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CRISPR-Cpf1 correction of muscular dystrophy mutations in human cardiomyocytes and mice
Yu Zhang1,2,3, Chengzu Long1,2,3, Hui Li1,2,3
1Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
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.
Insights
Gene editing using Cpf1 corrected Duchenne muscular dystrophy (DMD) mutations in patient cells and mice. This approach restored dystrophin and improved muscle function, offering a promising step for DMD gene therapy.
Area of Science:
- Genetics
- Molecular Biology
- Biotechnology
Background:
- Duchenne muscular dystrophy (DMD) is a severe genetic disorder caused by mutations in the dystrophin gene (DMD).
- Cardiomyopathy is a frequent and lethal complication of DMD.
- Current treatments for DMD are limited, highlighting the need for novel therapeutic strategies.
Purpose of the Study:
- To evaluate the efficacy of Cpf1, a CRISPR-Cas12a system, for correcting DMD mutations.
- To assess the potential of Cpf1-mediated gene editing in patient-derived cells and an animal model of DMD.
- To determine if Cpf1 editing can restore dystrophin expression and improve cellular and organismal function.
Main Methods:
- Utilized Cpf1, a class 2 CRISPR effector, for genomic editing.
- Applied Cpf1 to correct DMD mutations in human induced pluripotent stem cells (iPSCs) and mdx mice.
- Differentiated edited iPSCs into cardiomyocytes to assess functional recovery.
- Performed germline editing in mdx mice to evaluate systemic correction.
Main Results:
- Cpf1 successfully corrected DMD mutations in human iPSCs by excising an exon or fixing a nonsense mutation.
- Restored dystrophin expression and enhanced contractile function in differentiated cardiomyocytes derived from edited iPSCs.
- Corrected key pathophysiological features of muscular dystrophy in mdx mice following germline editing.
- Demonstrated the efficiency of Cpf1-mediated gene editing in both human cells and a preclinical animal model.
Conclusions:
- Cpf1-mediated gene editing is an effective strategy for correcting DMD-causing mutations.
- This approach shows promise for restoring dystrophin expression and function in DMD.
- Cpf1 editing represents a significant advancement toward the therapeutic translation of gene editing for DMD.
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