{"doi":"10.1101/2023.12.19.572404","title":"A programmable dual-targeting di-valent siRNA scaffold supports potent multi-gene modulation in the central nervous system","abstract":"ABSTRACT Di-valent short interfering RNA (siRNA) is a promising therapeutic modality that enables sequence-specific modulation of a single target gene in the central nervous system (CNS). To treat complex neurodegenerative disorders, where pathogenesis is driven by multiple genes or pathways, di-valent siRNA must be able to silence multiple target genes simultaneously. Here we present a framework for designing unimolecular “dual-targeting” di-valent siRNAs capable of co-silencing two genes in the CNS. We reconfigured di-valent siRNA – in which two identical, linked siRNAs are made concurrently – to create linear di-valent siRNA – where two siRNAs are made sequentially attached by a covalent linker. This linear configuration, synthesized using commercially available reagents, enables incorporation of two different siRNAs to silence two different targets. We demonstrate that this dual-targeting di-valent siRNA is fully functional in the CNS of mice, supporting at least two months of maximal target silencing. Dual-targeting di-valent siRNA is highly programmable, enabling simultaneous modulation of two different disease-relevant gene pairs (e.g., Huntington’s disease: MSH3 and HTT ; Alzheimer’s disease: APOE and JAK1 ) with similar potency to a mixture of single-targeting di-valent siRNAs against each gene. This work potentiates CNS modulation of virtually any pair of disease-related targets using a simple unimolecular siRNA.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":393953,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9559,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":749478,"name":"Qi Tang","orcid":"0000-0002-8913-0519","position":1,"is_corresponding":false},{"id":1168746,"name":"Sam Hildebrand","orcid":null,"position":2,"is_corresponding":false},{"id":1007566,"name":"Ashley Summers","orcid":"0000-0002-5425-0457","position":3,"is_corresponding":false},{"id":662289,"name":"Ellen Sapp","orcid":"0000-0002-0905-4940","position":4,"is_corresponding":false},{"id":398074,"name":"Dimas Echeverria","orcid":"0000-0002-1040-0855","position":5,"is_corresponding":false},{"id":1168747,"name":"Dan O’Reilly","orcid":null,"position":6,"is_corresponding":false},{"id":310200,"name":"Eric Luu","orcid":null,"position":7,"is_corresponding":false},{"id":1030866,"name":"Brianna Bramato","orcid":"0000-0001-6966-7696","position":8,"is_corresponding":false},{"id":256682,"name":"Sarah E. Allen","orcid":"0000-0002-1646-629X","position":9,"is_corresponding":false},{"id":868823,"name":"David Cooper","orcid":"0000-0003-1356-1707","position":10,"is_corresponding":false},{"id":398076,"name":"Julia F. Alterman","orcid":"0000-0002-6195-0857","position":11,"is_corresponding":false},{"id":722996,"name":"Ken Yamada","orcid":"0000-0002-5714-8298","position":12,"is_corresponding":false},{"id":474623,"name":"Neil Aronin","orcid":"0000-0003-1209-8925","position":13,"is_corresponding":false},{"id":662295,"name":"Marian DiFiglia","orcid":"0000-0003-4155-8177","position":14,"is_corresponding":false},{"id":302206,"name":"Anastasia Khvorova","orcid":"0000-0001-6928-8071","position":15,"is_corresponding":false},{"id":1007565,"name":"Jillian Belgrad","orcid":"0000-0002-2577-2336","position":0,"is_corresponding":true}],"reference_count":46,"raw_metadata":null,"created_at":"2026-07-19T01:19:10.334330Z","pmid":"38187561","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}