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

doi:10.1126/science.aau1549

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., Harron, R., Stathopoulou, T.-R., Massey, C. A., Shelton, J. M., Bassel-Duby, R., Piercy, R. J., & 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	Nov 7, 2018
Journal	SCIENCE
Print ISSN	0036-8075
Electronic ISSN	1095-9203
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