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Biochemical Mechanisms in Friedreich Ataxia Robert B. Wilson, M.D., Ph.D.

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. Protein.

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Biochemical Mechanisms in Friedreich Ataxia Robert B. Wilson, M.D., Ph.D.

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  1. Biochemical Mechanisms in Friedreich AtaxiaRobert 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. Protein DNA Encodes Proteins by Transcription and Translation

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

  7. Protein DNA Encodes Proteins by Transcription and Translation

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

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

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

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

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

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

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

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

  16. FA Treatment Pipeline - 2009 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 Available to Patients Santhera Phase III (Definitive Trial) ApoPharma University of South Florida And Children’s Hospital of Phila INSERM - Hôpital Robert Debré Phase II (Human Safety and Efficacy Trial) Lundbeck IPSEN Penwest MUV, Austria & Other groups Protective Cytokines / EPO –like compounds Wells Center for Pediatric Research, Indianapolis, IN Phase I (Human Safety Trial) MD Anderson, Houston, TX & Murdoch Children’s Research Institute, Australia University of Madrid and University of Oxford Repligen University of Pennsylvania &University of California, Davis University of Minnesota and Mayo Clinic Scripps Institute, La Jolla, CA Mayo Clinic, Rochester, MN University of Pennsylvania Multiple Groups Pre-Clinical (Testing in Laboratory) NIH/Harvard Iron Chelator – Deferiprone Epigenetic Varenicline / Chantix Research (Finding Potential Therapies/Drugs) EPO & EPO mimetics Mitochondrial Function FRDA Gene Transcription HDACs - New HDAC - Leading Frataxin Mt Gene Therapy TAT Frataxin HSV-1 FRDA Fe-S clusters A0001 Pioglitazone EGb761 Small RNAs Idebenone 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 Neuro- protection Neuro- Transmission Modifying Therapy High-Throughput Screening for New Drug Discovery

  17. 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

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