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

作者：Żaneta Matuszek, Mandana Arbab, Maheswaran Kesavan, Alvin Hsu, Jennie C. L. Roy, Jing Zhao, Yu Tian, Ben Weisburd, Gregory A. Newby, Neil J. Doherty, Muzhou Wu, Shota Shibata, Ana Cristian, Yong Tao, Liam G. Fearnley, Melanie Bahlo, Heidi L. Rehm, Jun Xie, Guangping Gao, Ricardo Mouro Pinto, David R. Liu · 发表于：Nature Genetics · 年份：2025 · DOI：10.1038/s41588-025-02172-8 · 被引用次数：28 · 研究领域：Genetic Neurodegenerative Diseases、CRISPR and Genetic Engineering、Mitochondrial Function and Pathology

Trinucleotide repeat (TNR) diseases are neurological disorders caused by expanded genomic TNRs that become unstable in a length-dependent manner. The CAG•CTG 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 G•C>A•T and A•T>G•C 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.