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

文献类型： 外文期刊

作者： Li, Guoling 1 ; Dong, Xue 1 ; Luo, Jiamin 1 ; Yuan, Tanglong 2 ; Li, Tong 1 ; Zhao, Guoli 3 ; Zhang, Hainan 1 ; Zhou, Jingxing 1 ; Zeng, Zhenhai 3 ; Cui, Shuna 1 ; Wang, Haoqiang 1 ; Wang, Yin 1 ; Yu, Yuyang 1 ; Yuan, Yuan 1 ; Zuo, Erwei 2 ; Xu, Chunlong 6 ; Huang, Jinhai 3 ; Zhou, Yingsi 1 ;

作者机构： 1.HuidaGene Therapeut Co Ltd, Shanghai, Peoples R China

2.Chinese Acad Agr Sci, Agr Genom Inst Shenzhen, Guangdong Lab Lingnan Modern Agr, Shenzhen Branch,Key Lab Synthet Biol,Minist Agr &, Shenzhen, Peoples R China

3.Fudan Univ, Chinese Acad Med Sci, Eye & ENT Hosp, Eye Inst,Key Lab Myopia, Shanghai 200030, Peoples R China

4.Fudan Univ, Eye & ENT Hosp, Chinese Acad Med Sci, Dept Ophthalmol,Key Lab Myopia, Shanghai 200030, Peoples R China

5.Shanghai Res Ctr Ophthalmol & Optometry, Shanghai 200030, Peoples R China

6.Lingang Lab, Shanghai, Peoples R China

期刊名称：NATURE COMMUNICATIONS （ 影响因子：15.7； 五年影响因子：17.2 ）

ISSN：

年卷期： 2024 年 15 卷 1 期

页码：

收录情况： SCI

摘要： 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. Engineered TadA variants in cytosine base editors (CBEs) offer advantages like smaller size and reduced off-target effects. Here, authors develop an advanced CBE (aTdCBE) through ortholog screening and protein engineering, successfully enabling exon skipping in Duchenne muscular dystrophy model.

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