哈佛医学院George M. Church小组的最新研究提出了通过定向进化减少旁观者编辑的工程碱基编辑器。相关论文于2025年12月18日发表在《自然—生物技术》杂志上。

在这里，研究组提出了一种并行工程方法，优化引导RNAs和脱氨酶，在不牺牲活性的情况下最大限度地减少旁观者编辑。该课题组设计了一个3'扩展向导RNAs库，并确定了上下文相关的变体，提高了特异性。利用精确驱动的噬菌体辅助进化系统和蛋白质语言模型，该研究组进化出了比腺嘌呤碱基编辑器ABE8e精确两到三倍的腺嘌呤碱基编辑器变体，同时在体外的人类致病环境文库中保持高效率。他们的发现为碱基编辑器的精确工程建立了一个可扩展的框架，解决了基因组编辑中的一个主要挑战。

研究人员表示，碱基编辑器可以实现精确的基因组修饰，但受到旁观者编辑的限制，限制了它们的适用性。现有的提高精度的策略往往会损害效率，并且仍然高度依赖于序列。

附：英文原文

Title: Engineered base editors with reduced bystander editing through directed evolution

Author: Perrotta, Ramiro M., Vinke, Svenja, Ferreira, Raphal, Moret, Michal, Mahas, Ahmed, Chiappino-Pepe, Anush, Riedmayr, Lisa M., Mehra, Anna-Thrse, Lehmann, Louisa S., Church, George M.

Issue&Volume: 2025-12-18

Abstract: Base editors enable precise genome modification but are constrained by bystander edits that limit their applicability. Existing strategies to enhance precision often compromise efficiency and remain highly sequence dependent. Here we present a parallel engineering approach that optimizes both guide RNAs and the deaminase enzyme to minimize bystander editing without sacrificing activity. We designed a library of 3′-extended guide RNAs and identified context-dependent variants that improved specificity. Using a precision-driven phage-assisted evolution system and protein language models, we evolved adenine base editor variants two- to threefold more precise than adenine base editor ABE8e while maintaining high efficiency across a library of thousands of human pathogenic contexts in vitro. Our findings establish a scalable framework for precision engineering of base editors, addressing a major challenge in genome editing.

DOI: 10.1038/s41587-025-02937-w

Source: https://www.nature.com/articles/s41587-025-02937-w