Engineering a transposon-associated TnpB-ωRNA system for efficient gene editing and phenotypic correction of a tyrosinaemia mouse model

Zhifang Li, Ruochen Guo, Xiaozhi Sun, Guoling Li, Zhuang Shao, Xiaona Huo, Rongrong Yang, Xinyu Liu, Xi Cao, Hainan Zhang, Weihong Zhang, Xiaoyin Zhang, Shuangyu Ma, Meiling Zhang, Yuanhua Liu, Yinan Yao, Jinqi Shi, Hui Yang, Chunyi Hu (), Yingsi Zhou () and Chunlong Xu ()
Additional contact information
Zhifang Li: Lingang Laboratory
Ruochen Guo: Lingang Laboratory
Xiaozhi Sun: Lingang Laboratory
Guoling Li: HuidaGene Therapeutics Inc
Zhuang Shao: Lingang Laboratory
Xiaona Huo: Lingang Laboratory
Rongrong Yang: Lingang Laboratory
Xinyu Liu: State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Xi Cao: Lingang Laboratory
Hainan Zhang: HuidaGene Therapeutics Inc
Weihong Zhang: HuidaGene Therapeutics Inc
Xiaoyin Zhang: Lingang Laboratory
Shuangyu Ma: Shanghai Key Laboratory of Reproductive Medicine, Shanghai JiaoTong University School of Medicine
Meiling Zhang: Innovative Research Team of High-level Local Universities in Shanghai, School of Medicine, Shanghai Jiao Tong University
Yuanhua Liu: State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Yinan Yao: State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Jinqi Shi: Lingang Laboratory
Hui Yang: State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Chunyi Hu: National University of Singapore
Yingsi Zhou: HuidaGene Therapeutics Inc
Chunlong Xu: Lingang Laboratory

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract Transposon-associated ribonucleoprotein TnpB is known to be the ancestry endonuclease of diverse Cas12 effector proteins from type-V CRISPR system. Given its small size (408 aa), it is of interest to examine whether engineered TnpB could be used for efficient mammalian genome editing. Here, we showed that the gene editing activity of native TnpB from Deinococcus radiodurans (ISDra2 TnpB) in mouse embryos was already higher than previously identified small-sized Cas12f1. Further stepwise engineering of noncoding RNA (ωRNA or reRNA) component of TnpB significantly elevated the nuclease activity of TnpB. Notably, an optimized TnpB-ωRNA system could be efficiently delivered in vivo with single adeno-associated virus (AAV) and corrected the disease phenotype in a tyrosinaemia mouse model. Thus, the engineered miniature TnpB system represents a new addition to the current genome editing toolbox, with the unique feature of the smallest effector size that facilitate efficient AAV delivery for editing of cells and tissues.

Date: 2024
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DOI: 10.1038/s41467-024-45197-z

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