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Science. 2016 Jan 22;351(6271):403-7. doi: 10.1126/science.aad5143. Epub 2015 Dec 31.

In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy.

Author information

1
Department of Biomedical Engineering, Duke University, Durham, NC, USA. Center for Genomic and Computational Biology, Duke University, Durham, NC, USA.
2
Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO, USA.
3
Gene Therapy Center, Departments of Genetics, Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
4
Broad Institute of MIT and Harvard, Cambridge, MA, USA. Society of Fellows, Harvard University, Cambridge, MA, USA.
5
Broad Institute of MIT and Harvard, Cambridge, MA, USA. Graduate Program in Biophysics, Harvard Medical School, Boston, MA, USA. Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA, USA.
6
Broad Institute of MIT and Harvard, Cambridge, MA, USA. McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
7
Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO, USA. Department of Neurology, University of Missouri, Columbia, MO, USA.
8
Department of Biomedical Engineering, Duke University, Durham, NC, USA. Center for Genomic and Computational Biology, Duke University, Durham, NC, USA. Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC, USA. charles.gersbach@duke.edu.

Abstract

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.

PMID:
26721684
PMCID:
PMC4883596
DOI:
10.1126/science.aad5143
[Indexed for MEDLINE]
Free PMC Article

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