I AM ALAN GUTTMACHER, DIRECTOR OF THE EUNICE KENNEDY SHRIVER CHILD HUMAN HEALTH AND DEVELOPMENT, IT'S MY PLEASURE TO WELCOME YOU TO OUR MEETING IN OUR MORE INTIMATE QUARTERS THAN PERHAPS WE'RE USED TO. WE'RE FOLLOWING GOVERNMENT DIRECTION TO HAVE MEETINGS IN FEDERAL BUILDINGS. THIS IS SOMEWHAT UNUSUAL THAT WE'VE ACTUALLY GOT COFFEE WITHIN LIKE A SHORT WALK OF WHERE WE ARE. TOO BAD WE CAN'T PAY FOR IT FOR YOU. THERE IS FREE WATER IN THE BACK, THOUGH, JUST TO SHOW THAT WE SPARED NO EXPENSE IN TRYING TO TREAT YOU WELL. THIS NOT GIVING YOU COFFEE, REALLY PROMISES TO BE A GREAT MEETING. YOU'VE SEEN PROBABLY A WONDERFUL AGENDA. WHY DON'T START BY GOING AROUND THE TABLE FIRST AND THEN THE PERIPHERY, INTRODUCING OURSELVES. IF YOU WOULD NOTE FOR THE RECORD WHETHER YOU ARE -- IF YOU ARE A MEMBER OF THE COORDINATING COMMITTEE ITSELF, MENTION THAT. I'D ALSO ASK YOU TO MAKE SURE TO USE YOUR MICROPHONE WHEN YOU SPEAK SINCE WE ARE BEING HEARD IN THE ROOM BUT WE'RE ALSO BEING WEBCAST SO THAT EVERYONE WHO IS WATCHING FROM THEIR OFFICES OR HOME CAN HEAR. BUT BEFORE WE DO THAT, THANKS TO ALL OF YOU FOR BEING HERE. THIS IS A MEETING THAT WE HAVE NOT THAT FREQUENTLY AND IS VERY IMPORTANT TO THE COORDINATION OF THE EFFORTS THAT GO ON ACROSS THE NIH AND LOTS OF OTHER PLACES IN TERMS OF MUSCULAR DYSTROPHY. SO THANK YOU FOR SPENDING THE TIME BOTH TO GET HERE, TO BE HERE AND PREPARE FOR THIS MEETING, AND IN RETURN, WE PROMISE THAT WE'VE HAD, I THINK, BOTH A GOOD MEETING AND THAT AS YOU'LL HEAR IN TERMS OF STRATEGIC PLAN AND OTHER THINGS, WE'RE REALLY MOVING A ALONG IN TERMS OF ADVANCING THE MISSION OF ALL OF OUR ORGANIZATIONS AND SPECIFICALLY OF THE COMMITTEE. SO DR. LANDIS, I'LL TURN IT TO YOU. >> I'M DR. LANDIS, THE DIRECTOR OF THE NATIONAL INSTITUTE FOR NEUROLOGICAL DISORDERS AND STROKE, AND I GUESS I'M A MEMBER. >> YES. >> OKAY, I'M A MEMBER. >> [INAUDIBLE] AT THE NIH AND A MEMBER OF THE COMMITTEE. >> I'M VALERIE SWIK, CHIEF MEDICAL AND SCIENTIFIC OFFICER AND A MEMBER OF THE COMMITTEE. >> BRIAN DEN JER, COLLABORATIVE PROGRAMS AT STRAY TORE FOR PARENT PROJECT MUSCULAR DYSTROPHY AND A MEMBER OF THE COMI EE. >> WANDA SALZER, DIRECTOR OF THE CONGRESSIONALLY DIRECTED NATIONAL RESEARCH PROGRAMS AND MEMBER OF THE COMMITTEE. >> MARIELENA MCGUIRE, PROGRAM MANAGER FOR THE MUSCULAR DYSTROPHY RESEARCH PROGRAM UNDER THE CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAM. >> I'M PAT FUR LONG, PRESIDENT OF PPMD AND I'M NOT A MEMBER. >> CARSTEN BONNEMANN, NINDS INTRAMURAL PROGRAM, I'M NOT A MEMBER OF THE COMMEMBER OF THE COMMITTEE. >> CHAD FROM UNIVERSITY OF ROCHESTER, CLINICAL NEUROLOGIST AND MUSCULAR RESEARCHER AND I'M A NOT A MEMBER. >> JOHN WHITE, STAKEHOLDER HE ENGAGEMENT AT THE FDA. >> GLEN NUCKOLLS, PROGRAM COLLECTOR FOR MUSCLE DISEASES WITH NIAMS HERE AT NIH AND I'M NOT A MEMBER. >> JUSTIN FALLON, PROFESSOR OF NEUROSCIENCE AT BROWN UNIVERSITY AND I'M NOT A MEMBER. >> I'M JUNE -- EXECUTIVE DIRECTOR OF THE FSH SOCIETY, I AM NOT A MEMBER. >> JULIE BOWLEN WITH CENTERS FOR DISEASE CONTROL AND PREVENTION AND MY TEAM ADMINISTERS A MUSCULAR DYSTROPHY PROGRAM AT CDC. >> I'M ANNE RUTKOWSKI, CO-CHAIR OF CURE CMD AND I'M A MEMBER. >> ASSOCIATE DIRECTOR FOR RARE DISEASES AT FDA CENTER FOR DRUG EVALUATION AND RESEARCH AND I AM A MEMBER. >> BONNIE STRICKLAND, DIRECTOR OF THE DIVISION OF SAN FRANCISCOS FOSERVICES FORCHILDREN AND YOUTH AND I AM A MEMBER. >> STEVE KATZ, I AM A MEMBER. >> JOHN PORTER, PROGRAM DIRECTOR IN NINDS, EXECUTIVE SECRETARY OF THIS COMMITTEE BUT NOT A MEMBER. >> >> I'M COLLEEN FOR THE INSTITUTE OF ARTHRITIS, MUSCULOSKELETAL AND SKIN DISEASES. >> -- FELLOW AT NINDS. >> HEATHER REESE, OFFICE OF SCIENCE POLICY AND PLANNING AT NINDS. >> LISA KAY SER, LEGISLATION AND PUBLIC POLICY, NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT. >> DAVID ECKSTEIN, HEALTH SCIENTIST ADMINISTRATOR IN THE OFFICE OF RARE DISEASES RESEARCH AT NCATS. >> JASON MARIN, HEALTH POLICY MANAGER. >> I'M JOAN MCGOWAN, DIRECTOR OF THE DIVISION OF MUS MUSCULOSCEL CAL DISEASES AT NIAMS. >> PROGRAM ASSISTANT NINDS. >> THANK YOU ALL VERY MUCH. WHILE WE'RE TALKING ABOUT COMMITTEE MEMBERSHIP, I SHOULD JUST NOTE THAT WE'VE HAD TWO RESIGNATIONS SINCE WE LAST MET FROM THE COMMITTEE ITSELF. JACK SHOL AND MARK SWANSON, MARK HAS RETIRED FROM CDC, THEY'VE RESIGNED FROM THE COMMITTEE. NOW I'M GOING TO TURN IT OVER TO JOHN TO INFORM FOLKS ABOUT THE CONFLICT OF INTEREST ISSUES AND RULES. >> LIKE THE LAST MEETING, I'M GOING TO FOREGO READING THE CONFLICT OF INTEREST STATEMENT. ALL THE COMMITTEE MEMBERS -- THERE'S TOO MUCH LEGALESE IN THIS THING. ALL THE COMMITTEE MEMBERS SHOULD TAKE A LOOK, COMMITTEE MEMBERS, IT'S IN THE LEFT SIDE OF YOUR FOLDER. TAKE A LOOK AT THIS AND THE BOTTOM LINE BEING THAT YOU NEED TO RECUSE YOURSELF FROM EITHER REAL OR PERCEIVED CONFLICTS OF INTEREST. JUST SOME LOGISTICS COMMENTS. I THINK EVERYBODY'S FOUND THE CAFETERIA RIGHT ACROSS THE HALLWAY, SO THAT'S GOING TO BE THE SOURCE OF COFFEE AND LUNCH. SO THERE'S NOTHING ELSE REALLY NEAR THIS BUILDING, SO REALLY THAT'S KIND OF IT FOR LUNCH OPTIONS. THE RESTROOMS, THE WOMEN'S ROOM IS ON THIS SIDE, THE MEN'S ROOM, YOU'VE GOT TO WALK PAST THE ELEVATOR LOBBY AND IT'S ON THE LEFT PAST THE ELEVATOR. SEE I GET TO TALK ABOUT ALL THE INTERESTING STUFF HERE. SO ANYONE THAT WANTS TO MAKE PUBLIC COMMENTS THAT'S NOT A COMMITTEE MEMBER, LIKE TO MAKE A COMMENT AT THE END OF THE SESSION, I THINK SINCE WE'RE WEBCASTING IT, WE HAVE LESS FOLKS HERE, BUT ANYONE THAT WANTS TO MAKE A COMMENT NEEDS TO SIGN UP AT THE DESK HERE IN ADVANCE OF THAT OCCURRING. AND THEN JUST A COUPLE AK JMENTS. >> YOU DON'T MEAN THAT PEOPLE HERE SHOULDN'T MAKE COMMENTS. >> NO, I THINK WE RUN THIS MEETING VERY OPEN AND I THINK PEOPLE SHOULD JUMP IN AND ASK QUESTIONS AND EVERYTHING, RIGHT, ALAN? PEOPLE SHOULD JUMP IN ANY TIME. BUT IF ANYONE WANTS TO MAKE KIND OF AN OFFICIAL -- >> WE'VE GOT THE WRONG GROUP AROUND THE TABLE. >> RIGHT. YOU WANT TO MAKE AN OFFICIAL STATEMENT, PLEASE SIGN UP AT THE END AND THEN JUST IN TERMS OF ACKNOWLEDGMENT, SO LIZ AND RON ALREADY INTRODUCED THEMSELVES. FOR THOSE OF YOU THAT HAD TRAVEL ARRANGED BY US, SO LIZ MADE ALL OF THE ARRANGEMENTS. SHE'S AN ASSISTANT FOR MIKE LUSTER, I DON'T THINK THERE'S ANYBODY BETTER WITH TRAVEL IN THE INSTITUTE. SO HOPEFULLY EVERYBODY HAD NO PROBLEMS. SHE'S A PROGRAM ANALYST WITH OUR CLUSTER, CERTAINLY DID AN AWFUL LOT OF THE WORK MAKING THIS HAPPEN. THEN FINALLY RUTH LYNNE, THE COMMITTEE MANAGEMENT OFFICER FOR NINDS, REALLY HELPS PUT TOGETHER ALL THE APPOINTMENTS AND MAKING SURE THAT WE ADHERE TO ALL THE REGULATIONS. THIS IS A FEDERAL ADVISORY COMMITTEE ACT COMMITTEE WHICH MEANS WE HAVE TO ADHERE TO A SET OF POLICIES AND REGULATIONS WITHIN THE GOVERNMENT. THE APPOINTMENTS ARE MADE BY THE SECRETARY OF DEPARTMENT HEALTH AND HUMAN SERVICES. IN TERMS OF THE TWO RESIGNATIONS, WE ARE ABOUT TO NOMINATE ANOTHER PUBLIC MEMBER TO THE COMMITTEE TO REPLACE CHUCK SHAW, JULIE BOW LEN IS HERE REPRESENTING CDC AND THEY'RE GOING TO BE PUTTING FORWARD A NAME TO REPLACE THE RETIREMENT THERE. I THINK THAT'S IT, ALAN. >> THANKS. SO JUST IN TERMS OF AN OVERVIEW OF THE AGENDA, YOU WILL HAVE SEEN THAT WE'VE WOVEN SEVERAL DIFFERENT KINDS OF PRESENTATIONS INTO THE DAY. WE HAVE A NUMBER FROM MEMBER ORGANIZATIONS THAT WILL HELP INFORM THE ACTION PLAN PROCESS, AND THEN WE ALSO HAVE FOUR OTHER TALKS THAT HAVE BEEN INVITED, ONE OF THEM, THE FIRST OF THEM WILL BE A SCIENTIFIC UPDATE, AND THEN THREE TALKS THAT REALLY ADDRESS SPECIFIC TYPES OF MUSCULAR DYSTROPHY, BUT WE THOUGHT WOULD BE OF USE TO THE GROUP BECAUSE WE'VE ASKED THE SPEAKERS TO RELATE LESSONS LEARNED FROM SOME OF THE THINGS IT THEY'VE GONE THROUGH THAT WOULD HELP, WE THINK, THE BROADER COMMUNITY THINK OF ISSUES WITHIN THEIR OWN ORGANIZATIONS, THEIR OWN SPECIFIC DISORDER OF INTEREST, ET CETERA. SO I THINK IT'S A REALLY NICE COLLECTION OF TALKS, GREAT SPEAKERS AS ALWAYS, ET CETERA. AND THE OTHER THING I SHOULD -- WE WILL KEEP AN EAGLE EYE ON THE TIME, WE WILL TRY TO MAKE EVERYONE ADHERE TO THE TIME. ON THE OTHER HAND, WE DO KNOW WE CAN ALWAYS MAKE IT A WORKING LUNCH. SO WE WILL CERTAINLY END, THOUGH, ON TIME SO THAT EVERYONE CAN MAKE COMMITMENTS TO GET OUT OF TOWN, ET CETERA. SO WITHOUT FURTHER ADO, I THINK I'LL TURN IT OVER TO STORY TO INTRODUCE OUR FIRST SPEAKER SINCE HE COMES FROM HER PROGRAM. >> SO I AM DELIGHTED TODAY TO INTRODUCE DR. CARSTEN BONNEMANN. WE WERE FORTUNATE TO RECRUIT HIM A AWAAWAY FROM CHILDREN'S HOSPITAL IN PHILADELPHIA AT THE UNIVERSITY OF PENNSYLVANIA IN 2010, AND HAD HIM COME INTO OUR INTRAMURAL PROGRAM, AND I KNOW THAT ANNE AND OTHERS HAVE WORKED WITH HIM EXTENSIVELY THERE. HE RECEIVED HIS M.D. DEGREE IN GERMANY, COMPLETED PEDIATRIC TRAINING. HE CAME TO THIS SPACE AND DID A RESIDENCY IN PEDIATRIC NEUROLOGY AT MASS GENERAL HOSPITAL HARVARD AND THEN WORKED WITH LEWIS KONKEL AT CHILDREN'S HOSPITAL ON THE MOLECULAR GENETICS OF MUSCULAR DYSTROPHY. MOVED TO UNIVERSITY OF PENNSYLVANIA AND WE RECRUITED HIM FROM THERE. HE WAS A PEW FELLOW, RECEIVED AN AWARD IN HEU NEUROLOGICAL SCIENCES. HIS LAB COMBINES BOTH CLINICAL AND BASIC SCIENCEi] STUDIES TO LOOK AT A„i NUMBER OF THE RARER MUSCULAR DYSTROPHY. I THINK WE'RE REALLY FORTUNATE TO HAVE HIM IN OUR INTRAMURAL PROGRAM, HE'S PART OF OUR NEUROGENETICS BRANCH HEADED BY CURT FISCHBECK. >> THANK YOU FOR THE DINED INTRODUCTION AND THANK YOU FOR RECRUITING ME TO NINDS. IT'S BEEN A GREAT THREE YEARS, ALMOST FOUR YEARS SO FAR. THANK YOU TO THE COMMITTEE FOR GIVING A FORUM TO THE CONGENITAL MUSCULAR DYSTROPHIES. THERTHEY ARE COMPLEX BUT IMPORTANT DISORDERS IN THE GROUP OF MUSCULAR DYSTROPHIES. WHAT I THOUGHT I WOULD DO TODAY IN MY OVERVIEW IS TO GIVE YOU, BECAUSE NOT EVERYONE IS FAMILIAR WITH THIS GROUP OF DISORDERS, TO GET YOU AN OVERVIEW OF THE CLINICAL SPECTRUM OF THE THREE MOST COMMON FORMS OF THE CONGENITAL MUSCULAR DYSTROPHIES, AND THEN HIGHLIGHT FOR EACH OF THEM SOME OF THE TRANSLATIONAL OPPORTUNITIES BASED ON THE KINDS OF THESE DISORDERS WHERE WE COULD PERHAPS SEE IN THE NEXT FEW YEARS SOME MOVING FORWARD TO TRANSLATE SOME OF THE SCIENCE -- THERAPEUTIC APPROACHES. I'M NOT AS OLD AS YOU WILL AS DUE SHEN MUSCULAR DYSTROPHY BUT IT'S BEEN RECOGNIZED FOR MORE THAN 100 YEARS STARTING WITH WORK IN LONDON, THE SAME DOCTOR WHO ALSO DESCRIBED THE STENOSES AND HE DESCRIBES -- WITH CONGENITAL ONSET -- THAT OFTEN DON'T GET TO WALKING BUT THEY ARE VERY BRIGHT, THE DISORDER SEEMS TO BE MORE STABLE OVER THE YEARS, AND YOU SEE THESE ARE VERY GOOD DESCRIPTIONS OF SOME OF THE FORMS PROBABLY THE -- THAT HE GAVE AT THE TIME. THE DIAGNOSIS OF CONGENITAL MUSCULAR DYSTROPHY IS BASED ON VERY SIMPLE CRITERIA. REALLY THE CRITERIA, THE ORIGINAL CRITERIA FOR CONGENITAL MUSCULAR DYSTROPHY IS THE ONSET OF THE DISORDER IS AT BIRTH OR BEFORE ACQUISITION OF MOTOR MILESTONES, SOMETIMES THE RECOGNITION IS DELAYED EVEN THOUGH THE ONSET IS REALLY QUITE EARLY BUT YOU SEE THAT EACH AND EVERY ONE OF THE TYPES OF CONGENITAL MUSCULAR DYSTROPHY HAS A SPECTRUM. THEN THE MUSCLE BIOPSY THAT'S NOT CHARACTERISTIC OF NEUROGENIC DISORDER BUT SHOWS FEATURES OF DEGENERATION AND REGENERATION, HENCE THE MUSCULAR DYSTROPHY. SO THESE ARE VERY LOOSE CRITERIA OF IT. IF YOU TAKE THEM TOGETHER, THEY'RE REALLY THE MOST COMMON GROUP OF ONSET, MEANING BEFORE ACQUISITION OF WALKING MUSCLE DISEASE IN CHILDHOOD. SO AS A GROUP, THEY'RE COMING OUT AS QUITE SIGNIFICANT DISORDERS. I DON'T HAVE TO SHOW A NORMAL MUSCLE TO THIS GROUP OF PEOPLE BUT THIS IS JUST TO REMIND US THAT MUST SELLS ARE VERY NICELY SET UP TISSUE TO GENERATE FORCE BUT I WANT TO SHOW YOU WHAT MUSCLE BIOPSIES TYPICALLY LOOK LIKE IN A CONGENITAL MUSCULAR DYSTROPHY IN COMPARISON. SO THIS IS ONE OF THE BIOPSIES THAT WE COMMONLY SEE, THIS HAPPENS TO BE A COLLAGEN 6 DISORDER, AND YOU CAN SEE THERE IS TREMENDOUS PROLIFERATION OF EXTRACELLULAR MATRIX, FIBROSIS, LOTS OF INTERNALIZED NUCLEI AS A SIGN OF ONGOING REGENERATIVE ACTIVITY, AND SOMETIMES WE ALSO FIND WE SIGNIFICANT INFLAMMATION IN THE BIOPSY VERY EARLY ON. THIS HAPPENS TO BE A BIOPSY TAKEN AT JUST ABOUT A YEAR OF AGE AND YOU CAN SEE ALREADY IN THIS MUSCLE, TRE MEN DISPROLIFERATION OF CONNECTIVE TISSUE, AS WELL AS ONGOING ATTEMPTS AT REGENERATION AS WELL AS ONGOING DEGENERATION. SO VERY EARLY ON, VERY ACTIVE DISEASE IN THIS PARTICULAR CONDITION, AND THAT MAKES IT A CHALLENGING GROUP OF DISORDERS TO THINK ABOUT THERAPIES. THIS IS THE CURRENT CMD CLASSIFICATION, THE MOLECULAR CLASCLASSIFICATION AND IT LOOKS REALLY QUITE COMPLEX. THAT IS BECAUSE THE DIAGNOSTIC CRITERIA ARE SO LOOSE EARLY ONSET, BUT IF WE REALLY LOOK AT IT CAREFULLY, WE SEE THAT THE MOST IMPORTANT DISORDERS FALL INTO THE REALM OF EXTRACELLULAR DISORDERS. I'LL SHOW THAT TO YOU IN A DIAGRAM A LITTLE LATER. ITS CONNECTION TO MUSCLE, WE ALSO HAVE A FEW FORMS THAT ARE IN THE INTRACELLULAR SPACE OF MUSCLE AND OFTEN THESE FORMS HAVE OTHER PRESENTATIONS, ONSET OF CMD AS WELL. NOW WITHIN THE EXTRACELLULAR MATRIX FORMS THESE THREE ARE THE MOST COMMON. -- HAVE ONLY BEEN DESCRIBED OVER THE LAST 20 YEARS IN THREE PATIENTS. BUT THESE THREE FORMS, THERE ARE MANY GENES I WILL SHOW YOU, LAMA2 AND THE COLLAGEN 6 MEU TAKE, THOSE ARE THE THREE BIG PLAYERS IN THE CONGENITAL MUSCULAMUSCULARMUSCULAR DYSTROPHIES, AND I F YOU TAKE THOSE, YOU COVER MOST OF THEM JUST BY NUMBERS SO I WILL FOCUS BY THOSE IN THE FOLLOWING REMARKS. THERE IS A DIAGRAM THAT IS HOPING TO SHOW WHAT THE MOLECULAR SETUP IS OF THE MUSCLE MEMBRANE. THIS IS DYSTROPHIN, HERE'S THE PLASMA MEMBRANE, AND THIS COMPLEX REALLY FORMS THE MOLECULAR LINK TO THE PLASMA MEMBRANE TO THE EXTRACELLULAR MATRIX. THE MOST IMPORTANT RECEPTOR HERE FOR THE EXTRACELLULAR MATRIX IS -- IS THE OTHER RECEPTOR FOR THE MATRIX ON MUSCLE. THEN WE HAVE THE SETUP HERE OF THE MEMBRANE WITH LAMININ-211, THE TYPICAL COLLAGEN -- IS IN THERE AS WELL AS YOU'LL HEAR LATER, AND THEN WE HAVE COLLAGEN TYPE SIX LINKING UP TO THE MEMBRANE WITH UNCLEAR BINDING ACTIVITIES. THESE THREE FORMS ARE THE MOST IMPORTANT OF THE CONGENITAL MUSCULAR DYSTROPHIES. SO WE HAVE A MOLECULAR FOCUS HERE IN THE CONGENITAL MUSCULAR DYSTROPHY THAT WILL HELP US TO GO THROUGH THEM. >> [INAUDIBLE] >> YES, I'LL COME TO THAT. IF I KEEP TO MY TIME I'LL COME TO THAT AT THE VERY END. SO LET'S START WITH RECEPTIVE -- THE REASON WHY THERE'S SOME RECESSIVE GENES IS BECAUSE THE THE SETUP IS REALLY A SETUP OF AN ABNORMALITY OF A PARTICULAR GLOI GEICGLYCOEPITOPE. THERE IS A GLYCOEPITOPE THAT'S A PREPARATORY GLYCOEPITOPE FOR THE FINER -- CALLED THE LARGE GLIE KIN -- THE GENE THAT ADDS IT ON IS CALLED THE LARGE GENE. THAT'S THE NOMENCLATURE. THAT'S GLYCOEPITOPES BINDING ACTIVITY -- AS WELL AS TO OTHER LIOTHER -- ALL THESE MOLECULES HERE IN RED ARE GENES, ENZYMES THAT ARE MUTATED IN VARIOUS FORMS. YOU CAN SEE WE'RE UP TO, I THINK, 14, 15, AT THE MOMENT. THERE ARE EITHER CHAPERONE-LIKE ACTING MOLECULES THAT ARE -- THE UNIQUE MOLECULAR SETUP IN GLYCOBIOLOGY, SOME ENZYMES AND MOLECULES JUST FOCUSED ON THIS ONE PARTICULAR GLYCOEPITOPE IS QUITE UNIQUE IN BIOLOGY. BUT THE BOTTOM LINE IS, THE FINER END PRODUCT OF ALL OF THESE MUTATIONS IS AN ABNORMAL LARGE GLYCAN, BINDING GLYCOEPITOPE. THERE'S NO LOSS OF -- ITSELF KNOWN BECAUSE THAT WOULD PROBABLY BE PRENATALLY LETHAL. THERE'S ONLY ONE MOLECULAR MUTATION -- THE PROTEIN ITSELF WHICH ALSO IMPAIRS THE -- IT'S ALL IN THE SECONDARY MODIFICATION. NOT SURPRISINGLY, THERE'S A HUGE SPECTRUM OF MOLECULAR AND CLINICAL PHENOTYPES ASSOCIATED WITH THE MUTATIONS AND THIS IS JUST ONE OF THEM, I SHOW YOU EXAMPLES. FROM A VERY SEVERE MUSCULAR DYSTROPHY -- WITH COMPLETELY NORMAL INTELLIGENCE AND -- SEVERITY, THE ENTIRE SPECTRUM -- WITH EVERYTHING IN BETWEEN AND I'LL GET YOU SOME EXAMPLES OF THAT, MAKING THIS A VERY CHALLENGING PHENOTYPIC SPECTRUM TO DEAL WITH IF YOU THINK ABOUT NATURAL HISTORY STUDIES. SO THIS IS NOW THE LATEST -- WITH ALL THE GENES KNOWN SO FAR AND THE -- INDICATE THE CLINICAL SPECTRUM THAT IS COVERED BY EACH OF THESE GENES. YOU CAN SEE SOME OF THEM LIKE THIS RELATED PROTEIN COVER EVERYTHING FROM -- TO JUST -- SOME HAVE STAYED FOCUSED IN THE SPECTRUM BECAUSE THAT'S WHERE PEOPLE LOOK FOR THE GENES IN THE FIRST PLACE. BUT IT'S TO BE EXPECTED THAT MANY OF THE GENES WILL FILL IN THE SPECTRUM FROM VERY SEVERE BRAIN INVOLVEMENT TO INTERMEDIATE BRAIN INVOLVEMENT TO CONGENITAL MUSCULAR DYSTROPHY. JUST SOME EXAMPLES, THE MOST SEVERE OF THE GROUP, GOES ALONG WITH NOT ONLY A SIGNIFICANT NEUROMUSCULAR DISEASE AT BIRTH BUT ALSO WITH A VERY SIGNIFICANT BRAIN MALFORMATION, OFTEN HYDROSELF LUHYDROCEPHALUS -- THERE IS -- MILDER IN SEVERITY, THE SECOND MOST COMMON MUSCULAR DYSTROPHY IN JAPAN AFTER DUCHENNE'S. YOU CAN SEE SHE IS IT DISABLED, COGNITIVE IMPAIRMENTS, BUT SHE IS ABLE TO COMMUNICATE NONVERBALLY AND OPERATE HER WHEELCHAIR. HERE'S A PATIENT WITH BRAIN DISEASE FROM OUR CLINIC AT NIH. YOU CAN SEE HE'S ABLE TO WALK, HE HAS COGNITIVE IMPAIRMENT, SEVERE MYOPIA BUT ALSO SPASTICITY BECAUSE OF HIS BRAIN INVOLVEMENT. THEN THERE IS A PHENOTYPE OF -- MUSCULAR DYSTROPHY WITH MENTAL RETARDATION BUT NORMAL-APPEARING BRAIN AND MRI TELLING YOU THERE MUST BE SYNAPTIC DYSFUNCTION DISORDER IN THIS DISORDER AS WELL. HERE'S SOME OF THE ORIGINALLY DESCRIBED PATIENTS, WITH MUTATIONS IN GENES THAT OTHERWISE CAUSE WALKER WALL BERG SYNDROME HINTING AT THE SPECTRUM. SO QUITE NORMAL BRAIN BUT COGNITIVE IMPAIRMENT AND MILDER MUSCULAR DYSTROPHY. TWO PATIENTS WITH NO MENTAL RETARDATION THAT MAY EITHER BE CONGENITAL MUSCULAR DYSTROPHY IN SEVERITY OR -- HERE INITIATE -- THERE'S A PATIENT HERE WITH A MUTATION IN -- RELATED PROTEIN, SEVERE CONGENITAL MUSCULAR DYSTROPHY BUT NORMAL BRAIN AND NORMAL MENTATION TO THE VERY CLASSIC AGM2I, ALSO CAUSED BY A MUTATION -- HERE ONE PATIENT WHO IS STILL VERY MILD HERE AT THIS YOUNG AGE, AND THESE PATIENTS MAY HAVE DUCHENNE -- BECKER-LIKE PROGRESSION OF THEIR MUSCULAR DYSTROPHY OVER TIME. WHAT'S COMMON TO ALL OF THEM I TOLD YOU IS ABNORMAL GLYCOEPITOPE. YOU CAN SEE ANTIBODY STAINING, A PATIENT WITH -- BRAIN DISEASE. YOU USE AN ANTIBODY THAT'S SENSITIVE TO THE GLYCOEPITOPE, YOU CAN SEE IT'S QUITE DECREASED BUT IF YOU TAKE AN ANTIBODY THAT'S AT THE CORE OF -- IT APPEARS NORMAL. THAT POINTS TO WHAT THE GLYCOEPITOPE AS A DEFICIENCY HERE. IF YOU DO A GEL OVERLAY, YOU USE LAMB NEN, SEE IT BINDS VERY STRONGLY AND IN THE CASE FROM A PATIENT HERE, THERE IS SHIFTED BAND THAT'S MUCH WEAK NEER IN BINDING ACTIVITY, SO BINDING TO ITS LIGAND IS THE REALLY COMMON THING. SO WHAT ARE THE MECHANISMS? IT SEEMS LIKE I TOLD YOU THAT GLYCOEPITOPE IS REALLY THE IMPORTANT PART HERE FOR THE BINDING ACTIVITY. ACCOUNTING FOR THE BRAIN FEEN TIME. MUSCULAR DYSTROPHY IS PROGRESSIVE, THERE MAY BE ABNORMAL ?AIP TIC SYNAPTIC FUNCTION AS WELL. THERE IS INFLAMMATION AND FIBROSIS. ONE OF THE THERAPEUTIC APPROACHES THAT PEOPLE HAVE CONSIDERED IN THESE APPROACHES IS TO THINK, WELL, IF THIS -- IS SO IMPORTANT FOR ALL OF THEM, MAYBE I CAN COME UP WITH A STRATEGY THAT WOULD JUST JACK UP THE EXPRESSION OF THIS FINER GLYCAN -- OF THE LARGE GLYCAN APPROACH AND THEN THE THEORETICALLY YOU WOULD UPREGULATE THE GLYCOEPITOPE AND RE-ESTABLISH BINDING IRRESPECTIVE OF WHERE THE DEFECT IS BEFORE. SO THERE IS SOME PROOF OF PRINCIPLE THAT THIS MAY BE A VALID THERAPEUTIC APPROACH, SHOWN HERE AGAIN SCHEMATICALLY SO YOU HAVE LARGE -- AS GROUP OF PRINCIPAL MOLECULE, YOU MAY ESTABLISH BINDING AGAIN, YOU GET A BASEMENT MEMBRANE BACK, THE BASEMENT MEMBRANE IS OFTEN THICKER IN APPEARANCE AND SEEMS TO BE MORE SOLID. YOU CAN DO THAT IN A NORMAL OR DISEASE SITUATION. HERE'S AN EXAMPLE OF A MOUSE MODEL WITH PUM GMT1 WITH DELIVERY OF LARGE -- TRANSFERASE, UPREGULATION OF LARGE LEADS TO UP REGULATION OF GLYCOEPITOPE HERE IN THE MUSCLE AND SOME IMPROVEMENT IN THE PHENOTYPE. THE PROBLEM THAT HAS BECOME APPARENT RECENTLY IS THAT THIS LARGE GLYCOEPITOPE IS VERY FLEXIBLE, AND THAT'S WHAT THE MUSCLE NEEDS. IT SEEMS TO BE UPREGULATED MORE, IN MATURE MUSCLE IT'S DOWN MORE, IT TURNS OUT IF YOU UPREGULATE THIS TOO MUCH IN A DISEASE MODEL, FOR INSTANCE, IN AN SKRP-DEFICIENT MOUSE, IF YOU THEN UPREGULATE THE LARGE VERY MUCH, THEN YOU CAN ACTUALLY WORSEN THE PHENOTYPE IF YOU OVERDO IT. PERHAPS BY STRENGTHENING THE BASEMENT MEMBRANE TO A DEGREE THAT MAKES THE MUSCLE LESS FLEXIBLE AND MORE PRONE TO FRACTURE. SO IT LOOKS LIKE THIS IS A VALID APPROACH BUT IT HAS TO BE FINE-TUNED, MAKE IT REALLY MORE CHALLENGING TO PURSUE. THERE ARE OTHER POTENTIAL APPROACHES INCLUDING -- DELIVERY OF THE GENE PRODUCT, THEY'RE ALL SMALL, THEY WOULD FIT INTO ADENOVI RUSS, AND THEY ARE MOSTLY ENZYMES SO A LITTLE GOES A LONG WAY PROBABLY, AND YOU CAN THINK ABOUT OTHER APPROACHES THAT HAVE BEEN USED FOR OTHER ENZYME DEFICIENCY CAN DISORDERS SUCH AS -- OR CHAPERONE TREATMENT OF. THIS IS STEVE --'S SLIDE PUT TOGETHER FOR OUR VERY FIRST CMD SCIENCE MEETING. WE ASKED HIM TO COMMENT AND HE -- THAT MOST OF THE GENES ASSOCIATED WITH -- WOULD FIT VERY COMFORTABLY INTO -- SO IF THERE IS A FUNCTIONING -- DELIVERY TO MUSCLE, THESE WOULD BE GOOD CANDIDATES TO STUDY THIS WAY. THERE IS WE SEE THESE TO HAVE RAPID DECLINE THAT CAN BE REVERSED BY STEROID TREATMENT. SO WE'RE HOPING THAT THERE WILL BE AT SOME POINT AN INTERNATIONAL -- TO SEE WHETHER THAT CAN BE MADE A MORE STANDARD TREATMENT. LAMB NIN 211 AS OPPOSED TO THE -- IS ONE GENE, ONE DISEASE, SO -- THEY ALMOST ALL LEAD TO COMPLETE DEFICIENCY OF -- HENCE THE NAME -- DEFICIENT CONGEAL TALL MUSCULAR DYSTROPHY. VERY TYPICAL PHENOTYPE, VERY SEVERE PHENOTYPE RIGHT AT BIRTH, THESE CHILDREN ARE VERY, VERY SLOPPY WHEN THEY'RE BORN, THEY MAY LOZ STRENGTH IN THE FIRST WEEKS TO MONTH OF LIFE. ALMOST NO HEAD CONTROL, NO PULL AT THE BICEPS, NO PULL AT THE LEGS. SO A VERY SEVERE -- OFTEN THEY GET TO SITTING AND STANDING BUT ALMOST NEVER TO INDEPENDENT AMBULATION IF THE DEFICIENCY IS COMPLETE. SOME CHILDREN GET TO SITTING, EXAWN HERE'S A YOUNG CHILD SITTING BUT SHE'S NOT ABLE TO RAISE HER ARM ABOVE THE HORIZONTAL BECAUSE OF THE SEVERE PROXIMAL WEAKNESS THAT SHE HAS. CHILDREN HAVE A MOTOR NEUROPATHY CLEARLY NOT THAT SIGNIFICANT. 30% INCIDENCE OF SEIZURES, HOWEVER, NO INTELLECTUAL I IMPAIRMENT FOR MOST OF THEM. THESE PATIENTS -- BY LIMITATION MAY GET TO WALKING AND AMBULATION WITH THIS. VERY CHARACTERISTIC BRAIN FINDING AFTER A WHITE MATTER THAT HAS INCREASED -- WATER CONTENT -- IT'S NOT A LEUKODYSTROPHY, IT'S JUST PROBABLY A PROBLEM WITH THE BLOOD-BRAIN BARRIER IN THESE REGIONS. THE MECHANISMS FOR -- HAVE BEEN WORKED OUT QUITE A BIT BETTER BECAUSE THEY'RE VERY GOOD MOUSE MODELS THAT MIMIC THE DISORDER QUITE, QUITE WELL. IT SEEMS THE LINKAGE AGAIN BETWEEN THE BASEMENT MEMBRANE AND MUSCLE IS THE CRUCIAL PARTY, WHENEVER YOU FIX THAT LINKAGE, THE DISEASE GETS MUCH BETTER, BUT ITS DOWNSTREAM EFFECT IN PARTICULAR -- INCREASED INFLAMMATION AS WELL AS AUTOPHAGIC ABNORMALITIES AND INCREASED -- ACTIVITY. JUST FOCUSED ON THE FIRST TWO HERE, THE LINKAGE AND THE APOPTOSIS. THERE'S PROVE OF PRINCIPLE THAT YOU CAN ACTUALLY RE-ESTABLISH THE LINKAGE BY REPLACEMENT MOLECULES. NOT UNLIKE THE -- WSH YOU HAVE DYSTROPHIN MISSING AND THERE'S A BACKUP MOLECULE THAT'S ABLE TO BACK THIS UP. THERE IS A LAMININ -- ONE ISOFORM THAT IS VERY SIMILAR TO THE ALPHA 2 ISOFORM BUT IT'S NOT EXPRESSED IN MATURE MUSCLE AND HENCE CAN'T TAKE UP ITS ROLE. BUT IF YOU OVEREXPRESS IT IN TRANSGENIC EXPERIMENTS IN MUSCLE, YOU'RE ABLE TO RE-ESTABLISH BINDING TO -- GLYCAN WITH LAMININ 111 HE TROA TRY MER, AND THAT HE TROA TRY MER IS ABLE TO REPLACE LAMININ 211 TO QUITE A SIGNIFICANT DEGREE, AND YOU CAN SEE THESE MICE LOOK MUCH CLOSER TO -- ACTUALLY QUITE SIMILAR TO WILD TYPE. SO IT TURNS OUT IF YOU DO THAT POST NATELY THAT YOU CAN TURN OFF AFTER BIRTH TO SEE IF YOU CAN RESCUE THIS LATER ON, YOU CAN, BUT THE LATER YOU DO THIS, THE LESS EFFICIENT IT IS, SO IF YOU WANT TO INTERVENE THIS WAY, YOU HAVE TO BE QUITE EARLY DOING THAT, AND IF YOU REMEMBER THE CLINICAL PHENOTYPE, THIS IS VERY CHALLENGING, BECAUSE THE DISEASE IS ESTABLISHED SO EARLY AND WITH SUCH SEVERITY. THERE IS AN APPROACH THAT IS NOW TAKEN TO DEVELOP A PROTEIN THERAPY TO SEE WHETHER THIS LAMININ 111 HE TROA TRYMER CAN BE DEVELOPED AND THAT'S UNDER DEVELOPMENT AS WELL. TO RE-ESTABLISH THE LINKAGE IS TO PUT IN AN ARTIFICIAL LINGER THAT WILL BE ABLE TO BIND ON THE ONE END THEN TO ANOTHER LAMININ ISOFORM THAT'S STILL PRESENT IN THE BASEMENT MEMBRANE, WHICH IS LAMININ 411 ON THE OTHER END. AND PEOPLE IN SWITZERLAND, MARCUS WOOD'S GROUP, HAS DESIGNED A MINI AGRIN, WHICH IS AN AGRIN CONSTRUCT THAT CONTAINS A -- AND A LAMININ BINDING SITE. IT'S QUITE SMALL, IT FITS INTO -- IF DO YOU THAT IN TRANSGENIC EXPERIMENTS, IT CAN ACTUALLY RE-ESTABLISH THE LINKAGE BETWEEN -- AND -- MEMBRANE, BUT AGAIN, IF DO YOU THAT POSTNATALLY, THE LATER YOU DO IT, THE LESS EFFICIENT IT IS. AGAIN THE BOTTOM LINE IS, YES, IT'S A VIABLE APPROACH IN PRINCIPLE, BUT YOU HAVE TO ACT AT THE RIGHT STAGE OF THE DISEASE. THE DOWNSTREAM EFFECT THAT'S BEEN ESTABLISHED IN THESE MOUSE MODELS IS APOPTOSIS, MEANING MASSIVE DEATH AS A RESULT OF LACK OF LINKAGE TO THE MATRIX. THAT IS KNOWN AS ANNOY CUSS IN BIOLOGY AND IT'S A AN IMPORTANT PRINCIPLE FOR INSTANCE -- GOES INTO THE WRONG EXTRACELLULAR ENVIRONMENT, HERE IN THE MUSCLE IT LOOKS LIKE THIS LINKAGE, THIS RUP TIER LEADRUPTURE LEADS TO INCREASED AP OP TICK ACTIVITY IN THE MUSCLE. AGAIN WE HAVE SOME PROOF OF PRINCIPAL EXPERIMENTS HERE WHERE A PRO APOPTIC GENE IN ACTIVATION OF -- 2 WHICH IS A PROTECTIVE GENE, OVEREXPRESSION, REALLY AMELIORATES THE PHENOTYPE OF THE -- MOUSE MODEL. THE PRO APOPTIC GENE -- YOU CAN SEE THE LIFE EXPECTANCIES OF THE OF THE ANIMALS IS VERY POOR. IF IT'S COMPLETELY INACTIVATED, THE LIFESPAN IS REALLY RESCUED AND IN THE HE TRO HE HETEROZYGOUS -- HERE'S A MOUSE WITH THE -- DEFICIENCY -- COMPLEEN TH BETWEEN THE COMPLETE KNOCKOUT AND THE WILD TYPE. SO YOU DON'T -- THERE IS THE POTENTIAL OF INTERVENTION HERE THAT WE COULD TAKE ADVANTAGE OF. THERE'S A PHARMACOLOGICAL APPROACH TO DO THAT, TO INTERVENE WITH APO APOPTOSIS. ONE OF THE COMPOUNDS THAT IS CURRENTLY BEING INVESTIGATED IS CALLED OMEGAPILL, DISCOVERED AS A DRUG TRIED IN PARKINSON'S AND ALS TO PREVENT NEURONAL APOPTOSIS. IT FAILED IN CLINICAL TRIALS, IT'S BEEN USED IN MOUSE MODELS. IF YOU DO IT, DO YOU IT EARLY, YOU HAVE SOME BENEFITED LOCOMOTION, YOU HAVE SOME IMPROVEMENT IN THE HISTOLOGY. IF YOU DO IT LATER, THE EFFECT IS MUCH LESS PRONOUNCED. BUT IT LOOKS LIKE IT'S A PHARMACOLOGICALLY VIABLE DRUG TO BE GIVEN TO HUMANS WITH GOOD SAFETY -- SO THAT'S A CANDIDATE MOLECULE TO TEST IN PATIENTS WITH THESE DISORDERS AS WELL. LASTLY, THERE IS INFLAMMATION AND FIBROSIS THAT IS SO PRONOUNCED. ONE APPROACH THAT'S BEEN LATELY TAKEN IS TO USE -- RECEPTOR BLOCKER THAT'S BEEN USED IN DUCHENNE MODELS AS WELL AS IN -- SYNDROME TO SEE WHETHER WE CAN INTERFERE WITH A TGF BETA PATHWAY AND IMPROVE THE CONDITION HERE, AND THERE IS THREE INDEPENDENT PAPERS THAT TELL US YES, THAT MAY HAVE ANOTHER AMELIORATING EFFECT HERE SO HERE'S ONE OF THE PAPERS WHERE YOU CAN SEE THE DEGREE OF FIBROSIS HERE AND -- TREATMENT THAT DEGREE OF FIBROSIS IS QUITE A BIT FOUND, AND THERE IS SOME IMPROVEMENT IN SKELETAL MUSCLE PHENOTYPE AND THE FUNCTION OF PHENOTYPE AND WELL. THIS IS A DRUG THAT IS IN HUMAN USE, THAT WILL BE ANOTHER CANDIDATE TO STUDY AS A THERAPEUTIC DRUG. LASTLY TO THE KO COLLAGEN SIX DISORDER, HERE WE HAVE THREE GENES AND THE MUTATIONAL MECHANISMS ARE BOTH RECESSIVE AS WELL AS DOMINANT, MAKING OUR LIFE A LITTLE BIT MORE DIFFICULT. IT IS ON THREE GENES AS I SAID BEFORE, POLYPEPTIDES CONSTRUCTED HERE FROM THE GENES. THEY FORM A MONOMER, A DIMER, A TETRAMER, THE TETRA MER NOW HAS 12 DIFFERENT POLYPEPTIDES IN IT, SECRETED TO FORM A -- MATRIX AROUND MUSCLE THAT FOR SOME REASON, SOME MECHANISM THAT'S NOT QUITE KNOWN YET LINKS TO ITS BASEMENT MEMBRANE, AN IMPORTANT LINK OF MUSCLE TO THE EXTRACELLULAR MATRIX. THE PHENOTYPE IS THAT OF A MUSCULAR DYSTROPHY THAT IS REALLY AN OVERLAP SYNDROME BETWEEN MUSCULAR DYSTROPHY AND CONNECTIVE TISSUE DISEASE, SO MANY OF THE FEATURES HERE IN THESE PATIENTS ARE REALLY -- THEY HAVE HYPERLACKSITY, THEY HAVE ABNORMAL SKIN, ABNORMAL SCAR FORMATION, BUT THEY ALSO HAVE CONTRACTURES THAT DEVELOP OVER TIME AND SIGNIFICANT MUSCLE WEAKNESS SO IT'S AN OVERLAP BETWEEN CONNECTIVE TISSUE AND MUSCLE DISEASE. -- IS MUCH LESS ELEVATED NORMAL TO ONLY SLIGHTLY ELEVATED AND THERE IS PROGRESSION AS I WILL SHOW YOU OVER TIME IN THESE DISORDERS AS WELL. NO BRAIN INVOLVEMENT, NO MENTAL INVOLVEMENT. HERE'S A TYPICAL PATIENT AT BIRTH. PATIENTS WITH THIS CONDITION MAY GET TO WALKING BUT LOSE AMBULATION OFTEN BY 10 YEARS OF AGE OR MAY NEVER GET TO AMBULATION OR BLAIT ON THEIR KNEEAMBULATE ON THEIRKNEES, HE'S UNABLE BE CAUSE OF TERRIFIC CONTRACTURES AT THE KNEES. YOU CAN ALSO SEE THE SOMEBODY CONTRACTURES. -- INITIALLY DESCRIBED IN HOLLAND WHERE THE MUSCLE WEAKNESS IS MUCH LESS PRONOUNCED BUT THERE'S AGAIN A VERY STRIKING CONTRACTURE PHENOTYPE OF CONTRACTURES OF THE ELBOWS, ACHILLES TENDONS AND FINGER FLEXORS. THESE PATIENTS WALK INTO -- THINGS GET MORE DIFFICULT IN THE FOURTH AND FIFTH DECADE OF LIFE, OFTEN INHERITED IN FAMILIES IN A DOMINANT FASHION. THEN OF COURSE THIS BEING A GENETIC DISORDER, THERE ARE PHENOTYPES THAT ARE INTERMEDIATE BETWEEN THE TWO SUCH AS THIS YOUNG WOMAN WHO IS ABLE TO WALK, NOT RUN, BUT SHE ALSO HAS A TRACHEOSTOMY IN PLACE BECAUSE OF RESPIRATORY FAILURE 10 YEARS BEFORE THIS WAS TAKEN, TELLING YOU THAT THERE IS A VERY SIGNIFICANT RESPIRATORY ASPECT TO THIS DISORDER THAT'S DIFFERENT FROM OTHER NEUROMUSCULAR DISORDERS WHILE THEY'RE STILL AM BLANT AND YOU WOULDN'T KNOW THEY'RE GOING INTO A RESPIRATORY DECLINE PHASE. SO REAGAN FOLEY WHO WORKED WITH US, AND OTHERS, COMING BACK TO US AT NIH HOPEFULLY IN THE NEAR P FUTURE DID A LARGE RETROSPECTIVE STUDY AROUND THE WORLD COLLECTING -- TO RECONSTRUCT THE NATURAL HISTORY OF RESPIRATORY DECLINE IN THESE DISORDERS. YOU CAN SEE HOW DRASTIC IT LOOKS FOR INTERMEDIATE AND MUCH LESS FOR THE -- PHENOTIE. THERE'S A VERY PREDICTABLE DECLINE -- OVER THE YEARS THAT REALLY INFORMS THE NATURAL HISTORY IN A VERY SIGNIFICANT WAY. IF YOU TRANSLATE INTO A -- VENTILATION FREEDOM, THIS IS WHAT IT LOOKS LIKE. EVERY CHILD STARTS OUT NON-VENTILATED, BUT THEN AS THE YEARS GO ON, AT 20, ALMOST EVERY PATIENT WITH -- CONGENITAL MUSCULAR DYSTROPHY NEEDS TO BE ON NIGHTTIME RESPIRATORY SUPPORT. IF THAT DOESN'T HAPPEN, THE NATURAL HISTORY OF THIS DISORDER, OF COURSE, LOOKS LIKE DEATH BEFORE 20, AND THAT'S WHAT IT LOOKED LIKE UNTIL WE WERE ABLE TO INTERVENE WITH THIS, AND NOW THE NATURAL HISTORY IS WELL INTO THE 40s. WE REALLY DON'T KNOW WHAT THE NATURAL HISTORY LOOKS LIKE NOW. WITH THIS SIMPLE BUT EXTREMELY IMPORTANT INTERVENTION. I BELIEVE ANNE WILL TALK MORE ABOUT THIS. VERY REMINISCENT TO ANOTHER FORM OF CONGENITAL MUSCLE DISEASE WITH A VERY SIMILAR STORY OF EARLY DEATH IN MANY PATIENTS UNTIL THIS WAS REALIZED TO BE A A VERY SIMILAR -- THIS IS -- RIGID SPINE CONGENITAL MUSCULAR DYSTROPHY. THESE DISORDERS ARE CHARACTERIZED BY VERY EARLY SELECTIVE DIE FRAG MATIC INVOLVEMENT WHICH DRIVES THE RESPIRATORY DECLINE IN THESE DISORDERS. ESTABLISHED A NATURAL HISTORY STUDY TO REALLY UNDERSTAND THIS MORE IN BOTH THE MAYOR IS INDY FISHT AND COLLAGEN SIX DEFICIENT TIME. WE ARE NOW IN OUR FIFTH YEAR, THEN WE'LL BE ABLE TO LOOK AT VARIOUS MOTOR FUNCTIONS OVER TIME TO SET THE GROUNDWORK FOR INTERVENTIONAL STUDIES IN THESE DISORDERS EVENTUALLY. ONE OF THEM, MOST IMPORTANT MEASURES WE USE IS MOTOR FUNCTION MEASURE 32, YOU CAN ALREADY SEE THE DECLINE IN THIS REALLY MIMICS THE DECLINE IN THE -- CAPACITY, SO I THINK AT THE END OF THIS, WE WILL HAVE VERY SOLID NATURAL HISTORY DATA THAT ALLOW US TO GO INTO CLINICAL STUDIES IN THESE DISORDERS, RECOGNIZING HOPEFULLY THAT WE HAVE SOMETHING TO OFFER TO THE PATIENT SOON. ONE OF THE MECHANISMS HERE, THE MOST IMPORTANT ONE THAT'S BEEN ESTABLISHED SO FAR IS ALSO APOPTOSIS INCREASE IN APOPTOSIS, HAMPERED BY MOUSE MODELS ARE REALLY NOT GOOD MODELS OF THE DISEASE -- YOU -- UNIQUE FEATURE TO THIS DISORDER IS THE COLLAGEN SIX NOT MADE BY THE MUSCLE ITSELF, HERE'S A PICTURE FROM MY LAB CONSTRUCTING THIS COLLAGEN 6 IN GREEN AND THE -- YOU CAN SEE KOL GIN SIX WAS MADE BY THE P FIBROBLAST AND REACHES OUT AND CONTACTS THE MUSCLE FIBERS, SO IT'S -- VERY UNIQUE IN THAT RESPECT. SO APOPTOSIS AND YOU DON'T HAVE TO READ EVERYTHING ON THIS SLIDE BUT APOPTOSIS HAS BEEN ESTABLISHED AS A MECHANISM IN A COLLAGEN SIX DEFICIENT MOUSE MODEL THAT WAS GENERATED -- AND YOU CAN SEE HERE A NUMBER OF APOPTIC NUCLEI, AND IF YOU BLOCK THE MY TO MITOCHONDRIA CONDITION WITH SOMETHING LIKE CYCLOSPORIN A WHICH INTERFERES WITH -- D, THEN YOU CAN INCREASE THE NUMBER OF APOPTIC NUCLEI, A AND THERE'S SOME INDICATION THAT THEN THE DISEASE GETS BETTER AS WELL. THIS IS WHAT THAT LOOKS LIKE. HERE'S -- DRIVER OF APOPTOSIS. SPILL INTO THE CYTOPLASM, AND THIS CAN BE PREVENTED BY INTERFERING WITH THE -- BUT OTHER DRUGS LIKE THE OMEGAPILL THAT I MENTIONED EARLIER INTERFERES WITH THE -- DRIVEN APOPTOSIS -- ALSO ABLE TO PREVENT OPENING OF THE MITOCHONDRIA PERMEABILITY TRANSITION FOR MAKING OMEGA -- AN ATTRACTIVE COMPOUND TO STUDY IN BOTH TYPES -- AS WELL AS KOL GIN SIX DEFICIENT CONGENITAL MUSCULAR DYSTROPHY. THAT'S ON THE WAY AS A PK STUDY NOW IN CHILDREN WITH BOTH TYPES OF CONGENITAL MUSCULAR DYSTROPHY -- PHARMACEUTICALS. LASTLY, I HAVE FIVE MORE MINUTES, RIGHT? THIS IS JUST OUR OWN APPROACH TO THESE DISORDERS JUST OH GET YOU A LOOK INTO OUR LAB HERE, COME BACK TO THE QUESTIONS WHAT ARE THE HOT SPOTS IN THE COLLAGEN SIX GENES. IT TURNS OUT MOST ARE DOMINANT NEGATIVE ACTING MUTATION, EITHER DELETIONS OR -- THAT ARE VERY COMMON IN OTHER COLLAGEN DISORDERS AS WELL. MAKING THIS A CHALLENGE TO TREAT BECAUSE THESE DISORDERS ARE ACTING IN A DOMINANT NEGATIVE WAY SO GENE REPLACEMENT IS NOT AN OPTION REALLY FOR THESE DISORDERS. SO THE APPROACH THAT WE HAVE TAKEN IS TO SEE WHETHER WE CAN ACTUALLY KNOCK DOWN THE DOMINANT ALLELE SELECTIVELY BECAUSE -- INSUFFICIENCY ONLY HAVING HALF MODEL OF COLLAGEN SIX HAS NO PHENOTYPE, SO BEING ABLE TO TAKE OUT THE DOMINANTLY INTERFERING ALLELE, WE MAY BE ABLE TO AMELIORATE THIS. THIS IS THE APPROACH WE'VE TAKEN IN THE LABORATORY, DESIGNING -- AGAINST THE MUTANT JUNCTION HERE, DELETION MUTATION, HOPING THAT THE NORMAL ALLELE WILL SURVIVE AND THE TARGETED ALLELE WILL BE TAKEN DOWN. THIS IS ACTUALLY INITIALLY SUPPORTED BY THE MDA AND CHILDREN'S HOSPITAL OF PHILADELPHIA WHERE THEY STARTED THIS WORK. YOU CAN SEE HERE, THIS IS WILD TYPE, MUTANT ALLELE. SOME OF THESE THAT WE'VE TESTED ARE VERY EFFICIENT IN KNOCKING DOWN THE MUTANT BUT NOT THE WILD TYPE ALLELE. AS THE EFFECT OF THAT, HERE'S AN UNTREATED -- CULTURE OF CELLS FROM PATIENTS IN CULTURE, YOU CAN SEE ALL THE CELLS ARE CHOCK FULL OF MUTANT COLLAGEN 6. IF YOU TREAT THEM WITH THE SELECTIVE -- AGAINST THE MUTANT ALLELE, THE COLLAGEN SIX IS LEB RATLIBERATED OUT OF THE CELL AND BROUGHT INTO THE MATRIX. THIS IS COLLAGEN SIX IN THE CELLS, SCRAMBLED OLIGO, MOBILIZED, GOES INTO THE EXTRACELLULAR MATRIX. PROOF OF PRINCIPLE THAT IF YOU RELEASE A DOMINANT NEGATIVE HOLD ON THE COLLAGEN SIX -- IT WILL BE ABLE TO RE-ESTABLISH A MATRIX AND YOU CAN QUANTIFY IT SO THAT'S AN APPROACH WE'RE NOW TAKING INTO THE ANIMAL MODEL TO DO ALLELE-SPECIFIC SLEK ITTIVE KNOCKDOWN OF THE DOMINANT ALLELE. IT'S JUST BEEN PUBLISHED IN MOLECULAR THERAPY --. I WILL THANK ALL OF THE PEOPLE WHO HAVE CONTRIBUTED TO THIS WORK THAT I JUST TOLD YOU AT THE END WITH -- A GREAT CLINICAL TEAM AT NIH THAT HELPS WITH THE NATURAL HISTORY STUDY -- COLLABORATORS SPEARHEADING THAT. MANY COLLABORATORS AROUND THE WORLD AND AROUND THE COUNTRY THAT REALLY HELP US UNDERSTAND THESE DISORDERS PUT TOGETHER COHORTS, PUT TOGETHER OUR UNDERSTANDING OF IT, WHICH ALREADY HAVE -- TWO PUBLICATIONS THAT DEFINE THE CONSENSUS STATEMENT ON THE STANDARDS OF CARE AS WELL AS THE DIAGNOSTIC APPROACHES IN THESE -- ALL OF THEM COLLABORATIVE APPROACHES WITH ALL THESE CLINICIAN ACE CROSS THE COUNTRY AND THE WORLD, SO IT'S A COMMUNITY COMING TOGETHER, COMING TO A POINT NOW WHERE WE CAN REALLY, I THINK, BE EFFECTIVE IN TRANSLATING SOME OF THESE SCIENCE APPROACHES INTO ACTUAL THERAPEUTIC APPROACHES. THANK YOU. >> THANK YOU, CARSTEN. LOVELY TALK COVERS A LOT OF GROUND. WE HAVE TIME FOR ONE QUESTION. SO WHO HAS THE ONE QUESTION THEY'D LIKE TO BRING UP? I'M SURE CAR 10 WIL CARSTEN WILL BE AVAILABLE LATER FOR PEOPLE THAT WANT TO TALK DURING THE BREAK. >> CARSTEN, GREAT TALK, GREAT SUMMARY. I'M GOING TO ASK MY QUESTION IN TWO PARTS. [LAUGHTER] >> THAT'S WHAT WE DO AT THE DIRECTORS' TABLE. THE FIRST IS, TO THE SIRNAs, THE TARGETING YOUR DOMINANT NEGATIVE GENE, DO YOU NOTE WHETHER THEY HOME TO THE RIGHT CELLS? NUMBER ONE. AND NUMBER TWO, THERE IS LOTS OF EVIDENCE NOW THAT -- I'M DELIGHTED IT TO HEAR YOU TALKING ABOUT PROTEIN THERAPY. THERE'S LOTS OF EVIDENCE SHOWING IN THESE RES RECESSIVE DISEASES -- WHERE PROTEIN SOMEHOW FINDS ITS WAY TO THE RIGHT PLACE, SO IT'S REALLY PROTEIN-REPLACEMENT THERAPY. SO >> ABSOLUTELY FANTASTIC QUESTION. THE SIRNA, IN OUR IN VITRO WORK, IT REALLY GOES VERY EFFICIENTLY TO THE CELL ARE ORIGIN WHICH IS FIBROBLASTS. WE NEED TO TARGET THE FIBROBLASTS. IN VIVO, THAT'S MUCH LESS CLEAR. ALSO SIRNA IS IN VIVO A LITTLE BIT PROBLEMATIC, SO WE NOW HAVE EVALUATED OLIGOS THAT ARE MORE STABLE, LIKE LNA OLIGOS AND OTHERS THAT CAN BE GIVEN SYSTEMICALLY INTO ANIMAL MODELS, AND WE'LL BE TRACING THEM IN THE ANIMAL TO SEE IF THAT -- TO THE RIGHT -- IT'S AN IMPORTANT QUESTION TO ASK. THE PROTEIN THERAPY, FOR ME IT'S STILL A MYSTERIOUS -- SIMILAR KIND OF STRIKING DATA FOR LAMININ 111, WHICH YOU WOULDN'T THINK SHOULD GO ANYWHERE, BUT IT SEEMS TO BE GOING TO THE MUSCLE AND TO THE BASEMENT MEMBRANE. PERHAPS ANOTHER PROTEIN THAT CAN BE GIVEN IN PLACES WHERE YOU DIDN'T EXPECT IT TO GO. SO YES, IT'S MYSTERIOUS BUT IT'S A PHENOMENON THAT WE SHOULD TAKE ADVANTAGE OF, I THINK. >> CARSTEN, SO GREAT TALK. YOU TOUCH ON A THEME THAT'S COMMON, WE'RE DEALING WITH THAT COMMITTEE AND THAT IS TARGETING THERAPEUTICS. WHEN YOU'RE DEALING WITH MULTI-CYSMULTI-SYSTEMIC DISORDERS LIKE THE CMDs, SO YOU HAVE TO WORRY ABOUT BRAIN TARGETING, OTHER DISORDERS HAVE TO WORRY ABOUT HEART TARGETING, DIFFERENT FROM SKELETAL MUSCLE TARGETING. SO THIS IS A PROBLEM PARTICULARLY WHEN YOU'RE TALKING ABOUT THERAPEUTICS LIKE GENE THERAPY -- PROTEIN THERAPEUTICS, ACCESS TO TISSUES. SO IS THE STRATEGY BASICALLY TO TRY TO ADDRESS THE MUSCLE PROBLEM IN PRECLINICAL STUDIES IN CLINICAL TRIALS AND THAT THESE OTHER SYSTEMS ARE GOING TO COME LATER? IS THAT THE MESSAGE? >> THAT'S KIND OF TRUE. THERE IS, OF COURSE IF YOU GO TO THE -- THE BRAIN FEE PHENOTYPE IS TWOFOLD. -- PRESENT AT BIRTH YOU AND CAN'T CHANGE IT. BUT WE -- DEPENDENT ON -- AND I THINK THAT MAY BE -- SO THAT COULD BE THERAPEUTICALLY ADDRESSED BUT ONLY WITH COMPOUNDS THAT CROSS THE BLOOD-BRAIN BARRIER WILL GO THERE. SO FOR INSTANCE, IF WE THINK GENE THERAPY, WE HAVE TO TARGET BOTH INTRATHECALLY AS WELL AS SYSTEMICALLY IF WE WANT TO GO THAT ROUTE. >> THANK YOU AGAIN, CARSTEN. FOR THOSE THAT HAVE OTHER QUESTIONS, GRAB HIM DURING THE BREAK. BECAUSE WE SHOULD MOVE ON, WE HAVE THE FIRST OF SEVERAL TALKS WE PROMISED DEALING WITH SPECIFIC ORGANIZES AND DISORDERS, BUT REGARDING THEIR ACTIVITIES UNDERTAKEN DURING THE TENURE OF OUR ACTION PLAN FOR THE MUSCULAR DYSTROPHY WE THOUGHT WOULD BE ILLUMINATING FOR ALL OF US. THE FIRST IS BY ANNE, PUBLIC MEMBER OF THE GROUP, CO-FOUNDER AND FORMER CHAIR OF CURE CMD. SO TAKE IT AWAY. >> THANK YOU VERY MUCH. I DON'T KNOW IF EVERYBODY CAN HEAR ME. DR. CATS TO GET BACK TO YOUR POINT, I ACTUALLY MET WITH THE TEAM THAT DEVISED THE THERAPY FOR THE DYSTROPHIC EPIDERMAL LYSIS -- THE TWO CHALLENGES OF -- FOR COLLAGEN SIX IS THE FACT THAT YOU HAVE THREE DIFFERENT STRANDS THAT NEED TO COME TOGETHER, SO DEVELOPING THAT IN A RECOMBINANT FORM IS ACTUALLY VERY CHALLENGING. THE SECOND ISSUE IS THE PH STABILITY OF THE RECOMBINANT PROTEIN IF ADMINISTERED, AND THAT WOULD BE A CHALLENGE WHEN WE LOOKED AT IT FOR COLLAGEN 6. SO UNFORTUNATELY PROBABLY LESS LIKELY OF AN OPTION IN COLLAGEN SIX. SO I'M REALLY EXCITED TO BE BACK HERE, I'VE TAKEN A LITTLE BIT IN ABSENCE BECAUSE OF A RECENT BIRTH OF MY THIRD CHILD AND IT'S GREAT TO KIND OF BE BACK IN WASHINGTON, D.C. AND TO BE ABLE TO PROVIDE WITH YOU AN UPDATE OF WHERE THINGS STAND FOR THE CONGENITAL MUSCULAR DYSTROPHIES. WHAT I'M GOING TO DO IS PROVIDE YOU WITH A REVIEW OF THE LAST FIVE YEARS, KIND OF WHERE WE HAVE BEEN AND WHERE WE ARE GOING. I THOUGHT I WOULD START WITH -- THESE MISSION STATEMENT WHICH I THINK REALLY NICELY ENCAPSULATES THE MISSION OF ALL OF US AS WE SEEK TO MOVE FORWARD IN OUR PARTICULAR SUBTYPE AREAS AND IS KIND OF GLOBALLY REPRESENTATIVE OF WHAT WE'RE TRYING TO DO, SO THE MISSION IS TO BRING RESEARCH, A CURE FOR CONGENITAL MUSCULAR DYSTROPHY. CURE CMD WILL ACHIEVE THIS MISSION BY WORKING GLOBALLY TOGETHER WITH PARENT, GOVERNMENT AND RESEARCH AD ADVOCATE, AND BY FOCUSING ON THIS MISSION, CURE CMD WILL FIND AND FUND HYPOTENSION RESEARCH AND CLINICAL TRIALS AND SUCCESS WILL BE DETERMINED BY CLINICAL APPLICATIONS THAT IMPROVE THE LIVES OF THOSE AFFLICTED WITH CMD. SO IN MY PRESENTATION TODAY, I'D LIKE TO REVIEW PROGRESS THAT WE'VE MADE AND I'LL FOCUS ON FIVE DIFFERENT AREAS WHICH I BELIEVE ARE CRITICAL TO FOCUS ON IN ORDER TO GET THE CLINICAL TRIALS STARTING WITH CLINICAL CARE, THEN ADDRESSING BASIC SCIENCE AND TRANSLATIONAL SCIENCE, CLINICAL TRIAL READINESS AND CLINICAL RESEARCH, AND THEN END WITH ONE SLIDE THAT ADDRESSES THE CHALLENGES AND PRIORITIES IN PARTICULAR FOR THE CMDs. THROUGHOUT MY SLIDES, YOU'RE GOING TO SEE THESE BARS HIGHLIGHTED IN GREEN, AND THIS IS A REFERENCE TO THE FANTASTIC PLAN THAT WAS PUT FORTH, THE MUSCULAR DYSTROPHY COORDINATING COMMITTEE ACTION PLAN, AND WHERE WE HAVE ACHIEVED THOSE OBJECTIVES, I HAVE LISTED THOSE ON THE SLIDES. SO ONE OF OUR FIRST STEPS FORWARD AS AN ORGANIZATION WAS TO ORGANIZE A CENSUS STATEMENT LED BY MYSELF AND OTHERS, WE BROUGHT TOGETHER 81 INTERNATIONAL SUBSPECIALIST, 30 FAMILIES IN AN INITIAL SURVEY, AND USING THE DELPHI METHOD, BROUGHT TOGETHER 40 OF THOSE 81 SPECIALISTS TO EUROPE AND THEN CRAFTED THIS CONSENSUS STATEMENT. THIS CONSENSUS STATEMENT WAS THEN ADAPTED TO A FAMILY-FRIENDLY VERSION BY TWO INCREDIBLY DEDICATED MOMS, AND IT REALLY KIND OF DEMYSTIFIED THE MEDICAL TERMINOLOGY AND MADE IT MUCH MORE ACCESSIBLE TO FAMILIES SO THAT FAMILIES COULD REALLY START TO ADVOCATE FOR OPTIMAL CARE. SINCE THE PUBLICATION OF THE CONSENSUS SEDATEMENT, CURE CMD EAZ REAL FOCUS HAS BEEN IN TWO AREAS, ONE ON DIAGNOSIS AND TWO ON PULMONARY HEALTH, WHICH WE BELIEVE ARE REALLY THE TWO CRITICAL AND OFTEN MISSING STEPS FOR OUR PARTICULAR GROUP OF DISORDERS. THIS LAST YEAR,, THERE WAS A PUBLICATION OF THE DIAGNOSTIC APPROACH WHICH REALLY PUTS FORTH THE PATTERN RECOGNITION THAT IS NECESSARY AS WELL AS A RATIONAL ALONG RHYTHMIC APPROACH TO SORTING THROUGH ALL OF THE VARIABLES WHEN YOU ARE CONFRONTED WITH A PATIENT WITH CONGENITAL ONSET MUSCLE DISEASE. WE HOPE IN THE NEXT YEAR OR TWO TO PUT FORWARD AN ONLINE COMPUTER-BASED ALGORITHM TO ASSIST THOSE WHO MAY NOT HAVE ACCESS TO THE NIH AND TO CARSTEN OR TO THE TRAVELING CLINICS THAT WE RUN TO HOPEFULLY EXPEDITE DIAGNOSIS FOR THESE PATIENTS. THEN IN DECEMBER, WE HAD A FOLLOW-UP WORKSHOP TO A WORKSHOP I PUT TOGETHER IN WASHINGTON, D.C. LAST SUMMER. THE ONE IN DECEMBER WAS LED BY MYSELF AND THREE P PULMONOLOGISTS AND THIS WAS AN -- WORKSHOP THAT FOCUSED ON RESPIRATORY PHYSICIAN KOLG IN OUR GROUP OF DISORDERS, WHICH REAL IMPLICATIONS FOR SURVEILLANCE, CLINICAL RESEARCH AND SCIENTIFIC RESEARCH TO BETTER UNDERSTAND THE UNDERLYING PHYSIOLOGY. TO ADDRESS ONE OF OUR REAL ISSUES WHICH IS GENE IDENTIFICATION AND OBTAINING GENETIC CONFORMATION, WE HAVE LAUNCHED A TRAVELING LOCAL CLINIC, WE CALL IT TLC PROGRAM TOGETHER WITH CARSTEN. THIS IS A TRAVELING CLINIC THAT IS BOTH NATIONAL AND INTERNATIONAL. WE GO AND TEAM UP WITH A LOCAL TEAM TO EVALUATE THEIR PATIENTS WITH PRESUMED CONGENITAL MUSCLE DISEASE. THEY CAN BE BOTH CHILDREN AND ADULTS, AND WE HAVE BEEN FORTUNATE ENOUGH TO EVALUATE OVER 200 PATIENTS WITH, YOU CAN SEE, A VARIETY OF ULTIMATE CLINICAL AND GENETIC DIAGNOSES, AND HAVE USED TWO RESEARCH BASED GENETIC TESTING PLATFORMS IN ORDER TO MAKE GENETIC TESTING ACCESSIBLE TO MANY OF THESE PATIENTS, ONE THAT WAS FUNDED THROUGH THE MDA AT EMORY GENETICS, AND ONE THAT IS A BENCH TO BED TYPE GRANT BETWEEN -- AND THE NIH. I WANT TO HIGHLIGHT THE REASON FOR THE LACK OF GENETIC CONFIRMATION IN FAMILIES WITH CMD. THERE ARE REALLY FOUR MAIN REASONS. ONE, THAT A CLINICIAN FEELS THAT THERE IS NO NEED TO OBTAIN GENETIC CONFIRMATION IN A DISEASE GROUP WITHOUT A TREATMENT OR A CURE. SECOND, THAT THE CLINICIAN IS NOT BECAUSE THESE KISS ORDERS DISORDERS AR E RARE, REALLY TUNED INTO THE SPECIFICS ON A CLINICAL EXAM ALONG WITH ANCILLARY TESTING THAT CAN PROVIDE CLUES, SEVERAL TESTS HAVE BEEN OBTAINED, THEY'VE ALL COME BACK NEGATIVE, AND THERE'S A SENSE OF FRUSTRATION AND I DON'T KNOW WHERE TO GO NEXT. THIRD IS A LACK OF INSURANCE COVERAGE IN PARTICULAR FOR OUR ADULT PATIENTS, AND FOURTH IS LIVING IN A COUNTRY WITHOUT ACCESS TO GENETIC TESTING. ALL OF THIS IN MY MIND REALLY PLAYS TO THE IMPORTANCE OF PROVIDING LOW COST GENE PANEL TESTING AND MAKING THAT ACCESSIBLE TO ALL IN THE COMMUNITY, BECAUSE IT REALLY GETS RID OF POTENTIALLY THE NEED FOR SUBTYPE SPECIFIC EXPERTISE, IF YOU TAKE MORE OF A SHOTGUN APPROACH TO GENETIC TESTING, AND WOULD -- IF IT'S LOW COST ENOUGH, REALLY OPEN UP THIS FIELD TO ALL. SO THE CMDIR, WHICH IS THE CONGENITAL MUSCLE DISEASE INTERNATIONAL REGISTRY, WHICH I DIRECT, HAS TAKEN A VERY PROACTIVE STANCE, AND OUR IDEA IS TO GO AFTER CERTAIN OF THE SUBTIEPTS THASUBTYPES THAT WE REGISTER THA T WE THINK ARE RIGHT FOR CLINICAL TRIALS. SO I'M GOING TO TELL YOU ABOUT ONE OF THE DISEASES THAT WE REGISTER. AND OUR IDEA WAS TO IDENTIFY PHARMACEUTICAL SPONSORS WHO WOULD HELP SUPPORT GENETIC TESTING, DEVELOP STRICT INCLUSION AND EXCLUSION CRITERIA THAT WE COULD MEET THROUGH THE REGISTRY, POST THIS ON CLINICALTRIALS.GOV AND THEN GO AFTER PATIENTS WHO ARE BOTH REGISTERED AND WHO ARE NOT REGISTERED TO START TO DEVELOP GENETICALLY CONFIRMED COHORT, AND THEN TO COMBINE THIS WITH A PROSPECTIVE EVENT STUDY WHERE WE ARE ASSESSING THE RATE OF HOSPITAL UTILIZATION AND IN-HOME SERVICES FOR THESE VERY SEVERELY AFFECTED PATIENTS TO DETERMINE A BASELINE EVENT RATE, AND THIS IS ALL BEING LED BY A VOLUNTEER WHO'S EXTREMELY DEDICATED, AND IS ONE OF OUR VOLUNTEER STAFF AT THE CMDIR, AND AS A RESULT OF THESE EFFORTS, WE HAVE BEEN ABLE TO IDENTIFY THE NUMBER OF PEOPLE IN THE REGISTRY ALIVE AND DECEASED, HIGHLIGHT THE NUMBER OF FEMALE MANIFESTING CARRIERS, WHICH HAS BEEN VERY INTERESTING TO US, AND ABOUT THER DEFINE A COHORT OF GENETICALLY CONFIRMED PATIENTS WITH THE IDEA OF MOVING PEOPLE WHOSE STATUS IS UNKNOWN INTO THE GENETIC TESTING STUDY, AND CONFIRMING THEM. WE HAVE ALSO BEEN ABLE TO IDENTIFY PATIENTS NOW WHO HAVE BEEN LABELED AS MYOTUBULAR MYOPATHY BASED ON CLINICAL AND MUSCLE FINDINGS THAT IN FACT ARE -- PATIENTS. SO THIS HAS BEEN EXTREMELY IMPORTANT. OUR NEXT GOAL IS TO LAUNCH AN RYR1 GENETIC TESTING STUDY BY THE END OF THIS YEAR IN ANTICIPATION OF A WONDERFUL BENCH TO BEDSIDE GRANT THAT WAS AWARDED AT THE NIH AND SICK KIDS TORONTO THAT WILL LAUNCH AN ROIR1 TRIAL AND THEN TO LAUNCH A LAMA IT 2 GENETIC TESTING STUDY. SO I'D LIKE TO MOVE NOW TO BASIC SCIENCE AND TRANSLATIONAL SCIENCE. WE REALLY KICKED OFF KIND OF AN INTEREST IN THE CMDs AS CARSTEN MENTIONED WITH HIS FIRST CONFERENCE IN JULY OF 2009, THERAPEUTIC TARGETS IN THE CMDs, AND THIS WAS REALLY A WONDERFUL CONFERENCE LED BY CARSTEN, FUNDED BY THE OFFICE OF RARE DISEASE MDA AND PHARMACEUTICAL COMPANIES AS WELL AS CURE CMD, AND THEN THAT SAME YEAR, CURE CMD LAUNCHED OUR ANNUAL RESEARCH GRANT PROGRAM AND WE HAVE NOW FUNDED OVER 1.5 MILLION IN THE ANNUAL RESEARCH GRANTS. EACH GRANT IS FOLLOWED ON A QUARTERLY BASIS BY MYSELF WITH A 60 MINUTE WEBINAR CALL WITH A SCIENTIST TO FOLLOW UP ON DELIVERABLES, HURDLES AND BARRIERS, AND MAKE CONNECTIONS WITH OTHER SCIENTISTS IN THE COMMUNITY. I THINK THAT HAS BEEN INSTRUMENTAL TO REALLY MOVING SCIENCE FORWARD. AND THEN WE FOLLOWED UP THAT FIRST VERY SUCCESSFUL CONFERENCE WITH A SECOND CONFERENCE THAT WAS LED BY DEAN BURRKIN IN APRIL 2012 AT THE UNIVERSITY OF NEVADA, AND THIS IS CALLED THE MYOMATRIX CONFERENCE, AND WAS FOCUSED ON REALLY DEFINING THE ROLE OF THE EXTRACELLULAR MATRIX IN MUSCLE DISEASE, BOTH FROM A DEVELOPMENTAL, REGENERATIVE STANDPOINT, AS WELL AS THE INVOLVEMENT OF TENDONS AND JOINTS. THE NEXT COUPLE OF SLIDES HIGHLIGHT THE RESEARCH THAT WE HAVE FUNDED. THOSE IN ITALICS HAVE LED TO PUBLICATIONS, AND CAN YOU SEE HOW WE'VE COVERED A BROAD RANGE OF SOME OF THE EARLY OBJECTIVES AS I SAY A FANTASTIC MAP THAT WAS CREATED BY THE INITIAL ACTION PLAN. ONE OF OUR KEY FOCUS AREAS HAS REALLY BEEN TO INVEST HEAVILY IN THE DEFINITION AND CHARACTERIZATION OF KEY ANIMAL MODELS IN OUR GROUP OF DISORDERS BECAUSE WE THINK LINKING FUNCTIONAL END POINTS WITH BIOMARKERS AND DOING THIS IN THE MOUSE WILL HAVE BIG PAYOFFS. SO WE'VE DONE THIS BOTH IN THE DMW MOUSE OF LAMA2 -- NOW IN THE -- A MODEL WITH A REAL POE CUSS ON THE CARDIAC DISEASE THAT MANIFESTS IN ELEMENT A CMD. IN TERMS OF -- THERAPEUTICS, WE'VE LOOKED AT PRIMARY PROTEIN REPLACEMENT ACTUALLY USING STEM CELLS, NOT IN TERMS OF THEIR ABILITY TO DIFFERENTIATE INTO MUSCLE, LOOKING AT X ON SKIPPING, GENE THERAPY APPROACHES, AND THEN SMALL AND HIGH THROUGHPUT SCREENING FOR DRUGS. FIBROSIS AND REGENERATION AND THEN FROM THE GET-GO, HAVE INVESTED IN BIOMARKERS. BECAUSE OF THE DISEASE CHRONICITY, THE FLOW RATE OF CHANGE OVER 12 MONTHS, WE REALLY THINK THAT IDENTIFYING BIOMARKERS IS GOING TO BE CRITICAL FOR OUR GROUP OF CONDITIONS. THEN HAVE INVESTED IN THE DEVELOPMENT OF INFRASTRUCTURE SO NEW ANTIBODIES FOR -- PLACING MOUSE MODELS AT JACKSON WHICH STARTED FIRST WITH THE DYW MODEL AND IS NOW CONTINUING WITH SEVERAL OTHER MODEL, AND THEN IN APRIL OF 2013, JOHN AND MIKE WAHLEER LED A CMD PRECLINICAL RIGOR WORKSHOP, WHICH WAS COFUNDED WITH THE AFM AND HAS NOW LED TO DEFINING 10 STANDARD OPERATING PROTOCOLS ON OUR -- MODEL WITH TWO OUT OF THREE PLANS SUBMITTED, JOE'S PUBLICATIONS, THAT REALLY REACHED ACROSS ISSUES AND OPERATING PROTOCOLS FOR THE CONGENITAL MUSCLE DISORDERS. SO IN TERMS OF CLINICAL TRIAL READINESS, REALLY KIND OF THE CENTRAL HUB OF OUR PLATFORM IS THE REGISTRY, THIS REGISTRY WAS LAUNCHED IN 2009 WITH ORIGINALLY FOCUSED ON CONGENITAL MUSCULAR DYSTROPHY AND HAS BEEN EXPANDED TO INCLUDE THE CONGENITAL MYOPATHIES AND CONGENITAL MYOSCENIC SYNDROMES. YOU CAN SEE THE TOTAL NUMBER OF REREGISTRANTS OUT OF 67 COUNTRIES, WE'RE HOPING TO HAVE SPANISH AND PORTUGUESE ONLINE TRANSLATION AVAILABLE, AND WE'LL EXPAND THAT TO OTHER LANGUAGES. EACH REGISTRANT COMPLETES CONTACT INFORMATION, AN 80-QUESTION INTAKE SURVEY, A LONGITUDINAL FOLLOW-UP SURVEY THAT REALLY ASSESSES MORE ADVERSE EVENTS AND MEDICATIONS AS WELL AS THEIR PULMONARY AND CARDIAC HEALTH WHERE APPLICABLE. WE OBTAINED MEDICAL RECORDS WHICH ARE CURATED AND TREND SOME OF THESE KEY -- SO THEY CAN FOLLOW THEIR OWN VITAL CAPACITY OR WEIGHT OVER TIME. AND THIS REGISTRY IS SUPPORTED BY THREE DIFFERENT NON-PROFIT ORGANIZATIONS. WE HAVE COME IN THE LAST YEAR OR TWO TO REALLY IDENTIFY THREE KEY AREAS WHERE WE THINK THE REGISTRY CAN CONTRIBUTE TO DISEASE KNOWLEDGE. ONE IS IN THESE GENETIC TESTING STUDIES, TWO IS IN HIGHLIGHTING DISEASE-SPECIFIC ADVERSE EVENTS AND COMPLICATIONS, SO WE ARE PLANNING A SERIES OF CASE STUDIES THAT HAVE REALLY BEEN BROUGHT TO LIGHT THROUGH THE REVIEW OF RECURRENT ISSUES IN MEDICAL RECORDS FOR MANY OF OUR PATIENTS, SO THE IDEA AND THE REAL ISSUE OF SPONTANEOUS -- BOTH SPONTANEOUS RECURRENT PNEUMOAUTHOR SEES AS WELL AS SINGLE INDIVIDUAL PNEUMOAUTHOR SEES HIGHLIGHTING THAT COLLAGEN SIX IS TRULY AN EXTRACELLULAR MATRIX DISEASE AND IN THAT SENSE IS IMIS LAR TO OTHER EXTRACELLULAR MATRIX DISEASES WITH REAL TREATMENT IMPLICATIONS BECAUSE OF THE PROGRESSIVE DECLINE IN RESPIRATORY CAPACITY THAT CARSTEN HAS HIGHLIGHTED. GASTROINTESTINAL SYMPTOMS THAT HERALD WORSENING CARDIAC DYSFUNCTION AND -- DIFFICULT AIRWAYS THAT HAVE LED TO THE DEATH OF ONE CHILD AND HAVE LED TO POSTPONED SCOLIOSIS SURGERY FOR FOUR ADDITIONAL CHILDREN THAT THEN HAVE TO UNDERGO ELECTIVE TRACHEOSTOMY FIRST, THEN THE THIRD AREA OF FOCUS FOR THE REGISTRY HAS BEEN ON ENSURING EARLY AND COMPLETE ENROLLMENT IN CLINICAL TRIALS, SO FOR CMD COMMON COLLAGEN SIX, AND THERE ARE TWO OTHER ANTICIPATED CLINICAL TRIALS THAT WILL HAPPEN LATER ON THIS YEAR THAT WE HOPE TO BE INSTRUMENTAL IN ENSURING EARLY ENROLLMENT. THIS IS JUST TO TOUCH UPON THE NATURAL HISTORY STUDY THAT CARSTEN HAS ALREADY HIGH LIGHT, A FIVE-YEAR STUDY, THE FIRST TWO YEARS WERE REALLY A PILOT PHASE TO DETERMINE THE FEASIBILITY OF OBTAINING THESE PATIENTS WITH CONGENITAL MUSCULAR DYSTROPHY AND LOOKING AT INTERRELATED RELIABILITY AND THEN TRENDING THESE PATIENTS THEN OVER AN ADDITIONAL THREE YEARS TO LOOK AT THE ANNUAL RATE OF CHANGE. YOU CAN SEE OUR RATE OF ATTRITION HAS BEEN REALLY LOW. WE'VE REGISTERED AND ENROLLED HALF LAMA2, HALF COLLAGEN SIX AND ABOUT HALF MALE, HALF FEMALE. THE IDEA FOR THIS NATURAL HISTORY STUDY CAME OUT OF AN ENMC WORKSHOP THAT I LED WITH FRANCESCA AND CARSTEN IN 2010 WHERE WE BROUGHT TOGETHER INNATIONAL PHYSICAL THERAPISTS AND NEUROLOGISTS TO IDENTIFY WHAT WE THOUGHT WOULD BE THE BEST OUTCOME MEASURES AND FOLLOWED THAT UP WITH AN OUTCOME MEASURE CONFERENCE IN LONDON. IN THE FIRST YEAR OF THE NATURAL HISTORY STUDY, WE ASSESSED REALLY ONLY THE TOP FIVE ASSESSMENTS, AND NE WERE ASSESSED MULTIPLE TIMES ON THE SAME CHILD BY DIFFERENT RATERS. WE EXPANDED IT IN THE SECOND YEAR TO ADDITIONAL ASSESSMENTS WITH A REAL FOCUS ON UPPER EXTREMITY ASSESSMENTS, AND WHAT WE LEARNED IN THIS PILOT PHASE, THE MANUSCRIPT WILL BE SUBMITTED IN THE NEXT MONTH, THAT CERTAIN MEASUREMENTS WERE NOT FEASIBLE, FOR EXAMPLE, THE MSM32 REQUIRED A REVISED SCORING SHEET BECAUSE OF THE CONTRACTURES SO THAT THE PATIENTS COULDN'T I ACTUALLY GET INTO THE STARTING POSITION REQUIRED. IN ADDITION, WE RESTRICTED OURSELVES TO CERTAIN KEY MUSCLE GROUPS AND JOINTS BECAUSE IT WAS CHALLENGING TO IDENTIFY POINTS OF REFERENCE TO GET RELIABLE READINGS ON AN ANNUAL BASIS THAT WE COULD FOLLOW. WE ALSO LEARNED THAT MORE IS NOT NECESSARILY BETTER. THERE'S A CERTAIN LEVEL OF PARTICIPANT FATIGUE AND RATER FATIGUE AND WE REALLY HAVE TO FOCUS ON WHAT IS TRULY RELEVANT, AND THEN WITH THIS NEED FOR UPPER EX-FREMENT MEASURES, THERE IS AN IN PARALLEL NATURAL HISTORY STUDY FOR THE DISTROA GLYCANNOPATHYS. WHILE WE LAUNCHED THE -- WE THEN PARTNERS WITH -- TO LAUNCH A BIOBANK IN ORDER TO SUPPORT SCIENCE. CURRENTLY THESE ARE THE TOTAL NUMBER OF SPECIMENS THAT ARE IN THEIR CATALOG THAT ARE COULD CONGENITAL MUSCLE DISEASE. YOU CAN SEE THE INCREASING NUMBER OF SPECIMENS THAT HAVE BEEN ORDERED ON AN ANNUAL BASIS, AND THE KEY SUBMITTERS WHO HAVE SUBMITTED, CARSTEN IS AT THE TOP AND WE'RE INCREDIBLY THANKFUL FOR ALL OF THESE SUBMISSIONS. YOU ALSO SEE THAT PATIENTS AND FAMILIES ARE NOW DIRECTLY SUBMITTING THEIR OWN SPECIMENS, WHICH IS FANTASTIC, BECAUSE THERE ARE SOME REAL CHALLENGES TO IF YOU ARE A CLINICIAN PUTTING IN PLACE A PROTOCOL THAT WILL ALLOW YOU TO DE-IDENTIFY SPECIMENS AND GET THEM TRANSFERRED. THOSE ARE THE TOTAL NUMBER OF SPECIMENS PER SUBTYPE, SO YOU SEE WE COVER A WIDE VARIETY. LAST YEAR WE LAUNCHED A TISSUE REPOSITORY AT THE MEDICAL COLLEGE OF WISCONSIN. MIKE LAW LER IS HEADING THAT UP TOGETHER WITH STACEY CASSETTE AND THE IDEA FOR THE TISSUE REPOSITORY IS TO REPATRIATE MUSCLE BIEPS, COLLECT FRESH MUSCLE BIOPSIES AND COLLECT AUTOPSY SPECIMENS TO REALLY FURTHER THE SCIENCE AND OUR OH UNDERSTANDING OF THE DISEASE AND TISSUE FROM INDIVIDUALS WITH THESE CONDITIONS. THE CONGENITAL MUSCULAR DYSTROPHIES AND CONGENITAL MUSCLE DISEASE COMMUNITY HAS BEEN A LITTLE SLOW TO COME AROUND TO THE IDEA OF THEIR NEED FOR ACTIVE IT ENROLLMENT AND ENGEAJMENT TO GET TO CLINICAL TRIALS SO THE CMDIR IS GOING TO BE LAUNCHING AN ADVERTISING CAMPAIGN WITH FOUR SIMPLE MESSAGES, THE IDEA IS THAT ONE NEEDS TO CONNECT TO THE COMMUNITY THROUGH SOCIAL MEDIA, NUMBER TWO, TO REGISTER IN THE CMDIR, TO IF ONE WOULD LIKE TO, CONSENT TO THE CMD BIOBANK AND TISSUE REPOSITORY, AS WELL AS TO A PROTOCOL AT THE BEGS LAB, DEPENDING ON WHAT SUBTYPE YOU HAVE, AND THEN TO ACTUALLY FOLLOW THROUGH AND DONATE TISSUE. SO THESE WILL BE FOUR SIMPLE MESSAGES THAT WILL BE RELEASED IN A STAGED FORMAT TO THIGHS COMMUNITIES. ATHESE COMMUNITIES. WE ARE EXTREMELY INTERESTED IN BETTER UNDERSTANDING THE ROLE OF PULMONARY SURVEILLANCE AND MANAGEMENT FOR OUR PARTICULAR CONDITIONS. PART OF THE REASON FOR THIS IS GIVEN THE CONGENITAL ONSET, THE CHEST WALL CONTRACTURES AND EARLY DIE FRAG MATIC INVOLVEMENT, WE REALLY FEEL THAT THERE IS A NEED TO PURSUE WHETHER EARLY INTERVENTION WITH RESPIRATORY ENGAGEMENT, CHEST WALL STRETCHING EXERCISES AND BETTER TIMING OF NIGHTTIME INVASIVE VENTILATION AND DAY TIME NONINVASIVE VENTILATION WILL MAKE A DIFFERENCE IN THE LONG RUN IN TERMS OF THE DOWNWARD DECLINE IN FORCED VITAL CAPACITY. SO WE LAUNCHED A TWO-PART SURVEY WITH FOUR PEDIATRIC PU MOA KNOLL GISTS WHOSE NAMES YOU CAN'T QUITE SEE DOWN HERE AND A WONDERFUL STATISTICIAN AT CINCINNATI CHILDREN'S, AND THIS TWO-PART STUDY WE CALL CMD BRIEF. ONE WAS A PULMONOLOGIST-FOCUSED SURVEY THAT WAS AN ONLINE SURVEY. WE RECEIVED 103 RESPONSES TO 18 QUESTIONS THAT WERE INITIALLY BETA TESTED, AND THE SECOND IS A FAMILY SURVEY THAT WAS A ONE-TIME TELL P PHONE SURVEY, 78 QUESTIONS, AND WE RECEIVED 140 INTERVIEWS THAT WERE COMPLETED. WE ARE CURRENTLY ANALYZING THE FAMILY SURVEY DATA, BUT I WANT TO SHARE WITH YOU JUST TWO QUICK SLIDES FROM THE PULMONOLOGIST SURVEY DATA CURRENTLY BEING WRITTEN UP AS A MANUSCRIPT. HE WE BROKE DOWN THE ANSWERS REGIONALLY -- >> ANNE, WE'RE GOING OVER. CAN I ASK YOU TO HURRY UP? >> NO PROBLEM. IN PEDIATRIC NEUROMUSCULAR DISEASE, SO I'M JUST GOING TO FOCUS ON ONE OF THE QUESTIONS THAT WAS ASKED, AND THIS WAS A QUESTION ASKED OF PUL PULMONOLOGISTS TO HIGHLIGHT WHICH STRATEGIES THEY USE IN THEIR PEDIATRIC NEUROMUSCULAR PATIENTS AND THEY COULD CHOOSE AS MANY AS THEY WANTED. AND WHAT YOU CAN SEE THREE MAIN POINTS, NUMBER ONE, THE USE OF NIGHTTIME VENTILATION AND NONINVASIVE VENTILATORY SUPPORT IS COMMONLY ENDORSED, WHICH IS FANTASTIC. HOWEVER, FOR MANY OF OUR CONDITIONS, THESE ARE PROGRESSIVE CONDITIONS, AND WE SHOULD SEE THE USE OF DAY TIME VENTILATORY SUPPORT AS HIGH AS NIGHTTIME VENTILATORY SUPPORT. AND THE OTHER THING IS THE USE OF SUPPLEMENTAL OXYGEN, WHICH I THINK IS A MARKER FOR NON-OPTIMAL VENTILATION AND THE NEED OF THE PATIENTS WITH THIS OXYGEN DRIVE AND HUNGER TO USE OXYGEN. HERE IS MY LAST SLIDE. THIS IS OUR CLINICAL TRIAL THAT WE LAUNCHED LAST NOVEMBER. IT IS A PR PROSPECTIVE CLINICAL TRIAL AND COLLAGEN SIX RELATED MYOPATHY TO RANDOMIZE PATIENTS TO A DAILY HYPERINU.S. FLATION THERAPY, AND IT IS BETWEEN AGES OF 5 AND 20 AND CHILDREN WITH A FORCED VITAL CAPACITY BETWEEN 30 AND 80. IT IS TAKING PLACE AT TWO SITES AND HAS BEEN SPONSORED BY NHLBI AND CURE CMD. I WANT TO JUST MY LIGHT VERY BRIEFLY SOME OF THE ENROLLMENT STATS WHICH I THINK HIGHLIGHT SOME OF THE ISSUES IN OUR GROUP OF DISEASES. SO WE'VE ENROLLED 22, 10 MET ENROLLMENT CRITERIA BUT DECLINED TO PARTICIPATE, SOME WERE EXCLUDED. WE FOUND THREE PATIENTS WHO ACTUALLY THOUGHT THEY HAD COLLAGEN SIX WHO DO NOT HAVE KOL GIN SIX WHICH IS AN ISSUE. 13 HAVE NOT EVER HAD GENETIC TESTING, AND 12 HAVE NOT HAD PFTs IN THE LAST YEAR. OUT OF THOSE 12, NINE HAVE NEVER HAD PFTs AND ONLY RECEIVED PFTs AS A RESULT OF BEING ENROLLED IN THIS TRIAL. I DON'T THINK THAT'S REALLY APPROPRIATE. SO OUR CHALLENGES, CMD IS NOT ONE DISEASE BUT MANY. THIS IS VERY CHALLENGING IN TERMS OF TRYING TO FIGURE OUT PRIORITIES AND ALLOCATE RESEARCH FUNDING DOLLARS. THE SECOND IS GENETIC TESTING REMAINS A REAL CHALLENGE FOR US. FUNDING TO CONTINUE TO SUSTAIN INFRASTRUCTURE DEVELOPED AND LEAD TO A ADDITIONAL NATURAL HISTORY STUDIES WHICH ARE REQUIRED. MOVING FORWARD BIOMARKERS, AND THEN ACCOUNTABILITY AND CLINICAL RESEARCH, WHICH HAS BEEN MISSING, IN PARTICULAR FOCUS ON PULMONARY HEALTH. SO I WANT TO STOP THERE AND APOLOGIZE FOR RUNNING OVER, AND THANK ALL OF THE PEOPLE WHO HAVE CONTRIBUTED TO MOVING THIS FORWARD. [APPLAUSE] >> THANK YOU FOR A REALLY IMPRESSIVE ARRAY OF ACTIVITIES AND A NUMBER OF GENERALIZABLE LESSONS INCLUDING CLINICAL RESEARCH -- THANK YOU FOR THAT. UNFORTUNATELY BECAUSE OF THE TIME, WE'RE NOT GOING TO HAVE TIME FOR QUESTIONS BUT I KNOW ANNE WILL BE AROUND FOR THE REST OF THE DAY, SO DURING BREAKS, ET CETERA, ET CETERA. CETERA, PLEASE TALK WITH HER MORE ABOUT SOME OF THE WONDERFUL THINGS SHE BROUGHT UP. NEXT WE'RE GOING TO GO TO GLEN NUCKOLLS WHO'S GOING TO GIVE US AN OVERVIEW OF ACTION PLAN RELATED ACTIVITIES OF THE WELLSTONE COOPERATIVE MUSCULAR DYSTROPHY CENTERS, WHICH OF COURSE ARE NIH'S CENTER OF EXCELLENCE PROGRAM IN MUSCULAR DYSTROPHY. SO GLEN, TAKE IT AWAY. >> THANK YOU. IT'S MY PLEASURE TO GIVE YOU AN UPDATE ON THE WELLSTONE MUSCULAR DYSTROPHY CENTERS PROGRAM. IN PARTICULAR, WE'RE A LITTLE OVER 10 YEARS INTO THE PROGRAM AND I THOUGHT THIS WOULD BE A GOOD OPPORTUNITY TO KIND OF TAKE A BIG PICTURE LOOK AT KEY ACCOMPLISHMENTS FROM THE WELLSTONE CENTERS PROGRAM. SO JUST A REMINDER, WELLSTONE CENTER IS OUR CENTERS OF EXCELLENCE PROGRAM IN MUSCULAR DYSTROPHY RESEARCH DESCRIBED IN THE M.D. CARE ACT. IT'S SUPPORTED BY COOPERATIVE AGREEMENTS THAT ARE MOSTLY FIVE-YEAR, I'LL GIVE YOU ONE EXAMPLE OF WHERE IT'S A FOUR-YEAR AWARD. WE HAVE A TOTAL OF SIX CENTERS THAT ARE FUNDED WITH SUPPORT FROM FOUR DIFFERENT NIH INSTITUTES, AND I KNOW THAT SEVERAL OF THE CENTERS ARE ALSO GETTING SUPPORT FROM ADVOCACY GROUPS THAT ARE REPRESENTED HERE AT THE COMMITTEE. JOHN WILL BE TELLING YOU KIND OF OVERALL PICTURE OF MUSCULAR DYSTROPHY RESEARCH AND NIH SUPPORT. WELLSTONE CENTERS REPRESENT ABOUT 12% OF OUR TOTAL -- THERE'S REALLY SOME IMPRESSIVE ACCOMPLISHMENTS COMING OUT OF THESE CENTERS. THIS SLIDE SHOWS THE HISTORY OF AWARDS MOUNTAI IN THE WELLSTONE PROGRAM. EACH OF THE BARS REPRESENTS A GRANT TO ONE OF THE CENTERS, AND THE COLOR INDICATES WHICH OF THE NIH INSTITUTES IS SUPPORTING THAT CENTER. YOU CAN SEE WITH HAVE PERIODIC EXE TIG OF WELLSTONE CENTERS TO ALLOW FOR EITHER RENEWALS OR FOR PEOPLE TO COMPETE FOR NEW CENTERS. WE'VE HAD SOME TURNOVER IN THE CENTERS, AND I THINK THAT JUST SPEAKS TO HOW THERE'S VERY KEEN COMPETITION AND A LOT OF INTEREST FROM OUTSTANDING INVESTIGATORS TO COMPETE FOR THIS PROGRAM, SO LAST YEAR AT THE MDCC MEETING, I TOLD YOU ABOUT A COMPETITION THAT WE HAD IN 2013 THAT RESULTED IN THE RENEWAL OF THE ROCHESTER CENTER AND A CENTER AT BOSTON UMASS, BUT AT THAT TIME, THE REVIEWERS WERE NOT SUFFICIENTLY ENTHUSIASTIC ABOUT THE OTHER APPLICATIONS TO WARRANT A THIRD AWARD IN THAT COMPETITION, SO WE DECIDED TO ALLOW RECOMPETITION, ALLOW PEOPLE TO COME BACK WITH NEW SUBMISSIONS OR APPLICATION. WE'VE REVIEWED THOSE AND ARE HAPPY TO ANNOUNCE WE'LL SOON BEING MAIGIN MAKING AN AWARD, WE'RE JUST WAITING FOR THEIR IRB APPROVAL BUT THAT WILL BE THE THIRD CENTER P IN THAT COHORT AND IT WILL BE A FOUR-YEAR AWARD RATHER THAN A FIVE-YEAR TO BRING IT BACK INTO SYNC WITH THE OTHER CENTERS IN THAT COHORT. SO THIS SLIDE SHOWS THE CURRENT THEMES OF RESEARCH IN THE SIX CURRENTLY FUNDED WELLSTONE CENTERS, SO THERE'S A CENTER FOCUSING ON FSHD, THERE'S A CENTER FOCUSING ON MYOTONGUE MYOTONIC -- WE FOCUS ON DUCHENNE MUSCULAR DYSTROPHY AND THEN THE IOWA CENTER FOCUSES ON DISTROA GLYCANNOPATHYS, PRIMARILY CON CONGENITAL MUSCULAR DYSTROPHIES -- SO THE PEN CENTER FOCUS ON FEATURES COMMON TO A VARIETY OF DIFFERENT TYPES OF MUSCULAR DYSTROPHY, INFLAMMATION, FIBROSIS AND FAT ACCUMULATION, AND THEN THE NEW CENTER AT SEATTLE WILL TAKE ADVANTAGE OF JEFF CHAMBERLAIN AS P EXPERTISE IN GENE THERAPY, FOCUSING ON DUCHENNE, BUT ALSO NOW ON FSHD AND -- LOOKING AT BIOMARKERS AND I UNE MECHANISMS. SO WHEN WE AT NIH HAVE BEEN SELECTING WELLSTONE CENTERS TO SUPPORT, WE REALLY DEPEND ON PEER REVIEW, AND WE'VE BEEN FORTUNATE TO GET THIS BROAD DISTRIBUTION OF DIFFERENT TYPES OF DYSTROPHY COVERED IN THE CENTERS PROGRAM JUST FROM PICKING THE TOP SCORES. SO THAT'S WORKED OUT RILEY WELL, AND I THINK THERE'S A LOT OF ADVANTAGE TO HAVE THE CENTERS PROGRAM INVOLVE VARIOUS FORMS OF MUSCULAR DYSTROPHY. WE DO A LOT OF THINGS TO TRY AND PROMOTE COMMUNICATION AND COORDINATION AMONG THE WELLSTONE CENTERS, AN ANNUAL MEETING OF THE CENTERS, LOTS OF COMMUNICATION BETWEEN THE DIFFERENT INVESTIGATORS, AND THIS ALLOWS FOR ADVANCES IN ONE FORM OF DYSTROPHY TO HOPEFULLY BE QUICKLY TRANSLATED TO OTHER FORMS WHERE IT'S APPLICABLE SO THAT ALL OF BOATS RISE TOGETHER. SO THIS MAP SHOWS WHERE THE PRIMARY SITES OF THE CURRENT WELLSTONE CENTERS ARE AND THE SATELLITE SITES FOR EACH OF THOSE CENTERS. THE LINES INDICATE COLLABORATIONS AM TH AMONG THE CENTERS. WHAT WE'VE SEEN AS THE PROGRAM HAS EVOLVED IS MORE INVESTIGATORS THAT RI ARE INVOLVED OR SUPPORTED BY MORE THAN ONE WELLSTONE CENTER. WE THINK THIS IS A GOOD THING, IT HELPS TO CROSS LINK THE CENTERS, IT LEADS TO BETTER COMMUNICATION AND COLLABORATION AND COORDINATION AMONG THE CENTERS. SO IN PREVIOUS YEARS, I'VE PRET PRETTED PROGRESS ON ALL OF THE DIFFERENT ASPECTS OF THE CENTER, SO CENTERS HAVE TO HAVE THEIR RESEARCH PROJECT, THEY HAVE A SHARED CORE FACILITY, PROVIDING SERVICES OR RESOURCES TO THE REST OF THE MUSCULAR DYSTROPHY COMMUNITY. THEY ALSO HAVE A CORE FACILITY THAT'S ORIENTED TOWARDS CAREER DEVELOPMENT AND PATIENT OUTREACH, AND IN PREVIOUS YEARS AT THE COMMITTEE, I'VE TOLD YOU ABOUT WHAT THE CENTERS HAVE BEEN DOING ON EACH OF THOSE FRONTS, AS WELL AS SOME SCIENTIFIC ADVANCES. SO TODAY WHAT I'D LIKE TO DO IS SPEND OF REST OF MY TALK FOCUSING ON KIND OF A BIG PICTURE VIEW OF WHAT HAS BEEN THE IMPACT OF THE WELLSTONE CENTERS, WHAT ARE THE KEY DISCOVERIES, AND WHAT ARE THE NEW THEORETICAL MODELS THAT HAVE ARISEN OUT OF RESEARCH SUPPORTED BY THE WELLSTONE CENTERS. SO WHAT I'LL BE TELLING YOU ABOUT IS SOME EXAMPLES OF CURRENT CLINICAL TRIALS THAT YOU CAN TRACE BACK KEY DISCOVERIES FROM THE WELLSTONE CENTERS THAT HAVE MADE THOSE TRIALS POSSIBLE AND ALSO GIVE YOU EXAMPLES OF NEW EVIDENCE-BASED CONCEPTUAL MODELS THAT HAVE BEEN SUPPORTED THROUGH DISCOVERIES AT WELLSTONE CENTERS, OF COURSE ALSO DISCOVERIES FROM OTHER TYPES OF GRANTS. SO THIS SLIDE SHOWS THE HISTORY OF THE EVOLVING STORY OF NITRIC OXIDE SIGNALING IN DYSTROPHIC MUSCLE. KEVIN CAMPBELL AND YVONNE DEMONSTRATED THE EFFECTS OF PHOSPHODIAS TRACE INHIBITORS ON ANIMAL MODELS OF MUSCULAR DYSTROPHY, HOW IT CAN RESTORE NORMAL NITRIC OXIDE SIGNALING AND ELIMINATE OR REDUCE THE IMPACT OF POST EXERCISE FATIGUE ON THESE ANIMALS. SO THAT WAS A KEY DISCOVERY FROM WELLSTONE CENTER, AND THEN LATER ON, LEE SWEENEY DID SOME TESTING IN DOGS OF TWO OF THESE INHIBITORS. THAT LED TO A SMALL CLINICAL TRIAL THAT WAS DONE BU DONE IN BECKER PATIENTS, THEN RON VICTOR CAME TO NIAMS FOR SUPPORT OF A CLINICAL TRIAL PLANNING GRANT, AND IN THE PROCESS OF CONDUCTING THAT CLINICAL TRIAL PLANNING, HE WAS TALKING WITH ELI LILLY TO GET THE DRUG USED IN THE TRIAL AND ELI LILLY HAS DECIDED TO GO AHEAD AND SUPPORT THIS TRIAL. SO -- IS A VERY LARGE TRIAL, 306 BOYS WITH DUCHENNE, 52 CLINICAL SITES IN 13 COUNTRIES, AND IT'S RECREWING CURRENTLY. AND YOU CAN SEE HOW THIS HAS BEEN A REALLY RAPID PROGRESS LEADING FROM THIS IMPORTANT DISCOVERY FROM THE IOWA WELLSTONE CENTER. SO THERE'S A LOT OF EXCITEMENT IN THE FIELD ABOUT MORPHOLY KNOW BASED -- TRIALS FROM -- THERAPEUTICS THAT HAVE GENERATED A LOT OF INTEREST IN THIS AREA. I'D LIKE TO POINT OUT THAT ONE OF THE KEY PIECES OF INFORMATION THAT HAS LED TO THE RATIONALE FOR THOSE CLINICAL TRIALS CAME FROM ERIC HOFFMAN'S WELLSTONE CENTER AT CHILDREN'S NATIONAL MEDICAL CENTER, WHERE HE PUBLISHED A PAPER DEMONSTRATING SYSTEMIC DELIVERY OF THESE MORPHOLINO -- OLIGOS COULD RESCUE -- EXPRESSION AND IMPROVE FUNCTION IN A DOG MODEL FOR DUCHENNE MUSCULAR DYSTROPHY. YOU MAY HAVE SEEN ERIC'S VIDEO THAT HAS BEEN SHOWN OF THE TREATED DOG HAPPILY RUNNING DOWN THE CORRIDOR. IT WAS SHOWN ON OUR LOCAL ABC NEWS AFFILIATE, AND THAT WAS SUPPORTED WITH FUNDS FROM THE WELLSTONE CENTER. ONE OF THE ORIGINAL WELLSTONE CENTERS WAS FOCUSED ON GENE THERAPY TO JOE GLORIOSO AT THE UNIVERSITY OF PITTSBURGH. IT WAS A SUBCONTRACT FROM THAT WELLSTONE CENTER TO JERRY MAN DELL TO CONDUCT A CLINICAL TRIAL OF AAV DELIVERY OF ALPHA SAR COGLYCAN FOR LIMB GIRDLE MUSCULAR DYSTROPHY PATIENT. THAT WAS A DIRECT MUSCLE INJECTION CLINICAL TRIAL, AND IT DEMONSTRATED THAT THE DELIVERY WAS SAFE AND EFFECTIVE, AND THAT THE ALPHA SAR COGLYCAN FROM THAT DELIVERY WAS EXPRESSED IN TWO OF THE THREE PATIENTS FOR AT LEAST SIX MONTHS. SO THAT WAS A KEY PIECE OF INFORMATION THAT LED TO THE NEW TRIAL THAT'S JUST RECRUITING CURRENTLY WITH SUPPORT FROM NIAMS AND NINDS, AND HE'S NOW DOING AAV DELIVERY OF ALPHA SAR COGLYCAN THROUGH A VASCULAR DELIVERY APPROACH IN THE LOWER LIMBS OF LIMB GIRDLE MUSCULAR DYSTROPHY PATIENTS. AND THIS VASCULAR APPROACH IF SUCCESSFUL COULD LEAD TO FUNCTIONAL IMPROVEMENT IN LOWER LIMBS OF PATIENTS INVOLVED IN THE TRIAL, AND THIS COULD ALSO BE A NEW MODEL OF DELIVERY OF GENE DELIVERY OF THERAPEUTIC GENES TO THE LOWER LYMPH PATIENTS FOR A WIDE RANGE OF MUSCLE DISORDERS. SO THERE HAVE ALSO BEEN IMPORTANT PUBLICATIONS THAT HAVE COME OUT OF WELLSTONE CENTERS THAT HAVE CONTRIBUTED TO THE KNOWLEDGE IN THE FIELD AND THAT BUILT ON NEW CONCEPTUAL MODELS. THOSE NEW CONCEPTUAL MODELS THEN FUEL THERAPY DISCOVERY, BETTER UNDERSTANDING OF MECHANISMS OF DISEASE, AND VARIOUS ADVANCES IN THE FIELD. I'D LIKE TO JUST WALK YOU THROUGH A COUPLE OF EXAMPLES OF THAT. SO AS CARSTEN ALREADY EXPLAINED, THAT THR IS A VERY IMPORTANT ROLE FOR GLIE COST LAITION OF ALPHA DISTROA GLYCAN. THROUGH THE IOWA WELLSTONE CENTER, KEVIN CAMPBELL'S CENTER, THEY'VE PUBLISHED A SERIES OF EXTREMELY HIGH IMPACT PUBLICATIONS ADVANCING AND UNDERSTANDING OF HOW THE MECHANISMS OF -- CONTRIBUTES TO CONGENITAL MUSCULAR DYSTROPHIES, LIMB GIRDLE MUSCULAR DYSTROPHIES. IN PARTICULAR, THEY'VE BEEN FOCUSING ON THIS ENZYME CALLED LARGE AND ITS ROLE IN A VERY UNUSUAL POST TRANSLATIONAL MODIFICATION OF ALPHA DISTRA GLYCAN. SO IT'S ALSO IMPORTANT TO CONSIDER THAT LARGE AND ALPHA DISTROA GLYCAN ARE EXPRESSED IN A VARIETY OF DIFFERENT CELL TYPES BEYOND MUSCLE, AND THIS WORK MAY IMPACT ON OTHER FIELDS. SO FOR EXAMPLE, LAST YEAR KEVIN CAMPBELL WAS COLLABORATING WITH ANOTHER GROUP TO DEMONSTRATE THE IMPORTANCE OF LARGE AND ALPHA DISTROA GLYCAN GLIE COST LAITION IN PROSTATE CANCER METASTASIS. SO THIS IS AN EXAMPLE OF HOW THE CUTTING EDGE RESEARCH IN THE MUSCULAR DYSTROPHY FIELD CAN REALLY HAVE AN IMPACT ON OTHER DISEASE AREAS. THERE'S ALSO A REALLY EXCITING STORY THAT'S EMERGING ON GENETIC MODIFIERS OF DUCHENNE MUSCULAR DYSTROPHY AND OTHER FORMS OF MUSCULAR DYSTROPHY, AND THIS IS LARGELY SUPPORTED THROUGH THE WELLSTONE CENTERS. SO IT'S BETH MCNALLY AT CHICAGO, SHE'S THE CO-DIRECTOR OF PENN WELLSTONE CENTER IN COLLABORATION WITH KEVIN FLANAGAN AT THE NATIONWIDE CHILDREN'S WELLSTONE CENTER, BUT ALSO WORK FROM LISSA SPENCER AND ERIC KAUFMAN HAVE LED TO THE IDENTIFICATION OF SEVERAL GENES THAT AFFECT THE EITHER SEVERITY OF THE MUSCULAR DYSTROPHY OR THE RATE OF PROGRESSION IN CONNECTION WITH MUTATIONS IN DYSTROPHIN. SO THESE GENES ARE NOW -- AND THE ANNEX INSIX STORY IS REALLY HOT OR THE PRESSES. BETH MA NALY'S PAPER ON ANIMAL ANALYSIS OF ANNEXIN 6 IS JUST BEING RELEASED TODAY, SO A LITTLE MORE WORK HAS BEEN DONE ON -- AND LTBP4 CORRELATING ITS FUNCTION NOT ONLY IN ANIMAL MODELS FOR MUSCULAR DYSTROPHY BUT ALSO IN PATIENT COHORTS. SO EACH OF THESE GENES HAS ONE VARIANT THAT LEADS TO A MORE SEVERE FORM OR ONE VARIANT THAT'S PROTECTIVE OF MUSCULAR DYSTROPHY IN CONNECTION, OF COURSE, WITH DYSTROPHIN MUTATIONS. THERE'S GROWING EVIDENCE OF THE FUNCTIONS OF THESE VARIANTS, HOW IT AFFECTS THE PROTEIN AND HOW THAT LEADS TO EVENTUAL PHENOTYPES. SO FAR EXAMPLE, BETH MCNALLY AND KEVIN FLANAGAN HAVE PUBLISHED A PAPER DEMONSTRATING THAT THE VTTT HAPLOTYPE OF LTB P4 IS ASSOCIATED WITH A QUICKER TIME TO WHEELCHAIR OF PATIENTS AND REDUCED RESPONSE TO STEROIDS, WHEREAS THE IAAM HAPLOTYPE IS PROTECTIVE. SO TEASE GENETIC MODIFIERS COULD BECOME PROGNOSTIC BIOMARKERS TO HELP UNDERSTAND FUTURE COURSE OF DISEASE OF PATIENTS. THEY COULD ALSO BE USED TO HELP STRATIFY PATIENTS IN CLINICAL TRIALS, THEY COULD POTENTIALLY BE DRUGGABLE PARGTS TARGETS, AND IT'S ALSO IMPORTANT TO CONSIDER HOW THEY MAY ALSO BE IMPORTANT MODIFIERS OF DISEASES BEYOND THE MUSCULAR DYSTROPHIES. SO FOR EXAMPLE, TGF BETA IS INVOLVED IN FIBROSIS AND INFLAMMATION IN A WIDE RANGE OF DISEASES, AND IT'S POSSIBLE THAT THESE VARIANTS ARE ALSO AFFECTING DISEASE PROGRESSION THERE. SO THERE'S AN EXAMPLE OF WHY IT'S REALLY IMPORTANT TO CONDUCT THESE TYPES OF STUDIES IN A CENTER ENVIRONMENT. BECAUSE THE DISCOVERIES GET IMPLEMENTED INTO OTHER INVESTIGATORS' STUDIES VERY QUICKLY WHEN THEY'RE ALL PARTICIPATING IN THE SAME CENTER. SO FOR EXAMPLE, BETH MCNALLY, GLEN WALTER -- ARE ALL MEMBERS OF THE PENN WELLSTONE CENTER. CHRISTA AND GLEN ARE CONDUCTING A NATURAL HISTORY STUDY OF MAGNETIC RESONANCE IMAGING AND FUNCTIONAL OUT COME MEASURES IN DUCHENNE CALLED THE IMAGING DMD, AND THEY'VE ALREADY INCORPORATED GENETIC TESTING OF OSTEOUPON TIN AND LTBP4 INTO THAT NATURAL HIS FRI STUDY. SO THE LAST EXAMPLE I WANTED TO GIVE YOU OF SIGNIFICANT ADVANCES THAT HAVE COME 40 WELLSTONE CENTERS IS OF COURSE THE ROCHESTER WELLSTONE CENTER, WHICH IS THE LOCKES LONGEST CONTINUALLY SUPPORTED WELLSTONE CENTER. I'M SURE CHAD WILL BE TELLING YOU MORE LATER. THERE'S REALLY BEEN RAPID ADVANCE IN UNDERSTANDING NOT ONLY THE MECHANISMS OF MYOTON. IC DYSTROPHY, HOW THE TOXIC RNA CONTRIBUTES TO DISEASE PATHOPHYSIOLOGY, BUT ALSO TAKING THAT KNOWLEDGE AND DEVELOPING POTENTIAL THERAPEUTICS. THAT CAN RESTORE MORAL SPLICING EVENTS. SO NOT ALL OF THE WORK IN THIS AREA HAS BEEN DONE THROUGH THE WELLSTONE CENTER, BUT THE ROCHESTER CENTER HAS REALLY HAD SUPPORT FOR CHARLES THORTON EARLY COLLABORATIONS WITH MARI SWANSON AND LONG-STANDING INTERACTIONS WITH THE OTHER PEOPLE AT ROCHESTER, DICK MOXLEY AND OTHER INVESTIGATORS, THAT HAS REALLY CONTRIBUTED QUITE SIGNIFICANTLY TO THIS RAPID ADVANCE OF UNDERSTANDING NOT ONLY OF THE MECHANISMS OF DISEASE, BUT ALSO OF THERAPY DEVELOPMENT. AND I THINK THAT THIS IS AN EXAMPLE OF WHY IT'S IMPORTANT TO SUPPORT THESE TYPES OF STUDIES THROUGH A CENTER ENVIRONMENT, AND HOW THE RETURN ON INVESTMENT CAN BE GREATER THAN WHAT MIGHT BE EXPECTED THROUGH INVESTMENT AND INDIVIDUAL RO1s. THE ROCHESTER CENTER BY FOCUSING ON MYOTONIC DYSTROPHY, BY SUPPORTING INTERDISCIPLINARY COLLABORATION, DISEASE MECHANISMS, THERAPY DEVELOPMENT, CLINICAL STUDIES, EVEN CLINICAL TRIALS WITH THE TRIAL THAT THEY DID IN -- HAS REALLY LED TO A FOCUSED EFFORT, IT'S ATTRACTED INDUSTRY INVOLV INVOLVEMENT, IT'S NOW WORKING WITH THEM TO DEVELOP THERAPEUTICS, IT'S RESULTED IN RESOURCES THAT THEY SHARE WITH THE REST OF THE COMMUNITY, AND IT'S LED TO OUTSTANDING TRAINING AND CAREER DEVELOPMENT FOR THE NEXT GENERATION OF MUSCULAR DYSTROPHY INVESTIGATORS AND LATER WE'LL BE HEARING FROM CHAD, WHO'S A PERFECT EXAMPLE OF THE PRODUCT OF THE ENVIRONMENT OF THE WELLSTONE CENTER THERE AT ROCHESTER. SO IN SUMMARY, WE FIND THAT THE WELLSTONE CENTERS ARE REALLY CONDUCTING EXTREMELY HIGH QUALITY RESEARCH, VERY HIGH IMPACT RESEARCH IN A WIDE RANGE OF MUSCULAR DYSTROPHIES. SOME OF THE PRODUCT THAT THEY'VE GENERATED IS PROBABLY MORE THAN YOU WOULD EXPECT FROM AN EQUIVALENT INVESTMENT IN RO1 GRANTS, CERTAINLY VERY HIGH IMPACT PUBLICATIONS, AND A LOT OF ACCOMPLISHMENTS GIVEN THE 12% OF OUR OVERALL FUNDING THAT'S GOING TO THE CENTERS PROGRAM. THERE ARE QUITE A NUMBER OF ONGOING CLINICAL TRIALS THAT YOU CAN TRACE BACK TO KEY DISCOVERIES FROM WELLSTONE CENTERS. AND MANY OF THE HIGH IMPACT PUBLICATIONS COMING FROM THE WELLSTONE CENTERS HAVE CREATED THESE NEW CONCEPTUAL MODELS ALONG WITH OTHER RESEARCHERS IN THE FIELD, AND THAT'S HAVING AN IMPACT ON THERAPY DEVELOPMENT FOR THE MUSCULAR DYSTROPHIES, AND ALSO GOING BEYOND THE MUSCULAR DYSTROPHIES TO IMPACT ON OTHER DISEASE AREAS AND KNOWLEDGE IN OTHER FIELDS. AND LASTLY, I'D JUST LIKE TO SAY HOW IT'S A PLEASURE TOIPT ACT WITH THE OTHER PROGRAM STAFF THAT ARE INVOLVED IN THIS PROGRAM. IT'S A REAL TEAM EFFORT INVOLVING AMANDA BOYS, JOHN CULTMAN -- AND OTHERS. THANK YOU. [APPLAUSE] >> THANK YOU, GLEN. I THINK WE HAVE TIME FOR ONE QUESTION, ESPECIALLY IF IT'S NOT DR. KATZ. >> I'LL ALWAYS TAKE QUESTIONS. >> MANY OF THE INVESTIGATORS WHO ARE CURRENTLY IN WELLSTONES ACTUALLY ORIGINALLY GOT THEIR START WITH STANDARD RO1 FUNDING. >> THAT'S CERTAINLY TRUE. GLAND THEY CONTINUE TAND THEY CONTINUE TO HAVE INDIVIDUAL RO16789s. >RO1s. >> THANK YOU INVESTMENT OUR NEXT SPEAKER IS MARIELENA MCGUIRE. WE HAVE NUMBER OF PEOPLE AROUND THE ROOM WHO SERVE ON THE INTEGRATION PANEL FOR THIS RESEARCH PROGRAM, AND MARIELENA WILL ADDRESS SOME OF THE RANGE OF DOD ACTIVITIES UNDERTAKEN DURING THE TENURE OF THE ACTION PLAN. >> OKAY. HOPEFULLY EVERYONE CAN HEAR ME OKAY? OKAY. AND I KNOW I STAND BETWEEN YOU AND A BREAK, SO I WILL MOVE QUICKLY, AND PROBABLY SOME SLIDES BECAUSE FROM OUR PREVIOUS SPEAKERS, I THINK GLEN PARTICULARLY HAS SORT OF SET UP A LOT OF -- OR LED INTO A LOT OF THE THINGS I'LL BE TALKING ABOUT TODAY. SO WHEN JOHN PORTER SPOKE TO ME AND COLONEL SALAZAR ABOUT WHAT HE WOULD LIKE PRETTE PRESENTED AT TODAY'S MEETING WAS TO REALLY KIND OF GIVE A SURVEY OR SUMMARY OF WHAT THE MUSCULAR DYSTROPHY RESEARCH PROGRAMS HAVE BEEN AT CDMRP. THESE RESEARCH PROGRAMS HAVE SORT OF CHANGED OVER TIME SO I WANT TO GIVE YOU AN OVERVIEW OF HOW THAT'S WORKED. SO IN CASE ANYONE IS NOT FAMILIAR WITH THE CDMRP, THE CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS, IT'S A PART -- IT'S UNDER THE U.S. ARMY'S MEDICAL RESEARCH AND -- COMMAND WHICH AS YOU CAN FOLLOW ON THE DIAGRAMS HOW IT CONNECTS WITH THE DEPARTMENT OF THE ARMY AND FINALLY THE DEPARTMENT OF DEFENSE. MRMC IS THE COMMAND THAT OVERSEE OVERSEES MAD CALORIE SECH, DEVELOPMENT, AS WELL AS ACQUISITIONS IN MEDICAL LOGISTICS FOR THE ARMY. AND AS I SAID, THE PROGRAMS ON MUSCULAR DYSTROPHIES THAT CDMRP HAS MANAGED OVER THE YEARS HAS EVOLVED, PROGRAM FEATURES, OUR OFFICE MANAGES FUNDS THAT ARE DIRECTED BY CONGRESS FOR SPECIFIC DISEASES OR CONDITIONS, SO FORTH WHERE THE MONEY IS COMING FROM, ITS INTENT, SO FORTH, AND WE ARE USING A TWO TIER REVIEW PROCESS AND YOU'LL HEAR MORE ABOUT THAT AS I GO ALONG. THESE FUNDS WERE INSTITUTIONALLY DIRECTED. SO WE SET UP WHAT WE CALL OUR INSTITUTIONALLY BASED RESEARCH PROGRAMS, MEANING THAT THESE FUNDS WERE DIRECTED TO SPECIFIC INSTITUTIONS, AND YOU CAN SEE THERE ARE THREE LISTED HERE THAT WERE PARTICULARLY FOR THE MUSCULAR DYSTROPHIES, ONE AT THE UNIVERSITY OF PITTSBURGH WITH OUR, THEN WE HAD ANOTHER ONE TO CHILDREN'S MEDICAL CENTER DOWNTOWN, WHERE ERIC KAUFMAN WHO IS THE LEAD DIRECTOR OF THAT PROGRAM, AND THEN WE RECEIVED A, TO THE JACKSON LABORATORIES, DR. GREGORY COX IS THE PI LEADING THAT EFFORT. WE AFFECTIONALLY CALL THEM IBRPs. THEY WERE REALLY MORE SORT OF LIKE A PROGRAM PROJECT TYPE GRANT, WHERE IT DIDN'T FUND JUST ONE RESEARCH PROJECT BUT SEVERAL RESEARCH PROJECTS, NOT ALWAYS AT THAT SAME INSTITUTION. THE CMC IBRP Ps FUNDED MANY INVESTIGATORS AND PROJECTS OUT SIDE OF CHILDREN'S. AS WELL AS RESEARCH AT THE INSTITUTION ITSELF. SO HOW DO WE SORT OF GO ABOUT MANAGING THESE PROJECTS OR WHAT WAS FUNDED. THAT REALLY CAME DOWN TO FIGURING OUT WHAT WAS THE INTENT OF CONGRESS WHEN THEY PROVIDED THESE YEARLY APPROPRIATIONS. AND SO THE WAY WE WOULD GO ABOUT THAT IS ALL THE INSTITUTIONS WILL SUBMIT A WHITE PAPER DESCRIBING WHAT IS GOING TO BE THE SCOPE OF THE RESEARCH. WE FIND WHAT THAT IS AND THEN WE WORK WITH THE LEAD INVESTIGATOR, FOR EXAMPLE, ERIC KAUFMAN OR JOHNNY -- TO WORK OUT WHAT SORTS OF RESEARCH PROJECTS THEY WOULD LIKE TO FUND WITH THAT SPECIFIC APPROPRIATION. SO THEY SUBMIT A PREAPPLICATION, WORK WITH THE INVESTIGATOR ON THE PROJECT TO MAKE SURE THEY REALLY FELL INTO THE SCOPE OF WHAT CONGRESS HAD APPROPRIATED FUNDS FOR, THEN MEET THE NEEDS, GO AHEAD AND SUBMIT YOUR FORMAL APPLICATION. ONCE WE RECEIVE THE APPLICATIONS, THEY WERE SENT OUT FOR EXTERNAL PEER REVIEW. I KNOW OVER THE YEARS, I THINK EVEN ONE TIME, JOHN, YOU EVEN SAT ON WITH YOU OF THE PEER REVIEWS FOR ONE OF THESE PROJECTS. YOU MAY OR MAY NOT REMEMBER. ONCE WE RECEIVED THE EXTERNAL PEER REVIEW, WE THEN -- IN HOUSE IN OUR OFFICE, WOULD DO A SECOND LEVEL REVIEW WHERE WE WOULD LOOK AT STRENGTHS. WEAKNESSES OF THE APPLICATION, WORK WITH THE P.I. TO WORK WITH THE WEAKNESSES THAT HAVE BEEN IDENTIFIED TO REALLY DEVELOP, MAKE SURE WE HAD A VERY STRONG SCIENTIFICALLY STRONG PROPOSAL, AND THEN WE'D WORK TO GO AHEAD AND FUND THOSE. AND SO OVER THE PAST EIGHT YEARS OR SO, THERE ARE MANY PROJECTS THAT WERE FUNDED THROUGH THIS -- THESE MECHANISMS THROUGH FISCAL YEAR 2010, AND THEN THINGS CHANGED, AND WE RECEIVED ACTUALLY -- GO BACK TO -- THE DIRECTED APPROPRIATION, THIS TIME IT WAS SPECIFICALLY DIRECTED FOR DUCHENNE'S MUSCULAR DYSTROPHY, BUT NOW WASN'T DIRECTED TO ANY SPECIFIC INSTITUTION. -- MOST OF THE PROGRAMS WE HAVE AT CDMRP WHERE WE MANAGE IT AND WE WERE ALLOWED TO CONDUCT MORE OF A STAKEHOLDERS' APPROACH AND REVIEW OF THE FIELD, AND FOLLOW OUR SETUP WHERE WE HAVE AN ADVISORY BOARD, WHAT WE CALL OUR INTEGRATION PANEL, TO DIRECT THE RESEARCH IN WHAT TYPES OF PROJECTS, FOCUS AREAS, SO FORTH, THAT THE RESEARCH PROGRAM SHOULD FOCUS ON FOR THE YEAR. SO THIS NEW INVOLVEMENT OF THE PROGRAM ALLOWS EACH OF THE PROGRAMS THROUGH THEIR INTEGRATION PANEL, THEIR ADVISORY BOARD, TO LOOK AT WHERE THE FIELD IS TODAY FOR OUR -- THE NEW PROGRAM, OUR -- MUSCULAR DYSTROPHY RESEARCH PROGRAM, WE JUST ACTUALLY HAD OUR MEETING EARLIER IN MARCH, WE'RE GOING TO LOOK AT WHERE THE FIELD IS TODAY, THE APPLICATIONS THAT WE'VE RECEIVED IN THE LAST YEAR AND WHAT WE DECIDE TO FUND AND WHAT ARE THE INTERESTS OF THE PROGRAM NOW FOR THE COMING YEAR. WE WANT TO CHANGE WHAT WE ARE FOCUSING ON, THE VISION, THE MISSION OF THE PROGRAM, WHAT IS NEEDED RIGHT NOW. ANOTHER KEY FEATURE FOR OUR PROGRAM IS THE INVOLVEMENT OF CONSUMER ADVOCATES. THE ADVOCACY COMMUNITY. THEY ARE INVOLVED NOT ONLY IN THE FIRST STEPS WHEN WE GO TO CONGRESS AND EXPLAIN THE NEED FOR THESE FUNDS, BUT ALSO IN THE REVIEW PROCESS AS PART OF OUR INTEGRATION PANEL THAT IS RECOMMENDING WHAT APPLICATIONS TO FUND, WHERE THE RESEARCH NEEDS TO GO FOR THE COMING YEARS. SO THOSE ARE SOME OF THE MANY KEY FEATURES OF CDMRP RESEARCH PROGRAM. SO AGAIN, WITH THE INTEGRATION PANEL, NOT ONLY IS IT MAKING THE RECOMMENDATIONS OF WHAT THE PROGRAM SHOULD FOCUS ON, BUT HOW WE SHOULD INVEST THOSE FUNDS, AS WELL AS DOING THE UPPER LEVEL PROGRAMMATIC REVIEW OF THE APPLICATIONS THAT CAME IN. THE FIRST PEER REVIEW IS THE TECHNICAL REVIEW, PROGRAMMATIC REVIEW, KNOW THE SCORES, HOW THEY REVIEWED SCIENTIFICALLY, NOW HOW WELL DO THESE PROJECTS ADDRESS WHAT'S IMMEDIATELY NEEDED IN THE FIELD AND OUR EXISTING PORTFOLIO, WHAT WE'VE ALREADY INVESTED IN, AND MAKES RECOMMENDATIONS ON WHAT SHOULD BE FUNDED. SO THIS IS OUR CURRENT INTEGRATION PANEL. SEVERAL OF THE FOLKS SITTING AT THE TABLE TODAY ARE PART OF THAT INTEGRATION PANEL, AS WELL AS SOME INVESTIGATORS OUTSIDE, INCLUDING REPRESENTATION FROM INDUSTRY. SO WHERE THE INTEGRATION PANEL IS INVOLVED TO PRESCREENING THE APPLICATIONS THAT COME IN TO PRE-OPPREAPPS TO DECIDE WHICH PROJECTS ARE WE MOST INTERESTED IN, SO INSTEAD OF HAVING INVESTIGATORS SUBMIT A FULL APPLICATION AND THE REALITY IS OF ALL THESE APPLICATIONS, THERE'S ONLY ABOUT 40% OF THEM REALLY INTERESTED AND MEETING SORT OF THE FOCUS, AREAS OF INTEREST FOR THE PROGRAM THIS YEAR, THAT HAVE THEM SUBMIT A SHORT TWO, THREE PAGE PREAPPLICATION, SCREEN THOSE AND INVITE WHAT WE ARE MOST INTERESTED IN, AND HAVE THOSE CONTINUE ON FOR THE FULL APPLICATION RECEIVED AND REVIEWS. SO HERE IS OUR CURRENT PROGRAM, THE DMRDP, OR DMDRP. THE NUMBER -- THE AMOUNT OF MONEY THE PROGRAM HAS RECEIVED OVER THE PAST 40 YEARS FROM FY11 TO '13, WE RECEIVED $10.4 MILLION AND FOR FY14, WE HAVE 3.2 AVAILABLE TO INVEST. THIS PROGRAM, FROM OUR INITIAL STAKEHOLDERS MEETING AND OVER THE YEARS, HAS FOCUSED PRIMARILY ON TRANSLATIONAL RESEARCH, PARTICULARLY FOCUSING ON THEIR PEW IT TICSTHERAPEUTICS AND HELPING TO MOV E THESE THERAPEUTICS FROM THE BENCH IN THE LABORATORY, THERE'S LATER STAGES OF TRANSLATIONAL WORK AND MOVING IT TO THE POINT WHERE IT'S GETTING INTO THE CLINIC. AND OF COURSE ON OTHER TYPES OF PROJECTS, FOR EXAMPLE, BIOMARKERS, BIG NEED FOR IDENTIFYING CLINICAL BIOMARKERS THAT CAN HELP IN THE EVALUATION OF HOW GOOD THE THEIR PEW IT TICKS ARE AS WELL AS MONITORING THE DISEASE PROGRESSION, ITS TREATMENT AND SO FORTH. THE PROGRAM HAS USED PRIMARILY TWO TYPES OF RESEARCH MECHANISMS, ONE IS A STANDARD INVESTIGATOR INITIATED RESEARCH AWARD. AGAIN THE PRIMARY FOCUS AND GUIDANCE TO THESE INVESTIGATORS IS ON LATER STAGE TRANSLATIONAL PROJECTS, INCLUDING EVEN SOME EARLY PHASE CLINICAL TRIALS. ANOTHER AWARD MECHANISM THAT WE OFFERED IN FY12, WE'RE NOT ABLE TO OFFER IN 2013 DUE TO JESS TRAITION, IT'S THE THERAPEUTIC MECHANISM, FOCUSED ON IDENTIFYING NEW POTENTIAL THEIR PEW IT TICKS. WE DID FUND ONE CIA AWARD IN 2012 TO ELIZABETH MCNALLY. I'LL GIVE YOU A LITTLE BIT ABOUT THAT IN THE NEXT SLIDE. SO HOW HAVE THE CDMRP PROGRAMS ADDRESSED THE ACTION PLAN? SO THESE FIVE MAJOR TOPICS, WHEN THEY WENT THROUGH THE PORTFOLIO, FOUND THAT SUPPORTED PROJECTS HAVE ADDRESSED ALL FIVE AREAS, A MAJORITY OF THE PORTFOLIO HAS FOCUSED ON THEIR PEW IT TICKS A AND MUSCULAR DYSTROPHY OR THERAPY OF MUSCULAR DYSTROPHY, BUT WE HAVE SUPPORTED PROJECTS THAT DPO TOUCH O DO TOUCH ON SEVERAL OF TH E TOPICS INCLUDING INFRASTRUCTURE. SO JUST TAKING A LOOK AT THESE FIRST TWO MECHANISMS OF MUSCULAR DYSTROPHY AND DIAGNOSIS SCREENING, YOU CAN SEE WE'VE HEARD ABOUT TRYING TO COUNTERACT OR TREAT THE MUSCLE ISCHEMIA THAT WE SEE IN DMD, SO ONE OF THESE FOUR AWARDS -- DR. YALE THOMAS, LOOKING AT TESTING A DRUG WHICH IS A NITRIC OXIDE DONOR AND TESTING ITS EFFECTS AND REDUCING MUSCLE ISCHEMIA AND IMPROVEMENT OF MUSCLE BLOOD FLOW AND FUNCTION, BOTH SKELETAL AND IN THE HEART. FROM ONE OF OUR IBRPs, DR. -- DOWN AT CHILDREN'S HAS BEEN TESTING SOME INHIBITORS OF -- RECEPTORS, SEEN SOME BENEFIT THERE. FOR SCREENING, SOME WORK BY GLEN WALTERS, TESTING OUT VARIOUS TYPES OF NEAR INFRARED IMAGING TECHNIQUES TO BE ABLE TO DISTINGUISH DAMAGE FROM NORMAL HEALTHY MUSCLES, AS WELL AS DEVELOPING IT AS METHODS TO ACTUALLY MONITOR MUSCLE CELL RESPONSE DURING TREATMENT AS WELL AS DELIVERY OF THERAPEUTIC AGENTS. SO THAT'S WORK THAT IS ONGOING. AGAIN, DR. WALTERS WAS ONE OF OUR FOUR AWAR DES THE FIRST YEAR OF THE PROGRAM. AS I MENTIONED, RESEARCH INFRASTRUCTURE HAS BEEN AN AREA THAT THE IBRPs HAVE BEEN INSTRUMENTAL IN SUPPORTING OVER THE YEARS. THE IBRP TO JACKSON LABS WAS PRIMARILY SET UP TO ESTABLISH A MOUSE REPOSITORY DEDICATED TO IMPORTING, CHARACTERIZING AND MAKING AVAILABLE TO THE FIELD MUSCULAR DYSTROPHY MOUSE MODELS, AS WELL AS WORKING ON DEVELOPING OTHER NOVEL PRECLINICAL MOUSE MODELS FOR DUCHENNE'S THAT BETTER MIMIC THE DISEASE, THE HUMAN DISEASE IN THESE MOUSE MODELS, SOMETHING BETTER THAN OUR STANDARD MDX MOUSE MODEL. THERE IS ALSO A MOUSE PRECLINICAL CORE DOWN AT CHILDREN'S DEDICATED TO TRYING TO CARRY OUT MUCH OF THE PRECLINICAL ANIMAL TESTING AND TRYING TO CARRY THAT OUT USING STANDARD OPERATING PROCEDURES THAT THEY'VE DEVELOPED FOR THE TESTING, AND THIS IS OPEN TO NOT ONLY INVESTIGATORS AT CHILDREN'S, BUT TO THE ENTIRE FIELD, INCLUDING INDUSTRY AS WELL AS ACADEMIA. ANOTHER INFRASTRUCTURE SUPPORT WE HAD WAS AN AWARD TO DR. CANAN DONE AT CHILDREN'S ESTABLISHING A COORDINATING CENTER FOR THE SYNERGY GROUP TO FACILITATE THE CLINICAL TRIALS THAT ARE GOING ON AND THAT ARE SPONSORED THROUGH SYNERGY CENTERS. WITH -- MUSCULAR DYSTROPHY, WE HAVE AN AWARD FROM THE FIRST YEAR OF THE PROGRAM TO DR. CANAAN LOOKING AT TRYING TO ESTABLISH MINIMAL -- MINIMALLY IMPORTANT DIFFERENCES IN OUT COME MEASURES FOR DUCHENNE'S AND THIS IS BEING DONE BY EXTENDING THE NATURAL HISTORY STUDY THAT'S GOING ON WITH BEING HEADED UP BY DR. MACDONALD. SO THEY SAID A LOT OF -- THE MAJORITY OF THE PROJECTS THAT WE HAVE FUNDED HAVE BEEN FOCUSED ON THERAPY FOR MUSCULAR DYSTROPHY. THIS IS JUST A FEW. YOU CAN SEE AS GLEN HAD MENTIONED THE LTBP4, THAT PROJECT RIGHT NOW BY BETH MCNALLY IS ACTUALLY TARGETING, IS LOOKING AT TARGETING LTBP4 AND ITS POTENTIAL AS A TARGET BY USING AN ANTIBODY AGAINST IT TO PREVENT CGF BETA RELEASE. THAT PROJECT JUST GOT STARTED LAST YEAR, SO THAT'S SOMETHING WE'RE LOOKING FORWARD TO. FROM THE UNIVERSITY OF PITTSBURGH, THAT PROGRAM HAS PRIME MAYORLY FOCUSED ON SORT OF CELL-BASED THERAPIES, LOOKING AT MUSCLE DERIVED STEM CELLS AND USING THESE MD SCs TO TRY AND RESTORE DISFRO FIN EXPRESSION AND DYSTROPHIC MUSCLES AND ASSISTANCE IN TISSUE REGENERATION. THEY HAVE TESTED OUT VARIOUS PROTEIN-BASED THERAPEUTICS WITH -- AND MMP1, AGAIN, HERE IN THIS CASE, HELPING TO EITHER INHIBIT FIBROSIS OR ACTUALLY DIGESTING SCAR TISSUE IN MUSCLES AND THE EFFECTS LONG TERM OF MUSCLE REGENERATION. ANOTHER PROJECT THAT'S ACTUALLY ONGOING IS THE USE OF THE MDSCs FOR TREATING CARDIOMYOPATHY AND ACTUALLY INJECTING THESE MDSCs INTO DUCHENNE'S MOUSE MODEL INTO THE HEART AND ITS EFFECTS ON INHIBITING THE CARDIOMYOPATHY. ANOTHER AREA THAT PROVIDED SOME SUPPORT WAS THE SORT OF EARLY INVESTIGATION AS WELL AS SOME OF THE IND-ENABLING STUDIES FORT DEVELOPMENT OF THE BBP15 DRUG THAT HAS BEEN DEVELOPED BY VAL DISBIOPHARMA AS SOMETHING -- ANOTHER DRUG THAT BETTER THAN THE OTHER GLUCOKOIDS OUT THERE WE'RE TRYING TO GET RID OF THE SORT OF MORE NEGATIVE SIDE EFFECTS OF GLUCOCORTICOIDS TREATMENTS AND REALLY FOCUS ON GETTING MORE OF THE POSITIVE BENEFITS. THIS VPP15 APPEARS TO BE DOING JUST THAT. NOURISH FINALLY HERE, EXPLORE ATHE LOT OF PROJECTS IN GENE THERAPY AS WELL AS THE CARDIOPULMONARY THERAPY. WE ARE FUNDING THE CLINICAL TRIALS COQ10 AND -- HEADED BY PAULA CLEMENS AS WELL AS A NEW PROJECT WITH RAFAEL COURTNEY LOOKING AT OPTIMIZING SOME OF THE -- PATHWAY INHIBITORS, AND OPTIMIZATION OF THOSE STRATEGIES FOR TREATMENT. SO I'LL LEAVE YOU WITH JUST OUR SORT OF COMMENT FROM ONE OF THE COULCONSUMER ADVOCATES, PICTURE OF HIM WITH HIS SON AND HIS IMPRESSIONS OF PARTICIPATING IN OUR PROGRAM AS WELL AS OTHER PROGRAMS, IN THE HOPE THAT IT HAS GIVEN HIM AND HIS FAMILY ON THE PROGRESS THAT HAS BEEN MADE SO FAR OVER THE PAST 10 YEARS OF THE ACTION PLAN AS WELL AS THE MD CARE ACT. SO THANK YOU, AND ANY QUESTION, I WILL BE AROUND. >> THANK YOU VERY MUCH. [APPLAUSE] >> WE HAVE TIME FOR ONE QUESTION. DR. KATZ HAS ALREADY PREREGISTERED HIS. MY QUESTION IS, THE CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAM. THIS COMES UNDER THAT NEW $200 MILLION ALLOCATION, IS THAT CORRECT? FOR ALL CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS? THERE WAS AN ANNOUNCEMENT SOME TIME AGO. OR IS THAT A DIFFERENT PROGRAM? >> THAT'S A DIFFERENT PROGRAM. THE PEER REVIEW MEDICAL RESEARCH PROGRAM WAS INCREASED BY CONGRESS THIS YEAR, DUCHENNE'S HAS ITS OWN LINE OF FUNDING. >> RIGHT, BUT ARE THESE MUSCULAR DYSTROPHIES ELIGIBLE FOR SOME WORK UNDER THAT PROGRAM AS WELL? >> NO STATISTICALLY, NO. BUT THERE ARE 25 TOPIC AREAS UNDER THAT PROGRAM. >> BUT THAT'S NOT ONE OF THE TOPICS? >> NO, DUCHENNE'S IS NOT ONE. >> ANOTHER QUESTION? IF NOT, WHY DON'T WE GO TO THE BREAK AND SINCE WE'RE RUNNING A LITTLE BIT LATE, WE WILL BREAK UNTIL QUARTER OF, BUT THEN WE WILL START PROMPTLY AGAIN AT QUARTER OF. SEE YOU BACK THEN. >> SO WHEN JOHN CONTACTED ME ABOUT GIVING THIS TALK, HE ASKED THAT I PROVIDE AN OVERVIEW OF MDA'S ACTIVITY SINCE THE ACTION PLAN WAS DEVELOPED WHICH, AS WE KNOW, WAS JUST ABOUT 10 YEARS AGO. HIS IP STRUXE INSTRUCTIONS WERE TO STAY OUT OF THE WEEDS, DO IT IN 20 MINUTES OR LESS. IT'S ABOUT A HUNDRED PAGES LONG AND HAS DOZENS OF OBJECTIVES, SO I'M GOING TO GIVE A PRETTY HIGH LEVEL OVERVIEW OF MDA'S ACTIVITIES. MDA'S MISSION IS TO IMPROVE AND SAVE LIVES FOR THOSE LIVING WITH MUSCLE DISEASE, AND WE DO IT THROUGH FOUR PILLAR PROGRAMS. OUR RESEARCH PROGRAM, HEALTHCARE SERVICES, ADVOCACY AND PUBLIC AND PROFESSIONAL EDUCATION. AND I BRING THOSE UP BECAUSE EACH OF THESE PROGRAMS TOUCHES ON VARIOUS ASPECTS OF THE PLAN. SINCE 2006, MDA HAS FUNDED 567 GRANTS IN THE MUSCULAR DYSTROPHIES. TOTALING ABOUT $170 MILLION IN FUNDING. AND WE'RE GETTING READY TO ANNOUNCE 17 NEW AWARDS IN THE NEXT WEEK OR SO. AND HERE'S THE BREAKDOWN OF FUNDING FOR THE VARIOUS IT DYSTROPHIES. WITH DUCHENNE AND BECKER BEING THE LARGEST COMPONENT OF THAT, BUT CERTAINLY SIGNIFICANT AMOUNTS DEDICATED TO THE OTHER DYSTROPHIES AS WELL. THERE'S NOT ALWAYS CLEAR DISTINCTION BETWEEN THE FUNDING FOR THE VARIOUS DYSTROPHIES BECAUSE THERE'S OFTEN OVERLAP IN THE GRANTS AS TO THE DYSTROPHIES THAT THEY MAY TOUCH OR THE DISEASES THAT THEY MAY IMPACT. THIS IS A SLIDE THAT I SHOWED LAST AUGUST AT NEATING AN MEETING AND I'VE NOT UPDATED IT FOR THE 10-YEAR PERIOD, BUT 2010 THROUGH 2013, THE MAJORITY OF THE GRANTS HA WE FUNDED ARE IN THE BASIC RESEARCH CATEGORY. PRECLINICAL WORK, WITH SOME TRANSLATIONAL GRANTS AND ALSO SOME TRAINING GRANTS. BUT CERTAINLY OUR SWEET SPOT HAS BEEN IN MORE BASIC RESEARCH AND TRANSLATIONAL RESEARCH. THAT HASN'T CHANGED SIGNIFICANTLY OVER THE YEARS. WHEN I WAS THINKING ABOUT HOW TO APPROACH THIS, HOW DO WE THINK ABOUT WHAT MDA HAS DONE TO IMPLEM THE ACTION PLAN WHEN THE PLAN IS SO BROAD. I THINK JOHN PUT TOGETHER THIS GRID THAT'S ON THE MDCC WEBSITE, AND IT'S THE ACTION PLAN IMPLEMENTATION GRID AND IT SHOWS HOW THE VARIOUS AGENCIES AND ADVOCACY GROUPS HAVE CONTRIBUTED TO THE IMPLEMENTATION OF THE PLAN. SO I TOOK THAT SAME GRID AND INSTEAD OF THE VARIOUS AGENCIES AND ADVOCACY GROUPS ACROSS THE TOP, I USED THE X AXIS TO HIGHLIGHT MDA'S PROGRAMS AND THEIR INVOLVEMENT IN THE IMPLEMENTATION OF THE PLAN, AND YOU CAN SEE THAT MDA HAS IMPACTED BASICALLY ALL ASPECTS OF THE ACTION PLAN. TO VARYING DEGREES. VARIOUS PROGRAMS UNDER OUR UMBRELLA AND WITHIN MDA, CERTAINLY IMPACT ALL OF THESE AREAS. LIVING WITH MUSCULAR DYSTROPHY. AND THEN RESEARCH INFRASTRUCTURE FOR MUSCULAR DYSTROPHY. AND I'M GOING TO HIGHLIGHT JUST A FEW ITEMS FROM EACH OF THESE CATEGORIES. SO WE THINK ABOUT MECHANISMS OF MUSCULAR DYSTROPHY, AS I MENTIONED, BASIC RESEARCH IS A VERY LARGE COMPONENT OF MDA'S PORTFOLIO. AND THE ULTIMATE GOAL IS TO DEVELOP THERAPIES BUT, YOU KNOW, BASIC RESEARCH IS STILL CRITICALLY IMPORTANT TO GETTING TO THAT POINT, AND I THINK THAT WAS WELL HIGHLIGHTED BY DR. LANDIS' BLOG IN RECENT DAYS ABOUT THE IMPORTANCE OF BASIC RESEARCH IN GETTING US TO DEVELOPING THERAPIES. I THINK ANOTHER EXAMPLE OF THAT IS THE GENE THERAPY EFFORTS FOR DUCHENNE MUSCULAR DYSTROPHY. THE ONLY CLINICAL TRIAL OF GENE THERAPY IN DUCHENNE MUSCULAR DYSTROPHY WAS LAUNCHED IN 2006, AND WE HAVE SINCE LEARNED ABOUT SOME OF THE CHALLENGES TO GENE THERAPY IN DUCHENNE MUSCULAR DYSTROPHY, AND I THINK IT HIGHLIGHTS THE IMPORTANCE OF BASIC RESEARCH IN THIS SPECTRUM OF THERAPY DEVELOPMENT. SO WE GOT ALL THE WAY TO THE POINT OF A PHASE 1 CLINICAL TRIAL IN 2006, BUT EVEN AT THAT TIME, THERE WAS STILL A LOT OF WORK GOING ON AT THE -- ON THE LEFT SIDE, IN THE VERY BASIC AREA. OPTIMIZING THE -- NOT ONLY THE VECTORS BUT THE GENES THEMSELVES, DO WE USE MICRO DYSTROPHIN, OTHER FORMS OF THE DYSTROPHIN GENE, SO EVEN WHEN WE WERE ALREADY IN A CLINICAL TRIAL, THERE WAS STILL A LOT OF WORK GOING ON AT THE BASIC LEVEL. AND WE'VE ALSO LEARNED ABOUT SOME OF THE CHALLENGES OF GENE THERAPY, HAVING TO DO EARLIER WORK AGAIN. SO BASIC RESEARCH IS STILL A VERY CRITICAL AND IMPORTANT PIECE OF WHAT WE AS A COMMUNITY NEED TO FOCUS ON. THE OTHER AREA THAT TENDS NOT TO GET AS MUCH ATTENTION IS INFRASTRUCTURE. AND SUPPORT FOR INFRASTRUCTURE. AND MDA SUPPORTS A VERY SELECT NUMBER OF INFRASTRUCTURE GRANTS. THESE ARE GENERALLY TOOLS, TECHNIQUES AND RESOURCES THAT CAN HELP THE RESEARCH COMMUNITY. THIS IS NOT SEXY RESEARCH. AND SO IT TENDS NOT TO GET THE SAME KIND OF ATTENTION THAT OTHER PROJECTS DO. AND THE UTILITY OF INFRASTRUCTURE SUPPORT NEEDS TO BE VALIDATED BY THE RESEARCH COMMUNITY. SO WE WILL NOT FUND AN INFRASTRUCTURE GRANT IF WE DON'T HAVE INP PUT FROM TH INPUT FROM THE BROADE R RESEARCH COMMUNITY THAT THIS WILL BE A VALUABLE TOOL OR RESOURCE TO THE COMMUNITY. I THINK THE OTHER PIECE OF INFRASTRUCTURE GRANTS THAT ARE IMPORTANT TO REMEMBER IS THAT THE EXPERTISE TO SUPPORT AN INFRASTRUCTURE PROJECT MAY ONLY EXIST AT A LIMITED NUMBER OF SITES, SO WE SHOULD BUILD ON THAT EXPERTISE AND MAKE CERTAIN THAT WE ARE TAKING ADVANTAGE OF IT. AND THESE KINDS OF PROJECTS ARE COSTLY TO DUPLICATE, SO LET'S MAKE CERTAIN THAT WE ARE USING ECONOMIES OF SCALE FOR THESE KINDS OF PROJECTS. I'VE HIGHLIGHTED HERE SOME OF THE RESEARCH INFRASTRUCTURE GRANTS THAT MDA HAS SUPPORTED OVER THE PAST 10 YEARS OR SO, INCLUDING THE DEVELOPMENT OF THE NEUROMUSCULAR RESEARCH CHIP THAT ANNE HIGHLIGHTED EARLIER, THIS IS NOW A TOOL THAT'S AVAILABLE AND CAN BE USED FOR DIAGNOSTIC TESTING BUT WE DON'T KNOW AT THIS POINT HOW MUCH IT'S BEING USED. A SECOND PROJECT WAS THE MDA MONOCLONAL ANTIBODY RESEARCH THAT WE'VE BEEN SUPPORTING FOR A NUMBER OF YEARS AND WE CERTAINLY KNOW THE RESEARCH COMMUNITY HAS BEEN USING THIS. THIS IS GLEN MORRIS' APT BODY COLLECTION. AND THIS IS NOW TRANSITIONING TO OUTSIDE FUNDING. WE'VE RECENTLY STARTED SUPPORT SUPPORTING -- IN EARLY STAGES, WE DON'T KNOW YET HOW EFFECTIVE THIS TOOL WILL BE. -- PRECLINICAL MOUSE FACILITY AT CNMS HAS BEEN VERY SUCCESS FELL SO FAR, AND AGAIN, FUNDING IS TRANSITIONING TO A NEW MODEL. IN A LITTLE BIT, WE'LL HEAR FROM CHAD HEATWOLE. SO I IF WE GO TO THE NEXT CATEGORY, WHICH WAS DIAGNOSIS AND SCREENING, CERTAINLY MDA HAS SUPPORTED THE IDENTIFICATION OF MANY MUSCULAR DYSTROPHY GENES, GENETIC MODIFIER, UNDERSTANDING THE PATHOPHYSIOLOGY OF THE DISEASE AS A RESULT OF THOSE GENETIC MUTATIONS AND AGAIN THE NEUROMUST CLR CHIMUSCULAR CHIP. THE IMPORTANT PIECE IS ALSO THE CLINICAL PIECE. AND IT'S IMPORTANT THAT WE MAKE CERTAIN THAT WE ARE ENCOURAGING OUR CLINICIANS AND OUR CLINIC TEAMS TO INCLUDE GENETIC COUNSELORS ON THEIR TEAMS. AT MDA'S CLINICAL CONFERENCE LAST MONTH, WE HEARD ABOUT THE IMPORTANCE OF THIS, AND WE ALSO HEARD THERE IS A SHORTAGE OF GENETIC COUNSELORS ACROSS THE COUNTRY, SO THAT IS A CHALLENGE TO US AS A NEUROMUSCULAR COMMUNITY, AND IT'S SOMETHING THAT MDA IS EXPLORING. HOW DO WE MEET THE NEEDS OF THE UNDERSERVED? BOTH IN GEOGRAPHICALLY REMOTE AREAS SUCH AS THE NORTHERN -- STATES WHERE WE HAVE LOW POPULATION DENSE AT THIS TIME, WE MAY NOT HAVE THE EXPERTISE IN THOSE AREAS THAT WE NEED TO SERVE THOSE FAMILIES, AS WELL AS EVEN LARGER METROPOLITAN AREAS, AGAIN, WHERE THERE IS A SHORTAGE OF GENETIC COUNSELORS. AND AN ADDITIONAL INITIATIVE HAS BEEN NEWBORN SCREENING, AND WE HAVE HOSTED TWO SYMPOSIA ON NEWBORN SCREEN FOR DUCHENNE MUSCULAR DYSTROPHY, AND ARE DEVELOPING PLANS FOR EXPANDING NEWBORN SCREENING EFFORTS. MOVING TO THE CATEGORY OF THERAPIES FOR MUSCULAR DYSTROPHIES, CERTAINLY THAT IS A FOCUS OF EVERYBODY IN THIS ROOM. MDA HAS A HAD LONG PORTFOLIO OF GRANTS, BUT COUPLE THINGS I WANT TO HIGHLIGHT ARE THE FACT THAT MDA CLINICS AND MDA'S NEWLY LAUNCHED REGISTRY, WHICH I'LL TALK ABOUT IN A LITTLE BIT, ARE INTEGRAL AND WILL BE INCREASINGLY IMPORTANT AS WE GO FORWARD IN THERAPY DEVELOPMENT AND IMPLEMENTATION OF MORE CLINICAL TRIALS FOR NEUROMUSCULAR DISEASES AND MUSCULAR DYSTROPHIES. MDA HAS BEEN SUPPORTING TWO MUSCULAR DYSTROPHY RESEARCH NETWORKS, THE DUCHENNE RESEARCH NETWORK AND THE MYOTONIC NETWORK, AND WE'VE ALSO BEEN SUPPORTING EFFORTS IN CARDIOPULMONARY CARE, WHICH WAS ONE OF THE OBJECTIVES IN THE ACTION PLAN AS WELL. AT OUR RECENT CLINICAL CONFERENCE LAST MONTH, WE DEVOTED AN ENTIRE HALF DAY TO CARDIAC AND PULMONARY CARE FOR MUSCLE DISEASES, AND WE'VE ALSO BEEN SUPPORTING THE CARDIOMYOPATHY REGISTRY AT INDIANA UNIVERSITY THAT BILL GROH HAS BEEN RUNNING AND HAS REALLY BEEN ABLE TO PUBLISH SOME VERY IMPORTANT DATA ON THE CARE OF INDIVIDUALS WITH MYOTONIC DYSTROPHY. LIVING WITH MUSCULAR DYSTROPHY IS A VERY BIG AND BROAD CATEGORY AND I'M JUST GOING TO HIGHLIGHT A FEW POINTS WITHIN THAT CATEGORY. ONE OF THE AREAS THAT WE HAVE BEEN FOCUSING ON IS THE DEVELOPMENT OF CLINICAL END POINTS FOR DUCHENNE MUSCULAR DYSTROPHY. AND PARTICULARLY TWO POPULATIONS THAT HAVE BEEN TRADITIONALLY EXCLUDED FROM CLINICAL TRIALS. AS WE ALL KNOW IN DUCHENNE MUSCULAR DYSTROPHY, CLINICAL TRIALS ARE PRIMARILY CONDUCTED IN BOYS OVER THE AGE OF 4, AND TYPICALLY UP TO ABOUT AGE 15 AND THOSE STILL WALKING. THAT MEANS WE ARE NOT INCLUDING THE VERY YOUNG CHILDREN WITH DUCHENNE MUSCULAR DYSTROPHY, WHO ARE AN IMPORTANT POPULATION AS WE THINK ABOUT INSTITUTING THERAPIES AND INSTITUTING THEM AS EARLY AS POSSLE, AND ALSO THE NON-AMBULATORY POPULATION. AND THROUGH MDA'S DUCHENNE CLINICAL RESEARCH NETWORK, ANNE CONNELLY AT WASHINGTON UNIVERSITY HAS REALLY LED TWO IMPORTANT STUDIES LOO LOOKING AT OUTCOME MEASURES IN THESE TWO POPULATIONS. SHE'S ALREADY PUBLISHED THE BASELINE MEASURES IN INFANTS AND VERY YOUNG CHILDREN WITH DUCHENNE MUSCULAR DYSTROPHY, AND THE FOLLOW-UP LONGITUDINAL STUDY IS DUE TO BE PUBLISHED SOON. SHE'S ALSO AGAIN LOOKED AT OUT COME MEASURES IN THE NON-AMBULATORY MEASURES FOR PATIENTS WITH DUCHENNE'S MUSCULAR DYSTROPHY AND THERE'S A PAPER UNDER REVIEW CURRENTLY. SO WE HOPE THAT WILL BE PUBLISHED SOON. BUT THE OUTCOME OF THIS AND THE RESULTS OF THE INFANT STUDY AND THE VERY YOUNG CHILD STUDY IS THE START OF CLINICAL TRIAL OF CART COSTEROIDS IN INFANTS AND YOUNG CHILDREN WITH DUCHENNE'S MUSCULAR DYSTROPHY. SO ONE OF THE QUESTIONS WE DON'T HAVE AN ANSWER TO IS WHEN SHOULD WE START STEROIDS IN DUCHENNE'S MUSCULAR DYSTROPHY. CERTAINLY CORTICOSTEROIDS ARE STANDARD OF CARE IN INFANTS OR IN CHILDREN WITH DUCHENNE'S MUSCULAR DYSTROPHY BUT THERE'S NOT CLEAR CONSENSUS AT WHAT AGE WE SHOULD START THEM, AND THERE IS A BROAD RANGE OF WHEN PEOPLE ARE STARTING STEROIDS. SO THIS TRIAL IS DESIGNED TO LOOK AT THE VERY YOUNGEST CHILDREN, CHILDREN UNDER THE AIFNLG 30 MONTHS WILL BE ENROLLED IN THIS TRIAL, AND THEY WILL BE TREATED -- IT'S AN OPEN LABEL TRIAL, THEY'LL BE TREATED WITH WEAKENED DOSING OF CORTICOSTEROIDS, AND THEY WILL BE -- TO LOOK AT NOT ONLY THE STRENGTH HOW IT COMES BUT THE IMPACT ON GROWTH AND OTHER FACTORS RELATED TO CORTICOSTEROID USE. ALSO UNDER THE CATEGORY OF LIVING WITH MUSCULAR DYSTROPHY ARE THE ITEMS PATIENT AND FAMILY EDUCATION, SOCIAL PARTICIPATION IN THE COMMUNITY, AND PHYSICIAN TRAINING. IN REGARDS TO PATIENT FAMILY EDUCATION, THIS HAS BEEN A FOCUS OF MDA FOR A LONG TIME. WE'VE HAD LOCAL SEMINARS ACROSS THE COUNTRY FOR MANY YEARS, AND THESE HAVE REALLY DEVELOPED INTO MUCH LARGER MUSCLE SUPPLEMENTS WHICH REALLY COVER A BROAD RANGE OF TOPICS INCLUDING NOT JUST INFORMATION ABOUT DISEASE AND MEDICAL MANAGEMENT, BUT ALSO THE OTHER ASPECTS OF LIVING WITH MUSCULAR DYSTROPHY. INCLUDING THINGS LIKE FINANCIAL PLANNING, TRANSITIONS AND ISSUES RELATED TO LONG-TERM CARE, SO THEY'VE REALLY BECOME QUITE COMPREHENSIVE SEMINARS, AND NOW OCCUR IN MULTIPLE LOCATIONS AROUND THE COUNTRY. WE HOST AN ANNUAL BECKER MUSCULAR DYSTROPHY CONFERENCE. WE HAVE A WEBINAR SERIES THAT INCLUDES TOPICS THAT ARE DISCUSSED BY STAFF AT MDA BUT ALSO WE INVITE OUTSIDE EXPERTS TO HOST THESE WEBINARS. THE MOST RECENT ONE WAS A WEBINAR ON THE FORD DMD TRIAL. THIS CAME OUT OF THE LAST MEETING WHEN WE WERE HERE IN AUGUST WHEN WE HEARD -- FOR DUCHENNE MUSCULAR DYSTROPHY WAS LAGGING. AND THERE WAS CONCERN ABOUT THE ABILITY TO ENROLL FULLY IN THE STUDY. SO WE HAVE BEEN WORKING WITH STAFF AT THE UNIVERSITY OF ROCHESTER AND ALSO AT NIH TO HELP PUBLICIZE THAT TRIAL. AND THE WEBINAR HAS BEEN ARCHIVED AND POSTED ON OUR WEBSITE. THEN FINALLY, FOR THE FIRST TIME AS PART OF OUR MDA2014 CLINICAL CONFERENCE, WE HOSTED A FAMILY FORUM. SO MDA HOSTS THE CLINICAL CONFERENCE EVERY TWO YEARS, WE INVITE OUR CLINIC TEAMS FROM ACROSS THE COUNTRY, AS WELL AS OTHER GUESTS TO PARTICIPATE IN THE CONFERENCE, AND IT'S TYPICALLY ATTENDED BY PHYSICIANS, BY ALLIED HEALTH PROFESSIONALS, BY INDUSTRY PARTICIPANTS, BUT WE'VE NOT EVER HAD A FAMILY COMPONENT TO THE MEETING. SO AS A SATELLITE MEETING TO THE CLINICAL CONFERENCE, WE HOSTED A FAMILY FORUM AGAIN WHICH WE LIVE STREAMED AND RECORDED AND HAVE POSTED ON OUR WEBSITE. AN IMPORTANT ASPECT OF SOCIAL PARTICIPATION IN THE COMMUNITY IS THE SUCCESSFUL TRANSITION FROM ADOLESCENT TO ADULTHOOD. THIS IS AN INCREASINGLY IMPORTANT AREA AS WE ARE MAKING INROADS ON IMPROVING MEDICAL CARE AS WELL AS DEVELOPING THERAPIES AND THINK ABOUT THE POPULATION OF YOUNG PEOPLE WHO ARE -- WE NEED TO MAKE CERTAIN THAT THAT TRANSITION IS SUCCESSFUL. SO FOR A NUMBER OF YEARS NOW HAS DEVELOPING OUR TRANSITIONS PROGRAM, AND I TALKED A LITTLE BIT ABOUT THIS AT THE AUGUST MDCC MEETING SO I'M NOT GOING TO -- ON THIS ENTIRE LIST, BUT I DO WANT TO HIGHLIGHT THAT THIS IS THE MOST ACTIVELY VISITED PART OF OUR WEBSITE CURRENTLY, THE GROWTH IN THIS IS TO THE TRANSITION CENTER ON OUR WEBSITE HAS BEEN ASTRONOMICAL, IN THE LAST YEAR OR SO. SO CLEARLY, THERE IS A NEED FOR THIS AND WE NEED TO KEEP WORKING TO HELP OUR YOUNG POPULATION TRANSITION SUCCESSFULLY. AN IMPORTANT PIECE OF SOCIAL PARTICIPATION IN THE COMMUNITY IS MAKING CERTAIN THAT OUR PHYSICIANS ARE WELL EDUCATED. AND THIS IS NOT SOMETHING THAT PHYSICIANS HAVE FOCUSED ON IN THE PAST. OUR CLINICAL TEAMS TRADITIONALLY HAVE BEEN MORE FOCUSED ON MEDICAL MANAGEMENT AND THERAPIES AND HAVEN'T AS MUCH THOUGHT ABOUT THE SOCIAL ASPECTS OF LIVING WITH MUSCULAR DYSTROPHY. SO AGAIN AS PART OF OUR CLINICAL CONFERENCE LAST MONTH, WE ADDED A SECTION ON SOCIAL PARTICIPATION IN THE COMMUNITY, AND REALLY WE'RE THINKING ABOUT THIS AS SOMETHING THAT WOULD BE ATTRACTIVE TO OUR ALLIED HEALTH PROFESSIONALS WHO WOULD BE ATTENDING THE MEETING BUT WE WERE VERY PLEASANTLY SURPRISED THAT A LOT OF OUR PHYSICIANS AND CLINICAL DIRECTORS ATTENDED A PORTION OF THE MEETING AS WELL. WE HAD THREE MAIN TOPICS IN THAT SESSION, BEHAVIORAL AND EMOTIONAL HEALTH, ADDRESSING THE NEEDS OF SIBLINGS OF CHILDREN WITH MUSCULAR DYSTROPHY, AND NAVIGATE AGO SUCCESSFUL TRANSITION FROM ADOLESCENCE TO ADULTHOOD. AND THIS IS A PHOTOFROM THAT CLINICAL CONFERENCE AND THIS WAS NOT THE SESSION ON SOCIAL PARTICIPATION, THIS WAS ACTUALLY A SESSION ON MUSCLE IMAGING, WHICH IS ANOTHER COMPONENT OF THE ACTION PLAN. SO WE WERE ADDRESSING THAT AT THE MEETING AS WELL. PHYSICIAN TRAINING IN ADDITION TO MAKING CERTAIN THAT OUR PHYSICIANS ARE KNOWLEDGEABLE ABOUT THE PSYCHOSOCIAL ASPECTS OF MUSCULAR DYSTROPHIES, WE ALSO NEED TO MAKE CERTAIN THAT WE HAVE A PIPELINE OF CLINICIANS AND RESEARCHERS WHO ARE WILLING TO TAKE THE REINS AS OUR -- SOME OF OUR MORE SENIOR CLINICIANS AND RESEARCHERS BEGIN TO RETIRE, SO WE NEED TO MAKE CERTAIN THAT WE'RE TRAINING PEOPLE FOR THE FUTURE. ONE OF THE PROGRAMS THAT MDA HAS HAD IN PLACE NOW FOR ABOUT SEVEN OR EIGHT YEARS IS OUR CLINICAL RESEARCH TRAINING GRANT. AND WE'VE BEEN TRYING TO DETERMINE HOW WE CAN MEASURE WHETHER THIS PROGRAM IS EFFECTIVE. ONE OF THE THINGS WE LOOKED AT IS WHETHER OR NOT OUR CLINICAL RESEARCH TRAINING GRANTEES ARE STILL WORKING IN THE FIELD. SO WE LOOK AT THESE TWO BAR GRAPHS, AND LOOK AT THE CLINICAL RESEARCH TRAINING GRANTEES THAT WE FUNDED AND THOSE WHO APPLIED FOR FUNDING BUT DID NOT RECEIVE A TRAINING GRANT, VIRTUALLY ALL OF THEM ARE STILL IN NEUROLOGY AND I THINK WE'VE FUNDED ABOUT A DOZEN OF THEM SO FAR. SO WITH THE EXCEPTION OF ONE PERSON, ALL ARE STILL WORKING IN NEUROLOGY. BUT THOSE ARE -- WHO ARE DOING CLINICAL RESEARCH IN THE FIELD, THOSE WHO WERE FUNDED THROUGH THE CLINICAL RESEARCH TRAINING GRANT, HAVE CERTAINLY DONE VERY WELL, WHILE THOSE WHO HAVE NOT BEEN FUNDED ARE NOT DOING CLINICAL RESEARCH AND THE WAY WE MEASURED THAT WAS THROUGH PUBLICATIONS AND A SURVEY OF THOSE GRANTEES AND APPLICANTS. RESEARCH INFRASTRUCTURE IS ANOTHER POINT ON THE GRID. MDA HAS LONG HAD ITS CLINICAL RESEARCH NETWORK ACROSS THE COUNTRY, WHICH CAN SERVE AS AND DOES SERVE AS CLINICAL RESEARCH AND TRIAL INFRASTRUCTURE IN MUSCULAR DYSTROPHIES, IN 2013, ACROSS OUR CLINICS THROUGHOUT THE COUNTRY, WE BEGAN PILOTING A NEUROMUSCULAR DISEASE REGISTRY. WE'RE PILOTING AT ABOUT 25 CLINICS ACROSS THE COUNTRY. WE WANT TO MAKE CERTAIN THAT WE ARE WORKING OUT THE BUGS BEFORE WE ROLL OUT TO ALL 200 CLINICS ACROSS THE COUNTRY. THIS IS CLINICIAN ENTERED DATA, AND SOME KEY COMPONENTS OF IT ARE TO LOOK AT THE PRACTICE OF PHYSICIANS, WHAT IS THEIR COMPLIANCE WITH PUBLISHED CARE GUIDELINES FOR THE MUSCULAR DYSTROPHIES, AND WE ALSO WANT TO LOOK AT CORRELATION OF MEDICAL INTERVENTIONS WITH CLINICAL OUTCOMES. WHILE WE'RE ALL WORKING ON THERAPY DEVELOPMENT, WE ALSO NEED TO BE LOOKING VERY CLOSELY AT MEDICAL MANAGEMENT, BECAUSE HOW WE CARE FOR PATIENTS CAN HAVE A SIGNIFICANT IMPACT ON CLINICAL OUTCOMES. TO DATE, WE HAVE OVER 407 INDIVIDUALS WITH DUCHENNE IN THE REGISTRY, BUT THE BIGGEST BARRIER IS DATA ENTRY. IT'S GOING TO BE AN ISSUE THAT WE NEED TO SOLVE, SO WE'RE LOOKING AT WAYS TO REDUCE THAT BARRIER. AND IN 2015, WE'RE PLANNING TO ADD MYOTONIC MUSCULAR DYSTROPHY, FSHD, AND PATIENT-REPORTED OUTCOMES. AND FINALLY, THIS IS NOT SOMETHING THAT WAS INCLUDED IN THE GRID BUT I THINK AN IMPORTANT PIECE OF EVERYTHING WE DO IS COLLABORATION, THAT'S WHAT THIS GROUP IS ALL ABOUT, NO ONE OF US, NO SINGLE AGENCY OR PATIENT ADVOCACY GROUP HAS THE RESOURCES TO DO EVERYTHING WE NEED TO DO AS A MUSCULAR DYSTROPHY COMMUNITY, SO I THINK WE NEED IT TO CONTINUE TO FOCUS ON COLLABORATION AND HERE ARE JUST A FEW OF THE OUTCOMES OF VARIOUS COLLABORATIONS, THE DEVELOPMENT OF CARE GUIDELINES, THAT A NUMBER OF GROUPS AND AGENCIES HAVE BEEN INVOLVED IN, AS WELL AS THE AMERICAN ACADEMY OF NEUROLOGY, WE'RE WORKING WITH NINDS ON A GENE THERAPY SYMPOSIUM LATER THIS MONTH, AND CERTAINLY THE COLLABORATIVE EFFORTS OF ALL THE PATIENT ADVOCACY GROUPS FOR THE AUTHORIZATION OF THE MD CARE ACT IN 2001 AND ITS RE-AUTHORIZATION IN 2008, AND HOPEFULLY AGAIN IN 2014. SO I'LL STOP THERE. THANK YOU. [APPLAUSE] >> THANK YOU VERY MUCH, VALLEY, ANVALERIE,AND BECAUSE OF TIME WEE GOING TO BE MOVING ON TO OUR NEXT SPEAKER. I'M SURE VALERIE WILL BE AVAILABLE FOR CONVERSATION DURING THE REST OF THE DAY. JUNE, OF COURSE, IS THE EXECUTIVE DIRECTOR OF THE FSH SOCIETY. SHE ALSO CHAMPIONS THE GROUP -- SHE'S GOING TO TELL US SOMETHING ABOUT THE RANGE OF ACTIVITIES INVOLVING FSHD UNDERTAKEN DURING THE TENURE OF THE MDCC ACTION PLAN. SO JUNE, THANKS FOR BEING HERE TODAY AND THANK YOU FOR SPEAKING TO US. >> HI, THANK YOU SO MUCH FOR HAVING ME HERE. I'M GOING TO BE REPRESENTING THE FSHD COMMUNITY AS A WHOLE, SO I'M GIVING MORE OF A 10,000-FOOT VIEW OF THE ACTIVITIES AND TRYING TO SPEAK ON BEHALF OF THE 12 OR MORE ORGANIZATIONS AROUND THE WORLD THAT ARE FUNDING AND ADVOCATING FOR FSHD RESEARCH. SO JUST A FEW TO FAMILIARIZE YOU WITH FHSD, IT IS A GENETIC DISORDER, TRANSMITTED IN I'D SAY ROUGHLY AN AUTO SOMOL DOMINANT FASHION WITH INCOMPLETE PENETRANCE. IT'S A VERY COMPLEX GENETIC DISORDER. ABOUT 30% OF CASES ARISE SPONTANEOUSLY IN FAMILIES THAT HAVE NO PREVIOUS HISTORY. AN ESTIMATED 500,000 PEOPLE WORLDWIDE HAVE FSHD AND ABOUT 1 TO 2% OF THE POPULATION ACTUALLY CARRIES THE GENETIC MECHANISM IMPLICATED IN FSHD. IT'S VERY INTERESTING. THERE'S SEVERAL HUNDRED FOLD DIFFERENCE BETWEEN ACTUAL EXPRESSION OF THE DISEASE AND THE EXISTENCE OF THE GENETIC RISK FACTOR. IT'S PROGRESSIVE, LIFELONG, IT AFFECTS ALL OF THE SKELETAL MUSCLES, TYPICALLY STARTING IN, AS YOU CAN SEE IN THIS PATIENT HERE, FACE, LOSS OF FACIAL EXPRESSION BECAUSE OF LOSS OF FACIAL MUSCLE, SCAPULAR WINGING, DEGENERATION OF THE MUSCLES IN THE ARMS, BACK, AND LEGS. THE SYMPTOMS MAY BE EVIDENT AT BIRTH OR DURING CHILDHOOD, BUT MORE TYPICALLY THEY FIRST MANIFEST IN ADOLESCENCE AND EARLY ADULTHOOD. AND IT CAN BE PROFOUNDLY DISABLE DISABLING. IT IS NOW KNOWN TO BE ONE OF THE MOST COMMON MUSCULAR DYSTROPHIES, THE PREVALENCE IS ESTIMATED SOMEWHERE BETWEEN 1 IN 15,000 TO 1 IN 20,000, BUT WE FEEL -- WE KNOW IT'S SIGNIFICANTLY UNDERDIAGNOSED. WE TALKED TO FAMILIES WHERE THERE ARE KNOWN GENETIC HISTORY AND YET FAMILY MEMBERS WHO HAVE NEVER BEEN FORMALLY CLINICALLY DIAGNOSED. THE AVERAGE TIME OF IT DIAGNOSIS FROM THE ONSET OF SYMPTOMS IS SOMETHING LIKE 11 YEARS. AND ABOUT 24% OF PATIENTS WILL REQUIRE A WHEELCHAIR, AND THERE'S RESPIRATORY INVOLVEMENT IN ABOUT 10% OF MODERATELY AFFECTED ADULTS, VERY RECENTLY PUBLISHED STUDY FROM UNIVERSITY OF ROCHESTER. SO IT CAN BE -- IT HAS BEEN DESCRIBED IN THE PAST AS KIND OF ONE OF THE -- IT IS ONE OF THE MILDER MUSCULAR DYSTROPHIES, YET IT CAN BE SEVERELY DISABLING AND LIFE SHORTENING, AND AS AN ADULT MUSCULAR DYSTROPHY, IT AFFECTS PATIENTS' ABILITY TO SUPPORT THEIR FAMILIES, CARE FOR THEIR CHILDREN, THERE'S A LOT OF PAIN INVOLVED IN MANY CASES. AND IT DOES HAVE A PEDIATRIC MANIFESTATION IN INFANTS AND YOUNG CHILDREN, AS IN THIS 5-YEAR-OLD GIRL HERE. I'VE BEEN ASKED TO REPORT ON PROGRESS IN FSHD WITH REGARD TO THE ACTION PLAN, SO I'LL TRY TO -- KIND OF A LAUNDRY LIST OF OBJECTIVES AND I'LL TRY TO GO THROUGH THEM BUT TRY TO WEAVE A BIT OF A NARRATIVE AROUND THEM. SO WITH REGARD TO DISEASE-SPECIFIC PATHOGENIC MECHANISMS, THERE HAS BEEN ABSOLUTELY AMAZING PROGRESS OVER THE LAST DECADE, ESPECIALLY IN THE LAST FIVE YEARS, WITH THE ELUCIDATION OF THE MECHANISM FOR FSHD TYPE 1, WHICH ACCOUNTS FOR 95% OF FSHD, AND THEN THE REMAINING 5% OF FSHD TYPE 2, ABOUT HALF OF THOSE HAVE NOW BEEN LINKED TO MUTATIONS IN THE GENE FOR SMDH1, AND WE KNOW FROM THE HETEROGENEOUS MANIFESTATION OF THIS DISEASE THAT THERE HAVE TO BE GENETIC MODIFIERS, AND INDEED THE FIRST WAS DISCOVERED LAST YEAR, AND IT TURNS OUT TO BE SMCHD1, VERY FASCINATING, AND THIS GENE HAS MUTATIONS ALL OVER IT. IT'S GENES THAT MANY OF THESE MUTATIONS ARE SUBLETHAL AND MAY BE MUCH MORE COMMON IN THE POPULATION THAN WE REALIZE, AND THEY'RE INTERACTING WITH THE FSHD TYPE 1 MECHANISM ON CHROMOSOME 4, SO THIS IS AN AREA, A LOT OF ACTIVITY, AND DISCOVERIES ARE JUST COMING OUT EVERY FEW MONTHS. IT'S VERY EXCITING. THERE IS ALSO A CONSENSUS NOW THAT DUKS4 IS A KEY PLAYER. THAT WAS A TOPIC OF MUCH CONTROVERSY, BUT AT OUR MOST RECENT INTERNATIONAL CONSORTIA MEETING, 100 SCIENTISTS AROUND THE WORLD GATHERED TOGETHER IN A ROOM AND THERE WERE NO VOCAL DISSENTERS, THERE WERE MANY FLAVORS OF -- P BUT IT IS A CRITICALLY IMPORTANT PLAYER AS NOW AGREED UPON. IT'S ACTUALLY A VERY ATTRACTIVE THERAPEUTIC TARGET BECAUSE IT'S ECTOPICALLY EXPRESSED IN ADULT MUSCLE, IT'S NOT SUPPOSED TO BE THERE, AND IT'S NOT EXPRESSED IN OTHER ADULT TISSUE WITH THE EXCEPTION OF THE MALE GERMLINE, SO IT'S AN ATTRACTIVE TARGET TO TRY TO KNOCK DOWN. THERE ARE NOW ALSO -- THERE'S A LOT OF WORK GOING ON ON THE UPSTREAM REGULATORS OF DUKS4 WITH A NUMBER OF INTERESTING POTENTIAL PLAYERS THERE. AND ALSO DOWNSTREAM TARGETS INCLUDING PATHWAYS INVOLVED IN APOP TOE SIEVEAPOPTOSIS, OXIDATIVE STRESS. SO THERE'S BEEN GOOD PROGRESS MADE ON ORGANISMS AND -- MODEL ORGANISMS AND CELLULAR MODELS, BUT IT'S BEEN VERY CHALLENGING. THERE HAVE BEEN A NUMBER OF ATTEMPTS TO MODEL FSHD TYPE 1 IN MICE, AND THERE IS NOW A MOUSE THAT RECAPITULATES THE KEY MOLECULAR FEATURES BUT THE PHENOTYPE IS NOT THERE, IT DOESN'T HAVE A DYSTROPHIC PHENOTYPE. THERE IS A ZEBRAFISH MODEL THAT EXHIBITS THE VERY INTRIGUING MUSCLE A PATHOLOGY THAT MIMICS FACIAL EYE/EAR INVOLVEMENT AND THE ASYMMETRIC OF FSHD, BUT IT IS A FISH, IT'S NOT A MAMMALIAN MODEL, SO THAT MAY BE AN ISSUE. THERE'S A XENOGRAFT MODEL, MUSCLE GRAFTED ON TO THE LEG OF A MOUSE, THAT WAS JUST PUBLISHED. AND THERE ARE ALSO A NUMBER OF INDUCED IMPOTENT STEM CELL LINES INCLUDING THOSE USED FOR DRUG SCREENING, AND THERE'S BEEN A VERY ACTIVE AREA OF RESEARCH LOOKING AT THE ROLE OF -- OF THE D4D4 REGION. I WANTED TO MENTION, THE SCIENCE AROUND FSHD 1 OR FSHD IS REALLY CUTTING EDGE. IT HAS KIND OF OPENED UP NEW UNDERSTANDING OF THE ROLE OF THE OF THESE REGIONS, PREVIOUSLY CALLED JUMP DNA REGIONS IN THE REGULATION OF GENES, AND SO IT'S OPENING UP A WHOLE NEW BIOLOGY WITH, I BELIEVE, GREAT IMPORTANT AND PROFOUND IMPLICATIONS FOR UNDERSTANDING HUMAN HEALTH. TO STORY LANDIS' POINT, BASIC RESEARCH IS GOING TO BE SO IMPORTANT IN HELPING TO ELUCIDATE THIS, HOW IS THE CHROMATIN STRUCTURE MODIFIED, WHAT'S REGULATING IT, WHAT ARE THE PLAYERS INVOLVED. SO THAT'S, I BELIEVE, GOING TO BE VERY CRITICAL, AND RESEARCH ON THIS DISEASE IS CONTRIBUTING GREATLY TO THE BASIC UNDERSTANDING OF THESE MECHANISMS, AND WE ARE REACHING OUT VERY ACTIVELY TO THE BASIC SCIENCE COMMUNITY TO HELP US IN THIS EFFORT. THERE'S BEEN PROGRESS IN THE AREA OF THERAPY DEVELOPMENT, FOCUSED ON DUKS4 AND MECHANISM OF REGULATION OF DUKS4, SO THERE HAVE BEEN EFFORTS TO DEVELOP -- AND THEN OF MORE RECENT GENOMIC ENGINEERING TECHNOLOGIES THAT ARE GENERATING A LOT OF EXCITEMENT LIKE TA LONS AND CRISPER. THERE'S BEEN A LOT OF PROGRESS TOO IN THE TECHNOLOGY FOR DIAGNOSTIC TESTING, NOT YET VALIDATED BUT REALLY PROMISING FINDINGS AROUND SOME POTENTIAL BLOOD BIOMARKERS, GENE EXPRESSION PROFILING, THE USE OF MAGNETIC RESONANCE IMAGING, NOT ONLY TO IMAGE WHERE THE DYSTROPHIC MUSCLES ARE BUT TO POTENTIALLY IDENTIFY PREDICTIVE CHANGES AROUND EDEMA AND INFLAMMATION THAT SEEMS TO APPEAR RIGHT BEFORE A MUSCLE GOES THROUGH WHAT'S ACTUALLY A FAIRLY RAPID PROCESS OF DYSTROPHIC CHANGES, INFILTRATION AND SO FORTH. WE NOW IS COMMERCIAL GENETIC TESTS FOR FSHD 1, AND GENETIC TESTING FOR FSHD 2 IS AVAILABLE THROUGH RESEARCH LABS, AND I EXPECT IT WILL BE AVAILABLE COMMERCIALLY MAYBE BUT COMPLICATED BECAUSE THERE ARE SOME MUTATIONS IN THAT. GENETIC COUNSELING IS AVAILABLE THROUGH THE TESTING LABS FROM OUR OWN INFORMAL SURVEYS. IT'S NOT AS UNIFORMLY AVAILABLE THROUGH THE CLINICS AS HAS BEEN POINTED OUT AND THAT'S AN AREA THAT WE NEED TO ADDRESS. WE'VE DONE A LOT OF WORK ON DEVELOPING RESOURCES FOR THE RESEARCH COMMUNITY. THERE IS IMPORTANTLY THE NATIONAL REGISTRY AT THE UNIVERSITY OF ROCHESTER IN EUROPE AND THE U.K., THERE ARE NOW REGISTRIES THROUGH THE MUSCULAR DYSTROPHY CAMPAIGN, AND WE'RE VERY HAPPY TO HEAR ABOUT THE MDA REGISTRY COMING ALONG. THE WELLSTONE CENTERS HAVE PLAYED A REALLY CRITICAL ROLE, THANK YOU TO THE NIH VERY MUCH FOR THAT. THERE ARE BIOSPECIMEN REPOSITORIES SET UP AT THE UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL, AND WHICH COLLABORATES CLOSELY WITH KENNEDY KRUEGER INSTITUTE. WE HAVE AN INCREDIBLY WELL CHARACTERIZED SET OF MUSCLE TISSUE AND DNA FROM 48 FAMILIES. WE HAVE AT LEAST ONE AFFECTED AND ONE UNAFFECTED MEMBER. A VERY IMPORTANT INSIGHT THAT CAME FROM THAT REPOSITORY IS THAT A NUMBER OF WHAT WERE THOUGHT TO BE UNAFFECTED FAMILY MEMBERS TURNED OUT TO HAVE GENETICALLY FSHD, SO OF COURSE THIS IS AN EXTREMELY IMPORTANT INSIGHT AND IT'S NOW BEING FOLLOWED UP TO LOOK FOR THE POTENTIAL MODIFYING FACTORS THAT WOULD ACCOUNT FOR SOMEONE NOT HAVING ANY PHENOTYPE AND YET HAVING THE GENETIC -- GENETICS FOR FSHD. THE FSHD SOCIETY IS ACTIVELY INVOLVED ALL THE TIME MAKING SURE THE RESEARCH COMMUNITY IS IN COMMUNICATION. WE ORGANIZE AND SPONSOR AN ANNUAL MEETING, AND THAT BRINGS TOGETHER RESEARCHERS AROUND THE WORLD, AND THAT MEETING HAS JUST GROWN, THE QUALITY OF THE WORK BEING PRESENTED IS JUST RACHETING UP AT A VERY EXCITING PACE. AS JOHN MENTIONED, TWO YEARS AGO, SHORTLY AFTER I JOINED THE FSH SOCIETY, WE FORMED SOMETHING CALLED THE FSHD CHAMPIONS, WHICH IS AN INFORMAL ALLIANCE OF -- I'M TRYING TO COUNT -- AT LEAST 12 INTERNATIONAL ORGANIZATIONS IN CANADA, U.K., ACROSS THE U.S., AUSTRALIA, AND ACROSS EUROPE. WE MEET MONTHLY VIA CONFERENCE CALL TO DISCUSS WHAT'S GOING ON IN EACH AREA. WE CARRY OUT AN INVENTORY OF ALL RESEARCH FUNDING AND WHAT WE'RE FUNDING SO THAT WE CAN MOVE TOWARDS HAVING A GLOBAL PICTURE OF WHAT'S GOING ON AND THEN THIS YEAR WE'RE JUST COLLABORATING MUCH MORE CLOSELY AROUND -- I WOULD SAY AROUND GLOBAL STRATEGY TO INCREASE AWARENESS, TO DIRECT OUR FUNDING IN THE MOST EFFECTIVE WAYS, TO PARTNER TOGETHER TO FUND IMPORTANT INITIATIVES FOR THE COMMUNITY. SO THAT'S BEEN A VERY POSITIVE DEVELOPMENT. RESOURCES, I THINK WE HAVE -- I CAN GO THROUGH THESE PRETTY QUICKLY. WE HAVE PROTOCOLS FOR MUSCLE BIOPSIES, WE HAVE -- I REFERRED TO, EPIDEMIOLOGY, THE FSH SOCIETY WORKS WITH THE CENTERS FOR DISEASE CONTROL WITH IMPORTANT INITIATIVES IN THIS AREA. I UNDERSTAND THERE WILL BE MORE COMING ALONG IN THAT AREA. WE'RE VERY MUCH LOOKING POORD TO THAT BECAUSE THAT IS A HUGE GAP FOR FSHD. WE REALLY DON'T HAVE VERY SOLID PREVALENCE DATA. THE STUDIES THAT HAVE BEEN DONE SO FAR ARE SMALLER, AND THE RATES, PREVALENCE ESTIMATES RANGE OVER SEVERAL MULTIPLES, AND WE NEED MUCH MORE SOLID DATA, WE NEED TO KNOW WHERE PATIENTS ARE, WHAT KIND OF CARE THEY'RE RECEIVING, WHAT THEIR STANDARD OF CARE IS, AND SO ON. NEWBORN SCREENING WORKSHOP, THAT'S A COMPLICATED ISSUE FOR US WITH FSHD, I WON'T GO INTO THAT RIGHT NOW, BUT WE HAVE LOOKED AT ANTI-INFLAMMATORY DRUGS IN A STUDY BY SERENA SICONI, PATIENTS WHO INITIALLY HAD BEEN MISDIAGNOSED, TREATED WITH PREDNISONE, AND HER DATA SUGGESTS THAT PREDNISONE IS ACTUALLY DETRIMENTAL IN THESE PATIENTS, SO AGAIN VERY IMPORTANT -- VERY DISEASE-SPECIFIC, YOU CAN'T ALWAYS GENERALIZE ACROSS ALL DISEASES THAT -- SOMETHING THAT MIGHT BE BENEFICIAL IN ONE MUSCULAR DYSTROPHY -- THAT SAID, INFLAMMATION IS STILL AN IMPORTANT TARGET. THERE MAY BE OTHER DISEASES TARGETING DIFFERENT ASPECTS OF INFLAMMATION THAT ARE STILL OF GREAT INTEREST. THERE WAS A CLINICAL TRIAL WITH MYOSTATIN WHICH YOU PROBABLY ARE FAMILIAR WITH. IN TERMS OF TRANSLATIONAL BASIC AND PRECLINICAL TRANSLATIONAL STUDIES, THERE ARE A NUMBER OF INDUCED STEM CELL LINES ESTABLISHED THAT ARE PROVING TO BECOME QUITE USEFUL. THERE ARE EFFORTS NOW TO APPLY GENOMIC ENGINEERING METHODS TO CORRECT THE GENETIC DEFECT IN THOSE CELLS AND THERE'S AN EMBRYONIC STEM CELL LINE THAT HAS BEEN ESTABLISHED IN AUSTRALIA, THERE'S WORK ON ADENO VIRUSES IN A VARIETY OF MOUSE MODELS, AND I REFERRED PREVIOUSLY TO THE PUBLICATION OF THE FIRST HIGH THROUGHPUT SMALL MOLECULE SCREENING STUDY PUBLISHED EARLIER THIS YEAR. SO I JUST WANTED TO MENTION -- THAT'S AN INCREDIBLY FAST RATE OF PROGRESS GOING FROM THE KIND OF CLEAR ELUCIDATION OF THE GENETIC MECHANISM JUST THREE YEARS AGO TO HIGH THROUGHPUT DUG SCREENING STUDY TODAY. THERE IS A LOT OF ONGOING EFFORT, QUALITY OF LIFE MEASURES, THERE HAVE BEEN MEETINGS HELD ON THIS ISSUE. AND I'M GOING TO QUICKLY MOVE THROUGH THESE. CLINICAL END POINTS RESEARCH IS ONGOING. I THINK CHAD WILL ADDRESS SOME OF THAT, I'LL LET HIM TAKE CARE OF THAT. THERE IS AN EFFORT UNDERWAY TO SET UP A CLINICAL TRIAL NETWORK INVOLVING MULTIPLE CENTERS INTERNATIONALLY. IT WAS INITIATED A YEAR AGO AT A CONFERENCE WITH REPRESENTATIVES FROM ALL OF THESE LABS AND FSH SOCIETY WAS INVOLVED WITH THAT TO REALLY NAIL DOWN WHAT ARE THE BIOMARKERS, HOW DO WE GET TO A CONSENSUS SET OF BIOMARKERS, IMAGING MARKERS AND CLINICAL TRIAL END POINTS. THE RESEARCH HAS BROUGHT US VERY CLOSE WITH THE MATTER OF GETTING MULTIPLE LABS TO JUST AGREE ON A SET THAT THEY WILL THEN USE GOING FORWARD IN THE DESIGN OF CLINICAL TRIALS. THERE HAVE BEEN CONSENSUS GUIDELINES FOR CARE PUBLISHED. IN 2010, THERE WAS AN ENMC WORKSHOP ON EVIDENCE-BASED STANDARDS OF CARE AND THERE IS A MANUSCRIPT THAT HAS BEEN -- AND I'M NOT QUITE SURE WHY IT HASN'T BEEN PUBLISHED YET BUT FOR THE AMERICAN ACADEMY OF NEUROLOGY FOR A WHILE, SO -- BUT THAT IS A CONSENSUS DOCUMENT ON STANDARDS OF CARE, SO WE HOPE TO SEE THAT COME OUT SOON CH THERE HAS BEEN .THERE HAS BEEN A CLINICAL TRIAL NOW THAT HAS DEMONSTRATED A SIGNIFICANT AMOUNT OF EXERCISE WITH COGNITIVE BEHAVIORAL THERAPY IN REDUCING CHRONIC FATIGUE IN FSHD, AND I WANT TO MENTION CHRONIC FATIGUE IS MAYBE NOT SOMETHING THAT WAS CLASSICALLY LOOKED AT FOR A MUSCLE DISORDER, MORE LIKELY LOOKING AT MUSCLE WEAKNESS MEASURES, BUT IN ASKING PATIENTS WHAT WAS AFFECTING THEIR QUALITY OF LIFE, FATIGUE WAS MENTIONED BY MORE THAN 70%, SO THAT WAS USED AS AN ENDPOINT FOR THE STUDY DONE IN EUROPE, AND THIS COMBINATION OF MODERATE EXERCISE AND COGNITIVE BEHAVIORAL THERAPY REDUCED THE RATE OF PEOPLE RECORDING CHRONIC FATIGUE FROM 70% TO UNDER 30%, SO VERY DRAMATIC EFFECT, BUT THAT IS NOW SOMETHING WE CAN GO OUT TO THE PATIENT COMMUNITY AND WE NEED TO EDUCATE THE CARE PROVIDERS ABOUT THAT AS WELL. WE HAVE HAD SOME WORK ON I THINK THE NATIONAL REGISTRY AT ROCHESTER HAS PLAYED AN IMPORTANT PART IN LOOKING AT THE PREVALENCE OF SECONDARY CONDITIONS AND I THINK THERE'S STILL ONGOING WORK NOW TO SAY WHAT CAN WE DO ABOUT THOSE TYPES OF ONGOING CONDITIONS. RESPIRATORY INVOLVEMENT IS ACTUALLY TURNING OUT TO BE QUITE IMPORTANT AND LIFE SHORTENING FOR PATIENTS WHO ARE ON THE MORE SEVERE END OF THE SCALE, AND THERE NEED TO BE BETTER CARE GUIDELINES AROUND THAT. HOW MUCH TIME DO I HAVE? >> ABOUT ONE MINUTE. >> OH, NO! OKAY. EDUCATION GOING ON, ANNUAL CONFERENCES BY US, BY FSHD GLOBAL, U.K. GROUPS, AND WE HAVE -- THIS IS JUST A VERY ACTIVE AREA. ALL OF THESE WEBSITES, A LOT OF INFORMATION BEING PUBLISHED, A LOT OF INFORMATION BEING EXCHANGED. WE GIVE OUT OUR INFORMATION FOR FREE TO ALL OF THESE OTHER ORGANIZATIONS, SO THERE'S KIND OF COORDINATION AND NOBODY NEEDS TO REINVENT THE WHEEL THERE. I THINK WE'VE GONE THROUGH MOST OF THESE TOPICS. I JUST WANTED TO SHOW YOU, THIS IS OUR MAP OF THE FSHD CHAMPIONS ORGANIZATIONS. GOING FORWARD, DUKS4 IS OBVIOUSLY AN AREA OF GREAT INTEREST. BOTH BASIC RESUCK RESEARCH REMAINS REALLY CRITICAL ALONG WITH TRANSLATIONAL WORK TO START DEVELOPING THERAPEUTIC CONCEPTS AIMING AT DUX4. DISEASE MODELS, WE NEED BETTER ANIMAL MODELS AND THERE'S WORK ON DEVELOPING AN INDUCIBLE MOUSE MODEL BECAUSE DUX4 IS REALLY LETHAL EMBRYONICALLY. AND ZEBRAFISH MIGHT SHOW PROMISE FOR SCREENING PURPOSES. WE HAVE NO HIGHER VERTEBRATE MODELS, SO THAT'S SOMETHING WE NEED TO LOOK AT. INTERVENTION, IN DEVELOPMENT THERE. OBVIOUSLY A LOT MORE INVESTMENT NEEDS TO BE DONE THERE. CLINICAL STUDIES, I THINK THERE'S GOOD PROGRESS AND I HOPE CHAD WILL SPEAK ABOUT SOME WORK IN THE NATURAL HISTORY OF FSHD. WE ARE, AS I MENTIONED, THE CLINICAL TRIALS NETWORK IS BEING PLANNED BUT NOT YET FUNDED, AND THAT'S SOMETHING THAT WILL BE A HIGH PRIORITY FOR US. AS I MENTIONED BEFORE, BET TER DATA ON PREVALENCE. WE NEED TO IMPROVE THE RATES OF DIAGNOSIS OF FSHD. WE NEED TO -- THE POINTS OF CARE WHERE PATIENTS ENTER THE MEDICAL SYSTEM, I DON'T THINK THEY'RE GETTING ENOUGH INFORMATION ABOUT FSHD EDUCATION AT THAT POINT, SO WE NEED TO ADDRESS THAT. AND WE NEED TO AT THE SAME TIME DISSEMINATE THESE NEW STANDARD OF CARE GUIDELINES THAT ARE COMING OUT. FUNDING, GOOD NEWS IS FUNDING FOR FSHD HAS INCREASED MARKEDLY. THERE'S SOME FEELING AMONG ADVOCACY ORGANIZATIONS THAT THE AMOUNT INVESTED BY NIH IS DISPROPORTIONATELY SMALL RELATIVE TO THE SIZE OF THE POPULATION AND IMPORTANCE OF THIS DISEASE. AND WE'RE BUILDING ON PROGRESS, I GUESS SMALLNESS OF FUNDING IS A BIG CONCERN FOR US BECAUSE WE ARE STILL A SMALL FIELD. WE HAVE INCREDIBLE SCIENTISTS WORKING ON THIS, BUT THERE ARE NOT MANY, AND THEY'RE NOT GETTING FUNDED RIGHT NOW IN THIS ENVIRONMENT, AND THE LOSS OF EVEN ONE LAB, ONE RESEARCHER IS REALLY DEVASTATING. IF THEY CANNOT CONTINUE IN THEIR CAREERS. SO ESPECIALLY AT THIS TIME, WE CAN'T AFFORD TO SLOW DOWN. WE'VE SET THE STAGE FOR TREMENDOUS PROGRESS TO GO FORWARD. SO IT'S A TIME FOR REALLY INCREASING FUNDING SIGNIFICANTLY, AND I BELIEVE IF WE DO SO, WE WILL HAVE THE FIRST EFFECTIVE TREATMENTS WITHIN THE NEXT FIVE TO 10 YEARS. SO THANK YOU VERY MUCH, AND THERE'S MY CONTACT INFORMATION. PROBABLY NO TIME FOR QUESTIONS. >> YOU'RE RIGHT. THANK YOU VERY MUCH FOR A GREAT TALK. THE FAULT IS NOT THE SPEAKERS FOR GOING OVER, IT'S THAT IT'S OUR FAULT FOR NOT SAYING MEETING SHOULD GO TO 8:00 P.M., AND/OR THE FAULT OF SO MANY ORGANIZATIONS DOING SUCH INCREDIBLE WORK OVER THE LAST FEW YEARS. SO EITHER WE HAVE TO SLOW DOWN THE WORK OR MAKE THE MEETINGS LONGER. I THINK JOHN ALSO HAS A COMMENT. >> SO JUST ONE REALLY QUICK COMMENT. I THINK WITH THE DISEASES AROUND THE TABLE, WE SEE A MICROCHASM WITH THE TRAJECTORY OF RESEARCH IN DISEASE, IN RARE DISEASE. THE MOST STUNNING THING FOR ME WITH FSH IS THAT THE INTEGRATED PLEAK LAR MODEMOLECULAR MODEL WAS JUST PUBLISHED, THERE WERE AT LEAST A HALF DOZEN COMPANIES REPRESENTED AND I'D NEVER SEEN THAT -- AT LEAST, RIGHT? I'VE NEVER SEEN THAT IN AN FSH DECIDING MEETING BEFORE. SO INTEGRATED MODEL IN NOVEMBER 2011 TO FALL 2013, HALF A DOZEN COMPANIES REPRESENTED THERE. I THINK WHAT IT SAYS IS WE HAVE TO MAKE THE OPPORTUNITIES: WE HAVE TO GET THINGS TO A CERTAIN POINT AND MAKE THE OPPORTUNITY. >> SO NEXT IS SOMEONE -- HELLO? HELLO? [INAUDIBLE] CHAD, THANK YOU FOR BEING HERE. >> HELLO? CAN YOU HEAR ME? HELLO? YOU GUYS HEAR ME? THANK YOU VERY MUCH FOR THAT INTRODUCTION. IT REALLY IS A PLEASURE TO BE HERE WITH YOU ALL. I GREW UP JUST RIGHT DOWN THE ROAD, SO IT'S VERY NICE TO GET BACK TO THIS PART OF THE COUNTRY THIS TIME OF YEAR. SO I'LL BE TALKING ABOUT THE DEVELOPMENT AND USE AND IMPLEMENTATION OF PATIENT-REPORTED OUT COME MEASURES IN BOTH MYOTONIC DYSTROPHY AND FSHD DYSTROPHY. BEFORE I START, I'D LIKE TO THANK DIFFERENT ORGANIZATIONS WHO HAVE PROVIDED FUNDING OVER THE YEARS FOR OUR RESEARCH, INCLUDING NIAMS THROUGH A K AWARD AND MORE RECENTLY -- THE MDF, AND I'M THE FOUNDER OF THE NEUROMUSCULAR INSTITUTE OF QUALITY OF LIFE STUDIES. I WANT TO START WITH A QUOTE THAT HAS BEEN ATTRIBUTED TO ALBERT EINSTEIN, REPORTEDLY THIS WAS ON A PLAQUE IN HIS OFFICE WHEN HE WORKED AT PRINCETON, AND HE SAID, "NOT EVERYTHING THAT COUNTS CAN BE COUNTED, AND NOT EVERYTHING THAT CAN BE COUNTED COUNTS." AND I THINK THIS IS REALLY TRUE IN GENERAL, BUT ESPECIALLY TRUE IN PATIENT-REPORTED OUTCOMES AND OUTCOME MEASURE USE FOR MUSCULAR DYSTROPHIES. IT REALLY IS ESSENTIAL TO HAVE IDEAL AND OPTIMAL OUTCOME MEASURES FOR OUR CLINICAL TRIALS BEFORE WE CAN MOVE FORWARD WITH OPTIMAL EXPERIMENTAL THERAPEUTIC TRIALS, WE REALLY HAVE TO HAVE THE INFRASTRUCTURE AND THE OUTCOME MEASURES THAT ARE CAPABLE OF MEASURING CLINICALLY RELEVANT END POINTS DURING OUR TRIALS. AND THE DANGERS OF A BAD OUT COME ARE IMMENSE. THERE'S THE POTENTIAL TO REJECT A THERAPY THAT HAS A BENEFIT IN AN AREA NOT MEASURED BY A CHOSEN OUTCOME, BUT PERHAPS MORE DEVASTATING IS TO APPROVE A THERAPY BASED ON A STATISTICAL SIGNIFICANT CHANGE IN AN AREA THAT IS MEANINGLESS TO A PATIENT. I THINK BOTH OF THESE SITUATIONS HAVE HAPPENED IN THE PAST IN MUSCULAR DYSTROPHY RESEARCH. SO WE STARTED DEVELOPING AN INSTRUMENT FOR MYOTONIC DYSTROPHY TYPE 1, WE STARTED THIS SEVERAL YEARS AGO, AND AS MANY OF YOU KNOW, THIS IS AN AUTO SOMOL DOMINANT DISORDER THAT IS CAUSED BY CTG REPEAT EXPANSION ON CHROMOSOME 19. HERE WE SEE AN EXAMPLE OF WHAT'S CALLED JE NE IT TICK ANTICIPATION. ON THE LEFT, YOU SEE A FATHER AND ON THE RIGHT HIS SON, AND YOU SEE THAT THE SYMPTOMS ACTUALLY PROGRESSED FROM ONE GENERATION TO THE OTHER. THE SON HAS MORE MARKED PTOSIS OR EYELID DROOPING ATROPHY AT HIS TEMPLE REGION AND FOREARM. AND CURRENTLY THERE'S NO CURE FOR THIS DISEASE, BUT PATIENTS LIVE WELL INTO A ADULTHOOD, SO MORTALITY IS NOT REALLY AN OPTIMAL OUTCOME IN THIS POPULATION, SO THE USE OF A PATIENT-REPORTED OUT COME, WHICH IS CAPABLE OF REALLY DETERMINING THE PATIENT'S OWN PERCEPTION OF THEIR DISEASE, IS A GOOD IDEA. BUT NOT JUST ANY OUT COME IS OPTIMAL OR WILL DO, ESPECIALLY FOR A PATIEN PATIENT-REPORTED OUT COME MEASURE. IT MUST BE MEANINGFUL TO PATIENTS, MUST MEASURE SOMETHING MEANINGFUL, MUST BE RELIABLE, AND IT MUST HAVE THABILITY TO DETECT CHANGE IN A LONGITUDINAL FASHION, MUST HAVE -- YOU CAN'T HAVE HIGH CEILING OR FLOOR EFFECT. YOU HAVE TO HAVE INTERITEM CORRELATION, WHICH IS STATISTICAL COMPONENT OF THE INSTRUMENT. YOU HAVE TO HAVE LIMITED PATIENT BURDEN, IT'S NOT FEASIBLE TO GIVE AN INSTRUMENT THAT TAKES AN HOUR, HOUR AND A HALF, OR IS UNCOMFORTABLE FOR A PATIENT TO COMPLETE. YOU HAVE TO HAVE A GOOD REASONABLE RECALL PERIOD, YOU CAN'T ASK A PATIENT HOW HAVE YOU BEEN DOING OVER THE LAST YEAR, BECAUSE REALLY THEY CAN'T REMEMBER, AND MOST IMPORTANTLY, IT HAS TO BE VALID. IN ORDER TO ACCOMPLISH THE TASK OF DEVELOPING DISEASE-SPECIFIC PATIENT-REPORTED OUT COME MEASURES, WE CREATED A NETWORK CENTER AT THE UNIVERSITY OF ROCHESTER, THIS INCLUDED NIH MEMBERS OF PROMISE, NEURO-QOL, EPIDEMIOLOGISTS, STATISTICIANS, LINK GISES, NEUROLOGY PATIENTS. WE WERE REALLY FORTUNATE TO HAVE SOME GUIDANCE PROVIDED BY THE FDA. THEY KIND OF LAUNCHED THE BOMBSHELL IN 2009 BY PRODUCING THIS GUIDANCE FOR INDUSTRY OF HOW PATIENT-REPORTED OUT COME MEASURES ARE NOT ONLY USEFUL IN TRIALS BUT CAN BE USED TO SUPPORT LABELING CLAIMS IF THEY ARE DEVELOPED CORRECTLY. WHAT WE DID IS WE REALLY SET OUT TO MEET ALL OF THEIR GUIDELINES THAT THEY SET FORTH AND ACTUALLY GO BEYOND THOSE BECAUSE SO MUCH IS AT STAKE FOR DEVELOPING GOOD OUT COME MEASURES FOR THIS POPULATION. SO THE FIRST QUESTION WE THOUGHT WAS ESSENTIAL TO ASK IS WHAT SYMPTOMS AND ISSUES HAVE THE GREATEST EFFECT ON MYOTONIC DYSTROPHY PATIENTS? SO WE WANTED TO START FROM THE VERY BEGINNING AND FIGURE OUT WHAT WE SHOULD BE MEASURING DURING OUR CLINICAL TRIALS. THIS LED TO THE PRISM 1 STUDY, WHICH IS PATIENT-REPORTED IMPACT OF SYMPTOMS FOR MYOTONIC DYSTROPHY TYPE 1. WE SUBSEQUENTLY PUBLISHED THIS IN 2012 IN THE GREEN NEUROLOGY JOURNAL SO YOU CAN READ MORE ABOUT THAT THERE. AND OUR SPECIFIC AIMS WERE TO USE DIRECT PATIENT INPUT TO IDENTIFY THE SYMPTOMS THAT ARE MOST COMMON TO AI ADULT MYOTONIC DYSTROPHY PATIENTS AND WHAT IS MOST IMPORTANT TO THEM. WE DIDN'T THINK THAT THESE WOULD BE THE SAME. OUR PARTICIPANTS WERE ADULTS, GENETICALLY CONFIRMED DM1, AND WE UTILIZED MEMBERS OF THE NATIONAL REGISTRY OF DM1 AND PATIENTS AND FAMILY MEMBERS HEADQUARTERED AT UNIVERSITY OF ROCH ROCHESTER. THERE ARE TWO PHASES TO THE TRIAL, FIRST WITH QUALITATIVE INTERVIEWS WITH DM1 PARTICIPANTS, THE SECOND ONE WAS A LARGE CROSS-SECTIONAL VALIDATION STUDY, SO PHASE 1, WE ASKED OPEN-ENDED QUESTION, WE JUST BRIEFLY SAID TELL US WHAT SYMPTOMS AND ISSUES HAVE THE HIGHEST IMPACT ON YOUR LIFE. WE LIST THEM, REPORT IT, ANALYZE WHAT THEY SAID, WE COLLECTED OVER A THOUSAND QUOTES, SO WE TOOK THOSE THOUSAND QUOTES, WE HAD A TEAM TO ANALYZE THESE QUOTES AND WE IDENTIFIED 221 POTENTIALLY IMPORTANT SYMPTOMS TO MYOTONIC DYSTROPHY. WE FURTHER BROKE THOSE DOWN TO IDENTIFY 14 MAJOR THEMES REPRESENTING PHYSICAL HEALTH, MENTAL HEALTH, SOCIAL HEALTH, THEN DM1 SPECIFIC HEALTH. SO WHAT DID WE COME UP WITH? WELL, SOME OF THESE WERE SURPRISING, SOME WERE NOT. PROBLEMS WITH HANDS OR ARMS, FATIGUE, MYOTONIA, SLEEP OR DAY TIME SLEEPINESS, INABILITY TO DO ACTIVITIES, GASTROINTESTINAL ISSUES, PAIN, PROBLEMS WITH VISION, HEARING, SMELL, DECREASED PERFORMANCE IN SOCIAL SITUATIONS, EMOTIONAL ISSUES, COMMUNICATION ISSUES, DIFFICULTY THINKING. THIS IS ONE OF THE MOST DIVERSE SYMPTOMATIC DISEASES KNOWN TO HUMANS AND WE ACTUALLY KIND OF VALIDATED THAT. BUT JUST BECAUSE PATIENTS TOLD US IN INTERVIEWS, THAT'S NOT NECESSARILY CORRECT. YOU MIGHT GET A PATIENT THAT IS SAYING THINGS NOT REPRESENTATIVE OF THE GREATER POPULATION, SO WE FELT A VALIDATION STUDY WAS NEEDED SO WE TOOK ALL OF THESE SYMPTOMS, ALL OF THESE, WE SENT THEM TO A LOT OF PATIENTS, WE HAD THEM BASICALLY SAY, A, DO YOU HAVE THE SYMPTOM, IF SO, HOW MUCH IMPACT DOES IT HAVE ON YOUR LIFE? THIS IS AN EXAMPLE OF OW WE DID THIS, SO FOR INSTANCE WE SAY DO YOU HAVE PROBLEMS WITH YOUR HANDS OR FINGERS AND THEY'LL CHECK I DON'T EXPERIENCE THIS, I EXPERIENCE IT, BUT IT DOES NOT AFFECT MY LIFE, IT AFFECTS MY LIFE A LITTLE, MODERATELY, VERY MUCH OR SEVERELY. SO 278 PATIENTS PARTICIPATED AS ONE OF THE LARGEST DM1 TRIALS THAT'S BEEN COMPLETED. THE 52% RESPONSE RATE, WE DID NOT PAY PATIENTS, SO THIS WAS -- WE WERE HAPPY WITH THAT RESPONSE RATE. 43 STATES IN THE UNITED STATES WERE REPRESENTED, AS WAS CANADA. WE HAD WHITE, BLACK, ASIAN AMERICAN, ALASKAN, LATINO AMERICANS WERE ALL REPRESENTED, AND ALL TOGETHER, THEY RESPONDED TO OVER 40,000 QUESTIONS. 53% WERE MEN, 47% WERE WOMEN, MEAN AGE WAS 47, WE GAVE THE OPTION TO RESPOND BY PHONE BECAUSE SOME PATIENTS HAVE SEVERE WEAKNESS OF THEIR HANDS AND WOULD NOT BE ABLE TO FILL OUT A QUESTIONNAIRE. IN GENERAL, THIS WAS A HIGHLY EDUCATED POPULATION OF MYOTONIC DYSTROPHY PATIENTS. ABOUT 34% HAD A COLLEGE EDUCATION. 16% HAD EITHER A MASTER'S OR DOCTORATE DEGREE. THIS IS JUST KIND OF AN OVERALL SUMMARY, STARTED WITH 20 PATIENTS, GOT A THOUSAND QUOTES, WE IDENTIFY 221 POTENTIAL ISSUES OF IMPORTANCE, REPRESENTING THESE THEMES, WE THEN SEND IT 278 PATIENTS SAID IF THEY HAD THESE SYMPTOMS, WE GOT PREVALENCE OF THE SYMPTOMS, RELATIVE IMPORTANCE. WE WERE ALSO ABLE TO DEVELOP SOME RELATIONSHIPS BETWEEN PATIENT AGE, GENDER, CTG, REPEAT LENGTH, DURATION OF SYMPTOMS AND SEVERITY OF THESE SYMPTOMS. SO WHAT WAS THE MOST IMPORTANT? 93.5% OF PATIENTS HAD PROBLEMS WITH THEIR HANDS, 90% HAD FATIGUE, 90% HAD MYOTONIA, AND 87% HAD SLEEP OR DAY TIME AREAS, BUT AMONGST ALL OF OUR THEMES THAT WE IDENTIFY INITIALLY WITH OUR QUALITATIVE INTERVIEWS, ALL OF THEM HAD A PREVALENCE GREATER THAN 50%. WHAT WAS REALLY INTERESTING IS WHEN YOU GRAPH THESE OUT BY AGE, HERE YOU SEE THE PREVALENCE OF DIFFERENT THEMES, AND ON THE BOTTOM WE HAVE DIFFERENT DECADES OF AGE, 21 TO 30, 31 TO 40, 41 TO 50, 51 TO 60, AND 60. THERE WAS A MARKED JUMP IN THE PREVALENCE OF MANY OF THESE ISSUES BETWEEN THE 21 TO 30 AND 31 TO 40-YEAR-OLD DECADE. PERHAPS SUGGESTING THAT A PROGRESSION OF DISEASE DEVELOPMENT OCCURS DURING THAT TIME. THOSE WERE THE THEMES, THE 221 SYMPTOMS, SLIGHTLY DIFFERENT. ENERGY, DECREASED ENERGY, DAY TIME SLEEPINESS, MYOTONIA, HAND WEAKNESS, DIFFICULTY OPENING JARS, AND TIRED MUST ELSE WERE ALL FREQUENTLY REPORTED BY PATIENTS. BUT WHAT IS MOST PREVALENT IN A POPULATION IS NOT ALWAYS WHAT'S MOST IMPORTANT. SO WE WENT TO LOOK AT THIS. THEY SCALED IT OR THEY ACTUALLY PROVIDE THIS DATA, ZERO NO IMPACT, UP TO 4, IT AFFECTS THEIR LIFE SEVERELY FOR EACH OF THE SYMPTOMS THEY HAD, AND IT WASN'T THE SAME AS WHAT WAS MOST PREVALENT. IN FACT, THE SYMPTOM THAT HAD THE GREATEST IMPACT ON THIS POPULATION'S LIFE WAS ACTUALLY FATIGUE. WASN'T MYOTONIA, WASN'T MOBILITY AND WASN'T HAND WEAKNESS, ALTHOUGH ALL OF THOSE WERE ALSO IMPORTANT. SO WHAT WERE THE KEY POINTS OF THAT STUDY? THERE ARE MANY ISSUES THAT AFFECT A POPULATION WITH MUSCULAR DYSTROPHY. MOST FREQUENT OCCURRING ARE NOT THE ONES THAT ARE MOST IMPORTANT IN ALL CASES. THERE'S THE DRAMATIC INCREASE IN FREQUENCY AND IMPACT OF DISEASE BETWEEN 25 AND 35 YEARS OF A AGE. AND ONE OF THE INTERESTING THINGS WE FOUND IS WHY THE PREVALENCE OF DISEASE INCREASE WITH AGE, THE IMPACT DID NOT NECESSARILY DO THIS. SO THE OLDER PATIENTS ACTUALLY WEREN'T AS SEVERELY AFFECTED BY SOME OF THESE ISSUES. PERHAPS FINANCIAL REASONS, EXPERIENCE REASONS, SOCIAL NETWORKS, ET CETERA. SO THEY HAD THESE COPING MECHANISMS THAT WERE ABLE TO KIND OF COUNTERACT THE DISEASE. DM1 MEN AND WOMEN EXPERIENCE A SIMILAR DISEASE BURDEN. THE ONE EXCEPTION IS WE FOUND THAT MEN HAD HIGHER OR MORE DIFFICULTY WITH COMMUNICATION THAN WOMEN. WE THOUGHT MAYBE THAT WAS DUE TO THE Y CHROMOSOME AND MAYBE NOT THE DISEASE PROCESS. OKAY. SO WHY DID WE DO THIS? I THINK IT PROVIDED INTERESTING OVERVIEW OF MYOTONIC DYSTROPHY, BUT WHAT WE REALLY WANTED TO DO IS USE THIS INFORMATION TO TRANSITION AND BUILD THE IDEAL MYOTONIC DYSTROPHY -- FOR THEIR PEW IT TICK TRIALS. THIS IS HOW WE DID IT. HERE ARE THE PATIENT INTERVIEWS, LITERATURE REVIEW, WE GOT POTENTIAL AREAS OF IMPORTANCE, WE SEND IT TO THE REGISTRY, THEN WE GOT VALIDATED AND RANKED LIST OF SYMPTOMATIC ISSUE AND THEMES, WE PARTNERED WITH PROMIS, NEURO-QOL, WE TESTED IT THOROUGHLY BACK IN OUR MYOTONIC DYSTROPHY FIESHTS CREATE THE MYOTON YIK DYSTROPHY HEALTH INDEX. SO HOW DID WE SELECT THE QUESTION? WE STARTED OUT WITH THE 221 ISSUES THAT PATIENTS TOLD US WERE IMPORTANT. BUT NOT ALL OF THOSE ARE GOING TO LAND IN THE INSTRUMENT. SO WE GOT RID OF THE ONES THAT HAVE LOW RELEVANCE TO THE DM1 POPULATION. PATIENTS SAID ONE OF THE THINGS THAT AFFECTS MY LIFE IS MY FRIENDS DON'T UNDERSTAND H ME. WE'RE NOT GOING TO HAVE A THERAPEUTIC -- SOME PATIENTS SAY HEY, LOOK, I DON'T LIKE BEING PERCEIVED BY OTHERS AND DUMB. THIS IS POTENTIALLY -- WE DROPPED THESE QUESTIONS. SOME WERE VAGUE, AND THESE ARE PATIENTS' DIRECT WORDS INITIALLY IN OUR INITIAL RESEARCH. SO THEY SAID I HAVE WRITING DIFFICULTY. AT FIRST GLANCE, THIS MIGHT BE A GOOD QUESTION. BUT YOU KNOW, WHAT DO THEY MEAN? IS IT ACTUALLY WRITEING WITH A PEN OR PENCIL OR IS IT I HAVE DIFFICULTY WRITING A GREAT AMERICAN NOVEL? WE'RE NOT SURE, SO WE DROPPED SOME OF THESE. REDUNDANT QUESTIONS, LETHARGY WAS DETERMINED BY OUR LINGUIST TO BE TOO ADVANCED TERMINOLOGY, SO THAT WAS DROPPED. THEN SOME QUESTIONS WERE TIED TO AFFLUENCE, LIKE I HAVE DIFFICULTY UNCORKING MY WINE OR SNOW SKIING IN VALE, SO THESE QUESTIONS WERE DROPPED. WE THEN PROCESSED IT THROUGH FACTOR ANALYSIS WIT TO DETERMINE THE INTERNAL CONSISTENCY WITHIN EACH SUBGROUP OR THEME. WE WANTED TO MAKE SURE THAT QUESTIONS FIT TOGETHER AND THAT THE PATIENTS THAT WERE ANSWERING ONE QUESTION ONE WAY AND THE SAME THEME WERE ANSWERING THE SAME QUESTIONS IN A SIMILAR WAY. WE GOT STATISTICIANS TO HELP US WITH THIS AND BASICALLY MOVED QUESTIONS FROM ONE BANK TO ANOTHER. FOR INSTANCE, DIFFICULTY OPENING JARS, FOR WHATEVER REASON, FIT BETTER WITH INABILITY TO DO ACTIVITY SUBSCALE. WE ALSO IDENTIFIED THREE UNIQUE STATISTICAL THEMES THAT WE ADDED, CHOKING OR SWALLOWING DIFFICULTIES, HEARING DIFFICULTIES, AND BREATHING DIFFICULTIES WERE ADDED TO THE THEMES. SO THIS IS THE INSTRUMENT. IT'S ACTUALLY 17 SUBSCALES IN ONE, AND SO THERE'S 17 SUBSCALES ON THE ONE INSTRUMENT, AND THEY EACH UNIQUELY MEASURE THAT PARTICULAR THEME IN THIS POPULATION. SO THERE'S A MOBILITY SUBSCALE, 13 QUESTIONS, FATIGUE SUBSCALE. G.I. SUBSCALE, THINKING OR COGNITIVE SUBSCALE, PAIN SUBSCALE, ALL SPECIFICALLY SET FOR MYOTONIC DYSTROPHY TYPE 1. SO WHEN A PATIENT COMPLETES THIS, THEY GET 17 SCORES FOR EACH ONE OF THESE AREAS, BUT WE ALSO HAVE A COMPOSITE SCORE THAT IS WEIGHTED BASED ON HOW IMPORTANT THESE RELATIVE AREAS ARE TO THEIR LIVES. THAT WASN'T ENOUGH, WE SENT IT TO 10 PATIENTS TO DO BETA TESTING, SAID WHAT DO YOU THINK OF THIS INSTRUMENT, WHAT DO YOU THINK EACH SUBSCALE IS MEASURING, ARE THE INSTRUCTIONS CLEAR, DO YOU LIKE THE COLORS, CAN YOU COMPLETE IT, DO YOU GET FATIGUED WHEN YOU DO IT? WE DROPPED ONE QUESTION IN THIS PROCESS. VISUAL SPATIAL DIFFICULTY. EVERY PATIENT TOLD US EXACTLY, THEY KNEW EXACTLY WHAT THAT MEANT, AND THEY ALL TOLD US SOMETHING COMPLETELY DIFFERENT. SO WE DROPPED THAT QUESTION. SIX QUESTIONS WERE REWORDED, A LOT OF OUR WOMEN PATIENTS WERE NICE AND SAID CRAMPING, YOU KNOW THERE'S DIFFERENT TYPES OF CRAMPING, SO WE HAD TO CHANGE THE WORDING AT SOME TIMES. AN THESE PATIENTS TOOK IN A THOROUGH EVALUATION OF THIS INSTRUMENT. IT TOOK THEM AVERAGE TIME OF 19 MINUTES. SO REALLY LOOKING IT THOROUGHLY OVER. SINCE THEN, WE THINK PATIENTS CAN COMPLETE THIS IN A LOT QUICKER TIME, ABOUT 10 MINUTES. THE SCORING ALGORITHM AS I MENTIONED, YOU COMPLETE THE SCORE, YOU GET 17 SCORES, THEN YOU GET A COMPOSITE SCORE. ZERO TO 100, IT'S A WEIGHTED SCORE. EACH QUESTION IS NOT A 1 TO 1 RATIO, IT'S WEIGHTED BASED ON HOW IMPORTANT IT IS TO THE POPULATION. SO WE THEN WANTED TO KNOW HOW RELIABLE THIS INSTRUMENT WAS. WE SENT IT TO 22 JENNETTE KRI CONFIRMED DM1 PATIENTS, THEY COMPLETED IT AT BASELINE, THE SECOND TIME WITHIN 30 DAYS. IT WAS IDEALLY VERY STRONG RELIABILITY WITH AN ICC OF .95. TWO QUESTIONS WERE DROPPED BECAUSE THEY WERE NOT RELIABLE. ONE OF THEM HAD TO DO WITH FOOT PAIN, THE OTHER ONE SIDE EFFECTS FROM MEDICATION. HERE'S A GRAPH OF OUR RELIABILITY DATA. YOU CAN SEE THE BASELINE VERSUS THE REPEAT TESTING AND VERY LINEAR,ICC OF .95. HOW VALID IS THIS INSTRUMENT? CAN IT DIFFERENTIATE BETWEEN GROUPS THAT ARE THOUGHT TO HAVE DIFFERENT LEVELS OF DISEASE OR DIFFERENT SEVERITIES OF DISEASE. WE BASICALLY GAVE IT TO DIFFERENT GROUPS, HIGHLY EDUCATED OR NOT HIGHLY EDUCATED, SYMPTOMS FOR LONG PERIOD OF TIME VERSUS SHORT PERIOD OF TIME, MALE AND FEMALE, AND WHAT WE FOUND IS THAT THIS INSTRUMENT WAS VERY WELL -- COULD DIFFERENTIATE BETWEEN THESE GROUPS OF MORE OR LESS SEE VEER DISEASE. YOU SEE THE RED VERSUS THE BLUE IS EMPLOYED VERSUS NON-EMPLOYED, HIGH VERSUS LOW CTG REPEAT LENGTH, AND THE TOTAL SCORE IS ACTUALLY ABLE TO DIFFERENTIATE BETWEEN THESE DIFFERENT GROUPS OF PATIENTS. WE ALSO LOOKED AT EACH ONE OF THE SUBSCALES AS IF THEY WERE WERE BEING USED IN ISOLATION AND WE SAW THE SAME THING, THAT THESE SUBSCALES WERE ABLE TO DIFFERENTIATE BETWEEN HIGHLY AFFECTED AND LESS AFFECTED PATIENTS. WE RECENTLY PUBLISHED THIS IN MUSCLE AND NERVE SO YOU CAN READ MORE ABOUT IT THERE. THEN WE DID THE COMFORT STUDY. THIS COMFORT STUDY WAS AN ADD-ON STUDY TO OUR WELLSTONE STUDY THAT WE'RE CURRENTLY DOING. WE WANTED TO DO HEAD TO HEAD COMPARISON OF THE MD HIGH VERSUS FUNCTIONAL AND OTHER TRADITIONAL OUT COME MEASURES THAT WE'VE USED HISTORICALLY IN OUR EXPERIMENTAL THERAPEUTIC TRIALS, SO WE DID A CROSS-SECTIONAL STUDY OF OUR DM1 PATIENTS COMPARED TO FUNCTIONAL TESTS, 18 GENERIC PROs, SEVEN PHYSICIAN ASSESSMENTS. WE COMPARED IT AGAINST -- SIX MINUTE WALK, LABORATORY TESTING, EMG DATA, STRENGTH TESTING, TIME TO GET UP AND GO, ABOUT EVERYTHING THAT'S EVER HISTORICALLY BEEN USED IN MYOTONIC DYSTROPHY TRIALS, WE COMPARED IT. 70 PATIENTS PATS PATE PARTICIPATED IN THIS. I KNOW THIS IS A LITTLE BIT SMALL, BUT I THINK THIS IS SUCH A STRIKING DATA SLIDE THAT I WANT TO GO THROUGH IT WITH YOU. SO UP AT THE TOP ARE OUR MD HIGH SCORE, SO THIS IS OUR COMPOSITE SCORE AND EACH OF OUR SUBSCALE SCORES ACROSS, AND THESE ARE THE FUNCTIONAL TESTS THAT WE GOT MMT SCORES, SIX-MINUTE WALK, EMG, ET CETERA, AND INITIALLY, WE THOUGHT THERE WOULD BE CORRELATION BETWEEN CERTAIN THINGS AND THESE FUNCTIONAL SCALES. THESE ARE WHAT WE CALLED BEFORE WE ACTUALLY DID THE STUDY, WHICH IS THE LITTLE X, SO THESE ARE WHAT WE THOUGHT WILL CORRELATE. AND WHAT THE RED IS ACTUALLY A STATISTICALLY SIGNIFICANT LESS THAN .05 P VALUE CORRELATION BETWEEN WHAT OUR INSTRUMENT FOUND AND WHAT THESE FUNCTIONAL MEASURES FOUND. SO IN A NUTSHELL, IF MMT WAS ABLE TO FIND THE DIFFERENCE IN A POPULATION, OUR MD HIGH WAS ALREADY THERE. SO THIS IS REALLY REASSURING DATA. IN FACT, THE MD HIGH WAS ABLE TO PREDICT EVERY ONE OF THESE FUNCTIONAL MEASURES EXCEPT PERDUE PEG BOARD TEST, I DON'T KNOW WHY THAT WASN'T A GOOD TEST, BUT IT SHOULD BE NOTED THAT OIR SUBSCALE OF HAND ARM AND EXTREMITY FUNCTION AND ABILITY TO ACTIVITY DID CORRELATE WITH THAT PARTICULAR TEST. SO HOW ARE WE USING THIS? WE ARE USING IT IN AN FDA FUNDED RANDOMIZED CLINICAL TRIAL, DOUBLE BLIND CLINICAL TRIAL. WE'RE USING IT IN OUR WELLSTONE LONGITUDINAL STUDIES, OUR D1 NETWORK STUDY. IT IS BEING USED IN EUROPEAN OPTIMISTIC TRIAL WHICH IS A LARGE SCALE MULTICENTER CLINICAL TRIAL IN EUROPE. IT'S BEING USED IN MULTIPLE SMALLER STUDIES THROUGHOUT THE COUNTRY, INCLUDING UNIVERSITY OF UTAH PREGNANCY STUDY. MULTIPLE OTHER TM1 RESEARCH INITIATIVES AND MULTIPLE DRUG COMPANIES HAVE COME TO ME AND SAID CHAD, THIS IS A TAPING POINT FOR US, BAW WE NOW HAVE AN OUT COME MEASURE, WE ARE MUCH MORE PRONE TO GO INTO THIS FIELD AND DO RESEARCH IN THIS FIELD BECAUSE WE HAVE AN END STAGE INFRASTRUCTURES HERE THAT WE CAN ACTUALLY MEASURE CLINICALLY RELEVANT BENEFIT DURING THERAPEUTIC TRIAL. SO THAT'S BEEN REASSURING TO ME. THE FINAL INSTRUMENT, 114 QUESTION, 17 AREAS OF SUBSCALE HEALTH, WE'VE LOOKED AT CONTENTS CONSTRUCT, RELIABILITY, REUPON SIEVENESS. WE'RE ALSO STUDYING THIS OVER A THREE YEAR PERIOD IN OUR WELLSTONE TRIAL. PATIENT BURDEN IS LOW, PATIENTS DO NOT MIND ANSWERING THESE QUESTIONS BECAUSE THEY'RE RELEVANT TO THEM, AND THE CONCURRENT VALIDITY IS ASSURED. OUR FUTURE DIRECTIONS IS, LIKE I SAID, WE HAVE ONE YEAR AND THREE YEAR DATA. WE HAVE -- WE'RE GOING TO DETERMINE THE MINIMALLY CLINICALLY IMPORTANT DIFFERENCE OF THIS INSTRUMENT AND ITS SUBSCALES, ADDITIONAL RESPONSIVENESS DATA. WE WANT AN MD HIGH ONLINE, WE WANT TO USE IT IN OUR NEUROMUSCULAR CLINICS, OUR MDA CLINICS. WE WANT TO USE IT AS A MODEL FOR DEVELOPMENT OF OTHER DISEASE-SPECIFIC INSTRUMENTS, AND WE ARE DOING THAT. WE HAVE ANOTHER INSTRUMENT FOR FSHD CALLED THE FSHD-HI, WHICH IS NEARLY COMPLETED AT THIS POINT. AND WHAT'S INTERESTING IS THE QUESTIONS ARE DIFFERENT AND THE THEMES ARE DIFFERENT, EVEN AMONGST ANOTHER SIMILAR ADULT MUSCULAR DYSTROPHY. AND WE ARE VALIDATING THAT WITH THE CROM FISH STUDY, THIS IS SUPPORTED THROUGH NIAMS AND PARTIALLY THROUGH FSH SOCIETY, AND THIS IS DESIGNED TO BE AMONGST A VALIDATION STUDY, IT'S DESIGNED TO AB SPRING TBORD FOR FSHD THERAPY PEW TICK TRIALS AND CLINICAL TRIAL READINESS. WE ALSO HAVE INSTRUMENTS AT DIFFERENT LEVELS OF DEVELOPMENT, ONE FOR DM2. WE FIGURED OUT HOW TO DO WITH THIS KIDS WITH CONGENITAL MYOTONIC DYSTROPHY, WE HAVE VERY GOOD DATA FOR THAT. WE ALSO HAVE ONE FOR CMT1A, WE'RE WORKING ON INCLUSION BODY MYOSITIS, WE HOPE TO START WITH FMA SHORTLY, AND WE'VE WORKED WITH CURT FISCHBECK TO DEVELOP ONE FOR KENNEDY'S DISEASE. THAT'S IT, THANK YOU. [APPLAUSE] >> THANKS VERY MUCH. WE HAVE TIME FOR ONE QUESTION BEFORE LUNCH. [INAUDIBLE] WHAT IS THE LIFE SPEEXPECTANCY -- [INAUDIBLE] >> ALTHOUGH THE EXACT LIFE EXPECTANCY FOR DM1 HAS NEVER BEEN SPECIFICALLY STATED, WE SUSPECT THAT IT'S LATE 60s, EARLY 70s, SO NOT A DRAMATIC REDUCTION IN LIFE EXPECTANCY. THE TAILING OFF OF THE PREVALENCE AND THE VERY HIGH -- THE ADVANCED AGE PATIENTS WITH DM1, I THINK IS AN ARTIFACT, IS A SURVIVAL BIAS ARTIFACT, IN THAT THE PATIENTS THAT PARTICIPATED THAT WERE IN THEIR 70s WERE, BY DEFINITION, PROBABLY HEALTHIER PATIENTS THAN THE REST OF THE PATIENTS, AND SO OUR THOUGHT WAS THE DROPOFF IN THE PREVALENCE OF SOME OF THE SYMPTOMS IN THAT AGE GROUP WAS REALLY NOT BECAUSE THEY GET BETTER AS THEY GET OLDER, BUT RATHER SURVIVAL ARTIFACTS. >> VERY GOOD. LET'S BREAK FOR LUNCH NOW. WE WILL START AGAIN IN 20 MINUTES. [INAUDIBLE] SO LET'S COME BACK FROM LUNCH IN 20 MINUTES. >> I HATE TO INTERRUPT, WE'RE OBVIOUSLY HAVING INTERESTING AND I EXPECT FRUITFUL CONVERSATIONS IN DIET, TRIADS AND OTHER -- DYADS TRIADS AND OTHER SMALL GROUPS BUT WE THOUGHT IT WOULD BE GOOD TIME TO HAVE A MORE GENERAL DISCUSSION AND FOLLOW-UP WITH SOME QUESTIONS THAT MAY HAVE ARISEN DURING THE MORNING PRESENTATION EITHER ABOUT PRESENTATIONS SPECIFICALLY OR ABOUT THE PRESENTATIONS IN GENERAL. THEMES THAT EMERGEDDED FROM THE CENTER. SO I (INAUDIBLE) 15, 20 MINUTES OF CONVERSATIONS, QUESTIONS, DISCUSSION, BEFORE WE TURN IT OVER TO JOHN FOR HIS PRESENTATION. >> I WOULD LIKE TO MAKE A QUICK COMMENT. (OFF MIC) >> MY COMMENT TO JIM BUT A GENERAL COMMENT, THAT IS THAT ONE OF THE THINGS THAT THE FSH GROUP THAT'S REALLY DONE VERY, VERY WELL, IS TO POINT OUT TO THE INVESTIGATORS THE FUNDING OPPORTUNITY ANNOUNCEMENTS THAT COME NOT ONLY FROM THE NIH BUT OTHER ORGANIZATIONS AND ONE OF THE GREAT CHALLENGES WE HAVE AT THE NIH IS COMMUNICATION. IT JUST -- PEOPLE ARE SO BUSY, JUST SO BUSY, THEY'RE INUNDATED WITH INFORMATION THAT'S COMING FROM THEIR UNIVERSITIES AND ACADEMIC HEALTH CENTERS, SO FOR US WHAT WE 'ALLY TRY TO DO IS, WE AS AN INSTITUTE SEND OUT INFORMATION TO PEOPLE WHO ARE PART OF OUR COALITION, TO REALLY ALMOST ANYBODY WHO WILL GIVE US THEIR ADDRESS FOR OUR FUNDING OPPORTUNITIES. AND I THINK IT EYE REALLY IMPORTANT AND I THINK DAN ACTUALLY DID THAT, STARTED DOING THAT AND DID IT VERY, VERY WELL SO THE IMMUNITY IS AWARE OF NOT ONLY WHAT GOES ON AT NIH BUT ELSEWHERE, TRAINING OPPORTUNITIES, EVERY ONE OF THE FUNDING OPPORTUNITIES, IT'S A REALLY IMPORTANT THING. THAT ALSO IS REALLY A PART OF OUR PARTNERSHIP IN TERMS OF MOVING THE FIELD FORWARD. >> I JUST WANTED TO MAKE A GENERAL COMMENT THAT -- SORRY. JUST THE ACT OF BRINGING THESE ORGANIZATIONS TOGETHER LIKE THIS ON A REGULARRING BASIS -- THIS IS MY FIRST TIME HERE BUT I HAVE LEARNED SO MUCH AND I'M JUST LIKE SCRIBING DOWN THE GREAT IDEA -- SCRIBBLING DOWN THE GREAT IDEAS AND THINKING I GOT TO BRING THIS BACK TO MY ORGANIZATION. AND I CAN ALSO IMAGINE THAT THAT KIND OF CROSS-FERTILIZATION IS ALREADY OCCURRING AND IS RESPONSIBLE FOR A LOT OF THE PROGRESS THAT'S TAKING PLACE. SO THAT'S JUST MY COMMENT. >> AND I THINK IN SOME WAYS THAT'S SET UP FOR THE CONVERSATION WE WILL HAVE TOWARDS THE END OF THE DAY HOW TO WE CAN BE COORDINATING MORE EFFECTIVELY AMONG OUR ORGANIZATIONS THAN WE CAN CURRENTLY ARE SO I THINK THAT'S AN IMPORTANT POINT. OTHER THOUGHTS, DISCUSSIONS, QUESTIONS, MAYBE EVEN THINGS THAT SPEAKERS DIDN'T GET TO SAY BECAUSE I PULLEDDED THEM OFF WITH A HOOK. >> ACTUALLY, I HAVE A QUESTION FOR CHAD. HOW DO YOU SEE THE PATIENT REPORTED OUTCOMES THAT YOU ALL ARE WORKING ON FOR THE NEUROMUSCULAR DISEASES INTERSECTING OR NOT WITH THE COMMON DATA ELEMENTS THAT NINDS HAS BEEN TRYING TO FORMALIZE FOR CLINICAL STUDIES? >> YEAH. I THINK THAT'S A VERY GOOD QUESTION AND I THINK IT'S SOMETHING TO POINT OUT AND TO HIGHLIGHT. IF WE HAVE THIS CONVERSATION IN FIVE YEARS, MAYBE THE MDHI IS PART OF THAT FOR THE MYOTONIA DYSTROPHY STUDIES. I THINK RIGHT NOW I THINK IT'S WORTHWHILE TO MAYBE KEEP IT A LITTLE BIT MORE OPEN, NOT REQUIRE RESEARCHERS TO PUT THINGS IN UNLESS THEY ABSOLUTELY HAVE TO. BUT I THINK AT A CERTAIN POINT ONCE ALL THE DATA COMES BACK, THAT MIGHT BE SOMETHING THAT YOU CAN POTENTIALLY INCLUDES TO THE COMMON DATA. >> SO CHAD, WE HAVE YOU INVOLVED IN EITHER THE MYOTONICKER FOR THE FSH GROUP, RIGHT? WE'RE LARGING CDEs FOR THOSE TWO DISEASES, CTE EFFORT. WE HAVE YOU INVOLVED IN ONE OF THOSE GROUPS, RIGHT? >> YEAH. >> YOU'RE THE MYOTONIC, THAT'S RIGHT. >> I'LL HIGHLIGHT SOMETHING. SO VALERIE MENTIONED I THINK NICE EXAMPLE WITH THE MENDELL GENE THERAPY TRIAL, THAT WE MADE PROGRESS BUT THAT YOU HAVE TO DOUBLE BACK AND HAVE TO KEEP RE-EVALUATING THINGS AND TAKE WHAT YOU LEARN FROM THAT AND TRY TO MOVE FORWARD. SO MDA AND NIH SAW THERE WERE THE SAME ISSUES IN OUR FUNDING FOR GENE THERAPY AND NEUROMUSCULAR DISEASES. THE ISSUES BEING WHAT'S THE APPROPRIATE RATIONALE TO LAUNCH A CLINICAL TRIAL? WHAT SORTS OF INFORMATION, HOW DO THE STUDIES NEED TO BE DONE BEFORE YOU DO THAT? WHAT ARE THE KEY REGULATORY QUESTIONS THAT HAVE TO BE ASKED AROUND GENE THERAPY SPECIFICALLY IN TALKING WITH CBER AND TRYING TO FORMULATE THOSE. FINALLY, WHAT ARE THE INTELLECTUAL PROPERTY ISSUES AND COMMERCIALIZATION AND HOW DO WE GET THERE? BECAUSE THERE'S ONLY ONE APPROVEDDED GENE THERAPY WORLDWIDE GLIBERA AND IT'S ONLY APPROVED IN EUROPE. FROM WHAT I UNDERSTAND THAT WAS FACILITATED A LITTLE BIT TO MOVE IT ALONG. WE SAW THE SAME -- MDA AND NIH SAW THE SAME ISSUES, SO THAT WORKSHOP THAT VALERIE MENTIONED WHICH I'LL JUST REITERATE WHEN I GO THROUGH ANIMY TALK, WE DECIDED TO DO THIS TOGETHER, IT'S SMALL WORKSHOP SO THERE'S LOT OF GOOD INTERACTION. BUT WE'RE GOING TO WEBCAST IT. SO IT WILL BE AVAILABLE ON THE NIH WEBCAST SITE AND WE CAN COPY EVERYBODY HERE WITH THE LINK. BUT APRIL 22ND, THAT WORKSHOP WILL BE STREAMED SO THAT ANYBODY THAT WANTS TO GET TO IT WILL BE ABLE TO GET TO IT. >> I WOULD JUST LIKE TO FLOWUP ON STORY'S QUESTION TO CHAD. ANNA TOUCHED ON IT AS WELL. WE'RE LOOKING AT A LOT OF DIFFERENT KINDS OF OUTCOME MEASURES. AND YOU MENTIONED THAT, YOU KNOW, WE'RE SORT OF OVERBURDENING PATIENTS, AND EVEN EVALUATORS, THEY GET TIRED. SO I THINK AS WE'RE GOING FORWARD WITH ALL THESE MEASURES THAT WE'RE DEVELOPING, WE HAVE TO BE VERY CAREFUL THAT THE OUTCOMES TRULY ARE MEASURING WHAT WE NEED THEM TO MEASURE AS CHAD SAID NICELY ELOQUENTLY HIGHLIGHTED. BUT IT'S SOMETHING THAT WE HAVE SEEN IN THE DUCHENNE COMMUNITY FOR A LONG TIME. WE NEED TO MAKE CERTAIN THAT WE DON'T JUST TRY AND CAPTURE SO MUCH THAT THE DATA WE'RE CAPTURING IS NOT GOING TO BE GOOD./m% >> MY FEELING IS THAT WE SHOULD REALLY START TO THINK ABOUT PATIENTS WITH MUSCLE DISEASE FROM A FUNCTIONAL CLASSIFICATION STANDPOINT AND THEN GROUP PATIENTS TOGETHER. SO EVEN THOUGH, YOU KNOW, THE PATIENT SPECIFIC OR DISEASE-SPECIFIC OUTCOME MEASURES ARE BEING DEVELOPED, I THINK THERE'S A LOT OF VALUE-ADDED FOR EXAMPLE, WHEN I COMPARE A PATIENT WITH COLLAGEN 6 WHO IS NON-AMBULANT ANDMYOPATHY PATIENT ON AMBULANT, THERE'S A LOT OF CROSS TALK AND KIND OF SHARED INTELLECTUAL CAPABILITY AND ADAPTIVE MEASURES THAT HAVE BEEN DEVELOPED TO DEAL WITH THEIR DISABILITY. AND I THINK THAT MAYBE WHAT WE SHOULD SPEND SOME OF OUR TIME THINKING ABOUT IS DOES IT MAKE SENSE TO GROUP PATIENTS INTO FUNCTIONAL CATEGORIES BASED UPON AMBULATORY STATUS, WHEN THE LOSS OF AMBULATION OCCURRED AND WHETHER THEY HAVE ANY COGNITIVE IMPAIRMENT AND REALLY START TO MORE FROM A GLOBAL POINT OF VIEW, LOOK AT WHAT TYPE OF OUTCOME MEASURES WOULD BE APPROPRIATE. WHEN CATEGORIZED IN THAT WAY. >> IN TERMS OF PATIENT REPORTED OUTCOMES? >> IN TERMS OF CLINICAL TRIAL ASSESSMENTS, PATIENT-REPORTED OUTCOMES, IN TERMS OF MANAGEMENT STRATEGIES, I MEAN, YOU COULD REALLY EXPAND IT. >> I THINK ONE OF THE BENEFITS OF DOING THIS OUTLAY IS SOCIAL SECURITY ADMINISTRATION ALLOWS THEIR DISABILITY DETERMINATION BASED UPON (INAUDIBLE) YOU DO HAVE A NICE STANDARDIZED WAY OF MEASURING THEM (INAUDIBLE) PATIENT REPORTED OUTCOMES TO MEASURE THEM, THEN IT ALLOWS THAT PROCESS TO MOVE A LOT FASTER. >> I THINK THIS IS MUCH LIKE WE SEE IN SOME OTHER RESEARCH COMMUNITIES ERE OBVIOUSLY THE BIOLOGIC ETIOLOGY MAYBE DISTINCT IN SOME WAYS BUT THE FUNCTIONAL IMPACT ARE SO SIMILAR, SO THE QUESTION IS HOW DO YOU -- WHERE DO YOU MUSH THINGS TOGETHER WHERE IT'S USEFUL TO DO THAT AND WHERE DO YOU ALSO SEPARATE THINGS OUT WHERE IT'S REALLY THE ONLY WAY TO MOVE FORWARD. I GUESS THE MOST IMPORTANT THING I HAVE OBSERVED OVER THE YEARS IS TO MAKE -- TO KNOW WHEN YOU'RE MUSHING AND KNOW WHEN YOU'RE SEPARATING. BECAUSE IT'S EASY TO LOSE TRACK OF THAT AND DO SOME OF THE -- BUT IF YOU'RE REALLY THOUGHTFUL ABOUT IT THEN CLEARLY IN TERMS OF THE FUNCTIONAL -- YOU CAN HAVE A FUNCTIONAL MEASURE, IT'S FUNCTION THAT DICTATES THAT KIND OF THING NOT ETIOLOGY WHILE IT CAN BE FORMATIVE IS LESS H THE FOCUS THERE. SO I THINK IN SOME WAYS IT ALSO SPEAKS IN SOME WAYS TO THE DOUBLE-EDGE SWORD OF HAVING SO MANY ORGANIZATIONS BE THEY NIH INSTITUTES OR HEALTH SPECIFIC ORGANIZATIONS THAT ARE AROUND THE TABLE. WE BRING DIFFERENT FOCI AND SOMETIMES IT'S VERY IMPORTANT THAT A REAL SYNERGY TO HAVE THOSE DIFFERENT FOCI AND SOMETIMES IT GETS A LITTLE BIT IN OUR WAY SO WE ALL NEED TO THINK TOGETHER ABOUT WHERE DO WE TAKE ADVANTAGE OF THESE MULTIPLE STREAMS AND WHEN IS IT MOST ADVANTAGEOUS TO COMBINE THEM. OTHER THOUGHTS OR QUESTIONS? OTHERWISE WE'LL HAVE TO MAKE JOHN GET UP AND GIVE US HIS TALK. >> THAT'S A VERY GOOD POINT. THANK YOU. THERE ARE NEW PEOPLE WHO HAVE ARRIVED. SINCE YOU'RE NEW AND ARRIVED YOU DON'T KNOW WE WENT AROUND ORIGINALLY AND INTRODUCED OURSELVES. THOSE THAT INTRODUCED OURSELVES ARE NOT GOING TO DO IT AGAIN IN CASE WE GET CAUGHT IN SOME INCONSISTENCY. HOWEVER THOSE NOT HERE AT THE START OF THE DAY WE WOULD LIKE YOU JUST IF YOU WOULD TO SAY WHO YOU ARE AND WHAT ORGANIZATION IF ANY, YOU REPRESENT, WHY ARE YOU HERE. >> HI, I'M RYAN FISHER, I'M THE DIRECTOR OF OUTREACH AND ADVOCACY FOR PROJECT MUSCULAR DYSTROPHY. >> I'M ALLISON (INAUDIBLE) A LOBBYIST, I WORK AT KING AND SPALDING AND WE REPRESENT MDA AND I'M ALSO A FAMILY MEMBER WHOSE FAMILY IS AFFECTED BY MYOTONIA MUSCULAR DYSTROPHY. >> I'M RICHARD INGRAM, I'M SCIENTIFIC REVIEW OFFICER FOR THE SKELETAL MUSCLE EXERCISE PHYSIOLOGY STUDY SECTION HERE AT CSR. >> HI, I'M DIANE BERRY, HEAD OF POLICY AND GOVERNMENT AFFAIRS FOR SREPTA. >> VERY GOOD. DR. PORTER, WOULD YOU LIKE TO TAKE THE STAGE? >> SURE. >> I GUESS YOU WANT AN INTRODUCTION, EVERYONE ELSE DID, I DON'T WANT TO (INAUDIBLE) YOUR SLIDES JOHN. JOHN T PROGRAM DIRECTOR, HERE AT NINDS, AND HE'S GOING TO GIVE US AN OVERVIEW OF NIH ACTIVITIES NOT JUST NINDS BUT NIH ACTIVITIES IN GENERAL UNDERTAKEN DURING THE TENURE OF THE MDCC ACTION PLAN. JOHN. >> THANKS. >> JOHN WHILE YOU'RE GETTING THAT READY SINCE I HAVE INTRODUCED YOU I'M TWOING THE TAKE ADVANTAGE OF THE MOMENT BEING THE CHAIR, MANY IF NOT EVERYONE IN THE ROOM ARE AWARE AND HAVE HEARD THAT JOHN IS PLANNING TO RETIRE FROM THE FEDERAL WORK FORCE. LUCKILY FOR US IT'S A SLOW RETIREMENT. HE WON'T BE LEAVING US UNTIL NEXT JANUARY. HE'S OBVIOUSLY BEEN SUCH AN IMPORTANT PART OF THIS WHOLE EFFORT THAT WE'RE GLAD HE WILL BE AROUND TO MAKE SURE THAT WE DO A COUPLE OF VERY IMPORTANT THINGS BEFORE HE LEAVES. WE IN FACT WILL PROBABLY HAVE A CHANCE TO GET TOGETHER AGAIN IN SEPTEMBER AS A GROUP BEFORE HE LEAVES. BUT THE FOUR INSTITUTES THAT ARE REPRESENTED HERE, NINDS, NIAMS, NICHD, NHLBI BY LEADERSHIP GOT TOGETHER STRESSING NO GOVERNMENT FUNDS FOR THIS, THOUGHT TO MARK OUR THANKS TO JOHN FOR EVERYTHING HE'S DONE. WE HAVE GONE OUT AND WILL SERVE Y'ALL WONDERFUL CUP CAKES DURING THE AFTERNOON BREAK IN HONOR OF JOHN AND ALL THAT HE'S DONE FOR US. JOHN, WE REALLY DO THANK YOU FOR EVERYTHING YOU HAVE DONE TO MOVE FORWARD THE AGENDA OF THIS GROUP TO DO IT IN SUCH A REALLY COLLABORATIVE FASHION, ET CETERA. SO CUB CAKES ARE THE LEAST -- CUB CAKES ARE THE LEAST WE CAN -- CUP CAKES ARE THE LEAST WE CAN DO TO THANK YOU. >> THANKS. I'M TRYING TO FIGURE OUT THE SYMBOLIC MESSAGE OF CUPCAKES. >> OKAY. I GUESS I TALKED WITH ALL THE OTHER SPEAKERS ABOUT WHAT WE'D LIKE THEM TO DO AND THEN I LOOKED AT THE NIH PORTFOLIO AND I THOUGHT HOW THE HELL AM I GOING TO DO THAT WITH THE NIH PORTFOLIO? SO I'M GOING TO TAKE A LITTLE BIT DIFFERENT APPROACH. I'M GOING TO TALK ABOUT WHAT ACTIVITIES WE HAVE UNDERTAKEN. SO IT'S GOING TO BE MORE ACTIVITY-BASED, LESS ON ACCOMPLISHMENTS. BUT I'LL TRY TO SLIP IN SOME OF THE ACCOMPLISHMENTS. AND AS GLENN SAID, I THINK, WELL, WHAT I'M GOING TO SUMMARIZE IS REALLY REPRESENTS THE ACTIVITIES OF THE FOUR MAJOR INSTITUTES THAT ARE FUNDING MUSCULAR DYSTROPHY. ONE OF THE GREAT -- THE GREAT THING ABOUT ANY JOB IS WHO YOU HAVE TO WORK WITH. AND I THINK WORKING WITH GLENN, MELISSA, TINA, AND JOHN FROM THE OTHER INSTITUTES HAS REALLY MADE THIS A LOT OF FUN, I THINK WE HAVE DONE A LOT OF COORDINATION ACROSS THE DIFFERENT COMPONENTS OF THE NIH AND TRYING TO HELP THINGS WORK MORE SMOOTHLY. ONE OF MY MANTRAS HAS REALLY BEEN TO -- I THINK WE HAVE TO OPERATE LESS IN A CREDIT MODEL IF WE'RE REALLY GOING TO GET AHEAD, AND PEOPLE NEED TO BE MORE WILLING TO LEVERAGE EACH OTHER'S RESOURCES AND TAKE LESS IN TERMS OF PERSONAL CREDIT FOR THINGS AND THAT'S THE ONLY WAY WE'RE GOING TO MAKE THINGS HAPPEN. SO I TRY -- I ALWAYS TRY TO EMPHASIZE WHAT GROUPS WORKED TOGETHER ON THINGS. I ACTUALLY, IT'S SO HARD BECAUSE WE'RE ALL DOING SO MUCH IN THIS DISEASE SPACE SO THE FIRST THING I WANT TO DO IS PUT UP AN APOLOGY, I WILL TALK ABOUT THINGS THAT INVOLVE MORE THAN ONE GROUP REPRESENTED HERE OR REPRESENTEDDED OUTSIDE OF HERE, AND IF I FAIL TO MENTION YOUR CONTRIBUTION TO THE EFFORT, IT'S JUST BECAUSE THERE'S SO MUCH GOING ON, LIKE I SAID, THE ONLY WAY WE'RE GOING TO GET ANYWHERE IS TO WORK TOGETHER. BUT I DON'T INTENTIONALLY LEAVE YOU OUT. I APOLOGIZE FOR THAT. SO THESE ARE THE 11 INSTITUTES PLUS THE DIRECTOR'S OFFICE AND THE ROADMAP PROGRAM THAT ARE CURRENTLY INVOLVED IN FUNDING RESEARCH IN MUSCULAR DYSTROPHY. THE ONES THAT ARE HIGHLIGHTED IN RED ARE THE ONES THAT HAVE REPRESENTATIVES ON THIS COMMITTEE. NHLBI, NIAMS NICHD, NINDS, THESE REPRESENT, I TOTALED THIS UP THIS WEEKEND, ABOUT 84% OF THE FUNDING IN MUSCULAR DYSTROPHY CODED FOR THAT YOU CAN FIND ON THE NIH REPORTER WEBSITE. SO THERE'S STILL SUBSTANTIAL CONTRIBUTIONS FROM OTHER INSTITUTES HERE. ONE OF THE ONES I WANT TO MENTION, I HIGHLIGHTED NIGMS, GENERAL MEDICAL SCIENCES, BECAUSE THAT -- WE TALKED A LOT ABOUT HOW IMPORTANT BASIC RESEARCH IS AND IN THE EMORY DRY FUSS MUSCULAR DYSTROPHIES NOT REPRESENTED ON THE THIS COMMITTEE, A LOT OF WORK IS STILL MECHANISTIC AND A LOT INVOLVES THE NUCLEAR ENVELOPE AND INTERACTIONS BETWEEN THE CYTOSKELETON AND NUCLEAR SKELETON. AND GMS FUNDS A LOT OF THAT. THAT'S REALLY IMPORTANT. THEY ALSO FUND A FAIR AMOUNT OF MYOTONIA DYSTROPHY IN TERMS OF GENERAL PROPERTIES OF TRIPLE REPEAT DISORDERS. BUT THIS IS REALLY THE GROUP OF AGENCIES THAT WE'RE TALKING ABOUT SUPPORTING RESEARCH IN MUSCULAR DYSTROPHY. THE MOST CURRENTLY RELEASED DATA FROM NIH WHICH IS FISCAL 2013. IN THE TALK TODAY, I WANT TO GIVE FIRST A BROAD REVIEW OF NIH FUNDING FOR THE TIME FRAME OF THE ACTION PLAN. SO ABOUT 8 YEARS. AS THEY SAY IT REFLECTS MAINLY THE ACTIVITIES OF THESE FOUR INSTITUTES BUT THERE IS THAT 16% CONTRIBUTION FROM OTHER INSTITUTES IN FUNDING. THEN TAKE A LOOK AT WHAT INITIATIVES WE HAVE UNDERTAKEN AND WHAT WORKSHOPS AND HOW THESE HAVE CONTRIBUTED TO ADVANCING THE FIELD OF MUSCULAR DYSTROPHY. TALK A BIT ABOUT OPTIMIZING OUR EFFORTS WITH MORE RIGOR AND THOSE OF YOU IN ADVOCACY GROUPS KNOW THAT YOU HAVE GOTTEN EMAILS FROM ME ALMOST MONTHLY OVER THE LAST YEAR WHEN WE'RE TRYING TO PUSH THE IDEA OF DOING THE PRE-CLINICAL STUDIES MUCH MORE RIGOROUSLY MAKING SURE WHAT GOES TO CLINICAL TRIALS HAS BEEN CHECKED OUT. I'LL TALK A LITTLE BIT ABOUT THAT EFFORT AS WELL AS SOMETHING WE'RE STARTING TO LOOK AT WITH NINDS, LESSONS LEARNED FROM RUNNING THESE LARGE TRANSLATIONAL PROJECTS. SOMETHING MENTIONED ALREADY, VALERIE PARTICULARLY TOUCHED ON IT AND GLENN CERTAINLY TOUCHED ON IT WITH THE WELLSTONE IS THE IDEA OF NEXTGEN TRAINING, THE NEXT GENERATION OF NEUROLOGISTS AND BASIC RESEARCHERS AND CARDIOLOGISTS AND EVERYBODY ELSE THAT WORKS ON THE MUSCULAR DYSTROPHIES AND HOW WE'RE GOING DO THAT OR NOT DOING THAT, MAYBE HOW WE NEED TO DO THAT BETTER THAN WHETHER WE'RE DOING. FINALLY THEN SAY A COUPLE OF WORDS ABOUT WHAT'S NEXT FOR THE EFFORT. SO THIS IS A GRAPH I SHOW EVERY SINGLE TIME AT THIS MEETING. AND IT SHOWS THE PROGRESSION OF FUNDING IN THE MUSCULAR DYSTROPHIES, NIH FUNDING IN THE MUSCULAR DYSTROPHIES STARTING WITH 1998 WHERE IT'S LESS THAN 20 MILLION TO THE CURRENT YEAR WHERE THE TOTAL MUSCULAR DYSTROPHY FUNDING IS ABOUT 76 MILLION. SO IN 2004 WE STARTEDDED CODING FOR SUBPOPULATIONS OF MUSCULAR DYSTROPHY SO YOU SEE THE NUMBERS OF DUCHENNE AND BECKER MYOTONIC AND IF THE HAD HERE. AS -- FSHD HERE. THERE'S NOT ENOUGH MONEY FOR THE MUSCULAR DYSTROPHIES, EVERYBODY FEELS THE FUNDING LEVELS COULD BE HIGHER. THERE'S A NUMBER OF FACTORS THAT INFLUENCE THAT THAT WE CAN TALK ABOUT. BUT THIS IS THE OVERALL FUNDING PATTERN. TWO THINGS I WANT TO NOTE FOR THIS, FIRST THIS BIG JUMP IN 2009, 2010. MISDEMEANOR THAT'S WHEN THE STIMULUS PACKAGE KICKED IN. THE AMERICAN RECOVERY AND P REINVESTMENT ACT FOR THOSE TWO YEARS. TO SHOW YOU IMPACT DURING THAT TIME I PUT THE GREEN LINES ACROSS THOSE TWO BARS TO SHOW YOU WHERE THE FUNDING WOULD BE IF WE DIDN'T HAVE THE STIMULUS PACKAGE. SO IT CONTRIBUTED ABOUT 17 MILLION IN 2009 AND ABOUT 12 MILLION IN 2010. SO I THINK YOU CAN SEE IT DEFINITELY HAD AN IMPACT BUT HEARSAY YOU SEE THE IMPACT OF THE LOSS OF THAT FUNDING AND WHERE THE FIELD BASICALLY DROPPED DOWN TO WHERE WE ARE TODAY. THE OTHER THING I WANT TO POINT OUT IS THAT THE ACTION PLAN WAS APPROVEDDED BY THIS COMMITTEE IN 2006. I'M NOT SAYING THAT IT WAS DIRECTLY RESPONSIBLE FOR THE GROWTH BUT I THINK WE HAVE BEEN ABLE TO HELP MANAGE THIS GROWTH AND HELP ENCOURAGE CERTAIN TYPES OF ACTIVITIES. THROUGH USE OF THE PLAN AND NOT ONLY NIH BUT ACROSS ALL YOUR OTHER ORGANIZATIONS. MAYBE I JUST PAUSE A SECOND HERE. ANY QUESTIONS ON THE DATA HERE? ANY COMMENTS ON THE DATA HERE? >> I WOULD JUST SAY IT'S PRETTY EXTRAORDINARY THAT DESPITE THE FACT THAT NIH ACROSS THE BOARD GOT A 5.7% CUT WITH THE SEQUESTER, THAT YOU DON'T SEE A DRAW IN THE FUNDING FOR MUSCULAR DYSTROPHY. >> SO THIS IS 2013 IS THE LATEST DATA HERE. >> SO 2013 YOU SHOULD HAVE SEEN. >> SHOULD HAVE SEEN A LITTLE BIT. YES. >> NO, 5%. I DON'T SEE A 5% CUT. I MEAN, THAT'S AMAZING. FOR PARKINSON'S AND EPILEPSY IT WAS PRETTY SIGNIFICANT DECREASE WHICH WE HAD TO TRY TO FIGURE OUT WHY. AMAZING. >> ANYTHING ELSE? GOOD. SO WHAT I DID IS I TABULATED THE DOLLARS ACROSS THE YEARS, THE EIGHT YEARS OF THE ACTION PLAN. THAT'S WHAT I'M SHOWING HERE. SO THE RCDC CATEGORY, RCDC IS HOW WE CODE DISEASES, THERE'S AN AUTOMATED PROCESS FOR THAT NOW, IT USED TO BE DONE BY INDIVIDUAL PROGRAM DIRECTORS, NOW IT'S DONE BY COMPUTER FINGERPRINT THAT WE HAVE GENERATED. THESE ARE THE CATEGORYD REQUIRED BY CONGRESS TO REPORT ON FOR MUSCULAR DYSTROPHY. SO OVER THAT TIME, SINCE WE LAUNCHED THE ACTION PLAN YOU CAN SEE $538 MILLION IN FUNDING FOR MUSCULAR DYSTROPHY FROM THE NIH ACROSS THAT TIME. SO I THINK THAT'S A PRETTY IMPRESSIVE NUMBER. WE -- WITHIN THAT CATEGORY WE SUBCODE, AS I SAID, CURRENTLY THREE TYPES, CONGENITAL MUSCULAR DYSTROPHY HAS BEEN ADDED FOR 2014. WHICH THAT'S AS I SAY CONGRESS ASKS US TO ADD PARTICULAR DISEASE CATEGORIES SO YOU CAN DRAW YOUR OWN CONCLUSIONS AROUND THE TABLE. DUCHENNE BECKER 233 MILLION DURING THAT TIME, FSH 36 MILLION, AND MYOTONIA DYSTROPHY, 78 MILLION. AND AGAIN, -- MYOTONIC DYSTROPHY, 78 MILLION. I KNOW WE UNDERSTAND THERE COULD BE A LOT MORE FUND FOR EACH CATEGORY BUT THIS IS WHERE WE ARE AS FAR AS MUSCULAR DYSTROPHY FOR THIS TIME FRAME. YEAH. (OFF MIC) >> RIGHT. WELL, SO PERCENTAGE WISE, RIGHT, GLENN? IT'S PERCENTAGE WISE THINGS ARE DIVIDED BETWEEN CATEGORIES. NO? OKAY. SO IT'S CROSS CODED. YOU SEE THEY ALSO DON'T ADD UP TO THE 538 MILLION. THAT DOESN'T MEAN THAT THERE'S A TON OF MONEY IN EMILY DRY FUSS MUSCULAR DYSTROPHY OR DISTAL MUSCULAR DYSTROPHY OR SOMETHING. THAT MEANS THINGS IN THE M.D. CATEGORY HAS RELEVANCE TO MAJOR CODED TYPES BUT THE WORDS THAT THE APPLICANT SHOWS TO USE IN ABSTRACT THE SPECIFIC AIMS DID NOT CAUSE IT TO MEET THE THRESHOLD TO BE CALLED DUCHENNE OR CALLED MUSCULAR DYSTROPHY. OKAY? BUT IF YOU WANT TO LOOK AT EVERYTHING GO TO THE M.D. CATEGORY. THIS IS AVAILABLE IN REPORTER, WHAT I TELL EVERYBODY IS IF YOU GOOGLE NIH DISEASE DOLLARS YOU ACTUALLY GET THE LIST BY CATEGORY. YOU CAN GET THE LIST ON CATEGORY, CLICK ON THE DOLLAR AMOUNT AND GET THE LIST OF GRANTS AND READ THE ABSTRACTS FOR THOSE GRANTS. IN TERMS OF INITIATIVES, I'M GOING TO GO OVER THE INITIATIVES WE UNDERTAKE AND GIVE YOU A CROSS SEC. I SHOULD BACK UP A SECOND. THE BULK OF THESE AWARDS, OVERWHELMINGLY ARE DUE -- ARE THROUGH INVESTIGATOR-INITIATED APPLICATIONS THAT ARE NOT IN RESPONSE TO ANY INITIATIVE. SO THE GROWTH THAT'S HAPPENING IN CONGENITAL MUSCULAR DYSTROPHY IS LARGELY HAPPENING BY INVESTIGATOR-INITIATED APPLICATIONS. SO THAT'S THE BULK OF IT. BUT I WANT TO GO THROUGH THE INITIATIVES WE HAVE UNDERTAKEN DURING THE TIME COURSE OF THE ACTION PLAN AND GIVE YOU A LITTLE BIT OF THE FLAVOR ABOUT WHAT KIND OF THINGS HAVE GONE ON. SO THE FIRST OF THESE IS TRANSLATION R-21 PROGRAM WHICH HUNDRED DOLLARS DID IN CONJUNCTION WITH NIAMS. AND DURING THE TIME OF THESE TWO INITIATIVES, SO WE HAD TWO SEPARATE INITIATIVES, FOUR TRANSLATIONAL R-21s WHICH ARE STARTER GRANTS ESSENTIALLY, THE $275,000 OVER TWO YEARS TO LAUNCH THERAPY DEVELOPMENT EFFORTS, THERE'S BEEN 16 AWARDS. THEY HAVE RANGED ACROSS MULTIPLE TYPE OF MUSCULAR DYSTROPHY COB GENITAL MUSCULAR DYSTROPHY, MYOTONIC DYSTROPHY, DUCHENNE, FSH AND LIMGIRDLE AND I HAVE ONE AS PAN MUSCULAR DYSTROPHY WHERE THE STRAND COULD POTENTIALLY APPLY ACROSS THE BOARD AND THAT HAS TO DO WITH MYOSTATIN INHIBITION. SO I WANT TO HIGHLIGHT A COUPLE OF THINGS. FIRST OF ALL, THERE'S TWO AWARDS ON HERE, ONE OF THE PIs IS IN THE ROOM, TWO R-21s TO CHARLES THORNTON ROCHESTER AND JUSTIN FALLON AT BROWN AND YOU'LL HEAR FROM HIM IN A WHILE. BOTH LED TO LARGER THERAPY DEVELOPMENT AWARDS FROM -- THROUGH OUR PROGRAMS THAT ARE NOW MOVING ACTUALLY THEY BOTH HAVE BEEN -- ONE'S BEEN THROUGH A PRE-IND, JUSTIN HAS A PREIND COMING UP THAT I'M SURE HE'LL TALK ABOUT BUT THE INITIAL SMALL R-21 LEVERAGED THINGS TO MOVE ALONG. JUST TO MENTION A COUPLE OF OTHERS, IT'S ALREADY BEEN SAID THAT STAN FRENOR WORKED ON THE NMOS PATHWAY AND THE IDEA THAT ATTACKING THE NNOS PATHWAY WAS A PARTICULAR THERAPEUTIC ANGLE FOR DUCHENNE MUSCULAR DYSTROPHY. SO HE GOT SOME OF THAT DATA OUT OF THIS R-21 BUT THIS HAS ACTUALLY LEVERAGE AD DRUG REPURPOSING GRANT THEY'LL TALK ABOUT LATER THROUGH AN N CATS PROGRAM THAT HAD I THINK A LOT OF ITS POTENTIAL DERIVED FROM THE SMALL R-21 THAT STAN GOT. JUNE MENTIONED IN PASSING MICHAEL KYBA'S THERAPY DEVELOPMENT, SMALL MOLECULE DRUG SCREENING PROGRAM. SO WE FUNDED THAT. THE REASON I WANT TO HIGHLIGHT IT, SO THIS IS SMALL MOLECULE SCREEN FOR DRUGS THAT IMPACT DUX-4 THAT SHE IDENTIFIED AS A MAJOR MECHANISM FOR FSHD. THAT APPLICATION CAME IN, WAS SET UP FOR CO-FUNDING FROM A COUPLE OF DIFFERENT FSH ORGANIZATIONS SO AT LEAST YOU GUYS AND ONE OR TWO MORE. RIGHT? (OFF MIC) >> I THINK FRAN'S WAS THE THIRD SO I THINK THERE WERE THREE LETTERS OF COMMITMENT. JUST HOW IMPORTANT IS THAT? WHEN OUR REVIEWERS LOOKED AT THAT, ONE OF THE COMMENTS WAS FOR A TWO YEAR $275,000 GRANT THAT THIS IS PRETTY OVER AMBITIOUS. THEY SAID THAT ON ONE HAND. BUT ON THE OTHER HAND THEY NOTED THIS CO-FUND CONTRIBUTION FROM THE THREE DIFFERENT FSH GROUPS AND SAID, WELL, OKAY, IT'S NOT AS AMBITIOUS BECAUSE HE'S GOT THIS EXTRA MONEY TO HELP STRETCH THINGS FURTHER. THAT'S HOW IMPORTANT I THINK THE COLLABORATIONS ARE. I THINK IT MADE A DIFFERENCE FOR THE FUNDING OF THIS AWARD. THAT THE FSH GROUPS HAD PUT IN THIS COMPANION FUNDING TO GO ALONG WITH THAT. AND HELP MAKE THAT HAPPEN. SO WE ALSO HAD SOME AWARDS THROUGH -- SO THESE -- THIS WAS A SPECIALIZED PROGRAM FOR MUSCULAR DYSTROPHY AND LATER WE EXPANDED IT FOURNEAU MUSCULAR DISEASE, THE FIRST EXAMPLE, THESE 16 AWARDS. OKAY? WE ALSO HAVE A GENERIC PROGRAM WHICH ANY NEUROLOGICAL DISORDER COULD COME IN, WE HAVE MADE ADDITIONAL AWARDS THROUGH THAT. AND I JUST AGAIN WANT TO HIGHLIGHT A COUPLE OF THESE. JOSH SELSBY WHO TRAINED WITH ELISSE SEENNY AT PENN, HE GOT A PIG MODEL FOR BECKER'S MUSCULAR DYSTROPHY THROUGH THAT SO HE'S TRYING TO DEVELOP THAT, HAVE THAT POTENTIALLY AVAILABLE FOR THERAPEUTIC TESTING. THE OTHER ONE OF THESE PLUS WAS ALSO MENTIONED BY JUNE, THAT KATHERINE WAGNER AT HOPKINS HAS THIS XENOGRAPH MODEL FOR FSHD THAT -- SO VERY HARD DISEASE TO REPLICATE IN AN ANIMAL MODEL. THIS HAS BEEN SAID, THE ONE ANIMAL MODEL THAT'S BEEN MADE HAS ALL THE MOLECULAR CHARACTERISTICS OF FSH BUT DOESN'T SHOW A PHENOTYPE. SO IN TRYING TO GET AT THAT, TRYING TO HAVE A MODEL THAT IS POTENTIALLY VALUABLE THERAPY DEVELOPMENT, KATHERINE WAGNER GOT ONE OF THESE TRANSLATIONAL R-21s TO LOOK AT THAT. IN TERMS OF OUR LARGER PROGRAMS, THE UO-1 PROGRAM, THESE ARE DESIGNED TO MOVE FROM PROOF OF CONCEPT TO AN IND SUBMISSION. TAKING CARE OF THE NUTS AND BOLTS ABOUT GETTING THINGS SUBMITTED TO THE FDA FOR APPROVAL TO DO A CLINICAL TRIAL. WE MADE FOUR AWARDS THROUGH THIS PROGRAM, JUSTIN GOT ONE OF THESE THAT WAS A DIRECT RESULT OF HIS TRANSLATIONAL R-21. HE'LL TALK ABOUT THAT. THAT'S FOR GLYCAN FOR DUCHENNE MUSCULAR DYSTROPHY. DENNIS GUTREDGE HAS ONE OF THESE FOR FN KAPPA B INHIBITION FOR DUCHENNE AND WE HEARD FROM IAN THEY'RE ALSO WORKING WITH HIM ON THIS APPROACH FOR CONGENITAL MUSCULAR DYSTROPHY. KI LU IS WORKING WITH SERAPTO SKIPPING ON OLIGOFOR DUCHENNE AND SO THE THREE OF THOSE ARE STILL ACTIVE. THEY'RE MEETING MILESTONES, THIS IS A VERY CONTROLLED PROGRAM THAT WE EXPECT ANNUAL MILESTONES TO BE MET BEFORE IT MOVES -- BEFORE FUNDING CONTINUES, H HANSEL STEADMAN HAD ONE OF THESE FOR GENE THERAPY FOR UTROFIN AND THAT FAILED TO MEET EFFICACY MILESTONE FAIRLY EARLY ON SO THAT'S BEEN TERMINATED BUT THIS IS WHAT WE FUNDED THROUGH OUR SPECIFIC MUSCULAR DYSTROPHY PROGRAM, WE HAVE ALSO FUNDED OTHERS THROUGH OUR GENERIC TRANSLATIONAL PROGRAM. SO LEE SWEENEY AND JERRY MANDEL HAD THE LARGE U-54s WHICH ARE MULTI-COMPONENTS, SO THEY'RE GOING AFTER TWO OR MORE CANDIDATE THERAPEUTICS. THE ONE LEE SWEENEY WITH PTC THERAPEUTICS, THAT'S ENDD AND -- ENDED AND THEY HAVE A DEVELOPMENT CANDIDATE FOR UTROFIN UP-REGULATION. THINK THE COMPANY IS GETTING IT APPROVED. I HAVEN'T SEEN IT FURTHER BUT THEY HAVE A DEVELOPMENT CANDIDATE. DO YOU KNOW ANYTHING ABOUT THAT, PAT? (OFF MIC) >> OKAY. SO THEN THERE'S A COUPLE OF OTHER MECHANISMS, A SMALL BUSINESS GRANT TO MCFEE, AND BIO THAT FAILED TO MEET MILESTONES. WE INVESTED IN JOE KORNEGAY WHO EVERYBODY AT THE TABLE KNOWS HAS A DYSTROPIC DOG MODEL AND P A LOT OF GROUPS AT THE TABLE INVESTED IN THIS. THAT FAILED TO MEET MILESTONES AND WE ENDED UP TERMINATING THAT. HE'S SINCE MOVED FROM CHAPEL HILL TO TEXAS A AND M AND I THINK HE'S GOTTEN MORE UNIVERSITY SUPPORT FOR HIS EFFORTS THERE AND HOPEFULLY THAT WILL MOVE THINGS ALONG. THEN FINALLY, AS I SAID, CHARLES THORNTON BENEFITED FROM THE R-21 PROGRAM TO MOVE INTO ONE OF THESE LARGER THERAPY DEVELOPMENT GRANTS. AND I REALLY LIKE TALKING ABOUT THIS ONE. SO IT STARTED OUT WITH THIS $275,000 FOR TRANSLATIONAL R-21. THEN HE WAS ABLE TO MOVE THAT INTO A UO1 AT ABOUT $1 MILLION A YEAR, IN COLLABORATION WITH AN ANTI-SENSE OLIGO COMPANY ISYS BIOPHARMA. SINCE THIS STARTED BIOGEN LOOKED AT THAT TIME PROJECT BECAUSE THEY HAVE DONE OTHER COLLABORATIONS WITH ISIS AND THEY JUMPED IN WITH UP TO $200 MILLION IN MILESTONE-DIRECTED FUNDING THAT WOULD TAKE THIS ALL THE WAY THROUGH PHASE 3 IF IT KEEPS MEETING MILESTONES. SO THAT'S AGAIN, THAT'S WHY I TRY TO EMPHASIZE PARTNERING BECAUSE THAT KIND OF THING WE COULD HAVE NEVER MADE HAPPEN. BUT HAVING THE COLLABORA6hf MOVE ALONG LIKE THAT AND GETTING BIOGEN INVOLVED, I THINK, IF IT KEEPS -- IF IT KEEPS MEETING MILESTONES, THIS WILL GO THROUGH PHASE 3. OKAY. SO IN TERMS OF WHAT WE'VE THOUGHT OF IN TERMS UNDERSTUDIED MUSCULAR DYSTROPHY, SO FSH, SEVERAL YEARS AGO WE DID THIS PARTICULAR INITIATIVE TO TRY TO GET THINGS MOVING MORE IN THOSE DISEASES, WE HAD AN RFA, WE ENDED UP FUNDING THREE RO1s, ONE IN FSHD AND TWO IN EMORY DREIFUS MUSCULAR DYSTROPHY. FSHD MOVED FURTHER ALONG T INVESTIGATOR GOT ANOTHER GRANT AND IS TAKING THAT FURTHER. AND WE DID THIS IN PARTNERSHIP WITH THE MDA SO SHARONESTERLY WAS WITH MDA AT THE TIME AND WE FUNDED OURS, THEY IN TURN PICKED UP AND MADE ADDITIONAL AWARDS THROUGH THIS RFA. SO I THINK THAT'S ONE WAY THAT WE HAVE TRIED TO INFLUENCE THIS PARTICULAR SUBSET OF DISEASES. JUST TO GO THROUGH SOME OF THE OTHER THINGS QUICKLY. NIAMS GENERATE AD CORE GRANT PROGRAM THAT JOHN DAY WHEN HE WAS AT MINNESOTA, ERIC HOFFMAN AND MELISSA SPENCER RECEIVED LARGE CORE GRANT AWARDS TO HELP SUPPORT GROUP EFFORTS AT THEIR INSTITUTIONS. CHILD HEALTH HAD THIS PAR ON DEVELOPING THERAPIES FOR DISEASES THAT IF THERE WAS A THERAPY THERE WOULD BE A GOOD CHANCE OF DISEASE ENDING UP ON THE NEWBORN SCREENING PANELS. ADDED TO NEWBORN SCREENING PANELS. WE HAVEN'T HAD TO THE BEST OF MY KNOWLEDGE, WE HAVEN'T HAD AN AWARD IN ANY OF THE MUSCULAR DYSTROPHYs YET BUT THERE'S BEEN SUCCESSFUL APPLICATIONS IN SMA IN POMPEII AND SO THIS IS CERTAINLY AN OPPORTUNITY FOR THE MISDEMEANORS TO GET THINGS FUNDED THROW THAT. -- THROUGH THAT. FINALLY THE WELLSTONE CENTERS, I WANT TO SAY ONE THING ABOUT IT. GLENN DID A TERRIFIC JOB SUMMARIZING THESE. THE THING I LIKE ABOUT THIS PROGRAM AND GLENN DID MAKE THIS POINT, IS IT'S BEEN DISEASE AND STAGE OF PROGRESS-AGNOSTIC. SO WHAT I MEAN BY THAT IS NO MATTER WHAT STAGE OF THERAPY DEVELOPMENT YOUR DISEASE IS AT, IF YOU HAVE BEEN TRYING TO PUSH THESE EFFORTS A LONG TIME LIKE DUCHENNE OR JUST GETTING THINGS MOVING, YOU JUST GOT THE MECHANISM LIKE FSHD, THE PROGRAM HAS BEEN ABLE TO SUPPORT WHAT YOU DO. PEOPLE HAVE BEEN ABLE TO WRITE SUCCESSFUL APPLICATIONS AND GET THEM FUNDED. I THINK THAT'S A TREMENDOUS DEGREE OF FLEXIBILITY THAT THE WELLSTONE PROGRAM HAS SHOWN. OTHER MECHANISMS. NCATS HAS FUNDED ONE THROUGH THEIR TREND PROGRAM AND ANOTHER THROUGH THEIR REPURPOSINGING PROGRAM. ONE OF THESE HAD BEEN TALKED ABOUT ALREADY. BBP 15 BUT THEY FUNDED TWO MAJOR EFFORTS. AND AS I SAID AT THE BEGINNING, I HAVE TO APOLOGIZE THAT I FORGOT ABOUT THE DOD FUNDING FOR THIS WHEN I PUT THIS TOGETHER BUT THE TREND PROGRAM HAS BEEN PARTNERED WITH THE MDA IN FUNDING THIS. MORE RECENTLY THROUGH THIS DRUG REPURPOSING PROGRAM, KATHERINE WAGNER AND STAN FROEHNER ARE REPURPOSING A DRUG CYCLASE ACTIVATOR THAT CAME OUT OF THE MNOS WORK, THE RATIONALE CAME OUT OF THE NNOS WORK BUT THAT'S THE OTHER THING THAT THEY'RE FUNDING AT THIS TIME. NIAMS HAS FUNDED UO-1s ON OUTCOMES DEVELOPMENT, WE HEARD FROM CHAD ABOUT FSHD PROGRAM HE'S WORKING ON AND PAN MUSCULAR DYSTROPHY WITH HAHNN LOOKING AT OUTWARD DEVELOPMENT FOR OUTWARD EXTREMITY, PARTICULARLY ACROSS THE DIFFERENT TYPES OF MUSCULAR DYSTROPHY. THERE'S THREE CURRENTLY ACTIVE PROGRAM PROJECTS IN MUSCULAR DYSTROPHY. I THINK THESE ALL FEEL VERY UNIQUE NICHE -- FILL UNIQUE NICHES. SO BETH MCNALLY IS LOOKING AT FIBROSIS IN MUSCULAR DYSTROPHY. THE CAUSES IN POTENTIAL THERAPY DEVELOPMENT TARGETS IN DIFFERENT SIGNALING PATHWAYS RELATED TO FIBROSIS. LAURA RANUM, WE HAVE VERY FEW FUNDED GRANTS ON THE CNS CONSEQUENCES OF MYOTONIC DYSTROPHY. SO AS WE TALKED ABOUT EARLIER, THESE ARE MULTI-SYSTEM DISORDERS, A LOT OF OUR DISRD ORDERS. AND I THINK -- DISORDERS. HAVING THE RANUM GROUP GO AFTER THE CNS CONSEQUENCES IS REALLY IMPORTANT. IT'S NIGH HOW THEY CONSTRUCTED IT. THEY HAVE TWO BASIC SCIENCE, TWO Ph.D.s WORKING ON MOUSE MODELS TO UNDERSTAND THE AREAS THAT ARE INVOLVED IN THE CNS AND THE MISPLACING CHANGES -- MISSPLICING CHANGES IN AREAS OF CNS AND THEN JOHN DAY DOING NEUROPSYCHOAND IMAGING TO CORRELATE THE FINDINGS FROM THE MOUSE STUDIES. SO I THINK THAT'S A REALLY GOOD APPROACH. THEN P FINALLY, STEVEN TAPSCOTT, THIS IS THE GROUP THAT PROPOSED A MECHANISTIC MODEL OF FSHD AND SAID WE'RE GOING TO GO ABOUT CAREFULLY TESTING THIS AND TOOK IT A LONG WAY TOWARD DEVELOPING THAT MODEL DEVELOPED IN 2011. SO FINALLY, I THINK GLENN MENTIONED SOME OF THESE, THEY HAVE ALL COME UP TODAY, CLINICAL TRIALS THAT ARE FUNDED IN LIMGIRDLE AND DUCHENNE AND A DMD PLANNING GRANT FOR TATELAFIL (PHONETIC). IN DUCHENNE MUSCULAR DYSTROPHY. NOW OPTIMIZING THE RETURN ON INVESTMENTS. THIS IS ONE AREA WE HAVE GOTTEN INTERESTED IN AND AS I SAID, IF YOU'RE AN ADVOCACY GROUP YOU HAVE GOTTEN TONS OF EMAILS FROM ME ON THE TOPIC. JUST THE IDEA CAN WE AVOID SOME OF THE CLINICAL TRIAL FAILURES? CERTAINLY NOT YOU WILL OF THEM ARE DUE TO THIS BUT CAN WE AVOID CLINICAL TRIAL NAIL YOURS THAT ARE -- FAILURES DUE TO POOR CLINICAL RATIONALE. SO THERE'S BEEN A NUMBER OF STUDIES THAT HAVE SHOWN A LOT OF THE PRE-CLINICAL STUDIES THAT HAVE DRIVEN CLINICAL TRIALS HAVE HAD BEEN DUE TO UNDERPOWERED STUDIES. SO IN THE ALS FIELD THEY TOOK SOMEWHAT UPWARDS OF 30 DRUGS INTO THE CLINIC, THEY ALL FAILED. THEY HAD ANIMAL RATIONALE FOR ALL OF THEM. WHEN THEY WEPT -- WHEN ALS TDI WENT BACK THEY COULDN'T REPLICATE THE PRE-CLINICAL STUDIES WHEN THEY DID THEM RIGOROUSLY. SO IT WON'T PREVENT ALL CLINICAL TRIAL FAILURES BUT WE SHOULDN'T HAVE THINGS GOING TO THE CLINIC ON FLIMSY PRE-CLINICAL DATA. SO THAT'S REALLY WHAT THIS IS ABOUT. THIS EFFORT WAS REALLY STARTED BY AN NINDS PROGRAM DIRECTOR SHY SILVERBERG AND SHOWS WHAT ONE PERSON CAN ACCOMPLISH. SO SHY STARTED PUSHING THIS AND THE END RESULT TO THIS POINT IS THAT SEVERAL MAJOR JOURNALS HAVE ADOPTED RIGOROUS STANDARDS FOR PUBLICATION. SO IF YOU COME INTO THE SCIENCE JOURNALS, NATURE JOURNALS AND OTHERS ADDED TO THE LIST YOU HAVE TO MEET THESE CRITERIA BEFORE THEY PUBLISH IT. THE OTHER THING HAPPENING IS THERE'S NIH EFFORTS DOING PILOT STUDIES ON REPLICATION, ON TRAINING OF INDIVIDUALS, TRAINING PACKAGES FOR TRAINEES IN RIGOR, DO YOU WANT THE SAY ANYTHING ABOUT THIS STORY? >> THEY'RE DOING A VERY NICE JOB COVERING IT. >> SO I THINK THAT'S REALLY IMPORTANT -- >> STEVE HAS REMIND MED THAT LARRY AND FRANCIS, LARRY TABAK AND FRANCIS COLLINS, THE PRINCIPLE DEPUTY DIRECTOR AND DIRECTOR OF NIH HAD A VERY NICE ARTICLE, A COMMENTARY IN NATURE. AND THERE ARE CONTINUING EFFORTS TO PUBLICIZE THE NEED FOR LOOKING CAREFULLY AT STUDY DESIGN AND EDUCATE AND THE MOST RECENT INTEREST IS NOW GMS HAS DISCOVERED THAT MANY OF THE CELL LINES THAT PEOPLE USE AREN'T ACTUALLY THE CELL LINE THAT YOU THINK YOU'RE USINGING. SO IT'S A MAJOR EFFORT AT NIH. >> SO THE OTHER PIECE OF IT THAT I HOPE IT'S OKAY THAT I TALK ABOUT THIS, STORY, THAT ISN'T OUT THERE YET -- (OFF MIC) >> NEXT STEP HERE. SO WITHIN NINDS WE GOT INTO THE IDEA OF THE CLINICAL CONCEPT OF MORBIDITY AND MORTALITY ANALYSES WHICH QUICKLY MORPHED TO LESSONS LEARNED SO IT PUT A POSITIVE SPIN ON IT. BUT I THINK THE MORBIDITY AND MORTALITY ANALSIS CARRIES A NICE ANALOGY IN THAT IT'S MEANT TO BE SORT OF A SAFE HAVEN FOR -- IF YOU THINK ABOUT THOSE ANALYSIS IN HOSPITALS. THEY'RE MEANT TO BE A SAFE HAVEN FOR PHYSICIANS TALKING ABOUT WHAT WENT WRONG IN THEIR CASE. BUT THAT IT ISN'T TO CRUCIFY THE PHYSICIAN, IT'S TO LEARN SOMETHING FROM THAT THAT HELPS THE REST OF THE FIELD. WE'RE STARTING TO DO THIS WITHIN NINDS WITH OUR LARGE TRANSLATIONAL PROJECTS, PARTICULARLY THINGS THAT ARE MILESTONED. SO PRE-CLINICAL TRANSLATION AS WELL AS CLINICAL TRIALS. SO WE REALLY EXTRACT VALUE HOW WE CAN DO THINGS BETTER IN THE FUTURE. YOU ARE GOING TO START HEARING ABOUT THIS FROM ME ONCE WE HAVE THIS FURTHER ALONG. BUT I THINK IT'S ANOTHER BEST PRACTICES, IN ADDITION TO RIGOR AND REPLICATION, I THINK CAREFUL ANALYSIS BY EACH OF OUR ORGANIZATIONS, ABOUT WHAT WENT RIGHT, WHAT WENT WRONG AND HOW WE CAN DO THINGS BETTER, HOW WE CAN MAKE BETTER DECISIONS BECAUSE THAT'S WHAT THERAPY DEVELOPMENT IS ALL ABOUT, RIGHT? IN GOING FORWARD. SO WE'RE HOPING TO LEARN SOMETHING FROM THIS, THAT HAS BROADER VALUE. FINALLY THE PARTNERING IDEA THAT WE NEED A LOT MORE CROSS TALK AND CO-FUNDING. THE EXAMPLES THERE JUSTIN IS GOING TO TALK ABOUT HOW THINGS HAD TO COME TOGETHER, I HOPE, FOR BIGLYCAN AND I ALSO POINT OUT TO THE FSH CHAMPIONS GROUP. I HAVE BEEN ON NUMBER OF CALLS WITH THAT GROUP OVER THE PAST YEAR AND I THINK THE WAY THAT FIELD HAS COME TOGETHER IS REALLY BEEN TREMENDOUS. I'M PROBABLY PUSHING MY TIME, AREN'T I, ALAN? IN TERMS OF NIH WORKSHOPS, I'M JUST LISTING SOME HERE WE HAVE DONE OVER THE YEARS. I DON'T KNOW THAT I'LL GO THROUGH THESE IN PARTICULAR, THERE'S BEEN REALLY NICE WORKSHOP WE DID IN ASSOCIATION WITH TREAT-NMD LOOKING HOW TO IMPROVE TRANSLATIONAL MEDICINE ACROSS ALL THE NEUROMUSCULAR DISEASES, THAT WAS IN BRUSSELS IN 2009. P FROM ANN PARISNER AND I DID THIS WORKSHOP TOGETHER ON NIH FDA ANTI-SENSE OLIGO FOR NEUROMUSCULAR DISORDERS, SO WE LOOKED FOR SPECIFIC DISORDERS BUT IT HAS APPLICABILITY ACROSS THE MAP. VALERIE AND I BOTH TALKED ABOUT THE WORKSHOP THAT NIH IS DOING WITH MDA ON TRYING TO ARRIVE AT BETTER PRACTICES FOR GENE THERAPY. AND FINALLY THERE'S THIS WORKSHOP THAT NHLBI IS DOING IN CONJUNCTION WITH PARENT PROJECT MUSCULAR DYSTROPHY ON CARDIAC ISSUES IN DUCHENNE MUSCULAR DYSTROPHY AND TRYING TO MOVE FORWARD. AND THAT LOOKS REALLY NICE SO IT'S A SMALL GROUP WORKSHOP, LOTS OF INTERACTION LIKE THIS GROUP HERE TODAY. SO I THINK THAT WILL BE A VERY GOOD THING. WE FUNDED A BUNCH OF COUCHES CONFERENCES, SO THERE'S 20 R-13 GRANTS, OUR CONFERENCE GRANTS THAT ARE LISTED HERE. THESE ARE ARE OFTEN PARTNERED USUALLY MANY ORGANIZATIONS ARE CO-FUNDING ALONG WITH US. ONE OF THE PIPELINE -- WE TALKED SEVERAL TIMES IN THIS COMMITTEE ABOUT THE DERTH OF A NEW INVESTIGATORS IN MUSCULAR DYSTROPHY. I THINK IT'S A REAL PROBLEM FOR ALL OF US. THAT WE HAVE PEOPLE GETTING Ph.D.s, POST DOCS, FELLOWSHIPS, CLINICALLY TRAINED, THAT ARE GOING TO BE REPLACING LIKE WHEN THEY FINALLY CARRY BIRCH GRIGGS OUT OF HIS OFFICE IN A BOX THERE'S SOMEBODY TO REPLACE HIM. JERRY, THEY HAVE BEEN THERE FOREVER BUT WE HAVE TO HAVE MORE CHADS, NO HANGING CHADS. >> JOHN, THAT'S NOT A VERY PRETTY I WILL IMAGINE. >> SO WE NEED MORE CHADS. SO THESE ARE JUST SOME ACTIVITIES. WHAT I WOULD REINFORCE IS KIND OF THE DERTH HERE. SO THERE'S A TIGHTLY FOCUSED INSTITUTIONAL TRAINING GRANT TO DENNIS GUTTRIDGE IN NATIONWIDE CHILDREN'S THAT IS OHIO STATE THAT PROVIDES THEM WITH FUNDS TO ACCEPT PEOPLE THAT ALREADY HAVE THE MONEY TO FUND THEM, PLUS THERE'S THESE INDIVIDUAL AWARDS. BUT LOOK AT THE NUMBERS IN TERMS OF ACTIVE PRE-DOCTORAL AWARDS, WE HAVE GOT TWO IN MUSCULAR DYSTROPHY SPACE RIGHT NOW. IN TERMS OF ACTIVE POST DOC AWARDS WE HAVE JUST GOT SEVEN. THESE ARE PRETTY LOW NUMBERS FOR FEEDING THE FIELD. K AWARDS, SO THINGS ARE LOOKING A LITTLE BIT BETTER THERE, PARTICULARLY IN TERMS OF NHLBI, I DON'T KNOW HOW THIS IS HAPPENING BE YOU GUYS HAVE GOTTEN SOME GREAT PEOPLE IN TO CAREER DEVELOPMENT AWARDS AND IN THE K-99 R-00 PATHWAY TO INDEPENDENCE AWARDS THAT TWO OF THE THREE ARE NHLBI TRAINEES, -- (OFF MIC) Q. SO THEY VARY. SOME RKO-1s, FUNNY YOU ASK THAT QUESTION. HERE ARE SOME SAMPLES. SO THERE'S A KOA TO DWAYNE TOWNSEND AT THE UNIVERSITY OF MINNESOTA WHO IS A DVM Ph.D. AND HE'S LOOKING AT HOW THE ABSENCE OF DISTROPHY AND SARCOGLYCAN MAY PERTURB CORONARY ARTERY FLOW WHICH IS A REALLY UNIQUE ANGLE ON PATHOGENESIS OF MUSCULAR DYSTROPHY. I HAD NO IDEA THIS AWARD EXISTED UNTIL I WAS LOOKING THROUGH THINGS THIS WEEKEND. ANOTHER KO-8 TO JENNIFER STRAND MEDICAL COLLEGE WISCONSIN WHO IS A CARDIOLOGIST, USING HUMAN DUCHENNE IPSC DERIVED CARDIOMYOCITES TO UNDERSTAND HOW DIFFERENT DYSTROPHY MUTATIONS RELATED TO THE DEVELOPMENT OF OXIDATIVE STRESS AND CELL DEATH. SO THE CORRELATION BETWEEN GENOTYPE EFFECTIVELY, MICRO GENOTYPE WITH FACTORS RELATED TO CARDIOMYOCITE DEATH. A THIRD -- HERE IS YOUR VARIETY, STEVE. A K-25 TO SOMEONE AT CHILDREN'S CINCINNATI CHILDREN'S HOSPITAL, WHO IS A PHYSICIST WHO'S TRANSITIONING FROM A BACKGROUND IN MRI IMAGING INTO STUDYING PETE'S CARDIOMYOPATHY -- NOT DUCHENNE M.D. BUT LIMB GIRDLE MUSCULAR DYSTROPHY AND SHE'S LOOKING AT INFLAMMATION AND FIBROSIS IN A MOUSE MODEL. AND FINALLY, THERE'S NICHD GRANT TO INVESTIGATOR AT PITTSBURG LOOKING AT THE RELATIONSHIP BETWEEN ACTIVITY LEVELS, PATIENT ACTIVITY LEVELS, QUALITY OF LIFE, AND MRI MEASURES. SO THIS IS STARTING TO GET AT VALIDATING THE MRI MEASURES TO FUNCTIONAL THINGS SO THICK BE USED IN CLINICAL TRIALS. JUST A COUPLE OF OTHER THINGS REALLY QUICKLY. THERE WAS A RECENT DP-5 AWARD, A DIRECTOR'S AWARD EARLY INDEPENDENCE, IT BASICALLY HELPS PERSON SKIP THE POST DOC. AND THIS WAS TO ERIC LANG AT MICT WHOSE WORK IN MYOTONIC DYSTROPHY. NIAMS HAD SOME TRAINING INITIATIVES THAT HAVE BEEN REALLY PRODUCTIVE IN THE KO8 REALM, THERE'S O ONE CURRENTLY ACTIVE AND THEY HAVE HAD SIX PRIOR AWARDS TO THAT. ULTIMATELY IN -- FOR THE CLINICIANS, YOU WELL UNDERSTAND THE DIRECTORS HERE WELL UNDERSTAND THE PROBLEM IS THAT CLINICIANS GET A K AWARD BUT THEN HAVE TROUBLE TRANSITIONING TO OUR REGULAR RESEARCH PROJECT GRANT SERIES AWARDS. AND HOW DO WE FACILITATE THAT? IT'S A VERY COMPETITIVE WORLD, HARD ENOUGH TO GET NIH GRANTS. BUT WHEN A PRACTICING CLINICIAN WHO HAS CLINICIAN ACTIVITIES AND CHAD CAN CERTAINLY COMMENT ON THIS, HOW DO THEY MAKE THE TRANSITION? HOW DO WE RESCUE MORE PEOPLE AND HELP MOVE THEM ALONG? (OFF MIC) >> LIKE THE AWARDS VALERIE WAS TALKING ABOUT. (OFF MIC) >> RIGHT. SO THIS IS REALLY THE NEXT STEP, SO HOW DO WE GET -- WHERE DO WE REALLY HAVE TO GO? I THINK WE HAVE TO THINK ABOUT BETTER COMMUNICATION, AND WE'RE GOING TO HAVE DISCUSSION AT THE END OF THE DAY HOW TO BETTER COORDINATE OUR ACTIVITIES. LEVERAGE EACH OTHER'S RESOURCES BECAUSE NOBODY IS GOING TO GET THERE WITHOUT THIS. AND BETTER PLANNING. AND I JUST NOTE THAT THE ACTION PLAN, YOU HAVE ALREADY RECEIVED THE DATES, THE FACE TO FACE MEETING OF THE WORKING GROUPS IS GOING TO BE JULY 28 AND 29. MDCC IS INVITEDDED TO THAT, HOPEFULLY ACTIVELY PARTICIPATE IN THAT. AND BEFORE THE END OF THE YEAR WE GET AN UPDATE OF THE ACTION PLAN FOR MUSCULAR DYSTROPHY. THANKS. [APPLAUSE] >> THANKS VERY MUCH, JOHN. ANY QUICK QUESTIONS FOR JOHN? >> JOHN JUST A FOLLOW-UP ON THE TRAINING GRANTS. YOU WERE CONCERNED ABOUT THE SMALL NUMBERS. SOME OF THE TYPES. >> RIGHT. >> IS THE ISSUE YOU'RE NOT GETTING ENOUGH APPLICATIONS OR THE CANDIDATES AREN'T SUCCESSFUL, A COMBINATION OF THE TWO? BECAUSE WE SEE SOME OF THE SAME THINGS IN PART WE DON'T GET VERY MANY APPLICATIONS. >> WE GENERALLY DON'T TALK ABOUT NUMBERS OF APPLICATIONS AT NIH. I MAYBE CRUCIFIEDED IF I THROW OUT APPLICATION NUMBERS. BUT I THINK THE APPLICATION NUMBERS ARE LOW. I THINK THE NUMBERS ARE LOW. THANKS. >> SO WE WILL CONTINUE OUR TOUR OF FEDERAL FACILITIES BY GOING TO JULIE BOLEN FROM THE NATIONAL CENTER FOR DISEASE CONTROL AND CDC AND JULIE WILL GIVE AN OVERVIEW OF CDC ACTIVITIES. >> GOOD AFTERNOON. I'M HAPPY TO BE HERE WITH YOU AND HAVE THIS OPPORTUNITY TO TELL YOU A LITTLE BIT ABOUT CDC'S ACTIVITIES OVER THE PAST 12 YEARS. JUST TO ORIENT YOU TO WHERE WE SIT AT CDC, WE'RE PART OF THE NATIONAL CENTER ON BIRTH DEFECTS AND DEVELOPMENTAL DISABILITIES. WE'RE IN THE DIVISION OF HUMAN DEVELOPMENT AND DISABILITY AND THE MUSCULAR DYSTROPHY WORK IS ADMINISTERED OUT OF THE RARE DISORDERS AND HEALTH OUTCOMES TEAM. WE ALSO DO SPINA BIFIDA AND FRAGILE X SYNDROME ON OUR TEAM. I ALWAYS LIKE TO JUST REMIND PEOPLE THAT PUBLIC HEALTH APPROACHES THINGS DIFFERENTLY. WHEN YOU LOOK AT CLINICAL MEDICINE YOU'RE FOCUSING ON INDIVIDUAL HEALTH, THERE'S LOTS OF EMPHASIS ON TREATMENT AND CURES AS THERE IS HERE AT AT THE MDCC THE -- AND OUR EMPHASIS IS ON PREVENTION AND INTERVENTION. AND WHEN WE THINK ABOUT PREVENTION IN TERMS OF MUSCULAR DYSTROPHY WE'RE REALLY THINKING ABOUT PREVENTING THE EFFECTS OF THE DISEASE -- THEM DOWN. THIS SLIDE SUMMARIZES A LOT OF WHAT WE DO AT CDC, WE START AT THE BOTTOM WITH DATA. WE TRY TO DESCRIBE THE POPULATION IN TERMS OF DEMOGRAPHICS, HEALTH STATUS, QUALITY OF LIFE, CO-MORBID CONDITIONS, HEALTH SERVICES USE. ANOTHER THING WE SPENT QUITE A BIT OF EFFORT ON IS DEVELOPING METHODS TO LOOK AT MUSCULAR DYSTROPHY IN POPULATIONS. IT'S A RARE CONDITION, IT'S NOT EASY TO FIND AND THERE'S LOTS OF BARRIERS. YOU'LL HEAR MORE ABOUT THAT IN A MOMENT. WE BEGIN WORKING EARLY IDENTIFICATION IN TERMS OF TRYING TO DECREASE THE DIAGNOSTIC DELAY AND WE CITED WORK IN NEWBORN SCREENING. THE VAST MAJORITY OF OUR WORK FALLS IN THE NEXT TIER IMPROVING CARE AND SERVICES FOR PEOPLE WITH MUSCULAR DYSTROPHY. WE'VE COLLABORATED WITH MANY OF YOU IN THE ROOM TO DEVELOP CARE STANDARDS, DISSEMINATE THOSE TO CLINICIANS AND TO PATIENTS. AND TO MONITOR CLINICAL CARE AND OUTCOMES. AND ALL THIS IS POINTED TOWARDS ENHANCING THE QUALITY OF LIFE WITH PEOPLE WITH MUSCULAR DYSTROPHY. WE WANT THEM TO HAVE FULL PARTICIPATION IN SCHOOL WORK AND SOCIAL LIFE AND BE ABLE TO ACHIEVE SUCCESS AS THEY DEFINE IT. WE STARTED OUR WORK AT CDC IN 2002 AS A RESULT OF THE MD CARE ACT. AND CONGRESS DIRECTED US TO WORK IN TWO AREAS. THE FIRST TO DEVELOP CARE STANDARDS FOR THE CLINICAL MANAGEMENT OF DUCHENNE MUSCULAR DYSTROPHY AND USE THAT AS A MODEL TO DEVELOP CARE STANDARDS FOR THE OTHER DYSTROPHIES. WE ALSO WERE DIRECTED TO ESTABLISH A MUSCULAR DYSTROPHY EPIDEMIOLOGY PROGRAM. BUT DID THAT THROUGH THE MD START ACT PROJECT THE MUSCULAR DYSTROPHY SURVEILLANCE TRACKING AND RESEARCH NETWORK. CURRENTLY WE'RE -- AS PART OF THE MD STAR WE'RE DOING A PILOT OF POPULATION BASED SURVEILLANCE FOR NINE MISDEMEANORS IN FOUR STATES. SINCE 2002 WE HAVE BEEN COLLECTING LONGITUDINAL DATA FOR DUCHENNE MUSCULAR DYSTROPHY. THIS IS A QUOTE FROM A PRESS RELEASE FROM THE MDA. THE PRESS RELEASE WAS ABOUT A BRIEFING IN CONGRESS RECENTLY FOR THE RE-AUTHORIZATION OF THE MD CARE ACT. I THINK IT SUMMARIZES NICELY HOW OUR WORK SUPPORTS THE MD CARE ACT. THE LAW ALSO AIMS TO STANDARDIZE CLINICAL CARE FOR MUSCULAR DYSTROPHY THROUGHOUT THE U.S. BY MANDATING THE DEVELOPMENT OF CARE STANDARDS FOR EACH FORM OF THE DISORDER. THE GOAL TO EBB SURE EVERY MD PATIENT RECEIVES OPTIMAL CARE, WHETHER THAT CARE IS DELIVERED IN MAJOR MEDICAL CENTER OR SMALL COMMUNITY PRACTICE. AND -- AS EVERYBODY KNOWS IT'S A HUGE ISSUE THAT CARE IS ALL OVER THE MAP AND WE WON'T GET EVERYONE ON THE SAME PAGE UNTIL WE HAVE STANDARDS AND WE CONVINCE EVERYBODY TO USE THEM AND MEASURE THEIR IMPACT ON OUTCOMES. SO I'LL GO QUICK HUH THROUGH HISTORICAL ACTIVITIES SO I CAN GET TO THE CURRENT ACTIVITIES. IN TERMS OF EARLY SCREENING, IN 2004 WE HAD A STAKEHOLDER MEETING ON NEWBORN SCREENING FOR DUCHENNE MUSCULAR DYSTROPHY AND OUT OF THAT MEETING AROSE TWO PROJECTS. ONE WAS A NEWBORN SCREENING PILOT THAT WAS A MODEL FOR STATE-BASED DUE MUSCULAR DYSTROPHY NEWBORN SCREENING. THIS WAS AWARDED TO (INAUDIBLE) IN OHIO AND HE DEVELOPED A NEW TWO TIER METHOD USING CK SCREENING AND IN SUBSEQUENT DNA ANALYSIS USING THE SAME DRY BLOOD SPOT. I FEEL LIKE THIS WORK HAS REALLY MADE NEWBORN SCREENING FOR DUCHENNE FEASIBLE AND HAS CERTAINLY ADVANCED THE EFFORT. THERE WAS ANOTHER PROJECT ON INFANT SCREENING LOOKING AT SCREENING ONE-YEAR-OLD MALES THROUGH A PEDIATRIC PROVIDERS AND WE FOUND THAT WAS FEASIBLE. BUT IT WOULD REQUIRE QUITE A BIT OF WORK TO INCORPORATE THAT INTO ROUTINE PRACTICE. PARENTS AND SPRAIDERS WERE FOUND SUPPORTIVE AT SCREENING FOR DUCHENNE. THIS WAS A PROJECT WE FUNDED ON BARRIERS TO GENETIC AND DIAGNOSTIC TESTING LOOKING AT DISPARITIES. AND WHAT CAME OUT OF THIS WAS THAT BLACKS HISPANICS OF OLDER AGE OF INITIAL EVALUATION CK AND DNA EVALUATION THOSE WITH FAMILY HISTORY WERE YOUNGER AT INITIAL EVALUATION. WE FUNDED ANOTHER PROJECT ON EARLY IDENTIFICATION, THERE WAS A PILOT EDUCATION OUTREACH PROGRAM FOR DUCHENNE BECKER IN MISSISSIPPI IN 2006 AND THAT PROGRAM EXPANDED TO INCLUDE OTHER CHILDHOOD ONSET NEUROMUSCULAR DISORDERS. FROM THAT, THAT LED TO CREATION OF THE NATIONAL TASK FORCE FOR THE EARLY IDENTIFITIVECATION OF NEUROMUSCULAR DISORRERS AND P THE GOAL WAS TO IMPROVE TIME TO DIAGNOSIS IN CHILDREN FROM SIX MONTHS TO FIVE YEARS. THERE WERE MANY REPRESENTATIVES FROM PATIENT ORGANIZATIONS FEDERAL AGENCIES AND PROFESSIONAL ASSOCIATIONS ON THIS TASK FORCE. THIS LED TO THE DEVELOPMENT OF A WEBSITE FOR PRIMARY CARE PROVIDERS CALLED CHILDMUSCLEWEEK WEAKNESS.ORG. ONE OF THE NICE FEATURES OF THIS IS IT HAS VIDEOS OF CHILDREN EARLY IN THE DISEASE PROCESS WHERE PROVIDERS CAN ACTUALLY SEE THE VIDEOS AND SEE WHAT THIS LOOKS LIKE WHEN THEY ARE EXAMINING KIDS. CHILDMUSCLEWEAKNESS.ORG. THERE'S A MOTOR DELAY ALGORITHM FOR CK TESTING AND TOOL POINT OF CARE TOOLS, RESOURCES FOR FAMILIES AND THE ALGORITHM AND CORE TEALS HAVE BEEN ENDORSED BY THE AMERICAN ACADEMY OF PEDIATRICS. THERE WAS A BIG EFFORT TO DEVELOP CARE STANDARDS ON DUCHENNE MUSCULAR DYSTROPHY AND THOSE ARE CALLED THE CARE CONSIDERATIONS. THEY WERE PUBLISHED IN 2010 IN LANSETT NEUROLOGY. AND THERE IS A FAMILY FRIENDLY VERSION OF THESE TRANSLATED INTO MANY LANGUAGES AND ARE USED ACROSS THE WORLD. THERE WAS AN INTERNATIONAL GROUP OF 84 PRACTITIONERS THAT WORKED TO DEVELOP THESE CARE GUIDELINES AND THEY QUICKLY FOUND THAT THEY NEEDED TO SUPPLEMENT THE SCIENTIFIC PUBLISHED EVIDENCE WITH THE COLLECTIVE JUDGMENT OF EXPERTS AND THIS WAS DONE THROUGH THE RAND APPROPRIATENESS METHOD. THERE WERE PANELS FOR EACH OF EIGHT DOMAINS WHERE THE PANELS INDEPENDENTLY RATED INTERVENTIONS AND ASSESSMENTS. THAT'S THE EIGHT SECTIONS OF THE CARE CONSIDERATIONS. CDC FACILITATED THIS PROJECT THAT IT WAS -- WE RELIED HEAVILY ON MANY SETS IN THIS ROOM WORKED ON THIS PROJECT. PATIENT ORGANIZATIONS AS WELL AS OTHER GOVERNMENT AGENCIES. SO ON TO OUR CURRENT ACTIVITIES. WE WORK WITH THE AMERICAN ACADEMY OF PEDIATRICS, THEY DEVELOPED A CLINICAL REPORT ON MOTOR DELAY THAT WORKS IN PARALLEL WITH THE CHILD MUSCLE WEAKNESS WEBSITE. SO THIS ALGORITHM FOR SURVEILLANCE AND SCREENING VERY SIMILAR TO THAT, DEVELOPED BY THE TASK FORCE, WAS PUT INTO THIS CLINICAL REPORT PUBLISHED IN PEDIATRICS AND WENT OUT TO EVERY PEDIATRICIAN IN THE UNITED STATES. WE'RE CONTINUING OUR WORK WITH AAP TO DEVELOP PLAIN LANGUAGE MATERIALS ON MOTOR DELAYS FOR PARENTS TO HELP ENCOURAGE EARLIER DIAGNOSIS. WE FUNDED THE AMERICAN ACADEMY OF NEUROLOGY TO DEVELOP EVIDENCE-BASED GUIDELINES FOR FOUR OF THE MUSCULAR DYSTROPHY LYNN GIRDLE FSH MYOTONIC AND CONGENITAL. THESE WERE NOT INTENDED TO BE COMPREHENSIVE REVIEW BUT THEY ANSWER SPECIFIC CLINICAL QUESTIONS. AGAIN, THEY RAN INTO THE PROBLEM JUST LIKE WE DID WITH DUCHENNE MUSCULAR DYSTROPHY, PUBLIC LITERATURE DOESN'T ADDRESS EVERYTHING BY ANY MEANS AND P THERE'S REALLY TO DO A COMPREHENSIVE GUIDELINE THERE HAS TO BE A CONSENSUS BASED COMPONENT. THESE ARE SLATED TO BE PUBLISHED STARTING IN THE FALL OF 2014 AND SO WE'RE VERY MUCH LOOKING FORWARD TO SEEING THOSE IN PRINT AND THOSE IN NEUROLOGY. WE'RE FUNDING AN EVALUATION A PILOT EVALUATION OF THE UPTAKE OF DUCHENNE CARE CONSIDERATIONS AT THE CLINIC LEVEL IN FOUR STATES, THAT'S STARTING THIS YEAR. WE ALSO ARE LOOKING AT UPDATING CARE CONSIDERATIONS, THAT IS PART OF THE RE-AUTHORIZATION OF THE MD CARE ACT AND WE WANTED TO TAKE A LOOK AT THE LITERATURE TO DETERMINE WIDOW MAINS NEED UPDATING AND P JUST HOW BIG THE EXTENT OF THE REVISIONS WOULD BE. SO WE BROUGHT TOGETHER THE STEERING COMMITTEE WHO LOOKING AT THE LITERATURE TO HELP US DECIDE THE BEST APPROACH FOR UPDATE. WE'RE CONDUCTING A LITERATURE OF ACUTE CARE PRIMARY CARE TRANSITION AND ADULT CARE. IT'S RECOMMENDED THAT GUIDELINES ARE UPDATED EVERY THREE TO FIVE YEARS. SO WE ARE COMING UP ON THE FOURTH YEAR OF CARE CONSIDERATIONS. THE NEXT TWO PROJECTS I'M GOING TO TALK ABOUT UTILIZES ADMINISTRATIVE DATA. THIS IS ANOTHER APPROACH TO SURVEILLANCE OF MUSCULAR DYSTROPHY IN POPULATIONS. SO THE FIRST PROJECT IS WITH THE STATE OF SOUTH CAROLINA TO STUDY LOOKING AT ADOLESCENTS AND YOUNG ADULTS WITH RARE CONDITIONS. THIS IS MUSCULAR DYSTROPHY FRAGILE X AND SPINA BIFIDA. SOUTH CAROLINA HAS A UNIQUE SITUATION WHERE THEY HAVE A STATE AGENCY THAT RECEIVES DATA FROM MANY OTHER STATE AGENCIES AND THAT DATA COMES IN THERE AND THEY LINK IT ACROSS PERSONS. SO THAT GIVES US A VERY RICH SOURCE OF DATA TO LOOK AT MUSCULAR DYSTROPHY. AND WE'RE -- SOME OF THE THINGS WE'RE LOOKING AT ARE HEALTH STATUS, EDUCATION, PARTICIPATION AND STATE EMPLOYMENT PROGRAMS, SECONDARY CONDITIONS, FREQUENCY AND TYPE OF HEALTHCARE. THE PROJECT IS FOCUSEDD ON WELL BEING AND SERVICE USE FOR 15 TO 24-YEAR-OLDS. THERE'S A COUPLE OF SCIENTIFIC PAPERS THAT ARE IN PROCESS, ONE DEALS WITH EMERGENCY DEPARTMENT VISITS AND HOSPITALIZATIONS, FOR THIS AGE GROUP WITH MUSCULAR DYSTROPHY, THERE'S ALSO A METHODS PAPER DESCRIBING THIS PROCESS. THE SECOND PROJECT IS A PILOT SURVEILLANCE PROJECT FOR RARE DISORDERS, AGAIN MUSCULAR DYSTROPHY SPINA BIFIDA AND FRAGILE X, COLLABORATION ACROSS THREE STATES THAT HAVE DIFFERENT LEVELS OF SURVEILLANCE INFRASTRUCTURE. THE NOTION HERE IS THERE'S LOTS AND LOTS OF DATA EXISTING AND IF WE CAN FIGURE HOW TO IDENTIFY EFFECTIVELY PEOPLE WITH MUSCULAR DYSTROPHY IN THIS EXISTING DATA, WE CAN LEARN A LOT ABOUT WHAT'S GOING ON IN STATES AND IN THE POPULATION. SO THIS PILOT PROJECT IS TO DESIGN PILOT TEST AND EVALUATE THE FEASIBILITY OF THE NATIONAL SURVEILLANCE SYSTEM FOR RARE DISORDERS. AND THEY ARE IN THEIR LAST YEAR SO WE WILL BE SEEING SOME RESULTS FROM THAT RELATIVELY SOON. SO STAR NET IS THE BIGGEST PROJECT THAT WE FUNDED, IT'S BEEN FUNDED SINCE 2002, THERE'S THREE PHASES TO STAR NET. SO THE FIRST PHASE IS THE DUCHENNE AND BECKER MUSCULAR DYSTROPHY LONGITUDINAL DATA COLLECTION WHICH BEGAN IN 2002. WE COMPLETED DATA COLLECTION AT THE END OF 12 AND WE'RE CONTINUING TO ANALYZE THE DATA. THERE'S LOTS AND LOTS OF DATA TO LOOK AT ON THAT PROJECT. PHASE 2 STARTED IN 2011 AND WE WERE LOOKING AT THAT TIME FEASIBILITY OF SURVEILLANCE FOR ALL NINE OF THE MAJOR MUSCULAR DYSTROPHY. THAT IS COMPLETING THIS YEAR. PHASE 3 WILL START THE FALL OF 2014 AND THIS IS A LARGER SCALE SURVEILLANCE AN RESEARCH FOR THE NINE MISDEMEANORS. AND WE WILL -- MISDEMEANORS. AND WE WILL PICK BACK UP -- MUSCULAR DYSTROPHY WE WILL PICK BACK UP SO THERE WON'T BE A BREAK IF IN DATA. SO PHASE 1 WE HAVE DONE THE MOST WORK ON, THESE ALREADY GOALS OF PHASE 1, IT WAS FUNDED IN '02 TO GENERATE POPULATION-BASED PREVALENCE ESTIMATES OVER TIME AND BY RACE ETHNICITY. TO IDENTIFY EARLY SIGNS AN SYMPTOMS, DESCRIBE MEDICAL AND SOCIAL SERVICES RECEIVED AND QUALITY OF LIFE FOR FAMILIES AND INVESTIGATE FACTORS THAT IMPACT SEVERITY OR COURSE OF THE CONDITION. WE HAVE A POPULATION POPULATION COHORT WITH DUCHENNE AND BECKER MUSCULAR DYSTROPHY. A STRINGENT CASE DEFINITION. WITH WE LOOK AT PEOPLE BORN SINCE JANUARY 1, 1982, THEY HAD HAD THE CLINIC VISIT BEFORE DECEMBER 31st, 2011 AND TO RESIDE WITHIN AN MD STAR NET SIGHT AT SOME POINT DURING THEIR LIFE. SO FIVE STATES AND 12 COUNTIES IN WESTERN NEW YORK THAT WERE PART OF THIS PROJECT. THERE WAS INITIAL EXTRACTION OF MEDICAL RECORDS AND ANNUAL FOLLOW-UP ABSTRACTIONS. THERE HAVE BEEN A THUMB OF PAPERS THAT ARE COMING OUT OR PUBLISHED ON FROM THIS DATA SET THERE WAS A POPULATION BASED PREVALENCE PAPER SEVERAL YEARS AGO AND NEW ONE WITH UPDATED DATA THAT WILL ADDRESS PREVALENCE BY RACE AND ETHNICITY. THERE'S A SURVIVAL PAPER AT A JOURNAL RIGHT NOW SO WE HOPE THAT WILL BE PUBLISHED SOON. THIS YEAR THERE WAS AN ARTICLE PUBLISHED ON GROWTH CURVES AND IT LOOKED AT HEIGHT AND WEIGHT AMONG BOYS WITH DUCHENNE 0 TO 12 WHO WERE STEROID NAIVE. SO THERE'S A GROWTH CURVE FOR DND AND ALSO A GROWTH CURVE FOR KIDS IN THE GENERAL POPULATION, SO YOU CAN COMPARE THOSE TWO THEY FOUND EVEN WITHOUT STEROIDS THE BOYS ARE SHORTER IN STATURE THAN THEIR COUNTER PARTS IN THE GENERAL POPULATION AND THEY TEND TO BE EXTREMES OF WEIGHT EITHER VERY SMALL OR HEAVY. THERE'S SEVERAL PAPERS ON CORTICOSTEROIDS. A COUPLE ON COMPLIMENTARY AND ALTERNATIVE MEDICINE. THERE'S ONE UNDER REVIEW AT A JOURNAL ON RISK FACTORS FOR FIRST FRACTURE AND PAPER ON PALLIATIVE CARE. THERE'S MORE BUT THAT'S A FLAVOR. PHASE 2 WAS TO PILOT TEST SURVEILLANCE OF THE NINE MDs. SO WE FOCUSED TO DO THIS WE FOCUSED ON DATA COLLECTION FOR FEWER VARIABLES. AND WENT TO MANY MORE PLACES THAN WE DID FOR THE DUCHENNE SURVEILLANCE. PART OF THIS WAS A PILOT TO SEE COULD WE DO IT AND WHAT WAS THE MOST EFFECTIVE APPROACH TO DO IT. IN ADDITION, THE STATES FUNDED TO DO THE PILOT ALSO WERE FUNDED TO CONDUCT A VARY TO ASSESS TRANSITION FROM CHILDHOOD TO ADULTHOOD TO YOUNG MEN WITH DUCHENNE. THAT DATA HAS JUST BEEN FINISHEDDED, WE JUST RECENTLY RECEIVED THE DATA SET SO WE'LL START ANALYSIS ON THAT. THE -- A LITTLE BIT MORE ABOUT THE TRANSITION SURVEY, WE RECRUITED CARE GIVERS AND AFFECTED MALES 16 AND OLD FRESH THE FIVE SITES. WE LOOKED AT INDEPENDENCE AND SELF-CARE AN MEDICAL TREATMENT BY AGE, FUNCTIONAL HEALTH AND HEALTHCARE HEALTHCARE TRANSITION AND WE WILL BE COMPARINGING THE EXPERIENCE OF MALES WITH DUCHENNE AND BECKER TO UNAFFECTED MALES IN TERMS OF EDUCATION, EMPLOYMENT AND OTHER INDICATORS OF LIFE STAGES. PHASE 3 WILL START THIS FALL. AND WE'LL BE LOOKING AT ALL NINE MDs, WE DID FEEL LIKE WE COULD SUCCESSFULLY DO THAT IN OUR PILOT. ONE THING WE'RE GOING TO DO FROM THE START IS TO REACH OUT TO ALL PATIENT ORGANIZATIONS TO MAKE SURE THEY'RE INVOLVED IN DETERMINING HIGH PRIORITY QUESTIONS. FOR EACH PARTICULAR TYPE OF MUSCULAR DYSTROPHY AND TRY TO SEE WHAT WE CAN DO WITH THE DATA COLLECTION THAT WE HAVE USING MEDICAL RECORDS TO TRY TO ANSWER SOME OF THOSE QUESTIONS. OUR HOPE IS WE WILL FUND SOME STATES WITH INCREASED RACIAL AND ETHNIC DIVERSITY AND THIS WILL START OUT WITH AN EVALUATION PLAN ALL OF THE SITES WILL GET TOGETHER AND DEVELOP AN EVALUATION PLAN AND ALSO BE A COMMUNICATION PLAN. AGAIN WE WILL BE RELYING ON OUR PARTNER ORGANIZATIONS TO HELP US GET THE INFORMATION BACK OUT TO THE PATIENT POPULATION. SO THIS SLIDE SUMMARIZES BASICALLY WHERE WE'RE TRYING TO IMPACT PUBLIC HEALTH. WE DO A FAIR AMOUNT OF WORK IN FAMILY -- LOOKING AT FAMILIES AN CAREGIVERS. WE'RE VERY INTERESTED IN HEALTH OUTCOMES AND WE ARE HOPEFUL THE INFORMATION THAT WE PRODUCE FROM THIS PROJECT WILL INFORM POLICY MAKERS. THERE'S MANY POLICY ISSUES GOING ON RIGHT NOW, PARTICULARLY AROUND TRANSITIONS AND ACCESS TO EDUCATION EMPLOYMENT FOR YOUNG MEN WITH DUCHENNE, PEOPLE ARE LIVING MUCH LONGER THAN THEY DID IN THE PAST. AND WE WANT TO MAKE SURE THE WAY IT'S CLEAR FOR THEM TO GO AHEAD WITH THEIR LIFE. MY LAST SLIDE, WHITE IT MATTERS. WORKING IN PUBLIC HEALTH, WE'RE AVERY SMALL PROGRAM BY COMPARISON TO MANY THINGS YOU HEAR TODAY. YOU CAN FUND US WITH ONE GRANT FROM A WELLSTONE CENTER AND HAVE MONEY LEFT OVER. SO WE'RE NOT BIG. BUT ANYWAY, OUR GOAL IS TO ENSURE EVERY MD PATIENT RECEIVES OPTIMAL CARE NO MATTER WHERE THEY SHOW UP FOR CARE. WE'RE DOING THIS BY DEVELOPING AND IMPLEMENTING CARE STANDARDS, HOPING THE LIST ALL BOATS TO BRING ALL PATIENTS WITHIN TO THE SAME HIGH LEVEL OF CARE. AND WE ARE TRYING TO DEVELOP EPIDEMIOLOGY FOR MUSCULAR DYSTROPHY SO WE CAN BETTER DESCRIBE THE MD POPULATION AND IDENTIFY THEIR HEALTHCARE AND SERVICE NEEDS. WE BELIEVE IN IMPROVING THE LEVEL OF CARE FOR EVERYONE WITHIN THE LESSONS THAT IMPACT THE DISEASE. NOT ONLY ON INDIVIDUAL BUT THEIR FAMILY, THE COMMUNITY AND HEALTHCARE SYSTEM. SO THERE IS MY CONTACT INFORMATION AND PLEASE FEEL FREE TO EMAIL ME OR TALK TO ME WHILE I'M HERE. [APPLAUSE] >> THANK YOU VERY MUCH. I THINK AGAIN KEEP AN EYE ON THE CLOCK WE'RE GOING TO MOVE ALONG TO OUR NEXT SPEAKER. PAT FURLONG WITH FOUNDING PRESIDENT AND CEO OF PARENT AND PROJECT MUSCULAR DYSTROPHY BUT PAT ACTUALLY WILL NOT BE SPEAKING ABOUT PARENT PROJECT MUSCULAR DYSTROPHY PER SE BECAUSE BRIAN WILL BE DOING THAT IN THE NEXT -- AS THE NEXT SPEAKER. PAT INSTEAD WILL FOCUS ON EFFORTS SHE'S WITH BEEN LEADING TO DEVELOP DRAFT GUIDELINES FOR SPONSORS WORK WITH FDA. TO DEVELOP DRUGS FOR DUCHENNE MUSCULAR DYSTROPHY. ANOTHER ONE OF OUR INVITED TALKS ON A SCIENTIFIC TOPIC. WELCOME. (OFF MIC) AROUND THE TAKE AND OUR END USER WE HOPE TO DELIVER THERAPIES FOR IN THE NEAR FUTURE. SO MY SLIDES ARE THANKS TO ROD FISHER DIRECTOR OF OUT REACH AS WELL AS TIM FRANCIS WHO HELPED COMPILE THE SLIDES. MAYBE I SHOULD GO ON IN THE INTEREST OF TIME. SO WHAT DID I JUST DO? OKAY. WHY ARE WE HERE? BECAUSE THE PDUFA AND FDSHA WERE SIGNED IN TO LAW WITH THE REQUIREMENTS TO SAY TO THE FDA THANK YOU FOR INCORPORATING THE DATA PATIENT VOICE AND PLEASE INCORPORATE IT MORE AND LISTEN TO THEM ON EVERY LEVEL, OBVIOUSLY WE ARE END USERS AND ANXIOUS TO HAVE THERAPIES. SO THIS IS THE PATIENT, I DON'T KNOW WHO HAVE AUDIO BUT THIS IS LITTLE SAM KILLIAN AND WHAT HE WILL CELL YOU IS HE HAD DUCHENNE MUSCULAR DYSTROPHY THAT MEANS HIS MUSCLE TISSUE IS TURNING TO SCAR TISSUE AND HE THINK HE IS WON'T HAVE LIFE EXPECTANCY OF HIS FRIENDS BUT CERTAINLY WOULD LIKE TO HAVE THAT. SO THAT IS WHY WE'RE HERE TODAY. IT'S A BRAVE NEW WORLD IN DUCHENNE WHEN MY SONS WERE DIAGNOSED IN 1984, THERE WAS NO PIPELINE FOR DUCHENNE MUSCULAR DYSTROPHY. NOTHING FOR DUCHENNE MUSCULAR DYSTROPHY NOT EVEN OPT MALT CARE. WHEN I -- OPTIMAL CARE. WHEN I WORRIED ABOUT CARDIAC AND PULMONARY STATUS IT WAS DISMISSED BECAUSE IT WAS THOUGHT TO OCCUR IN THE 20s. THEY DIED AT 15 AND 17 SO THE ADVOCATES CAME TO THE HILL T MUSCULAR DYSTROPHY ASSOCIATION, PPMD AND ENCOURAGED CONGRESS TO HELP THINK ABOUT THIS DIFFERENTLY AND AS YOU KNOW CONGRESS PASSED THE MD CARE ACT IN 2001 AND I THINK THAT MUSCULAR DYSTROPHY CARE ACT AND IMPACT OF THAT OVER THOSE YEARS HAVE GALVANIZED THE COMMUNITY, THE CLINICIANS, THE PATIENTS, THE ADVOCATES, AND ALSO INDUSTRY BECAUSE WITH THAT SPEND WHICH IS WHAT JOHN AND GLENN DEMONSTRATED TODAY, THIS BROUGHT US TO THE POINT OF CHARACTERIZING THESE DISEASE DISEASES AND DELIVERS FOR DUCHENNE MUSCULAR DYSTROPHY A PIPELINE FULL OF OPPORTUNITIES THAT WE ARE FEEL MORE THAN BLESSED AND MORE THAN EXCITED ABOUT. SO AS PART OF OUR ADVOCACY STRATEGY, PPMD WE THOUGHT IT WOULD BE A GOOD IDEA TO BEGIN THE THINK ABOUT TALKING TO THE FDA ABOUT DUCHENNE MUSCULAR DYSTROPHY. I THINK THEY HAVE AN INCREDIBLE JOB ON THEIR HANDS TO KNOW ALL THESE RARE DISEASES AND ALL THE MUSCULAR DYSTROPHY AND NUANCES OF THE MUSCULAR DYSTROPHY AND WE FELT IT WAS MAYBE WORTH US TRYING TO PARTNER WITH THE FDA AND SHARE WITH WE KNEW ABOUT THIS UNMET NEED AND SHARE OUR GOALS AND ASPIRATIONS WERE SO THAT WE CAN IN FACT HELP THEM BE MORE FLEXIBLE IN THEIR REVIEW, ASSIST THEM IN TERMS OF ANSWERING QUESTIONS, AND LET THEM HAVE SOME INSIGHT INTO WHAT IT IS LIKE TO LIVE WITH DUCHENNE MUSCULAR DYSTROPHY. SO WE BEGAN VISITING WITH THEM IN 2012 AND WE STARTED WITH THIS UNMET NEED AND DESCRIBED FROM THE PATIENT'S POINT OF VIEW ACROSS THE SPECTRUM OF THE ILLNESS WHAT IT'S LIKE TO GET A DIAGNOSIS, WHAT'S IT'S LIKE TO SEE A CHILD GO OFF HIS FEET AND KNOW HE'LL NEVER WALK AGAIN, WHAT IT'S LIKE THE SEE YOUR CHILD UNABLE TO FEED THEMSELVES AND FINALLY HAVE TO THINK ABOUT YOUR CHILD REALLY BEING FULLY DEPENDENT AND EVEN NOW AS WE SPEAK, WITH THE MEAN AGE BEING EXTENDED NOW WE ALSO HAVE THE FURTHER COMPLICATING FACTOR OF OLDER PARENTS AND ADULT MEN WHO REALLY NEED FULL TIME CARE. SO THAT REALLY CULMINATED IN A MEETING IN DECEMBER WHEN OR I SHOULD SAY IN JULY WHEN WE MET WITH THE FDA AND WE TALKED TO THEM ABOUT THE GUIDANCE THAT WAS RELEASED WITH BY THE EMA. SO IN SPRING OF LAST YEAR THE EMA RELEASED GUIDELINES ABOUT DUCHENNE MUSCULAR DYSTROPHY AND WE FELT LIKE THAT WAS PRETTY IMPORTANT. SO WE PREPARED OURSELVES WITH THAN IN LIGHT OF FDUCA BY CREATING A WHITE PAPER CALLED PUTTING PATIENTS FIRST TO LOOK AT HOW DOES DUCHENNE FIT IN THE POLICY, WHAT ARE RECOMMENDATIONS WE CAN MAKE LOOKING IN THE CONTEXT OF POLICY? AND THIS IS TO EXPAND USE OF ACCELERATED APPROVALS, ISSUE CLEAR GUIDANCE ON THE LEVEL OF EVIDENCE REQUIRED TO USE SURROGATE END POINTS. THINK ABOUT ADAPTIVE APPROVAL THROUGH SERIOUS AN LIFE THREATENING DISEASES AND GIVE GREATER WEIGHT TO THE PATIENTS. AND THEIR VIEW OF THIS DISEASE. AND WHAT'S THE NEEDS. WE ALSO THEN TALKED TO THE FDA AND LATER MEETING ABOUT BENEFIT RISK AND SAID THE BENEFIT RISK EQUATION IS DIFFERENT. I THINK AS PARENTS WE TALK ABOUT THAT ALL THE TIME, IT'S DIFFERENT AND WE RUN THIS IF THEN EQUATION, IF THIS HAPPENS THEN MY CHILD DOESN'T GO OFF THEIR FEET, IF THIS HAPPENS MY CHILD CAN FEED THEMSELVES SO IN ORDER TO ADDRESS THAT WITH DATA, WE THEN EMBARKED ON A BENEFIT RISK PROJECT. THIS WAS DONE BY HOLLY PA INSIDE PPMD, VICE PRESIDENT OF EDUCATION, AND SHE AND JOHN BRIDGES FROM HOPKINS DESIGNED THIS PROJECT AND IT'S A PILOT BENEFIT RISK AND IT PILOTED WITH 119 PARENTS. BASICALLY WE LEARNED THAT THE EQUATION IS INDEED DIFFERENT. PARENTS ARE WILLING TO TAKE ON RISK, THAT THEIR HIGHEST PRIORITY IS TO STABILIZE DISEASE PROGRESSION. AND P THAT WAS WHAT WE ASSUMED AND THAT IS CERTAINLY WHAT WE LEARNED IN THE BENEFIT RISK PROJECT. CURRENTLY WE HAVE BEEN IN DISCUSSION WITH FDA ABOUT EXPANDING THAT PROJECT TO ASK IF THE YOUNG ADOLESCENTS AND ADULT VERSUS THE SAME BENEFIT RISK EQUATION AS THEY'RE WILLING TO TAKE ON RISK AND WHAT LEVEL OF RISK, FOR WHAT LEVEL OF BENEFIT. I CAN TELL YOU FROM A PARENT'S POINT OF VIEW I THINK FIVE MINUTES OF STABILITY WHICH I KNOW WE CAN'T TRACK OR MEASURE WOULD BE A REAL GREAT DIFFICULT GIFT. SO WE'RE TALKING WHAT LEVEL OF BENEFIT AND THEN HOW MUCH RISK ARE YOU WILLING TO TAKE ON. SO THIS PROJECT WILL BE EXPANDED. THIS IS THE EMA GUIDANCE THAT WAS ISSUED IN 2013 SPRING FOLLOWED BY A MEETING IN LONDON WHERE THE WHOLE PATIENT CLINICAL COMMUNITY SCIENTIFIC COMMUNITY GOT TOGETHER AND TALKED TO EMA ABOUT GUIDANCE AND DISCUSSED THINGS THAT WERE CONTROVERSIAL OR DISAGREED WITH OR AGREED WITH SO WE COULD GET ON THE SAME PAGE. AND THEN WHEN WE MET WITH THE FDA HERE, IN AUGUST WE ASKED DR.S WOODCOCK IN THE NEUROLOGY DIVISION IF THEY WERE INTERESTED IN WRITEING A SIMILAR GUIDANCE. THEY SAID NO. WE WOULDN'T. SO YOU CAN IMAGINE WRITING GUIDANCE FOR ALL THE MUSCULAR DYSTROPHY OR ALL RARE DISEASES WOULD BE QUITE A TASK AND PROBABLY NOT EVEN REASONABLE TO ASSUME. BUT WHAT THEY SUGGESTED TO US IS THAT WE COULD WRITE GUIDANCE, WE COULD GRAB THE COMMUNITY AND ENGAGE THE ENTIRE COMMUNITY AND WRITE GUIDANCE AND THEY WOULD BE WILLING TO RECEIVE THAT. SO WE EMBARKED ON THE PROJECT OF WRITING GRAFT GUIDANCE FOR DUCHENNE MUSCULAR DYSTROPHY. SO WE STARTED OFF WITH A POLICY FORUM IN DECEMBER AND THE POLICY FORUM WAS REALLY TO RECREATE THE LONDON MEETING TO USE THE BASIS OF THE EMA GUIDANCE AND TO TALK ABOUT WHAT HAPPENS IN LONDON AND BRING THAT OVER SO THAT WE WERE REALLY HAVING CONSISTENCY IN EUROPE AS WELL AS THE UNITED STATES. SO DIRECT GUIDANCE WOULD BE PROMISED, NOT SURE WE'LL REGRET THAT PROMISE, WE'LL HAVE IT READY TO GO BY MAY OF 2014. WE PROMISE WE WOULD HAVE COMMUNITY ENGAGEMENT THROUGHOUT THIS PROCESS, WE HAVE A STRUCTURED THAT INCLUDES STEERING COMMITTEE WORKING GROUPS AN COMMUNITY ADVISORY PAM P. I WILL TELL YOU -- PANEL. I WILL TELL YOU ABOUT EACH. THIS IS THE ORGANIZATIONAL STRUCTURE, THE STEERING COMMITTEE CONSISTS OF NINE MEMBERS, REPRESENTATIVE OF INDUSTRY, CLINICAL COMMUNITY AND SCIENTIFIC COMMUNITY AND PATIENTS. SO YOU CAN SEE HERE WHO IS HERE, WHO IS ON STEERING COMMITTEE JOHN P PORTER CHAIRS THE BIOMARKERS 1. I CHAIR THE LAST WORKING GROUP WHICH IS NOW WAS CALLED POLICY AND WE RECERTAINLY CHANGED TO IMPERATIVE -- RECENTLY CHANGED TO IMPERATIVE. SO ESTABLISH THE KEY TOPICS, THEY WILL INCLUDE IN THEIR WORKING GROUPS MEMBERS OF THE COMMUNITY, CLINICAL COMMUNITY, SCIENTIFIC COMMUNITY AS WELL AS INDUSTRY. THEY WILL ENCOURAGE FDA'S INVOLVEMENT WHEN RELEVANT AND WE HAVE LEARNED THAT WE'RE GOING TO REALLY SUBMIT THIS TO A DOCKET, THEY'RE GOING TO OPEN IT TO RECEIVE IT AND P FDA CAN'T CONTRIBUTE OPINIONS ALONG THE WAY. SO WE ARE HAVING THEIR WORKING -- THEY WILL REVIEW AND WILL REPORT ON ALL WORKING GROUP ACTIVITIES. AND THEY WILL FINALIZE THE LAST -- THE WORK -- THE GUIDANCE THAT OCCURS. SO THE WORKING GROUPS ARE THESE. BENEFIT RISK CHAIRED BY JOHN BRIDGES HOPKINS, DIAGNOSIS KEVIN FLANAGAN, NATURAL HISTORY CRAIG MCDONALD. BIOMARKERS ONE WHICH IS MUSCLE BIOPSY JOHN PORTER, BIOMARKERS 2 MR, SERUM AND URINE, THAT'S LEE SWEENEY. CLINICAL TRIALS DESIGN OUTCOME MEASURES LAWRENCE FROM SHIRE PHARMACEUTICALS AN IMPERATIVES WHICH IS CHAIRED BY ME. SO THIS IS IS THE WORKING GROUP, THEY ARE REALLY GOING TO IDENTIFY -- REVIEW LITERATURE, REALLY DETERMINE POINTS OF AGREEMENT AND TOPICS THAT REQUIRE FURTHER DISCUSSION OR FURTHER EXCHANGES NEED. THEY WILL PROVIDE DIRECTION TO AN EXPERT WRITER WHICH WILL LEARN TAYLOR SMART FROM THE HIV COMMUNITY. THEY WILL COMMENT ON THE DRAFTS AND LET THIS GO FORWARD TO THE FINAL GUIDANCE OR THE FINAL WORKING GROUP WHICH WILL GO TO THE STEERING COMMITTEE. SO BENEFIT RISK, I'M GOING TO GO THROUGH SO YOU CAN SEE WE HAVE A REPRESENTATION ON ALL WORKING GROUPS WHICH INCLUDES INDUSTRY, PATIENT, COMMUNITY, SCIENTIFIC AND CLINICAL COMMUNITY. BENEFIT RISK. WORKING GROUP OF DIAGNOSIS, AND YOU'LL RECOGNIZE A LOT OF THESE PEOPLE ON NATURAL HISTORY, YOU WILL SEE A LOT OF FOLKS YOU KNOW AND I'LL RUN THROUGH THESE IN THE INTEREST OF TIME. WORKING GROUP 5 IS BLOOD URINE AND MRI, I KNOW NIH HAS FUNDED A LOT OF THE MRI WORK WHICH IS INCREDIBLE TO REALLY SEE HOW THINGS COME TOGETHER AND AS A COMMUNITY THIS HAS BEEN A VERY UNIFYING POINT OF ALL OF US. WORKING GROUP 6 IS CLINICAL TRIALS AND OUTCOME MEASURES. 7 IS POLICY. NOW CHANGED TO IMPERATIVE. AND ON THIS YOU WILL NOTICE THAT WE HAVE STEVE GROFT, MARLENE IS THERE, JEFF WATKINS THE FATHER OF A 31-YEAR-OLD DUCHENNE MUSCULAR DYSTROPHY, AND FOLKS FROM FASTER CURES AND ALBERT ALLEN, A BIOETHICIST. AND WE ARE ADDING A STATISTICIAN AS WELL TO THIS GROUP. SO THE PROFESSIONAL WRITER AS I MENTIONED IS TAYLOR SMART, FROM THE HIV COMMUNITY, HE WAS RESPONSIBLE WITH MARK HERRINGTON FOR ACT -- IF ANY OF YOU KNOW THE HIV COMMUNITY AND HAS BEEN IN HIS WRITTEN GYNOFOR TUBERCULOSIS AS WELL AS HIV WE HAVE SECRETARIATE AND THAT IS MARK KRUGER AND ASSOCIATES, ALSO RAN AMFAR AND HE'S WITH KRUGER AND ASSOCIATES OR IT'S HIS COMPANY AND HE PROVIDES GUIDANCE TO US AND TO INDUSTRY AS WELL. THE COMMUNITY ADVISORY BOAR, THIS IS CHAIRED AND ORCHESTRATED BY RYAN FISHER AND THIS IS REALLY TO ENGAGE THE WHOLE REST OF THE COMMUNITY THAT'S NOT SERVING ON A WORKING GROUP. SO WE HAVE PUBLICLY OFFERED ANYONE TO JOIN THIS ADVISORY COMMITTEE AND REACHED OUT TO THE COMMUNITY. YOU'LL SEE THEIR CHARGE IS TO ARTICULATE THE NEEDS OF THE COMMUNITY TO MAKE SURE THEY'RE REVIEWING THE DOCUMENTS AND SAYING WHAT'S MISSING, WHAT NEEDS TO CHANGE, WHAT THEY FEEL IN TERMS OF THEIR OPINION, AND GET THIS BACK TO THE WORKING GROUPS AND THEN TO THE STEERING COMMITTEE. THE COMMUNITY ADVISORY BOARD MEMBERS REPRESENT PARENTS ACROSS THE SPECTRUM OF THE ILLNESS THE THEY REPRESENT PATIENTS ADOLESCENT PES AND YOUNG ADULTS AND REPRESENT FOUNDATIONS, MOST THAT YOU ARE PROBABLY FAMILIAR WITH IN TERMS OF THE UNITED STATES AS WELL AS INTERNATIONAL ORGANIZATION. WHY NOW? WE'RE AT A PIVOTAL POINT IN DUCHENNE MUSCULAR DYSTROPHY AND THE VOICE OF DUCHENNE REALLY HAS TO BE HEARD AND HAS TO BE RAISED. WE FELT LIKE THIS WAS A WONDERFUL OPPORTUNITY, DR. WOODCOCK SUGGESTED TO US THOUGH I WILL BE HONEST WHEN SHE SAID WRITE GUIDANCE I WAS LIKE WHO WAS GOING TO DO THAT. SO WE FEEL LIKE THIS IS AN AMAZING WAY TO BRING THE COMMUNITY TOGETHER, TO DISCUSS THE ISSUES THAT ARE CONCERNING US, THAT ARE RELEVANT TO DUCHENNE, THAT MAYBE WE FEEL IS OPTICAL IN THE PROCESS OF GETTING DRUGS DEVELOPEDDED AND GIVING THEM CHILDREN WHO NEED ACCESS AND YOUNG ADULTS. SO WE FEEL THIS IS IMPORTANT, WE FEEL THIS IS A SUSTAINABLE PROCESS. WE ARE HOPEFUL THAT THIS IS A THOUGHTFUL PROCESS AND ONE THAT CAN BE UTILIZED WIDELY IN THE RARE DISEASE COMMUNITY. I THINK MANY OF YOU STATED IT, IT'S NOT GOOD TO DO THESE N EQUAL ONES AND P REPEAT IT. THESE PATIENTS ARE IN NEED IN GREAT NEED OF THINGS THAT WILL HELP THEM WILL CHANGE THE COURSE OF THEIR ILLNESS. SO WE ARE HOPEFUL THIS IS A MODEL THAT OTHERS CAN USE. SO WHERE ARE WE? HERE IS OUR TIME LINE. WE STARTED IN ACTUALLY DECEMBER WITH THE POLICY FORUM AND JANUARY WE BEGAN BY IDENTIFYING THE STEERING COMMITTEE. IN FEBRUARY THE WORKING GROUPS, IN MARCH WE STARTED ON THE MEETINGS AND IDENTIFY THE COMMUNITY ADVISORY BOARD. WE ARE IN APRIL NOW, ALL THE WORKING GROUPS HAVE NOW MET. THEY ARE -- HAVE PRELIMINARY DOCUMENTS, WE HAVE A TABLE OF CONTENTS THAT'S NOW FINALIZED. THE COMMUNITY ADVISORY BOARD HAS MET AND BY MAY, END OF MAY, WE'RE HOPEFUL THAT WE WILL HAVE A COMPLETION OF THE DRAFT GUIDANCE THE FDA AGREED TO OPEN A DOCKET AND BY JULY WE HOPE TO HAVE OPEN PUBLIC MEETING TO DISCUSS THE GUIDANCE. SO THESE ARE THE WORKING GROUP TOPIC AND AGAIN IN THE INTEREST OF TIME I'LL LET YOU TAKE A LOOK AT THEM AND BENEFIT RISK ANALYSIS TO LOOK AT THIS EQUATION AN EXPAND THROUGHOUT THE ADOLESCENT YOUNG ADULT POPULATION, TO TALK ABOUT BENEFIT RISK, WHAT LEVEL OF EVIDENCE IS REQUIRED IN TERMS OF WHAT WE NEED TO KNOW ABOUT THIS COMMUNITY. FROM TO ASSESS RISK IN THE VERY YOUNG PATIENTS. BECAUSE ALL THESE THERAPIES I THINK WE CAN AGREE PROBABLY THE EARLIER INTERVENING THE BETTER THE OUTCOME SO WE WANTED TO KNOW FROM YOUNGER PATIENTS AS WELL. MANY DIAGNOSIS, WHO KNEW AS A PARENT WITH TWO BOYS WITH DUCHENNE LONG AGO I THOUGHT DIAGNOSIS WAS EASY. I HAVE COME TO LEARN IT'S NOT NECESSARILY EASY. CERTAINLY AS WE LOOK AT BIOMARKERS, WE MAY FIND DIFFERENCES IN THOSE DIAGNOSES SO WE WANTED TO LOOK AT DIAGNOSIS AND HAVE VERY SPECIFIC CRITERIA. NATURAL HISTORY. THIS IS CERTAINLY BEEN INTERESTING TO FOLLOW OVER THE YEARS. I CAN SHARE AN EXAMPLE WITH YOU ONE YOUNG BOY IN THE LAWRENCE STUDY IN THE EARLY LAWRENCE STUDY DIAGNOSED WITH DUCHENNE, NO UNBIOPSY NO DYSTROPHIN AND ON DISTENSION AND CELEBRATED HIS 21st BIRTHDAY WALKING YESTERDAY SO WE DON'T KNOW A LOT ABOUT THESE CASE KIDS IN TERMS OF NATURAL HISTORY, WE'RE LEARNING AND WANT TO LEARN MORE SO IT'S QUITE INTERESTING SO NATURAL HISTORY GROUP IS A FASCINATING GROUP MOVING FORWARD. BIOMARKERS 1 AND 2, WE SEPARATED BIOMARKERS BECAUSE THE APPROACHING REPLACEMENT OF NEUTRAFIN AND DYSTROPHIN IS DIFFICULT AND CONTROVERSIAL, HOW DO YOU ANALYZE AN EXPRESS IT AND WHAT IT MEANS AND PROGRESSION OF THE ILLNESS. BIOMARKERS 1 SHOULD BE SEPARATEED FROM THE OTHERS SO THEY CAN TACKLE SOME SOFT THOSE DIFFICULTIES AS A GROUP. BIOMARKERS TWO MRI SERUM AND BLOOD AND URINE AND WE FELT LIKE THIS WAS ALSO A SEPARATE WORKING GROUP TO BE DEALT WITH SEPARATELY. SO THESE ARE GROUPS WORKING TOGETHER CHAIRED BY JOHN PORTER AND LEE SWEENEY AS I MENTIONED. CLINICAL TRIALS. BOY, ONE OF THE DIFFICULTIES OF CLINICAL TRIALS IS TYPICALLY TARGET AN AMBULATORY POPULATION. OFTEN IT'S MORE NARROW THAN AMBULATORY POPULATIONS, NOT AMBULATORY, IT'S AMBULATORY AFTER 7 OR FIVE YEARS OLE AND IS CERTAIN NUMBER OF METERS AS THE PRIMARY OUTCOME SO AS A PARENT WITH A CHILD WHO IS FIVE THAT DOESN'T -- THAT FEELS LIKE YOU'RE LEFT OUT AT A TIME YOU REALLY WANT TO PRESERVE WHAT THAT YOUNG BOY HAS AND WANTS HIM TO KEEP THAT. AND THEN IF YOU'RE FASTER THAN THE SIX MINUTE WALK TEST CRITERIA, YOU'RE RIGHT ON THE EDGE OF NOT BEING ABLE TO PARTICIPATE WHICH MAKES PARENTS THINK WELL MAYBE I SHOULD TEACH HIM TO WALK SLOWER AND GO WHICH IS DEFEATING THE PURPOSE OF THE TRIAL BUT IT'S WHAT A PARENT MIGHT DO. I KNOW THEY ALSO TEACH HOW TO DO THE SIX MINUTE WALK TEST AND GET IT RIGHT IN THAT WEDGE. FOR THE PARENT WHOSE CHILD IS NO LONGER AMBULATORY, FEELS LIKE YOU'RE LEFT OFF THE BUS AND MAY ALWAYS BE IN THE BACK OF THE BUS SO DESIGNING CLINICAL TRIALS THAT ARE APPROPRIATE THAT INCLUDE THE SPECTRUM OF THE ILLNESS WE FELT IS VERY IMPORTANT. IT'S REALLY IMPORTANT TO THE PATIENT POPULATION BECAUSE IT'S HARD TO FEEL LEFT OUT OF SOMETHING THAT HAS REAL POTENTIAL TO IMPACT THE LIVES OF THE PEOPLE CARE ABOUT. SO CLINICAL TRIALS DESIGNS AN OUTCOME MEASURES ARE GOING TO BE IMPORTANT. THEN THE IMPERATIVES GROUP, THIS IS GOING TO BE THE VOICE OF THE PATIENT. WE TALK ABOUT THIS AND WE HAVE GATHERED TOGETHER O ON THE PHONE A COUPLE OF TIMES, WE TALK ABOUT THE TIME THAT FROM THE FDA RANDOMIZED PLACEBO CONTROL TRIALS BUT IT'S HARD TO THINK YOUR SON WOULD BE ON A PLACEBO WHILE MUSCLE FIBERS ARE DYING. HOW WE GET AROUND, HOW DO WE AVOID THE USE OF PLACEBO. ALSO IN FAMILIES MORE THAN ONE CHILD WE WANT SPONSORS TO PRE-SPECIFY WHAT'S GOING TO HAPPEN. IF ONE CHILD FITS INCLUSION CRITERIAND OTHERS DONE BECAUSE THEY'RE TOO YOUNG NOT THE MEET INCLUSION CRITERIA FOR FUNCTIONAL OUTCOME, THERE HAS TO BE A PLAN TO INCLUDE THE OTHER CHILD. AT SOME POINT IT HAS TO BE PRE-SPECIFIED AND WELL DEFINED FOR THE FAMILY BECAUSE OTHERWISE THE FAMILY JUST IT'S GOSSIP POSSIBLE TO IMAGINE ONE CHILD MIGHT BE DOING BETTER ON A GIVEN COMPOUND AND I KNOW THAT'S THE PURPOSE OF THE EXPERIMENT BUT AT THE SAME TIME IF THERE'S A PLAN, WHEN SAFETY IS ESTABLISHED THE OTHER CHILD CAN HAVE THE DRUG, IT'S GOING TO BE IMPORTANT, EXTRAPOLATION IS A ISSUE IF YOU'RE SETTING A NARROW POPULATION HOW WILL WE GIVE THE BABIES, ASSURE THERE'S NO LINES DRAWN AGAINST OR SO THAT IT -- NON-AMBULATORY PATIENTS ARE ABLE TO ACCESS THAT. ALSO FOR SPONSORS TO PRESPECIFY WHAT PLANS ARE WHETHER THEY'RE INTERESTED OR WILLING TO DO COMPASSIONATE STUDIES, WHETHER INTERESTED IN OR WILLING TO DO A SAFETY STUDY ON LITTLE KIDS, PRE-SPECIFY SOME OF THAT BECAUSE OTHERWISE AS YOU MIGHT IMAGINE PATIENTS GET TO GO TO CLINIC, AND THEY MEET THE PI AND THEY ASK THE PI WILL THERE BE AN EXTENSION PROGRAM AND THAT PI MIGHT SAY I DON'T KNOW BUT IF THEY SMILE THAT PROBABLY MEANS YES. SO IT'S PERCEPTION OF WHAT HAPPENS AT THE CLINIC, PERCEPTION OF WHAT YOU WANT IT TO BE AND I THINK IF IT'S PRE-SPECIFIED WE ALWAYS WILL BE ON THE SAME PAGE SO WE KNEW AND CAN CAN COUNT ON WHAT PEACE GOING TO HAPPEN UNDER CERTAIN CIRCUMSTANCES SO THESE ARE THE IMPERATIVES THAT WE'RE TALKING ABOUT. WE INCLUDE BIOETHICIST FOR THE RECENT FORWARD-LOOKING STATEMENT ABOUT IF PATIENTS RULED THE WORLD THAT'S WHAT THE WORLD WOULD LOOK LIKE. SO WE KNOW THAT'S NOT PART OF THE ACTUAL GUIDANCE BUT WE WANT IT IN THERE ANYWAY AS PATIENTS. THE NEXT STEPS OR THE WORKING GROUP IS STEERING COMMITTEE HAS MET IN MARCH, THEY WILL MEET AGAIN, THE TABLE OF CONTENTS IS FINALIZED AND THE FIRST DRAFT GUIDANCE WILL BE COMPLETED BY EARLY APRIL FOR REVIEW BY THE COMMUNITY ADVISORY BOARD. THIS IS AGAIN OUR TIME LINE, WE INTEND TO STICK TO IT FOR THE FDA GUIDANCE AND WE ARE THRILLED. DO WE HAVE AUDIO? GOOD. I THINK THIS IS IMPORTANT. AGAIN TO END WITH PATIENTS BECAUSE I THINK OF ALL THE THINGS IN THE WORLD THAT ARE IMPORTANT, IT'S THESE YOUNG MEN WITH DUCHENNE IN OUR CASE. >> HI, I'M (INAUDIBLE) TODAY I'M GOING TO TELL YOU ABOUT WHAT'S IMPORTANT FOR ME. THE MOST IMPORTANT IS MY HEART AMONG (INDISCERNIBLE) SO WITHOUT THE VENTILATOR IT WOULD BE GREAT TO DO THINGS AS NORMAL AS POSSIBLE. WITH AS LESS EQUIPMENT AS POSSIBLE. AND THEN SECONDLY MY ARMS ARE VERY IMPORTANT FOR ME WITHOUT THEM YOU CAN'T REALLY DO A LOT. MY HANDS ARE MOST IMPORTANT, TO USE TYPING OR FOR EXAMPLE WITH THE REMOTE CONTROL, THIS WHEELCHAIR BECAUSE FOR ME IT'S ALSO I LIKE THIS WHEELCHAIR WOULD LIKE TO BE ABLE TO DRIVE IT AS LONG AS POSSIBLE BECAUSE IT'S NOT THAT BIG NORMAL ELECTRIC POWER CHAIRS. BUT FOR THIS WHEELCHAIR IT'S IMPORTANT TO MOVE YOUR WHOLE ARM AND NOT JUST YOUR HANDS. I CAN TELL YOU WHEN I DRIVE TO MOVE YOUR WHOLE ARM FORWARD AND BACKWARDS LIKE THIS SO IT'S VERY IMPORTANT THAT YOU CAN JUST MOVE YOUR ARMS -- MY HANDS MOST IMPORTANT THEN LOWER ARMS THEN MY UPPER ARMS SO I WOULD LIKE TO SHOW YOU, WHAT I'M ABLE TO DO RIGHT NOW. AND WHAT WOULD BE TO KEEP THE SAME FOR IMPROVE OF IT. SO NOW THE DIFFICULT TO GET MY ARMS ON THE TABLE SO THIS WAY. WHICH HURTS THE FINGERS SO WOULD BE BETTER IF YOUR UPPER ARM IS STRONGER SO YOU CAN PUT YOUR ARM ON THE TABLE ITSELF SO YOU CAN KEEP TYPING ON THE COMPUTER. WHEN I WANT TO READ SOMETHING I CAN WALK WITH MY FINGERS. -- WORK WITH MY FINGERS. IT WOULD BE GREAT. MY FINGERS JUST KEEP WORKING THE WAY THEY DO. MY LOWER ARMS THEY'RE QUITE -- THEY'RE UP ENDED LIKE THIS IT WOULD BE EASIER -- YEAH. IF I COULD DO IT WITHOUT WRESTLING IT FROM THE TABLE, JUST IN MIDAIR. SO THAT'S IMPORTANT TO ME. >> EYE GOALING THE TAKE YOU BACK THE SAM BECAUSE I THINK IT'S IMPORTANT FOR YOU TO HEAR SAM'S MESSAGE, IT'S MUCH BETTER THAN I CAN DO. >> IT'S A PRETTY MUCH A DISEASE THAT MAKES MY MUSCLES WEAKER AS MY LIFE GOES ON. I WILL PROBABLY DIE YOUNGER THAN MY FRIENDS. I USUALLY DON'T THINK ABOUT THAT. IT'S JUST SCAR TISSUE, I DON'T KNOW HOW I HAVE GOTTEN THE SCAR TISSUE BUT IT'S JUST SCAR TISSUE. >> SO WHEN YOU IT WILL THEM AND THEY ASK ABOUT YOUR CAST. >> I JUST TELL THEM -- I GOT TO HAVE A LITTLE FUN WITH IT. >> RIGHT. >> THANK YOU. >> ONE OF THE THINGS I HAVE NOTICED MEETING THESE NEW BOYS THAT ARE THE SAME AS SAM, IS THAT THEY'RE ALL THE SAME IN THEIR PHYSICAL DISABILITIES BUT ALL DIFFERENT PERSONAL CITY WISE, NOT ONE OF THEM HAS THE SAME PERSONAL SAY, THAT'S WHAT I THINK IS REALLY GREAT. >> CATHY AND I -- [APPLAUSE] >> THANK YOU VERY MUCH. YOU GET THE CHAIR'S GOLD MEDAL FOR COMING IN UNDER TIME WHICH MEANS THE PENALTY IS YOU'RE SUBJECTED TO ANY GRILLING FROM THE REST OF THE GROUP. YOU DID THAT NOT FIGURATIVELY BUT LITERALLY BRINGING THE BOY'S VOICE TO THE TABLE. THANK YOU FOR DOING THAT. ARE THERE ANY QUESTIONS FOR PAT? (OFF MIC) >> THESE GUIDANCE DOCUMENTS ARE USUALLY PREPARING, AS YOU'RE ASKED TO PREPARE THEM FROM THE COMMUNITY TO COME TO THE FDA, AT LEAST WHEN WE WERE TALKING ABOUT OSTEOARTHRITIS SOME TIME AGO, THEY REALLY ASKED THE NIH TO CONVENE THE GROUP, YOU HAVE CONVENED IT VERY BEAUTIFULLY WITH THE PPMD BUT IS THAT THE MODUS OPERANDI THAT THE FDA ORDINARILY USES THE FDA DOESN'T WRITE THE GUIDANCE DOCUMENT BUT THEY ASK THE COMMUNITY TO WRITE THE GUIDANCE DOCUMENT? >> THAT WOULD ACTUALLY BE AN UNUSUAL CASE. >> TO ASK THE IMMUNITY. Q. USUALLY IT'S WRITTEN BY THE FDA. BUT THERE IS -- IT'S ALWAYS PUBLISHED AS A DRAFT, ALWAYS OPPORTUNITY FOR COMMENT BUT IN SOME SITUATIONS PARTICULARLY ARE LYING ON PATIENT OR TREATING PHYSICIAN INPUT, THEN OFTEN ADVISORY COMMITTEES OR WORKSHOPS BEFORE THE GUIDANCE IS WRITTEN. AS A WAY OF GETTING INPUT. THERE HAVE BEEN A FEW EXAMPLES, THERE WAS A CANCER GUIDANCE A COUPLE OF YEARS AGO THAT WAS DONE PREDOMINANTLY BY FRIENDS OF CANCER RESEARCH AND (INAUDIBLE) >> SINCE THE SYSTEM IS WORKING I WOULD LIKE TO USE IT. SO NEXT WE DO AS I SAID HAVE ACTUALLY PARENT PROJECT MUSCULAR DYSTROPHY ITSELF, BRIAN WILL BE TALKING TO US ABOUT SOME OF THEIR ACTIVITIES UNDERTAKING UNDER THE TENURE OF THE ACTION. BRIAN, THANKS FOR BEING HERE TO DO THIS. >> THANK YOU. SO MY NAME IS LISTED AS THE PRESENTER BUT THIS EFFORT ACTUALLY IS A CULMINATION OF THE WORK OF SEVERAL PEOPLE I HAVE TO THANK, SHARON HESTERLY AND CATHY AND HOLLY PA FOR HELPING ME COLLECT THE DATA. PPMD HAS BEEN VERY INVOLVED OVER THE NUMBER OF YEARS SINCE THE CREATION OF THE ACTION PLAN AND THEIR HELP WAS EXTREMELY VITAL IN PUTTING THIS WORK TOGETHER. SO SINCE THE INITIATION OF THE ORIGINAL ACTION PLAN, A LOT HAS CHANGED IN TERMS OF THE POTENTIAL THERAPEUTICS FOR DUCHENNE MUSCULAR DYSTROPHY I RECALL EARLY ON THE FOCUS PRIMARILY HAPPENED TO BE WITH GENE REPLACEMENT THERAPY AND MYOBLAST TRANSFERS AND WHILE THAT WORK DOES CONTINUE TODAY, THE CURRENT APPROACHES ARE ARE MORE DIRECTED, MORE TARGETED TO GENE CORRECTION THERAPIES AS THE NEXT SKIPPING AND STOP CO-DON READ THROUGH AND OTHER WORK FOCUSES ON FIBROSIS INFLAMMATION, STRENGTHENING OF MUSCLES, SIGNALING ERRORS IN DUCHENNE MUSCULAR DYSTROPHY. OVER THE YEARS BECAUSE OF THAT PPMD HAD TO TAKE A LOOK AT CHANGING ITS FOCUS AND TAILORING ITS PROGRAMS TO THOSE PARTICULAR CHANGES IN THE LANDSCAPE. IT BRINGS AS SOME OF THESE PRODUCTS GO TO CLINICAL TRIAL, WE'RE SEEING A WHOLE DIFFERENT SERIES OF CHALLENGES AND PPMD IS CERTAINLY AT THE FOREFRONT OF TRYING TO TRYING TO GUIDE THE COMMUNITY AS WE HEAD THROUGH THAT THROUGH THOSE CHANGES. SO I'M NOT GOING TO GO TOO DEEPLY INTO THE INDIVIDUAL DOMAINS OF THE FIVE DOMAINS IN THE ACTION PLAN, THE MECHANISM OF MUSCULAR DYSTROPHY DIAGNOSIS AND SCREENING THERAPY LIVING WITH AND INFRASTRUCTURE BUT SUFFICE IT TO SAY DUCHENNE MUSCULAR DYSTROPHY IS A MULTI-SYSTEM DISORDER SO IT REQUIRES A MULTI-FACETTED APPROACH TO TRY TO WORK ON THERAPY. WHILE THAT IS OCCURRING, FAMILIES HAVE TO LIVE WITH THE CONDITION AS WELL. PPMD IS EXTREMELY FOCUSED ON ALL ASPECTS OF LIVING WITH MUSCULAR DYSTROPHY, IMPROVING CARE TO PATIENTS SO THAT YOU HEARD FROM PRIOR SPEAKERS, THE OUTLOOK FOR FAMILIES LIVING IN AN URBAN AREA ARE VERY DIFFERENT IN TERMS OF CLINICAL OUTCOMES AS THEY ARE IN A MORE RURAL SETTING. PPMD IS WORKING TO TRY TO IMPROVE SOME OF THOSE ASPECTS. WE'RE LOOKING AT -- WE HAVE TOOLS LIKE DUCHENNE CONNECT WHICH ARE RESOURCES FOR PROVIDERS AND FAMILIES THAT LINK THE COMMUNITY THROUGH REGISTRY AND PROVIDE INFORMATION. IT'S A TWO WAY COMMUNICATION DEVICE SO THAT WE ARE COLLECTING INFORMATION AND WE'RE ALSO ABLE TO FEEDBACK TO THE COMMUNITY INFORMATION ABOUT THE DISORDER. LOOK AT THERAPIES WE HAVE THE CONNECT CONFERENCE. FOR 20 YEARS PPND HOSTED A CONFERENCE THAT BROUGHT TOGETHER INVESTIGATORS AND CLINICS AND FAMILIES AND -- CLINICIANS AND FAMILIES AND SPOKEN ABOUT THE TOPICS THAT AFFECT FAMILIES LIVING WITH MUSCULAR DYSTROPHY, AND HELP THE CLINICIANS TO GET TOGETHER TO COLLABORATE AND TO EXPAND ON EFFORTS TO HELP FOSTER IMPROVED RESEARCH. P PPMD WORKS WITH THE CDC UNDER CARE CONSIDERATIONS, WE -- PPMD HOSTED A NUMBER OF WORKSHOPS THAT HAVE BEEN VITAL TO IMPROVING THE UNDERSTANDING OF MUSCULAR DYSTROPHY. THROUGH ADVOCACY, RESEARCH, PPMD TRIED TO PUSH THE ENVELOPE AND TRIED TO IMPROVE THE OUTCOME FOR FAMILIES AFFECTED BY MUSCULAR DYSTROPHY. ADDITIONALLY PPMD HAS DONE WHAT JOHN PORTER HAS URGED ALL OF US TO DO. WE LOOK TO LEVERAGE RESEARCH OUT THERE. CRISTA VAN D ENBO AREN Z WAS RECIPIENT OF A DUCHENNE GRANT DURING THE A CONTRACTCAL TIME THAT HELPED HER TO CONTINUE ON TO RECEIVE LARGE NIH GRANT THAT HELPED HER PROJECT WHICH IS LOOKING TO VALIDATE MRI AS A POTENTIAL OUTCOME MEASURE HOPEFULLY TO REPLACE MUSCLE BIOPSY IN TERMS OF DETERMINING WHETHER OR NOT WE ARE SEEING IMPROVEMENT OR WHAT IS HAPPENING IN MUSCLE IN A PATIENT WITH MUSCULAR DYSTROPHY. ADDITIONALLY THIS PROJECT LED TO OTHER PROJECTS THAT ARE, IT'S ONE PROGRAM IS BEGETTING SUCCESS OF ADDITIONAL PROGRAMS. BY SUPPORTING WORKSHOPS PPMD NOT ONLY IS IMPROVING COLLABORATION, BUT INTERNATIONAL HI WE'RE EXPLORING AND EXPLOITING ALL OPPORTUNITIES AVAILABLE TO IMPROVING THE OUTCOME AND UNDERSTANDING OF DUCHENNE MUSCULAR DYSTROPHY AMONG RESEARCHERS, AMONG CLINICIANS. AND PPMD WHILE WE MAY NOT HAVE FUNDED THE ENTIRE PROGRAM OR THE ENTIRE CONFERENCE SESSIONS HAVE BEEN FUNDED, WE HAVE BEEN VERY, VERY -- WE HAVE BEEN VERY, VERY SUPPORTIVE OF MANY OF THESE PROGRAMS TO HELP TO INCLUDE -- TO INCREASE THE UNDERSTANDING OF DUCHENNE MUSCULAR DYSTROPHY AND MUSCLE SCIENCE. WORKING WITH TREAT MD PPMD HELPED TO WITH TRANSLATIONAL RESEARCH REVIEW. IN PRE-CLINICAL AND IN CLINICAL DRUG DEVELOPMENT PROJECTS. AS PAT OUTLINED ONE IMPORTANT ASPECT WE FACE TODAY IS A WORKING RELATIONSHIP WITH REGULATORS CONCERNING CLINICAL TRIALS PROCESS. SO WHAT IS THE IDEAL CONFIGURATION FOR DUCHENNE MUSCULAR DYSTROPHY ACROSS A SPECTRUM OF ABILITY? OF AGES? OF DIFFERENT ISOFORMS OF A SINGLE COMPOUND. THESE ARE ALL QUESTIONS WE NEED TO ANSWER IF PPMD IS TRYING TO LEAD THE WAY TO IMPROVE THIS PROCESS SO THAT ALL AFFECTED BY DUE DEW CHEN MUSCULAR DYSTROPHY CAN FEEL LIKE THEY HAVE AN EQUAL CHANCE AS SUCCESS IN THE CLINICAL TRIALS PROCESS. PPMD IS A LEADER IN DEVELOPING APPROXIMATE DISSEMINATING EDUCATIONAL MATERIALS. THROUGH THE ORGANIZATION WEBSITE, THROUGH THE DUCHENNE CONNECT PATIENT REGISTRY, WORKING WITH CDC FUNDED CHILD MUSCLE WEAKNESS -- CHILDMUSCLEWEAKNESS.ORG WEBSITE. THE ANNUAL CONFERENCE AND NUMBER OF OTHER ACTIVITIES, THE OPPORTUNITY FOR FAMILIES TO LEARN ABOUT CLINICAL CARE, RESEARCH, WHAT IS IMPORTANT TO THEM AND COMMUNICATION THROUGH SOCIAL MEDIA SO THEY CAN LEARN VARIOUS ASPECTS OF LIVING APPROPRIATELY CARING FOR THEIR CHILD, GETTING THE RIGHT INFORMATION, WHAT TO ANTICIPATE HOW TO NAVIGATE VARIOUS PROCESSES WHETHER IT WOULD BE INSURANCE, SPECIAL EDUCATION, THESE ARE ALL COMPONENTS THE PPMD SPENT MUCH TIME DEVELOPING AND IS AVAILABLE THROUGH A NUMBER OF THESE PARTICULAR PROGRAMS. AGAIN, MENTIONED EARLIER, THE CHILDMUSCLEWEAKNESS.ORG SCREENING AN ACCURATE DIAGNOSIS IS EXTREMELY IMPORTANT TO THE COMMUNITY. TRYING TO ENSURE THAT INDIVIDUALS WITH MUSCULAR DYSTROPHY ARE IDENTIFIED EARLY AS MORE THERAPIES COME ON BOARD GO TO CLINICAL TRIAL, INTERVENTION EARLY INTERVENTION IS GOING TO BE APPROPRIATE AND BEING ABLE TO IDENTIFY THESE INDIVIDUALS IN A MUCH EARLIER AGE, H LEAD TO A BETTER OUTCOME. BY FOCUSING ON APPROPRIATE THERAPY. WE CAN IMPROVE THE WITHOUT COME FOR THESE INDIVIDUALS, PPMD DEVELOPED A NUMBER OF PROGRAMS TO HELP INDIVIDUALS. WHAT HAPPENS AT 3 O'CLOCK IN THE MORNING? THAT'S TYPICALLY WHEN MOST EMERGENCIES HAPPEN AND YOU'RE NOT THINKING CLEARLY. PPMD WORKED WITH DOUG BIGGERS TO DEVELOP AN EMERGENCY CARD. MUCH INFORMATION IS ALSO AVAILABLE ABOUT APPROPRIATE CARE IN THERAPIES THROUGH THE PPMD WEBSITE. PPMD HAS ALSO PUT TOGETHER A NUMBER OF WEBINARS TO IMPROVE UNDERSTANDING ABOUT CARDIAC ISSUES. WE ARE WORKING ON A PROGRAM TRANSFORMING DUCHENNE CARE INITIATIVE TO TAKE A LOOK AT WHAT'S AN APPROPRIATE SET FOR A CLINIC. WHAT TYPE OF TOOLS ARE IMPORTANT FOR FAMILIES, WHAT SPECIALTIES ARE NEED AND HOW FAMILIES IDENTIFY AN APPROPRIATE CLINIC FOR THEM. WE PUT TOGETHER A NUMBER OF FACT SHEETS FOR VARIOUS ASPECTS OF COMORBIDITIES IN DUCHENNE MUSCULAR DYSTROPHY FACT SHEETS AND WAS MENTIONED EARLIER A PLANNED WORKSHOP WITH NHLBI ON CARDIAC ISSUES IN DUCHENNE MUSCULAR DYSTROPHY IS ON OUR HORIZON. PROBABLY ONE OF THE GREATEST STRENGTHS WITHIN THE COMMUNITY IS SUPPORT FOR ONE ANOTHER. CERTAINLY PARENT PROJECT CONFERENCES PLENTY OF OPPORTUNITY FOR FAMILIES TO NETWORK. PPMD RECOGNIZED THAT THE VOICE OF THE PATIENT IS VITALLY IMPORTANT AS A PARENT OF A YOUNG MAN WITH DUCHENNE MUSCULAR DYSTROPHY I THINK I KNOW A LOT ABOUT THE CONDITION BUT TO KNOW MORE INTIMATELY ABOUT VARIOUS ASPECTS ABOUT WHAT IS IMPORTANT, ABOUT ASPECTS OF CARE, WHETHER OR NOT SOMETHING IN A CLINICAL TRIAL IS ACTUALLY RELEVANT, I ACTUALLY HAVE TO SPEAK WITH MY SON. AND I THINK THAT THERE IS AN EXAMPLE OF THIS IN THIS PHOTOGRAPH OF WHAT WE CALL EXPERT PANEL WHERE YOUNG MEN LIVING WITH MUSCULAR DYSTROPHY TALK ABOUT VARIOUS ELMMENTS WITHIN THEIR LIFE. IT'S ENLIGHTENING NOT ONLY FOR FAMILIES WITH YOUNGER INDIVIDUALS WITH DUCHENNE MUSCULAR DYSTROPHY BUT EVEN THEIR OWN FAMILIES HEAR ASPECTS ABOUT THEIR SONS ISSUES THAT THEY BRING UP THAT THEY PROBABLY HAD NEVER REALIZED. PPMD ALSO WORKED WITH CDC ON THE DEVELOPMENT OF A NEUROMUSCULAR QUALITY OF LIFE PROGRAM, HOLLY PA WORKED ON A CLINICAL TRIALS EXPERIENCE AND SURVEY AND STUDY ON BARRIERS EXPECTATIONS AND CONCERNS THAT FAMILIES HAVE AS WELL AS THE RISK BENEFITS SURVEYS. PPMD ALSO SUPPORTS AN UNDERSTANDING OF WHAT THE IMPACT IS ON THE CAREGIVERS, WHAT IS THE WELL BEING OF MOTHERS LOOK LIKE. PROBABLY ONE OF THE MOST ROBUST TOOLS IS THE DUCHENNE CONNECT PATIENT REGISTRY. I USE THIS SLIDE IS HIGHLIGHTED HOW IT'S INTERACTED AND IT DOES COVER MANY OF THE ASPECTS WITHIN THE ACTION PLAN. MECHANISTICALLY, THERAPY, IN TERMS OF DIAGNOSIS AND SCREENING. IT'S A GREAT TOOL, IT'S A PATIENT REPORTED REGISTRY, FAMILIES ARE COLLECTED A LOT OF DATA THAT HAS BEEN USEFUL TO NOT ONLY INDUSTRY IN TERMS OF WHO IS OUT THERE AND GENOTYPES WE'RE LOOKING AT BUT ALSO TO ACADEMIA. WHAT INFORMATION IS AVAILABLE. NATURAL HISTORY DATA IS BEING COLLECTED ABOUT VICTIMS WITH DUCHENNE MUSCULAR DYSTROPHY -- INDIVIDUALS WITH DUCHENNE MUSCULAR DYSTROPHY. THIS IS LED TO THE OUTCOME OR THE PUBLICATION OF SEVERAL PAPERS ABOUT INFORMATION RELATED TO INDIVIDUALS WITH DUCHENNE MUSCULAR DYSTROPHY BASED ON THE DATA COLLECTED ON THIS PARTICULAR WEBSITE. SO ULTIMATELY PPMD IS MOVING DUCHENNE CARE RESEARCH IN CLINICAL PROGRAMS THROUGH ITS COLLABORATIONS. WE WORKED INTIMATELY WITH A NUMBER OF INDIVIDUALS HERE PROFESSIONAL, ACADEMIC AND OTHER VOLUNTEER ORGANIZATIONS. LEVERAGING DOLLARS. FOCUSING ON BIG PICTURE, FAMILIES RALLYING TOWARD THE NEWEST CLINICAL TRIALS, THERE ARE SOME MANY, MANY OTHERS WHO ARE -- WHO WILL BE LEFT WITHOUT A RESOURCE OR POTENTIAL THERAPY PROMISED BY A TRIAL AS WELL AS INDIVIDUALS WHO ARE MUCH OLDER WHO ARE GOING TO NEED CONTINUATION OF CARE. PPMD IS FOCUSED ON MAKING SURE THAT EVERYBODY HAS A SEAT AT THE TABLE AND EVERYONE IS ADEQUATELY REPRESENTED. PPMD IS INTERESTED IN TRANSITIONS FROM PEDIATRIC TO ADULT CARE. WHAT DOES THAT LOOK LIKE. WHAT DOES IT LOOK LIKE FOR THEIR FAMILY. PPMD CONSIDERS ALL OPPORTUNITIES AND POSSIBILITIES IN DUCHENNE MUSCULAR DYSTROPHY. THANK YOU. [APPLAUSE] >> THANK YOU VERY MUCH, RYAN. WE HAVE TIME FOR QUESTION OR TWO. >> ABSOLUTELY >> ANY QUESTIONS FOR BRIAN? I GUESS THAT'S A SMART (INAUDIBLE) FOR THE CUP CAKE EDITION OF THE AGENDA. I CAN TELL YOU THIS, WE HAVE ABUNDANCE THANKS TO -- WE HAVE ABUNDANT CUP ATHLETE CAKES FOR EVERYONE ON THE COMMITTEE, EVERYONE ELSE L AROUND THE TABLE, EVERYONE ELSE AROUND THE ROOM, EVERYONE ELSE THAT'S WANDERING THROUGH ON THEIR WAY TO THE CAFETERIA AND GOTTEN LUCKY. BUT WE WILL TAKE THE BREAK NOW AND WE'RE ACTUALLY RIGHT ON SCHEDULE, STRANGELY ENOUGH. SO WE WILL RECKON AS PER THE AGENDA AT 2:50. CUPCAKES IN HAND OR STOMACH OR WHATEVER. SEE YOU THEN. >> SO WELCOME TO OUR FINAL SESSION. SOME HOW HAVING FOUND OURSELVES ON TIME WE'RE GOING TO START ON TIME. OUR NEXT SPEAKER, JUSTIN FALLON COMES TO US FROM BROWN UNIVERSITY WHERE I BELIEVE STARTING WITH AN RO-1 FUNDED BY UP AND CALLED THE NATIONAL CHILD HEALTH AND HUMAN DEVELOPMENT. >> YOU BELIEVE CORRECTLY. >> A NOTE WAS GIVEN FROM SOMEBODY ELSE TO REMIND ME, JUST STATING THE FACTS. HE'S GONE ON TO VERY INTERESTING DEVELOPMENTS IN TERMS OF TRYING TO DEVELOP THERAPEUTICS APPLICABLE TO DUCHENNE SO E WE ASKED HIM TO SPEAK ABOUT THAT. JUSTIN, ALL YOURS. >> THANK YOU VERY MUCH FOR MANY REASONS BUT OPPORTUNITY TO PRESENT THE WORK BUT YOU IN THE ROOM REPRESENT THE REASON THE WORK GETS DONE. WHEEL BASIC SCIENCE GOT DONE AND HOW WE'RE ABLE TO TRANSITION FROM BASIC SCIENCE TO THERAPEUTIC DEVELOPMENT IS SO MUCH HERE SO I'M GRATEFUL FOR THAT. ALSO I WOULD LIKE TO SHOUT OUT THE INSTITUTE DIRECTORS FOR FRONTING THE CUPCAKES SO EVERYBODY HAS A SUGAR RUSH. SINCE I'M THE LAST SPEAKER MAYBE THAT WILL KEEP IT GOING FOR MAYBE 20 OF THE 30 MINUTES. AFTER THAT YOU'RE ON YOUR OWN. SO GOING TO TALK ABOUT BIGLYCAN MUSCULAR DYSTROPHY AND AS JOHN ASKED I'M GOING TO EMPHASIZE THE PROCESS BY WHICH WE GOT TO WHERE WE ARE SO I WILL SALT IN DATA, I HAVE TO. BUT I WILL TRY TO CONTEXTUALIZE AS MUCH AS I CAN. HOW THAT HAPPENS, STAGES AN CRITICAL JUNCTURES ALONG THE WAY. DISCLOSURE, I'M A FOUNDER SHALED OF TIGRIS FARM SUIT CAMS -- PHARMACEUTICALS, AND BRING IN TO THE CLINIC. AND SO THIS IS LESSONS LEARNED AND I SHOULD SAY WE'RE STILL LEARNING EVERY DAY. BUT I'LL BRING YOU UP TO DATE. AND SO YOU KNOW ABOUT APPROACHES TO MT TREATMENT. TO ORIENT YOU OWE EAR HERE FOR THE MEMBRANE STABILIZATION EWE THROW FIN REGULATION. BY LOGIC AND RATIONAL FOR EWE THROW FIN DIRECTED THERAPY AND -- EWE TOE PIN AND DYSTROPHY -- THERE IS UTROPHIN SUSTAINS BUT NOT PRESENT THE MUSCLE CELL BE WILL DIE. THED IDEA HERE IS TO USE BIGLYCAN, WHOSE NORMAL FUNCTION IS REGULATE UTROPHIN AND TURN IT INTO A THERAPEUTIC AND BRING BACK A RECAPITULATE AND COMPENSATE FOR THE LOSS OF DYSTROPHY. SO OBVIOUSLY, A PIPELINE YOU'RE VERY AWARE OF, AND HAVE COME TO KNOW VERY WELL, AND THIS WAS FROM THE NATURE MEDICINE ARTICLE. WITH BIGLYCAN WE COVERED MANY BASES. WE HAD A AS ALAN SAID, WE HAVE A LONG NIH BASIC RESEARCH EFFORT FUNDED LARGELY BY CHILD HEALTH. APPRECIATE THAT. WE ALSO HAD TREMENDOUS SUPPORT ALG WHAT WAY FROM THE PHILANTHROPIC ORGANIZATIONS AND BLUEPRINT PROGRAMS AS JOHN PORTER POINTED OUT ALREADY WELL. WE HAVE TAKEN ADVANTAGE OF THE NIH SUPPORTED SCREENING, IN THIS CASE, PHYSIOLOGY COURSE, CONTRACT RESEARCH ORGANIZATIONS, NOT SO MUCH CONSORTIA CLINICS BUT CLINICS EXPERIENCED IN THIS SPACE WHO ARE AGREED TO WORK WITH US ON THE CLINICAL TRIAL PART. AND SO THERE'S A VERY ALREADY COMPLICATED AS YOU'RE AWARE, TERRAIN TO NAVIGATE AND TO COORDINATE, COORDINATION IS EXTREMELY IMPORTANT. SO WHERE ARE WE? WE ARE IN THE PRE-IN TOE WE HAVE SCHEDULED METING WITH THE FDA IN JUNE -- MEETING WITH THE FDA JUNE THIS YEAR TO PRESENT OUR RESULTS AND OUR PROGRESS AND TO GET GUIDANCE ON DESIGN IN OUR CLINICAL TRIAL DESIGN AND GUIDANCE ON OUR INDEN ABLELING TOXICOLOGY AND CLINICAL -- ENABLING CLINICAL TRIAL DESIGN SO WE'RE CLOSE. FOR US THIS IS A TO PARAPHRASE JOE BIDEN, A BIG DEAL. SO THE -- JUST A CONTEXT H CHURLIZED -- CONTEXTUALIZE HOW THIS CAME ABOUT, I WANT TO SAY WE DIDN'T START OUTLOOKING FOR ATHER THINK FOR MUSCULAR DYSTROPHY, WE TARTED OUT -- THERAPY FOR MUSCULAR DYSTROPHY WE STARTED LOOKING AT HOW THE EXTRA CELLULAR MEMBRANE AT THE SYNAPSE AND THEN IN THE SARCOLEMA SO THE PATH TO BIGLYCAN MEMBRANEFUL WHEN I WAS A POST DOC IN JEFF MCMAHAN'S LAB NINDS THAT FUNDED HIS LAB MANY YEARS, ONE OF THE MAJOR OUTPUT WAS DISCOVERY OF AGRIN, EXTRA CELL ALREADY MATRIX MOLECULE IMPORTANT FOR ORGANIZING THE NEUROMUSCULAR JUNCTION. IN MY LAB WE ASKED HOW THE EXTRA CELLULAR MATRIX MOLECULE CONNECT WITH AND SIGNAL INTRACELLULARLY, AND SO WE DISCOVERED THAT AGRAN BINDS THE GLYCAN, THIS WAS IN 1994 WHEN WE REPORTED THIS. DISTRAY GRAY CAN WAS JUST DISCOVERED WITH -- THE RESULTS WERE RELATED TO MUSCULAR DYSTROPHY. AT THE SAME TIME KAY DAVIES AND OTHERS SHOWED THAT (INDISCERNIBLE) SHOWED THAT EWE THROW FIN IS ALSO PRESENT IN THE MAYBE AMENABLE THE APPROACHING AN TARGET THERE. THIS IS BASIC SCIENCE SUPPORT, CHILD HEALTH, NINDS, VPA AN MMDA FUNDED POST-DOCS DURING THIS STAGE AND POST DOC RACIALLY IMPORTANT. WE THEN DISCOVERED THAT DISTRA GLYCAN, WE ASK WHAT ELSE IT BINDS, IT BINDS TO BIGLYCAN. MORE ABOUT THAT, BUT LET ME -- THESE SPHERES ARE THE GLYCAN IMMUNOGLYCAN SIDE CHAINS NOT RELEVANT TO THERAPEUTIC BUT THAT IS HOW WE CAME INTO IT BUT BIGLYCAN EXISTS AS SECOND FORM, GLYCO FORM IN MUSCLE, AND IT'S A PART OF THE THE DYSTROPHIN PROTEIN COLLECTION, A MATURE FORM WITH THE NAME NON-GLEE CAFFEINATED BIGLYCAN. THAT MEANS THAT IT IS A GLYCO O PROTEIN BUT IT DOESN'T HAVE ANY GLYCOSIDE CHAINS SO THAT'S A NATURAL HI OCCURRING FORM AND THAT'S TURNED OUT TO BE VERY IMPORTANT. WE ALSO SHOW THAT BY MAPPING STUDIES WITH CONSTRUCTS THAT WERE PROVIDED TO US THAT BIGLYCAN BINDS TWO SUBGLYCANS ALPHA AND GAMMA, THOSE ARE IMPORTANT BECAUSE THOSE ARE THE TWO SPECIFIC FOR HEART AND SKELETAL MUSCLE SO THAT SUGGESTED THERE MAYBE SOMETHING PARTICULAR ABOUT WHAT BIGLYCAN'S ROLE IS IN SKELETAL MUSCLE. OTHERS HAVE SHOWN BIGLYCAN BINDS COLLAGEN 6, I'LL GET BACK TO THAT AT THE END OF THE TALK. BUT WE KNOW COLLAGEN 6 OF COURSE WILL CAUSE A CONGENITAL MUSCULAR DYSTROPHY, BIGLYCAN BINDS TOCAL 6 AND BIGLYCAN REGULATES IN THE PRESENCE OF DYSTROPHIN A COMPLEX OF PROTEINS THAT CENTRO FEN AND EMNOS, ALL WORK FROM BIGLYCAN KNOCKOUT MICE. AND CELL CULTURE AND BIOCHEMISTRY. AND THEN WE LATER THEN LEARNED MORE CAREFULLY AT THE -- I'LL SHOW YOU THE DATA PUBLISHED, IS BIGLYCAN ALSO REGULATES EXPRESSION OF EWE THROW FEN AT THE MEMBRANE. AND -- UTROPHIN AT THE MEMBRANE. IF WE HAVE A MOLECULE THAT REGULATE AS WELL AS COMPRESSION OF PROTEINS, IT'S EXTRA CELLULAR SO IT CAN BE IN THEORY DELIVERED. AND ENDOGENOUS PROTEIN THAT ALSO HAS THIS SELECTIVE BINDING TO BINDING TO SARCOGLYCANS SO THIS WAS VERY IMPORTANT, AGAIN MORE POST DOCS K-12 AWARD FROM CHILD HEALTH AND THE DUCHENNE AWARD WAS VERY IMPORTANT HERE AND WE WERE STILL RO-1 FUNDED AS WELL. SO BIGLYCAN. SO BIGLYCAN IS A SMALL LEUCINE RETCH REPEAT PROTEIN 27-KILODALTONS, THIS IS HIGHLIGHTING THE RICH REPEATS. THERE'S TWO SITES OF GLYCOSYLATION, CONVENTIONAL END LINKED AND SISTINE BOTH ENDS, THERE IS -- THERE ARE SITES FOR ADDITION OF GLYCO IMMUNOGLYCAN SO BIGLYCAN IS A PART TIME PROTEOGLYCAN BUT WE FIRED THAT PART AND SO WE HIRED THE ONE THAT'S OOH FULL TIME NON-GLYCONATED PROTEIN, WHICH HAS ABSOLUTELY NO GAG CHAIN. THAT TURNED OUT TO BE SUPER IMPORTANT. SO AS I MENTIONED EARLIER, TO OUR SURPRISE, WHEN WE LOOKED IN BIOCHEMICALLY WHAT WAS EXPRESSED IN MUSCLE, BOTH IN THE MEMBRANES AS WELL AS THE ISOLATED DYSTROPHIN COMPLEX, MARY ANN YOUNG DISCOVERED THIS THIS IS A DYSTROPHIN GLYCAN AND IT SEEMS TO ME MADE THE KNOCKOUT MICE WHICH WAS VERY IMPORTANT. SO THAT'S A PROTEOGLYCAN, BUT THERE'S ALSO NON-GLYCONATED FORM. HERE AND HERE. THE QUESTION BECOMES WHICH IS ACTIVE? WHICH ONE IS ACTIVE? IT TURNS OUT NON-GLYCONATED RECOMBINANT BIGLYCAN IS THE THERAPEUTICALLY ACTIVATED FORM. THAT'S VERY IMPORTANT. THIS I GOT THE SAY WAS JUST LUCK. IS THAT THERE IS A -- WE KNOW THAT THE NON-GLYCONATED UP REGULATED THROW FIN AND N NOTS, NOT THE PROTEOGLYCAN, THE IMPROVED MUSCLE HEALTH AND FUNCTION, STABILIZES SYNAPTIC SPECIALIZATION, THIS IS ALL THE NON-GLYCONATED FORM, BUT WE HAVE A NICE SET OF EXPERIMENTS TO SHOW THAT THE PROTEOGLYCAN IS A DANGER SIGNAL THAT ACTIVATES A TLR 24 SYSTEM SO IT'S PROINFLAMMATORY, THAT ABSOLUTELY REQUIRE IT IS GAG CHAIN. SHE'S REQUIRES THE GAG CHAIN. SHE'S DONE THAT WE REMEET PEATED THAT. THIS IS A MULTI-MERIC CHARGED LPS AND BUT THIS DID NOT ACTIVATE THE PATHWAYS SO NOT ONLY DOES THE PROTEOGLYCAN NOT WORK, IT'S NON-DESIRABLE IN TERMS OF DELIVERING THE THERAPEUTIC. OBVIOUSLY A -- ONE EVEN CONTEMPLATED MAKING A RECOMBINANT PROTEIN WITH GAG CHAIN THAT'S EXTREMELY DIFFICULT TO DO. SO ALL THOSE REASON IT IS NON-GLYCONATED FELL OUR WAY. BIGLYCAN IS A THERAPY THE RATIONALE PUBLISHED AND WILL JUST GO THROUGH IT. WE KNOW REGULATES EXPRESSION OF EWE THROW FEN AND OTHER COMPLEX PROTEINS, TICKNAL PATROL CULLS. WE KNEW WE COULD DELIVER IT SYSTEMICALLY AND ACTIVE FOR PROLONGED PERIODS. THIS WAS AT A TIME WHEN PEOPLE DIDN'T THINK THAT MATRIX PROTEINS COULD BE DELIVERED SYSTEMICALLY AND WOULD GO THE TO A -- HAVE A THERAPEUTIC OR HAVE EFFICACY. WE NOW HAVE SEVERAL EXAMPLES WHERE THAT'S TRUE BUT BACK IN THESE DAYS, IT WAS A BIG SURPRISE. AND IT TOOK A SMART POST DOC TO WAIT UNTIL I WAS OUT OF TOWN TO DO EXPERIMENTS ABOUT SHOW ME THE DATA. THE WAY WE SHOWED THAT IS RECOMBINANT BIGLYCANS THE MARK 1 VERSION WE MADE RECOMBINANT, THIS IS PROTEOGLYCAN AND NON-GLYCONATE SOD WE CAN SEPARATE THEM OUT, TEST THE BIOLOGICAL ACTIVITY OF EACH INDIVIDUALLY AND BIGLYCAN NULL MICE. AGAIN, THIS IS HOW WE KNOW THAT THE NON-GLYCONATED IS THERAPEUTICALLY ACTIVE. AT THIS POINT, THIS IS WHEN WE BEGAN OUR TRANSITION TO DRUG DEVELOPMENT, NATURE OF THE WORK CHANGE THE FUNDING SO THE R-# 1 FROM NIAMS WAS CRITICAL IN THIS EARLY STAGE, THAT LED TO THE UO#, THE IN DUE CHIP AWARD BRIDGED US BETWEEN THE TWO, AND THEN NMDA AND TYROSINE LATER ON SUPPORTING THE WORK PARTICULARLY OUTSIDE THE LAB. SO AS A BY SICK SCIENCE WHAT'S A LESSON I LEARNED HERE? I SPENT MY CAREER HERE IN BASIC SCIENCE, YOU START WITH A QUESTION, YOU GET DATA, GOAL IS THE MOST IMPACTFUL NEW KNOWLEDGE WHETHER OR NOT IT'S SPECIFIC AIMS. IF IT'S INTERESTING AN COOL YOU GO FOR IT. WHICH WAS A SUCCESSFUL MODEL IF IT WAS IMPACTFUL. SO GOOD BUT BASICALLY OPEN ENDED PROCESS, INVESTIGATOR INITIATED RESEARCH OF COURSE. THERAPY DEVELOPMENT IS DIFFERENT. SO IN THIS PARTICULAR CASE WITH WE STARTED WITH BASIC SCIENCE, NOT LOOKING BUT APPRECIATED IT SO NOW WE HAVE AN IDEA FOR THERAPY. THE IDEA FOR THERAPY GOES TOWARD A POINT. AND ON THE WAY ALONG THERE ARE CRITICAL EVENTS THAT MUST BE MET SUCH CHEMISTRY MANUFACTURING CONTROLS PHARMACOLOGY, SAFETY, EFFICACY AND ANIMAL MODELS, THOSE ARE ALL, IF YOU WILL, THOSE TRANSFORM INTO GO, NO GO DECISIONS, YOU HAVE TO DO THAT, IF YOU DON'T HIT THOSE YOU CAN NOT GO FORWARD. SO THAT OBVIOUSLY IS CRITICAL FOR THAT. THAT THEN IS GETS YOU ACROSS THE FIRST LINE THE CLINICAL TRIALS. BUT IT'S VERY DIRECTED YOU START AT THE END AND GO TO THE BEGINNING IF YOU WILL. VERY DIFFERENT THAN THIS MODEL. YOU WILL NOTE NONE OF THESE THING HAS ANYTHING ABOUT MECHANISM ON THEM. WHY DO WE CARE ABOUT MECHANISM NOW? WE DO. KNOWLEDGE MECHANISM OF ACTION IS INVALUABLE FOR CRITICAL STEPS AN THERAPY DEVELOPMENT, APPROPRIATE BIOASSAYS, POTENCY, BATCH TO BATCH CONSISTENCY, WHICH BIOCHEMICAL ASSAYS RELEVANTTOR IN SRI EFFICACY, I'LL SHOW YOU THAT, THIS IS PART OF THE CMC EFFORT. ESSENTIAL GUIDES FOR MANUFACTURING. NECESSARY FOR EVER STEP IN DEVELOPMENT, BECOME MORE IMPORTANT AS THE PROGRAM MOVE TOWARDS CLINICAL TRIALS BECAUSE OBVIOUSLY YOU NEED TO KNOW A LOT ABOUT YOUR MOLECULE, YOU NEED TO KNOW THE RIGHT THINGS AND WHAT PROPERTIES ARE THE MOLECULE ARE MOST IMPORTANT FOR WHAT THE FUNCTION AND THERAPEUTIC EFFICACY THAT YOU'RE AFTER AND OBVIOUSLY ESTABLISHING BIOMARKERS ALSO CRITICAL AND MECHANISM HELPS YOU THERE TOO. SO MECHANISM REALLY GOES HAND IN HAND. IN DRUG DEVELOPMENT. AND IT CAN GET YOU OUT OF THE SOUP. SO ONE EXAMPLE, PUBLISHED SYSTEMIC ADMINISTRATION OF RECOMBINANT BIGLYCAN, REDUCES MUSCLE PATHOLOGY, IN INFILTRATION GOES DOWN, IN ADDITION, -- I SHOULD SAY THIS IS THE RECOMBINANT BIGLYCAN THE WILD TYPE NON-GLYCONATED WHAT WE INITIALLY USE, THE MARK 1 VERSION I TOLD YOU ABOUT. WE ALSO MADE ANOTHER VERSION. WHICH CANNOT HAVE ADDITION OF IMMUNOGLYCANS SO IT OBVIATES THAT WITH WITHIN THE GAG CHAINS CHAINS SO WHEN WE TESTED T-2 THROUGH THE SAME PACES FORD CENTRAL NUCLEI DIAGRAM AND HIND LIMB, THIS IS SYSTEMIC INJECTION AND INCREASE IN UTROPHIN. OF COURSE IT'S ALSO REALLY IMPORTANT TO DEMONSTRATE EFFICACY P IN A FUNCTIONAL CONTEXT, SO WE DID THIS EXPERIMENTATION. ONCE WITH EACH COMPONENT, EACH FORM. SO THIS IS AN EARLY EMPERIMENT, THIS IS PUBLISHED WITH (INDISCERNIBLE) WHO DID THESE MEASUREMENT.S AND THIS SHOWS THE ECCENTRIC CONTRACTION DAMAGE AFTER SUCCESSIVE LENGTHENING CONTRACTIONS OF THE MUSCLE, THE AMOUNT OF DAMAGE INCURRED OR INDUCED IS REDUCED AFTER, AND THIS IS A THREE MONTHS OF TREATMENT OF BIGLYCAN, THIS NCI THIS PARTICULAR CASE THREE MONTHS AND DOSED EVERY THREE WEEKS. 16 MUSCLES PER CONDITION, SO VERY GOOD. AS WE MOVE TO THERAPEUTIC FORM, THE T-2 BIGLYCAN WE NEEDED TO REPEAT IT TO MAKE SURE IT WAS ALSO WORKING. WE ALSO WANTED TO DO NOW MORE PHARMACOLOGY AND DOSE FREQUENCY STUDIES. SO TAKING OUT THE DOSE WE HAD FOUND, WE THEN DOSED EITHER ONCE EVERY ONE WEEK, EVERY TWO WEEKS, EVERY THREE WEEKS. AND THESE ARE JUST THE ECCENTRIC ACTION CURVES, THIS WORK WAS DONE BY BETH MARTIN, THIS IS THE WAY SHE PUBS HER DATA. SO LOOKING AT THE ECCENTRIC CONTRACTION THE FIFTH CONTRACTION, LOWER IS BETTER, THIS THE DAMAGE AND LEVEL OF DAMAGE IN THE VEHICLE. THIS IS EVERY THREE WEEKS, THIS IS EVERY TWO WEEKS ABOUT EVERY ONE WEEK. WE HAVE STATISTICAL SIGNIFICANCE AT TWO WEEKS AND AT EVERY -- AT WEEKLY DOSING. Q-7. ALSO VERY IMPORTANT THIS WAS DONE COMPLETELY OUTSIDE THE LABORATORY. IN THIS CASE THE DRUG WAS MANUFACTURED BY A CONTRACT RESEARCH ORGANIZATION. WE THEN SHIPPED THE DRUG TO JACK RESEARCH SERVICES IN SACRAMENTO, THEY DID THE ANIMAL HUSBANDRY AND THE DOSING OF THE ANIMALS. THEY THEN SHIPPED THE MICE FROM SACRAMENTO TO FILL PHILADELPHIA. WHERE BETH MARTIN'S GROUP DID MUSCLE MECHANICS AN CONTRACTION SO BOTH DRUG AN MICE SURVIVED TRANSCONTINENTAL TRAVEL AND THIS OF COURSE DONE BLIND TO CONDITIONS SO THAT VERY IMPORTANT THAT IS THE T 2. THAT'S IMPORTANT. THE EFFICACY IS IT SOMETHING DELIVERED, IS IT STABLE SO WE HAVE DONE BIDISTRIBUTION AND PHARMACOKINETIC STUDIES. A COUPLE OF EXAMPLES, HERE IS AN EXAMPLE WHERE SYSTEMICALLY INJECTED BIGLYCAN, AND HERE YOU CAN SEE IT BUT IN 14 DAYS IT REMAINS STABLY ASSOCIATED OF SYSTEMIC INJECTION WITH THE SURFACE OF THE MUSCLE AND THE EXTRA TRAY CELLULAR MATRIX SO IT IS STABLE. WE CONFIRM THIS NOW WITH MATERIAL INJECTED INTO THE MICE AS WELL. IN ADDITION THIS IS THE OUTDATED MATERIAL NOW WE LOOK AT SPECK IMAGING, ANIMALS INJECT AND DISSECTING OUT HEART DIAPHRAGM CAROTID AND TIBIAL HIS AND BIGLYCAN GOES TO ALL TISSUE IT IS STRIATAL AS WITH WELL AS CARDIAC MUSCLE AFFECTED IN DUCHENNE SO THIS IS VERY GOOD FOR THE STRIATED -- THE HEART WERE JUST BEGINNING TO WORK ON BUT WE DO HAVE A SIGNAL THAT WE'RE GETTING POSITIVE IN THE HEART AS WELL AS THE LARGER TAKE HOME OF THIS SLIDE WHICH IS DO WE SEE ANY EVIDENCE OF TOXICITY. EMPHASIZE THIS IS NOT FORNAL TOXICITY STUDY BUT THERAPEUTIC DOSES, THREE MONTHS OF DOSING SO AT THE THREE MONTHS WORTH OF DOSING LOOKING AT THE BODY WEIGHT, THE ORGAN WEIGHTS THE MUSCLE WEIGHTS, ARE ALL THE SAME WITH A COUPLE OF IMPORTANT EXCEPTIONS I WILL TELL YOU IN A SECOND AND WE SEE THE LIVER AND THE KIDNEY ENZYMES ARE ALSO WELL WITH OUR INDISTINGUISHABLE BETWEEN THE TWO COHORTS SO AT THIS -- UNDER THESE CONDITIONS WE DO NOT SEE ANY CHANGE. WE DO SEE REDUCTION IN THE SIZE OF THE WEIGHT OF HEART. AND THAT'S GOOD, IN THE RIGHT DIRECTION, BECAUSE EVEN AT THIS AGE THESE ANIMALS ARE ABOUT FOUR MONTHS OLE NOW THERE IS CARDIOMYOPATHY AND PATHOLOGICAL ENLARGEMENT OF THE HEART. THE FACT THE HEART ARE GETTING SMALLER SUGGEST RESPONDING TO BIGLYCAN. I'LL EMPHASIZE THESE ARE YOUNG, CARDIOMYOPATHY HAS NOT SET IN YET AND SHOWS WORKING WITH OLDER ANIMALS BUT IT IS ENCOURAGING CERTAINLY. MUSCLE ALSO GETS SOMEWHAT LARGER. OKAY. SO EFFICACY, AND PHARMACOLOGY GOOD SIGNALS ON DISTRIBUTION AS WELL AS IN PHARMACOKINETICS WE CAN DOSE, WEAKLY OR LESS FREAKILY THAN THAT. SO WHAT HAVE WE SPENT TIME ON AFTER THAT? WE SPENT THE LARGE PART OF THE LAST TWO AND A HALF YEARS, IS CHEMISTRY MANUFACTURING AND CONTROLS. SO THIS IS A PROTEIN, PROTEINS ARE VERY COMPLEX. IT IS IMPOSSIBLE TO FULLY CHARACTERIZE THE PROTEIN. THERE ARE ALWAYS VARIATIONS, GLYCOSYLATION, SOME SORTS OF MIXTURE. WHAT YOU NEED TO KNOW ARE WHAT ARE THE IMPORTANT ASPECTS OF THAT PROTEIN THAT TELL YOU WHETHER IT'S GOING TO BE EFFECTIVE? THAT'S THE KEY. THAT'S WHY THE RUE BICS CUBE. WHAT YOU'RE DOING IS LOOKING AT PHYSIOCHEMICAL FEATURES OF THE MOLECULE AND WHETHER THEY'RE GOING AFFECT BIODISTRIBUTION, ARE THEY IMPORTANT FOR DASIS WHAT YOU COTHEN, WHAT WE HAVE DONE IS WE HAVE A LARGE SUITE OF PROTEIN BINDING AWE SAYS. BIOACTIVITY IN MOUSE AND HUMUS L CELLS ACTIVE IN HUMAN CELLS AS WELL WHICH IS GOOD. IMPORTANT TO KNOW THE PROTEIN CREATED A -- PROCESS DEVELOPMENT, SLIGHTLY 2-GRAMS PER LITER SO RESPECTABLE YIELD. WE SPENT A VERY LARGE AMOUNT OF TIME ON THIS UPSTREAM PROCESS DEVELOPMENT AND DOWNSTREAM PROCESS DEVELOPMENT BECAUSE WE REALIZE THAT OUR INITIAL WHEN WE SCALED UP WE WERE GETTING MIXTURES OF DIFFERENT FORMS OF THE BIGLYCAN. THAT TURNED OUT TO BE VERY IMPORTANT. BECAUSE ALONG WITH THIS AS WE BEGAN OUR SCALE UP WE ALSO BEGAN TO SEE, UNUSUAL DOSE RESPONSE CURVE WHICH WHILE BIGLYCAN WORKED IT WORKED IN A RELATIVELY NARROW RANGE. ONE ENTITY WHICH IS NOT MENTIONED HERE I DON'T THINK IS TACT. SO WHEN PPMD FUNDED US, ONE OF THEIR REQUESTS WAS THAT WE SUBMIT TO TACT. TACT LOOKED AT OUR DATA AND SAID THIS LOOKS REALLY GOOD BUT WHAT'S GOING ON WITH THE DOSE RESPONSE CURVE. SO THAT WAS TWO AND A HALF YEARS AGO, THAT'S WHAT WE HAVE BEEN SPENDING OUR TIME. AND NOW WE HAVE SUCCEEDED IN UNDERSTANDING THE NATURE OF THAT, WE CAN HAVE A CONVENTIONAL DOSE RESPONSE CURVE, IT WAS ALL ABOUT THE MANUFACTURING MANUFACTURING UPSTREAM PROCESSING DEVELOPMENT, DOWNSTREAM PROCESS DEVELOPMENT, VERY GRINDED OUT CLUMP OF DUST KIND OF WORK. BUT YOU HAD TO DO IT IN A CONTEXT WHERE YOU HAVE A SUFFICIENTLY ROBUST SWEET OF MIENINGFUL ASSAYS THAT WILL ALLOW YOU TO MATCH PROTEIN WITH EFFICACY AT THE END OF THE DAY. THAT COORDINATION, THERE ARE LABORATORIES SEVERAL CONTACT RESEARCH ORGANIZATIONS INVOLVED HERE WITH DIFFERENT ASPECTS COORDINATING THOSE, KEEPING THEM ALIGNED, GHETTO THE RIGHT ANSWER, IS ONE OF THE BIGGEST CHALLENGES AND ONE OF THE THINGS THAT WAS THE MOST DIFFICULT TO DO BUT ALSO ULTIMATELY REWARDING. SO THAT'S THE PROTEIN. ONE WE PURIFY OPTIMIZED BIGLYCAN IT'S STABLE. THAT'S IMPORTANT. SO WE SIX MONTHS AT FOUR DEGREES THEN WE ANALYZE IT IN THIS CASE BY SIZE EXCLUSION CHROMATOGRAPHY, THERE'S A SUITE OF FORMULATION STUDIES UP AND -- GOING UP RIGHT NOW. BUT FOR A BIOCHEMIST THIS IS THE LOVELY THING BECAUSE THERE'S NO AGGREGATES THAT ARE EVIDENT AND THERE'S ALSO NO MATERIAL IN THE POSITION WHERE WE SEE THE INACTIVE FORM BUT ONLY ACTIVE FORM HERE STAYS STABLE SO YOU CAN MAKE IT, IT'S STABLE. SUPER IMPORTANT, ALSO HAS A DOSE RESPONSE CURVE CENTRAL NUCLEI HERE FROM ONE THROUGH 20-MILLIGRAMS PER KILOGRAM BEFORE SEEING RETURN TO BASELINE, LOTS OF EFFICACY AT -- WE SEE NO EVIDENCE OF THAT NOW. BECAUSE NOW WEE EAR DEALING WITH A HOMOGENOUS PREPARATION. SO THE LINEAR TREND HERE IS SIGNIFICANT AT .002, 12 TO 16 MUSCLES PER GROUP AND T TESTS ARE ALSO BOTH ARE SIGNIFICANT. OKAY. SO VERY GOOD. THIS IS WHERE WE ARE NOW. SO NOW WE UNDERSTAND THE MOLECULE, WE ALSO HAVE IN COMPANION DEVELOPED SCALABLE METHODOLOGYIES FOR SCALABLE REPRODUCIBLE AND WELL CHARACTERIZED UPSTREAM AND DOWNSTREAM, THIS IS ONE THING TO KNOW WHAT YOU WANT, ANOTHER TO MAKE IT. AND TO MAKE IT IN QUANTITY AND QUALITY AND REPRODUCIBILITY THAT YOU NEED IN ORDER TO GIVE TO PATIENTS. DEFINITELY HAVE TO HAVE THAT. SO WE'RE DOING THAT AND WE HAVE DONE THAT. IN THE LAST FEW MINUTES LET ME DO A LITTLE SCIENCE AND BIT OF A SURPRISE, I THINK IT IS IMPORTANT. SO BIGLYCAN IN CONGENITAL MUSCULAR DYSTROPHY? I MENTIONED BIGLYCAN HAS FUNCTION IN YOUNG MUSCLE. WE KNEW THAT BECAUSE LOOKING AT THE BIGLYCAN NULL MICE WE KNEW THERE WAS DECREASE, THERE WERE DECREASES IN THE CENTRO FINS, THE -- CENTRO FANS, THE -- DYSTROPHIN, THIS WAS A BIGLYCAN NULL MOUSE. INTERESTINGLY LOOKING AT THE COLLAGEN SIX NULL MICE TISSUE PROVIDED BY PAULO R,NALDO, IT HAS A REMARKABLY SIMILAR PROFILE. AND WORKING WITH CATHY NORTH LOOKING AT ULRIK'S PATIENT THERE'S A REMARKABLY SIMILAR PROFILE. SO THIS IS QUITE INTERESTING TO US BECAUSE IT SUGGESTS THE PART OF BIGLYCAN ACTIVITY MAYBE INVOLVE MUSCULAR DYSTROPHY THOSE MECHANISMS WHICH ARE AT FAULT. AND CONGENITAL MISDEMEANORS. AS CARSTEN MENTIONED THE MICE HAVE A BORING PHENOTYPE. WE REPORTED WITH MUCH DISAPPOINTMENT THE BIGLYCAN NULLS DO NOT HAVE A STRONG PHENOTYPE. YOU CAN SEE THE PHENOTYPIC DIFFERENCES IN HISTOLOGY BUT THEY'RE MILD. YOU WOULD NOT TAKE THIS UP. BUT WE REVISITED THAT QUESTION NOW. THE LAST COUPLE OF MINUTES, AGAIN, THIS IS JUST AN EXAMPLE OF THE N -- BIGLYCAN TREATMENT UP REGULATES THAT'S THE EXPRESSION INCLUDING NNOT AND MUSCLE, THAT'S VERY IMPORTANT TOO, NOT ONLY THROW FIN BUT END NOTES AND UTROPHIN BY ITSELF DOES NOT REGULATE NNOS SO THERE IS A PATHWAY HERE DOWN TO THAT. SO HOW WOULD YOU TEST THIS? >> WHAT HE DONE SINCE WE HAVE BEEN COLLABORATING WITH THOMAS AT BROWN AND WE'RE DOING BEHAVIORAL STUDIES. WE TALKED ABOUT RELIABLY REPRODUCIBILITY RATER TO RATE IRVARYIBILITY, SENSITIVITY, ALL THINGS THAT ARE USUALLY NOT SYNONYMOUS WITH BEHAVIORAL TESTING. THE CAPRICIOUSNESS OF BEHAVIORAL TESTING VEXES MANY, MANY DIFFERENT STUDIES SO WHAT THOMAS HAS DONE IS AUTOMATED BEHAVIORAL ASSESSMENT TOOL. SO THIS IS AUTOMATED HOME PAGE MONITORS FOR BEHAVIORAL PHENOTYPE AND IN THIS PARTICULAR CASE WE USE BIGLYCAN NULL, THIS WAS OUR FIRST -- SO THIS IS AN EXAMPLE OF A MOUSE, MONITORED FOR SEVEN DAYS 24 HOURS. THE COMPUTER MAKES THESE -- SO THE COMPUTER MAKE IT IS CALLS OVER THIS ENTIRE TIME PERIOD. AT THE END OF THE SESSION, SO THE -- IT GOES FOR SEVEN DAYS TAKES COMPUTERS ABOUT SEVEN DAYS TO MAKE THE CALLS, BUT THEN THE VALIDITY OF THOSE CALLS IS CHECKED BY MANUAL BY RANDOM SAMPLING OF THE DATA TO MAKE SURE THAT WHAT THE COMPUTE IRCALLING IS REAL. THAT'S DONE BY UNDERGRADUATES, $10 AN HOUR WOULDN'T KNOW IT IF IT HIT THEM IN A DARK ALLEY. SO THEY POWER THROUGH, IT'S COMPLETELY DEPENDENT. SO IT ENABLES YOU THEN TO DO THIS AT SCALE, SO THIS IS AN EXAMPLE WHERE THIS IS THE -- ALL THESE ANIMALS ARE MONITORED. YOU CAN GET A SENSE OF HOW THE COMPUTER IS MAKING THEIR CALLS. THERE'S HIRE HANG, REARING WALKING GROOMING SNIFFING, SKY IS NOT MOVING -- THIS GUY IS NOT MOVING MUCH. THIS IS THE BIGLYCAN NULL. SO THIS WAS AN UNDERGRADUATE PROJECT. LOOKING AT THESE BIGLYCAN NULLS THERE'S A REMARKABLE FINDING. SO NOW LOOKING AT THE NEURAL MOTOR PHENOTYPES BY GLYCAN NULL MICE, THIS IS THE HOME PAGE MONITORING DATA WE'RE LOOK TAG THE AGGREGATE DATA, SO THIS IS NIGHTTIME WHEN RODENTS ARE ACTIVE, DAYTIME WHEN LESS ACTIVE, NIGHTTIME AGAIN THIS IS SEVEN DAYS WORTH OF DATA SLOTTED FROM EACH TIME FOR EACH BEHAVIOR. AND WHAT YOU CAN SEE READILY IS THAT THEIR HANG TIME IS -- STATISTICALLY SIGNIFICANT DECREE WITH BIGLYCAN NULLS AN REARING IS ALSO DECREASED. NOW, VERY INTERESTINGLY, TRADITIONAL TESTING ON THE SAME ANIMALS IN A BEHAVIOR CAGE YOU TEST A HALF HOUR, FROM STRESSED, EVEN QUALIFIED PEOPLE DOING THIS, NO GRIP STRAIN DEFECT. WE DID SEE OPEN FIELD SO THIS IS FAR MORE SENSITIVE AS WELL AS REPRODUCIBLE AND SCARABLE FOR THIS -- SCALABLE FOR THIS. WE WENT TO SIX MONTHS OLD ANIMALS NOTHING, NOW WE SAW WIRE HEADING GRIP STRENGTH OPEN FIELD BUT YOU CAN SEE THAT THESE ANIMALS ARE REALLY SEVERELY AFFECTED, THEY HAVE A MOTOR PHENOTYPE WITHOUT ANY QUESTION. THAT WAS MISSED BY LOOKING AT THE MUSCLE AND OBVIOUSLY THIS KIND OF -- THIS IS SEVEN DAYS CONTINUOUS MONITORING, VERY AMENABLE TO SCALE UP. FINALLY AT EIGHT MONTHS WE GOT A DEFECT. SIX MONTHS AFTER WE SAW GOOD SIGNS OF ACTIVITY SO OBVIOUSLY I PRESENT THIS HERE BECAUSE YOU CAN THINK OF PUT YOUR MODEL IN THIS AND IT WOULD BE VALUABLE. I WILL SAY THAT AGAIN, AS I SAID EARLIER, THE OVERALL SYSTEM ACCURACY VALIDATED BY HUMAN ANNOTATORS, 80%. INTERANNOTATEED CONSISTENCY IS 87% SO COMPUTER VERY CLOSE TO THE HUMAN, HUMANS TO GET THIS KIND OF DATA WOULD TAKE LITERALLY TEN YEARS. TO ANALYZE THAT MUCH VIDEOTAPE FOR THIS THESE METHODS, ALL THE HUMAN ERROR THAT IS THERE. AND JUST BE HAPPY TO TALK ABOUT THIS WITH ANYBODY BUT TO LET YOU -- JUST TO REPEAT, THE SOFTWARE IS WRITTEN BY (INDISCERNIBLE) WE DID THE ANIMAL BEHAVIOR WITH KEVIN BATH. THE CODE IS OPEN SOURCE. THE HARDWARE IS OFF THE SHELF. YOU NEED COMPUTING POWER BUT BASICALLY JUST A LOT OF PCs WORKING TOGETHER SO IT'S SOMETHING THAT CAN BE DONE, THERE'S NOTHING PROPRIETARY HERE. OKAY. SO A FEW LESSONS LEARNED, HOPE TO CONVEY THESE OVER THE COURSE, YOU ARE FROM THE END TO BEGINNING. BASIC SCIENCE THAT'S HARD BECAUSE YOU WOULDN'T DO IT UNLESS YOU THOUGHT THERE WAS SOMETHING NEWEN AND UNEXPECTED. KEEP OPEN TO OPPORTUNITIES, WORK WITH EXPERTS, REALLY IMPORTANT. LET ME SAY ONE THING THE NIH AND ADVOCACY GROUP HAS DONE IS ASSEMBLE TEAMS OF EXPERTS THAT ARE ACCESSIBLE. THAT'S IMPORTANT AND PEOPLE LIKE TACT WHO CAN PROVIDE VALUABLE INPUT. THAT'S BEEN IMMENSELY IMPORTANT. THIS IS A PARTNERSHIP INDUSTRY CONTRACT RESEARCH ORGANIZATIONS, NIH AND CLINICAL. THESE HAVE TO BE MANAGED BECAUSE THEY'RE NOT NECESSARILY ALIGNED. A CONTRACT RESEARCH ORGANIZATION THEY WANT TO GET THINGS DONE AS QUICKLY AS POSSIBLE. THEY DON'T KNOW WHAT'S RIGHT UNLESS YOU TELL THEM SO YOU HAVE TO BE CAREFUL ABOUT THE KIND OF OUTPUT YOU GET FROM THAT AND WE HAD THIS EXPERIENCE SO YOU HAVE TO BE INCREDIBLY AWARE OF THAT AND HAVE THE TOOLS TO BE ABLE TO MEASURE IT AND STAY ON TOP OF IT. DATA RULES ALWAYS. THE PEOPLE WHO DID THE EXPERIMENTS, THIS IS THE BIGLYCAN TEAM AND THE LABORATORY (INDISCERNIBLE) SARA MENSER, WE HAD WONDERFUL COLLABORATORS, THE TWO SETS OF MECHANIC STUDIES BUT (INDISCERNIBLE) JEFF MILLER, WE'RE COLLABORATING WITH THOMAS SARA WHERE THE AUTOMATED HOME PAGE MONITORING KATHERINE NORTH DID WORK WITH THE URICS AND WE HAVE COMPLEX CARBOHYDRATES AN JACKSON LABORATORIES, UNLESS OF COURSE THE FUNDING I POINTED OWL ALL THE WAY ALONG, WE WOULD NOT BE HERE AND READY TO TAKE THE NEXT STEP WITHOUT REALLY THE COMMITMENT AND SUPPORT AND WORK OF ALL FUNDERS. I'M GRATEFUL FOR THAT. THANK YOU VERY MUCH. [APPLAUSE] >> THANK YOU VERY MUCH JUSTIN, I THINK YOU DID TELL US SOMETHING ABOUT THE SPECIFIC CASE BUT GENERALIZABLE TAKE HOME POINTS FROM IT. ARE THERE QUESTIONS? DISCUSSION POINTS PEOPLE WOULD LICK TO BRING HOME? >> QUESTION ON THE -- WHEN YOU WERE REVIEWING THE -- COMPARING THE MUSCLE LEVEL PROTEIN EXPRESSION -- >> THAT'S RIGHT. >> IT LOOKED LIKE IN THE COLLAGEN SIX KNOCK OUT MODELS THERE WAS UP REGULATION OR DECREASE (INAUDIBLE) >> EXACTLY RIGHT. GOOD EYE. WE THINK THAT'S IMPORTANT. >> APPROPRIATELY LOCALIZED? >> YES. IT'S QUITE CLOSE TO THE MEMBRANE. >> CAN CAN YOU REPEAT THAT? NOT SURE EVERYONE -- >> I'M SORRY. THE QUESTION WAS IN THE MOUSE MODEL, I PUT ON THAT SUMMARY SLIDE THAT THERE WAS UP REGULATION OF BIGLYCAN. AND YES, THERE WAS. THEN THAT WAS BY IMMUNOCYTOCHEMISTRY AND THE LOCALIZATION OF THE BIGLYCAN IS ANOTHER THE PERIPHERY OF THE MUSCLE FIBER. IT'S IN THE THE INTERSTITIAL MATRIX BUT WITH THE SARCOLIMA FOR THE MATRIX PROTEIN IT MAKES A DIFFERENCE WHERE YOU ARE WHETHER OR NOT YOU'RE IN POSITION OR IN A POSITION TO INFLUENCE THE ORGANIZATION IN SIGNALING OF THE CELL. AND DESPITE IMMUNO THE BIGLYCAN IS IN THAT PLACE,. >> LOCALIZATION STUDIES TO GET A BETTER (INAUDIBLE)? >> NOT YET. THAT WILL DO A SUPER RESOLUTION. >> I THINK WE'LL FEED THE DISCUSSION WE'RE ABOUT TO HAVE, YOU MADE THE POINT THE FUNDERS NOT JUST THE MONEY YOU OBVIOUSLY WERE APPRECIATIVE OF THAT SUPPORT BUT IT WAS THE ACCESSIBLE TEAMS OF EXPERTS -- >> YES. >> FUND THE ORGANIZATIONS HELPED MAKE AVAILABLE TO YOU, CAN CAN YOU TALK A LITTLE BIT MORE HOW THAT ACCELERATED (INAUDIBLE)? >> I THINK THAT STARTED WITH THE R-21. WHERE I GOT VERY GOOD ADVICE, AS I HAVE CONSISTENTLY FROM PROGRAM WHO SAID PUT IN THERE A PLAN FOR DEVELOPMENT, IT'S ONLY R-21 BUT I WANT TO THINK ABOUT WHAT'S NEXT AFTER THIS. SO WE BEGAN TO THINK ABOUT IT. IN THE UO-1 THAT WAS OBVIOUSLY VERY IMPORTANT. SO WHAT WE DID THERE WAS ACTUALLY CREATED A LABEL FROM THE DRUG, IF YOU WILL, A TARGET WHAT IT WOULD LOOK LIKE AND THAT WAS THE END POINT, IF YOU WILL, OF IT. TO SHAPE THE THINKING. THAT WAS DEMANDED BY THE UO-1, AN EXCELLENT THING. WE ALSO ENGAGE CONSULTANTS WHO HAVE DRUG DEVELOPMENT EXPERIENCE TO HELP US IN SHAPING THAT WITH THE THINKING ABOUT IT. THAT HAPPENED, THEN AS I MENTIONED DURING THE TALK, BY PPMD, THE TACT, ALSO HAD VERY GOOD INPUT. SO AT EACH STEP. AS MUCH AS POSSIBLE, AGAIN WORKING FROM THE END TO THE BEGINNING. WHAT WILL WE NEED IN THREE YEARS? AND WHAT DO WE HAVE NOW TO SAY WE'LL HAVE IN THREE OR FOUR YEARS? WHAT MAKE AS DIFFERENCE TO THE PATIENTS? ALL THOSE THINGS LOOKING OUT AHEAD, THOUGH YOU DON'T KNOW THE ANSWERS YOU KNOW WHERE YOU WANT TO GO. >> JUST ANOTHER ONE OF YOUR LESSONS I CAN THROW THIS OUT, PARTICULARLY WITH COMPLEX THERAPEUTIC LIKE THIS, BUT I THINK TRUE FOR LOT OF CLASSES OF THERAPEUTIC, ONE THING THAT WAS HUGELY INSIGHTFUL IS WHEN YOU DESIGN THE UO1 YOU PUT IN THERE TO DO EFFICACY CHECKS, HE KNOWSES WHAT'S COMING BECAUSE WE TALKED -- I WANT TO REINFORCE THE POINT. YOU PUT IN THERE EFFICACY CHECKS ON ALL SORTS OF STAGES ALL THE WAY THROUGH. >> YES. >> BACK INTO THE MOUSE, MAKE SURE THINGS ARE STILL WORKING. >> RIGHT. >> AND LIKE I SAID, THAT WAS HUGELY INSIGHTFUL BECAUSE YOU DID ENCOUNTER ISSUES THAT IF YOU HADN'T RECHECKED IT, YOU WOULD HAVE KEPT GOING WITH YOUR PRODUCT AND NOT DISCOVERED THAT YOU HAD A PROBLEM UNTIL YOU GOT TO TRIAL. >> ABSOLUTELY THAT. IS EXACTLY RIGHT. I WILL SAY THAT THIS WAS AN INSIGHT FROM CONSULTANTS. EARLY ON WHEN WE WERE FORMULATING UO1 THAT SAID WE KNOW HOW TO MAKE THIS. I DID PROTEIN CHEMISTRY 30 YEARS. BUT YOU THINK YOU HAVE YOUR PROTEIN, YOU HAVE A CELL CULTURE EFFICACY, YOU'RE GOOD. SO THAT WAS VERY IMPORTANT. THAT WAS PUT IN PLACE INITIALLY SUGGESTEDDED STRONGLY BY THE CONSULTANTS, THAT WAS SOMETHING AT THE TIME, I SAID OH, WHY? NOW I KNOW. >> THANKS VERY MUCH. JUST AS A HOUSEKEEPING -- >> JUST ONE SECOND. YOU LEFT YOUR GLASSES UP HERE? >> SO NOW WE CAN ALL SEE CLEARLY. JUST AS A HOUSEKEEPING THE LAST I KNEW NO ONE SIGNED UP FOR PUBLIC COMMENT PERIOD. IS THAT STILL THE CASE OR IS SOMEONE WANT TO MAKE PUBLIC COMMENT? IF NOT THAT HELPS TO STRUCTURE OUR TIME. THAT DOESN'T MEAN WE NEED TO GO TO 4:30, (INAUDIBLE). LET ME FIRST SAY I THOUGHT THE TALKS WERE GREAT TODAY. -- (INDISCERNIBLE) SPECIFIC POINTS ABOUT VERY FOCUSED EFFORTS BUT VERY GENERALIZABLE TO ALL OF US I THINK THEY AND SOME OF THE DISCUSSION ON THE TABLE ALSO HIGHLIGHTED THE KINDS OF THINGS INCREDIBLE FIBERS MADE BUT INCREDIBLE CHALLENGES THAT REMAIN AND THE FUNCTION OF THE ORGANIZATIONS REPRESENTED HERE AND THE ORGANIZATION THE MDCC REPRESENTED HERE. SO I THINK OUR TASK FOR THE NEXT HALF HOUR TO HOUR IS DISCUSS TWO KINDS OF COLLABORATIONS, THAT IS WITH ONE IN THE PROGRAM LEVEL, IDEAS OF COLLABORATIONS, THAT ARE ALREADY ONGOING, THERE COULD BE ACCELERATED OR ONES NOT FORMED YET, THE FOLKS AT THE TABLE CAN THINK ABOUT DOING TOGETHER. AND CERTAINLY SPECIFICALLY SECOND KIND OF CONVERSATION. ARE THERE WAYS WE CAN REFASHION THE FUNCTIONING OF THE MDCC TO BETTER ESTABLISH THE TASK OF MOVING THE FIELD FORWARD. THAT CAN INCLUDE MORE THIS OR THAT WE'RE ALREADY DOING OR INCLUDE NEW ACTIVITIES, I THINK WE'RE OPEN TO WHATEVER IS BEST WHEN ADVANCING SO AGAIN, IDEAS BOTH ABOUT SPECIFIC PROGRAMS WHETHER THE MDCC IS INVOLVED OR NOT, THE COMMUNITY TOGETHER WE SHOULD BE THINKING ABOUT BUT THEN ALSO SPECIFICALLY THE WAY WE MIGHT BETTER UTILIZE MDCC TO MOVE THINGS FORWARD. SO WITH THAT, THE FLOOR IS OPEN FOR IDEAS, POINTS. >> I HAVE ODE CUPCAKE FOR DISCUSSION. >> I'LL TRY TO BE -- MEMBERS OF THE MDCC AND EVEN OTHERS FOR THE MEETINGS IN JULY WOULD BE MOST HELPFUL IN TERMS OF KNOWING THAT WE'RE GOING TO HAVE A -- GOING TO UPDATE THE STRATEGIC PLAN. AND ONE -- MAYBE JOHN WANTS TO SAY SOMETHING ABOUT IT BUT WE ARE ALWAYS OPEN TO SUGGESTIONS, WE DON'T HAVE YET AN ABSOLUTE SLATE. >> WE DO HAVE AN ABSOLUTE SLATE. WHERE WE'RE AT NOW IS WE HAVE AN RFI, WE GAVE THE GENERAL COMMUNITY THE OPPORTUNITY TO HAVE INPUT INTO HOW THEY THOUGHT WE HAD DONE RELATIVE TO THE EXISTING OBJECTIVES OF THE PLAN AND WHAT OBJECTIVES THEY WOULD RECOMMEND FOR THE PLAN. SO WE HAD A FORMAL RFI. WE'VE ALSO HAD INFORMAL INPUT IN A LOT OF -- FOR MANY OF THE PEOPLE AROUND THE TABLE. THE ORGANIZATIONS HERE HAVE GIVEN US A LOT. OF INPUT. MEMBERS WERE GIVEN OPPORTUNITY TO SUGGEST PARTICIPANTS IN THE WORKING GROUP. WE HAVE HAD ABOUT 50% TURN-OVER IN THE WORKING GROUPS FROM LAST TIME. THAT WAS IN PART INTENTIONAL, WE WANTED HISTORICAL MEMORY BUT ALSO WANTED TO BRING NEW FOLKS INTO THE PROCESS. THIS SESSION TODAY IS ADDITIONAL INPUT WITH THE PROCESS, BECAUSE WE WANTED TO KNOW MORE ABOUT WHAT ACTIVITIES YOU HAVE UNDERTAKEN THE LAST YEAR. SO ACTUALLY THERE'S MULTIPLE LEVELS OF INFORMATION, I PUT A LOT OF IT ALREADY FOR THE WORKING GROUPS BUT WILL TAKE TODAY AND PUT THAT IN FROM TOO. THERE'S A LOT -- WE TRIED TO ASSESS EVERY STAGE. SO THE REST IS THE MDCC MEMBERS ARE INVITED TO JULY 28, 29 MEETING, WE WANT YOU TO JUMP IN AT THAT MEETING. AFTER THAT MEETING A DRAFT OF THE OVERALL PLAN WILL BE PUT TOGETHER PUT OUT FOR COMMUNITY COMMENT. I FORGET WHAT WE CALL THE MECHANISM IT'S NOT AN RFA. MADE AVAILABLE ON THE WEB FOR COMMUNITY COMMENT THEN A PLAN BACK TO A MEETING IN THE FALL OF THIS GROUP FOR YOU GUYS TO GIVE US ANY ADDITIONAL INPUT BEFORE YOU VOTE TO APPROVE THE PLAN. I THINK WE HAVE INTENTIONALLY DESIGNED MULTIPLE LEVELS OF INPUT. I HOPE THAT'S STATICALLY. >> I HAVE A QUESTION. IN TERMS OF THE DESIGN OF THE TWO DAYS, IS THERE TIME LEFT OVER FOR DISCUSSION? >> YES. THAT'S ONE REASON IT'S SPREAD OVER ROUGHLY A DAY AND A HALF WE'RE SPREADING IT OVER. THE WAY IT WORKED LAST TIME WHICH THE MDCC WASN'T AT THE MEETING LAST TIME, WAS THESE WORKING GROUPS PREPARED THE RECOMMENDATIONS AHEAD OF TIME AND THEY CAME TO THE MEETING WITH -- AND WENT THROUGH THINGS DIRECTLY ONE, TWO, THREE, FOUR EACH OF THE OBJECTIVES. PART OF THE REASON WE DID IT THAT WAY IS BECAUSE SOMEBODY IS IN ONE WORKING GROUP DOESN'T MEAN THEY DON'T HAVE TONS OF EXPERTISE FOR ANOTHER WORKING GROUP. SO THAT LED TO MUCH BROADER VETTING OF RECOMMENDATIONS THAN THE FIVE PEOPLE WE HAD ON AVERAGE LAST TIME, THIS TIME WE GOT 7 OR 8 PEOPLE PER GROUP. I CAN TELL YOU WHY. BUT WE HAD TO EXPAND TO INCREASE EXPERTISE. >> I DO HAVE A A QUESTION, I'M A LITTLE NEW TO THIS GROUP, THIS ISN'T MY AREA OF SPECIALTY SO I APOLOGIZE IF IT'S A QUESTION WE ALL KNOW THE ANSWER TO. I HEARD THE REFERENCE TO (INAUDIBLE) DEVELOPED. MY QUESTION IS FROM A PLAN OR SOMETHING IN PLACE WHERE THERE'S GOING TO BE DATA SHARING, THERE WILL BE A DATABASE LICK THE DATABASE WE HAVE NOW? >> SO WE DON'T HAVE PLANS FOR THAT AT THIS POINT. THE CDE -- THEY ROSE OUT OF AN NINDS EFFORT TO GET COMMON DATA ELEMENTS FOR OUR DISEASES, WITH THE IDEA THAT FOLKS DOING FIRST CLINICAL TRIALS WE SUPPORTED WERE USING THE SET OF COMMON DATA ELEMENTS. AND WHAT WE TRY TO DO IS SPREAD MORE BROADLY THAN THAT SO VALERIE MAY WANT TO COMMENT BUT REGISTRIES, REGISTRY MDA PUT IN PLACE IS USING THE NEUROMUSCULAR DISEASE CEs SO WE'RE -- THE GOAL IS TO TRY TO GET MORE EFFORTS EVERYBODY USING THESE. >> IF I COULD JUST SAY A WORD ABOUT -- THE FUNDING FORFEITBER CAME FROM THE DEPARTMENT OF DEFENSE, DIDN'T COME FROM NIH, IT WAS AN EXTRAORDINARY GIFT. DEPARTMENT OF DEFENSE IS CONTINUING TO FUND THAT. WHAT'S PARTICULARLY NICE ABOUT THE DATABASE IS THAT DOD DATA WILL GO INTO IT, THERE ARE SEVERAL OTHER MAJOR TBI STUDIES THAT WILL GO INTO IT. BUT THERE HASN'T BEEN THAT KIND OF FINANCIAL OPPORTUNITY TO CREATE A SIMILAR DATABASE. THE DATABASE THAT FITBER CAME FROM WAS BASED ON DATABASE THAT WAS CREATED FOR AUTISM, SO THAT WAS USED AS A RESOURCE AND WE AND DEPARTMENT OF DEFENSE SIGNIFICANTLY FROM THE HARD WORK THAT WAS DONE TO CREATE THAT AUTISM DATABASE. >> THANK YOU. FOR THE FITBER DATABASE MORE FUNDING WAS AVAILABLE IN OUR PROGRAM FOR MUSCULAR DYSTROPHY QUITE SMALL. >> THERE WAS $10 MILLION. >> RIGHT. >> AND ONGOING. ONGOING. TBI MONEY SET ASIDE, IT'S PART OF THE PRESIDENT'S INITIATIVE ON TBI AND PTSD. FEDERATED INFORMATION TBI FITBER -- IT WAS SPECIFIC THROUGH GEARED TOWARDS TBI. IT -- I'M A LITTLE EMBARRASSED, IT IS USE THE COMMON DATA HE WILLN'TS CREATED FOR TBI AND IT WILL TAKE IN DATA FROM OLD TBI STUDIES SO WE RECENTLY REASON A TRIAL THAT FAILED WITH PROGESTERONE, TRAUMATIC BRAIN INJURY AND TAKE THOSE DATA IN OTHER HISTORIC DATA, THERE'S SOMETHING LIKE 10,000 PERSON STUDY OR MAYBE MORE THAN THAT BETWEEN U.S., EUROPE AND CANADA. THAT IS COLLECTING DATA, OBSERVATIONAL DATA ON PATIENTS WHO HAD TRAUMATIC BRAIN INJURY WHO HAVE BEEN TREATED WITH VARIOUS PARADIGMS TO TRY TOUGHER ROT OUT WHAT ARE THE DIAGNOSTICS AND TREATMENTS AND COME UP WITH A BETTER RATIONALE FOR ONGOING TRIALS IN TERMS OF PEDIATRIC TRIAL. ALL THE DEPARTMENT OF DEFENSE DATA, THEY'RE COLLECTING WILL GO TO THIS DATABASE. SO IT'S HUGE. >> TO EXPAND THAT MORE THE PURPOSE OF THE FITBER DATABASE WAS TO ONE INVESTIGATORS TO REPORT DATA IN A SIMILAR MATTER SO THAT -- (OFF MIC) >> RIGHT. >> COLLECT IT. AND SUPPORT IT. Q. RIGHT. SO THAT YOU CAN COMPARE ACROSS CLINICAL TRIALS AND BASIC RESEARCH TRIALS AN EVEN IMAGING. AND THEN PUT IT INTO A CENTRAL BATE DATABASE WHERE THERE'S DATA SHARING IF YOU RECEIVE FUNDING THROUGH THE DOD FOR TRAUMATIC BRAIN INJURY, YOU MUST PUT YOUR RESULTS IN TO THE FITBR DATABASE AN AFTER A PERIOD OF TIME, I BELIEVE ONE YEAR AFTER THE PEER PERFORMANCE IS CLOSED THAT DATA BECOMES AVAILABLE TO THE PUBLIC SO YOU CAN THEN ASK LIKE AUTISM DATABASE THEY HAVE ACCESS TO IT AND COMPARE ACROSS STUDIES SO IF YOU'RE INTERESTED IN A PARTICULAR OUTCOME, YOU CAN LOOK ACROSS STUDIES AND MAKE COMPARISONS ON A BROADER EXTENT SO IT ALLOWS YOU TO ACCELERATE THE FIELD FASTER BECAUSE YOU CAN COMPARE THE SAME WAY AND LOOK ACOST STUDIES. >> FOR THE TRACK PBI STUDY NINDS IS FUNDING, THOSE DATA HAVE TO GO IN. AS WELL AS THE DATA FROM THE EUROPEAN STUDY AND THE CANADIAN STUDY. SO AS A CONSEQUENCE OF GETTING THE MONEY IS THAT YOU HAVE TO PUT YOUR DATA IN TO THE -- I THINK ONE OF THE MODELS HAS BEEN THE ALZHEIMER'S DISEASE NEUROIMAGING PROJECT WHERE THE DATA ARE PUT IN AS THEY'RE COLLECTED LIVE AND THERE'S SOMETHING LIKE 155 PAPERS THAT HAVE BEEN PUBLISHED ON THE ADNY DATA, NOT INCLUDING THOSE FROM THE INVESTIGATORS. THERE YOU PUT THE DATA IN RIGHT AWAY AND THEN IT'S AVAILABLE HERE, THERE'S A GRACE PERIOD BETWEEN FINISHING COLLECTION AND PUTTING IT IN AND MAKING IT OPEN SOURCE. >> SO IT'S ALSO MADE SO IT CAN BE YOUR DATABASE. SO YOU COULD BUILD YOUR OWN DATABASE WITHIN YOUR OWN INSTITUTION, YOU CAN USE THAT AS YOUR DATABASE ONGOINGING. >> YOU BRING UP A GOOD POINT, WE HAVE DISCUSSED THIS WITH OTHER MDCC MEETINGS WHAT IS THE OVERALL PUMP OF THIS MEETING AND HOW IT'S EVOLVING OVER TIME. IS THERE A SHARED COLLECTIVE OBJECTIVE ACROSS THE MUSCULAR DYSTROPHY THAT COULD BENEFIT FROM A COLLECTIVE VISION. ONE THING WE TALKED ABOUT, SHARON YOU PROBABLY AS WELL, IS THIS IDEA OF A SHARED DAYTIME BASE WHERE DATA -- DATABASE WHERE DATA FROM MULTIPLE MODELS, VALIDATED LONGITUDINALELY CAN BE VERY USEFUL WHAT PEOPLE (INAUDIBLE) ON THAT. >> IT'S A VERY IMPORTANT TOPIC TO DISCUSS, IT REPRESENTS A CULTURE CHANGE ON THE PART OF INVESTIGATORS AN FUNDERS AND ALSO REPRESENTS A FINANCIAL NEED, THESE THINGS AS YOU HAVE HEARD ARE NOT INEXPENSIVE TO EITHER -- I THINK LOTS OF FOLKS NEW TO IT FOCUS ON GETTING UP AND RUNNING, THAT'S A MAJOR TASK. BUT THEN YOU HAVE TO MAINTAIN IT. SO THAT IS ACTUALLY A SIGNIFICANT LIFETIME COST. BUT I THINK KNOWING THOSE THINGS, IT'S WORTH TALKING ABOUT HOW COULD EVEN IF WE DON'T SUDDENLY WAVE A MAGIC WAND MAKE THAT HAPPEN, HOW WE CAN MOVE IN THAT DIRECTION AS A COMMUNITY, I THINK IT'S DEFINITELY WORTHWHILE THING TO BE TALKING ABOUT. THOUGHTS ABOUT THAT. Q. YES, I'M GLAD YOU BROUGHT THAT UP, I HAVE BEEN INTERESTED IN THE DUCHENNE CONNECT. REGISTRY OR PATIENT POWER NETWORK. (OFF MIC) >> (INAUDIBLE). >> I THINK MYOTONIC DYSTROPHY DEVELOPED A REGISTRY USING THE SAME PLATFORM AND WE'RE LOOKING AT THE SAME PLATFORM AND THAT PLATFORM I BELIEVE IS ALL GOING INTO -- THE RARE DISEASE. SO SEEMS LIKE THERE'S ALREADY THE TECHNOLOGICAL STRUCTURE TO FACILITATE CREATION OF (INAUDIBLE) REGISTRY. >> WELL, I THINK YOU CAN -- YOU CAN ALREADY DO THAT, BUT I'M THINKING MORE ON THE -- AS WELL AS YOU PROBABLY HAVE DIFFERENT BRANDING TO BRING IN O THE PATIENTS BUT WHEN WHEN WE LOCK TO DEVELOP WE WANT DATA CURE RATION, GENETIC COUNSELORS TO TALK TO PATIENTS WHO DON'T KNOW HOW TO (INAUDIBLE) AS A CONSULTING SERVICE BUT THEIR NUMBER OF -- THERE'S NUMBER OF STAFFING NEEDS THAT MIGHT CUT ACROSS THESE (INAUDIBLE) DATA ELEMENTS THERE'S GOING TO BE SPECIFIC DATA ELEMENTS, TALKING WITH -- INCORPORATING THEIR WORK AND CRAIG DONALD'S GROUP BUT, AGAIN, >> SO HOLLY ISN'T HERE SO I'M REALLY -- THIS IS BEEN HER INITIATIVE EVER SINCE WE -- I WAS -- I WAS PART OF THE DEVELOPMENT OF IT BUT CERTAINLY NOT -- ONCE HOLLY CAME ON BOARD BUT WE HAVE ALWAYS WANTED TO INCORPORATE THIS. AS YOU PROBABLY SAW FROM BRIAN'S TALK, WE HAVE BEGUN CERTIFYING CLINICS SO WE WORK WITH A TEAM OF PEOPLE TO BEGIN CERTIFICATION PROCESS AND P ALONG WITH THAT PROVIDING A STIPEND TO CLINICS WE CERTIFY, WE WILL INSIST THEY ALSO UTILIZE DUCHENNE CONNECT AS THE PATIENT REPORTED OUTCOME AND WE FEEL THE MORE WE CAN COLLABORATE THESE RESOURCE THIS IS ANYWAY, THE BETTER. FIRST JUST LIKE TO MENTION DIFFICULT TO DEVELOP BUT MORE DIFFICULT TO SUSTAIN OVER TIME. SO TO THE DEGREE WE COULD PULL THIS TOGETHER, I THINK THAT WOULD BE VERY IMPORTANT TO DO EXACTLY THAT. AND WE ARE TRYING TO DO THAT AND WE CONTINUE TO TRY TO ADVANCE THE IDEA. LOOK AT THE DATA TRYING TO UNDERSTAND HOW THEY IMPROVE LIVES OF PATIENTS. IT'S A HARD ONE. INVOLVING MANY CONDITIONS SOME WHICH I THINK FOLKS AROUND THE TABLE ARE FAMILIAR WITH THE BASIC LESSONS BUT I WONDER WHAT YOU MIGHT ADD. >> I WANT TO MENTION A LOT STILL DONE, A LOT OF FANFARE AROUND THE LAUNCH OF THE GRDR, THE GLOBAL AWARE DISEASE CLINICAL RESEARCH -- PATIENT DATABASE RIGHT NOW THE INITIAL CONTRACT ENDED BUT WORK IS STILL DONE ON COMMON DATA ELEMENTS. THERE'S THINGS CONTINUING TO BE DEVELOPED, THEY'RE WORKING WITH NATIONAL LIBRARY OF MEDICINE TO SERVE AS REPOSITORY, SO THE HOPE IS PEOPLE WILL SUBMIT THEIR COMMON DATA ELEMENTS DEVELOPED, THEY WILL BE IN A LIBRARY FORMAT AT NLM AND SO AS YOU'RE GOING TO START A REGISTRY OR A CLINICAL STUDY YOU CAN GO THROUGH THIS LIBRARY OF QUESTIONS AND DATA ELEMENTS, PICK OUT THE WITNESSES THAT PERTAIN TO YOU SO YOU -- ONES THAT PERTAIN TO YOU SO YOU DON'T HAVE TO REINVENT THE WHEEL EACH TIME SO TIME BEING FOCUS IS PROVIDING THE TOOLS, CONSENT FORMS, THINGS LIKE THAT THAT ARE NECESSARY TO STANDARDIZE ACROSS PATIENT REGISTRIES AND HOPEFULLY CLINICAL STUDIES. IS THERE SOMEONE SPECIFIC AT ORDR THAT CAN FIGURE THAT OUT? DR. REUBENSTEIN IN OUR OFFICE HAS BEEN THE LEAD H AND I CAN PROVIDE YOU WITH HER CONTACT INFORMATION. >> THANK YOU. >> SEEMS TO ME THIS IS SOMETHING THAT COULD CERTAINLY BE DISCUSSED IN TERMS OF THE NEW PLAN GOING FORWARD. COLLECTION OF INFORMATION ABOUT THE DIFFERENT REGISTRIES, COMMON DATA ELEMENTS AND FORMS THAT ARE OUT THERE, AND SOME NOTION OF WHAT NEEDS TO BE DONE TO SYNTHESIZE THAT AND ORGANIZE IT IN A WAY THIS TO BENEFIT ALL THE MUSCULAR DYSTROPHY. SORRY JOHN. >> I FEEL -- >> I WAS REFERRING TO A RESEARCH DATABASE NOT PATIENT SELF-REPORTED OR PATIENT MEDICAL DATA SO THE AUTISM ONE IS AND FITBER AND PARKINSON DISEASE BIOMARKERS PROJECT ARE ALL RESEARCH DATABASE BUT THAT DOESN'T PRECLUDE UTILITY OF NON-RESEARCH DATABASES. ALTHOUGH THE PATIENT DATABASES CAN SERVE >> OTHER AREAS IN TERMS OF THE PLAN OR FUNCTION OF THIS COMMITTEE PER SE. >> BIOMARKERS ARE COLLABORATIVE ACTIVITY, THERE ARE SHARED PATHOLOGIC MECHANISMS IDENTIFIED ACROSS VARIOUS FORMS OF MUSCLE DISEASE AND THAT WOULD BE SUPER IDEAL TO BANK THOSE RESULTS IN ONE DATABASE. >> ANY OTHER THOUGHTS? KEEP GOING. >> I HAVE MY LITTLE WISH LIST. I ALSO AS I EMPHASIZE IN MY TALK, REALLY FEEL THERE IS A TREMENDOUS ROOM FOR ENGAGEMENT OF THE PULMONOLOGY COMMUNITY AND THE PULMONARY INTERVENTIONS AND THERE'S REALLY A LOT OF WORK THAT LIES AHEAD OF US AND I THINK THIS IS ANOTHER AREA THAT CUTS ACROSS DIFFERENT FORMS OF MUSCLE DISEASE AND IF WE STANDARDIZE DATA OUTPUT FROM PULMONOLOGY CLINICS AND COLLECTED IT LONGITUDINALLY, IT WOULDN'T MATTER WHAT YOU HAVE, THAT WOULD BE EXTREMELY INTERESTING TO KNOW WHEN WAS A INTERVENTION INITIATED, WITH THE FREQUENCY OF HOSPITALIZATIONS, HOW DID THEIR CAPACITY TREND OVER TIME, WHEN WAS DAYTIME VENTILATION INITIATED, DO THEY HAVE A TAKE, DO THE BIOLEVEL WERE THEY INITIATED CPAP, SLEEP STUDY READ OUTS. I THINK WE'RE MISSING A OPPORTUNITY OPPORTUNITY TO INTERVENE BUT MEASURE AND MANAGE PATIENTS. >> I THINK YOU'RE RIGHT ABOUT THAT. THERE'S A SMALL GROUP OF I MENTION A FEW THE OTHER DAY. WHEN DO YOU INTERVENE, OBVIOUSLY PULMONARY FUNCTION TEST BUT THESE YOUNG MEN WITH DUCHENNE REALLY EXPERIENCE A GREAT DEAL OF FATIGUE BEFORE THAT HAPPENS. YOU MAY WONDER IF IT'S A EARLY SIGN OF RESPIRATORY IMPAIRMENT AND (INAUDIBLE) IN AUSTRALIA THEY DID A SMALL PILOT GIVING THE NON-INVASIVE VENTILATION WHICH IMPROVED DAY TIME SCHOOL PERFORMANCE SO A VERY SMALL MYOPY LOT THAT MAY MEAN NOTHING OR SOMETHING BUT WORTH INVESTIGATING BECAUSE YOU HAVE TO WONDER WHAT HAPPENS TO -- WHEN YOU GET TO CRITICAL THRESHOLD THE KIDS YOU CAN'T CATCH THEM BACK SO IT SEEMS TO ME IF WE THOUGHT ABOUT INTERVENING EARLY IT MIGHT IMPROVE THEIR FATIGUE LEVEL, SCHOOL PERFORMANCE AND PROLONG ABILITY TO BREATHE ON THEIR OWN WITHOUT DAYTIME VENTILATION. >> SOME WOULD ARGUE THE SAME TRUE ABOUT CARDIOVASCULAR DISEASE, AND RATHER THAN SETTING UP PARALLEL PROCESSES THE KEY ISSUE IS ENGAGING THESE COMMUNITIES LISTENING TO THE TALK ABOUT THE KIND OF DESCRIPTIONS THEY'RE GIVING, SOUNDS SIMILAR TALK ABOUT POSITIONS THAT WE HAVE WITH OUR (INAUDIBLE) AND IS THERE HYPERVENTILATING AT NIGHT AND HAVE THE EQUIVALENT PROBLEMS IF NATIONAL CENTER FOR SLEEP DISORDER SEARCH LOCATED IN THE LUNG DIVISION WITHIN THE HEART LUNG AND BLOOD INSTITUTE. SO I THINK ONE OF THE KEY CONVERSATIONS MIGHT BE WHICH GROUPS OF INVESTIGATORS DO WE WANT TO BE SURE THAT WE'RE ENGAGING IN THIS TO MAKE IT NOT TOO -- SO IT'S NOT TOO NARROW BUT YOU'RE ADDRESSING ALL OF THEM OVER (INAUDIBLE). (OFF MIC) >> I WOULD HOPE IT WOULD HAVE A BROADER FOCUS THAN THAT. IN GENERAL WHEN YOU'RE LOOKING TO INTERVENE UP TO INTERVENE WHILE THERE'S STILL -- BY THE TIME PEOPLE ARE HAVING (INAUDIBLE) >> SUSAN, TO YOUR POINT WHAT HAPPENS WHEN WE TALK WITH THE DIFFERENT DISEASES REPRESENTED AROUND THIS TABLE, MANY TIMES IT'S THE USUAL SUSPECTS, BEING ROUNDED UP, EXPERTS AND THAT'S NOT DISTINCTLY NOT EFFICIENT. SO THE SAME PEOPLE THAT ANNA IS USING, PAT IS USING, IT'S THE SAME PULMONOLOGISTS THERE. >> I KNOW WHO THEY ARE. >> MUCH MORE EFFICIENTLY. >> I HAPPEN TO KNOW WHERE YOU'RE COMING FROM. WE CERTAINLY -- WE HAVE THIS EXPERIENCE, THE HIV DOCTORS WANT TO LOOK AT PULMONARY DISEASE SO THEY GET A BUNCH OF HIV DOCS TOGETHER. IT ACTUALLY DOESN'T WORK VERY WELL. SO ONE OF THE KEY THINGS THAT WE HAVE DONE IS TO TRY TO SERVE A CONVENING FUNCTION AND TO IDENTIFY WHAT SOME OF THE KEY AREAS OPPORTUNITIES ARE TO MAKE A REQUIREMENT THAT THERE BE CO-PIs DIFFERENT SETS OF EXPERTISE TO THE TABLE. I THINK FOR -- IN TERMS OF PLANNING FOR THE JULY MEETING, IT MIGHT BE REALLY GOOD OPPORTUNITY TO ENGAGE THE AMERICAN THORACIC SOCIETY IS TAKING PLACE SHORTLY AND A NUMBER OF OTHER OPPORTUNITIES TO HAVE SOME OF THOSE KINDS OF CONVERSATIONS WHICH IS (INAUDIBLE). >> THAT TO ME IS A NICE SEGUE THAT'S COME UP A COUPLE OF TIMES. I SEE PEOPLE PACKING UP, LET'S TALK ABOUT THIS BEFORE THEY DO. THE CONVENING POWER OF THIS GROUP, ACTUALLY VERY USEFUL. ARE THERE WAYS WE CAN BE EVEN MORE EFFECTIVE SHOULD WE HAVE THEME MEETINGS ON CARDIO PULMONARY STATUS OR WAYS WE CAN USE THESE MEETINGS, THERE'S A LOT TO TRY TO SQUEEZE IN THESE MEETINGS BUT ARE THERE WAYS WE COULD MAKE THEM EVEN MORE USEFUL OR -- ET CETERA. >> I THINK TO HAVE AN ADVOCACY UPDATE BUT THERE SHOULD BE ONE MEETING WITH MORE DISCUSSION TIME AND IS A THEMED MEETING WHERE WE CAN ACCOMPLISH SOMETHING ACROSS THE GROUPS. AND BACK TO YOUR POINT, SUSAN, IN THE MEETING THAT WE HAD IN DECEMBER, ONE THING THAT CAME OUT OF THAT IS WE DO NOT KNOW THE ONSET OFTEN IN SOME OF THESE CONDITIONS THEY HAVE SLEEP APNEA PRIOR TO HAVING NOCTURNAL PIPE CAP KNEEIA OR HYPOVENTILATION. SO ONE OF THE MANDATES THAT CAME FROM THAT MEETING IS IN THE CONGENITAL ONSET DISORDERS IT WOULD BE TOTALLY TIMELY TO GET A SLEEP STUDY AT TIME OF DIAGNOSIS PROBABLY MISSING OPPORTUNITIES TO INTERVENE. IF YOU DID CONGENITAL AND CHILDHOOD ONSET NEUROMUSCULAR DISEASE YOU HAVE A BROAD MANDATE THERE, THAT WOULD MAKE -- >> I THINK THAT FALLS INTO THE CHILD MUSCLE WEAKNESS THAT WAS LOOK AT SIX MONTHS, FIVE YEARS EARLY ONSET. ANOTHER HUGE GAP HERE, PERHAPS ACROSS SOME OF THE MUSCULAR DYSTROPHY IS THE GI SMOOTH MUSCLE IS IGNORED, NO ONES IS INTERESTED, YOU HAVE TO WONDER WHEN THEY GET INTO THESE ISSUES HOW THAT HAPPENED, ARE THEY -- ARE THE PARAFORM SINUS CLOGGED UP AND THEY'RE GETTING INTO THIS GUNG IF THEIR FLOAT THEY CAN'T GET RID OF. ELIMINATION IS A PROBLEM, THEY HAVE FREQUENCY AND URGENCY. TIMES THESE KIDS YOU WONDER IF EARLY SIGNS OF STOMACH ISSUE MIGHT TELL US ABOUT THE HEART AND INABLE TO -- EARLY SIGNS OF HEART DISEASE. SO THESE ARE ALL WRAPPED UP. I ALSO KNOW IN STEROID USE THERE ARE SOME OF THESE KIDS THAT JUST GIGANTICALLY TWO TYPES OF SKINNY AND BIG BUT THERE'S CHILDREN WHO DO BLOW UP WITH STEROIDS AN THINKING ABOUT INSULIN RESISTANCE, WHETHER OR NOT YOU CAN MEASURE IT. AND BECAUSE SOME OF THE KIDS RESPOND WELL TO METAPHORMAN. SO THESE ARE ISSUES WE JUST ARE LOOKING AT AND STEROID USE IS A -- SOME OF THESE KIDS TO BE IN A MESS. >> I AGREE, THERE'S A HOST OF MEDICAL COMPLICATIONS OF DISEASE ITSELF OR TREATMENTS WE CAN BE LOOKING AT ACROSS DISEASES. I THINK WE KNOW MORE ABOUT COMPLICATIONS IN DUCHENNE THAN OTHER DISORDERS BUT RIGHT QUESTIONS AND OTHER DISORDERS, BONE HEALTH AND CONGENITAL MUSCULAR DYSTROPHY AND THE CONGENITAL MYOPATHYINGS. I SAY I DON'T KNOW TOO MUCH ABOUT THOSE AND RESERVE ISSUE IN DUCHENNE. ACROSS THE DISEASES ARE THERE'S A MEDICAL COMPLICATIONS THAT WE SHOULD PROBABLY LOOK AT. >> I'M HEARING FROM THE GROUND MAYBE FOR A THEMED MEETING WHERE WE TALK ABOUT THE MUSCULAR DYSTROPHY BUT NOT ALLOWED TO TALK ABOUT DYSTROPHY. THE MULTI-SYSTEM -- >> WHAT'S COMMON IN SYSTEMS WHAT'S NO COMMON AND WHERE THEY FIT IN. THERE'S THINGS WE DONE RECOGNIZE. WE KNOW THE MIDDLE GROUP THAT FOLLOWED PREDICTABLE PATTERN. BUT THE KIDS ON BOTH CONGENITAL AND DUCHENNE AND OTHERS WE DON'T KNOW WHAT THEY DO AND WHY THEY DO IT. >> OTHER THINGS WE SHOULD MAKE SURE TO DISCUSS BEFORE EVERYONE SAFELY GOES HOME? >> ABSOLUTELY. ABSOLUTELY. >> A THEME THAT MAYBE WOULD HIGHLIGHT SOME OF THE OTHER AGENCIES OR OTHER OPPORTUNITIES WITHIN NIH OTHER THAN BASIC TRANSLATIONAL RESEARCH, IS THIS ON? SO WHEN WE -- WE TALKED ABOUT THE LIVING AND TRANSITIONS OR ADULT ONSET DISORDERS. SO MAYBE WHERE ARE THE OPPORTUNITIES WITHIN NICHD, WE HAVE HRSA HERE, TRANSITIONS WHICH ARE COMMUNITY HEALTH CENTERS AND MEDICAL HOMES SO LIFE BEYOND THE CLINICAL SETTING OR HOW THE CLINICAL SETTING TRANSLATES INTO THE HOME, WE HAVE SOCIAL SECURITY AD MINUTE STRAIGHT AND CMS WHO COULD BE AT THE TABLE AND WE COULD BE TALKING HOW WE SUPPORT AWE TON MY AND INDEPENDENCE -- AUTONOMY AND INDEPENDENCE FOR ADULTS, IMPORTANT THEMES FOR EVERYTHING THAT HAPPENS EXCEPT FOR YOUR CLINICAL SPACES. REALLY IMPORTANT THEMES FOR ADULTS AND THIS COMMITTEE WOULD BE VERY IMPORTANT HELPING DRIVE THE SYNERGIES, U THINK OUR ADVOCACY GROUPS WORK TOGETHER IN SPHERES BUT IT WOULD HELP PROMOTE COLLABORATIONS AND WHEN WE LOOK AT THE NIH I THINK THERE ARE A LOT OF OPPORTUNITY TO LOOK AT RESEARCH OPPORTUNITIES ACROSS THE INSTITUTES AND THESE REALMS AND AREAS ALSO. AND THAT MIGHT BE A FORWARD DIRECTION FOR MUSCULAR DYSTROPHY COMMUNITY AS WE AGE WHICH IS A GREAT PRODUCT OF RESEARCH FUNDED HERE. >> ONE MORE ABOUT AGING. IT IS IMPORTANT TO THINK ABOUT CAREGIVERS, THINKING BENEFIT RISK STUDY IN SERVING IN 119 PARENT BASICALLY SUGGESTED THAT THE CARE OF THEMSELVES IS LOWEST ON THEIR LIST, AS THE MEAN AGE OF DEATH IN DUCHENNE AND OTHERS INCREASES WE HAVE OLDER CAREGIVERS GIVING COMPLETE CARE TO PATIENTS THAT ARE ADULTS, WE ARE -- I'M HEARING MORE FROM THESE PATIENTS ABOUT MOM AND DAD DIVORCING AND WANTING TO RUN AWAY AND NOT HAVING A PLACE TO GO SO I THINK WE HAD TO TAKE CARE OF THE CAREGIVER. >> THIS IS CERTAINLY SOMETHING WE SEE IN CITY STICK FIBROSIS COMMUNITY, DOWN SYNDROME, COMMUNITY, ET CETERA, WHERE CONDITIONS THAT USED TO BE UNIFORMLY LETHAL, TRANSITION TO ADULT MEDICAL CARE, TRANSITION INTO DIFFERENT KIND OF INDEPENDENT LIVING SITUATIONS, ET CETERA AND TRANSITION FOR THE PARENTS AND SIBLINGS THAT DON'T GET ATTENTION THEY WARRANT. IN ALL THIS. ANYTHING ELSE? HAVING PLANNED OUT THE NEXT SEVERAL YEARS WORTH OF MEETING AS WELL AS GIVING US A LITTLE BIT MORE SKELETON FOR THE JULY MEETING. >> I'LL NEED THE LIST. >> THANKS, JOHN. YOU WON'T GET OFF BECAUSE YOU'LL BE HERE THE NEXT COUPLE OF MEETINGS. THANK YOU ALL VERY MUCH. IT HAS BEEN AN ENJOYABLE DAY AND I THINK A VERY USEFUL ONE SO DO TRAVEL SAFELY, THANKS FOR COMING TO THESE. [APPLAUSE]