{"doi":"10.1016/j.omtn.2023.03.017","title":"GOLGA8 increases bulk antisense oligonucleotide uptake and activity in mammalian cells","abstract":"Antisense oligonucleotides (ASOs) are short synthetic nucleic acids that recognize and bind to complementary RNA to modulate gene expression. It is well established that single-stranded, phosphorothioate-modified ASOs enter cells independent of carrier molecules, primarily via endocytic pathways, but that only a small portion of internalized ASO is released into the cytosol and/or nucleus, rendering the majority of ASO inaccessible to the targeted RNA. Identifying pathways that can increase the available ASO pool is valuable as a research tool and therapeutically. Here, we conducted a functional genomic screen for ASO activity by engineering GFP splice reporter cells and applying genome-wide CRISPR gene activation. The screen can identify factors that enhance ASO splice modulation activity. Characterization of hit genes uncovered GOLGA8, a largely uncharacterized protein, as a novel positive regulator enhancing ASO activity by ∼2-fold. Bulk ASO uptake is 2- to 5-fold higher in GOLGA8-overexpressing cells where GOLGA8 and ASOs are observed in the same intracellular compartments. We find GOLGA8 is highly localized to the trans -Golgi and readily detectable at the plasma membrane. Interestingly, overexpression of GOLGA8 increased activity for both splice modulation and RNase H1-dependent ASOs. Taken together, these results support a novel role for GOLGA8 in productive ASO uptake.","journal":"Molecular Therapy — Nucleic Acids","year":2023,"id":342459,"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":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.953,"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":1079405,"name":"Meghdad Rahdar","orcid":null,"position":1,"is_corresponding":false},{"id":1079406,"name":"Swagatam Mukhopadhyay","orcid":null,"position":2,"is_corresponding":false},{"id":55673,"name":"Huynh‐Hoa Bui","orcid":null,"position":3,"is_corresponding":false},{"id":39984,"name":"Christopher E. Hart","orcid":"0000-0003-0726-5071","position":4,"is_corresponding":false},{"id":1079407,"name":"Sagar Damle","orcid":null,"position":5,"is_corresponding":false},{"id":1079408,"name":"Margo Courtney","orcid":null,"position":6,"is_corresponding":false},{"id":3006,"name":"Michael W. Baughn","orcid":"0000-0001-8525-8024","position":7,"is_corresponding":false},{"id":227272,"name":"Don W. Cleveland","orcid":"0000-0002-1934-3682","position":8,"is_corresponding":false},{"id":124980,"name":"C. Frank Bennett","orcid":"0000-0001-9887-6251","position":9,"is_corresponding":false},{"id":1078970,"name":"Moira A. McMahon","orcid":"0000-0001-9810-8623","position":0,"is_corresponding":true}],"reference_count":40,"raw_metadata":null,"created_at":"2026-07-19T01:11:12.506815Z","pmid":"37096163","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":[]}