A motif preferred adenine base editor with minimal bystander and off-targets editing

Mengyu Shang, Yinuo Li, Qiuyu Cao, Jingxuan Ren, Yuqiang Zeng, Jinxin Wang, Rachel V. L. Gonzalez and Xiaohui Zhang ()
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Mengyu Shang: Chinese Academy of Medical Sciences & Peking Union Medical College
Yinuo Li: Chinese Academy of Medical Sciences & Peking Union Medical College
Qiuyu Cao: Chinese Academy of Medical Sciences & Peking Union Medical College
Jingxuan Ren: Chinese Academy of Medical Sciences & Peking Union Medical College
Yuqiang Zeng: Chinese Academy of Medical Sciences & Peking Union Medical College
Jinxin Wang: Chinese Academy of Medical Sciences & Peking Union Medical College
Rachel V. L. Gonzalez: Columbia University
Xiaohui Zhang: Chinese Academy of Medical Sciences & Peking Union Medical College

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract 47% of hereditable diseases are caused by single C•G-to-T•A base conversions, which means efficient A-to-G base editing tools (ABEs) have great potential for the treatment of these diseases. However, the existing efficient ABEs, while catalyzing targeted A-to-G conversion, cause high A or C bystander editing and off-target events, which poses safety concerns for their clinical applications. To overcome this shortcoming, we have developed ABE8e-YA (ABE8e with TadA-8e A48E) for efficient and accurate editing of As in YA motifs with YAY > YAR (Y = T or C, R = A or G) hierarchy through structure-oriented rational design. Compared with ABE3.1, which is currently the only ABE version with a YAC motif preference, ABE8e-YA exhibits an average A-to-G editing efficiency improvement of an up to 3.1-fold increase in the indicated YA motif while maintaining reduced bystander C editing and minimized DNA or RNA off-targets. Additionally, we demonstrate that ABE8e-YA efficiently and precisely corrects pathogenic mutations in human cells, suggesting its high suitability for addressing 9.3% of pathogenic point mutations, higher than that of ABE8e and ABE9. Moreover, by using ABE8e-YA, we efficiently and precisely generate hypocholesterolemia and tail-loss mouse models mimicking human-associated disease, as well as performed in vivo mouse proprotein convertase subtilisin/kexin type 9 (Pcsk9) base editing for hypercholesterolemia gene therapy. Together these data indicate its great potential in broad applications for disease modeling and gene therapy.

Date: 2025
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DOI: 10.1038/s41467-025-64203-6

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