Base editing of trinucleotide repeats that cause Huntington&#39;s disease and Friedreich&#39;s ataxia reduces somatic repeat expansions in patient cells and in mice

Matuszek, Z; Arbab, M; Kesavan, M; Hsu, A; Roy, JCL; Zhao, J; Yu, T; Weisburd, B; Newby, GA; Doherty, NJ; Wu, M; Shibata, S; Cristian, A; Tao, YA; Fearnley, LG; Bahlo, M; Rehm, HL; Xie, J; Gao, G; Mouro Pinto, R; Liu, DR

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(s): Matuszek, Z; Arbab, M; Kesavan, M; Hsu, A; Roy, JCL; Zhao, J; Yu, T; Weisburd, B; Newby, GA; Doherty, NJ; Wu, M; Shibata, S; Cristian, A; Tao, YA; Fearnley, LG; Bahlo, M; Rehm, HL; Xie, J; Gao, G; Mouro Pinto, R; Liu, DR;
Details: Publication Year 2025-06,Volume 57,Issue #6,Page 1437-1451
Journal Title: Nature Genetics
Abstract: 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.
Publisher: Springer Nature
Keywords: *Friedreich Ataxia/genetics; Animals; *Huntington Disease/genetics; *Trinucleotide Repeat Expansion/genetics; Humans; Mice; *Gene Editing/methods; Huntingtin Protein/genetics; Disease Models, Animal; *Trinucleotide Repeats/genetics; Frataxin
Research Division(s): Genetics and Gene Regulation
PubMed ID: 40419681
Publisher's Version: https://doi.org/10.1038/s41588-025-02172-8
Open Access at Publisher's Site: https://doi.org/10.1038/s41588-025-02172-8
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-05-29 02:03:11

Last Modified: 2025-06-26 09:56:59