2026年9月9日，美国哥伦比亚大学Dieter Egli等科学家在《自然》（Nature）发表研究，发现在人类胚胎中可对PCSK9基因实现高效碱基编辑，且编辑后的胚胎能正常发育至囊胚阶段。

基于Cas9的工具能够实现可编程的DNA损伤，用于研究修复结果、基因功能和基因组校正。在人类胚胎中，Cas9诱导的DNA双链断裂具有基因毒性，会导致频繁的非整倍体和大片段缺失。在此，研究人员评估了碱基编辑器在人类胚胎PCSK9和HBG位点引入的切口和错配所导致的DNA修复结果。在受精时将ABE8e-V106W以蛋白质形式递送，实现了对所有PCSK9等位基因的编辑，支持发育至囊胚阶段以及纯合编辑干细胞系的衍生。尽管发生了罕见的靶向染色体断裂和染色体异常，但未检测到插入或缺失。然而，旁观者和脱靶位点的编辑是嵌合性的，并且将编辑器以mRNA形式引入会因不依赖向导的脱氨酶活性而导致频繁的胚胎停滞。因此，与Cas9诱导的DNA断裂不同，碱基编辑器诱导的损伤能够被高效修复。然而，可能对基因组和发育产生不良后果，目前排除了其在生殖中的临床使用。

附：英文原文

Title: Highly efficient base editing at PCSK9 and normal human embryo development

Author: Jerabek, Stepan, Jung, Chanju, Kappy, Michelle, Zhao, Qiaojin, Sung, Julie, Wang, Ning, Kim, Euihyun, Kim, Jimin, Kulmann, Marcos Iuri Roos, King, Madeleine Bliss, McAndrew, Mitchell John, Li, Meng, Bhatele, Sakshi, Isado, Melisa, Jang, Hong-Su, Dolezal, Michal, Prosser, Robert, Xu, Shuangyi, Hwang, Gue-Ho, Pichova, Iva, Xu, Jia, Marin, Diego, Woo, Jae-Sung, Bae, Sangsu, Treff, Nathan, Lapinaite, Audrone, Egli, Dieter

Issue&Volume: 2026-09-09

Abstract: Cas9-based tools enable programmable DNA lesions for studying repair outcomes, gene function, and genome correction. In human embryos, Cas9-induced DNA double-strand breaks are genotoxic, causing frequent aneuploidy and large deletions1,2. Here, we evaluate DNA repair outcomes at nicks and mismatches introduced by base editors at the PCSK9 and HBG loci in human embryos. Delivering ABE8e-V106W as a protein at fertilization achieved editing at all PCSK9 alleles, supporting development to the blastocyst stage and the derivation of homozygous edited stem cell lines. No insertions or deletions were detected, although rare on-target chromosome breakage and chromosomal abnormalities occurred. Nevertheless, editing at bystander and off-target sites was mosaic, and the introduction of the editor as mRNA caused frequent embryo arrest due to guide-independent deaminase activity. Thus, unlike Cas9-induced DNA breaks, base editor-induced lesions are efficiently repaired. However, undesirable consequences for the genome and development can occur, currently precluding clinical use in reproduction.

DOI: 10.1038/s41586-026-11118-x

Source: https://www.nature.com/articles/s41586-026-11118-x