GENE THERAPY FOR IMMUNE DEFICIENCIES

免疫缺陷的基因疗法

• 批准号: 6160676
• 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/6160676
• 关键词: Mycobacterium; NAD(P)H dehydrogenase; adolescence (12-20); cellular immunity; child (0-11); chronic granulomatous disease; clinical research; clinical trial phase I; gene therapy; genetic disorder; human genetic material tag; human subject; human therapy evaluation; hydrogen peroxide; immunotherapy; inborn immunodeficiency; laboratory mouse; monocyte; neutrophil; phagocytic dysfunction; superoxides; tuberculosis

This project studies gene transfer into hematopoietic stem cells for the treatment of disorders of the immune system. specifically, the goal of the project is to develop gene therapy for chronic granulomatous disease (CGD). Patients with CGD have recurrent life-threatening infections because phagocytic cells (neutrophils and monocytes) have a defect in the enzyme that produces microbicidal superoxide and hydrogen peroxide. A clinical trial of a single cycle of gene therapy for the most common autosomal form of CGD (p47phox deficiency) was conducted. Long term followup (18 months) demonstrates the safety of procedures involving transfer of genes to peripheral blood progenitors in culture with intravenous administration of gene corrected progenitors. Corrected autologous progenitors engrafted in the patients providing functionally corrected neutrophils at 1 per 2000 to 30,000 for three to six months. This represents an important first step in demonstrating the feasibility of this approach. In related studies a p47phox-deficient CGD mouse model was used to demonstrate that gene therapy could achieve sufficient corrected neutrophils in peripheral blood (2-10%) to provide improved resistance to infection challenge. In other studies we demonstrated development of a new retrovirus vector construct which could correct the rare p67phox deficient autosomal recessive form of CGD. These clinical, animal and laboratory studies represent important steps toward development of clinically beneficial gene therapy for CGD.

该项目研究基因转移到造血干细胞中 治疗免疫系统的疾病。具体而言，目标的目标 该项目是为慢性肉芽肿性疾病开发基因治疗 （CGD）。 CGD患者患有复发生命的感染 因为吞噬细胞（中性粒细胞和单核细胞）在 产生微生物超氧化物和过氧化氢的酶。 最常见的基因治疗周期的临床试验 进行了CGD的常染色体形式（P47Phox缺乏）。长期 后续（18个月）证明了涉及的程序的安全性 将基因转移到培养物中的外周血祖细胞中 基因校正祖细胞的静脉注射。纠正 植入提供功能的患者的自体祖细胞 在每2000年以1到30,000的纠正，为三到六个月，以1分为130,000。 这代表了证明可行性的重要第一步 这种方法。在相关研究中，P47Phox缺乏CGD小鼠模型 被用来证明基因疗法可以实现足够的 外周血（2-10％）中的中性粒细胞纠正 抵抗感染挑战。在其他研究中，我们证明了 开发新的逆转录病毒向量构建体，该构造可以纠正 CGD的稀有P67PHOX缺乏常染色体隐性形式。这些临床， 动物和实验室研究代表着重要的步骤 开发CGD的临床上有益基因疗法。