{"doi":"10.1101/2025.06.24.661398","title":"Blocking somatic repeat expansion and lowering huntingtin via RNA interference synergize to prevent Huntington’s disease pathogenesis in mice","abstract":"Huntington's disease (HD) is a progressive neurodegenerative disorder with no approved therapies. Two major molecular drivers-somatic expansion of inherited CAG repeats and toxic mutant HTT (mHTT) variants-lead to neuronal dysfunction. Despite multiple trials, HTT-lowering strategies have not shown meaningful clinical benefit. Using therapeutic divalent siRNAs, we assessed the long-term impact of silencing MSH3 (a key regulator of somatic expansion), HTT, or both. In Q111 HD mice (>110 CAGs), which exhibit robust expansion, mHTT inclusions, and transcriptional dysregulation by 12 months, long-term MSH3 silencing blocked expansion, reduced inclusions, and reversed gene expression changes. HTT silencing alone had limited effect, but combined MSH3/HTT targeting synergistically eliminated inclusions and restored transcriptomic profiles. Parallel treatment in wild-type mice showed no toxicity, supporting the safety of long-term intervention. These findings position somatic expansion as a promising therapeutic target and demonstrate the potential of RNAi-based co-silencing of MSH3 and HTT as a disease-modifying strategy for HD.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":554827,"datarank":0.32958368660043297,"base_score":2.1972245773362196,"endowment":2.1972245773362196,"self_citation_contribution":0.32958368660043297,"citation_network_contribution":0.0,"self_endowment_contribution":0.32958368660043297,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9537,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1007566,"name":"Ashley Summers","orcid":"0000-0002-5425-0457","position":1,"is_corresponding":false},{"id":1174152,"name":"Christian Landles","orcid":"0000-0001-9715-6447","position":2,"is_corresponding":false},{"id":306093,"name":"Jonathan Greene","orcid":null,"position":3,"is_corresponding":false},{"id":667631,"name":"Samuel Hildebrand","orcid":"0000-0002-6633-3495","position":4,"is_corresponding":false},{"id":398075,"name":"Emily G. 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