITH MAXIMAL BENEFIT TO -- AND MINIMAL RISK TO ONE WAITING. IT'S A DRUGGABLE ACT. >> I'M SORRY TO INTERRUPT BUT SARA BROUGHT UP STATISTICS I THINK IN THE RARE DISEASE SPACE WE SHOULD KEEP AN OPEN MIND AND TRY TO FIND STATISTICAL MODELS THAT ARE BEST ADAPT TO THE RARE DISEASE COMMUNITY WHERE YOU MAY NOT HAVE THE LUXURY OF A CASE CONTROL. FOR EXAM IT WILL BILL THE BAYESIAN ANALYSIS IS ONE APPROVED BY THE FDA FOR DEVICES AND IS MORE -- BEING MORE USED IN RARE DISEASE AS WELL. IT ALLOWS FOR CONTINUOUS LEARNING MODEL, THAT DRAWS FROM NATURAL HISTORY INSTEAD OF USING A CONTROL. >> I CAN'T PASS UP THE OPPORTUNITY IS TO SPEAK IN FAVOR OF PLACEBO CONTROLS. DRUG DEVELOPMENT IS A VERY TOUGH BUSINESS. IF MOST PRODUCTS FAIL AND IF THE PEOPLE WHO GO INTO DRUG DEVELOPMENT AND THE ONES WHO SUCCEED, THAT I BELIEVE IN THEIR PRODUCTS. THAT I BELIEVE THEIR PRODUCTS WORK. IT'S NOT UNUSUAL THAT THEY WILL DO AN INITIAL TRIAL AND COME TO US WITH DATA AND SAY LOOK AT HOW WONDERFUL THIS EFFECT IS AND WE'LL LOOK AT DATA AND SAY I CAN'T TELL ANYTHING IS HAPPENING. YOU HAVE GOT TO DO TRIALS THAN CONVINCE PEOPLE WHO DON'T ALREADY BELIEVE YOUR PART WORKS. IN MANY CASES THE QUICKEST WAY TO FIND GOOD EVIDENCE IS WITH PLACEBO CONTROLS. AND IS AS MENTIONED EARLIER BY DR. SPENSON SCIENCE MOVES FORWARD BY FIGURING WHICH THINS WORK, WHICH DON'T WORK SO YOU CAN PUT ASIDE THE ONES THAT DON'T WORK QUICKLY. AND MOVE ON TO THE NEXT THING. PLACEBO CONTROLS ALLOW US TO DO THAT. >> INTERESTING TOPIC THAT HAS COME UP AND RECENT WORKSHOPS AND CONFERENCES, IF A PATIENT PARTICIPATES IN A GENE THERAPY TRIAL OR ASO TRIAL WOULD THEY BE ABLE TO PARTICIPATE IN OTHER CLINICAL TRIALS? OR RECEIVE ANY OTHER TYPE OF THERAPY? >> IT'S A LITTLE BIT OF CRYSTAL BALL. I THINK THE MORE UBIQUITOUS GENE THERAPY TREATMENTS AND AVAILABILITY BECOMES TRIALS WILL HAVE TO BE DESIGNED IN THE MODEL OF YOU HAVE AN EXISTING TREATMENT WITH ENZYME REPLACEMENT, YOU ARE NAVIGATING A GENE THERAPY TRIAL AROUND EXISTING THERAPY. I WILL SAY MOST TRIALS ARE INITIALLY DESIGNED TO SURVIVE JUST ADS MENTIONING, IF ISOLATING TO POINT OF CONTROL VERSUS TREATMENT ADDING IN AVAILABLE TREATMENT OR ANOTHER THERAPEUTIC AGENT CAN BE CHALLENGING. WE ARE GOING TO WATCH I UNFOLD WITH THE GENE THERAPY WITH SMA BUT I'M NOT SURE. >> JUST MENTION ON THAT NOTE, KIDS ARE GETTING BOTH. SO IN THAT CASE IT WASN'T EXCLUSION CRITERIA. PEOPLE GOING INTO THE ALEXIS TRIAL ALREADY KNOW. SO MOST CASE IT IS ETHICS ARE SUCH THAT WE WON'T BE ABLE TO PREVENT -- SEPARATE BUT IT DOES COMPLICATE THE OUTCOMES BECAUSE NOW YOU DON'T KNOW PRODUCT IF THERE IS AN EFFECT. ONCE PRODUCT IS APPROVED, INTO A DIFFERENT ZONE T STANDARD OF CARE. >> THE INTERESTING THING THAT WILL EVOLVE IS LIKELY A PAIR WILL COVER BOTH FORMS OF THERAPY. SO THE -- THOUGH THERE'S REGULATORY APPROVAL, IT'S VERY CHALLENGING TO RECEIVE APPROVAL FROM A FINANCIAL PERSPECTIVE AT LEAST INITIAL THERAPY WAS -- THAT'S THE ONLY WAY COMMERCIAL THERAPY WAS AD ON TOP OF IT. >> I THINK IN GENERAL GOING INTO A GENE THERAPY TRIAL, INVESTIGATIONAL PRODUCT GO TO THAT TRIAL YOU SHOULD UNDERSTAND YOU WILL PROBABLY BE INELIGIBLE FOR OTHER INVESTIGATIONAL TRIALS OTHER AGENTS. THE NEXT DRUG DEVELOPER DOESN'T WANT TO TAKE THE RISK TO HAVE COMPLICATIONS DUE TO THAT GENE THERAPY YOU RECEIVED BEFORE AND THOSE COMPLICATIONS WILL BE ATTRIBUTED TO THE SECOND PART. IF WE LOOK AT PROTOCOLS WE GET IND FOR, HAVING RECEIVED GENE THERAPY BEFORE, IS ALMOST ALWAYS EXCLUSION CRITERIA. >> WE SHOULD HASTEN TO ADD AS BARRY DID IN OUR CONVERSATION YESTERDAY. FULLY AGREE THAT THE NEW -- THE NEXT DRUG DEVELOPER IS GOING TO BE VERY RELUCTANT TO ENTER SUCH A PATIENT INTO THEIR CLINICAL TRIAL. ON THE OTHER HAND IF THAT CLINICAL TRIAL IS SUCCESSFUL, THERE'S NOWHERE WRITTEN EXCEPT MAYBE REIMBURSEMENT PAYERS THAT YOU WOULDN'T BE ELIGIBLE TO RECEIVE A SECOND TREATMENT. NOT PARTICIPATE IN CLINICAL TRIALS BUT IF THAT SECOND TREATMENT IS APPROVED, YOU WOULD BE ELIGIBLE TO RECEIVE THE TREATMENT IF YOU CAN FIND PAYER WILLING TO PAY. Q. THE EARLY STAGE COMPLICATIONS ARE NOTWITHSTANDING, COMBINATORIAL THERAPIES ARE THE MAIN STAY OF CANCER TREATMENT, THEY ARE LIKELY TO BE PART AND PARCEL OF TREATING RARE DISEASES AS WELL. IT IS NOT GOING TO BE EARLY DEVELOPMENT, THERE HAS TO BE STUDY DECEMBER SIGNED SPECIFICALLY TO SAY HAVE YOU HAD THERAPY A HOW MIGHT YOU BENEFIT FROM THERAPY B AND THERE WILL BE EITHER JOINT VENTURES OR SOME OTHER MECHANISM FOR DOING THAT. >> GREAT. ANY LAST WORDS FROM ANY OF THE PANELISTS? WE DIDN'T ASK THE LAST QUESTION ON OUR LIST OF WILSON ABOUT FROM THE FDA PERSPECTIVE WHAT SHOULD WE ALL DO TO PREPARE OUR PATIENT GROUPS FOR CLINICAL TRIALS. MANY OF THESE DISEASES AS YOU KNOW, THESE GENETICALLY DEFINED DISEASES ARE EXTREMELY RARE, AND HAS BEEN SUGGESTED EARLIER, WE DON'T KNOW THE NATURAL HISTORY OF THESE DISEASES. AND IF WE DON'T KNOW NATURAL HISTORY OF THE DISEASE IT MAKES IT VERY DIFFICULT TO DESIGN THE CLINICAL TRIALS. IT'S A STRONG PROPONENT OF WORKING, GETTING THE SCIENTISTS AND CLINICIANS AND ADVOCACY GROUPS, PATIENTS TOGETHER VERY EARLY, LONG BEFORE CLINICAL TRIALS AND ANIMAL STUDIES FIRST STARTED, TO TRY TO GET NATURAL HISTORY DATA SO THAT WHEN IT'S TIME TO DO CLINICAL TRIALS YOU HAVE THE NECESSARY INFORMATION TO DESIGN THOSE TRIALS. >> WE HAVE BEEN GIVEN A COUPLE MORE MINUTES. ANY QUESTIONS FROM THE AUDIENCE THAT WE HAVEN'T ADDRESSED? WE TRIED TO ANTICIPATE THE THINGS YOU WOULD WANT TO ASK. PLEASE P >> HAVE YOU TALKED ABOUT AAV, CAN YOU ADDRESS OTHER TECHNOLOGIES THAT ARE BEING DEVELOPED TO GET GENE THERAPY INTO THE BRAIN LIKE PARTICLES OR WHATEVER ELSE TO THINK ABOUT AND TO HOW YOU REGULATE THE DOSE IN BRAIN AND THREE HOW TO TRANSFECT MORE AREAS OF BRAIN RATHER THAN CORTEX. >> I CAN COMMENT. THERE ARE SOME PROGRAMS USING EX-VIVO GENE THERAPY WITH LENTIVIRAL VECTORS TO ALTER HEMATOPOIETIC STEM CELLS WIDOW HAVE THE ABILITY IN SOME SUBSET TO BECOME LEUKOCYTES GO INTO THE BRAIN AND SECRETE, THERE'S THAT -- REGARDING ALS THERAPY, THAT CAN BE DONE NOT ONLY WITH CELL PRODUCTS BUT A GENE MODIFIED CELL PRODUCT AND SO THAT'S AN EXAMPLE. THE DEEP BRAIN STRUCTURES IS NOT A LOT IS KNOWN. IN SOME OF THE STUDIES WHERE THERE'S SPECIFIC BRAIN REGIONS MOST VULNERABLE JUST AS IN DIRECT DELIVERY OF STEM CELLS THERE ARE EFFORTS TO DIRECT GENE THERAPY VECTORS TO THOSE STRUCTURES. THANKS TO SKILLED NEUROSURGEONS WHO CAN HAVE A NEW TOOL QUITE I THINK COLLEAGUES THAT I HAVE IN THAT AREA ARE QUITE EXCITED ABOUT PARTICIPATING IN THAT WORK. SO YES, THERE ARE STRATEGIES THAT ARE BEING EMPLOYED TO BEYOND THE CORTICAL TRANSDUCTION. >> A LOT OF INVESTIGATORS IN THE PRE-CLINICAL ARENA ARE DEFINITELY DIFFERENT TYPES OF ADMINISTRATIONS TO MAKE SURE THAT BOTH THEY HAVE FOUND WITH SOME ANIMAL MODEL, LYSOSOMAL STORAGE DISORDERS AS WELL THAT YOU HAVE TO GET THE SPINAL CORD AS WELL AS DISTRIBUTION THROUGHOUT THE BRAIN. AND SO DOING COMBINATORIAL TYPES OF INJECTION, DOING INTRATHECAL AND INTERVENTRICULAR TO MAKE SURE YOU ARE GETTING BOTH ASPECTS, BRAIN AND SPINAL CORD AND REGARDING THE THINGS LIKE MID BRAIN DEEP IN THE BRAIN, WE ARE FUNDING A CLINICAL TRIAL WHERE THEY ARE DOING MRI GUIDED INJECTION OF THE VECTOR INTO THE DEEP REGIONS OF THE BRAIN. AND SO FAR IT LOOKS EXTREMELY GOOD AS FAR AS THEY CAN DETECT BY MRI THE DISTRIBUTION WITHIN THAT REGION OF THE BRAIN AND HOW THE PATIENTS ARE DOING LONG TERM. >> THANK YOU VERY MUCH. I APPRECIATE YOUR COMMENTS. MY QUESTION IS ABOUT IT SEEMS LIKE THE TEMPLATE HERE IS MONOGENIC DISORDERS HERE. FOR ALL GOOD REASONS IT SEEMS LIKE -- BUT MY QUESTION IS AGE RELATED NEUROLOGICAL DISEASE TEND TO BE VAST MAJORITY SPORADIC IN NATURE SO YOU CAN ENVISION OR EVEN AUTISM COMES IN MIND WHERE HUNDREDS OR MORE GENES COULD BE IMPLICATED. HOW DO YOU ENVISION GENE THERAPY FOR MULTI-GENIC DISORDERS WHOSE LEVELS COULD BE TIGHTLY REGULATED, IN OTHER WORDS TOO MUCH OR TOO LITTLE OF THE THESE GENES COULD BE DETRIMENTAL, DO YOU ENVISION THIS BEING A ROADBLOCK AND IS THIS ON STACKCLE WE SHOULD BE DISCUSSING NOW. >> IT IS A BIGGER CHALLENGE BUT AT THE RECENT AMERICAN SOCIETY GENE THERAPY MEETING THAT KEYNOTE LECTURE BY GEORGE CHURCH HIGHLIGHTED WORK THEY ARE DOING TO DO UP TO HUNDREDS OF EDITING EVENTS AT ONCE USING GENE THERAPY VECTORS. CONCEIVABLY IF ONE WORKS OUT PROPER BALANCE OF THOSE THINGS IT DOESN'T NEED TO BE ONE TARGET AT A TIME OBVIOUSLY THERE ARE GREATER RISKS UNDER THOSE SIXER BUT IT'S A MATTER OF TIME UNTIL THE TECHNIQUES THEY USE TO CREATE THAT KIND OF ENGINEERED CELL ENVIRONMENT ALREADY APPLIED IN VIVO. >> YOU CAN IMAGINE HUNDREDS OF VECTORS IN A SINGLE DOSE. >> THAT DO EDITING. THE GUIDE RNAs ARE TO DIRECT GENE, THE CUTTING -- THE CAS 9 IS SAME AND GUIDE RNAs COULD BE ALL OVER THE PLACE. OBVIOUSLY THAT INCREASES THE RISK OF OFF TARGET EFFECTS BUT THIS IS BEING STUDIED NOW IN HIS LABORATORY. IN NON-CLINICAL MODELS. Q. FROM RIGHT NOW THERE ARE EFFORTS THAT HAVE BEEN MADE, ON THAT THIS IS NOT MY AREA BUT TROPIC FACTORS THAT HAVE BEEN FOUND TO BE BENEFICIAL FOR NEURODEGENERATIVE DISEASE HAVE BEEN TRIED OR YOU CAN IMAGINE IF THERE ARE COMMON PATHWAYS IN A DISEASE, KNOCKING DOWN A PARTICULAR PROTEIN THAT IS ACCUMULATING SO THERE ARE OTHER TYPES OF APPROACHES. IT'S MUCH MORE DIFFICULT. >> I STARTED OFF BEING OPTIMIST. BUT YOU FIXED THAT. I JUST THINK IT IS -- AND INDEED MANY DISEASES OBVIOUSLY ARE MAJOR HEALTH ISSUES FOR THIS COUNTRY, ALZHEIMER'S DISEASE, STROKE, SO MANY BAD DISEASES, BUT TRYING TO BEAT A DISEASE WHEN YOU DON'T UNDERSTAND THE DISEASE IS EXTREMELY DIFFICULT. UNTIL THE SCIENCE ADVANCES, SO THAT WE UNDERSTAND KEY STEPS IN THE PATHOPHYSIOLOGY OF THESE DISEASES. I JUST THINK CHOOSING THE RIGHT TARGETS AND YEAH, WE MAY GET SOMETHING THAT HAS WHAT I CALL INCREMENTAL EFFECT AND LITTLE EFFECT HERE AND THERE BUT IF WE REALLY WANT TO CHANGE THESE DISEASES, WE HAVE GOT TO HAVE THE SCIENCE THAT BETRULY UNDERSTAND. I THINK IN MANY CASES, WE ARE NOT THERE YET AND WE MAYBE QUITE A WAYS AWAY. WE WILL GET THERE. I'M NOT QUITE SO OPTIMISTIC. >> MY NAME IS AMBER FEED WITH SLC 6A 1 CONNECT. MY TWO-YEAR-OLD SON HAS MUTATION ON SLC 6A 1. MY QUESTION IS FOR YOU, WE ARE DEVELOPING A GENE THERAPY TO TREAT THIS CONDITION, IT'S A MONOGENIC LOSS OF FUNCTION. AS A PARENT YOU CAN -- MY VIEWPOINT NBA NOT Ph.D., AND IS THAT YOU CAN DO BASIC SCIENCE AND UNDERSTAND THE DISEASE. ALMOST INTO PERPETUITY. SO IT IS HARD FROM MY STANDPOINT TO BALANCE WHERE THAT STOPS AND WHERE HERE IS A SOLUTION DO WE NEED TO UNDERSTAND EVERYTHING IN ORDER TO TREAT IT. >> I THINK WE KNOW WELL THAT YOU DON'T HAVE TO UNDERSTAND EVERYTHING BUT YOU HAVE TO UNDERSTAND SOMETHING -- SOME KEY STEP IN THE PATHOPHYSIOLOGY. FOR EXAMPLE LOOK AT MULTIPLE SCLEROSIS. WE DON'T UNDERSTAND MULTIPLE SCLEROSIS. BUT WE HAVE GOOD TREATMENTS FOR MULTIPLE SCLEROSIS, NOT PERFECT BUT GOOD TREATMENTS. BECAUSE IT'S CLEAR THE IMMUNE SYSTEM IS A KEY STEP IN THE PATHOPHYSIOLOGY OF MULTIPLE SCLEROSIS. SO YOU DON'T HAVE TO UNDERSTAND EVERYTHING BUT YOU HAVE GOT TO UNDERSTND SOMETHING VERY WELL AND LET ME SAY, ONE OF THE BEST THINGS HAPPENING, GENE THERAPY, NO DISRESPECT TO ANYONE IN THE ROOM. BUT GENE THERAPY HAS BEEN AND STILL IS PRIMARILY AN ENTERPRISE BY ACADEMIC INVESTIGATORS AS SCIENTISTS. OVER THE LAST FEW YEARS WE HAVE SEEN THE PHARMACEUTICAL INDUSTRY GET INVOLVED MORE. THAT INVOLVEMENT BY PHARMACEUTICAL INDUSTRY IS A GOOD THING BECAUSE TOO OFTEN WE SEE SCIENTISTS AND ACADEMIC INSTITUTIONS WHO WERE TO STUDY AND STUDY AND CHANGE THAT MOLECULE A BIT AN CHANGE -- JUST DRIVES ME NUTS. BUT PHARMACEUTICAL INDUSTRY, THEY WILL CHOOSE A MOLECULE AND THEY WILL PUSH IT FORWARD. AND THEY WILL -- THEY DON'T STAY FOREVER IN PRE-CLINICAL. SO THAT I WANT TO TARGET BRINGING SOMETHING TO THE MARKET TO PATIENTS IS MENTALITY THAT PHARMACEUTICAL COMPANIES HAVE OFTEN MUCH MORE THAN THE ACADEMIC INVESTIGATOR. GETTING INDUSTRY INVOLVED IN GENE THERAPY HELPS TO MOVE THINGS FORWARD AND RARE DISEASES ARECAL LENNING BUT HOPEFULLY UNDERSTAND THE SCIENCE OF THESE THINGS WELL ENOUGH TO HAVE GOOD TARGETS AND FIND THESE FOR FOLKS. WE HAVE INDULGED YOU WAY TOO MUCH IN TAKEN 15 MORE MINUTES FROM YOUR RECEPTION AND POSTER SESSION SO PLEASE JOIN ME IN THANKING THESE WONDERFUL FAMILIES.