Delivery of anti-sense oligonucleotide (AO) drugs has been shown to restore dystrophin protein production in mouse, dog and human muscle. Intravenous systemic delivery of AO drugs has been successful in improving muscle structure and function, however this has been done for only a few ofthe 79 exons ofthe dystrophin gene, and the mutations in animal models in general do not have genetic counterparts in human mutations in Duchenne muscular dystrophy (DMD) patients. Extensive genotype/phenotype studies in inframe Becker muscular dystrophy (BMD) patients by us and others have shown that different in-frame mutations can show regions, key domains), differential RNA splicing patterns, and protein stability at the membrane. These genotype/phenotype studies are in general agreement with biophysical and biochemical studies of dystrophin structure and function. The goal ofthis project is to define the molecular determinants of biochemical rescue of muscle by in-frame BMD-like dystrophin proteins. We focus on AO drugs directed against exons 45, 51 and 53 because collectively, skipping of one of these exons will result in potential treatment for the greatest number of DMD patients. The proposed experiments will define reasons underlying the observed dramatic variability in dystrophin quantities in patients harboring the same in-frame deletion (eg. 5%-80% of del45-47).
Aim 1 focuses on molecular studies of our existing muscle tissue bank, and additional biopsies obtained from Project 3 and Core C.
Aim 2 focuses on generating transgenic mouse models corresponding to in-frame deletions for which few or no patients exist in our clinical trial network census.
Aims 1 and 2 make extensive use of Core B to provide assessments of dystrophin protein function in vitro and in vivo.
Aim 3 will integrate the molecular data with the clinical data obtained in the natural history study of in-frame patients in Project 3.An impact ofthe proposed research will be to provide a data-driven expectation ofthe efficacy of AO drug therapy forthe most common DMD mutations. Resource sharing includes new transgenic models of semi-functional dystrophin that can be distributed to basic science laboratories interested in dystrophin stmcture/function. A fibroblast cell culture bank with wellcharacterized in-frame deletions will also be made freelv available to the research public (Core CV)

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
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Special Emphasis Panel (ZAR1-KM)
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Children's Research Institute
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