914. Recombinant AAV Gene Delivery of Follistatin for Muscle Enhancement in Models of Muscular Dystrophy
Authors: Liza Rizo, Chris Shilling, Amanda Haidet, Priya Umapathi Umapathi, Zarife Sahenk, Jerry R. Mendell, Brian K. Kaspar
Journal: Molecular Therapy (2006)

Objective: To determine the efficacy of recombinant adeno- associated virus (rAAV) delivering follistatin (FS), a potent inhibitor of myostatin, to a mouse model for limb-girdle muscular dystrophy and wild-type animals.Background: LGMD2D is a debilitating muscle disease of children and young adults. There is no proven treatment to delay the disease progression. Inhibition of myostatin, a negative growth modulator for muscle, can functionally improve normal or dystrophic muscle. This has been observed across species lines, through genetic manipulation, naturally occurring mutations or protein-specific antibodies. We have employed a novel gene therapy approach using a rAAV vector carrying a FS transgene.Design/Methods: Four-week-old wild-type, mdx, or alpha- sarcoglycan deficinet mice were injected bilaterally into the quadriceps and tibialis anterior muscles with 1x10e10 viral genomes of rAAV1-FS and evaluated for muscle strength and endurance using hindlimb and forelimb grip strength as well as Rotarod. At age 120 days, gross muscle evaluation and analysis of muscle weight, fiber number, and cross-sectional area (CSA) on HandE sections was performed with the addition of a FS ELISA assay.Results: We found increased serum FS levels accompanied by a local and remote increase in muscle mass in treated animals (p<0.05). Muscle hypertrophy was observed in rAAV-FS mice versus controls. Motor function tests showed statistically significant improvements in muscle strength in FS-treated mice.Conclusions/Relevance: This data supports a therapeutic effect in muscular dystrophy by myostatin inhibition. This approach represents a clinically applicable gene therapy method to enhance muscle mass and function in muscular dystrophy with potential for treatment of other muscle diseases. No toxicity was encountered. The FS transgene could also be used to complement gene replacement therapy. For example, adding muscle mass in patients with more advanced dystrophies could improve their candidacy for gene replacement therapy. Objective: To determine the efficacy of recombinant adeno- associated virus (rAAV) delivering follistatin (FS), a potent inhibitor of myostatin, to a mouse model for limb-girdle muscular dystrophy and wild-type animals. Background: LGMD2D is a debilitating muscle disease of children and young adults. There is no proven treatment to delay the disease progression. Inhibition of myostatin, a negative growth modulator for muscle, can functionally improve normal or dystrophic muscle. This has been observed across species lines, through genetic manipulation, naturally occurring mutations or protein-specific antibodies. We have employed a novel gene therapy approach using a rAAV vector carrying a FS transgene. Design/Methods: Four-week-old wild-type, mdx, or alpha- sarcoglycan deficinet mice were injected bilaterally into the quadriceps and tibialis anterior muscles with 1x10e10 viral genomes of rAAV1-FS and evaluated for muscle strength and endurance using hindlimb and forelimb grip strength as well as Rotarod. At age 120 days, gross muscle evaluation and analysis of muscle weight, fiber number, and cross-sectional area (CSA) on HandE sections was performed with the addition of a FS ELISA assay. Results: We found increased serum FS levels accompanied by a local and remote increase in muscle mass in treated animals (p<0.05). Muscle hypertrophy was observed in rAAV-FS mice versus controls. Motor function tests showed statistically significant improvements in muscle strength in FS-treated mice. Conclusions/Relevance: This data supports a therapeutic effect in muscular dystrophy by myostatin inhibition. This approach represents a clinically applicable gene therapy method to enhance muscle mass and function in muscular dystrophy with potential for treatment of other muscle diseases. No toxicity was encountered. The FS transgene could also be used to complement gene replacement therapy. For example, adding muscle mass in patients with more advanced dystrophies could improve their candidacy for gene replacement therapy.