Gene therapy for chronic granulomatous disease
Gene therapy for chronic granulomatous disease
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DOI：
10.1159/000072457
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发表时间：
2003-10-01
影响因子：
2.4
通讯作者：
Dinauer, MC
中科院分区：
文献类型：
--
作者：
Goebel, WS;Dinauer, MC
导致白细胞功能障碍的基因突变的鉴定沿着基因转移技术的应用，使得对此类疾病的遗传纠正成为可能。大部分吞噬细胞遗传性疾病的分子治疗研究都集中在慢性肉芽肿病（CGD）上。CGD是由编码呼吸爆发NADPH氧化酶（吞噬细胞中产生活性氧中间体所需的酶复合物）的必需亚基的四种基因中的任何一种突变引起的。吞噬细胞氧化剂的缺乏导致CGD患者易患复发性细菌和真菌感染以及炎性肉芽肿，与显著的发病率和死亡率相关。异基因骨髓移植可以治愈CGD，但移植相关的毒性和匹配供体的有限性限制了其更广泛的应用。由于引起CGD的基因缺陷是已知的，并且CGD是可通过骨髓移植治疗的干细胞疾病，因此CGD已经成为靶向造血系统的体细胞基因治疗的有前景的疾病。多个报告已经证明通过基因转移到体外培养的人CGD骨髓和细胞系中来重建NADPH氧化酶活性。CGD小鼠模型已经通过基因破坏开发，并且使用重组逆转录病毒载体对这些动物进行的临床前研究已经证明了功能正常的中性粒细胞的重建和对病原体如烟曲霉、洋葱伯克霍尔德氏菌和金黄色葡萄球菌的抗性增加。尽管这些鼠研究的结果令人鼓舞，但在CGD患者中进行的人类I期临床研究尚未产生长期临床有益的校正中性粒细胞数量。提高基因转移到人造血干细胞中的效率和增加转导干细胞的植入的努力正在进行中。版权所有（C）2003 S. Karger AG，巴塞尔。
Identification of gene mutations responsible for leukocyte dysfunction along with the application of gene transfer technology has made genetic correction of such disorders possible. Much of the research into molecular therapy for inherited disorders of phagocytes has been focused on chronic granulomatous disease (CGD). CGD results from mutations in any one of the four genes encoding essential subunits of respiratory burst NADPH oxidase, the enzyme complex required for the production of reactive oxygen intermediates in phagocytes. The absence of phagocyte oxidants results in a predisposition to recurrent bacterial and fungal infections and inflammatory granulomas in CGD patients, associated with significant morbidity and mortality. Allogeneic bone marrow transplantation can cure CGD, but transplant-related toxicity and the limited availability of matched donors have restricted its wider application. Because the gene defects causing CGD are known, and CGD is a stem cell disorder treatable by marrow transplantation, CGD has emerged as a promising disease for somatic gene therapy targeted at the hematopoietic system. Multiple reports have demonstrated the reconstitution of NADPH oxidase activity by gene transfer to human CGD marrow and cell lines cultured in vitro. CGD mouse models have been developed by gene disruption, and preclinical studies on these animals using recombinant retroviral vectors have demonstrated reconstitution of functionally normal neutrophils and increased resistance to pathogens such as Aspergillus fumigatus, Burkholderia cepacia and Staphylococcus aureus. Although the results of these murine studies are encouraging, human phase-I clinical studies in CGD patients have yet to produce clinically beneficial numbers of corrected neutrophils for extended periods. Efforts to improve gene transfer efficiency into human hematopoietic stem cells and to increase engraftment of transduced stem cells are ongoing. Copyright (C) 2003 S. Karger AG, Basel.