A modified glycosylase base editor without predictable DNA off-target effects

IF 3.5 4区生物学 Q1 Biochemistry, Genetics and Molecular Biology FEBS Letters Pub Date : 2024-06-30 DOI:10.1002/1873-3468.14970

Meng Lian, Tao Chen, Min Chen, Xiaohua Peng, Yang Yang, Xian Luo, Yue Chi, Jinling Wang, Chengcheng Tang, Xiaoqing Zhou, Kun Zhang, Chuan Qin, Liangxue Lai, Jizeng Zhou, Qingjian Zou

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Abstract

Glycosylase base editor (GBE) can induce C-to-G transversion in mammalian cells, showing great promise for the treatment of human genetic disorders. However, the limited efficiency of transversion and the possibility of off-target effects caused by Cas9 restrict its potential clinical applications. In our recent study, we have successfully developed TaC9-CBE and TaC9-ABE by separating nCas9 and deaminase, which eliminates the Cas9-dependent DNA off-target effects without compromising editing efficiency. We developed a novel GBE called TaC9-GBE^YE1, which utilizes the deaminase and UNG-nCas9 guided by TALE and sgRNA, respectively. TaC9-GBE^YE1 showed comparable levels of on-target editing efficiency to traditional GBE at 19 target sites, without any off-target effects caused by Cas9 or TALE. The TaC9-GBE^YE1 is a safe tool for gene therapy.

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改良的糖基化酶碱基编辑器不会产生可预测的 DNA 脱靶效应。

糖基化酶碱基编辑器（GBE）可在哺乳动物细胞中诱导 C-G 转换，在治疗人类遗传疾病方面前景广阔。然而，Cas9 的转基因效率有限，而且可能产生脱靶效应，这限制了其潜在的临床应用。在最近的研究中，我们通过分离 nCas9 和脱氨酶，成功开发了 TaC9-CBE 和 TaC9-ABE，在不影响编辑效率的前提下消除了依赖于 Cas9 的 DNA 脱靶效应。我们开发了一种名为 TaC9-GBEYE1 的新型 GBE，它分别利用 TALE 和 sgRNA 引导的脱氨酶和 UNG-nCas9。TaC9-GBEYE1 在 19 个靶位点的靶上编辑效率与传统的 GBE 相当，而且没有 Cas9 或 TALE 引起的任何脱靶效应。TaC9-GBEYE1 是一种安全的基因治疗工具。

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来源期刊

FEBS Letters 生物-生化与分子生物学

CiteScore

7.00

自引率

2.90%

发文量

303

审稿时长

1.0 months

期刊介绍： FEBS Letters is one of the world''s leading journals in molecular biology and is renowned both for its quality of content and speed of production. Bringing together the most important developments in the molecular biosciences, FEBS Letters provides an international forum for Minireviews, Research Letters and Hypotheses that merit urgent publication.