San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy.
Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (IRGB-CNR), Milan, Italy.
Front Immunol. 2020 Nov 19;11:607926. doi: 10.3389/fimmu.2020.607926. eCollection 2020.
Genetic defects in recombination activating genes (RAG) 1 and 2 cause a broad spectrum of severe immune defects ranging from early severe and repeated infections to inflammation and autoimmune manifestations. A correlation between recombination activity and immune phenotype has been described. Hematopoietic cell transplantation is the treatment of care; however, the availability of next generation sequencing and whole genome sequencing has allowed the identification of novel genetic RAG variants in immunodeficient patients at various ages, raising therapeutic questions. This review addresses the recent advances of novel therapeutic approaches for RAG deficiency. As conventional myeloablative conditioning regimens are associated with acute toxicities and transplanted-related mortality, innovative minimal conditioning regimens based on the use of monoclonal antibodies are now emerging and show promising results. To overcome shortage of compatible donors, gene therapy has been developed in various RAG preclinical models. Overall, the transplantation of autologous gene corrected hematopoietic precursors and the use of non-genotoxic conditioning will open a new era, offering a cure to an increasing number of RAG patients regardless of donor availability and severity of clinical conditions.
RAG 1 和 2 基因重组激活基因缺陷导致广泛的严重免疫缺陷，从早期严重和反复感染到炎症和自身免疫表现。已经描述了重组活性与免疫表型之间的相关性。造血细胞移植是治疗的关键；然而，下一代测序和全基因组测序的可用性允许在不同年龄的免疫缺陷患者中鉴定新型遗传 RAG 变体，提出了治疗问题。这篇综述讨论了 RAG 缺乏症的新治疗方法的最新进展。由于传统的清髓性调理方案与急性毒性和移植相关死亡率相关，现在出现了基于使用单克隆抗体的创新最小化调理方案，并显示出有希望的结果。为了克服相容供体的短缺，基因治疗已在各种 RAG 临床前模型中得到发展。总体而言，自体基因纠正造血前体的移植和非遗传毒性调理的使用将开创一个新时代，为越来越多的 RAG 患者提供治愈机会，无论供体可用性和临床状况的严重程度如何。
