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

Leonela Amoasii, John C.W. Hildyard, Hui Li, Efrain Sanchez-Ortiz, Alex Mireault, Daniel Caballero, Rachel Harron, Thaleia Rengina Stathopoulou, Claire Massey, John M. Shelton, Rhonda Bassel-Duby, Richard J. Piercy, Eric N. Olson

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90 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)86-91
Number of pages6
JournalScience
Volume362
Issue number6410
DOIs
Publication statusPublished - Oct 5 2018

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Cite this

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