GENE THERAPY FOR IMMUNE DEFICIENCIES

免疫缺陷的基因疗法

• 批准号: 5200545
• 负责人: H L MALECH
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5200545
• 关键词: Actinomycetales infection; NAD(P)H dehydrogenase; adolescence (12-20); cell differentiation; child (0-11); chronic granulomatous disease; gene therapy; genetic transduction; human subject; inborn immunodeficiency; leukocyte oxidative burst; monocyte; myeloid stem cell; neutrophil; opportunistic infections; superoxides; tissue /cell culture; tuberculosis

This project studies gene therapy for chronic granulomatous diseases (CGD) and other inherited immune diseases affecting human phagocytes, and also studies use of gene therapy to augment phagocyte host defense against chronic intracellular infections such as tuberculosis and other mycobacterial infections. CGD are a group of 4 distinct genetic disorders with common phenotype characterized by life-threatening recurrent infections caused by failure of blood neutrophils and monocytes to produce superoxide and hydrogen peroxide. CGD results from the failure to produce any of the components of the NADPH oxidase. We now have achieved retrovirus mediated gene transfer to functionally correct all four genetic forms of CGD by transfer of normal oxidase genes into CD34+ hematopoietic myeloid progenitor cells from CGD patients resulting in full correction of superoxide production by 5% to 80% of phagocytes differentiated from the progenitors. A closed plastic bag system for large scale growth and efficient retrovirus transduction of CD34+ progenitors has been developed in collaboration with Baxter Healthcare. Large scale production of the clinical grade replication defective retrovirus substantially free of animal proteins was developed in collaboration with Somatix Therapy Corp. Also, a sensitive FACS analysis system was developed to follow funtional correction of oxidase after gene transfer correction of CGD progenitors. These scientific accomplishments allowed approval by regulatory agencies of a Phase I clinical trial of gene therapy for the p47phox deficient form of autosomal recessive CGD. This clinical trial has begun and analysis of these studies is in progress. The development of an animal protein free growth and transduction regimen together with a completely closed system for growth and transduction of CD34+ blood progenitors is a major advance in enhancing safety of gene therapy and will provide a general platform for other applications of gene transfer technology based on targeting of hematopoietic progenitor cells.

该项目研究慢性肉芽肿性疾病的基因治疗 （CGD）和其他影响人吞噬细胞的免疫疾病，以及 还研究使用基因疗法来增强吞噬细胞宿主防御 反对慢性细胞内感染，例如结核病和其他 分枝杆菌感染。 CGD是一组4个不同的遗传 具有威胁生命的特征的常见表型的疾病 由血液中性粒细胞和单核细胞失败引起的复发感染 产生超氧化物和过氧化氢。 CGD来自 无法产生NADPH氧化酶的任何成分。 我们现在 已经实现了逆转录病毒介导的基因转移以在功能上正确 通过将正常氧化酶基因转移到CGD中的所有四种遗传形式 来自CGD患者的CD34+造血髓样祖细胞 在完全校正超氧化物的吞噬细胞中，超氧化物的产生5％至80％ 与祖细胞区分开。 一个封闭的塑料袋系统 CD34+的大规模生长和有效的逆转录病毒转导 祖细胞已与Baxter Healthcare合作开发。 临床级复制的大规模生产有缺陷 逆转录病毒基本上没有动物蛋白 与Somatix Therapy Corp.合作。此外，敏感的FACS分析 开发系统以跟随基因后的氧化酶进行官能校正 CGD祖细胞的转移校正。 这些科学成就 允许接受I期临床试验的监管机构的批准 常染色体隐性CGD的p47phox缺乏形式的基因治疗。 该临床试验已经开始，对这些研究的分析是 进步。 无动物蛋白质生长的发展和 转导方案以及完全封闭的生长系统 CD34+血祖的转导是一个重大进展 提高基因疗法的安全性，并将为 基因转移技术的其他应用基于 造血祖细胞。