GENE THERAPY IN PRIMATES

基因治疗可能有益于人类神经系统疾病， 阿尔茨海默病（Alzheimer’s disease，AD）。 将细胞移植到大脑， 通过基因改造产生神经营养因子， 神经递质或其它治疗剂可以实现特定的 在慢性和耐受性良好的 方式 在AD中，基因治疗可以提供一种方法， 将神经营养因子如NGF递送到退化的 胆碱能基底前脑和其他区域的神经元，或 来增强大脑皮层的神经递质功能 海马体和其他区域。 基因治疗也可以 最终提供了一种操纵 参与产生AD病理的各种基因。 上 这项赠款的五年期，最佳参数转导 原代灵长类细胞产生神经营养因子， 体外神经递质已经被开发出来。 最优 将转基因细胞移植到大脑的条件 确立了习 当移植到胆碱能基底前脑时， 产生神经生长因子的细胞表达神经生长因子蛋白并阻止胆碱能 神经元变性至少8个月。 新模式 自发性年龄相关胆碱能神经元变性 也被定性。 这种灵长类动物接下来的五年 该项目将确定1）NGF基因治疗是否会预防 病变引起的和自发的年龄相关的基础 前脑胆碱能神经元形态和行为功能 长达两年的长期，2）如果神经递质 基因治疗的替代将改善病变引起的， 胆碱能生物化学和自发性与年龄相关的下降 行为功能，如最近在大鼠中所示，和3）如果在 基因治疗的体内有效性和安全性，用于未来的临床试验， AD可以通过连续MRI和PET成像增强，使用 用于控制体内基因表达的可调控启动子，和 原代神经系统细胞的直接体内遗传修饰 例如通过腺病毒，腺相关病毒， 和艾滋病毒载体。

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.