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Muscle-specific CRISPR/Cas9 dystrophin gene editing ameliorates pathophysiology in a mouse model for Duchenne muscular dystrophy
Journal article   Open access   Peer reviewed

Muscle-specific CRISPR/Cas9 dystrophin gene editing ameliorates pathophysiology in a mouse model for Duchenne muscular dystrophy

Niclas E. Bengtsson, John K. Hall, Guy L. Odom, Michael P. Phelps, Colin R. Andrus, R. David Hawkins, Stephen D. Hauschka, Joel R. Chamberlain and Jeffrey S. Chamberlain
Nature communications, Vol.8(1), pp.14454-14454
02/14/2017
DOI: https://doi.org/10.1038/ncomms14454
PMID: 28195574
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Muscle-specific CRISPR/Cas9 dystrophin gene editing2.61 MBDownloadView
Open Access CC BY V4.0
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https://doi.org/10.1038/ncomms14454View
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Abstract

Genetics
Gene replacement therapies utilizing adeno-associated viral (AAV) vectors hold great promise for treating Duchenne muscular dystrophy (DMD). A related approach uses AAV vectors to edit specific regions of the DMD gene using CRISPR/Cas9. Here we develop multiple approaches for editing the mutation in dystrophic mdx(4cv) mice using single and dual AAV vector delivery of a muscle-specific Cas9 cassette together with single-guide RNA cassettes and, in one approach, a dystrophin homology region to fully correct the mutation. Muscle-restricted Cas9 expression enables direct editing of the mutation, multiexon deletion or complete gene correction via homologous recombination in myogenic cells. Treated muscles express dystrophin in up to 70% of the myogenic area and increased force generation following intramuscular delivery. Furthermore, systemic administration of the vectors results in widespread expression of dystrophin in both skeletal and cardiac muscles. Our results demonstrate that AAV-mediated muscle-specific gene editing has significant potential for therapy of neuromuscular disorders.

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