Hematopoietic Stem Cell Gene Therapy for Adenosine Deaminase-Deficient Severe Combined Immunodeficiency Leads to Long-Term Immunological Recovery and Metabolic Correction
Hematopoietic Stem Cell Gene Therapy for Adenosine Deaminase-Deficient Severe Combined Immunodeficiency Leads to Long-Term Immunological Recovery and Metabolic Correction
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DOI：
10.1126/scitranslmed.3002716
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发表时间：
2011-08-24
影响因子：
17.1
通讯作者：
Thrasher, Adrian J.
中科院分区：
文献类型：
--
作者：
Gaspar, H. Bobby;Cooray, Samantha;Thrasher, Adrian J.
嘌呤回收酶腺苷脱氨酶(ADA)的遗传缺陷导致严重的联合免疫缺陷(SCID)，导致T、B和自然杀伤细胞系的严重枯竭。人类白细胞抗原相合的异基因造血干细胞移植(HSCT)提供了一种成功的治疗选择。然而，缺乏匹配捐赠者的个人必须接受不匹配的移植，这与相当大的发病率和死亡率有关。酶替代疗法(ERT)治疗ADA-SCID是可行的，但相关的免疫缺陷的次优纠正使患者容易感染。在这里，6名儿童接受了CD34阳性的自体骨髓干细胞和祖细胞的治疗，这些干细胞和祖细胞是用编码人ADA基因的常规伽玛逆转录病毒载体转导的。所有患者在输注基因修饰细胞之前都停止了ERT并接受了温和的化疗。所有患者均存活，中位随访时间为43个月(24至84个月)。六名患者中有四名在植入基因校正细胞后恢复了免疫功能。在两名患者中，治疗失败是因为疾病特定和技术原因：两人都重新启动了ERT，并保持良好。在四名康复的患者中，有三名仍未接受酶替代治疗。此外，这四名患者中有三名停止了免疫球蛋白替代，并且都显示出有效的代谢解毒作用。所有患者都没有感染，两名患者清除了有问题的持续性巨细胞病毒感染。没有出现不良的白血病副作用。因此，ADA-SCID的基因治疗是安全的，具有有效的免疫学和代谢纠正作用，可能为传统的无血缘关系的供者HSCT提供一种可行的替代方案。
Genetic defects in the purine salvage enzyme adenosine deaminase (ADA) lead to severe combined immunodeficiency (SCID) with profound depletion of T, B, and natural killer cell lineages. Human leukocyte antigen-matched allogeneic hematopoietic stem cell transplantation (HSCT) offers a successful treatment option. However, individuals who lack a matched donor must receive mismatched transplants, which are associated with considerable morbidity and mortality. Enzyme replacement therapy (ERT) for ADA-SCID is available, but the associated suboptimal correction of immunological defects leaves patients susceptible to infection. Here, six children were treated with autologous CD34-positive hematopoietic bone marrow stem and progenitor cells transduced with a conventional gammaretroviral vector encoding the human ADA gene. All patients stopped ERT and received mild chemotherapy before infusion of gene-modified cells. All patients survived, with a median follow-up of 43 months (range, 24 to 84 months). Four of the six patients recovered immune function as a result of engraftment of gene-corrected cells. In two patients, treatment failed because of disease-specific and technical reasons: Both restarted ERT and remain well. Of the four reconstituted patients, three remained off enzyme replacement. Moreover, three of these four patients discontinued immunoglobulin replacement, and all showed effective metabolic detoxification. All patients remained free of infection, and two cleared problematic persistent cytomegalovirus infection. There were no adverse leukemic side effects. Thus, gene therapy for ADA-SCID is safe, with effective immunological and metabolic correction, and may offer a viable alternative to conventional unrelated donor HSCT.