Preclinical Testing of Integrin Enhancing Molecules for the Treatment of Muscular

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DESCRIPTION (provided by applicant): Duchenne Muscular Dystrophy (DMD) is a lethal muscle wasting disease for which there is currently no cure or effective treatment. DMD is caused by mutations in the gene encoding dystrophin resulting in an absence of the dystrophin protein, a critical component of the laminin binding dystrophin glycoprotein complex in muscle. Loss of dystrophin results in reduced sarcolemmal integrity and increased susceptibility to muscle damage. The 1721 integrin is also a major laminin receptor in muscle that is increased in DMD patients and the mdx mouse model. These observations led to the hypothesis that the 1721 integrin is a major modifier of disease progression in DMD. In support of this idea, transgenic over-expression of the 17 integrin in muscle alleviates muscle disease in dystrophic mice, while loss of 17 integrin in dystrophic muscle results in more severe disease. Together these results indicate pharmacological interventions which promote increased 17 integrin expression in muscle may be an effective therapeutic approach for the treatment of DMD. Recently, using a novel muscle cell-based assay and drug discovery technology, we have identified several compounds that increase 17 integrin expression in cultured muscle cells. In this study we will initiate preclinical testing of these compounds in mouse models of DMD. Our studies will determine the optimal dose of these compounds and determine if they increase longevity and prevent muscle disease progression in DMD mouse models. Compounds will also be tested to determine if they prevent the development of dilated cardiomyopathy associated with muscular dystrophy using echocardiography and if they prevent deterioration in muscle function. Together these aims will allow us to test the hypothesis that compounds which increase 17 integrin gene expression can prevent muscle disease progression in mouse models of DMD. The identification of compounds that increase 17 integrin expression and prevent muscle disease in mouse models of DMD will form the basis of future studies that will translate our basic biomedical research into the development of drugs for clinical trials for DMD. PUBLIC HEALTH RELEVANCE: Duchenne Muscular Dystrophy (DMD) is a devastating muscle disease that affects nearly 50,000 children in the United States and European Union. Increased expression of 17 integrin has been shown to be enormously beneficial in DMD mouse models. This study aims to conduct preclinical testing of novel drugs that enhanced 17 integrin expression in muscle to determine if they maybe of therapeutic value to DMD patients.