biostudies-literatureUnknown9(22)Meng X<h4>Abstract</h4>Recombination activating gene 1 (RAG1) is essential for variable diversity joining recombination during early T- and B-cell development. Null mutations cause a complete block in receptor rearrangement, resulting in T-B- severe combined immunodeficiency (SCID). Patients with RAG1-SCID require hematopoietic stem cell transplantation for survival. Our phase I/II clinical trial (NCT04797260) is currently evaluating lentiviral RAG1 gene addition in autologous hematopoietic stem and progenitor cells (HSPCs). However, studying early human T-cell development is challenging due to limited access to thymic tissue. The artificial thymic organoid (ATO) system offers a promising in vitro model to study human T-cell differentiation. Here, we show that ATO cultures efficiently support T-Blood advances5920-5934https://www.ebi.ac.uk/biostudies/studies/S-EPMC12666348biostudies-literatureRAG1 lentiviral gene therapy restores T-cell development of RAG1-SCID patient cells in artificial thymic organoids.PMC12666348van der Holst RBerghuis DLankester ACStaal FJTMeng Xvan Eggermond MLangerak AWde Kivit SVloemans SCante-Barrett KPike-Overzet Kde Mooij BOtt de Bruin LMMelsen JEfalseRAG1 lentiviral gene therapy restores T-cell development of RAG1-SCID patient cells in artificial thymic organoids.<h4>Abstract</h4>Recombination activating gene 1 (RAG1) is essential for variable diversity joining recombination during early T- and B-cell development. Null mutations cause a complete block in receptor rearrangement, resulting in T-B- severe combined immunodeficiency (SCID). Patients with RAG1-SCID require hematopoietic stem cell transplantation for survival. Our phase I/II clinical trial (NCT04797260) is currently evaluating lentiviral RAG1 gene addition in autologous hematopoietic stem and progenitor cells (HSPCs). However, studying early human T-cell development is challenging due to limited access to thymic tissue. The artificial thymic organoid (ATO) system offers a promising in vitro model to study human T-cell differentiation. Here, we show that ATO cultures efficiently support T-2025-01-01T00:00:00Z2025 Nov2026-06-05T21:50:23.473Z2026-05-22T03:15:20.706ZS-EPMC126663484082911410.1182/bloodadvances.2025016970