In vivo CRISPR–Cas9 genome editing in mice identifies genetic modifiers of somatic CAG repeat instability in Huntington’s disease
Huntington's disease, one of more than 50 inherited repeat expansion disorders<sup>1</sup>, is a dominantly inherited neurodegenerative disease caused by a CAG expansion in HTT<sup>2</sup>. Inherited CAG repeat length is the primary determinant of age of onset, with human genetic studies underscoring that the disease is driven by the CAG length-dependent propensity of the repeat to further expand in the brain<sup>3-9</sup>. Routes to slowing somatic CAG expansion, therefore, hold promise for disease-modifying therapies. Several DNA repair genes, notably in the mismatch repair pathway, modify somatic expansion in Huntington's disease mouse models<sup>10</sup>. To identify novel modifiers of somatic expansion, we used CRISPR-Cas9 editing in Huntington's disease knock-in mice to enable in vivo screening of expansion-modifier candidates at scale. This included testing of Huntington's disease onset modifier genes emerging from human genome-wide association studies as well as interactions between modifier genes, providing insight into pathways underlying CAG expansion and potential therapeutic targets.
Authors
- Eduarda Mota‐Silva (ORCID: https://orcid.org/0000-0002-4305-8216)
- Emanuela Elezi
- Jessica Ulloa (ORCID: https://orcid.org/0009-0007-4874-987X)
- Zoe Burch
- Shota Shibata (ORCID: https://orcid.org/0000-0002-9131-5408)
- Maheswaran Kesavan
- Jeffrey B. Carroll (ORCID: https://orcid.org/0000-0003-1711-8868)
- James F. Gusella (ORCID: https://orcid.org/0000-0003-0681-9263)
- Ricardo Mouro Pinto (ORCID: https://orcid.org/0000-0001-6744-2805)
- Antonia Vitalo
- Marina Kovalenko (ORCID: https://orcid.org/0000-0002-4296-8189)
- Tammy Gillis
- Ryan Murtha (ORCID: https://orcid.org/0000-0002-1209-6914)
- Marion J. Riggs (ORCID: https://orcid.org/0000-0002-7310-1107)
- Kevin Correia (ORCID: https://orcid.org/0000-0001-7130-1765)
- Brigitte Demelo
- Steven Crescenti
- Vanessa C. Wheeler (ORCID: https://orcid.org/0009-0004-8259-5796)
- António Azevedo
- Cameron J. Douglas (ORCID: https://orcid.org/0000-0003-2334-1652)
- Esaria Oliver
- Marcy E. MacDonald
Institutions
- Broad Institute (US)
- Harvard University (US)
- University of Washington (US)
- Massachusetts General Hospital (US)
- Boston VA Research Institute (US)
- Center for Systems Biology (US)
- Université Laval (CA)
Publication Details
- Journal
- Nature Genetics
- Published
- 2025-01-22
- DOI
- https://doi.org/10.1038/s41588-024-02054-5
- Citations
- 44
- Primary Topic
- Genetic Neurodegenerative Diseases
- Type
- article
- Field-Weighted Citation Impact
- 39.09
Funders
- Huntington's Disease Society of America
- Harvard NeuroDiscovery Center
- National Ataxia Foundation
- Pfizer
- CHDI Foundation
- Dana-Farber/Harvard Cancer Center
- Broad Institute
- National Institutes of Health
- National Cancer Institute
- Office of Extramural Research, National Institutes of Health