PRECLINICAL STUDIES OF LIVER DIRECTED GENE THERAPY IN NON HUMAN PRIMATES

非人类灵长类动物肝脏定向基因治疗的临床前研究

• 批准号: 6247289
• 负责人: GARY B BASKIN
• 金额: $ 6.02万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-09 至 1998-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6247289
• 关键词: Mammalia; Primates; biotechnology; gene therapy; immunology; liver; model design /development; technology /technique development; virus

In order to develop a preclinical model of liver-directed gene therapy in nonhuman primates, we compared the efficacy of 2 different vectors, 2 modes of delivery, 2 reporter genes and of immunosuppression in 8 rhesus monkeys. We inoculated 2 monkeys with an adenovirus vector containing the lacZ gene as a reporter and compared these with 2 other monkeys inoculated with a lacZ-containing plasmid in liposomes. Two from each group were inoculated via a mesenteric vein and 2 via the bile duct. The adenovirus resulted in much more gene expression than the liposome vector, and mesenteric vein inoculation was far superior to bile duct administration. The monkeys developed an immune response to the adenoviral vector, resulting in hepatitis and loss of transgene expression within 2 weeks. We immunosuppressed 2 monkeys with steroids and cytoxan and inoculated them with the adenoviral vector, 1 via the saphenous vein and 1 via a mesenteric vein. Both routes were equally effective, and there was prolonged transgene expression and no hepatitis. We next immunosuppressed 2 monkeys for only 2 weeks and inoculated them via the saphenous vein with adenovirus containing either lacZ or luciferase as a reporter gene. Hepatitis and loss of transgene expression occurred as soon as the immunosuppressive drugs were discontinued. Both reporter genes were easily detected. We plan to continue these studies with more advanced vectors and more refined methods of immunosuppression in order to develop a good model for preclinical testing of products for gene therapy.

为了建立肝导向基因的临床前模型