1. John H. Ferguson MD, Medical Consultant, ORDR/NCATS/NIH

2.  No relationships to disclose or list

3.  Rare Diseases  Office of Rare Diseases Research (ORDR)  National Center for Advancing Translational Sciences – NCATS  Therapeutics for Rare and Neglegted Diseases –TRND  Ataxia research with ORDR, NCATS and TRND

4.  18 - 25million people in the US are affected - Exact Prevalences Unknown  Estimated 6%-8% of Population  Prevalence definition: < 200,000 people in the USA  > 7000 Genetic and Acquired Rare Diseases  Need Collaborative Efforts of the Rare Diseases Community  Academic Researchers  Federal Research and Regulatory Programs  > 1100 Patient Advocacy Groups/Philanthropic Foundations  Industry  Congressional Rare Diseases Caucus Established

5.  19 Consortia supported by ORDR, NINDS, NIAMS, NICHD, NHLBI, NIDDK, NIAID, NIDCR and NCI  Required  3 diseases longitudinal studies of patients, Encouraged : Phase I, II and III trials; Training of Investigators in clinical research of rare diseases; Pilot studies/demonstration projects Collaboration with Patient Advocacy Groups  Data Management Coordinating Center DMCC  > 192 Institutions World-wide, 42 International Sites, > 200 Diseases  9393 patients enrolled in 68 studies

6. Collaborative Clinical Research Public Resources and Education Centralized Data Coordination and Technology Development Training The Data Management and Coordinating Center Coalition of Patient Advocacy Groups (CPAG) Chronic Graft Versus Host Disease Consortium

7. To catalyze the development of innovative methods and technologies that will enhance the development, testing, and implementation of diagnostics and therapeutics across a wide range of human diseases and conditions

8. Clinic Access Phase iv Phase I Phase III Phase II Stage 1 Drug Discovery Stage 2 Pre-clinical Stage 3 Clinical Trials Stage 4 FDA Review 6.5 years6 years1.5 years IND Submitted NDA Submitted

9.  Components of Molecular Libraries Program  Therapeutics for Rare and Neglected Diseases  Office of Rare Diseases Research  Bridging Interventional Development Gaps (BrIDGs)  Clinical and Translational Science Awards (CTSA)  FDA-NIH Regulatory Science  Cures Acceleration Network

10. NCATS STRUCTURE Division of Pre-Clinical Innovation Chris Austin Division of Clinical Innovation Josie Briggs (Acting) Office of the Director Tom Insel (Acting Director) Kathy Hudson (Acting Deputy Director) Executive Office Erin Shannon (Acting) Office of Grants Management & Review Jane Steinberg (Acting) Office of Pol icy, Communications, & Strategic Alliances Kathy Hudson (Acting) Council CAN Board Office of Rare Diseases Research Steve Groft

11.  Clinical and Translational Science Activities  CTSAs Clinical Translational Science Awards  Rare Diseases Research and Therapeutics  Office of Rare Diseases Research ORDR  Therapeutics for Rare and Neglected Diseases (TRND)  Re-engineering Translational Sciences  NIH Chemical Genomics Center/Molecular Libraries program  Bridging Interventional Development Gaps BrIDGs  Toxicology in the 21 st Century

12.  Academia  Government  Biopharmaceuticals  Patient Advocacy Groups

13.  Successful applicants don’t receive grants  Form joint project teams with TRND  Receive in kind support from TRND scientists, laboratory and contract resources  Goal is advancing compounds to FDA IND  clinical trials in humans

14.  Niemann- Pick C  Hereditary Inclusion Body Myopathy  Sickle cell anemia -  IND received  Chronic Lymphocytic Leukemia  IND received  Shistosomiasis

15.  Duchenne Muscular Dystrophy  Fragile X  Cryptococcal Meningitis  Core binding factor leukemia

16.  An inhibitor compound for Rx of fibrodysplasia ossificans  Applicant is academic MD  Compound shows efficacy in mouse model  Novel Rx for creatine transporter deficiency  Applicant is a pharmaceutical Co.  Mouse model show incr. brain metabolism and cognative function  Compount for Rx of neonatal herpes simplex  Applicant is academic pediatrician  Compound can penetrate CNS, NIAID studied

17.  Deuterimum modified compound for shistosomiasis  Applicant is pharmaceutical co.  Enables lower and less frequent dosing  Drug candidate for Duchenne MD  Applicant is pharmaceutical co.  Drug is for a specific subgroup mutation  Rx for autoimmune pulmonary alveolar proteinosis  Applicant is academic MD  Developed as an inhaled Rx

18.  If no effect in animal models  Too much toxicity in preclinical testing  Poor bioavailability – can’t be absorbed

19.  Cures Acceleration Network (CAN)  Address challenges that impede translational research  Rescuing and Repurposing Drugs e.g. lithium  Designing a Tissue Chip for Drug Screening  With FDA and the Defense Advanced Research Projects Agency (DARPA)  “organ on a chip”  Identifying and Validating Drug Targets

20.  Many potential drug targets for new compounds heard at AIM 2012  High throughput screening at NCATS of thousands of molecules already being used by ataxia researchers  Rescuing and repurposing drugs is NCATS program and many examples given at AIM 2012  Programs at ORDR, NeuroNext, NCATS and TRND should offer HUGE opportunities for ataxia research ncats.nih.gov

21. NIH OFFICE OF RARE DISEASES RESEARCH - STAFF  Steve Groft PharmD  Ms. Mary Demory  Dr. David Eckstein  Ms. Marita Eddy (Angel Flight)  Dr. John Ferguson  Dr. Rashmi Gopal-Srivastava  Mr. Christopher Griffin  Ms. Henrietta Hyatt-Knorr  Dr. Lata Nerurkar  Ms. Susan Orr Lowe  Ms. Geraldine Pollen  Dr. Yaffa Rubinstein  Dr. William Gahl (Clinical Director, NHGRI)  Dr. P.J. Brooks (NIAAA)