Weiqi Zhang
Qiaoyan Yang
Yu Kang
Yanling Fan
Jingkuan Wei
Zunpeng Liu
Shaoxing Dai
Hao Li
Zifan Li
Lizhu Xu
Chu Chu
Jing Qu
Chenyang Si
Weizhi Ji
Guang-Hui Liu
Chengzu Long
Yuyu Niu
1 Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming 650500, China;
2 Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China;
3 Institute for Stem Cell and Regeneration, Chinese Academy of Science, Beijing 100101, China;
4 CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China;
5 China National Center for Bioinformation, Beijing 100101, China;
6 University of Chinese Academy of Sciences, Beijing 100049, China;
7 The Leon H Charney Division of Cardiology, New York University School of Medicine, New York, NY 10016, USA;
8 State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China;
9 State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China;
10 Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China;
11 Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY 10016, USA;
12 Department of Neurology, New York University School of Medicine, New York, NY 10016, USA
Funds: This work was supported by the National Key Research and Development Program (2016YFA0101401), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16010100), the National Key Research and Development Program (2018YFA0801403, 2018YFC2000100), the National Natural Science Foundation of China (Grant Nos. 81921006, 81625009, 91749202, 91949209, 81822018, 91749123, 81671377) and Youth Innovation Promotion Association of CAS (2016093).
Received Date: 2020-04-09
Rev Recd Date:2020-05-11
Abstract
Abstract
Many human genetic diseases, including HutchinsonGilford progeria syndrome (HGPS), are caused by single point mutations. HGPS is a rare disorder that causes premature aging and is usually caused by a de novo point mutation in the LMNA gene. Base editors (BEs) composed of a cytidine deaminase fused to CRISPR/Cas9 nickase are highly efficient at inducing C to T base conversions in a programmable manner and can be used to generate animal disease models with single amino-acid substitutions. Here, we generated the first HGPS monkey model by delivering a BE mRNA and guide RNA (gRNA) targeting the LMNA gene via microinjection into monkey zygotes. Five out of six newborn monkeys carried the mutation specifically at the target site. HGPS monkeys expressed the toxic form of lamin A, progerin, and recapitulated the typical HGPS phenotypes including growth retardation, bone alterations, and vascular abnormalities. Thus, this monkey model genetically and clinically mimics HGPS in humans, demonstrating that the BE system can efficiently and accurately generate patient-specific disease models in non-human primates.Keywords: base editing,
non-human primate,
HGPS
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