Clinical Studies of Protease Inhibition in Duchenne Muscular Dystrophy

University Of Pennsylvania, Philadelphia PA

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Abstract

Currently, corticosteriods are the only treatment with demonstrated benefti in reducint ghe progressive muscular weakness of patients with Duchenne muscular dystrophy (DMD). Despite the reported benefits, the use of corticosteroids in these patients is limited by their side effects, especially when used chronically. The identification of novel therapeutic agents with low toxicity profiles would be of benefit in offering other treatment options for DMD patients. Loss of dystrophin in muscle fibers results in the activation of proteases which play an active role in dystrophic muscle necrosis. Recently, it has been shown in Lee Sweeney's laboratory that mdx mice treated with the protease inhibitor, Bowman-Birk Inhibitor Concentrate (BBIC), had significant improvement in musclemass ahnd strength. The proteases affected by BBIC in dystrophin-deficient muscle are unclear, but may include those required for myostatin activation, as studied in Se-Jin Lee's laboratory. BBIC is currently under investigation in clinical trials for other diseases and has shown a favorable toxicity profile, suggesting that it has promise as a therapy for DMD. To examine the utility of BBIC treatment for DMD, we plan to pursue the following Specific Aims: 1. Determine the toxicity and tolerability of BBIC by performing a phasel, undblinded, dose escalation trial in children with DMD. 2. Determine the feasiblity of BBIC as a treatment for patients with DMD by performing a phase II, doubleblinded, placebo-controlled trial using quantitive muscle testing, muscle mass, and enzyme markers of muscle damage as the primary endpoints.