A split and inducible adenine base editor for precise in vivo base editing

Hongzhi Zeng, Qichen Yuan, Fei Peng, Dacheng Ma, Ananya Lingineni, Kelly Chee, Peretz Gilberd, Emmanuel C. Osikpa, Zheng Sun () and Xue Gao ()
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Hongzhi Zeng: Rice University
Qichen Yuan: Rice University
Fei Peng: Baylor College of Medicine
Dacheng Ma: Rice University
Ananya Lingineni: Rice University
Kelly Chee: Rice University
Peretz Gilberd: Rice University
Emmanuel C. Osikpa: Rice University
Zheng Sun: Baylor College of Medicine
Xue Gao: Rice University

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract DNA base editors use deaminases fused to a programmable DNA-binding protein for targeted nucleotide conversion. However, the most widely used TadA deaminases lack post-translational control in living cells. Here, we present a split adenine base editor (sABE) that utilizes chemically induced dimerization (CID) to control the catalytic activity of the deoxyadenosine deaminase TadA-8e. sABE shows high on-target editing activity comparable to the original ABE with TadA-8e (ABE8e) upon rapamycin induction while maintaining low background activity without induction. Importantly, sABE exhibits a narrower activity window on DNA and higher precision than ABE8e, with an improved single-to-double ratio of adenine editing and reduced genomic and transcriptomic off-target effects. sABE can achieve gene knockout through multiplex splice donor disruption in human cells. Furthermore, when delivered via dual adeno-associated virus vectors, sABE can efficiently convert a single A•T base pair to a G•C base pair on the PCSK9 gene in mouse liver, demonstrating in vivo CID-controlled DNA base editing. Thus, sABE enables precise control of base editing, which will have broad implications for basic research and in vivo therapeutic applications.

Date: 2023
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DOI: 10.1038/s41467-023-41331-5

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