Update on Therapeutics for Muscle Regeneration

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
'Mighty mouse' gene helps super-strong boy
Überkinder!
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
Superman Lives
Muscular German boy sheds new light on muscle
development and genetics
Muscle boy shows way for super athletes
Muscle Boy
Genetic mutation
turns tot into superboy
Muscle size and strength increased in
myopathic mouse model lacking myostatin
2.5
0.6
P<0.001
P<0.01
Force (N)
2
0.4
0.3
0.2
1.5
1
0.5
0.1
wt
mdx
0
gast
0
tric
Weight (g)
0.5
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
4d
7d
mstn-/-
60
P<0.04
50
*
40
*
30
20
10
0
uninjured
7 7day
14 15
30 days
uninjured
day0 1 day
day
30
Fiber diameter
Fiber diameter
control
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
[email protected]
443-923-9525