Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany.
Gene and RNA Therapy Center, Faculty of Medicine, University of Tübingen, Tübingen, Germany.
Nat Biotechnol. 2023 Nov;41(11):1526-1542. doi: 10.1038/s41587-023-01927-0. Epub 2023 Sep 21.
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.
RNA 碱基编辑是指在完整的 RNA 分子内改写遗传信息，具有多种功能，如逃避内源性免疫系统和调节蛋白质功能。为了实现这一目标，人类细胞中发现了某些酶，这些酶能催化一种核苷酸碱基转化为另一种。这种自然过程可以被利用来操纵和重新编码靶转录物中的任何碱基。与 DNA 碱基编辑不同，引入 RNA 中的类似变化不是永久性的或可遗传的，而是允许可逆和可调节的效应，这对各种治疗应用具有吸引力。目前的 RNA 碱基编辑实践涉及腺嘌呤和胞嘧啶的脱氨作用，它们分别转化为肌苷和尿苷。在这篇综述中，我们总结了目前的靶向 RNA 碱基编辑策略，并强调了最近在提高编辑效率、精度、密码子靶向范围和体内递送到相关疾病组织方面的成就。除了工程化的编辑效应子，我们还专注于利用作用于 RNA 的内源性腺苷脱氨酶（ADAR）酶的策略，并讨论了应用这些工具在基础研究和治疗模式中的局限性和未来展望。我们预计该领域将很快实现第一个 RNA 碱基编辑药物，可能是针对一种明确的遗传疾病。然而，长期的挑战将是在该技术的安全和可调节剂量的方式下，找到其独特能力可用于调节信号转导、代谢或其他临床相关过程的最佳点。
