Base editing of trinucleotide repeats that cause Huntington’s disease and Friedreich’s ataxia reduces somatic repeat expansions in patient cells and in mice
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.
Authors
- Guangping Gao (ORCID: https://orcid.org/0000-0003-0097-9012)
- Jing Zhao (ORCID: https://orcid.org/0000-0002-2439-2876)
- Muzhou Wu
- Heidi L. Rehm (ORCID: https://orcid.org/0000-0002-6025-0015)
- Shota Shibata (ORCID: https://orcid.org/0000-0002-9131-5408)
- Mandana Arbab (ORCID: https://orcid.org/0000-0001-9216-5096)
- Yong Tao (ORCID: https://orcid.org/0000-0002-1351-2094)
- Żaneta Matuszek (ORCID: https://orcid.org/0000-0001-5627-0593)
- Jun Xie (ORCID: https://orcid.org/0000-0001-9565-1567)
- Maheswaran Kesavan
- Jennie C. L. Roy (ORCID: https://orcid.org/0000-0003-3968-9637)
- Gregory A. Newby (ORCID: https://orcid.org/0000-0001-7869-2615)
- Ricardo Mouro Pinto (ORCID: https://orcid.org/0000-0001-6744-2805)
- Liam G. Fearnley (ORCID: https://orcid.org/0000-0003-2198-5411)
- Melanie Bahlo (ORCID: https://orcid.org/0000-0001-5132-0774)
- Ben Weisburd (ORCID: https://orcid.org/0000-0001-9898-9109)
- David R. Liu (ORCID: https://orcid.org/0000-0002-9943-7557)
- Alvin Hsu (ORCID: https://orcid.org/0000-0003-4034-2788)
- Ana Cristian (ORCID: https://orcid.org/0000-0001-9403-5455)
- Neil Doherty (ORCID: https://orcid.org/0000-0003-4699-9027)
- Yu Tian (ORCID: https://orcid.org/0000-0003-2283-0366)
Institutions
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- Johns Hopkins University (US)
- The University of Melbourne (AU)
- University of Massachusetts Chan Medical School (US)
- Walter and Eliza Hall Institute of Medical Research (AU)
- Johns Hopkins Medicine (US)
- Harvard University Press (US)
- Massachusetts General Hospital (US)
- Université Laval (CA)
Publication Details
- Journal
- Nature Genetics
- Published
- 2025-05-26
- DOI
- https://doi.org/10.1038/s41588-025-02172-8
- Citations
- 20
- Primary Topic
- Genetic Neurodegenerative Diseases
- Type
- article
- Field-Weighted Citation Impact
- 18.18