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

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

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 t...

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Bibliographic Details
Main Authors: 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., Church, G. M., Wagers, A. J., Yan, Winston Xia, Cong, Le, Zhang, Feng
Other Authors: Institute for Medical Engineering and Science
Format: Article
Published: American Association for the Advancement of Science (AAAS) 2017
Online Access:http://hdl.handle.net/1721.1/112733
https://orcid.org/0000-0002-3067-479X
https://orcid.org/0000-0003-2782-2509
Description
Summary: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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