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CRISPR-Cpf1 correction of muscular dystrophy mutations in human cardiomyocytes and mice.
Sci Adv. 2017 Apr; 3(4):e1602814.SA

Abstract

Duchenne muscular dystrophy (DMD), caused by mutations in the X-linked dystrophin gene (DMD), is characterized by fatal degeneration of striated muscles. Dilated cardiomyopathy is one of the most common lethal features of the disease. We deployed Cpf1, a unique class 2 CRISPR (clustered regularly interspaced short palindromic repeats) effector, to correct DMD mutations in patient-derived induced pluripotent stem cells (iPSCs) and mdx mice, an animal model of DMD. Cpf1-mediated genomic editing of human iPSCs, either by skipping of an out-of-frame DMD exon or by correcting a nonsense mutation, restored dystrophin expression after differentiation to cardiomyocytes and enhanced contractile function. Similarly, pathophysiological hallmarks of muscular dystrophy were corrected in mdx mice following Cpf1-mediated germline editing. These findings are the first to show the efficiency of Cpf1-mediated correction of genetic mutations in human cells and an animal disease model and represent a significant step toward therapeutic translation of gene editing for correction of DMD.

Authors+Show Affiliations

Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28439558

Citation

Zhang, Yu, et al. "CRISPR-Cpf1 Correction of Muscular Dystrophy Mutations in Human Cardiomyocytes and Mice." Science Advances, vol. 3, no. 4, 2017, pp. e1602814.
Zhang Y, Long C, Li H, et al. CRISPR-Cpf1 correction of muscular dystrophy mutations in human cardiomyocytes and mice. Sci Adv. 2017;3(4):e1602814.
Zhang, Y., Long, C., Li, H., McAnally, J. R., Baskin, K. K., Shelton, J. M., Bassel-Duby, R., & Olson, E. N. (2017). CRISPR-Cpf1 correction of muscular dystrophy mutations in human cardiomyocytes and mice. Science Advances, 3(4), e1602814. https://doi.org/10.1126/sciadv.1602814
Zhang Y, et al. CRISPR-Cpf1 Correction of Muscular Dystrophy Mutations in Human Cardiomyocytes and Mice. Sci Adv. 2017;3(4):e1602814. PubMed PMID: 28439558.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CRISPR-Cpf1 correction of muscular dystrophy mutations in human cardiomyocytes and mice. AU - Zhang,Yu, AU - Long,Chengzu, AU - Li,Hui, AU - McAnally,John R, AU - Baskin,Kedryn K, AU - Shelton,John M, AU - Bassel-Duby,Rhonda, AU - Olson,Eric N, Y1 - 2017/04/12/ PY - 2016/11/13/received PY - 2017/02/14/accepted PY - 2017/4/26/entrez PY - 2017/4/26/pubmed PY - 2018/10/10/medline KW - Duchenne muscular dystrophy KW - Skeletal muscle KW - dystrophin KW - exon skipping KW - guide RNA KW - iPSC SP - e1602814 EP - e1602814 JF - Science advances JO - Sci Adv VL - 3 IS - 4 N2 - Duchenne muscular dystrophy (DMD), caused by mutations in the X-linked dystrophin gene (DMD), is characterized by fatal degeneration of striated muscles. Dilated cardiomyopathy is one of the most common lethal features of the disease. We deployed Cpf1, a unique class 2 CRISPR (clustered regularly interspaced short palindromic repeats) effector, to correct DMD mutations in patient-derived induced pluripotent stem cells (iPSCs) and mdx mice, an animal model of DMD. Cpf1-mediated genomic editing of human iPSCs, either by skipping of an out-of-frame DMD exon or by correcting a nonsense mutation, restored dystrophin expression after differentiation to cardiomyocytes and enhanced contractile function. Similarly, pathophysiological hallmarks of muscular dystrophy were corrected in mdx mice following Cpf1-mediated germline editing. These findings are the first to show the efficiency of Cpf1-mediated correction of genetic mutations in human cells and an animal disease model and represent a significant step toward therapeutic translation of gene editing for correction of DMD. SN - 2375-2548 UR - https://www.unboundmedicine.com/medline/citation/28439558/CRISPR_Cpf1_correction_of_muscular_dystrophy_mutations_in_human_cardiomyocytes_and_mice_ L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/28439558/ DB - PRIME DP - Unbound Medicine ER -