Journal
SCIENCE
Volume 362, Issue 6410, Pages 86-90Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aau1549
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Funding
- NIH [HL130253, AR-067294]
- Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center grant [U54 HD 087351]
- Robert A. Welch Foundation [1-0025]
- Cure Duchenne
- Exonics Therapeutics
- Wellcome Trust [101550/Z/13/Z]
- Muscular Dystrophy UK [RA3/3077]
- Joining Jack
- Duchenne Ireland
- Wellcome Trust [101550/Z/13/Z] Funding Source: Wellcome Trust
- Muscular Dystrophy UK [RA3/3077] Funding Source: researchfish
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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.
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