Suppression of Huntington’s Disease Somatic Instability by Transcriptional Repression and Direct CAG Repeat Binding

Ella W. Mathews, Sydney R. Coffey, Annette Gärtner, Jillian Belgrad, Robert M. Bragg, Daniel O’Reilly, Jeffrey P. Cantle, Cassandra McHugh, Ashley Summers, Joachim Fentz, Tom Schwagarus, Antje Cornelius, Ioannis Lingos, Zoe Burch, Marina Kovalenko, Marissa A. Andrew, C. Frank Bennett, Holly B. Kordasiewicz, Deanna M. Marchionini, Hilary Wilkinson, Thomas F. Vogt, Paolo Beuzer, Ricardo M. Pinto, Anastasia Khvorova, David Howland, Vanessa C. Wheeler and Jeffrey B. Carroll ()
Additional contact information
Ella W. Mathews: University of Washington
Sydney R. Coffey: Western Washington University
Annette Gärtner: Evotec SE
Jillian Belgrad: University of Massachusetts Chan Medical School
Robert M. Bragg: University of Washington
Daniel O’Reilly: University of Massachusetts Chan Medical School
Jeffrey P. Cantle: University of Washington
Cassandra McHugh: Western Washington University
Ashley Summers: University of Massachusetts Chan Medical School
Joachim Fentz: Evotec SE
Tom Schwagarus: Evotec SE
Antje Cornelius: Evotec SE
Ioannis Lingos: Evotec SE
Zoe Burch: Massachusetts General Hospital
Marina Kovalenko: Massachusetts General Hospital
Marissa A. Andrew: Massachusetts General Hospital
C. Frank Bennett: Ionis Pharmaceuticals
Holly B. Kordasiewicz: Ionis Pharmaceuticals
Deanna M. Marchionini: the company that manages the scientific activities of CHDI Foundation Inc
Hilary Wilkinson: the company that manages the scientific activities of CHDI Foundation Inc
Thomas F. Vogt: the company that manages the scientific activities of CHDI Foundation Inc
Paolo Beuzer: the company that manages the scientific activities of CHDI Foundation Inc
Ricardo M. Pinto: Massachusetts General Hospital
Anastasia Khvorova: University of Massachusetts Chan Medical School
David Howland: the company that manages the scientific activities of CHDI Foundation Inc
Vanessa C. Wheeler: Massachusetts General Hospital
Jeffrey B. Carroll: University of Washington

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-64936-4

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