In vivo base editing of Chd3 rescues behavioural abnormalities in mice

Kan Yang^#^{1

2

3}, Wei-Ke Li^#⁴, Yi-Xiao Geng^#^{5

6}, Shu-Qian Zhang^#⁷, Shi-Hao Wu^#⁸, Yan-Bo Cheng^#^{9

10}, Jun-Wen Wang⁵, Zhan-Kui Xu¹¹, Wen-Xin Wang^{5

12}, Tan-Ying Zhang¹¹, Pei-Ye Wang^{5

6}, Yi-Ting Yuan⁵, Juan Fan¹¹, Jun Wu⁵, Ruo-Chuan Xu⁶, Yue-Fang Zhang⁵, Gong-Jia Tao⁵, Zheng-Hui Li¹³, Chen-Xi Lin⁶, Tian-Shu Li⁵, Xin-Yi Zhang⁴, Jie Li⁴, Ru Zhang¹¹, Wen-Xiu Yang⁸, Jia-Shuo Wen⁸, Zun-Yuan Yang¹⁴, Li Gong¹⁴, Wen Zeng¹⁴, Ai-Lian Du⁵, Jin-Song Li^{9

10}, Fei Li¹⁵, Tian-Lin Cheng¹⁶, Zilong Qiu^{17

18}

Affiliations

¹ Department of Developmental and Behavioral Pediatric and Child Primary Care, Brain and Behavioral Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children's Environmental Health of Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. kanyang@shsmu.edu.cn.
² Department of Neurology, Songjiang Hospital, Songjiang Research Institute, State Key Laboratory of Eye Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China. kanyang@shsmu.edu.cn.
³ College of Materials and Chemical Engineering, Hunan Institute of Engineering, Xiangtan, China. kanyang@shsmu.edu.cn.
⁴ Institute of Pediatrics, National Children's Medical Center, Children's Hospital, Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China.
⁵ Department of Neurology, Songjiang Hospital, Songjiang Research Institute, State Key Laboratory of Eye Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁶ College of Basic Medical Science, Shanghai Jiao Tong University School of medicine, Shanghai, China.
⁷ Department of Pediatrics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
⁸ School of Medicine, Yunnan University, Kunming, China.
⁹ State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
¹⁰ School of Life Science and Technology, Shanghai Tech University, Shanghai, China.
¹¹ College of Materials and Chemical Engineering, Hunan Institute of Engineering, Xiangtan, China.
¹² College of Biological Science and Medical Engineering, Donghua University, Shanghai, China.
¹³ Qianweichang College, Shanghai University, Shanghai, China.
¹⁴ PriMed Non-human Primate Research Center, Sichuan PriMed Shines Bio-tech, Ya'an, China.
¹⁵ Department of Developmental and Behavioral Pediatric and Child Primary Care, Brain and Behavioral Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children's Environmental Health of Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. feili@shsmu.edu.cn.
¹⁶ Institute of Pediatrics, National Children's Medical Center, Children's Hospital, Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China. chengtianlin@fudan.edu.cn.
¹⁷ Department of Developmental and Behavioral Pediatric and Child Primary Care, Brain and Behavioral Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children's Environmental Health of Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. qiuzilong@shsmu.edu.cn.
¹⁸ Department of Neurology, Songjiang Hospital, Songjiang Research Institute, State Key Laboratory of Eye Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China. qiuzilong@shsmu.edu.cn.

^# Contributed equally.

PMID: 41708849
DOI: 10.1038/s41586-026-10113-6

In vivo base editing of Chd3 rescues behavioural abnormalities in mice

Kan Yang et al. Nature. 2026.

. 2026 Feb 18.

doi: 10.1038/s41586-026-10113-6. Online ahead of print.

Authors

Affiliations

¹ Department of Developmental and Behavioral Pediatric and Child Primary Care, Brain and Behavioral Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children's Environmental Health of Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. kanyang@shsmu.edu.cn.
² Department of Neurology, Songjiang Hospital, Songjiang Research Institute, State Key Laboratory of Eye Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China. kanyang@shsmu.edu.cn.
³ College of Materials and Chemical Engineering, Hunan Institute of Engineering, Xiangtan, China. kanyang@shsmu.edu.cn.
⁴ Institute of Pediatrics, National Children's Medical Center, Children's Hospital, Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China.
⁵ Department of Neurology, Songjiang Hospital, Songjiang Research Institute, State Key Laboratory of Eye Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁶ College of Basic Medical Science, Shanghai Jiao Tong University School of medicine, Shanghai, China.
⁷ Department of Pediatrics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
⁸ School of Medicine, Yunnan University, Kunming, China.
⁹ State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
¹⁰ School of Life Science and Technology, Shanghai Tech University, Shanghai, China.
¹¹ College of Materials and Chemical Engineering, Hunan Institute of Engineering, Xiangtan, China.
¹² College of Biological Science and Medical Engineering, Donghua University, Shanghai, China.
¹³ Qianweichang College, Shanghai University, Shanghai, China.
¹⁴ PriMed Non-human Primate Research Center, Sichuan PriMed Shines Bio-tech, Ya'an, China.
¹⁵ Department of Developmental and Behavioral Pediatric and Child Primary Care, Brain and Behavioral Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children's Environmental Health of Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. feili@shsmu.edu.cn.
¹⁶ Institute of Pediatrics, National Children's Medical Center, Children's Hospital, Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China. chengtianlin@fudan.edu.cn.
¹⁷ Department of Developmental and Behavioral Pediatric and Child Primary Care, Brain and Behavioral Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children's Environmental Health of Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. qiuzilong@shsmu.edu.cn.
¹⁸ Department of Neurology, Songjiang Hospital, Songjiang Research Institute, State Key Laboratory of Eye Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China. qiuzilong@shsmu.edu.cn.

^# Contributed equally.

PMID: 41708849
DOI: 10.1038/s41586-026-10113-6

Abstract

Neurodevelopmental disorders that arise from de novo mutations in chromatin-remodelling genes lack targeted treatments. Snijders Blok-Campeau syndrome (SNIBCPS)¹, which is caused by pathogenic variants in CHD3, manifests with intellectual disability, autistic-like behaviours and motor deficits². Whether somatic gene correction can reverse such phenotypes in vivo remains unknown. Here we show that modelling the recurrent CHD3 variant p.R1025W in a humanized mouse model (Chd3^hR1025W/+) recapitulates key features of SNIBCPS, including reduced CHD3 protein levels and abnormalities in social communication, cognition and motor coordination. We engineered a TadA-embedded adenine base editor (TeABE) and delivered it brain-wide using a dual adeno-associated virus (AAV) system and achieved efficient on-target A•T-to-G•C correction across multiple cortical and hippocampal regions with minimal bystander activity. This intervention restored CHD3 levels and ameliorated behavioural abnormalities in vivo. Furthermore, intrathecal dual AAV delivery in nonhuman primates resulted in widespread neuronal transduction and efficient TeABE reconstitution, a result that supports its translational feasibility. These findings establish in vivo base editing as a viable therapeutic approach for CHD3-related neurodevelopmental disease. More broadly, they demonstrate that precise single-base correction in the postnatal brain can restore protein dosage and function, thereby offering a framework for the treatment of monogenic neurodevelopmental disorders.

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Conflict of interest statement

Competing interests: The authors declare no competing interests.

References

1. Snijders Blok, L. et al. CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language. Nat. Commun. 9, 4619 (2018). - PubMed - PMC - DOI
1. Tie, X. et al. Insights from a novel splicing variant and recurrent arginine variants in the CHD3 gene causing Snijders Blok–Campeau syndrome. Am. J. Med. Genet. https://doi.org/10.1002/ajmg.a.63930 (2024).
1. Gillentine, M. A., Wang, T. & Eichler, E. E. Estimating the prevalence of de novo monogenic neurodevelopmental disorders from large cohort studies. Biomedicines https://doi.org/10.3390/biomedicines10112865 (2022).
1. Coursimault, J. et al. Hypersociability associated with developmental delay, macrocephaly and facial dysmorphism points to CHD3 mutations. Eur. J. Med. Genet. 64, 104166 (2021). - PubMed - DOI
1. Mizukami, M. et al. A de novo CHD3 variant in a child with intellectual disability, autism, joint laxity, and dysmorphisms. Brain Dev. 43, 563–565 (2021). - PubMed - DOI

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In vivo base editing of Chd3 rescues behavioural abnormalities in mice

Affiliations

In vivo base editing of Chd3 rescues behavioural abnormalities in mice

Authors

Affiliations

Abstract

Conflict of interest statement

References

LinkOut - more resources

Full Text Sources

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