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Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy

Amoasii, L; Hildyard, J C W; Li, H; Sanchez-Ortiz, E; Mireault, A; Caballero, D; Harron, R; Stathopoulou, T-R; Massey, C A; Shelton, J M; Bassel-Duby, R; Piercy, R J; Olson, E N

Authors

L Amoasii

J C W Hildyard

H Li

E Sanchez-Ortiz

A Mireault

D Caballero

R Harron

T-R Stathopoulou

C A Massey

J M Shelton

R Bassel-Duby

R J Piercy

E N Olson



Abstract

Mutations in the gene encoding dystrophin, a protein that maintains muscle integrity and function, cause Duchenne muscular dystrophy (DMD). The deltaE50-MD dog model of DMD harbors a mutation corresponding to a mutational “hotspot” in the human DMD gene. We used adeno-associated viruses to deliver CRISPR gene editing components to four dogs and examined dystrophin protein expression 6 weeks after intramuscular delivery (n = 2) or 8 weeks after systemic delivery (n = 2). After systemic delivery in skeletal muscle, dystrophin was restored to levels ranging from 3 to 90% of normal, depending on muscle type. In cardiac muscle, dystrophin levels in the dog receiving the highest dose reached 92% of normal. The treated dogs also showed improved muscle histology. These large-animal data support the concept that, with further development, gene editing approaches may prove clinically useful for the treatment of DMD.

Citation

Amoasii, L., Hildyard, J. C. W., Li, H., Sanchez-Ortiz, E., Mireault, A., Caballero, D., …Olson, E. N. (2018). Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy. Science, 362(6410), 86-91. https://doi.org/10.1126/science.aau1549

Journal Article Type Article
Acceptance Date Aug 17, 2018
Publication Date Oct 5, 2018
Deposit Date Nov 3, 2018
Publicly Available Date Mar 29, 2024
Journal SCIENCE
Print ISSN 0036-8075
Publisher American Association for the Advancement of Science
Peer Reviewed Peer Reviewed
Volume 362
Issue 6410
Pages 86-91
DOI https://doi.org/10.1126/science.aau1549
Public URL https://rvc-repository.worktribe.com/output/1385693

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