A series of precise and controllable base editors with split-TadA-8e.

Mol Ther Nucleic Acids

State Key Laboratory of Common Mechanisms Research for Major Diseases, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, China.

Published: September 2025


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Article Abstract

Adenine base editors (ABEs) enable efficient A-to-G base conversions in genomic DNA, serving as powerful tools for basic research and clinical disease treatment. TadA-8e with high processive and compatibility makes ABE8e to be the most widely used adenine base editor and has also facilitated the creation of more elegant base editors based on TadA-8e fusion, such as AYBE and eA&C-BEmax. However, ABE8e has more off-target events including DNA off-target and RNA off-target, which raises safety concerns for precision gene editing. Here, we split the TadA-8e of ABE8e (sABE8e) to enable controlled adenine base editing through rapamycin-induced dimerization between FRB and FKBP12. sABE8e has comparable on-target adenine editing activity to ABE8e while maintaining reduced DNA and RNA off-target effects. Harnessing this site of split TadA-8e, we have also developed controllable AYBE (sAYBE) and eA&C-BEmax (seA&C-BEmax), which both offer similar or slightly low base editing efficiency with decreased off-targets compared to AYBE or eA&C-BEmax. These precise and controllable base editing tools will advance the future application of base editors in basic research and clinical disease treatment.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC12408220PMC
http://dx.doi.org/10.1016/j.omtn.2025.102672DOI Listing

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