Antisense oligonucleotide–mediated MSH3 suppression reduces somatic CAG repeat expansion in Huntington’s disease iPSC–derived striatal neurons
Expanded CAG alleles in the huntingtin (<i>HTT</i>) gene that cause the neurodegenerative disorder Huntington's disease (HD) are genetically unstable and continue to expand somatically throughout life, driving HD onset and progression. MSH3, a DNA mismatch repair protein, modifies HD onset and progression by driving this somatic CAG repeat expansion process. <i>MSH3</i> is relatively tolerant of loss-of-function variation in humans, making it a potential therapeutic target. Here, we show that an <i>MSH3</i>-targeting antisense oligonucleotide (ASO) effectively engaged with its RNA target in induced pluripotent stem cell (iPSC)-derived striatal neurons obtained from a patient with HD carrying <i>125 HTT</i> CAG repeats (the 125 CAG iPSC line). ASO treatment led to a dose-dependent reduction of MSH3 and subsequent stalling of CAG repeat expansion in these striatal neurons. Bulk RNA sequencing revealed a safe profile for <i>MSH3</i> reduction, even when reduced by >95%. Maximal knockdown of MSH3 also effectively slowed CAG repeat expansion in striatal neurons with an otherwise accelerated expansion rate, derived from the 125 CAG iPSC line where <i>FAN1</i> was knocked out by CRISPR-Cas9 editing. Last, we created a knock-in mouse model expressing the human <i>MSH3</i> gene and demonstrated effective in vivo reduction in human <i>MSH3</i> after ASO treatment. Our study shows that ASO-mediated MSH3 reduction can prevent <i>HTT</i> CAG repeat expansion in HD 125 CAG iPSC-derived striatal neurons, highlighting the therapeutic potential of this approach.
Authors
- Gabriel Balmus (ORCID: https://orcid.org/0000-0003-2872-4468)
- Susan Li (ORCID: https://orcid.org/0000-0001-5238-514X)
- Jonathan Brenton (ORCID: https://orcid.org/0000-0002-2381-8484)
- Matthew Tegtmeyer (ORCID: https://orcid.org/0000-0002-9032-8207)
- Darren G. Monckton (ORCID: https://orcid.org/0000-0002-8298-8264)
- Sarah J. Tabrizi (ORCID: https://orcid.org/0000-0003-2716-2045)
- Mina Ryten (ORCID: https://orcid.org/0000-0001-9520-6957)
- Holly B. Kordasiewicz (ORCID: https://orcid.org/0009-0004-0945-0769)
- Michael Flower (ORCID: https://orcid.org/0000-0001-5568-6239)
- Robert E. Handsaker (ORCID: https://orcid.org/0000-0002-3128-3547)
- Joseph Hamilton (ORCID: https://orcid.org/0000-0001-9592-529X)
- Mihai Miclăuș (ORCID: https://orcid.org/0000-0001-7969-2393)
- Emma L. Bunting
- Steven A. McCarroll (ORCID: https://orcid.org/0000-0002-6954-8184)
- Jessica Olive (ORCID: https://orcid.org/0000-0001-5875-1542)
- Brendon Ford
- Jasmine Donaldson (ORCID: https://orcid.org/0000-0001-6699-0674)
- Sarah A. Cumming (ORCID: https://orcid.org/0000-0002-0201-3660)
- Won‐Seok Lee (ORCID: https://orcid.org/0000-0001-8633-4682)
- Hien Zhao (ORCID: https://orcid.org/0009-0000-0904-8201)
- Elizabeth L Broom (ORCID: https://orcid.org/0009-0006-1439-4591)
Institutions
- Broad Institute (US)
- Harvard University (US)
- University of Cambridge (GB)
- Ionis Pharmaceuticals (United States) (US)
- Great Ormond Street Hospital (GB)
- UK Dementia Research Institute (GB)
- Institute of Child Health (IN)
- Romanian Institute of Science and Technology (RO)
- National Hospital for Neurology and Neurosurgery (GB)
- University College London (GB)
- University of Glasgow (GB)
Publication Details
- Journal
- Science Translational Medicine
- Published
- 2025-02-12
- DOI
- https://doi.org/10.1126/scitranslmed.adn4600
- Citations
- 24
- Primary Topic
- Genetic Neurodegenerative Diseases
- Type
- article
- Field-Weighted Citation Impact
- 21.82
Funders
- CHDI Foundation
- Wellcome Trust
- Ministerul Cercetării, Inovării şi Digitalizării
- UK Dementia Research Institute
- Medical Research Council