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

Author

Listed:
  • Ella W. Mathews

    (University of Washington
    Western Washington University)

  • Sydney R. Coffey

    (Western Washington University)

  • Annette Gärtner

    (Evotec SE)

  • Jillian Belgrad

    (University of Massachusetts Chan Medical School)

  • Robert M. Bragg

    (University of Washington
    Western Washington University)

  • Daniel O’Reilly

    (University of Massachusetts Chan Medical School)

  • Jeffrey P. Cantle

    (University of Washington
    Western Washington University)

  • 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
    Massachusetts Hospital and Harvard Medical School
    the Broad Institute of M.I.T. and Harvard)

  • Jeffrey B. Carroll

    (University of Washington
    Western Washington University)

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.

Suggested Citation

  • 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 & An, 2025. "Suppression of Huntington’s Disease Somatic Instability by Transcriptional Repression and Direct CAG Repeat Binding," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64936-4
    DOI: 10.1038/s41467-025-64936-4
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    References listed on IDEAS

    as
    1. Michael Kosicki & Felicity Allen & Frances Steward & Kärt Tomberg & Yangyang Pan & Allan Bradley, 2022. "Cas9-induced large deletions and small indels are controlled in a convergent fashion," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Zachariah L. McLean & Dadi Gao & Kevin Correia & Jennie C. L. Roy & Shota Shibata & Iris N. Farnum & Zoe Valdepenas-Mellor & Marina Kovalenko & Manasa Rapuru & Elisabetta Morini & Jayla Ruliera & Tamm, 2024. "Splice modulators target PMS1 to reduce somatic expansion of the Huntington’s disease-associated CAG repeat," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    Full references (including those not matched with items on IDEAS)

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