哈佛大学和麻省理工学院的布罗德研究所David R. Liu小组近日取得一项新成果。经过不懈努力，他们提出了基于先导编辑安装抑制性tRNA实现疾病无关型基因组编辑。相关论文于2025年11月19日发表于国际顶尖学术期刊《自然》杂志上。

在这里，研究人员提出了引物编辑介导的过早终止密码子（PERT）的读透，这是一种通过主题化引物编辑永久地将可缺性的内源性tRNA转化为优化的sup-tRNA，以疾病不可知的方式拯救无义突变的策略。通过对所有418种人类tRNAs变体的迭代筛选，鉴定出具有最强的超tRNAs潜力的tRNAs。课题组人员优化了引物编辑剂，在没有过表达的情况下将工程化的sup-tRNA安装在单个基因组位点上，并在Batten病、Tay-Sachs病和囊性纤维化的人类细胞模型中观察到过早终止密码子的高效读取和蛋白质拯救。在体内递送单个引物编辑器，将内源性同源tRNA转化为超tRNA，广泛地挽救了Hurler综合征模型中的疾病病理。PERT没有诱导检测到的天然终止密码子的读通，也没有引起显著的转录组学或蛋白质组学变化。他们的发现表明，疾病不可知的治疗性基因组编辑方法具有潜力，这种方法只需要一种物质组成就可以治疗多种遗传疾病。

据介绍，精确的基因组编辑技术，如碱基编辑和引物编辑，可以纠正大多数致病基因变异，但由于需要为每种突变开发新的治疗药物，它们的广泛临床应用受到阻碍。对于由过早终止密码子引导的疾病，抑制tRNAs（sup- tRNAs）提供了一种更普遍的策略。然而，现有的靶向sup- tRNAs的治疗方法需要终身给药，或者表现出适度的效力，这就需要潜在的毒性过表达。

附：英文原文

Title: Prime editing-installed suppressor tRNAs for disease-agnostic genome editing

Author: Pierce, Sarah E., Erwood, Steven, Oye, Keyede, An, Meirui, Krasnow, Nicholas, Zhang, Emily, Raguram, Aditya, Seelig, Davis, Osborn, Mark J., Liu, David R.

Issue&Volume: 2025-11-19

Abstract: Precise genome-editing technologies such as base editing1,2 and prime editing3 can correct most pathogenic gene variants, but their widespread clinical application is impeded by the need to develop new therapeutic agents for each mutation. For diseases that are caused by premature stop codons, suppressor tRNAs (sup-tRNAs) offer a more general strategy. Existing approaches to use sup-tRNAs therapeutically, however, require lifelong administration4,5 or show modest potency, necessitating potentially toxic overexpression. Here we present prime editing-mediated readthrough of premature termination codons (PERT), a strategy to rescue nonsense mutations in a disease-agnostic manner by using prime editing to permanently convert a dispensable endogenous tRNA into an optimized sup-tRNA. Iterative screening of thousands of variants of all 418 human tRNAs identified tRNAs with the strongest sup-tRNA potential. We optimized prime editing agents to install an engineered sup-tRNA at a single genomic locus without overexpression and observed efficient readthrough of premature termination codons and protein rescue in human cell models of Batten disease, Tay–Sachs disease and cystic fibrosis. In vivo delivery of a single prime editor that converts an endogenous mouse tRNA into a sup-tRNA extensively rescued disease pathology in a model of Hurler syndrome. PERT did not induce detected readthrough of natural stop codons or cause significant transcriptomic or proteomic changes. Our findings suggest the potential of disease-agnostic therapeutic genome-editing approaches that require only a single composition of matter to treat diverse genetic diseases.

DOI: 10.1038/s41586-025-09732-2

Source: https://www.nature.com/articles/s41586-025-09732-2