{"doi":"10.1016/j.omtm.2024.101216","title":"B cell focused transient immune suppression protocol for efficient AAV readministration to the liver","abstract":"Adeno-associated virus (AAV) vectors are used for correcting multiple genetic disorders. Although the goal is to achieve lifelong correction with a single vector administration, the ability to redose would enable the extension of therapy in cases in which initial gene transfer is insufficient to achieve a lasting cure, episomal vector forms are lost in growing organs of pediatric patients, or transgene expression is diminished over time. However, AAV typically induces potent and long-lasting neutralizing antibodies (NAbs) against capsid that prevents re-administration. To prevent NAb formation in hepatic AAV8 gene transfer, we developed a transient B cell-targeting protocol using a combination of monoclonal Ab therapy against CD20 (for B cell depletion) and BAFF (to slow B cell repopulation). Initiation of immunosuppression before (rather than at the time of) vector administration and prolonged anti-BAFF treatment prevented immune responses against the transgene product and abrogated prolonged IgM formation. As a result, vector re-administration after immune reconstitution was highly effective. Interestingly, re-administration before the immune system had fully recovered achieved further elevated levels of transgene expression. Finally, this immunosuppression protocol reduced Ig-mediated AAV uptake by immune cell types with implications to reduce the risk of immunotoxicities in human gene therapy with AAV.","journal":"Molecular Therapy — Methods & Clinical Development","year":2024,"id":429972,"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":21,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9572,"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":290766,"name":"Roland W. Herzog","orcid":"0000-0002-7213-998X","position":1,"is_corresponding":false},{"id":663956,"name":"Maite Muñoz-Melero","orcid":null,"position":2,"is_corresponding":false},{"id":826655,"name":"Kentaro Yamada","orcid":"0000-0001-5454-4554","position":3,"is_corresponding":false},{"id":393004,"name":"Sandeep Kumar","orcid":"0000-0002-0533-219X","position":4,"is_corresponding":false},{"id":876121,"name":"Anh K. Lam","orcid":"0000-0002-8830-9349","position":5,"is_corresponding":false},{"id":938146,"name":"David M. Markusic","orcid":"0000-0002-3774-0825","position":6,"is_corresponding":false},{"id":320631,"name":"Dongsheng Duan","orcid":"0000-0003-4109-1132","position":7,"is_corresponding":false},{"id":290764,"name":"Cox Terhorst","orcid":"0000-0001-6233-7029","position":8,"is_corresponding":false},{"id":275253,"name":"Barry J. Byrne","orcid":"0000-0002-7302-1756","position":9,"is_corresponding":false},{"id":108769,"name":"Manuela Corti","orcid":"0000-0002-6391-4139","position":10,"is_corresponding":false},{"id":290763,"name":"Moanaro Biswas","orcid":"0000-0002-2889-5905","position":11,"is_corresponding":false},{"id":393005,"name":"Jyoti Rana","orcid":"0000-0001-9683-4592","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-19T01:59:11.328802Z","pmid":"38440160","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":[]}