1. Biochemical Mechanisms in Friedreich Ataxia Robert B. Wilson, M.D., Ph.D. Friedreich’s Ataxia Symposium 14 November 2009

2. Potential Conflicts of Interest Penwest Apopharma

3. DNA is a Double Helix Comprising Four Bases

4. DNA is Packaged by Histone Proteins

5. DNA Encodes Proteins by Transcription and Translation Protein

6. The FRDA Gene Normal: <40 GAA repeats Friedreich’s ataxia: ~100 to >1700 GAA repeats GAAGAAGAAGAAGAAGAAGAAGAAGAAGAA GAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAA

7. DNA Encodes Proteins by Transcription and Translation Protein

8. From Pandolfo, Archives of Neurology, 2008 GAA Repeat Expansions in the FXN Gene May Silence the Gene by Multiple Mechanisms

9. The FRDA Gene Encodes Frataxin Normal FRDA Gene (GAA) <40 Energy Mitochondrion

12. The FRDA Gene Encodes Frataxin Normal FRDA Gene (GAA) <40 Energy Mitochondrion

13. GAA Repeat Expansions Decrease Frataxin Expression Energy Mitochondrion Oxidants FRDA Gene with Expansion (GAA) >100

14. Iron-Sulfur Cluster Assembly Simplified Fe S S S S Frataxin e-e- e-e- Energy

15. Iron-Sulfur Cluster Assembly in FRDA Fe Frataxin e-e- e-e- Oxidants Fe S S e-e- e-e- Energy

16. Fe-S ROS Fe Underlying Vicious Cycle in FA Idebenone (Phase III trial) MitoQ (Early clinical) A0001 (Pre-clinical) Deferiprone (Phase II trial) Additional Iron Chelators (Pre-clinical) Frataxin HDACi (Pre-clinical) EPO (Early clinical) Protein replacement (Pre-clinical)

17. Fe-S ROS Fe Underlying Vicious Cycle in FA Idebenone (Phase III trial) MitoQ (Early clinical) A0001 (Pre-clinical) Deferiprone (Phase II trial) Additional Iron Chelators (Pre-clinical) Frataxin HDACi (Pre-clinical) EPO (Early clinical) Protein replacement (Pre-clinical)

18. Research (Finding Potential Therapies/Drugs) Pre-Clinical (Testing in Laboratory) Phase I (Human Safety Trial) Phase II (Human Safety and Efficacy Trial) Phase III (Definitive Trial) Available to Patients Decrease Oxidative Stress and/or Increase Mitochondrial Function Decrease Iron Toxicity & Increase Fe-S clusters Increase Frataxin or FA gene Expression Gene Therapy Frataxin Protein- Replacement High-Throughput Screening for New Drug Discovery Idebenone HDAC - Leading HDACs - New Iron Chelator – DeferiproneFe-S clusters HSV-1 FRDA TAT Frataxin EPO & EPO mimetics Santhera Penwest ApoPharma Mitochondrial Function Frataxin FRDA Gene Transcription NIH/Harvard Repligen Scripps Institute, La Jolla, CA University of Madrid and University of Oxford Wells Center for Pediatric Research, Indianapolis, IN University of Pennsylvania &University of California, Davis Mayo Clinic, Rochester, MN MD Anderson, Houston, TX & Murdoch Children’s Research Institute, Australia Pioglitazone INSERM - Hôpital Robert Debré FARA has supported, and is supporting, these efforts by providing various combinations of direct funding, essential clinical infrastructure, advocacy and awareness efforts. 7 Clinical Trials 8 Approaches A0001 FA Treatment Pipeline - 2009 Mt Gene Therapy University of Minnesota and Mayo Clinic Varenicline / Chantix University of South Florida And Children’s Hospital of Phila Neuro- Transmission Modifying Therapy University of Pennsylvania Small RNAs Neuro- protection EGb761 IPSEN MUV, Austria & Other groups Protective Cytokines / EPO –like compounds Epigenetic Multiple Groups Lundbeck

19. Acknowledgements David Lynch, M.D., Ph.D. Ron Bartek Jennifer Farmer, M.S. Felicia DeRosa Friedreich’s Ataxia Research Alliance William Hartnett, Marianne Wilcox, Martin Ohman and the rest of the EDS team Our patients and their families