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

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Science  30 Aug 2018:
eaau1549
DOI: 10.1126/science.aau1549

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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 “hot spot” 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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