GENE THERAPY IN PRIMATES

灵长类动物的基因治疗

• 批准号: 6299330
• 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: 2000
• 资助国家: 美国
• 起止时间: 2000-03-15 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6299330
• 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，例如 阿尔茨海默病（AD）。 将细胞移植到大脑中 经过基因改造以产生神经营养因子， 神经递质或其他治疗剂可以达到特定的效果 慢性且耐受性良好的实质内药物递送 方式。 在 AD 中，基因治疗可以提供一种方法 向退化细胞输送神经营养因子，如 NGF 胆碱能基底前脑和其他区域的神经元，或 用于增强皮质中的神经递质功能， 海马体和其他区域。 基因疗法还可以 最终提供了一种操纵表达的手段 AD 病理学的产生涉及多种基因。 在第一个 这笔赠款的五年期，转换的最佳参数 原代灵长类细胞产生神经营养因子和 体外神经递质已被开发出来。 最佳的 将转基因细胞移植到大脑的条件 已成立。 当移植到胆碱能基底前脑时， NGF产生细胞表达NGF蛋白并预防胆碱能 神经元变性至少8个月。 新型号的 自发性年龄相关性胆碱能神经元变性 也得到了表征。 这种灵长类动物的下一个五年 项目将确定 1) NGF 基因治疗是否会预防 病变引起的和自发的与年龄相关的基础基础下降 前脑胆碱能神经元形态和行为功能 长达两年的长时间，2) 如果神经递质 基因疗法的替代将改善病变诱发和 与年龄相关的胆碱能生物化学自发下降和 行为功能，如最近在大鼠中所显示的，以及 3）如果 基因治疗的体内疗效和安全性，用于未来的临床试验 AD 可以通过连续 MRI 和 PET 成像、使用 用于控制体内基因表达的可调节启动子，以及 原代神经系统细胞的直接体内遗传修饰 例如腺病毒、腺相关病毒的神经元和神经胶质细胞， 和艾滋病毒载体。