{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T14:06:21Z","timestamp":1787580381095,"version":"build-2736575974"},"reference-count":34,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2024,8,1]],"date-time":"2024-08-01T00:00:00Z","timestamp":1722470400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Nucleic Acid Therapeutics"],"published-print":{"date-parts":[[2024,8,1]]},"abstract":"<jats:p>\n                    Huntington\u2019s disease (HD) is an autosomal dominant neurodegenerative disease caused by CAG repeat expansion in the first exon of the huntingtin gene (\n                    <jats:italic toggle=\"yes\">HTT<\/jats:italic>\n                    ). Oligonucleotide therapeutics, such as short interfering RNA (siRNA), reduce levels of huntingtin mRNA and protein\n                    <jats:italic toggle=\"yes\">in\u00a0vivo<\/jats:italic>\n                    and are considered a viable therapeutic strategy. However, the extent to which they silence huntingtin mRNA in the nucleus is not established. We synthesized siRNA cross-reactive to mouse (wild-type)\n                    <jats:italic toggle=\"yes\">Htt<\/jats:italic>\n                    and human (mutant)\n                    <jats:italic toggle=\"yes\">HTT<\/jats:italic>\n                    in a divalent scaffold and delivered to two mouse models of HD. In both models, divalent siRNA sustained lowering of wild-type\n                    <jats:italic toggle=\"yes\">Htt<\/jats:italic>\n                    , but not mutant\n                    <jats:italic toggle=\"yes\">HTT<\/jats:italic>\n                    mRNA expression in striatum and cortex. Near-complete silencing of both mutant HTT protein and wild-type HTT protein was observed in both models. Subsequent fluorescent\n                    <jats:italic toggle=\"yes\">in situ<\/jats:italic>\n                    hybridization analysis shows that divalent siRNA acts predominantly on cytoplasmic mutant\n                    <jats:italic toggle=\"yes\">HTT<\/jats:italic>\n                    transcripts, leaving clustered mutant\n                    <jats:italic toggle=\"yes\">HTT<\/jats:italic>\n                    transcripts in the nucleus largely intact in treated HD mouse brains. The observed differences between mRNA and protein levels, exaggerated in the case of extended repeats, might apply to other repeat-associated neurological disorders.\n                  <\/jats:p>","DOI":"10.1089\/nat.2024.0027","type":"journal-article","created":{"date-parts":[[2024,7,18]],"date-time":"2024-07-18T10:56:52Z","timestamp":1721300212000},"page":"164-172","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":9,"title":["mRNA Nuclear Clustering Leads to a Difference in Mutant Huntingtin mRNA and Protein Silencing by siRNAs\n                    <i>In Vivo<\/i>"],"prefix":"10.1177","volume":"34","author":[{"given":"Sarah","family":"Allen","sequence":"first","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"O\u2019reilly","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael","family":"Miller","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA."},{"name":"Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Sapp","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"Summers","sequence":"additional","affiliation":[{"name":"RNA Therapeutics 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