UT Southwestern?s U54 grant application, entitled ?Myoediting of Duchenne Muscular Dystrophy,? is a request to join the Wellstone MDCRC Network and describes myoediting, a revolutionary new approach for treating DMD by CRISPR/Cas9-mediated genomic editing. The goal is to molecularly edit dystrophin gene mutations in striated muscle cells, permanently eliminating the genetic cause of this devastating muscle disease, and restoring muscle structure and function for the lifetime of the target cell. Myoediting will circumvent many of the technical hurdles plaguing other DMD therapeutic strategies. Based on our extremely promising preliminary results and the rapid pace of this field, we feel this is an opportune time to launch this new approach to permanently correct the muscle abnormalities that cause DMD. As a shared resource, the Wellstone Myoediting Core will bring CRISPR/Cas9 myoediting in DMD-iPSC derived striated muscle cells, an entirely new functionality, to the entire Wellstone MDCRC. This will be a high value and easily accessible service for the entire Consortium. Indeed, in the first year, we intend to invite each of our co-MDCRCs to submit one DMD patient to the Wellstone Myoediting Core. Each patient submitted to the Core will undergo clinical phenotyping, next generation DNA sequencing coupled to analysis of dystrophin sequences in the Duchenne Skipper Database for designing guide RNAs. Coupled to this, the Wellstone Myoediting Core will generate patient-specific iPSCs from erythroblasts for CRISPR/Cas9 and guide RNA mediated exon skipping, followed by evaluation of dystrophin rescue in cardiac and skeletal muscle disease-in-a-dish models and teratomas. Together with our colleagues in the Wellstone Network, we will fulfill our goal of bringing a new CRISPR/Cas9 based myoediting therapy to DMD patients within the 5-year time line of this U54 grant proposal.
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