{"doi":"10.1016/j.ymthe.2025.05.034","title":"Quantifying the mutational landscape of retroviral and lentiviral vectors in gene therapy patients","abstract":"Adenosine deaminase severe combined immunodeficiency (ADA-SCID) is a monogenic disorder caused by mutations in the ADA gene. Gene therapy using γ-retroviral and lentiviral vector gene addition approaches have shown curative results. We sequenced the ADA transgene in transduced CD3 + T cells, and in peripheral blood cells from patients treated with autologous CD34 + cells transduced with either a γ-retroviral or lentiviral ADA gene vector to assess transgene mutational profiles. In both CD3 + T cells and ADA-SCID patients' cells treated with the lentiviral vector, we observed significantly higher occurrences of guanine (G)-to-adenosine (A) base substitutions than with the γ-retroviral vector. We hypothesized that this G-to-A mutational signature was due to the APOBEC3 cytosine deaminase protein family. By knocking out APOBEC3 genes in HEK239T packaging cells, APOBEC3-mediated mutagenesis decreased by 91.2% along the transgene in CD34 + transduced cells in comparison to CD34 + cells transduced with lentiviral supernatant packaged in parental HEK293T cells.","journal":"Molecular Therapy","year":2025,"id":533797,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9549,"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":282024,"name":"Ralph Valentine Crisostomo","orcid":"0000-0001-8966-2139","position":1,"is_corresponding":false},{"id":1416429,"name":"Annika Mittelhauser","orcid":null,"position":2,"is_corresponding":false},{"id":462131,"name":"Lingyu Zhan","orcid":"0000-0001-6718-878X","position":3,"is_corresponding":false},{"id":1416430,"name":"Nika Kononov","orcid":null,"position":4,"is_corresponding":false},{"id":447633,"name":"Kathryn Bradford","orcid":"0000-0002-5858-7954","position":5,"is_corresponding":false},{"id":3656,"name":"Donald B. Kohn","orcid":"0000-0003-1840-6087","position":6,"is_corresponding":false},{"id":225658,"name":"Kevyn L. Hart","orcid":"0000-0002-7567-1744","position":0,"is_corresponding":true}],"reference_count":26,"raw_metadata":null,"created_at":"2026-07-19T02:51:43.451278Z","pmid":"40450520","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":[]}