Biochemical Mechanisms in Friedreich Ataxia Robert B. Wilson, M.D., Ph.D. Friedreich’s Ataxia Symposium 14 November 2009
Potential Conflicts of Interest Penwest Apopharma
DNA is a Double Helix Comprising Four Bases
DNA is Packaged by Histone Proteins
DNA Encodes Proteins by Transcription and Translation Protein
The FRDA Gene Normal: <40 GAA repeats Friedreich’s ataxia: ~100 to >1700 GAA repeats GAAGAAGAAGAAGAAGAAGAAGAAGAAGAA GAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAA
DNA Encodes Proteins by Transcription and Translation Protein
From Pandolfo, Archives of Neurology, 2008 GAA Repeat Expansions in the FXN Gene May Silence the Gene by Multiple Mechanisms
The FRDA Gene Encodes Frataxin Normal FRDA Gene (GAA) <40 Energy Mitochondrion
The FRDA Gene Encodes Frataxin Normal FRDA Gene (GAA) <40 Energy Mitochondrion
GAA Repeat Expansions Decrease Frataxin Expression Energy Mitochondrion Oxidants FRDA Gene with Expansion (GAA) >100
Iron-Sulfur Cluster Assembly Simplified Fe S S S S Frataxin e-e- e-e- Energy
Iron-Sulfur Cluster Assembly in FRDA Fe Frataxin e-e- e-e- Oxidants Fe S S e-e- e-e- Energy
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)
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)
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 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
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