{
  "abstract": "Genetic modifiers of Huntington's disease (HD) disease onset and progression implicate somatic instability (SI) of the expanded CAG repeat as a key pathogenic driver, with MSH3 emerging as a therapeutic target. Here, we generated a computational model that uses HD patient data to infer therapeutic effects of reducing SI and in parallel designed an artificial miRNA to lower MSH3 mRNA (miMSH3) after delivery with AAV-DB-3, a previously described medium spiny neuron (MSN)-targeting AAV capsid variant. AAV-DB-3.miMSH3 achieved 48-94% MSH3 mRNA reduction in MSNs of nonhuman primates (NHPs), which when applied to predictive modeling predicts 50-120 % slowing of HD progression as measured by change from baseline in the composite Unified Huntington Disease Rating Scale. Additionally, AAV-DB-3.miMSH3 reduced SI reduction by up to 46% in HdhQ111 mice. Cumulatively, the preclinical experimental data and the computational model support the translational potential of AAV-DB-3.miMSH3 as a disease-modifying therapy for HD.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "research support, non u.s. gov't",
  "arxiv": null,
  "author_total": 17,
  "authors": [
    {
      "name": "Bryan P. Simpson",
      "orcid": "0000-0003-0192-6027"
    },
    {
      "name": "Paul T. Ranum"
    },
    {
      "name": "David E. Leib"
    },
    {
      "name": "Luis Tecedor",
      "orcid": "0000-0001-7101-3544"
    },
    {
      "name": "Ryan C. Giovenco",
      "orcid": "0009-0006-2690-0391"
    },
    {
      "name": "Icnelia Huerta-Ocampo"
    },
    {
      "name": "Amiel A. Hundley"
    },
    {
      "name": "Noah Smith"
    },
    {
      "name": "Christopher M. Fluta"
    },
    {
      "name": "Christopher P. Cali"
    },
    {
      "name": "Jamie Benoit"
    },
    {
      "name": "Jenna C. Soper"
    },
    {
      "name": "John Connelly"
    },
    {
      "name": "George J. Yohrling"
    },
    {
      "name": "P. Peter Ghoroghchian"
    },
    {
      "name": "Jang-Ho J. Cha",
      "orcid": "0000-0002-0458-3931"
    },
    {
      "name": "Beverly L. Davidson",
      "orcid": "0000-0002-3715-6290"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/398bb978csp4b.bib",
  "cited_by": 0,
  "doi": "10.1038/s41467-026-78769-2",
  "fulltext_url": "https://europepmc.org/articles/PMC13716904",
  "id": "398bb978csp4b",
  "issns": [
    "2041-1723"
  ],
  "landing_url": "https://www.nature.com/articles/s41467-026-78769-2",
  "language": "eng",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "2804|Genetic Neurodegenerative Diseases"
    ]
  ],
  "openalex": "W7224083701",
  "pdf_url": "https://www.nature.com/articles/s41467-026-78769-2.pdf",
  "pmcid": "PMC13716904",
  "pmid": "42951910",
  "published": "2026-10-28",
  "publisher": "Springer Science and Business Media LLC",
  "ris": "https://research.draconitic.com/paper/398bb978csp4b.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:39Z",
      "native_id": "10.1038/s41467-026-78769-2",
      "source": "crossref",
      "url": "https://www.nature.com/articles/s41467-026-78769-2"
    },
    {
      "first_seen": "2026-10-31T00:20:33Z",
      "native_id": "MED:42951910",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42951910"
    },
    {
      "first_seen": "2026-11-02T12:21:19Z",
      "native_id": "PMC13716904",
      "source": "pmc",
      "url": "https://doi.org/10.1038/s41467-026-78769-2"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2804|Genetic Neurodegenerative Diseases",
      "subfield": "neuroscience"
    }
  ],
  "title": "Computational modeling and preclinical evaluation support targeting somatic instability for Huntington’s disease treatment",
  "title_text": "Computational modeling and preclinical evaluation support targeting somatic instability for Huntington’s disease treatment",
  "type": "peer-reviewed",
  "updated_at": "2026-11-02T12:21:19Z",
  "url": "https://research.draconitic.com/paper/398bb978csp4b",
  "venue": "Nature Communications",
  "versions": []
}