A drug-based approach for integrin-mediated alleviation of muscular dystrophy

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DESCRIPTION (provided by applicant): Duchenne Muscular Dystrophy (DMD) is a severe muscle wasting disease that leads to premature death. Currently, there is no cure or effective treatment for this devastating neuromuscular disease. Expression of the 17 integrin is increased in the muscle of DMD patients and the mdx mouse model. Mice lacking both dystrophin and the 17 integrin exhibit severe muscular dystrophy and die before 4 weeks of age. Recently we demonstrated that enhanced transgenic expression of the 17 integrin in skeletal muscle can increase the viability of dystrophic mice. Together these studies show that the 17 integrin is a major genetic modifier in the muscle of DMD patients and mdx mice and suggest that compounds that up-regulate 17 integrin gene expression may serve as a potential therapy for DMD. In this study we will initiate a small-molecule discovery program to identify compounds that target 17 integrin gene expression. We will use a clonal muscle cell line isolated from transgenic mice to develop a fluorescent assay system for integrin gene expression. This system will allow an assessment of 17 integrin promoter activity in its normal cellular and genomic context. This cell-based system will be tested with compounds known to increase 17 integrin gene expression. The validated cell-based assay will then be applied to an automated high throughput drug screen to identify compounds that increase 17 integrin gene expression in cultured mouse muscle cells. Positive compounds will be tested in cultured murine and human muscle cells to determine drug efficacy, toxicity and ability to translate to human muscle cells. Together these aims will allow us to test the hypothesis that small compounds can increase 17 integrin gene expression in murine and human muscle cells. The identification of small compounds that increase 17 integrin gene expression will form the basis of future studies which will translate our basic biomedical research studies to the development of drugs for future human clinical trails.Project Narrative Duchenne Muscular Dystrophy is a devastating muscle disease that affects nearly 50,000 children in the United States. Increased expression of 17 integrin has been shown to be enormously beneficial to mouse models for this disease. This study aims to identify drugs that increase 17 integrin gene expression which may prove to be of therapeutic value to patients that suffer from DMD.