美国麻省理工学院Robert Langer研究团队提出了以最小的基因组错误设计初始编辑器。相关论文于2025年9月17日发表在《自然》杂志上。

在这里，研究团队发现缺口端降解，与竞争性的5'链不稳定一致，可以通过cas9 -缺口酶突变来促进缺口定位。该课题组研究人员利用这一机制来设计高效的初级编辑器，其索引错误非常低。将这种错误抑制策略与最新的效率提升架构相结合，研究人员设计了下一代初始编辑器（vPE）。与以前的编辑器相比，vPE具有相当的效率，但索引错误降低了60倍，使编辑：索引比率高达543:1。

据了解，启动编辑通过将新序列写入被切割的DNA 3'末端的延伸，从而对基因组进行程序化修改。这些经过编辑的3'新链会取代竞争的5'链来安装编辑，然而，保留竞争的5'链的偏见会阻碍效率，并可能导致错误。

附：英文原文

Title: Engineered prime editors with minimal genomic errors

Author: Chauhan, Vikash P., Sharp, Phillip A., Langer, Robert

Issue&Volume: 2025-09-17

Abstract: Prime editors make programmed genome modifications by writing new sequences into extensions of nicked DNA 3′ ends1. These edited 3′ new strands must displace competing 5′ strands to install edits, yet a bias towards retaining the competing 5′ strands hinders efficiency and can cause indel errors2. Here we discover that nicked end degradation, consistent with competing 5′ strand destabilization, can be promoted by Cas9-nickase mutations that relax nick positioning. We exploit this mechanism to engineer efficient prime editors with strikingly low indel errors. Combining this error-suppressing strategy with the latest efficiency-boosting architecture, we design a next-generation prime editor (vPE). Compared with previous editors, vPE features comparable efficiency yet up to 60-fold lower indel errors, enabling edit:indel ratios as high as 543:1.

DOI: 10.1038/s41586-025-09537-3

Source: https://www.nature.com/articles/s41586-025-09537-3