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Nat Med. 2019 Mar;25(3):427-432. doi: 10.1038/s41591-019-0344-3. Epub 2019 Feb 18.

Long-term evaluation of AAV-CRISPR genome editing for Duchenne muscular dystrophy.

Author information

1
Department of Biomedical Engineering, Duke University, Durham, NC, USA.
2
Center for Genomic and Computational Biology, Duke University, Durham, NC, USA.
3
Gene Therapy Center, University of North Carolina Chapel Hill, Chapel Hill, NC, USA.
4
Department of Surgery, Duke University Medical Center, Durham, NC, USA.
5
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA.
6
Department of Biomedical Engineering, Duke University, Durham, NC, USA. charles.gersbach@duke.edu.
7
Center for Genomic and Computational Biology, Duke University, Durham, NC, USA. charles.gersbach@duke.edu.
8
Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC, USA. charles.gersbach@duke.edu.

Abstract

Duchenne muscular dystrophy (DMD) is a monogenic disorder and a candidate for therapeutic genome editing. There have been several recent reports of genome editing in preclinical models of Duchenne muscular dystrophy1-6, however, the long-term persistence and safety of these genome editing approaches have not been addressed. Here we show that genome editing and dystrophin protein restoration is sustained in the mdx mouse model of Duchenne muscular dystrophy for 1 year after a single intravenous administration of an adeno-associated virus that encodes CRISPR (AAV-CRISPR). We also show that AAV-CRISPR is immunogenic when administered to adult mice7; however, humoral and cellular immune responses can be avoided by treating neonatal mice. Additionally, we describe unintended genome and transcript alterations induced by AAV-CRISPR that should be considered for the development of AAV-CRISPR as a therapeutic approach. This study shows the potential of AAV-CRISPR for permanent genome corrections and highlights aspects of host response and alternative genome editing outcomes that require further study.

PMID:
30778238
PMCID:
PMC6455975
DOI:
10.1038/s41591-019-0344-3
[Indexed for MEDLINE]
Free PMC Article

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