An inducible human neuronal model for evaluating therapeutic modulation of somatic CAG repeat expansion in Huntington’s disease [Conference Abstract]

Stone, Joseph, Binda, Caroline, Wills, Christopher, Richer, Madeleine, Marzec, Paulina, Heraty, Laura, Holmans, Peter ORCID: https://orcid.org/0000-0003-0870-9412, Allen, Nicholas ORCID: https://orcid.org/0000-0003-4009-186X, Benn, Caroline L. and Massey, Thomas ORCID: https://orcid.org/0000-0002-9804-2131 2026. An inducible human neuronal model for evaluating therapeutic modulation of somatic CAG repeat expansion in Huntington’s disease [Conference Abstract]. Journal of Neurology, Neurosurgery and Psychiatry 97 (Supp 2) , A148. 10.1136/jnnp-2026-ehdn.332

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Abstract

Background: Somatic CAG repeat expansion is a key driver of Huntington’s disease (HD) pathogenesis and an emerging therapeutic target. Human genetic studies and experimental models have identified the mismatch repair proteins MSH3 and PMS1 as important modulators of repeat expansion, making them attractive therapeutic targets. Aims: To develop a scalable human neuronal model of somatic CAG repeat expansion suitable for evaluating genetic and pharmacological modulators of expansion. Methods: Patient derived HD109 induced pluripotent stem cells (iPSCs) were engineered with a doxycycline-inducible NGN2 cassette to enable rapid differentiation into glutamatergic cortical neurons. FAN1 was knocked out to increase the rate of somatic CAG repeat expansion. Expansion was quantified over time and the effects of PMS1 knockout and pharmacological inhibition of MutSb (MSH2 - MSH3) were assessed. Results: The model exhibited progressive CAG repeat expansion over six weeks, with weighted mean repeat lengths increasing by approximately one CAG repeat during this period. Using this model, we showed that CRISPR-mediated knockout of PMS1 ablated expansion. Treatment with a novel MutSβ (MSH2 - MSH3) inhibitor also reduced expansion rates in a dose-dependent manner, with the highest dose completely preventing expansion. Conclusions: We have generated a reproducible human neuronal model of somatic CAG repeat expansion that is amenable to medium-throughput screening. This system recapitulates the effects of genetic and pharmacological modulation of key expansion drivers and provides a platform for evaluating therapeutic approaches targeting somatic expansion in HD.

Item Type:	Short Communication
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine Schools > Biosciences
Publisher:	BMJ Publishing Group
ISSN:	0022-3050
Last Modified:	27 Oct 2026 15:15
URI:	https://orca.cardiff.ac.uk/id/eprint/190471

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