(394h) A split and inducible adenine base editor for precise in vivo base editin
AIChE Annual Meeting
2023
2023 AIChE Annual Meeting
Food, Pharmaceutical & Bioengineering Division
Biomolecular Engineering II: The design, modulation, and analysis of engineered proteins and peptides for therapeutic applications
Wednesday, November 8, 2023 - 4:42pm to 5:00pm
1Department of Chemical and Biomolecular Engineering, Rice University, Houston, Texas 77005, USA
2Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine, Houston, Texas 77030, USA
3Department of Bioengineering, Rice University, Houston, Texas 77005, USA
4Department of Biosciences, Rice University, Houston, Texas 77005, USA
5Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA
6Department of Chemistry, Rice University, Houston, TX 77005, USA
â These authors contributed equally.
* To whom correspondence should be addressed: xue.gao@rice.edu (X.G.), zheng.sun@bcm.edu (Z.S.)
Abstract Text
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 Aâ¢T base pair to a Gâ¢C base pair on the PCSK9 gene in mouse liver, demonstrating the first 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.
Keywords
chemically induced dimerization | adenine base editor | gene therapy | protein engineering | inducible gene editing
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