{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T21:02:44Z","timestamp":1790715764174,"version":"4.1.0"},"posted":{"date-parts":[[2026,6,10]]},"group-title":"Genetics","reference-count":58,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Huntington\u2019s disease (HD) is a fatal, dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion in Huntingtin (\n                  <jats:italic>HTT<\/jats:italic>\n                  ) exon 1. Further progressive CAG repeat expansion occurs in somatic cells, particularly in neurons, and drives the timing of clinical onset. Therefore, therapeutic strategies to slow somatic expansion are predicted to be disease-modifying. Somatic CAG expansion is driven by mismatch repair protein MSH3, a leading therapeutic target supported by human genetic data. To gain insight into the impact of targeting MSH3 at different stages of the disease process we used somatic CRISPR-Cas9 editing to knock out\n                  <jats:italic>Msh3<\/jats:italic>\n                  in\n                  <jats:italic>Htt<\/jats:italic>\n                  <jats:sup>Q111<\/jats:sup>\n                  mice at ages of 6, 16, 24 weeks exhibiting progressively increasing somatic expansion. Intervention at all three ages slowed striatal CAG expansion, reduced nuclear huntingtin pathology and suppressed transcriptional dysregulation, with earlier intervention having greater impact.\n                  <jats:italic>Msh3<\/jats:italic>\n                  knockout also suppressed the production of the exon 1\n                  <jats:italic>Htt1a<\/jats:italic>\n                  transcript. The results of our study provide important preclinical information relevant to an MSH3 therapeutic in humans that would be expected to impact a subset of cells in the brain, provide insight into the influence of timing of intervention on therapeutic effectiveness and deepen our understanding of how targeting MSH3 could alter the trajectory of HD.\n                <\/jats:p>","DOI":"10.64898\/2026.06.08.730940","type":"posted-content","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T02:10:13Z","timestamp":1781143813000},"source":"Crossref","is-referenced-by-count":2,"title":["Somatic CRISPR editing of\n                  <i>Msh3<\/i>\n                  mitigates Huntington\u2019s disease pathology in mice"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-7003-4347","authenticated-orcid":false,"given":"Esaria","family":"Oliver","sequence":"first","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General 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