CORRECTION OF INHERITED PROTEIN DEFICIENCEIS BY GENE THERAPY

与遗传有关的正常和异常蛋白质的特性 影响神经系统的疾病允许分离cdna和 可用于开发遗传性疾病治疗方法的基因组DNA 使用基因疗法治疗疾病。特别适合于最初的尝试 在基因治疗中，系统性和全身性精神障碍 这种疾病的神经学表现是 更容易获得的骨髓来源细胞的异常。 在这些情况下，将正常基因转移到骨髓祖细胞 细胞是一种基本的治疗方法。利用溶酶体障碍 以高谢病为模型发展更有效的基因检测技术 我们已经成功地利用逆转录病毒载体转移和 人葡萄糖脑苷酶在小鼠和高雪病患者细胞系中的表达 还有纸巾。受体和脂质体介导，以及直接裸露DNA 转移到特定组织中的其他策略包括 调查过了。对小鼠子宫内基因转移的研究也在进行中， 可能需要有效地治疗影响 神经系统。这项研究的一个初步目标是应用 遗传性疾病非神经病表型的基因治疗 在某些情况下，这也会影响神经系统。转基因 利用靶向同源重组建立了动物模型 在胚胎干细胞中产生人类疾病的小鼠模型 这些动物模型被用来测试新的治疗策略。我们有 成功使用编码人葡萄糖脑苷酶的逆转录病毒载体 纠正酶缺乏和脂肪在组织中的反向储存 在高谢病的小鼠模型中。我们还使用了逆转录病毒 神经递质合成酶的介导性转移 酪氨酸羟基酶对DOPA的体内外校正作用 缺乏状态。重组工程细胞(例如， 成纤维细胞)产生酪氨酸羟化酶已被用作 L-多巴的释放并已被移植到神经系统中 动物模型。当我们对慢性阻塞性肺疾病的致病机制的理解 遗传性神经和精神疾病随着技术的进步和发展 用于基因在特定组织和细胞中的转移和表达 变得更可预测，我们也许能够扩大基因的使用 其他影响神经的疾病的治疗方法 系统。

The characterization of normal and abnormal proteins involved in genetic disorders affecting the nervous system permits the isolation of cDNA and genomic DNA that can be used to develop treatments for inherited disorders using gene therapy. Particularly suited for initial attempts at gene therapy have been those disorders in which the systemic and neurologic manifestations of the disorder are the consequence of abnormalities of the more readily accessible bone marrow derived cells. In these instances the transfer of normal genes to bone marrow progenitor cells is a rationale therapeutic approach. Using the lysosomal disorder Gaucher disease as a model to develop more efficient techniques for gene transfer, we have successfully used retroviral vectors to transfer and express human glucocerebrosidase in mouse and Gaucher patient cell lines and tissues. Receptor and liposome mediated, as well as direct naked DNA transfer into specific tissues are among other strategies being investigated. In utero gene transfer in mice is also being studied, and may be required for effective treatment of disorders affecting the nervous system. An initial goal of this research is the application of gene therapy to the non-neuronopathic phenotypes of genetic disorders that can, in some cases, also affect the nervous system. Transgenic animal models have been developed using targeted homologous recombination in embryonic stem cells to generate mouse models of human disease and these animal models are used to test novel treatment strategies. We have successfully used retrovirus vectors encoding human glucocerebrosidase to correct the enzyme deficiency and reverse storage of lipid in tissues in murine models of Gaucher diseases. We have also used retroviral mediated transfer of neurotransmitter synthesizing enzymes such as tyrosine hydroxylase for both the in vitro and in vivo correction of DOPA deficiency states. Recombinantly engineered cells (for instance, fibroblasts) producing tyrosine hydroxylase have been used as depots of L-DOPA release and have been transplanted into the nervous system of animal models. When our understanding of the pathogenetic mechanisms of inherited neurologic and psychiatric disease improves and as technologies for the transfer and expression of genes in specific tissues ad cells becomes more predictable, we may be able to extend the use of gene therapy to treatment of other selected disorders affecting the nervous system.