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Transl. Med."],"published-print":{"date-parts":[[2026,3,18]]},"abstract":"<jats:p>\n                    Lowering\n                    <jats:italic toggle=\"yes\">huntingtin (HTT)<\/jats:italic>\n                    transcript levels has been a major focus of therapeutic development for Huntington\u2019s disease (HD), but which transcript should be lowered? HD is caused by a CAG repeat expansion in exon 1 of the\n                    <jats:italic toggle=\"yes\">HTT<\/jats:italic>\n                    gene, and the rate of somatic expansion of this CAG repeat throughout life drives the age of onset and rate of disease progression. As the CAG repeat expands, the extent to which the\n                    <jats:italic toggle=\"yes\">HTT<\/jats:italic>\n                    mRNA is alternatively processed to generate the\n                    <jats:italic toggle=\"yes\">HTT1a<\/jats:italic>\n                    transcript and highly aggregation-prone and pathogenic HTT1a protein increases. Several HTT-lowering modalities have entered clinical trials that target either both\n                    <jats:italic toggle=\"yes\">HTT<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">HTT1a<\/jats:italic>\n                    together or full-length\n                    <jats:italic toggle=\"yes\">HTT<\/jats:italic>\n                    alone. We have developed siRNAs that target the\n                    <jats:italic toggle=\"yes\">Htt1a<\/jats:italic>\n                    mouse transcript (634\/486) and used these, together with a potent\n                    <jats:italic toggle=\"yes\">Htt<\/jats:italic>\n                    -targeting siRNA (10150), to compare the efficacy of lowering either full-length\n                    <jats:italic toggle=\"yes\">Htt<\/jats:italic>\n                    or\n                    <jats:italic toggle=\"yes\">Htt1a<\/jats:italic>\n                    . zQ175 and wild-type mice were treated with 10150 or 634\/486 alongside control groups at 2 months of age and euthanized at 6 months, at 2 months and again at 6 months and euthanized at 10 months, or at 6 months and euthanized at 10 months. The siRNA potency and durability were most effective in the hippocampus. Although both strategies showed benefits, despite the greater potency of 10150, targeting\n                    <jats:italic toggle=\"yes\">Htt1a<\/jats:italic>\n                    was more effective at delaying HTT aggregation and transcriptional dysregulation than targeting full-length\n                    <jats:italic toggle=\"yes\">Htt<\/jats:italic>\n                    . These data support HTT-lowering strategies that are designed to target the\n                    <jats:italic toggle=\"yes\">HTT1a<\/jats:italic>\n                    transcript, either alone or together with lowering full-length\n                    <jats:italic toggle=\"yes\">HTT<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adw2495","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T17:58:36Z","timestamp":1773856716000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":7,"title":["Lowering the\n                    <i>HTT1a<\/i>\n                    transcript as an effective therapy for Huntington\u2019s disease in a knockin mouse model"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4939-8756","authenticated-orcid":true,"given":"Aikaterini Smaragdi","family":"Papadopoulou","sequence":"first","affiliation":[{"name":"Huntington\u2019s Disease Centre and Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, London WC1N 3BG, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6195-0857","authenticated-orcid":true,"given":"Julia","family":"Alterman","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9715-6447","authenticated-orcid":true,"given":"Christian","family":"Landles","sequence":"additional","affiliation":[{"name":"Huntington\u2019s Disease Centre and Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, London WC1N 3BG, 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USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8019-6703","authenticated-orcid":true,"given":"Jemima","family":"Phillips","sequence":"additional","affiliation":[{"name":"Huntington\u2019s Disease Centre and Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, London WC1N 3BG, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7080-1221","authenticated-orcid":true,"given":"Maria","family":"Canibano-Pico","sequence":"additional","affiliation":[{"name":"Huntington\u2019s Disease Centre and Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, London WC1N 3BG, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iulia M.","family":"Nita","sequence":"additional","affiliation":[{"name":"Huntington\u2019s Disease Centre and Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, London WC1N 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