TadA reprogramming to generate potent miniature base editors with high precision

Shuqian Zhang, Liting Song, Bo Yuan, Cheng Zhang, Jixin Cao, Jinlong Chen, Jiayi Qiu, Yilin Tai, Jingqi Chen, Zilong Qiu (), Xing-Ming Zhao () and Tian-Lin Cheng ()
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Shuqian Zhang: Fudan University
Liting Song: Fudan University
Bo Yuan: Chinese Academy of Sciences
Cheng Zhang: Fudan University
Jixin Cao: Fudan University
Jinlong Chen: Fudan University
Jiayi Qiu: Fudan University
Yilin Tai: Fudan University
Jingqi Chen: Fudan University
Zilong Qiu: Chinese Academy of Sciences
Xing-Ming Zhao: Fudan University
Tian-Lin Cheng: Fudan University

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract Although miniature CRISPR-Cas12f systems were recently developed, the editing efficacy and targeting range of derived miniature cytosine and adenine base editors (miniCBEs and miniABEs) have not been comprehensively addressed. Moreover, functional miniCBEs have not yet be established. Here we generate various Cas12f-derived miniCBEs and miniABEs with improved editing activities and diversified targeting scopes. We reveal that miniCBEs generated with traditional cytidine deaminases exhibit wide editing windows and high off-targeting effects. To improve the editing signatures of classical CBEs and derived miniCBEs, we engineer TadA deaminase with mutagenesis screening to generate potent miniCBEs with high precision and minimized off-target effects. We show that newly designed miniCBEs and miniABEs are able to correct pathogenic mutations in cell lines and introduce genetic mutations efficiently via adeno-associated virus delivery in the brain in vivo. Together, this study provides alternative strategies for CBE development, expands the toolkits of miniCBEs and miniABEs and offers promising therapeutic tools for clinical applications.

Date: 2023
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DOI: 10.1038/s41467-023-36004-2

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