{"doi":"10.15252/emmm.202013545","title":"Modeling, optimization, and comparable efficacy of T cell and hematopoietic stem cell gene editing for treating hyper‐IgM syndrome","abstract":"Precise correction of the CD40LG gene in T cells and hematopoietic stem/progenitor cells (HSPC) holds promise for treating X-linked hyper-IgM Syndrome (HIGM1), but its actual therapeutic potential remains elusive. Here, we developed a one-size-fits-all editing strategy for effective T-cell correction, selection, and depletion and investigated the therapeutic potential of T-cell and HSPC therapies in the HIGM1 mouse model. Edited patients' derived CD4 T cells restored physiologically regulated CD40L expression and contact-dependent B-cell helper function. Adoptive transfer of wild-type T cells into conditioned HIGM1 mice rescued antigen-specific IgG responses and protected mice from a disease-relevant pathogen. We then obtained ~ 25% CD40LG editing in long-term repopulating human HSPC. Transplanting such proportion of wild-type HSPC in HIGM1 mice rescued immune functions similarly to T-cell therapy. Overall, our findings suggest that autologous edited T cells can provide immediate and substantial benefits to HIGM1 patients and position T-cell ahead of HSPC gene therapy because of easier translation, lower safety concerns and potentially comparable clinical benefits.","journal":"EMBO Molecular Medicine","year":2021,"id":157359,"datarank":0.5926865577872142,"base_score":3.9512437185814275,"endowment":3.9512437185814275,"self_citation_contribution":0.5926865577872142,"citation_network_contribution":0.0,"self_endowment_contribution":0.5926865577872142,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":51,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9468,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":663874,"name":"E. Mercuri","orcid":"0000-0002-1005-3443","position":1,"is_corresponding":false},{"id":663875,"name":"Genni Enza Marcovecchio","orcid":"0000-0002-4994-1595","position":2,"is_corresponding":false},{"id":462039,"name":"Maria Carmina Castiello","orcid":"0000-0003-2581-9648","position":3,"is_corresponding":false},{"id":663876,"name":"Giulia Schiroli","orcid":"0000-0002-9812-8728","position":4,"is_corresponding":false},{"id":663877,"name":"Luisa Albano","orcid":"0000-0002-0013-4741","position":5,"is_corresponding":false},{"id":664368,"name":"Carrie M. Margulies","orcid":null,"position":6,"is_corresponding":false},{"id":70599,"name":"Frank A. Buquicchio","orcid":"0000-0002-9910-4947","position":7,"is_corresponding":false},{"id":425756,"name":"Elena Fontana","orcid":"0000-0001-8853-3335","position":8,"is_corresponding":false},{"id":663878,"name":"Stefano Beretta","orcid":"0000-0003-4375-004X","position":9,"is_corresponding":false},{"id":663879,"name":"Ivan Merelli","orcid":"0000-0003-3587-3680","position":10,"is_corresponding":false},{"id":663880,"name":"Andrea Cappelleri","orcid":"0000-0003-3729-528X","position":11,"is_corresponding":false},{"id":663881,"name":"Paola M. V. Rancoita","orcid":"0000-0001-9345-691X","position":12,"is_corresponding":false},{"id":663882,"name":"Vassilios Lougaris","orcid":"0000-0003-2303-9533","position":13,"is_corresponding":false},{"id":663883,"name":"Alessandro Plebani","orcid":"0000-0002-2003-3307","position":14,"is_corresponding":false},{"id":663884,"name":"Maria Kanariou","orcid":"0000-0003-0923-2118","position":15,"is_corresponding":false},{"id":281917,"name":"Arjan C. Lankester","orcid":"0000-0002-6703-2993","position":16,"is_corresponding":false},{"id":356715,"name":"Francesca Ferrua","orcid":"0000-0002-5695-4490","position":17,"is_corresponding":false},{"id":663885,"name":"Eugenio Scanziani","orcid":"0000-0003-3996-5048","position":18,"is_corresponding":false},{"id":330265,"name":"Cecilia Cotta‐Ramusino","orcid":null,"position":19,"is_corresponding":false},{"id":281851,"name":"Anna Villa","orcid":"0000-0003-4428-9013","position":20,"is_corresponding":false},{"id":598833,"name":"Luigi Naldini","orcid":"0000-0002-7835-527X","position":21,"is_corresponding":false},{"id":663886,"name":"Pietro Genovese","orcid":"0000-0001-9507-9003","position":22,"is_corresponding":false},{"id":663873,"name":"Valentina Vavassori","orcid":"0000-0002-3805-0420","position":0,"is_corresponding":true}],"reference_count":79,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:44:17.471040Z","pmid":"33475257","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":[]}