1. Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy.
- Author
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Amoasii L, Hildyard JCW, Li H, Sanchez-Ortiz E, Mireault A, Caballero D, Harron R, Stathopoulou TR, Massey C, Shelton JM, Bassel-Duby R, Piercy RJ, and Olson EN
- Subjects
- Adenoviridae, Animals, CRISPR-Cas Systems, Disease Models, Animal, Dogs, Dystrophin metabolism, Female, Gene Transfer Techniques, Male, Dystrophin genetics, Gene Editing methods, Muscular Dystrophy, Duchenne therapy
- 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., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2018
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