CORRECTION OF INHERITED PROTEIN DEFICIENCEIS BY GENE THERAPY

参与遗传学的正常和异常蛋白质的表征 影响神经系统的疾病允许分离cDNA， 基因组DNA，可用于开发治疗遗传性 使用基因治疗的疾病。 特别适合初次尝试 在基因治疗中， 这种疾病的神经学表现是以下原因的结果： 更容易接近的骨髓衍生细胞的异常。 在这些情况下，正常基因转移到骨髓祖细胞， 细胞是一种合理的治疗方法。 利用溶酶体紊乱 戈谢病作为一种模型，以开发更有效的基因治疗技术 转移，我们已经成功地使用逆转录病毒载体转移， 在小鼠和Gaucher患者细胞系中表达人葡糖脑苷脂酶 和纸巾。 受体和脂质体介导，以及直接裸DNA 转移到特定的组织中是其他策略之一， 研究了 小鼠子宫内基因转移也在研究中， 可能需要有效治疗影响 神经系统本研究的一个初步目标是应用 遗传性疾病的非神经元病表型的基因治疗 在某些情况下，也会影响神经系统。转基因 已经使用靶向同源重组开发了动物模型 在胚胎干细胞中产生人类疾病的小鼠模型 这些动物模型用于测试新的治疗策略。 我们有 成功使用编码人葡糖脑苷脂酶的逆转录病毒载体 纠正组织中酶的缺乏和脂质的逆转储存 在戈谢病的小鼠模型中。 我们还使用了逆转录病毒 介导的神经递质合成酶的转移， 用于多巴的体外和体内校正的酪氨酸羟化酶 不足的国家。 基因工程细胞（例如， 已将产生酪氨酸羟化酶的成纤维细胞）用作 左旋多巴的释放，并已被移植到神经系统的 动物模型 当我们了解了 遗传性神经和精神疾病的改善， 用于在特定组织和细胞中转移和表达基因 变得更加可预测，我们也许能够扩展基因的使用， 治疗其他选定的影响神经系统的疾病 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.