{"doi":"10.1101/2024.03.30.24305115","title":"Antisense oligonucleotide depletion of <i>CCDC146</i> is a broad-spectrum therapeutic strategy for ALS","abstract":"Amyotrophic lateral sclerosis (ALS) is a heritable and incurable disease defined by the degeneration of motor neurons (MNs), yet the genetics of ALS remain partially understood. Using a genomic deep learning-powered whole-genome analysis of 6,715 ALS patients, we identify four rare noncoding variants associated with patient survival, including chr7:76,009,472:C&gt;T which is linked to a 70.6% reduction in survival. Genetic editing of this variant into iPSC-derived MNs increases CCDC146 expression and exacerbates ALS-specific phenotypes including TDP-43 mislocalization. We reveal that CCDC146 was located within the basal body of primary cilia in human MNs, and that cilia structure and function is impaired by CCDC146 overexpression but is restored by its depletion. Suppressing CCDC146 using an antisense oligonucleotide (ASO) completely rescues ALS-specific survival defects in neurons derived from both sporadic and familial patients, and it extends survival and reverses TDP-43 pathology in an aggressive ALS mouse model. Taken together, CCDC146 is a new modifier of ALS survival that acts via the primary cilia of MNs. ASO targeting of CCDC146 is a potential therapeutic approach for both sporadic and genetic forms of ALS, particularly because congenital absence of CCDC146 is well tolerated.","journal":"medRxiv","year":2024,"id":485495,"datarank":0.27782815274537676,"base_score":1.791759469228055,"endowment":1.791759469228055,"self_citation_contribution":0.26876392038420827,"citation_network_contribution":0.009064232361168515,"self_endowment_contribution":0.26876392038420827,"citer_contribution":0.009064232361168515,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":3,"citers_with_citation_signal":1,"citers_with_endowment":1,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9567,"is_data_producer":true,"deposit_databanks":{"figshare":["10.6084/m9.figshare.25444534"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":557190,"name":"Tobias Moll","orcid":"0000-0001-5928-2514","position":1,"is_corresponding":false},{"id":1056819,"name":"Jasper Rubin-Sigler","orcid":null,"position":2,"is_corresponding":false},{"id":1056820,"name":"Sharon Tu","orcid":null,"position":3,"is_corresponding":false},{"id":1328499,"name":"Shuya Li","orcid":"0000-0002-7263-0365","position":4,"is_corresponding":false},{"id":1328500,"name":"Enming Yuan","orcid":"0000-0003-0755-9109","position":5,"is_corresponding":false},{"id":1195436,"name":"Menghui Liu","orcid":"0000-0001-6021-4447","position":6,"is_corresponding":false},{"id":1328955,"name":"Marriane King","orcid":null,"position":7,"is_corresponding":false},{"id":1328956,"name":"Elham Alhalthli","orcid":null,"position":8,"is_corresponding":false},{"id":1328957,"name":"Connie Treanor","orcid":null,"position":9,"is_corresponding":false},{"id":1328958,"name":"Alison Twelvetrees","orcid":null,"position":10,"is_corresponding":false},{"id":1274769,"name":"Marcel Weinreich","orcid":"0009-0003-1576-3385","position":11,"is_corresponding":false},{"id":1328959,"name":"Sam Bonsall","orcid":null,"position":12,"is_corresponding":false},{"id":557191,"name":"Calum Harvey","orcid":"0000-0001-5033-9385","position":13,"is_corresponding":false},{"id":1328960,"name":"Sarah Gornall","orcid":null,"position":14,"is_corresponding":false},{"id":1274771,"name":"Allan C. Shaw","orcid":"0000-0002-7321-7994","position":15,"is_corresponding":false},{"id":1328961,"name":"Johanna Ganssauge","orcid":null,"position":16,"is_corresponding":false},{"id":19987,"name":"Akshay Bhinge","orcid":"0000-0003-2939-099X","position":17,"is_corresponding":false},{"id":557193,"name":"Cleide Dos Santos Souza","orcid":"0000-0001-5314-6263","position":18,"is_corresponding":false},{"id":557196,"name":"Laura Ferraiuolo","orcid":"0000-0001-9118-5714","position":19,"is_corresponding":false},{"id":237404,"name":"Eran Hornstein","orcid":"0000-0002-5534-1924","position":20,"is_corresponding":false},{"id":32221,"name":"Ophir Shalem","orcid":"0000-0002-2267-0801","position":21,"is_corresponding":false},{"id":1328962,"name":"Anna Avila","orcid":null,"position":22,"is_corresponding":false},{"id":681689,"name":"Tatyana A. Shelkovnikova","orcid":"0000-0003-1367-5309","position":23,"is_corresponding":false},{"id":1328963,"name":"Charlotte H. van Dijk","orcid":null,"position":24,"is_corresponding":false},{"id":809832,"name":"Ilia Sarah Timpanaro","orcid":null,"position":25,"is_corresponding":false},{"id":296802,"name":"Kevin P. Kenna","orcid":null,"position":26,"is_corresponding":false},{"id":554368,"name":"Jianyang Zeng","orcid":"0000-0003-0950-7716","position":27,"is_corresponding":false},{"id":21347,"name":"Philip van Damme","orcid":"0000-0002-7124-8949","position":28,"is_corresponding":false},{"id":11259,"name":"Philip S. Tsao","orcid":"0000-0001-7274-9318","position":29,"is_corresponding":false},{"id":347598,"name":"Pamela J. Shaw","orcid":"0000-0002-8925-2567","position":30,"is_corresponding":false},{"id":296734,"name":"Justin K. Ichida","orcid":null,"position":31,"is_corresponding":false},{"id":237401,"name":"Johnathan Cooper‐Knock","orcid":"0000-0002-0873-8689","position":32,"is_corresponding":false},{"id":5648,"name":"Michael P. Snyder","orcid":"0000-0003-0784-7987","position":33,"is_corresponding":false},{"id":557189,"name":"Sai Zhang","orcid":"0000-0001-5996-6086","position":0,"is_corresponding":true}],"reference_count":109,"raw_metadata":null,"created_at":"2026-07-19T02:07:52.536246Z","pmid":"38633814","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":[]}