Studies of inherited neurodegenerative disease ; mutation analysis and gene therapy

我们研究了酶缺陷引起的神经退行性疾病的突变分析和基因治疗。我们确定并基因分型神经病戈谢病（GD）的患者表现出独特的表型，脑积水，瓣膜钙化和角膜混浊。该患者为D409H突变纯合子。我们进行了病理检查的患者与2型GD治疗酶替代疗法。本研究提示，应用亲神经性载体进行基因治疗是治疗2型GD的必要手段。治疗组小鼠的肝脏和脾脏的病理学异常得到改善，尿糖胺聚糖也减少。只有侧脑室直接注射重组腺病毒才能将酶转导入脑。我们成功地将葡萄糖醛酸酶基因在逆转录病毒载体中高效转移到人造血祖细胞中。这些数据为基因治疗由酶缺陷引起的神经退行性疾病提供了鼓励。

We investigated the mutation analysis and gene therapy for neurodegenerative disorders caused by enzyme defect. We identified and genotyped a patient with neuronopathic Gaucher disease (GD) presenting unique phenotype, hydrocephalus, valvur calcification and corneal opacities. This patient was homozygous for D409H mutation. We performed pathological examinations of a patient with type 2 GD treated with enzyme replacement therapy. This study suggest that gene therapy using neurotropic vector should be required for treating type 2 GD.We produced recombinant adenovirus that express human glucuronidase and this recombinant adenovirus to animal model intravenously. Pathological abnormalities in liver and spleen were improved, and the urinary glycosaminoglycans were also reduced in treated mice. Transduction of enzyme into brain was seen only by adminstration of direct injection of recombinant adenovirus into the lateral ventricles. We succeeded in efficient transferring glucuronidase gene in a retroviral vector to human hematopoietic progenitor cells. These data provide encouragement that gene therapy for neurodegenerative disorders caused by enzyme defect is efficacious.