Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy

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Science  31 Jan 2015:
DOI: 10.1126/science.aad5725

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CRISPR/Cas9-mediated genome editing holds clinical potential for treating genetic diseases, such as Duchenne muscular dystrophy (DMD), which is caused by mutations in the dystrophin gene. To correct DMD by skipping mutant dystrophin exons in postnatal muscle tissue in vivo, we used adeno-associated virus-9 (AAV9) to deliver gene editing components to postnatal mdx mice, a model of DMD. Different modes of AAV9 delivery were systematically tested, including intra-peritoneal at postnatal day (P) 1, intra-muscular at P12, and retro-orbital at P18. Each of these methods restored dystrophin protein expression in cardiac and skeletal muscle to varying degrees and expression increased from 3 to 12 weeks post-injection. Postnatal gene editing also enhanced skeletal muscle function, measured by grip strength tests 4 weeks post-injection. This method provides a potential means of correcting mutations responsible for DMD and other monogenic disorders after birth.

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