Evaluating a novel pathway for treatment of Duchenne muscular dystrophy

University Of Washington, Seattle WA

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Abstract

DESCRIPTION (provided by applicant): Duchenne Muscular Dystrophy is a severe degenerative muscle disease characterized by loss of ambulation at 10 years of age, and death in the third decade of life. There is no treatment other than corticosteroids, which have severe side effects that limit the duration of use. DMD is caused by mutations in the X-linked dystrophin gene. Gene correction approaches are being studied aggressively but are unlikely to be in wide use in the near future. Affordable treatments that slow muscle degeneration are urgently needed now until effective gene correction techniques become widely available and cost effective. We have robust proof-of-concept evidence that the HMG CoA-reductase inhibitor, Simvastatin, markedly improves the dystrophic phenotype in skeletal and cardiac muscle in the mdx mouse model of DMD. This novel finding might be considered unexpected since statins are known to occasionally cause myopathy and, as a consequence, are contraindicated for use in individuals with muscle diseases, including DMD. However, long-term treatment of mdx mice with Simvastatin dramatically reduces plasma creatine kinase levels, increases diaphragm specific force and improves cardiac diastolic function. First, we will evaluate the dose response of two statins, Simvastatin and Rosuvastatin, in mdx mice using randomized, double blind, placebo-controlled studies. Established methods will be used to examine improvements in muscle contractile function and histological abnormalities in diaphragm and extensor digitorum longus muscles. In a second aim, the ability of statins to reverse cardiac and diaphragm dysfunction in aged mdx mice will be studied. Finally, we will determine if statins improve the lifespan of severely dystrophic mdx:utrophin double knockout mice. The goal of these studies is to obtain robust data, using rigorous methodology, that support further clinical development of statins as a treatment of DMD and possibly other muscular dystrophies.