GENE THERAPY IN PRIMATES

基因治疗可能有益于人类神经疾病，如 阿尔茨海默病~S病(AD)。将细胞移植到大脑中 通过基因改造产生神经营养因子， 神经递质或其他治疗剂可以达到特定的 一种耐受性良好的慢性脑实质内给药 举止。在阿尔茨海默病中，基因治疗可以为 神经生长因子等神经营养因子在退行性变中的作用 胆碱能基底前脑和其他区域的神经元，或 为了增强大脑皮层的神经递质功能， 海马体等区域。基因疗法也可以 最终提供了一种操纵 多种基因参与了AD病理的发生。在第一个 这笔赠款的五年期限，传感器的最佳参数 原生灵长类细胞产生神经营养因子和 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是 已经建立了。当移植到胆碱能基底前脑时， 神经生长因子产生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。新机型 自发性老年性胆碱能神经元变性 也被刻画出来了。这种灵长类动物的下一个五年时期 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与行为功能 长达两年，2)如果神经递质 基因治疗的替代将改善由损伤引起的和 胆碱能生化和胆碱能的自发年龄相关性下降 行为功能，就像最近在老鼠身上显示的那样，以及3)如果在 基因治疗在未来临床试验中的体内有效性和安全性 AD可以通过序列MRI和PET成像来增强，使用 用于控制体内基因表达的可调节启动子，以及 直接体内遗传修饰原代神经系统细胞 如腺病毒、腺相关病毒、神经元和胶质细胞， 以及艾滋病毒传播媒介。

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.