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

years disability

Myostatin inhibition IGF-1 stimulation Androgens Selective Androgen Receptor Modulators (SARMS)

wt mstn-/-

Myostatin is a TGF-β family member expressed predominantly in skeletal muscle

McPherron AC, Nature 387: 83-90, 1997

Myostatin mutants

Myostatin function is conserved in humans

Schuelke M et al., NEJM 350: 2682-2688, 2004

Muscular German boy sheds new light on muscle development and genetics

Genetic mutation turns tot into superboy

Strong Boy Could Benefit Research on Muscular Dystrophy

Muscle Boy

Bulked-up Boy Teaches Docs About Muscle Protein

Über berkinde der!

One Strong Tyke: Gene mutation in muscular boy may hold disease clues

Superm an Lives

Muscle boy show s w ay for super athletes

'Mighty mouse' gene helps super-strong boy

Weight (g)

tric gast

P<0.001

Force (N)

P<0.01

mdx wt

0.5 .5 1 1.5 .5 2 2.5 .5

0.1 0.2 0.3 0.4 0.5 0.6

Wagner KR et al., Ann Neurol 54: 832-836, 2002

Muscle size and strength increased in myopathic mouse model lacking myostatin

Wagner KR et al., Ann Neurol 54: 832-836, 2002

myopathic myopathic/ no myostatin normal mouse

Improved regeneration and reduced fibrosis in the absence of myostatin

Loss of myostatin leads to faster regeneration

control mstn-/- 4 d 7 d

10 20 30 40 50 60 uninjured day 1 day 7 day 15 day 30

Fiber diameter Fiber diameter

uninjured

0 7 14 30 days

Wagner KR et al., PNAS 102: 2519-2524, 2005

P<0.04 * *

• 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

Fibrosis and Fat

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

• 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.

Myostatin Inhibitors developed for clinical trials

Gartner Hype Cycle

Myostatin inhibition

• 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.

Summary

Acknowledgements

Funding:

MDA NIH/NICHD Charley’s Fund

wagnerk@kennedykrieger.org 443-923-9525

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