A development of novel vectors and an establishment of a new generation of hepatic gene therapy for congenital metabolic diseases

基因治疗可能是许多先天性代谢性疾病最有前途的治疗方法。其临床应用的最大障碍是目前没有能够在体内实现高基因转导效率和序列性基因长期表达的载体，而这两者是治疗先天性代谢性疾病所必需的。本研究的目的是建立腺逆转录嵌合载体和免疫原性较低的内脏腺病毒载体，并利用它们建立新的肝脏基因治疗方法。我们构建了腺逆转录嵌合载体，并对其功能进行了研究。我们制备了腺病毒内脏载体，并对其功能进行了研究。我们研究了肝再生和肝细胞死亡的机制，特别是肝细胞生长因子和肝素结合egf的生物学作用和治疗潜力。我们利用腺病毒载体开发了一些新的治疗顽固性疾病的基因疗法。<未来计划>我们将在各种动物模型上进一步研究这些载体和肝脏基因治疗的治疗潜力和不良反应。

<Aim>Gene therapy may be the most promising therapeutics for many of congenital metabolic diseases. The largest obstacle of its clinical application is currently no available vector that is capable of in vivo high gene transduction efficiency and the sequential long-term gene expression, both of which are necessary for treating congenital metabolic diseases. The aim of the present study is to develop adeno-retro-chimeric vector and less immunogenic gutted adenoviral vector and to establish novel hepatic gene therapy using them.<Results>1. We developed adeno-retro-chimeric vector and studied their function.2. We developed gutted adenoviral vector and studied their function.3. We studied mechanisms of hepatic regeneration and hepatocyte death, especially biological roles and therapeutic potentials of hepatocyte growth fadctor and heparin-binding EGF.4. We developed some novel gene therapy for inveterate diseases using adenoviral vector.<Future plan>We will further study the therapeutic potential and adverse effects of these vectors and hepatic gene therapy in various animal models.