TY - JOUR TI - Gene Editing Rescues In vitro T Cell Development of RAG2-Deficient Induced Pluripotent Stem Cells in an Artificial Thymic Organoid System AU - Gardner, Cameron L. AU - Pavel-Dinu, Mara AU - Dobbs, Kerry AU - Bosticardo, Marita AU - Reardon, Paul K. AU - Lack, Justin AU - DeRavin, Suk See AU - Le, Kent AU - Bello, Ezekiel AU - Pala, Francesca AU - Delmonte, Ottavia M. AU - Malech, Harry AU - Montel-Hagan, Amelie AU - Crooks, Gay AU - Acuto, Oreste AU - Porteus, Matthew H. AU - Notarangelo, Luigi D. T2 - Journal of Clinical Immunology AB - Severe combined immune deficiency (SCID) caused by RAG1 or RAG2 deficiency is a genetically determined immune deficiency characterized by the virtual absence of T and B lymphocytes. Unless treated with hematopoietic stem cell transplantation (HSCT), patients with RAG deficiency succumb to severe infections early in life. However, HSCT carries the risk of graft-versus-host disease. Moreover, a high rate of graft failure and poor immune reconstitution have been reported after unconditioned HSCT. Expression of the RAG genes is tightly regulated, and preclinical attempts of gene therapy with heterologous promoters have led to controversial results. Using patient-derived induced pluripotent stem cells (iPSCs) and an in vitro artificial thymic organoid system as a model, here we demonstrate that gene editing rescues the progressive T cell differentiation potential of RAG2-deficient cells to normal levels, with generation of a diversified T cell repertoire. These results suggest that targeted gene editing may represent a novel therapeutic option for correction of this immunodeficiency. DA - 2021/03/01/ PY - 2021 DO - 10.1007/s10875-021-00989-6 DP - Springer Link J2 - J Clin Immunol LA - en SN - 1573-2592 UR - https://doi.org/10.1007/s10875-021-00989-6 Y2 - 2021/03/03/20:53:57 ER -