Vision Research: Breakthroughs & Clinical Care

Vision Research: Breakthroughs & Clinical Care


>>GOOD MORNING, THANK YOU TO THE ACD AND FRANCIS FOR THE OPPORTUNITY TO DESCRIBE SOME OF WHAT’S HAPPENING IN THE VISION RESEARCH, OBVIOUSLY THIS IS QUICK AND LIMITED TOUR. ANY FIELD HAS A BREADTH AND DEPTH TO IT THAT CANNOT BE SUMMARIZED IN 40 MINUTES. I WANT TO SPEND TIME IN TWO AREAS, FIRST ON ANY ADO SHUTS GOALS INITIATIVE AND THEN TURN TO SOME OF THE INTERESTING VENTURES AND BREAK THROUGHS THAT COME OUT OF GENETICS OF EYE DISEASE. SO LET ME START WITH THE AUDACIOUS GOALS INITIATIVE. THIS IN VERY BRIEF SUMMARY IS A 12 TO 15 YEAR EFFORT TO CATALYZE INNOVATION AND VISION RESEARCH. THE GOAL, THE GOAL IS TO REGENERATE NEURONS AFT ARE AND NEURAL CONNECTS IN EYE VISUAL SYSTEM AND PAYING PARTICULAR ATTENTION TO PHOTO RECEPTORS AT THE OTHER END OF A THIN NEURAL RETINAL TISSUE RETINAL GANG — GANGLION CELLS AND OPTIVE NERVE. LET’S CONSIDER WHAT HAVE WOULD BE AUDACIOUS? IT HAS TO BE BIG AND BOLD. IT OUGHT TO INSPIRING AND WHEN IT’S DONE IT SHOULD HAVE BEEN WORTH THE EFFORT. IT SHOULD FUNDAMENTALLY ADVANCE IN OUR CASE VISION RESEARCH AND ULTIMATELY VISION CARE. SOME THING ARE SOMEWHAT OBVIOUS, NEEDS TO BE ON THE EDGE OF AND EVEN BEYOND CURRENT TECHNOLOGIES, WE HAVE TO PUSH BOUNDARIES WITH THIS AND IT NEEDS TO HAVE MAJOR IMPLICATIONS WHEN IT COMES TO FRUITION AND IN SHORT, IT NEEDS TO BE MORE THAN AN RO-1. I BROACHED THIS TOPIC TO THE NATIONAL ADVISORY EYE COUNCIL SEVERAL YEARS AGO WITH A SLIDE SIMILAR TO THIS. IT SEEMED TO ME AT THAT POINT AND STILL THAT THE TIME IS RIGHT. WE HAVE HAD A REMARKABLE DECADE OF BIOLOGY LEVERAGING PUBLICATION OF HUMAN GENE COMPLIMENT FOR VISION WE HAVE HAD HUMAN OCULAR GENE THERAPY, WORKING WITH STEM CELL BIOLOGY INCLUDING IN PATIENTS. WE KNOW PATHOBIOLOGY AND WHEN I WAS A RESIDENT 30 SOMETHING YEARS AGO COULD BE ONLY DREAMED ABOUT. AND IN FACT HERE, WE NOW IN 2011 HAVE SELF-ORGANIZING NEURAL TISSUE, THREE DIMENSIONAL TISSUE CULTURES. SO WITH THAT, AS A STARTING POINT THE ADVISORY EYE COUNCIL BOUGHT INTO THIS ENTHUSIASTICALLY. AT THAT TIME THE AMERICA COMPETES RE-AUTHORIZATION ACT WAS FRESH AND THE IDEA OF DOING CHALLENGE PRIZES WAS IN THE WIND SO WE INCORPORATED THAT. THE VENTURE WAS NOT TO HAVE ANY EYE TELL THE VISION COMMUNITY WHAT TO DO BUT HAVE THE VISION COMMUNITY TELL ITSELF WHAT TO DO. WE CREATED TEN PRIZES WITH THE ENORMOUS AMOUNT OF $3,000. ENORMOUS BECAUSE THAT CATCHES THE ATTENTION OF A GRADUATE STUDENT OR POST DOC. AND EVEN AFTER TAXES YOU CAN BUY YOUR FRIENDS A BIG LUNCH. SO WE PUT A CHALLENGE PRIZE OUT, THAT NETTED 550, 548 SUBMISSIONS. NUMBER FROM OVERSEAS AND TO OUR GRATITUDE A NUMBER OF THESE HAD NO PREVIOUS NIH GRANTING EXPERIENCE. THESE WERE DULY DEIDENTIFIED AND JUDGED BY 81 REVIEWERS ORDERED AND ULTIMATELY TEN IDEAS SURFACED IN SIX TOPIC AREAS. WE THEN TOOK THIS THREE YEARS AGO IN FEBRUARY 2013, TO A MEETING OF 200 INVITED ATTENDEES. YOU MAY RECOGNIZE A FEW OF THESE PEOPLE. JOSH SANE IN THE FRONT ROW, HAS BEEN INSTRUMENTAL CENTRAL L IN THE BRAIN INITIATIVE, CONNIE SETGO, CALVIN PANG FROM HONG KONG, A GENETICIST FROM WORKING WITH CHINESE GENES. IF THERE ARE SUMP THINGS. — SUCH THINGS. AND TONYA REX IN THE FRONT, YOU DON’T KNOW HER BUT SHE’S AN ASSISTANT PROFESSOR AT VANDERBILT AND ONE OF THE TEN PRIZE WINNERS WITH THE IDEA OF LET’S FIX THE OPTIC NERVE AFTER OPTIC NERVE INJURY SUCH AS, FOR INSTANCE, GLAUCOMA. SO WITH THESE IDEAS IN MIND WE PROCEEDED FOR TWO AND A HALF DAY OF DISCUSSION. FRANCIS JOINED US ON THE THE OPENING SESSION ON A SUNDAY NIGHT, THANK YOU, FRANCIS, FOR GENEROUSLY TAKING THE TIME. AND I USE THIS QUOTE AS A MESSAGE TO THE VISION COMMUNITY BUT I THINK IT’S GENERALLY TRUE, IT’S OFTEN, SAYS FRANCIS, SEEMS TO ME THAT VISION RESEARCH IS A CAN COUPLE OF STEPS HAPPENING IN BIOMEDICAL RESEARCH, CLEAR VISION RESEARCH PLAYED A LARGE SHARE IN SCIENTIFIC BREAK THROUGHS, I CAN THINK OF THINGS IN THIS CASE THINGS SUCH AS THE FIRST CRYSTAL STRUCTURE OF A G PROTEIN COUPLED RECEPTOR. RHODOPSIN, A LOT HAS BEEN DONE WITH THAT WONDERFUL MOLECULE. OVER THE PAST DECADE, THE FIRST IN CLASS ADVANCES IN HUMAN GENE THERAPY, FOR AN EYE DISEASE AND FIRST HUMAN IPS CELL AND ES CELL APPLICATIONS. THE EYE AUDACIOUS GOAL, REGENERATE NEURONS AND CONNECT THEM, MAKE NEURAL CONNECTIONS IN THE EYE AND VISUAL SYSTEM, THIS WOULD ADDRESS THE PATHOPHYSIOLOGY OF A NUMBER OF SERIOUS EYE DISEASES. LARGE SCALE EYE DISEASES, AGE RELATED MACULAR DEGENERATION ARCMD. GLAUCOMA. A GENETIC FORM OF OPTIC NEUROPATHY AFFECTING THE MITOCHONDRIA IN THE OPTIC NERVE. A BROAD CRASS OF RETINAL DEGENERATIONS. BEYOND VISION, CERTAINLY THIS WOULD HAVE IMPLICATIONS FOR REGENERATIVE THERAPY IN OTHER NEURAL TISSUES, CNS AND SPINAL CORD. PLASTICITY, THE VISUAL SYSTEM IS A WONDERFUL PLACE TO STUDY PLASTICITY AND THIS WOULD ADDRESS CONDITIONS OF (INDISCERNIBLE) AND CENTRAL VISUAL PROCESSING DEFICITS. SO HOW DID WE APPROACH THIS? MY IDEA WAS TO ACCELERATE THE TRAJECTORY OF SCIENCE. WE WANT TO GO TO AN END LOCATION. WE DIDN’T KNOW THOUSAND GET THERE YET. WE NEED TO BE ADAPTABLE AND AGILE AS ADVANCES WERE MADE, TO MAKE ADJUSTMENTS TOWARD THAT END GOAL. I VALUE ALL RESEARCH. BUT IN THIS CONTEXT I VALUE RESEARCH THAT WILL GET US TO NEURAL REGENERATION. TO THAT END WE SET UP INDEPENDENT SCIENTIFIC LEADERSHIP COMMITTEE FROM OUTSIDE NEI ROTATING BASIS. WE INVOKED MULTI-DISCIPLINARY, IT’S A BIG WORD BUT MEANS A LOT OF PEOPLE KNOWING A LOT OF THINGS. I WANTED THIS TO BE ANCHORED IN THE ADVISORY EYE COUNCIL, THEY ARE I TOLD THEM RESPONSIBLE FOR MAKING THIS WORK. THE STEERING COMMITTEE, SOME OF THESE NAMES YOU WILL RECOGNIZE. MARK BLOOMENCRANS HAPPENED TO BE A BIOLOGICALLY GROUNDED OPHTHALMOLOGIST, CHAIR AT STANFORD UNTIL JUST RECENTLY. TRANSLATIONAL. THIS STEERING COMMITTEE IS A WORKING GROUP OF COUNCIL AND REPORTS BACK TO COUNCIL. IT NEEDS TO HELP CONCEIVE THE TRAJECTORY OF THIS. AND AS THE TRAJECTORY CHANGES WE WILL HAVE NEW PEOPLE TO SUIT THE TASK. OBVIOUSLY WE NEED TO KNOW WHERE TO GO AND WHAT THE GAPS ARE. AND WE NEED TO MONITOR THE PROGRESS. I WANT SOME OF THAT MONITORING TO HAPPEN FROM THE OUTSIDE. AT THE SAME TIME THIS WAS A BIG VENTURE, IS A BIG VENTURE, IT’S ONGOING. AND I WOULD PARTICULARLY APPLAUD FOR PROGRAM DIRECTORS DON TOM GREENWELL SHERRY WAKE AND MIKE STEINMETZ INSTRUMENTAL MAKING THINGS HAPPEN ALONG WITH A NEW HIRE STEVE BURKE WHO HAS BEEN ABSOLUTELY STELLAR. THIS GROUP CONSIDERS AND INTEGRATES RECOMMENDATION OF THE STEERING COMMITTEE HAVE TO MONITOR PROGRESS MAKE RECOMMENDATIONS TO THE EYE COUNCIL AND TO ME. AND PROVIDES LOGISTICAL SUPPORT NOT THE LEAST OF WHICH IS TO DRAFT THE FUNDING ANNOUNCEMENTS. THE FIRST PUBLIC VENTURE ON THIS WAS A YEAR AGO AT SOCIETY OF NEUROSCIENCE ON THE TOPIC OF RESTORING VISION AND REGENERATING THE OPTIC NERVE. 30 LEADING RESEARCHERS, IT WAS A CLOSED MEETING. AN IDEA GENERAL RIOTING MEETING TO — I ASKED PEOPLE TO CHAIR THE MEETING JEFF GOLDBERG. AT UCSD WORKING AMOCK THE BEST CURRENT WORK IN RETINAL CELL GANGRENION OPTIC NEXT AND BILL GUIDEO LOOKING IN LOWER SPECIES IN THE ORGANIZATION OF THE VISUAL PROCESSING CENTRAL PROCESSING. AND THE TOPICS THAT CAME UP WERE QUITE SIMPLE, GOLDFISH CAN REGENERATE NERVES. AND RETINAS. WHY CAN’T HUMANS DO THAT? HOW DO WITH WE REGENERATE THE RETINAL AXONS? INSUFFICIENT ASSAYS, LARRY BENOWITZ AT MET HAS A VIGOROUS PROGRAM IN OPTIC NERVE REGENERATION, THAT’S AFTER OPTIC NERVE CRUSH. IT WAS THOUGHT, BELIEVED DEEMED AT THIS MEETING THAT WE NEEDED TO QUICKLY MOVE TO A — SEVERING THE OPTIC NERVE AND LOOKING FOR RECONNECTIONS ACROSS THE AIR SPACE BETWEEN THE SEVERED ENDS. THAT MIGHT HAVE TAKEN LARRY SOME TIME TO DO ON HIS OWN BUT THE COMMUNITY PUSHED TO DO THIS IS VERY VIGOROUS. AND NOTE THAT THE FIRST OF THOSE MEETINGS WAS AT THE SOCIETY FOR NEUROSCIENCE, I’LL RETURN TO THAT IDEA IN A MOMENT. SIX MONTHS LATER CONVENIENTLY SIX MONTHS LATER THE ASSOCIATION FOR RESEARCH AND VISION AND OPHTHALMOLOGY LARGE MEETING 20, 25,000 VISUAL SCIENTISTS, MEETS IN THE SPRING EVERY YEAR. AND THIS YEAR IT MAY 2015, DAVID GAMBLE AND RACHEL WONING CONVENED ALSO A CLOSED MEETING AN IDEA GENERATING MEETING ON PHOTO RECEPTOR REGENERATION. DAVID GAN IS THE CURRENTLY LEADING PERSON IN THE COUNTRY GENERATING HUMAN ROD PHOTO RECEPTORS FROM IPS CELLS. AND RACHEL WONING IS THINKING ABOUT HOW THE CIRCUITRY IN THE RETINA IS ESTABLISHED AND OBVIOUSLY IF YOU TRANSPLANT PHOTO TOE RECEPTORS YOU NEED TO GET THEM CONNECTED SO THAT’S AN INTERESTING MATCH. AND DAVID RACHEL DIDN’T REALLY KNOW EACH OTHER BUT FOR THIS. SO THERE IN IS ONE OF THE OUTCOMES OF ADVENTURE LIKE THE AUDACIOUS GOALS INITIATIVE. EXPERTS ASSEMBLE TO LOOK AT THE OPPORTUNITIES AROUND PHOTO TOE RECEPTOR REPLACEMENT. THE WHITE PAPER ON THIS IS PUBLISHED AND IS RELEASED ON THE NEI WEBSITE, P YOU CARE TO LOOK, AMONG TOPICS OF WHAT ENDOGENOUS AND ENDOGENOUS SOURCES FOR PHOTO RECEPTORS TO BE TRANSPLANTED. RODS AND CONES, VERY DIFFERENT CELLS. NEURAL INTEGRATION. THE END COAL IS TO GET TO HUMANS SO WE’RE GOING TO NEED TO HAVE OUTCOMES ASSESSMENT WAYS TO KNOW MRS. SMITH MT. CHAIR BENEFIT FROM THIS. THAT MEANS WE NEED TO WORK OUR WAY THROUGH ANIMAL MODELS AND IDENTIFY TARGET PATIENT POPULATIONS. AND THEN TWO MONTHS AGO AGAIN RETURNING TO THE SOCIETY FOR NEUROSCIENCE IN OCTOBER 2015 IN CHICAGO, RECONNECTING NEURONS NOW WE MADE THIS AN OPEN FORUM. IT WAS A SATELLITE EVENT, AN OFFICIAL SATELLITE EVENT OF THE SOCIETY FOR NEUROSCIENCE WHICH IS SOMETHING QUITE NEW FOR THE NATIONAL EYE INSTITUTE. MIKE PRAYER AN CAROL MASON CHAIRED THIS, CAROL SOME OF YOU MAY KNOW IS THETY MEDIATE PAST PRESIDENT FOR SOCIETY FOR NEUROSCIENCE, LOOKING FOR TARGET ENGAGEMENT, WE WANTED TO MAKE THIS OPEN, WHICH IT WAS SO WE CAN ATTRACT THE INPUT FROM THE 30,000 VISION — EXCUSE ME, 30,000 NEUROSCIENTISTS WHO WERE ASSEMBLED IN CHICAGO. AND NOW LOOKING AHEAD TO THE SPRING UPCOMING IN MAY 2016, NOW WE’RE GOING TO HAVE A TOWN HALL MEETING AT THE VISION RESEARCH MEETING. ON THE TOPIC OF OCULAR DISEASE. WE HAVE OUR HANDLE — HANDS AROUND THE CONCEPTS OF BADE SICK BIOLOGY BUT IF WE ENGAGE HUMAN POPULATIONS,’S NEVER TOO EARLY TO THINK ABOUT THE DISEASES AND HOW ONE DOES THAT AND THAT MEANS ENGAGING CLINICIANS. I WOULD EXPECT THAT THIS IS GOING TO BE A SEVERAL-YEAR PROCESS FOR CLINICIANS TO REALLY THINK ABOUT WHAT IS APPROPRIATE TO DO AND FIRST THING TO DO. NOW, WITH ALL THOSE IDEAS IN HAND, WE ARE ABLE TO GET MONEY ON THE STREET. AND THE FIRST OF THE AUDACIOUS GOALS INITIATIVE AGI AWARDS WERE PUT OUT IN MAY, THIS PAST MAY, 2015. ON FUNCTIONAL IMAGING. YOU WILL KNOW THAT OPHTHALMOLOGY OPHTHALMOLOGISTS ARE TAKING IMAGES OF THE HUMAN EYE REGULARLY IN THE EYE CLINIC. BUT THOSE ARE STRUCTURAL STATIC IMAGES AND WE WANT TO MOVE THIS TO FUNCTIONAL IMAGING. THAT GETS TO SOME PRETTY BIG WORDS SUCH AS INTERFERON METRIC OPTO PHYSIOLOGY WHICH MEANS THAT WHEN THE RETINAL GANG GLEION CELLS GANGLION CELLS RECEIVES INPUT FROM THE NEURAL TISSUE RETINA, WHEN THE GANGLION CELL FIRES, A SIGNAL DOWN THE OPTIC NERVE THE CELL BODY TWITCHES. AND THROUGH PHASE CONTRAST INTERFERONOMETRY, ONE CAN LOOK AT THAT TWITCHING GANGLION CELL IN MRS. SMITH AND THE CHAIR, AT LEAST THAT’S WHERE IT’S HEADED. WE CAN DO IT IN ANIMALS, NOW WE IMMEDIATE TO MOVE THIS TO PEOPLE, THAT’S THE FIRST OF THOSE US A TIN (INDISCERNIBLE) AND YOU CAN SEE THAT THE OTHER FOUR ALSO HAVE THE THEME OF FUNCTIONAL IMAGING, SOME INTERESTING NAMES, CONNIE SETGO IS THERE, BOTO ROSCA WHO HAS A MAJOR ADDRESS AT THE SOCIETY FOR NEUROSCIENCE LAST YEAR. SOME — VERY GOOD PEOPLE SO THE THEME NOW ON THE LEFT SIDE OF THIS SLIDE ON THE BOTTOM FOUR BOXES, FOAs ISSUED, APPLICATIONS RECEIVED, REVIEWED, AND PAYMENT PLANS ANNOUNCED, THAT STANDARD NIH BUSINESS. WHAT HAVE WE HAVE ADDED THAT IS NEW AT LEAST FOR THE EYE INSTITUTE, IS THE TOP ON THE LEFT, THE TOP THREE BOXES, VIGOROUS COPIOUS INPUT FROM THE BROAD SCIENCE COMMUNITY. ON THE RIGHT SIDE, WE ARE LOOKING TO CHANGE THE SOCIOLOGY HOW THINGS ARE DONE. WE ARE ASKING POLITELY BUT ACTUALLY REQUIRING STRONGLY THERE BE COLLABORATION COOPERATION WITHIN THE GROUP SO THAT GROUP OF FIVE AWARDS ON FUNCTIONAL IMAGING HAS AN OVERSIGHT COMMITTEE EXTERNAL OVERSIGHT COMMITTEE BUILT INTO IT, AT ANNUAL MEETING TO GET THE PEOPLE TO SIT AND TALK AND WORK TOGETHER. OBVIOUSLY THIS IS GOING TO TAKE BROAD EXPERTISE FROM MANY DISCIPLINES, NEUROSCIENCE, YES. MOLECULAR GENETICS, I HAPPEN TO LIKE THAT. DEVELOPMENTAL BIOLOGY, STEM CELL BIOLOGY, BIOINFORMATIC, THERE’S SOMETHING HERE FOR EVERYONE. BUT IT MEANS NO SINGLE LABORATORY HAS THE WHERE WITH ALL TO PUT ALL THIS TOGETHER. TO START WITH FUNDAMENTAL BIOLOGY AND HAVE INSIGHTS, AND BREAK THROUGHS, FOR INSTANCE, RECONNECTING NEURONS WOULD BE A BREAK THROUGH, A BASIC BIOLOGY BREAK THROUGH. AND THAT IS GOING TO BE ESSENTIAL IN ORDER TO MOVE DOWN THE PATHWAY TO INTEGRATING INFORMATION AND ULTIMATELY CONDUCTING CLINICAL THERAPY TRIALS. SO THIS IS NOT IN ONE SENSE A TRANSLATIONAL SCHEME, THIS TAKES BASIC DISCOVERY ONGOING AND THEN INTEGRATING THAT INTO A GOAL. WE WANT TO GET SOMEWHERE. THE SPECIFICS SOMEWHERE. TIME LINE, WELL WE’RE ACTIVELY MANAGING THIS, I WOULD THANK STEVE BECKER FOR HELPING THE PROGRAM DIRECTORS TO HELPING TO ACTIVELY MANAGE THIS, WE HAVE MONEY ON THE CRETE THAT ON THE BOTTOM, THE BLUE BOX, WITH WE HAVE A ROUND CIRCLE DEADLINE IN JANUARY 16 FOR ANOTHER RFA, WE ARE PUTTING MONEY ON THE STREET. OBVIOUSLY MONEY ATTRACTS INTEREST IN THE VISION COMMUNITY. SO THAT’S THE AUDACIOUS GOALS INITIATIVE. NOW, A WORD FROM OUR SPONSOR. WORD FROM OUR SPONSOR. NATIONAL EYE INSTITUTE, JUST A FEW SLIDES. BUT WE HAVE A MISSION STATEMENT, THE SECOND LINE SAID — SAYS WITH RESPECT TO BLINDING EYE DISEASES, VISUAL DISORDERS MECHANISMS, WE WANT TO ADVANCE KNOWLEDGE OF THE VISUAL SYSTEM, WANT TO HELP PREVENT AND TREAT EYE DISEASE, IMPROVE QUALITY OF LIFE FOR PEEP. PARTICULARLY VISION QUALITY OF LIFE. TO DO THAT THE AMERICAN TAXPAYER COMMITTED THIS PAST YEAR APPROXIMATELY 670, $670 MILLION. WE HAVE 257 FTEs, THESE NUMBERS ARE IMPORTANT BECAUSE THESE ARE THE PEOPLE WHO DO THE WORK. THAT GET AGI TO HAPPEN. WE HAVE DOUBLE THE CONTRACTORS FOR A STAFF APPROACHING 600 PEOPLE, MONEY IS DISTRIBUTED IN A WAY INSTITUTES DISTRIBUTE THE MONEY, 82% GOES TO EXTRAMURAL RESEARCH PROGRAM. WE DO HAVE AN INTRAMURAL AND WE HAVE ADMINISTRATIVE COST AND TAPS. LOOKING AT THAT BIG CHUNK OF MONEY, THE EXTRAMURAL FUNDING, NEI RECEIVES 850 TO 900 ROI APPLICATIONS A YEAR, THE MAJORITY GOES TO FUNDS RO-1 APPLICATIONS, WHICH MEANS THAT WE — THE EYE INSTITUTE FUNDS SOMEWHAT MORE RO1s RELATIVE TO BASE THAN DO MANY OTHER INSTITUTES WE FUND CURRENT YEAR 18 TO 20% OF THE APPLICATIONS THAT COME IN. BUT THIS IS A VERY ACTIVE PORTFOLIO, NEW PROJECTS MU IDEAS, A THIRD OF THOSE APPLICATIONS ARE FOR NEW IDEAS AND NEW PROJECTS. AND ONE-THIRD OF THOSE APPLICATIONS ARE COMING FROM NEW INVESTIGATORS. WE TAKE PARTICULAR CARE FOR NEW INVESTIGATORS AND NEW INVESTIGATOR SUCCESS RATE HIGHER FOR ESTABLISHED INVESTIGATORS SUBMITTING NEW APPLICATIONS. WE ACTIVELY MANAGE THE PORTFOLIO, BOTTOM TWO POINTS PERHAPS ESOTERIC FOR MANY ACD MEMBERS BUT NOT FOR NIH PROCESS. ONE OF SEVEN GRANTS IS PAID OUT OF ORDER FOR PROGRAMMATIC RELEVANCE. A NUMBER ARE SELECT PAY, AGAIN TO FUND NEW INVESTIGATORS. AND A NEW CONCEPT THAT IS EVOLVING, YOU CAN ASK JIM ANDERSON ABOUT THIS LATER IF YOU WISH. OVERLAP FUNDING CO-EFFICIENT AT NEI IS THE HIGHEST AT NIH. THE INTRAMURAL PROGRAM, WE COMMIT ABOUT $50 MILLION A YEAR, STAFF A LITTLE OVER 300 PEOPLE, 25 LABORATORY SECTIONS ORGANIZED IN FIVE THEME LABORATORIES. SCIENTIFIC CORES BUT I PARTICULARLY HERE POINT TO THE CLINICAL ACTIVITY THAT WE DO, THE OFFICE OF CLINICAL DIRECTOR, WE HAVE AN ACTIVE OUTPATIENT CLINIC. QUESTION SEE A GOODLY NUMBER OF INDIVIDUALS EVERY YEAR, 8500 IN 50 ACTIVE CLINICAL PROTOCOLS. VIGOROUS CONSULT SERVICE TO PEOPLE THAT PROVIDE 3,000 CLINICAL CONSULTS A YEAR, THIS IS SERVICE TO THE NIH CLINICAL CENTER INTO THE OTHER ICs. LAST, IF YOU THINK EVERYTHING IS LOOKING INWARD TO VISION ALONE, WE ARE EXTREMELY PLEASED TO PARTICIPATE WITH THE BRAIN INITIATIVE. OTHER 15 MEMBERS ON THE INITIAL BRAIN WORKING GROUP, FOUR WERE VISION BASED INCLUDING BILL KNEWSOME FROM STANFORD WHO CO-CHAIRED THAT GROUP. AND PETER MCLEISH, DICK NORMAN, JOSH SINGS. THE FIRST AWARD WERE PUT OUT IN 2014, VISION RESEARCH I’M PLEASE PLEASED TO SAY DID FINE. THANK YOU. WE VISION RECEIVED 41% OF THE AWARDS AND 47% OF THE FUNDS BECAUSE OF THE ORGANIZED THE NEURAL STRUCTURE ANOTHER RETINA. GREAT DISCOVERY HOW NEURAL SYSTEMS ARE ORGANIZED. THE SECOND TRANCHE 2015 AWARDS, 20% WENT TO VISION. LET ME RETURN THEN TO SOME IDEAS OF ADVANCES THAT ARE HAPPENING IN EYE AND VISION. AND THE EYE OBVIOUSLY I FIND IT A FASCINATING TISSUE WHEN I SEE PATIENTS AND LOOK AT IDEAS THAT ARE FLOWING PAST MY DESK. AT THE FRONT OF THE EYE WE HAVE A VERY NOVEL TISSUE, THE ONLY OPTICALLY CLEAR TISSUE IN THE BODY. THERE’S IN WAY TO LOOK AT THE KIDNEY THROUGH THE SKIN BUT YOU CAN LOOK AT THE NEURAL RETINAS FROM — THROUGH THAT CLEAR TISSUE. THAT FOCUSES LIGHT ON THE BACK OF THE EYE. THE NEURAL RETINA AT THE BACK OF THE EYE NICELY ORGANIZED IN LAYERS THAT ARE BY KITLY CONNECTED AND SERVE TO PROCESS SIGNALS FROM THE PHOTO TOE RECEPTORS, THE RODS HERE IN BLACK, THIN BLACK RODS AND RED GREEN AND BLUE CONES. SO LEST YOU THINK THAT EVERYTHING IS FOCUSED ON THE RETINA, IN FACT WE HAVE VIGOROUS ACTIVITY AT THE FRONT OF THE EYE, THE CORNEA LENS ALSO. THIS IS A DIFFERENT WAY TO LOOK AT WHAT I’M GOING TO BE PRESENTING. THESE ARE VISION DISEASES THAT HAVE A GENETIC BASIS. THE LENS, CATARACT. YOUNG CHILD LOOKING AT YOU CROSS EYED WITH STRABISMUS. GENES DRIVE THAT. IRIS COLABOMA A DEHIZENS OF THE EYE AT INSERTION HERE. MACULA, MACKLOPOTHY, STAR GART, ABCA 4 TRANSPORTER MACK HOPTHY. AGE RELATED MACULAR DEGENERATION WITH THE — IMAGINE WHAT YOUR RETINA LOOK LIKE IF YOU HAVE BLOOD, YOU LOSE VISION IN AGING FROM MACULAR DEGENERATION. OPTIC NERVE AXON LOSS ENLARGES THE CUP IN GLAUCOMA. IT’S BEEN A REMARKABLE DECADE FOR THESE GENETIC BASE VISION DISEASES, I WOULD ANCHOR THIS BACK HA A STRONG PIVOT POINT IN 2001 WITH HUMAN GENE COMPLIMENT BEING PUBLISHED. SO VIGOROUS IS THE ACTIVITY IN THE GENETIC BASIS OF UNDERSTANDING OUR SYSTEMS THAT WE CAN NOW MAP OUT SYSTEMS BIOLOGY PHOTO TRANSDUCTION GENES THAT INVOLVE TRANSDUCTIONS IN THE GENES, ABCA 4 I MENTIONED FOR STAR GART A VITAMIN A TRANSPORTER FROM PHOTO RECEPTOR THE TO PIGMENT DISEASE. MACULAR DEGENERATION. TO DOES A GREEN PHOTO RECEPTOR, THEY DON’T MAKE THEM GREEN BUT IN THE ILLUSTRATION IT’S GREEN. AT THE TOP THE BLUE RETINAL PIGMENT EPITHELIUM CELL VISION CYCLE RETINOID PROCESS GENES THAT CAUSE DISEASE, NUMBER LISTED HERE, DISEASE INCLUDING RHODOPSIN IDENTIFIED IN 1989 OR 1990. ONE IS A GENE CALLED RS 1 X LINKED RETINA SKSIS. I WENT TO FRANCIS IN HIS LAB AND SAID HOW DO I DO THIS GENETIC STUFF? AND HE SAID HE SAID FIRST YOU HAVE TO FIND THE GENE. SO THE GENE WAS LAB HERE AT NIH, ONE DIRECTOR MAINTAINS A LABORATORY, I HAVE BEEN PUSHED THE RETINA PROTEIN AROUND, WE HAVE NICE CRYO-EM IMAGES OF THIS MOLECULE THIS SUMMER AT FOUR ANGSTROM RESOLUTION, INTERESTING TO GO FROM A DISEASE CONCEPT TO A MOLECULE. NOW WE HAVE THIS IN CLINIC, INTERESTING TO MY SIDE TO WORK THROUGH THE PROCESS OF FILING AN IND WITH THE FDA. I LEARNED A LOT. IN THAT PROCESS. THAT WILL BE HELP MISDEMEANOR THE NEXT TRANCHE, THAT’S NOT ALL, IT’S GLAUCOMA. HERE ARE GENES COMMON ADULT ONSET OPEN ANGLE PRIMARY OPEN ANGLE GLAUCOMA POAG. GENES, MANY GENES NOW THAT HAVE SMALL, RISK FACTORS. OR GENES THAT HAVE LARGE EFFECT APPROACHING MENDELIAN TRAITS FOR NORMAL TENSION GLAUCOMA, ONTY NEURON. LARGE EFFECT GENES SMALL EFFECT GENES RARE DISORDERS, COMMON DISORDERS. THE GLAUCOMA STORY IS STARTING TO BE PUT TOGETHER. THIS IS BEING LED BY JANIE WIGS AND IT IS A NETWORK THAT NEI ESTABLISHED OF NEIGHBOR AND NEIGHBORHOOD NETWORK. OF ABOUT 10 OR 12 INSTITUTIONS AN INVESTIGATORS. HERE THE CHILD IS LOOKING AT YOU WITH CROSSED EYES MISALIGNED EYES. ELIZABETH ENGLE IS A LEADING PERSON IN THIS. THIS CHILD IS NOT SLOPEY, AT THE BOTTOM TRYING TO LOOK AT YOU AND LOOKING JUST THROUGH — CHILD CAN’T OPEN THE LIDS. OFTEN WITH OCULAR ALIGNMENT GOES LID PROBLEMS. ELIZABETH HAS FAMILIES SHE’S ACCUMULATED, ACQUIRED ACTIVELY SOUGHT OUT AND GWAS IS GOING ON BUT AT THE SAME TIME WE HAVE IN THE PAST DESAID SINCE 2001 ANOMALY COME TO UNDERSTAND THE DEVELOPMENTAL — GENES THAT CONTROL DEVELOPMENTAL REGULATION FROM THE NUCLEI TO CONTROL THE EYE POSITION IN THE EXTRAOCULAR MUSCLES. THESE GENES WHICH ARE DEVELOPMENTALLY IMPORTANT IN MOUSE, ET CETERA, MUTATIONS CAUSE HUMAN DISEASES. DWAYNE SYNDROME, NOBODY IN THIS ROOM KNOWS DWAYNE SYNDROME. BUT IF YOU’RE RESIDENT IN OPHTHALMOLOGY YOU LEARN ABOUT THAT BECAUSE IT’S A OCULAR STRIBISMIC PROBLEM AND IT IS A MISINNERVATION OF EXTRAOCULAR MUSCLES, THE NEURAL PATHWAY HERE IS DEVELOPMENTALLY DEVIATES FROM THE PROPER LOCATION, SO THIS IS COMING ON VERY NICELY. MEANWHILE THE VISION COMMUNITY HAS BEEN THOUGHTFUL AND ACTIVE IN DOING SOMETHING ABOUT THIS. HUMAN GENE THERAPY, OCULAR GENE THERAPY, RP-65 REPLACEMENT RESTORES VISION. LET ME TELL YOU THIS STORY QUICKLY, CONGENITAL AMOROSIS THESE ARE PATIENTS I SAW AS A RESIDENT, I LEARNED LCA BLIND KITS, PIPELINE KITS IN 1969 WHEN DR. THEODORE LABOR DESCRIBED A FEW. USUALLY IT’S E RECESSIVE SO NO FAMILY HISTORY, THE EYES ARE BOBBING AROUND SWINGING, THEY HAVE NYSTAGMUS, ELECTRICAL FUNCTION OF THE RETINA, NONE EXIST SO THIS WAS A SIMPLE IDEA. NOW, THERE ARE 19 GENES ASSOCIATED WITH LCA, AT LEAST AS OF RECENT DATE. ONE OF THOSE RP 65 FUNCTIONENING THE RPE, HERE IS A PHOTO RECEPTOR IN THE RPE, IT’S VITAMIN A CYCLE GENE, IT IS THE RETINOID ISOMERASE IN THEMENT EPITHELIUM THAT ASSISTS MOLECULE IN VITAMIN A CYCLE CRITICAL FOR VISION. WITHOUT H THAT THE PHOTO ACCEPTTOR STRUCTURE CAN BE DO THERE BUT IT THE DOESN’T FUNCTION. YOU CAN HAVE A CAR WITH THE PERFECT MOTOR BUT NO GAS, IT DOESN’T RUN. THIS IS THE ENZYME THAT CONVERTS CARROTS VITAMIN A, TO THE MOLECULAR FORM THAT’S USEFUL FOR VISION. THE STORY STARTS HERE AT NIH IN 1993 MIKE REDMOND IN THE EYE INSTITUTE IDENTIFY AD COPIOUS GENE COPIOUSLY EXPRESSED IN THE RETINA. FUNCTION UNKNOWN, ABUNDANT PROTEIN, RP 65. HE MAKE A KNOCK OUT MOUSE AND FOUND THE MOUSE WAS BLIND AND A RETINOID PROCESSING PROBLEM. A YEAR LATER, IN SWEDEN A DOG WAS IDENTIFIED WITH AN RP-65 MUTATION ACTUALLY FOUR BASE PAIR DELETION FOUND HUMAN, AND WITHIN TEN YEARS CONVERTED TO HUMAN GENE THERAPY. SHOWN HERE MACGUIRE JEAN BENNETT NOW MACGUIRE PIONEERED THIS. THIS IS CORRY, IF YOU LOOK UP CORRY IN RP-65 ON THE WEB YOU FIND NICE CLIPS OF PUBLIC TV. GOOD ADVERTISINGS FOR NIH. BUT I WOULD SAY THAT IT’S NOT JUST GENE — SIMULTANEOUSLY THERE’S THREE INDEPENDENT GROUPS WHO PUBLISHED THIS FINDING. OF SUCCESS IN HUMAN OCULAR GENE THERAPY FOR RP-65, VIGOROUS DEEP VISION RESEARCH COMMUNITY. DIFFERENT VECTORS. DIFFERENT PROMOTERS. AND SUCCESS ALL AROUND. NOW IN 2015, WE HAVE THE FOLLOWING CLINICAL TRIALS AT THE TOP, RP-65, NCI MERTK IS BEING TRIED IN A SAUDI POPULATION, THIS IS COMING OUT OF ENGLAND. SOME IN DIRECT WAYS OF MODERATING AMELIORATING AMD. NOT NECESSARILY SUCCESSFUL BUT BEING TRIED STAR GART, VERY BIG GENE, ONE OF THE BIGGEST KNOWN, IT’S HARD TO FIT INTO AAB SO IT’S PUT INTO A LENTIVIRUS, WHICH TARGETS THE RPE BUT THE GENE IS FUNCTIONING IN THE PHOTO TOE RECEPTOR, NOT SURE THAT IS GOING TO WORK. USHER IS DEAFNESS AND BLINDNESS, MULTI-SENSORY. RETINA SKESIS, I STARTED THIS TRIAL IN NIH IN FEBRUARY, WE HAVE DOSED NINE PEOPLE AND ARE ON OUR WAY TO SEEING WHAT HAPPENS. ACHROME TOP SEEIA STARTED BY (INDISCERNIBLE) FOUR WEEKS AGO IN GERMANY AND I ADDED THIS, THIS WILL BE AN NIH VENTURE, DR. WU AT THE EYE INSTITUTE HAS THE PRE-CLINICAL WORK WELL UNDERWAY. IT’S BEEN A REMARKABLE DECADE FOR US. THOSE ARE MONOGENIC DISEASE. WHAT ABOUT THE COMMON COMPLEX DISEASES? TO MY AMAZEMENT 2005 COMMON FACTOR H, FIRST USE OF THE INTERNATIONAL HAT MAP THANK YOU TO THE GENETICS LEADERSHIP INCLUDING HERE AT NIH. COMMON REFRACTORY FOR AMD, AMD THE SCOURGE OF VISION LOSS AS ONE GETS OLDER IN 2 MILLION AMERICANS, 8 MILLION AT RISK. WE’RE ALL GETTING OLDER, WATCH OUT. HERE IS A HEMORRHAGE, YOU CAN’T LOOK THROUGH THAT HEMORRHAGE, AWFUL THING FOR THE DOCTOR TO SEE, WORSE FOR PATIENT. THE NEURAL TISSUES BECOME ATROPIC, THE CELLS DIE. PREMONITIONS OF AMD YOU CAN SEE CLINICALLY, DON’T KNOW HOW TO HANDLE IT YET. WE DON’T KNOW THE PATHWAYS. WE DON’T KNOW MECHANISMS. COMPARED TO A NORMAL EYE. SO THE FINDS OF COMPLIMENT FACTOR H, ACTUALLY IT WAS FIVE GROUPS SIMULTANEOUSLY, AGAIN, THE DEPTH OF WORK OR MAYBE IT’S THE FOCUS OF WORK, IN THE VISION COMMUNITY, RATHER ASTONISHING I THINK, FIVE GROUPS SOME PUBLISHING IN THE SAME ISSUE OF SCIENCE, I HIGHLIGHT THIS BECAUSE EMILY WHICH YOU IS HERE AT NATIONAL EYE INSTITUTE, JOHN PAUL SANGIAVANNI AND RICK FAIRS, THIS STUDY WAS DONE ON BASIS OF AGE RELATED EYE DISEASE PATIENTS WHO WERE SEEN HERE AT THE NIH CLINICAL CENTER. SO COMPLIMENT PATHWAY GENE. THEN A YEAR LATER IN 2006 TWO MORE COMPLIMENT FACTORS, FACTOR B AND C 2, THOSE THREE GENES HAVE A REMARKABLE CUMULATIVE RISK. FOR ARCMD. THE PACE OF GENE DISCOVERY GOES ON NOW IT IS UP TO 34 LOCI WITH 52 INDEPENDENT GENETIC EFFECTS HOW DO WE PUT THAT STORY TOGETHER, THAT IS NATURE GENETICS, EMINENTLY. THIS IS A AMD NETWORK THE NEI FORMED AND IT IS NOW TAKEN ON INDEPENDENT LIFE, ACCUMULATING SOMETHING LIKE 35,000 AMD CASES AND CONTROLS, THAT GIVES THE DEPTH OF PATIENT PATHOLOGY TO NET 52 INDEPENDENT GENES. SO WHERE ARE THESE GENE? THEY’RE IN THE COMPLIMENT CASCADE, AT LEAST THE INITIAL TRANCHE. OTHERS ARE INVOLVING LIPID METABOLISM. OTHERS INFLAMMATORY FACTORS. COMPLIMENT FACTOR H SITTING RIGHT AT A CONTROLLING POINT, FOR ALL THREE PATHWAYS C-2 AND FACTOR B WERE THE SECOND GENES SET OF GENES FOUND THOSE THREE ACCOUNT FOR HIGH CUMULATIVE RISK FOR DEVELOPING AMD. FACTOR D IS INTERESTING, IT’S ALSO IMPLICATED AND ONE OF THE CLINICAL TRIALS CURRENTLY GOING ON IS ANTI-FACTOR D COMPOUND THAT LOOKS LIKE IT MIGHT HAVE LIFE TO IT. (OFF MIC)>>THAT’S — THANK YOU, THAT’S AN INTERESTING QUESTION, IT’S DRY OR WET. THESE CAME OUT OF WET. AND THE QUESTION IS, THE RELATIONSHIP OF DRY TO WET. ATROPIC TO HEMORRHAGIC. NOT FULLY UNDERUNDERSTAND WHAT THAT — UNDERSTOOD WHAT THAT RELATIONSHIP IS. I SAID ANTI-FACTOR D LOOKS HOPEFUL BUT MEAN CHILD WHILE 43 TRIALS ARE UNDERWAY MAJORITY WHICH ARE TARGETING FACTORS IN THE COMPLIMENT CASCADE AND THE OVERWHELMING MAJORITY OF WHICH ARE PROVING NOT SUCCESSFUL SO WE NEED TO GO BACK AND UNDERSTAND THE BASIC BIOLOGY. MEANWHILE, WE’RE NOT DOING JUST GENETICS BUT TREATING PATIENTS, HERE IS A CLINICAL PROTOCOL T FOR DIABETIC MACULAR ADEE MA HEAD TO HEAD COMPARISON. THIS IS THE FIRST ADVANCE IN THE LAST 40 YEARS. THIS CAME OUT THIS YEAR, IT IS GOING TO CHANGE THE COURSE OF MEDICINE. STEM CELL THERAPY, ACT HAS THE FIRST HUMAN ES THERAPY, THESE ARE CELLS PUT INTO THE SUBRETINAL SPACE, LITTLE CELLS ON CLINICAL IMAGING, CELLS PUT INTO SUBRETINAL SPACE OF PATIENTS WITH AMD. IPS CELLS, NOW THIS IS BEING WORKED ON HERE AT THE EYE INSTITUTE, ONE OF OUR INVESTIGATORS AUTOLOGOUS CELL BASED THERAPY FOR AMD USING IPD DERIVED RPE CELLS, BLOOD REPROGRAMMED TO NET HUMAN RPE CELLS, THIS PROCESS HAS BEEN VETTED THROUGH THE FDA AND THEY’RE MORE THAN PLEASED WITH IT. SO WE ARE ON TRACK TO FILE THE FIRST IN THE THIS COUNTRY IPS BASED IND IN THIS CASE FOR AMD, A LOT OF CODE WORDS. WE STARRED WITH CENTER FOREIGN GENRETIVE MEDICINE FRANCIS SET UP, WE OBTAINED SEED FUNDING AND NOW SUCCESSFUL IN THERAPEUTIC CHALLENGE WORK BY NIH MATCHING THOSE FUNDS OFF AND RUNNING HAVING PICKED UP DOD MONEY IN ADDITION TO DO THIS, THEY’RE INTERESTED IN 3-D OCULAR TISSUES AND PARTNERING, A LOT OF PARTNERING. N CATS, CELLULAR DYNAMICS MADISON CLINICAL CENTER. THAT PARTNERING IS IMPORTANT, IT’S SOMETHING THE EYE INSTITUTE IS CONTRIBUTING TO THE CLINICAL CENTER. WE SET UP A RELATIONSHIP WITH CDI IN MADISON, WISCONSIN. THEY HAVE GLP AND GMP MANUFACTURING PROCESSES, THEY TOOK OUR PROTOCOLS, HAVE PUT THEM THROUGH THEIR MODIFIED PROCESSES, DELIVERED THEM TO US AND THESE WILL GO INTO HUMAN PATIENTS, IN THE CLINICAL CENTER, MEANWHILE THIS IS BEING TRANSFERRED TO THE CLINICAL CENTER FOR USE BY ANYONE HERE AT NIH. IN A PIG MODEL YOU CAN SEE A SINGLE LINE HERE BUT A DOUBLE LINE, THE DOUBLE LINE IS THE TRANSPLANT IN THE SUBRETINAL SPACE OF A PIG, RPE TRANSPLANT. THAT GREEN EYE BALL NATURE 2001 MAKING EYES FROM ES CELLS,. THAT CERTAINLY HOLDS PROMISE. I WOULD THINK IF ALL GOES WELL, 40 YEARS FROM NOW WE WON’T FIX THE TISSUE, WE CERTAINLY WON’T CAT RISE IT WITH LASER, WE’RE GOING TO RE– QUAD RISE IT WITH LASER. WE’LL REPLAICE IT. WE HAVE SOME ACTIVITY GOING ON THERE, COURTESY OF HOUSE APPROPRIATIONS REPORT WHICH DIRECTED THE COMMITTEE DIRECTS NEI TO A CHALLENGE PROGRAM, THAT’S THE SPEED OF BASIC RESEARCH TO CURE DISEASE SO WE ARE DEVELOPING CHALLENGE EXETITION TO DEVELOP AND USE 3-D RETINAL ORGANOIDS, OBVIOUSLY GOOD TO GIVE DISEASE INCITE RETINAL DISEASE INSIGHT AND TEST THERAPIES. SO THEN SUMMARY SLIDE, DISCOVERIES OF THE LAST DECADE PRESENTED REMARKABLE OPPORTUNITIES FOR VISION RESEARCH. THE NEI SUPPORTS A FULL SPECTRUM OF RESEARCH FROM BASIC DISCOVERY TO TRANSLATIONAL. AND INTO CLINICAL TRIALS THAT AFFECT CLINICAL PRACTICE. THE OPPORTUNITIES, WE NEED TO BE ANCHORED IN MECHANISTIC BASED TREATMENTS AND THAT IS AN EFFORT BY AGI TO CONVERT BASIC DISCONSERVATIVE INTO A CLINICAL APPLICATION. BUT IT STARTS, IT’S GROUNDED IN BASIC DISCOVERY, NEIHI PUTS A SPOTLIGHT WHERE WE WANT TO GO, WHERE — THE PLACE WE WANT TO REACH. AND IT WILL REQUIRE COLLECTIVE AND CONCERTED ACTION, MANY LABORATORIES, IN WAYS THAT I THINK IS CURRENTLY UNUSUAL. THIS PROCESS SO FAR IS EMBRACED BY SCIENTISTS IN MANY DISCIPLINES AND I THINK THE MOMENTUM THAT WE HAVE HOLDS PROMISE. COMING DOWN THE ROAD. SO THANK YOU FOR THE OPPORTUNITY TO SPEAK WITH YOU. AND IF ANYONE WANTS TO SIGN UP FOR STARTING A VISION RESEARCH LAB, LET ME KNOW. [APPLAUSE]>>THANK YOU PAUL, AMAZING ARRAY OF ADVANCES THAT HAVE HAPPENED IN THE COURSE OF JUST THE LAST FEW YEARS, YOUR AUDACIOUS GOALS WILL DRIVE IT HARDER AND FURTHER. ARE THERE QUESTIONS, COMMENTS THE GROUP WOULD LIKE TO PUT INTO THIS? YES.>>I AD TWO QUESTIONS. FIRST, YEAH, SPECTACULAR — SPECTACULAR TO SEE THIS HAPPEN. ONE IS ON LC, WONDERING DO THESE KITS HAVE ALTERED CIRCADIAN RHYTHMS OR INCREASE INCIDENCE IN PSYCHIATRIC DISEASE? EXPOSURE THE LIGHT. THAT’S MY FIRST QUESTION. SECOND, I REMEMBER READING THE SUGGESTION, BASICALLY EPIDEMIOLOGICAL SUGGESTING THAT LACK OF EXPOSURE TO UV LIGHT LED TO EPIDEMIC OF MYOPIA. IS THERE ANY CREDENCE TO THAT?>>TWO RATHER DIFFERENT QUESTIONS, ON LCA CIRCADIAN RHYTHM. THERE’S A FULL SPECTRUM, 19 GENES IMPLICATED, THEY EACH HAVE THEIR OWN PECULIARITIES, SPECIAL PROPERTIES ON A CLINICAL SCALE. MOST OF THE INDIVIDUALS DO HAVE SOME RESIDUAL VISION PARTICULARLY AT VERY HIGHLIGHT LEVELS WHICH MEANS THEY KNOW WHEN THE SUN IS UP AND AS LONG AS YOU CAN DETECT THE DIFFERENCE BETWEEN LIGHT AND DARK CIRCADIAN RHYTHM REMAINS INTACT AND CYCLING PROPERLY. SO THAT IS GENERALLY NOT THE CASE FOR THE LCA CHILDREN, IT HAS BEEN DEMONSTRATED IN SOME OTHER FORMS OF COMPLETE BLINDNESS SUCH AS BILATERAL NO EYES, THEY DO HAVE DISTURBED SLEEP RHYTHMS OF. ON MYOPIA AND UV LIGHT. ONE OF THE DRIVERS OF MYOPIA SEEMS TO BE LIGHT GOING PHOTO RECEPTORS BIPOLAR CELLS, AMICINE DOPAMINE SECRETION WHICH FILTERS BACK AND ALTERS THE SHAPE OF THE EYE. HOW MUCH OF THAT IS DRIVEN SPECIFICALLY BY UV EYE DON’T KNOW. AND THERE IS ALSO A — SOME KIND OF FOCUSING COMPONENT TO THIS DEPTH OF THE FOCUSING SO THE ASIAN CHILDREN NOT SPENDING AS MUCH TIME OUT OF DOORS DO CERTAINLY DEVELOP MYOPIA AT HIGHER RATES AND THE GENES SO FAR FOR MYOPIA HAVE BEEN CLONED OUT OF ASIAN SOCIETIES.>>THAT WAS REALLY COOL, FIRST I WANTED TO MENTION I TRIED, I DON’T KNOW IF I SUCCEEDED TO SEND Y’ALL ON THE COMMITTEE, FROM DAN GOLDMAN, ABOUT RETINAL REGENERATION, IT’S JUST A VERY COOL ANIMATION, HE’S NEI FUNDED INVESTIGATOR BUT I LIKE IT TO BE BECAUSE IT’S A COLLABORATION BETWEEN THE VISUAL ARTISTS, HIS BROTHER AND HIM AND IT SHOWS TRANSCRIPTIONAL REGULATION AND PROTEINS AND REGENERATION SO IT’S JUST A COOL VISUAL THING. SORT OF JUST A COUPLE OF COMMENTS, ONE IS THAT IT’S INTERESTING NEUROSCIENCE INSTITUTE EVERY YEAR WE TALK TO PEOPLE ABOUT THE PROGRESS. AND TO ME THE PEOPLE WHO HAVE BEEN DOING THE VISUAL STUFF ESPECIALLY RETINAL RELATED STUFF, FROM YEAR-TO-YEAR YOU SEE DRAMATIC PROGRESS THAT I SEE ACROSS DIFFERENT NEUROSCIENCE, IN OTHER AREAS YOU SEE LITTLE BREAK THROUGHS HERE AND THERE IN INCREMENTAL CHANGES THAT THE VISUAL STUFF IS JUST AMAZING TAKING — IT’S JUST THE FIELD SEEMS RIPE FOR REALLY TRANSFORMATIVE STUFF, SO IT MUST BE REALLY EXCITING FOR YOU TO BE IN THAT — AT THIS TIME IN THIS FIELD, IT’S ABSOLUTELY REMARKABLE. MICRORNA STEM CELL GENETICS, ANIMAL MODELS, ET CETERA, AMAZE. I KNOW YOU KNOW THAT, LOOKING AT IT AS SOMEBODY NODDING THE — WATCHING PEOPLE, I JUST WANTED TO ECHO. WHAT YOU WERE SAYING. FINALLY, I HAVE THIS ODD INTERACTION WITH SOMEBODY WHO HAS BEEN IN SOLITARY CONFINEMENT FOR OVER 20 YEARS, IT WAS THE TRIPLE A MEETING ABOUT SOLITARY CONFINEMENT AND THEY WANTED A POINT OF VIEW OF A NEUROSCIENTIST AND WHEN I TALKED TO THE GUY THE MOST IMMEDIATE AND DISCONCERTING THING HE TALKED ABOUT IS THE VISUAL CHANGES, HE SAID WHEN YOU NEAR A TINY PLACE THE SIZE OF A KING SIZE BED, THE FIRST THING THAT YOU NOTICE YOUR VISION GOES. VERY DISORIENTING. HE COULD ARTICULATE THAT MUCH BETTER THAN ANY AFFECTIVE CHANGES OR DEPRESSION OR ANYTHING LIKE THAT AND EVEN THINKING BACK ON IT 20 YEARS BACK IT WAS LIKE EXTREMELY — WHEN YOU SAID SOMETHING ABOUT DEPTH PERCEPTION, HE LOST HIS DEPTH PERCEPTION. THEN WHEN HE EVENTUALLY GOT — THIS WAS A VERY BIG CHALLENGE FOR HIM AFTER — SO IT’S KIND OF AN INTERESTING POPULATION KIND OF ENVIRONMENTAL UNUSUAL ENVIRONMENTAL CHALLENGE FOR OVER 20 YEARS, MY GOODNESS BUT EVEN FOR SHORTER PERIOD. SO RANDOM ASSOCIATION.>>THANK YOU, IF YOU WANT AN NEI GRANT PLEASE APPLY.>>FIRST THANK YOU FOR THE PRESENTATION, I JUST HAVE A COUPLE OF QUESTIONS, YOU TALKED ABOUT OVERLAMP CO-EFFICIENT ZONE NUMBER. WHAT WAS THAT CO-EFFICIENT YOU TALKED ABOUT EARLIER?>>WE HAD A LONG DISCUSSION WE COULD HAVE AT THE COFFEE BREAK.>>I PREFACE A COUPLE OF QUESTIONS.>>YOU SAW YESTERDAY WHEN I SHOWED THE DATA MIKE LOWERY HAS BEEN GENERATING OVERLAP BETWEEN FUND AND UNFUNDED GRANTS IN THAT AREA, THIS IS A MEASURE OF THE DEGREE OF OVERLAP BETWEEN DISTRIBUTIONS AND MIKE CAN TELL YOU MORE.>>YOUR — WHAT IS YOUR CO-EFFICIENT THAT YOU EXPRESSED?>>IT’S>>THIS IS A MEASURE OF THE HISTOGRAM THAT LARRY SHOWED, YOU SEE DISTRIBUTION OF GRANTS AWARDED AND NOT AWARDED ACCORDING TO PERCENTILE SCORE AND THERE’S A TRIANGULAR AREA IN THE MIDDLE OF OVERLAP SO NEI IS ONE OF THE HIGHEST AMOUNTS OF OVERLAP FOR AMONG ALL THE INSTITUTES HERE.>>SO WHAT IS YOUR CO-EFFICIENT AND WHAT IS THE RANGE?>>.3. AND THE RANGE IS FROM.– A LOW OF .11 TO A HIGH OF .3.>>ONE OTHER POINT — ONE OF THE QUESTIONS I HAVE HAD, AND P WE TALKED A COUPLE OF TIMES, WITH TALK ABOUT THE FACT THAT THIS COULD ENCOURAGE NEW INVESTIGATORS OR LOOK AT DIFFERENT PROGRAMMATIC AREAS, MY QUESTION HAS BEEN TO WHAT EXTENT HAS THIS BEEN USED TO INCREASE OR IN SOME CASES DECREASE DIVERSITY OF THE RECIPIENT OF GRANTS. FOR YOU INSTITUTE WHAT’S THE AFFECT OF THAT OVERLAP ZONE IN TERMS OF RACIAL ETHNIC DIVERSITY OF THE RECIPIENT OF NEI GRANTS.>>THAT’S A VERY INTERESTING QUESTION, TWO COMMENTS, FIRST THE IDEA OF THIS OVERLAP ANALYSIS MIKE AND OTHERS, HAVE RECENTLY BEGUN TO DO THAT SO WE DON’T KNOW THE FULL PLAY-OUT EVEN AT THE MOMENT ACROSS ALL INSTITUTES. SECOND WOULD BE I THINK WE CAN LOOK AT THAT PROSPECTIVELY BUT WE DON’T HAVE DATA AT THIS POINT TO ADDRESS YOUR IMPORTANT QUESTION.>>I WANT TO EXPRESS A CONCERN WITH THAT THAT WE HAVE HAD COMMITTEE MEETINGS OVER THE YEARS TO TALK ABOUT HOW WE’RE INCREASING DIVERSITY, THERE WAS A DISCUSSION HAVING A CONTEXT IN TERMS OF BEING ABLE TO DO THAT. BUT WE HAVE CREATED POLICIES AN PROCEDURE AND PROGRAMS TO CREATE THESE OVERLAPS ZONES, ACROSS DIFFERENT INSTITUTES, WITHOUT LOOKING AT WHAT THE EFFECTS WERE, I HAVE SPOKEN ABOUT IT.>>JUST TO SO WE HAVE LOOKED AT IT NOT IN THE EXACT WAY PAUL DESCRIBED BECAUSE THIS IS A NEW APPROACH TO EXPLAIN THE DATA. IT’S RACE NEUTRAL. WE LOOKED. IT IS RACE NEUTRAL. NOW YOU CAN ARGUE WHY AREN’T YOU USING IT TO ENHANCE DIVERSITY AND INDEEDS SOME INSTITUTES HAVE REPORTED THEY ARE IN FACT DOING THAT BUT THAT IS ONLY ONE OF MANY CONSIDERATIONS THAT GO INTO THEIR FORMULA. SO OUR CONCLUSION LOOKING AT THE AGENCY AS A WHOLE IS THAT THE ISSUE OF SKIPS OR SELECT PAY IS RACE-NEUTRAL.>>I WOULD ARGUE IF THAT DOES MEAN —
IN THE WORLD OF RACE NEUTRAL, THAT MEANS ONE HAS AN OVERLAP ZONE WHERE ONE IS SKIPPING ONE AREA, NOT SKIPPING THE OTHER AREA, IN THAT ZONE THERE ARE HIGHLY MERITORIOUS APPLICATIONS, INDIVIDUALS WHO ARE RACIALLY ETHNICALLY DIVERSE, THAT THOSE INDIVIDUALS SHOULD NOT BE SKIPPED. IT MAYBE OVERALL RACE NEUTRAL IN TERMS OF BECAUSE YOU’RE SKIPPING AND THEN PEOPLE, LATINO OR ASIAN APPLICANT CAN BE FUNDED NON-MAYBE BUT I’M SAYING MY CONTENTION IS IF IT MEANS THERE ARE INDIVIDUALS THAT ARE SKIPPED OVER WITH MORE MERITORIOUS APPLICATION BY SCORE WHO ARE RACIAL ETHNICALLY DIVERSE, THOSE INDIVIDUALS SHOULD BE FUNDED. THAT’S THE POINT I MADE.>>AND AGAIN, CATO, WE HAVE DONE THE ANALYSIS, WE HAVEN’T PUT IT IN THE FORMAT THAT PAUL AND MIKE SPOKE TO. IT IS RACE NEUTRAL. LOOKING AT THE AGENCY AS A WHOLE.>>JUST SAYING I THINK THERE’S AN OPPORTUNITY HERE THOUGH THAT ONE IS INTERESTED IN PROMOTING AND INCREASING DIVERSITY THAT THE END POINT SHOULDN’T BE NEUTRAL, P ONE IS USING — OBVIOUSLY THE OTHER AREAS, INCREASING THE NUMBER OF YOUNG INVESTIGATORS, IS NOT NEUTRAL, IT’S HAVING A PURPOSE, HAVING A ROLE AND BEING EFFECTIVE IN TERMS OF DOING THAT, AND IT SO WE SHOULD BE THINKING ABOUT THAT IN TERMS OF USING AS AN INSTRUMENT.>>I WANT TO DOUBLE DOWN ON SOMETHING HOUDA SAID. THE QUALITY OF RESEARCH AND ADVANCES THAT HAND AT THE NEI IS REALLY SPECTACULAR. I THINK THAT THAT’S PARTLY BECAUSE SMART PEOPLE LIKE TO BE WITH OTHER SMART PEOPLE AND THERE HAVE BEEN VERY SMART PEOPLE IN SPECIFICALLY IN VISUAL NEUROSCIENCE, LIKE REST OF NEUROSCIENCE LOOKED UP TO THEM AND (INAUDIBLE) BUT I THINK IT’S ALSO A SIGN OF THE LEADERSHIP OF THE NEI CONSISTENTLY AND SUPPORTIVE SCIENCE AND REAL PROTECTION AND PROMOTION OF RESEARCH, BEST RESEARCH AND PARTNER SHIP WITH RESEARCHERS. I THINK IT’S’S A VERY GOOD REPUTATION IN THE EXTRAMURAL COMMUNITY AS AN INSTITUTE THAT WORKS EXTREMELY WELL WITH SCIENTISTS. IT’S GREAT TO SEE THAT AT EVERY LEVEL FROM MOLECULAR TO CLINICAL. Q. I WAS GOING TO ASK YOU QUESTION CORRY JUST PROPOSED WITH WHICH IS WHAT DO YOU ATTRIBUTE THE SUCCESS, IS THERE A CULTURAL ISSUE WITHIN — BEST PRACTICES THAT CAN BE DISSEMINATED. YOU’RE MAKING THIS PRESENTATION TO US AND BUT WHAT ARE THE PROBLEMS THAT YOU SEE? WHAT ARE THE CHALLENGES THAT IMPEDE THAT KIND OF PROGRESS GOING FORWARD TO MAKE IT BETTER?>>I CAN HINT OUT QUICKLY AT THE MOST OBVIOUS LACK OF FUNDING. WHEN I HAVE BEEN ASKED AT OUR CURRENT BUDGETS AND WHAT COULD WE USE INSTEAD OF ANSWERING THAT QUESTION, I ANSWER THE QUESTION OF ARE CURRENT SUPPORTED PI, NUMBER OF PIs VERSUS PEAK POPULATION 2008 AND WE ARE DOWN BY 16, 18%, MASSIVE THREAT. AT THE TIME THAT WE ARE MOVING IN TO TARGETED FOCUSED IN THE FUTURE AUDACIOUS GOAL, WE PUT TO PUT NEURONS IN THE DATA EXTRINSIC OR INTRINSIC AND GET THEM TO CONNECT AND SEE WHERE THAT LEADS US IN HEALTHCARE. AT THE SAME TIME THAT WE ARE DOING THAT, WE DON’T HAVE THE RESOURCES TO FUND THE FULL VIBRANCY OF OUR EXTRAMURAL APPLICATION POOL. TO MY WAY OF THINKING, THAT IS THE PRINCIPLE LIABILITY THAT WE HAVE>>THANK YOU SO MUCH FOR YOUR PRESENTATION, I’M TEACHENING THE SPRING AND TAKING NOTES, STUDENTS LOVE THE EYE FOR REASONS ELOQUENTLY EXPLAINING YOUR PRESENTATIONS, TWO QUESTIONS FOR YOU. ARE YOU DOING ANY WORK ON HEALTH DISPARITIES OR FUND PROGRESS APOLOGETICS RELATED TO HEALTH DISPARITIES AND VISION? AND ALSO I WAS CURIOUS, YOU DIDN’T TALK ABOUT THE ARTIFICIAL RETINA AND RETINAL IMPLANT OF ARE THERE ANY DISCOVERIES ON THAT FRONT?>>HEALTH DISPARITIES, ONE OF THE HEALTH DISPARITIES IS BIOLOGIC IN OUR ZONE. HISPANIC AND BLACK POPULATION VERSUS HIGHER INCIDENCE OF GLAUCOMA. THAT IS A LIABILITY FOR THAT POPULATION, CONVERSELY IT’S AN OPPORTUNITY FOR US, WE HAVE GENE DISCOVERY WORK GOING ON WITH IN AFRICAN COUNTRIES TO TRY TO IDENTIFY WHAT THAT FACTOR IS. WE HAVE OTHER HEALTH DISPARITY WORK GOING ON IN THIS COUNTRY PARTICULARLY IN GLAUCOMA. OTHER APPROACHES WE HAVE TAKEN HAVE BEEN ON THE YOUNGER GENERATION, EDUCATION TRAINING. WE HAVE SOMETHING CALLED DIVERSITY IN VISION RESEARCH. THAT IS QUITE SUCCESSFUL IN ATTRACTING OR AT LEAST ENROLLING MINORITY POPULATION STUDENTS IN OUR SUMMER INTERNSHIP PROGRAM, A NUMBER OF THEM STAY SPEND A YEAR AND MATRICULATE IN BRANCH RATE WAIT OR PROFESSIONAL PROGRAM AFTER THAT. SO WE ARE INTERESTED IN THAT. ON THE RETINA CHIP THAT’S WONDERFUL, IT’S THE FIRST VISION PROSTHESIS APPROVED REGISTER FOR SALE, THE ARGUS 2, IT GIVES SOMETHING TO VISION, IT GIVES PREACCEPT, IT DOES NOT RESTORE VISION. YOU AND I HAVE 100 MILLION ROD CONE PHOTO RECEPTORS IN THE EYE, DEVICE SAYS 30 ELECTRODES YOU CAN REPLICATE 100 MILLION BY 30. IT’S GENERATING SOME VERY IMPORTANT UNDERSTANDING OF THE PHYSIOLOGY OF HUMAN RECEPTION AT THE SURFACE. WE’RE GOOD AT PHOTO RECEPTORS, WE UNDERSTAND HOW THEY’RE ORGANIZED AND WHAT THE CIRCUITS ARE AND HOW TO STIMULATE, ET CETERA BUT AT THE SURFACE OF THE RETINA IT GETS MORE VAGUE. THIS IMPLANT GOES AT THE SURFACE OF THE RETINA. SO IT PROVIDES ENTRE TO STUDY THAT COME CAN PARTMENT OF VISION. I PERSONALLY LIKE BIOLOGY MORE THAN RETINA CHIPS.>>WHAT IS THE LATEST ON THE DURABILITY OF THE GENE THERAPY STRATEGIES FOR RPE 65, WHICH OBVIOUSLY SUBJECT OF ENORMOUS INTEREST AND IT WAS IMPRESSIVE AT FIRST TO SEE SUSTAINABILITY OF THE IMPROVEMENT IN VISION THAT HAPPENED WITH JUST ONE ADMINISTRATION BUT I GATHER IT DOESN’T LAST FOREVER. IT BEGINS TO WEAR OFF. WHAT TEASE GENERAL SENSE ABOUT WHAT THERE’S A WAY TO INCREASE THE SUSTAINABILITY OR CAN YOU KEEP READMINISTER SOMETHING>>YOU ASKED A VERY INTERESTING QUESTION THE SHORT ANSWER WILL TAKE AN HOUR, LET ME GIVE YOU THE SHORT ANSWER. IF YOU HOLD THE PERSONAL SHARES OF GENE THERAPY COMPANY STOCKS YOU MIGHT QUESTION YOUR ADVISOR’S WISDOM AT THE MOMENT.>>NOBODY HERE DOES, [LAUGHTER]>>SO WE’RE ALL SAFE, LARRY.>>I’M GOING TO NEED A BREAK RIGHT NOW. [LAUGHTER]>>SO HOW LONG DOES THAT RP-65 GAIN OF VISION SURVIVE? HOW DURABLE IS IT FOR THESE CHILDREN WITH LABOR CONGENITAL AMAUROSIS SEVERE VISION IMPAIRMENT FROM BIRTH? THE VISION GAINS ARE IMPRESSIVE AT LEAST BY NUMBER SCORES, LOG ORDERS OF IMPROVED SENSITIVITY, LIGHT SENSITIVITY. THAT IS PERSISTING IN THOSE CHILDREN BUT QUESTIONS WERE ASKED BY S TREATMENTLY ASTUTE SCIENTIST SAMUEL JACOBSON UNIVERSITY OF PENNSYLVANIA OVER THE PAST YEAR. AS TO WHETHER THE STRUCTURE IS ALSO BEING MAINTAINED, ARE THE PHOTO RECEPTORS THERE? THEY’RE WORK BUG ARE THERE AS MANY NOW AS FIVE YEARS AGO? THE ANSWER IS NO. CAN THAT BE IMPROVED IN? PROBABLY. WHAT IS THE APPROPRIATE DOSE OF PENICILLIN TO TAKE? IT’S NOT 10-MILLIGRAMS, IT’S HIGHER THAN THAT. AND THE GENE PERTY TRIALS WITH WERE ONE DOSE TRIALS WE NEED TO KNOW WHETHER INCREASING THE DOSE WILL INCREASE THE DURABILITY, WE NEED TO KNOW WHETHER INCREASING THE GEOGRAPHIC, THE REGION THAT’S TREATED, THEY TREATED A SMALL REGION, IF YOU INCREASE THAT, DOES THAT INCREASE SURVIVAL OVERALL OF THE ENTIRE PAST? THERE’S MANY QUESTIONS, ONE DOWN SIDES OF HUMAN GENE THERAPY IS IT TAKES FIVE OR MORE, TEN YEARS TO REALLY UNDERSTAND WHAT THE NEXT QUESTION IS GOING TO BE. SO WE NEED SOME WAY TO SPEED THIS UP. BUT PERSONALLY I’M STILL ROOTING STRONGLY FOR OPPORTUNITIES IN GENE THERAPY. HAS DOWN SIDES BUT IT’S ONE WAY TO HELP SOME PEOPLE AND LEARN GREAT BIOLOGY T.>>DO YOU SEE AN ALTERNATIVE TRYING TO UNDERSTAND WHAT WORKS MANY THOSE CREATURES THAT CAN REGENERATE AND TRY AND UNDERSTAND DIFFERENCES BETWEEN THOSE SPECIES AND US AND SEE IF WE CAN REPLICATE THAT AND MAKE IT MORE INTRINSIC MECHANISM AS OPPOSED TO GENE THERAPY? INHIBITORS THAT PREVENT US FROM REGENERATION?>>THANK YOU, I THINK YOU RECAPITULATED A CHUNK OF THE REPORT WE HAVE OUT — THOSE ARE THE IDEAS, WE NEED TO START WHERE THERE IS SPECIES WHERE ONE CAN FIND THESE PHENOMENA, FIND DIFFERENCES THAT PREVENT THAT IN THE NEXT RANGE OF SPECIES TO LOOK FOR INHIBITOR FACTORS AND THE UNDERLYING PRINCIPLES, BUT THE PUSH HERE IS TO TAKE WHAT WE HAVE AND NOT STUDY IT DEEPER. WE HAVE GOT A LOT OF RO-1 GRANTS ON THE STREET WHICH THAT’S GOING TO CONTINUE TO BE AVAILABLE. BUT TO TAKE WHAT WE KNOW AND TO MOVE IT ALONG A PATHWAY TO SEE IF WE CAN GET THIS ACTIVE ULTIMATELY IN HUMAN.>>IT’S BEEN A WONDERFUL PRESENTATION AND GREAT DISCUSSION, MANY THANKS FOR BYING THE GREAT SCIENCE TO US. WE BENEFITED AND ENJOYED IT ENORMOUSLY. THANK YOU. [APPLAUSE]

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