美国哈佛大学David R. Liu研究团队近日取得一项新成果。经过不懈努力，他们探明了对导致亨廷顿氏病和弗里德赖希共济失调的三核苷酸重复序列进行碱基编辑，可减少患者细胞和小鼠体内的体细胞重复扩增。该研究于2025年5月26日发表于国际一流学术期刊《自然—遗传学》杂志上。

在这里，研究团队对胞嘧啶和腺嘌呤碱基进行编辑，以减少患者细胞和小鼠中TNR的重复。基础编辑器在CAG和GAA重复处引入了G•C>A•T和A•T>G•C中断，模仿人类自然存在的稳定的非致病性等位基因。AAV9在Htt中提供优化的碱基编辑器。Q111亨廷顿氏病和YG8s弗里德赖希共济失调小鼠在转导组织中进行了有效的编辑，并显著减少了中枢神经系统中的重复扩增。这些发现表明，在体内引入致病性TNR的中断可以减轻TNR疾病的一个关键神经学特征。

研究人员表示，三核苷酸重复（TNR）疾病是由扩展的基因组TNR引起的神经系统疾病，以长度依赖的方式变得不稳定。CAG•CTG序列存在于大约三分之一的致病性TNR位点，包括导致亨廷顿氏病的HTT基因。弗里德里希共济失调是最常见的遗传性共济失调，是由FXN基因GAA重复扩增引起的。

附：英文原文

Title: Base editing of trinucleotide repeats that cause Huntington’s disease and Friedreich’s ataxia reduces somatic repeat expansions in patient cells and in mice

Author: Matuszek, Zaneta, Arbab, Mandana, Kesavan, Maheswaran, Hsu, Alvin, Roy, Jennie C. L., Zhao, Jing, Yu, Tian, Weisburd, Ben, Newby, Gregory A., Doherty, Neil J., Wu, Muzhou, Shibata, Shota, Cristian, Ana, Tao, Y. Allen, Fearnley, Liam G., Bahlo, Melanie, Rehm, Heidi L., Xie, Jun, Gao, Guangping, Mouro Pinto, Ricardo, Liu, David R.

Issue&Volume: 2025-05-26

Abstract: Trinucleotide repeat (TNR) diseases are neurological disorders caused by expanded genomic TNRs that become unstable in a length-dependent manner. The CAGCTG sequence is found in approximately one-third of pathogenic TNR loci, including the HTT gene that causes Huntington’s disease. Friedreich’s ataxia, the most prevalent hereditary ataxia, results from GAA repeat expansion at the FXN gene. Here we used cytosine and adenine base editing to reduce the repetitiveness of TNRs in patient cells and in mice. Base editors introduced GC>AT and AT>GC interruptions at CAG and GAA repeats, mimicking stable, nonpathogenic alleles that naturally occur in people. AAV9 delivery of optimized base editors in Htt.Q111 Huntington’s disease and YG8s Friedreich’s ataxia mice resulted in efficient editing in transduced tissues, and significantly reduced repeat expansion in the central nervous system. These findings demonstrate that introducing interruptions in pathogenic TNRs can mitigate a key neurological feature of TNR diseases in vivo.

DOI: 10.1038/s41588-025-02172-8

Source: https://www.nature.com/articles/s41588-025-02172-8