Tags

Type your tag names separated by a space and hit enter

Muscle-specific CRISPR/Cas9 dystrophin gene editing ameliorates pathophysiology in a mouse model for Duchenne muscular dystrophy.
Nat Commun. 2017 02 14; 8:14454.NC

Abstract

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 mdx4cv 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, multi-exon 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.

Authors+Show Affiliations

Department of Neurology, University of Washington, Seattle, Washington 98195-7720, USA. Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Washington, Seattle, Washington 98195-7720, USA.Department of Neurology, University of Washington, Seattle, Washington 98195-7720, USA. Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Washington, Seattle, Washington 98195-7720, USA.Department of Neurology, University of Washington, Seattle, Washington 98195-7720, USA. Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Washington, Seattle, Washington 98195-7720, USA.Department of Pathology, University of Washington, Seattle, Washington 98195-7720, USA.Department of Medicine, University of Washington, Seattle, Washington 98195-7720, USA. Department of Genome Sciences, University of Washington, Seattle, Washington 98195-7720, USA.Department of Medicine, University of Washington, Seattle, Washington 98195-7720, USA. Department of Genome Sciences, University of Washington, Seattle, Washington 98195-7720, USA.Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Washington, Seattle, Washington 98195-7720, USA. Department of Biochemistry, University of Washington, Seattle, Washington 98195-7720, USA.Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Washington, Seattle, Washington 98195-7720, USA. Department of Medicine, University of Washington, Seattle, Washington 98195-7720, USA.Department of Neurology, University of Washington, Seattle, Washington 98195-7720, USA. Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Washington, Seattle, Washington 98195-7720, USA. Department of Medicine, University of Washington, Seattle, Washington 98195-7720, USA. Department of Biochemistry, University of Washington, Seattle, Washington 98195-7720, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28195574

Citation

Bengtsson, Niclas E., et al. "Muscle-specific CRISPR/Cas9 Dystrophin Gene Editing Ameliorates Pathophysiology in a Mouse Model for Duchenne Muscular Dystrophy." Nature Communications, vol. 8, 2017, p. 14454.
Bengtsson NE, Hall JK, Odom GL, et al. Muscle-specific CRISPR/Cas9 dystrophin gene editing ameliorates pathophysiology in a mouse model for Duchenne muscular dystrophy. Nat Commun. 2017;8:14454.
Bengtsson, N. E., Hall, J. K., Odom, G. L., Phelps, M. P., Andrus, C. R., Hawkins, R. D., Hauschka, S. D., Chamberlain, J. R., & Chamberlain, J. S. (2017). Muscle-specific CRISPR/Cas9 dystrophin gene editing ameliorates pathophysiology in a mouse model for Duchenne muscular dystrophy. Nature Communications, 8, 14454. https://doi.org/10.1038/ncomms14454
Bengtsson NE, et al. Muscle-specific CRISPR/Cas9 Dystrophin Gene Editing Ameliorates Pathophysiology in a Mouse Model for Duchenne Muscular Dystrophy. Nat Commun. 2017 02 14;8:14454. PubMed PMID: 28195574.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Muscle-specific CRISPR/Cas9 dystrophin gene editing ameliorates pathophysiology in a mouse model for Duchenne muscular dystrophy. AU - Bengtsson,Niclas E, AU - Hall,John K, AU - Odom,Guy L, AU - Phelps,Michael P, AU - Andrus,Colin R, AU - Hawkins,R David, AU - Hauschka,Stephen D, AU - Chamberlain,Joel R, AU - Chamberlain,Jeffrey S, Y1 - 2017/02/14/ PY - 2016/04/03/received PY - 2016/12/30/accepted PY - 2017/2/15/entrez PY - 2017/2/15/pubmed PY - 2018/11/14/medline SP - 14454 EP - 14454 JF - Nature communications JO - Nat Commun VL - 8 N2 - 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 mdx4cv 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, multi-exon 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. SN - 2041-1723 UR - https://www.unboundmedicine.com/medline/citation/28195574/Muscle_specific_CRISPR/Cas9_dystrophin_gene_editing_ameliorates_pathophysiology_in_a_mouse_model_for_Duchenne_muscular_dystrophy_ L2 - http://dx.doi.org/10.1038/ncomms14454 DB - PRIME DP - Unbound Medicine ER -