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Long-term evaluation of AAV-CRISPR genome editing for Duchenne muscular dystrophy.
Nat Med. 2019 03; 25(3):427-432.NMed

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.

Authors+Show Affiliations

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

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

30778238

Citation

Nelson, Christopher E., et al. "Long-term Evaluation of AAV-CRISPR Genome Editing for Duchenne Muscular Dystrophy." Nature Medicine, vol. 25, no. 3, 2019, pp. 427-432.
Nelson CE, Wu Y, Gemberling MP, et al. Long-term evaluation of AAV-CRISPR genome editing for Duchenne muscular dystrophy. Nat Med. 2019;25(3):427-432.
Nelson, C. E., Wu, Y., Gemberling, M. P., Oliver, M. L., Waller, M. A., Bohning, J. D., Robinson-Hamm, J. N., Bulaklak, K., Castellanos Rivera, R. M., Collier, J. H., Asokan, A., & Gersbach, C. A. (2019). Long-term evaluation of AAV-CRISPR genome editing for Duchenne muscular dystrophy. Nature Medicine, 25(3), 427-432. https://doi.org/10.1038/s41591-019-0344-3
Nelson CE, et al. Long-term Evaluation of AAV-CRISPR Genome Editing for Duchenne Muscular Dystrophy. Nat Med. 2019;25(3):427-432. PubMed PMID: 30778238.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Long-term evaluation of AAV-CRISPR genome editing for Duchenne muscular dystrophy. AU - Nelson,Christopher E, AU - Wu,Yaoying, AU - Gemberling,Matthew P, AU - Oliver,Matthew L, AU - Waller,Matthew A, AU - Bohning,Joel D, AU - Robinson-Hamm,Jacqueline N, AU - Bulaklak,Karen, AU - Castellanos Rivera,Ruth M, AU - Collier,Joel H, AU - Asokan,Aravind, AU - Gersbach,Charles A, Y1 - 2019/02/18/ PY - 2018/08/07/received PY - 2018/12/21/accepted PY - 2019/2/20/pubmed PY - 2019/5/14/medline PY - 2019/2/20/entrez SP - 427 EP - 432 JF - Nature medicine JO - Nat. Med. VL - 25 IS - 3 N2 - 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. SN - 1546-170X UR - https://www.unboundmedicine.com/medline/citation/30778238/Long_term_evaluation_of_AAV_CRISPR_genome_editing_for_Duchenne_muscular_dystrophy_ L2 - http://dx.doi.org/10.1038/s41591-019-0344-3 DB - PRIME DP - Unbound Medicine ER -