Bunting, Emma L;
Donaldson, Jasmine;
Cumming, Sarah A;
Olive, Jessica;
Broom, Elizabeth;
Miclaus, Mihai;
Hamilton, Joseph;
... Tabrizi, Sarah J; + view all
(2025)
Antisense oligonucleotide–mediated MSH3 suppression reduces somatic CAG repeat expansion in Huntington's disease iPSC–derived striatal neurons.
Science Translational Medicine
, 17
(785)
, Article eadn4600. 10.1126/scitranslmed.adn4600.
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Abstract
Expanded Huntington’s disease (HD) associated HTT-CAG alleles are genetically unstable and continue to somatically expand throughout life, driving disease onset. MSH3, a DNA mismatch repair protein, modifies HD onset and progression by driving CAG repeat expansion. MSH3 is relatively tolerant of loss-of-function variation in humans, making it an ideal therapeutic target. Here, we show that an MSH3-targeting antisense oligonucleotide (ASO) effectively enters and engages its target in HD patient induced pluripotent stem cell (iPSC)-derived striatal neurons. ASO treatment led to a dose-dependent reduction of MSH3, and subsequent stalling of CAG repeat expansion. Maximal knock-down also effectively slowed CAG repeat expansion in FAN1-/- neurons, which otherwise have an accelerated expansion rate. Bulk RNA sequencing showed a safe profile for MSH3 lowering in the iPSC-derived neuronal context. Finally, we created a novel humanised MSH3 knock-in mouse model and demonstrated effective in vivo modulation of human MSH3 RNA, providing an important tool for future translation of MSH3-targeting compounds. Our study validates the use of ASO-mediated MSH3 lowering to delay onset and slow disease progression in HD patients, which we show can prevent HTT CAG repeat expansion in an HD patient-derived model system.
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