CORRECTION OF INHERITED PROTEIN DEFICIENCIES BY GENE THERAPY

正常和异常蛋白质的分离和鉴定 影响神经系统的遗传性疾病允许分离 cDNA和基因组DNA可用于纠正遗传蛋白 基因治疗的缺陷。 特别适合初次尝试 在基因治疗是那些疾病（如戈谢病，最 常见的鞘脂病），其中全身和神经系统 这种疾病的表现是异常的后果， 造血细胞，比如巨噬细胞。 在这种情况下， 正常基因与特定组织或骨髓祖细胞的结合 是一种合理的治疗方法。 利用溶酶体疾病戈谢病 疾病作为模型，我们利用逆转录病毒载体转移和表达 小鼠和Gaucher患者细胞系中人葡糖脑苷脂酶。 的 戈谢成纤维细胞中葡萄糖脑苷脂酶活性的完全校正 在文化中提供了动力，以评估逆转录病毒介导的 将葡萄糖脑苷脂酶基因转移到高雪氏病小鼠模型中 疾病 逆转录病毒介导的酪氨酸羟化酶的转移， 还研究了DOPA缺陷态的校正。 受体介导 也正在研究将基因转移到组织中。 的最初目标 本研究是将基因治疗应用于非神经元病 表型 转基因动物模型是利用靶向 在胚胎干细胞中同源重组以产生小鼠模型 人类疾病。 有害操作的细胞作为L- 多巴释放用于移植到动物的神经系统中 模型 当我们对遗传性疾病的致病机制的理解 神经和精神疾病的改善，并作为逆转录病毒介导的 基因在特定组织和细胞中的表达变得更可预测， 我们可以将基因疗法的应用扩展到特定疾病的治疗， 影响神经系统

The isolation and 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 consequences of abnormalities of hematopoietic cells, like the macrophage. In these instances that 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 utilized retroviral vectors to transfer and express human glucocerebrosidase in mouse and Gaucher patient cell lines. The complete correction of glucocerebrosidase activity in Gaucher fibroblasts in culture has provided the impetus for evaluation of retroviral mediated gene transfer of the glucocerebrosidase gene into a mouse model of Gaucher disease. Retroviral mediated transfer of tyrosine hydroxylase for the correction of DOPA deficiency states is also studied. Receptor mediated gene transfer into tissues is also 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. Recombinantly manipulated cells that act as depots of L- DOPA release are used for transplantation into the nervous system of animal models. When our understanding of the pathogenic mechanisms of inherited neurological 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.