CRISPR-Cpf1 correction of muscular dystrophy mutations in human cardiomyocytes and mice

Yu Zhang, Chengzu Long, Hui Li, John R. McAnally, Kedryn K. Baskin, John M. Shelton, Rhonda Bassel-Duby, Eric N. Olson

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numbere1602814
JournalScience advances
Volume3
Issue number4
DOIs
StatePublished - Apr 1 2017

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Clustered Regularly Interspaced Short Palindromic Repeats
Duchenne Muscular Dystrophy
Muscular Dystrophies
Cardiac Myocytes
Mutation
Inbred mdx Mouse
Induced Pluripotent Stem Cells
Dystrophin
Animal Disease Models
X-Linked Genes
Striated Muscle
Nonsense Codon
Dilated Cardiomyopathy
Exons
Animal Models

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Zhang, Y., Long, C., Li, H., McAnally, J. R., Baskin, K. K., Shelton, J. M., ... 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

CRISPR-Cpf1 correction of muscular dystrophy mutations in human cardiomyocytes and mice. / Zhang, Yu; Long, Chengzu; Li, Hui; McAnally, John R.; Baskin, Kedryn K.; Shelton, John M.; Bassel-Duby, Rhonda; Olson, Eric N.

In: Science advances, Vol. 3, No. 4, e1602814, 01.04.2017.

Research output: Contribution to journalArticle

Zhang Y, Long C, Li H, McAnally JR, Baskin KK, Shelton JM et al. CRISPR-Cpf1 correction of muscular dystrophy mutations in human cardiomyocytes and mice. Science advances. 2017 Apr 1;3(4). e1602814. https://doi.org/10.1126/sciadv.1602814
Zhang, Yu ; Long, Chengzu ; Li, Hui ; McAnally, John R. ; Baskin, Kedryn K. ; Shelton, John M. ; Bassel-Duby, Rhonda ; Olson, Eric N. / CRISPR-Cpf1 correction of muscular dystrophy mutations in human cardiomyocytes and mice. In: Science advances. 2017 ; Vol. 3, No. 4.
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