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Cryoviva India - Possible Approaches to Therapy for Muscular Dystrophy

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Cryoviva India - Possible Approaches to Therapy for Muscular Dystrophy

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  1. Possible Approaches to Therapy for Muscular Dystrophy • Gene Replacement Therapy - Stem cells Viral delivery of dystrophin mini-gene Delivery of growth factors • DNA/RNA manipulation • Pharmacological agents - Drugs that will turn on the utrophin gene Drugs that will cause read-through of a premature stop codon Drugs/factors to promote muscle repair and/or decrease damage

  2. Gene Replacement Therapy Stem cells Muscle-derived (SP cells) Bone Marrow-derived SP cells Bone Marrow-derived Mesenchymal Stem Cells Viral delivery of dystrophin mini-gene AAV / micro-dystrophin Lentivirus / mini-dystrophin Viral or cellular delivery of growth factors to promote muscle repair IGF-I Anti-myostatin

  3. Major Hurdles Facing Stem Cell-Based Gene Therapy for Muscular Dystrophy • Culturing sufficient numbers of cells without losing their stem cell potential • Delivery and targeting • Commitment to become muscle

  4. Schematic of a Dystrophin Mini-gene For Viral-Based Gene Therapy Truncated Human dystrophin Muscle- Specific Promoter PolyA

  5. Major Hurdles Facing Viral-Based Gene Therapy for Muscular Dystrophy • Delivery • Size limitation • Immune response

  6. DNA/RNA manipulation DNA mutation correction Chimeraplasts -correction of point mutations or small deletions RNA splicing modification Oligonucleotides directed at splice junctions to produce exon slipping -production of truncated dystrophin

  7. Major Hurdles Facing DNA/RNA Correction Therapies for Muscular Dystrophy • Delivery • Large deletions not correctable by chimeraplasts • Unclear how functional all possible truncated dystrophins will be

  8. Dystrophin Gene

  9. Pharmacological agents Factors that will turn on the utrophin gene Heregulin Screening for new compounds Drugs that will cause read-through of a premature stop codon Aminoglycosides Screening for new compounds Drugs that will increase muscle regeneration and/or decrease susceptibility to damage Anti-myostatin Protease Inhibitors (Leupeptin, BBIC)

  10. Muscle Growth Protein Degradation Satellite Cell Fusion Protein Synthesis Apoptosis Muscle Loss

  11. Muscle Growth and Regeneration HGF HGF

  12. Factors to promote muscle repair • IGF-I • Anti-myostatin

  13. Multiple benefits of increasing IGF-I or decreasing myostatin levels in dystrophic muscle IGF-I Regenerative Capacity Fibrosis Hypertrophy Muscle Survival

  14. Major Question to be Answered In a dog or a human, would this approach lead to depletion or sparing of satellite cells?

  15. Administration of Protease Inhibitors to slow muscle breakdown • Leupeptin (calpain inhibition) • BBIC (proteosome inhibition?)

  16. Protein Degradation Pathways in Muscle Three primary pathways: 1. 2. 3. Lysosomal proteolysis pathway – endocytosed and membrane proteins Ca2+-dependent proteolysis pathway – soluble proteins, initial cleavage ATP-dependent ubiquitin-proteasome pathway – 70% of soluble proteins Ca2+-dependent proteolysis ATP-dependent ubiquitin-proteasome Perrin and Huttenlocher, 2002 Ikemoto et al., 2002

  17. Targeting Protein Degradation •Approach: Provide food supplemented with 1.0% Bowman-Birk’s Inhibitor concentrate (BBIC) • Bowman-Birk’s Inhibitor (BBI) – Small 8 kD, soy-derived serine protease inhibitor – Dose-dependent inhibition of proteolysis • Lung, kidney, and liver – Increased life-span of mice consuming 1.0% BBI concentrate (BBIC) – Being evaluated as an anticarcinogenic agent in human trials

  18. BBIC attenuates muscle loss associated with unloading

  19. Fiber size loss attenuated by BBIC consumption

  20. Major Question to be Answered What are the long term effects of reduced protein turnover on function of the muscle?

  21. Planned Steps Toward Clinical Trials for Muscular Dystrophy What has happened to date? • Phase 1 trial for AAV2/α-sarcoglycan (LGMD) – Halted prematurely at lower than efficacious dose • Gentamicin trials for DMD with premature stop codons – CK levels dropped, but no dystrophin expression detected • Phase 1 trial for CMV/dystrophin plasmid DNA – Low level expression seen in subset of patients

  22. Planned Steps Toward Clinical Trials for Muscular Dystrophy What is likely to happen over the next 5 years? • Validation of new diagnostics - MRI for non-invasive assessment of therapeutic correction Improved strength testing for target muscles • Phase 1 trial for myostatin inhibition • Phase 1/2 trials for premature stop codon suppression • Phase 1 trials for AAV/α- and γ-sarcoglycan (LGMD) and AAV/truncated dystrophin • Evaluation of protease inhibitors • Screens for new drugs

  23. Acknowledgements Elisabeth Barton Carl Morris Jennifer Elmer Linda Morris Pedro Acosta Support from: NIAMS MDA PPMD MDA

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