Chinen Javier, Puck Jennifer M
Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Curr Opin Allergy Clin Immunol. 2004 Dec;4(6):523-7. doi: 10.1097/00130832-200412000-00008.
Standard therapies for patients with severe primary immunodeficiencies include bone marrow transplantation and, for adenosine deaminase deficiency, enzyme replacement. In the last decade, gene therapy has been developed as an alternative for these conditions. We summarize the recent advances in gene therapy for primary immunodeficiencies and discuss the unexpected occurrence of leukemia in a gene therapy trial for X-linked severe combined immunodeficiency.
Eight of 10 infants with X-linked severe combined immunodeficiency who received autologous hematopoietic stem cells transduced with a retroviral vector carrying the IL2RG complementary DNA achieved immune reconstitution. However, the two youngest patients developed leukemic expansions of gene-corrected cells. The first case had proliferation of a gamma delta T cell clone, and the second case had three alpha beta T cell clones derived from a single transduced progenitor. Leukemic cells in both patients aberrantly expressed the LIM domain only-2 transcription factor due to retroviral vector insertions in this locus. After receiving anti-leukemic treatment one patient achieved a lasting remission, but the other relapsed. Four adenosine deaminase deficient severe combined immunodeficiency patients also developed functional immunity after receiving autologous hematopoietic stem cells transduced with the adenosine deaminase gene complementary DNA following submyeloablative chemotherapy. Chronic granulomatous disease, Wiskott-Aldrich syndrome, JAK3 deficiency and RAG2 deficiency are other immunodeficiencies being studied as candidates for gene therapy.
Gene therapy is a promising therapeutic option for some primary immunodeficiencies, especially when cells expressing the correct gene have a selective advantage. More clinical trials with closer patient monitoring are under way to define which patients may benefit from this approach, and strategies are being developed to understand and ultimately reduce the risk of leukemia secondary to retroviral vector insertion.
重度原发性免疫缺陷患者的标准治疗方法包括骨髓移植，对于腺苷脱氨酶缺乏症患者则采用酶替代疗法。在过去十年中，基因治疗已被开发作为这些病症的替代疗法。我们总结了原发性免疫缺陷基因治疗的最新进展，并讨论了在X连锁重症联合免疫缺陷基因治疗试验中意外发生白血病的情况。
10名接受携带IL2RG互补DNA的逆转录病毒载体转导的自体造血干细胞的X连锁重症联合免疫缺陷婴儿中有8名实现了免疫重建。然而，两名最年幼的患者出现了基因校正细胞的白血病性扩增。第一例是γδT细胞克隆增殖，第二例有三个源自单个转导祖细胞的αβT细胞克隆。由于逆转录病毒载体插入该位点，两名患者的白血病细胞均异常表达仅含LIM结构域-2转录因子。一名患者接受抗白血病治疗后实现了持久缓解，但另一名患者复发。4名腺苷脱氨酶缺乏的重症联合免疫缺陷患者在接受亚清髓性化疗后接受携带腺苷脱氨酶基因互补DNA的自体造血干细胞转导后也产生了功能性免疫。慢性肉芽肿病、威斯科特-奥尔德里奇综合征、JAK3缺乏症和RAG2缺乏症是正在作为基因治疗候选对象进行研究的其他免疫缺陷病。
基因治疗对于某些原发性免疫缺陷是一种有前景的治疗选择，特别是当表达正确基因的细胞具有选择性优势时。正在进行更多的临床试验并加强对患者的监测，以确定哪些患者可能从这种方法中受益，同时正在制定策略来理解并最终降低逆转录病毒载体插入继发白血病的风险。
