title: Functional disruption of the dystrophin gene in rhesus monkey using CRISPR/Cas9.
abstract: 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.
authors: Yunnan Key Laboratory of Primate Biomedical Research, Kunming 650500, China, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650500, China, Kunming Biomed International and National Engineering Research Center of Biomedicine and Animal Science, Kunming, 650500, China and.
authors: Yongchang
authors: Y
authors: Chen
authors: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 10010, China.
authors: Yinghui
authors: Y
authors: Zheng
authors: Yunnan Key Laboratory of Primate Biomedical Research, Kunming 650500, China, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650500, China, Kunming Biomed International and National Engineering Research Center of Biomedicine and Animal Science, Kunming, 650500, China and.
authors: Yu
authors: Y
authors: Kang
authors: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 10010, China.
authors: Weili
authors: W
authors: Yang
authors: Yunnan Key Laboratory of Primate Biomedical Research, Kunming 650500, China, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650500, China, Kunming Biomed International and National Engineering Research Center of Biomedicine and Animal Science, Kunming, 650500, China and.
authors: Yuyu
authors: Y
authors: Niu
authors: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 10010, China.
authors: Xiangyu
authors: X
authors: Guo
authors: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 10010, China.
authors: Zhuchi
authors: Z
authors: Tu
authors: Yunnan Key Laboratory of Primate Biomedical Research, Kunming 650500, China, Kunming Biomed International and National Engineering Research Center of Biomedicine and Animal Science, Kunming, 650500, China and.
authors: Chenyang
authors: C
authors: Si
authors: Yunnan Key Laboratory of Primate Biomedical Research, Kunming 650500, China, Kunming Biomed International and National Engineering Research Center of Biomedicine and Animal Science, Kunming, 650500, China and.
authors: Hong
authors: H
authors: Wang
authors: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 10010, China.
authors: Ruxiao
authors: R
authors: Xing
authors: Yunnan Key Laboratory of Primate Biomedical Research, Kunming 650500, China, Kunming Biomed International and National Engineering Research Center of Biomedicine and Animal Science, Kunming, 650500, China and.
authors: Xiuqiong
authors: X
authors: Pu
authors: Department of Physiology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
authors: Shang-Hsun
authors: SH
authors: Yang
authors: Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, 30322, USA.
authors: Shihua
authors: S
authors: Li
authors: Yunnan Key Laboratory of Primate Biomedical Research, Kunming 650500, China, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650500, China, Kunming Biomed International and National Engineering Research Center of Biomedicine and Animal Science, Kunming, 650500, China and xli2@emory.edu wji@kbimed.com.
authors: Weizhi
authors: W
authors: Ji
authors: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 10010, China, Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, 30322, USA, xli2@emory.edu wji@kbimed.com.
authors: Xiao-Jiang
authors: XJ
authors: Li
mesh_terms: D000818:Animals; D064112:Clustered Regularly Interspaced Short Palindromic Repeats; D004195:Disease Models, Animal; D016189:Dystrophin / Q000235:genetics* / Q000378:metabolism; D004720:Endonucleases / Q000378:metabolism*; D005260:Female; D018390:Gene Targeting / Q000379:methods*; D006801:Humans; D008253:Macaca mulatta / Q000235:genetics* / Q000378:metabolism; D008297:Male; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000378:metabolism; D009154:Mutation
chemical_list: D016189:Dystrophin; D004720:Endonucleases