Journal
SCIENCE
Volume 351, Issue 6271, Pages 403-407Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aad5143
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Funding
- Muscular Dystrophy Association [MDA277360]
- Duke-Coulter Translational Partnership Grant
- Hartwell Foundation Individual Biomedical Research Award
- March of Dimes Foundation Basil O'Connor Starter Scholar Award
- NIH Director's New Innovator Award [DP2-OD008586]
- Duke/UNC-Chapel Hill CTSA Consortium Collaborative Translational Research Award
- NIH Director's Pioneer Award [DP1-MH100706]
- NIH [R01DK097768, R01HL089221, P01HL112761, R01NS90634]
- Waterman Award from the NSF
- Keck Foundation
- Damon Runyon Foundation
- Searle Scholars Foundation
- Merkin Family Foundation
- Vallee Foundation
- Simons Foundation
- Paul G. Allen Foundation
- New York Stem Cell Foundation
- Bob Metcalfe
- Hope for Javier Foundation
- Hartwell Foundation Postdoctoral Fellowship
- American Heart Association Predoctoral Fellowship
- National Institute of General Medical Sciences [T32GM007753]
- Paul and Daisy Soros Fellowship
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Duchenne muscular dystrophy (DMD) is a devastating disease affecting about 1 out of 5000 male births and caused by mutations in the dystrophin gene. Genome editing has the potential to restore expression of a modified dystrophin gene from the native locus to modulate disease progression. In this study, adeno-associated virus was used to deliver the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system to the mdx mouse model of DMD to remove the mutated exon 23 from the dystrophin gene. This includes local and systemic delivery to adult mice and systemic delivery to neonatal mice. Exon 23 deletion by CRISPR-Cas9 resulted in expression of the modified dystrophin gene, partial recovery of functional dystrophin protein in skeletal myofibers and cardiac muscle, improvement of muscle biochemistry, and significant enhancement of muscle force. This work establishes CRISPR-Cas9-based genome editing as a potential therapy to treat DMD.
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