Whole-brain in vivo base editing reverses autistic-like behaviors in mice
Whole-brain in vivo base editing reverses autistic-like behaviors in mice
Abstract Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder associated with deficits in social communication and stereotypical behaviors. Numerous ASD-related genetic mutations have been identified and genome editing methods have been developed but successful genome editing in the whole-brain scale to alleviate autistic-like behaviors in animal models has not been achieved. Here we report the development of a new CRISPR-mediated cytidine base editor (CBE) system, which converts C·G base pairs to T·A. We demonstrate the effectiveness of this system by targeting an ASD-associated de novo mutation in the MEF2C gene (c.104T>C, p.L35P). We constructed a Mef2c L35P knock-in mouse and observed that Mef2c L35P heterozygous mice displayed autistic-like behaviors, including deficits in social behaviors and repetitive behaviors. We programmed the CBE to edit the C·G base pairs of the mutated Mef2c gene (c.104T>C, p.L35P) to T·A base pairs and delivered it via a single dose intravenous injection of blood brain barrier (BBB)-crossing AAV-PHP.eB vector into the mouse brain. This treatment restored MEF2C protein levels and reversed impairments in social interactions and repetitive behaviors in Mef2c L35P heterozygous mice. Together, this work presents an in vivo gene editing strategy in which correcting a single nucleotide mutation in the whole-brain scale could be successfully achieved, further providing a new therapeutic framework for neurodevelopmental disorders.
Yuan Yiting、Yuan Bo、Shan Shifang、Xu Min、Chen Jinlong、Cheng Tianlin、Chen Zhifang、Qiu Zilong、Han Wenjian、Peng Wanling、Xue Zhenyu、Li Weike、Zhu Shujia、Wang Jincheng
Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of SciencesInstitute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of SciencesInstitute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of SciencesInstitute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of SciencesInstitute of Pediatrics, Children?ˉs Hospital, Institutes for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan UniversityInstitute of Pediatrics, Children?ˉs Hospital, Institutes for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan UniversityInstitute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of SciencesInstitute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of Sciences||National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University||Clinical Neuroscience Center, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineInstitute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of SciencesInstitute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of SciencesDepartment of Anesthesiology, Shanghai Ninth People?ˉs Hospital, Shanghai Jiao Tong University School of MedicineInstitute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of SciencesInstitute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of SciencesInstitute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of Sciences
神经病学、精神病学生物科学研究方法、生物科学研究技术基础医学
Yuan Yiting,Yuan Bo,Shan Shifang,Xu Min,Chen Jinlong,Cheng Tianlin,Chen Zhifang,Qiu Zilong,Han Wenjian,Peng Wanling,Xue Zhenyu,Li Weike,Zhu Shujia,Wang Jincheng.Whole-brain in vivo base editing reverses autistic-like behaviors in mice[EB/OL].(2025-03-28)[2025-05-05].https://www.biorxiv.org/content/10.1101/2022.01.25.477781.点此复制
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