>> GOOD MORNING, EVERYONE. WELCOME TO RARE DISEASES DAY 2012. FEBRUARY 29th, PROBABLY THE RAREST DAY OF THE YEAR. THE RAREST DAY IN FOUR YEARS. THIS IS A FIFTH CELEBRATION OF RARE DISEASES DAY THROUGHOUT THE WORLD. THE SECOND HERE AT NIH. WE HAD OUR FIRST LAST YEAR VERY WELL ATTENDED AND THIS YEAR IS BETTER ATTENDED THOUGH THERE'S STILL HOLES IN THE AUDIENCE AS FAR AS THE CHAIRS PEOPLE WILL BE JOINING AS THE DAY GOES ON SO THANK YOU FOR JOINING US. IT TRULY IS A CELEBRATION OF THE ACCOMPLISHMENTS OF SO MANY INCLUDING THE SCIENTISTS, THE INDUSTRY, THE REGULATORY AGENCIES AN PARTICULARLY THE THE PATIENT ADVOCACY GROUPS AND THEIR LEADERS, DOES REFLECT SOME FANTASTIC ACCOMPLISHMENT AND COMMITMENTS TO FINDING TREATMENTS AND DIAGNOSTICS FOR THE RARE DISEASES. SO WE HAD AN EXCITING PROGRAM TODAY AND THIS IS ALL PART OF A TWO-DAY PROGRAM, THE SECOND PART WILL BE TOMORROW AT THE FOOD AND DRUG ADMINISTRATION WITH THE OFFICE OF ORPHAN PRODUCTS DEVELOPMENT SO LOOKING FORWARD TO THIS IN COLLABORATION WITH BOTH GROUPS, WE STARTED BACK IN 1982 AND EVEN BEFORE 1982 WHEN THE OFFICE OF ORPHAN PRODUCTS WAS INITIATED AT FDA AND EVEN SOME ACTIVITIES HERE AT THE NIH WITH RESPECT TO VARIOUS RESEARCH PROGRAMS FOR DIFFERENT RARE DISEASES. SO THIS IS ABOUT THE 30th ANNIVERSARY OF US GETTING STARTED AND ABOUT 7 OR 8 DAYS FROM TODAY IN 1982 THERE WAS A HEARING HELD IN CONGRESS THAT REFLECTED ON THE NEED FOR A MORE ACTIVE PRESENCE BY THE FEDERAL SECTOR. IT WAS REALLY THE START OF MANY ACTIVITIES WITH RESPECT TO RARE DISEASES. VERY, VERY SIGNIFICANT YEAR FOR MANY OF US. FIRST I WANT TO THANK OUR PLANNING COMMITTEE CHAIRED BY DAVID HE CANSTEIN FROM OUR OFFICE. YOU CAN SEE THE VARIOUS FOLKS WHO HAVE BEEN ABLE TO MAKE THIS DAY A GO. SO WE APPRECIATE THEIR EFFORTS TO HELP US GET THINGS MOVING AND TO CONTACT YOU. WE HAVE A TREMENDOUS TURN-OUT NOT ONLY OF YOU AS INDIVIDUALS TO LISTEN AND TO PARTICIPATE WITH QUESTIONS LATER ON BUT ABLE TO GET LARGE OF INDIVIDUAL ORGANIZATIONS TO PRESENT POSTERS AND HAVE TABLE EXHIBITS THAT ARE IN THE HALLWAYS LEADING INTO THE AUDITORIUM FROM THE SOUTH LOBBY HERE. SO PLEASE, DURING LUNCHTIME, TAKE THE OPPORTUNITY TO VISIT THE INDIVIDUALS WHO MADE THE EFFORT TO COME AND POST THEIR ACTIVITIES AND MAKE THEM AVAILABLE TO YOU. SO TODAY, THE EMPHASIS OF THE ENTIRE PROGRAM AS MANY OF YOU KNOW THE DIFFICULTIES OBTAINING A DIAGNOSIS FOR THE TREATMENT OF RARE DISEASES IS TREMENDOUS. SO WE WE'LL HAVE NEWER TECHNOLOGIES THAT ARE IN PLACE DEVELOPING FOR DIAGNOSIS AND TREATMENT OF RARE DISORDERS. WEAL TALK ABOUT MANY -- WEAL TALK ABOUT EXCITING NEW TRANSLATIONAL RESEARCH APPROACHES THAT HAVE BEEN INITIATED AND ARE BEING INITIATED HERE AT THE NIH AND I THINK AT THE END OF THE DAY YOU'LL SEE A NUMBER OF NEW ACTIVITIES PERHAPS YOU HAVEN'T HEARD ABOUT BUT THERE ARE THINGS YOU SHALL LEARN ESPECIALLY WITH THE NUMBER OF DISEASES THAT THEY WILL BE APPLICABLE TO IN THE FUTURE. SO SIT'S IMPORTANT TO SORT OF HEAR AND LISTEN AND ABSORB WHAT'S GOING ON AND VISIT THE WEBSITE AND THEN FOLLOWING THAT BE IN TOUCH WITH THE PROGRAM PEOPLE RESPONSIBLE FOR THESE VARIOUS TRANSLATIONAL RESEARCH PROGRAMS HERE AT THE NIH. WE WILL THEN CLOSE TO THE THE END OF THE DAY I HOPE MANY ARE ABLE TO STAY THE ENTIRE DAY, HEAR THE VIEWS OF THE PATIENT ADVOCACY GROUPS FOR TODAY, THE NATIONAL ORGANIZATION FOR RARE DISORDERS AND THE GENETIC ALLIANCE. AND THEN WE WILL HAVE ABOUT A HALF HOUR AT THE END OF THE DAY TO HAVE A COMMUNITY FORUM, OPEN MICS FOR PEOPLE TO BRIEFLY ASK QUESTIONS AND PROVIDE US COMMENTS THAT YOU WOULD LIKE US TO CONSIDER MOVING FORWARD. SO IT IS AN OPPORTUNITY TO TELL US WHAT WE SHOULD BE THINKING ABOUT DOING AND YOUR SUGGESTIONS ARE ALWAYS WELCOME. WE'LL LOOK FOR WAYS TO IMPLEMENT THEM. SO PLEASE TAKE ADVANTAGE OF THAT OPPORTUNITY. IF YOU'RE UNCOMFORTABLE TO US TALKING TO THE MICROPHONE AND THE GROUP, PLEASE CATCH SOME OF US IN -- DURING THE DAY HERE AND WE'LL MAKE ARRANGEMENTS TO TALK WITH YOU AFTER THE MEETING. SO BACKGROUND, I'M GOING THROUGH THIS QUICKLY BECAUSE DR. COLLINS IS ON A TIEG SCHEDULE AND WE WANT TO -- TIGHT SCHEDULE. THE EXTENT OF THE PROBLEM, PROBABLY 18 TO 25 MILLION PEOPLE IN THE UNITED STATES ARE AFFECTED BAY RARE DISEASE, WE DONE KNOW EXACT NUMBER BUT SOME STUDIES DONE THROUGHOUT THE WORLD ESTIMATE THAT BETWEEN 68% OF THE POPULATION DO HAVE A RARE DISORDER. YOU CAN SO YOU CAN SEE THE PROBLEM IS EXTENSIVE, IT'S A GLEEBL PUBLIC HEALTH -- GLOBAL PUBLIC HEALTH PROBLEM WITH PARTICIPATION AROUND THE WORLD. HERE IN THE UNITED STATES WE DIFFER FROM EUROPE. WE BASE THE ORPHAN PRODUCT DESIGNATION AND STATUS ON PREVALENCE OF LESS THAN 200,000 PEOPLE IN THE UNITED STATES, EUROPE HAS PREVALENCE LESS THAN 1 IN 2,000 PEOPLE SO THERE'S A LITTLE DIFFERENCE WE WORKED THROUGH. THERE'S A GROWING NUMBER OF GENETIC ACQUIRED RARE DISEASES. WE HAVE AN ACTIVE LIST OF SLIGHTLY OVER 7,000. GAYATRI RAO MAY HAVE NEW PRODUCTS OR FAN PRODUCTS FOR RARE DISEASES, AVAILABLE FOR APPROXIMATELY 250 DIFFERENT RARE DISEASES. SO YOU CAN SEE THE ACCOMPLISHMENTS HAVE BEEN GREAT BUT WHEN YOU LOOK AT THE TOTAL FIGURE OF 7,000 RARE DISEASE YOU SEE HOW FAR WE HAVE TO GO YET. I GUESS ONE OF THE HALLMARKS OF RARE DISEASES AND ORPHAN PRODUCTS IS IF YOU DONE HAVE AN ACTIVE INDUSTRY SPONSOR TO MOVE THINGS FORWARD YOU ARE GOING TO NEED COLLABORATIVE EFFORTS. AND I SHOULD SAY IF YOU DO HAVE AN INDUSTRY SPONSOR YOU STILL NEED THAT COLLABORATIVE EFFORT WITH MANY PARTNERS INCLUDING THE ACADEMIC RESEARCH INVESTIGATORS, MEDICAL SPECIALISTSES, THE FEDERAL RESEARCH AND REGULATORY PROGRAMS BOTH THE INTRAMURAL AND EXTRAMURAL PROGRAMS THAT FUND RESEARCH. YOU NEED WORK IN COLLABORATION WITH PATIENT ADVOCACY GROUPS AND PHILANTHROPIC FOUNDATIONS AND SERVE THE INDUSTRY, AS A PARTNER SOMEWHERE ALONG THE LINE, WE NEED THEM TO CONTINUE THE DEVELOPMENT OF PRODUCTS. BECAUSE THEY ARE SO RARE MANY PEOPLE WHO ARE INVOLVED IN THE ACTUAL RESEARCH WE HAVE CONFLICTS OF INTEREST THAT OCCUR. WE HAVE BEEN GOOD AT IDENTIFYING RESEARCH, NOW WE HAVE TO FIND WAYS TO MANAGE THESE INTERESTS THAT DO HAVE CONFLICTS. BECAUSE THE EXPERTISE AND KNOWLEDGE IS THERE AND I THINK WE HAVE TO WORK WITH THOSE CONFLICTS AND TRY TO CONTROL THEM AS MUCH AS POSSIBLE, THAT WILL ENABLE PRODUCTS TO MOVE FORWARD. THERE IS A GROWING NEED FOR PUBLIC AND PRIVATE PARTNERSHIPSCH EVERYONE UNDERSTANDS THE BUDGET ISSUES. WE NEED THESE PRIVATE PARTNERSHIPS TO MAKE THINGS WORK APPROPRIATELY. THERE WAS A CONGRESSIONAL RARE DISEASE CAUCUS ESTABLISHED TO FOCUS ON RARE DISEASES WITHIN OUR CONGRESS. I WANT TO MENTION SEVERAL FEDERAL GOVERNMENT EMPHASIS, THE VARIOUS PROGRAMS AN I WANT TO THANK, WE OWE A TREMENDOUS THANK YOU TO DR. FRANCIS COLLINS AT THE NIH FOR FOSTERING MANY PROGRAMS WITH RESPECT TO RARE AND NEGLECTED DISEASES. IT'S BEEN ABOUT ALMOST TWO YEARS THAT HE'S BEEN WORKING ON THIS AND WE CAN START TO SEE OUTCOMES NOW. IT DOES TAKE A LOT OF TIME BUT WE'RE TRYING TO STIMULATE THIS WHOLE ACTIVITY. WE'LL HAVE PRESENTATIONS LATER TODAY SO I WON'T TALK ABOUT A LOT OF THESE BUT THE NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES AND THE CURES ACCELERATION NETWORK. THERE'S NUMEROUS OTHER NIH INSTITUTE SPECIFIC, DISEASE SPECIFIC TRANSLATIONAL RESEARCH PROGRAMS AND WE'LL HEAR FROM SEVERAL TODAY DURING THE WHOLE MEETING. THE FDA CERTAINLY HAS AN EXPANDED INTEREST IN THE REVIEW DIVISIONS AND WITHIN THE OFFICE OF ORPHAN PRODUCTS DEVELOPMENT TO CONTINUE THEIR EMPHASIS ON RARE DEES AN ORPHAN PRODUCTS. WE'RE LOOKING FORWARD TO THE OPPORTUNITIES THAT DR. COLLINS WORKED OUT WITH THE NIH AND PHARMA COLLABORATION ON RESCUE AND REPURPOSE FOR RARE NEGLECTED DISEASES, WE LOOK FORWARD TO RIVALLING MORE PRODUCTS ON THE SHELF READY FOR DISTRIBUTION TO PATIENTS. I THINK ONE MAJOR AREA WE HAVE BEEN TALKING ABOUT FOR YEARS IS TRYING TO FIND BETTER WAYS TO PREDICT DRUG SAFETY AND EFFICACY TO REDUCE THE RISK OF FAILURE. SO THE NEW NIH DARPA FDA COLLABORATION TO TRY TO DEVELOP THESE PROGRAMS EVEN FURTHER AND THERE'S QUITE A BIT OF INFORMATION ON THE NIH WEBSITE I WOULD REFER YOU TO. WE REALIZE THAT THERE IS A GLOBALIZATION OF THE INDUSTRY AND WE HAVE SEEN AN EXPANDED EMPHASIS BY THE PHARMACEUTICAL BIOTECHNOLOGY DEVICE IN THE PAST SEVERAL YEARS RELATED TO RARE DISEASES AND THIS CONTINUES TO GROW. PART OF THIS IS DUE TO DOUBLING OF THE NIH BUDGET THAT OCCURRED A FEW YEARS AGO. WE ARE REAPING THOSE BENEFITS, BASIC RESEARCH GRANTS THAT WERE FUNDED AND CLINICAL GRANTS. WE'RE NOW SEEING THESE OPPORTUNITIES ARE EXPANDING AND AVAILABLE TO TREATMENT SO IT HAS A PROFOUND IMPACT. HERE IS THE NATIONAL TRANSLATIONAL SCIENCES DECEMBER DECEMBER 23RD. YOU CAN SEE NCATS IS LED BY TOM INSELL AND CATHY HUDSON. THERE WILL BE AN ADVISORY COUNCIL AND CURES ACCELERATION NETWORK BOARD THAT WE WILL BE WORKING WITH. YOU CAN SEE THE VARIOUS OFFICES. INCLUDING OUR OFFICE OF RARE DISEASE RESEARCH, THE EXECUTIVE OFFICE HANDLING MANY ADMINISTRATIVE RESPONSIBILITIES. WE WILL HAVE OUR OWN OFFICE OF GRANTS MANAGEMENT AND REVAW. THE OFFICE OF POLICY COMMUNICATIONS AN STRATEGIC ALLIANCE IS BEING LED. CATHY HUDSON IS WEARING NUMEROUS HATS AN EMAILS ARE COMING AT DIFFERENT HOURS OF THE DAY AND NIGHT. SO EXTREMELY BUSY PERSON AND WE'RE THANKFUL FOR HER. MANY ACTIVITIES YOU'LL HEAR FROM ONE OF THESE TODAY IS THE PRE-CLINICAL AND THE EFFORTS IN DIVISION OF PRE-CLINICAL BY JOE JOCIE BRIGGS. HERE IS SOME INCLUDED THE MOLECULAR LIBRARY PROGRAM, THE TREND IN THE PROGRAM THAT'S BEEN SO SUCCESSFUL AND MOVING POSSIBLE PRODUCTS INTO RESEARCH AND FILL GAPS NECESSARY TO BE MET IN ORDER TO PERMIT THE PRODUCT TO MOVE INTO HUMANS. OUR OFFICE OF RARE DISEASES RESEARCH. THE BRIDGES PROGRAM FORMALLY IT WAS THE RAPID ACCESS TO INTERVENTIONAL DEVELOPMENT PROGRAM. THE CTSA PROGRAM HAS BEEN INCLUDED IN THE NCATS AND THERE'S A SEPARATE GROUP ON FDA REGULATORY SCIENCE ISSUES. WHAT WE'RE LOOKING AT TODAY IS SOMETHING QUITE DIFFERENT AND THIS IS A SLIDE CATHY HUDSON USED. AND THIS IS A SIMPLISTIC SLIDE OF THE STAGES OF DEVELOPMENT. I THINK WHAT WE'RE LOOKING AT TODAY IS THE CAPABILITIES OF MOVING ANY PRODUCT ANY INTERVENTION WE'RE LOOKING AT WHICH THERE'S A GREAT DEAL OF EMPHASIS OR SUPPORT FROM THE INDUSTRY INTO A STAGE OF DEVELOPMENT THAT WILL ENABLE A LARGE AND HUGE STEP TO BE TAKEN TO ENABLE THE CONTINUUM TO MOVE FORWARD, THAT WE DON'T LOSE TIME WAITING FOR A CERTAIN STUDY TO BE DONE. WE NOW HAVE THE CAPABILITY AND I THINK IT WILL BE EXPANDED IN THE NOWTURE WITH MANY MORE INSTITUTES INVOLVED TO BE ABLE TO MOVE QUICKLY FROM THE DRUG DISCOVERY STAGE THROUGH THE VARIOUS STAGES OF CLINICAL TRIALS INTO A STAGE. WE'RE VERY GRATEFUL FOR THE FLEXIBILITY THAT FDA CONTINUES TO EXHIBIT IN THE REVIEW PROCESS. WE HAVE MANY, MANY DIFFERENCES TODAY THAN FIVE AND TEN YEARS AGO, THE RESULT OF TREMENDOUS COMMITMENT BY INDIVIDUALS. SO HERE ARE SOME OF THE PROGRAMS, AND WE WILL PUT THESE SLIDES UP AFTER SO YOU WILL HAVE ACCESS TO THESE VARIOUS ACTIVITIES PARTICULARLY WITH NCATS THE DIVISION OF PRE-CLINICAL INNOVATION AND THE DIVISION OF CLINICAL INNOVATION WE HAVE THERE. IT'S IMPORTANT TO REALIZE MANY EXISTING PROGRAMS WILL CONTINUE TO EXIST. AND THEY'LL CONTINUE TO FUND RESEARCH AND DEVELOPMENT FOR THERAPEUTICS. WE LOOK AT THE FBI, THE SMALL BUSINESS INNOVATIVE RESEARCH AND YOU CAN SEE TREMENDOUS AMOUNT OF MONEY AVAILABLE FOR THESE PROGRAMS TO ASSIST SMALL BUSINESS. SO WE WANT TO MAKE USE OF THOSE RESOURCES AS WELL. OTHER PROGRAMS THAT YOU HAVE HEARD ABOUT AND WILL HEAR ABOUT, NATIONAL CANCER INSTITUTE, NEUROLOGICAL DISORDERS AND STROKE. THE NATIONAL INSTITUTE OF ALLERGY INFECTIOUS DISEASES, CHILD HEALTH AND HUMAN DEVELOPMENT AND BEST PHARMACEUTICALS FOR CHILDREN ACT. THE HEART LUNG AND BLOOD INSTITUTE IS WORKING ON TWO NEW PROGRAMS TO ACCELERATE INNOVATION WITH RESPECTED DIFFERENT DISORDERS AND PARTICULARLY A NEW PROGRAM AND VAST INTERVENTIONS AN INNOVATIONS AN THERAPEUTIC ADVANCES. OUR OFFICE AN RARE DISEASES CLINICAL DISEASE RESEARCH CONTINUES TO MAKE TREMENDOUS PROGRESS. JUST TO BRIEFLY MENTION JOHN GALLIN IS HERE AND THERE ARE CHANGES COMING AND OPPORTUNITIES IN THE BENCH TO BENEFIT SIDE RESEARCH PROGRAM. WE HAVE BEEN ABLE TO FUND A FEW PROJECTS EACH YEAR, CERTAINLY NOT WHAT EVERYBODY WOULD LIKE AND DOESN'T REFLECT THE EXTENT OF THE APPLICATIONS THAT COME IN BECAUSE THERE'S TREMENDOUS NUMBER. WE CONTINUE TO FOSTER AND SCIENTIFIC CONFERENCES PROGRAM AND IF ANY HAVE NOT HAD THE SCIENTIFIC CONFERENCE IN THREE OR FOUR YEARS PLEASE CONTACT OUR OFFICE. WE NEED YOU TO WORK WITH US AND THE INSTITUTES TO CREATE THIS EMPHASIS FOR THE RARE DISORDERS. SO WE WANT YOU TO WORK WITH US TO DEVELOP THAT. WE WILL SOON HAVE AVAILABLE A MIDDLE SCHOOL CURRICULUM MODULE IN RARE DISEASES AND SIGN ACTIVIC INQUIRY TO INCREASE THE EMPHASIS AN UNDERSTANDING OF RARE DISEASES. THERE WILL BE A WORKSHOP IN MAY THAT WE ARE SPONSORING WITH THE PROGRAM, NATURAL HISTORY STUDIES AND UNDERSTANDING THE VALUE OF STUDIES IN AN APPROPRIATE WAY. TO HELP IDENTIFY END POINTS THAT MIGHT BE USEFUL IN CLINICAL TRIALS AS WE MOVE FORWARD. WE RECENTLY PUBLISH REQUEST FOR INFORMATION ON PATIENT REGISTRY AND DATA REPOSITORY THAT WE LIKE YOU TO PERHAPS READ AND PARTICIPATE. WE'RE IN THE PROCESS OF DEVELOPING A WEB-BASED SEARCHABLE REGISTRY OF BIOSPECIMEN REPOSITORIES THAT NOW IS AVAILABLE AND DR. RUBENSTEIN FROM OUR OFFICE IS RESPONSIBLE FOR THESE PROGRAMS. ONE OTHER SIGNIFICANT EVENT OCCURRED OR ANOTHER SIGNIFICANT EVENT OCCURRED, THE IDENTIFICATION OF THE AMOUNT OF RESEARCH IN THE PROJECTS GOING ON WITH RESPECT TO RARE DISEASES. AND THIS CAME OUT OF THE RCDC PROJECT, RESEARCH CONDITION DISEASE CATEGORIZATION. FOR THE FIRST TIME WE DO HAVE A ACCURATE ASSESSMENT OF THE AM OF RESEARCH GOING ON WITH RARE DISEASES AND ORPHAN PRODUCTS. AND YOU CAN SEE THE NUMBER OF OF RESEARCH PROJECTS THAT ARE ONGOING AND HAVE BEEN VALIDATED BY THE INSTITUTE. SO IT'S ABOUT 3 1/2 BILLION DOLLARS OF RESEARCH FOR A LITTLE OVER 9400 RESEARCH PROJECTS. INCLUDED IN THAT IS A 749 MILLION OR SO FOR ORPHAN DRUGS RESEARCH. SO YOU CAN SEE IT IS A TREMENDOUS COMMITMENT BY THE NIH AND ALL THE INSTITUTES WITH RESPECT TO THE RARE DISEASES. AND THIS IS APPROXIMATELY 11.38% OF THE NIH RESEARCH BUDGET WHICH IS A LARGE AMOUNT OF MONEY. SO YOU CAN FIND ALL THE RESEARCH PROJECTS IF YOU VISIT THE WEBSITE AND GAIN ACCESS TO IT. SO I WILL END WITH THAT AND WE'LL GET THE PROGRAM MOVING BY WELCOMING DR. FRANCIS COLLINS WHO IS THE DIRECTOR OF THE NIH AND AGAIN, AS I MENTIONED EARLIER, MANY OF OUR ACTIVITIES CANNOT HAVE BEEN POSSIBLE WITHOUT THE GUIDANCE AN LEADERSHIP AND COMMITMENT THAT HE HAS MADE TO THE RARE DISEASE COMMUNITY. WE ARE EXTREMELY GRATEFUL FOR WHAT HE HAS DONE TO ENABLE EVERYTHING TO CONTINUE TO MOVE FORWARD IN THE WHOLE RESEARCH AND DEVELOPMENT PROCESS. DR. COLLINS WILL HAVE YOU JOIN US. [APPLAUSE] >> WHAT WE CAN DO GOING FORWARD FOR THOSE THOUSANDS OF RARE DISEASES WHICH COLLECTIVELY AS YOU HEARD AFFECT SOMETHING LIKE 25 MILLION PEOPLE IN THE UNITED STATES AND MORE ACROSS THE GLOBE. IT'S A PLEASURE TO BE PART OF THIS FIFTH RARE DISEASE DAY. I WORE MY JEANS. I HOPE YOU DID TOO. AS WE ALL TRY TO FOCUS OUR ATTENTION ON THIS RARE DAY INDEED ARC LEAP DAY. I GUESS WHAT WE WANT TO DO ON LEAP DAY IS TALK ABOUT HOW WE MIGHT LEAPśSfz FORWARD IN THIS CRITICALLY IMPORTANT AREA OF BIOMEDICAL RESEARCH. IT'S WONDERFUL TO HAVE NIH CHOSEN AS THE HOME FOR TODAY'S CELEBRATIONS AND WE PARTICULARLY I WANT TO THANK ALL THOSE REPRESENTING RARE DISEASE ADVOCACY ORGANIZATIONS WHO JOIN US HERE FOR WHAT WILL BE A FASCINATING DAY. SO YES, 25 MILLION PATIENTS AFFECTED. IN FACT, ONE CAN EVEN MAKE THE CASE THE IMPACT OF RARE DISEASES GOES WELL BEYOND THAT WHEN YOU CONTEMPLATE ALL THE WAYS IN WHICH THAT INFLUENCES FAMILIES IN WHICH THOSE DISEASES HAVE OCCURRED. CERTAINLY IF WE WANT TO LOOK AT THE CONSEQUENCES OF UNDERSTANDING THESE RARE DISEASES ACROSS ALL OF ME SIN, IT'S CLEAR OVER AND OVER AGAIN, AS WE UNRAVEL THE CAUSES OF A RARE ILLNESS, WE OFTEN SHED LIGHT ON A COMMON DISORDER. WE LEARN THAT LESSON OVER AND OVER AGAIN, IT'S NOT A NEW LESSON, BAITSON, ONE OF THE FIRST TO APPRECIATE THE GENETICS COULD BE UTILIZED PRODUCTIVELY TO UNDERSTAND HUMAN TRAITS AND CONDITIONS HAD THIS WONDERFUL THREE WORD QUOTE WHICH MANY OF US WHO WORK IN THE FIELD OF MEDICAL GENETICS HAVE USED IN VARIOUS OCCASIONS, HE SIMPLY SAID TREASURE YOUR EXCEPTIONS. SO RARE DISEASES MAYBE SEEN BY MANY PEOPLE AS EXCEPTIONS BUT WE TREASURE THEM, BECAUSE OF THEIR IMPORTANCE TO THOSE AFFLICT AND THEIR FAMILY, BECAUSE OF INSIGHTS THEY PROVIDE INTO HOW LIFE WORKS AND HOW WHEN SOMETHING GOES AWRY WE CAN LEARN FROM THAT BOTH FOR INDIVIDUALS WHO WE STUDY DIRECTLY AND THEN OFTENTIMES WITH ALL THE IMPACT THAT HAS ACROSS OUR UNDERSTANDING OF DISEASE IN GENERAL. SO IT'S GREAT TO HAVE A DAY TO CELEBRATE THAT AND THE LINEUP OF PRESENTERS TODAY IS QUITE REMARKABLE. SO I THINK YOU'RE IN FOR A REALLY WONDERFUL EXPERIENCE. AS YOU'VE HEARD, THERE ARE SOME 7,000 OF THESE RARE DISEASES. WE KEEP TRACK OF HOW MANY OF THEM HAVE HAD THEIR MOLECULAR CAUSES ACTUALLY DISCERNED. AND THE NUMBER HAS BEEN RISING WITH GREAT SPEED. NOW STANDS AT OVER 4,000. SO MORE THAN 4,000 DISEASES, MANY OF WHICH HAVE JUST HAD THEIR MOLECULAR UNDERPINNINGS UNCOVERED IN THE LAST FEW YEARS. WE'RE ON THE BRINK OF A DELUGE OF ADDITIONAL DISCOVERIES OF THAT SORT AS YOU'LL HEAR DURING COURSE OF TODAY BECAUSE OF ADVANCES AND ABILITY TO DO HIGH THROUGH PUT LOW COST DNA SEQUENCING AND OTHER KINDS OF APPROACHES. THAT'S THE GOOD NEWS. MORE THAN 4,000 DISEASES WHICH WE HAVE THE MOLECULAR CAUSE. THE SOBERING NEWS S YOU SAW THIS QUICKLY ON ONE OF STEVE'S SLIDES, WE ONLY HAVE TREATMENT FOR ABOUT 250 OF THOSE. ENORMOUS GAP BETWEEN WHAT WE KNOW AND ABLE TO DO ABOUT IT. MY FRIEND NANCY WEX LER A LONG TIME AGO CHASING THE CUSS OF O HUNTINGTON'S DISEASE AND HOPING TO YIELD AN OPPORTUNITY TO DO SOMETHING TO PREVENT OR TREAT THAT DISEASE WAS FOND OF A QUOTE FROM A GREEK PLAY FROM TYRESIUS AND EDIPUS THE KING, IT IS SORROW TO BE WISE WHEN WISDOM PROFITS NOT. WE'RE DERIVING A GREAT DEAL OF WISDOM ABOUT THE CAUSES OF RARE DISEASES, BUT WE NEED FOR THAT WISDOM TO BE PROFITABLE TO THOSE SO AFLICKED. HENCE, THE -- AFFLICTED. HENCE THE IMPORTANCE OF TURNING OUR ATTENTION WITH MORE INTENSE VIGOR THAN EVER TO THE DEVELOPMENT OF INTERVENTIONS. THERE'S GOOD NEWS THERE AS WELL. AS ONE CAN START TO SEE ADVANCES THAT ARE HAPPENING. IT WAS MORE THAN 20 YEARS AGO THAT MY LAB IN MICHIGAN WORKING WITH ANOTHER LAB IN TORONTO UNCOVERED THE CAUSE OF CYSTIC FIBROSIS BY DISCOVERING MUTATION MS. THE GENE CFTR. A FEW MONTHS AGO WE HAVE SEEN THAT COME FORWARD WITH THE FDA APPROVAL OF CALIDECO A DRUG WHILE ONLY TREATS 4 OR 5% OF INDIVIDUALS WITH C FSH, IT IS SPECIFIC FOR THE G-551D MUTATION, IT APPEARS REMARKABLY EFFECTIVE IN TREATING THAT DISEASE IN THOSE INDIVIDUALS. THAT IS REALLY A WONDERFUL THING TO SEE COMING FORWARD AND IS IN MANY WAYS PROOF OF PRINCIPLE FOR THE ABILITY TO APPLY SMALL MOLECULE THERAPEUTICS FOR RECESSIVE DISEASE, SOMETHING MANY PEOPLE MIGHT PRESUMABLY HAVE BEEN SKEPTICAL ANT SINCE YOU'RE NOT TRYING TO ACCOMMODATE SOMETHING OVEREXPRESSED, BUT EXEP SATE FOR SOMETHING NOT FUNCTIONING IN THE NORMAL WAY. WE CELEBRATE BUT IT TOOK 21 YEARS. CAN WE CONTEMPLATE SPEEDING UP THIS PROCESS? A PROSECT IN A PROJECT IS ONE OF THE RARE DISEASES, THE MOST DRAMATIC FORM OF AGING. HERE THERE IS A LITTLE BIT MORE OFY)Ť– OPTIMISTIC VIEW ON BASIS OF THE TIMETABLE THAT'S BEEN POSSIBLE BECAUSE A POST-DOC IN MY LAB DISCOVERED THE CAUSE OF THIS DISEASE IN 2003 AND BY 2007 A CLINICAL TRIAL WAS UNDERWAY. WE WERE FOR GNAT BY BEING ABLE TO LOOK AT THE MUTATION AN DISCOVER SOMETHING ALMOST IMMEDIATELY AB WHAT AN INTERVENTION MIGHT LOOK LIKE BECAUSE A WONDERFUL BASIC SCIENCE THAT HAD GONE ON ON THAT PARTICULAR PATHWAY, THAT PARTICULAR PROTEIN OVER THE PRECEDING SEVERAL DECADES SO WE STOOD ON THE SHOULDERS OF WONDERFUL BIOCHEMISTS WHO NEVER EXPECTED US TO CLIMB ON THEIR SHOULDERS AND TALK ABOUT THIS RARE DISEASE AND WE'RE ABLE TO MOVE FORWARD WITH A THERAPEUTIC IDEA LEADING TO THIS TRIAL IN THIS CASE A REPURPOSING TRIAL, TAKING A DRUG DEVELOPED FOR CANCER AND REALIZE IT MIGHT HAVE PROPERTIES FOR TREATING THE RARE DISEASE AND THAT TRIAL IS ONGOING TODAY. BUT WE NEED TO I THINK SYSTEMATICALLY LOOK AT THE WAY IN WHICH WE'RE DEVELOPING THERAPEUTICS. THAT HAS BEEN A STRONG MOTIVATION OVER SEVERAL YEARS AT NIH TO TRY TO SEE ARE WE BRINGING TOGETHER ALL CAPABILITIES OF THIS REMARKABLE SET OF 27 INSTITUTES AND CENTERS IN A WAY THAT WILL KNOCK DOWN SOME OF O THOSE BARRIERS TO THERAPEUTIC DEVELOPMENT. AND THAT HAS LED OVER THE COURSE OF THE LAST FEW YEARS TO THE NIH CHEMICAL GENOMIC SEN TORE THERAPEUTICS FOR RARE AN NEGLECTED DISEASE PROGRAM WHICH HAS GOT A DIRECT IMPACT ON WHAT WE'RE TALKING ABOUT TODAY. AND NOW MOST RECENTLY AS YOU HER FROM STEVE IN THE FORMATION OF THE FIRST SENOR AT NIH IN QUITE A LONG TIME, THE NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES JUST NOW GETTING UNDERWAY WITH GREAT AMBITIONS AND GREAT DETERMINATIONS TO KNOCK DOWN THE BARRIERS THAT HAVE MADE IT DIFFICULT TO GET TO THERAPEUTIC SUCCESSES IN LESS THAN 14 OR 15 YEARS AS YOU SAW FROM THE DIAGRAM STEVE SHOWED. THIS WILL NOT BE AN EASY UNDERTAKING. WE NEED NOT TO BE NAIVE HOW CHALLENGING IT WILL BE. BUT IT IS EXHILARATING TO SEE THE SCIENCE E MECIALGED IN A PLACE TO MAKE THIS KIND OF DREAM POSSIBLE. NCATS WILL HAVE AS ITS GOAL A FOCUS ON SPECIFIC BOTTLENECKS IN THE WAY OF ALMOST EVERY THERAPEUTIC DEVELOPMENT PROJECT. WORKING WITH INSTITUTES WITH RARE DISEASE ADVOCACY ORGANIZATIONS THAT REPRESENT PATIENTS AND PARTICULARLY WITH INDUSTRY WHO IS I THINK A WONDERFULLY MOTIVATED PARTNER THIS THIS CIRCUMSTANCE WE'RE DEVELOPING LOTS OF GOOD IDEAS AB WAYS TO WORK TOGETHER. WE AIM TO TRY TO GET THROUGH THOSE BOTTLENECKS IN A SYSTEMATIC WAY THAT WILL ADVANCE THE PROCESS OF THERAPEUTIC DEVELOPMENT. ACROSS THE BOARD FOR MANY DISEASES. BUT PARTICULARLY THIS NEED I THINK IS FELT. RARE DISEASES WE'RE OFTEN TIMES COMMERCIAL MOTIVATION IS INSUFFICIENT FOR THE PRIVATE SECTOR ALONE TO TAKE ON THE CHALLENGE. AND SO NIH AIMS TO THROUGH THESE VARIOUS ENTERPRISES PLUNGE IN TO LOOK AT THOSE 4,000 DISEASES FOR WHICH WE HAVE NOW A MOLECULAR UNDERSTANDING BUT DON'T HAVE THERAPEUTIC AND FIGURE HOW TO GET START AND DERISK THOSE PROJECTS FAR ENOUGH DOWN THE PATHWAY TO BECOME ATTRACTIVE FOR COMMERCIAL INVESTMENT. WE NEED THAT TO SEE SOMETHING GO ALL THE WAY THROUGH THE PIPELINE TO FDA APPROVAL AND GENERAL PUBLIC ACCESS. SO CHALLENGING TIMES BUT EXCITING TIMES. I THINK WE SHOULD TODAY RECOGNIZE BOTH OF THOSE THINGS. ONE THING I WANT TO PUT IN FRONT OF YOU AS PART OF THIS OPENING SET OF REMARKS. THAT IS TO MAKE AN ANNOUNCEMENT. AN ANNOUNCEMENT OF A NEW RESOURCE WHICH I AM PUBLICLY ANNOUNCING THE FIRST TIME TODAY HERE AT RARE DISEASE DAY. AND THIS IS A RESOURCE TO HELP CARE GIVERS, HEALTHCARE PROVIDERS, RESEARCHERS, ANYBODY INTERESTED IN HOW TO GET ACCESS TO INFORMATION ABOUT GENETIC TESTS TO DO SO IN A FASHION READILY ACCESSIBLE AND STANDARDIZED IN WAY TO FIGURE OUT WHAT THE INFORMATION REPRESENTS. SO IF I COULD HAVE THAT SLIDE UP ON THE SCREEN, WHAT I WOULD LIKE TO TELL YOU ABOUT, THIS IS BEING ANNOUNCED RIGHT NOW FOR THE FIRST TIME, THE GENETIC TESTING REGISTRY AND ENTERPRISE OF NIH, VERY MUCH SUPPORTED BY LOTS OF PEOPLE WHO WORKED HARD ON THIS BUT PARTICULARLY FROM OUR GOOD FRIENDS AT NCBI, NATIONAL CENTER FOR BIOTECHNOLOGY INFORMATION. SO LET ME SAY THIS PARTICULAR RESOURCE THAT'S IN THE WORKS FOR A NUMBER OF MONTHS WITH CONSULTATIONS FROM MANY GROUPS IS IN FACT WHAT YOU SEE RIGHT HERE. AND PLEASE SCRIBBLE DOWN THE URL THERE IF YOU WANT TO LOOK AT THIS LATER I WILL DRIVE YOU THROUGH THIS IN REAL TIME WHICH IS RIS SKI DOING IT IN FRONT OF THE AUDIENCE AND YOU NEVER KNOW WHETHER THE INTERNET WILL C HAVE A HICCUP ON LEAP DAY, BUT LET'S HOPE EVERYTHING GOES WELL. GENERAL POINTS ABOUT THIS. THE GTR HAS BEEN AN EFFORT PARTICULARLY BETWEEN CATHY HUDSON WHOSE NAME YOU HEARD ABOUT EARLIER, VERY MUCH A DRIVER OF THIS EFFORT FROM THE PERSPECTIVE OF THE NIH DIRECTORS OFFICE. FROM JINA STEL AT NCBI, REMARKABLY GIFTED IN PUTTING TOGETHER RESOURCES OF THIS SORT AND RECEIVING LOTS OF INPUT FROM LOTS OF PEOPLE. OTHERS WHO HAVE BEEN VERY MUCH INVOLVED IN THIS, CATHY FORMIS STEPHANIE DEVANI, SARA CARR AND THE PRIMARY PERSON TO TALK TO ABOUT THIS WAS WENDY RUBENSTEEN. THIS IS A RESOURCE IN ITS CURRENT VERSION HAS INFORMATION BUT THAT WILL GROW WE BELIEVE QUITE RAPIDLY. SO CURRENTLY WHAT'S DONE IS TO TAKE INFORMATION ABOUT GENETIC TESTS ARE FROM AN EXISTING NIH RESOURCE YOU ARE FAMILIAR WITH, GENE TEST AND MIGRATE INTO GTR. GENE TESTS WILL CONTINUE TO BE THERE UNTIL WE'RE AT THE POINT WHERE ALL THE INFORMATION IS COMPLETELY MYGRAITD OVER BUT GTR WILL HAVE MORE INFORMATION IN TERMS OF ADDITIONAL DATA FIELDS TO HELP YOU AS YOU TRY TO FIGURE OUT WHAT A TEST CAN DO, WHAT ITS PARTICULAR PROPERTIES ARE AS FAR AS ANALYTICAL VALIDITY, CLINICAL VALIDITY AND UTILITY. SO GTR WILL GAIN IN ITS FULL POTENTIAL OVER THE COURSE OF THE NEXT FEW MONTHS AND WE WORKED WITH A NUMBER OF LABORATORIES EXCITED ABOUT MIGRATING THEIR SPECIFIC INFORMATION INTO GTR. SO WHAT I'LL DO IS TO GO NOW TO THE WEB AND WE WILL SEE NOT BAD, MAYBE WE'LL MAKE IT FULL SCREEN. I WANT TO DRIVE YOU THROUGH SOME OF THE PROPERTIES OF THIS THAT YOU MIGHT WANT TO KNOW ABOUT. SO WE'RE NOW LIVE. YOU CAN SEE A NUMBER OF TABS HERE AT THE TOP WHERE YOU CAN DO A SEARCH ACROSS THE ENTIRE REGISTRY OR YOU CAN CHOOSE A TEST, A CONDITION, A PHENOTYPE, A SPECIFIC GENE, A SPECIFIC LAB OR YOU CAN GO TO THE GENE REVIEWS RESOURCE WHICH IS A VERY VALUABLE RESOURCE WHICH WILL CONTINUE TO BE CLOSELY LINKED TO GTR, WHICH GIVES YOU UP TO THE MINUTE CURATED REVIEWS OF RARE DISEASES WRITTEN BY EXPERTS IN THE FIELD. A FEW THINGS THAT I MIGHT WANT TO POINT OUT TO YOU, IN CASE YOU WANT TO PLAY WITH THIS LATER, THERE ARE A COUPLE OF YOUTUBE VIDEOS, ONLY THREE MINUTES LONG EACH ONE AND THEY'LL WALK YOU THROUGH SOME OF THE FEATURINGS OF THE GTR. NOTICE THIS DISCLAIMER HERE, THIS IMPORTANT NOTE. WE ARE DEPENDING UPON THE TEST PROVIDERS TO SUBMIT INFORMATION TO GTR ON A VOLUNTARY BASIS, WE ARE NOT THEREFORE PROVIDING GOOD HOUSEKEEPING SEAL OF APPROVAL BUT COUNTING UPON THE LABORATORIES TO PROVIDE THE INFORMATION. AND DOWN FURTHER IN THE PAGE THERE IS AN EXPECTATION HERE ABOUT GOOD BEHAVIOR WHICH WE WILL ASK THE LABORATORIES TO LIVE UP TO. IN TERMS OF WHAT OTHER INFORMATION YOU CAN SEE ON THE HOME PAGE, DOWN A LITTLE BIT, OVER HERE ON THE LEFT SIDE YOU'LL SEE VARIOUS GENERAL FEATURES HOW TO USE THE RESOURCE, HOW TO CONTACT GTR, HOW TO SUBMIT TO GTR IF YOU'RE LABORATORY AND HERE IS THE CODE OF CONDUCT WHICH BASICALLY IS THAT SUBMITTERS AGREE TO ABIDE BY THESE PARTICULAR PRINCIPLES OF INTEGRITY AND ACURA SAIND MAKE NO CLAIM IT IS GOVERNMENT IMPROVE OR ENDORSE TESTS THAT ARE SUBMITTED. AGAIN, I THINK THE LABORATORIES THAT DO THIS RESPONSIBLY ARE QUITE HAPPY TO LIVE UP TO THAT CODE OF CONDUCT AND LOOK FORWARD THE SEEING IF INFORMATION APPEAR IN SIGNIFICANT NUMBERS HERE. ON THE RIGHT SIDE OF THE HOME PAGE YOU SEE DIRECT LINKS TO LOTS OF INTERESTING USEFUL RESOURCES INCLUDING GENE REVIEWS I MENTIONED A MINUTE AGO. O OMIM, ORPHAN NET, THE TALKING GLOSSARY OF GENETIC TERMS AND ALSO RESOURCES HOW TO LOCATE A GENETICS PROFESSIONAL FROM ACMG AND SGC AND SO ON AS WELL AS CONSUMER RESOURCES. SO LOTS OF INFORMATION ON THE HOME PAGE. IF YOU WANT TO THEN ACTUALLY GO AFTER INFORMATION ABOUT A SPECIFIC TEST YOU THEN WANT TO ENTER SOMETHING INTO THE SEARCH. JUST AS AN EXAMPLE, ONE WE ALREADY HAD SUBSTANTIAL INFORMATION ENTERED BY COLLEAGUES AT HARVARD, I'M GOING TO ENTER IN HEREDITARY HEARING LOSS. IF I CAN SPELL CORRECTLY. IT HELPS ME ONCE I GET FAR ENOUGH INTO THE INTRI. SO LET'S SEARCH AND SEE WHAT WE GET. HERE YOU SEE WHAT IS ENTERED UNDER THE PARTICULAR DIAGNOSIS. THE SNOW MED IDENTIFIER. AN EXEMPT FROM THE GENE REVIEW. BELOW THAT THE FULL TEXT OF THE GENE REVIEW IS LISTED. SO FOR INSTANCE IF YOU WANTED TO GO FROM THAT AND SEE WHAT EXPERTS SAID ABOUT THIS PARTICULAR CONDITION, HERE IT'S WITH ONE CLICK TO GIVE YOU THE BACKGROUND BEEN DELVING INTO TEST AVAILABILITY. YOU CAN LOOK FURTHER, WHAT INFORMATION IS HERE. IN THIS CASE THERE'S A SINGLE TEST ENTERED INTO THE SYSTEM SO FAR. WE'LL GO TO THAT IN A MINUTE. BUT LOOK DOWN BELOW, IT WILL ALSO TELL YOU SIN WE HAVE ENTERED A FAIRLY GENERAL TERM, HEREDITARY HEARING LOSS AND DEAFNESS, THERE'S A VARIETY OF DIFFERENT MOLECULAR CONDITIONS THAT INCLUDE THAT. SOME OF THEM ARE SYNDROMIC LIKE PINDRID SYNDROME OR USHER SYNDROME WHICH INVOLVES HEARING AND VISUAL PROBLEMS OR WARDENBERG SYNDROME, SOME ARE NON-SYNDROMIC HEARING LOSS AND ALL THESE THINGS ARE THINGS YOU WANT TO KNOW ABOUT BEFORE DECIDING THEST TO ORD -- THE TEST TO ORDER. LET'S LOOK AT THE AVAILABLE TEST. IN THIS CASE WE CLICK AND THIS PARTICULAR TEST IS CALLED THE OTOCHIP, OFFERED BY LABORATORY FOR MOLECULAR MEDICINE AT PARTNERS, NOT ADVERTISING FOR THEM AT ALL, JUST THEIR DATA HAPPENS TO BE READILY AVAILABLE HERE FOR THIS DEMO. AND IF UP TO LEARN NO MORE ABOUT THE ODO CHIP TEST, IT TELLS YOU BY THESE COLORED BOXES IT INVOLVES SEQUENCE ANALYSIS OF CODING REGION AND TARGET MUTATION ANALYSIS, THAT'S SOMETHING YOU WOULD WANT TO KNOW. IF YOU GO TO THE ODO CHIP CLICK, SEE WHAT'S THERE, IT WILL GIVE YOU QUITE A LOT OF INFORMATION. SO THIS IS AN EXAMINE L PL OF THE KIND OF INFORMATION WE WANT TO SEE THERE FOR A LONG LIST OF GENETIC TESTS THAT GO BEYOND WHAT YOU CURRENTLY FINE IN THE GENE TEST RESOURCE. SO YOU CAN FIGURE HOW TO ORDER IT, WHAT'S THE INDICATION, WHAT'S THE METHODOLOGY, WHAT PERFORMANCE CHARACTERISTICS, HOW DO YOU INTERPRET AND HOW TO CONTACT THE LABORATORY. JUST AS AN EXAMPLE, WE DON'T TAKE TOO MUCH MORE TIME HERE LET ME CLICK ON METHODOLOGY. SO IT WILL TELL YOU HOW ARE THEY DOING THIS PARTICULAR ANALYSIS. AND IT WILL TELL YOU THAT IF YOU SPEND TIME READING THIS BASICALLY DOING A OLIGONUCLEOTIDE BASED TARGET CAPTURE, TAKING DNA AND USING A HYBRIDIZATION APPROACH TO TARGET A SPECIFIC LIST OF GENES AND THEN THEY ARE DOING NEXT GENERATION SEQUENCING OF WHAT IS CAPTURED USING THAT HYBRIDIZATION APPROACH. HERE ARE THE GENES WHICH ARE INCLUDED IN THAT CAPTURE WHICH WILL HAVE EXONS SEQUENCED AS PART OF THIS TEST SO QUITE A BROAD NET THEY ARE CASTING HERE. TO TRY TO IDENTIFY POTENTIAL MUTATIONS IN A SIGNIFICANT LIST OF GENES ASSOCIATED WITH ONE FORM OR ANOTHER OF HEREDITARY HEARING LOSS. IF YOU WANT TO KNOW PERFORMANCE CHARACTERISTICS, HOW GOOD IS THIS TEST AT FINDING SOMETHING? THIS IS AN INTERESTING EXAMPLE, WORTH LOOKING AT WHAT THEY SAY HERE, ANALYTICAL VALIDITY, ODO CHIP IS GREATER THAN 99% SENSITIVE FOR DETECTING SUBSTITUTION VARIANTS AND 95% SENSITIVE FOR DETECTING INSERTIONS OR DELETIONS FOR ONE TO TWO BASE PAIR INSERTIONS OR DELETIONS, IT GOES DOWN AS THEY GET LARGER. VERY SPECIFIC INFORMATION BUT INFORMATION YOU MIGHT WANT TO KNOW ABOUT. IN TERMS OF LIKELIHOOD OF DISCOVERING SOMETHING IN A PATIENT THAT YOU MIGHT HAVE IN FRONT OF YOU, YOU ALSO WANT TO KNOW ABOUT CLINICAL VALIDITY. THIS IS CHALLENGING. BECAUSE IF YOU TALK ABOUT ALL INDIVIDUALS WITH HEREDITARY HEARING LOSS WHILE WE HAVE A LONG LIST OF LOCI RESPONSIBLE FOR SOME CASES, WE HAVEN'T DISCOVERED ALL. SO A EVEN A PERFECT TEST FOR THIS SET OF LOCI IS NOT EXPECTED TO GIVE YOU 100% RECOVERY. SO HERE IS THE INFORMATION. CLINICAL SENSITIVITY BASED ON PHENOTYPE OF NON-SYNDROMIC HEARING LOSS BASED ON THE FIRST 175 CASES SO TELLING YOU THEY HAVE DONE SO FAR. FOR NON-SYNDROMIC THEY'RE GETTING AN DEFINITE ANSWER OF 14% BECAUSE WE DONE HAVE THE FULL LIST OF GENES INVOLVED IN THIS. INCONCLUSIVE, MIGHT BE SOMETHING TO CALL THE LAB ABOUT, I GUESS THOSE ARE SITUATIONS THEY FIND SOMETHING LIKE A NON-SYNONYMOUS CHANGE IN AMINO ACID BUT DON'T KNOW WHETHER IT'S CAUSATIVE OR WHETHER JUST ONE OF THOSE THINGS THAT HAPPEN. NEGATIVE, THAT IS NO ABNORMALITIES FOUND. IN USHER SYNDROME WITH A SHORTER LIST OF CANDIDATE GENES, THE POSITIVE GOES UP TO ALMOST 50%. SO DETAILED BUT USEFUL DATA FOR PEOPLE TRYING TO DECIDE WHETHER OR NOT THIS TEST IS INDICATED AND WHO THEY -- HOW THEY SHOULD INTERPRET THE RESULTS. LET ME JUST QUICKLY WIND THIS UP BY SAYING IF UPPED TO KNOW MORE ABOUT THE LABORATORY THAT OFFERS THIS YOU CAN CLICK ON THAT TOO. THIS WILL TELL YOU HOW TO CONTACT THEM AND WHO THE PERSONNEL ARE BUT ALSO TELL YOU WHAT OTHER TESTS DOES THAT LAB OFFER SO YOU CAN GET A SENSE IS THIS A SINGLE DISEASE LABORATORY OR ONE THAT'S DIVERSE. IN THIS CASE THIS LABORATORY OFFERED 134 TESTS FOR 124 CONDITIONS. SO HOPE YOU GET A SENSE HOW THIS RESOURCE COULD BE A VALUABLE ADJUNCT TO THE WAY IN WHICH DIAGNOSTICS ARE APPLIED FOR THIS VERY LONG LIST OF THOUSANDS OF RARE DISEASES AND ONE THAT GROWS EVERY DAY IN TERMS OF DIAGNOSTIC OPPORTUNITY BUT WHICH THERE HAS NOT BEEN A CENTRAL CLEARINGHOUSE FOR INDIVIDUALS INTERESTED IN THE INFORMATION TO GO AND GET THAT IN A FASHION THAT'S STANDARDIZED. THAT IS ADHERING TO CERTAIN PRINCIPLES ABOUT THE QUALITY OF DATA AND WHERE YOU CAN IN FACT FIND OUT NOT ONLY ABOUT THE TEST BUT ALL THE WAY DOWN TO THE POINT HOW TO ORDER IT. SO I HOPE THIS HAS BEEN A VALUABLE ADDITION TO THE DAY. I THOUGHT IT WOULD BE FUN TO ROLL OUT TODAY. BECAUSE OF WHAT WE'RE ALL HERE TO DO. THIS HAS BEEN IN THE WORKS FOR MORE THAN A YEAR, AND THANKS TO YOU WILL THOSE WHO MADE IT POSSIBLE AND GAVE ME A CHANCE TO DRIVE IT FOR YOU WHEN I DIDN'T DO A LOT TO SAY YOU SHOULD ADD THIS OR THAT)S"Ö BUTTON AN MAGICALLY IT HAPPENS. SO LET ME FINISH BY SAYING WONDERFUL TO BE HERE ON THIS SPECIAL DAY, I WANT TO THANK ALL THOSE WHO WORKED HARD TO MAKE IT HAPPEN, THANK THE SPEAKERS, SOME WHOM CAME LONG DISTANCES TO TAKE PART IN THIS. I'M GOING TO DASH IN AND OUT BECAUSE THERE'S OTHER THINGS GOING ON BUT I VERY MUCH LOOK FORWARD TO HEARING A LITTLE SNIP PETS OF THINGS PRESENTED BY THE REMARKABLE LINEUP OF PRESENTERS THAT HAVE BEEN AGREED TO COME TAKE PART TODAY. HOORAH FOR RARE DISEASE DAY. THANKS FOR THOSE WHO WORE THE JEANS, IF NOT THAT'S O CAIRKS WAIT UNTIL NEXT YEAR AND A JOY TO BE HERE NEXT TO ALL OF YOU. [APPLAUSE] >> THANK YOU VERY MUCH, FRANCIS, HE'S ABSOLUTELY CORRECT. HE SORT OF LOOKS AT SOME OF THESE BUTTONS BUT REMEMBER HE HAS TO PUSH THE BUTTONS TOO AND MAKE THINGS HAPPEN QUICKLY SO DON'T FORGET THAT. AND WITHOUT HIM AGAIN SO MUCH EMPHASIS ON RARE DISEASES AND ORPHAN PRODUCTS, REALLY IS A TRIBUTE TO HIS COMMITMENT TO THE COMMUNITY. SO THANK YOU VERY MUCH. AND IT IS GREATLY APPRECIATED. ONE THING HE MENTIONED BRIEFLY WAS THE MOLECULAR DIAGNOSIS FOR THOSE 4,000 OR SO DIFFERENT DISEASES. YOU'RE GOING TO SEE THIS CHANGING IN THE INTERNATIONAL CLASSIFICATION OF DISEASE AS WE GO FORWARD. THERE'S A PROJECT COMING, MAYBE ALREADY INITIATED HERE AT NIH TO LOOK AT THE MOLECULAR DIAGNOSIS BUT IN THE ENSUING YEARS WE WILL SEE A GREATER EMPHASIS ON MOLECULAR DIAGNOSIS. SO STAY TUNED FOR THAT AND I THINK THERE WILL BE TREMENDOUS IMPROVEMENT. SO PAR OF WHAT WE'RE GOING TO DO TODAY IS UTILIZE TECHNOLOGIES RIGHT NOW AND APPLIED TO FUTURE DIAGNOSTICS AND TREATMENT OUR FIRST SPEAKER DR. LES BIESECKER FROM THE NATIONAL HUMAN GENOME RESEARCH INSTITUTE TALKING HYPOTHESIS GENERATION MODES OF RESEARCH USING NEXT GENERATION SEQUENCING. SO LES, WE'RE READY TO GO. SO JOIN US, PLEASE. [APPLAUSE] >> THANK YOU VERY MUCH FOR INVITING ME TO CM AN KICK THIS OFF WITH DATA TODAY. YOU GUYS HAVE IN FRONT OF YOU A GREAT LINE UCH OF SPEAKERS WHO WILL TALK A NUMBER OF APPLICATIONS OF NEW EXCITING TECHNOLOGIES AND SO I'M JUST A LITTLE LOCAL DOG HERE NOT ONE OF THE BIG DOGS SO WHAT I DID IS LOOKED AT THE PROGRAM AND I SAW YOU HAVE GOT LIVE TOP TALKING -- LIFTON TALKING ABOUT NEXT GENERATION DISEASES AND CINDY ACTIVITY TALKING ABOUT THE RARE DISEASES PROGRAM. WHAT CAN I DO TO ADD TO THIS WONDERFUL AGENDA OF NEXT GEN SEQUENCING AND TECHNOLOGY. SOY THOUGHT I WOULD TRY SOMETHING DIFFERENT, SOMETHING THIS AUDIENCE WILL BE INCREASINGLY ENGAGED WITH AND KEY PART OF OVER TIME. WHICH IS THIS NEW APPROACH CALLING HYPOTHESIS GENERATING RESEARCH. SO WHAT I'M GOING TO TALK ABOUT THIS MORNING SINCE I'M FIRST SPEAKER, BASICS OF NEXT GEN SEQUENCING IS OR MASSIVELY PARALLEL SEQUENCING, TWO WORDS FOR THE SAME THING, AN EXAMPLE OF RARE DISEASE, GENETICS APPROACH AND MOVE TO THIS NOVEL WAY OF DOING CLINICAL RESEARCH AND THEN TALK A LITTLE BIT ABOUT HOW THIS MIGHT AFFECT THE CLINICAL CARE THAT OUR PATIENTS ARE RECEIVING. SO WHAT IS MASSIVELY PARALLEL SEQUENCING? THESE ARE A SET OF TECHNOLOGIES, THIS IS ONE PARTICULAR ITERATION OF THE TECHNOLOGY THAT AGAIN I'M NOT ENDORSING BUT USE AS AN EXAMPLE HOW THIS CAN BE DONE. WHICH IS TO TAKE DNA FROM USUALLY PERIPHERAL BLOOD OR INFECTED TISSUE, CHOP THAT DNA INTO VERY SMALL PIECES, AND THEN BASICALLY ATTACH THAT DNA TO A SOLID MATRIX, IN THIS CASE SOMETHING THAT LOOKS LIKE A MICROSCOPE SLIDE, AND IS ABOUT THE SIZE OF A MICROSCOPE SLIDE. AMPLIFY THAT DNA IN PLACE SO EACH MOLECULE BECOMES COPIES OF MOLECULES IN THAT PLACE ON THAT SLIDE. AND THEN SEQUENCE THAT LITTLE CLUSTER OF DNA MOLECULES ON THAT SPOT ON THAT SLIDE IN A WAY DEPENDING WHICH NUCLEOTIDE ADDED TO THE DOUBLE STRAND MOLECULE, LIGHT OR COLOR SIGNAL IS EMITTED FROM THAT SEQUENCING REACTION. AND THAT COLOR CAN BE CAPTURED BY TAKING A PICTURE OF THE SLIDE. REACTSc?JL SEQUENCING DNA. SO WHAT THAT DOES IS GENERATE A SERIES OF PHOTOGRAPHS OF THE SLIDE, THE SPOTS DON'T MOVE SO YOU CAN KEEP TRACK OF WHICH SPOT IS WHICH. AND THEN YOU FOLLOW THE COLORS SO BLUE T YELLOW G ORIGIN C, -- ORANGE C, ET CETERA AND YOU READ THE COLORS OF THE SLIDE. THIS SOUNDS SIMPLE AND CLER AND WHAT SO MASSIVELY PARALLEL IS THERE'S A LOT OF THESE LITTLE CLUSTERS OF DNA MOLECULES ON THE SLIDE. IN FACT THERE ARE BILLIONS OF THESE CLUSTERS ON THE SLIDE. A MICROSCOPE SLIDE IS SO MUCH TERRITORY THAT THEY ACTUALLY TAKE THAT SLIDE AND DIVIDE INTO SEPARATE AREAS OR CHANNELS BECAUSE IT'S TOO MUCH TO DO AT ONCE SO THIS MASSIVE PARALLEL APPROACH TO SEQUENCING GENERATES BILLIONS OF BASE PAIRS, MORE THAN 300 BILLION BASE PAIRS OF DNA SEQUENCE PER SLIDE PER RUN OF THE INSTRUMENT. THAT CHANGED HOW WE THINK ABOUT GENETICS AND GENOMICS AND IT ACTUALLY ALLOWED US TO BEGIN TO THINK ABOUT CLINICAL GENOMICS AND CLINICAL GENOMIC DIAGNOSIS. HERE IS AN IMAGE OF ONE OF THESE SLIDES. YOU TAKE MULTIPLE PICTURES OF THIS SLIDE, STACK THEM UP AND HAVE A COMPUTER LOOK AT THE IMAGES AND SAY OH, THIS SPOT IS YELLOW ON THIS IMAGE BUT ON NEXT ONE IS BLUE AND KEEP TRACK OF THE SEQUENCE OF EVERY ONE OF THESE MOLECULES, PUT THAT TOGETHER AND THAT IS TRANSFORMED TO SEQUENCE READS. WHICH ARE ALIGNED TO THE REFERENCE GENOME AND THE SEQUENCE OF A DNA SAMPLE CAN BE DERIVED FROM THAT DATA. SO WE CAN TAKE OTHER SHORT CUTS. THE GENOME TAKES 20,000 OR SO GENESCH GENES COMPRISE A RELATIVELY SMALL PART OF THE GENOME, MUTATIONS IN GENES AS YOU'RE AWARE CAUSE DISEASES THAT ARE INHERITED IN MENDELIAN OR SIMPLE GENETIC FASHION. BUT THE WORKING PARTS OF GENES ONLY COMPRISE ONE TO ONE AND A HALF PERCENT OF THE GENOME. THAT'S WHERE MUTATIONS ARE AND YOU'RE INTERESTED IN THAT KIND OF MUTATION, WHY SEQUENCE THE 98.5% WHEN WHAT YOU WANT FROM THE 1.5%? SO WE CAN FOCUS ON THAT 1.5% BY GRABBING THAT DNA. THERE ARE SEVERAL TECHNOLOGIES THAT ALLOW US TO DO THAT. THIS IS ONE OF SEVERAL. BASICALLY TAKE THE DNA FROM THE PATIENT, CHOP AGAIN INTO PIECES AND THEN USE COMPLIMENTARY DNA OR RNA MOLL QUEUE CIEWLS -- MOLECULES TO STICK TO THE DNA YOU'RE INTERESTED IN SEQUENCING. CAPTURE THOSE, IN THIS CASE USING LITTLE MAGNETIC BEADS THAT ARE ATTACHED TO THE DNA AND THEN YOU JUST SEQUENCE THE STUFF YOU'RE INTERESTED WHICH IS THAT 1 1/2%. DR. COLLINS REFERRED TO THE TECHNOLOGIES AND THE FALLING COSTS. THIS IS A SLIDE THAT OUR INSTITUTE IS FOND OF SHOWING. IT'S AN INCREDIBLE GRAPH WHEN YOU THINK ABOUT IT. THIS IS A LOG SCALE OF COST AND COST PER MILLION BASE PAIRS OF SEQUENCING, HOWP DOES IT COST TO SEQUENCE A MILLION BASE PAIRS OF DNA? TEN YEARS AGO THAT WAS 7 OR $8,000. AND IT HAS DECLINED OVER TIME TO A POINT WHERE IT'S NOW LESS THAN THAN $1 TO SEQUENCE A MILLION BASE PAIRS OF DNA. THAT IS AN ENORMOUS CHANGE. THIS STRAIGHT LINE HERE IS THE SO-CALLED MOORE'S LAW. THIS IS THE LAW IF YOU WILL OF COMPUTERS SUCH THAT THE COMPUTING POWER DECREASES AT A LOGARITHMIC RATE OVER TIME. THIS IS WHAT LEADS US TO HAVE, FOR EXAMPLE, IN MANY OF YOUR POCKETS ARE SMART PHONES. THAT HAVE MORE PROCESSING POWER THAN SOME MAINFRAME COMPUTERS DID 20 YEARS AGO. SO THIS IS WHAT ALLOWED YOU HAVE A SMART PHONE WITH MORE PROCESSING POWER THAN A MAINFRAME COMPUTER. IMAGINE HOW THAT HAS CHANGING YOUR LIFE AND THEN HAVE A FASTER CHANGING CURVE APPLY TO HOW GENOMICS CHANGES BIOMEDICINE. YOU CAN BEGIN TO UNDERSTAND THE POSSIBILITIES OF THE CHANGES THAT WE ARE FACING AND THAT'S AN INCREDIBLY EXCITING THING. SO WHAT. TECHNOLOGY, GWIZ, COOL, COST FALLING, ET CETERA, WHAT CAN WE DO WITH THIS? IT HAS DRAMATICALLY CHANGED THE RESEARCH LANDSCAPE, AS DR. COLLINS MENTIONED, IT HAS RESULTED IN A DELUGE OF DISCOVERIES THAT IS INCREASING IN FACT IN ITS RATE OF FINDING THE CAUSE OF INHERITED AND SOMATIC DISEASES IN PATIENTS. SO SEQUENCING PATIENTS WITH MENDELIAN OR SIMPLE GENETIC DISORDERS, WHERE WE COULDN'T EVEN NOT THAT WE COULDN'T AFFORD IT FIVE, TEN YEARS AGO, IT WAS TECHNICALLY NOT POSSIBLE TO FIGURE OUT WHERE THE GENES WERE BUT NOW YOU CAN SEQUENCE THE WHOLE WHOLE GENOME IN ONE SHOT. AND COMPARE AFFECTED TISSUE TO UNAFFECTED TISSUE. IT HAS MOST OBVIOUS IMPLICATIONS IN CANCER GENETICS AND GENOMICS WHICH YOU'LL HEAR ABOUT LATER. I WANT TO TALK ABOUT THE NOTION OF NEW WAYS OF DOING RESEARCH. I WANT TO GO BEYOND THAT AND TALK HOW IT WILL CHANGE CLINICAL DIAGNOSTICS. EXONLY AND GENOME SEQUENCING IS NOT MAGIC. NOTHING IS. WHAT DOES IT NOT DO AND WHAT'S THE REALITY HERE? IF YOU HAVE A DISEASE CAUSED BY THING NOT ACCESSIBLE TO AB EXONLY -- AN EXOME OR GENOME YOU'RE IN TROUBLE. WHAT IS IS THE EXOME ALL FROM THE GENOME AND YOU SEQUENCE THAT, WHAT'S NOT THERE? TURNS OUT SOME GENES ARE NOT THERE AT ALL. THAT CAN LEAD TO PROBLEMS. SOME PARTS OF SOME GENES ARE NOT INCLUDED IN THOSE DATA. PARTS OF GENES OUTSIDE OF THE ACTUAL GENE THAITS CONTROL HOW THE GENE WORKS MAY NOT BE THERE. SPLICING CONTROL ELEMENTS MAY NOT BE INCLUDED. YOU CAN'T READILY ASSESS STRUCTURAL DNA CHANGES COPY NUMBER CHANGES THAT CAUSE A NUMBER OF DISEASES. AND MITOCHONDRIAL DNA IS NOT IN MOST EXOME SEQUENCES AND THESE IMPORTANT ELEMENTS CALLED MICRORNAs AND OTHER SMALL RNAs MIGHT NOT BE INCLUDED. IF YOUR DISEASE IS CAUSED BY ONE OF THESE THINGS, NEXT GEN SEQUENCEING IS NOT THE ANSWER, IT WON'T WORK. SO THE GOOD RESEARCH TEAMS ARE THE TEAMS THAT HAVE THE ABILITY TO CHOOSE WHICH DISEASES ARE GOOD TARGETS FOR THIS TECHNOLOGY AND APPLY THE TECHNOLOGY WHERE IT THAT HAS MOST CHANCE OF WORKING. OFF TO RARE DISEASE GENETICS. I'M GOING TO TALK ABOUT A DISORDER CALLED COMBINED MALONIC ETHELDEMIA. SO THIS IS A WORK WE DID WITH VAN DUTTI'S LAB, HE'S AN EXPERT IN METABOLIC DISEASE, THIS IS A DISEASE WE THOUGHT WAS THIS, WE THOUGHT IT WAS A TYPICAL ORGANIC ACIDOSIS WITH CHILDHOOD ONSET, THE CHILDREN ARE BORN HEALTHY AND NORMAL AND THEN BECAUSE OF DIETARY INTAKE OF PROTEIN WHICH STRESSES BIOCHEMICAL SYSTEM BECAUSE THEY HAVE A MUTATION IN A GENE THAT DEGRADES PROTEIN, THEY UNDERGO METABOLIC DECOMPENSATION REACTION AT SOME POINT IN THEIR LIFE IN CHILDHOOD AND SUFFER CNS DAMAGE BECAUSE IT INFARCTS AND BRAIN DAMAGE WHICH IS IRREVERSIBLE, SOMETIMES SO SEVERE IT LANDS THEM IN A COMA. IT'S INHERTZED IN AN AUTOSOMAL RECESSIVE FORM. SO WE PICKED ONE OF CHUCK'S FAMILIES AND SEQUENCE AD TRIO. ONE AFFECTED PERSON AND TWO PARENTS. THIS GIVES YOU A FLAVOR OF WHAT EXOME TECHNOLOGY CAN CAN DO. TEN YEARS AGO WE DID POSITIONAL CLONING STUDIES, MULTIPLE FAMILIES AND FAMILY STRUCTURES BEGIN TO LOCALIZE THE GENE WITH EXOME SEQUENCING YOU DON'T NECESSARILY NEED THAT. SO WE SEQUENCED THREE PEOPLE, AND THEN WE DID WHAT'S CALLED FILTERING, YOU GET LOTS OF RESULTS OF VARIANT AND LOTS OF GENES AN YOU HAVE TO DECIDE WHICH ONE IS REAL. WE FILTERED ON A NUMBER OF CRITERIA, I WON'T GO THROUGH THE DETAIL BUS AFTER FILTERING BASED ON WHAT WE UNDERSTOOD ABOUT DISEASE AND VARIANTS IN THE EXOMES WE SEQUENCED WE WERE LEFT WITH 12 GENES CANDIDATE GENES FOR THIS DISORDER. WHEN JENNIFER JOHNSON SENIOR TECHNICIAN IN MY GROUP LOOKED AT THOSE SHE RECOGNIZED ONE GENE PRODUCT HAD WHAT'S CALLED A MITOCHONDRIAL LEADER SEQUENCE ON IT. AND SINCE THIS IS VERY LIKELY A DISEASE OF MITOCHONDRIAL DYSFUNCTION SHE REASONED THAT WAS THE CAUSATIVE GENE. SO EXOMES IN THREE PATIENTS VARIANTS IN ONE GENE CONFIRMED THEN WE TOOK SEVEN MORE PATIENTS WITH THAT SAME DISEASE. AND ASKED IF THOSE PATIENTS HAD MUTATIONS IN THE GENE. IT TURNED OUT SIX OUT OF 7 ADDITIONAL PATIENTS THAT WE EVALUATED HAD TWO MUTATIONS IN THAT GENE, CONFIRMING THAT IT IS THE GENETIC CAUSE OF THIS DISORDER. WHAT IS THIS GENE? THIS WAS A WHAT'S CALLED AN ORPHAN ACETYL TRANSFERASE GENE, KNOWN TO BE -- TO HAVE A FUNCTION IN BIOCHEMICAL PROCESSING OF ORGANIC ACIDS THAT COUPLES THEM TO THIS CARRIER MOLECULE CALLED CO-ENZYME A. THIS WAS ACTUALLY DISCOVERED THROUGH SOME WONDERFUL BASIC RESEARCH IN OF ALL THINGS A NITROGEN FIXING BACTERIUM. THEY FIGURED OUT THIS GENE WAS THE ACETYL CO-A SYNTHASE IN BACTERIA, ORTHOLOGOUS TO THE GENE IN HUMANS. THAT'S YOUR CLASSIC NOW CLASSIC WE TALK ABOUT CLASSIC BECAUSE THIS IS SO NEW, EXAMPLE OF HOW YOU TAKE A MENDELIAN DISEASE, RECESSIVE IN THIS CASE, APPLY NEXT GENERATION SEQUENCING TO UNDERSTAND THE BIOCHEMICAL AND MOLECULAR BASIS OF AN INHERITED DISEASE. YOU WILL HEAR MORE GREAT EXAMPLES ABOUT THAT BUT I WANT TO GO BEYOND THAT. SO NOW I WANT TO TALK ABOUT CLIN SEEK, IT'S A COHORT STUDY WE LAUNCHED IN COLLABORATION WITH COLLEAGUE IN THE NATIONAL HEART LUNG AND BLOOD INSTITUTE TO STUDY COMMON DISEASE TRAITS, IN A RARE DISEASE APPROACH ENVIRONMENT. I'LL TELL YOU HOW THAT WORKS. WE ENROLLED MORE THAN 900 PEOPLE AT THE NIH CLINICAL CENTER TO STUDY THIS TRAIT. WHAT THESE PATIENTS ARE ARE VERY DIFFERENT FROM WHAT I HAVE BEEN TALKING ABOUT IN RARE DISEASE. THESE ARE ADULTS BETWEEN 45 AND 65 AND ARE PRIMARY BUT NOT SOLE PHENOTYPIC INTEREST IS CARDIOVASCULAR DISEASE SPECIFICALLY ATHEROSCLEROSIS, MYOCARDIAL INFARCTION. WE TOOK A NOVEL APPROACH TO THIS COHORT. WE DIDN'T SAY WE WERE GOING TO STUDY HEART DISEASE, BUT WE SAID WE WERE GOING TO DO IS INTERROGATE THE ENTIRE GENOMES AND EXPLORE ALL POTENTIAL DOWNSTREAM PHENOTYPES IN A CREATIVE WAY. SO THE PATIENTS ARE CONSENTED FOR FULL OF GENOMIC INTERROGATION. COMPLETE SEQUENCING, RNA SEQUENCING, PROTEOMICS, ANYTHING YOU CAN IMAGINE THESE SUBJECTS ARE CONSENTED FOR, CONSENTED FOR DATA SHARING AND INTERESTINGLY ENOUGH CONSENTED FOR RETURN OF RESULTS WHICH IS A KEY THING BECAUSE IT ALLOWS US TO TAKE GENOMIC FINDINGS IN THE PATIENT AND ASK QUESTIONS OF WHAT IS THE PHENOTYPIC CONSEQUENCE OF A GENOMIC FINDING. THAT'S A NEW WAY OF DOING RESEARCH. SO WE CAN THEN BRING THE PATIENTS BACK AND ASK IF WE MAY PHENOTYPE THEM FOR ADDITIONAL ATTRIBUTES WE DIDN'T THINK ABOUT WHEN WE FIRST CONSENTED THEM TO THE STUDY. BECAUSE OF COURSE YOU CAN'T ANTICIPATE EVERY TRAIT AND WHAT MIGHT -- YOU MIGHT FIND IN ANY GENOME. YOU HAVE TO DO THIS ITERATIVELY AND PROSPECTIVELY. SO WE NOW HAVE ALMOST 600 EXOMES AND WE CAN INTERROGATE THOSE SOME WE LOOKED, TOOK VARIANTS FROM THE C -- AND ASKED THE QUESTION HOW MANY OF OUR PATIENTS WERE CARRIERS. WE WANT TO UNDERSTAND THE FREQUENCY OF THIS DISEASE IN THE POPULATION, REASONING THAT THESE WERE ADULTS, THEY SHOULDN'T HAVE THE DISEASE, THEY COULD BE CARRIER, HOW OFTEN DO WE SEE THAT. SO WE DID OUR CALCULATION ALLELE IS 1 IN 30,000 WHICH IS COMMON FOR A METABOLIC DISEASE. THESE ARE WHAT THE DATA LOOK LIKE. SO WHEN YOU SEQUENCE INDIVIDUALS YOU CAN JUST BEGIN TO BROWSE THE DATA AND SEE WHAT KIND OF VARIANTS YOU HAVE IN YOUR COHORT. AND THESE -- THIS IS THE ACTUAL OUTPUT FROM A PROGRAM CALLED VAR SECTOR A POST-DOC CREATED WHICH ALLOWS YOU TO BROWSE GENOMES AND SEE WHAT VARIANTS ARE THERE. IT GIVES YOU A NUMBER OF ATTRIBUTES, THE AMINO ACID CHANGE, HOW DAMAGING IT'S LIKELY TO BE. HOW MANY PEOPLE WE TYPED AND WHAT THE STATUS IS, WHETHER HOMOZYGOUS FOR REFERENCE OR NORMAL SEQUENCE. WHETHER HETEROZYGOUS OR CARRIERS WHICH IS WHAT WE'RE INTERESTED IN OR WHETHER THEY'RE HOMOZYGOUS FOR THE VARIANT. THOSE OF YOU WHO HAVE SHARP EYES MIGHT NOTICE THIS. WE HAVE A PATIENT HERE. AND THIS SAMPLE SEEMS TO BE HOMOZYGOUS FOR A VERY RARE VARIANT IN THE GENE THAT CAUSES COMBINED MALONIC ACIDEMIA. SO THE OBVIOUS CONCLUSION IS THIS IS A MISTAKE, BECAUSE THIS VARIANT MUST NOT CAUSE THE DISEASE. THESE ARE 50 TO 65-YEAR-OLD PEOPLE, THEY DON'T HAVE CHILDHOOD ONSET METABOLIC DISEASE. WHAT WE CAN DO IS BRING THE PATIENTS BACK AND THEN ASK MORE QUESTIONS AND BEGIN TO UNDERSTAND WHAT THE RELATIONSHIP MAYBE BETWEEN GENOTYPE AN PHENOTYPE. SO WE BRING THE PATIENT BACK AND SHE'S NOW A 65-YEAR-OLD LADY. WE DID MORE HISTORY AND GOT MORE DETAILED INFORMATION AND HAVING TROUBLES RECENTLY. SHE'S HAD FOUR CAR ACCIDENTS, UNEXPLAINED REASONS WHERE SHE HAD REDUCED CONSCIOUSNESS AND DIDN'T UNDERSTAND WHAT WAS HAPPENING TO HER. MEMORY DIFFICULTIES AND BLADDER INCONTINENCE. BECAUSE WE CAN DO ITERATIVE RESEARCH, AN mRNARI SCAN ON HER, SHE HAS MULTIPLE SMALL INTENSITY, LESIONS COMPATIBLE WITH SMALL STROKES OR INFARCTS WHICH IS INTRIGUING BECAUSE THE CHILDREN HAVE SEVERE INFARCTS AND COMA, COULD THIS BE RELATED? MAYBE, MAYBE NOT. WE CAN ALSO DO BIOCHEMICAL TESTING ON HER. WHEN WE DO THAT, WE FIND OUT COME TO UNDERSTAND SHE HAS 100 TIMES IN HER PLASMA, 100 TIME IT IS UPPER LIMIT OF NORMAL LEVEL OF METHYL MELONIC ACID IN HER PLAZ MARKS THIS IS NOT A LITTLE ABNORMAL, THIS IS WAY ABNORMAL, SHE HAS 70 TIME IT IS UPPER LIMIT IN URINE AND HAS MEASURABLE AMOUNTS OF MALONIC ACID FROM THIS DISORDER, ALSO IN HER PLASMA. THIS LADY HAS A MILD FORM OF COMBINED MALONIC AND METHYL MALONIC ACIDEMIA. I WAS TRYING TO THINK OF A CLEVER SLIDE TO USE TO THINK ABOUT OKAY, WHAT SHOULD I TELL THE AUDIENCE ABOUT HOW SMART WE ARE AND CLEVER WE ARE AND COOL OUR TECHNOLOGY IS. BUT THIS IS WHAT WE SHOULD BE DOING. THIS IS A BIG MOMENT FOR CLINICIANS AND SCIENTIST RESEARCHERS TO THINK WE HAVE BEEN MISSING OBVIOUS THING HERE. IT'S NOT SHE HAD UNDIAGNOSED DISEASE, SHE DIDN'T KNOW SHE HAD A DISEASE, WE DIDN'T KNOW WE SHOULD BE STUDYING UNTIL WE INTERROGATED HER GENOME, LOOKED AT THE GENOME AND ASKED THE QUESTION WHAT IS THIS VARIATION DOING TO THIS PATIENT. IT TOLD US THAT THERE IS A DISEASE WE DIDN'T KNOW WE SHALL BE LOOKING FOR IN A PATIENT, TOLD US WHAT THE PATHOPHYSIOLOGY IS AND NEW WAYS TO THINK ABOUT THIS DISEASE WE NEVER CONSIDERED STUDYING. SO THAT IS A FORM OF HYPOTHESIS, WHAT WE CALL HYPOTHESIS GENERATING RESEARCH. SO THE GENOME TOLD US WE SHALL HAVE A HYPOTHESIS THAT THIS VARIANT WAS CAUSING DISEASE THAT WE DIDN'T EVEN UNDERSTAND. HOW YOU DO THAT IS ASSEMBLE A COHORT OF SUBJECTS AND GENERATE THE DATA UP FRONT. BECAUSE OF THESE TECHNOLOGICAL ADVANCES YOU CAN GENERATE HIGH THROUGH PUT DATA AT REASONABLE COST AND USE THOSE DATA NOW IN CREATIVE WAYS. TEN YEARS AGO IT WOULD BE NUTTY TO PROPOSE SEQUENCING 600 HEALTHY PEOPLE THINKING YOU MIGHT FIND SOMEBODY WITH THIS DISEASE. NO ONE WOULD DO THAT. BUT BECAUSE OF TECHNOLOGY THIS IS ESSENTIALLY ALMOST FREE DATA, SINCE WE'RE USING IT FOR MANY PURPOSES WE CAN DO THAT. WE PARSE THE DATA FOR PATTERNS, PERTURBATIONS AND MAKE THE HYPOTHESIS WHAT WE THINK THE PHENOTYPE IS BASED ON WHAT THE GENOTYPE6# WAS. THAT'S THE RESEARCH IMPLICATIONS. SO WHAT ABOUT CLINICAL IMPLICATIONS? THE CURRENT CLINICAL PRACTICE PARADIGM MANY OF US PRACTICE AND ARE I WOULD ARGUE INORDINATELY FOND OF IS THIS. MANY PATIENTS HAVE BEEN THROUGH THIS A LOT. GATHER THE HISTORY, EXAMINE THE PATIENT AND USE THAT INFORMATION TO GENERATE A DIFFERENTIAL DIAGNOSIS. A LIST OF DISEASE POSSIBILITIES THAT MAY EXPLAIN THE COMPLAINT THE PATIENT HAS ASSUMING THE PATIENT KNOWS ENOUGH AND HAS ENOUGH SYMPTOMS TO GO TO A DOCTOR RECOGNIZING THEY HAVE A DISEASE WHICH ISN'T ALWAYS TRUE. WE USE THAT DIFFERENTIAL DIAGNOSIS TO SELECT THE TESTS THAT WE WANT TO ORDER. SO WE USE THIS INFORMATION AND THE CLINICIAN ACTS AS A TEST SELECTOR TO ORDER TESTS THAT WILL EXPLAIN WHAT IS WRONG WITH THE PATIENT. WE INTERPRET THOSE RESULTS THAT ALLOWS US TO MAKE A DIAGNOSIS OR LIMIT DIFFERENTIAL DIAGNOSIS AND THEN HOPEFULLY TREAT THE PATIENT. HOWEVER, MOST OF YOU IN THE RARE DISEASE WORLD KNOW TOO WELL THAT THIS IS WHAT HAPPENS. YOU GO THROUGH THE CYCLE OVER AN OVER AND OVER AGAIN OVER YEARS OF TIME IN A FASHION A CLINICIAN IS COMFORTABLE WITH AND SOME ARE FOND OF OUR ABILITY TO DO THIS. DIFFERENTIAL DIAGNOSIS TO ORDER TESTS AND FIGURE OUT WHAT'S WRONG WITH PATIENTS. WE'RE FOND OF THIS. THE PATIENTS HATED IT. THIS IS MISERABLE TO G THROUGH. THEY DON'T LIKE GOING THROUGH THIS. THEY WANT THE ANSWER AND THEY WANT TREATMENT. SO WE GOT TO FIGURE HOW TO GET THERE FASTER. SO HERE MIGHT BE A PARADIGM THAT COULD ALLOW US TO ACCELERATE THAT. APPLY GENOMIC TEST FIRST TO THE PATIENT. DON'T SELECT THE TEST. APPLY A GENOMIC TEST TO THE PATIENT. TAKE THE GENOME TO THAT HYPOTHESIS GENERATING RESEARCH AND INTERPRET THE RESULTS AND DEVELOP HYPOTHESES BASED ON GENOMIC OR OTHER OMIC DATA, METABALOMIC DATA AND DO A FOCUSED EVALUATION OF THE PATIENT BASED ON HYPOTHESES YOU HAVE GENERATED FROM THE GENOME TO FOCUS YOUR ENERGIES ON WHAT THE PATIENT MAY ACTUALLY HAVE INSTEAD OF CHASING TESTS BASED ON SYMPTOMS. ALLOW US TO DIAGNOSE AND HOPEFULLY TREAT SOONER. THAT IS NOT WHERE WE ARE TODAY. HOW ON EARTH DO WE GET HERE? I THINK THE RARE DISEASE COMMUNITY IS THE BEST COMMUNITY TO DEVELOP THE PARADIGM. THIS IS THE COMMUNITY WHERE IT'S THE MOST NEEDED AND WHERE IT IS CLEAR THAT WE NEED TO MAKE CHANGES THAT MAKE THINGS BETTER. SO HOW DO WE GET THERE? SOME ARE FOND SAYING GENOMICS WILL REVOLUTIONIZE MEDICINE. SO WE HAVE BEARDED GUYS, REVOLUTIONARIES AN EVOLUTIONARIES. SO I AM NOT SO FOND OF REVOLUTIONS. THESE ARE VERY MESSY THINGS, LOTS OF PEOPLE GET HURT, THINGS GET DESTROYED IN THE PROCESS AND I THINK THIS IS THE SOLUTION WE OUGHT TO BE THINKING ABOUT. WE SHOULD EVOLUTIONIZE MEDICINE. YOUR COMMUNITY, THE RARE DISEASE COMMUNITY IS THE IS THE IDEAL COMMUNITY DO THAT IN BECAUSE IT'S WHERE IT WORKS FIRST. AND IT'S CLINICS AND FAMILIES DEALING WITH THESE DISEASES HELP THE MEDICAL COMMUNITY LEARN DO THINGS IN NEW AND CREATIVE WAYS TO USE THIS PARADIGM TO GO FORWARD, IMPROVE DIAGNOSIS, IMPROVE CARE AND GET TO TREATMENTS FASTER. THANK YOU VERY MUCH FOR YOUR TIME. LOTS OF PEOPLE HELPED WITH THIS PROJECT. [APPLAUSE] STEVE SAYS WE HAVE TIME FOR A QUESTION OR TWO IF WE THERE IS ONER TWO. >> IF NOT WE'LL ASK DR. RAO TO JOIN US FOR THE NEXT PRESENTATION. (OFF MIC) >> GREAT QUESTION FROM THE AUDIENCE. IF YOU DO EXOME SEQUENCING YOU'RE PREFERRING FOR A SIMPLE MENDELIAN TRAIT WHAT PERCENTAGE DO YOU IDENTIFY AND WHAT PERCENTAGE DO YOU MISS? THIS WAS QUITE THE TOPIC OF DISCUSSION AT THE GENOMICS AND GENETICS GORDON CONVERSATION THIS SUMMER. THE NUMBER THROWN AROUND I THINK WAS IN THE RANGE OF IT WORKS 30 TO 40% OF THE TIME. NOT QUITE HALF. THAT'S A FUNCTION OF PICKING THE RIGHT TARGETS. WHAT THE COMMUNITY SEES AN COLLEAGUES SEE ARE PUBLICATIONS AND OUR PUBLICATIONS ARE OUR SUCCESSES AND NOT FAILURES SO THERE'S BIAS THERE. SO THAT'S WHY I HAD THAT SLIDE UP THAT EXOME AND GENOME SEQUENCING IS NOT MAGIC AND DOES NOT ALWAYS WORK AND WE NEED TO THINK CAREFULLY HOW TO APPLY THIS. >> KEN KRAMER. WONDERFUL TALK, I WAS INTRIGUED BY THE EXAMPLE THAT YOU SHOWED WITH IT, THE RARE DISEASE WITH THE YOUNG PATIENT WAS SEVERELY INVOLVED AND THEN YOU HAVE AN OLDER WOMAN WHO HAD A MUTATION IN THE SAME GENE BUT WAS VERY MILD. WHY DO YOU THINK SHE WAS MILD COMPARED TO THE OTHER? DO YOU THINK THERE ARE ADDITIONAL GENES THAT ARE MODIFYING THAT? IS IT THE PARTICULAR CHANGE IN THE DISEASE WHERE SHE HAS AFFECTED? >> GREAT QUESTION. IT COULD BE EITHER OR BOTH. WE DO NOT HAVE ENOUGH MUTATIONS YET TO DO GENOTYPE PHENOTYPE CORRELATIONS OF THE MUTATIONS IN THIS GENE WITH THIS PHENOTYPE. SO WE HAVEN'T YET EXCLUDED THAT SIMPLE CORRELATION WITH THE PRIMARY LOCUST. IN GENERAL MODIFIERS ARE IMPORTANT FOR ALL TRAITS. ONLY A QUESTION OF HOW IMPORTANT THEY ARE, NOT WHETHER THEY ARE IMPORTANT. SO I THINK THAT'S SOMETHING WE WILL NEED TO UNDERSTAND AND REFINE OVER TIME SO I THINK BOTH. WE'LL FIGURE IT OUT OVER TIME >> PLEASE IDENTIFY YOURSELF. WE HAVE ONE MORE QUESTION, PLEASE. >> JANICE SMITH. ARE YOU FINDING DISEASES PREVIOUSLY CLASSIFIED AS RARE ACTUALLY NOT RARE BUT JUST DIFFICULT TO DIAGNOSE? >> GREAT QUESTION. DISEASES WE TWHOWGHT WERE RARE BUT ACTUALLY UNDERDIAGNOSED. I THINK ACTUALLY DR. LIFTON'S TALK WILL BE THE PERFECT TALK TO TALK zjT COMMON -- THE RARE DISEASE ACTUALLY MASQUERADE AS COMMON DISEASE AND WE NEED TO DISSECT THAT. THERE'S THIS WONDERFUL REPORT THAT CAME OUT OF THE INSTITUTE OF MEDICINE THIS PAST FALL THAT TALKS ABOUT COMPLETELY REORGANIZING OUR UNDERSTANDING OF GENETICS, GENOMICS AND THE RELATIONSHIP OF GENES TO DISEASES IN OUR HIERARCHY OF DISEASES, ORGANIZING THINGS ALONG THE LINES YOU'RE ASKING, DISSECTING COMPLEX DISEASES INTO SETS OF RARE SUBSET DISEASES, MOSTLY ON A MOLECULAR BASIS INSTEAD OF A CLINICAL BASIS. THAT IS SOMETHING VERY MUCH UNDER STUDY AND IS AN EXCITING AREA AND WILL HELP US UNDERSTAND THE HETEROGENEITY OF PATIENTS, THE HETEROGENEITY HOW THEY RESPOND OR DON'T RESPOND TO TREATMENTS ONCE WE DISSECT THE MOLECULAR PATHOPHYSIOLOGY INSTEAD OF THINKING EVERYBODY WHO HAS HIGH BLOOD PRESSURE HAS HIGH BLOOD PRESSURE WHICH IS THE SAME REASON WHICH IS SORT OF WHAT WE DO NOW, CLEARLY NOT WORKING AND WHAT YOU'LL HEAR [APPLAUSE] >> CHEERS FROM NHLBI BUT MORE FROM RICK LIFTON, SO I'LL LET HIM DO THAT. >> THANK YOU VERY MUCH. >> THANK YOU ALL. [APPLAUSE] >> BEFORE GETTING TO DR. RAO I WANT TO INTRODUCE DR. JIM ANDERSON T DIRECTOR OF THE DIVISION OF PROGRAM COORDINATION PLANNING AN STRATEGIC INITIATIVE. DPKPSI. JIM HAS BEEN HERE SINCE OCTOBER OF 2010. I DON'T SEE BLADES ON THERE BUT HE JUST KEEPS ROLLING, IT'S UNBELIEVABLE. IF YOU HAVEN'T LOOKED AT DPKPSI, IT'S RELATIVELY NEW OFFICE, PLEASE LOOK AT THE WEBSITE AND SEE THE NUMBER OF ACTIVITIES THAT ARE ONGOING. HERE AT NIH WE'RE UNDERGOING A NUMBER OF CHANGES AND DIFFERENT ORGANIZATIONAL CHANGES AND THEN JIM AND HIS GROUP THEY'RE DOING WONDERFUL THINGS THERE. PLEASE LOOK AT THEIR WEBSITE AND SEE NEXT YEAR JIM WE'LL GET YOU ON THE AGENDA, SO LOCK IN THE DATE OF FEBRUARY 28 OR MARCH 1, WE'LL WORK WITH FDA SO PUT IT ON THE THE CALENDAR AND WE'LL LOCK YOU IN. THANK YOU VERY MUCH. THANK YOU FOR YOUR SUPPORT WHILE THE OFFICE OF RARE DISEASES WAS UNDER YOUR DIRECTION. WE APPRECIATE IT. SOME OF THE SUNDAY AFTERNOON DISCUSSIONS WERE VERY GOOD. THANK YOU. OUR NEXT SPEAKER, WE HER ABOUT STEM CELLS AND REGENERATIVE MEDICINE AND ABLE TO HAVE DR. MA HEN DRA RAO, APPOINTED THIS YEAR, A NEW APPOINTMENT AS DRK TOFORT NIH SENOR FOR REGENERATIVE MEDICINE WITHIN NATIONAL STAWT OF ARTHRITIS AND MUSCULO SKELETAL AN SKIN DISEASES INSTITUTES. SO RAO, PLEASE JOIN US. >> PLEASURE TO BE HERE AGAIN, AND I'M GOING TRY TO BUILD ON WHAT YOU HEARD FROM THE PREVIOUS TWO SPEAKERS. WHAT YOU HEARD FROM DR. COLLINS WAS THAT A SINGLE INVESTIGATOR CAN TAKE SOMETHING THEY DISCOVERED ON THE GENETIC SIDE AND MOVE IT TOWARDS AN IND OR CLINIC USING FUNCTIONAL ASSAYS. YOU HEARD FROM LES EARLIER ABOUT HOW YOU CAN COLLECT A VAST SET OF GENOMIC INFORMATION. AND AS POINTED OUT, ONCE YOU HAVE THE GENOMIC INFORMATION YOU NEED TO COLLATE THE FUNCTION. SO WHAT I'M GOING TO TALK ABOUT TODAY IS OUR EFFORTS HOW YOU CAN BUILD SOME SORT OF FUNCTIONAL ASSAY. AND FOR ME WHAT THAT MEANS IS WHILE WE CAN DO IT WITH PREVENTIONS AND WE CAN LOOK AT PATIENTS, IT'S HARD TO DO IT IN THAT ONE STEP AT A TIME AND IT TAKES A LONG EFFORT SO WHAT YOU NEED TO DO IS BUILD FUNCTIONAL ASSAY IN CELLS IN CULTURE. WHAT YOU HEAR IN THE REST OF MY TALK IS OUR EFFORTS THE TRY TO MAKE SURE THAT YOU CAN DO THIS. WHAT IS IMPORTANT ALSO TO REMEMBER THINKING FUNCTIONAL ASSAYS IS THE FOLLOWING. YOU CAN'T BUILD IT IN A GENERIC CELL. MANY THINGS WHICH AFFECT DISEASES WHICH AFFECT CELLS AFFECT SUBTYPE OF CELLS AND YOU DON'T SEE THE PHENOTYPE UNLESS YOU HAVE THAT SUBTYPE AVAILABLE. WHEN YOU MODEL CELLS YOU DONE SEE THE PHENOTYPE IN THE SAME WAY YOU SEE OTHERWISE SO WHAT I'M GOING TO TELL YOU TODAY ABOUT IS INDUCE PLURIPOTENT CELLS AND DEVELOPING THOSE CELLS THE FASTEST. SO RIGHT FROM THE BEGINNING BEFORE YOU START DEVELOPING ANYTHING NEW YOU HAVE TO ASK YOURSELF WHAT KINDS OF CELLS ARE AVAILABLE. AND WHAT KIND OF PRIMARY CELLS ARE AVAILABLE. AND THE NIH MADE A BIG EFFORT IN THIS OVER THE PAST SEVERAL YEARS. THAT SUMMARIZED IN THIS SLIDE. AND WHAT I'M GOING TO TELL YOU HERE IS WE CAN GET CELLS FROM VARIOUS SOURCES, ADULTS, WE CAN GET CELLS LIKE BONE MARROW DERIVATIVES, MOST HEMATOPOIETIC STEM CELL DERIVATIVES FOR THE SENOR. FOR THE CENTRAL NERVOUS SYSTEM WE CAN GET CELLS FROM IMMORTALIZED CELL LINES OR TUMORS AND FROM EITHER FETAL TISSUE OR INDUCED PLURIPOTENT CELLS. INDUCED PLURIPOTENT CELLS HAVE AN ADVANTAGE, YOU CAN GET THEM NOT JUST FROM A INDIVIDUAL, YOU CAN GET IT FROM A SPECIFIC INDIVIDUAL WHO CARRIES THE GENETIC ABNORMALITY AND COMPARE IT THE OTHER ADVANTAGE, YOU HEARD FROM COST PURPOSES IS THAT IF THE COST IS REASONABLE, YOU CAN REALLY CHECK LARGE ENOUGH PANELS OF CELLS. SOILY EMPHASIZE THOSE TWO POINTS IN THE NEXT SET OF SLIDES. MOST IMPORTANT THING, WHY IS THIS IMPORTANT OR WHY SHOULD I PRESENT IT IN RARE DISEASE PROGRAM OR IN VENUES LIKE THIS. AND THE IMPORTANT THING HERE IS TWOFOLD. WHEN YOU CHECK GOOD PATIENT HISTORY AND GOOD TISSUE SAMPLES, THAT'S IMPORTANT BECAUSE THE NIH CAN DO THAT BECAUSE THE CLINICAL CENTER IS ONE OF THE LARGEST RESEARCH BASED CLINICAL CENTERS WITH THE LARGEST COLLECTION OF RARE DISEASE PATIENT POPULATIONS THAT THEY CAN FOLLOW AND ALSO HAVE PATIENT HISTORY. IF WE COULD ACCESS THOSE TISSUES, AND IF WE CAN MAKE LIFE WE WOULD HAVE SOLVED TWO PROBLEMS, ONE YOU HAVE LARGE ENOUGH PANELS OF LINE TO LOOK AT THESE THINGS IN LARGE ENOUGH SCALE WHICH IS THE ADVANTAGE WITH IPSC CELLS AN SECONDLY CORRELATE THE CLINICAL INFORMATION WITH THE FUNCTIONAL INFORMATION THAT YOU GET IN CULTURE BECAUSE YOU COULD FOLLOW THE PATIENTS MUCH LIKE YOU HER WITH CLIN SEEK. HOW DOES THE NIH PROPOSE TO DO THIS? THAT'S WHERE I COME IN. WE HAVE A CENTER AND WHAT WE CAN DO IS SOURCE CELLS, DEVELOP THE APPROPRIATE DRCHESIATION PROTOCOLS TO GET THE RIGHT -- DIFFERENTIATION THE CELLS, WE CONSULT THE CELLS TO GET IMPORTANT DIFFERENTIATED PHENOTYPE THAT MAYBE INTERESTED IN. WE CAN DEVELOP THE LAB SCALE ASSAYS AN READ-OUTS FOR THIS AND THEN THANKS TO THE NCATS THERE'S A SCREENING CENTER AVAILABLE HERE SO WE CAN THEN WORK TO UP SCALE THE SCREENING TO THE APPROPRIATE SITE SO YOU CAN RUN DRUG REPURPOSES SCREENS OR ANY OTHER KINDS OF SCREENS YOU HEARD ABOUT. AND WE CAN GET THESE CELLS, SO IT BECAME GET THE CELLS IN THE RIGHT ASSAY FORMAT, WORK WITH THE GROUPS TO GET ASSAYS IN THE RIGHT DYNAMIC RANGE AND MAKE SURE WE CAN UNDERSTAND WHICH IS THE APPROPRIATE LIBRARY WHICH WE NEED TO USE TO BE ABLE TO PERFORM THOSE SORTS OF SCREENS. WHAT I'M GOING TO TELL YOU THE NEXT FEW SLIDES IS HOW WE MOVE FORWARD ON THAT FRONT. FIRST WE LEARNED YOU CAN JUST DEVELOP ASSAY IN A PATIENT SPECIFIC POPULATION. YOU NEED TO HAVE REFERENCES AND CONTROL LINES THAT YOU NEED TO MAKE. SO THAT BECAME A FIRST JOB. CAN WE MAKE REFERENCE AND CONTROL LINES AND CAN WE MAKE THEM WIDELY AVAILABLE. SO I'M GOING TO SHOW YOU RECENT RESULTS HERE, WE NEEDED TO MAKE INDUCED PLURIPOTENT CELL LINES, WE NEEDED TO MAKE SURE THEY WERE MADE IN AN INTEGRATION-FREE METHOD SO THEY WOULD NOT CARRY ANY SORT OF POTENTIAL CARRIERS TO INTERPRETATION BECAUSE OF INTEGRATION OF GENES AND WE NEED THE MAKE SURE THEY WERE AVAILABLE IN SOME REPOSITORY SO THEY WERE WIDELY AVAILABLE AND THE DATA SETS FOR THIS WAS AVAILABLE. SO THAT'S WHAT WE HAVE BEEN ABLE TO DO. WE WORK WITH SEVERAL GROUPS TO GET THEM, MORE THAN 10, 20 LINES AVAILABLE WHICH HAVE -- THE SEQUENCE -- CELL LINES ARE SEQUENCED SO THAT WE HAVE THE GENOMIC DATA AS WELL AS THE EXPRESSION DATA AVAILABLE AND IT'S A PANEL OF CELLS THAT WILL BE DEPOSITED IN A PUBLIC DEPOSITORY SO YOU CAN THEN ACCESS THEM ANY TIME YOU FEEL FOR YOUR OWN RESEARCH. THE ADVANTAGE OF THIS IS OFTEN IN RARE DISEASE PROGRAM IS THE FOLLOWING. ANY TIME YOU WORK WITH A PARTICULAR CELL LINE AND COMPARE DATA IT'S NOT TRUE YOU HAVE TO GET THE OTHER REPOPULATION AS WELL IN YOUR LAB.iSu IF YOU COMPARE AGAINST A CONTROL OR STANDARD, YOU CAN GO BACK AND THEN HAVE THE OTHER GROUP COMPARE IT AGAINST THE SAME CONTROL OR STANDARD WHICH IS WIDELY AVAILABLE AND SO YOU CAN GET DATA AND COMPARE ACROSS SAMPLE SETS. HOWEVER, WHEN YOU WANT TO RUN ASSAY, YOU DONE NEED A WAY TO MAKE CONTROL LINES, YOU ALSO NEED TO BE ABLE TO HAVE LINE WHICH IS CARRY AN APPROPRIATE REPORTER SO WE MAY NEED TO ENGINEER AS WELL. PLUS LARGE PANELS OF CELLS COLLECT OR ACCESS TO DATA USEFUL FOR LARGE SCALE GENOMICS EFFORTS, SO NOT JUST OUR EFFORT BUT SEVERAL INSTITUTES WORKING TO COLLECT NIH APPROPRIATE SAMPLES AND INDUCED PLURIPOTENT CELL LINES AND USE THE SAME PROTOCOLS TO DIFFERENTIATE THEM INTO APPROPRIATE PHENOTYPES. HERE IS A PARTIAL LISTING OF WHAT WILL HAPPEN IN THE COMING YEAR. STY TUNED. IN PARTICULAR I WANT TO EMPHASIZE THE WORK THAT WE'RE DOING WITH THE NEW YORK STEM CELL FOUNDATION. THIS IS WORK DONE IN COLLABORATION WITH THE ORPHAN AND RARE DISEASE PROGRAM WHERE WE HAVE IDENTIFIED TISSUE SAMPLES FROM CERTAIN SETS OF PATIENTS AN OFFERED TO MAKE IPS LINES FROM ALL THOSE AND MAKE SURE THEY'RE AVAILABLE IN THE PANELS. WIDELY DISTRIBUTED AVAILABLE TO THE APPROPRIATE RESEARCH COMMUNITY. I'LL TALK ABOUT THAT WHEN I TALK ABOUT PARKINSON'S DISEASE FURTHER DOWN. THE SECOND THING WE HAVE DONE IS MAKE ENGINEERS LINED FOR ASSAYS. I WON'T SPEND TIME ON THESE ASSAYS EXCEPT I'LL DESCRIBE A LITTLE BIT TECHNOLOGY AS BECOME SUCH THAT WE CAN MAKE REPORTERS AND TARGETED SITES RELATIVELY EASILY. WHEN YOU MAKE LARGE PANELS THAT YOU HAVE REPORTERS OF THE APPROPRIATE TYPE THAT YOU MAY NEED FOR YOUR ASSAY AND YOU CAN DEVELOP THAT AT A RELATIVELY LOW COST. THIS IS WHAT I WANT TO EMPHASIZE IN THE SLIDE. THE COST FOR DOING THIS IS BECOMING MUCH LOWER THAN IT USED TO BE EVEN THREE OR FOUR YEARS AGO THAT. IMPORTANT OF TECHNOLOGY. 50,000 TO $100,000 PER LINE AND NOW TALKING AS A TENFOLD REDUCTION OF THAT PRICE IN TERMS OF BEING ABLE TO MAKE IT WHEN WE MAKE LINES. AND PUTTING IN REPORTERS AS IN THE SAME REDUCTION IN COST AS WELL. BOTH IN TIME AND EFFORT. THE REASON THAT'S POSSIBLE THE SORT OF EFFORT WE HAVE BEEN PARTICIPATING IN IS TO AUTOMATE THE PROCESS SO THAT YOU CAN MAKE IT HIGH THROUGH PUT OR PARALLEL PROCESS. THIS IS WORK IN COLLABORATION WITH THE NEW YORK STEM CELL FOUNDATION AND THE NEW YORK BLOOD BANK AND CAROLINAS BLOOD BANK. WHAT WE'RE TRYING TO DO IS SAY WHICH ARE THE SOURCES OF TISSUE WHICH ARE AVAILABLE IN LARGE ENOUGH NUMBERS SO THAT IF YOU WANT TO GET CLINICAL HISTORY AND MAKE LARGE NUMBERS OF LINES THE IDEA BLOOD BANKS AND CORED BLOOD BANKS HAVE LARGE SAMPLES, 200,000 OR MORE, MANY OF THE BANKS SO WE SHOULD CHECK SAMPLE IN LARGE NUMBERS. IF YOU COULD PROCESS IT SO YOU CAN DO IT IN A 96 PLATE WELL FORMAT YOU CAN TAKE ADVANTAGE OF THE INFORMATION THAT EXISTED AND YOU SHOULD BE ABLE TO MAKE LARGE NUMBERS OF LINES FOR RELATIVELY LOW COST. SO WE WORK WITH THE NEW YORK STEM CELL FOUNDATION TO DEVELOP AN MAWT AUTOMATION PROCESS AND YOU HEAR MORE FROM THEM AT DIFFERENT VENUES. BUT THE GOAL HERE WAS THAT A SINGLE INDIVIDUAL SHOULD BE ABLE TO MAKE 100 TO 200 LINES WITHIN A CUP CAN L OF MONTHS AT REASONABLE COST SO YOU DON'T NEED HUGE EXPENSE IN INFRASTRUCTURE. THAT WORK IS PROGRESSING QUITE WELL AND WE USED THIS AS A DEMONSTRATION, SHOWCASE TO START MAKING PARKINSON DISEASE LINES AND I SHOW SMALL AMOUNT OF DATA ON THAT. SO THE NEXT PIECE THAT WE LOOK TED AT IN THIS WAS CAN WE DO THIS IN PRIMARY CELLS AND RUN ASSAYS OF SCREENS. I WON'T GO THROUGH ANY OF THE DATA EXCEPT TO USE THIS AS A PUBLISHED PAPER FROM OUR GROUP BUT SEVERAL OTHER GROUPS HAVE DONE THIS AS WELL. CAN BE IDENTIFY -- CAN WE IDENTIFY SMALL MOLECULES THAT WORK IN A SMALL ASSAY SCREEN LIKE THIS AND CAN IT BE DONE WITH A PROCESS STRUCTURE INFRASTRUCTURE THAT EXISTS HERE? THE ANSWER WAS YES AND SEVERAL OTHER GROUPS HAVE DONE THAT AS WELL. THE NEXT QUESTION WAS OKAY, NOW YOU CAN MAKE IPSC CELLS, YOU CAN AUTOMATE THE PROCESS, REDUCE THE COST, YOU CAN HAVE THE RIGHT SIZE SORT OF PATIENT COLLECTION PROCEDURES IS THAT YOU CAN GET APPROPRIATE CLINICAL DATA AND GENOMIC DATA TO MATCH WITH THE LINES YOU MAKE. CAN YOU DIFFERENTIATE ALL THESE INTO AN APPROPRIATE PHENOTYPE THAT YOU MAY NEED. AND AGAIN, I WANT TO SHOWCASE COUPLE OF PAPERS AND SAY THIS ANSWER WAS YES. WE CAN DO IT FROM ADULT TISSUE AND TAKE IPS CELLS AN DIFFERENTIATE THEM INTO MOST MAJOR PHENOTYPES WE WANT TO LOOK AT FOR THESE SORTS OF DISEASES. LAST SMALL DATA SLIDE, IT'S A HIGH LEVEL SLIDE SO I WON'T WORRY TOO MUCH ABOUT DETAILS. WE NEED TO TEST WHETHER THE HYPOTHESIS IS IS TRUE, CAN YOU TAKE IPS CELLS, DIFFERENTIATE THEM INTO A PHENOTYPE, CAN YOU DO IT IN A T 6 WELL FORMAT AND RUN AN ASSAY IN A FULLY DIFFERENTIATED CELL TYPE AND IS THE SIGNAL TO NOISE RATIO SUCH THAT YOU CAN RUN THAT ASSAY. WE TOOK AN EXAMPLE WITH WHAT WE THOUGHT WAS A DIFFICULT CELL AND THAT'S PAR KIN SEASON'S DISEASE CAUSED BY A LOSS OF PARTICULAR NEURON CALLED THE DOPAMINERGIC NEURON PRESENT IN THE MID BRAIN AND ASKED CAN WE GENERATE THIS NEURON? IT'S LATE STAGE DEVELOPMENT THAT TAKES EFFORTS TO DO IT. CAN WE GET IT OF SUFFICIENT PURITY TO RUN AN ASSAY AND CAN WE RUN -- WHAT KINDS OF ASSAYS CAN WE RUN? YOU SEE AN ASSAY RUN WITH A TOXIC -- LOOKING AT A PROTECTION BASED ASSAY. SO MGPP AND OTHERS ARE KNOWN TO BE NON-TOXINS FOR THE DOPAMINERGIC NEURON AND WE WANTED TO ASK CAN WE IN A DISH IDENTIFY MOLECULES PROTECTANT AND ASK A STEP FURTHER, DO WE IDENTIFY MOLECULES KNOWN TO BE PROTECTED IN VIVO FROM WHAT'S KNOWN AND ASK THAT WHETHER WE FIND SOMETHING NEW, WHETHER THAT IS USEFUL IN VIVO AS WELL OR USE IN A SECONDARY OR TERTIARY SCREEN, THE ANSWER WAS YES, WE CAN USE -- WE CAN DO A PARALLEL TEST WITH MPP, A SECOND TOXIN, YOU CAN SELECT THE HITS, TAKE THE HITS AND TEST IN VIVO TO SEE WHETHER THAT WAS TRUE AS WELL. AGAIN, IT'S NOT AS MUCH THAT IT'S IMPORTANT, REMEMBER, IF YOU HAVE IPS LINES WHICH CARRY DIFFERENT MUTATIONS YOU SHOULD BE ABLE TO NOW DO THIS IN A COMPARATIVE SCREEN TO ASK FOR PROTECT WHAT WILL EFFECT ONE PARTICULAR CELL TYPE OR NOT AFFECT A SECOND CELL TYPE. IT'S PUBLISH SOD I WON'T GO INTO TOO MUCH DETAIL IN ANY OF THIS. SO THIS IS WHAT IS MORE IMPORTANT FOR YOU AS A MODEL IN TERMS OF THINKING FOR ORPHAN AND RARE DISEASE. SO ALL OF YOU ON THE CLINICAL SIDE PROBABLY HAVE PATIENT POPULATIONS AND COHORTS THAT YOU COULD COLLECT TISSUE FROM. THE PROBLEM WITH SHARING THAT TISSUE HAS BEEN IT'S LIMITED, A LIMITED AMOUNT. IF YOU IMMORTALIZE OR MAKE A CELL LINE IT HAS CERTAIN CHARACTERISTICS LIMITED TO THE PHENOTYPE YOU'RE LOOKING AT SO WE ASK CAN CAN WE TAKE THIS AS A MODEL AND SAY HERE IS A COHORT OF PATIENTS OR COHORT OF MUTATIONS THAT HAVE BEEN IDENTIFIED IN FAMILIES. QUESTION COLLECT TISSUE SAMPLES FROM THIS AND BEING LIMITED BY THAT NUMBER, CAN CAN WE EXPAND BY MAKING IPS LINES. IF WE HAVE THEM CAN WE DIFFERENTIATE THEM AND SEE A PHENOTAPE THAT'S PRESENTED IN THE FUTURE BE USED AS AN -- IN AN ASSAY. SO WE CHOSE PARKINSON'S DISEASE BECAUSE NINDS HAD AN EFFORT IN PARKINSON DISEASE AND ON THE EXTRAMURAL SIDE THEY CHECKED TISSUE SAMPLES FROM MORE THAN 26 PARKINSON PATIENTS ALONG WITH CONTROLS. WE EXTENDED THE STUDY BY COLLECTING ADDITIONAL SAMPLES FROM SPORADIC PARKINSON AND WORKING WITH THE MICHAEL J. FOX FOUNDATION, NOT FORMAL COLLABORATION, IT'S STILL AN OPERATIVE WORD IN THIS CASE TO COLLECT ADDITIONAL PATIENT SAMPLES AS LONG TERM COHORT THEY'RE FLUOROFOLLOWING FOR THEIR OWN STUDIES. SO WE HAVE A SAMPLE SET, 40, 50, 100 DEPENNING WHERE WE END UP WITH SPORADIC POPULATION. WE KNOW WE CAN COLLECT THE TISSUE AND WE HAVE SPORADICS TO LOOK AT PERSPECTIVE WAY WHAT COULD P HAPPEN. WHAT WE HAVE DONE IS SAID CAN WE AUTO MAITD THE PROCESS -- AUTOMATE THE PROCESS AND DO IT IN A COST EFFECTIVE MANNER AS A DRY RUN, AS AN EXAMPLE FOR THE ORPHAN AND RARE DISEASE PROGRAM? THE ANSWER IS YES, ONGOING, THIS IS THE RESULT WHICH HAVE BEEN GENERATED IN LESS THAN A YEAR. SO OUT OF 50 WE STARTED AS A TARGET WE HAVE MADE 18 NOW. WE HAVE BEEN MADE STEM CELLS AN DOE MYNERGIC NEURONS FROM THEM, WE HAVE AUTOMATED THIS PROCESS AND TESTED IT AND NOW WE' WE'RE IN THE PROCESS OF DOING SOME OF THE SCREENS. SO THAT TELLS YOU TECHNOLOGY IS MOVING FORWARD, SO WE CAN APPLY TO RARE DISEASE AND BE ABLE TO PERFORM THESE ASSAYS. SO THERE WAS ONE MORE PIECE WHICH WAS A ROADBLOCK A LOT OF PEOPLE TOLD US WAS IMPORTANT WE HAD TO CONSIDER, WHEN YOU DOP AN ASSAY YOU DON'T WANT TO MAKE A STABLE LINE WITH AN REPORTER WHICH IS INTEGRATED PERMANENTLY YOU WANT TO RUN 50 KINDS OF ASSAYS AND YOU MIGHT NEED TO DO TRANSGENE EXPRESSION METHODOLOGIES SO THAT YOU CAN RUN AN ASSAY RELATIVELY QUICKLY. WHEN YOU DO THINGS TRANSYENLY WHAT YOU HAVE TO WORRY ABOUT, IS IT CONSISTENT. IF IT'S NOT CONSISTENT IT'S NOT A GOOD ASSAY FOR ANY HIGH THROUGH PUT SCREENING. SO WE LOOK AT DIFFERENCE TECHNOLOGIES TO DO EPISOMAL EXPRESS AND SEE WHETHER WE CAN DELIVER THIS AS RELATIVELY HIGH EFFICIENCY. I'M LOOK USING THIS AS ONE EXAMPLE. CAN WE USE BACULA VIRUS THAT DELIVERS TO A WIDE VARIETY OF CELLS AND YOU CAN EXTEND THE STRAINS BY MANIPULATIONS. CAN WE USE THIS IN MOST MITOTIC NEURONS AND OTHER DIFFICULT TO INFECT CELLS AND THE ANSWER WAS YES, WE COULD DO IT. SO THE TAKE HOME MESSAGE, NOT ONLY CAN YOU MAKE STABLE LINES BUT ALSO RAPIDLY DEVELOP A PROTOTYPE AND ASSAY IN A LINE USING EPISOMAL VECTORS. THAT'S JUST AN EXAMPLE OF THAT. THE LAST PIECE I WANT TO TELL YOU ABOUT IN A COUPLE OF MINUTES IS SIMPLY THE NEXT PROGRESS THAT PEOPLE HAVE MADE IN ENGINEERING. HISTORICALLY WHENEVER WE WANTED TO MAKE A STABLE REPORTER LINE OR ANY ASSAY WE SIMPLY USE LENTIVIRUS. OR RETROVIRUS, OR SOME INTEGRATE VIRUS, THERE WAS RANDOM INTEGRATION AND EACH TIME YOU MADE A NEW LINE YOU DIDN'T KNOW WHERE IT WAS INTEGRATED. YOU DIDN'T KNOW WHAT THE OFF TARGET EFFECTS OF JUST THAT INTE PROCESS WERE GOING TO BE. SO THE GOAL HERE WAS TO SAY WELL, IF YOU CAN MAKE IPS LINES YOU CAN MAKE THEM WITHOUT AN INTEGRATION METHOD CAN YOU NOW TARGET TO A SPECIFIC SITE SO THAT YOUR REPORTER WITH RESPECT TO WHICH OF THE MULTIPLE LINES YOU MAKE WILL NOT HAVE OFF TARGET EFFECTS. SO CAN YOU FIND A SAFE HARBOR SITE OR IF YOU'RE GOING TO PERFORM ENGINEERING, MAKE SURE IT'S EFFICIENT ENOUGH SO IN WHICHEVER SITE YOU DO, YOU DON'T NECESSARILY HAVE TO SAY I DID IT IN THIS ONE LINE AND IT TOOK ME A YEAR TO DO IT. AND NOW CAN DO IT IN ANY LINE BUT I CAN DO 50 LINES WITH THE SAME SITE IF I NEED TO IN AN EASY WAY. THE TECHNOLOGIES WE HAVE BEEN LOOKING AT ARE THESE TWO. ZINC FINGER NUCLEASES AN TRANSIF HE CANTOR. THEY TOOK THE STANDARD METHODOLOGY FROM HOMOLOGOUS RECOMBINATION AND IMPROVED EFFICIENCY OF THAT BY 10 TO 100 FOAL. WE ARE ALSO ABLE TO WORK WITH DIFFERENCE GROUPS TO IDENTIFY FOUR OR FIVE SAFE HARBOR SITES TO TARGET WITH THESE SORTS OF TECHNOLOGY. SO WHAT THAT MEANT WAS THAT WE CAN MAKE THESE PATIENT SPECIFIC IPS LINES, TARGET TO A SPECIFIC SITE, AND THEN WE COULD ALSO TARGET HOMOLOGOUS RECOMBINATION TO A GENE TO PERFORM A REPAIR OR RESCUE AND DO IT IN A RELATIVELY EFFICIENT WAY. I WON'T GO THROUGH THE DATA AND DIFFERENT GROUPS WITHIN THE NIH THAT ARE WORKING ON THIS. THE IMPORTANT THING TO REMEMBER IS THIS CAN BE DONE. SO THE LAST TWO SLIDES, I SHOW YOU THE METHOD, NOT TO WORRY ABOUT DETAILS BUT THE IMPORTANCE OF THESE TWO SLIDES IS SIMPLY THIS. THE TECHNOLOGY IS NO DIFFERENT IN TERMS OF BENCH WORK THAN WHAT WE'RE DOING IN MOLECULAR BIOLOGY FOR MANY YEARS, NOT THAT THERE'S A HUGE LEARNING CURVE BUT ACCESSING THE TECHNOLOGY AND MAKING SURE YOU CAN USE IT YOURSELF. THIS IS THE SITE I WANTED TO EMPHASIZE. THE S-1 SITE WELL KNOWN AS A SAFE HARBOR SITE, THE IT WAS A SITE MANY YEARS AGO PEOPLE USING ADINOVIRUS, ADINOVIRUS CAN INTEGRATE THE CHROMOSOME BECAUSE OF THE HOMOLOGOUS SITE IN THE HUMAN GENOME. IT'S A SINGLE SITE BUT BECAUSE WE KNOW THAT SINGLE SITE AND WE KNOW INTEGRATION INTO THAT IS RELATIVELY SAFE AND DOESN'T CAUSE EFFECTS, WE COULD DESIGN ZINC FINGER OR TALENT TO THAT SIDE SO THAT WE COULD INTEGRATE ANY GENE OF CHOICE INTO THAT SITE AND DO IT WITH RELATIVELY HIGH EFFICIENCY. AND THE ANSWER WE TESTED ALL THIS AND IT WAS NOT JUST CELLS, SEVERAL OTHER GROUPS HAVE DONE THAT, THE ANSWER WAS YES, IT CAN BE DONE AND IT'S BEEN DONE. WE HAVE REPORTER SITES WE HAVE MADE WITHIN THIS SITE AS PART OF THE INTRAMURAL EFFORT TO DISTRIBUTE THE KEY REPORTER LINES FOR CLINICAL TRANSLATION STUDIES. I WILL SKIP THIS SLIDE. THIS IS A LIST OF DIFFERENT LINES THAT WE USE. THERE ARE STANDARD LINES BUT YOU CAN IMAGINE FOR PARKINSON DISEASE WE KNOW ABOUT THE BIOLOGY SO WE KNOW SEVERAL TRANSCRIPTION FACTORS WHICH ARE IMPORTANT IN THE WHOLE DIFFERENTIATION OF DOPAMINERGIC NEURONS. ECONOMIC REPORTER LINES IN EACH STAGES SO WE CAN ASK OURSELVES DOES THIS MUTATION AFFECT DOPAMINERGIC NEURONS AT X OR Y STAGE IN A STRAIGHT FORWARD FASHION. THE LAST SLIDE, ALL I'M GOING TO SAY I SPEND A LOT OF TIME ON SCREENING RATHER THAN ON CELL BASED THERAPY SIMPLY BECAUSE THAT IS THE LOW HANGING FRUIT AND WE'LL HAVE RESULTS RELATIVELY SOON. I WANT TO SAY MANY OF THE THINGS THAT I SHOWED YOU HERE, CAN ALSO WORK QUITE WELL IN GETTING SPECIFIC LINES AS LONG AS WE CAN DO PROCESSENING A GMP FACILITY, LUCKY BECAUSE OF THE CLINICAL CENTER WE HAVE ACCESS TO A GMP FACILITY. SO WE HAVE BEEN WORKING WITH SOME GROUPS SIMPLY TO MAKE SURE THIS PROCESS CAN WORK. THE REASON I HIGHLIGHT THIS, THE NIH CLINICAL CENTER IS VERY WELL GEARED TO RUN THESE SORT OF RESEARCH EXEMPTIONS OR SINGLE PATIENT OR SMALL CLINICAL TRIALS RELATED TO THE PATIENTS THAT MIGHT BE INVOLVED IN AN ORPHAN DISEASE PROGRAM SHOULD RESULTS LOOK ENTOURAGE -- ENCOURAGING ENOUGH. I'LL END HERE AND BE HAPPY TO TAKE ANY QUESTIONS. [APPLAUSE] >> ANY QUESTIONS FOR DR. RAO? (OFF MIC) >> IT'S WORK DONE IN THE CENTER FOR GENOMIC SCREENS AND YOU SEE SOME OF THAT WORK FROM DR. MC DR. MCMCKEWNE LATER IN THE SESSION. >> MOHAMMED (INAUDIBLE) FROM DUKE UNIVERSITY. HAVE YOU USED THE INDUCED PLURIPOTENT STEM CELLS FROM PARKINSON DISEASE TO DIFFERENTIATE NEURAL CELL -- NEURAL CELL LINES AND FANTASTIC PHYSIOLOGY OF THAT AND HOW THAT AFFECTS IT AND BECAUSE THAT HAS IMPLICATIONS FOR EPILEPSY FOR OTHER O DISORDERS. >> THE ANSWER IS YES. SO FAR OF ALL MUTATIONS WE HAVE LOOKED AT, WE HAVEN'T COMPLETED THE LIST. NO PROBLEM MAKING NEURAL STEM CELLS FROM THESE CELLS. THE LAST TWO MIEWMATIONS -- MUTATIONS, HAS AN EFFECT ON THE NUMBER OF DOPAMINERGIC NEURONS GENERATED IN A STANDARD DIFFERENTIATION PROCESS WE CAN RESCUE BY RESCUING THE LOCK ACTIVITY. HOWEVER, IN TERMS OF MAKING OTHER NEURONS WE CAN CERTAINLY MAKE NEURONS RELATIVELY EASILY. >> JASON BAIRD FROM NORD. THANK YOU FOR THE PRESENTATION. IT WAS VERY INFORMATIVE, ONE PLUG FOR THE BREAK, IF Y'ALL WOULD TAKE A MOMENT DURING THE BREAK OR SOMETIME DURING THE DAY TO VISIT THE RARE DISEASE DAY.U.S. WEBSITE, I ENCORP RAJ EVERYBODY TO PARTICIPATE, THERE'S A NUMBER OF WAYS TO PARTICIPATE, CERTAINLY TO EXTENT EMAIL TO FRIENDS, FAMILY, PARTICULARLY ITEM THERE AT THE TOP CALLED HAND PRINTS ON THE HILL, THIS IS NIH AND SUCH BUT EVERYONE HERE OR A SIZABLE PERCENTAGE ARE VOTERS. I ENCOURAGE YOU TO LET YOUR ELECTED OFFICIALS KNOW. AND THERE'S AN ITEM ON RARE DISEASE DAY.U.S. TO LET YOU DO SO. THE QUESTION. THANK YOU, FOR -- AS FAR AS THE -- ADDING GENES INTO THAT PARTICULAR SITE ON CHROMOSOME 19, COULD YOU SPEAK TO THE NEED TO GO TO THE NEXT STEP. HOW THE EPIGENETICS, THE AFFECTS MIGHT IMPACT THE EXPRESSION OF A GENE. THERE'S CONTEXT BASED BUT FOR GENES THAT ARE IN AN ENZYME REPLACEMENT CONTEXT, OR SOMETHING MORE STRUCTURAL LIKE A COLLAGEN FIBER, I HAVE A FEELING IT'S IMPORTANT WHEN LOOKING AT ANY INTERVENTION. THANK YOU. >> IT'S COMPLICATED QUESTION BUT I'LL SAY FOR ANY EPIGENETIC EFFECTS YOU NEED A FUNCTIONAL ASSAY AND YOU HAVE TO HAVE A FUNCTIONAL ASSAY AND RIGHT CELL TYPE WHERE YOU CAN TEST HOW TO MODULATE THE CHANGES THAT OCCUR IN A PARTICULAR DISEASE. SO WE FEEL THIS IS A USEFUL WAY TO GO AND A USEFUL WAY TO DO A SCREEN TO UNDERSTAND WHETHER THE AFFECT BECAUSE OF FUNCTION OR BECAUSE OF AN EPIGENETIC AFFECT OR BECAUSE OF COPY NUMBER VARIATION FOR EXAMPLE. SO SOME LIMITATIONS ARE DOING SEQUENCING BY MATCHING THE GENOMIC SEQUENCING WITH THE FUNCTIONAL READ-OUTS FROM THE SAME CELL TYPES. WE EMPHASIZE IF YOU COLLECT GENOMIC INFORMATION IT MAYBE USEFUL TECHNIQUE TO COLLECT CELLS AND HAVE THEM READY OR STORED SO IN THE FUTURE YOU CAN MAKE INDUCED PLURIPOTENT CELLS OR HAVE ENOUGH CELLS TO RUN THIS KEY FUNCTIONAL ASSAYS. MAYBE IT WASN'T COLOR IN MY TALK, WE HAVE ARRANGED SO IF YOU HAVE TISSUE SAMPLES WHICH ARE RARE OR IMPORTANT, YOU HEARD ABOUT THE BIOSPECIMEN REPOSITORY PROGRAM FOR THE ORPHAN RARE DISEASE PROGRAM AND QUITE HAPPY FOR A CERTAIN NUMBER TO BE ABLE TO MAKE IPS LINES FROM THEM AS LONG Z YOU COMMIT TO HAVING THEM WIDELY DISTRIBUTE TO OTHER INVESTIGATORS WHO NEEDED THEM AS WELL. [APPLAUSE] >> THANK YOU, DR. RAO. JUST TO ADD ON TO JASON'S COMMENT, THERE ARE ACTIVITIES IN 60 COUNTRIES AROUND THE WORLD TODAY RELATED TO RARE DISEASES. SO I THINK YOU CAN SEE THE SPREAD OF THE EMPHASIS UPON RARE DISEASE THROUGHOUT THE WORLD. WE'RE VERY,VERY HAPPY TO SEE THAT GROWTH. SO OUR O NEXT SPEAKER IS DR. RICHARD LIFTON FROM YALE UNIVERSITY, DEPARTMENT CHAIR OF THE DEPARTMENT OF GENETICS AND HE WILL BE TALKING ABOUT DISCOVERING ARE NEW GENES THAT CAUSE MENDELIAN CONDITIONS. >> THANKS VERY MUCH. THRILLING TO BE HERE TO SHARE IN THE CELEBRATION OF RARE DISEASE DAY, AS EVERYONE IN THIS ROOM KNOWS, DISEASES MAYBE INDIVIDUALLY RARE BUT COLLECTIVELY QUITE PREVALENT AND PLACE BURDEN ON PATIENT WHOSE SUFFER FROM THEM. THEY ALSO FREAKILY ARE ENORMOUSLY ILLUMINATING ABOUT MORE COMMON DISEASES. AND THEREFORE NOT JUST QIJLY RARE BUT PREVALENT IN OUR SOCIETY. LES BIESECKER GAVE A WONDERFUL DISCUSSION ABOUT NEW OPPORTUNITIES COMING FROM GENOMIC TECHNOLOGIES AND IN THAT CONTEXT NIH AND NHGRI RECOGNIZE OPPORTUNITIES ARISING FROM NEW TECHNOLOGIES AND ABOUT A YEAR AND A HALF AGO DECIDED TO LAUNCH A NEW PROGRAM IN MENDELIAN GENOMICS THAT HAS NOW COME TOGETHER AND IS FUNDING THREE SITES. AND THE GENERAL GOAL IS TO SOLVE ALL OF THE REMAINING RARE DISEASES OF HUMANS. THAT'S OBVIOUSLY AN AUDACIOUS GOAL BUT THE TECHNOLOGY IS UP TO IT AND I'M ENTHUSIASTIC ABOUT THE POSSIBILITIES. FRANCIS IN HIS INTRODUCTORY REMARKS EMPHASIZED HOW FAR WE HAVE COME AND HOW MUCH WE KNOW BUT FAIR TO POINT OUT WE REALLY UNDERSTAND THE CONSEQUENCE OF MUTATION IN ABOUT 20% OF THE GENES IN THE HUMAN GENOME AND THESE ARE ELEMENTS WE ACTUALLY UNDERSTAND. WE WOULD LIKE TO KNOW WHAT IS THE CONSEQUENCE OF MUTATION OF ALL OF THE FUNCTIONAL ELEMENTS OF THE HUMAN GENOME. AND THIS CENTERS FOR MENDELIAN GENOMICS PROJECT IS TAKING ON THIS TASK. SO THERE ARE THREE GROUPS THAT ARE FUNDED IN THIS CONSORTIUM. THE UNIVERSITY OF WASHINGTON WITH JAY SHENDURI, INVENTOR OF THE EXOME TECHNOLOGY, DEBBIE NICKERSON EXOME SEQUENCE, MYSELF AND SHRI KANMANI. JOSH HAWKINS LED BY DAVID VALLEY, BAILOR COLLEGE OF MEDICINE LED BY JIM WEBSKI, THESE GROUPS ARE COMING TOGETHER TO TACKLE THESE PROBLEMS AND IDENTIFY THE UNDERLYING MOLECULAR BASIS. SO AS I INDICATED, THE GOAL IS TO IDENTIFY THE MOLECULAR BASIS OF ALL MENDELIAN DISEASES OF HUMANS. WE BELIEVE THERE ARE MANY P PREVIOUSLY UNRECOGNIZED MENDELIAN TRAITS AND I'LL COME BACK TO THAT AND LES BUY SICKER'S TALK POINTED TO THAT AS WELL. AND WE WANT TO DEVELOP AND IMPROVE TECHNOLOGIES FOR METHODS ANALYSIS AND SHARE THESE RESOURCES AND FINDINGS TO FACILITATE NOT JUST DISCOVERIES BUT UNDERSTANDING OF HOW TO GO ABOUT BETTER DIAGNOSING AND TREATING DISEASE. THE SUCCESS OF THIS PROGRAM WILL RISE AND FALL BASED UPON SUCCESS IN AS CERTAININGING, RECRUITING AND ANALYZING LARGE RELEVANT COHORTS OF PATIENTS. AND THIS IS ONE OF MY ROLES HERE TODAY. TO PROS THEY WILL ADVERTISE -- PROS LATIZE THOSE IN THE RARE DISEASE COMMUNITY, THERE ARE OPPORTUNITIES FOR PATIENTS AN GROUPS OF SAMPLES TO ANALYZE USING CUTTING-EDGE TECHNOLOGY. SO WE'RE ENTHUSIASTIC ABOUT ENGAGING THIS COMMUNITY AND LOVE TO DISCUSS THIS WITH ANYONE INTERESTED AND MOREOVER, THOSE THAT ARE INTERESTED, THERE IS A WEBSITE. WE HAVE BEEN ONLY BEEN IN PIS TENSE A COUPLE OF MONTHS AND WE'RE GETTING SET UP. WE HAVE A WEBSITE UP THAT ALSO HAS EMAIL ACCESSIBILITY SO I WOULD ENCOURAGE ANY OF YOU INTERESTED YOU CAN FOLLOW-UP THROUGH THESE SITES. SO AS WE HAVE BEEN DISCUSSING THIS MORNING, WE HAVE GONE THROUGH THREE DIFNT ERAS OF GENE DISCOVERY, TWO HAVE BEEN SPECIFICALLY RELEVANT TO RARE DISEASES. THE FIRST WAS DRIVEN BY THE DEVELOPMENT OF COMPLETE GENETIC MAPS THAT LED TO THE MAPPING AND IDENTIFICATION OF THE 3,000 MENDELIAN VERGING ON 4,000 MENDELIAN TRAITS SOLVED TO DATE. WE THEN WENT THROUGH AN ERA OF ASSOCIATING COMMON VARIANTS WITH COMMON DISEASE. AND WHAT HAS CHANGED THAT SPURRED OUR ENTHUSIASM IN THIS ERA, NEW ERA HAS BEEN DRIVEN BY THE PRECIPITOUS DROP IN THE COST OF DNA SEQUENCING. SO AS LES DISCUSSED, THE COST OF SEQUENCING HAS COME DOWN BY SIX ORDERS OF MAGNITUDE SINCE WE STARTED THE HUMAN GENOME SEQUENCING PROJECT IN 1998. TO NOW. THIS IS DRIVEN BY BOTH INCREMENTAL AND SALTTORY CHANGES IN TECHNOLOGY. SO THE FIRST MASSIVELY PARALLEL INSTRUMENT T 454 INSTRUMENT WAS INTRODUCED AND RESULTED IN A DRASTIC DROP IN THE COST OF SEQUENCING. THE ALUMINA PLATFORM HAS BECOME ROBUST AND THE COST OF SEQUENCING IS NOW DOWN TOP 10 CENTS FOR A MILLION BASES OF SEQUENCE. THERE ARE NEW TECHNOLOGIES THAT ARE ON THE HORIZON. THAT PROMISE TO REDUCE THE COST OF SEQUENCING BY FACTOR OF FIVE PERHAPS. AND THIS HAS GOTTEN US TO THINK THAT THE COST OF SEQUENCING WILL -- ANALYZING GENOMES ALMOST A ROUNDING ERROR IN THE COST -- OVERALL COST OF CARE WITH PATIENTS WITH SEVERE DISEASES. WE CAN SEQUENCE COMPLETE EXOMES FOR WELL LESS THAN A THOUSAND DOLLARS, WE EXPECT TO BE ABLE TO SEQUENCE WHOLE GENOMES FOR LESS THAN A THOUSAND DOLLARS BY THE END OF THIS YEAR, IF SOME OF THE TECHNOLOGY PROMISES PAN OUT. SO THE OPPORTUNITIES WE THINK ARE GREAT. SO LES GAVE A BEAUTIFUL INTRODUCTION TO THE ANALYSIS OF EXOMES, THE REDUCED SET OF OF PARTS OF THE GENOME THAT WE KNOW ARE FUNCTIONAL. THIS COMPRISES ONLY 1% OF THE GENOME SO WE CAN SELECT BY HYBRID CAPTURE THAT 1% OF THE GENOME. AND THEN WE AND OTHERS DEVELOPED ALGORITHMS TO ANNOTATE THESE GENOMES FOR VARIATIONS FROM THE REFERENCE SEQUENCE AND THEN SORT THROUGH THESE TO IDENTIFY THOSE WHICH ARE FUNCTIONALLY IMPORTANT IN THE CONTEXT OF INDIVIDUAL PATIENTS. SO AT THE CURRENT LEVEL WE PRODUCE TYPICALLY LES INDICATED HOW MUCH INFORMATION YOU GET FROM A SINGLE LANE OF DNA SEQUENCE SO WE CAN GET 6 EXOMES PER INDIVIDUAL LANE. AND SEQUENCE AT SUFFICIENT DEPTH THAT WE CAN IDENTIFY ABOUT 96 TO 97% OF ALL THE HETEROZYGOUS POSITIONS THAT ARE DIFFERENT FROM THE REFERENCE SEQUENCE, THE SPECIFICITY OF THESE HETERO SOI GOAT WE EMPHASIZE HIGH SPECIFICITY SO YOU DONE CHASE VARIANTS TO PROVE NOT TO BE REAL AND OUR SPECIFICITY RUNS 99.8% BEFORE DOING SAENGER VALIDATION. THE COSTS CONTINUE TO COME DOWN, PRESENTLY IT ABOUT $800, BY THE END OF THIS YEAR WE EXPECT IT TO BE ABOUT $500. AT YALE WE PRODUCE 500 HUMAN EXOMES PER MONTH AND SEQUENCED ABOUT 5,000 HE CAN ONLIES IN TOTAL -- EXOMES IN TOTAL THUS FAR. THIS IS THE KIND OF DATA THAT YOU GET OUT OF JUST THE QAQC FOR EXOME AND I WON'T TAKE YOU THROUGH IT. IN THIS PARTICULAR CASE FIVE INDIVIDUALS HAD EXOMES SEQUENCED IN THE SINGLE LANE OF ALUMINA SEQUENCE. AND YOU CAN SEE THAT ABOUT 95% OF ALL BASES WERE READ AT LEAST 8 TIMES AND THIS CORRELATES QUITE WELL WITH WITH A SOMEWHAT HIGHER FRACTION OF THE HETERO ZYGOSITY CAPTURED. YOU CAN SEE ABOUT 5% OF ALL THE VARIANTS THAT YOU IDENTIFY ARE NOVEL AND HAVE NOT BEEN SEEN BEFORE. SO THIS IS WHAT YOU GET OUT OF A TYPICAL HUMAN EXOME. SO IF WE WERE TO SEQUENCE ANYONE IN THIS ROOM WHO IS OF EUROPEAN ANCESTRY, WE WOULD FIND THAT AT PRESENT WITH 5,000 EXOMES FROM OUR WORK AN ANOTHER 10 O THOUSAND OR SO THAT ARE IN PUBLIC DATABASES FROM AROUND THE WORLD, WE WOULD FIND ABOUT 60 PROTEIN ALTERING VARIANTS THAT HAVE NEVER BEEN SEEN BEFORE. THIS OF COURSE POSES DIFFICULTIES IN HOW WE'RE GOING TO INTERPRET THESE, IF WE SIMPLY SEQUENCE ONE INDIVIDUAL AND FIND ONE PARTICULAR MUTATION. WE CAN'T SHARPEN OUR ANALYSIS TOO GREATLY BY SIMPLY LOOKING FOR HIGHLY CONSERVED POSITIONS THAT ARE MUTATED, THERE ARE 15 OF THESE IN EACH PERSON OF EUROPEAN ANCESTRY. THE NUMBERS ARE LARGER IN PEOPLE OF AFRICAN ANCESTRY BECAUSE THIS IS AN OLDER POPULATION WITH GREATER INTRINSIC VARIATION AS A CONSEQUENCE. THIS I THINK SIMPLY MAKES THE POINT IT'S VERY DIFFICULT WITH A SINGLE INDIVIDUAL TO FIND A MUTATION AND CONCLUSIVELY DECIDE, AHA, THIS IS THE HUATION THAT CAUSES THIS DISEASE AND THIS COMES BACK TO LES'S POINT OF HYPOTHESIS GENERATING FROM SINGLE INDIVIDUALS. RARE DISEASE GROUPS ON THE OTHER HAND WHO HAVE COHORTS OF PARTICULAR -- PARTICULAR PHENOTYPES HAVE A PARTICULAR ADVANTAGE THOUGH OF HAVING MANY INDIVIDUALS FREQUENTLY WHO HAVE A PARTICULAR DISEASE CATEGORY AND IF YOU FIND TWO OR THREE OR MORE RARE VARIANTS IN THE SAME GENE, IT'S EXCEEDINGLY LIKELY THAT WE CAN DEFINITIVELY ASSOCIATE MUTATION IN PARTICULAR GENES WITH PARTICULAR DISEASES. HENCE, RARE DISEASE GROUPS I THINK HAVE A PARTICULARLY IMPORTANT ROLE TO PLAY GOING FORWARD, PARTICULARLY AS MANY OF THE DISEASES THAT REMAIN UNSOLVE REDIRECT EXAMINATION EXCEEDINGLY RARE. SO WHEN THINKING HOW TO APPLY THE TECHNOLOGY, WE THINK THERE'S TREMENDOUS OPPORTUNITY FOR DISCROIFER BOTH OF TRAITS THAT HAVE BEEN DIFFICULT TO MAP UP TO NOW, BUT ALSO THERE ARE MANY TRAITS THAT DO NOT HAVE DEFINITIVE EVIDENCE THAT THEY'RE ACTUALLY SINGLE GENE GENETIC TRAITS. FOR EXAMPLE, THERE ARE A NUMBER OF TRAITS THAT WE SUSPECT BEING CAUSED BY MUTATION AND ACT AS AUTOSOMAL DOMINANT TRAIT BUT BECAUSE THEY IMPAIR REPRODUCTIVE LIKELIHOOD, THEY ARE OFTEN CAUSED BY DE NOVO MUTATION SO FREAKILY WE MAY ONLY FIND A SINGLE INDIVIDUAL IN ALL THE -- SINGLE INDIVIDUAL IN FAMILIES IN ALL THE CASES THAT CAN BE ASCERTAINED AROUND THE WORLD. A SECOND CASE WHERE THERE'S BEEN DIFFICULTY IN MAPPING AND HENCE LITTLE PROGRESS, RECESSIVE TRAITS WITH HIGH LOCUST HETEROGENEITY WHERE EACH INDIVIDUAL IS LIKELY TO HAVE MUTATION IN A DIFFERENT GENE, THERE ARE LARGE NUMBER OF GENES THAT WHEN MUTATED CAN PRODUCE THE SAME PHENOTYPE. THESE HAVE BEEN NOTORIOUSLY DIFFICULT TO MAP AND THERE'S LIKELY GREAT PROGRESS TO BE MADE FROM THESE. SEMATIC MUTATIONS IN TUMORS, CANCER IS INHERENTLY GENETIC DISORDER AND THIS TECHNOLOGY IS WELL SUITED. AND THEN RARE MUTATIONS WITH MODERATE EFFECT IN COMMON DISEASE. WE KNOW FROM EXPERIMENTS THAT HELEN HOBBS AND OUR GROUPS DID IN THE LAST DECADE THAT IN MANY CASES YOU CAN FIND RARE VARIANTS THAT CONTRIBUTE TO COMMON DISEASE STARTING WITH GENES WHERE YOU KNOW THE HOMOZYGOUS STATE CAUSES A SEVERE DISORD, -- DISORDER, THE HETEROZYGOUS STATE CAUSES MILD DISOARD. AND CLINICAL DIAGNOSIS IS ALSO A KEY OPPORTUNITY HERE. JUST TO DWELL ON THIS A MOMENT. CLINICAL TESTING FOR BRCA-1 AND 2 MUTATIONS, TYPICAL CHARGE $13,000 TO $3,500 FOR CLINICAL TESTING. WHEN HE CAN YOU CAN SEQUENCE 21, 22,000 TO 25,000 THE PATH FORWARD WILL BECOME CLEAR THAT WE WILL SEQUENCE COMPLETE EXOMES OR GENOMES OR FRACTIONS RELEVANT FOR PARTICULAR DIAGNOSTIC TESTS AND NOT A ONE GENE AT A TIME BUT SEQUENCING ALL THE POTENTIAL GENES ONE IS INTERESTED TO MAKE A CLINICAL DIAGNOSIS. SO I'LL GIVE A FEW EXAMPLES FROM RESEN WORK THAT ADDRESSES SOME OF THESE IDEAS. THESE ARE PHOTOGRAPHS FROM TWO INDIVIDUALS WITH AN EXCEPTIONALLY RARE DISORDER CALLED (INDISCERNIBLE) WITH CONFETTI. WHY THERE'S THE NAME OF THIS DISEASE, THERE'S A BRIGHT RED BACKGROUND SKIN AND ON TOP THOUSANDS OF WHITE SPOTS WHEN BIOPSIED TURN OUT TO BE CLINICALLY NORMAL SKIN. SO THERE WERE 7 PATIENTS WITH THIS DISEASE IDENTIFIED WORLDWIDE AND USING NEXT GENERATION SEQUENCING WE DEMONSTRATED THIS IS KEITH CHOKE WHO IS A DERMATOLOGIST WHO AS CERTAIN THESE PATIENTS AND DEMONSTRATED THEY ALL HAVE MUTATIONS IN A SINGLE GENE KERATIN 10 AND ALL SEVEN PATIENTS, THESE FAMILIES HAVE DE NOVO MUTATIONS THAT INTRODUCE FRAME SHIFTING MUTATIONS IN TO KERATIN 10. ALL SEVEN HAVE FRAME SHIFTS IN THE ALTERNATIVE READING FRAME TO PRODUCE A HIGHLY ARGININE RICH PEPTIDE IN THE C TERMINAL PORTION OF KERATIN 10. INTERESTINGLY, ALL THESE WHITE SPOTS PROVE TO HAVE ARISEN BY INDEPENDENT CLONAL REVERSES OF MUTATION AND ALL ARE LOST IN EACH CASE BY INDEPENDENT MITOTIC RECOMBINATION EVENTSCH HEARSAY THE FIRST EXAMPLE OF EXTREMELY HIGH FREQUENCY SOMATIC REVERSION OF HUMAN DISEASE, THIS IS THE INVERSE OR THE MIRROR IMAGE OF THE TUMOR SUPPRESSOR MECHANISM. YOU HAVE ONE NORMAL COPY, ONE MUTANT COPY, YOU LOSE THE MUTANT COPY, AND THE SKIN REVERTS TO TO NORMAL IN THE INDIVIDUAL CLONAL SPOTS. GETTING BACK TO LES'S POINT ABOUT HYPOTHESIS GENERATING RESEARCH THIS IS AN MRI OF A NORMAL 3-YEAR-OLD BOY, MRIs OF YOUNG INDIVIDUALS WITH SEVERE CONGENITAL MALFORMATIONS OF CORTICAL BRAIN DEVELOPMENT. SO SHOWN HERE IS A CHECKED COHORT OF 500 INDIVIDUALS WITH BRAIN ABNORMALITIES THAT ROSE IN A UNION BETWEEN FIRST COUSINS WHO MARRIED AND HAD OFFSPRING WITH SEVERE MALL FORMATIONS OF CORTICAL DEVELOPMENT. MANY OF THESE WERE UNCLASSIFIED IN PART BECAUSE IF ONE PHYSICIAN SEE AS PATIENT OF CORTICAL DEVELOPMENTMENT. SO HE SIMPLY STARTED SEQUENCEING LOOKING FOR NOVEL MUTATIONS AND BACK TO THE THE LARGER COHORT AND SEQUENCING THOSE GENES IN THE LARGER COHORT, AND A NUMBER OF INTERESTING THINGS STARTED QUICKLY FALLING OUT AND SHOWN HERE ARE THREE OF THESE. THE FIRST WAS A HOMOZYGOUS GENE MUTATION IN WDR-62 NOT KNOWN TO PLAY A ROLE IN BRAIN DEVELOPMENT. THERE IS A HOMOZYGOUS FRAME SHIFT MUTATION IN THIS PATIENT AND TURNED OUT IN HIS COLLECTION TO BE SEVEN ADDITIONAL INDIVIDUALS WITH HOMOZYGOUS LOSS OF FUNCTION MUTATIONS IN THIS GENE. AND WHEN YOU LINE UP THEIR MRIs, IT TURNED OUT THEY ALL HAD A HIGHLY SIMILAR CLINICAL FEATURES, THEY HAD PROFOUND LOSS OF CEREBRAL CORTEX, THICKENED CORTEX AT THE THE SURFACE AN LOSS OF CORTICAL FOLDING. THIS DEFINE AD NEW CLINICAL PHENOTYPE AS WELL AS MOLECULAR BASIS. HERE ARE TWO OTHER EXAMPLES THAT GO ALONG THE SAME LINE. THESE INDIVIDUALS WITH MUTATION IN LAMIN C-3 HAVE SPECIFIC LOSS OF FOLDING OF THE OCCIPITAL CORTEX THAT RESULTS IN A SEIZURE DISORDER AND PATIENTS WITH MUTATIONS IN DEE-1 HAVE PROFOUND LOSS OF NORMAL CORTICAL DEVELOPMENT. THIS IS AN EXAMPLE WHERE STARTING WITH A VERY HETEROGENEOUS GROUP OF CLINICAL PHENOTYPES A NUMBER OF NEW GENES ARE BEING IDENTIFIED AND THIS IS PROVIDING NEW INSIGHT AND STARTING POINTS FOR UNDERSTANDING HOW THESE GENES PLAY A ROLE IN NORMAL BRAIN DEVELOPMENT. IN OUR OWN WORK OVER THE LAST 25 YEARS, WE HAVE TAKEN AS LES ALLUDED TO A GENERAL IT CAN APPROACH TO LOOKING AT EXTREME OUTLIERS OF A COMMON DISEASE HYPERTENSION, HYPERTENSION AFFECTS A BILLION PEOPLE WORLDWIDE, AND IS A MAJOR CONTRIBUTOR TO MYOCARIAL INFARCTION AND CONGESTIVE HEAR FAIL YIEWRKS WE IDENTIFIED TEN GENES IN THE HIGH END OF DISTRIBUTION, ANOTHER THAT DRIVE HIGH BLOOD PRESSURE TO THE LOW END OF THE DISTRIBUTION. AND ONE TANTALIZING OUTCOME OF THIS WORK IS IN FIVE OF THESE CASES, THIS GENES AT THAT TIME LOW END AND THE HIGH END ARE ACTUALLY THE SAME GENES WITH LOSS OF FUNCTION MUTATIONS DRIVING BLOOD PRESSURE TO THE LOWEST COMPATIBLE AND GAIN OF FUNCTION MUTATION IN THE IDENTICAL GENES RESULTING IN EXTREME FORMS OF HYPERTENSION. THESE CONVERGE ON THE RENAL SALT HANDLING PATHWAY AND MUTATIONS THAT I KNOW CREASE SAL REABSORPTION RAISE BLOOD PRESSURE IN MUTATIONS THAT DECREASE SALT ABSORPTION LOWER BLOOD PRESSURE. IN THE CONTEXT OF THESE RARE DEES KNOWING THE MOLECULAR BASIS OF THESE INDIVIDUAL EXTREME CASES WE CAN PROVIDE GOOD THERAPY FOR MANY INDIVIDUALS WITH SPECIFIC DRUGS THAT ARE TAILORED TO THE SPECIFIC UNDERLYING ABNORMALITY. IN OTHER CASES DEFINITIVE TREATMENTS HAVE BEEN DEVELOPED BASED ON MOLECULAR KNOWLEDGE THAT FOR EXAMPLE PATIENTS WITH BARTER SYNDROME OR LITTLE SYNDROME CAN HAVE RENAL TRANSPLANTATION KNOWING THAT THIS PRIMARY CAUSE OF THIS DISEASE LIES EXCLUSIVELY IN THE KIDNEY. THESE PATIENTS CAN HAVE SYNDROMES CORRECTED BY RENAL TRANSPLANTATION. BUT SEVERAL DISEASES REMAINED ON OUR RADAR SCRIEN THAT HAD NOT BEEN SOLVED BY CLASSIC MENDELIAN APPROACHES. ONE IS ELDOSTERONE PRODUCING ADENOMA. IF WE WATCH INTO ANY O WALK INTO ANY CLINIC AROUND THE WORLD, 5 TO 10% WITH SEVERE HYPERTENSION HAVE TUMORS OF THE ADRENAL GLAND. TYPICALLY DIFFICULT TO DIAGNOSE BUT QUITE AMENABLE TO SURGICAL TREATMENT IF THEY'RE IDENTIFIED. THEY HAD FEATURES QUITE STRIKING. THE FIRST IS THAT ALTHOUGH THIS IS A NEOPLASTIC DISEASE THESE ARE INVARIABLY BENIGN TUMORS THAT NEVER INVADE OR METASTASIZE BUT THEY SECRETE A HORMONE CALLED ELDOSTERONE THAT TELL IT IS KIDNEY TO HANG ON TO SALT OR WATER AND RAISE IT IS QUESTION WHETHER THERE'S UNDERLYING MECHANISMS THAT LINK CON CONSTITUTIVE ITERATION AND NORMAL REERS AND SE QNSING CONSTITUTIONAL DNA AND TUMOR DNA IN A HANDFUL OF PATIENTS LED TO THE RECOGNITION THAT A SINGLE MUTATION IN A POTASSIUM CHANNEL, ONE OF TWO MUTATIONS ACCOUNTS FOR ABOUT 50% OF ALL OF THESE TUMORS WORLDWIDE. SO IN A RECENT COHORT OF 287 OF THESE TUMORS, THIS SPECIFIC POTASSIUM CHANNEL KCNJ-5 HAS ONE TWO MUTATIONS, POSITION 151 OR POSITION 168 EACH A QUARTER OF THE PATIENTS, THERE'S ANOTHER MUTATION THAT IS QUITE UNCOMMON, AND THESE ACCOUNT COLLECTIVELY FOR 47% OF ALL OF THESE TUMORS. THERE'S AN INTERESTING GENDER DIFFERENCE THAT IS HIGHLY SIGNIFICANT BUT AS YET UNEXPLAINED. WE HAVE BEEN ABLE TO STARTING WITH THIS GENETIC MUTATION TO ELUCIDATE THE MOLECULAR MECHANISM BY WHICH THESE MUTATIONS ACT. THE POTASSIUM -- EVERY POTASSIUM CHANNEL IN THE BIOLOGICAL WORLD HAS A SELECTIVITY FILTER THAT PERMITS POTASSIUM TO PASS THROUGH IT BUT NOT OTHER IONS. THESE MUTATIONS THAT ARE FOUND IN ELDOSTERONE PRODUCING ADENOMAS ALTER A HIGHLY CONSERVING RESIDUE AT THE SELECTIVITY CHANNEL AND ONE OTHER RESIDUE THAT ABUTS THE SELECTIVITY CHANNEL NEAR BIM THESE MUTATIONS IN FACT MAKE THE CHANNEL LESS SELECTIVE FOR POTASSIUM AND ALLOWS SODIUM TO BE CONDUCTED THROUGH THE CHANNEL. THAT EXPLAINS THE PATHOPHYSIOLOGY OF THESE TUMORS. TURNS OUT THE ADRENAL GLUMERIALOSA IS MAINTAINED IN A HYPERPOLARIZED STATE BY HAVING CONSTITUTIVELY OPEN POTASSIUM CHANNELS AND THESE MUTATIONS INTRODUCE A CONDUCTTANTS THAT DEPOLARIZE THE CELL AND ACUTE DEPOLARIZATION IS SIGNAL FOR ACT VISION OF A VOLTAGE GATED CALCIUM CHANNEL THAT ACTIVATES THE RATE LIMITING STEP IN ELDOSTERONE PRODUCTION, SYNTHASE AND INTRACELLULAR CALCIUM IS THE SINGLE FOR CELL PROLIFERATION. SO THIS IS SUFFICIENT TO PRODUCE THE CARDINAL FEATURES OF THIS TUMOR. IN FACT THERE'S A MENDELIAN FORM OF THIS DISEASE AS WELL. AND THESE ARE THREE FAMILIES WITH INHERITED MUTATIONS IN THIS SAME GENE, TWO HAVE THE IDENTICAL MUTATIONS THAT ARE PREVALENT IN THESE TUMORS. IN FACT ALL THESE PATIENTS REQUIRE ADRENALECTOMY PROFOUND TO HYPERTENSION AND ELDOSTERINISM BECAUSE EVERY CELL IS TRYING TO BEHAVE LIKE A TUMOR AND HAVE MASSIVE HYPERPLASIA IN THE ADRENAL CORTEX AS CONSEQUENCE. ONE LAST EXAMPLE THAT GETS TO WHAT IS FREQUENTLY I DON'T WANT TO CALL IT A DIRTY SECRET BUT IT'S SOMETHING WE DON'T FREQUENTLY ACKNOWLEDGE. WE DECLARE VICTORY WHEN WE FINE THE GENE OR GENES THAT ATTRIBUTE TO A PARTICULAR TRAIT AND LEFT UNSAID IS THAT THIS FREQUENTLY IS AN INCOMPLETE DESCRIPTION OF THE DISEASE. ONE EXAMPLE WHERE EXOME EM ONLY SEQUENCING ADDRESS THIRD DEGREE ISSUE. ELDOSTERONE IS THE TWO SETTINGS IN SETTING VOLUME DEPLETION LEADS TO INCREASED SECRETION OF ELDOSTREONE. IN THE SETTING OF HYPERRER THIS LEADS THE INCREASED POTASSIUM SECRETION. HOW DOES THE KIDNEY KNOW WHEN IT SEES ELDOSTERONE WHETHER IT'S MAXIMIZING SALT REABSORPTION OR POTASSIUM SECRETION,? THERE'S A LAYER THAT MEDIATES THAT WAS PREVIOUSLY COMPLETELY UNRECOGNIZED FROM PHYSIOLOGIC ANALYSIS BUT IDENTIFIED FROM STUDY OF RARE PATIENT WHOSE COULD NO LONGER MAKE THE DISTINCTION AND THEY HAD A MUTATION THAT ENABLED THEM ONLY TO USE IT TO MAXIMIZE SODIUM REABSORPTION BUT NEVER TO AUGMENT POTASSIUM SECRETION. THE FIRST TWO GENES WERE IDENTIFIED BY RICK WILSON IN THE LAB SHOWN HERE WHO IDENTIFIED MUTATIONS IN A NOVEL FAMILY OF SERINE 3 ANINE KINASES CALLED WINK 1 AND 4 THAT NO LONG ALLOW THE KIDNEY TO DISCRIMINATE BETWEEN POTASSIUM EXCESS AND REDUCED PLASMA VOLUME. AND SUBSEQUENT WORK HAS DEMONSTRATED THAT THESE KINASES ARE GOVERNING THE BALANCE BETWEEN SALT REABSORPTION AND POTASSIUM SECRETION. THE DIRTY SECRET IS THERE WERE A TOTAL OF SEVEN FAMILIES WORLDWIDE THAT HAD MUTATIONS IN THESE KINASES BUT WE HAD IN OUR COLLECTION 48 FAMILIES THAT HAD THE SAME OSTENSIBLY THE SAME PHENOTYPE WITHOUT MUTATIONS IN EITHER OF THE WINK KINASES. TYPICALLY AS IS FOUND FOR MANY SUCH SITUATIONS, THE FAMILIES WE WERE ABLE TO IDENTIFY WERE ONES THAT WE WERE ABLE TO MAP, BECAUSE THERE WERE MANY AFFECTED INDIVIDUALS. CONTRAST THE ONES THAT DID NOT HAVE MUTATIONS TYPICALLY HAD VERY FEW AFFECTED INDIVIDUALS. SO WE APPLIED EXOME SEQUENCING AND IN A RELATIVELY SHORT PERIOD OF TIME WE'RE ABLE TO REDUCE THE PROBLEM TO AND RECOGNIZE ITS SOLUTION. TURNS OUT THERE ARE TWO GENES THAT CAUSE THIS PHENOTYPE AND FOR ONE GENE THERE'S DOMINANT AND RECESSIVE TRANSMISSION THAT WAS NOT RECOGNIZED FROM SIMPLE FAMILY DESCRIPTIONS PRIOR TO THE MOLECULAR WORK. ONE GENE IS A GENE CALLED CELLCH LIKE 3. KLH-3, 60 FAMILIES HAD DOMINANT MUTATIONS BY EXOME SEQUENCING. 8 WITH RECESSIVE MUTATIONS AN THESE CO-SEGREGATE WITH -- UNDER TOM NANT AND RECESSIVE MODELS AND HIGHLY SIGNIFICANT IN EACH CASE. CLSH-3 IS A UBIQUITIN LIGASE, A PARTNER THROUGH BTD DOMAIN WITH A PROTEIN CALLED COLON 3. TOGETHER THEY RECRUIT A RING LIGASE THAT TRANSFERS UBIQUITIN TO SUBSTRATES THAT ARE BOUND BY THE KELSH LIKE PROTEINS. SO KELSH-3 WAS MUTATED IN HALF THE REMAINING FAMILIES. AND PERHAPS NOT SURPRISENING SOME WAYS BUT VERY SURPRISENING OTHERS, TURNED OUT THE REMAINING FAMILIES HAD MUTATIONS IN COLON 3. THE SURPRISE IS COLON 3 IS EXPRESSED INLP„ VIRTUALLY EVERY CELL IN THE BODY CONTAINING PROTEINS THAT TARGET DIVERSE SUBSTRATE MOLECULES FOR DEGRADATION. SO SATISFYINGLY IN THAT REGARD THE MUTATIONS TURN OUT TO BE MUTATIONS THAT OCCUR ANYWHERE IN THE MOLECULE BUT ALL ARE DE NOVO MUTATIONS THAT SIMPLY CAUSE A HOMOGENOUS DEFECT, THAT IS A DEFECT IN SLICING OF ONE EXON, EXON 9. IN EACH CASE THE SKIPPING OF EXON 9 WITH CONSEQUENCE YOU'RE DELETEING A 57 AMINO ACID SEGMENT THAT LIES IN THE HINGE REGION AND WE INFER IS IMPAIRING THE THE ABILITY OF UBIQUITIN LIGASE TO TRANSFER TO SUBSTRATES UNIQUE FOR KLHL-3 BUT SPARE OTHER TARGETS OF OTHER KLH LIKE MOLECULES THAT INTERACT WITH COLON 3. SO WHAT I WANT TO CLOSE WITH IS THESE ARE SIMPLY EXAMPLES OF HOW WE CAN USE THIS NEW TECHNOLOGY TO SOLVE RARE DISEASES. AND THE HOPE OF APPLYING MORE BROADLY TO RARE DISEASES THAT HAVE NOT YET BEEN SOLVED. I THINK NIH HAS BEEN VERY FORWARD THINKING IN TRYING TO MOVE THIS FORWARD. WITH THE EXPECTATION THAT WHEN WE UNDERSTAND THESE DISEASES LEAD TO NEW OPPORTUNITIES FOR DEFINITIVE DIAGNOSIS BUT ALSO LONG RUN FOR NEW APPROACHES THE TREATMENT. THANKS VERY MUCH FOR YOUR ATTENTION. [APPLAUSE] HAPPY TO TAKE ANY QUESTIONS. >> FEW QUESTIONS BEFORE WE TAKE THE BREAK? (OFF MIC) >> THE QUESTION WAS HOW MANY DISEASES DO I THINK HIGH BLOOD PRESSURE ACTUALLY IS? A GREAT QUESTION. WE KNOW FROM GENOME WIDE ASSOCIATION STUDIES THAT FROM ONE OF THE HE ROW WICK STUDIES OF MORE THAN 200,000 INDIVIDUALS, THERE'S AT LEAST 29 LOCI THAT SIGNIFICANTLY CONTRIBUTE TO BLOOD PRESSURE VARIATION. THOSE 29 LOCI EXPLAIN ABOUT 1% OF THE TOTAL RAREIATION IN BLOOD PRESSURE. SO THE EXPECTATION I THINK IS LIKELY THAT THERE WILL BE RARE VARIANTS THAT CONTRIBUTE QUITE SIGNIFICANTLY COLLECTIVELY TO VARIATION IN BLOOD PRESSURE. DOING THOSE KINDS OF STUDIES WHICH I DIDN'T TALK ABOUT TODAY, IS QUITE CHALLENGING, IT REQUIRES RELATIVELY LARGE COHORT SIZES. MOST ESTIMATES ARE THAT TO FIND GENES THAT HAVE ODDS RATIOS OF 2 FOR RISK OF A COMMON DLEEZ NEED TO SEQUENCE AB 6,000 CASES AND 6,000 CONTROLS SO THESE ARE NOT EXPERIMENTS TO BE DONE BY THE FAINT OF HEART. >> >> QUICK FOLLOW-UP TO THAT QUESTION, THERE'S 108 MOUSE GENE KNOCK OUTS THAT HAVE AS A MAJOR PHENOTYPE HYPERTENSION. >> YES. SO OF COURSE THE MOUSE AND -- MOUSE IS NOT A VERY GOOD MODEL FOR HUMAN IN MANY AREAS, BLOOD PRESSURE I THINK IS A FAIR ONE TO POINT OUT. IT'S NOT ALWAYS THE CASE. THERE ARE STRONG EFFECTS OF GENES THAT AFFECT BLOOD PRESSURE IN MOUSE. THE CORRELATION IS NOT PERFECT. I'M A BIG FAN OF TRANSLATING HUMAN FINDINGS THROUGH MOUSE MODELS. I HAVE TO SAY I'M VERY FOND OF THE HUMAN AS A MODEL ORGANISM. WHEN ONE THINKS HOW WE DO GENETIC STUDIES IN MODEL ORGANISMS WE RARELY REACH THE LEVEL OF DEPTH THAT WE HAVE MANY THE HUMAN POPULATION. WITH A 3 BILLION BASE PAIR GENOME AND 7 BILLION INDIVIDUALS, 14 BILLION COPY OS OF THE HUMAN GENOME ON THE PLANET AND NOW WE UNDERSTAND SOMETHING ABOUT HUMAN MUTATION RATES IT'S FAIR TO SAY THAT EVERY BASE IN THE HUMAN GENOME THAT CAN BE MUTATED AND IS COMPATIBLE WITH SURVIVAL IS WALKING AROUND SOMEWHERE AROUND THE PLANET TODAY. THE RARE DISEASE COMMUNITY IS A COMMUNITY THAT WELL UNDERSTANDS THAT RARE ALLELES IN HUMANS EXIST AND ARE ENORMOUSLY INFORMATIVE. SO I THINK I'M EXTREMELY ENTHUSIASTIC ABOUT MAXIMIZING OUR UNDERSTANDING OF -- >> LET ME MAKE ONE PREDICTION. I THINK WHAT YOU'RE GOING TO FIND WHEN YOU ACTUALLY FIND THE CAUSAL ALLELE IN THE HUMAN POPULATION THERE'S A LOT MORE CORRELATION TO WHAT'S FOUND IN THE MOUSE KNOCK-OUT FEE NO, MA'AM THAN- WHAT'S FOUND CORRELATING THE GW SARKS FINDINGS. >> I'M HAPPY TO ACCEPT THAT AS A HYPOTHESIS. THE I WOULD SUGGEST WE KNOW A GREAT DEAL ABOUT THE FINAL PATHWAYS THAT ARE CRITICAL TO REGULATION OF BLOOD PRESSURE AND WE HAVE LEARNED A FAIR AMOUNT AND I DON'T WANT TO ARGUE QUANTITY BUT WE HAVE LEARNED A FAIR AMOUNT FROM STUDY OF RARE HUMANS, I THINK THIS REMAINS A GOOD MODEL. NOT JUST FOR IDENTIFYING GENES THAT ALTER BLOOD PRESSURE BUT ALSO UNDERSTANDING WHAT WILL TURN OUT NEW TARGETS FOR THERAPEUTIC BLOOD VES SURE. >> THE BEST TREATMENT CLUSTERS OF DIFFERENT CAUSAL BASIS. >> WE AGREE. [APPLAUSE] >> THANK YOU VERY MUCH. THAT TAKES US INTO A BREAK AND IF COWIOM BACK AT 11, WE'LL TRY TO CATCH UP ON NEXT SESSION BUT IN ALL LIKELIHOOD WE'LL PROBABLY HAVE TO TAKE A SHORTENED LUNCH BUT PLEASE EVEN DURING THIS BREAK WALK AROUND TO THE VARIOUS TABLES AND THE POSTERS THAT MIGHT BE UP ALREADY AND JUST HAVE SOME QUESTIONS FOR THEM. THANK YOU VERY MUCH. >> WE'RE READY TO START THE NEXT SESSION WHICH RELATES TO NEW RESEARCH PARADIGM. AND OUR FIRST SPEAKER IS DR. GAYATRI RAO FROM THE FOOD AND DRUG ADMINISTRATION, ACTING DIRECTOR OF THE OFFICE OF ORPHAN PRODUCTS DEVELOPMENT AT THE FDA. SHE REACCEPTLY TOOK OVER THE REIGNS AN HAPPY TO HAVE HER AS COLLEAGUE AND LOOK FORWARD TO POSSIBILITY OF A PERMANENT P POSITION. GAYATRI, PLEASE. >> GOOD MORNING. I CAN'T TELL YOU HOW EXCITED I AM TO BE HERE AT NIH TODAY ON RARE DISEASE DAY OF ALL DAYS. I WANTED TO THANK STEVE AND OFFICE OF RARE DISEASE RESEARCH FOR INVITING FDA TO PARTICIPATE. WE WORKED CLOSELY WITH HIS OFFICE AND LOOK FORWARD TO DOING IT IN THE FUTURE. MY TALK IS REALLY A DIFFERENCE PERSPECTIVE FROM WHAT WE HAVE BEEN HEARING THUS FAR. WHAT I HOPED TO FOCUS ON THE NEXT 15 MINUTES AND TRY TO STICK TO TIME, IS WHAT FDA'S ROLE HAS BEEN IN RARE DISEASE RESEARCH COLLABORATION AND DEVELOPMENT. I THOUGHT THE BEST MOST EFFECTIVE WAY TO DO THAT IS TO TALK ABOUT TWO EXAMPLES. SO I PICKED TWO RECENT EXAMPLES, ONE ON DRUG SIDE AND ONE ON DEVICE SIDE. WHICH I THINK REALLY ILLUSTRATES THE ROLE FDA HAS PLAYED IN THE DEVELOPMENT OF PRODUCTS. OBVIOUSLY THESE PRODUCTS HAVE COME TO THE MARKET. THROUGH HARD WORK AND COLLABORATION THROUGH MANY ENTITIES. I WANT TO HIGHLIGHT WHAT FDA'S ROLE IS IN THIS PROCESS. AS DR. COLLINS ECHOED PREVIOUSLY TO YOU, WE WERE EXCITED TO HAVE CALIDECO AND IT WAS APPROVED LAST MONTH FOR TREATMENT OF CYSTIC FIBROSIS IN PATIENTS AGE 6 AND OLE OAR WHO HAVE THE G-551D MUTATION. THE REASON THIS IS AN EXCITING APPROVAL, IT'S EXCITING FOR A NUMBER OF REASONS. BUT AS DR. COLLINS INDICATED EARLIER THIS WAS A TREATMENT APPROVED THAT TARGETS DEFECTIVE FDR PROTEIN, THE OTHERS THAT ARE APPROVED OBJECT MARKET FOCUS ON SYMPTOMS. AS MENTIONED CALIDECO FOCUSES ON THE -- IT WORKS PRIMARILY IN MUTATIONS WITH THE G-551D MUTATION. AS THIS OCCURS AS INDICATED IN 4 TO 5% OF PATIENTS WITH CYSTIC FIBROSIS. FOLKS WITH THIS MUTATION WHRK'S HAPPENING IS PROTEIN IS FORMED, MAKING ITS WAY TO THE CELL MEMBRANE BUT THERE'S SOMETHING DEFECTIVE ABOUT THE PROTEIN THAT IS IMPEDING CHLORIDE TRANSPORT THROUGH THE PROTEIN, THROUGH THE MEMBRANE. SO WHAT IT DOES IS ACTS AS A CSTR POTENT YEAHTOR. I DON'T WANT TO GET INTO THE -- IT'S PUBLISHED ALL PUBLICLY AVAILABLE BUT IT WAS ESSENTIALLY APPROVED BASED ON TWO RANDOMIZED CONTROL TRIALS. WHAT THEY FOUND IS THAT INDIVIDUALS WHO WERE ON CALIDECO SHOWED A SIGNIFICANT IMPROVEMENT IN LUNG FUNCTION EVALUATED BY FEZ-1. HERE IS WHAT I REALLY WANTED TO FOCUS ON WHICH IS WHAT FDA'S ROLE HAD BEEN IN ALL OF THIS. THE APPROVAL OF CALIDECO WAS BASED ON A FAST TRACK AND PRIORITY REVIEW. WHAT THAT MEANS IS THAT FDA DETERMINED THAT THIS DRUG WAS FOR A SERIOUS LIVE THREATENING DISEASE OR CONDITION AND DESIGNATED IT AS A FAST TRACK DRUG. THAT MEANT THAT DRUG WAS ELIGIBLE FOR CERTAIN THING, INCREASED COMMUNICATION WITH WITH FDA, ELIGIBLE FOR APPROVAL, AMONG OTHER THINGS IT WAS ALSO ELIGIBLE FOR PRIORITY REVIEW. WHAT PRIORITY REVIEW MEANS IS THAT TYPICALLY WHEN A MANUFACTURER SCHMITZ A MARKETING APPLICATION, TO FDA IT TAKES TEN MONTHS, IT'S COMMITTED TO TEN MONTHS TO COMPLETE THE REVIEW OF AN NDA APPLICATION. WHEN YOU'RE UNDER PRIORITY REVIEW, THAT IS SHORTENED TO SIX MONTHS. FROM START TO FINISH IT TOOK THREE MONTHS WHICH IN FDA'S TIME LINE IS LIGHTNING SPEED. TO PO FOCUS MORE ABOUT WHAT FDA'S ROLE HAS BEEN IN THE DEVELOPMENT OF BEYOND THE REVIEW AND APPROVAL OF THE STUDY AND THE DRUG, IS EARLY ON BACK IN 2006 FDA SPECIFICALLY OUR OFFICE, OFFICE OF ORPHAN PRODUCTS DEVELOPMENT DESIGNATE THIRD DEGREE DRUG AS AN ORPHAN DRUG. WHAT DOES THAT DECISION NATION GET YOU? MOST IN THIS ROOM MIGHT KNOW THE ANSWER. IF DESIGNATED AS ORPHAN DRUG YOU'RE ELIGIBLE FOR SOME SERIOUS FINANCIAL INCENTIVES TO CONTINUE TO DEVELOP THAT PRODUCT. FIRST YOU'RE ELIGIBLE FOR TAX CREDITS FOR QUALIFIED TESTING, ELIGIBLE FOR 50% TAX CREDITS. THE SECOND WHICH IS A BIG FINANCIAL INCENTIVE IS THAT THERE'S A WAIVER OF USER FEE FOR MARKETING APPLICATIONS. RIGHT NOW WHEN A SPONSOR SCHMITZ APPLICATION TO FDA, YOU PAY $1.8 MILLION, SMALL BUSINESS WAIVER EXCEPTION BUT IT COSTS $1.8 MILLION IN APPLICATION FEES ALONE. IF YOU'RE DESIGNATED AS ORPHAN DRUG, THAT FEE IS WAIVED. LASTLY, THIS IS PROVEN TO BE THE MOST -- THE BIGGEST INCENTIVE WHICH IS A 7 YEARS MARKETING EXCLUSIVITY. IF YOU'RE THE FIRST DRUG ON THE MARKET FOR THAT INDICATION, YOU GET 7 YEARS OF EXCLUSIVITY. SO A SEVEN YEAR MONOPOLY MARKETING THAT DRUG FOR THAT INDICATION. SO HOW DO YOU GET DESIGNATED AS ORPHAN DRUG? SUBMIT AN APPLICATION TO OUR OFFICE. WE LOOK TO SEE WHETHER YOUR VIEWS FOR THE PREVENTION, TREATMENT, FOR DIAGNOSIS OF RARE DISEASE IN THE UNITED STATES, HOW DO WE DEFINE RARE? AS STEVE INDICATED PREVIOUSLY, A DISEASE THAT AFFECTS LESS THAN 200,000 PEOPLE IN THE UNITED STATES. OUR OFFICE HAS A SMALL GRANTS PROGRAM SMALL COMPARED TO NIH. WE HAVE ACTUALLY ALSO FUNDED A PHASE 2 STUDY FOR CALIDECO. AND THE RESULTS OF THE STUDY WERE SUBMITTED IN SUPPORT OF APPROVAL. SO THE SAME IDEA OF DESIGNATION, GRANT FUNDING AND APPROVAL PATHWAY AS WE DISCUSSED ON THE DRUG SIDE, ALSO EXISTS ON THE DESIZE SIDE. THE EXAMPLE I WOULD LIKE TO TALK ABOUT IS BERLIN HEARTS. IT WAS AN APPROVAL AT THE END OF LAST YEAR. IT'S A VERY INNOVATIVE DEVICE. THIS DEVICE IS A PEDIATRIC VENTRICULAR ASSIST DEVICE, IT'S DESIGNED SIMILAR TO ADULT VENTRICULAR ASSIST DERICE BUT MODIFIED TO SATISFY THE PEDIATRIC COMMUNITY. THE PURPOSE IS TO PROVIDE TRANSPLANTS OF KIDS AT END STAGE HEART DISEASE AND WAITING FOR A HEART TRANSPLANT. THIS DEVICE IS INTENDED TO INCREASE SURVIVAL TO WHEN HEARTS ARE AVAILABLE TO THEM. JUST LIKE A DESIGNATION PROGRAM ON THE DRUG SIDE WE HAVE A PROGRAM ON DEVICE SIDE. BACK IN 2001 THIS DEVICE IS DESIGNATED A A HUMANITARIAN USE DEVICE. THE STANDARD FOR DESIGNATION IS DIFFERENCE THAN FOR A DRUG. WHAT THE STANDARD IS FOR DEVICE, WE DESIGNATED DEVIS TO PRODUCE TREAT OR PREVENT DIAGNOSIS AFFECTING FEWER THAN 400,000 INDIVIDUALS A YEAR. THIS IS A NUMBER AS OPPOSED TO 2 HN THOUSAND PREVALENCE ON THE DRUG SIDE. THE INCENTIVE FOR GETTING A HIGH DESIGNATION ARE NOT WHAT THEY ARE FOR DRUGS WHICH IS PROBABLY REASON WE DONE SEE AS MANY. WHAT YOU DO GET FOR DESIGNATED AS HUD IS ELIGIBLE FOR APPROVAL THROUGH HUMANITARIAN DEVICE PATHWAY. WE'LL TALK ABOUT THAT IN A SECOND. THIS DEVICE DID MEET HUD CRY CRITERION BACK IN 2001. IT WAS APPROVED BY THE HDE PATHWAY. NOW, WHAT IS IT ABOUT THIS PATHWAY THAT MAKES IT AN INTERESTING PATHWAY FOR DEVICES FOR RARE DISEASE? THE BEAR HIN HEART EXPORT DEVICE IS A HIGH RISK DEVICE. IF THAT DEVICE WERE TO SUBMIT A NORMAL APPLICATION TO THE FDA TO CDRH AN FDA THEY HAVE TO SUBMIT A PRE-MARKET APPROVAL APPLICATION BECAUSE IT'S A HIGH RISK DEVICE. SIMILAR TO AN MDA IN THE SENSE YOU HAVE TO SHOW A REASONABLE ASSURANCE OF SAFETY AN EFFECTIVENESS. IF YOU ARE DESIGNATED AS HUD YOU'RE ELIGIBLE FOR APPROVAL VIA ALTERNATIVE PATHWAY, HTE PATHWAY. YOU HAVE TO SHOW RANNABLE ASSURANCE OF SAFETY. SO THAT STANDARD EXISTS. BUT YOU'RE NOT REQUIRED TO SHOW EFFECTIVENESS. INSTEAD OF SHOWING EFFECTIVENESS YOU'RE ONLY REQUIRED TO SHOW THE PROBABLE BENEFIT OUTWAYS THE RISK SO THIS IS A DIFFERENT LOWER STANDARD THAN EFFECTIVENESS. SO IT PROVIDES EASIER PATHWAY TO MARKET. THIS DEVICE JUST LIKE CALEDECO FUBD THROUGH OR FARN PRODUCTS PROGRAM RECEIVED CLOSE TO $1.2 MILLION IN FUNDING WHICH FOR OUR GRANT PROGRAM IS SUBSTANTIAL. AND THE STUDY WE ENDED UP FUNDING WAS IN SUPPORT OF PIVOTAL STUDY THAT ENABLED THIS DEVICE TO ACHIEVE MARKETING APPROVAL. THIS GIVES YOU BACK GROWN ON WHAT THE BASIS OF APPROVAL WAS, ON A PROSPECTIVE MULTI-CENTER SINGLE ARM STUDY, ABOUT 200 PATIENTS AND PRIMARILY FOUND THAT KIDS ON THIS DEVICE SURVIVAL RATES WERE SIGNIFICANTLY BETTERS THAN KIDS WHO WESTERN. THIS WAS TAKEN TO THE DEVICE PANEL AT FDA AND THERE WAS A UNANIMOUS VOITD TO RECOMMEND APPROVING IT. -- VOTE TO RECOMMEND APROVING I. THE ONE CAVEAT IS CONCERN IT MIGHT BE ASSOCIATED WITH NEUROLOGICAL EVENTS AND SOME THROMBOSIS. SO THERE'S A POST APPROVAL STUDY UNDERWAY. THESE PRODUCTS AGAIN DEMONSTRATE HOW FDA THROUGH THE PROCESS OF DESIGNATION AN THROUGH GRANTS HAS HELPED THE DEVELOPMENT OF PRODUCTS AND HELPED IT TO COME TO APPROVAL. SO OUR ROLE WASN'T AT THE END OF THE MARKETING APPROVAL STAGE. SO A QUICK BIT ABOUT THE GRANTS PROGRAM. AGAIN, IT'S COMPARED TO NIH'S BUDGET, A SMALL GRANTS PROGRAM, $14 MILLION. WHAT WE FUND ARE CLINICAL STUDIES. WE LOOK AT CLINICAL STUDIES THAT LOOK AT PRODUCTS FOR RARE DISEASES. SO ANYTHING, DRUG, DEVICES, MEDICAL FLUIDS ALL APPLY. THE ONE INTERESTING NOTE ABOUT THIS PROGRAM IS IT HAD TREMENDOUS SUCCESS RATES IN TERMS OF FUNDING PROJECTS THAT END UP GOING ON TO GET APPROVAL. THAT IS IN PART, WHEN WE'RE REVIEWING THE GRANTS, GOING THROUGH THE REVIEW CYCLE WE INVOLVE THE REVIEW DIVISION WHO WHY WOULD WHIEL THEY DON'T VOTE THE GRANTS DO WEIGH IN ON HOW SUCCESSFUL THE REGULATORY PATHWAY MIGHT BE FOR THIS PRODUCT. THE GRANT PROGRAM HAS BEEN SUCCESSFUL AND WE HAVE SEEN UPTICK IN THE NUMBER OF GRANTS WE HAVE GOTTEN IN THE LAST TWO YEARS. WE WENT FROM 94 WHICH FOR US IS PRETTY HIGH TO 125 APPLICATIONS. WE FUNDED 14 GRANTS LAST YEAR E STILL IN THE PROCESS THIS YEAR. I WANTED TO SWITCH GEARS A LITTLE BIT. WE HAVE ANOTHER GRANT PROGRAM OUR OFFICE OF MINISTERS CALLED THE PEDIATRIC DEVICE CONSORTIA GRANT PROGRAM, THIS IS A SMALL PROGRAM BUT IT'S A VERY INTERESTING ONE, THE WHOLE IDEA IS THIS PROGRAM FUNDS CONSORTIA SO THIS CONSORTIA IS MADE OF CLINICIANS, SCIENTIST, BUSINESS FOLKS, REGULATORY FOLK, ALL COMING TOGETHER TO DEVELOP DEVICES AND VO RIDE ADVICE TO OTHER O DEVELOPERS AS THEY STUDY AND AND MOVE DEVICE DEVELOPMENT PATHWAYS FORE. THE REASON BEHIND THIS IS A LOT OF TIMES DEVICES DO WELL IN THE PROTOTYPE STAGE AND THE PRE-CLINICAL STAGE. AND SOMETHING HAPPENS BETWEEN PRE-CLINICAL TO CLINICAL WHERE THINGS FALL OFF A CLIFF. AND SO THIS IDEA OF BRINGING BUSINESS FOLKS AND REGULATORY FOLKS TO THE TABLE WITH SCIENTISTS AND CLINICS WOULD HELP THE DEVELOPMENT ALONG. THIS PROGRAM IS VERY MUCH IN ITS INFANCY BUT WE HAVE SEEN POSITIVE THINGS COMING OUT OF IT. HERE A COUPLE OF EXAMPLES THAT I LISTED WHERE CONSORTIA WE'RE FUNDING, THESE ARE PROJECTS THEY'RE ASSISTING IN. SO THERE'S A IMPLANT FOR SCOLIOSIS, A PEDIATRIC ARTIFICIAL KIDNEY, ABSORB BALL HEART VALVE FOR CARDIAC DEFECTS ALL IN DIFFERENT STAGES OF DEVELOPMENT. WE HOPE ONE OR MORE WILL FINE ITS WAY TO THE MARKET. IN ADDITION TO WHAT WE DO, IN THE OFFICE, VIS-A-VIS DESIGNATION AND DIFFERENT GRANT PROGRAMS WE WORK WITH INTERNATIONAL ORGANIZATIONS TO PROMOTE THE DEVELOPMENT OF PRODUCTS FOR RARE DISEASES. I HAVE LISTED TWO THAT WE ARE ACTIVELY INVOLVED IN. A QUICK NOTE, IT'S EARLY IN ITS STAGES AND IT TOO IS A CONSORTIA OF ESSENTIALLY FUNDING ORGANIZATIONS. THEY FUND VARIOUS PROJECTS IN ORPHAN DISEASE. OF MANY GOALS THEY HAVE IS TO LOOK AT WHAT'S DEVELOPED, WHAT'S FUNDED TO IDENTIFY WHAT UNMET NEEDS MIGHT BE. AN TO TRY TO CHANNEL MONEY TO TARGET UNMET NEEDS. LASTLY, THIS IS REPETITIVE BUT SOMETHING STEVE MENTIONED. WE SPONSOR WITH NIH AND COUPLE OF WORKSHOPS WE DO THEN OUR OWN TO HELP RESEARCHERS, ACT DEMISSION, FDA REVIEW IRS TO DEVELOP AND REVIEW STUDIES FOR RARE DISEASE, WORKING ON NATURAL HISTORIES WORKSHOP WITH (INAUDIBLE) WE'RE ALSO DOING A WORKSHOP LATER IN THE YEAR ABOUT DESIGNATIONS AND ABOUT OUR ORPHAN GRANTS PROGRAM. DOES ANY OF THESE WORKSHOPS ARE OF INTEREST TO YOU THEY'RE OPEN. WE LOOK FORWARD TO HAVING YOU THERE. PLEASE JOIN US. THAT'S ALL I HAVE. IF THERE ARE QUESTIONS, WE CAN TAKE SOME. [APPLAUSE] >> THANK YOU, DR. RAO FOR A FINE PRESENTATION. YOU SPOKE A GOOD BIT ABOUT THE WONDERFUL INCENTIVES AND AXEL RANTS AVAILABLE FOR ORPHAN PRODUCT DEVELOPMENT. AND OBSERVATION OF THOSE WONDERFUL INCENTIVES IS THAT ALL OF THEM OCCUR LATE IN THE DEVELOPMENT PROCESS. MOSTLY MARKET REVIEW AND APPROVAL. BUT I TAKE THE POINT THAT THEY'RE GREAT -- GREAT INCENTIVES FOR THE DRUG COMPANIES TO GET INVOLVED IN THE FIRST PLACE. WHAT I'M WONDERING IS WHAT PROS SPECKIOUS SEE FOR SUCH INCENTIVES AND AXEL RANTS MUCH EARLIER IN THE PROCESS. >> SURE. >> THE POINTS MADE TODAY BY SEVERAL SPEAKER, WE HAVE 7,000 RARE DISEASES, ONLY 250 TREATMENTS, MOST PEOPLE IN THIS ROM ARE STUCK IN THE VERY EARLY STAGES. WE CAN'T EVEN GET THE CLINICAL TRIALS, CAN'T GET INDs APPROVED FOR THE TREATMENTS. SO ACCELERATING REVIEW PROCESS FOR EARLY STAGE OR MAYBE CONSIDERING HOW MUCH MORE RISK TOLERANT OUR DISEASE POPULATION IS THAN REVIEWERS. OUR RESK IS WITHOUT INTERVENTION OUR -- RISK IS WITHOUT INTERVENTION OUR KIDS DIE. WE'RE TRYING TO FIND SOME WAY WHERE THE REVIEWER HAS METRICS FOR RISK TOLERANCE THAT HELPS THAT REVIEWER SAY IT'S TIME TO GO WITH WITH THIS TRIAL. THE PATIENTS ARE WILLING TO ACCEPT MORE RISK. >> I APPRECIATE THE COMMENTS VERY MUCH. IF I MAY CLARIFY. LET ME SEPARATE THE DESIGNATION PROCESS FROM THE GRANTS PROCESS. CERTAINLY IN ORPHAN PRODUCT GRANT WORLD WE LIVE IN WE FUN CLINICAL TRIALS BUT THE DESIGNATION PROCESS THE INCENTIVES THAT APPLY TO DESIGNATION HAPPENS EARLY IN THE REVIEW PROCESS SO WE DESIGNATE DRUGS ON ANIMAL MODELS, IF THERE AREN'T APPROPRIATE ANIMAL MODELS WE LOOK AT IN VITRO DATA. OUR PREFERENCE IS CLINICAL DATA BUT WE'RE IN THE LOOKING FOR RANDOMIZED CLINICAL TRIALS PER SE, WE LOOKED AT SOME CLINICAL DATA, SO DESIGNATION DOES ACTUALLY HAPPEN EARLY IN THE REVIEW PROCESS. I TAKE YOUR POINT THOUGH THAT DESIGNATION IS ONE THING, IT DOES PROVIDE INCENTIVES BUT HOW DO YOU MAKE THAT LEAP? WHERE DO YOU GO FROM THERE TO ACTUAL APPROVAL? THAT'S A TOUGH QUESTION BUT AS HAS BEEN DEMONSTRATED BY SOME OF THE WORK THAT WE HAVE DONE INTERNALLY AND ALSO IN THE STUDY LAST YEAR FDA DEMONSTRATED MARKETED FLEXIBILITY IN ITS REVIEW OF DRUGS FOR RARE DISEASES. SO THE STANDARD TO RANDOMIZE CONTROL TRIALS WITH HUGE POPULATION SIZES, DOESN'T NECESSARILY APPLY IN THE RARE DISEASE SPACE. SO FDA HAS THE AUTHORITY AND USES THAT AUTHORITY TO INFUSE FLEXIBILITY IN HOW DRUGS ARE BEING APPROVED. HAVING SAID THAT, I'M NOT SAYING WE'RE ALL THE WAY THERE, WE RECOGNIZE THAT WE HAVE A WAYS TO GO. BUT I THINK THE ISSUE IS NOT JUST WHAT'S HAPPENING AT THE END GAME, IT'S ALL ALONG THE DEVELOPMENT PROCESS WE HAVE TO FOCUS ON THAT. >> DR. RAO CORRECT MANY IN SAYING THE LATEST VERSION THEY ASKED THE FDA TO FORMALIZE STATEMENTS ABOUT THAT FLEXIBILITY. CAN YOU TALK A LITTLE BIT ABOUT THAT? >> SURE. I KNOW THERE HAS BEEN AN INTEREST AND A REQUEST THAT FDA FORMALIZE ITS POLICY ON FLEXIBILITY. FDA IS, AS YOU KNOW, FDA DOES EXERCISE A GREAT DEAL OF FLEXIBILITY IN REVIEWING PRODUCTS FOR RARE DISEASES. THEY'RE CURRENTLY CONSIDERING THIS PROPOSAL, AND WE'RE ACTIVELY WORKING ON IT. SO WE HOPE TO HEAR SOMETHING SOON ABOUT‡3d THAT. THANKS VERY MUCH. [APPLAUSE] >> IF YOU'RE NOT ABLE TO ATTEND THE FDA CELEBRATION RARE DISEASES DAY TOMORROW THE MORNING SESSION WILL BE WEBCAST, WILL BE AVAILABLE. SO PLEASE IF YOU HAVEN'T MADE PLANS TO JOIN IN TOMORROW PLEASE DO SO. THE NEXT THREE SPEAKERS ARE GROUPS OF SPEAKERS HERE WILL BE TALKING MORE ABOUT THE MODELS THAT CAN BE USED AND HOW TO MOVE FORWARD IN DEVELOPING POTENTIAL PRODUCTS FOR DIFFERENT RARE DISORDERS AND COMMON DISORDERS, AS A MATTER OF FACT. SO I THINK WHAT IT DOES INDICATE IS NEED FOR CAREFUL PLANNING AND WORKING TOGETHER, CONSULTING WITH DIFFERENT GROUPS OUR OFFICE NEURONEXT AND NHLBI PROGRAMS AN VARIOUS PROGRAMS THAT EXIST HERE TO TALK WITH THE PROGRAM PEOPLE EARLY ON TO SEE WHERE ARE YOU GOING AND WHAT ARE YOUR NEEDS. THAT WILL HELP YOU DEVELOP A PLAN A LITTLE BIT MORE TO UNDERSTAND WHAT IS NECESSARY. SO THE NEXT SPEAKER TO TALK ABOUT NEURONEXT, A RELATIVELY NEWER PROGRAM AT THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKES IS DR. PETRA KAUFMANN. PETRA. [APPLAUSE] >> I THINK STEVE GROFT AND HI TEAM FOR AALLOWING ME TO PARTICIPATE IN THE RARE DISEASE DAY. AS A NEUROLOGIST MOST PATIENTS I HAVE TAKEN CARE OF HAVE RARE DISEASES AND I WILL NOW TELL YOU A LITTLE BIT ABOUT THE INITIATIVE WE HAVE AT THE NATIONAL SUBSTITUTE OF NEUROLOGIC DISOFERREDs AND STROKE. HOWEVER, I THINK THAT MANY OF THE GOALS OF THIS INITIATIVE PROBABLY ALSO APPLY TO ANY OTHER RARE DISEASE. SO WHEN WE DESIGN OR DEVELOP THE INITIATIVE WE WANT TO TEST THE MOST PROMISING THERAPEUTICS IN PHASE 2 CLINICAL TRIALS. THE LAST QUESTION WAS A GOOD SEGUE TO THIS AREA. THIS IS AN INITIATIVE MEANT TO SUPPORT THE EARLIER PHASES OF DRUG DEVELOPMENT IN RARE DISEASES. WE WANTED TO HAVE SOMETHING THAT WOULD BE ABLE TO ENCOURAGE EXPLORATORY TRIALS THAT USE BIOMARKERS AVAILABLE SPECIFICALLY VERY ROBUST CLINICAL TRIALS SO THAT BEFORE EMBARKING ON A VERY LARGE HIGHER RISK PHASE 3 OR MORE PIVOTAL TRIAL, THAT IT WOULD HAVE ALL THE INFORMATION NEEDED SO THAT THOSE THREE TRIALS THAT REQUIRED SIGNIFICANT RESOURCES AND RELATIVELY LARGE NUMBER OF PATIENTS COULD BE STRATEGICALLY PLANNED AND RESERVED IN THOSE CASES WHERE WE HAVE ENOUGH INFORMATION FROM PHASE THE 2. SO ONE GOAL IS TO HAVE PHASE 2 TRIALS TO HELP US PRIORITIZE AND GIVE US GO, NO GO DECISIONS. ANOTHER BACKGROUND ISSUE THAT WE HAVE SEEN, IT TAKES VERY LONG TO IMPLEMENT THE CLINICAL TRIALS SO WE WANTED TO CREATE AN INFRASTRUCTURE TO HELP ACCELERATE OUR PHASE 2 CLINICAL TRIALS. TYPICALLY FOR EACH TRIAL WE PLAN THE INFRASTRUCTURE BEING CREATED. AFTER THE TRIAL IS PLEATED ITS GOALS AND THE WHEEL IS REINVENTED MANY TIMES OVER. SO WE THOUGHT IT BETTER TO HAVE SOME INFRASTRUCTURE SUPPORT. ANOTHER PROBLEM THAT WE HAVE SEEN IS THAT THERE IS OFTEN NOT VERY EFFECTIVE SHARING OF EXPERTISE AMONG DIFFERENT RARE NEUROLOGICAL DISEASES WHEN IT COMES TO CLINICAL TRIAL IMPLEMENTATION EXPERTISE. IN DIFFERENCE AREAS THE LENGTH OF O EXPERIENCE VARY RIS. SOME DEVELOP MORE THERAPEUTIC, SO WE CAN CROSS FERTILIZE BETWEEN FIELDS AN OVERALL IMPROVE THE SITUATION. WE HAVE AT THE NINDS GOOD EXPERIENCE WITH CLINICAL TRIALS NETWORK. ONE FOR PARKINSON DISEASE AND EMERGENCY CLINICAL TRIALS. IN THESE NETWORKS TRIALS HAVE TYPICALLY BEEN VERY GOOD QUALITY AND WERE COMPLETED WITHIN THE PROJECTED TIME LINE. I WOULD SUGGEST NET T WORK FOR ALL DISEASE Z BUT THAT'S NOT AN OPTION, WE WANTEDDEDDED THIS NETWORK TO HAVE AN OPPORTUNITY TO RESPOND TO THE DIFFERENCE THERAPEUTIC APPROACHES. IN DIFFERENT DISEASES AS THEY ARRIVE. SO GIVEN A MULTITUDE OF DISORDERS, WE HAVE TO BE READY FOR TRIALS IN ADULT AND PEDIATRIC DISEASE AND IN PARTICULAR RARE DISEASE. AS A POSITIVE BENEFIT AS WELL WE THINK THIS HELPS EXPAND THE PL OF CLINICAL INVESTIGATORS AND RESEARCH STAFF TO IMPLEMENT THEok MULTI-CENTER CLINICAL TRIALS. AS YOU KNOW, IN TERMS OF BACK GROUND THERE'S TWO KEY FACTORS THAT DELAY STARTUP IN CLINICAL TRIALS. ONE, THE REVIEW OF MULTI-CENTER PROTOCOL AT EACH PARTICIPATING SITE. IT'S FELT REDONE DAN AND NOT CLEAR HOW MUCH VALUE IT ADDS AND THERE SEEMS TO BE A GOOD TIE BECAUSE THE ADVANCE IN ORDER TO MAKE THE DISCUSS THE POSSIBILITY OF HAVING CENTRAL IRB NOW SUCCESSFUL MODELS OF INITIATIVES THAT USE CENTRAL IRBs SO WE THOUGHT THIS WOULD BE SOMETHING TO LOOK INTO FOR OUR INITIATIVE. ANOTHER IMPORTANT AREA OF CONTRACTING, THE MOST SIGNIFICANT FACTOR IN DELAY IN TRIAL WITH MULTI-CENTER TRIALS IS GETTING SUBCONTRACTS TO THE MULTIPLE SITES. SO WE HAVE IN OUR EMERGENCY TREATMENT NETWORK EXPERIENCES HAVING STANDING MASTER TRIAL AGREEMENTS WHICH SIGNIFICANTLY ACCELERATES THE PROCESS. IN TIMES OF FISCAL CONSTRAINT IT'S IMPORTANT THE PUBLIC PRIVATE SECTOR COORDINATE. THAT MEANS THAT YOU WANT TO HAVE A NETWORK TO TEST THERAPEUTICS WHETHER ACADEMIC INVESTIGATORS OR INDUSTRY INVESTIGATORS. THE INDUSTRY IS OFTEN GOOD POSITION THE BRING NOVEL THERAPEUTICS TO THE FIELD AND ULTIMATELY TO TAKE THEM FURTHER INTO PHASE 3 AND TO THE PATIENT COLLABORATION NEEDED DOWNSTREAM. AND THE -- ALSO WANT TO IN THIS NETWORK ENCOURAGE EARLY INVOLVEMENT OF PATIENT GROUPSCH THIS IS IMPORTANT BECAUSE WE NEED TO BE CONFIDENT THE QUESTIONS WE ASK MATTER TO PATIENTS. I THINK THAT'S NOTHING WORSE THAN IF A TRIAL IS SUBMITTED, PEER REVIEWED, FUNDED AND IS OPEN AND THEN THE PATIENTS EVEN IN RARE DISEASES JUST DON'T ENGAGE AND PARTICIPATE. THAT IS LOSS OF INVESTMENT, LOSS OF EFFORT. AND IT WOULD HAVE BEEN BETTER IF THE STAKEHOLDERS COMMUNICATED EARLIER ON IN THE CONCEPTION OF THE PROJECT TO MAKE SURE THE PROJECT IS IMPORTANT TO BENEFIT FROM IT AND NONE MORE THAN PATIENTS. IT'S ALSO IMPORTANT IN A PRESSING MATTER THAT THE BURDEN B IN THE PROTOCOL IS ACCEPTABLE AND THAT THE CONSENT PROCESS IS SUCCESSFUL WITH PATIENTS EARLY ON. SO BASICALLY AS -- WITH THIS BACK GROWN IN MIND WE THINK -- IS IT WORKING NOW? WITH THIS BACKGROUND IN MIND WE CREATE THIRD DEGREE NETWORK INFRASTRUCTURE THAT HAS A CLINICAL COORDINATING CENTER DATA MANAGEMENT CENTER, AND 25 CLINICAL SITES. AND IN PARTICULAR FOLLOWING (INDISCERNIBLE) SELECT AD SITE TO BE GOOD GEOGRAPHIC DIRECTION BUT MORE IMPORTANT CAPACITY TO CONDUCT CLINICAL TRIALS IN CHILDREN AS WELL AS ADULTS. IN RARE DISEASE POPULATIONS. HAVING ONE CENTRAL CLINICAL COORDINATING CENTER IS VERY EFFECTIVE, EFFICIENT BECAUSE AS MENTIONED EARLIER, CURRENTLY WE BUILD INFRASTRUCTURE FOR EACH TRIAL HERE WE HAVE AN EXPERIENCED GROUP OF PROFESSIONAL WHOSE RUN THE TRIALS SO THAT EVEN IN A DISEASE AREA WHERE THE INVESTIGATORS HAVE LESS OF A TRACK RECORD IMPLEMENTING MULTI-CENTER TRIALS THEY CAN BENEFIT FROM HAVING THIS WELL RUN EXPERIENCED GROUP OF PEOPLE HELP THEM. I WANTED TO ADVANCE THEM, IT DOESN'T WORK ANY MORE. SO BASEICALLY -- WHERE WE STAND WITH THIS NOW IS THAT -- THANK YOU. THANK YOU. I TALK ABOUT THIS CLINICAL COORDINATING SENT E WE HAVE A DATA MANAGEMENT CENTER WHICH BRINGS COUPLE OF THINGS. ONE IS WE HAVE LOOKED FOR EXPERTS IN DESIGN OF SMALL TRIALS IN TERMS OF STATISTICS AND THIS IS A GREAT ADVANTAGE WHEN INVESTIGATORS, FEW AVAILABLE PATIENTS ARE INTERESTED IN WORKING WITH THE NETWORK. ANOTHER IS STANDARDIZED PROCEDURES, COMMUNICATION AND THAT THE RESEARCH STAFF AT THE SITES CAN WORK WITH ONE DATA MANAGEMENT SYSTEM. IMPORTANTLY WE CAN ALSO THEN HAVE ONE QUALITY CONTROL APPROACH AND HAVE QUALITY BY DESIGN BUILDING PLANS INTO THE PROTOCOL UP FRONT TO HOPEFULLY ACCELERATE THINGS AN REDUCE COSTS. AT THE LOCAL SITE, OUR SUPPORT LEGAL HELP ENGAGE CLINICIANS AND INVESTIGATORS BUT ALSO COMMUNITIES SO WE HAVE ASKED MANY SITES TO HAVE A HUB AND SPOKE SYSTEM NETWORK AND ENGAGE PATIENTS EARLY ON AS WELL AS TO ENGAGE NEW INVESTIGATORSCH THIS IS A MAP, I MENTIONED EARLIER THERE IS A FAIRLY REASONABLE GEOGRAPHIC DISTRIBUTION OF THE SITES AND HERE IS LIST OF THE MAJOR ACADEMIC MEDICAL CENTERS, TWO DESIGNATED CHILDREN'S HOSPITALS AN MOST ALSO HAVE CLINICAL TRIAL AWARDS OR CONTRACT IS A PROGRAMS. IT'S ORGANIZED BY HAVING BASICALLY THE SITES AT THE BASE AND THESE TWO COORDINATING CENTERS AND THEN AN EXECUTIVE COMMITTEE THAT CONSISTSES OF PEOPLE FROM NETWORK AN NINDS AS WELL AS EXTERNAL ADVISORY COMMITTEE TO GIVE FEEDBACK AS INITIATIVE PROGRESSES. SO KEY FEATURES, WE WANTED TO BE ABLE TO ENGAGE BIOPHARMA INDUSTRY AND FOUNDATIONS AND PARTNER SHIPS SO WE HAVE THE ABILITY TO CONTRACT IN A COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT OR CREDA WITH PRIVATE SECTOR PARTNERS TO WORK WITH THE NETWORK. WE HAVE ALSO ACTUALLY IMPLEMENTED THE STANDARD MASTER TRIAL AGREEMENT PROGRAM THAT I MENTIONED EARLIER WHERE WE HAVE THE TRIAL COSTCAL CALCULATED ON FEE FOR SERVICE BASIS BUT OTHER FACTORS PRENEGOTIATED AND IT WILL SPEED UP THE CONTRACTING PROCESS. WE HAVE BEEN SUCCESSFUL IN GETTING ALL 25 PARTICIPATING SITES TO CREED THEIR REVIEW TO A CENTRAL IRB AT THE CLINICAL COORDINATING CENTER. IN BOSTON. THEY HAVE DEVELOPED APPLIANCE AGREEMENTS AND WILL BE BASICALLY ONLY ONE FULL PROTOCOL REVIEW. ALL SITES WILL BE ON THE SAME CYCLE, AND ONLY THIS ONE COMMITTEE WILL REVIEW THE OPPORTUNITIES FOR LOCAL LOCAL INPUT BUT NOT MULTIPLE IRB REVIEWS. THE CENTRAL IRB WILL MANAGE THE RENEWALS AND REPORTING OF ANY ISSUES THIS IS OF COURSE ONLY POSSIBLE USING WEB-BASED AND WE WILL FOR THIS NETWORK HAVE MANY INSTITUTES HAVE DATA AND SAFETY MONITORING BOARD OVERSIGHT FOR THE MULTI-CENTER TRIALS. HERE AGAIN WE WILL CENTRALIZE AN STANDARDIZE SO THERE'S NOT MULTIPLE MEETINGS THAT THE INVESTIGATOR VERSUS TO COME TO, THAT IS ALL COORDINATED. WE ALSO WANTED TO BE SURE THAT IN RARE DISEASES THE TRUE VALUE OF THESE RARE DATA SETS AND SPECIMEN COLLECTIONS MATERIALIZED BY HAVING THEM NOT GO AWAY AFTER THE PARTICULAR TRIAL IS OVER BUT BY HAVING BIOSPECIMENS SUBMITTED TO A REPOSITORY AND HAVING DATA AVAILABLE FURTHER USE. WE THINK THE FACT ALL THIS DATA ARE MANAGED TO ONE DATA MANAGEMENT CENTER WILL BE HELPFUL. WE ENCOURAGE USE OF COMMON DATA ELEMENTS USING DATA CENTERS UP FRONT MAKES IT EASIER LATER TO USE THE DATA IN META ANALYSES OR PLANNING OF FUTURE TRIALS. WE ENCOURAGE CENTRAL REPOSITORIES, SPINAL MUSCULAR ATROPHY AND THERE THE INVESTIGATORS ASK TO SUBMIT ALL SPECIMEN TO THE REPOSITORY. WE THINK THAT CAN SK REAL RATE -- ACCELERATE PROGRESS GOING FORWARD. THREE POSSIBLE WAYS OF WORKING WITH THIS NETWORK. ONE FOR ACADEMIC INVESTIGATOR, ONE FOR SMALL BUSINESS ENTITIES AND FINALLY ONE IS SPECIFICALLY FOR INDUSTRY AND IT ALLOWS VERY RAPID TIME LINES BECAUSE WE UNDERSTAND THAT IS ONE OF THE CONCERNS. IT HAS OTHER FEATURES WITH WITH REGARDS TO IP THAT WE THINK WILL FACILITATE PARTNERSHIPS. THE REVIEW WILL BE DIFFERENCE BECAUSE THERE ARE MORE DRUG DEVELOPMENT EXPERTS AS WELL AS ETHICS AND PATIENT REPRESENTATION. AND JUST TO LET YOU KNOW THIS IS A NEW INITIATIVE SO I CAN'T REPORT ON OUTCOMES YET BUT BASICALLY WE HAVE NETWORK ESTABLISHED, WE HAVE A MEETING AND FIRST STUDY, A BIOMARKER STUDY IN SPINAL MUSCULAR ATROPHY SLATED TO BEGIN IN APRIL. SO YOU EXPERIENCE SUGGESTIONS NETWORKS AND THERAPEUTICS DEVELOPMENT AND PARTICULAR IMPORTANT FOR RARE DISEASES BECAUSE EXPERIENCE CAN BE SHARED T. INCREASED EFFICIENCY IS AN IMPORTANT FACTOR AND CAN ACCELERATE DRUG OR THERAPEUTICS DEVELOPMENT AND PRIVATE PUBLIC MART NER SHIP ARE NEED SOD IT'S IMPORTANT TO PLAN TO SET UP NET WORKS BECAUSE SHARED INFRASTRUCTURE ARE PARTICULARLY IMPORTANT FOR RARE DISEASE. HERE IS SOME CONTACT INFORMATION ON HOW TO -- IF YOU'RE INTERESTED IN NETWORK OF SCIENTIFIC AS WELL AS LEGAL PERSPECTIVES. AND OF COURSE TEAM EFFORT. MANY PEOPLE CONTRIBUTE AT THE NINDS AND MOST IMPORTANTLY AT THE ACADEMIC SITES FOR INVESTIGATOR MEETING HELD IN NOVEMBER. THANK YOU. [APPLAUSE] >> JOHN FERGUSON, OFFICE OF RARE DISEASES RESEARCH. PETRA, VERY INTERRING AND VERY THOROUGH. I WONDER IF YOU HAD ANY CHANCE TO LOOK AT OUR EXPERIENCE WITH WITH THE RARE DISEASE CLINICAL RESEARCH NETWORK AND OFFICE OF RARE DISEASE AND YOUR INSTITUTE AND OTHERS BECAUSE MANY OF THE THINGS THAT YOU HAVE GONE THROUGH WE WENT THROUGH STARTING IN 2003 AND WITH SOME BURPS AN STARTS YOU COULD POSSIBLY BENEFIT FROM NOT ONLY SUCCESSES BUT FROM OUR DIFFICULTIES. I WONDER IF YOU HAVE HAD ANY CHANCE TO TALK TO DR. (INDISCERNIBLEER OR TO STEEF ABOUT SOME OF THE PROBLEMS THAT WE HAVE HAD. >> IN THE INTEREST OF TIME I WASN'T ABLE TO MENTION BUT CLEARLY ONE INITIATIVE THAT INSPIRED US. THERE'S SOME COMMONALITY CERTAINLY WE THINK THE CENTRAL DATA MANAGEMENT IS KEY THE DIFFERENCE IS THAT THERE THE CONSORTIA ARE ORGANIZED BY PARTICULAR RARE DISEASE OR PARTICULAR GROUP OF RARE DISEASES. AND THAT WOULD HAVE NECESSITATED THAT WE HAVE BASICALLY A NUMBER OF NETWORKS WITHIN THE NINDS AND YOU ALREADY PROVIDE A GREAT SUPPORT IN THAT SPACE. SO WE WANTED TO HAVE SOMETHING THAT IS SIMILAR BUT MORE GENERIC IN TERMS OF THE DISEASES. >> ONE OTHER COMMENT, THAT IS NOTICE YOU TALK ABOUT A CENTRAL IRB, THAT'S WONDERFUL. I HOPE THAT WORKS AND HOPE YOU CAN EVERYBODY TO TAKE PART IN THAT. OTHER THING WAS CENTRAL DATA SAFETY AND MONITORING BOARD. ONE, AND IF YOU WOULD LIKE LONG RENDITION ON ONE DATA SAFETY MONITORING BOARD TO HANDLE 50 DISEASES OR SO I WOULD BE MAIN TO TALK TO YOU FOR FIVE -- HAPPY TO TALK TO YOU FOR FIVE OR SIX HOURS. >> THAT'S A CHALLENGE. ONE BOARD CAN SERVE OUT -- NOW WE HAVE AT OUR INSTITUTE FOR EACH TRIAL WE HAVE A -- CHART IDEAS SO HERE SOME OF THE PLAYERS IN THE DATA MANAGEMENT CENTER CLINICAL COORDINATING CENTER HAVE TO COME TO THIS MEETING SO WHAT I WAS TALKING ABOUT WAS NOT HAVING ONE GROUP OF PEOPLE VIEW ALL TRIALS BUT RATHER ORGANIZING IT IN A STREAMLINED FASHION SO THAT MAYBE THEY WOULD MEET TWICE A YEAR IN P PERSON AND IN BETWEEN ON THE PHONE DURING STANDARD TIME LINE SO WE CAN MINIMIZE ANY REDUNDANCY THERE AND USE UNIFORM REPORTS AND SO ON. >> MY NAME IS CHERYL FIELDS, I WORK WITH MEBO RESEARCH OUT OF KANSAS CITY. I HAD A -- FIRST OF ALL, IT WAS A WONDERFUL PRESENTATION, THANK YOU. BUT MY QUESTION IS, CAN YOU Y'ALL FLIP THE SCREEN BACK SO I CAN WRITE DOWN THOSE -- >> I DON'T KNOW IF I CAN DO THAT BUT PROBABLY -- >> WE CAN GET COPIES. >> I'LL BE HAPPY TO GIVE YOU MY CARD. IF YOU GOOGLE NEURONEXT IT WILL COME UP. ALL THE EMAILS ARE ON THAT SITE. >> THANK YOU. >> OUR NEXT PRESENTATION IS FROM THE NATIONAL HEART LUNG AND BLOOD INSTITUTE. WE'RE GOING O TO CHANGE ORDER OF SPEAKERS, DR. ZORNA GALIS WILL LEAD DISCUSSION, CENTERS FOR ACCELERATED INNOVATION AND THE VASCULAR INTERVENTIONS INNOVATIONS AND THERAPEUTIC AT VAPSES FOR HER -- ADVANCES FOR HEART LUNG AND BLOOS DIDS OR ORDERS. -- AND BLOOD DISORDERS. SO ZORNA, WE'LL START WITH YOU. [APPLAUSE] >> I'M VERY GLAD TO BE ANNOUNCING THIS NEW PROGRAM. I'M ACTUALLY GOING TO START BY PRESENTING THE VITA PROGRAM, VASCULAR INTERVENTIONS INNOVATIONS AND THERAPEUTIC ADVANCES. THEN STEVE FLAME WILL CONTINUE -- STEVE FLAIM WILL DESCRIBE THE INNOVATIONS. THIS PROGRAM WAS DESIGNED FOR MANY CONCERNS AN SUGGESTIONS FROM THE COMMUNITY. IN 2010 WE CONVENED TRANSLATIONAL RESEARCH WORKSHOP WHERE WE INVITED PEOPLE FROM THE INDUSTRY, ACADEMIA, AS WELL AS ANY OTHER INTERESTED PARTIES TO HELP US FOCUS ON THE UNMET MEDICAL NEEDS. SO WE IDENTIFIED SEVERAL CONDITIONS THAT ARE WIDESPREAD YET NEGLECTED BY THE INDUSTRY. AND ARE FOCUSING THIS PROGRAM ON VASCULAR AND THROMBOTIC DISORDERS AND PULMONARY HYPERTENSION. WE ALSO INVITED OUR GRANTEES TO INFORM US OF THE MANY OPPORTUNITIES THAT EXIST OUT THERE'S SPECIALLY FROM THE PHYSICIANS WHO MEET PATIENTS EVERY DAY. WE FOUND OUT THAT THERE ARE MANY IDEAS FOR NEW DIAGNOSTIC, THERAPEUTIC AGENTS AND DEVICES, OR NOVEL WAYS OF USING ALREADY EXISTING INTERVENTIONS. IN THE SAME TIME AS WE HEARD SEVERAL TIMES, WE KNOW THERE IS A SCARCITY OF FUNDING FOR VERY EARLY MEDICAL CONCEPTS NOT READY FOR PRIME TIME. WE DECIDED THAT WE ARE GOING TO SPECIFICALLY TARGET THE VALLEY OF DEATH, NOW IN PRODUCT DEVELOPMENT, THAT ACTUALLY MAKES MANY GREAT MEDICAL IDEAS DIE BEFORE THEY COME IN TESTING. SO WE WILL PROVIDE SUPPORT VERY EARLY IN EARLY STAGE DEVELOPMENT. ANOTHER SUGGESTION THAT WE HER FREQUENTLY FROM OUR GRANTEES IS THAT WHILE THEY HAVE A LOT OF GREAT IDEAS, THEY HAVE EXTREMELY REWARDING ACADEMIC CAREERS TAKING CARE OF PATIENT, TEACHING RESIDENTS, DOING VERGE, THAT THEY DO NOT WANT TO QUIT IN ORDER TO JUST SOME VERY EARLY CONCEPTS. SO WE REMOVE THE REQUIREMENT OF REGARDING AFFILIATION SO ANYBODY CAN APPLY REGARDLESS WHETHER THEY'RE PART OR NOT OF A COMPANY. THE LACK OF KNOW HOW IS SOMETHING THAT COMES FREQUENTLY INTO DISCUSSION AND THE LOCAL ACCESS TO EXPERTISE NEEDED IN ORDER TO ENGAGE IN PRODUCT DEVELOPMENT. SO WE WILL CREATE SUPPORT IN TERMS OF REGULATORY ADVICE PROJECT MANAGEMENT SO FORTH NEEDED SO ANYBODY CAN ENGAGE IN THIS EXERCISE. SO SMALL UNIVERSITIES FROM REMOTE LOCATIONS OR BIG ACADEMIC CENTERS WHO HAVE THE LOCAL EXPERTISE ALL WELCOME TO COME. ONE CONCERN THAT IS FREQUENT THESE DAYS IN FISCAL CONSTRAINT IS THE FACT WE'RE DIVERTING MONEY FROM BASIC RESEARCH FOR RISKY TESTING VERY RISKY IDEAS. MILESTONE DRIVEN, THAT MEANS GO, NO GO DECISIONS TO STOP FUNNING IF THE IDEA PROVE TO BE TOO EARLY OR NOT WORTHWHILE. SO WE BASICALLY CREATED A SAND BOX OF DEVELOPMENT WHERE THE NHLBI, THE NATIONAL HEART LUNG AND BLOOD INSTITUTE WILL REQUIRE THAT THE PROJECT FOCUSES ON A SPECIFIC MEDICAL CONDITION AND WE DEFINE WHAT IS IN AND WHAT IS NOT. THE FUNDING MECHANISM AS WELL AS MAXIMUM AMOUNT OF TIME IN FUNDING THAT WILL BE ALLOWABLE, THE APPLICANTS HAVE NO RESTRICTION IN TERMS OF GEOGRAPHICAL OR INSTITUTIONAL AFFILIATION, THEY DO NOT HAVE TO HAVE PREVIOUS EXPERTISE OR EXPERIENCE IN PRIOR DEVELOPMENT BUT THEY CAN INFORM US THE TYPE OF PRODUCT, SPECIFIC GOAL, MILESTONES AND HOW TO BEST USE THE MONEY THAT'S GOING TO BE MADE AVAILABLE. SO WE ARE GOING TO MANAGE THE IDEA LIKELY BUT THE PROCESS TIEGLY. SO I BROUGHT THIS SLIDE HERE TO ILLUSTRATE THE CONCEPT THAT BY HAVING ONE VERY CLEAR GOAL HERE MAKING NOW, YOU CAN SEE AN ARRAY OF AMAZING CREATIVITY, THERE ARE MANY DIFFERENT EXPRESSION AND SOLUTIONS TO THIS SINGLE GOAL, THEY COME IN VARIOUS SIZES, MADE OF VARIOUS MATERIALS, GLASS, PRECIOUS METALS OR STONE, PAPER OR RECYCLED MATERIALS. SO JUST GIVING ONE VERY CLEAR FOCUS BUT TAKING INTO ACCOUNT THE CREATIVITY OF EACH OF THESE ARTISTS AND THE LOCAL RESOURCES IN TERMS OF THE MATERIALS AND THE THE CRAFTSMANSHIP TRADITION, YOU CAN HAVE BASICALLY UNLIMITED ARRAY OF RESPONSES TO A VERY (INAUDIBLE). THE VITA PROGRAM IS GOING TO ADDRESS THE NEEDS IN THE VALLEY OF DEATH VERY EARLY IN PRODUCT DEVELOPMENT. THOSE IDEAS THAT ARE LOOKING FOR PROOF OF PRINCIPLE DEMONSTRATE OF PROOF OF PRINCIPLE, WE LIKE THAT CONCEPT TO POP, THAT MEANS PROO OF PRINCIPLE, VALIDATION. AND A LITTLE BIT FURTHER DOWN DEVELOPMENT POT WAY, THOSE WHO HAVE A PROOF OF PRINCIPLE BUT STILL NEED ADDITIONAL STUDIES BEFORE THEY CAN CAN FILE FOR FDA APPROVAL. YOU JUST HEARD A TALK ABOUT THAT. THE AMOUNT OF INVESTMENT WILL DEPEND ON THE STAGE. AGAIN, ALL THESE PROJECTS WILL BE MILESTONE DRIVEN AND MAY STOP ACTUALLY EARLIER THAN INITIALLY PROJECTED BASED ON HOW THEY ACHIEVE THEIR MILESTONE. AGAIN, THIS IS THE STRUCTURE OF THE VITA PROGRAM. SO BASICALLY WE CREATE A CLOUD OF PRODUCT DEVELOPMENT, THAT MEANS ANYBODY ENGAGE FROM WHERE THEY ARE. THEY WILL RECEIVE SUPPORT FROM A PROGRAM COORDINATING CENTER, THEY WILL BE -- THEY WILL BE OVERSIGHT BY THE NATIONAL HEART, LUNG AND BLOOD INSTITUTE AN MAYBE GOOD TIME TO SAY MORE THAN HALF OF THE TEAM THAT HAS BEEN DEVELOPING VITA HAS INDUSTRY EXPERIENCE AND ACADEMIC EXPERIENCE. SO WE UNDERSTAND WELL THE CHALLENGES, WE ALSO ENGAGE IN EXTERNAL ADVISORY COMMITTEE WITH PEOPLE WHO WORK IN INDUSTRY AND HAVE EXPERIENCE IN PRODUCT DEVELOPMENT. NOR TO HELP PEOPLE MOVE ALONG THE PRODUCT DEVELOPMENT PATHWAY. SO I BRIEFLY TRADE TO DESCRIBE HOW VITA IS GOING TO START VERY EARLY, EARLY AS MEDICAL PRODUCT CONCEPT AND WILL HELP PEOPLE ADVANCE ALONG THE PATHWAY OF PRODUCT DEVELOPMENT AND DR. FLAIM WILL DESCRIBE CENTERS FOR EXCELLENCE INNOVATION AND HOW THEY WILL INTERACT WITH INITIATIVES SUCH AS VITA, PROJECT ORIENTED INITIATIVES. SO OUR O FOCUS IS ON A SPECIFIC MEDICAL PRODUCT REGARDLESS OF LOCATION AN NOW THE NATIONAL CENTERS OF INNVATION WILL POTENTIALLY SUPPORT FOR SUCH A PROGRAM TO THE THE RISK OF TECHNOLOGIES WHERE THE POINT THEY'RE INTERESTING TO THE INDUSTRY. I'M GOING TO PASS ON THE MICROPHONE AND HANDLE THE QUESTIONS. >> THANKS VERY MUCH. PLEASURE TO BE HERE TODAY. CAN YOU HEAR ME? GREAT. I'M HERE TO TELL YOU ABOUT THE NATIONAL HEART LUNG AND BLOOD INSTITUTE CENTERS FOR ACCELERATED INNOVATION. LIKE VITA THIS PROGRAM IS DESIGNED TO WORK WITH TECHNOLOGIES EARLY IN THEIR STAGES WITHIN THE RESEARCH INSTITUTIONS TO ALLOW THEM TO BECOME RECOGNIZABLE AS POTENTIAL COMMERCIAL OPPORTUNITIES FOR PRIVATE SECTOR COMPANY FUNDING. THIS IS IMPORTANT BECAUSE IT'S EXPENSIVE TO DEVELOP TECHNOLOGIES AN DEPLOY THEM TO PATIENTS. SO THIS PROGRAM WAS THE RESULT OF ACTUALLY A WORKING GROUP MEETING THAT OCCURRED BACK IN NOVEMBER OF 2010. CONVENED THAT HAD A GROUP OF STAKEHOLDERS FROM RESEARCH -- FROM THE RESEARCH INSTITUTIONS FROM THE NIH, FROM THE PRIVATE SECTOR COMPANIES, THE FUNDING COMPANIES LIKE VENTURE CAPITAL FIRMS AN NON-PROFIT ORGANIZATIONS. THESE STAKEHOLDERS CAME ONE THE IDEA THAT LED TO THIS PROGRAM. SO AS YOU KNOW, THE WAY THIS PROCESS WORKED IN THE PAST IS BASIC RESEARCH INSTITUTIONS DO ALL THE WORK THAT'S NECESSARY TO DO DISCOVERY OF NEW TECHNOLOGY. IT'S FUNDED BY THE NIH AND STATE FUNDING ORGANIZATIONS. AND TRADITIONALLY THAT'S HANDED OFF TO R&D COMPANIES, FUNDED BY ANGEL GROUPS, VENTURE CAPITAL FIRMS AN INDUSTRY ITSELF TO DO THE VALIDATION PRE-CLINICAL TESTING DEVELOPMENT WORK THAT'S REQUIRED FOR CLINICAL TRIALS AND TO FDA APPROVAL OUT TO THE COMMERCIAL SECTOR. SO WHAT WE HAVE REALIZED THE LAST FIVE OR SO YEARS, MAYBE LONGER, IS THE TECHNOLOGIES WHEN THEY EXIT THE RESEARCH INSTITUTIONS ARE DEEMED TOO RISKY FOR THESE FUNDING GROUPS TO ACTUALLY INVEST IN. SO THERE A PULL AWAY OF THIS STEP FROM THE ACTUAL SOURCE OF THE TECHNOLOGIES. WHAT WE DID IS LOOK AT FUND RIG SOURCES AVAILABLE AT THE NIH AS WELL AS NIH ASSISTANCE PROGRAMS AVAILABLE AND REALIZE THERE IS QUITE A GAP HERE. CENTERS FOR ACCELERATED INNOVATION HAS BEEN PUT INTO PLACE TO BASICALLY BRIDGE THE GAP BETWEEN THESE TWO SECTORS. SO THE CENTERS TARGET DISCOVERIES IN TECHNOLOGIES WHERE A COMMERCIAL PRODUCT IS ENVISIONED BUT ADDITIONALLY FEASIBILITY WORK IS NEEDED AND INVESTIGATORS ARE UNSURE HOW TO TAKE FIRST STEPS WITH THESE TECHNOLOGIES. SO THESE ARE DEE ELEMENTS, A VISION CENTER FUNNED ACCEPTOR IS A CON SOURCE YM OF RESEARCH PERFORMING INSTITUTIONS THAT HAVE ACCESS TO A GOOD DEAL OF DIAGNOSTICS, DEVICESSER THERAPEUTICS TREATMENTS TOOLS TECHNOLOGIES THAT WILL BE LATE STAGE IN THE DISCOVERY AREA WITH PROOF OF CONCEPT OR AT LEAST PROOF OF CONCEPT STAGE AND THOSE TECHNOLOGIES COME FROM THE PARTICIPATING INSTITUTIONS IN THE CENTER. THOSE -- THAT GROUP OF TECHNOLOGIES AND CENTERS CANNING GEOGRAPHICALLY IN A SIMILAR ZONE BUT NOT REALLY REQUIRED. SO THE CENTER WILL HAVE A ABILITY TO SOLICIT TECHNOLOGYS FROM THE INSTITUTIONS. AN EARLY STAGE FUNDING TO DO THE NEXT STEP INTO THE DEVELOPMENT PROCESS. SO O LET'S LOCK MORE CAREFULLY FOCUSING ON SOLICITATION AND SELECTION OUT THERE. THE CENTERS SOLICIT AND SELECT THE BEST DISCOVERIES WITHIN THOSE INSTITUTIONS THAT FALL UNDER THE MISSION OF THE NATIONAL HEART LUNG AND BLOOD INSTITUTE. THESE WILL ADDRESS UNMET MEDICAL NEEDS, WILL OFFER GREAT SCIENTIFIC OPPORTUNITY AND THEY WILL ALSO HAVE AN IMMEDIATE COMMERCIAL OR OTHERWISE PRESENT COMPELLING REASON FOR CONTINUED -- TECHNOLOGIES THAT TARGET RARE NEGLECTED DISEASES. THE CENTERS WILL HAVE TO REACH OUT AND ATTRACT AND ENGAGE INVENTORS EARLY ON IN THIS PROCESS EVEN IF INVENTORS THEMSELVES DON'T REALIZE THE TECHNOLOGIES HAVE COMMERCIAL OPPORTUNITIES. IN ADDITION THE CENTERS WILL HAVE TO FACILITATE ABILITY OF THEIR TECHNOLOGY INSTITUTIONS AND TECH TRANSFER OFFICES WITHIN THE INSTITUTIONS TO DEVELOP A GOOD WORKING RELATIONSHIP TO FACILITATE MOVEMENT OF THE TECHNOLOGY OUT OF THE INSTITUTION TOWARDS THE COMMERCIAL ENVIRONMENT. WHAT WE ENVISION THE SENOR TO LOOK LIKE IS IS SHOWN HERE. ESSENTIALLY THE CENTER IS HERE, CONSORTIUM OF RESEARCH PERFORMING INSTITUTIONS WITH GOOD TECHNOLOGY IS AVAILABLE, THOSE TECHNOLOGIES ARE SOLICITED AND SELECTED TO MOVE INTO THE CENTER USING SCIENTIFIC AND BUSINESS REVIEW PROGRAMS AN GROUPS, TECHNOLOGIES ACCEPTED INTO THE PROGRAM AN RECEIVE ADDITIONAL CAPITAL IN THE CENTER. THOSE TECHNOLOGIES WILL ENTER INTO TECHNOLOGY BUSINESS DEVELOPMENT PROCESS WHICH WILL LEVERAGE AND TAKE ADVANTAGE OF ALL KEY TALENTS REQUIRED TO DO THESE EARLY STEPS INCLUDING PROJECT MANAGEMENT, PRODUCT DEVELOPMENT WORK, INTELLECTUAL PROPERTY DEVELOPMENT AND PLANNING, REGULATORY PLANNING AN BUSINESS DEVELOPMENT. TECHNOLOGIES, THAT EMERGE FROM THIS PROGRAM WILL BE AT A STAGE THEY WILL BE ABLE TO ATRACK ADDITIONAL FUNDING FROM EXTERNAL SOURCES. SO THOSE TECHNOLOGIES WILL THEN EXIT THE SENOR AND EITHER BE PICKED UP HOPEFULLY BY FOR PROFIT ORGANIZATIONS FUNNED BY NON-PROFIT ORGANIZES OR PROVIDE THE BASIS FOR THE FORMATION OF NEW COMPANIES. DURING THIS DEVELOPMENT PROCESS THE CENTERS USE ALL THE RESOURCES AVAILABLE AT THE NIH AND THE NHLBI TO HELP WITH THE DEVELOPMENT PROCESS AND TECHNOLOGIES REJECTED AT THE STAGE OF SELECTION OR REPUBLICAN DEEMED TO BE NOT REALLY FOR COMMERCIALIZATION YET. WILL THEN BE RETURNED TO THE INSTITUTIONS FOR FURTHER WORK. SO THE CENTER WILL HAVE EDUCATION SKILLS DEVELOPMENT COMPONENT. THE CENTER WILL TRAIN AND MENTOR INNOVATORS ABOUT THE DESIGN AND CONDUCT PRODUCT DEFINITION. THE TRAINING COMPONENT WHERE INNOVATORS LEARN ABOUT EARLY STAGE IN PRODUCT DEVELOPMENT AND MAKE TECHNOLOGIES LOOK COMMERCIALLY ATTRACTIVE. THERE WILL BE A NUMBER OF DIDACTIC TYPE TRAINING ACTIVITY THERE IS AS WELL AS MENTORING WITH PEOPLE IN THAT SECTOR OF TRANSITIONING TECHNOLOGIES FROM RESEARCH INSTITUTIONS TO PRIVATE SECTOR. THIS PICTURE SHOWS HOW WE SEE THE CENTER INTERACTING WITH ALL THE OTHER RESOURCES SURROUNDING IT IN THE FEDERAL PROGRAMS AVAILABLE. THE CENTERS ARE HERE DEVELOPING TECHNOLOGIES, THEY WILL COME FROM ACADEMIC INSTITUTIONS AN RESEARCH PERFORMING INSTITUTIONS AND WE SEE THE VITA PROGRAM THAT ZORNA SPOKE ABOUT PARTICIPATING AT THIS STAGE. THE CENTER FOR DEVELOPMENT PROCESS WILL TAKE ADVANTAGE OF RESOURCES AVAILABLE AT THE NIH INCLUDING NCATS AND TECHNOLOGY DEVELOPMENT RESOURCES AT THE HEART LUNG AND BLOOD INSTITUTE. THE CLINICAL TRIALS NETWORKS AND PARTNERS AT THE FDA AND U.S. PATENT TRADEMARK OFFICE WHO BOTH AGREED TO WORK WITH US ON THIS PROJECT. TECHNOLOGIES EMERGING FROM THE CENTER WILL PROVIDE A BASIS FOR GOOD STRONG STTR GRANT OPPORTUNITIES AND THEY WILL HOPEFULLY BECOME DERISKED TO THE POINT THEY CAN GO OUT INTO NON-PROFIT ORGANIZATIONS, FOR PROFIT COMPANIES OR FORM THE BASIS FOR STARTUP COMPANIES. WE THINK THIS PROGRAM IS IMPORTANT TO INCREASE THE SBIR GRANT APPLICATIONS WE GET. SO THE BENEFITS OF THIS PROGRAM AND ALSO THE VITA PROGRAM TOGETHER BASICALLY WILL BENEFIT PUBLIC HEALTH BY IDENTIFYING ACCELERATING INCREASING NUMBER OF HIGHLY INNOVATIVE SCIENTIFIC DISCOVERIES TRANSLATED INTO MARKETABLE PRODUCTS. THESE PROGRAMS WILL ADDRESS THE CRITICAL BOTTLENECKS IN GAPS THAT WE KNOW EXIST IN THIS PROCESS. THEY WILL HELP TO DECREASE TIME FROM PRODUCT DEPLOYMENT TO THE PATIENT. THESE PROGRAMS INCREASE THE CHANCE OF TECHNOLOGIES BEING SUCCESSFUL. WE ENCOURAGE PUBLIC PRIVATE PARTNERSHIPS TO OCCUR WITHIN THE INTEGRATED ENVIRONMENT OF THE RESOURCESES AND ULTIMATELY WE WILL BE FOSTERING A CULTURE NEEDED FOR SUSTAINED TECHNOLOGY DEVELOPMENT. SO THIS SLIDE SUMMARIZES THE TIMING FOR BOTH PROGRAMS, THEY BOTH STARTED IN MIDDLE TO FALL OF 2010. AND BOTH PROGRAMS WILL BE SEEING THEIR FIRST GRANT TIMING OCCUR IN THE FALL OF 2013. BOTH PROGRAMS WERE THE RESULT OF STRONG TEAM EFFORT FROM VARIOUS DIVISIONS WITHIN THE NATIONAL HEART LUNGEN BLOOD INSTITUTE FOR VITA AND NCAI PROGRAM AND EXTERNAL PARTNERS THE FDA AND U.S. PATENT AND TRADEMARK OFFICE. THESE ARE POINTS OF CONTACT AND I THINK WE'RE BOTH AVAILABLE TO ANSWER QUESTIONS IF THERE ARE ANY. THANK YOU VERY MUCH. [APPLAUSE] >> WE HAVE TO HOLD QUESTIONS. IF ANYONE HAS QUESTIONS OF ZORNA OR STEVE COME DOWN AT THE LUNCH BREAK AND SAME WITH JOHN AND NEXT GROUP. BUT I THINK IT DOES SHOW THE OVERWHELMING NEED AND RESPONSE. OUR NEXT SPEAKER OR GROUP OF SPEAKERS WILL RELATE TO NPC DISEASE FOR COLLABORATIVE DEVELOPMENT FOR KNEEMAN PC, AND JOHN MCKEW WITH THE RARE DEES PROGRAM WITH N CATS, COME UP AND WE'LL GET YOU STARTED. THANK YOU, STEVE FOR INVITING THE TREND PROGRAM AND COLLABORATIVE PROJECT TEAM TO SHARE A LITTLE BIT ABOUT SOME OF THE THINGS WE DO. WHAT WE DECIDED TO DO IS GIVE YOU FIRST A ONE SLIDE UPDATE OF TREN PROGRAM RARE NEGLECTED DISEASE PROGRAMS AN HIGHLIGHT A PILOT PROJECT. SINCE IT IS A COLLABORATIVE DRUG DISCOVERY PROGRAM WE DECIDED TO MAKE THIS A COLLABORATIVE TALK AND INCLUDE SOME OF OUR COLLEAGUES FROM JOHNSON AND SON JOHNSON AS WELL AS DANNY PORTER, A CLINICIAN AT THE CLINICAL CENTER. FOR THOSE WHO DON'T KNOW ABOUT THE THERAPEUTICS RARE NEGLECTED DISEASE PROGRAM, IT'S A COLLABORATION BETWEEN NIH INTRAMURAL LABS WITHIN NCATS WITH PRE-CLINICAL DRUG DISCOVERY EXPERIENCE AND EXTRAMURAL LABS WHO BRING TO US RARE DISEASE OR NEGLECTED TROPICAL DISEASE PROJECTS AND THERAPEUTIC IDEAS AND WE WORK ON THOSE TOGETHER TO DERISK THOSE PROJECTS AND MOVE THEM FURTHER DOWN THE DRUG DISCOVERY PIPELINE. THE PROJECTS ENTER AT VARIOUS STAGES, ANY TIME AFTER I WOULD SAY HIT VALIDATION WITH A DEFINED HIT OR LEAD SERIES AND WE TAKE THEM TO THE POINT SOMEBODY ELSE IS INTERESTED OR SIGNIFICANTLY DERISKED TO FINALIZE THE CLINICAL DEVELOPMENT. WE ALSO LIKE THIS PARTNERSHIP TO DEVELOP NEW PLATFORM TECHNOLOGIES THAT WOULD BE BROADLY APPLICABLE ACROSS THE RARE OR NEGLECTED DISEASE SPACE. ELIGIBLE APPROXIMATE P PLI CAN'TS INCLUDE EVERYBODY, GOVERNMENT LABS NON-PROFITS FOUNDATIONS LARGE BIOTECH AN PHARMA. AND WE ACCEPT APPLICATIONS OUTSIDE THE US. JUST A QUICK NOTE ON INTELLECTUAL PROPERTY, PARTNERSHIPS ARE CREATIVE SO THERE MAYBE A POSSIBILITY TO GENERATE JOINLY HELL I CANP -- JOINTLY HELD IP AGREEMENTS AND WE FIND THAT COVERING THESE PROJECTS DEPENDING ON WHETHER THERE WILL BE INTELLECTUAL PROPERTY GENERATED. ONLY TWO MORE TO SAY ABOUT THIS. THE WEBSITE AT THE BOTTOM HAS THE INFORMATION ON THE TREND PROGRAM. AND WE EXPECT TO HAVE ANOTHER OPEN SOLICITATION IN THE MAY, JUNE TIME FRAME. SO IF YOU CONTINUE TO WATCH THE WEBSITE YOU'LL GET THE INFORMATION YOU NEED AND THE CONTACT INFORMATION FOR THE TREND PROGRAM WILL BE THERE. SO NOW TO SHIFT GEARS AND TALK ABOUT ONE OF THE PILOT PROJECTS WE STARTED TO WORK ON, WE'LL GIVE A QUICK EXAMPLE HOW THE PROJECT CAME TOGETHER AND WHAT ALL THE CONTRIBUTIONS OF THE COLLABORATIVE DRUG DISCOVERY PROCESS ARE. KNEEMAN P 3 DISEASE IS AN AUTOSOMAL RECESSIVE DISEASE, TWO MUTATIONS MPC-1 AND 2. IT IS A RARE DISEASE AND MANY CASES AFFECT KIDS UNDER AGE 10. IT IS ONE OF A GROUP OF LYSESOMAL STORAGE DISEASES, IN THIS CASE UNSER FID LES ROLL WILL BILL IN THE LYSESOMES IT IS FIRST SEEN IN CLINICAL MANIFESTATIONS IN THE SPLEEN AND LIVER BUT PROBLEMS COME LATER WHEN YOU GET PROGRESSIVE NEUROLOGICAL DISORDERS AFFECTING PER KINK CELLS -- PER KIN JI CELLS. SO WHAT THE PATIENTS ARE UP AGAINST IS NO APPROVED THERAPIES. THERE IS A STAT IN EUROPE APPROVED WHICH IS REPURPOSES OF THE GALSHA MOLECULE. IT'S NOT A MOLECULE TARGETED TREATMENT BUT HELPS SOME PATIENTS. HERE IS A CARTOON SHOWING CHOLESTEROL COMING TO O THE LYSESOME, MPC-1 AND 2, CHAPERONING IT TO THE THE MEMBRANE WHERE IT'S PUSHED TO THE DR AND WHEN THOSE PROTEINS ARE NON-FUNCTIONAL IT ENLARGES. YOU CAN SEE WHEN YOU COMPARE WILE TYPE FIBROBLASTS WITH PATIENT DERIVED FIBROBLASTS FROM MPC-1 AND 2 MUTATION IT IS BLUE SPOT ARE NUCLEI AND THE RED SPOTS ARE LYSESOMES WRITE SIGNIFICANTLY LARGER IN THE PATIENT BECAUSE THEY'RE STORING A HUGE AM OF CHOLESTEROL THAT THERE WOULDN'T BE WILD TYPE. OUR EARLY PROJECT STRATEGY WAS TO DEVELOP A TEAM TO PROVIDE RESOURCES NEEDED TO ADVANCE THE PROJECT. OUR VISION WAS TO SCREEN PATIENTS IN A PHENOTYPIC ASSAY. WE CHOSE OUTLINES FOR THE MOST RELEVANT SOURCE OF INFORMATION. THERE'S CHALLENGES GROWING LARGE AMOUNTS OF THESE AN DETERMINING WHICH PATIENT LINE TO USE. SO WE USED A SMALLER SCREENING SET, WE CHOSE A SCREEN OF APPROVED DRUGS AND A REPURPOSING APPROACH. SO WE'RE IN THE REPURPOSING PART OF THE DRUG DISCOVERY DEVELOPMENT PATHWAY IN LEAD DEVELOPMENT, EARLY LEAD OPTIMIZATION. SO THE REASON WE WOULD GO DOWN THIS ROAD IS TRADITIONAL HIGH THROUGH PUT SCREEN AND FOLLOW-UP ON A HIT REQUIRES A HUGE AMOUNT OF HIGH THROUGH PUT SCREENING SO YOU NEED AN ASSAY THAT'S VIABLE AS WELL AS CELLS THAT YOU CAN GROW IN A LARGE CONCENTRATION. QUITE A NUMBER OF YEARS TO DEVELOP THE HITS FROM THAT THROUGH TO SOMETHING THAT MIGHT GET INTO CLINICAL TRIALS TO VALIDATE THE MOLECULE. IF YOU START WITH APROVED DRUG, AND WORK YOU WAY BACK, YOU HAVE THE POTENTIAL TO FIND THE RIGHT MOLECULE AND IT HAS A CORRECT TOXICOLOGY PACKAGE APPROPRIATE TO USE IT NOW AND YOU'RE USING THE SAME MODE OF ADMINISTRATION, HAVE A CHANCE TO TEST THIS IDEA IN PATIENTS. SO HOW THIS STARTED IS THE TREND PROGRAM RECEIVED A GRANT FROM MPC FOUNDATION CALLED THE MEDICAL RESEARCH FOUNDATION TO PERFORM REPURPOSING SCREEN. SO WE'RE GOING TO SCREEN OUR COLLECTION OF APPROVED DRUGS AND WE ALSO AGREE TO SCREEN 60 POTENTIAL DRUGS THAT THE PATIENT COMMUNITY WAS INTERESTED IN LOOKING AT. SO WE BUILT A COLLABORATIVE TEAM THAT INCLUDED MANY OF THE FOLKS LISTED HERE, SO RESEARCHERS AT THE NIH AND LEADING ACADEMICS IN THE MPC FIELD AND WE HAD A LOT OF CONTACT WITH PATIENT ADVOCACY GROUPS, THE SORE FOUNDATION AND (INAUDIBLE) FOUNDATION. AND W EARKSI VANG DID THE ASSAY DEVELOPMENT AND SCREENING. WE STARTED WITH A GROUP OF 58 FIBROBLAST CELL LINES THAT WE CHECK FOR SUITABILITY, WE DEVELOPED A NUMBER OF ASSAY, SOME HIGH THROUGH PUT, SECONDARY ORTHOGONAL ASSAYS TO CONFIRM ACTIVITY AND WE SET ABOUT DOING A SCREEN OF REPURPOSINGING COLLECTION. I JUST WANT TO MAKE ONE NOTE THAT WE STARTED THIS IN THE 2008, 2009 TIME FRAME. IT TOOK QUITE A WHILE TO RUN THIS ASSAY. WE USED A NUMBER OF DIFFERENT CELL LINES ACROSS THE COLLECTION. IT WAS A CHALLENGING ASSAY TO RUN. WE HAVE HAD A NUMBER OF MOLECULES THAT DID NOT AT ALL IMPACT THE AMOUNT OF CHOLESTEROL IN THE LYSESOME, SOME DECREASED WHICH IS WHAT WE WERE LOOKING FOR AND OTHERS THAT INCREASED IT. WE FOLLOWED UP ON A NUMBER OF MOLECULES ALONG THE WAY, VERY INTERESTING ONES WE FOUND BUT ONE THAT DID COME UP WAS BETA CYCLE DEX TRIN, A MOLECULE KNOWN TO COMPLEX1+g CHOLESTEROL AND WAS IN THE LITERATURE HAVING THE ABILITY TO TRANSPORT CHOLESTEROL OUT OF CELLS. SO A QUICK SNAP SHOT OF ALLY SEW TRACKER. SO YOU CAN SEE VISUALLY THE SAME EFFECT THAT I SHOWED YOU PATIENT AND WILD TYPE CELLS. NUCLEAR STAINING, THE LYSOSOME SETS THAT WE TRY TO ACHIEVE. MPC-1 PATIENT CELLS ARE ON THE BOTTOM LEFT. AS YOU GO ACROSS IN A DOSE DEPENDENT FASHION YOU SEE DECREASE IN THE SIZE OF LYSOSOMES DEPENDING ON THE AMOUNT OF BETA CYCLE DEXTRIN THAT YOU ADD. SO T IT'S A WEAK INHIBITOR AND WE HAD TO LOOK CLOSE TO FIND IT. THERE WAS A SIGNIFICANT AMOUNT OF INTEREST GROWING IN THE COMMUNITY ABOUT THIS MOLECULE. IN EARLY 2009 ONE COLLABORATOR STEVE WALKLEY PUBLISHED THIS STUDY IN KNOCK-OUT -- MPC-1 KNOCKOUT MICE WHICH SHOWS SIMPLY HERE IS SURVIVAL PLOT FOR UNTREATED MPC-1 KNOCK-OUT MICE. IF YOU LOOK AT MPC-1 KNOCKOUT MICE IT'S PURPLE LINE SO THAT COMES DOWN HERE. SO VERY SIGNIFICANT INCREASE IN SURVIVAL TIME FOR MICE. OTHER COMBINATIONS WERE TRIED INCLUDING THINGS THAT MIGLASTAT IN THE LITERATURE AT THE TIME BUT REALLY, THIS ACT OF CYCLE DEXTRIN ALONE CAUSED EXCITEMENT IN THE FIELD. I THINK IT'S INDICATIVE OF THE PATIENT GROUPS RIGHT NOW AND THE PERSISTENCE OF THE LITERATURE THAT THIS ONE INDIVIDUAL MOTHER OF PATIENTS SAW THIS INFORMATION PUBLISHED AND SHE WENT AND WORKED TO ASK THE FDA FOR PERMISSION TO TEST IN KIDS AND DO IV ADMINISTRATION FOR BETA CYCLE DEXTRIN TO HER KIDS. YOU SEE THAT IN SEPTEMBER OF 2009 SO THE SAME YEAR THE PAPER WAS PUBLISHED THOSE GIRLS WERE BEING GIVEN IV CYCLE DEXTRIN, BY AUGUST 2010, PERMISSION TO DO INTRAFECAL ADMINISTRATION STRAIGHT TO THE THE CNS OF THESE FOLKS. SO WHEN THE TREND PROGRAM WAS TRYING TO DECIDE WHICH MOLECULE WE WERE ACTIVELY EXPLORING IN AND IN VITRO ASSAY, WE REACHED OUT TO THE FOUNDATION, THE SORE FOUNDATION PRIMARILY AND TRY TO GET A SENSE WHAT WHAT WERE THEY LIKE? WOULD THEY LIKE TO BETTER UNDERSTAND BENEFITS AN RISING OF BETA CYCLE DEXTRIN OR CONTINUE TO EXPLORE OTHER MOLECULES WE KNOW LESS ABOUT, MIGHT TAKE LONGER TO GET INTO A CLINICAL TRIAL? AND THE ANSWER WAS PRETTY RESOUNDING LET'S LOOK AT BETA CYCLE DEXTRIN TO ANSWER THE QUESTION FOR THE REST OF THE PATIENTS WITHOUT AN INDIVIDUAL TREATMENT IND SO WE BUILT A BIGGER TEAM THAT WOULD ALLOW US TO GO INTO THE CLINIC WITH THIS EXPERIMENT. THIS IS JUST A LIST OF SOME. I WANT TO HIGH LIZ OT,ENGER, SHE GLUED THIS TOGETHER. YOU'LL BE HEARING FROM J AN J IN A LITTLE BIT ABOUT THEIR CONTRIBUTIONS AS WELL AS TO DENNY PORTER. FROM NICHD, THE CLINICIAN THAT WE'RE WORKING WITH. SO OUR GOALS REALLY WERE TO USE THE COLLABORATIVE RESOURCES OF THIS BROAD GROUP OF RESEARCHERS WE'RE WORKING WITH. SODANY PORTER HAD AN ON GOING NATURAL HISTORY TRIAL, DEVELOPED BIOMARKERS AND A PATIENT GROUP TO EXPLORE THE USE OF THE THERAPEUTIC IN A CONTROL TRIAL. DAN ORI DEVELOPED AND WOULD PROVIDE BIOANALYTICAL SUPPORT FOR BETA CYCLE DEXTRIN AN JOHNSON AND JOHNSON HAS YEARS OF EXPERIENCE USING CYCLE DEXTRIN AS EXCIPIENT, SO IT'S NOT AN APPROVED DRUG BUT IT IS AN EXCIPIENT APPROVED FOR USE IN HUMANS. SO THERE'S A DISTINCTION BUT THAT'S THE DISTINCTION THAT ALLOWED THIS INTO THE CLINIC QUICKLY. WHAT WE WANTED IN PHASE 1 CLINICAL TRIAL AND DETERMINE A SAFE EFFICACIOUS DOSE OF BETA CYCLE DEXTRIN, WE WANTED TO KNOW PHARMACOKINETICS AND ALSO WANTED TO DEFINE BIOMARKERS TO USE TO IN THE LEAST TO WHERE WE'RE GETTING TO THE TARGET AND ABLE TO MOBILIZE CHOLESTEROL. THAT WAS OUR GOAL. SO IN ORDER TO WORK BACKWARD FROM THIS GOAL, WE HAD TO BUILT AN ENTIRE PRE-CLINICAL DEVELOPMENT PROGRAM ON EXISTING DATA WHERE IS WHERE WE WANT TO GO. SO AT THIS I'M GOING TO STOP AND TURN OVER TO STEVE AN MARK CATO TALK AB JOHNSON AND JOHNSON CONTRIBUTIONS TO THE PROJECT TEAM. [APPLAUSE]: >> GOOD MORNING, EVERYONE. HOPE YOU CAN HEAR ME. FIRST I WANT TO LET EVERYBODY KNOW HOW PROUD I AM TO BE REPRESENTING JOHNSON AND JOHNSON AND JANSON RESEARCH AND DEVELOPMENT AT THIS WONDERFUL CONFERENCE WHICH BRINGS TOGETHER SO MANY RESEARCHERS AN DEMONSTRATES THE TREMENDOUS PROGRESS BEING MADE IN THE TREATMENT OF RARE GENETIC DISEASES. I WANT TO THANK JOHN AND LATER HEARING FROM DENY AND MY COLLEAGUES MARKok KAO, A FANTASTIC PRE-CLINICAL PHARMACO CI NET CYST AND PHARMACOLOGIST AS WELL AS MARK BRUISER IN BELGIUM WHO KNOWS MORE ABOUT THE PHARMACEUTICAL CHEMISTRY OF CYCLE DEXTRIN THAN ANYONE IN THE WORLD AND THESE TWO FOLKS HAVE DONE HEAVY LIFTING CONCERNING OUR CONTRIBUTION TO THIS PROGRAM. YOU'LL HEAR LATER FROM MARK. ALSO ACKNOWLEDGE ALEENA SCOTT WHO HELPED WITH THE DIFFICULT REGULATORY HURDLES WE HAD THE TO OVERCOME. I WANT TO START OFF BY SAYING TO ALL OF THE WORK WE HAVE DONE FOR THIS PROGRAM, AS WELL AS SOME OF THE OTHER DEVELOPMENT PROGRAMS THAT YOU'LL HEAR ABOUT LATER ARE PHILANTHROPIC. JOHNSON AND JOHNSON HAS NO COMMERCIAL INTEREST IN THIS PROGRAM OR ANY PROGRAMS I'LL TALK ABOUT. HAVING SAID THAT SHOULD -- WE'RE FOR GNAT ENOUGH TO SEE CYCLE DEXTRIN PROVEN SAFE AND EFFICACIOUS, AT SOME POINT IN THE FUTURE HOPEFULLY WE'LL SEE A SPONSOR AND POTENTIALLY JOHNSON AN JOHNSON REGISTER THIS PRODUCT. IF WE DO SO WE HAVE NO COMMERCIAL INTEREST AND IT WOULD BE ENTIRELY FILL PHILANTHROPIC. WHY ARE WE HERE? TO TALK ABOUT PATIENTS WITH MPC, I WANT TO SAY EVERYONE HAS GIVEN PERMISSION TO SHOW PICTURES AND TALK AB THEM. JOHN MENTIONED PATTY AND CASSIDY, TWINS WITH MPC AND THEIR MOTHER IS HERE TODAY. AND I WANT TO SAY HELLO TO HER WHEREVER SHE MAY BE. HI, CHRIS. AND THE STORY BEHIND OUR INVOLVEMENT IS QUITE UNUSUAL. ABOUT THREE YEARS AGO I THINK IT WAS, CHRIS, CHRIS CALLED JAY AND J, SHE HAD DONE TREMENDOUS WORK AS JOHN INDICATED INTO POTENTIAL THERAPIES FOR HER TWINS WHO WERE FOLLOWING THE TYPICAL CLINICAL COURSE FOR NPC AN SUFFERING NEUROLOGICAL DEGENERATION AND SHE DISCOVERED NO APPROVED TREATMENT. SHE ALSO FOUND OUT THAT CYCLE DEXTRIN WAS AN EXCIPIENT IN A PRODUCT CALLED INTRACONASOL. AND THE REMARKABLE AND POTENTIALLY CONVERGENCE OF EVENS THAT RESULTED IN THIS IS APPROXIMATELY 25 YEARS AGO AS DRUG DEVELOPERS WERE TRYING TO FIND AN SOLUBLIZER TO COMPARE AN INTRAVENOUS FORMULATION TO TREAT SYSTEMIC FUNGAL INFECTIONS THEY CAME ACROSS CYCLE DEXT RIRKSN AND IT WORKED. SO NOW WE HAVE THE INTRAVENOUS PRODUCT. THE AMOUNT REQUIRED TO SOLUBLIZE INTRACONOSOL IS SO GREAT WE DID A COMPLETE PRE-CLINICAL PROGRAM AS WELL AS PHARMACOKINETICS AN TOX COLOGIC WORK THAT HAS TO BE DONE BEFORE YOU GO INTO MAN. SO WE HAD A VERY EXTINSIVE DRUG MASTER FILE, DMF DEVELOPED 25 YEARS AGO. SO CHRIS CALLED JOHNSON AND JOHNSON, SHE HAD A LITTLE TROUBLE PENETRATING THE HIERARCHY, I HAD A GROUP CALLED ESTABLISH PRODUCTS WITH ABOUT 80, 20th CENTURY MOLECULES, SMALL MOLECULES WE CONTINUE TO SUPPLY AROUND THE WORLD, VERY COST EFFECTIVELY TREATING MEDICAL DISEASES GLOBALLY. AND ONE IS INTRACONOSOL. THROUGH THE CHAIN I CALL CHRIS ONE SATURDAY MORNING AND SHE DESCRIBED HER CONUNDRUM THAT SHE HAD A MEETING WITH FDA THAT WEEK AND WITHOUT SAFETY DATA WAS PROBABLY NOT GOING TO HAVE HER IND. DR. HASTINGS WAS THE PRINCIPLE INVESTIGATOR WAS NOT GOING TO HAVE THE COMPASSIONATE USE IDN APPROVED WITHOUT SAFETY DATA. SO WE ASSEMBLED A GROUP OF PEOPLE AND CONVEYED TO THE FDA PERMISSION TO USE THE DMF THAT RESULTED IN THE IND APPROVED AND TREATMENT OF THE TWIBS. LATER WE DISCOVERED THAT THE NIH PERFORMED A STUDY JOHN DESCRIBED AND DENY WILL GO INTO FURTHER. WE WERE ABLE TO DO THE SAME THING FOR THE NIH AS WE WERE FOR CHRIS. I BELIEVE THAT THE EXISTENCE OF OUR WORK MANY YEARS AGO IN CREATING A DNF ALLOWED THIS PROGRAM TO ACCELERATE. WITHOUT THAT SAFETY DATA THERE -- A LOT OF YEARS WOULD HAVE BEEN SPENT, MONEY SPENT TO DEVELOP THE SAFETY DATA REQUIRED TO GO INTO MAN.zv'Ť JOHNSON AND JOHNSON IS COMMITTED TO A NUMBER OF THINGS THE PREVIOUS SPEAKERS, DR. CROFT AND COLLINS HAVE SPOKEN ABOUT IN TERMS OF COLLABORATION WITH WITH INDUSTRY, WITH GOVERNMENT ORGANIZATION SUCH AS NIH, FDA, OTHER FUNDERS TO FOSTER THESE KINDS OF COLLABORATIONS THAT ADVANCE WORK IN RARE DISEASES AS WELL AS NE GECTED -- NEGLECTED DISEASES. AS HE AS WELL AS THIS OLD PORTFOLIO OF DRUGS WE MANAGE THERE'S MOLECULES TO BE REPURPOSED AS HAPPENED WITH CYCLE DEXTRIN. FINALLY WE MADE A SUBSTANCE PHILANTHROPIC CONTRIBUTION TO MANY -- MUCH OF THE GLOBAL WORK GOING ON TO FIND CURES FOR TROPICAL DISEASES WHICH AFFECT LITERALLY MILLIONS OF PEOPLE AROUND THE WORLD: CONSISTENT WITH OUR CREDO WHICH SAYS OUR RESPONSIBILITY IS TO DOCTORS NURSES AN PATIENTS AND WE ARE RESPONSIBLE FOR THE COMMUNITIES WHICH WE LIVE AND WORK SO WE'RE VERY HAPPY WE CAN PARTICIPATE IN THIS EFFORT. THERE ARE A NUMBER OF J AND J COLLABORATIONS RIGHT NOW WITH GOVERNMENT INSTITUTIONS, WE HEARD ABOUT NPC. WE'RE ALSO INVOLVED IN EFFORTS TO DEAL WITH POTENTIAL BIOTERRORISM ATTACKS, WE HAVE GOTTEN APPROVAL FOR ANTHRAX WHICH IS APPROVED AND WE SUBMITTED TO THE FDA A DOSSIER THAT WILL -- NDA TO SUPPORT THE USE OF LEVA FLOXOCIN IN THE TREATMENT OF PLAGUE. UNFORTUNATE ENOUGH TO SUFFER SUCH AN EVENT. ALL THESE EVANS ARE ENTIRELY PHILANTHROPIC. IN ADDITION WE VERY MUCH OVER THE LAST FEW YEARS INVESTED IN WORKING WITH A NUMBER OF ORGANIZATIONS INCLUDING CHILDREN WITHOUT WARRANTS PROGRAM TO DONATE MILLIONS OF DOSES OF ANOTHER DRUG, ANOTHER OLD PRODUCT, MABENDOSOL FOR SOIL BORN DISEASES AND MOST RECENTLY AND MOST SIGNIFICANTLY, WORKING WITH THE GATES FOUNDATION, OTHER GOVERNMENTAL ORGANIZATIONS AROUND THE WORLD AND FUNDERS TO DEVELOP FLU BENDAZOL, ANOTHER ANTI-(INAUDIBLE) DRUG FOR THE TREATMENT OF FILLORIAL DISEASE WHICH COULD CURE THE SCORNLG WHICH AFFECTS APPROXIMATELY 300 MILLION PATIENTS, THE ENTIRE POPULATION OF THE UNITED STATES WITH A NUMBER OF CLINICAL MANIFESTATIONS OF THIS TERRIBLE WORM INFESTATION. WITH THAT, THANK YOU FOR YOUR ATTENTION AND I WOULD LIKE THE TURN THE MICROPHONE OVER TO DR. MARK KAO WHO WILL GO INTO DETAILS AB THE RESEARCH WE HAVE DONE ON BEHALF OF PATIENTS AND THE VARIOUS CLINICAL PROGRAMS ONGOING IN CYCLE DEXTRIN FOR NPC. MARK, THANK YOU VERY MUCH. TAKE IT AWAY. [APPLAUSE] >> CAN YOU HEAR ME? GOOD MORNING, EVERYBODY. THIS IS CYCLE DEXTRIN, THIS IS RING SHAPED SUGAR BASED MOLECULE, QUITE LARGE THAT CONTAINS ABOUT 6 TO 8 SUGARS AND IS IMPORTANT PART OF THE PROPERTIES OF THESE COMPOUNDS. THE DEGREE OF -- AND ALSO THE TYPE THE TYPE MAKE THE PRODUCT DIFFERENT IN DIFFERENT CYCLE DEXTRIN. WE HAVE BEEN WORKING ON THIS FOR YEARS AN THIS IS THE ONE WE COME UP WITH THAT WORKS THE BEST. TO DELIVER THE DRUG SYSTEMICALLY FOR THOSE PARTICULAR HYDROPHOBIC COMPOUNDS. AND HAPPENS TO BE THIS -- WE HAVE EXTENSIVE SAFETY DATA AND HUMAN EXPERIENCES. JUST IMAGINE THIS IS A POCKET OR A RING YOU CAN FIT COMPOUNDS, CHOLESTEROL. WE HAVE NEVER USED THIS COMPOUND FOR ANY PHARMACEUTICAL PURPOSES BUT POTENTIAL TO DO A LOT OF GOOD THINGS, COULD TRAP CHOLESTEROL AND MOVE CLES RAL OUT OF SYSTEMIC AND INTRACELLULAR COMPARTMENTS AND THEREFORE RELIEVE SOME SYMPTOMS. (INDISCERNIBLE) INTRAVENOUSLY. IN OUR CLINICAL STUDY WE REALLY RARELY SEE ANY TYPE OF PROBLEMS, ISSUES, IT HAS POTENTIAL TO BE RENAL TOXIC BUT WE HAVE NOT SEEN THAT IN HUMAN TRIALS. PARTICULARLY WITH CASEY'S TRIAL, 25-MILLIGRAM PER KILOGRAM A DAY AND DIDN'T SHOW ANY TYPE OF RENAL TOXICITY. SO STEVE TALK ABOUT HOW WE GET INVOLVED, TALKING WITH CHRIS HIMPLE AND TEAMS TO WORK ON THE IND. BECAUSE OF OUR EXPERIENCE WITH WITH CYCLE DEXTRIN WE HAVE A LOT OF TOXICOLOGY, SAFETY DATA. PHARMACOKINETIC INFORMATION, WE HAVE TROUBLE MANUFACTURING PROCESSING INFORMATION SO WE GIVE THEM ALL THE INFORMATION. WITH THAT INFORMATION I BELIEVE FDA WAS COMFORTABLE FOR THE IND TO MOVE FORWARD. THAT WAS THE FIRST STEP WE WERE ABLE TO HELP THEM W. THE IV TRIAL WE HELP THE HIMPLE TEAM TO DO BIOANALYSIS. WE HAVE INTERNAL METHOD DEVELOPED SO WE CAN ANALYZE THE CONCENTRATION OF CYCLE DEXTRIN IN THE PLASMA. SO WEoT DETERMINE THE CARM COCAINE TICK PROPERTIES -- O WE DETERMINE THE PHARMACOKINETIC PROPERTIES. WE SHOW THE HALF LIFE OF IT IS REALLY SHORT. SO THERE'S CONTINUED DISCUSSION HOW TO IMPROVE THE HALF LIFE OF THE COMPOUND AND THREE DIFFERENT DELIVERY ROUTES TO THE PATIENTS. ALSO WE HELP THE HIMPLE TEAM TO GO THROUGH THIS IT TRIAL AND IN PARTICULAR THE USE OF DELIVERY PUMP. WE WORK WITH MEDTRO ONIC WITH THE DEVICE AN PERFORM THE TEST FOR THEIR PUMP. AND THE PURPOSE WAS TO UNDERSTAND THE STABILITY AND EXTRACT ANY KIND OF MATERIAL OUT OF THE PUMP COMPONENTS. THIS STUDY IS DONE AND WE WERE ABLE TO DEMONSTRATE THAT THE CYCLE DEXTRIN AND WE SHOULD BE ABLE FOR THE TEAM TO MOVE FORWARD WITH THE IT TRIAL. WE ALSO COMMITTED TO DETERMINE THE CYCLE DEXTRIN CONCENTRATION IN CSF, ONCE THE STUDY IS INITIATED. WE ALSO TRY TO PROVIDE THE HIMPLE TEAM WITH THE DRUG SUBSTANCE IN FORMULATION. BECAUSE OF THE TRIAL WITH THE CASE, HALF LIFE ISSUES NEVER RESOLVED IN PRE-CLINICAL STUDIES. WE TALK TO RESEARCHERS IN THE FIELD AND TRY TO UNDERSTAND BETTER IN TERMS OF HOW IT WORKS. FINALLY THE CAT MODEL THAT WE KNOW INTRAFECAL IS DELIVERED CYCLE DEXTRIN INCREASES THE LIFE OF NPC CATS AN DECREASE THE NEUROLOGIC DEGRADATION OF THE CATS. SO WE THINK (INAUDIBLE) DELIVER INTRAFECALLY, HOW LONG DOES IT STAY THERE AND WHERE DID IT GO? SO ONE THING THAT WE DID WAS THE -- WE CONDUCTED A C-14 STUDY IN THE CAT AND TRY TO UNDERSTAND WHERE THE -- THEY COME IN GO, WHICH COMPARTMENT OF THE BRAIN. FORTUNATELY IN THE FIRST STUDY WE UNDERSTAND THE HALF LIFE WAS SHORT IN THE CSF SO WE ONLY CONDUCT THE STUDY IN FOUR HOURS. AT FOUR HOURS AFTER TREATMENT THE CONCENTRATIONS GO HIGH IN THE BRAIN AND WE DON'T KNOW WHEN IT WILL DECREASE SO WE'LL DECREASE THE SECOND STUDY. SO WE CAN DO A LONGER TRIAL TO UNDERSTAND HOW LONG CYCLE DEXTRIN STAY IN THE BRAIN AT WHAT CONCENTRATION. WE ALSO BECAUSE OF THE LIMIT OF THE BIOLOGICAL METHOD AVAILABLE TODAY WE WORK WITH WASHINGTON UNIVERSITY TO DERIVE A NEW METHOD, HOPE WE CAN HAVE A 10 TO 100 FOAL MORE SENSITIVITY TO ANALYZE SAMPLES IN DIFFERENT BIOLOGICAL MATRICES. THEN WE GOT A CHANCE WORK WITH NIH, AND WE WORK WITH VARIOUS INSTITUTIONS AND PROVIDE ALSO THE DRUGS MASTER FILE AND WE ARE CURRENTLY WORKING ON THIS IN USE TEST FOR MY RESERVOIR AND HOPEFULLY WE'LL HAVE SUCCESS WITH WITH THE STUDY SO MAKE MOVE FORWARD WITH THE CLINICAL TRIAL. WE ALSO DO LUNG CANCER SUPPORT AN CONSULTATION IN PARTICULAR, WE JOIN THE IND MEETING, PRE-IND MEETING WITH TREND. WE DEVELOP A PATH, ONE STUDY IS AN ICV TOXICOLOGY STUDY PROGRAM, WE ALSO ARE HELPING TRYING TO FINISH A STUDY, ORIGINALLY A PHARMACOLOGY STUDY NOW HELPING TO CONVERT INTO A TOXICOLOGY STUDY REPORT. SO IT'S THOSE AND OTHER FARM MOW KINETIC -- PHARMAKINETIC DATA THAT WE WILL MOVE THE PILOT FORWARD. WE WILL DO BIOCHEMICAL WORK IN THE CLINICAL SETTINGS. WE CAN -- WE WORK WITH WASHINGTON UNIVERSITY TO DEVELOP METHOD, THEN WE CAN DO VARIOUS DIFFERENCE TYPE OF WORK TO MAKE THE METHOD WORK, THEN WE WILL VALUE DATE A METH AND DO ANALYSIS AND HOPEFULLY HAVE METHODS TO DO CLINICAL AND NON-CLINICAL PROGRAM. SO THAT IS IT. THANK YOU VERY MUCH. [APPLAUSE] >> SO I THINK ONE COMMON THING FOR EVERYBODY IN THIS ROOM, WE'RE INTERESTED IN DEVELOPING THERAPIES FOR OUR PARTICULAR RARE DISEASE. WE ALL PROBABLY START WITH A LIST, THERAPEUTIC TRIAL ISSUES BUT I ALSO WANT WHILE I GO THROUGH THIS TALK THE WORK DOESN'T START WITH THE MOLECULE. YOU HAVE TO START THE WORK PRIOR THE THAT. SOME ITEMS ARE COMMON TO ALL THE DISEASES. RARE DISEASES BY DEFINITION IS WHAT WE'RE HERE ABOUT TODAY BUT SOME ARE SPECIFIC. IN AN MPC WE HAVE A HETEROGENEOUS PHENOTYPE NOT UNIQUE TO N PBC, VARIABLE AGE ONSET AND SYMPTOM COMPLEX. IT MAKES THINKING ABOUT ONE SOME TOM TO FOCUS ON AS THE TREATABLE CLINICAL SYMPTOM DIFFICULT. CLINICAL PROGRESSION OCCURS OVER YEARS. SO A CLINICAL TRIAL FOCUSED ON A CLINICAL OUTCOME MEASURE REQUIRES A LARGE INVESTMENT OF TIME. IN NPC WE'RE PROBABLY NOT GOING TO REVERSE NEUROLOGICAL PROBLEMS THAT HAVE OCCURRED. SO OUR GOAL IS STABILIZATION OR DELAY OF NEUROLOGICAL DISEASE. THE OPTIMAL TIME TO TREAT PATIENTS IS ACTUALLY PRIOR -- PROBABLY PRIOR TO THE ONSET OF NEUROLOGICAL SIGNS AN SYMPTOMS. GIVEN PATHOLOGY OF THIS DISEASE BY THE TIME YOU HAVE NEUROLOGICAL SIGNS AND SYMPTOMS, YOU PROBABLY HAVE A LARGE DEGREE OF NEURONAL DEATH THAT'S ALREADY OCCURRED. FINALLY, A MAJOR COMPLICATION WHEN WE THINK ABOUT THE CLINICAL TRIAL FOR NPC IS THERE'S LACK OF DEFINED ACCEPTED OUTCOME MEASURES. IT WAS THIS LATER PROBLEM THAT WE STARTED TO WORK ON PROBABLY ABOUT FIVE OR SIX YEARS AGO. WE STARTED BY SETTING UP LONGITUDINAL NATURAL HISTORY STUDY. I THINK OF THE NATURAL HISTORY STUDIES AREN'T THE MOST ATTRACTIVE SCIENCE, AREN'T THE MOST SEXY PART OF DEVELOPING A DRUG BUT THEY LAY THE GROUND WORK FOR THERAPEUTIC TRIAL. THE GOALS OF STUDY WERE TO IDENTIFY BIOCHEMICAL MARKERS USED IN FUTURE THERAPEUTIC TRIAL. WE WANTED TO QUANTIFY DISEASE PROGRESSION IN MPC-1. WE WANTED TO CORRELATE BIOMARKERS WITH DISEASE STATUS. WE WANTED THE IDENTIFY CLINICAL OUTCOME MEASURE TO EVALUATE THERAPEUTIC EFFICACY IN A LONG TERM TRIAL. A SECOND GOAL WAS ALSO TO IDENTIFY A BIOCHEMICAL MARKER USED FOR DIAGNOSTIC TESTING AND SCREENING. AND THE REASON FOR THAT IS THISp DIAGNOSTIC DLAIRKS PROBABLY MANY PARENTS IN THE ROOM ARE TOO FAMILIAR WITH THIS. IN OUR COHORT OF PATIENTS IT'S FOUR TO FIVE YEARS, FROM THE TIME OF FIRST SYMPTOM THE DIAGNOSIS BEING MADE. WE SAW THAT REYIT RAYTIVE PROCESS EVERYBODY HATES EARLIER ON. IN NPC A CONTRIBUTOR TO THIS IS DIAGNOSIS IS DIFFICULT TO MAKE. THERE WAS NO BLOOD BASED TO TEST TO MAKE THE DIAGNOSIS. YOU HAD TO DO A SKIN BIOPSY WITH SPECIALIZED TESTING. ONLY A COUPLE OF LABS IN THE U.S. THAT PERFORM THE TESTING. SINCE THAT TIME WE ENROLLED 65 PATIENTS. YOU CAN SEE THE DEMOGRAPHICS HERE. AND JUST WANT TO POINT OUT A NUMBER OF ISSUES. WE TRIED TO COME UP WITH A SCORE RATING THAT ENCOMPASS THE HETEROGENEOUS SYMPTOMS THAT WE SEE IN PATIENTS. THIS IS ONE EXAMPLE. WE USED THE LIKE EETART SCALE. THIS IS ONE DOMAIN, WE HAVE NINE AND MINOR DOMAINS THRK MAJOR DOMAIN IS A FINE MOTOR SKILL AND YOU CAN SEE PROGRESS UP WITH A HIGHER SCORE AS YOU INCREASE IN PARAMOUNT. ONE THING I WANTED TO BRING UP ABOUT DEVELOPING A SCALE LIKE THIS, WE'RE APPLYING IT TO THESE PATIENTS BUT THIS STUDY STARTED IN 2005 SO THE LONG -- 2006, SO THE LONGEST PATIENTS HAVE ONLY BEEN WITH US FIVE YEARS. THIS DISEASE PROGRESSES OVER DECADES. NPC WAS STUDIED BY A GROUP OF INVESTIGATORS AT THE NIH AND NINDS. STARTING IN THE EARLY '90s. WE WERE ABLE TO GO BACK, POOL THE RECORDS AN APPLY TO THE MEDICAL RECORDS. SO THOSE MEDICAL RECORDS THAT EXIST HAVE INFORMATION THAT GIVE HISTORICAL NATURAL HISTORY DATA. WE HAVE WORKED WITH NOTRE DAME IN A CLASS AND WE TAUGHT STUDENTS TO GO THROUGH THE RECORDS AND AS CERTAIN THE DATA FOR US. FOR THE REST OF THE TALK I WANT TO FOCUS ON THE IDEA OF BIOMARKERS. THE CLASS CALL WAY OF THINKING BIOMARKERS ARE AS SURROGATES FOR CLINICAL EFFECTS. TO LOOK AT BIOMARKER AND HAVE A SURROGATE FOR A CLINICAL END POINT. BUT IT IS A LONG PROCESS TO VALIDATE BIOMARKERS AS A SURROGATE. SO IN A LOT OF WAYS I LOOK AT BIOMARKERS IN THE RARE DISEASES TO BE A POTENTIAL TOOL. AND YOU HAVE THE CASES OF -- YOU CAN HAVE A GREAT BIOMARKER BUT -- AND THERAPEUTIC EFFECT AFFECTS IT BUT THERE'S NO CLINICAL EFFECT OR THAT YOUR BIOMARKER -- YOU HAVE A GOOD THERAPEUTIC INTERVENTION BUT THE BIOMARKER ISN'T GOOD. IT IS A LONG PROCESS TO VALIDATE. ANOTHER WAY TO THINK ABOUT THE BIOMARKERS AS TOOLS TO HELP TRY TO GUIDE RATIONAL DEVELOPMENT OF THERAPEUTIC INTERVENTIONCH THIS IS BORNT BECAUSE WE DOPE HAVE PATIENTS. SO WE HAVE TO EXTRACT AS MUCH INFORMATION OUT OF EACH EXPERIMENT THAT WE DO IN PATIENTS. TO KNOW IF WE'RE ON THE RIGHT TRACK OR NOT. WE HAVE VARIOUS PATHOLOGICAL PROCESSES. CAN WE GET BIOMARKERS THAT LET US INFER THE STATE OF THE PATHOLOGICAL PROCESSES. LET ME GIVE EXAMPLES OF A NUMBER OF BIOMARKERS OVER THE LAST FEW YEARS. ONE HAS TO DO WITH OXY STERILES. THERE'S OCCASION PRODUCTS OF CHOLESTEROL AND YOU HEARD EARLIER CLOAS ROLL ACCUMULATES IN MPC. WE BELIEVE IN NPC WHAT WE HAVE IS A SITUATION WHERE THE OXI STERILES REFLECT COMBINATION OF INCREASED OXIDATIVE STRESS, A GENERAL PATHOLOGICAL MECHANISM PRESENT IN MANY DISORDERS WITH THE UNIQUE PATHOLOGICAL MECHANISM OF INTRACELLULAR ACCUMULATION OF UNSER FID CHOLESTEROL. THIS IS A -- SHOWS THAT THERE'S INCREASE OXIDATIVE STRESS OR LESS OX -- ANTIOXIDANT CAPACITY IN NPC 1 PATIENTS COMPARED TO AGE MATCH PATIENTS. FIBER BLASTS FROM NPC 1 PATIENT ACCUMULATING THIS CHOLESTEROL. SO IT'S THE COMBINATION OF THIS DISEASE SPECIFIC AN DISEASE NON-SPECIFIC PAJ LOGICAL PROCESS -- PATHOLOGICAL PROCESS AND GIVES RISE INTO CREASED OXIDATION PRODUCTS. WE FOUND THAT WAS THE CASE. I'M SHOWING THE HUMAN DATA BUT WE HAVE SIMILAR DATA FROM THE MOUSE MODEL. WE FOCUSED ON TWO PLASMA OXYSTEROLS, THREE BETA 5 ALPHA, 6 BETA CHOLESTEROL TRIAL, SO I JUST CALL IT TRIAL. AND 7 KITO CHOLESTEROL. WHAT YOU CAN SEE IS HERE FOR THE TRIAL, HERE IS FOR THE 77 KETO O CHOLESTEROL, THERE'S MARKEDLY INCREASED LEVELS IN THE MPC-1 PATIENTS COMPARED TO AGE MATCHED CONTROLS. YOU ALSO NOTE THE HETEROZYGOTES PRIMARILY OUR PARENTS, HAVE A SLIGHTLY INCREASED LEVEL OF STEROLS. HOW CAN YOU USE THAT? TRYING TO GET AROUND THE LONG DIAGNOSTIC DELAY. WE FELT IF WE HAD AN EASIER BLOOD BASED THE TEST TO DIAGNOSE OR SCREEN FOR NPC WE CAN CUT INTO THE DIAGNOSTIC DELAY. THIS SHOWS DATA WE PUBLISHED IN COLLABORATION WITH DAN ORI, WASHINGTON UNIVERSITY. FIRST THE ELEVATIONS INOXI STEROLS IS RELATIVELY SPECIFIC FOR NPC COMPARED TO OTHER LYSOSOMAL STORAGE DISEASE. THIS IS ONE OF FEW PLACES, I WORK IN THE CLINICAL CENTER TO WALK AROUND THE HALL AND GATHER SERUM OR PLASMA SAMPLE FROM INDIVIDUALS WITH THESE RARE DISEASES BUT IT UNDERSCORES THE UTILITY OF CREATING THOSE BIOREPOSITORIES FOR THESE RARE DISEASES SO THAT PEOPLE CAN ACCESS THEM FOR QUESTIONS OTHER THAN WHAT'S THE INITIAL QUESTION WAS FOR. SO IT APPEARS SPECIFIC FOR NPC, AN APPEARS SENSITIVE WITH REGARDS TO DISTINGUISHING NPC PATIENTS FROM CONTROLS. THIS IS THE ROS OR O RECEIVER OPERATOR CURVE. ON THE ORDER OF 97% AN SPECIFICITY WAS 100% COMPARED TO CONTROLS. ANOTHER GROUP ARE CEREBRAL SPINAL FLUID PROTEIN. THIS IS A NEUROLOGICAL DISEASE SO WE FELT WE COULDN'T JUST LOOK IN THE BLOOD. WE ALSO NEEDED TO LOOK AS CLOSE TO THE BRAIN AS WE COULD GET P. AND THAT WAS CEREBRAL SPINAL FLUID AND THE GOAL WAS TO GAIN INSIGHTS INTO PATHOLOGY AND GET TOOLS OR BIOMARKERS TO GUIDE THERAPEUTIC TRIALS. AND A COUPLE OF EXAMPLES. ONE IS CALBENDIN D, A MARKER OF CEREBELLAR PER KING GERKS, THE SECOND IS A PROTEIN FATTY ACID OR FAB-3. IT'S PROBABLY A MARKER OF NEURONAL DAMAGE BUT I SHOULD REMARK THAT STHFS HYPOTHESIS -- THIS Žc$ HYPOTHESIS DRIVEN ONE. WE HYPOTHESIZED CALBENDIN D WAS INCREASED DUE TO KNOWN PATHOLOGY OF THE DISEASE. THIS WAS DUE TO A PROTEIN WE PICKED UP ON PROTEOMIC STUDY OF MOUSE CEREBELLUM. THE BASIC SCIENCE WORK CAN LAY SIGNIFICANT GROUND WORK FOR THESE CLINICAL TRIALS. CALBENDID, D, THESE ARE SAJ TALL SECTIONS THROUGH THE MOUSE CEREBELLUM AND THE RED IS A STAIN FOR CALBENDIN D THAT STAINS THE PURKINGE CELLS WITH THEIR PROCESSES. THIS IS A CONTROL ANIMAL AND MPC-1 AB MALL AND THE PURRKINGE CELLS BECAME DYSFUNCTIONAL OR WERE LOST THEY COULD PROTECT POTENTIALLY SPILL OUT CALBENDIN D INTO THE CEREBRAL SPINAL FLUID. THESE ARE CFSs FROM AGE MATCHED CONTROLS AND YOU CAN SEE VERY LOW LEVELS OF CALBENDIN D COMPARED TO ELEVATED LEVELS OF CALLBENDIN D. WE HAVE A LARGE DEGREE OF VARIABILITY DUE TO HETEROGENEITY. FATTY THE ACID BINDING, SIMILARLY WE FOUNDED MARKED LEVELS IN PATIENTS COMPARED TO CONTROLS, IN THE APPROPRIATE BLACK AND WHITE FORMAT. BUT ONE THING THAT WE ALSO NOTED, THESE ARE NPC-1 PATIENTS UNTREATED AND THESE ARE NPC-1 PATIENTS ON MIGLOSTAT, OFF LABEL BUZZ NOT APPROVED YET IN THE US. AND YOU COULD PICK OUT, THIS WAS ACTUALLY A SIGNIFICANT DIFFERENCE BUT A HUGE DEGREE OF OVERLAP BECAUSE OF THE VARIABILITY THAT WE SEE IN THIS DISEASE. WHEN YOU TOOK INDIVIDUAL PATIENTS AND LOOKED AT PATIENTS UNTREATED VERSUS PATIENTS THAT WERE TREATED AT BOTH TIME POINTS AND COMPARED THE PERCENT CHANGE VERSUS PATIENTS WHERE WE HAD PRE POST, YOU CAN SEE IN A SUBGROUP OF PATIENTS WHERE WE HAD COMPARISONS BEFORE THEY STARTED ON MIGLASTATIN AFTER, THERE WAS A MARKED DECREASE IN IN THE AMOUNT OF FA FATTY ACID BINDING PROTEIN 3 IN THE CSF. THUS TRY TO INFER IT'S AN INDICATOR THERE'S LESS NEURONAL DAMAGE OCCURRING. SO OUR GOAL IS TO GET -- LAY THE FOUNDATION AND GET TO A THERAPEUTIC TRIAL. WHAT WE'RE FOCUSED ON NOW IS A TRIAL ON HYDROXY PROPYL BETA CYCLE DEXTRIN. OUR GOAL IS TO ESTABLISH A SAFE EFFECTIVE DOSING REGIMEN FOR TREATMENT OF CHILDREN WITH MPC-1. THE APPROACH, SYSTEMATIC CONTROLLED AND SCIENTIFICALLY RIGOROUS. THIS IS IMPORTANT. IT TAKES TIME AND TIME IS OUR PRECIOUS COMMODITY AND PARENTS TIME AS MOST PRECIOUS COMMODITY. BUT WE WANT TO GET IT RIGHT AND WHEN WE GET TO THE END WE WANT TO KNOW IT WORKS, WE CAN STATE IT WORKS WE CAN MAKE IT AVAILABLE FOR EVERYBODY OR FINE OUT IT DOESN'T WORK, HOPEFULLY NOT THE CASE BUT IF SO WE CAN MOVE ON AND NOT GET STUCK WITH THE IDEA MAYBE IT'S WORKING. IT LISTEN STEP WISE, A BIOCHEMICALLY EFFECTIVE DOSE. STEP 2, UTILIZE CSF BIOMARKERS TO INFER PATHOLOGICAL EFFICACY IN A RELATIVELY SHORT TERM TRIAL AND STEP 3 IF EVERYTHING HOLDS TOGETHER IS DETERMINE THE ABLE OF HYDROXY PROPYL BETA DEXTRAN TO IMPACT SYMPTOMS. THIS IS A PROLONGED LONG TERM TRIAL TO SHOW THAT. PHASE 1 IS INTRACEREBRAL DELIVERY. CYCLE DEXTRAN DOESN'T CROSS THE BLOOD BRAIN BARRIER SO WE PUT IT ON THE OTHER SIDE THE BLOOD BRAIN BARRIER. THIS IS A COLLABORATION AND I HOPE YOU HEARD THAT EARLIER. IT'S A COLLABORATION BETWEEN VARIOUS INTRAMURAL INSTITUTES INCLUDING N CATS AND TREND, EXTRAMURAL, WASHINGTON UNIVERSITY, UNIVERSITY OF PENNSYLVANIA EINSTEIN, AND INDUSTRY WITH JOHNSON AND JOHNSON PLAYING A MAJOR ROLE AND MAJOR BENEFIT TO HAVE INVOLVED. FINALLY WITH THE PARENT AND PATIENT SUPPORT ORGANIZATIONS. I SHOULD ALSO ADD ON HERE THEY'RE NOT A FORMAL COLLABORATOR BE WE HAD A NUMBER OF&– DISCUSSIONS IN PRE-IND MEETINGS WITH THEIR ASSISTANCE AN GUIDANCE WORKING WITH US HAS BEEN A HUGE BENEFIT AND WILL BENEFIT OUR PATIENTS. JUST TO CLOSE YOU HAVE SEEN THE LIST OF NAMES SO I WOULD LIKE TO CLOSE WITH A DIFFERENT CLOSING SLIDE THAT IS MORE THE REASON WHY WE DO THIS. [APPLAUSE] >> UNFORTUNATELY WE DON'T. IF YOU COULD STOP TO VISIT WITH THE SPEAKERS OF THE PAST PRESENTATION AND THE PREVIOUS PRESENTATION BEFORE THAT WOULD HELP BECAUSE WE'RE ON A VERY SHORT TIME SCHEDULE FOR LUNCH. SO I NEED DIRECTION, DAVID. ECKSTEIN. ARE YOU HERE? WE WANT TO START BACK ONE A PRESENTATION FROM SCOTT SHIRLEY WITH UPLIFTING ATHLETES. AT 1:30. SO IF YOU CAN COME BACK SOMEWHERE AROUND 130BG, 135BG, THAT WOULD BE GOOD. THAT'S -- 1:30, 1:35. THE CAFETERIA IS ON THE B LEVEL. SO PLEASE, IF YOU CAN RUSH YOUR LUNCH AND VISIT THE POSTERS AND THE TABLES AN COME BACK AROUND 1:30, THAT WOULD BE VERY HELPFUL. THANK YOU. >> GOOD AFTERNOON. MY NAME IS SCOTT SHIRLEY, DIRECTOR OF UPLIFTING ATHLETES. JOINING ME FOR SPECIAL PRESENTATION IS DR. STEVE GROFT, DIRECTOR OF THE OFFICE OF RARE DISEASE RESEARCH FOR THE NATIONAL INSTITUTES OF HEALTH. AS EXECUTIVE DIRECTOR OF UPLIFTING ATHLETES I HAD THE PRIVILEGE OF WORKING WITH CLEMG FOOTBALL PLAYERS ACROSS THE COUNTRY TO RAISE MONEY AND AWARENESS FOR RARE DISEASE RESEARCH. WE HAVE DOUBLED SIZE EVERY REAR FROM ONE TO 2 TO 4 TO 8 ON OUR WHICH TO 16. OUR CHAPTERS ARE RUN BY CURRENT STUDENT FOOTBALL ATHLETES INCLUDING PLAYERS AT SCHOOLS IKE PENN STATE, NORTHWESTERN UNIVERSITY,BOSTON, COL GATE UNIVERSITY AND SO ON. OUR PRESENTATION TODAY IS TE ANONS THE 2012 UPLIFTING ATHLETES RARE DISEASE CHAMPION. WHICH IS HONOR PRESENTED ANNUALLY. TO A COLLEGE FOOTBALL PLAYER OR LEADER IN COLLEGE FOOTBALL WHO REALIZES THE POSITION THEY'RE IN ON THE COMMUNITY. WE'RE OVERWHEM MED WITH STORIES OF PLAYERS COACHES, ORGANIZATIONAL LEAD THEARS HAVE AFIN FI FOR PERSONAL CONNECTION TO A RARE DISEASE AND USE A PLATFORM THEY HAVE AS COLLEGE FOOTBALL PLAYERS OR AS LEADERS IN COLLEGE FOOTBALL TO RAISE AWARENESS, MONEY AND MAKE A DIFFERENCE IN THE RARE DISEASE COMMUNITY. PREVIOUS WINNERS INCLUDE THE AMERICAN COLLEGE OF FOOTBALL ASSOCIATION WITH SHANE'S E MUS SKEWER LAR DYSTROPHY. IAN MITCHELL A QUARTERBACK FROM DICKINSON UNIVERSITY WHO RAISED MONEY FOR CHILDHOOD BRAIN CAWRNS RESEARCH AND JOL DON A RUNNING BACK FROM PRINCETON UNIVERSITY WHO LAST YEAR USES RETURN TO THE FIELD TO PROMOTE APLASTIC ANEMIA DISEASE WHICH HE OVERCAME. OUR FOUR FINALISTS THIS YEAR WERE REX BURKHEAD FROM UNIVERSITY OF NEBRASKA WHO BEFRIENDED A BOY NAMED JACK. AND HE USED THAT RELATIONSHIP TO HELP PEDIATRIC LOW GRADE BRAIN TUMORS WAYNE CRAWFORD A SENOR FOR NCC STATE UNIVERSITY FOR LEUKEMIA RESEARCH IN HONOR OF HIS COACH DIAGNOSED WITH THIS DISEASE. APLASTIC ANEMIA TO RETURN TO THE FIELD AND USE AS A WAY TO EDUCATE PEOPLE AND CHALLENGES FACED BY FELLOW PATIENTS AND DAVID LEARNER FROM UNIVERSITY OF FLORIDA DIAGNOSED WITH PEDIATRIC CROHN'S DISEASE AN OVERCOME THAT TO BE SUCCESSFUL IN THE FIELD AND TO EDUCATE PEOPLE TO OVERCOME ADVERSITY. WITHOUT FURTHER ADIEU THE WINNERRER OF THE 2012 CHAMPION IS REX BURKHEAD FROM THE UNIVERSITY OF NEBRASKA. JOIN ME IN CONGRATULATING REX, WE'RE HAPPY TO GIVE HIM THIS AWARD FOR HIS WORK AN DEAD CIG AND RELATIONSHIP WITH JACK HAUFMAN AND WHAT THEY WERE ABLE TO DO TO PROMOTE THE RARE DISEASE THAT AFFECTED THEIR FAMILY AND TEAM. SO THANK YOU. [APPLAUSE] >> GOOD AFTERNOON, EVERYBODY. MY NAME IS JOHN GALLIN, DIRECTOR OF THE NIH CLINICAL CENTER AND -- GALLIN AND I HAVE BEEN ASKED TO WELCOME YOU TO THE AFTERNOON SESSION OF RARE DISEASES DAY, IT'S A PLEASURE TO DO THAT. I WAS ASKED TO TELL YOU A TINY BIT ABOUT THE PLACE YOU'RE AT. THE NIH CLINICAL CENTER, THE LARGEST HOSPITAL IN THE WORLD TOTALLY DEDICATED TO CLINICAL RESEARCH. I WANTED TO BRIEFLY TELL YOU ABOUT THIS AND THEN INTRODUCE THIS AFTERNOON'S FIRST SPEAKERS. SO THIS IS THE NIH CLINICAL CENTER. IT'S THE LARGEST BUILDING ON THIS CAMPUS, IT'S BIG, ABOUT 4 MILLION SQUARE FEET FOR THE COMPLEX. AND IT REPRESENTS ABOUT 25% OF THE SPACE ON THIS CAMPUS AND IS A HOSPITAL SURROUNDED BY RESEARCH LABORATORIES. WE HAVE A VERY SIMPLE VISION AS AMERICA'S RESEARCH HOSPITAL WE WILL LEAD THE GLOBAL EFFORT IN TRAINING INVESTIGATORS AND DISCOVERING TOMORROW'S CURES YOU MAY SAY THAT'S OBNOXIOUS BUT WE BELIEVE IT AND WE PURPOSELY PUT TRAINING AHEAD OF DISCOVERY BECAUSE OF THE IMPORTANCE FOR SUSTAINING DISCOVERY FOR A LONG PERIOD OF TIME. WE'RE PROUD THE HOSPITAL RECEIVED THE LASKER BLOOMBERG PUBLIC HEALTH SERVICE AWARD THIS YEAR FOR SERVING SENSE INCEPTION AS A MODEL RESEARCH HOSPITAL PROVIDING INNOVATIVE THERAPY AND HIGH QUALITY PATIENT CARE TREATING RARE AND SEVERE DISEASES AND PRODUCING OUTSTANDING PHYSICIAN SCIENCE COLLECTIVE WORD AND SET A STANDARD OF EXCELLENCE IN BIOMEDICAL RESEARCH. THIS IS THE FIRST TIM THIS AWARD HAS GONE TO AN INSTITUTION RATHER THAN AN INDIVIDUAL SO WE WERE VERY PROUD OF THAT. OUR PROFILE IS SHOWN ON THIS SLIDE, MORE THAN 450,000 PATIENTS COVM TO THIS -- HAVE COME TO THIS HOSPITAL SINCE IT OPEN OD IN 1953. TODAY WE HAVE 250 BEDS OPEN AND A BUDGET OF $195 MILLION. EVERY PATIENT HERE IS ON A RESEARCH PROTOCOL, CARE IS FREE. ONE OF THE FEW MAYBE THE ONLY HOSPITAL IN THE COUNTRY THAT HAS THAT. PATIENT TRAVELING AN HOUSING IS PROVIDEDDED AS NEEDED. B THERE'S ABOUT 2200 PEOPLE WHO WORK FOR THE THE HOSPITAL AND 4,000 THAT WORK FOR THE 17 INSTITUTES THAT USE THIS HOSPITAL, REPRESENTING 6,000 EMPLOYEES WHO MAKE UP THE WORK FORCE IN THIS PLACE. OF THOSE, ABOUT 1255 ARE CREDENTIALED PHYSICIANS AND THE ENGINE THAT DRIVES ARE THE ACTIVE CLINICAL PROTOCOLS OF WHICH THERE ARE OVER 1500, HALF ARE NATURAL HISTORY STUDY, THE OTHER HALF ARE CLINICAL TRIALS MOSTLY PHASE 1 AND 2.e SO OUR MISSION IS TO TRY TO DO THE BEST IN SCIENCE TRAINING, IN COME BY FACE WITH PATIENT CARE AN SAFETY. I PICK AD FEW HIGHLIGHTS TO GIVE YOU A FLAVOR FOR YOU AS TAXPAYERS WHAT YOU HAVE GOT P FOR YOUR INVESTMENT. THE DEVELOPMENT OF CHEMOTHERAPY FOR CANCER, LYMPHOMA AN HODGKIN'S DISEASE AND WITH THAT CAME THE DEVELOPMENT OF PLATELET AND GRANULOSITE TRANSFUSIONS IN FIRST BLOOD FLOW SEPARATOR. IN THE MENTAL HEALTH INSTITUTE THE YOUTH OF LITHIUM FOR BIPOLAR DISORDERS IN IN INFECTIOUS DISEASES COMING FROM THE WORK OF BOB GALLO AND LATER HARVEY HALTER. THE BLOOD TEST FOR AIDS AND HEPATITIS. THE FIRST GENE THERAPY FOR DENOSINE AND THE PATHWAY AN TREATMENT FOR AIDS CAME WITH AZT CAME FROM WORK FROM SAM BROADER AND HIS TEAM. THE FIRST ARTIFICIAL MITRAL HEART VALVE, THE USE OF DRUGS FOR NON-MALIGNANT DISEASE AND FLUORIDE TO PREVENT DENTAL CAF TAIS -- CAVITIES CAME FROM WORK HERE. WE THINK IT'S A GREAT TRACK RECORD. SOME OF THE MORE RECENT THINGS ARE SHOWN ON THIS SLIDE, INCLUDING PARTNERSHIPS WITH SUBURBAN JOHNS HOPKINS ONIOUS OF CARDIAC MRI IN PATIENTS WITH CHEST PAIN TO IDENTIFY HIGH AND LOW RISK INDIVIDUALS. THE USE OF ADOPTIVE TRANSFER AS IMMUNE THERAPY FOR METASTATIC MELANOMA. THE FIRST USE OF IMIMMUNOTOXIN TO TREAT MALIGNANCY BY THE NEXT SPEAKER IRA PASTAN. THE GENETIC IDENTIFICATION OF GENETIC BASIS OF KIDNEY CANCER WHICH LED TO NEW THERAPEUTIC APPROACHES BY LINIHAN AB HIS TEAM AND USE OF PET SCANS TO IDENTIFY ABNORMALITIES AND SCHIZOPHRENIA AND DISCOVERY OF AUTOINFLAMMATORY DISEASES BY DAN CAST NER SO NOTICE A LOT OF RARE DISEASES LISTED ON THIS AND THE PREVIOUS SLIDE. WE DID TWO THINGS WE LIKE TO SAY HERE, FIRST IN HUMAN WITH NEW THERAPEUTICS AND STUDY OF PATIENTS WITH RARE DISEASE. CURRENTLY WE'RE STUDYING 400 COHORTS OF PATIENTS WITH RARE DISEASES. 383. NUMBER OF RARE DISEASE PATIENTS STUDIED HERE TODAY IS OVER 40,000 AND NUMBER OF PROTOCOLS IS 600 AND YOU SEE THE DISTRIBUTION IN CLINICAL TRIALS NATURAL HISTORY BEING THE MAJOR BULK OF THESE STUDIES. WHAT DO WE HAVE HERE THAT MAKES THIS PLACE DIFFERENT? WE HAVE SPECIAL CAPACITY FOR PHENOTYPING PATIENTS WITH RARE DISEASES AS WELL AS OTHERS, INCLUDING A BIOMECHANICS LAB WHICH STUDIES MOVEMENT AND LO COMOTION. METABOLIC CHAMBERS FOR CARBOHYDRATE AND FAT TAB LISM, SECOND BY SECOND WHILE PATIENTS ARE DOING VARIOUS ACTIVITIES. IN OUR PHARMACY DEPARTMENT WE HAVE A GMP FACILITY FOR FORMULATING DRUGS THAT INDUSTRY MAY NOT BE INTERESTED IN INITIATING, WE WILL DO THEM AND MAKE THEM AVAILABLE TO OUR INVESTIGATORS HERE AND OUR PLAN SO TO MAKE THEM AVAILABLE TO OUTSIDE INVESTIGATORS. WE HAVE STRONG IMAGING CAPABILITY IN PART BECAUSE WE HAVE LINKED TO OUR HOSPITAL AND MRI CENTER THAT BUILDS NEW MRI MACHINES OR THE 240 BED HOSPITAL, 27 MRI MACHINE ASSOCIATED WITH THIS FACILITY FOR STUDYING HUMANS AN ANIMALS. AND OUR PET PROGRAM INCLUDES THREE CYCLE TRONS FOR -- A POWERFUL TOOL FOR MAKING RADIOACTIVE LIGANDS FOR USING IN PET SCANNING. I WANT TO SHOW YOU THE CAPACITY OF PHARMACEUTICAL DEVELOPMENT SERVICE THAT MAKE IN AN 8 HOUR DAY THE PRODUCTIOUS SEE LISTED ON THIS SLIDE. MY LAST SLIDE IS THIS ONE, IT REPRESENTS A CHANGE IN THE VISION OF THE CLINICAL CENTER WHICH WAS BROUGHT ABOUT BY A REVIEW OF THE NIH CLINICAL SENOR BY CONGRESSIONALLY MANDATED COMMITTEE CALLED THE SCIENTIFIC MANAGEMENT REVIEW BOARD WHICH AMONG VERY FIRST DUTIES WAS TO REVIEW THE CLINICAL SENOR, THE FIRST THING THEY SAID IS THAT WE SHOULD KEEP THE CLINICAL SENOR, WHICH WARMED MY HEART. THE SECOND THING THEY SAID WAS THAT WE SHOULD CHANGE OUR VISION AND THAT THE ROLE OF THE NIH CLINICAL CENTER SHOULD BE TO SERVE AS STATE-OF-THE-ART NATIONALY- RESOURCE. WITH RESOURCES OPTIMALLY MANAGED TO ENABLE INTERNAL AND EXTERNAL INVESTIGATOR USE. NIH IS SPENDING A LOT OF EFFORT FRANCIS COLLINS TO MAKE THIS HAPPEN I RECOMMEND YOU KEEP YOUR EYES OPEN BECAUSE THERE'S GOING TO BE PROBABLY A NEW GRANT ANNOUNCEMENT RELEASED LATER THIS YEAR ON BEDSIDE TO BENCH AWARDS BRINGING TOGETHER EXTRAMURAL AN INTRAMURAL INVESTIGATORS AND SOME OF THE SERVICES I SHOWED YOU ARE GOING TO BE MADE AVAILABLE TO GRANTEES AND OTHERS WHO WANT TO TAKE ADVANTAGE OF THIS. WITH THAT BRIEF BACKGROUND I HAVE THE PLEASURE OF INTRODUCING OUR FIRST AFTERNOON SPEAKER, DR. IRA PASTAN, AN NIH DISTINGUISHED INVESTIGATOR AND CO-CHIEF OF THE LABORATORY OF MOLECULAR BIOLOGY IN THE NATIONAL CANCER INSTITUTE. HE'S BEEN AT THE NIH FOR QUITE SOME TIME, HE ARRIVED HERE IN 1959. AND IF I HAD TO THINK OF ONE PERSON WHO REPRESENTS THE BEST OF SCIENCE AN BEST OF MENTORING I WOULD TURN TO IRA PASTAN. MANY OF THE DISTINGUISHED GRADUATES OF THE NIH HAVE COME THROUGH HIS PROGRAM INCLUDING ONE NO BELL LAUREATE. -- NOBEL LAWYER RATE. -- LAUREATE. THEY TARGETED CANCER THERAPY TODAY WITH GENETIC ENGINEERING TO CREATE NOVEL PROTEINS HE CALLS RECOMBINANT IMMUNOTOXINS, ONE BEING FROM THE PSEUDOMONUS EXOTOXIN A COUPLED WITH ANTIBODIES TO SELECTIVELY TARGET AND KILL CANCER CELLS. DR. PASTAN EARNED HIS M.D. FROM TUFTS AND COMPLETED MEDICAL TRAINING AT YALE AND RECEIVED RESEARCH TRAINING LATER HERE AT THE NIH AND HE'S A MEMBER OF THE INSTITUTE OF MEDICINE, THE NATIONAL ACADEMY OF SCIENCES, AS WELL AS THE AMERICAN SOCIETY FOR CLINICAL INVESTIGATION. IT IS MY PLEASURE TO WELCOME HIM TO THE PODIUM TO SHARE HIS RESEARCH TODAY, THE TITLE OF WHICH IS ON THE SLIDE RECOMBINANT IMMUNOTOXIN FOR THE TREATMENT OF B CELL MALIGNANCIES AN MESOTHELIOMA. >> THANK YOU. [APPLAUSE] >> SO THANKS VERY MUCH FOR INVITING ME TO PARTICIPATE IN RARE DISEASES DAY. I ASKED JOHN WHAT A RARE DISEASE WAS, HE SAID I THINK PREVALENCE OF 3 HN THOUSAND CASES PER YEAR, SOME NUMBER LIKE THAT. AND THE DISEASE I TREAT 3,000 AND 1,000 ARE WELL WITHIN THAT RANGE. SO WE HAVE A TEAM THAT WORKS IN THIS FIELD DEE FITS JERL WHO WORKS WITH BASIC TOXIN SCIENCE. BOB CRIEKMAN B CELL MALIGNANCIES, MESOTHELIOMA AND ALAN WAYNE PEDIATRIC ONCOLOGY AND ALL IN CHILDREN. SO LET ME GET STARTED. SO AS YOU PROBABLY MOSTLY KNOW, THERE ARE A LOT OF ANTIBODIES TO TREAT CANCER BUT MOST OF THE ANTIBODIES BIND AND DON'T WORK, ONLY A FEW LIKE HERCEPTIN ARE ACTIVE ANTI-CANCER DRUGS. SO WE TAKE ADVANTAGE OF SPECIFICITY OF BINDING TO BRING A POISSON TO THE CANCER CELL. AND THE POISSON WE USE IS A BACTERIAL TOXIN. NOW, THERE ARE ATTRACTIVE FEATURE, VERY POTENT NOT IMMUNOGENIC, THEY DON'T DAMAGE BONE MARROW. THE PROTEINS ARE IMMUNOGENIC AND I WILL DISCUSS HOW WE DEAL WITH THAT LATER. SO PSEUDOMO NIRKSS EXOTOXIN INACTIVATES ELONGATION FACTOR 2. IT ARRESTS PROTEIN SYNTHESIS AND INDUCES PROGRAM CELL DEATH. WE KNOW HOW BUT I WON'T TALK ABOUT THAT TODAY. HOW WE MAKE THESE AGENTS IS WE START WITH A PSEUDOMONISEXOTOXIN A THREE DOMAINS, BEHINDING PROCESS AND PHOSPHORYLATION AND WE PLACE THE DOMAIN WITH AN ANTI-BODY USE GENE SPLICING TECHNIQUE TO PUT DNA TOGETHER TO ENCODE A SPECIFIC FE IN TWO DOMAINS OF TOXIN. HOW DO THEY KILL CELLS? BINDING TO A SPECIFIC PROTEIN, IN THIS CASE CD 22 RECEPTOR. ON B CELL MALIGNANCIES INTERNALIZED THROUGH CLASSROOM INTO THE ENDOSITIC COMPARTMENT PROCESSED BY FIEWRN AND THE TOXIN THEN GOES THROUGH THE ER INTO THE CYTOSOL WHERE IT FINDS EF-2 ADP ARREST PROTEIN SYNTHESIS. THE MOST IMPORTANT STEP IS RECOGNITION AND CHOICE OF MOLECULES THAT ARE NOT EXPRESSED IN NORMAL CELLS AND MOSTLY EXPRESSED IN MALIGNANCIES AND FROM THE ONE WAY TO FIND SPECIFICITY IS TO USE A LINEAGE RESTRICTED DIFFERENTIATION ANTIGEN LIKE CD 22 ON B CELL MALIGNANCIES AND MESOTHELIN ON MESOTHELIOMA TO PREVENT SIDE EFFECTS. SO CD 22 SURFACE PROTEINS B CELL AN B CELL MALIGNANCIES NOT IN STEM CELLS. IF YOU KILL NORMAL B CELLS THEY REGENERATE QUICKLY WITHIN A FEW WEEKS. IT'S RAPIDLY INTERNALIZED WHICH BRINGS THE IMMUNOTOXIN INTO THE CELL QUICKLY. THE NAME OF THE AGENT WE WORK WITH NOW IS LIKENED TO MED IMMUNE CALLED (INDISCERNIBLE) USED TO BE CALLED AH-22, IT HAS A HIGH AFFINITY APT CD 22 SE STABILIZED BY (INDISCERNIBLE) TO THE TOXIC. -- TOXIN. SO WE HAVE BEEN DOING PHASE 1 TRIALS IN PATIENTS WITH CD 22 POSITIVE MALIGNANCIES HAVE FAILED STANDARD CHEMOTHERAPY, FOR EXAMPLE IN HARRY CELL LEUKEMIA, CD8 ENDOSTATIC RO TOX MIGHT BE, EVERY OTHER DAYTIMES THREE, COULD BE GIVEN MORE FREQUENTLY BUT THAT'S HOW WE BEGAN, THAT'S THE MAXIMUM TOLERATED DOSE, BLOOD LEVEL OF MICROGRAM PER ML. IN HARRY CELL LEUKEMIA WE DID A TRIAL TREATING PATIENTS EVERY 21 DAYS. SO LET ME SAY ABOUT THIS DISEASE, IT'S A RARE DISEASE, ABOUT A THOUSAND CASES A YEAR. HIGH CD 22 EXPRESSION. THE PATIENTS GET PAN CYTOPENIA, SPLE KNOW MEGALY, SO THEY SUFFER FROM BLEEDING AND INFECTION. THERE'S A GOOD TREATMENT, CDA OR DCF WITH HIGH RESPONSE RATES BUT SOME PATIENTS DON'T RESPOND, PATIENTS WHO RESPOND MAY RELAPSE AND THOSE ARE THE PATIENTS WE TREAT. THOSE NOT RESPONDED. THIS IS A TYPICAL PATIENT WHO COMES IN AS YOU CAN SEE WITH LOW NEUTROPHIL, LOW PLATELETS AND HEMOGLOBIN AN GETS TREATED EVERY THREE DOSES ONE WEEK SECOND CYCLE, 3, 4, SO ON. YOU CAN SEE THE LEUKEMIC CELLS PLUM MET BUT THERE ARE CELLS IN THE BONE MARROW AND WE KEEP TREATING UNTIL THE BONE MARROW IS CLEAR. THIS PATIENT YOU CAN SEE HAS NOW SEVERAL YEARS OUT AND DOING FINE. SO WE TREAT AD PHASE 1 TRIAL DOSE ESCALATION AND THEN AT THE HIGHEST DOSE, BOB TREATED 26 MORE PATIENTS AND RESPONSE WAS COMPLETE RESPONSES SO NORMALIZATION OF BLOOD COUNTS, NO DETECTABLE MARROW THAT'S CLEAN IN ALMOST TWO-THIRDS OF THE PATIENTS AND OVERALL RESPONSE RATE OF OVER 90%, SO A VERY ACTIVE AGENT IN THIS DISEASE. THIS IS JUST AN NAILSIS OF THE DURATION OF THE RESPONSE AND YOU CAN SEE OUT 40 MONTHS AND LONGER PATIENTS ARE STILL IN COMPLETE REMISSION. WE HAD A PRED SEDSOR DRUG WHICH WE HAVE HAD SOME PATIENTS IN COMPLETE REMISSION OUT FOR TEN YEARS. SO VERY DURABLE. SIDE EFFECTS ARE MOSTLY FALL IN ALBUMIN SHOWN HERE, RISES IN LIVER ENZYMES AND EDEMA. THIS IS CALLED CAPILLARY LEAK SYNDROME. IT'S NOT DOSE LIMITING IN THIS TRIAL AND I'LL TALK ABOUT IT MORE LATER. SO PRODUCES MANY CRs AN REFRACTORY HARRY CELL LAW CHEMOIA LONG LASTING RESPONSES. NOW ALAN WAYNE IS DOING A TRIAL OF THIS AGENT IN KIDS WITH ALL HERE IN THE PEDIATRIC PROGRAM. WE'RE GIVING THE DRUG MORE FREQUENTLY EVEN OTHER DAYTIMES SICK. THIS IS THE HISTORY OF ALL TREATMENT SHOWING THE GREAT PROGRESS, I WAS IN MEDICAL SCHOOL BEFORE. 1968. IT WAS A FATAL DISEASE. WITH TIME COMBINING CHEMOTHERAPIES, RESPONSE RATES HAVE GONE UP AND UP SO NOW 15 TO 20% ARE NOT CURED, MOST ARE CURED. THESE KIDS WE'RE TREATING WHO ARE NOT CURED. THE TREATMENT ITSELF IS VERY COMPLICATED AND THERE ARE LOTS OF SIDE EFFECTS IN THE ADULTS WHO RECOVER FROM THIS DISEASE. BUT THEY ARE CURED. STILL WE HAVE THIS 15 OR 20%. SO WE HAVE BEEN DOING A DOSE ESCALATION TRIAL, ALAN WAYNE HAS, THE RESPONSE RATES ARE NOT AS HIGH, SO WE SEE ONE COMPLETE RESPONSE AT EACH DOSE LEVEL AND WE HAVE SEEN RECENTLY TWO PLEAT RESPONSES AT 50. SO THE RESPONSE RATE FOR CR IS VERY GOOD IN THIS VERY REFRACTORIED HEAVILY TREATED POPULATION, 25, 30% BUT NOT ASgs GOOD AS HARRY CELL LEUKEMIA. WE HAVE BEEN STUDYING WHY BUT DON'T HAVE TIME TO TALK ABOUT THAT. THIS IS BONE MARROW BEFORE AN AFTER TREATMENT AND YOU CAN SEE THE STAINING HERE, BROWN STAIN, MALIGNANT CELLS THAT ARE GONE IN THIS PATIENT, COMPLETE REMISSION. HERE IS A CHILD THAT HAS BONE MARROW DISEASE AS YOU CAN SEE IN A PET SCAN ACTIVE TWO CYCLES. SO ACTIVE AGENT. WHERE DO WE STAND IN THIS DRUG IN LICENSED MED IMMUNE PHASE 3 TRIAL IN HARRY CELL LEUKEMIA NOW DISCUSSED WITH CTEP, HOPEFULLY WILL HAPPEN. PHASE 1 TRIAL SHOWS GOOD RESPONSES. AND THE TRIALS IN CLL AND NHL ARE FURTHER BEHIND. THAT'S ONE RARE DISEASE OR TWO RARE DISEASESCH I WANT TO TALK A LITTLE BIT ABOUT TARGETING MESOTHELIN AND SOLID TUMOR THERAPY WHICH IS A SLIGHTLY DIFFERENT INTERESTING DIFFERENT ISSUES. SO MESOTHELIN IS A PROTEIN DISCOVERED SOME YEARS AGO, IT'S A CELL SURFACE GLYCO PROTEIN, LINEAGE RESTRICTED SO IT'S A DIFFERENTIATION ANTIGEN EXPRESSED IN MESOTHELIAL CELLS OF THE LINING OF THE PERICARDIUM BUT NOWHERE ELSE. AND IT'S EXPRESSED IN MANY CANCERS. IT'S NOT SURPRISING THAT IT'S HIGHLY EXPRESSED IN MESOTHELIOMA BUT IT'S ALSO EXPRESSED IN TWO-THIRDS OF OVARIAN CANCER, ALMOST ALL PANCREATIC CANCER, MANY STOMACH CANCERS, CARCINOMAS, MANY LUNG CANCER, IT'S TURNED ON FOR SOME REASON IN MANY CANCERS. NOW, THE GENE ENCODES A PRECURSOR PROTEIN WHICH IS CLEAVED BY FURIN SO THIS IS SHED IN THE BLOOD, I WON'T TALK ABOUT IT. AND THIS IS WHAT STAYS IN THE CELL SURFACE WE CALL MESO THELIN A 40-KILODALTON GLYCO PROTEIN WITH THIS DISTRIBUTION. IT'S THIS WE TARGET WITH IMMUNOTOXIN WHICH HAS AN ANTI-ME SEW THEE LYNN F 1E. IT'S CALLED FF 1P. AND THE CURRENT HAS BEEN LICENSED TO COMPANIES CURRENTLY IS BEING DEVELOPED BY NCI. SO (INDISCERNIBLE) DID PHASE 1 TRIALS SEVERAL YEARS AGO WITH THIS AGENT AND WE FOUND IT WAS WELL TOLERATED. 45 MICROGRAMS PER KILO WAS THE DOSE MT AND THE DOSE WOULD BE EXPECTED FROM SOMETHING THAT'S ON YOUR FLORA. WE SAW SOME MINOR RESPONSES BUT NOTHING AS DRAMATIC AS WE SAW IN THESE HEME LOGICAL MALIGNANCIES. SO WE THOUGHT WE HAD TO TRY TO COMBINE WITH CHEMOTHERAPY AND DID SOME EXPERIMENTS IN CELL CULTURE AND NEVER SAUCY NER JI. BUT WE WENT INTO AN ANIMAL MODEL, WE SAW AMAZING SYNERGY. AND NOT SHOWN IN THIS SLIDE, THIS IS A TUMOR WHICH EXPRESSES MESOTHELIN, GROWS RAPIDLY SHOWN HERE F. YOU TREAT WITH TAXOL YOU GET TRANSIENT RESPONSE AND TUMOR TAKES OFF. THREE DOSES OR IMMUNOTOXIN, YOU GET A STABILIZATION DISEASE AND TAKES OFF BUT WHEN YOU COMBINE THEM YOU GET COMPLETE REMISSION. REAL SYNERGY. VERY STRIENGING. SO WE SPENT TIME TO FIGURE OUT WHAT'S GOING ON O. WHAT'S GOING ON IS AS FOLLOWS. TUMORS ARE MADE UP OF SOLID TUMORS OF NESTS OF CELLS FED BY A CAPILLARY WITH A 200-MICRON IN DIAMETER. SO IF YOU SEE ANTIBODY IMMUNOTOXIN COME IN HERE, COMES IN THE CAPILLARY DIFFUSES INTO THE REGION AN BINDS TO ANTIGEN, IT HAS TO SATURATE THE ANTIGEN ON THE OUTSIDE OF THE LITTLE NOD NO DUAL OF CELLS BEFORE IT GETS INSIDE. WE CAN'T ALWAYS SATURATE BECAUSE WE CAN'T GIVE HIGH DOSES YET. YET. WHEN YOU TREAT THIS TUMOR WITH CHEMOTHERAPY, THIS IS AN HNE STAIN, DAY 2 AND 3 YOU CAN SEE THEY'RE NOW SPACES BETWEEN THE TUMOR CELLS AND THERE'S A LOT OF NECROSIS, EPITOSIS. THAT CHANGES THE TUMOR ENVIRONMENT SO THE CELLS ARE FAR APART, NOT PACKED TOGETHER INTERSTITIAL PRESSURE GOES DOWN AND THING CONSIST GET IN AND OUT REALLY EASILY SO NOW WHEN YOU GIVE AN IMMUNOTOXIN OR ANN BODY IT CAN GET BETWEEN CELLS AN REACH MORE CELLS. IN A MOUSE MODEL. WE PUT THAT INTO PRACTICE. THIS IS A PATIENT WITH MESOTHELIOMA, THE STANDARD THERAPY IS (INDISCERNIBLE), IT'S STILL A TERRIBLE DISEASE WITH HALF PATIENTS DYING WITHIN A YEAR FROM THIS DISEASE. SO OUR PROTOCOL TO REPEAT HASAN'S PROTOCOL, TO GIVE CISPLATIN AND THREE DOSES OF SS 1P WITH THE FIST CYCLE AND WITH THE SECOND CYCLE AND KEEP TREATING WITH THE PERMATREXIB UP+V TO SIX CYCLES. NOW WE HAVE SEEN DRAMATIC RESPONSES IN MESOTHELIOMA. THIS PATIENT HAD HUGE INFILTRATION OF THE LUNG WHICH DIMINISHED BY 60, 70%. I WILL SHOW YOU THE PET SCAN TO CONVINCE YOU THE PET SCAN SHOWS THE SAME RESPONSE AND SUMMARIZE, SO THIS TRIAL IS FINISHED. THE TRIAL IN WHICH WE REACHED MTD OF 45 WITH CHEMOTHERAPY, WE TREATED NINE -- 13 PATIENTS WITH THE MTD AND WE HAVE SEEN TEN PARTIAL RESPONSES AND ONE STABLE DISEASE. IN MESOTHELIOMA PARTIAL RESPONSES ARE NOT COMMON. SO HISTORICALLY THIS IS MUCH BETTER THAN ONE COULD HAVE EXPECTED. WE ARE ENCOURAGED BY IT. WE'RE PLANNING BASED ON THAT WE FINISHED DOATION EXPANSION AND PLANNING TO GO TO THE FDA TO SEE IF WE CAN DO A TRIAL IN WHICH WE RANDOMIZE STANDARD CHEMOTHERAPY PLUS SS 1P TO REPRODUCE THIS IN PHASE 2 TRIAL IMMUNOLOGIC GROUP OF PATIENTS. SO THAT IS SUMMARY WHERE WE STAND IN CLINICAL ACTIVITY. SO WHAT ARE PROBLEMS WE NEED TO ADDRESS? ONE MAJOR PROBLEM IS PSEUDOMONIS EXXOTOXIN IS A FOREIGN PROTEIN SO IT PRODUCES AN ANTIGEN RESPONSE AND WE CAN GIVE CYCLES IN PATIENTS WITH NORMAL IMMUNE SYSTEMS. WE CAN IN HARRY CELL LEUKEMIA AND ALL BUT NOT PATIENTS WITH SOLID TUMORS. WE KNEW THIS WHEN WE BEGAN, FRANKLY I THOUGHT THAT MY FRIENDS IN IMMUNOLOGY WOULD HAVE SOLVED THE TOLERANCE PROBLEM AND KNOW HOW TO MANIPULATE THE IMMUNE SYSTEM. UNHAPPY TO SAY THEY HAVEN'T DONE IT. SO THIS IS DATA IN THE HA-22 TRIAL WE TREATED 35 PATIENTS, ONE ANN BODY AFTER ONE CYCLE, TWO AFTER SIX, THREE MORE AFTER SIX. DESPITE THIS WE HAD A 50, 60% CR RATE. IN MESOTHELIOMA AND OVARIAN CANCER 33 PATIENTS TREATED IN ONE TRIAL, 31 MET ANTIBODIES AFTER THREE DOSES ONE CYCLE SO WE NEED TO DO BETTER. THIS IS JUST FROM AN IMMUNOLOGY TEXTBOOK. SO WHAT CAN ONE DO? ON THE B CELL THERE'S A GERM LINE RECEPTOR, THE FIRST STEP IS BEHINDING HERE. IF WE ELIMINATE THE B CELL EPITOPE THIS WOULDN'T OCCUR. THE SECOND STEP IS AFTER THIS BINDS THIS IS PROCESSED, WE THOUGHT WE COULD DIMINISHED PROCESSING, I'LL TALK ABOUT THAT. THIRD STEP AFTER PROCESSING PRESENTATION OF MHC OF PEPTIDE TO THE T-CELL TO GET HELP AND WE THOUGHT WE COULD IDENTIFY AND CHANGE THE PEPTIDES. TO MAKE SOMETHING WITH LOW IMMUNOGENICITY IN HUMANS. SO WE BEGAN WORKING IN MICE AN HYPOTHESIZE MICE AND HUMANS HAVE SIMILAR B CELL EPITOPES SO WE MADE A BUNCH OF ANTI-P-38 ANTIBODIES AND USED THEM TO SHOW 7 EPITOPES. THE WAY WE DID IT IS BINDING STUDIES WITH EACH OF THE MONOCLONAL ANTIBODIES TO THE TOXIN IN THE PRESENCE OF ITSELF AND ALL THE OTHERS AND WE GET A COMPETITION MAP SO THIS GROUP COMPETES THAT DEFINES IN EPITOPE SO 7 COMPETING GROUPS OF 7 B CELL EPITOPES. WE HAD TO FIGURE OUT WHERE THE EPITOPES WERE AND HOW TO GET RID OF THEM SO WHAT WE DID TO FINE OUT WHAT THEY WERE IS MUTATED LARGE BULKY AMINO ACIDS ON THE SURFACE OF THE TOXIN. DOMAIN 2 AND 3, FRONT AND BACK. AND FOR EXAMPLE, ANY ONE OF THESE THREE RESIDUES, 490, 412, 575, THEY SOUND FAR APART IN THE LINEAR SEQUENCE BUT CLOSE TOGETHER IN THE SURFACE OF THE PROTEIN. THEN YOU DESTROY EPITOPE 5. WE DID THAT FOR ALL THE EPITOPES. SO WE MADE MUTATIONS AND FIGURED OUT WHERE EPITOPES WERE. THEN WE GOT RID OF THEM. SO WE STARTED WITH DOMAIN TWO. WE CAN GET RID OF ALL DOMAIN 2 BECAUSE OF A PARALLEL EXPERIMENT A POST DOC WAS DOING. SO WE THOUGHT WE WOULD TRY TO GET RID OF PROCESSING SITES BECAUSE I SHOWED ALREADY THAT YOU PROCESS THE TOXIN TO MAKE PEPTIDES FOR T-CELL EPITOPES. SO WE TREATED IMMUNOTOXINS, WHEN IT GOES TO THE CELL IT'S CLEAVED AND WE FOUND WHERE THE CUT SITES WERE. THEN WE MADE A SERIES OF MUTATIONS BUT THE FINAL MUTATION GOT RID OF ALL DOMAIN 2 EXCEPT A FURIN SITE NECESSARY FOR THE CELL TO SPRAY FROM THIS. WE CALL THAT HA-22LL LYSESOME RHESUS STAN. AS A CONSEQUENCE CLEARLY BECAUSE YOU HAVE GOTTEN RID OF EPITOPES IN DOMAIN 2. THIS MOLECULE IS KIND OF NICE BECAUSE IT RETAINS FULL ACTIVITY SOME CELLS FROM PATIENTS WITH CLL AND YOU TEST ITS ACTIVITY IN CULTURE RELATIVE TO HA-22, THE PARENT, YOU SEE A LOT MORE ACTIVE. IN THESE FIVE VARIES FROM 200 FOAL MORE ACTIVITY. MAYBE BECAUSE PROTEASES ARE DESTROYING THE IMMUNOTOXIN IN CLL CELLS AN THIS IS NOT HAPPENING SO THAT'S USEFUL, ACTIVE, MORE ACTIVE IN CLL AND WE GOT RID OF EPITOPES IN DOMAIN 2. IN DOMAIN 3 WE HAD POINT MUTATIONS BULKY AMINO ACIDS TO ALANINE. BY MAKING MUTATIONS AND COMBINATIONS WE ENDED UP WITH HA-22 LYSOSOME RESISTANT 8 MUTATIONS. THE 8 MUTATIONS ARE SCATTERED HERE IN DOMAIN 3. GLUTAMATE ALANINE, ARGININE, SO ON. THIS IS SCATTERED ON THE SURFACE. THIS MOLECULE IS FULLY ACTIVE, THIS IS A CYTOTOXICITY ASSAY IN A CELL LINE, THIS IS AN ANTITUMOR EXPERIMENT IN MICE WITH A CONTROL GOES LIKE THIS. THE PARENTAL HA-22 GIVEN AT THE MTD DOES THIS, THIS NEW MOLECULE WE CAN GIVE LARGE AMOUNTS BECAUSE IT'S NOT TOXIC TO MICE LIKE THE ORIGINAL MOLECULE, IS VERY, VERY ACTIVE GIVING COMPLETE RESPONSE AS SHOWN HERE. IT'S ACTIVE. THEN WE DID THE IMMUNOIN THISTY EMPERIMENTS IN MICE. WE -- O IMMUNOGENICITY EMPERIMENTS IN MICE. WE INJECT GREEN AND RED AND SO ON AND THIS IS THE IMMUNE RESPONSE TO THE PARENTAL ANTIBODY TITUS, DOES NOT INDUCE THE A SIGNIFICANT ANTIBODY RESPONSE IN MICE. WHAT IF WE PRECHALLENGE THE MICE AND ACTIVATE THE IMMUNE SYSTEM AND HAVE LOW LEVELS IN ANTIBODIES CHALLENGE AND THE PARENTAL HA-22, GOOD RESPONSE HERE NO RESPONSE. SO THIS MOLECULE IS NOT RECOGNIZED BY THE MOUSE IMMUNE SYSTEM WHEN GIVEN INTRAVENOUSLY AN CAN BE GIVEN MANY TIMES. THE ADDITIONAL BENEFIT, THIS IS SERENDIPITY, THE ADDITIONAL BENEFIT IS THAT THERE IS MODEL FOR VASCULAR CAPILLARY LEAK SYNDROME WE SEE IN OUR PATIENTS, IS IN RATS. WHAT HAPPENS IF YOU GIVE RATS IMMUNOTOXIN, AFTER 24 HOURS THEY'RE THICK AND THE CHEST IS FULL OF FLUID THAT LEAKED FROM THEIR LUNGS. THAT'S THE MODEL. THIS NEW MOLECULE HAS ADDITIONAL FEATURE THAT HAS THE LR DELETION AND THE 8 MUTATIONS OF NOT INDUCING CAPILLARY LEAK SYNDROME IN RATS. SO WE CAN GIVE 12 MGS PER KILO INSTEAD OF 3. SO WE PREDICT THE PATIENTS WILL HAVE LOWER IMMUNOGENICITY AND LESS CAPILLARY LEAK SYNDROME. FINALLY, WHAT ABOUT HUMANS? WE THOUGHT ANTIBODIES IN HUMANS AN MICE MIGHT BE SIMILAR BUT NOT IDENTICAL. OF COURSE SO IF IF YOU TAKE HUMAN ANTI-SERA, THIS IS HUMAN ANNSERA REACTING WITH THE NATIVE IMMUNOTOXIN 100%, YOU ASK HOW MUCH BETTER IS SOMETHING WITH A DOMAIN 2 DELETION LR, YOU CAN SEE IT'S LESS REACTIVE. IF YOU ADD IN AGO MUTATIONS LESS REACTIVE BUT STILL REACTIVE SO WE WANTED TO FIGURE OUT WHAT THE HUMAN EPITOPES WERE NOT REMOVED WHEN WE DEIMMUNIZED FROM THE MOUSE. TO DO THAT WE COULD NOT MAKE HYBRIDOMAS BUT COULD USE MOLECULAR TECHNOLOGY TECHNIQUES. WE COULD TAKE PATIENTS IN THE CLINICAL CENTER WHO MADE ANTIBODIES TO THE IMMUNOTOXIN, I TAKE THE B CELLS AN CLONE OUT O HEAVY AND LIGHT CHANGESQ#< AND DISPLAY THEM IN PHAGE. THEN WE PAN THE PAGE TO THE IMMUNOTOXIN TO ISOLATE THOSE THAT BOUND TO THE TOXIN, TO THE NAYSIVE TOK -- NATIVE TOXIN. WE HAD 710 CLONES WE GOT RID OF THOSE THAT BOUND TO DOMAIN 2 AND KEPT THOSE TO DOMAIN 3 AND EPITOPE MAPPING ON DOMAIN 3. THERE ARE A LIMITED NUMBER, 41 SPECIFIC FE'S THAT BOUND TO DOMAIN 3. BY LOOKING AT BINDING TO THE VARY YAWS MUTANTS THIS IS A PROTEIN THE D-403 ISA AND YOU CAN SEE THE BINDING OF THESE BUT NONE OF THE OTHERS. WE CAN DO EPITOPE MAPPING. SO WE FIND THAT APPROACH THERE ARE SIX MAJOR HUMAN EPITOPES. AND HERE IS WHERE THEY ARE. IN GREEN IS THE MOUSE I TALKED ABOUT, IN YELLOW, RED IS THE HUMAN AND IN YELLOW FOR BOTH. SO YOU CAN SEE THERE IS OVERLAP BUT ALSO DIFFERENCES. TO MY KNOWLEDGE THIS IS THE FIRST TIME THIS ANALYSIS HAS BEEN DONE. THIS IS THE FRONT VIEW, THIS IS THE BACK VIEW. WITH THAT INFORMATION WE CAN START MIXING AND MASHING -- MATCHING, BULKY AMINO ACIDS ARE REDUCED TO ALANINE. WE MADE THEM ALL LO 10, TWO OF THE MUTATIONS AND ADDED FOUR OTHER MUTATIONS THAT ARE HUMAN SPECIFIC. IT'S PRETTY ACTIVE, UNDOUBTEDLY ABOUT 6/10 ACTIVE ON CA-46 AB 3 OR 4/10 ACTIVE SO VERY ACTIVE BUT NOT 100% ACTIVE. THIS IS WHERE THE LOCATION OF MUTANTS ARE. THESE ARE MOUSE -- THINGS TO THE MOUSE EPITOPES, THESE GET RID OF THE HUMAN EPITOPES YOU CAN SEE IN DIFFERENT LOCATIONS THIS IS WHAT IS EXCITED ABOUT NOW BECAUSE OF DATA I'LL SHOW NEXT. IF YOU TESTED IN ANIMALS, IT'S ACTUALLY TURNS OW TO BE VERY ACTIVE IN OUR ANIMAL MODEL. IF YOU COMPARE IT WITH LR, IT IS ACTUALLY A LITTLE MORE ACTIVE AND CAN BE GIVEN LARGE AMOUNTS. DOES WORK FOR TUMOR REGRESSIONS. IF YOU LOOK IN THIS ASSAY WITH HUMAN ANTI-SERA, REMEMBER THIS IS 25 OF THE ONES WE ACT WITH THE NATIVE IMMUNOTOXIN THIS IS BETTER, 010 IS BEAR THAN THAT. THREE PATIENTS TREATED OVER TEN DAYS AGO THAT -- THAT STILL REACT AND MAYBE WHEN WE MADE THE IMMUNOTOXINS TEN YEARS AGO WE DIDN'T MAKE THEM AS CLEAN. WE'LL HAVE TO SEE. THAT'S WHERE WE STAND. I HAVE SHOWN WE GET RESPONSES IN PATIENTS AND WE HAVE ATTACKED THE PRBS OF IMMUNOGENICITY, IT'S MAJOR B CELL EPITOPES AND USE THE INFORMATION TO MAKE IMMUNOTOXINS WITH MUTATIONS THAT MAKE IT LESS ANTIGENIC. WHAT WE'RE PLANNING TO DO NOW, B AN T-CELL EPITOPES THAT I HAVEN'T TALKED TODAY IS TO PUT THESE TOGETHER TO MAKE A GENERATION OF IMMUNOTOXINS. WHICH I THINK HAVE LOW IMMUNOJE IN THIS AT THISTIVE AND NOT INDUCE CAPILLARY LEAK SYNDROME. AS FOR TESTING IN THE RELEVANT MODELS BEGINNING IN A FEW YEARS. THERE ARE A LOT OF PEOPLE IN MY LAB CONTRIBUTING TO THIS, FITZGERALD, WAIRN BUT OTHERS SHOWN HERE OVER THE YEARS MADE MAJOR CONTRIBUTIONS INCLUDING OF COURSE NURSES WHO LOOK AFTER OUR PATIENTS. I WANT TO THANK THE NCI WHICH HAS GIVEN WONDERFUL SUPPORT OVER THE YEARS. MED IMMUNE IN DEVELOPING (INDISCERNIBLE). THANKS. IF THERE ARE ANY QUESTIONS WE HAVE A FEW MINUTES, YOU CAN USE THE MICROPHONES. >> MAYBE I WOULD LIKE TO ASK YOU TO SPECULATE THE GENERALIZABILITY TO OTHER SOLID TUMORS, OBVIOUSLY BEAUTIFUL OPPORTUNITIES WITH CD 22 AND MESOTHELIN TO HAVE CELL SURFACE TARGETS FOR THIS ENTERPRISE. THERE'S WORK GOING ON TO IDENTIFYxGJ A SIMILAR CELL SURFACE PROTEIN USED FOR TARGET AD PROACHS TO SOLID TUMORS, YOUR OWN LAB IS DONE WORK AS WELL. HOW DO YOU THINK THEE WILL GO? WE LOVE TO SEE THIS TO BREAST CANCER, COLON CANCER, PROSTATE CANCER, LUNG CANCER AND ALL THOSE OTHER SOLID TUMORS DESPERATELY NEED NEW CREATIVE APROACH. >> WE DID USE THIS THERAPY TARGETING HER-2 NU BUT THERE'S ENOUGH IN THE LIVER TO GET LIVER TOXICITY. TUMORS HAVE A TEARIAL CIRCULATION SO IT TAKES FOREVER FOR THINGS TO GET IN. THEY HAVE NO CAPILLARIES SO EVERYTHING IS BY DIFFUSION, NOT CONVECTION. WE HAD ANOTHER ANTIGEN IN COLON CANCER. WE HAVE KIDNEY TOXICITY, SO IT'S HARD TO FIND A TARGET. WE LOOKED MANY YEARS IN PROSTATE AND BREAST. THINKING THAT MESOTHELIN SAYS I'M A MESOTHELIAL CELL. ONE INTERESTING THING IS IT GETS TURNED ON IN ALMOST ALL OVARIAN CANCER, ALMOST PANCREATIC CANCERS, STOMACH CANCERS, AND (INDISCERNIBLE) CAN KNOW MAS SO FRANCIS AT THE BOAG LSTEEN LECTURE HE POINTED OUT PATHWAYS ARE ACTIVATED SO THERE IS A PATHWAY THAT'S ACTIVATED, THAT TURNS ON MESOTHELIN IN OVARIAN OR LUNG CANCER AND THAT WOULD BE INTERESTING TO KNOW. THAT'S A SIDE EFNG. BUT WE DID NOT FIND IN PROSTATE OR BREAST SOMETHING THAT WE COULD TARGET THAT BY THIS HYPOTHESIS WOULD SAY BREAST AN BREAST CANCER AND NO WHERE ELSE. IT'S THE HOLY GRAIL OF THE PHARMACEUTICAL INDUSTRY. SO IN T AND B CELL MALIGNANCIES THERE'S DIFFERENTIATION ANTIGENS THERE AND THEY TARGET CD 20 MOST OBVIOUS BUT OTHERS SOLID TUMORS STILL THEY'RE NOT VERY MANY GOOD TARGETS. >> THANK YOU, EYE RA. WE'LL NOW GO ON TO OUR NEXT SPEAKER. WE'RE FORTUNATE HAS COME HERE TO PARTICIPATE IN SESSION. DR. H OORKSL DIETZ IS PROFESSOR OF FEED -- HAL DIETZ IS PROFESSOR OF MEDICINE GENETICS AT JOHNS HOPKINS SCHOOL OF MEDICINE. ALSO THE VICTOR KUSICK PROFESSOR OF MEDICINE IN GENETICS AT THE HOPKINS INSTITUTE OF GENETIC MEDICINE AS WELL AS HOWARD HUGHES MEDICAL INSTITUTE VAITOR. HE DEVELOPED THE CENTER FOR MARFAN CENTER FOR RESEARCH FOCUSED ON IMPROVING THE LIVES OF INDIVIDUALS WITH MARFAN SYNDROME THROUGH THE DEVELOPMENT OF DIAGNOSTIC AN TREATMENT STRATEGIES. EXTENSIVE AWARDS AND RECOGNITION INCLUDING THE INSTITUTE OF MEDICINE AND THE NATIONAL ACADEMY OF SCIENCES, WE'RE PLEASED HE'S COME TODAY TO ADDRESS MARFAN SYNDROME AND RELATED DISORDERS FROM MOLECULES TO MEDICINE. WELCOME. [APPLAUSE] >> SO IT'S REALLY A MEASURE AND A PRIVILEGE TO BE HERE TODAY AND TO JOIN YOU IN THIS IMPORTANT CAUSE OF PUBBLY SIZING RARE DISEASE RE-- PUBLICIZING RARE DISEASE RESEARCH. THE TITLE IS MARFAN SYNDROME AN RELATED DISORDERS FROM MOLECULES TO MEDICINE. I WALKED TO THE LIVING ROOM AND MY 15-YEAR-OLD WAS DESCRIBEING WHAT I DO FOR A LIVING. I WOULD LIKE THE SHARE THE QUOTE WITH YOU, IT WAS MARFAN SYNDROME, BLAH, BLAH, BLAH, BLAH, BLAH SO THAT WILL BE MY SUB TEXT FOR MY TALK TODAY. SO I WOULD LIKE TO START WITH A PERSONAL PHILOSOPHY. THAT THE STUDY OF MENDELIAN DISORDERS REPRESENTS AN OBLIGATION AN AN OPPORTUNITY, THE OBLIGATION RELATES TO THE FACT WHILE INDIVIDUALLY RARE THESE CONDITIONS ARE PERSONALLY BURDEN DENSOME AND CHECK TVLY COMMON. -- COLLECTIVELY COMMON. THESE PATIENTS WITH RARE GENETIC DISORDERS HAVE DISPROPORTIONATELY FUELED PROGRESS IN HUMAN GENETICS AN MOLECULAR THERAPEUTIC AT A PERSONAL COST DESPITE A REMOTE CHANCE OF PERM ADVANTAGE. THE OPPORTUNITY RELATES TO NATURE OF MENDELIAN DISEASE, THE SINGLE GENE BASIS OF THE DEFECT IMPLIES GENES AND PATHWAYS THAT SUFFICIENT TO CAUSE PHENOTYPES OF INTEREST AND TARGETABLE FOR THERAPEUTIC GAIN AND SUCH THERAPIES CAN BE EXPLORED IN MORE COMMON BUT COMPLEX PRESENTATIONS OF THE SAME PHENOTYPE. SO THE DISORDER WE HAVE CHOSEN TO STUDY FOR THE PAST 25 YEARS REALLY SERVES AS A WINDOW INTO THE PATHOGENESIS OF AORTIC ANEURYSM, A PHENOTYPE THAT KILLS 1 TO 2% OF EVERYONE IN INDUSTRIALIZED COUNTRIES. WE CHOSE TO STUDY THE MORE TRACKABLE PRESENTATION OF MARFAN SYNDROME AND AUTOSOMAL DOMINANCE CONDITION NOR TO GAIN A FOOTHOLD AND EXPLORE OUTWARD. AS MANY OF YOU KNOW MARFAN SYNDROME IS CONNECTIVE TIB SHOE WITH DOMINANT INHERITANCE AN PREVALENCE OF 1 IN 5,000. THE SYNDROME IS HIGHLY VARIABLE WITH CARDINAL FEATURES IN THE OCULAR SKELETAL AND CARDIOVASCULAR SYSTEMS INCLUDING DISLOCATION OF THE OCULAR LENS OVERGROWTH OF THE LONG BONES, BUT MOST IMPORTANTLY, PROGRESSIVE DILATION OF THE ROOT OF THE AORTA AT THE LEVEL OF THE SINUSES OF ALSALVA TO LEAD TO AORTIC TEAR RUNTURE AND EARLY DEATH IF UNTREATED. IN 1991 WE USED A POSITIONAL CANDIDATE APPROACH TO SHOW THAT MUTATIONS CAUSING MARFAN SYNDROME OCCUR IN THE GENE THAT ENCODES CONNECTIVE TISSUE PROTEIN FIBRILIN 1. WE KNEW THAT MONOMERS AGGREGATE TO FORM CLEX EXTRA CELLULAR STRUCTURES CALLED MICROFIBRIL AND THAT MICROFIBRILS CLUSTER AROUND THE END OF ELASTIC FIBER DURING EMBRYONIC GROWTH. THE SPATIAL AND TEMPORAL RELATIONSHIP LED TO THE THE FIRM BELIEF THAT YOU NEED A LATTICE OF MICROFIBRILS TO MAKE ELASTIC FIBER DURING EMBRYO GENESIS. AND P IF YOU THINK ABOUT IT, THIS BODED POORLY FOR DEVELOPMENT OF TREATMENT. IT SUGGESTED THAT CHILDREN WITH MARFAN SYNDROME ARE BORN WITHOUT ELASTIC FIBERS AND THEREFORE HAVE A OBLIGATE STRUCTURAL PRE-DISPOSITION FOR TISSUES TO FAIL LATER IN LIFE, THERE'S NOTHING YOU COULD DO AFTER BIRTH. I REMEMBER THE DAY AND EVEN THE MOMENT WALKING INTO A PATIENT ROOM SEEING FINGERS LIKE THESE THINKING THIS DOESN'T MAKE SENSE. WHY SHOULD WEAKNESS OF TISSUE CAUSE THE BONES TO OVERGROW? WHY SHOULD WEAKNESS OF IT SHALL SHIEWS CAUSE THE CRANIOFACIAL FEATURES OF MARFAN SYNDROME? ALL THESE WERE MORE SUGGESTIVE OF ALTERED CELLULAR PERFORMANCE RATHER THAN SIMPLE TISSUE WEAKNESS. TO SUMMARIZE FIVE YEARS OF WORK IN A SLIDE, WE SHOWED THAT MICROFIBRILS COMPOSED OF FIE BRING LYNN 1 BIND LARGE LATENT COMPLEX OF THE MULTI-POTENTIAL CYTOKINE TGF BETA. AND FAILURE OF SEQUESTRATION DUE TO INSUFFICIENCY OF MICROFIBRILS SUCH AS IN MARCH FAN SYNDROME LEADS TO TGF BETA ACTIVATION. FREE TGF BETA CAN INTERACT WITH CELL SURFACE RECEPTOR AND INITIATE AN INTRACELLULAR SIGNALING CASCADE THAT INCLUDES PHOSPHORYLATION OF SMAD 2 OR 3 AND PART MER WITH SMAD 4 OR TRANSLOW COLLATE TO NUCLEUS AN MEDIATE TRANSCRIPTIONAL RESPONSES MOST IMPORTANTLY WE SHOWED EXCESS OF TGF BETA SIGNALING HAS PHENOTYPIC CONSEQUENCES, INCLUDING EMPHYSEMA, MITRAL VALVE PROLAPSE AND SHOWING MANIFESTATIONS COULD BE RESCUED IN FIE BRING LYNN 1 DEFICIENT MICE BY INJECTING THE THE MICE WITH A PAN-SPECIFIC TGF BETA NEUTRALIZING ANTIBODY. HOW -- WE WENT ON TO ASK IS THERE A DRUG OR BETTER AN FDA APPROVED DRUG THAT MIGHT MIMIC THIS PROTECTIVE EFFECT? IT TUSHED TO THE ANGIOTENSI RECEPTOR LOZARTAN, GOOD FOR PEOPLE WITH ANEURYSM BUT ALSO SHOWN TO ATTENUATE TGF BETA ACTIVITY IN RODENT MODELS OF CHRONIC KIDNEY DISEASE. HOW DOES LOZARTIN WORK? ANGIOTENSIN 2 THROUGH INTERACTION WITH TYPE 1 RECEPTOR INCREASES PRODUCTION OF TGF BETA LIGANDS AND RECEPTORS AND STIMULATE EXPRESSION OF IMPORTANT ACTIVATORS SUCH AS THROMBO SPONDIN. IN CONTRAST ANGIOTEN SIN THROUGH TYPE 2 RECEPTOR ANTAGONIZES MANY OF THESE EVENTS. SO WE REASON THAT SELECTIVE AT 1 BLOCKADE WITH ANGIOTEN SIN RECEPTOR SUCH AS LOZARTIN NOT ONLY BLUNTS THE CULPRIT PATHWAY BUT STIMULATES SIGNALING THROUGH A PROTECTIVE PATHWAY. WE WENT ON TO DO A BLINDED TRIAL IN OUR MOUSE MODEL OF MARFAN SYNDROME AND FOUND THAT WILD TYPE ANIMALS HAVE A PREDICTABLE RATE OF AORTIC GROWTH OVER TIME THAT PLACEBO TREATED MARFAN MICE SHOW ACCELERATED AORTIC GROWTH. IF WE USE THE BETA ADROANERGIC RECEPTOR BLOCKER PROPRANOLOL THAT LOWERS BLOOD PRESSURE BUT DOES NOT ADDRESS TGF BETA WE SAW A BLUNTING OF AORTIC GROWTH BUT IT STILL REMAINED QUITE ABNORMAL AND THE ANIMALS DID GO ON TO HAVE AORTIC DISSECTION. IN CONTRAST WITH MARFAN MICE WITH LOZARTIN WE SAW FULL NORMALIZATION OF GROWTH BUT FULL PRODUCTIVE REMODELING OF THE AORTIC WALL WITH BLINDED OBSERVERS UNABLE TO DISTINGUISH MARFAN FROM WILD TYPE LITTER MATES BY A PARAMETER. AND THIS PROTECTION DID ASSOCIATE SIGNIFICANT ANTAGONISM WITH TGF BETA MEDIATED ACTIVATION OF SMAD 2. UP TO THIS POINT I FOCUSED ON SO-CALLED SMAD-DEPENDENT OR CONONCAL TGF BETA SIGNALING. BUT IT'S ALSO KNOWN TGF BETA ACTIVATED RECEPTORS CAN ALSO STIMULATE SO-CALLED NON-CONONCAL CASCADES INCLUDING THE MITE GENERAL ACTIVATED PROTEIN KINASES ERK JUNK AND P-38. SO WE DECIDED TO DETERMINE WHETHER THE NON-CANONCAL CASCADES PLAY AD ROLE IN DISEASE PATHOGENESIS. WHEN WE LOOKED AT THE ASCENDING AORTA IN THE MOUSE MODEL WE SAW EXCESSTIVE ACTIVATION OF SMAD 2 AS I HAVE SHOWN. BUT A MORE DRAMATIC ACTIVATION OF IRK MAP KINASE AN CORRESPONDING ACTIVATION OF MEK, THE ENZYME THAT PHOSPHORYLATES ERK, WE DIDN'T FIND EVIDENCE FOR INVOLVEMENT OF NON-CANONCAL CASCADES INCLUDING JUNK AND P-38. BASED ON WHAT I TOLD YOU, IF ERK IS IMPORTANT, IT MUST BE TGF BETA DEPENDENT BECAUSE TGF BETA NEUTRALIZING ANTIBODIES WORKS SO WELL. THIS TURNED OUT TO BE THE CASE, IF YOU TREAT MICE WITH TGF NEUTRALIZING ANTIBODY LEVELS GO BACK TO NORMAL. BASED UPON WHAT I TOLD YOU IF ERK IS IMPORTANT IT SHOULD BE A T-1 DEPENDENT AND THIS TURNED OUT TO BE TRUE IF YOU TREAT MARFAN MICE WITH LOZARTIN LEVELS ARE DRIVEN BELOW NORMAL. SO WHILE WE WENT ON TO ASK WHETHER ERK ANTAGONISM IS A PRODUCTIVE STRATEGY FOR MARFAN MICE, IN COLLABORATION WITH A GENOMICS INITIATIVE OF THE TREND PROGRAM, WE GAINED ACCESS TO ORALLY BIOAVAILABLE HIGHLY POTENT AND SELECTIVE ERK ANTAGONIST CALLED RDEA 119. WHEN WE TRIED IT IN OUR MARFAN MOUSE MODEL IT WAS EVERY BIT AS GOOD AS LOZARTIN PREINVENTORYING ABNORMAL GROWTH USING CURRENT DOSING REGIMENS, IT CAUSED A MODEST BUT SIGNIFICANT REGRESSION IN AORTIC SIZE OVER TIME. WE CAN SHOW THAT REA 119 IS HIGHLY SELECTIVE FOR ERK. IT HAD NO EFFECT ON ANY OTHER SIGNALING CASCADES THAT ARE KNOWN TO BE ACTIVATED BY TGF BETA. SO ALL NEWS ISN'T GOOD NEWS. WE DECIDED TO TEST OTHER ANTI-HYPERTENSIVE AGENTS AND OUR ATTENTION TURNED TO CALCIUM CHANNEL BLOCKERS BECAUSE THEY'RE CURRENTLY THE SECOND LINE ANTI-HYPERTENSIVE AGENTS IN MARFAN PATIENTS UNABLE TO TOLERATE BETA BLOCKERSCH THERE WAS INTERESTING IN THE LITERATURE THAT SUGGESTED THAT THIS WAS A PRODUCTIVE APPROACH. IT WAS SHOWN THE CALCIUM CHANNEL BLOCKER M LOAD PEEN REVERSES ERK ACTIVATION IN SPONTANEOUSLY HYPERTENSIVE RATS AND OTHER CALCIUM CHANNEL BLOCKERS CAN REDUCE ACTIVATION IN SYNERGY WITH ANGIOTEN SIN RECEPTOR BLOCKERS SUCH AS LOZARTAN. SO WE WERE ACTUALLY QUITE OPTIMISTIC INTO THIS TRIAL WHICH INVOLVED THE USE OF M LOAD PEEN AT DOSE OF 15-MILLIGRAMS PER KILO PER DAY. HERE I SHOW YOU THE ASCENDING AORTA OF WILD TYPE MOUSE, AND MARFAN MOUSE UNCRETED THERE'S SELECTIVE IN THE BASE EMBEDDED IN THE LEFT VENTRICULAR OUTFLOW TRACK. IF WE GAVE WILD TYPE M LOAD PEEN, NOT MUCH DIFFERENCE, THE SEN THE SENDING AORTA AND ARE LOOKING GENEROUS BUT WE LEN PED MARFAN MICE TREATED WITH LOADPEEN DEVELOPED MASSIVE ASCENDING AORTIC ANEURYSMS WITHIN SEVEN DAYS UP TO 21 DAYS OF TREATMENT AND BY 4 WEEKS AFTER INITIATING TREATMENT THEY'RE ALL DEAD DUE TO AORTIC DISSECTION. WHEN WE LOOK AT THE HISTOLOGY WE FOUND THAT ALL THE ABNORMALITIES SEEN IN OUR MARFAN MICE NOT TREATED INCLUDING THICKENING OF THE AORTIC WALL, FRAGMENTATION OF ELASTIC FIBERS AND ACCUMULATION OF MATRIX WERE GREATLY EXAGGERATED IN M LOAD PEEN MARCH FAN MICE TRULY INTENSE FIBROPROLIFERATIVE RESPONSE. WHICH WOULD BE INDICATIVE OF KNOWN ACTIVITIES OF TGF BETA OF A PRO FIBROTIC CYTOKINE. WE WENT TO QUANTIFY THIS RESULT. AND FOUND BOTH AORTIC ROOT GROWTH RATE AND DRAMATICALLY ASCEND AGO YOUR TICK GROWTH RATE ARE GREATLY ACCELERATED IN MARFAN MICE RECEIVING CALCIUM CHANNEL BLOCKERS. THIS PARTICULAR MOUSE MODEL DOES NOT EXPERIENCE DEATH DUE TO AORTIC DISSECTION WHEN LEFT UNTREATED BUT WHEN YOU TREAT WITH M LOAD PEEN YOU SEE DRAMATIC DECLINE DUE TO AORTIC DISSECTION. WE LOOK AT SIGNALING EVENTS AND FOUND THAT UNEX-PRESIDENTEDLY IS CAUSING ACCENTUATION OF BOTH SMAD AND IRK ACTIVATION IN THE ASCENDING AORTA OF MARFAN MICE AND WE SHOWED IDENTICAL RESULTS FOR OTHER CLASSES OF CALCIUM CHANNEL BLOCKERS INCLUDING NON-DI HYDRO PURE DEAN AGENTS SUCH AS (INAUDIBLE) SO THIS IS A CLASS EFFECT RARE THAN SPECIFIC TO M LOAD PEEN. WE WENT TO ASK IS,RK ACTIVATION THE CAUSE OF THIS SYNTHETIC PHENOTYPE AND THIS TURNED OUT TO BE THE CASE. IF YOU GIVE MARFAN MICE M LOAD PEEN YOU SEE INCREASE IN ASCEND AGO YOUR TICK GROWTH WITH 25% MICE DEAD AT THE TIME OF THIS ASSAY WHICH IS TWO MONTHS AFTER STARTING TREATMENT. IF YOU SIMULTANEOUSLY GIVE ERK ANTAGONIST YOU CAUSE DRAMATIC DECREASE IN ASCENDING AORTIC SIZE AND FULL PREVENTION OF LETHALITY DUE TO AORTIC DISSECTION SO THROUGH STUDY WE IDENTIFIED IMPORTANT GENE BY ENVIRONMENT INTERACTION THAT HAS DIRECT RELEVANCE TO PATIENTS WITH MARFAN SYNDROME AND WE'RE CURRENTLY COLLABORATING WITH THE GENTECK CONSORTIUM OF NHLBI TO EXPLORE RELEVANCE OFFER FININGS TO PEOPLE WITH MARFAN SYNDROME AN RELATED DISORDERS. THIS SIGNIFICANCE OF THESE FINDINGS EXTENDS BEYOND MARFAN SYNDROME. IN FACT, THERE'S NOW A LARGE GROUP OF CONDITIONS CALLED THE VASCULOPOTHY THAT SHOW VERY HIGH TGF BETA SIGNALING IN THE VESSEL WALL INCLUDING MARFAN SYNDROME, LORKSOWI DEET SYNDROME, THIS COMES IN MANY FLAVORS BASED UPON PHENOTYPE. ARTERIAL VIRTUE WOSTY SYNDROME, BICUSPID AORTIC VALUE FL WITH ANEURYSM, FAMILIAL AORTIC ANEURYSM AND RECESSIVE (INDISCERNIBLE). THE INTERESTING PERPLEXING FINDING IS THAT WHILE ALL OF THESE CONDITIONS ARE ASSOCIATED WITH TISSUE SIGNATURE FOR HIGH TGF BETA SIGNALING DURING ANNUAL REGRESSION SOME ARE ASSOCIATED WITH PRIMARY GENETIC DEFECT THAT WOULD INTUITIVELY LEAD TO TOO LITTLE TGF BETA SIGNALING. MUTATIONS IN THE KINASE DOMAIN OF THE TGF BETA RECEPTOR AND RECEPTOR SMAD 3 OR BETA LIGAND TGF BETA 2. THIS IS REALLY ENGENDERED CONTROVERSY IN THE FIELD. AND WE THOUGHT A PATH FORWARD WOULD BE TO IDENTIFY GENETIC MODIFIERS OF ANEURYSM PROGRESSION IN BOTH PEOPLE IN MICE WITH MARFAN SYNDROME. WE ASKED HOW DOES NATURE MODIFY? WE PERFORMED LINKAGE ANALYSIS IN FIVE TRULY EXCEPTIONAL FAMILIES THAT SHOWED DISCREET MODIFICATION OF THE ANEURYSM PHENOTYPE. AMONG MUTATION CARRIERS HALF THE INDIVIDUALS HAD TEN CENTIMETER AYOURTIES BY THE TIME THEY WERE 20 WHILE THE OTHER HALF HAD NORMAL DIMENSIONS AT THE AGE OF 630. IF THERE WAS LOCUST HETEROGENEITY WE WERE GOING TO BE UNSUCCESSFUL BECAUSE WE LACK THE POWER BUT ALL FIVE FAMILIES SHOWED THE SAME MODIFIER LOCUST LEADING TO A CUMULATIVE SCORE OF OVER O 4, A TRUE LOCUS FOR PROTECTION NOW MAPPED TO CHROMOSOME 6. THERE'S A 3 MILLION BASE PAIR FAMILIAR HAPLOTYPE SEGREGATED TO ALL 20 EFFECTED BUT PROTECTED INDIVIDUALS BUT ONLY UP TO 2 OF 19 UNPROTECTED INDIVIDUALS AND THIS WAS HIGHLY SIGNIFICANT. SO WE'RE WOKING OR WAY THROUGH THIS INTERVAL BUT EXCITED TO SEE A NUMBER OF GENES THAT ARE GOOD CANDIDATES INCLUDING THE MASS 1 GENE THAT ENCODES THE RECEPTOR FOR THE NATURAL ANTAGONIST OF ANGIOTENSIN TYPE 1 SIGNALING, ANGIOTENSIN 1-7. IG 2FR WHICH PARTICIPATES IN ACTIVATION AND MAP 3 K 4 AN IMPORTANT MAP KINASE KINASE. WE ALSO WANT TO EXPLORE THE CONCEPT IN MICE. THE OBSERVATION IS LITERALLY DOZENS OF MA EWE SCRIPPS DOCUMENT THE C-57 BLACK SIX BACKGROUND EXACERBATES TGF BETA DEFICIENCY PHENOTYPES INDUCED BY HOMOZYGOUS TARGETED SILENTING OF TGF BETA LIGANDS OR INTRACELLULAR SIGNALING OF RECEPTORS. INDUCES A RELATIVE DEFICIENCY STATE FOR TGF SIGNALING. THE OPPORTUNITY WAS TO DETERMINE WHETHER THE MARFAN ANEURYSM PHENOTYPE IS ATTENUATED OR ACCENTUATED ON THE BLACK SIX BACKGROUND, IF ATTENUATED AS WE PREDICT THIS PROVIDES SUPPORT FOR HIGH TGF BETA SIGNALING IN THE PATHOGENESIS OF ANEURYSM PROGRESSION. SO JEFF DOYLE IN MY LAB HAS COMPLETED THIS ANALYSIS AND THE BLACK 6 IS REMARKABLY PROTECTED. THERE'S VERY MODEST ROOT SIZE AND AORTIC GROUP GROWTH RATE WITH THE MUTATION ON THE BLACK 6 BACKGROUND AND ZERO DEATH DUE ATOR TICK -- AORTIC DISSECTION. IF YOU PLACE THE SAME ON THE HIGH TGF BACK GROWN, 129 BACKGROUND, THERE'S SIGNIFICANT INCREASE IN AORTIC SIZE, A DRAMATIC INCREASE IN GROWTH RATE AND FREQUENT DEATH DUE TO DISSECTION. WE HOPE TO BE ABLE TO MAP THE MODIFIERING OF DEFINED STRAIN DIFFERENCES, WE WERE TOLD THIS WAS NOT GOING TO BE SUCCESSFUL BECAUSE IT WOULD BE MANY LOCI. BUT WE DETERMINED TO DO IT ANYWAY AND TURNS OUT THERE'S A SINGLE LOCUS ON MOUSE CHROMOSOME 9 THAT ACCOUNTS FOR THIS VARIATION IN OUTCOMES WITH TGF BETA RELATED PHENOTYPES. SO WE'RE CURRENTLY WORKING OUR WAY THROUGH THIS REGION BUT THERE'S A NUMBER OF ATTRACTIVE CANDIDATES. SO NOW A DIFFERENCE PHENOTYPE, WE KNEW RELATIONSHIP TO FIBROTIC DISEASE AN THEREFORE DEVELOPED AN INTEREST IN SCLERODERMA, HARDENING OF THE SKIN DUE TO PROGRESSIVE FIBROSIS. IT'S MOST COMMON SEVERE PRESENTATION CALLED SYSTEMIC SCLEROSIS, A POSTNATALLY ACQUIRED PHENOTYPE IN YOUNG ADULT HOOD ASSOCIATED WITH PROGRESSIVE FIBROSIS OF THE SKIN AN VISCERA AN TENSE PERIPHERAL CONSTRICTION, PRODUCTION OF AUTOANTIBODIES AN LINKED TO TGF BETA. OBSTACLES TO PROGRESS IN THE STUDY OF SYSTEMIC SCLEROSIS INCLUDE GENETIC CONTRIBUTION, LACK OF LARNG FAMILIES AN ABSENCE OF ANIMAL MODELS SO AKIN TO OUR WORK WITH ANEURYSM THAT STARTED WITH MARFAN SYNDROME WE DECIDED TO FOCUS ON A RARE BUT MENDELIAN PRESENTATION OF SCLERODERMA CALLED STIFF SKIN SYNDROME. THIS IS A CONGENITAL PRESENTATION, THERE ARE NO AUTOANTIBODY, PERIPHERAL VASOCONSTRICTION, THERE'S 40 CASES IN THE LITERATURE, IT'S AUTOSOMAL DOMINANT WITH PEN TRANSAN FOUR EXTENDED PEDIGREES IN OUR CLINIC AT HOPKINS. THROUGH A LONG SERIES OF EVENTS THAT I CAN'T DESCRIBE GIVEN TIME LIMITS WE ULTIMATELY SHOWED THAT ALL THESE FAMILIES HAVE MUTATIONS IN FIE BRING LYNN 1. THE GENE WE STUDIED 25 YEARS DESPITE THE FACT THESE PATIENTS HAVE NO PHENOTYPIC MANIFESTATION OF MARFAN SYNDROME. UP LIKE THE SYNDROME WHERE MUTATIONS OCCUR ALONG THE LENGTH OF THE GENE IN PROTEIN N STIFF SKIN SYNDROME ALL MUTATIONS OCCUR IN THE 4TH 815 DOMAIN OF FIE BRING LYNN 1, THEY CREATE SISTINE REVENUES. IF YOU LOOK UPSTREAM IN THE DOMAIN YOU FIND CLASSIC MARFAN SYNDROME. IF YOU LOOK DOWNSTREAM SISTINE DOMAIN YOU FIND IDENTICAL MUTATIONS CAUSING CLASSIC MARFAN SYNDROME. SO THIS BEGS THE QUESTION, WHAT IS SO SPECIAL ABOUT THE FOURTH 8TH SISTINE DOMAIN OF FIEBRILIN ONE, IT'S THE ONLY DOMAIN THAT ENCODES AN RGC SEQUENCE MEDIATED BY BINDING TO CELLS. THERE ARE MULTIPLE INTEGRIN SUBTYPES INCLUDING ALPHA 5 BETA 1, ALPHA V BETA 6 KNOWN TO BIND TO THE THE RGD SEQUENCE IN FIBRILIN 1 SO TO BETTER UNDERSTAND THIS PROCESS WE MADE MOUSE MODELS OF STIFF SKIN SYNDROME, WE HAD THE TRYPTOPHAN ASSISTING SUBSTITUTION SEEN IN TWO FAMILIES WITH THIS DISORDZ, IN THE OTHER LINE WE CHANGED THE RGD SEQUENCE TO RGE WHICH LEADS TO OBLIGATE LOSS OF INTEGRIN BINDING ALLOW US TO ASK IS THIS TRULY THE CRITICAL INITIATING EVENT. AND TO OUR DELIGHT WE FOUND MICE WITH THE STIFF SKIN SYNDROME MUTATION SHOWED DENSE DERMAL FIBROSIS BY 3 MONTHS OF AGE, IF THIS MUTATION IS BRED TO HOMOZYGOSITY THE PROCESS IS ACCELERATED AND THE RGE MICE PERFECTLY RECAPITULATE THE SKIN FIBROTIC PHENOTYPE. WE FOUND IN CELLS FROM MOUSE LINES, THERE IS INCREASED EXPRESSION OF BETA 3 INTEGRIN AND BETA 1 INTEGRIN AT THE CELL SURFACE. THIS SUGGESTIONS WHEN LOSE THE ABILITY TO DETECT THEIR MATRIX LIGANDS THROUGH INTEGRINS, THERE'S A COMPENSATORY UP REGULATION OF BETA 1 AND 3 INTEGRIN. WE WANDERED WHAT WOULD HAPPEN IF WE TRICK THE CELLS TO BELIEVING THEY FOUND THEIR MATRIX LIGAND. SO WE TREATED THE MICE WITH A BETA 1 INTEGRIN ACTIVE ANTIBODY AND ASSESSED FOR PHENOTYPIC EMPERIMENT. -- BENEFIT. SO FOR THIS EXPERIMENT 8 IN THE LAB PICKED UP 15 MICE IN EACH GROUP AND GAVE A CLINICAL STIFFNESS SCORE. ALL DONE BLIENED TO GENOTYPE AND TREATMENT ARM. WE FOUND WITH FIELD TYPE MICE WITH RELEVANT IGG OR BETA 1 ANTIBODY THE STIFFNESS WAS LOW. IN RGE MOUSE LINE AND MOUSE LINE WHEN IGG WAS GIVEN THERE WAS VERY HIGH SKIN STIFFNESS. IN BPO LINES TREATMENT FOR SIX WEEKS WITH WITH BETA ONE INTEGRIN ACTIVATING ANTIBODY WAS ABLE TO PREINVENTORY SKIN FIBROSIS. WE CAN SHOW THAT THE BETA ONE INTEGRIN ACTIVATING ANTIBODY WAS HAVING THE DESIRED EFFECT BECAUSE AN ANTIBODY THAT ONLY RECOGNIZES BETA 1 GE GRIN AN ACTIVE CONFIRMATION SHOWS THIS INCREASE IN REACTIVITY UPON TREATMENT WITH THIS ACTIVATING ANTIBODY. TO DO THIS IN A QUANTITATIVE MANNER THE MOUSE WERE ANECESSARY ANESTHETIZED AN SHAVED ON THEIR BACK SKINS SO WE CAN STRETCH THE AREA TO TOTAL SKIN AREA. HERE ARE STIFF SKIN AN RGE MICE, YOU CAN APPRECIATE THEIR SKIN IS EXTREMELY STIFF. BUT IF THEY'RE TREATED WITH BETA 1 INTEGRIN ACTIVATING ANTIBODY THEY HAD A PERFORMANCE THAT INDISTINGUISHABLE FROM WILD TYPE ANIMALS. IF YOU LOOK AT SKIN HISTOLOGY, IF YOU GIVE A RELEVANT IGG, BOTH MUTANT MOUSE STRAINS HAVE DENSE DERMAL MYFIVEBOROSIS WITH COMPLETE LOSS OF FIBROSIS, BUT IF YOU TREAT WITH ACTIVATING ANTIBODY THE SKIN MORPHOLOGY IS NORMAL. WE WENT TO ASK IS TGF BETA INVOLVED? THIS IS A LITTLE BIT OF A DIFFERENT EXPERIMENT. HERE WE ALLOWED THE MICE TO ATTAIN ESTABLISHED SKIN FIBROSIS AT THREE MONTHS OF AGE AND THEN TREATED THEM WITH A PAN SPECIFIC TGF BETA NEUTRALIZING ANN BODY. WE THEN ASSESSED SKIN STIFFNESS AT SIX MONTHS OF AGE. ONCE AGAIN F YOU GIVE IGG OR NEUTRALIZING ANN BODY TO WILE TYPE ANIMAL THERE'S A LOW SKIN STIFFNESS IN UNTREATED MICE THERE'S HIGH STIFFNESS. HERE WITH SHOW TREATMENT WITH TGF BETA NEUTRALIZING ANTIBODY REVERSE ESTABLISHED SKIN FIBROSIS. HERE I SHOW HISTOLOGY, WINCE AGAIN -- ONCE AGAIN I'VE GIVING TGF BETA NEUTRALIZING ANTI-BE DI STORES SUB DERMAL FAT AND REDUCES COLLAGEN DEPOSITION. THESE DATA SUGGEST THAT TGF BETA IS INVOLVED, INTEGRINS ARE INVOLVED BUT THE MECHANISM OF INTERACTION WAS UNCLEAR. DOES ACTIVE BETA 3 INTEGRIN PROVIDE A CRITICAL CONTRIBUTION? SO TO ASSESS WE BRED OUR STIFF SKIN SYNDROME ANIMALS TO BETA 1 INTEGRIN TARGETED ANIMALS TO GENERATE HE ROSY GOATS OR NULL MICE FOR BETA 3 INTEGRIN N. WILD TYPE ANIMALS THIS TARGETING MADE NO DIFFERENCE. IN RG AND STIFF SKIN SYNDROME MICE WITH NORMAL 3 INTEGRIN ALLELES THERE WAS HIGH STIFFNESS AND TARGETING ONE ALLELE OR BOTH ALLELES WAS ABLE TO LEAD TO DRAMATIC PHENOTYPIC RESCUE. NOW WE RETURN TO THE MYSTERIOUS FORM OF SCLERODERMA. THIS IS EXPERIMENTS WE STUDY DERMAL FIBROBLASTS FROM THESE PATIENTS AN WE WERE SURPRISED AND DELIGHTED TO SEE CONCORDANT FINDINGS INCLUDING HIGH LEVELS BETA 12 INTEGRIN AND BETA 3 INTEGRIN AT THE CELL SURFACE. BROUGHT DOWN TO NORMAL WITH BETA INTEGRIN ANTIBODY. WE WENT TO ASK WHETHER BETA 1 INTEGRIN ACTIVATING ANN BODY OR TGF INHIBITORS REDUCE COLLAGEN EXPRESSION BY CELLS. SO AGAIN, SYSTEMIC SCLEROSIS FIBROBLASTS PRODUCE VERY LARGE AMOUNTS OF TYPES 1 AND 3 COLLAGEN. IF YOU GIVE IT ACTIVATING ANTIBODY OR TGF BETA INHIBITOR, THIS SYNTHETIC REPERTOIRE IS NORMALIZED. THIS TURNED OUT A VERY IMPORTANT EMPERIMENT. WE TAKE CONTROL FIBROBLASTS OR SCLEROSIS FIBROBLASTS, TREATING WITH TGF BETA IN PRESENCE OR ABSENCE OF BETA INTEGRIN ACTIVATING ANTIBODY OR BETA 3 INTEGRIN BLACKING ANTIBODY. WITH A CONTROL CELL YOU CAN SEE THE EXPECTED ACTIVATION OF SMAD 3 NOT INFLUENCED BY ANTIBODY TREATMENT AND VERY LITTLE IF ANYTHING GOING ON WITH ERK ACTIVATION. BUT IF YOU LOOK AT CELLS FROM PATIENTS WITH SYSTEMIC SCLEROSIS YOU SEE AN EXAGGERATED SMAD ACTIVATION RESPONSE WITH NO BLUNTING OF THIS WITH BETA 1 OR BETA 3 INTEGRIN MODULATING ANTIBODIES. LOOK WHAT HAPPENED TO ERK. IN THE PRESENCE OF HIGH BETA 1 AND 3 INTEGRIN, YOU NOW HAVE ROBUST ERK ACTIVATION IN RESPONSE IN RESPONSE TO LIGAND. THIS ABNORMAL RESPONSE IS NORMALIZED BY TREATMENT WITH ACTIVATING ANTIBODY OR BLOCKING ANTIBODY. THIS WASN'T A QUIRK OF CELL LINES, WE RECEIVE THE SAME TGF BETA LIGAND SUGGESTING IT IS A DIRECT EFFECT. SO OUR NEW MODEL IS WHEN INTEGRINS ARE FINDING THEIR MATRIX LIGAND AND IMPORTANT FOORKSIBRILIN 1 THAT IS ACTIVATING SMAD BUT SMALL EXTENT ACTIVATING ERK WHEN THERE'S UP REGULATION OF BETA 1 AND 3 INTEGRIN THIS INFLUENCES THE INTRINSIC PERFORMANCE OF TGF BETA RECEPTORS WHICH SHOWS INCREASE IN SIGNAL BUG A SPECIFIC NOW PREFERENCE FOR ERK ACTIVATION. SO WE WONDERED WHAT IS THE INTRACELLULAR MEDIATOR OF THIS FIBROTIC RESPONSE. WE WONDERED WHETHER MICRORNAs MIGHT BE INVOLVED A SPECIFIC MICRORNA MERE 29 MIGHT BE AT WORK. THIS IS BECAUSE OF PRIOR WORK BY THE OLSON LAB SHOWING MERE 29 SUPPRESSES THE EXPRESSION REA LAY WHO'S WHO OF TISSUE FIBROSIS INCLUDING COLLAGEN ONE AND 3. SO IT IS KNOWN DECREASE IN MERE 29 LEAD TO INCREASE IN HE CAN PRESENTATION CULMINATING IN FIBROSIS AND WE WONDERED WHETHER THIS CAN HAVE RELEVANCE TO SCLERODERMA. IN OUR STIFF SKIN MOUSE MODELS WE FOUND LOW LOAFLS OF MERE 29 EXPRESSION IN THE DERMIS BY RT PCR AND QUANTITATIVE NORTHERN ANALYSIS. WE FOUND LOW LEVELS OF MERE 29 IN SYSTEMIC SCHOAR ROWSIS FIBROBLASTS WHEN COMPARED THE TO CONTROLS. WE FOUND WHEN TREATED THESE SUBORO BLASTS WITH BETA ONE INTEGRIN ACTIVATING ANTIBODY, MERE 29 LEVELS SO BACK UP TO NORMAL IN A DOSE DEPENDENT MANNER AND EXPRESSION OF MERE 29 TARGETS INCLUDING BOTH TYPES ONE AND 3 COLLAGEN BACK DOWN TO NORMAL. WE CAN BLOCK OR NORMALIZE MERE 29 EXPRESSION BY TREATMENT WITH THE ERK ANTAGONIST UO 126. WHEN WE BLOCK ERK ACTIVITY MERE 29 LEVELS ARE BACK TO NORMAL. THERE'S A SIGNIFICANT REDUCTION IN COLLAGEN EXPRESSION. SO REMARKABLE SEVEN YEARS AGO WE HAD THIS MODEL. THAT CONNECTIVE IT SHALL SHOE DISORDERS CAUSED BY ABNORMALITIES CAUSE INTRINSIC MATRIX WEAKNESS LEADING TO TISSUE FAILURE AND THAT THERE'S NOTHING YOU CAN DO ABOUT IT. WE CURRENTLY USE MOUSE MODELS THAT HAVE SHOWN 8 DIFFERENCE EFFECTIVE THERAPIES FOR RELATED PHENOTYPES AND IMPORTANTLY ADD CAUTION WITH POTENTIAL USE OF OTHER MEDICAL THERAPIES. MY FINAL CONCLUSION IS FINAL UNDERSTANDING OF DISEASE PATHOGENESIS REVEALED UNANTICIPATED STRATEGIES FOR THE RESCUE OF MULTI-SYSTEM MASS FES STATIONS OF MARFAN SYNDROME, SCLERODERMA AND OTHER DISORDERS. THESE ARE ILLUSTRATIVE OF THE PROMISE THAT DISEASE GENE IDENTIFICATION OF HARDER WORK OF ELUCIDATING PATHOGENESIS FOR RARE MENDELIAN DISORRERS RESULT IN THE DEVELOPMENT OF NOVEL TREATMENTS WITH BROAD APPLICATION. I WOULD LIKE TO ACKNOWLEDGE THE TRULY REMARKABLE PEOPLE THAT I HAVE THE PRIVILEGE OF WORKING WITH EVERY DAY, THE PEOPLE IN MY LAB THAT DID THE WORK THAT I SPOKE ABOUT TODAY HIGHLIGHTED IN RED. ACKNOWLEDGE MY COLLABORATORS AT OTHER INSTITUTIONS THAT MADE IMPORTANT CONTRIBUTIONS AND MY FUNDING SOURCES. I THANK YOU FOR YOUR ATTENTION. [APPLAUSE] >> THANK YOU, DR. DIETZ. I THINK THIS PRESENTATION PROVIDES HOPE FOR SOME REMARKABLE DIFFICULT MEDICAL PROBLEMS FACING PATIENTS. I HAVE ALWAYS BEEN STRUCK BY THE END STAGE SCLERODERMA, FOR THOSE WHO AREN'T FAMILIAR WITH THAT, IT'S AS IF THE PATIENTS HAVE A -- ALMOST A STEEL COATING ON THEIR SKIN AN THEY CAN HARDLY MOVE. DO YOU THINK IN THAT STAGE THERE'S A OPPORTUNITY FOR TREATMENT? >> I WOULD ANTICIPATE AN OPPORTUNITY BASED ON MOUSE WORK. WE HAVE DONE FURTHER EXPERIMENTS ALLOWING FIBROSIS TO EXPRESS FURTHER IN THE MOUSE MODEL WHERE THEIR JOINTS ARE COMPLETELY IMMOBILE BECAUSE OF FIBROSIS. AND BOTH BETA ONE INTEGRIN ACTIVATING ANTIBODY AND TGF BETA NEUTRALIZING ANN BODY RETURN THEIR SKIN AND THEIR JOINT PERFORMANCE TO NORMAL. SO I DO BELIEVE THERE IS AN OPPORTUNITY. [APPLAUSE] >> NOT SEEING ANY OTHER QUESTIONS, I THINK IN VIEW OF THE HOUR, WE'RE GOING TO SKIP THE BREAK. MOVE ON TO OUR NEXT SESSION WHICH IS VERY CLOSELY LINKED TO WHAT YOU HAVE JUST HEARD. START WITH A PRESENTATION UNDER THE BROAD TOPIC OF NEW RARE DISEASES BY DR. DOUG CIEWN KUHNS, HEAD OF MONITORING LABORATORY THAT SUPPORTS RESEARCH IN THE LABORATORY OF HOST DEFENSES AN LABORATORY OF CLINICAL INFECTIOUS DISEASES IN THE NATIONAL INSTITUTE OF ALABAMA LER JI AN INFECTIOUS DISEASE. DR. KUHNS AND GROUP HAVE WORKED 20 YEARS TO STUDY NEUTRAFILL FUNCTION IN PATIENTS WITH RECURRENT INFECTIONS AND ABNORMAL INFLAMMATION AND HIS TEAM DEVELOPED A BATTERY OF TESTS USED TO IDENTIFY SPECIFIC DEFECTS WITH KNOWN UNKNOWN GENETIC IMMUNODEFICIENCIES. AND A MAYOR FOCUS OF HI LAB HAS BEEN ON THE DEVELOPMENT OF A PANEL OF DIAGNOSTIC TESTS THAT DETERMINE PROTEIN AND GENETIC DEFECTS IN PATIENTS WITH CHRONIC GRANULOMATIS DISEASE. DR. KUHNS WORKS CLOSELY WITH MY GROUP AND YOU'LL HEAR THE MOLECULAR GENETIC DIAGNOSIS OF PATIENTS WE DESCRIBED IN 1970. IT'S TAKEN SINCE 1970 TO FINALLY FIGURE OUT WHAT'S WRONG IN THE GROUP OF PATIENTS. THE TITLE OF HIS TALK IS ACTIN INTERACTING PROTEIN 1 DYSFUNCTION, NEW IMMUNODEFICIENCY WITH ABNORMAL CYTOSKELETAL FUNCTION. WELCOME. >> THANK YOU, JOHN. AS HE SAID, THIS TALK THE STUDY STARRED ALMOST 35 YEARS AGO. WHEN JOHN AND ANOTHER INVESTIGATOR HERE AT THE NIH HARRY M ACTIONLICK AND OTHERS PUBLISHED A PAPER IN 1978 DESCRIBING A YOUNG GIRL WHO CAME TO THE NIH IN 1976. WHEN SHE CAME SHE HAD A HISTORY OF RECURRENT INFECTION, THEY ACTUALLY NOTED ABNORMALITY IN BOTH RANDOM AND DIRECTED MIGRATION. THEY ALSO NOTED UNUSUAL MORPHOLOGY OF NEUTROPHILS. I'M A NEUTROPHIL BIOLOGIST. I WAS CLEARLY INTEREST IN THIS. THIS IS A PICTURE OF THE GIRL FROM 1976. THE OTHER MANIFESTATION OF THIS DISEASE WAS A SEVERE STOMA TIETIS. THIS GIRL UNFORTUNATELY DIED IN 1977 FROM DECEMBER SEMINATED VARICELLA. WHEN WE TALK UNUSUAL MORPHOLOGY, THIS IS ARE WE CAN SEE NORMAL NEUTROPHILS. YOU CAN SEE THE MUL LOAD NUCLEUS IN THE NEUTROPHILS ATTACHED TO A SUBSTRATE. HOWEVER, WHEN YOU LOOK AT THE PATIENT CELLS YOU SEE A VERY INTERESTING ABNORMALITY. YOU CAN SEE THE LEARNIATIONS AND THESE CONTAIN A NUCLEAR LOBES OF THE NEUTROPHIL. THIS ISN'T THE ONLY TIME THIS HAPPENED. EIGHT YEARS LATER A FAMILY, THIS IS FAMILY 2 WAS REFERRED TO DR. HARRY MALICK HERE AT THE NIH. WHEN -- THESE TWO BROTHERS CAME TO THE NIH AND THEY WERE REFERRED TO FOR NEUTROPENIA. WHEN HE LOOKED AT THE CELLS THESE ARE THE CELLS FROM ONE OF THE BROTHERS, YOU CAN SEE AGAIN THERE ARE HERNIATED NUCLEAR LOBES IN NEUTROPHILS AND IN THIS CASE WHAT YOU SEE IS AREAS WHERE THEY'RE DEVOID OF GRAND YULS. THIS IS A NORMAL NEUTROPHIL AND YOU CAN SEE THE GRANULES ARE UNIFORMLY DISTRIBUTED THROUGHOUT THE CYTOPLASM. IN THIS CASE THERE'S BROAD AREAS DEVOID OF GRANULES. SO NOW FORWARD TO 2006 WHEN A THIRD FAMILY ARRIVED AT THE NIH. THIS ONE SEEN BY DR. STEVE HOLLAND. THIS WAS A FAMILY FROM QATAR, TWO SISTERS FROM A CONSANGUEMOUS MARRIAGE. THEY HAD SKIN MUTATIONS AN UPPER AND LOWER RESPIRATORY TRACT REACTIONS AND NEUTROPENIA WITH SUSPECTED NEUTROPHIL DYSFUNCTION. THE YOUNGER SISTER HAD A TWIN WITH A SIMILAR PRESENTATION AND SHE DIED AT THE AGE OF 3 FROM A SEPTIC EVENT. THEY WERE FROM QATAR, WE DON'T KNOW A LOT OF HISTORY. THE YOUNGER SISTER HAD REPEATED ORAL INFECTIONS THAT RESULTED IN DEVELOPMENT OF ORAL STENOSIS. IN THIS CASE YOU CAN SEE HERE. AT ONE POINT THE OPENING IN THE MOUTH WAS SEVEN MILLILITERS WHICH WAS A QUARTER OF AN INCH AND SHE WAS FED BY A TUBE BECAUSE SHE COULDN'T OPEN HER MOUTH WIDE ENOUGH TO EAT. WHEN YOU LOOK AT HER AND OLDER SISTERS, THESE ARE NEUTROPHILS AND YOU CAN SEE LEARNIATIONS OF THE NUCLEAR LOBES SEEN HERE. IN THIS CASE THREE EXTENDED OUTSIDE THE CELL BODY AND AREAS DEVOID OF GRANULES. YOU CAN SEE ANYTIME THE OLDER SISTER THESE AREAS ARE DEVOID AND YOU CAN SEE THE NUCLEAR LEARNIATIONS. WE ALSO DID MANY FUNCTIONAL STUDIES ON THESE NEUTROPHILS. WE DID STUDIES AT CHEMOTAXIS, CELL SPREADING AND WE ALSO LOOK AT SHAPE CHANGE. ALL THESE STUDIES DEPEND ON REARRANGEMENT OF THE ACTIN CYTOSKELETON, IN THESE STUDIES THESE TWO SISTERS WERE DEFECTIVE. TO GIVE A LITTLE BACKGROUND ABOUT REGULATION OF ACTIN AND THE CYTOSKELETON I WANT TO G THROUGH BRIEFLY THERE'S TWO FORMS OF ACTIN GENERALLY FOUND, FREE ACTIN EXISTING AS MONOMERS, THIS IS CALLED G ACTIN OR GLOBULAR ACTIN. IT ALSO EXISTS AS A FILAMENT OR POLYMER. AND THIS IS A FILAMENT OR F ACTIN. IT HAS A POLARITY. THERE IS A POINTED END AND A BARBED END. ACTIN FILMS FORMED BY ADDITION OF MONOMERS TO THE BARBED END, WHEREAS DEPOLYMERIZATION OR BREAKDOWN OF THESE ACTIN FILMS OCCURS AT THE POINTED END. MANY FACTORS ARE INVOLVED IN REGULATION OF DYNAMICS BETWEEN MONOMERIC ACTIN. CO-FIE LYNN IS ONE SHOWN HERE, IT BINDS AND ACTUALLY SEVERS INTO SHORTER FIBRILS AND THEY GENERATE SMALLER ACTIN FILMS WITH BOTH ENDS FREE SO MONOMERS CAN ADD TO BASH BARBED IN. THERE'S PROBES TO LOOK AT ACTIN DINE MCS IN THE CELL AND WE DECIDED TO LOOK T ONE IN THE YOUNGER GIRL AND WE USED A PROBE WHICH BINDS TO FILAMENTIS ACTIN. IN THIS CASE THE RED IS A IN THE PATIENTS WE GET TWO POPULATIONS OF CELLS. THESE ARE BIEGHTLY STAINING WITH -- BIEGHTLY STAINING. SO -- BRIGHTLY STAINING. THESE ARE HIGHER LEVELS AN THESE ARE LOWER LEVELSCH THIS IS COMPARABLE TO NORMAL. WHEN YOU LOOK AT THE TWO CELLS IN THE MERGED IMAGE HERE YOU FIND OUT THOSE ARE CELLS THAT HAVE HERNIATED THEIR NUCLEI. IN PARTICULAR, THIS ONE IS ACTUALLY HERNIATING OUT OF THE PLANE TOWARDS YOU, WE HAVE FOUR LOBES BECAUSE THESE ARE NUCLEAR STAINS, IT HAS FOUR LOBES THAT ARE HERNIATED ALSO. SO IT LOOKS AS THOUGH WHAT WE AT THIS POINT WE HAVE DETERMINED THAT NUCLEAR LEARNIATION IN THE CMS IS ASSOCIATED WITH INCREASED LEVELS OF F ACTIN IN THE CELLS. WE HAVE TAKEN A NORMAL NEUTROPHIL CELL EXTRACT AND PATIENT CELL EXTRACT, YOU LABEL THE NORMAL EXTRACT WITH A GREEN FLUORESCE SEN DYE, YOU LABEL THE PATIENT EXTRACT WITH A RED FLUORESCENT DYE. MIX THE TWO TOGETHER AN RUN THEM UP ON A 2D GEL. THAT SEPARATES PROTEINS BASED ON CHARGE IN THE HORIZONTAL DIRECTION, SEPARATES THEM BASED ON MOLECULAR WEIGH IN THE VERTICAL DIRECTION. THEN YOU IMAGE YOUR GEL AN WHAT HAPPENS IS ANY PLACE YOU SEE A GREEN SPOT IS A PROTEIN EXPRESSED ONLY IN NORMAL. ANY PLACE YOU SEE A RED SPOT THAT'S A PROTEIN ONLY EXPRESSED IN THE PATIENT. WHERE YOU GET YELL SPOTS PATIENT AND NORMAL ARE EXPRESSED EIALLY AND -- EQUALLY AND RED AND GREEN MAKE YELLOW. FROM HERE WHAT YOU DO IS YOU THEN PICK SPOTS OF INTEREST AND DIGEST THOSE SPOTS AND IDAHO FI BY MASS SPECTROMETRY. WE HAD THE ADVANTAGE OF TWO PATIENTS TO RUN TWO PATIENTS AGAINST TWO NORMALS. WHAT THAT GAVE US IS ABILITY TO ELIMINATE ANY SPOTS NOT SEEN IN BOTH PATIENTS. WHAT WE ENDED UP WITH WAS A TOTAL OF 41 SPOTS TEN DID NOT AGREE. SO WHEN WE CAME DOWN TO IT WE HAD 31 SPOTS WE WERE ABLE TO FOCUS IN ON. WE THOUGHT WE WERE WORKING IN THE RIGHT DIRECTION BECAUSE AS YOU LOOK ALONG THE LINE HERE, MANY OF THESE WERE VARIANTS OF ACTIN. IF YOU LOOK CAREFULLY WE HAD SEVERAL PROTEINS THAT WERE REALLY INTERESTING BECAUSE IN THIS CASE SPOTS 14 AND 15 WERE INCREASED IN THE MORE MAP -- NORMAL COMPARED THE PATIENT, FOR AIP-1 AND HERE AT SLOT 16 AIP-1 WAS INCREASED IN PATIENT COMPARED TO NORMAL. WHAT DOES THAT MEAN? THREE SPOTS FOR AIP-1, THESE ARE A DOUBLEETTE SEEN PREDOMINANTLY IN NORMALS WHEREAS THIS SPOT HERE WERE SEEN IN THE PATIENT. SO WHAT IS AIP-1? IT TURNS OUT TO BE A VERY INTERESTING PROTEIN, IT HAS A UNIQUE STRUCTURE, IT'S A DOUBLE BETA PROPELLER. WHAT YOU SEE HERE IS THE END TERMINAL PROPELLER. YOU'RE LOOKING DOWN THE AXIS TESTIFY OF THE PROPEP LAR, IT'S MADE OF SEVEN BLADES, 1, 2, 3 4, 5, 6, 7, EACH BLADE IS MADE OF FOUR ANTI-PARALLEL SHEETS. IF YOU ROTATE THIS PROTEIN SLIGHTLY WHAT YOU SEE IS NOW LOOKING DOWN THE ACCESS OF THE C TERMINAL PROPELLER. AND YOU SEE HERE AGAIN, THERE'S SEVEN BLADES, EACH OF FOUR ANTI-PARALLEL BETA SHEETS. AN INTERESTING THING THAT I SHOULD POINT OUT ABOUT THIS IS THIS IS ACTUALLY THE C -- OR THE END TERMINUS. THE END TERMINUS MAKES UP THE OUTER BETA SHEET OF THIS PARTICULAR BLADE SO IT CUTS ACROSS HERE, GOES THROUGH THIS BETA PROPELLER AND COMES BACK, THIS IS THE C TERMINUS SO THE C TERMINUS ARE RIGHT NEXT TO EACH OTHER IN THE DRRKS TERMINAL BETHAT PROPELLER. SO WE DECIDED TO JUST LOOK BY STANDARD WESTERN BLOTTING AT AIP EXPRESSION IN THE TWO PATIENTS ALONG WITH THREE NORMALS AN UNAFFECTED SIB. WHEN WE LOOK AT THAT WE SAW WELL, FAIRLY NORMAL EXPRESSION OF AIP-1 IN BOTH PATIENTS BUT WE DECIDED TO TO SEQUENCE A,P MANUFACTURE 1 IN TWO PATIENTS. TURNS OUT THIS THE PEDIGREE FOR FAMILY TREE, THIS IS FAMILY WE WERE STUDYING, TURNED OUT THAT BOTH THE SISTER HAD HOMOZYGOUS MUTATION IN AIP-1 AT POSITION 76 CAUSING O A MISSENSE MUTATION WHICH CHANGES SPAR AT A TIME 26 TO ASPARE GENE T PARENTS TURNED OUT HETEROZYGOUS, THEY WERE FIRST COUSINS BOTH HETEROZYGOUS FOR THE SAME MUTATION. THE MATERNAL UNCLE ALSO HAD MUTATION AND A BROTHER WHO WAS A DONOR FOR A BONE MARROW TRANSPLANT THIS GIRL EVENTUALLY UNDERWENT HAD THE SAME -- HE WAS ALSO HETEROZYGOUS FOR THE SAME MUTATION. AS YOU GO THROUGH ALL THE PHENOTYPIC DATA THESE TWO SISTERS HAD A FAIRLY SEVERE PHENOTYPIC OUTCOME. BOTH HAD HERNIATED NUCLEAR MORPHOLOGY, SEVERE NEUTROPENIA, BOTH RECURRENT INFECTIONS, ONLY THIS SISTER HAD THE STO OMATITIS BUT ABNORMAL CHEMOTAXIS. WITH THIS WE DECIDED TO GO BACK TO DIG UP MATERIAL FROM THE PATIENT IN 1975. OR 76. WE TRIED TO DIG UP OLD PATHOLOGY SAMPLES BUT WE EARN ABLE TO GETNY. SO WE WENT ONLINE TO THE INTERNET AND FOUND PARENTS OF THIS GIRL. AND IT TURNS OUT THE MOTHER HAS A MISSENSE MUTATION IN ARCIP-1, TO ME THIONEINE, THIS IS A CONCERNED AMINO ACID IN THE AIP MOLECULE. AND DAD HAD A HETEROZYGOUS DELETION OF THREE NUCLEOTIDES IN FRAME AS A RESULT OF LYSINE 7 FROM THE PROTEIN. WE SEQUENCED THE SISTER OF THE GIRL WHO DIED WAS A -- CARRIER FOR THE SAME MUTATION AND ONE OF HER DAUGHTERS WAS ALSO A CARRIER. NCI THIS HAD WILD TYPE GENOTYPE AS PATERNAL AUNT. THERE'S PHENOTYPIC DATA FOR THIS PARTICULAR GIRL HAD AGAIN HERNIATED NUCLEAR MORPHOLOGY, SEVERE NEUTRAPEEN YARKS RECURRENT INFECTIONS, SEVERE STOMATITIS AND DIAGNOSED WITH ABNORMAL CHEMOTAXIS. AT THIS POINT WE SUSPECT SHE WAS A COMPOUND HETEROZYGOTE FOR THESE MUTATIONS IN A RKP-1. -- AIP-1. WE FOUND OUT TRACKED DOWN THE OTHER FAMILY, FAMILY 2, THE TWO BROTHERS THAT CAME IN 1986, WE WERE ABLE TO GET A BLOOD SAMPLE FROM FROM THE MOM, THE FATHER PASSED BUT WE WERE ABLE TO GET ONE BROTHER. MOM HAS A MISSENSE MUTATION IN AIP-1. IT IS A LEUCINE 285 VAI LIEN, A HIGHLY CONSERVED AMINO ACID IN THAT SITE. IT IS A HIGHLY CONSERVED PROTEIN. WHEN WE LOOK AT THE SUN HE HAD THE SAME, HETEROZYGOUS FOR THAT MUTATION BUT HETEROZYGOUS FOR A G 121 R MUTATION. AGAIN, A HIGHLY CONSERVED AMINO ACID THROUGH MANY SPECIES. IN THIS CASE THEY HAD A LESS SEVERE FORM OF THE DISEASE. IN BOTH CASES BROTHERS HAD BEEN REPORTED TO HAVE NUCLEAR MORPHOLOGY, THEY HAD HERNIATED CELLS AND NEUTROPENIA BUT HAVE NOT HAD REPORTED RECURRENT INFECTIONS OR STOMATITIS AND WE HAVE NOT DONE CHEMOTAXIS ON THEM YET. SO WHERE DO THESE PROTEIN OR THESE MUTATIONS FALL? IN FAMILY 3, WITH THE TWO SISTERS, THEIR MUTATIONS FALL IN THE CENTRAL ACCESS WITH THE BETA PROPELLER, FAMILY 2 ALSO FALLS IN THAT SAME REGION ON THESE BETA SHEETS THAT MAKE UP THE BLADES. GO TO FAMILY ONE, THE ONE THAT WAS ORIGINALLY DESCRIBED IN 1978, WHAT YOU SEE IS THE MUTATION IN THIS BETA SHEET OF THE C TERMINAL PROPELLER AND THE DELETION DAD HAD A K-7 DELETION OCCURS IN THIS REGION OF THE END TERMINUS THAT MAKES UP THIS BETA SHEET PROPELLER. ALL THESE MUTATIONS, WE HAVE FIVE IN TOTAL FALL ON THESE BETA SHEETS THAT MAKE UP THE BLADES ON THESE PROPELLERS. OUR HYPOTHESIS IS AIP-1 AND GENE NAME IS WRD-1 FOR WRD REPEAT PROTEIN 1. AND SHOWN IN GREEN ACTIVELY PROMOTES SEVERING ACTIVITY AND CAPTURING THE BARB END OF THE SEVERED FILMS. THAT YIELDS MORE SMALLER FRAGMENTS THAT CAN CANNOT POLYMERIZE BECAUSE IT BLOCKS THAT PARTICULAR -- THE ADDITION OF ANY NEW MONOMERS. SO ALLOWS A MORE EFFICIENT DEPOLYMERIZATION DOWN TO FREE MONOMERS. WE PROPOSE THAT WDR-1 MAY FAIL TO FIND TO THE BARBED END AND THEN PROMOTING THE ACCUMULATION OF INCREASED LEFS OF THE SHORTER FILAMENTS AND ALLOW MONOMER ADDITION SO YOU GET INCREASED LEVELS OF F ACTIN THAT MAY NOT BE AS LONG. DO WE HAVE DATA TO SUPPORT THAT? THE DATA WE HAVE IS BASED ON FIBROBLASTS. WE HAVEN'T BEEN ABLE TO GET NEUTROPHILS OF THEM ALL THE TIME SO WE WERE ABLE TO GET FIBROBLASTS FROM A SKIN BIOPSY. SO WE WERE DO GOING TO DO STUDIES TO DETERMINE DEFECT IN THE FIBROBLAST. SO WE USED A PROCEDURE CALLED MICROPATTERN ANALYSIS. A SLIDE THAT HAS A NON-ADHESIVE SURFACE SO CELLS DON'T BIND TO IT. THEN THEY ETCH OUT A REGION THAT THEY THEN COAT WITH FIBERNICTIN SO THE YELL COMBINES TO THE YELLOW REGION, WHEN YOU PUT FIBROBLASTS TO THE CELLS THEY WILL FOLLOW THE CONSTRAINTS PUT ON BY THE MICROPATTERN AND SO THE FIBROBLASTS FORM TRIANGLES. SO YOU LOOK AT A FIBROBLAST ATTACHED TO A MICROPATTERN AN WHAT HAPPENS HERE IS BECAUSE THE CELLS CANNOT BIND ACROSS THIS REGION ONLY TO THE VERT SEIZE THE CELLS CONNECT STRESS FIBERS. WHICH IS BASICALLY FILAMENTIS ACTIN, WE HAVE STAINED WITH FALOIDIN SO WHAT WHAT YOU SEE IN THESE NORMALS THEY HAVE IN THESE CASES, YOU SEE NICE STRESS FIBERS ACROSS THE VERITY SEIZE OF THESE MICROPA TENS. THEY CANNOT FORM STRESS FIBERS. YOU SEE A MORE DIFFUSE STAINING THROUGHOUT THE CELL BUT UNABLE TO FORM THESE NICE BRIGHT PATTERNING ON RIGHT SIDE. THIS SUGGESTS F ACTIN STAINING, BUT NOT ABLE TO FORM LONG FIBERS BUT MORE DIFFUSE FIBERS. IN THIS PARTICULAR CELL IT DOESN'T LOOK ABLE TO COMPLETELY ATTACH CORRECTLY TO MICROPATTERNS. IN CONCLUSION, WE THINK WE HAD IDENTIFIED A NEW IMMUNODEFICIENCY IN THREE FAMILIES WITH MUTATIONS IN THE GENE ENCODING PROTEIN ONE, A DOUBLE PROPELLER FOR PROTEIN THAT REGULATES ACTIN POLYMERIZATION. PHENOTYPICALLY THESE PATIENTS HAVE RECURRENT BACTERIAL INFECTIONS AND STOMATITIS. MACROPHAGE FUNCTION AND ABNORMAL FIBROBLAST STRESS FIBER FORMATION IN AT LEAST ONE PATIENT TESTED. THE DATA SUPPORT A CRITICAL ROLE OF ACTIN ENTERACTING PROTEIN 1 AND HOST OFFENSE AND WOUND HEALING. THANK YOU. I SHOULD MENTION THESE ARE THE PEOPLE IN MY LAB THAT DID THE WORK. UP IN THE LABORATORY OF MOLECULAR TECHNOLOGY AT SAIC FREDERICK, THEY DID THE SEQUENCING. (INDISCERNIBLE) DID THE ELECTRON MICROSCOPY. AMY SUE HELPED WITH THE PROTEIN MODELING, OI MCJOY IS HELPING US DEVELOP LENTIVIRAL STUDY TO TRY TO RESCUE THE PHENOTYPE AND I HAVE TO THANK JOHN GALLIN STEEF HOLLAND AND HARRY MALLICK FOR THEIR FUNDING TO BE ABLE TO DO THIS PROJECT. THANK YOU. [APPLAUSE] >> THANK YOU. TIME FOR QUESTIONS IF THERE ARE ANY. IF NOT, I THINK WHAT I HOPE YOU'VE GOTTEN FROM THESE THREE TALKS IS A SENSE WHEN YOU LOOK AT THEM COLLECTIVELY HOW OFTEN STUDYING ONE PATIENT CAN LEAD TO BEGINNING OF AN UNDERSTANDING OF A FUNDAMENTAL PROCESS THAT HAS WHEN YOU FIGURE OUT THE GENETICS AND THE MOLECULAR DIAGNOSIS I DON'T THINK YOU DISCOVER TARGETS FOR THERAPEUTICS POTENTIALLY FOR THAT DISEASE WITH THE HOPE YOU'RE GOING TO GIVE PATIENTS BUT THERE WILL BE A TREATMENT SHOWN SO ELEGANTLY BY DR. PASTAN AND DR. DIETZ. AT THIS POINT DR. GROFT IS GOING TO TAKE OVER AND INTRODUCE THE REMAINING SPEAKERS BECAUSE I HAVE TO RUN TO ANOTHER ACTIVITY. >> JOHN IS ALWAYS RUNNING LOOKING FOR MORE MONEY IN THE BUDGET SO LET HIM RUN AND HOPE IT'S MORE BENCH TO BEDSIDE FOR RARE DISEASE. WE'RE GOING TO CONTINUE IN OUR DISCOVERY OF NEW DISORDERS. OUR NEXT SPEAKER IS DR. SUSAN SWEDO, BRANCH CHIEF PEDIATRICS AND DEVELOPMENTAL NEUROSCIENCES BRANCH OF THE NATIONAL INSTITUTE OF O HEALTH AND SHE WILL TALK ABOUT PANDAS, ONE OF OUR FAVORITE ANIMALS BUT BUT NOT FAVORITE DISORDERS. >> I APPRECIATE THE OPPORTUNITY TO SPEAK THIS AFTERNOON. AND AS OF DECEMBER OF 2011 PANDAS IS ON THE VERGE OF BECOMING AS EXTINCTION AS THE PANDA SO ODD ACRONYM BUT MAY TURN OUT QUITE USEFUL. THE REASON IS BECAUSE SOME OF OUR COLLEAGUES WHO HAVE NOT ACCEPTED THIS DIAGNOSIS WELL IN DECEMBER OF 2011 PUBLISHED IT IN OPINION PIECE STATING THAT THERE WAS ABSOLUTELY NO EVIDENCE THAT STREP WAS INVOLVED IN ONSET OF ACUTE OBSESSIVE COMPULSIVE DISORDERRER, IT SHOULD BE REPLACED CAN, CHILDHOOD ACUTE NEUROPSYCHIATRIC DISORDER. I'M GOING TO SEN OUT A CHALLENGE I STRUGGLE WITH ALL THE TIME. IS THERE TRULY CONTINUED CONTROVERSY AROUND PANDAS OR HAVE WE DONE WHAT WE NEEDED TO ESTABLISH THIS DIAGNOSIS CAN BE MADE WITH THE IT LOGIC MENTION NISMS PROPOSED BEING -- IT LOGIC MECHANISMS ARE DG PROPOSED AND PERHAPS CASE CLOSED AT SOME POINT. IF NOT WE'LL COME BACK TO TALK ABOUT CANS. TO BE INCLUDED IN RARE DISEASE SYMPOSIUM, ONE SHOULD HAVE A SENSE IT'S A RARE DISEASE, I APOLOGIZE THERE TOO BECAUSE WE DON'T HAVE PREVALENCE OR INCIDENCE DATA FOR PANDAS, THERE HAVEN'T BEEN AN ABILITY TO DETERMINE HOW FREQUENT OR INFREAK IT IS. IT'S NOT -- INFREQUENT IT IS. IT IS NOT THE MOST COMMON CAUSE OF CHILDHOOD ONSET OCD, IT'S LESS THAN 1% OF CHILDREN AND ADOLESCENCE. OUR CASE, FIRST CASE TIN DEX CASE WAS SENT FOR PARTICIPATION IN A STUDY WE WERE DOING ON KOREA, IT'S ALSO KNOWN AS (INDISCERNIBLE) THE NEUROLOGIC MANIFESTATION OF RUEMATIC FEVER. THIS YOUNG MAN WAS THIRD SON IN FAMILY WHERE THE OLDEST BROTHER HAD TURRET SYNDROME. IT WAS AN EPISODIC COURSE AND THE MOM WAS A MED TECH NOT HOSPITAL AND WHEN THE OLDER BROTHERS TICKS GOT WORSE IT WAS TIME TO BRING HOME A THROAT CULTURE BECAUSE WITHIN A DAY HE WOULD HAVE SYMPTOMS OF STREP SO THAT FAMILY DESERVES CREDIT FOR THE CONNECT WHEN THE YOUNG EBROTHER DEVELOPED SYMPTOMS OF WILD MOVEMENTS HE WAS DIAGNOSED WITH (INAUDIBLE) KOREA, BUT ON CAREFUL EXAMINATION AND HISTORY IT BECAME CLEAR THOSE WEREN'T INVOLUNTARY MOVEMENTS BUT A COMPLEX BEHAVIORAL RITUAL HE WAS DOING IN RESPONSE TO THOUGHTS. HE ALSO HAD (INDISCERNIBLE) BUT MOST IMPRESSIVE WAS HIS HORDING COME PUDGES. HE HAD DEVELOPED OVER NIGHT A NEED TO HOLD ON TO ANY PIECE OF PAPER HE HAD VISUALIZED SO WHEN WHEN HE CAME TO THE NIH WE HAD TO CLEAR THE MAGAZINES OR HE WOULD FEEL COMPELLED TO TAKE THEM HOME. HE NEEDED TO HORDE HIS SALIVA SO HE CARRIED A CUP AROUND WITH HIM SO THAT HE COULD SPIT INTO THE CUP AND NOT HAVE TO LOSE HIS SALIVA. HE RECOGNIZED THESE SYMPTOMS AS SENSELESS IRRATIONAL WHICH IS A DEFINING FEATURE OF OBSESSIVE COMPULSIVE DISORDER SO THESE PARTICULAR CHILDREN ARE TORTURED BY THE FACT THEY HAVE THESE CRAZY THOUGHTS THEY CAN'T CONTROL COMING FROM THEIR MINE AND MAKING THEM DO THINGS THEY CONSIDER SENSELESS AND TIME WAISTING. ON EXAM HE HAD NO KOREA APPROXIMATE STREP WAS POSITIVE WHEN HE CAME TO NIH. (INDISCERNIBLE) WITH THE IMMUNOMODULATORY TREATMENTS WE WERE TRYING AT THAT TIME. SEND HOME WITH ANTIBIOTICS AND MARKEDLY REDUCED THE SYMPTOMS. HE WAS EVENTUALLY PUT ON A PROPHYLACTIC COURSE OF ANTIBIOTICS BECAUSE OF BROTHER HISTORY AND THEY BOTH ENDED UP DOING BETTER. THE CLINICAL MANIFESTATIONS ARE REALLY THE WAY THE DIAGNOSIS IS MADE. COMPLETELY A BEHAVIORAL CLINICAL DIAGNOSIS, THERE'S NO LABORATORY STUDIES TO CONFIRM THIS. AND CHARACTERIZED BY AN EXTREMELY ABRUPT COURSE. IN GENERAL OCD FAMILIES OFTEN AREN'T AWARE OF THE CHILD'S OBSESSIONAL THOUGHTS OR COMPULSIVE RITUALS UNTIL THEY'RE SEVERE ENOUGH OVER WEEKS OR MONTHS THE FAMILIES BEGINS TO NOTICE THINGS ARE OUT OF ORD NIER. IT DOESN'T SHOW UP FOR SCHOOL FOR A FEW MORE WEEKS OR MONTHS AFTER THAT SO IT'S SLOW GRADUAL INCREASE. PANDAS COMES ON 0 TO 60 OVER NIGHT PARENTS CAN TELL YOU THE HOUR IF NOT THE DAY THE SYMPTOMS STARTED. HAS A RELAXING AND REMITTING SYMPTOM COURSE THE CHILDREN CAN GET WELL AND THEN HAVE ANOTHER TRIGGER AND HAVE AN ABRUPT EXACERBATION AGAIN. IT'S A YOUNGEST CHILDREN AND IT'S BOYS AS WITH MANY CHILDHOOD PSYCHIATRIC DISORDERS BOYS OUTNUMBER GIRLS 3 TO 1. IN OUR SAMPLE TWO-THIRDS OF CHILDREN HAD BOTH OCD AND TICKS AND OTHER CO-MORBID SYMPTOMS ARE VERY, VERY COMMON. INCLUDING HARD TO SEE, BUT IT'S A VERY COMPREHENSIVE LIST OF EVERYTHING THAT SLEEP DISORDERS AND URINARY FREQUENCY TO BEHAVIORAL REGRESSION, DETERIORATIONS IN HANDWRITING, HYPE ACTIVITY, AND PROBABLY THE THE MOST TROUBLESOME FOR THE FAMILIES IS A COMPLETE PERSONALITY CHANGE FROM AN EASY GOING MODEL STUDENT TO A CHILD WHO JUST CAN'T BE COMFORTED OR CONSOLED AND CAN SCREAM FOR HOURS AT A TIME. IN PURPLE, WHICH DOESN'T ALSO SHOW UP VERY WELL, IS THE INDICATION THAT EATING DISORDERS HAPPEN IN 17% OF THESE PATIENTSCH IT'S FASCINATING AREA OF STUDY, IN THESE CHILDREN THERE ARE TWO WAYS THAT THE CHILDREN DEVELOP EATING DISORD OARS SIMILAR TO ANOREXIA. THE FIRST ONE THEY ACTUALLY DEVELOP THE BODY DISMORE FEEIA AND THINK THEY'RE TOO FAT STHIE STOP EATING AND THE SECOND THEY DEVELOP AN OBSESSIONAL FEAR OF VOMITING OR CHOKING OR THE FOOD IS POISSON SO THEY STOP EATING OR RESTRICT EATING AND BEGOIN LOSE WEIGHT AND ONCE THEY LOST ABOUT 10, 15% OF BODY WEIGHT THE BODY IMAGE DISTORTIONS BEGIN SO FASCINATING HOW THEY LOOK LIKE THE CLASSIC ANOREXIA WE MIGHT SEE AMONG YOUNG ADULT WOMEN AN YET THE ONSET IS SO DIFFERENT. WE DEVELOP THE PANDA SUBGROUP OR DEFINE THE SUBGROUP AS A RESEARCH SUBGROUP OF PATIENTS IN WHOM WE HOPED THAT THE ETIOLOGY AND PATHOPHYSIOLOGY IS MORE HOMOGENOUS THAN FOR OCD AS A WHOLE. OBSESSIVE COMPULSIVE DISORDER STARTS AFTER PSYCHOLOGICAL TRAUMA, IT'S FAMILIAL, HAS A LARGE NUMBER OF CAUSES AND IN THE PANDA SUBGROUP WE POSTULATED THAT LIKE RUEMATIC FEVER WHAT YOU HAD WAS AN ABNORMAL STREP BACTERIA IN A GENETICALLY VULNERABLE HOST THAT RESULTED IN ABNORMAL IMMUNE RESPONSE AND WAS MANIFESTED AS PANDAS WERE OCD AND TICKS. WE'LL GO THROUGH EACH OF THESE. ESTABLISHING A CAUSAL ROLE IN PANDAS HAS BEEN AS CHALLENGING AS IT IS FOR (INAUDIBLE) CREEIA. WE HAVE KNOWN SINCE 1950s THAT STREP WAS INVOLVED IN RUEMATIC HEART DISEASE AND IN CREE YARKS IT'S STILL NOT DEFINITIVELY PROVEN FOR EITHER. THERE'S NO ANIMAL MODELS TO INDUCE RUEMATIC CARDITIS BY INFECTING THE MOUSE OR RAT WITH STREP SO SEEMS TO BE A UNIQUELY HUMAN DISEASE. A LOT OF CIRCUMSTANTIAL EVIDENCE IS SUFFICIENT TO LEAD US TO CONCLUDE THERE HAS TO BE A RELATIONSHIP BETWEEN STREP AND RUEMATIC FEVER, WE ASSUME THE SAME IS TRUE IN PANDAS. THERE'S ONLY 10 OF 120 STRAINS OF STRESS, THAT CAUSE RUEMATIC FEVER SO SOMETHING UNIQUE ABOUT THE STREP BACTERIA. THE SECOND IS ANTIBIOTIC PROPHYLAXIS AND PREVENTION OF STREP INFECTION IS EFFECTIVE IN PREVENTING SYMPTOM ONSET AND WORSENING. SO TO MAKE THE DIAGNOSIS OF PANDAS, I'M LOOKING FOR THE THING. IS THERE A POINT ?ER I HAVE ONE RIGHT ON THE SCREEN. SO IN THE TOP PANEL PANDAS, RED LINE IS SYMPTOM CHECKLIST, YALE BROWN OBSESSIVE COMPULSIVE CHECKLIST, A RAPID RISE IN SYMPTOM AN SLOW DIM MUNITION, ASYMPTOMATIC PERIOD FOLLOWED BY INCREASE. YOU NOTICE THE ASO TITER TRAILS BEHIND THAT INCREASE IN THE SYMPTOMTOLOGY WHICH INDICATES THE INFECTION WAS RIGHT ABOUT HERE. AT THE POINT THE SYMPTOMS INCREASE IS WHEN THE STREP INFECTION IS LIKELY TO HAVE OCCURRED AND THERE'S A SIX TO EIGHT WEEK LAG IN THE RISE OF THE ANTI-STREP TO COCAL ANTIBODY TITERS. YOU SEE THEY HAVE TWO STREP INFECTIONS, ONE HERE AND ONE HERE WITH WITH THE CONCOMITANT IN TITERS AND A VARIABLE COURSE OF SYMPTOMS BUT THERE IS ABSOLUTELY NO CORRELATION BETWEEN THE TWO. WHEN WE USE SCHOOL RECORDS AND RETROSPECTIVE HISTORIES IN THIS GROUP OF PATIENTS WITH PANDAS WE FOUND THE CORRELATION WAS VERY TIGHT. APPROXIMATELY .9 BETWEEN INSIGHTING STREP INFECTION AND INCREASE IN SYMPTOM SEVERITY. THE SECOND THING SO EFFECTIVE IN RUEMATIC FEVER WAS PREVENTING INFECTIONS, PREINVENTORIED FURTHER EPISODES OF CARDITIS. SO WE PROPOSE IF OCD AND TICKS ARE SEQUELLA OF INFECTION SIMILAR TO DEZ DIZ KOREA RUE MATIC HEART DISEASE IF YOU CAN PROF LACK AGAINST INFECTIONS YOU CAN REDUCE EXACERBATIONS. THIS WAS A STUDY COMPLETED A NUMBER OF YEARS AGO COMPARING PENICILLIN VERSUS AZITHROMYCIN. THE RED LINE INDICATES THE START FOR THE CHILDREN. THESE ARE SYMPTOMATIC MONTHS PRECEDING AND DURING PROPHYLAXIS. WE EXPECTED IT TB A ACTIVE PLACEBO, IN AN EARLY STUDY WE HAD HAD SO MANY BREAK THROUGH INFECTIONS ON PENICILLIN PROPHYLAXIS WE THOUGHT WE WOULD HAVE THE SAME PROBLEM HERE. WE WEREU OWN BEST FR IENDS OR WORST ENEMIES BECAUSE WE WORKED HARD ON COMPLIANCE IN THIS GROUP SO THAT THE KIDS TAKING PENICILLIN TOOK IT EVERY 12 HOURS AS PRESCRIBED, SUPERB PROPHYLAXIS, NO STREP INFECTIONS IN THE PENICILLIN GROUP OR AZIT THROW MYOSIN GROUP. LEADING CRITICS TO CONCLUDE IT DIDN'T MAKE A DIFFERENCE BUT WHAT WE SAW IS THESE CHILDREN WHEN FROM 4 TO 9 MONTHS OF SYMPTOMS DOWN TO ONE OR TWO. AND MORE IMPORTANTLY WHEN THEY DID HAVE A SYMPTOMATIC MONTH SUCH AS THIS ONE IT WAS A SELF-LIMITED EPISODE THAT DISAPPEARED RELATIVELY QUICKLY. THE NEXT THING WAS A SUSCEPTIBLE HOST. HERE IT'S VERY COMPLEX BECAUSE THESE ARE YOUNG CHILDREN SO THERE MAYBE SOMETHING NEURODEVELOPMENTAL THAT MAKES THEM VULNERABLE. MORE LIKELY IMMUNOLOGIC, IT'S THE FIRST OR SECOND TIME EXPOSED TO THE STREP ANTIGEN. BUT THERE'S GENETIC SUSCEPTIBILITY AND PROBABLY THE TYPES OF EXPOSURES. IS IT A LINGERING ASYMPTOMATIC INFECTION RATHER THAT THAN VIRULENT STREP WITH FAIRN JIETIS. HOST SUSCEPTIBILITY IS SUGGESTED BY THE FACT WITH INCREASED FAMILIAR RATES OF OCD APPROXIMATE TIX, IN THIS GROUP OF PATIENTS AN COMPARABLE TO WHAT YOU SEE IN OTHER SAMPLES OF PATIENTS WITH OBSESSIVE COMPULSIVE DISORDER. THE SPECIFIC GENES AROUND YET KNOWN BUT IT'S CLEAR THERE'S A STRONG FAMILIAL AND PRESUMED GENETIC SUSCEPTIBILITY TO OBSESSIVE COMPULSIVE DISORDER AND TICK DISORDER SEEMED TO SHARE THE SAME (INDISCERNIBLE) IN THE PANDA PATIENT INCREASE RATES OF RUEMATIC FEVER. BECAUSE OF THE EFFECTIVENESS OF ANTIBIOTIC TREATMENT, THROAT CULTURES TO DIAGNOSE STREP RATES OF RUEMATIC FEVER HAVE GONE DOWN TO THE RARE DISEASE CATEGORY. IN THE PARENTS GENERATION WE COULDN'T MAKE THIS CONNECTION BUT LOOKING AT GREAT AUNTS, UNCLES AN GRAND PARENTS WE NOTICE MARKED INCREASE IN RATES OF RUEMATIC FEAR. FOR A SHORT BRIEF TIME WE HAD DEAL OF EXCITEMENT ABOUT A MONOCLONAL ANTIBODY THAT APPEARED TO NOT JUST RECOGNIZE ACUTELY ILL PATIENTS BUT RECOGNIZE THOSE SUSCEPTIBLE FROM RUEMATIC FEVER PATIENTS IN SOUTH AMERICA THE PREVALENCE OF POSITIVE IN PANDA PATIENT WAS 85% AS IT WAS AMONG THE RUEMATIC FEVER PATIENTS. BUT THE CLONE DIED AND SO DID THE HOPE OF ANOTHER MARKER. WE DONE HAVE ANOTHER WHO IS THE BEST IN THIS POINT IN TIME. THE BEST IS FAMILY HISTORY. THE ABNORMAL IMMUNE RESPONSE LISTENING TO THE PREVIOUS TALK I APOLOGIZE, FOR CALLING THIS ABNORMAL IMMUNE RESPONSE BECAUSE IT'S A HEALTHY NORMAL IMMUNE RESPONSE. IT JUST GETS MIXED UP BECAUSE OF THIS COMBINATION OF BAD STREP IN THE WRONG KIDS AND STREP SURVIVED BY PUTTING PROTEINS AN GLYCO PROTEINS ON CELL WALL THAT LOOK LIKE HUMAN HOST. THAT'S HOW IT EVADES THE IMMUNE SYSTEM LONG ENOUGH TO REPLICATE. IT'S EFFECTIVE AT DOING THAT. WHEN IT LINGERS MORE THAN 3 TO 5 DAYS ANN BODIES ARE PERFORMEDDED AGAINST THE ANTIGENS OF THE HUMAN HOST AN ANTIBODIES CROSS REACT. SO THIS NCI KOREA IN PANDAS YOU HAVE CROSS REACTIVE ANTIBODIES CROSSING DISEASE SYMPTOMS AND NOT A TRUE AB MORENALTY OF THE IMMUNE RESPONSE. THERE ARE SUGGESTIONS THAT PERHAPS THERE'S T-CELL DISRETIONLATION IN THE GROUP BUT WE DON'T HAVE ENOUGH EVERYDAY -- EVIDENCE TO SAY THAT DEFINITIVELY. AS WE THINK ABOUT POTENTIAL MODELS WE IDENTIFIED THREE AREAS OF ORGANIZATION. FIST WAS LOCAL, SET OUT TO IDENTIFY THE CROSS REACTIVE ANTI-NEURONAL ANTIBODIES. SECOND WAS REGIONAL BASED ON PATHOLOGIC REPORTS FROM KOREA SPECIFIC INFLAMMATION OF BAY ZILLION GANGLIA. CHANGES IN OUR GROUP OF PATIENTS AND SYSTEMIC THAT JUST THE CYTOKINES AN CHEMOKINES ACT AS NEUROTRANSMITTERS AS WELL AS IMMUNE MESSENGER CHEMICALS AN MIGHT BE RESULTING IN DYSFUNCTION. THE FIRST PLACE WE LOOK TODAY IS AT REGIONAL INFLAMMATION AN THIS SLIDE SHOWS IN GREEN HEALTHY CONTROL CHILDREN AGE AN SEX MATCHED TO A GROUP OF CHILDREN WITH PANDAS SHOWN IN THE PINK. WHAT YOU SEE IS A STATISTICALLY SIGNIFICANT GROUP DIFFERENCE IN THE SIZE OF THE GLOBES PALAMUS BUT NOT THALAMUS AN OVERALL BRAIN SIZE. THIS ISHW QUITE IMPRESSIVE AS A RESEARCH FIND BUG IS NOT MEANINGFUL FOR THE AVERAGE PATIENT. SO YOU CAN'T SEN THEM FOR AN MRI SCAN AND GET A CLINICAL RADIOLOGIST TO SAY YES, THEY HAVE BASAL GANGLIA ENLARGEMENT UNLESS IT WAS PROFOUND AS IN THIS YOWN MAN. HE WAS A 14-YEAR-OLD ASOCCER CAMP AND DEVELOPED AN OVERWHELMING NEED TO EXERCISE TO GET BOTH SIDES OF HIS BODY THE SAME SIZE. HE HAD SYMMETRY CONCERNED AND HE WAS A GYMNAST SO HE WAS USED TO ONE ARM PUSH UPS, HE HAD TO DO TEN RIGHT HANDED AND THEN TEN LEFTED EXACTLY THE SAME. OR HE WOULD START OVER. HE DID THIS MORE OVER AND OVER AGAIN. HE HAS FEARS SUCH AS SOMETHING TERRIBLE HAPPENING TO HIS PARENTS AN CHECKING RITUALS. WHEN WE FIRST E EVALUATED HIM THE HEAD WAS 20% LARGER THAN EXPECTED FOR HIS AGE, WEIGHT AB AND SEX AN AFTER TREATMENT WITH (INAUDIBLE) IT WENT DOWN TO NORMAL SIZE. MORE IMPORTANTLY HE HAD BEEN SPENDING 90% OF WAKING HOURS IN OBSESSIONAL THOUGHTS OR ACTING TO COMPULSIVE RITUALS AN FOLLOWING TREATMENT HE WAS CURED. HE LITERALLY HAD ZERO SYMPTOMS SO IT WAS IN THIS TRIAL THAT WE TREATED HIM AND IT WAS A RANDOMIZED IVIG AGAINST PLACEBO AN THOSE TWO GROUPS COMPARED AGAINST PLASMA EXCHANGE. PLASMA EXCHANGE WAS DONE OPENLY IN THE STUDY, WE ATTEMPTED TO DO A SHAM APHERESIS TRIAL TO SEE IF THERE WAS SOMETHING PLACEBO EFFECT OF THE APHERESIS BUT I TERMINATED IT BECAUSE IT DIDN'T FEEL ETHICALLY APPROPRIATE TO CONTINUE EXPOSING CHILDREN TO THE SHAM APHERESIS. IVIG WAS ONE GRAM PER KILOGRAM PER DAY, PLACEBO GIVEN A SALINE, IDENTICAL FASHION, THE TUBES WERE SEB UP, WE COULDN'T TELL. IN FACT IF ALL PATIENTS LEAVING THE HOSPITAL THEY ALL HAD GOTTEN ACTIVE TREATMENT. I DON'T KNOW IF IT'S BECAUSE THEY HAD POST LP HEADACHES AN NAUSEA OR IF WE JUST HAD DONE A GREAT JOB OF CONVINCING THEM THEY GOT THE REAL THING. BUT PLACEBO GROUP IN THE MIDDLE HAD NO CHANGE IN THEIR SYMPTOM SEVERITY. THE 40% REDUCTION IN OBSESSIVE COMPULSIVE GROUPS WERE SEEN IN THE IVIG GROUP AND 60% REDUCTION IN THE GROUP WHO RECEIVED PLASMA EXCHANGE. THIS GROUP WAS ABSOLUTELY MY FAVORITE TO BE TREATING AT THE TIME BECAUSE THEY STARTED GETTING BETTER. WE DID A SERIES OF FIVE SINGLE VOLUME EXCHANGES OVER 10 TO 12 DAYS. SO THEY WERE IN THE HOSPITAL FOR ALMOST TWO WEEKS. ONE IN THE FIRST INTERVIEW WAS UNABLE TO FINISH BECAUSE SYMPTOMS WERE SEVERE AND THAT NIGHT WENT THROUGH THREE LAUNDRY CARTS BECAUSE OF CONTAMINATION FEARS, SHE HAD TO HAVE HER SHEETS CHANGED EVERY TIME SHE SAW A SPECK. BY THE END OF TREATMENT SHE WAS HAVING BAKED CHOCOLATE CHIP COOKIES WITH HER AWN AND BEING ABLE TO TOUCH EVERYTHING INCLUDING THE SHARPS BOX WHICH IS FULL OF DIRTY NEEDLES. SO IT WAS DRAMATIC BECAUSE OF THE TIMING. THE GROUP TENDED TO RESPOND MORE OVER TWO OR THREE WEEKS THAN AT HOME. THE IVIG PLACEBO COMPARISON SHOULD HAVE BEEN SUFFICIENT TO WARRANT EFFICACY TREATMENT TRIALS, THE STATISTICAL DIFFERENCES WERE SO LARGE THERE WASN'T ANY POINT GOING FURTHER. BECAUSE OF THE CONTROVERSY IT'S NOT BEEN ACCEPTED WIDELY SO WE HAVE UNDERTAKE AN MUL SITE TRIAL OF IVIG, SAME DESIGN, BUT THIS TIME OUR COLLEAGUES AT YALE UNIVERSITY ARE DOING RATINGS BY VIDEO CONFERENCE. SO IT'S A WONDERFUL PLUG FOR THE NIH CLINICAL CENTER, WHAT A PRIVILEGE TO BE AT A PLACE WHERE WE CAN DO THE TREATMENT AND HAVE VIDEO INTERVIEWS BY COLLEAGUES AT YALE FROM YALE WITH THE KIDS HERE. ANTI-NEURONAL ANTIBODIES IS WHY I CONSIDER THIS CASE TO BE CLOSED. WE HAD SPECULATED THAT THESE CROSS REACTIVE ANTIBODIES WERE ACTIVATING CELLS ANs>N„ CAUSING IMMUNE MEDIATED DYSFUNCTION OF THE NERVOUS SYSTEM OR THEY MIGHT BE IMPACTING DIRECTLY ON NEUROTRANSMISSION. A SERIES OF ANTIBODY STUDIES HAVE BEEN DONE, HARVEY SINGER, IS ONE OF THOSE WHO WROTE THE PAPER SAYING PANDAS NEED TO BE ELIMINATED AND HAS FOUND NEGATIVE STUDIES WITH THE ANTIBODY OR A VERY HIGH PROPORTION OF POSITIVES IN THESE CONTROLS. SO ONE QUESTION IS HOW SPECIFIC ARE THEY AND MEANINGFUL ARE THESE ANTIBODIES? THIS IS A STUDY BY COLLEAGUES MADELINE CUNNINGHAM, UNIVERSITY OF OKLAHOMA AND CHRISTINE KERBAN AT UC DAVIS DEMONSTRATING PANDAS IN KEYIA SERUM SAMPLES DURING ACUTE ILLNESS REACTED DIFFERENCE THAN CONTROLS DID AND YOU CAN SEE A BIT OF A SENSE OF HOW THE STAINING DIFFERENCE BETWEEN THE PANDAS, AND THE CONTROLS. MORE IMPORTANTLY THEY HAVE BIOACTIVITY AS THEY INDUCE KINASE, PANDAS IN THE MIDDLE, AND THE NON-PANDAS CHILDREN HAVING SOME OVERLAP WITH THE THE LOWER LEVELS AND PANDAS BUT DEFINITELY NOT WITH THOSE IN THE HIGHER RANGE MUCH LESS THE CREE YASM THE REASON THIS IS SO EXCITING IS THE WAY THE CLINICAL MANIFESTATION OF THIS DISEASE GO. WE LOOKED AT KOREA BECAUSE OF HISTORICAL REPORTS THAT 2 TO 4 WEEKS BEFORE THE ONSET OF THE ADVENTITIOUS MOVEMENTS OF THE ST. VIET,S DANCE THE CHILDREN WERE EXPERIENCING OBSESSIVE COMPULSIVE THOUGHTS IDENTICAL TO THOSE OF OCD. THEY CM ON 2 TO 4 WEAX BEFORE THE MOVEMENT SO IT WASN'T A PSYCHOLOGICAL RESPONSE TO THE PHYSICAL DISABILITY BUT THEY PERSISTED LONGER SUGGESTING A DOSE RESPONSE EFFECT TO GIVE YOU OCD SYMPTOMS AT DOSE LESS THAN THAT OF KOREA. WHILE THESE DATA AREN'T DEFINITIVE THEY HAVE BEEN COMPLIMENTED IN ANIMAL STUDIES WHICH THEY HAVE BEEN NOT ONLY INDUCE ONSET OF HYPERAD ADVENTITIOUS MOVEMENTS, REPETITIVE FLIPPENING THESE MICE BY INFECTIONS WITH STREP, BUT DEMONSTRATED PASSIVE TRANSFER THE ANTIBODIES IN THE AFFECTED MICE INTO A GROUP OF NAIVE RECIPIENT MICE AN RESIP YANT MICE DEVELOPED BEHAVIORAL ABNORMALITIESCH THESE AS WELL AS OTHERS TO MORE EFFECTIVELY DEMONSTRATE REDUCTIONS IN SIMILAR TOLL FLOING ANTIBIOTIC FROF LACKSIS PROPHYLAXIS DEMONSTRATES IT LOGIC ROLE IN PANDAS SO I WOULD SAY WE HAVE GONE FROM TREATMENT MODEL TO TREATMENT AN PREVENTION, ANOTHER EDITORIAL WOULD BE FROM TOILET TRAINING TO PROF PROPHYLAXIS OVER NIGHT OR IN THE LAST 25 YEARS IN OUR CASE. ANTIBIOTIC PROPHYLAXIS ELIMINATES STRESS INFECTION AND -- STREP INFECTION AND REDUCES SYMPTOMS. WE HAVE IT HAPPENING ONLY IN CERTAIN GENETICALLY SUSCEPTIBLE HOSTS, THE ABNORMAL IMMUNE RESPONSE MAYBE BROADER THAN CROSS REACTIVE ANTIBODIES WHERE THE CURRENT AREA OF FOCUS IS NOW. BUT THROUGH IMMUNOMODULATORY THERAPIES WHICH KNOCK DOWN SYMPTOMS OR PROPHYLAXIS WHICH PREVENTS THEM IT IS POSSIBLE THE CURE AN INDEED PREVENT THIS DISORDER. THANK YOU. [APPLAUSE] I TALK FAST BUT I WAS AFFRAY I WHEN OVER TIME. ARE THERE ANY QUESTIONS? THANK YOU. >> THANK YOU. YOU CAN SEE THE DIFFICULTY OF NOT ONLY IDENTIFYING THE DISEASE BUT SUSTAINING AFTER IDENTIFIED AND SOME ARGUMENTS THAT GO ON IN THE SCIENTIFIC COMMUNITY. AS SOON AS WE GET DR. RAFAEL GOLDBACH-MANSKY WITH THE MICROPHONE SHE'LL TALK CHILDHOOD FEVERS AN RASHES. NOT YOU WILL ARE THE SAME. LESSONS FROM THE RARE AUTOINFLAMMATORY DISEASES. WE ARE GOING TO TRY TO FINISH ON TIME SO PEOPLE CAN GET MOVING FOR THE NEXT EVENT IN SILVER SPRINGS SO TRY TO KEEP ON SCHEDULE. IF YOU NEED A BIO BREAK IN BETWEEN SPEAKERS WHILE WE'RE GETTING THEM READY PLEASE TAKE A QEK BREAK AN COME BACK IN. -- QUICK BREAK AND COME BACK IN. >> I'M HERE BECAUSE I KNOW THERE'S SOME IN THE AUDIENCE WHO HAVE RARE DISEASES OF CHILDREN OR FRIENDS WITH A RARE DISEASE, I WANT TO SHOW YOU ON THE EXAMPLE OF FOUR PATIENTS THAT OUR ABILITY TO USE HIGH THROUGH PUT TECHNOLOGY TO INVESTIGATE THE GENOME CAN MAKE HUGE DIFFERENCES IN OUR STANDING UPPING OF THE PATHOGENESIS THAT DRIVES DISEASE AS WELL AS -- I HAVE TO GET MY TALK UP ACTUALLY. AS WELL AS ACTUALLY FINDING OTHER TREATMENT AND IN FINDING KNOWLEDGE GENERALIZABLE TO COME DISEASES. I THOUGHT I HAD A COMPULSIVE DISORDER AS WELL, ACTUALLY STRANGE. WRONG TALK. YES. I WAS NOT GOING TO TALK ABOUT -- THOUGH MANY TIMES IT IS AN ODYSSEY TO SEE PATIENTS, IT'S A LAST TALK ON SCREEN IN FRONT OF ME. ONE FURTHER DOWN. THIS ONE, THANK YOU. I MAY HAVE TO RAISE YOU THROUGH A NUMBER OF PICTURES BUT I WILL START WITH THE PATIENTS I SEE WITH FEVERS AN RASHES AN JOINT PAIN AND THEY ACTUALLY LOOK LIKE INFECTIONS BUT IT IS OFTEN FRUSTRATING THEY DO NOT HAVE INFECTIONS, AND DON'T RESPOND TO ANTIBIOTICS. BEFORE WE TALK IMMUNE ABNORMALITIES I WANT TO INTRODUCE YOU TO A BROAD CONCEPT OF INFLAMMATION, IT IS THE BODY'S RESPONSE TO ANY DANGER MAY COME FROM INFECTIONS OR MAY DIE FROM SUBSTANCES THAT ARE RELEASED FROM DYING CELLS. AND OUR IMMUNE SYSTEM HAS EVOLVED IN TWO WAYS. WE HAVE AN INNATE IMMUNE SYSTEM WHICH CONSISTS OF HARD WIRED RECEPTORS, GENETICALLY HARD WIRED AND RESPONSE PATTERNS WE INHERIT FROM OUR PARENTS AND THEN ADAPTIVE IMMUNE SYSTEM THAT CONSISTS OF CELLS UPON CONTACT WITH ANTIGENS AND TRIGGERS I THAT'S WHAT'S CALLED ADAPTIVE IMMUNE SYSTEM SO WHEN IT MESSES UP YOU CAN HAVE TWO CONDITIONS, REDUCED IN THE IMMUNE RESPONSES ARE REDUCED TO A DANGER SIGNAL, YOU GET IMMUNODEFICIENCY OR IMMUNE RESPONSE INCREASED AND YOU GET ADAPTIVE IMMUNE SYSTEM ALLERGIES AN AUTOIMMIEWTY OR AUTOINFLAMMATION. THAT CONCEPT WAS OF AUTOINFLAMMATORY DISEASE WAS DEFINED BY DAN CAST NER, MED TEAR YAINIAN FEVER AN TRAP AND ONE CAN UNDERSTAND AS ABNORMALITIES IN THE HARD WIRED IMMUNE SYSTEM THAT PRESENT WITH FEVERS AND SPECIFIC ORGANS LIKE SKIN, EYE, EARS, BRAINS, GUTS VESSELS AN BONES AND I WILL SHOW YOU EXAMPLES. THE GOAL OF OUR STUDY IS IN A COHORT OF PATIENTS WITH RARE INFLAMMATORY DISEASE TO IDENTIFY DISREGULATED KEY INFLAMMATORY PATHWAYS TO FIND GENETIC CAUSE AND BY UNDERSTANDING THE DISEASE BEAR DEVELOP TARGETED TREATMENTS IN LONG TERM SAFETY. USE ADVANCED TECHNOLOGIES TO "r CHARACTERIZE THE PATIENTS SO SINCE THE INITIAL DAYS OF TRAP -- OF FINDING THE GENETIC MEDITERRANEAN FEVER THERE'S A NUMBER OF MONOGENIC DISEASE THAT HELPS US UNDERSTAND IMMUNE PATHWAYS. I'M GOING TO SHOW YOU FOUR PATIENTS EACH OF THEM HAS ONE OF THE HIGHLIGHTED DISEASES. THESE ARE THE FOUR PATIENTS I WILL BE TALKING AB. THE FIRST WAS ACTUALLY SENT TO US AT AGE 8 YEARS. HE HAD FEVERS, HE HAD8ĚRASHES, HE WAS ACTUALLY RASH DEVELOPED SHORTLY AFTER HE WAS BORN. HE HAD DAILY HEADACHES MAINLY IN THE MORNING, HE HAD DEVELOPED HEARING LOSS WHEN FOUR YEARS OLE AND SIGNIFICANT HEARING LOSS BY AGE 8. HE HAD JOINT DEFORMITIES WITH ONE LEG SHORTER THAN THE RIGHT. HE WAS SHORT, HE WAS BELOW THE THIRD PRESENT FOR PERCENT FOR HEIGHT AN WEIGHT AND SOME PERIPHERAL VISION LOSS IN PATIENTS WITH LONGER STANDING DISEASE DEVELOP. THERE WAS NO FAMILY HISTORY WHEN WE EXAMINED HIM HE HAD LARGE VENTRICLES AN THIS IS THE BACK OF THE EYE AND YOU SEW A SWOLLEN NESH THAT STICKS OUT -- NESH THAT STICKS OUT -- NERVE THAT STICKS OUT. THE QUESTION WAS INTERESTINGLY TO FIND BEAR TREATMENT BECAUSE THOSE PATIENTS WITH DO NOT RESPOND TO STEROIDS OR OTHER DISEASE MODIFYING DRUGS THAT THEY USE TO TREAT RHEUMATOID ARTHRITIS. AT THE TIME WE AWE THIS HAUFMAN IN-- THEY GOT THE SAME RASH ADS OUR PARENT BUT UPON EXPOSURE TO COAL THEY GOT FEVER AN JOINT PAIN. HE HAD CHECKED SEVERAL FAMILIES BY CLONING APPROACH IDENTIFIED MUTATIONS AND OTHER GENE THAT WERE NOT DESCRIBED AND IS NOW CALLED NLRP-3. THERE ARE SOME SIMILARITIES THOSE FAMILIAR DISEASE WE VENTURE TO TEST PATIENTS FOR MUTATIONS IN THIS GENE AND TURNS ACTUALLY OUT THAT OUR PATIENT HAS A DE NOVO MUTATION, DE NOVO MUTATION THAT CAUSE DISEASE, PARENTS AN SIBLINGS WERE NEGATIVE, IT ALLOWED US TO UNDERSTAND A DISEASE THAT HAD QUITE SIGNIFICANT DIFFERENCES FROM FCAS AS A DISEASE SPECK TRUP, ALL THOSE DISEASE IT IS FAMILIAR FORMS AN SPORADIC FORMS ARE CAUSED BY THE SAME GENETIC MUTATION AND ARE A DISEASE SPECTRUM WITH NO (INAUDIBLE) MOST SEVERE END OF THE SPECTRUM AND AUTOINFLAMMATORY SYNDROME AT THE MOST MILDEST END OF THE SPECTRUM THE PROTEIN THAT'S ENCO-ED BY THE GENE WAS QUITE INTERESTING. BECAUSE IT ACTUALLY HAD FEATURES OF A RECEPTOR THAT INFORMED THE BLOOD FORM THAT HAVE THE BACTERIAL STIMULI AND UPON STIMULATION GOT ACTIVATED TO FORM -- TO ACTIVATE AN IMMATURE PRO INFLAMMATORY CYTOKINE OF A MEDIATOR. YOU GET FEVER INTO THE FORM. SO THIS GIVE US A CLUE MAYBE THIS DISEASE WAS ACTUALLY ONE IN WHICH ONE WAS PREFERABLY AND CONSTITUTIVELY ACTIVATED AND WE ASKED -- WE ANSWERED THIS QUESTION. SO DID THESE PATIENTS HAVE TOO MUCH I-1 AN COULD WE BLOCK IT? AT THE TIME WE SAW THE PATIENTS THERE WAS ACTUALLY A DRUG THAT CAN BLOCK THE PATHWAY APPROVED FOR THE TREATMENT OF RHEUMATOID AR THREE AT THIS. BUT WE USE THIS MEDICATION TO TREAT OUR PATIENTS AND WITHIN DAYS IN THE PATIENTS DIDN'T SEE PAIN MEDICATION. AND HAD INITIAL WITHDRAWAL STUDY WITH 18 PATIENTS. AFTER 11 WE STOPPED THE PHASE BECAUSE EVERY PATIENT WE WRIEW WITHDREW WITHIN TWO OR THREE DAYS DEVELOPED SEVERE SYMPTOMS OF THE DISEASE OFTEN TIMES MORE SEVERE THAN AT THE BEGINNING. NOW, THE IMPROVEMENT IS LONG TERM, THIS IS FIVE YEAR OUTCOME DATA WE HAVE CHECKED CHECKED AND ACUTE REACTION MEASURES OF THE INFLAMMATION IN THE BLOOD SO THOSE DROPPED DRAMATICALLY, IS SERUM ARC LEVELS COMMON MEASURES TO MEASURE INFLAMMATION IN THE BLOOD AND THEY ACTUALLY STAYED LOW NOW FOR FIVE YEARS. WHAT IS MORE EXCITING OR INTERESTING IS THE QUESTION WHETHER THE DAMAGE WE SEE IN THE DISEASE, THIS IS A VENTRICLE, A PATIENT WHO LOST BRAIN MASS, BRAIN ATROPHY, THIS IS A CHILD A PATIENT WAS BLIND BECAUSE THEY HAVE LOST ALL THE OPTIC NERVE FIBERS. THAT'S WHY IT'S SO WHITE AND THIS IS A PATIENT WHO HAD HEARING LOSS. WE WANTED TO KNOW WHETHER TREATMENT WITH A BLOBBING AGENT COULD PREVENT THAT ORGAN DAMAGE FROM FORMING. ONCE YOU ACTUALLY GROWN UP AND YOU HAVE LOST BRAIN MASS YOU WON'T REGAIN IT BUT THIS IS A CHILD WHO HAD HEADACHES INTRACRANIAL MEASURE AND IN THIS FLEXIBLE BRAIN OF A CHILD EARLY TREATMENT WAS IN COMPLETE NORMALIZATION OF THE VENTRICLE WHICH RAISED THE HOPE THAT WE CAN ALSO PREINVENTORY THE HORRIBLE OUTCOMES THAT SOME CHILDREN GET THAT ARE MENTAL RETARDATION, VISION AND HEARING LOSS. THIS IS A SWOLLEN NERVE BEFORE THE FIBER DIE, LONG TERM SWELLING LEADS TO FIBER LOSS. SWOLLENH 'Z NERVE, YOU SEE THE COLOR OF A HEALTHY DISC SO WE WERE NOT AGE ABLE TO REDUCE -- ABLE TO REDUCE THE BRAIN PRESSURE BUT EDEMA, AN VISION NORMAL. I DIDN'T SHOW ON THE SLIDE. SIMILARLY HEARING REMAINED STABLE UNTREATED PATIENTS AND IN YOUNG CHILDREN WE ENROLLED SINCE WE HAVE NOT SEEN ANY HEARING LOSS. AND WE HAVE IDENTIFIED, I DON'T HAVE A PICTURE HERE, THE HEARING LOSS CORRELATES TO THEi] COCHLEA TREATING WITH IL-1, SO WE LEARNED ABOUT THE PHENOTYPE IN THOSE PATIENTS AND IN ADDITION THE CHILD BELOW THE THIRD PERCENTILE FOR WEIGH AND HEIGHT BEFORE WE PUT IN THE STUDY WENT INTO NORMAL RANGE, HE'S IN COLLEGE NOW AND HAS A NORMAL ADULT HEIGHT. IS THIS A DISEASE MECHANISM THAT EXPLAIN AS RARE DISEASE OR DOES IL-1 PLAY A ROLE IN COMMON DISEASE? THE INFLAMMASOME PLATFORM IS QUITE AN INTERESTING SENSOR. IT NOT ONLY RESPONDS TO BACTERIAL STIMULI BUT IT ALSO RESPONDS TO DIENGER -- DANGER SIGNALS. CTP AND ATP ARE RELEASED WHEN CELLS ARE DYING, GLUCOSE AND I LET AMYLOID POLYPEPTIDE IS AN AMYLOID ME TAB LIESM THAT ACCUMULATES IN PANCREATIC ISLET CELLS IN PATIENTS WITH DIABETES. FREE FATTY ACIDS OX DATED CERAMIDE ACCUMULATE IN CELLS IN CRYSTALS IN BASICALLY THE ENDOTHELIUM OF PATIENTS WITH ATHEROSCLEROSIS, THEY ACTIVATE THE INFLAMMASOME AN LEAD TO EL-1 RELEASE. THIS IS ACTUALLY LED TO THE QUESTION OF RAISING THE QUESTION THAT WHETHER THE INFLAMMATORY MANIFESTATIONS OF GOUT, DIABETES WHICH CAN BE WHICH CAN WORSEN WHEN YOU DESTROY THE PANCREATIC ISLET CELLS WITH IL-1 OR ANOTHER DISEASE INFLAMMATORY DEES OR AT LEAST WITH SOME OF THE DISEASE SEVERITY SEEN WITH THOSE DISORDERS ARE MEDIATED BY IL-1. ALZHEIMERS THERE'S AN ANIMAL MODEL WHERE AMYLOID DEPOSITS TRIGGER ALZHEIMER'S DISEASE AND IL-1 RELEASE IN THE BRAIN. THIS HAS INITIAL PROOF OF CONCEPT STUDIES, WE KNOW THAT WE CAN ACTUALLY TREAT THE INFLAMMATORY MANIFESTATIONS WITH SHORT ACTING AND LONG ACTING IL-1 INHIBITORS, THEY HAD BEEN SUBMITTED FOR APPROVAL TO THE FDA OVER 17,000 PATIENT STUDY GOING IN LONG ACTING IL-1 INHIBITOR TO TREAT WITH CORONARY ARTERY DISEASE IN ATTEMPT TO SEE WHETHER ONE PREVENTS THE HEART ATTACK AND STROKE. THIS IS A CHILD WITH ANOTHER FORM OF IL-1 MEDIATED DISEASE. I GOT INVOLVED BY TELEPHONE AND RECEIVING THOSE X-RAYS. THAT WAS CHILD WITH SYSTEMIC INFLAMMATION. HE HAD RASHES AN THERE WERE NEUTROPHILS. PHYSICIAN WONDER IF HE HAD NEG BY TWO WEEKS OF AGE DEVELOPED, TREATED FOR CELLLITIS, DID NOT GET BETTER BY THREE WEEKS, ADMITTED TO THE HOSPITAL BECAUSE MOTHER WAS UNABLE TO HANDLE, HE SCREAMED EVERY TIME HE'S LISTED UP, HE ENDED UP IN THE ICU AND HAD BEEN IN THE ICU TREATMENTS INCLUDING HI DOSE STEROIDS WITHOUT MAJOR IMPROVEMENT SO THERE WASN'T MUCH LEFT TO DO. WE DECIDED TO PUT HIM ON (INAUDIBLE) AN THOUGHT WELL IF THIS CHILD RESPONDS MAYBE HE HAD A FORM OF NOMED AND WE NEED TO EXTEND THE PHENOTYPE. WHAT THIS CHILD ALSO HAS IS OSTEOLYTIC LESION. HE HAS THICKENING OF THE RIBS SO HE HAS INFLAMMATION BETWEEN BONE AND CARTILAGE. THIS IS WHAT THEY SAW IN THE ICU. THIS IS BEFORE TREATMENT, THREE DAYS AFTER TWO WEEKS OF TREATMENT WITH IL-1 INHIBITOR. BECAME CLEAR THIS CHILD DID NOT HAVE THE CNS MANIFESTATIONS AND OSTEOLYTIC LESIONS WE HADN'T SEEN BEFORE AND POST LAR LEAGUES IS SOMETHING WE HAVE NEVER SEEN IN THE PATIENTS SO THE RESEARCH FOR OTHER GENES THAT COULD BE MUTATED. AND THE (INAUDIBLE) DAN CASTNER'S LAB, THE THIRD GENE ON CANDIDATE LIST WAS THE RECEPTOR ANTAGONIST, THE IL-1 RECEPTOR ANTAGONIST BINDS AND IS A NEGATIVE REGULATOR. IT BLOCKS ALPHA AND BETA FROM BEHINDING AND THE RECEPTOR FROM SIGNALING SO BASICALLY DOWN REGULATES THE IL-1 MEDIATED SIGNAL AND IN FACT IS A RECOME BY NAN RECEPTOR ANTAGONIST DEVELOPED FOR TREATMENT OF RHEUMATOID ARTHRITIS. AND IT TURNED OUT THESE CHILDREN HAD THAT LED TO NON-EXPRESSION OF THE IL-1 RECEPTOR ANTAGONIST. SO WE WERE GIVING EXACTLY THE– PROTEIN THEY WERE LACKING. IL-1 ALPHA AND BETA BIND TO RECEPTOR AND ALPHA CAN CANNOT GET CONTINUED. SO WE HAVE IDENTIFIED PATIENTS AND IDENTIFIED SEVERAL MUTATIONS. THIS IS A CHILD FROM PUERTO RICO THAT HAS BONE LESION SIMILAR TO WHAT IS SEEN IN ADDITION TO OTHER FEATURES WHICH INCLUDES THE RECEPTOR ANTAGONIST AN FIVE ADDITIONAL GENES. INTERESTING THE MOUSE MODEL FOR THAT DISEASE. THE MICE DO NOT DEVELOP THE PHENOPHENOTYPE, SO WE SEE THIS A LOT THAT THE MOUSE DOES NOT MIMIC HUMAN DISEASE AND WE WOULD NEVER HAVE PREDICTED THESE WITH THE MOUSE POAL H MODEL. NOW WE HAVE FOUND MUTATIONS IN GENE IN MULTIPLE POPULATIONS WHICH DETERMINES THE FREQUENCY IN PUERTO RICO AND IN THE AREA WHERE THIS GENE IS COMING FROM 1 IN 20,000 WOULD HAVE THE DISEASE. IN FACT THERE ARE PROBABLY SIX KNOWN PATIENTS WITH THAT MUTATION CURRENTLY KNOWN. SO WE EXPANDED THE PHENOTYPE OF MEDIATED DISORDERS TO BONE DISEASE THAT COULD BE THAT IL-1 ALPHA MEDIATE IT IS BONE PHENOTYPE. LET ME GO TO A THIR PATIENT REFERRED TO US -- A THIRD PATIENT AS POSSIBLE MUTATION NEGATIVE PATIENT AS WELL. THIS PATIENT DURING THE FIRST WEEKS OF HIS LIFE STARTED DEVELOPING SWELLING OF THE FINGERS AN TOES AND HAD SWELLING AROUND HIS EYES AND A DIFFUSE RASH AND DURING THE FIRST AREA OF LIFE HE DEVELOPED LOW GRADE TEMPERATURES AND AFTER 12 MONTHS THE FEVERS GOT HIGHER. HE ALSO DEVELOPED JOINT PAIN AND THE RASH PHENOTYPE STARTED CHANGING AS CHILDREN GOT OLDER. WE COLLECTED A TOTAL OF NINE PATIENTS SWELL OF FINGERS, AS WE GET OLDER RASHES BECOME MORE -- THIS IS A PICTURE OF A PATIENT WHO DEVELOPED INFLAMMATION OF THE FAT. HE'S LOST PERIPHERAL FAT AND I SHOW YOU ANOTHER PICTURE THEY DEVELOP (INAUDIBLE) IN A ADDITION SHOWING FLUID IN THE SUPRAPATELLA POUCH OF THE KNEE. THIS IS THE PATIENT AFTER SEVERAL YEARS, HE LOST FAT AROUND THE CHEEKS COMPLETELY AND ACCUMULATING FAT IN HIS ABDOMEN SORKS THIS IS NOT FLUID, FLUID IS FAT THAT ACCUMULATES IN THE (INDISCERNIBLE) SO THROUGH INTERNATIONAL COLLABORATION, WE IDENTIFY THESE PATIENTS HAVE MUTATIONS CALLED (INDISCERNIBLE) SO MOST WERE HOMOZYGOUS IN THE PORTUGUESE SPANISH AND HIS PANIC PATIENTS BUT ALSO DE NOVO IN ONE PATIENT FROM THE US. U.S. AND THIS IS A PATIENT FROM EAST ROYAL. WHAT WE LEARN IS AT THE TIME WE FOUND A PAPER PUBLISHED BY ENDOCRINOLOGIST WHO SHOWED MUTATIONS CAN CAUSE THE PHENOTYPE. THESE PATIENTS, THEY WERE METABOLIC PHENOTYPE BUT IS THE IDENTICAL MUTATION WE FOUND AND LEARNED THAT DISEASE IS IN THE SPECTRUM OF WHAT WE HAD SEEN WITH OUR PATIENTS. TWO JAPANESE GROUPS IDENTIFIED ANOTHER MUTATION IN A SYNDROME THAT'S IN THE EARLY '80s AS (INDISCERNIBLE) SYNDROME. WE LEARNED FROM THE NATURAL HISTORY DISEASE WOULD LOOK LIKE BUT MANY CHILDREN ABOUT A THIRD DIE IN INFANCY. MUTATIONS OCCUR IN A UNIT, IN A EVOLUTIONARY CONSERVED UNIT THAT YOU ALSO FIND IN PRIMITIVE CELLS, THAT DEVELOPED TO CREATE POLYUBIQUITIN PROTEINS MARKED WITH DEGRADATION AND MAINLY STUDIED IN THE CONTEXT OF ANTIGEN PRESENTATION. BUT THERE WERE RECENT STUDIES IN POLYUBIQUITINATED PROTEIN TO VESES CELLS AN CAUSE THEM TO DIE. THAT COULD BE INDUCED BY INTERFERON. WE THEN WANTED TO ASK THE QUESTION IS THERE A SIGHKINE THAT'S A BETTER TARGET FOR BLOCKADE? THESE ARE TREATED WITH AN IL-1 AND I LR-6 INHIBITOR. SO WE THOUGHT THAT THE CYTOKINE OR INFLAMMATORY MEDIATED RESPONSE THAT DRIVES THIS DISEASE MIGHT BE OTHER THAN THOSE FOUR WE TESTED AND IN FACT WHAT WE FOUND IS VERY SIGNIFICANT INTERFERON SIGNATURE IN THE PROFILE OF THOSE PATIENTS AND THIS IS COMPARED TO NAR MALLS BUT WE ALSO COMPARED TO O THE DISEASE AND THERE WAS A VERY STRONG DIFFERENCE. THE SIGNATURE IS VERY SIMILAR WHAT -- TO WHAT HAS BEEN OBSERVED IN VERY YOUNG PEDIATRIC PATIENTS WITH EARLY ONSET LUPUS AND A CLINICAL PHENOTYPE IN OUR PATIENTS WITH (INAUDIBLE) SYNDROME. THIS LED TO THE HYPOTHESIS WITH AN INEFFICIENT PROTEOSOME AND BECAUSE IT CANNOT DEGRADE POLY EWE BICNATEED PROTEIN, THEY CAUSE STRESS AND MAYBE RELEASES INTERFERON AND THIS LEADS TO A VICIOUS CYCLE. THIS IS DOWNSTREAM WORK OF INTERFERON SIGNALING WITH INHIBITOR WE WESTERN ABLE TO GET BUT WE GET A CHECK # 2 INHICKTOR -- CHECK 2 INHIBITOR FOR THOSE CURRENTLY CONDUCTING THE STUDY. THE PATIENT HAD A RESPONSE TO A INHIBITOR SUGGESTIONING THE PATHWAY MIGHT INFECT WHAT IS NEEDED TO TREAT THOSE PATIENTS. BUT THIS IS VERY EARLY, WE NEED MORE DATA. THIS IS THE LAST PATIENT I WANT TO TALK TO YOU ABOUT. THIS PATIENT HAD POST LAR DISEASE AND PATIENT WAS REFERRED TO US FOR POSSIBILITY OF SCREENING FOR (INAUDIBLE) AND ALSO FOR THE POSSIBILITY OF RESPONDING TO AN R-1 INHIBITOR WHICH WASN'T ABLE TO -- WHICH THE PHYSICIANS OUTSIDE WEREN'T ABLE TO OBTAIN. THIS PATIENT AT AGE SIX MONTHS STARTED DEVELOPING A GENERALIZED POST LAR RASH WHICH LITERALLY COVERED HER BODY, SHE WAS SHEDDING SCALES AND WHEREVER SHE WAS SIT IT CAN MOTHER THIS WAS PICKING UP THE SCALES AN CLEANING UP, SHE COULDN'T GO TO DAY CARE BECAUSE SHE DEVELOPED HIGH FEVER AND WAS ADMITTED WITH THE POST LAR RASH TO THE ICU, SHE WAS TREATED WITH HIGH DOSE STEROIDS AND ANTIBIOTICS, GOT BETTER AND SHE WAS COMPLETELY UNRESPONSIVE TO METHYL TREX ATE AND TNF AND COMBINATIONS, WE TARTED HER ON INHIBITOR BUT WITH NO RESPONSE. BECAUSE OF SIMILARITIES ON HER BIOPSIES TO PSORIASIS THOUGH SHE HAD MORE NEUTRAFILLS THAN TYPICALLY IN PSORIASIS WE DECIDED TO TREAT WITH (INAUDIBLE) AN ANTIBODY VERY EFFECTIVE IN THE TREATMENT OF PSORIASIS, NOT FOR CHILDREN AND WITHIN THREE MONTHS SKIN WAS CLEARED. WE THEN DID GENERAL IT CAN APPROACH AND TRIED TO IDENTIFY THE GENE AND COLLABORATED WITH (INAUDIBLE) WHO HAD FOUND A GENE FOR MONOGENIC FORM OF PSORIASIS. THIS IS MORE GARDEN TYPE OR CLASSIC PSORIASIS AND NOT NECESSARILY POST LAR PSORIASIS THOUGH SOME PATIENTS HAD EARLY ONSET DISEASE. OUR PATIENT HAS DE NOVO MUTATION. THIS ALLOWED THE SPECTRUM OF INFLAMMATION FROM PLAQUE LIKE SORRYSIS TO A POST LAR PHENOTYPE. AND INTERESTINGLY IT IS MAINLY IN THE SKIN IN THE EPIDERMIS WHERE THERE'S FEW MYTOPO TICK CELLS THAT STAIN KERATINOCYTES SO THESE ARE TISSUE SPECIFIC CELLS. WHEN THESE WHEN SHE TRANSSECONDED OUR MUTATION AN FAMILIAL MUTATION INTO A KERATIN SITE CELL LINE, SHE ACTUALLY FOUND INCREASE IN NF KAPPA B ACTIVITY AND INTERESTINGLY CER LATING WITH PHENOTYPE LESS SEVERE IN THE FAMILIAL THAN SPORADIC FORM. MUCH HIGHER NF KAPPA B ACTIVITY, DONE BY I DON'T THINK CHING WHICH I AM IN THE LAB THAT CULTURED KERATIN SITE FROM THE PATIENT AND TO CONTROL KERATIN SITE CELL LINES AND FIND THAT CHEMOKINES THAT ARE ACTUALLY RELEASED TO ATTRACT CELLS TO THE SKIN COULD BE MADE IN KERATIN SIGHS, THEY MAKE IL-8, THEY MAKE ANOTHER CYTOKINE THAT RECENTLY WAS ASSOCIATED WITH SKIN INFLAMMATION THAN LARGER CONTROLLED SO THESE ARE CONSTITUTIVELY ACTIVATED KERATIN SITES AND WE HAVE THE MODEL THAT THE INFLAMMATORY TRIGGER MIGHT COME FROM KERATIN SITES LEAD TO RECRUITMENT OF HEMATOPOIETIC CELLS THAT LEAD TO AMPLIFICATION THAT KEEPS THE KERATIN SITE ACTIVATE AND LOCALIZATION OF INFLAMMATION OF THE SKIN. SO WE USE THIS AS A MODEL TO LEARN MORE ABOUT SKIN INFLAMMATION. THESE ARE EXAMPLES OF RARE PATIENTS AND THE ABILITY TO USE HIGH THROUGH PUT TECHNOLOGY TO PHENOTYPE MORE CAREFULLY AND OBTAIN ANSWERS. THERE ARE CHALLENGE, ACCESS TO COMMUNICATION IS A BATTLE. COMPANIES DON'T WANT TO GIVE DRUGS TO PATIENTS WITH RARE DISEASES AN MIGHT HAVE POTENTIAL OF SEVERE SIDE EFFECTS. SO WORKING WITH PHARMA AND FDA IS IMPORTANT TO OBTAIN ACCESS AND BE ABLE TO DO STUDIES TO ALLOW TEST HYPOTHESIS GENERATED FROM STUDYING THOSE PATIENTS. THE LOGISTICS OF GETTING PATIENTS TO THE NIH, SOME ARE FAR AWAY, SICK AND CAN'T TRAVEL WELL AND COST FOR EVALUATING PATIENTS COMPREHENSIVELY. SO IN SUMMARY, THE STUDIES OF THESE RARE INFLAMMATORY DISORDERS LED TO THE DISCOVERY OF KEY INFLAMMATORY PATHWAYS AN CONTINUE TO DO SO THAT PROVIDE RATIONALE FOR PROVIDING TARGETED THERAPIES. BLOCKING IL-1 IS VERY EFFECTIVE IN THE SUBSET OF THESE PATIENTS BUT OTHER PATHWAYS WE NEED TO ADDRESS. THE TREATMENT HAS SIGNIFICANTLY IMPROVED THE PATIENT'S LIFE, WE ARE CURRENTLY HYPOTHESIZING ANY OF THE ORGAN DAMAGE AND INFLAMMATION IN PATIENTS CAN BE PREVENTED WITH EARLY AGGRESSIVE TREATMENT AND WE ARE CONDUCTING A STUDY ENROLLING PATIENTS UNDER THE AGE OF 2. ONE PROBLEM IS EARLY RECOGNITION OF PATIENTS, THEY'RE NOT DIAGNOSED IN TIME. BUT THERE IS CERTAINLY MORE WORK THAT NEEDS TO BE DONE IN ORDER TO MAKE PHYSICIANS AWARE OF THESE CONDITIONS. THIS DISCOVERY OF IL-1 BETA ACTIVATING INFLAMMASOME THROUGH THE STUDY OF RARE DISEASE HAS INCREASED OUR STANDING OF INFLAMMATION IN PATIENTS WITH POLYGENIC DISEASES INCLUDING DIABETES, CORONARY ARTERY DISEASE AN PROOF OF CONCEPT STUDIES ARE ONGOING. THE DISCOVERY OF AUTOP INPROGRAMTORY DISEASE -- AUTOINFLAMMATORY DISEASE CONTINUE TO SPUR DRUG DEVELOPMENT. THESE RARE AUTOINFLAMMATORY DISEASE HAVE CLIN SIMILARITIES WITH OTHER RARE DISEASES INCLUDING (INAUDIBLE) DISEASE, CHRONIC RECURRING MULTI-FOCAL OSTEO MILYTIS AND POST LAR PSORIASIS. THESE ARE PROBABLY MORE HETEROGENEOUS DISEASES NOT MONOGENIC, WE ARE INVESTIGATENING COLLABORATIONS WITH TREATMENT APPROACHES IN CHILDREN WITH RARE AUTOINFLAMMATORY DISEASE MIGHT BE BENEFICIAL FOR TREATING PATIENTS WITH PHENOTYPICALLY RELATED DISEASE SO WE DESIGN STUDIES USING THE AGENTS. THERE ARE MORE CHALLENGE ACE HEAD. THESE WILL REPUBLICAN PICTURES OF PATIENTS WE HAVEN'T SORTED OUT AND WE HAVE ACTUALLY INVESTIGATING. IT TAKES A LOT OF PEOPLE TO DO THAT WORK. THESE ARE ALL THE COLLABORATORS IN NIRKSAMS. THIS IS MY GROUP. WE'VE DONE A LOT TOGETHER WITH NHGRI. YOU CAN SEE ALMOST EVERY INSTITUTE OF THE NIH HAS HELPED US PHENOTYPE PATIENTS AND WE STARTED WORKING WITH IMMUNOLOGY TO CHARACTERIZE THOSE PATIENTS. THESE ARE THE OUTSIDE COLLABORATORS THAT HAVE CONTRIBUTED TO -- ARE HELPED PUT TOGETHER THE STUDIES, KENDALL AN TEEN STUDIES MAINLY CONDUCTED BY (INAUDIBLE). AND I'LL TAKE QUESTIONS. [APPLAUSE] ARE THERE ANY QUESTIONS? >> THANK YOU, RAFAELIA. OUR NEXT SPEAKER IS FROM THE NIH UNDIAGNOSED DISEASES PROGRAM, THIS I THINK IS ONE OF THE MORE POPULAR PROGRAMS AS FAR AS INTEREST OF THE PUBLIC AND SO DR. ZINNIA ACTIVITY WILL TALK ABOUT UNDIAGNOSED DISEASE PROGRAM, OBVIOUSLY CONTINUES.’O„ WHAT ARE FAMILIES ASKING WHEN THEY TO US? OR ASKING WHEN THEY HAVE A CHILD I THINK THEY'RE ASKING WHAT DO I HAVE? WHATs THE DIAGNOSIS? WHY DID IT HAPPEN? PATHOGENESIS. WHAT WILL WHAT DO I HAVE? AN UNLESS YOU CAN ANSWER THAT QUESTION IT'S DIFFICULT TO ADDRESS THE NEXT FOUR. 6% OF THE PATIENTS CONTACTED IN OFFICE OIF RARE DISOR O DERS DONE HAVE DIAGNOSIS AT ALL. MANY LOVE WOULD BE REP ACTIVES OF THE ADVOCACY GROUPS, THEY DON'T HAVE A DIG KNOWSIS. A DIAGNOSIS. THE GOALS OF UNDIAGNOSED DISEASES PROGRAM WHICH STARTED IN MARCH OF 2008, Z AS A FIVE YEAR PILOT PROGRAM NOW COMPLETING YEAR 4 WERE TO RESPOND TO UNMET NEED BY ASSISTING PATIENTINGS WITH UNKNOWN REACH AN ACCURATE DIAGNOSIS. TO ADVANCE THE RESEARCH MISSION OF THE NIH BY DOING CLINICAL RESEARCH TO DISCOVER NEW DISEASES POTENTIAL THERAPIES THAT PROVIDE INSIGHT TON HUMAN PHYSIOLOGY AND GENETICS. SO A CLINICAL RESEARCH PIECE, TO CHANGE DISEASE PARADIGMS AN TRANSLATE THE PILOT PROJECT INTO THE EXTRAMURAL COMMUNITY. FAR TOO MANY UNDIAGNOSED PATIENTS TO HANDLE AT THE NIH. SO WHERE ARE WE AT 40 MONTHS OR FOUR YEARS INTO THE PROCESS? WE HAVE HAD MORE THAN 6,000 INQUIRIES AB THE PROGRAM. WE HAVE REVIEWED OVER 2,000 CHARTS. ONE PAGE AT TIME. WE ACCEPTED 450 PATIENTS HALF ARE CHILDREN. ABOUT 100 PATIENTS WE HAVE FOUND FIT MORE CLOSELY TYPE OTHER CLINICAL PROTOCOLS AT THE NIH AND OTHER INSTITUTES AND SO ARE SEEN BY COLLEAGUES. 350 PATIENTS ARE STILL ACTIVE AND WE REACH A DIAGNOSIS 20 TO 25% OF THE TIME. THE FLOW IS UNABATED AND YOU CAN SEE HERE OUR LEADER BILL GAL AND A DAY'S WORTH OF MAIL WE DREAD THE MAIL COMING IN. ACTUALLY THE MAIL SEN ME A CHART FOR PEDIATRICS TWICE THAT SIZE FOR A SINGLE PATIENT. WHAT TYPES OF PATIENT WHERE HE IS LOOKING FOR? PATIENTS WITH A COMPELLING PHENOTYPE WHO EVADED DIAGNOSIS DESPITE A VERY COMPREHENSIVE WORK WITH SOME OF THE MOST ILLUSTRIOUS ACADEMIC CENTERS IN THE COUNTRY OR MORE THAN ONE PERSON IN THE FAMILY AFFECTED. HEARSAY FI THESE PATIENTS TO ONE OF 21 PRIMARY PHENOTYPES AND INTERESTINGLY ENOUGH HALF THE TIME PATIENTS THAT WE ACCEPT HAVE SOME NEUROLOGIC COMPONENT TO THEIR PHENOTYPE SO I THINK THE BRAIN REPRESENTS ONE PLAYER WE HAVE YET TO LEARN ENOUGH ABOUT. PATIENTS COME FOR A WEEK AND GET A VARIETY OF TESTS TAYLORED TO THE PHENOTYPE, THESE ARE SOME THINGS WE CAN DO AND DO DO IN MANY PATIENTS AND THIS IS A CUSTOM EVALUATION FOR EACH PATIENT. I TELL PATIENTS THE REAL WORK STARTS WHEN YOU GO HOME WE HAVE OPERATING ASSUMPTIONS, THAT BEING THE DISEASE IS A, A NEW DISEASE, B, A RARE DISEASE, C, AN UNUSUAL PRESENTATION OF MORE COMMON DISEASE OR MORE THAN ONE DISORRER IN THE SAME PATIENT. WE HAVE USED A VARIETY OF SCREENING AND GENETIC TECH NOTHING TO A-- TECHNOLOGY TO ARRIVE. SOME INCLUDE CELL BASED ASSAYS IN FIBROBLAST TO SCREEN FOR SPECIFIC PHENOTYPES, PROBLEMS IN ENERGY METABOLISM OR PROBLEMS WITH VESICULAR TRAFFICKING. WE USE SNP ARRAYS. AND ALSO USING WHOLE GENOME AND EXONLY SEQUENCING THAT DR. BIESECKER AND OTHERS WERE TALKING ABOUT THIS MORNING. SO YOU HAVE HAD AN INTRODUCTION TO THAT. WE HAVE LEARNED A NUMBER OF THINGS REGARDING INDIVIDUAL PATIENTS, REGARDING THE PROCESS OF LAUNCHING THIS KIND OF .JJt2 THE EMERGING TECHNOLOGIES THAT I THINK ARE GOING TO HELP US DIAGNOSE PATIENTS. THE DIFFERENCE IN THIS PROGRAM AS OPPOSED TO MANY PROGRAMIOUS HEARD TODAY ARE FOR EACH PATIENT THEY ARE THEIR -- THEY ARE -- IT'S A ONE SITUATION, THERE'S A PHENOTYPE IN ONLY ONE PATIENT SO IT IS NOT A MATTER OF COLLECTING A NUMBER OF PATIENTS WHO SEEM TO HAVE THE SAME UNDERLYING GENETIC OR NON-GENETIC CONDITION, EACH FAMILY ARE THE OWN RESEARCH PROJECT. SO WE HAVE CONFIRMED A COUPLE OF NEW DISEASES, DUE TO EFFICIENCY OF CD 73, DR. GAL, MY BOSS HAS TALKED A NUMBER OF TIMES. WE HAVE SEEN A NUMBER OF LIKELY NEW DEES WE'RE IN THE PROCESS OF CONFIRMING AND WE HAVE SEEN RARE DISORDERS THAT WE HAVE MADE MAYBE THE SECOND OR THIR CASE REPORT ON, AND THEN A NUMBER OF OTHER RARE DISEASES. I HAVE HIGHLIGHTED SOME, I WAS GOING TO TALK ABOUT FOUR BUT IN THE INTEREST OF TIME I'LL TALK ABOUT THREE OF THEM. THEY ILLUSTRATE WAYS TO GO ABOUT ESTABLISHING DIAGNOSIS IN PATIENT BUSINESS THREE METHODS, THAT'S WHY I WANTED TO CHOOSE THESE THREE PATIENTS. WE AND OTHERS YOU HEARD TALK USE HOMOZYGOSITY MAPPING. THIS IS A FIVE-YEAR-OLD WITH CLUBBED FEET, LOW MUSCLE TONE AN BLEEDING DISORDER. YOU CAN SEE THAT THE PARENTS ARE RELATED TO EACH OTHER, THE PARENTS FIRST COUSINS. THIS IS THE AFFECTED CHILD AND THERE ARE THREE UNAFFECTED SISTERS. AND WE UTILIZE ALL GENETIC INFORMATION WE CAN FROM THE ENTIRE FAMILY NOT JUST FROM THE AFFECTED INDIVIDUAL. SO THIS BOY YOU CAN SEE HERE IS VERY BRUISED, CLUBBED FEET. HIS BRUISING, THIS IS FROM MINIMAL TRAUMA, THESE HYPEREXTENSABLE FINGERS AN OVER HERE TO HIS TOES. THIS IS HIM AS A BABY, HE'S IN HIS BRACE FOR HIS CONGENITAL HIP LIS LOCATION AN CLUB FEET, HE HAS SOFT SKIN AND THESE BIG BRUISES THAT APPEAR IN HIM EVERY TWO TO FOUR MONTHS CAUSED BY MINIMAL TRAUMA. FOR THAT REASON HE DOESN'T GO TO SCHOOL, HE LIMBS HIS ACTIVITIES AND HE WAS AFRAID TO DO ANYTHING BECAUSE HE'S AFRAID TO HAVE A BIG BLEED AND OBVIOUS THESE ARE UNCOMFORTABLE. SO LET ME INTRODUCE THE CON SEFT SINGLE NUCLEOTIDE POLYMORPHISMS OR SNPS, A GENERAL TECH TECHNOLOGY WE USE TO LOCALIZE GENES FOR THESE CONDITIONS. A SNP IS A DNA SEQUENCE VARIANT IN A SINGLE NUCLEOTIDE THAT DIFFERS BETWEEN MEMBERS OF SPECIESCH THERE ARE HUNDREDS OF THOUSANDS OF THEM IN EACH OF US. THE MORE FREQUENT OF THE TWO POSSIBLIES WE CALL A, THE LESS FREQUENT AT THAT SAME LOCUST WE CALL B. AND SO ALL THE SNP GENOTYPES WE CAN CALL A A B B OR A B. SO IN THIS PLOT YOU CAN SEE YOU CAN EITHER BE BB, THESE DOTS ARE INDIVIDUAL SINGLE NUCLEOTIDE POLYMORPHISMS, YOU CAN BE AA, TWO COPIES OF A, ONE COPY OF A, ONE OF B AND YOU WILL HAVE RECEIVED ONE OF THESE COPIES FROM EACH PARENT FOR EACH OF THE SNPS. YOU'LL FIND YOU HAVE NOTHING THAT INDICATES DELETION IN THAT PARTICULAR SNP OR PIECE OF DNA IS DELETED. SO WHAT WE WERE LOOKING FOR WERE A PLACE WHERE THE PATIENT AS OPPOSED TO THE SISTERS WHO DONE HAVE A PROBLEM OR MOTHER OR FATHER DIDN'T INHERIT ANY AB COPIES, GOT AAs OR BBs WHICH WOULD TELL US THIS IS STRETCH HOMOZYGOSITY, IN OTHER WORDS THE SAME GENETIC INFORMATION FROM BOTH MOM AND DAD. THE PARENTS WERE RELATED TO EACH OTHER AND IT'S MUCH MORE FREQUENT TO HAVE THESE RUNS OF HOMOZYGOSITY IF PARENTS ARE RELATED TO EACH OTHER, SO WE WERE LOOKING FOR AN AREA WHERE THIS CHILD WAS THE ONLY ONE THAT HAD A GAP. IF YOU LOOK ALL THE WAY DOWN THIS LINE YOU CAN SEE THIS IS THE ONLY LACE THIS CHILD HAS A GAP. WHEN YOU DO THAT THE SNP ARRAY SHOWS US THERE IS A 26 MEGA BASE REGION OF HOMOZYGOSITY WHERE THERE'S NO AB UNIQUE TO THE PATIENT AND 72 GENES IN IT. LOOKING OVER 72 GENES FROM THE LUNG AND BLOOD INSTITUTE RECOGNIZE CHS G-14 AS A POSSIBLE CANDIDATE A HOMOZYGOUS MUTANT WAS FOUND FOR THIS PATIENT AND THIS WAS THE CAUSE OF THE CONDITION. CHEST 14 ENCODES TRANSFERASE, ONE IT'S AN ENZYME IMPORTANT FOR DERMATIN SULFATE. IT'S ALSO HELPING YOU RESOLVE CLOTS WHY THE CHILD WAS UNABLE TO UNWIPE THESE CLOTS HE WAS HAVING. SO T IS POSSIBLE TO TREAT THE CHILD WITH DERMATIN SULFATE? THERE'S NONE AVAILABLE COMMERCIALLY THAT ONE CAN PRESCRIBE AT THIS PIPE SO WE'RE LEFT WITH DEFENDANTTY OF TRYING TO FIND A WAY TO GET IT AS AN INVESTIGATIONAL NEW DRUG FOR A SINGLE PATIENT, NOT A SMALL AMOUNT OF WORK. THE SECOND PATIENT SCENARIO INVOLVES AGNOSTIC INTERROGATION OF DATA. AGNOSTIC INTERROGATION MEANS LOOKING AT THE DATA TRYING TO PICK OUT SOMETHING THAT MIGHT BE IMPORTANT, HAVING NO IDEA AHEAD OF TIME WHAT WE'RE LOOKING FOR. THIS REVEALS MORE THAN ONE GENETIC CHANGE CAUSATIVE OR SI NR GISTIC. FINING GENES IS LIKE LOOKING FOR NEEDLES IN A HAY STACK. THIS WOULD BE LOOKING FOR NEEDLE IN A HAY STACK, FINDING ONE, BUT HAVING TO ASK THE QUESTION ARE OTHER NEEDLES IN THIS HAY STACK THAT MIGHT HAVE BEEN ONES THAT STUCK ME WHEN I SAT DOWN ON IT. SO THERE MAYBE A NUMBER OF THINGS CAUSATIVE. THIS IS ILLUSTRATED BY THE 12-YEAR-OLD, PEDIGREE WHO HAS VERY SEVERE OSTEOPOROSIS. , TWO NORMAL SIBLINGS, PARENTS NOT RELATED TO EACH OTHER. HIS PHENOTYPE WAS NORMAL PRE-NATALLY, AT BIRTH AND EARLY CHILDHOOD. AT 7 HE SHOWS SIGNS OF PROGRESSIVE OSTEOPOROSIS, EXPERIENCING MULTIPLE FRACTURES WITH MINIMAL TRAUMA. BOTH SIBLINGS ARE NORMAL AND THEY ARE NOW OLDER THAN THIS CHILD WHEN THIS CHILD SYMPTOMS BEGAN SO THEY WERE CONSIDERING THOSE AS NORMAL, NOT YOUNG PATIENTS JUST WAITING TO DEVELOP THEIR DISEASE. THIS IS AN EXAMPLE OF (INDISCERNIBLE) BODY. ON THE RIGHT IS A TYPICAL DEVELOPING CHILD WITH A SQUARE SHAPED VERTEBRAL BODY AND YOU CAN STEE COLUMN THE SQUARE SHAPE BODIES AN THIS AFFECTED CHILD IS FLATTENED WASHED OUT VER BRAY DUE TO OS YES PROSIS, HE DEVELOPED -- OSTEOPOROSIS. HE DEVELOPED COMPRESSION FRACTURES FROM THE WEIGHT OF HIS BODY ON SPINAL COLUMN. THESE ARE HIS LEGS. YOU CAN SEE HERE HE'S ACTUALLY HAD A PATHOLOGIC FRACTURE RIGHT THERE. YOU CAN SEE HE'S HAD HIS FEMUR, THE UPPER BONE IN HIS LEGS ROTTED BECAUSE THEY'RE UNSTABLE AND RECONCERNLY FRACTURE THAT HE NEEDS STABILITY AND THESE METAL RODS WERE PLACED IN THIS. HIS KNEES YOU CAN SEE THE KNEE STRUCTURE IS WASHED OUT HERE. AND I THINK I HAVE ONE MORE PHOTOGRAPH HERE IS A CHILD OF THE SAME AGE AND THIS CHILD. YOU CAN SEE HOW WASHED O OUT THESE BONES ARE, HOW THING THE CORTEX, THE HARD PART OF THE BONE IS, AND AGAIN HERE, THE DIFFERENCE IN HIS JOINTS HOW OSTEO PROPERTYIC THEY ARE. SO THIS CHILD IS EXTREMELY DISABLED FROM THIS CONDITION. WE DID OUR SNP ANALYSIS AND LOOKED AT EVERY CHROMOSOME BY SNP AN THERE WERE NO DELETIONS, NO INSERTIONS, THERE WERE NO RUNS OF HOMOZYGOSITY WE HAD SEEN IN THE PREVIOUS CHILD. THE OTHER THING SNPS CAN DO IS PROVIDE LINKAGE DATA TO SAY IT NARROWS THE PLACES WE HAVE TO LOOK. THERE WERE TWO UNAFFECTED SISTERS SO WE CAN LOOK SINCE YOU -- HAVE YOUR GENETIC FROM MOM, HALF FROM DAD WE CAN SEE ON AVERAGE YOU WILL INHER ABOUT A QUARTER OF THE SAME GENES AS SIBLINGS AND WE CAN SEE AN ASK THE QUESTION WHICH GENES OR WHICH AREAS DOES THIS AFFECT A CHILD HAVE THAT ARE NOT IN THE OTHER TWO HEALTHY CHILDREN. BY THAT YOU CAN NARROW THE REGION YOU LOOK FOR FROM 100% OF THE GENOME TO 9/16 GENOME OR HALF THE GENOME. STILL A LOT OF AREA TO COVER BUT AT LEAST YOU COULD NARROW IT DOWN. WHOLE EXONLY SEQUENCING OF FIVE FAMILY MEMBERS, THIS IS THE WAY WE GET POWER IN THESE EVALUATIONS IS TO BE ABLE TO LOOK AT WHOLE FAMILIES BY EXOME SEQUENCING AS OPPOSED TO JUST THE AFFECTED INDIVIDUAL. WE FOUND A TOTAL OF 110,000 VARIANTS AMONG ALL FIVE. EACH HAS ABOUT 20,000 VARIANTS FROM THE REFERENCE SEQUENCE. AND AFTER CONSIDERABLE BIOINFORMATIC WORK, CONSIDERABLE BY MY COLLEAGUES TOM MARK ELLO AN CO-WORKERS, THREE POSSIBLE CANDIDATE GENES PASSED THROUGH VARIOUS INHERITANCE FILTERS VALIDATED BY CONVENTIONAL SEQUENCING. THEY'RE LISTED HERE. I E WILL IT WILL YOU ABOUT EACH ONE OF THOSE. THIS MECHANISM IS COMPOUND HETEROZYGOUS RECESSIVE, YOU HAVE TO DEVELOP TWO ABNORMAL COPIES OF THE SAME GENE, IT WOULD BE THIS GENE AND YOU CAN HAVE MUTATIONS IN DIFFERENCE PARTS OF THE GENE BUT EACH ALLELE, EACH GENE THAT YOU HAVE, EACH HAS TO HAVE A MUTATION. THIS IS A GENE ON CHROMOSOME 20 CALLED OPEN READING FRAME 26. BECAUSE WE DONE ACTUALLY KNOW IT'S AN OPEN READING FRAME BUT WE DON'T KNOW THERE'S A GENE THAT DOES ANYTHING. SO THIS IS AN OPEN READING FRAME. IN THIS CHILD YOU CAN SEE FROM MOTHER INHERED A MUTATION THAT HIS SIBLINGS DID NOT. FROM THE FATHER INHERITED ANOTHER MUTATION THAT ALSO IS INHERITED BY BOTH SIBLINGS BUT ONLY THE AFFECTED CHILD GOT BOTH BOTH COPIES SO NOW HE HAS THOSE TWO OPEN READING FRAMES BOTH COPIES ARE DELETERIOUS. WE DONE KNOW THE FUNCTION OF THIS GENE SO IT MAY OR NOT BE HELPFUL. A NEW DOMINANT MUTATION, REMEMBER DOCUMENT MANT CONDITIONS -- DOMINANT CONDITIONS ARE THE STRONG GENE, YOU ONLY INHERIT ONE FOR THE PHENOTYPE. THIS GENE PIK-3CD OSTEOBLAST FORMATION AN MAINTENANCE, SO SOME RELEVANCE TO BONE, IN THIS SITUATION THE CHILD HAS A MUTATION THAT SIBLINGS DONE HAVE AN PARENTS DON'T HAVE SO WE CALL THIS A DE NOVO MUTATION. SO THE QUESTION IS WHETHER OR NOT THIS COULD BE CAUSATIVE THIRDLY, HE IS DOUBLING HETEROZYGOUS RECESSIVE FOR TWO DIFFERENT GENES THAT ARE INVOLVED IN THE SAME EXTRA CELLULAR MATRIX LAMIN PROTEIN. ONE ABNORMAL COPY IN EACH ONE. ONE FOR THE FATHER AND ONE FROM THE MOTHER FOR LAMINC-2. SO THE QUESTION NOT HAVING SOME MUTATIONS IN THESE TWO GENES COULD TOGETHER CREATE LAMIN MATRIX PROTEIN THAT DIDN'T WORK WELL SO THAT'S A THIR POSSIBILITY, A THIRD NEEDLE IN THE HAY STACK. SO WE THOUGHT WE WERE FINISHED. HOWEVER, THERE IS A FOURTH POSSIBILITY IN THIS PATIENT THAT HE HAS A VARIANT IN THE FGFR 3 LOCUST FIBROBLAST GROWTH FACTOR RECEPTOR 3 IS THE CAUSATIVE GENE IN THE COMMON SKELETAL DYSPLASIA , BUT IN THIS SCENARIO, THERE WAS A SITUATION WHERE THE MOTHER AN UNAFFECTED SISTER AND THIS PATIENT ALL HAVE THIS CHANGE YOU CAN SEE IT HERE. AND IF YOU LOOK IN THE HEMD REFERENCE DATABASE, THIS VARIANT IS ALSO DESCRIBED IN TWO FAMILIES WITH ATYPICAL OSTEOPOROSIS WHICH THE PROBE ENTHE CHILD HAS SEVERE OSTEOPOROSIS AND MILD IN ONE PARENT. NOW, WE HAVE NOT YET ASK ASKED PARENTS TO HAVE THEIR BONE DENSITY SCWANNED SO WE DONE KNOW IF THE MOTHER HAS TEN DANCE TOWARDS OSTEOPOROSIS. DR. BUY SICKER MADE AVAILABLE TO US THE 581 EXOMES FROM CLIN SEEK AN FOUR OF 581 PATIENTS IN THE LYNN SEEK DATABASE HAVE THIS VARIATION. THE QUESTION WOULD BE WHETHER OR NOT THESE FOUR PATIENTS ALSO HAVE SOME VARIANT FORM DECREASED BONE MASS. SO IT'S NOT ENOUGH JUST TO FIND A GENETIC CHANGE. IT IS IMPORTANT WITNESS YOU FINE ONE TO VERIFY IN FACT YES, THAT IS WHAT'S GIVING THE PHENOTYPE SO OUR WORK ON THIS CHILD IS NOT -- RILE IS NOT FINISHED DESPITE THE FACT WE FOUND FOUR GENETIC VARIATIONS. AND THE LAST CASE I WANT TO TALK ABOUT IS ELUSIVE DIAGNOSES LEAD TO DIFFERENCE ANALYTIC TOOL IT IS TRY TO UNDERSTAND THESE DISEASESCH THIS IS AN 11-YEAR-OLD CHILD I HAVE KNOWN SINCE THE DAY SHE WAS BORN. SHE HAS A CONGENITAL MYI DON'TOPATHY AND FINGER CON TRATTURES. SHE AS A SIBLING WHO DIED OF A VERY SIMILAR DISORDER. SHE'S BEEN ON THE DIAGNOSTIC ODYSSEY NOW FOR 11 YEARS. SHE WAS DECREASED FETAL MOVEMENT, LOW MUSCLE TONE, POOR FEEDING AND FINGER CON TRATTURE AT BIRTH. SHE WAS HOSPITALIZED FOUR MONTHS FOR POOR FEEDING AND BEGINNING TO ASPIRATE LIQUID. BY NINE MONTHS OLD SHE HAD DECREASED RESPIRATORY EFFORT WHICH REQUIRE AD TRAY CI OSMY AND NOW IS DEPENDENT ON VENTILATOR DAY AN NIGHT. SHE HAS NORMAL COGNITION, SHE IS AGE APPROPRIATE IN HER SCHOOL PLACEMENT, SHE HAS DIFFICULTY SPEAKING, DIFFICULT TO UNDERSTAND HER SOMETIMES AND SHE HAS A COMMUNICATION BOARD AND BELIEVE ME SHE MAKES HERSELF UNDERSTOOD THERE WAS NOTHING, THERE WAS SOME STRETCHES OF HOMOZYGOSITY BUT IT WAS NOTHING INTERESTING. AND NO GOOD CAN'T DATE GENES WHICH IS FRUSTRATING BECAUSE WE HAVE BEEN WORKING ON THIS CASE FOR A LONG TIME AND THERE WAS IN THE FAMILY WE THOUGHT WE WERE HOME FREE AN THIS WOULD BE EASY BUT IT WAS NOT LAST NOVEMBER THERE WAS APPROXIMATE ARTICLE PUBLISHED IN NATURE GENETICS THAT ONE OF OUR NINDS COLLEAGUES DREW OUR ATTENTION TO A MONTH AGO THAT DESCRIBED A MUTATION IN MEG F-10 AND THE PHENOTYPE OF THEIR INDIVIDUAL SEEMED SIMILAR O THE PHENOTYPE TO HAVE THIS CHILD. I ASKED THEM TO LOOK TO SEE WHETHER OR NOT YOU MISSED MANAGE IN THIS PARTICULAR GENE. AS IT TURNS OUT THERE WERE NO HOMOZYGOUS OR HETEROZYGOUS MUTATIONS IN THAT GENE. SO HE BASICALLY DIDN'T SEE ANYTHING. WHEN HE LOOKED BACK AT THE SNP CHIP HE COULD SEE JUST THESE TWO INDIVIDUAL SNPS, THESE TWO SINGLE BASE PAIR SNPS THAT LOOK LIKE THEY WERE POTENTIALLY DELETED IN THAT CHILD NEAR THIS MEG F-10 LOCUST. SO IF YOU BLOW THOSE UP THESE ARE TWO TINY DELETIONS NOT PRESENT IN THE MOTHER, THE FATHER OR UNAFFECTED BROTHER. I WILL TELL YOU THAT SNP ARRAYS ARE AVAILABLE COMMERCIALLY, YOU CAN ORDER ONE ON YOURSELF BUT IF IN THE COMMERCIAL WORLD IF THEY SEE DELETIONS IN ORDER TO CALL A DELETION THEY HAVE TO SEE MORE THAN AT LEAST TEN SNPS IN A ROW TO BE ABLE THE TO CALL THIS. THIS IS WAY BELOW THE LEVEL TO CALL THIS AS A DELETION. HOW FAR IT TURNED OUT TWO DELETIONS WERE IN THE MIDDLE OF EXON 7 OF THE MEG F-10 GENE WITHIN THIS CODING REGION. AS I IT TURNS OUT YOU CAN SEE HERE THESE ARE SNPS ON VARIOUS OTHER EDP PATIENTS, THESE ARE TWO SNPS IN QUESTION WHICH IS COMPLETED YOU CAN SEE HERE NEITHER A NOR B SO SHE'S DELETED NEAL IN HIS LAB ACTUALLY WORKED IT OUT, SHE IS DELETED FOR EX7 DEMONSTRATED ON A GEL HERE WHERE THIS IS THE PATIENT, PARENTS, UNAFFECTED BROTHER SO SHE'S MISSING THE EXOME WHICH WILL KNOCK OUT FUNCTION OF THIS GENE SO IN A VERY WEIRD WAY SHE TURNS OUT TO HAVE THE SAME CONDITION. SO WE HAVE NOW GONE BACK AND REINTERROGATED ALL OF OUR SNP DATA FOR THESE TINY LITTLE DELETIONS FOR OTHER PATIENTS WE MAY HAVE OVER AND WE HAVE OTHER HITS WE ARE CURRENTLY WORKING ON. MORE THAN 50 INVESTIGATORS AT THE NIH AT THE TIME REVIEWING WITH OUR PATIENTS. SO THIS IS SOMETHING THAT ALTHOUGH A FEW OF US ARE CHARGED WITH DOING, INVESTIGATORS THROUGHOUT THE NIH AND MANY INSTITUTES HAVE BEEN HELPFUL IN PROVIDING EXPERTISE. WE SEQUENCED A COUPLE OF HUNDRED EXOMES AN RUN ABOUT 770 SNP CHIPS. WE HAVE MORE THAN 30 INTRAMURAL AN EXTRAMURAL INVESTIGATORS USING THEIR LABORATORIES AND THEIR LABORATORY RESOURCES TO HELP VERIFY FUNCTIONALLY SOME GENETIC THINGS WE FIND. BECAUSE AS I TOLD YOU IT'S NOT ENOUGH TO FIND A MUTATION IN A GENE, YOU HAVE TO PROVE THAT THAT'S ACTUALLY CAUSING THE PHENOTYPE IN THE PATIENT. AND WE HAVE TO FIND NEW WAY TO CONSULT OUTSIDE EXPERTS IN ORDER FOR THEM TO PROVIDE EXPERTISE AND THIS IS THROUGH THE EDP CASE MANAGEMENT PORTAL, (INAUDIBLE) IN OUR GROUP HAS DEVELOPED THIS SO THAT WE CAN INPUT RADIO GRAPHIC DATA BIOPSY DATA, PAPER FILE, REPORTS ANONYMOUSLY WITHOUT PATIENT IDENTIFIERS AN THIS IS A WEB-BASED TOOL TO GET SPECIALISTS IN EUROPE, ASIA, ACROSS THE COUNTRY TO LOOK AT OUR PATIENTS AND SEE WHETHER OR NOT THEY HAVE MANAGE TO CRIB, SO THIS HAS BEEN GREAT. A FEW PATIENTS SOME OF THE ONES I DESCRIBE THE ODYSSEY IS OVER OR AT LEAST NEARING PORT. FOR OTHERS IT'S ONLY BEGINNING. I WILL TELL YOU THE HARDEST PART OF MY JOB EVERY MONTH IS HAVING TO WRITE REJECTION LETTERS TO FAMILIES NOT ABLE TO BRING TO THE NIH BECAUSE WE CAN'T APPLY APPLY. THIS IS AN EXAMPLE OF DESPERATION. MY NAME IS TAYLOR, I'M 11 YEARS OLE, I HAVE A SICKNESS NO ONE CAN FIGURE OUT. I NEED YOUR HELP AND I NEED IT BADLY. I'M SICK AN TIRED OF PEOPLE TELLING ME I AM FAKING OR STRESSED BUT THEY'RE NOT IN MY GUY. I HAVE ALWAYS WANTED TO BECOME AN ACT ACTRESS, MODEL OR TRY A SINGING CAREER BUT THE SICKNESS IS NOT HELPING ME GET CLOSER TO FULFILLING MY DREAM. I CRY EVERY NIGHT BEFORE I GO TO BED AND WHAT I AM -- FROM WHAT I AM GOING THROUGH. I NEED HELP. PLEASE, PLEASE IF YOU GUYS ARE REALLY GOOD DOCTORS TRY TO HELP ME FIGURE OUT WHAT IS WRONG WITH ME. I CAN'T TELL YOU HOW MANY OF THESE LETTERS WE GET FROM PARENTS AND KIDS. HILLY CLINTON WILL TELL YOU IT TAKE AS VILLAGE TO RAISE A CHILD, IT TAKE AS VILLAGE TO FIGURE OUT THESE CHILDREN AND ADULTS. AND THIS IS PART OF THE VILLAGE. CHIEF HERE, THAT GUY, AND THE REST OF US. THANK YOU. HAPPY TO ANSWER QUESTIONS. [APPLAUSE] >> IF THERE ARE NO QUESTIONS FOR CINDY, LET HER GET TOWARD NORTHERN BLT MORE FOR ANOTHER MEETING. SO THANK YOU VERY MUCH FOR SHARING YOUR EXPERIENCES. CON CON CONVEY OUR GRATITUDE TO THE INDIVIDUALS WITHIN THE UNDIAGNOSED DISEASES PROGRAM FOR ALL THEY DO TRYING TO OBTAIN DIAGNOSIS FOR ALL THESE DIFFICULT DISEASES. WE HAVE TWO MORE SESSIONS, NOW TO HEAR FROM THE PATIENT GROUP REPRESENTATIVES, AND PETER SALTONSTALL IS NOT ABLE TO JOIN US, HE'S PREPARING FOR THIS EVENING EVENT IN SILVER SPRING AN TIM COTE CHIEF MEDICAL OFFICER FROM NORD IS JOINING US, HAS SHARON TRRY BEEN ABLE TO MAKE IT? GOOD. COME UP, DONE HANG BACK THERE. WE'LL KEEP YOU UP HERE. WE'LL START WITH YOU. AND SHARON COME DOWN AND WE'LL GET YOU MICKED UP TOO. AT THE END WE HAVE AVAILABLE TIME UNTIL 5:30 FOR A COMMUNITY FORUM SO IF YOU STILL HAVE THE ENERGY WE WILL TRY TO LISTEN TO QUESTIONS AN GF YOU ANSWER, IF WE CAN ANSWER TRY TO FINE OUT O YOUR QUESTIONS AND THEN RESPONSE TO YOU AFTER TODAY. SO TIM, COME ON UP. FORMALLY DIRECT TOFER OFFICE OF ORPHAN PRODUCTS DEVELOPMENT AT THE FOOD AND DRUG ADMINISTRATION. SINCE HE RETIRED FROM THE PUBLIC HEALTH SERVICE AND FDA HAS TAKEN OVER AS CHIEF OFFICER AT NOR DO AND REGULAR LA TIR AFFAIRS AT TECH GRAD INSTITUTE IN CALIFORNIA. >> >> IT'S THE END OF A VERY LONG DAY. I LOOKED AT YOUR AGENT DARKS I HAVE BEEN HERE ONLY A FEW LECTURES. THEY HAVE BEEN INTENSE AN PACKED AND DETAILED AND NOBODY COMPLAINS WHEN THE LAST SPEAKER STOPS EARLY SO I'M GOING TO DO THAT SHORTLY BUT I HAVE A COUPLE OF TASKS HERE. ONE IS TO THE MOST IMPORTANT IS TO GIVE YOU A BIG THANK YOU FROM THE RARE DISEASE COMMUNITY FROM THE PEOPLE WHO AT THE END OF THE DAY HAVE THE FINAL WORD WHICH IS THE PATIENTS. THAT'S WHY I'M HERE TO REPRESENT. SO BIG THANK YOU TO ALL OF YOU FROM YOUR CLIEGS IN THIS COMMUNITY AT NORD THE NATIONAL ORGANIZATION FOR RARE DISORDERS WHICH BROUGHT YOU THE ORPHAN DRUG ACT IN 1983 AND OTHER GOOD THINGS SINCE THEN. AND IT TO LEAVE YOU WITH A FAIRLY LARGE THOUGHT OF MINE FOR US ENGAGED IN SCIENTIFIC ELUCIDATION OF WHAT RARE DISEASES ARE AND HOW TO TREAT THEM. TODAY HOWEVER YOU HEARD A LOT OF SCIENCE, YOU HEARD DREAMING SCIENTIFIC DREAMING AND FACTS. WHAT I WOULD LIKE TO IMPART IS WE KNOW WHAT NORMAL HUMAN BIOLOGY IS. THE ESSENCE OF MOST MATERIAL COMES FROM PEOPLE WITH RARE DISEASE AND WE OWE THEM, THERE IS AN OBLIGATION BECAUSE MOST REASONS WHY MOST PEOPLE IN THIS ROOM ARE DOCTORS AND PHARMACISTS AND PHYSICIANS AND Ph.D.s, MOST OF WHAT WE GENERATE, MOST OF WHAT WE KNOW COMES TO US FROM PEOPLE WITH RARE DISEASE, IT'S THE EXCEPTION THAT HAS TAUGHT US HUMAN BIOLOGY. TO WIT: THE CLOTTING CASCADE WHICH I HAVE HAD TO MEMLYZE 6 OR 7 -- MEMORIZE 6 OR O 7 TIMES IS SOMETHING WE HAVE COME TO KNOW, I HAVE A FACTOR 7 AND 8 AND 10 BECAUSE SOMEBODY DIDN'T. THAT'S ONLY REASON WE KNOW THOSE THINGS. WE KNOW THE ARIA CYCLE, HOW THE NORMAL CYCLE WORKS BECAUSE OF PEOPLE WITH UREA CYCLE DISORDER, ONLY BECAUSE A SICK CHILD APPEARS THIS WAY OR THAT WAY THAT WE UNDERSTAND THE FUNDAMENTAL HUMAN BIOLOGIES, ON AN HONOR MALL HUMAN MUSCLE PHYSIOLOGY IS KNOWN FROM CHILDREN WITH MUSCULAR DYSTROPHY. I SCRS LIKE FOR US TO REMEMBER THAT BECAUSE SO MUCH OF WHAT WE HAVE BEEN BEQUEATHED INTELLECTUALLY COMES FROM PEOPLE WITH RARE DISEASE. WE HAVE AN OBLIGATION. AN OBLIGATION AS WE MOVE FORWARD TO TRY TO FIND THERAPIES APPROXIMATE CURES LIKE ALZHEIMERS, MAJOR HEALTH IMPACT THAT WE ALSO HAVE AN OBLIGATION TO PEOPLE WHO TAUGHT US SO MUCH. I SPEND A LOT OF TIME IN THESE HALL, PROIGHT PROBABLY 8 YEARS OF MY CAREER HERE, FASCINATING PLACE FULL OF PEOPLE STUDYING RARE DEES ALL DAY LONG -- DEESS ALL DAY LONG. IT'S PART OF THE INTELLECTUAL ACTIVITY BUT AS YOU DO SO I ASK YOU GOING FORWARD TO PLEASE REMEMBER THOSE PEOPLE ARE STILL THERE, THEY STILL NEED HELP AS WE SAW, SO POIGNANTLY IN THAT LETTER FROM TAYLOR. THEY ARE STILL ASKING YOU FOR MORE. SO PLEASE FROM NORD WE THANK YOU SO MUCH FOR ALL YOU HAVE DONE SO FAR. AND LOOK FORWARD TO MORE SUCCESSES IN THE YEARS TO COME. THANK YOU SO MUCH. [APPLAUSE] >> THANK YOU VERY MUCH, TIM. OUR NEXT SPEAKER IS SHARON TERRY, THE CEO OF THE GENETIC ALLIANCE. SHARON BRINGS TREMENDOUS AMOUNT OF ENERGY AND ENTHUSIASM AND KNOWLEDGE ABOUT THE RARE DISEASE SITUATION AN GENETIC SITUATION AROUND THE WORLD. I WOULD MENTION THE ORGANIZATION HAS BEEN INVOLVED ONE PIECE OF LEGISLATION SIGNED BY THE PRESIDENT. AMONG OTHER THINGS SHAIRNS IS LEADER SO MANY YEARS, I DON'T RECALL WHEN SHE CAME HERE BUT SHARON COME ON UP, THANK YOU VERY MUCH FOR JOINING US EVEN AT THE LATE HOUR. [APPLAUSE] >> GLAD TO BE WITH Y'ALL, I STAND BETWEEN YOU ALL AND THE END O OF A VERY LONG DAY. I'M AFRAID I COULDN'T BE HERE FOR ALL T HIT STANDARDS COMMITTEE WAS ALSO MEETING TODAY. HOW DARE THEY TAKE FEBRUARY 29th TO DO ANYTHING ELSE. I THINK YOU STARTED THIS MORNING WITH A VERY BROAD PERSPECTIVE OF DR. FRANCIS COLLINS LOOKING AT THE LANDSCAPE, THE GENETIC TESTING REGISTRY AND DEEP AND FAR. THROUGHOUT THE DAY YOU HEARD WONDERFUL STORIES OF SUCCESS, GREAT PROGRESS IN A VARIETY OF DISEASES, AS A MOM OF TWO KIDS WITH A GENETIC DISEASE I'M GRATEFUL FOR THE WORK ON EVERY ONE OF THOSE CONDITIONS. I'M GOING TO END BROAD TOO BECAUSE I THINK WHILE IMPORTANT WE HAVE THESE ADVANCES BEFORE US THAT WE HAVE SEEN A GREAT DEAL OF PROGRESS THIS RARE IS NOT SO RARE ANY MORE, PEOPLE UNDERSTAND WHAT ORPHAN DISEASES ARE AND THAT EVEN MAJOR COMPANIES ARE UNDERSTANDING THEY NEED TO MOVE INTO THIS SPACE. WE NEED TO DO MORE. AND I'M GOING TO PROPOSE THAT WE UNDERSTAND OVER THE NEXT YEAR SO THAT WHEN WE STAND HERE NEXT YEAR WE CAN START TO TALK ABOUT HOW WE ARE A TEAM OF TEAMS. BY THAT I MEAN LET'S UNDERSTAND HOW IT IS THAT WE CAN'T CONTINUE TO IT RATE, SLIGHTLY IMPROVE OR MOVE THE NEEDLE A LITTLE BIT BUT WE CAN GO ON WITH BUSINESS AS USUAL. WE NEED TO FIND A WAY TO REALLY OPEN THE SYSTEMS THAT HAVE ESSENTIALLY FAILED COMMON DISEASES, WE'RE NOT PROUD HOW MUCH MONEY AN HOW MANY YEARS IT TAKES TO MOVE TOWARD DRUG DEVELOPMENT OR TREATMENT FOR COMMON DISEASE. SO LET'S HAVE RARE DISEASES LEAD THE WAY. WE'RE REALLY GOOD AN EASY IN A WAY CAPTIVE AUDIENCE, USED THE TO A LOT OF RISKS AND ABILITY TO TAITS RISK. WE'RE USE -- TAKE RISK. WE WORK TOGETHER BECAUSE WE CAN'T STAND ALONE. AND LOOK AT REALLY NOVEL WAYS TO NOT CONSIDER ANY TURF ANY MORE TO SEE WHERE WE DUPLICATE ACROSS AGENCIES, ET CETERA AN UNDERSTAND HOW IT IS THAT WE CAN MAKE A WE AN COME TOGETHER AS A TEAM OF TEAMS. THANK YOU. [APPLAUSE] >> ARE THERE ANY QUESTIONS FOR YOU, SHARON AN TIM? I SHOULD HAVE ASKED, IF ANYONE HAS ANY QUESTIONS, IF YOU DON'T MIND RESPOND TO ANY. IT'S BEEN A LONG DAY FOR MANY PEOPLE ESPECIALLY THOSE THAT TRAVELED IN LAST NIGHT. ANY QUESTIONS AT ALL? PLES USE THE MICROPHONE AND IDENTIFY YOURSELF. >> I'LL KELLY MCFEARRY AND MY QUESTION IS FOR SHARON, LOVE TO KNOW IF YOU CAN SITE CASES WHERE ELECTRONIC HEALTH RECORDS HAVE ACCELERATED DISCOVERY. AFTER A DAY OF MEANINGFUL USE ELECTRONIC HEALTH RECORDS, IN SOME LIMITED INSTANCES WE HAVE SEEN THAT IN SMALL SYSTEMS AND NOT SO SMALL, ENTERMOUNTAIN HEALTHCARE PLACES THAT USED ELECTRONIC RECORDS A LONG TIME HAVE SEEN INDIVIDUAL INSTANCE WHERE IS THEY COULD ACCELERATE THE DISCOVERY WE TALKED ABOUT TODAY. SO UNDIAGNOSED SITUATIONS ABLE TO SEE PATTERNS THAT WE WOULDN'T ABLE TO OTHERWISE. WHAT WE SEE WERE WE TO HOOK UP THESE POTENTIAL REGISTRIES IN TERMS OF CLINICAL RECORDS IS WE WOULD SEE PATTERNS, NEEDLES IN THE HAY STACK, STABBED BY OTHER NEEDLES THAT WE DIDN'T KNOW WERE IN THE HAY STACK, TO USE CYNTHIAs TERMS AND WE START TO UNDERSTAND WHERE WE PUT SYNERGIES TOGETHER. TOUGH IS STANDARDS SO RECORDS TALK TO EACH OTHER. I'M PLEASED WITH THE MEANINGFUL USE STAGE 2 FOR NOTICE OF PROPOSED RULE MAKING, ASKING THE PUBLIC TO COMMENT AND I THINK THIS COMMUNITY DEFINITELY SHOULD BECAUSE IT'S MOVING TOWARD WHERE PATIENT VERSUS A SAY. PATIENT INPUT IS A PART AND WE CAN FIGURE OUT WAYS TO ACCELERATE THAT IN THE RARE DISEASE COMMUNITY. I KNOW WE HAVE THE PROJECT WITH THE OFFICE OF RARE DISEASE RESEARCH TO PUT REGISTRIESING TO AND WE LOOK AT WAYS TO START TO PUT ELECTRONIC HEALTH RECORDS TOGETHER. GENETIC ALLIANCE PLATFORM PROJECT THREE EMRs TO DO A PILOT IN THE RARE DISEASE AGGREGATION. >> TO FOLLOW-UP ON THAT, ONE OF MY FAVORITE EXAMPLES FROM LAST YEAR INVESTIGATOR AT BOSTON UNIVERSITY BEN WOZEN, THEY HAD ACCESS TO THE VETERANS COMPLETE HEALTH RECORDS, SIX MILLION CASES. AND WHAT THEY FOUND WAS A DOSE DEPENDENT EFFECT ON LIKELIHOOD OF PROGRESSION OF ALZHEIMERS IN RESPONSE TO ANGIOTENSIN RECEPTOR BLOCKER. WE HAVE DEFINITELY IN RESPONSE TO HIS WORK THIS WAS MOTIVATED TO LOOK AT THAT AND IT IS A TOUGH BUSINESS BECAUSE THERE'S SO MANY CON FOUNDERS, YOU HAVE A MIXTURE OF DIABETICS AND STROKE TYPE ETIOLOGIES AND A LOT OF THINGS SO YOU'RE LOOKING FOR AN EFFECT IN THE CONTEXT OF VERY HETEROGENEOUS POPULATIONS. SO VERY WELL ILLUSTRATED IN THAT, WHAT'S THE RIGHT COMPARISON GROUP? WHAT WAS THE UNCATION FOR GIVING LOSARTIN SO YOU WANT TO LOOK FOR PEOPLE WITH EQUIVALENT AND RIGHT DRUG SO ALL THAT REASONING AND ANALYSIS IN THAT CONTEXT, VERY HARD BUT UNLESS THE DATA IS PUT IN THERE CLEANLY WITH THE VARIABLES THAT YOU WANT, YOU HAVE NO CHANCE OF FINDING STUFF LIKE THAT. THIS IS GOING TO BE A GOOD ONE. LOSARTIN IS A GOOD ONE. >> DAN ROSE FROM THE PULMONARY FIBROSIS FOUNDATION. I WANT TO FOLLOW-UP YOUR LAST STATEMENT BECAUSE I'M A BIG BELIEVER AND ADVOCATE OF THE PATIENT ADVOCACY ORGANIZES TO MOVE COLLABORATIVELY. THERE'S NOT A LOT OF TIME BUT DO YOU HAVE ANY SPECIFIC SUGGESTIONS, RECOMMENDATIONS OR SHOULD THIS BE DONE UNDER THE GUYS OF NORD BECAUSE IT'S IMPORTANT IN TERMS OF MEDICAL RESEARCH FUNDING, AND REGULATORY ISSUES WITH THE FDA AND THINGS OF THAT NATURE. >> I BELIEVE ONE SHOULD LEAD BY EXAMPLE AND I NEVER SHOULD BE POINTING THE FINGER. IF THERE'S A PROBLEM I SAY HOW AM I A PROBLEM FIRST NORD AN GENETIC ALLIANCE SHOULD BE WORKING HAND IN HAND ON THESE ISSUE, IT'S POSSIBLE THAT IN THIS DAY AND AGE WE SHOULD MERGE, WE SHALL PUT THAT ON THE TABLE. WE TALK HOW TO COMBINE RESOURCES TO BENEFIT THE DISEASE GROUPS AND THE DISEASE GROUPS THEMSELVES, IF WE SAY THIS ROOM WAS LOCKED IN THE ROOM FOR THE NEXT 48 HOURS AN HAD TO DETERMINE WHAT ARE WE GOING TO DO ABOUT 7,000 DISEASE, FORGET MY KIDS, FORGET EACH OF YOUR SPECIAL GUEST INTERESTS, WHAT ARE WE DO AB THE 7,000? WE COME ONE A DIFFERENCE ANSWER THAN CREATE ONE OR TWO DISEASE GROUPS FOR EVERY GROUP. LET'S CREATE A BOARD OF DIRECTORS FOR EVERY ONE, GET A BOOKKEEPER FOR EVERY ONE. LET'S GET AN OFFICE MANAGER FOR EVERY ONE. THIS IS STARTING TO SOUND CRAZY, RIGHT? IT WOULD NOT BE FUNDED BY ANYBODY I THINK WHAT WE IN THIS IMMUNITY NEED TO DO IS TO THINK LET'S PUT ASIDE WHAT WE'RE DOING RIGHT NOW AND WE NEED TO KEEP DOING IT BUT SIGNIFICANT AMOUNT OF TIME TO THINGS WHERE ORGANIZATIONS HAVE SPECIALTIES, LET'S CONCENTRATE ON SPECIALTIES AN PORE THOSE AN EACH OTHER TO PATHWAYS AND BUY LOGICAL SYSTEMS RATHER THAN STRICTLY AT PHENOTYPE OR DISEASES BY NAME. I THINK WOULD MAKE A HUGE DIFFERENCE FOR US, I MEAN THAT ACROSS THE BOARD. I'M A FIRM BELIEVER IN THE WAVE THAT'S OVERTAKEN THE ARAB WORLD, MUSIC, PUBLISHING, WHEN CONSUMERS INVOLVE AND TAKE HOLE OF SOMETHING THEY MAKE AMAZING TRANSFORMATION HAPPEN THAT EVERYONE SAYS WON'T HAPPEN. ELSEVERE SAID IT WON'T BE BUBBING OPEN ACCESS SO WE HAVEN'T GOTTEN THERE YET AS THIS IMMUNITY TO SAY WE CAN GIVE UP THE ANYMORE OF MY ORGANIZATION AND THINGS I'M DOING SPECIFICALLY FOR THE GOOD AS A WHOLE AND DOES THAT MEAN THEY'RE GOING TO PICK (INAUDIBLE) FIRST? NO BUT I NEED TO BE ABLE TO GIVE THAT UP IN ORDER FOR US TO PROGRESS. [APPLAUSE] >> I WILL LIKE TO JUST MAKE ONE COMMENT AS FAR AS SHARON'S CONCERN WHAT SHARON SAID. THERE ARE MANY OF US THAT LIVE WITH THESE RARE GENETIC CONDITIONS AND WE ARE THE LUCKY ONES, WE ARE LUCKY ONES TO BE DIAGNOSED. BECAUSE THEY'RE VERY FEW OF US THAT ARE DIAGNOSED. I WOULD LIKE TO BE ABLE TO ASK WHAT ARE WITH WE GOING TO DO IN ORDER TO TEACH THE GPs GET THE ACCESS AN INFORMATION AND EVERYTHING PRESENTED TODAY OUT TO MEDICAL PROFESSIONALS SO EVERYONE ELSE CAN GET DIAGNOSED SO THEY WILL KNOW ABOUT THESE GENETIC CONDITIONS. OUR CONDITION HAS TAKEN 20 YEARS, 20 YEARS AGO ONLY 5% OF US ARE DIAGNOSE SO THAT IS A SHORTCOMING AND PULL IN MEDICAL PROFESSIONALS INVOLVED AS WELL AS DO THE RESEARCH. >> GREAT POINT. THERE ARE TECHNOLOGIES THAT HELP US NOW, INSTEAD OF ONE GROUP OR ANOTHER TRYING TO GET THEIR STUFF ADDED TO HIPPOCRATES OR SNOW MED OR WHOEVER ELSE, WHAT ABOUT US WORKING TOGETHER AND THERE ARE SOME EFFORTS TO DO THAT AND THEY ARE MOVING FORWARD BUT I THINK AGAIN ALL OF US IF WE CAN TIE SOME TIME TO THE WHOLE WE WOULD GET MUCH FURTHER, MUCH FASTER. >> ANY OTHER QUESTIONS, THEN? DAVID, WERE THERE SOME PEOPLE WHO WANTED SOME MICROPHONE TIME TO RAISE A QUESTION, RAISE AN ISSUE? >> THEY'RE NOT HERE. DOES ANYONE HAVE ANOTHER QUESTION? I THINK THAT LAST QUESTION HOW CAN WE WORK BETTER AN BECOME MORE EFFECT AND EFFICIENT IN WHAT WE'RE DOING. WE'RE STARTING TO SEE CHANGES IN DRUG DEVELOPMENT BEFORE IT WAS DRUG BY DRUG BY DRUG AND SOME OF THE REPURPOSING REPOSITIONING AN EVEN THE NEW DRUG DEVELOPMENT THAT WE ARE NOTICING WITH SOME OF THE PHARMACEUTICAL INDUSTRY ARE STARRING WITH SMALL POPULATIONS AND MOVING TO POSSIBLE USES FOR A PARTICULAR PRODUCT. I THINK WE HAVE TO LOOK AT MORE OF THESE PATHWAYS AND IF WE APPLY THAT TO OURSELVES ESPECIALLY WITH THE PATIENT ORGANIZATION HOW DO WE WORK AS ORGANIZATIONS. WITHIN OUR RARE DISEASE CLINICAL RESEARCH NETWORK WE MAY HAVE 8 OR 10 PATIENT ORGANIZATIONS WORKING TOGETHER. INITIALLY EVERYONE IS INDEPENDENT AND THEY WANT THEIR DISEASE, THEIR TO BE ULTIMATE CONSIDERATION BUT THEY START TO REALIZE THAT SOMETIMES THE SCIENCE ISN'T THERE, THE UNDERSTANDING SEASON THERE QUITE YET BUT IF WE BEGIN TO WORK TOGETHER WE'LL GAIN THE COMMON KNOWLEDGE TO MOVE FOR ALL RARE DISEASES WITHIN THE GROUP. DR. CATS IS HERE. ROBERT. >> HELLO, EVERYBODY. ROBERT KATZ I WAS IN THE PAST DIRECTOR FOR METABOLIC DISEASE AT NIDDK. I WOULD LIKE THE BRING UP ONE ASPECT THAT FITS IN THE GENERAL PICTURE APPROACHING ALL DISEASES. I WOULD LIKE TO BRING UP THE ISSUE OF TRADITION AND THE POTENTIAL ROLE OF WHAT THOSE AFLICKED WITH SOME OF THESE DISORDERS CONSUME. THERE IS TREMENDOUS PROGRESS IN UNDERSTANDING THE ROLE OF ESSENTIAL FATTY ACIDS THESE DAYS AND THE LACK OF SOME OF THESE CONDITIONS AN IT WOULD BE EASY TO CORRECT THAT SITUATION BY SUPPLEMENTATION IF THERE WOULD BE DETERMINE NATION OF LACK OF SOME OF THESE. I WANT TO BRING THIS ISSUE UP. >> THANK YOU, ROBERT. I KNOW WE ALONG WITH OFFICE OF DIETARY SUPPLEMENTS AND SEVERAL INSTITUTES AND FDA HAVE BEEN LOOKING AT THAT ISSUE OF SUPPLEMENT FOR INBORN AREAS IN METABOLISM SO MORE INFORMATION COMING ON THAT AND WE CAN BEGIN TO EVALUATE BETTER. THOSE DISEASES WITH THE INTERVENTIONS TO GET A BETTER FEEL FOR WHAT ARE THE APPROPRIATE DOSES, EVEN DOSAGE FORM IS IT USED BEST AND VARIOUS COCKTAILS THAT ARE BEING USED IN METABOLIC DISORDERS SO SEVERAL THINGS WE'RE WORKING ON. I THINK THAT WILL COME INTO BETTER PUBLIC VIEW WITHIN THE NEXT SIX MONTHS OR SO. >> OTHER QUESTIONS? >> WHILE SOMEONE IS COMING TO THE MICROPHONE I WOULD LIKE TO LET YOU KNOW WE PROBABLY HAVE OVER 425 PEOPLE REGISTERED TO BE HERE IN PERSON WHICH WAS OUTSTANDING COMPARED TO LAST YEAR WE HAD 280. AT SEVERAL POINTS WITH APPROXIMATELY 325 PEOPLE VIEWING THE WEBCAST OF THE MEETING SO WE HAVE BEEN VERY PLEASED WITH THE TURN-OUT. AND WE'RE GLAD WE CHANGED THE VENUE. I THINK WE HAVE SOME TWEAKING TO DO OF THE AGENDA. AND PARTICIPANTS, I KNOW SOME PEOPLE GOT LOST IN THE SCIENCE OF IT ALL AND I THINK I HER AND WE WOULD LIKE YOUR FEEDBACK AFTER THE MEETING NOT TONIGHT BUT TOMORROW MORNING AB TELL US WHAT YOU WILL LIKE TO SEE NEXT YEAR. I THINK NEXT YEAR ONE OF THE THINGS WE WOULD LIKE TO DO IS PARTICULARLY HAVE PEOPLE LIKE SHARON AND TIM COME GIVE US THE KICK OFF FOR WHAT WE LIKE TO DO BA THEY FEEL ARE IMPORTANT ISSUES. WE NEED TO REVISE THE AGENDA A BIT BUT COME LEAD US NEXT YEAR IN EARLY MORNING DISCUSSIONS WHEN THERE'S LARGER AUDIENCE AN PEOPLE ARE FRESH. SO WE EEL MAKE THAT COMMITMENT NOW AND HONOR NEXT YEAR. YOUR NAME AND WHO YOU'RE WITH. >> THIS IS A WONDERFUL DAY, I'M PART OF THE SLOS FAMILY. I'M HOLDING MY FACEBOOK, AND WILL THERE'S PEOPLE ASKING HOW DO I GET THIS, HOW DO I DO THAT. IT'S JUST INCREDIBLE DETAILS, THERE'S NOT -- I DON'T THINK THERE'S A MEDICAL PERSON INVOLVED ON IT BUT THEY ARE ALL HELPING EACH OTHER AND TALKING. IT IS A VERY ACTIVE THING, FUN TO HAVE (INAUDIBLE). (OFF MIC) >> THANK YOU. I THINK EVERYBODY DOES POINT TO THE VALUE AND NEED FOR ACTIVE PATIENT ADVOCACY COMMUNITY AND PATIENT LEADERS. PATIENT LEADERS ARE ONES SO MANY TIMES WE ASK SO MUCH TO BE THE COMMUNICATOR TO THE PUBLIC, TO THE HEALTHCARE PROVIDERS, THE RESEARCH COMMUNITY, THE MEDIA, AND PART OF OUR RESPONSIBILITY IS TO MAKE SURE THEY HAVE THE INFORMATION AND KNOWLEDGE TO MAKE THEIR LIVES EASIER IN DEALING WITH ALL THE DEMANDS ON THEIR TIME. NOT ONLY TRYING TO MEET THE NEEDS OF EVERYONE INCLUDING OTHER PATIENTS WITH RARE DISEASE BUT FAMILY MEMBERS WITH A RARE DISORDER. WE SOMETIMES FORGET THOSE DEMANDS AND HOW MUCH ENERGY IS REQUIRED. WE DO OWE THEM A TREMENDOUS DEBT OF GRATITUDE FOR WHAT THEY DO AN CONTINUE TO DO. THE HOURS AND THE DAYS THAT ARE SPENT WORKING WITH EACH OTHER AND REASSURING OTHERS AND THIS GETS INTO STANDARDS OF CARE WE HAVE TO LOOK AT MORE CLOSELY AND TO DEVELOP. SO THERE ARE MANY ISSUES HOPEFULLY AS WE MOVE INTO THE NEW NCAS STRUCTURE THAT WE AS AN OFFICE PARTICIPATE MORE AND HAVE SUPPORT OF MANY MORE ORGANIZATIONS AN LARGER INFRASTRUCTURE THAT WE CAN TAP INTO NOT ONLY RARE DISEASE CLINICAL RESEARCH NETWORK BUT CTSA PROGRAM MAJOR ACADEMIC CENTERS AN GROUPS OF RESEARCH CENTERS WORKING TOGETHER. WE NEED TO LOOK AT HOW WE CAN BECOME MORE EFFECTIVE IN WHAT WE DO TO MAKE OURSELVES AND THE INFORMATION MORE READILY AVAILABLE TO THE ENTIRE UNIVERSE OF PHYSICIANS. PATIENTS, FAMILIES AND THE RESEARCH COMMUNITY SO WE HAVE A LOT OF CHALLENGES AHEAD BUT WE'RE OPTIMISTIC WHERE WE HAVE BEEN PLACED IN AN ORGANIZATIONAL STRUCTURE IS SOMETHING THAT WILL BENEFIT EVERYONE AS WE MOVE FORWARD HERE. OTHER COMMENT QUESTIONS OR COMMENTS? WE LOOK FORE TO YOUR YOUR FEEDBACK FOR OUR OFFICE. YOU CAN GO INTO THE WEBSITE AND WE HAVE A MAIL IN LINK, CHRIS GRIFFIN, I DON'T KNOW IF HE'S MONITORING THE MAIL NOW HE AT LEAST RECEIVING THE REQUEST AN FUNNELS OUT THE REST OF US AND TRY TO RESPOND TO HEM. DO NOT BE RELUCK TAN. STEP FORWARD WITH A STRONG PACE AND YOUR THOUGHTS. SHARON HAS GIVEN US A LOT LOT TO THINK AB. WEAVER AT -- MANY ALREADY AT FDA TOMORROW AND YOU'RE GOING TO HEAR MORE REGULATORY SCIENCE AND REGULATORY ISSUES AND I THINK ONCE YOU HEAR FROM BOTH THE RESEARCH -- NIH RESEARCH AND REGULATORY SCIENCE AN FOLKS THAT TRY TO PUT PIECING TO AND IF YOU HAVE QUESTIONS COMING OUT OF THESE TWO DAYS, PLEASE DO NOT FAIL TO CONTACT US AND I'M SURE DR. (INAUDIBLE) ROWL AN FOLK AT FDA ARE HAPPY TO RECEIVE YOUR QUESTIONS THERE AS WELL. THANK YOU. IF MEMBERS OF THE PLANNING COMMITTEE ARE STILL HERE, WHO HELPED ORGANIZE CAN YOU PLEASE STAND UP AND LET US THANK YOU APPROPRIATELY, IT'S BEEN A NUMBER OF HOURS, DAVID, PAT. [APPLAUSE] >> FINALLY A TREMENDOUS THANK YOU FOR JOINING US AN AS WELL FOR ALL YOUR COMMITMENTS TO RARE DISEASES THROUGHOUT THE YEAR AND YEARS THAT YOU DEKATE YOUR -- DEDICATED YOUR LIVES TO THE RARE DISEASES. THANK YOU, HAVE A SAFE TRIP HOME, LOOK FORWARD TO SEEING YOU TOMORROW PERHAPS OR EVEN NEXT YEAR OR DURING YEAR. THANK YOU VERY MUCH. [APPLAUSE]