Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy
Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy
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DOI：
10.1056/nejmoa012616
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发表时间：
2002-04-18
影响因子：
158.5
通讯作者：
Leiva, L
中科院分区：
文献类型：
--
作者：
Hacein-Bey-Abina, S;Le Deist, F;Leiva, L
背景：编码常见伽马(伽马链)的基因突变导致的X连锁严重联合免疫缺陷是一种致命的疾病，可通过异基因干细胞移植治愈。方法：采用逆转录病毒载体对5例X连锁重症联合免疫缺陷患儿的CD34+骨髓细胞进行体外转导。在基因转移后长达2.5年的时间里，对转基因γ蛋白的整合和表达、淋巴细胞亚群的发育及其功能进行了连续分析。结果：该过程没有不良反应。在四个月内，五名患者中有四名患者的血液中出现了转导的T细胞和自然杀伤细胞。T细胞的数量和表型、T细胞受体的谱系以及免疫后T细胞对几种抗原的体外增殖反应在治疗后两年内接近正常。原始T细胞和T细胞抗原受体表型的存在以及正常大小胸腺的发育证明了胸腺的生成。转导B细胞的频率很低，但免疫后血清免疫球蛋白水平和抗体产生足以避免静脉注射免疫球蛋白。免疫缺陷的纠正根除了既定的感染，使患者能够过上正常的生活。结论：用GAMAc进行体外基因治疗可以安全地纠正X连锁严重联合免疫缺陷患者的免疫缺陷。
Background: X-linked severe combined immunodeficiency due to a mutation in the gene encoding the common gamma(gamma) chain is a lethal condition that can be cured by allogeneic stem-cell transplantation. We investigated whether infusion of autologous hematopoietic stem cells that had been transduced in vitro with the gammac gene can restore the immune system in patients with severe combined immunodeficiency.Methods: CD34+ bone marrow cells from five boys with X-linked severe combined immunodeficiency were transduced ex vivo with the use of a defective retroviral vector. Integration and expression of the gammac transgene and development of lymphocyte subgroups and their functions were sequentially analyzed over a period of up to 2.5 years after gene transfer.Results: No adverse effects resulted from the procedure. Transduced T cells and natural killer cells appeared in the blood of four of the five patients within four months. The numbers and phenotypes of T cells, the repertoire of T-cell receptors, and the in vitro proliferative responses of T cells to several antigens after immunization were nearly normal up to two years after treatment. Thymopoiesis was documented by the presence of naive T cells and T-cell antigen-receptor episomes and the development of a normal-sized thymus gland. The frequency of transduced B cells was low, but serum immunoglobulin levels and antibody production after immunization were sufficient to avoid the need for intravenous immunoglobulin. Correction of the immunodeficiency eradicated established infections and allowed patients to have a normal life.Conclusions: Ex vivo gene therapy with gammac can safely correct the immune deficiency of patients with X-linked severe combined immunodeficiency.