Gene Editing Rescues In vitro T Cell Development of RAG2-Deficient Induced Pluripotent Stem Cells in an Artificial Thymic Organoid System.
Gene Editing Rescues In vitro T Cell Development of RAG2-Deficient Induced Pluripotent Stem Cells in an Artificial Thymic Organoid System.
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基因编辑在人工胸腺类器官系统中拯救RAG2缺陷诱导多能干细胞的体外T细胞发育。
DOI：
10.1007/s10875-021-00989-6
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发表时间：
2021-07
影响因子：
9.1
通讯作者：
Notarangelo LD
中科院分区：
文献类型：
--
作者：
Gardner CL;Pavel-Dinu M;Dobbs K;Bosticardo M;Reardon PK;Lack J;DeRavin SS;Le K;Bello E;Pala F;Delmonte OM;Malech H;Montel-Hagan A;Crooks G;Acuto O;Porteus MH;Notarangelo LD
由RAG1或RAG2缺陷引起的严重联合免疫缺陷（SCID）是一种遗传决定的免疫缺陷，其特征在于T和B淋巴细胞的实际缺乏。除非接受造血干细胞移植（HSCT）治疗，否则RAG缺乏症患者在生命早期就会死于严重感染。然而，HSCT具有移植物抗宿主病的风险。此外，非条件HSCT后移植失败率高，免疫重建差。RAG基因的表达受到严格调控，并且使用异源启动子的基因治疗的临床前尝试导致了有争议的结果。使用患者来源的诱导多能干细胞（iPSC）和体外人工胸腺类器官系统作为模型，在这里，我们证明了基因编辑将RAG2缺陷细胞的渐进性T细胞分化潜力拯救到正常水平，并产生多样化的T细胞库。这些结果表明，靶向基因编辑可能是纠正这种免疫缺陷的一种新的治疗选择。
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.
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影响因子：
12.4
作者：
Lagresle-Peyrou, Chantal;Benjelloun, Fatine;Cavazzana-Calvo, Marina
通讯作者：
Cavazzana-Calvo, Marina
影响因子：
64.8
作者：
Genovese, Pietro;Schiroli, Giulia;Escobar, Giulia;Di Tomaso, Tiziano;Firrito, Claudia;Calabria, Andrea;Moi, Davide;Mazzieri, Roberta;Bonini, Chiara;Holmes, Michael C.;Gregory, Philip D.;van der Burg, Mirjam;Gentner, Bernhard;Montini, Eugenio;Lombardo, Angelo;Naldini, Luigi
通讯作者：
Naldini, Luigi
影响因子：
14.8
作者：
Bak RO;Dever DP;Porteus MH
通讯作者：
Porteus MH
影响因子：
82.9
作者：
Charlesworth, Carsten T.;Deshpande, Priyanka S.;Porteus, Matthew H.
通讯作者：
Porteus, Matthew H.
影响因子：
7.5
作者：
Bosticardo, Marita;Pala, Francesca;Notarangelo, Luigi D.
通讯作者：
Notarangelo, Luigi D.