RNA base editing refers to the rewriting of genetic information within an intact RNA molecule and serves various functions, such as evasion of the endogenous immune system and regulation of protein function. To achieve this, certain enzymes have been discovered in human cells that catalyze the conversion of one nucleobase into another. This natural process could be exploited to manipulate and recode any base in a target transcript. In contrast to DNA base editing, analogous changes introduced in RNA are not permanent or inheritable but rather allow reversible and doseable effects that appeal to various therapeutic applications. The current practice of RNA base editing involves the deamination of adenosines and cytidines, which are converted to inosines and uridines, respectively. In this Review, we summarize current site-directed RNA base-editing strategies and highlight recent achievements to improve editing efficiency, precision, codon-targeting scope and in vivo delivery into disease-relevant tissues. Besides engineered editing effectors, we focus on strategies to harness endogenous adenosine deaminases acting on RNA (ADAR) enzymes and discuss limitations and future perspectives to apply the tools in basic research and as a therapeutic modality. We expect the field to realize the first RNA base-editing drug soon, likely on a well-defined genetic disease. However, the long-term challenge will be to carve out the sweet spot of the technology where its unique ability is exploited to modulate signaling cues, metabolism or other clinically relevant processes in a safe and doseable manner.
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We thank the University of Tübingen, the Deutsche Forschungsgemeinschaft (STA 1053/3-1, STA 1053/3-2, STA 1053/7-1, STA 1053/10-1, STA 1053/11-1, STA 1053/14-1), the European Research Council (CoG no. 647328, PoC no. 101069246), the VolkswagenStiftung (grant no. 96 876) and the International Rett Syndrome Foundation (grant no. 3806) for continuous generous support for our RNA base-editing research program. All figures were created with https://biorender.com. Fig. 5a was reprinted (adapted) with permission from Doherty et al.80 (copyright 2023, American Chemical Society). Additionally, we thank J.M. Preuss and D.T. Hofacker for proofreading as well as the other members of the Stafforst laboratory for insightful discussions.
L.S.P. is an inventor on patents related to RNA base editing. T.S. is a cofounder and shareholder of and consultant to AIRNA Bio and an inventor on patents related to RNA base editing.
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Pfeiffer, L.S., Stafforst, T. Precision RNA base editing with engineered and endogenous effectors. Nat Biotechnol 41, 1526–1542 (2023). https://doi.org/10.1038/s41587-023-01927-0