In vivo gene editing in dystrophic mouse muscle and muscle stem cells
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nihms-791917.pdf
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Author(s)
Tabebordbar, M.
Zhu, K.
Cheng, J. K. W.
Chew, W. L.
Widrick, J. J.
Maesner, C.
Wu, E. Y.
Xiao, R.
Ran, F. A.
Vandenberghe, L. H.
Date Issued
January 2016
Journal
Science
Publisher
American Association for the Advancement of Science (AAAS)
Citation
Tabebordbar, M. et al. “In Vivo Gene Editing in Dystrophic Mouse Muscle and Muscle Stem Cells.” Science 351, 6271 (December 2015): 407–411 © 2016 American Association for the Advancement of Science
Version
Author's final manuscript
Abstract
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.
MIT Department
Institute for Medical Engineering and Science
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
McGovern Institute for Brain Research at MIT
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1126/science.aad5177
