{"doi":"10.1101/2025.09.06.674645","title":"Anticodon Edited Transfer RNAs (ACE-tRNAs) Encoded as Therapeutic Nonviral Minimal DNA Vectors","abstract":"Nonsense mutations, resulting from a premature termination codon (PTC), make up ~11% of all genetic lesions causing disease, affecting millions of people worldwide. Nonsense suppressor anticodon-edited tRNAs (ACE-tRNAs) have emerged as a therapeutic modality for the rescue of PTCs. Delivery of ACE-tRNAs in vivo has been achieved by adeno-associated viral vector and RNA-lipid nanoparticle, however due to drawbacks associated with these approaches, DNA delivery remains an attractive approach. DNA-based approaches afford ease of manufacturing at a relatively low cost and exhibit improved therapeutic durability and safety as compared to viral vector- or RNA-based approaches. Due to the small size of human tRNA genes employed as ACE-tRNAs, in principle, DNA vectors <200 base pairs (bp) in size (minivectors) could be utilized for delivery of actively transcribed ACE-tRNAs. Here we demonstrate that linear DNA ACE-tRNA vectors as small as 200 bp effectively suppress several nonsense mutations in CFTR and REP1, and that ACE-tRNA minivectors display significantly improved bioavailability, reduced innate immune burden, and superior biostability as compared to conventional plasmid DNA vectors.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":574361,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9518,"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":830915,"name":"Wooree Ko","orcid":"0000-0002-3432-640X","position":1,"is_corresponding":false},{"id":1221403,"name":"Emily G. Sorensen","orcid":null,"position":2,"is_corresponding":false},{"id":1482126,"name":"Zachary Cheung","orcid":null,"position":3,"is_corresponding":false},{"id":572547,"name":"Tyler Couch","orcid":"0000-0002-2987-0400","position":4,"is_corresponding":false},{"id":1371569,"name":"J. Gabell","orcid":null,"position":5,"is_corresponding":false},{"id":1482127,"name":"Victoria Shwe","orcid":null,"position":6,"is_corresponding":false},{"id":1150313,"name":"Julia Hyatt","orcid":null,"position":7,"is_corresponding":false},{"id":1482128,"name":"Jennasea B. Licata","orcid":null,"position":8,"is_corresponding":false},{"id":1482129,"name":"Luke K. Peterson","orcid":null,"position":9,"is_corresponding":false},{"id":399633,"name":"David A. Dean","orcid":"0000-0001-7748-8073","position":10,"is_corresponding":false},{"id":830918,"name":"John D. Lueck","orcid":"0000-0002-1820-711X","position":11,"is_corresponding":false},{"id":395006,"name":"Joseph J. Porter","orcid":"0000-0002-4542-0338","position":0,"is_corresponding":true}],"reference_count":1,"raw_metadata":null,"created_at":"2026-07-19T02:57:40.686992Z","pmid":"40949995","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":[]}