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- Title
Engineering TadA ortholog-derived cytosine base editor without motif preference and adenosine activity limitation.
- Authors
Li, Guoling; Dong, Xue; Luo, Jiamin; Yuan, Tanglong; Li, Tong; Zhao, Guoli; Zhang, Hainan; Zhou, Jingxing; Zeng, Zhenhai; Cui, Shuna; Wang, Haoqiang; Wang, Yin; Yu, Yuyang; Yuan, Yuan; Zuo, Erwei; Xu, Chunlong; Huang, Jinhai; Zhou, Yingsi
- 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. 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.
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-52485-1