Prevention of Muscular Dystrophy in Mice by Gene Editing




Long, Chengzu

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Duchenne muscular dystrophy (DMD) is an inherited X-linked disease caused by mutations in the gene encoding dystrophin, a protein required for muscle fiber integrity. DMD is characterized by progressive muscle weakness and a shortened lifespan, often along with breathing and heart complications. There is no effective treatment. RNA-guided nucleases-mediated genome editing, based on Type II CRISPR/Cas systems, offers a new approach to alter the genome. It can precisely remove a mutation in DNA, allowing the DNA repair mechanisms to replace it with a normal copy of the gene. The benefit of this over other gene therapy techniques is that it can permanently correct the 'defect' in a gene rather than just transiently adding a 'functional' one. We used CRISPR/Cas9-mediated genome editing to correct the dystrophin gene (Dmd) mutation in the germline of mdx mice, a model for DMD, and then monitored skeletal muscle and heart structure and function. Genome editing produced genetically mosaic animals containing 2 to 100% correction of the Dmd gene. Histological analysis of skeletal muscle and heart from these corrected mice showed absence of the dystrophic muscle phenotype and restoration of dystrophin expression. In addition, the degree of muscle phenotypic rescue in mosaic mice exceeded the efficiency of gene correction, likely reflecting an advantage of the corrected stem cells and their contribution to regenerating muscle. Our experiments provide proof-of-concept that CRISPR/Cas9-mediated genomic editing can correct a causative germline mutation causing muscular dystrophy in a mouse model and prevent development of several characteristic features of the disease. With rapid technological advances of gene delivery systems and improvements to the CRISPR/Cas9 editing system, this strategy may allow correction of disease-causing mutations in the muscle tissue or iPSCs (induced pluripotent stem cells) from patients with genetic diseases.

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