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<p>Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by an expanded CAG repeat within exon 1 of the huntingtin (<i>HTT</i>) gene, resulting in a mutant protein that drives neuronal dysfunction and loss. A key event in the pathogenesis of HD is proteolytic cleavage of mutant HTT, which generates aggregation-prone N-terminal fragments that contribute to toxicity. Strategies that prevent this process thus hold therapeutic potential. Here we develop CRISPR base editors that generate proteolysis-resistant HTT isoforms by disrupting the splice acceptor of <i>HTT</i> exon 13, an exon that encodes critical proteolytic cleavage sites implicated in N-terminal fragment production. When delivered to the striatum of an HD rodent model, these editors reduced HTT fragment formation, decreased aggregation, improved functional deficits and attenuated brain atrophy. Collectively, these results demonstrate the potential of base editing and splice-site modulation to mitigate mutant HTT toxicity in HD.</p>

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In vivo CRISPR base editing for treatment of Huntington’s disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月29日

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  • Shraddha Shirguppe,
  • Michael Gapinske,
  • Devyani Swami,
  • Kyrollos Shenouda,
  • Angelo Miskalis,
  • Nicholas Gosstola,
  • Daniela Del Bosque Siller,
  • Isabelle Guerra,
  • Pankaj Acharya,
  • Dana Joulani,
  • Maddie G. Szkwarek,
  • Ananthan Nambiar,
  • Abhishek Bhattacharjee,
  • Anagha S. Dangi,
  • Norah Odle,
  • Gabrielle E. Nathan,
  • Gianna Elias,
  • Michelle Stilger,
  • Jackson Winter,
  • Wendy S. Woods,
  • Daphine Anand,
  • Colin K. W. Lim,
  • Sergei Maslov,
  • Thomas Gaj,
  • Pablo Perez-Pinera

摘要

Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by an expanded CAG repeat within exon 1 of the huntingtin (HTT) gene, resulting in a mutant protein that drives neuronal dysfunction and loss. A key event in the pathogenesis of HD is proteolytic cleavage of mutant HTT, which generates aggregation-prone N-terminal fragments that contribute to toxicity. Strategies that prevent this process thus hold therapeutic potential. Here we develop CRISPR base editors that generate proteolysis-resistant HTT isoforms by disrupting the splice acceptor of HTT exon 13, an exon that encodes critical proteolytic cleavage sites implicated in N-terminal fragment production. When delivered to the striatum of an HD rodent model, these editors reduced HTT fragment formation, decreased aggregation, improved functional deficits and attenuated brain atrophy. Collectively, these results demonstrate the potential of base editing and splice-site modulation to mitigate mutant HTT toxicity in HD.