GENE THERAPY IN PRIMATES

灵长类动物的基因治疗

• 批准号: 6098375
• 负责人: MARK H. TUSZYNSKI
• 金额: $ 18.43万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-01 至 2000-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6098375
• 关键词: Adenoviridae; Alzheimer's disease; Macaca mulatta; acetylcholine; aging; behavior test; cell transplantation; choline acetyltransferase; disease /disorder model; gene targeting; gene therapy; magnetic resonance imaging; nervous system regeneration; nervous system transplantation; neural degeneration; neurons; neurotransmitters; neurotrophic factors; nonhuman therapy evaluation; northern blottings; positron emission tomography; stereotaxic techniques; transfection /expression vector

Gene therapy may benefit human neurological disorders such as Alzheimer~s disease (AD). Grafting cells to the brain that are genetically modified to produce neurotrophic factors, neurotransmitters or other therapeutic agents can achieve specific intraparenchymal drug delivery in a chronic and well-tolerated manner. In AD, gene therapy could provide a means for delivering neurotrophic factors such as NGF to degenerating neurons in the cholinergic basal forebrain and other regions, or for augmenting neurotransmitter function in the cortex, hippocampus, and other regions. Gene therapy could also ultimately provide a means of manipulating the expression of various genes involved in generating AD pathology. In the first five-year period of this grant, optimal parameters for transducing primary primate cells to produce neurotrophic factors and neurotransmitters in vitro have been developed. Optimal conditions for grafting genetically modified cells to the brain have been established. When grafted to the cholinergic basal forebrain, NGF-producing cells express NGF protein and prevent cholinergic neuronal degeneration for at least 8 months. New models of spontaneous age-related cholinergic neuronal degeneration have also been characterized. The next five-year period of this primate project will determine 1) whether NGF gene therapy will prevent lesion-induced and spontaneous age-related declines in basal forebrain cholinergic neuronal morphology and behavioral function for prolonged periods of up to two years, 2) if neurotransmitter replacement by gene therapy will ameliorate lesion-induced and spontaneous age-related declines in cholinergic biochemistry and behavioral function, as recently shown in rats, and 3) if the in vivo efficacy and safety of gene therapy for future clinical trials in AD can be enhanced by serial MRI and PET imaging, use of regulatable promoters for controlling in vivo gene expression, and direct in vivo genetic modification of primary nervous system cells such as neurons and glia by adenovirus, adeno-associated virus, and HIV vectors.

基因疗法可能有益于人类神经系统疾病，如