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Science. 2016 Jan 22;351(6271):407-411. doi: 10.1126/science.aad5177. Epub 2015 Dec 31.

In vivo gene editing in dystrophic mouse muscle and muscle stem cells.

Author information

Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
Biological and Biomedical Sciences Program, Harvard Medical School, Boston, MA 02115, USA.
Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Division of Genetics and Program in Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
McGovern Institute for Brain Research, Department of Brain and Cognitive Science, and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Grousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, 20 Staniford Street, Boston, MA 02114, USA.
Contributed equally


Frame-disrupting mutations in the DMD gene, encoding dystrophin, compromise myofiber integrity and drive muscle deterioration in Duchenne muscular dystrophy (DMD). Removing one or more exons from the mutated transcript can produce an in-frame mRNA and a truncated, but still functional, protein. In this study, we developed and tested a direct gene-editing approach to induce exon deletion and recover dystrophin expression in the mdx mouse model of DMD. Delivery by adeno-associated virus (AAV) of clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 endonucleases coupled with paired guide RNAs flanking the mutated Dmd exon23 resulted in excision of intervening DNA and restored the Dmd reading frame in myofibers, cardiomyocytes, and muscle stem cells after local or systemic delivery. AAV-Dmd CRISPR treatment partially recovered muscle functional deficiencies and generated a pool of endogenously corrected myogenic precursors in mdx mouse muscle.

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