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Lowering mutant huntingtin has been proposed for treating HD, but genetic modifiers implicate somatic CAG repeat expansion as the driver of onset. We find that branaplam and risdiplam, small molecule splice modulators that lower huntingtin by promoting\n                    <jats:italic>HTT<\/jats:italic>\n                    pseudoexon inclusion, also decrease expansion of an unstable\n                    <jats:italic>HTT<\/jats:italic>\n                    exon 1 CAG repeat in an engineered cell model. Targeted CRISPR-Cas9 editing shows this effect is not due to huntingtin lowering, pointing instead to pseudoexon inclusion in\n                    <jats:italic>PMS1<\/jats:italic>\n                    . Homozygous but not heterozygous inactivation of\n                    <jats:italic>PMS1<\/jats:italic>\n                    also reduces CAG repeat expansion, supporting\n                    <jats:italic>PMS1<\/jats:italic>\n                    as a genetic modifier of HD and a potential target for therapeutic intervention. Although splice modulation provides one strategy, genome-wide transcriptomics also emphasize consideration of cell-type specific effects and polymorphic variation at both target and off-target sites.\n                  <\/jats:p>","DOI":"10.1038\/s41467-024-47485-0","type":"journal-article","created":{"date-parts":[[2024,4,12]],"date-time":"2024-04-12T06:02:06Z","timestamp":1712901726000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["Splice modulators target PMS1 to reduce somatic expansion of the Huntington\u2019s disease-associated CAG repeat"],"prefix":"10.1038","volume":"15","author":[{"given":"Zachariah L.","family":"McLean","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3638-8479","authenticated-orcid":false,"given":"Dadi","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Correia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3968-9637","authenticated-orcid":false,"given":"Jennie C. 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Their financial interests were reviewed and are managed by Massachusetts General Hospital (MGH) and Mass General Brigham (MGB) in accordance with their conflict of interest policies. J.F.G. consults for Transine Therapeutics, Inc. (dba Harness Therapeutics) and has previously provided paid consulting services to Wave Therapeutics USA Inc., Biogen Inc. and Pfizer Inc. V.C.W. is a scientific advisory board member of LoQus23 Therapeutics Ltd. and has provided paid consulting services to Acadia Pharmaceuticals Inc., Alnylam Inc., Biogen Inc., Passage Bio and Rgenta Therapeutics. R.M.P. and V.C.W. have received research support from Pfizer Inc. B.P.K. is a consultant for EcoR1 capital and Novartis Venture Fund, and is on the scientific advisory board of Acrigen Biosciences, Life Edit Therapeutics and Prime Medicine. B.P.K. has a financial interest in Prime Medicine, Inc., a company developing therapeutic CRISPR-Cas technologies for gene editing. 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