Suppression of Huntington’s Disease Somatic Instability by Transcriptional Repression and Direct CAG Repeat Binding
Huntington's disease arises from a CAG expansion in the huntingtin gene beyond a critical threshold. Current therapeutics primarily aim to reduce toxicity by lowering levels of mutant HTT mRNA and protein. Genetic data support a role for somatic instability in HTT's CAG repeat as a driver of age of motor dysfunction onset, but currently, the relationship between instability and HTT lowering remains unexplored. Here, we investigate various HTT-lowering modalities to establish the relationship between HTT lowering and instability in Huntington's disease knock-in mice. We find that repressing transcription of mutant Htt reduces instability, using genetic and pharmacological approaches. Remarkably, zinc finger proteins that target CAG repeats, but lack a repressive domain, protect from somatic instability despite not reducing HTT mRNA or protein levels. These results suggest that DNA-targeted HTT-lowering treatments may have advantages compared to other HTT-lowering approaches, and that steric blockage of CAG repeats may reduce instability while sparing HTT expression.
Authors
- Cassandra McHugh (ORCID: https://orcid.org/0009-0002-6184-3258)
- Anastasia Khvorova (ORCID: https://orcid.org/0000-0001-6928-8071)
- Marissa A Andrew
- Zoe Burch
- Joachim Fentz (ORCID: https://orcid.org/0000-0002-9334-1298)
- Paolo Beuzer
- Jillian Belgrad (ORCID: https://orcid.org/0000-0002-2577-2336)
- David Howland
- Jeffrey B. Carroll (ORCID: https://orcid.org/0000-0003-1711-8868)
- Hilary A. Wilkinson (ORCID: https://orcid.org/0000-0002-0401-9329)
- Sydney R. Coffey (ORCID: https://orcid.org/0000-0002-1477-2197)
- Holly B. Kordasiewicz (ORCID: https://orcid.org/0009-0004-0945-0769)
- Ricardo Mouro Pinto (ORCID: https://orcid.org/0000-0001-6744-2805)
- Marina Kovalenko (ORCID: https://orcid.org/0000-0002-4296-8189)
- Ella Mathews (ORCID: https://orcid.org/0000-0003-1183-1988)
- Tom Schwagarus
- Ashley Summers (ORCID: https://orcid.org/0000-0002-5425-0457)
- Ioannis Lingos (ORCID: https://orcid.org/0009-0008-5846-957X)
- Deanna M. Marchionini (ORCID: https://orcid.org/0000-0003-2071-1064)
- Annette Gärtner (ORCID: https://orcid.org/0000-0001-6189-9679)
- C. Frank Bennett (ORCID: https://orcid.org/0000-0001-9887-6251)
- Daniel O’Reilly (ORCID: https://orcid.org/0000-0003-0012-5623)
- Jeffrey P. Cantle (ORCID: https://orcid.org/0000-0001-6051-0465)
- Robert M. Bragg (ORCID: https://orcid.org/0000-0003-0619-8954)
- Thomas Vogt (ORCID: https://orcid.org/0000-0001-6155-3360)
- Vanessa C. Wheeler (ORCID: https://orcid.org/0009-0004-8259-5796)
- Antje Cornelius
Institutions
- Broad Institute (US)
- Harvard University (US)
- University of Massachusetts Chan Medical School (US)
- University of Washington (US)
- Ionis Pharmaceuticals (United States) (US)
- CHDI Foundation (US)
- Massachusetts General Hospital (US)
- Evotec (Germany) (DE)
- Western Washington University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-14
- DOI
- https://doi.org/10.1038/s41467-025-64936-4
- Primary Topic
- Genetic Neurodegenerative Diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Massachusetts General Hospital
- CHDI Foundation