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

IF 6.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Molecular Therapy. Nucleic Acids Pub Date : 2025-08-12 eCollection Date: 2025-09-09 DOI:10.1016/j.omtn.2025.102672

Jinxin Wang, Qingjing He, Yuqiang Zeng, Youming Wu, Mufeng Wang, Wenqing Xu, Zhizhi Wang, Xiaohui Zhang

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引用次数: 0

Abstract

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

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一系列精确和可控的碱基编辑器与分裂- tada -8e。

腺嘌呤碱基编辑器（ABEs）能够实现基因组DNA中a碱基到g碱基的高效转化，是基础研究和临床疾病治疗的有力工具。TadA-8e的高进程性和兼容性使得ABE8e成为使用最广泛的腺嘌呤碱基编辑器，也促进了基于TadA-8e融合的更优雅的碱基编辑器的诞生，如AYBE和eA&C-BEmax。然而，ABE8e有更多的脱靶事件，包括DNA脱靶和RNA脱靶，这引发了对精确基因编辑的安全性担忧。在这里，我们分离ABE8e的TadA-8e (sABE8e)，通过雷帕霉素诱导的FRB和FKBP12之间的二聚化，实现受控的腺嘌呤碱基编辑。sABE8e具有与ABE8e相当的靶上腺嘌呤编辑活性，同时保持减少的DNA和RNA脱靶效应。利用这一分裂的TadA-8e位点，我们还开发了可控的AYBE （sAYBE）和eA&C-BEmax (seA&C-BEmax)，它们与AYBE或eA&C-BEmax相比，具有相似或略低的碱基编辑效率，并且脱靶率降低。这些精准可控的碱基编辑工具将推动未来碱基编辑器在基础研究和临床疾病治疗中的应用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Therapy. Nucleic Acids MEDICINE, RESEARCH & EXPERIMENTAL-

CiteScore

15.40

自引率

1.10%

发文量

336

审稿时长

20 weeks

期刊介绍： Molecular Therapy Nucleic Acids is an international, open-access journal that publishes high-quality research in nucleic-acid-based therapeutics to treat and correct genetic and acquired diseases. It is the official journal of the American Society of Gene & Cell Therapy and is built upon the success of Molecular Therapy. The journal focuses on gene- and oligonucleotide-based therapies and publishes peer-reviewed research, reviews, and commentaries. Its impact factor for 2022 is 8.8. The subject areas covered include the development of therapeutics based on nucleic acids and their derivatives, vector development for RNA-based therapeutics delivery, utilization of gene-modifying agents like Zn finger nucleases and triplex-forming oligonucleotides, pre-clinical target validation, safety and efficacy studies, and clinical trials.