Functional disruption of the dystrophin gene in rhesus monkey using CRISPR/Cas9
Open accessAbstract
CRISPR/Cas9 has been used to genetically modify genomes in a variety of species, including non-human primates. Unfortunately, this new technology does cause mosaic mutations, and we do not yet know whether such mutations can functionally disrupt the targeted gene or cause the pathology seen in human disease. Addressing these issues is necessary if we are to generate large animal models of human diseases using CRISPR/Cas9. Here we used CRISPR/Cas9 to target the monkey dystrophin gene to create mutations that lead to Duchenne muscular dystrophy (DMD), a recessive X-linked form of muscular dystrophy. Examination of the relative targeting rate revealed that Crispr/Cas9 targeting could lead to mosaic mutations in up to 87% of the dystrophin alleles in monkey muscle. Moreover, CRISPR/Cas9 induced mutations in both male and female monkeys, with the markedly depleted dystrophin and muscle degeneration seen in early DMD. Our findings indicate that CRISPR/Cas9 can efficiently generate monkey models of human diseases, regardless of inheritance patterns. The presence of degenerated muscle cells in newborn Cas9-targeted monkeys suggests that therapeutic interventions at the early disease stage may be effective at alleviating the myopathy.
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Genome editing in nonhuman primates has been used to generate models of Duchenne muscular dystrophy by dystrophin disruption, microcephaly by MCPH1 disruption, and Rett syndrome by MECP2 disruption.
“used to generate models of neurological and related diseases: disruption of the dystrophin gene to model Duchenne muscular dystrophy29, disruption of the MCPH1 gene to model microcephaly30, and disruption of the MECP2 gene to model Rett syndrome31.”
From CRISPR-based functional genomics for neurological disease (2020) · cites this paper as [29]
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- Authors
- Chen, Y., Zheng, Y., Kang, Y., Yang, W., Niu, Y., Guo, X., Tu, Z., Si, C., Wang, H., Xing, R., Pu, X., Yang, S.-H., Li, S., Ji, W., & Li, X.-J.
- Affiliations
- Kunming University of Science and Technology (CN)
- Chinese Academy of Sciences (CN)
- National Cheng Kung University (TW)
- Emory University (US)
- Corresponding author
- Ji, Weizhi
- Li, Xiao-Jiang
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-04-09
- Volume
- 24
- Issue
- 13
- Pages
- 3764-3774
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC5007610
- OpenAlex
- W2121066313
- Cited by
- 241
- References
- 29
- Citations by year
- 2026: 12 · 2025: 8 · 2024: 14 · 2023: 19 · 2022: 23 · 2021: 27 · 2020: 24 · 2019: 20 · 2018: 26 · 2017: 30 · 2016: 25 · 2015: 13
- FWCI
- 13.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (2012AA020701, 91332206, 31271599, U1302227, 2012CBA01304)
- Chinese Academy of Sciences (XDB13000000, 2012CBA01304)
- National Institute on Aging (R01AG031153)
- National Institute of Neurological Disorders and Stroke (R01NS041669, R01NS036232, R01NS045016, R01NS095181, P30NS055077)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Animal Genetics and Reproduction
- Keywords
- CRISPR/Cas9, dystrophin gene, Duchenne muscular dystrophy, rhesus monkeys, genetic mosaicism, disease modeling, X-linked muscular dystrophy, muscle degeneration, targeted mutagenesis, nonhuman primate model
- MeSH terms
- Animals, Disease Models, Animal, Endonucleases, Female, Humans, Macaca mulatta, Male, Mutation, Dystrophin, Gene Targeting, Muscular Dystrophy, Duchenne, Clustered Regularly Interspaced Short Palindromic Repeats
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