Update on Therapeutics for Muscle Regeneration Kathryn R. Wagner, - PowerPoint PPT Presentation

Update on Therapeutics for Muscle Regeneration Kathryn R. Wagner, M.D., Ph.D. Center for Genetic Muscle Disorders The Kennedy Krieger Institute Johns Hopkins School of Medicine November 5, 2011

Natural History of Myopathies Myostatin inhibition IGF-1 stimulation Androgens Selective Androgen Receptor Modulators (SARMS) disability years

Myostatin is a TGF- β family member expressed predominantly in skeletal muscle mstn -/- wt McPherron AC, Nature 387: 83-90, 1997

Myostatin mutants

Myostatin function is conserved in humans Schuelke M et al., NEJM 350: 2682-2688, 2004

Über berkinde der! 'Mighty mouse' gene helps super-strong boy Strong Boy Could Benefit Research on Muscular Dystrophy Bulked-up Boy Teaches Docs About Muscle Protein One Strong Tyke: Gene mutation in muscular boy may hold disease clues Superm an Lives Muscular German boy sheds new light on muscle development and genetics Muscle boy show s w ay for super athletes Muscle Boy Genetic mutation turns tot into superboy

Muscle size and strength increased in myopathic mouse model lacking myostatin 2.5 .5 0.6 P<0.001 P<0.01 0.5 2 Weight (g) Force (N) 0.4 1.5 .5 0.3 1 0.2 0.5 .5 0.1 0 0 mdx wt tric gast Wagner KR et al., Ann Neurol 54: 832-836, 2002

Improved regeneration and reduced fibrosis in the absence of myostatin myopathic myopathic/ no myostatin normal mouse Wagner KR et al., Ann Neurol 54: 832-836, 2002

Loss of myostatin leads to faster regeneration control mstn-/- 60 4 d P<0.04 50 Fiber diameter * 40 * 30 7 d 20 10 0 uninjured day 1 day 7 day 15 day 30 uninjured 0 7 14 30 days Fiber diameter Wagner KR et al., PNAS 102: 2519-2524, 2005

Fibrosis and Fat • A common feature of chronic myopathies • Presumptive Consequences: – Impaired diffusion of nutrients – Reduced contractility – Reduced compliance – Self perpetuating process – Reduced muscle regeneration Implications for future therapies • – Myoblast transplantation – Gene transfer

Myostatin induces fibroblast proliferation in vitro Li ZB, Kollias HD and Wagner KR, J. Biol Chem, 2008

Myostatin induces fibrosis in vivo Li ZB, Kollias HD and Wagner KR, J. Biol Chem, 2008

Myostatin Inhibitors developed for clinical trials Myo-029 (neutralizing antibody, Wyeth) • – Safe in adults with muscular dystrophy – Although number of individuals treated was small, no efficacy found • RK35 (neutralizing antibody, Pfizer) ACE-031 (soluble receptor, Acceleron/Shire • – Potential for extraordinary efficacy with increased musculature measurable after single injection – Due to nose bleeds and new blood vessel growth, trial in Duchenne muscular dystrophy was terminated.

Gartner Hype Cycle Myostatin inhibition

Summary • Several different growth factors, including myostatin, influence muscle regeneration and can be exploited for treatment of myopathies • Blocking myostatin increases muscle growth and regeneration and decreases muscle fibrosis and fat. • Myostatin inhibitors are currently in clinical trials and have the potential to improve chronic myopathies.

Acknowledgements Center for Genetic Muscle Disorders: Zhao Bo Li, MD, PhD * Tracy Zhang, MS Naili Liu, DVM Adam Moyers, MS Geni Bibat, MD Doris Leung, MD Funding: MDA NIH/NICHD Charley’s Fund wagnerk@kennedykrieger.org 443-923-9525