Muscular dystrophies are neuromuscular disorders that cause progressive peripheral skeletal myopathy. Duchenne muscular dystrophy (DMD) is a recessive X-linked neuromuscular disorder resulting from mutation in the dystrophin gene. The subsequent loss of dystrophin expression in DMD patients leads to a cycle of muscle degeneration and regeneration, which ultimately leads to the development of progressive skeletal muscle wasting and atrophy and premature death. Unfortunately to date, there is no definitive therapy to reverse or cure DMD. Thus, the associated morbidity and mortality in DMD patients remain very high. Therefore, the use of innovative technologies are critically required if a cure for this devastating genetic disorder is to be discovered. Although synthetic oligonucleotide or drug based exon skipping, cell-based transplantation or gene therapy have all failed to produce meaningful and durable improvements in the strength of dystrophic muscle, a transformative new technology called CRISPR/Cas9 genome editing has recently emerged. Using this approach, the Olson Laboratory definitively rescued dystrophin function by correcting the point mutation in the classical mdx mouse, published in a landmark Science paper [Long et al Science 2014 345 (6201): 1184-1188]. Even more importantly, they have demonstrated proof-of-concept for CRISPR/Cas9 mediated permanent exon skipping in mdx-?E23 mice, a novel mouse line serendipitously produced by genome editing in mdx embryos. Translating this new technology, called myoediting, to young men with DMD is the fundamental goal of the UT Southwestern Wellstone MDCRC. Thus, Center?s central hypothesis is that genomic editing can genetically correct mutations within the human dystrophin gene. Therefore, in Project 2 we will focus on identifying patients with potential dystrophin mutations that can be corrected in vitro, while comprehensively assessing the molecular/clinical phenotypes of these patients. Project 2 will pursue the following three specific aims:
Specific Aim 1 : Correlate molecular and clinical phenotypes of adult patients with Duchenne muscular dystrophy.
Specific Aim 2 : Development of a DMD-in-a-dish model for evaluating the efficacy of myoediting and generating a Duchenne muscular dystrophy myoediting map.
Specific Aim 3 : Extend myoediting studies to carrier females with DMD-associated cardiomyopathy. Synergizing with Project 1 and the shared Myoediting Core, successful completion of these specific aims will produce a new therapy, and possibly even a cure, for DMD, that targets and molecularly rectifies the culprit genetic lesion in iPSCs and ultimately in the musculature of dystrophic patients. Thus, the proposed NIH U54 Grant Application is relevant to and in keeping with the mission of the NIH.
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