{"doi":"10.1016/j.omtn.2024.102196","title":"Enhanced transgene expression from single-stranded AAV vectors in human cells in vitro and in murine hepatocytes in vivo","abstract":"We identified that distal 10 nucleotides in the D-sequence in AAV2 inverted terminal repeat (ITR) share partial sequence homology to 1/2 binding site of glucocorticoid receptor-binding element (GRE). Here, we describe that (1) purified GR binds to AAV2 D-sequence, and the D-sequence competes with GR binding to its cognate binding site; (2) dexamethasone-mediated activation of GR pathway significantly increases the transduction efficiency of AAV2 vectors in human cells; (3) human osteosarcoma cells, U2OS, which lack expression of GR, are poorly transduced by AAV2 vectors, but stable transfection with a GR expression plasmid restores vector-mediated transgene expression; (4) replacement of the distal 10 nucleotides in the D-sequence of the AAV2 ITR with a full-length GRE consensus sequence significantly enhances transgene expression in human cells in vitro and in murine hepatocytes in vivo ; and (5) none of the ITRs in AAV1, AAV3, AAV4, AAV5, and AAV6 genomes contains the GRE 1/2 binding site, and insertion of a full-length GRE consensus sequence in the AAV6-ITR also significantly enhances transgene expression from AAV6 vectors, both in vitro and in vivo . These novel vectors, termed generation Y AAV vectors, which are serotype, transgene, or promoter agnostic, should be useful in human gene therapy.","journal":"Molecular Therapy — Nucleic Acids","year":2024,"id":429489,"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":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9585,"is_data_producer":false,"deposit_databanks":null,"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":415528,"name":"Chen Ling","orcid":"0000-0003-1527-1471","position":1,"is_corresponding":false},{"id":969121,"name":"Jakob Shoti","orcid":null,"position":2,"is_corresponding":false},{"id":350,"name":"Hua Yang","orcid":"0000-0002-4876-4072","position":3,"is_corresponding":false},{"id":1231624,"name":"Aneesha Nath","orcid":"0009-0008-4342-6657","position":4,"is_corresponding":false},{"id":1232169,"name":"Geoffrey D Keeler","orcid":null,"position":5,"is_corresponding":false},{"id":386526,"name":"Keyun Qing","orcid":null,"position":6,"is_corresponding":false},{"id":385394,"name":"Arun Srivastava","orcid":"0000-0003-1168-8034","position":7,"is_corresponding":false},{"id":544084,"name":"Lu Yuan","orcid":"0000-0001-5923-1581","position":0,"is_corresponding":true}],"reference_count":81,"raw_metadata":null,"created_at":"2026-07-19T01:59:06.668462Z","pmid":"38766527","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":[]}