Testing a Novel DMD Therapeutic in MDX Mice

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DESCRIPTION (provided by applicant): The pharmacological upregulation of utrophin has been proposed as a therapeutic strategy for treating DMD. Genetic studies show that increasing utrophin expression can compensate for the loss of dystrophin and correct dystrophic pathology in the mdx mouse. However, genetic approaches for utrophin upregulation are not yet feasible in humans. Biglycan is an extracellular protein that is a component of the Dystrophin complex and binds to a-dystroglycan (Bowe et al., 2000), a - and ?- sarcoglycan (Rafii et al., 2006). Recombinant biglycan protein can be delivered to muscle in vivo where it rescues the sarcolemmal expression of intracellular DAPC components in biglycan null mice (Mercado et al., 2006). In the proposed studies we will use mdx mice to test the potential efficacy of biglycan as a therapeutic for DMD. In preliminary experiments we have shown that purified recombinant biglycan protein delivered systemically to mdx mice upregulates utrophin expression and decreases myofiber death and mononuclear infiltration. Moreover, single doses at therapeutically-practical levels are effective for up to three weeks. In the proposed studies we will produce recombinant biglycan and use histopathological markers to determine the optimal dose, frequency and route(s) of administration for its use. Functional studies will then be carried out to determine whether biglycan treatment improves the function of skeletal muscle in mdx mice. Positive data from these studies would form the basis for a rapid translation of this therapeutic approach to clinical trials. Duchenne Muscular Dystrophy (DMD) is the most common form of inherited muscular dystrophy. Currently there are no effective treatments and affected boys are wheelchair bound by age twelve and die by their third decade. In the proposed studies we will perform critical preclinical studies to test a novel therapy for DMD.