Engineering TadA ortholog-derived cytosine base editor without motif preference and adenosine activity limitation

Guoling Li, Xue Dong, Jiamin Luo, Tanglong Yuan, Tong Li, Guoli Zhao, Hainan Zhang, Jingxing Zhou, Zhenhai Zeng, Shuna Cui, Haoqiang Wang, Yin Wang, Yuyang Yu, Yuan Yuan, Erwei Zuo (), Chunlong Xu (), Jinhai Huang () and Yingsi Zhou ()
Additional contact information
Guoling Li: Ltd.
Xue Dong: Ltd.
Jiamin Luo: Ltd.
Tanglong Yuan: Chinese Academy of Agricultural Sciences
Tong Li: Ltd.
Guoli Zhao: Chinese Academy of Medical Sciences
Hainan Zhang: Ltd.
Jingxing Zhou: Ltd.
Zhenhai Zeng: Chinese Academy of Medical Sciences
Shuna Cui: Ltd.
Haoqiang Wang: Ltd.
Yin Wang: Ltd.
Yuyang Yu: Ltd.
Yuan Yuan: Ltd.
Erwei Zuo: Chinese Academy of Agricultural Sciences
Chunlong Xu: Lingang Laboratory
Jinhai Huang: Chinese Academy of Medical Sciences
Yingsi Zhou: Ltd.

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: Abstract The engineered TadA variants used in cytosine base editors (CBEs) present distinctive advantages, including a smaller size and fewer off-target effects compared to cytosine base editors that rely on natural deaminases. However, the current TadA variants demonstrate a preference for base editing in DNA with specific motif sequences and possess dual deaminase activity, acting on both cytosine and adenosine in adjacent positions, limiting their application scope. To address these issues, we employ TadA orthologs screening and multi sequence alignment (MSA)-guided protein engineering techniques to create a highly effective cytosine base editor (aTdCBE) without motif and adenosine deaminase activity limitations. Notably, the delivery of aTdCBE to a humanized mouse model of Duchenne muscular dystrophy (DMD) mice achieves robust exon 55 skipping and restoration of dystrophin expression. Our advancement in engineering TadA ortholog for cytosine editing enriches the base editing toolkits for gene-editing therapy and other potential applications.

Date: 2024
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DOI: 10.1038/s41467-024-52485-1

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