{"doi":"10.1073/pnas.2210532119","title":"A blood–brain penetrant RNA-targeted small molecule triggers elimination of r(G <sub>4</sub> C <sub>2</sub> ) <sup>exp</sup> in c9ALS/FTD via the nuclear RNA exosome","abstract":"A hexanucleotide repeat expansion in intron 1 of the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia, or c9ALS/FTD. The RNA transcribed from the expansion, r(G 4 C 2 ) exp , causes various pathologies, including intron retention, aberrant translation that produces toxic dipeptide repeat proteins (DPRs), and sequestration of RNA-binding proteins (RBPs) in RNA foci. Here, we describe a small molecule that potently and selectively interacts with r(G 4 C 2 ) exp and mitigates disease pathologies in spinal neurons differentiated from c9ALS patient-derived induced pluripotent stem cells (iPSCs) and in two c9ALS/FTD mouse models. These studies reveal a mode of action whereby a small molecule diminishes intron retention caused by the r(G 4 C 2 ) exp and allows the liberated intron to be eliminated by the nuclear RNA exosome, a multi-subunit degradation complex. Our findings highlight the complexity of mechanisms available to RNA-binding small molecules to alleviate disease pathologies and establishes a pipeline for the design of brain penetrant small molecules targeting RNA with novel modes of action in vivo.","journal":"Proceedings of the National Academy of Sciences","year":2022,"id":253015,"datarank":0.47670807455219194,"base_score":3.1780538303479458,"endowment":3.1780538303479458,"self_citation_contribution":0.47670807455219194,"citation_network_contribution":0.0,"self_endowment_contribution":0.47670807455219194,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":23,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9568,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":390943,"name":"Samantha M. Meyer","orcid":"0000-0003-3353-6939","position":1,"is_corresponding":false},{"id":645685,"name":"Rita Fuerst","orcid":null,"position":2,"is_corresponding":false},{"id":645000,"name":"Yuquan Tong","orcid":"0000-0003-0793-7747","position":3,"is_corresponding":false},{"id":898295,"name":"Yue Li","orcid":"0000-0003-1461-0742","position":4,"is_corresponding":false},{"id":333358,"name":"Raphael I. Benhamou","orcid":"0000-0003-1743-0886","position":5,"is_corresponding":false},{"id":249552,"name":"Haruo Aikawa","orcid":"0000-0003-2536-900X","position":6,"is_corresponding":false},{"id":804221,"name":"Patrick R. A. Zanon","orcid":"0000-0002-8883-8275","position":7,"is_corresponding":false},{"id":839154,"name":"Quentin M. R. Gibaut","orcid":"0000-0001-6307-4910","position":8,"is_corresponding":false},{"id":335360,"name":"Alicia J. Angelbello","orcid":null,"position":9,"is_corresponding":false},{"id":238179,"name":"Tania F. Gendron","orcid":"0000-0002-7335-2627","position":10,"is_corresponding":false},{"id":241295,"name":"Yong‐Jie Zhang","orcid":"0000-0002-9900-4313","position":11,"is_corresponding":false},{"id":228616,"name":"Leonard Petrucelli","orcid":"0000-0003-2959-129X","position":12,"is_corresponding":false},{"id":463099,"name":"Torben Heick Jensen","orcid":"0000-0001-5127-1239","position":13,"is_corresponding":false},{"id":249554,"name":"Jessica L. Childs‐Disney","orcid":"0009-0001-7829-3240","position":14,"is_corresponding":false},{"id":249561,"name":"Matthew D. Disney","orcid":"0000-0001-8486-1796","position":15,"is_corresponding":false},{"id":401806,"name":"Jessica A. Bush","orcid":"0000-0001-9474-1608","position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:24:55.325369Z","pmid":"36409902","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":[]}