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

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