{"doi":"10.1093/nar/gkaf675","title":"ACE-tRNAs are a platform technology for suppressing nonsense mutations that cause cystic fibrosis","abstract":"Nonsense mutations arise from single nucleotide substitutions that result in premature termination codons (PTCs). PTCs result in little to no full-length protein production and decreased mRNA stability due to the nonsense-mediated mRNA decay (NMD) pathway. We provide evidence that anticodon-edited (ACE-) tRNAs efficiently suppress the most prevalent cystic fibrosis (CF)-causing PTCs, promoting significant rescue of endogenous cystic fibrosis transmembrane conductance regulator (CFTR) transcript abundance and channel function in different model systems. We show that our best-performing ACE-tRNA, which decodes all UGA PTCs to a leucine amino acid, markedly rescues CFTR function from the most prevalent CF-causing PTCs, all of which arose from nonleucine encoding codons. Using this single ACE-tRNA variant, we demonstrate significant rescue of CFTR function in an immortalized airway cell line and two different primary CF patient-derived intestinal cell models with CFTR nonsense mutations. Further, we demonstrate that leucine substitution CFTR variants are highly functional. Thus, ACE-tRNAs have promise as a platform therapeutic for CF and other nonsense-associated diseases.","journal":"Nucleic Acids Research","year":2025,"id":512195,"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":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9506,"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":395006,"name":"Joseph J. Porter","orcid":"0000-0002-4542-0338","position":1,"is_corresponding":false},{"id":1158823,"name":"Sacha Spelier","orcid":"0000-0003-3896-5038","position":2,"is_corresponding":false},{"id":1221403,"name":"Emily G. Sorensen","orcid":null,"position":3,"is_corresponding":false},{"id":566957,"name":"Priyanka Bhatt","orcid":"0000-0002-4531-6952","position":4,"is_corresponding":false},{"id":1371569,"name":"J. Gabell","orcid":null,"position":5,"is_corresponding":false},{"id":1371570,"name":"Isabelle van der Windt","orcid":null,"position":6,"is_corresponding":false},{"id":572547,"name":"Tyler Couch","orcid":"0000-0002-2987-0400","position":7,"is_corresponding":false},{"id":275318,"name":"K. Coote","orcid":"0009-0005-2653-8962","position":8,"is_corresponding":false},{"id":275321,"name":"Martin Mense","orcid":"0000-0003-0280-9789","position":9,"is_corresponding":false},{"id":879792,"name":"Jeffrey M. Beekman","orcid":"0000-0003-4886-3756","position":10,"is_corresponding":false},{"id":830918,"name":"John D. Lueck","orcid":"0000-0002-1820-711X","position":11,"is_corresponding":false},{"id":830915,"name":"Wooree Ko","orcid":"0000-0002-3432-640X","position":0,"is_corresponding":true}],"reference_count":84,"raw_metadata":null,"created_at":"2026-07-19T02:48:01.269605Z","pmid":"40650978","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":[]}