近日，上海自然科学院教授李大力及其研究小组开发出设计用于体内基因治疗的光激活a -to- i RNA碱基编辑器。2025年3月31日出版的《自然—生物技术》杂志发表了这项成果。

在这里，该课题组人员开发了一种光激活的RNA腺苷碱基编辑器（PA-rABE），利用紧凑的Cas13变体和分裂的ADAR2脱氨酶为主题的磁体系统，通过蓝光诱导的二聚化激活。PA-rABE实现了对内源性RNA的高效编辑，并具有最小的旁观者编辑和脱靶效应。PA-rABE通过编辑内源性CTNNB1基因的磷酸化位点，在体内稳定β-catenin蛋白并激活Wnt信号。利用腺相关病毒载体将PA-rABE与含有过早终止密码子的hF9变体一起传递，课题组发现在光照下血友病B小鼠的凝血缺陷得到改善。总之，PA-rABE为多种生物医学应用提供了一种可控的RNA碱基编辑技术，实现了可逆和时空特异性的调制。

据悉，调控外源性和内源性基因表达是提高基因治疗安全性和有效性的重要途径。目前的化学诱导系统受到小分子的快速扩散和扩展代谢以及相关副作用的限制。

附：英文原文

Title: Engineering a photoactivatable A-to-I RNA base editor for gene therapy in vivo

Author: Li, Huiying, Qiu, Yuhao, Song, Bowen, Quan, Xinyi, Zhang, Dan, Li, Xinru, Yang, Jingyun, Liu, Xiaohong, Zeng, Zhiyang, Jing, Ji, Yin, Shuming, Dai, Qi, Wang, Liren, Han, Honghui, Ye, Haifeng, Sun, Zhenliang, Cheng, Yiyun, Zhang, Xueli, Du, Bing, Liu, Mingyao, Li, Dali

Issue&Volume: 2025-03-31

Abstract: Tunable and reversible regulation of exogenous and endogenous gene expression would be useful for improving the safety and efficacy of gene therapy. Current chemically inducible systems are limited by the rapid diffusion and extended metabolism of small molecules, and associated side effects. Here we develop a photoactivatable RNA adenosine base editor (PA-rABE) by harnessing a compact Cas13 variant and a split ADAR2 deaminase fused with the Magnets system, which is activated through blue-light-induced dimerization. PA-rABE achieves highly efficient editing on endogenous RNA with minimal bystander editing and off-target effects. By editing a phosphorylation site of the endogenous CTNNB1 gene, PA-rABE stabilizes the β-catenin protein and activates Wnt signaling in vivo. Using adeno-associated virus vectors to deliver PA-rABE along with an hF9 variant containing a premature termination codon, we show amelioration of clotting defects in hemophilia B mice upon illumination. In summary, PA-rABE offers a controlled RNA base-editing technology for diverse biomedical applications, enabling reversible and spatiotemporally specific modulation.

DOI: 10.1038/s41587-025-02610-2

Source: https://www.nature.com/articles/s41587-025-02610-2