2018-05-15T07:55:58-05:00 2017-12-31 231518888 MAILLIE LLP 624 WILLOWBROOK LANE WEST CHESTER PA 19382 990 2017-01-01 522122720 FRIEDREICH'S ATAXIA RESEARCH ALLIANCE FRIE 4848796160 PO BOX 1537 SPRINGFIELD VA 22151 JENNIFER FARMER EXECUTIVE DIRECTOR 4848796160 2018-05-15 1 EDWARD FRONCZKOWSKI CPA P01259092 6106964353 2017 2022-09-23 18:48:47Z JENNIFER FARMER 533 W UWCHLAN AVENUE DOWNINGTOWN PA 19335 8646430 0 X WWW.CUREFA.ORG X 1998 VA TO TREAT AND CURE FRIEDREICH'S ATAXIA BY ADVANCING RESEARCH, AWARENESS AND PARTNERSHIPS. 19 18 11 500 0 0 5388847 7518776 0 0 47576 53104 -54930 -38343 5381493 7533537 4852904 5824049 0 0 463198 605722 0 0 101785 237062 382043 5553164 6811814 -171671 721723 4110033 4852978 484966 323194 3625067 4529784 X TO MARSHAL AND FOCUS THE RESOURCES AND RELATIONSHIPS NEEDED TO CURE FA BY RAISING FUNDS FOR RESEARCH, PROMOTING PUBLIC AWARENESS AND ALIGNING SCIENTISTS, PATIENTS, CLINICIANS, GOV'T AGENCIES AND PHARMACEUTICAL COMPANIES DEDICATED TO CURING FA AND RELATED DISORDERS. 0 0 5363415 5171280 RESEARCH AND GRANT PROGRAMIN 2017, FARA CONTINUED TO ACCELERATE THE PACE OF RESEARCH WITH A COMMITMENT TO FUNDING HIGH QUALITY RESEARCH PROJECTS TO MOVE US CLOSER TO EFFECTIVE TREATMENTS. IN TOTAL, FARA PROVIDED >$5.8M IN BASIC AND TRANSLATIONAL AND CLINICAL RESEARCH GRANTS, THE FRIEDREICH'S ATAXIA CENTER OF EXCELLENCE, SCIENTIFIC CONFERENCE SUPPORT AND CLINICAL RESEARCH INFRASTRUCTURE FUNDING. OVER THE PAST YEAR, 50 NEW LETTERS OF INTENT AND 25 GRANT APPLICATIONS WERE SUBMITTED TO FARA WITH A REQUEST FOR FUNDING. AFTER RIGOROUS PEER REVIEW, 15 GRANTS WERE DETERMINED MERITORIOUS AND AWARDED FUNDING IN 2017. IN ADDITION, BASED ON EXCELLENT PROGRESS, CONTINUATION FUNDING WAS PROVIDED FOR 14 PROJECTS, FOR A TOTAL OF 29 RESEARCH GRANTS AWARDED. THESE FUNDED PROJECTS ADDRESS NUMEROUS IMPORTANT RESEARCH QUESTIONS THAT DIRECTLY TARGET FARA'S STRATEGIC RESEARCH INITIATIVES, INCLUDING EVALUATING OF MECHANISMS OF DISEASE, DRUG DISCOVERY, PRE-CLINICAL AND CLINICAL STUDIES OF LEAD CANDIDATES IN THE TREATMENT PIPELINE, ADVANCES IN GENE AND CELL THERAPY APPROACHES, ADVANCES IN DIFFERENTIATION OF INDUCED PLURIPOTENT STEM (IPS) CELL LINES FROM FA PATIENTS INTO SENSORY NEURONS AND CARDIOMYOCYTES, DEVELOPMENT OF NEW ANIMAL MODELS, CARDIAC RESEARCH AND EVALUATION OF NOVEL BIOMARKERS. SEVERAL ARE CO-FUNDED WITH OUR FRIEDREICH'S ATAXIA ADVOCACY GROUP PARTNERS; THIS COLLABORATIVE APPROACH BOTH INCREASES THE NUMBER OF AVAILABLE RESEARCH DOLLARS AND HELPS TO MINIMIZE DUPLICATION OF EFFORT. OF NOTE, FA SHARES SIMILAR SYMPTOMS AND DISEASE MECHANISMS WITH OTHER DISEASES, BOTH RARE AND COMMON. RESEARCH INTO FA IS PROVIDING INSIGHTS AND ADVANCES IN OTHER DISEASES SUCH AS MITOCHONDRIAL DISEASES, MUSCULAR DYSTROPHIES, DIABETES, AND CARDIOMYOPATHY. 2017 FUNDED RESEARCH INITIATIVES:FRIEDREICH'S ATAXIA CENTER OF EXCELLENCE, PHILADELPHIA PATHE FA CENTER OF EXCELLENCE (COE) IS A TRANSLATIONAL RESEARCH AND CLINICAL CARE CENTER DEVOTED TO FRIEDREICH ATAXIA: EXPEDITING BASIC SCIENCE AND DRUG DISCOVERY FINDINGS TO NEW TREATMENTS AND DEDICATING RESOURCES TO CLINICAL RESEARCH AND CARE TO FURTHER UNDERSTAND THE DISEASE, INFORM DRUG DEVELOPMENT AND IMPROVE OUTCOMES FOR INDIVIDUALS LIVING WITH FA. THE CENTER WAS ESTABLISHED IN MARCH 2014, WITH A GIFT OF $3.25 MILLION (OVER 3 YEARS) TO PENN MEDICINE/ CHILDREN'S HOSPITAL OF PHILADELPHIA, PRESENTED BY FARA IN PARTNERSHIP WITH THE HAMILTON AND FINNERAN FAMILIES. IN 2017, THAT COMMITMENT WAS RENEWED FOR AN ADDITIONAL THREE YEARS. PROJECTS AND INVESTIGATORS BEING FUNDED INCLUDE DR. ROB WILSON- DRUG DISCOVERY, DR. DAVID LYNCH- TRANSLATIONAL AND CLINICAL NEUROSCIENCE RESEARCH, DR, IAN BLAIR- METABOLIC BIOMARKERS, DR. KIM LIN- CARDIAC RESEARCH AND DR. SHANA MCCORMACK- ENDOCRINOLOGIST. THE COE ESTABLISHED RESEARCH INFRASTRUCTURE CONSISTING OF FOUR CORE AREAS- NEUROLOGY, CARDIAC, BIOMARKER AND DRUG DISCOVERY. THE CENTER NOT ONLY SUPPORTS WORK WITHIN THESE DISCIPLINES, BUT ALSO FOSTERS EFFICIENT COLLABORATION AND SYNERGY ACROSS THEM. IN ITS FIRST FOUR YEARS, THE COE REACHED SEVERAL SIGNIFICANT RESEARCH MILESTONES WITH THE DISCOVERY OF POSSIBLE TREATMENT CANDIDATES, THE STUDY OF NEW BIOMARKERS TO MEASURE THE DISEASE, AND LAUNCH OF PROMISING NEUROLOGIC AND CARDIAC CLINICAL TRIALS AND STUDIES. SOME BRIEF HIGHLIGHTS OF RESEARCH OCCURRING AT THE CENTER ARE PROVIDED BELOW: CREATED A CARDIAC RESEARCH AND CLINICAL CARE CORE AND RECRUITED 3 CARDIAC STUDIES (CARDIAC MRI, SERUM BIOMARKERS AND EXERCISE TOLERANCE) WITH INTERNATIONAL COLLABORATION CREATED A BIOMARKER CORE AND IDENTIFIED 3 NEW BLOOD BASED BIOMARKERS CREATED A PATIENT-DERIVED CELL REPOSITORY IN COLLABORATION WITH DR. NAPIERALA AT UNIVERSITY OF ALABAMA BIRMINGHAM, > 50 CELL LINES ARE AVAILABLE AND BEING SHARED WITH THE RESEARCH COMMUNITY, > 8 COMPANIES AND >6 ACADEMICS SOURCING CELLS FOR DRUG DISCOVERY AND RESEARCH. ESTABLISHED 2 FA MOUSE MODEL COLONIES CURRENTLY TESTING DRUG CANDIDATES WITH >3 INDUSTRY AND 2 ACADEMIC PARTNERS ESTABLISHED A DRUG DISCOVERY CORE THAT ADVANCES INTERNALLY LED DRUG DISCOVERY AS WELL AS COLLABORATIONS WITH EXTERNAL PARTNERS. 3 NOVEL THERAPEUTIC DISCOVERIES HELPED INFORM EARLY STAGE WORK AND CLINICAL DEVELOPMENT STRATEGY (TRIALS IN FA PATIENTS) FOR 3 DRUG DEVELOPMENT PARTNERS BY SHARING INSIGHTS FROM FA PATIENT STUDIES OF CARDIAC OUTCOMES, METABOLIC AND MUSCLE METABOLISM AND THE LONGITUDINAL NATURAL HISTORY STUDY COMPLETED TWO COE FUNDED CLINICAL TRIALS- A STATIN STUDY AND A STEROID STUDY. THE STATIN STUDY COMES OUT OF BIOMARKER WORK IN DR. BLAIR'S LAB. THE STEROID STUDY COMES FROM CLINICAL OBSERVATIONS THAT TREATMENT WITH STEROIDS HAS IMPROVED FUNCTION IN PATIENTS.PUBLICATIONS FROM CENTER OF EXCELLENCE RESEARCH:LIQUID CHROMATOGRAPHY-HIGH RESOLUTION MASS SPECTROMETRY ANALYSIS OF PLATELET FRATAXIN AS A PROTEIN BIOMARKER FOR THE RARE DISEASE FRIEDREICH'S ATAXIA. GUO L, WANG Q, WENG L, HAUSER LA, STRAWSER CJ, ROCHA AG, DANCIS A, MESAROS C, LYNCH DR, BLAIR IA. ANAL CHEM. 2018 FEB 6;90(3):2216-2223. DOI: 10.1021/ACS.ANALCHEM.7B04590. EPUB 2018 JAN 11. . EARLY VGLUT1-SPECIFIC PARALLEL FIBER SYNAPTIC DEFICITS AND DYSREGULATED CEREBELLAR CIRCUIT IN THE KIKO MOUSE MODEL OF FRIEDREICH ATAXIA. LIN H, MAGRANE J, CLARK EM, HALAWANI SM, WARREN N, RATTELLE A, LYNCH DR. DIS MODEL MECH. 2017 DEC 19;10(12):1529-1538. DOI: 10.1242/DMM.030049. EARLY CEREBELLAR DEFICITS IN MITOCHONDRIAL BIOGENESIS AND RESPIRATORY CHAIN COMPLEXES IN THE KIKO MOUSE MODEL OF FRIEDREICH ATAXIA. LIN H, MAGRANE J, RATTELLE A, STEPANOVA A, GALKIN A, CLARK EM, DONG YN, HALAWANI SM, LYNCH DR. DIS MODEL MECH. 2017 NOV 1;10(11):1343-1352. DOI: 10.1242/DMM.030502. BIOMARKER INITIATIVEBIOMARKERS ARE BIOLOGICAL MEASURES THAT INDICATE CHANGE IN A DISEASE, AND THEY HAVE THE POTENTIAL TO SHORTEN THE LENGTH OF CLINICAL TRIALS. FARA LAUNCHED AN INITIATIVE TO LOOK FOR NOVEL BIOMARKERS FOR FA, STARTING WITH A NOVEMBER 2014 MEETING WHERE EXPERTS CAME TOGETHER TO PRIORITIZE POSSIBLE MARKERS. THEY DETERMINED THAT WE NEED BIOMARKERS TO: MEASURE DISEASE PROGRESSION (PARTICULARLY AT EARLY STAGES OF DISEASE) MEASURE DRUG EFFECTIVENESS IN TERMS OF AFFECT ON PRIMARY MECHANISMS OF DISEASE OR A SPECIFIC TARGET MEASURE DRUG EFFECTIVENESS AT TREATING SPECIFIC GROUPS OF SYMPTOMS, SUCH AS CARDIAC AND NEUROLOGICAL SYMPTOMS IDENTIFY SUBSETS OF PATIENTS WITH IDENTIFIABLE GENOTYPIC OR PHENOTYPIC PROFILES LIKELY TO BENEFIT FROM SPECIFIC THERAPEUTIC APPROACHES IN A GIVEN PERIOD OF TIME. THERE ARE 4 MAIN AREAS OF INVESTIGATION WITH PROJECTS UNDERWAY (DESCRIBED BELOW): FRATAXIN-PROTEIN, GENE EXPRESSION AND EPIGENETICS NEUROLOGICAL-SENSORY/PERIPHERAL AND BRAIN CARDIAC METABOLICPROJECTS ONGOING AND COLLECTING DATA IN 2017 INCLUDE:TITLE: EARLY AND LONGITUDINAL ASSESSMENT OF NEURODEGENERATION IN THE BRAIN AND SPINAL CORD IN FRIEDREICH'S ATAXIA. UNIVERSITY OF MINNESOTATITLE: NEUROPHYSIOLOGIC BIOMARKERS IN FRIEDREICH'S ATAXIA. HOPITAL ERASME, BRUSSELS AND CHILDREN'S HOSPITAL OF PHILADELPHIA, PATITLE: IN-VIVO CONFOCAL IMAGING OF MEISSNER'S CORPUSCLES AS A BIOMARKER IN FRIEDREICH'S ATAXIA. UNIVERSITY OF ROCHESTER, NYTITLE: INTERSTITIAL FIBROSIS, THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM AND BIOMARKERS IN THE CARDIAC DISEASE OF FRIEDREICH ATAXIA. MURDOCH CHILDRENS RESEARCH INSTITUTE, AUSTRALIA AND CHILDREN'S HOSPITAL OF PHILADELPHIA, PATITLE: LONGITUDINAL MEASUREMENT OF GAIT AND BALANCE IN FRIEDREICH ATAXIA. MURDOCH CHILDRENS RESEARCH INSTITUTE, AUSTRALIA AND UNIVERSITY OF SOUTH FLORIDA, TAMPA, FLTITLE: CLINICAL OUTCOME MEASURES OF EFFICACY IN TREATMENT OF FRIEDREICH'S ATAXIA. UNIVERSITY OF FLORIDA, FLTITLE: PROTEIN BIOMARKERS IN FRDA CARDIOMYOPATHY TO MONITOR DISEASE PROGRESSION AND THERAPEUTIC EFFICACY. DUKE UNIVERSITY, NCNEWLY AWARDED PROJECTS IN 2017:TITLE: MEASUREMENT OF THE TCA CYCLE RATE IN THE DENTATE NUCLEUS IN FRIEDREICH'S ATAXIA. UNIVERSITY OF MINNESOTATITLE: DEFINING THE MOLECULAR SIGNATURE OF FA TO IDENTIFY NOVEL BIOMARKERS. UNIVERSITY OF ALABAMAA FEW HIGHLIGHTED NEW RESEARCH GRANTS:2017 BRONYA J KEATS INTERNATIONAL RESEARCH COLLABORATION AWARD TITLE: SPEECH TREATMENT IN FRIEDREICH ATAXIA INVESTIGATORS: ADAM VOGEL, PHD-UNIVERSITY OF MELBOURNE, AUSTRALIA AND MATTHIS SYNOFZIK, PHD-UNIVERSITY OF TUBINGEN, GERMANYDISORDERED SPEECH IS A DEVASTATING AND INEVITABLE CONSEQUENCE OF MANY HEREDITARY ATAXIAS, PARTICULARLY IN FRIEDREICH ATAXIA (FRDA). DRS. VOGEL AND SYNOFZIK'S RESEARCH IN SPEECH AND ATAXIA HAS DESCRIBED THE INSIDIOUS FUNCTIONAL DECLINE, LOSS OF ABILITY TO CARRY OUT BASIC TASKS AND DIMINISHED QUALITY OF LIFE IN FRDA. THEIR SUCCESSFUL PILOT TRIAL OF A SPEECH TREATMENT IN HEREDITARY ATAXIAS USING PRINCIPLES OF MOTOR LEARNING (PML), NEUROPLASTICITY, AND BIOFEEDBACK, AS WELL AS INTERVENTIONS BY SYNOFZIK/SCHLS DELIVERED VIA PHYSIOTHERAPY OR HIGHLY MOTIVATING EXERCISE VIDEO-GAMING HAVE NOW PAVED THE WAY FOR FIRST EVIDENCE-BASED THERAPIES IN FRDA. 280759 26512 RESEARCH CONFERENCESFARA ORGANIZES AND SUPPORTS A NUMBER OF SCIENTIFIC CONFERENCES TO IMPROVE SHARING OF KNOWLEDGE, INSIGHTS AND ADVANCES AND BUILD COLLABORATIONS AND SYNERGISTIC CONNECTIONS BETWEEN FA RESEARCHERS. GENE THERAPY MEETING WITH CBERIN FOLLOW-UP TO FARA'S 2016 GENE THERAPY MEETING, FARA, ALONG WITH THE FOUR COMPANIES AND TWO UNIVERSITIES THAT ARE EACH ADVANCING AGGRESSIVE GENE THERAPY PROGRAMS IN FA, MET WITH THE CENTER FOR BIOLOGICS EVALUATION AND RESEARCH (CBER) OF THE FDA. IN ADDITION TO FULL REPRESENTATION FROM CBER, MANY OTHER FDA OFFICES VERY IMPORTANT TO THE FA COMMUNITY SENT THEIR LEADERS AND STAFF - E.G., THE OFFICES OF RARE DISEASE PROGRAMS, ORPHAN PRODUCT DEVELOPMENT, HEALTH AND CONSTITUENT AFFAIRS, BIOMARKER VALIDATION, AND ELSEWHERE THROUGHOUT THE FDA. THE CBER STAFF INDICATED THAT THIS WAS THE LARGEST MEETING OF ITS KIND THEY HAVE HAD. THE MEETING HELPED SET THE STAGE FOR CONTINUED DIALOGUE WITH THE FDA ABOUT FA GENE THERAPY PROGRAMS AND ACCELERATION OF THOSE PROGRAMS INTO CLINICAL TRIALS THAT WOULD LATER BE REVIEWED BY FDA PERSONNEL WITH A MUCH BETTER UNDERSTANDING OF FA AND OUR PATIENTS. INTERNATIONAL ATAXIA RESEARCH CONFERENCE (IARC)THE INTERNATIONAL ATAXIA RESEARCH CONFERENCE 2017 TOOK PLACE IN PISA, ITALY ON THE 27TH- 30TH OF SEPTEMBER, 2017. IARC 2017 WAS A RESEARCH CONFERENCE FOR ACADEMICS AND INDUSTRY SCIENTISTS INTERESTED IN BASIC AND TRANSLATIONAL RESEARCH IN THE ATAXIAS. FARA WAS ABLE TO PARTNER WITH INTERNATIONAL ATAXIA RESEARCH ORGANIZATIONS TO COHOST THE LARGEST ATAXIA RESEARCH CONFERENCE TO DATE. IARC2017 WAS CO-ORGANIZED BY GOFAR, ATAXIA UK AND FARA AND SIMPLY BY THE NUMBERS INCLUDED: OVER 400 ATTENDEES- RESEARCHERS, CLINICIANS, PATIENTS, AND GOVERNMENT, REGULATORY, AND INDUSTRY REPRESENTATIVES. REPRESENTATIVES FROM 22 COUNTRIES >15 PHARMA/ BIOTECH COMPANIES >30 PLATFORM PRESENTATIONS ON FA OVER 95 POSTER PRESENTATIONS ON FATHE FOCUS OF THE MEETING WAS A COMPREHENSIVE SCIENTIFIC REVIEW OF NEW RESEARCH FROM DISEASE DEFINITION TO THERAPEUTIC TREATMENTS. THE CONFERENCE INCLUDED FRIEDREICH'S ATAXIA AND OTHER RECESSIVE ATAXIAS (EG: ATAXIA WITH OCULOMOTOR APRAXIA), DOMINANT ATAXIAS (EG: SPINOCEREBELLAR ATAXIAS, DRPLA, EPISODIC ATAXIAS) AND AUTOIMMUNE ATAXIAS.I. MOLECULAR BASIS OF DISEASE: DIAGNOSIS AND IDENTIFICATION OF DISEASE PATHWAYS ASSOCIATED WITH DISEASE II. TRANSLATIONAL MODELS OF DISEASE: CELL AND ANIMAL MODELS OF ATAXIAS DRUG DISCOVERY O TOOLS FOR DISCOVERY O RECENT COMPOUNDS III. NATURAL HISTORY, BIOMARKERS, AND ENDPOINTS DEFINING DISEASE MEASURES FOR USE IN ADVANCING TREATMENT DEVELOPMENT IV. THERAPEUTICS, INTERVENTIONS AND CLINICAL DEVELOPMENT THERAPEUTIC APPROACHES TO ATAXIAS, INCLUDING GENE THERAPY REGULATORY CONSIDERATIONS IN TREATMENT TRIALSPATIENT FOCUSED DRUG DEVELOPMENT MEETING AND VOICE OF THE PATIENT REPORTIN 2017, FARA RELEASED THE FRIEDREICH'S ATAXIA "VOICE OF THE PATIENT" REPORT (LINK BELOW); A UNIQUE SUMMARY OF DIRECT TESTIMONY AND SURVEY RESPONSES FROM INDIVIDUALS LIVING WITH FRIEDREICH'S ATAXIA (FA). THIS REPORT IS BASED ON THE PROCEEDINGS SURROUNDING THE EXTERNALLY LED PATIENT FOCUSED DRUG DEVELOPMENT MEETING HELD ON JUNE 2, 2017 IN HYATTSVILLE, MD. THE GOAL OF THE MEETING WAS TO GIVE FA PATIENTS, AND THEIR FAMILIES, FRIENDS AND CAREGIVERS A FORUM TO DISCUSS THEIR PERSPECTIVES ON LIVING WITH THE DISEASE: WHAT SYMPTOMS PATIENTS EXPERIENCE, HOW IT AFFECTS THEIR LIVES, WHAT CONCERNS THEM ABOUT THE DISEASE, THEIR OPINIONS ON CURRENT AND FUTURE TREATMENT OPTIONS, AND EXPERIENCES WITH RESEARCH STUDIES AND CLINICAL TRIALS.THIS MEETING, AND THE REPORT, REPRESENT IMPORTANT ACCOMPLISHMENTS AND MILESTONES FOR OUR COMMUNITY. THIS WAS THE LARGEST FA MEETING EVER HELD WITH MORE THAN 400 PEOPLE PARTICIPATING IN PERSON OR ONLINE; INCLUDING >20 FDA REPRESENTATIVES, 25 DRUG COMPANY REPRESENTATIVES AND >350 FA PATIENT AND FAMILY PARTICIPANTS. IT WAS THE FIRST TIME FA PATIENTS AND OTHER MEMBERS OF THE FA COMMUNITY HAD AN OPPORTUNITY TO COMMUNICATE DIRECTLY WITH REPRESENTATIVES OF THE FOOD AND DRUG ADMINISTRATION. IMPORTANT THEMES AND INSIGHTS EMERGED THAT CAN INFORM DRUG DEVELOPMENT AND REGULATORY DECISION MAKING, SUCH AS THE CONCLUSION THAT "WHILE THE MAJORITY OF PATIENTS NOTED THAT BALANCE, DEXTERITY AND FATIGUE AFFECTED THEIR LIVES THE MOST NOW, MOST PATIENTS' GREATEST CONCERN FOR THEIR FUTURE IS THE DEVELOPMENT/ PROGRESSION OF CARDIOMYOPATHY IN THE FUTURE, BECAUSE IT IS LIFE SHORTENING".THIS DOCUMENT FAITHFULLY SUMMARIZES THE TESTIMONY, COMMENTS AND SURVEY RESPONSES SHARED BY INDIVIDUALS LIVING WITH FA AND THEIR FAMILY MEMBERS AND CAREGIVERS.THE REPORT CAN BE READ AT HTTP://CUREFA.ORG/PDF/NEWS/FA-VOICE-OF-THE-PATIENT.PDFA RECORDING OF THE MEETING IN ITS ENTIRETY CAN BE FOUND AT HTTPS://WWW.YOUTUBE.COM/WATCH?V=VA1D4SQRSFW 244313 EDUCATION, AWARENESS & OUTREACH PROGRAMSFRIEDREICH'S ATAXIA (FA) IS A RARE DISEASE; AFFECTING 1 IN 50,000 INDIVIDUALS. FARA IS DEDICATED TO RAISING AWARENESS FOR FA. FARA HAS UTILIZED BOTH TRADITIONAL AND SOCIAL MEDIA STRATEGIES TO BRING GREATER AWARENESS TO FA IN THE GENERAL PUBLIC AND TO ENGAGE AND EDUCATE THE FA COMMUNITY. FOR EXAMPLE, FARA CONDUCTED A SOCIAL MEDIA CAMPAIGN THAT ENCOURAGED COMMUNITY PARTICIPATION LEADING UP TO RARE DISEASE DAY AND FA AWARENESS DAY. FARA ALSO HOSTED WEBINARS TO INFORM THE COMMUNITY ABOUT THE LATEST DEVELOPMENTS IN FA RESEARCH AND SOME OF THE RESULTS OF FUNDED GRANTS.FARA CO-ORGANIZED TWO PATIENT SYMPOSIUMS WITH CLINICAL RESEARCH NETWORK SITES, UNIVERSITY OF IOWA (MARCH 3RD) AND CHILDREN'S HOSPITAL OF PHILADELPHIA (OCTOBER 16TH, 2016, KING OF PRUSSIA, PA), . THESE SYMPOSIUMS PROVIDE AN OPPORTUNITY TO EDUCATE THE PATIENT/FAMILY COMMUNITY ON RESEARCH ADVANCES, PROGRESS ON CLINICAL TRIALS AND ARE A UNIQUE FORUM FOR PATIENTS AND RESEARCHERS TO ENGAGE AND LEARN FROM EACH OTHER'S EXPERIENCES AND PERSPECTIVES. COMBINED THESE SYMPOSIA ACCOMMODATED MORE THAN 250 ATTENDEES.THE FARA AMBASSADOR PROGRAM WHICH WAS LAUNCHED IN 2011 WITH >20 PARTICIPANTS HAD A YEAR OF CONTINUED GROWTH AND ACTIVITY IN 2017. THE PROGRAM NOW INCLUDES 55 PARTICIPANTS. THE MISSION OF THE FARA AMBASSADORS IS TO BE POSITIVE, SUPPORTIVE, PEER REPRESENTATIVES FOR THE FA COMMUNITY; ACTIVELY RAISING AWARENESS AND FUNDS FOR FARA.IN 2017, FARA FACILITATED FORMAL TRAINING FOR THE AMBASSADOR LEADERSHIP TEAM AND AMBASSADORS. THE FOCUS FOR THE TRAINING WAS ON GENE THERAPY FOR FA- POSSIBLE APPROACHES, ROUTES OF ADMINISTRATION, AND ASSESSING RISK/ BENEFIT. THE AMBASSADOR BLOG FEATURED POSTS SUCH AS COMMUNITY EVENT SUMMARIES, MEET THE COMMUNITY INTERVIEWS WITH PEOPLE LIVING WITH FA, AND PATIENT PERSPECTIVES ON PARTICIPATING IN RESEARCH. IN 2017, THEY ACHIEVED >50 POSTS WITH OVER 14,500 VIEWS. THE AMBASSADORS ALSO CONTINUED A CARD PROGRAM IN WHICH THEY DESIGNED CARDS TO SEND TO THE VARIOUS STAKEHOLDERS AND COMMUNITY MEMBERS THROUGHOUT THE YEAR TO SAY THANK YOU OR TO OFFER ENCOURAGEMENT. THEY ARE AVERAGING ABOUT 20 CARDS PER MONTH. ANOTHER PROJECT FACILITATED BY THE AMBASSADOR GROUP ARE MONTHLY PEER GOOGLE HANGOUT GROUPS FOR THE GREATER FA COMMUNITY TO ATTEND AND CONNECT WITH ONE ANOTHER ONLINE. IN 2017, THE AMBASSADORS EXPANDED THIS EFFORT TO INCLUDE A HANG-OUT GROUP SPECIFICALLY FOR TEENS. FINALLY, THE AMBASSADORS HAVE CONTINUED IMPORTANT OUTREACH IN VISITING ACADEMIC LABORATORIES AND BIOPHARMACEUTICAL COMPANIES TO PROVIDE THE PATIENT PERSPECTIVE OF FA, AND SHARING THEIR PERSONAL EXPERIENCES AT FA SYMPOSIA. 715107 626257 CLINICAL RESEARCH INFRASTRUCTUREIN ADDITION TO RESEARCH GRANTS FARA FUNDS THE ONGOING DEVELOPMENT OF VITAL CLINICAL RESEARCH INFRASTRUCTURE. CLINICAL RESEARCH INFRASTRUCTURE REFERS TO THE RESOURCES NEEDED TO FACILITATE ANY TYPE OF RESEARCH, INCLUDING CLINICAL TRIALS THAT INVOLVE PATIENTS. THESE RESOURCES CAN INCLUDE THINGS LIKE: PATIENT REGISTRY : THE ONLY INTERNATIONAL FRIEDREICH ATAXIA PATIENT REGISTRY WITH MORE THAN 3000 INDIVIDUALS ENROLLED. THIS REGISTRY CAPTURES DEMOGRAPHIC AND CLINICAL INFORMATION ON INDIVIDUALS WITH FA AND IS USED TO RECRUIT INDIVIDUALS FOR CLINICAL TRIALS WORLDWIDE. IN 2017, THE PATIENT REGISTRY WAS USED TO RECRUIT FOR 5 CLINICAL TRIALS AND SEVERAL OTHER CLINICAL RESEARCH STUDIES. FA PATIENT REGISTRY : WWW.CUREFA.NET/REGISTRYCOLLABORATIVE CLINICAL RESEARCH NETWORK IN FA (CCRN IN FA): AN INTERNATIONAL NETWORK OF 10 CLINICAL RESEARCH CENTERS THAT WORK TOGETHER TO ADVANCE TREATMENTS AND CLINICAL CARE FOR INDIVIDUALS WITH FRIEDREICH'S ATAXIA. HAVING SUCH A NETWORK MEANS THAT THERE ARE TRAINED PHYSICIANS AND RESEARCH COORDINATORS READY TO DO CLINICAL RESEARCH STUDIES AND TRIALS. ALSO, THIS NETWORK IS BACKED BY A DATA COORDINATION CENTER THAT FACILITATES ALL ASPECTS OF DATA COLLECTION, DATABASE MANAGEMENT, AND STATISTICAL ANALYSIS OF STUDY DATA. TO LEARN MORE, VISIT WWW.CUREFA.ORG/NETWORK.HTMLNATURAL HISTORY STUDY: LONGITUDINAL DATA (USUALLY ABOUT 10 YEARS) ON INDIVIDUALS WITH A DISEASE THAT DESCRIBES AND QUANTIFIES THE PROGRESSION OF THE DISEASE ALONG WITH THE SYMPTOMS AND MANIFESTATIONS OF THE DISEASE. NATURAL HISTORY CAN SOMETIMES SERVE AS THE BASIS FROM WHICH MEASUREMENTS CAN BE MADE TO DETERMINE EFFECTS OF NEW TREATMENTS, DRUGS OR INTERVENTIONS.CLINICAL OUTCOME MEASURES : FUNCTIONAL PERFORMANCE TESTS (E.G., TIMED PEGBOARD OR WALK TESTS, VISION, HEARING OR SPEECH TESTS) THAT QUANTIFY HOW MUCH CHANGE TAKES PLACE IN A SPECIFIC AMOUNT OF TIME AND ARE USED IN CLINICAL TRIALS TO MEASURE WHETHER A DRUG IS ALTERING THE COURSE OF THE DISEASE.BIOMARKERS: ANYTHING THAT CAN BE USED AS AN INDICATOR OF A PARTICULAR DISEASE STATE - USUALLY PROTEINS, ENZYMES, GENETIC VARIANTS, IMAGING (MRI, CT OR PET SCANS). BIOMARKERS CAN BE USED TO ASSESS RISK OF DISEASE, DIAGNOSIS, OR OUTCOMES. USE OF BIOMARKERS IN DRUG DEVELOPMENT IS OF GREAT INTEREST BECAUSE BIOMARKERS CAN PROVIDE EVIDENCE OF BIOLOGICAL ACTIVITY, POTENTIALLY DEMONSTRATING THERAPEUTIC BENEFIT MORE QUICKLY THAN TRADITIONAL OUTCOME MEASURES. BIOREPOSITORY: A REPOSITORY OR BANK OF STORED BIOLOGICAL MATERIALS SUCH AS BLOOD SAMPLES, DNA, ORGANS, AND TISSUES (SUCH AS SKIN, MUSCLE, HEART) THAT CAN BE USED FOR RESEARCH.THROUGH THE CCRN IN FA WE HAVE COLLECTED ELEVEN YEARS OF NATURAL HISTORY DATA (ONGOING) IN MORE THAN 950 INDIVIDUALS WITH FA, VALIDATED CLINICAL OUTCOME MEASURES AND THE FARS SCALE, STUDIED SPEECH, VISION AND HEARING, LAUNCHED BIOMARKER STUDIES, ESTABLISHED DNA AND RNA REPOSITORIES, AND PROVIDED MANY BLOOD SAMPLES TO RESEARCHERS AROUND THE WORLD. THE CCRN IN FA INVESTIGATORS HAVE BEEN INVOLVED IN MULTIPLE CLINICAL TRIALS INCLUDING A FEW THAT WERE DESIGNED AND CONDUCTED SOLELY THROUGH NETWORK SITES. FARA CONTRIBUTED MORE THAN $XXX,000 IN 2017 TO CLINICAL RESEARCH INFRASTRUCTURE IN DIRECT FUNDING TO THE CCRN IN FA CENTERS AND RELATED CLINICAL RESEARCH ACTIVITIES.SELECTED CCRN IN FA PUBLICATION:IMPACT OF DIABETES IN THE FRIEDREICH ATAXIA CLINICAL OUTCOME MEASURES STUDY. MCCORMICK A, FARMER J, PERLMAN S, DELATYCKI M, WILMOT G, MATTHEWS K, YOON G, HOYLE C, SUBRAMONY SH, ZESIEWICZ T, LYNCH DR, MCCORMACK SE. ANN CLIN TRANSL NEUROL. 2017 JUL 26;4(9):622-631. DOI: 10.1002/ACN3.439. ECOLLECTION 2017 SEP. OBJECTIVE: FRIEDREICH ATAXIA (FA) IS A PROGRESSIVE NEUROMUSCULAR DISORDER CAUSED BY GAA TRIPLET REPEAT EXPANSIONS OR POINT MUTATIONS IN THE FXN GENE. FA IS ASSOCIATED WITH INCREASED RISK OF DIABETES MELLITUS (DM). THIS STUDY ASSESSED THE AGE-SPECIFIC PREVALENCE OF FA-ASSOCIATED DM AND ITS IMPACT ON NEUROLOGIC OUTCOMES.RESEARCH DESIGN AND METHODS: PARTICIPANTS WERE 811 INDIVIDUALS WITH FA FROM 12 INTERNATIONAL SITES IN A PROSPECTIVE NATURAL HISTORY STUDY (FA CLINICAL OUTCOME MEASURES STUDY, FACOMS). PHYSICAL FUNCTION WAS ASSESSED, USING VALIDATED INSTRUMENTS. MULTIVARIABLE REGRESSION ANALYSES EXAMINED THE INDEPENDENT ASSOCIATION OF DM WITH OUTCOMES.RESULTS: MEAN AGE OF PARTICIPANTS WAS 30.1 YEARS (SD 15.3, RANGE: 7-82), 50% WERE FEMALE, AND 94% WERE NON-HISPANIC WHITE. 9% (42/459) OF ADULTS AND 3% (10/352) OF CHILDREN HAD DM. INDIVIDUALS WITH FA-ASSOCIATED DM WERE OLDER (P < 0.001), HAD LONGER GAA REPEAT LENGTH ON THE LEAST AFFECTED FXN ALLELE (P = 0.037), AND MORE SEVERE FA (P = 0.0001). OF INDIVIDUALS WITH DM, 65% (34/52) WERE TAKING INSULIN. EVEN AFTER ACCOUNTING STATISTICALLY FOR BOTH AGE AND GAA REPEAT LENGTH, DM WAS INDEPENDENTLY ASSOCIATED WITH GREATER FA SYMPTOM BURDEN (P = 0.010), REDUCED CAPACITY TO PERFORM ACTIVITIES OF DAILY LIVING (P = 0.021), AND A DECREASE OF 0.33 SDS ON A COMPOSITE PERFORMANCE MEASURE (95% CI: -0.56-0.11, P = 0.004); THE RELATIVE IMPACT OF DM WAS MOST APPARENT IN YOUNGER INDIVIDUALS.CONCLUSIONS: DM-ASSOCIATED FA HAS AN INDEPENDENT ADVERSE IMPACT ON WELL-BEING IN AFFECTED INDIVIDUALS, PARTICULARLY AT YOUNGER AGES. IN FUTURE, EVIDENCE-BASED APPROACHES FOR IDENTIFICATION AND MANAGEMENT OF FA-RELATED DM MAY IMPROVE BOTH HEALTH AND FUNCTION.CRITICAL PATH INSTITUTE DATA COLLABORATION PROJECTIN 2017, FARA INITIATED A PROJECT WITH CRITICAL PATH INSTITUTE'S (C-PATH) DATA COLLABORATION CENTER (DCC) TO DEVELOP AN AGGREGATED DATABASE OF CLINICAL DATA FOR FA. USE OF THIS DATABASE WILL PROMOTE COLLABORATIVE RESEARCH TO SUPPORT THE UNDERSTANDING OF NATURAL HISTORY, POTENTIAL BIOMARKERS, AND POTENTIAL CLINICAL ENDPOINTS FOR PATIENTS WITH FA, WHICH WILL HELP RESEARCHERS DEVELOP MORE EFFICIENT CLINICAL TRIAL PROTOCOLS TO TEST NEW THERAPIES MORE QUICKLY AND EFFECTIVELY. THE PROJECT WILL ESTABLISH AN INTEGRATED DATABASE OF CLINICAL DATA FOR FA THAT CAN BE SHARED AND UTILIZED BY EXISTING FA RESEARCHERS. IT WILL ENLIST COMPANIES THAT HAVE CARRIED OUT CLINICAL TRIALS IN FA TO OBTAIN CONTRIBUTIONS OF CLINICAL DATA, AS WELL AS SHARING NATURAL HISTORY DATA COLLECTED BY FARA'S COLLABORATIVE CLINICAL RESEARCH NETWORK.THREE DATASETS HAVE BEEN PROMISED FOR THE PROJECT, WITH THE FIRST PLACEBO-ARM DATASET EXPECTED TO BE SHARED IN THE NEXT FEW WEEKS. SHARING ADDITIONAL DATASETS IS UNDER DISCUSSION. 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ONCE GRANTS ARE AWARDED THE ORGANIZATION REQUIRES REGULAR RESEARCH AND FINANCIAL REPORTS FROM THE INSTITUTIONS. 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ONCE GRANTS ARE AWARDED THE ORGANIZATION REQUIRES REGULAR RESEARCH AND FINANCIAL REPORTS FROM THE INSTITUTIONS. THOMAS HAMILTON BOARD MEMBER 1149883 CONTRIBUTIONS FROM BOARD MEMBER'S ORGANIZATION (CUREFA) TO FRIEDREICH'S ATAXIA RESEARCH ALLIANCE TO SUPPORT RESEARCH AND GRANT PROGRAMS. 0 X 12 360452 MARKET PRICE 0 0 0 FORM 990, PART III, LINE 4A THE CLINICAL SPACE FOR FRDA NOW URGENTLY WARRANTS AN EVIDENCE BASED SPEECH REHABILITATION PROGRAM THAT CATERS TO THE PHYSICAL, SENSORY AND MOTOR LIMITATIONS OF PEOPLE WITH FRDA. TO THAT END, THEY HAVE DESIGNED A HOME-BASED, INTENSIVE FOUR-WEEK SPEECH EXERCISE PROGRAM DESIGNED TO IMPROVE SPEECH IN PEOPLE WITH FRDA. SPECIFICALLY, THEIR AIM IS TO EVALUATE THE HYPOTHESIS THAT INTENSIVE SPEECH REHABILITATION USING BIOFEEDBACK WILL LEAD TO IMPROVED SPEECH INTELLIGIBILITY (I.E., ABILITY TO BE UNDERSTOOD) IN FRDA COMPARED TO EXISTING CARE. IF THIS HYPOTHESIS IS SUPPORTED, THEIR RESEARCH WILL CHANGE THE LANDSCAPE OF CLINICAL CARE FOR FRDA GLOBALLY BY INFLUENCING HEALTH POLICY AND IMPROVING PATIENT OUTCOMES IN THIS DISEASE GROUP AND LIKELY ALSO OTHER DEGENERATIVE ATAXIAS. 2017 KYLE BRYANT TRANSLATIONAL RESEARCH AWARD TITLE CRISPR / CAS9 MEDIATED DELETION OF THE HUMAN FXN INTRONIC TRINUCLEOTIDE REPEAT AS A THERAPEUTIC APPROACH FOR FRIEDREICH'S ATAXIA INVESTIGATORS: TONY HO, MD- CRISPR THERAPEUTICS AND MAREK NAPIERALA, PHD- UNIVERSITY OF ALABAMA AT BIRMINGHAM IN THIS GRANT, THE INVESTIGATORS PROPOSE TO USE THE CRISPR / CAS9 SYSTEM TO REMOVE THE EXPANDED REPEAT SEQUENCE FROM THE FXN GENE IN FA PATIENT-DERIVED STEM CELLS AND IN A FA MOUSE MODEL. THEY WILL SCREEN FOR AND IDENTIFY CRISPR REAGENTS THAT EFFICIENTLY REMOVE THE EXPANDED REPEAT SEQUENCES AND WILL OPTIMIZE THE DELIVERY OF THESE REAGENTS TO PATIENT-DERIVED CELLS AND TO THE FA-MODEL MOUSE. THEY WILL EXAMINE THE RESTORATION OF FRATAXIN PROTEIN FUNCTION AFTER REPEAT EXPANSION REMOVAL. THIS PROOF OF CONCEPT STUDY WILL ENABLE THE GENERATION OF CRISPR-BASED THERAPEUTIC REAGENTS AND STRATEGIES TO DELIVER THESE REAGENTS TO PATIENT CELLS THEREBY POTENTIALLY SUPPORTING THE DEVELOPMENT OF AN EFFECTIVE THERAPY FOR FA. 2017 GENERAL GRANT HIGHLIGHTS TITLE: SUPPRESSING THE IRON/SPHINGOLIPID/PDK/MEF2 PATHWAY IMPLICATED IN FA FOR THERAPEUTIC EVALUATION INVESTIGATOR: HUGO BELLEN, PHD- BAYLOR COLLEGE OF MEDICINE, TX MOST FRDA PATIENTS CARRY TRINUCLEOTIDE REPEAT EXPANSIONS IN BOTH ALLELES OF FRATAXIN (FXN). FXN IS EVOLUTIONARILY CONSERVED, WITH A SIMILAR GENE VERSION IN OTHER ANIMAL SPECIES, INCLUDING YEAST, PLANTS, AND FRUIT FLIES (3). DR. BELLEN'S LAB STUDIES THE FRUIT FLY FRATAXIN GENE (FH) IN PHOTORECEPTORS (PRS) OF THE FRUIT FLY EYE. THEY IDENTIFIED A LOSS OF FUNCTION MUTATION IN THE FH GENE THAT RESULTS IN LATE-PUPAL LETHALITY IN A FORWARD GENETIC SCREEN DESIGNED TO ISOLATE MUTATIONS THAT CAUSE NEURODEGENERATION. THEY DISCOVERED THAT LOSS OF FH CAUSES A RAPID FUNCTIONAL AND MORPHOLOGICAL LOSS OF PR IN MUTANT EYE CLONES. ADDITIONALLY, THEY OBSERVED AN ELEVATION OF IRON (I.E., FE2+ AND FE3+) IN NUMEROUS TISSUES IN FH MUTANTS. THIS ACCUMULATION OF FE ACTIVATES SPHINGOLIPID SYNTHESIS-LIPID MOLECULES THAT SERVE TO PROMOTE CERTAIN CELLULAR SIGNALS WITHIN A CELL. ACTIVATION OF SPHINGOLIPID SYNTHESIS IN TURN TRIGGERED THE PDK1/ MEF2 SIGNALING PATHWAY, A PATHWAY THAT IS REQUIRED IN MUSCLES DURING DEVELOPMENT (4). OVER ACTIVATION OF THE SPHINGOLIPID ACTIVATED PDK1/MEF2 PATHWAY CAUSES THE DEMISE OF NEURONS AND LEADS TO THE ENHANCED TRANSCRIPTION OF MUSCLE GENES IN MANY TISSUES. WHEN THEY REDUCE IRON TOXICITY, SUPPRESS SPHINGOLIPID BIOSYNTHESIS, OR DECREASE PDK1 OR MEF2 LEVELS, THEY CAN DELAY NEURODEGENERATION IN FH MUTANT CELLS. SIMILARLY, MICE ENGINEERED TO HAVE REDUCED EXPRESSION OF FXN IN THE BRAIN, HAVE A REDUCED LIFESPAN (4 MONTHS INSTEAD OF 2 YEARS), DISPLAY A SEVERE NEURODEGENERATIVE PHENOTYPE, EXHIBIT IRON ACCUMULATION AND SHOW AN ACTIVATION OF PDK1/MEF2 PATHWAY. INTERESTINGLY, HEARTS OF FRDA PATIENTS EXHIBIT AN IRON ACCUMULATION AND INCREASED PDK1/MEF2 SIGNALING. IN THE HEART, ACTIVATION OF THE MEF2 PATHWAY MAY UNDERLIE THE OBSERVED CARDIAC HYPERTROPHY, UNLIKE WHAT IS OBSERVED IN NEURONS. INDEED, OVEREXPRESSION OF MEF2 ISOFORMS IN THE HEART HAS BEEN SHOWN TO CAUSE A CARDIAC HYPERTROPHY. THESE DATA SUGGEST THAT THE IRON/SPHINGOLIPID/PDK1/MEF2 PATHWAY MAY PLAY AN IMPORTANT ROLE IN THE PATHOGENESIS OF FRDA AND PROVIDE AN AVENUE TO ATTENUATE OR DELAY SYMPTOMS IN PATIENTS AS THE PATHWAY IS EVOLUTIONARILY CONSERVED IN MAMMALS (5). CO-SPONSOR: CURE FA FOUNDATION TITLE: EVALUATING NOVEL CAPSID ENGINEERED FOR EFFICIENT CNS TRANSDUCTION, AS FRATAXIN GENE DELIVERY VEHICLES INVESTIGATOR: BENJAMIN DEVERMAN, PHD- CALIFORNIA INSTITUTE OF TECHNOLOGY, CA) AAV-BASED FXN GENE THERAPY IS A PROMISING APPROACH FOR THE TREATMENT OF FRIEDREICH'S ATAXIA (FA), ESPECIALLY FOR THE PREVENTION AND/OR REVERSAL OF HEART ABNORMALITIES ASSOCIATED WITH THE DISEASE. HOWEVER, TREATING THE PERIPHERAL AND CENTRAL NERVOUS SYSTEM ASPECTS OF FA WITH A GENE THERAPY HAS NOT BEEN POSSIBLE DUE TO THE UNSOLVED CHALLENGE OF ACHIEVING WIDESPREAD AND EFFICIENT GENE DELIVERY THROUGHOUT THE YOUNG ADULT CENTRAL AND PERIPHERAL NERVOUS SYSTEMS. USING NOVEL ADENO-ASSOCIATED VIRUSES (AAV) DR. DEVERMAN'S LAB RECENTLY EVOLVED FOR ENHANCED NONINVASIVE GENE TRANSFER TO BOTH THE CENTRAL AND PERIPHERAL NERVOUS SYSTEMS (1-2), THEY HAVE CREATED FRATAXIN (FXN) EXPRESSING VECTORS THAT CAN EFFICIENTLY RESTORE FXN EXPRESSION ACROSS MANY OF THE CELL TYPES THOUGHT TO BE MOST SENSITIVE TO REDUCED FXN LEVELS IN FA: CNS NEURONS AND GLIA, PERIPHERAL SENSORY NEURONS, AND CARDIAC MUSCLE. THEY ARE NOW TESTING WHETHER FXN EXPRESSION BY THESE VECTORS CAN AMELIORATE THE NEUROLOGICAL SYMPTOMS AND PATHOLOGIES IN THE FXN KIKO MODEL OF FA. THERE OBJECTIVES ARE IN LINE WITH FARA'S PROGRAM PRIORITIES FOR ADVANCING DRUG DISCOVERY WITH THE AIM OF DEVELOPING APPROACHES FOR INCREASING FXN PROTEIN LEVELS. CO-SPONSOR: FARA AUSTRALIA TITLE: SYSTEMATIC IDENTIFICATION OF PHARMACOLOGICAL ACTIVATORS OF THE REPRESSED FXN GENE TO TREAT FRIEDREICH ATAXIA INVESTIGATOR: MICHAEL GREEN, MD, PHD - UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL, USA FRIEDREICH'S ATAXIA IS CAUSED BY A GAAOTTC TRIPLET REPEAT EXPANSION IN THE FIRST INTRON OF THE FXN GENE (HEREAFTER CALLED THE TRIPLET REPEAT EXPANSION (TRE)-FXN GENE), WHICH REPRESSES FXN TRANSCRIPTIONREACTIVATION OF THE REPRESSED TRE-FXN GENE IS A POTENTIAL THERAPEUTIC APPROACH FOR FA THAT WOULD CORRECT THE ROOT CAUSE OF THE DISEASE RATHER THAN A SECONDARY, DOWNSTREAM CONSEQUENCE OF THE FRATAXIN DEFICIENCY. DR. GREEN HYPOTHESIZES THAT THERE ARE A NUMBER OF EPIGENETIC REPRESSORS WHOSE PHARMACOLOGICAL INHIBITION WILL LEAD TO UPREGULATED TRANSCRIPTION OF THE TRE-FXN GENE, RESULTING IN INCREASED FRATAXIN LEVELS AND DECREASED DISEASE SYMPTOMATOLOGY. AS PROOF-OF-CONCEPT, HE PERFORMED A SMALL-SCALE CANDIDATE-BASED RNA INTERFERENCE (RNAI) SCREEN, WHICH IDENTIFIED 10 EPIGENETIC REGULATORS OF THE TRE-FXN GENE; FOR CONVENIENCE HE REFESR TO THESE EPIGENETIC REGULATORS AS FXN REPRESSING FACTORS (FXN-RFS). HE THEN SHOWED THAT SMALL MOLECULE INHIBITORS OF THESE FXN-RFS CAN ALSO UPREGULATE TRANSCRIPTION OF THE TRE-FXN GENE. HIS PRELIMINARY RESULTS STRONGLY SUPPORT THE FEASIBILITY OF OUR APPROACH FOR IDENTIFYING SMALL MOLECULE FXN-RF INHIBITORS THAT UPREGULATE TRE-FXN TRANSCRIPTION. EXPERIMENTS IN THIS APPLICATION ARE FOCUSED ON THE DISCOVERY OF NEW SMALL MOLECULE FXN-RF INHIBITORS, AND DETERMINATION OF WHETHER TRANSCRIPTIONAL UPREGULATION OF TRE-FXN CAN CORRECT WELL-CHARACTERIZED MITOCHONDRIAL ABNORMALITIES IN FA NEURONS AND CARDIOMYOCYTES, WHICH ARE THE CELL TYPES MOST RELEVANT TO FA. THE RESULTS OF THE PROPOSED CELL-BASED EXPERIMENTS WILL IDENTIFY THE MOST EFFICACIOUS, LEAST CYTOTOXIC COMPOUNDS THAT IN FUTURE STUDIES CAN BE ANALYZED IN FA MOUSE MODELS. IN THE LONG-TERM, THE RESULTS OF OUR STUDY ARE LIKELY TO HAVE A MAJOR IMPACT ON THE FIELD OF FA THERAPEUTICS AND HAVE THE POTENTIAL TO LEAD TO DEVELOPMENT OF A NEW CLASS OF DRUGS THAT CAN AMELIORATE THIS DEVASTATING DISEASE. CO-SPONSOR: FARA IRELAND TITLE: ELUCIDATING THE MECHANISM BY WHICH SYNTHETIC MOLECULES STIMULATE FRATAXIN IN FRIEDREICH'S ATAXIA INVESTIGATOR: ASEEM ANSARI, PHD - UNIVERSITY OF WISCONSIN-MADISON, USA DR. ANSARI'S LAB HAS CREATED NOVEL BIFUNCTIONAL MOLECULES THAT SELECTIVELY BIND GAA REPEAT EXPANSIONS AND ACTIVELY ENABLE THE CELLULAR MACHINERY TO TRANSCRIBE ACROSS THE REPRESSIVE GAA REPEATS WITHIN FXN. WHEN SCRUTINIZED WITH GENOMIC APPROACHES, OUR SYNTHETIC TRANSCRIPTION ELONGATION FACTORS (SYN-TEFS) DISPLAY THE ABILITY TO SPECIFICALLY OVERCOME THE REPRESSIVE ROADBLOCKS TO TRANSCRIPTION AT FXN WITHOUT PERTURBING THE FUNCTION OF OTHER CELLULAR GENES. BASED ON THIS SPECIFICITY OF ACTION, WE PROPOSE TO UTILIZE SYN-TEFS TO EXAMINE UNDERLYING MOLECULAR MECHANISMS THAT CONTRIBUTE TO FXN SILENCING IN PATIENT CELLS. DEEPER MECHANISTIC UNDERSTANDING WILL GUIDE THE DESIGN OF NEXT GENERATION SYN-TEFS THAT ARE PRECISION-TAILORED FOR INDIVIDUALS WITH THE DISEASE. WE FURTHER PROPOSE TO TEST THE EFFICACY OF SYN-TEFS IN PATIENT-DERIVED NEURONS AND HEART CELLS - CELL TYPES IN WHICH FRATAXIN DEFICIENCY RESULTS IN ATAXIA AND MORBIDITY. FORM 990, PART III, LINE 4A TAKEN TOGETHER, THE PROPOSED EXPERIMENTS WILL AID IN THE DEVELOPMENT OF THIS CLASS OF MOLECULES AS POTENTIAL INDIVIDUAL-TAILORED PRECISION THERAPEUTICS. TITLES AND SUMMARIES OF MOST OF THE PROJECTS PRESENTLY FUNDED BY FARA AS WELL AS COMPLETE LISTINGS OF GRANTS AWARDED BY YEAR ARE AVAILABLE AT: HTTP://WWW.CUREFA.ORG/GRANT RESULTS REPORTED FROM FARA AWARDED GRANTS - IN 2017, THERE WERE >25 MEDICAL AND SCIENTIFIC PUBLICATIONS THAT WERE DETAILED REPORTS OF FARA FUNDED RESEARCH. SELECTED PUBLICATIONS: FRATAXIN DEFICIENCY IMPAIRS MITOCHONDRIAL BIOGENESIS IN CELLS, MICE AND HUMANS. JASOLIYA MJ, MCMACKIN MZ, HENDERSON CK, PERLMAN SL, CORTOPASSI GA. HUM MOL GENET. 2017 JUL 15;26(14):2627-2633. DOI: 10.1093/HMG/DDX141. SOMATIC INSTABILITY OF THE EXPANDED GAA REPEATS IN FRIEDREICH'S ATAXIA. LONG A, NAPIERALA JS, POLAK U, HAUSER L, KOEPPEN AH, LYNCH DR, NAPIERALA M. PLOS ONE. 2017 DEC 19;12(12):E0189990. DOI: 10.1371/JOURNAL.PONE.0189990. ECOLLECTION 2017. INDUCIBLE AND REVERSIBLE PHENOTYPES IN A NOVEL MOUSE MODEL OF FRIEDREICH'S ATAXIA. CHANDRAN V, GAO K, SWARUP V, VERSANO R, DONG H, JORDAN MC, GESCHWIND DH. ELIFE. 2017 DEC 19;6. PII: E30054. DOI: 10.7554/ELIFE.30054. COMPREHENSIVE ANALYSIS OF GENE EXPRESSION PATTERNS IN FRIEDREICH'S ATAXIA FIBROBLASTS BY RNA SEQUENCING REVEALS ALTERED LEVELS OF PROTEIN SYNTHESIS FACTORS AND SOLUTE CARRIERS. NAPIERALA JS, LI Y, LU Y, LIN K, HAUSER LA, LYNCH DR, NAPIERALA M. DIS MODEL MECH. 2017 NOV 1;10(11):1353-1369. DOI: 10.1242/DMM.030536. ACTIVATION OF FRATAXIN PROTEIN EXPRESSION BY ANTISENSE OLIGONUCLEOTIDES TARGETING THE MUTANT EXPANDED REPEAT. LI L, SHEN X, LIU Z, NORRBOM M, PRAKASH TP, O'REILLY D, SHARMA VK, DAMHA MJ, WATTS JK, RIGO F, COREY DR. NUCLEIC ACID THER. 2018 FEB;28(1):23-33. DOI: 10.1089/NAT.2017.0703. EPUB 2018 JAN 17. NICOTINAMIDE MONONUCLEOTIDE REQUIRES SIRT3 TO IMPROVE CARDIAC FUNCTION AND BIOENERGETICS IN A FRIEDREICH'S ATAXIA CARDIOMYOPATHY MODEL. MARTIN AS, ABRAHAM DM, HERSHBERGER KA, BHATT DP, MAO L, CUI H, LIU J, LIU X, MUEHLBAUER MJ, GRIMSRUD PA, LOCASALE JW, PAYNE RM, HIRSCHEY MD. JCI INSIGHT. 2017 JUL 20;2(14). PII: 93885. DOI: 10.1172/JCI.INSIGHT.93885. [EPUB AHEAD OF PRINT] FRIEDREICH ATAXIA: HYPOPLASIA OF SPINAL CORD AND DORSAL ROOT GANGLIA. KOEPPEN AH, BECKER AB, QIAN J, FEUSTEL PJ. J NEUROPATHOL EXP NEUROL. 2017 FEB 1;76(2):101-108. DOI: 10.1093/JNEN/NLW111. FORM 990, PART VI, SECTION B, LINE 11B COPIES OF 990 ARE DISTRIBUTED TO BOARD MEMBERS FOR REVIEW AND APPROVAL PRIOR TO FILING. FORM 990, PART VI, SECTION B, LINE 12C ALL NEW AND EXISTING BOARD MEMBERS REQUIRED TO ANNUALLY COMPLETE A CONFLICT OF INTEREST STATEMENT FORM 990, PART VI, SECTION B, LINE 15 EVALUATION AND COMPENSATION COMMITTEE PERFORMS EMPLOYEE EVALUATIONS AND DETERMINES SALARY INCREASES ON A YEARLY BASIS FOR ALL EMPLOYEES. COMMITTEE EXAMINES BENCHMARK DATA IN DETERMINING SALARIES FOR PRESIDENT AND EXECUTIVE DIRECTOR. FORM 990, PART VI, SECTION C, LINE 18 FORM 990 IS AVAILABLE ON THE ORGANIZATION'S WEBSITE AS WELL AS GUIDESTAR.ORG AND CHARITYNAVIGATOR.ORG FORM 990, PART VI, SECTION C, LINE 19 FINANCIAL STATEMENTS ARE AVAILABLE ON THE ORGANIZATION'S WEBSITE. THE GOVERNING DOCUMENTS, CONFLICT OF INTEREST POLICY AND FORM 1023 ARE AVAILABLE UPON REQUEST. FORM 990, PART VI LINE 17 THE ORGANIZATION IS ALSO REGISTERED TO SOLICIT CONTRIBUTIONS IN THE STATES LISTED. FORM 990, PART XII, LINE 2C FARA'S AUDIT COMMITTEE CONSISTS OF THE FINANCE COMMITTEE, EXECUTIVE DIRECTOR AND ONE AT-LARGE BOARD MEMBER. EACH YEAR THE AUDIT COMMITTEE SEEKS THE SERVICES OF AN OUTSIDE ACCOUNTING FIRM AND CONTRACTS FOR A FULL AUDIT, PREPARATION OF FINANCIAL STATEMENTS AND FILING OF THE 990. THE AUDIT COMMITTEE IS RESPONSIBLE FOR REVIEWING RECOMMENDATIONS FROM THE AUDIT AND PROPOSING NEW POLICIES AND PROCEDURES AS NECESSARY. THE AUDIT COMMITTEE ALSO PARTICIPATES IN DETAILED REVIEW OF FINANCIAL STATEMENTS AND 990 PRIOR TO SHARING WITH THE FULL BOARD FOR A VOTE. FARA'S BOARD OF DIRECTORS RECEIVES THE FINANCIAL STATEMENTS AND 990 FOR REVIEW AND VOTES TO APPROVE PRIOR TO PUBLIC FILING.