CORRECTION OF INHERITED PROTEIN DEFICIENCEIS BY GENE THERAPY

遗传性疾病中正常和异常蛋白质的特征 影响神经系统允许分离cdna和基因组 DNA可用于通过基因纠正遗传的蛋白质缺陷 心理治疗。特别适合于基因治疗的初步尝试的是 这些疾病(如高谢病，最常见的 鞘磷脂沉积症)的全身性和神经学表现 这种疾病是骨髓异常的结果。 细胞，比如巨噬细胞。在这些情况下，正常的 特定组织或骨髓祖细胞的基因是一种 治疗方法的基本原理。利用溶酶体障碍高雪病 以疾病为模型，我们利用逆转录病毒载体转移和表达 人葡萄糖脑苷酶在小鼠和高雪病患者细胞系中的表达。 受体介导的组织内基因转移是另一种策略 调查过了。这项研究的最初目标是应用 非神经病理性表型的基因治疗。转基因动物 在胚胎中使用靶向同源重组来开发模型 干细胞来产生人类疾病的小鼠模型。逆转录病毒 神经递质合成酶的介导性转移 酪氨酸羟基酶用于纠正DOPA缺乏状态也 学习。重组操纵的细胞，作为L-多巴的仓库 正在开发用于移植到神经系统的释放剂。 当我们对遗传致病机制的理解 神经和精神疾病得到改善，并通过逆转录病毒介导 基因在特定组织和细胞中的表达变得更多 可以预见的是，我们可以将基因疗法的使用扩展到治疗 选定的影响神经系统的疾病。

The characterization of normal and abnormal proteins in genetic disorders affecting the nervous system permits the isolation of cDNA and genomic DNA that can be used to correct inherited protein deficiencies using gene therapy. Particularly suited for initial attempts at gene therapy are those disorders (such as Gaucher disease, the most common sphingolipidosis) in which the systemic and neurologic manifestations of the disorder are the consequence of abnormalities of bone marrow derived cells, like the macrophage. In these instances the transfer of normal genes to either specific tissue or bone marrow progenitor cells is a rationale therapeutic approach. Using the lysosomal disorder Gaucher disease as a model, we utilize retroviral vectors to transfer and express human glucocerebrosidase in mouse and Gaucher patient cell lines. Receptor mediated gene transfer into tissues is another strategy being investigated. The initial goal of this research is the application of gene therapy to the non-neuronopathic phenotypes. Transgenic animal models are developed using targeted homologous recombination in embryonic stem cells to generate mouse models of human disease. Retroviral mediated transfer of neurotransmitter synthesizing emzymes such as tyrosine hydroxylase for the correction of DOPA deficiency states is also studied. Recombinantly manipulated cells that act as depots of L-DOPA release are being developed for transplantation into the nervous system. When our understanding of the pathogenetic mechanisms of inherited neurologic and psychiatric diseases improves and as retroviral-mediated expression of genes in specific tissues and cells becomes more predictable, we can extend the use of gene therapy to treatment of selected disorders affecting the nervous system.