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<p>Huntington’s disease arises from a CAG expansion in the <i>huntingtin</i> 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 <i>HTT</i>’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 <i>Htt</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月14日

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  • 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,
  • Jeffrey B. Carroll

摘要

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.