GENE THERAPY OF LIVER CIRRHOSIS ; BASIC RESEARCH AND A PROSPECT FOR CLINICAL TRIAL

肝硬化的基因治疗；

基本信息

批准号：
11470266
负责人：
FUJIMOTO Jiro
金额：
$ 8.9万
依托单位：
HYOGO COLLEGE OF MEDICINE
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470266/
关键词：
LIVER CIRRHOSIS GENE THERAPY HGF NAKED DNA HVJ-LIPOSOME LIVER FAILURE HGF

项目摘要

Liver cirrhosis has been regarded to be irreversible end of fibrous scaring with no effective therapy up to now.We recently established a novel gene therapy approach for rat liver cirrhosis by HVJ-liposome mediated muscle-directed gene transfer of hepatocyte growth facor (HGF). In this study, we performed following several experiments to apply this novel approach for human liver cirrhosis : a) analysis of detail mechanism of H.GF mediated anti-fibrogenesis b) safety evaluation of HVJ-liposome in nonhuman primates c) prevention of liver failure after hepatectomy in rat liver cirrhosis d) naked HGF gene therapy in rat liver cirrhosis e) naked HGF gene therapy in dog liver cirrhosis f) the effect of HGF gene expressionon growth of hepatoma.As the result of these experiments, we got much novel findings. HGF mediated anti-fibrogenesis was thought to act the enhancement of MMP expression by HGF rather than the suppression of TGFβ1 by activation of HGF in Kuppfer cells. Safety evaluation of HVJ-liposome showed the safety, feasiblity, and therapeutic potential of HVJ-liposome in primates. In liver cirrosis rats, HGF gene expression evaded liver failufe after hepatectomy. Naked HGF administration showed fine therapeutic effect not only rats but also dogs. HGF gene expression suppressed the tumor growth rather than tumor growing. These results suggested that HGF gene therapy is capable for treatment of human liver cirrhosis.

肝硬化被认为是纤维疤痕的不可逆转的终结，迄今为止还没有有效的治疗方法。我们最近通过HVJ脂质体介导的肝细胞生长因子（HGF）肌肉定向基因转移建立了一种针对大鼠肝硬化的新型基因治疗方法。在这项研究中，我们进行了以下几项肝脏实验，以将这种新方法应用于人类肝硬化：a) 分析 H.GF 介导的抗纤维形成的详细机制 b) 安全性评估非人灵长类动物中的 HVJ-脂质体 c) 预防大鼠肝硬化肝切除术后的肝衰竭 d) 大鼠肝硬化中的裸 HGF 基因治疗 e) 狗肝硬化中的裸 HGF 基因治疗 f) HGF 基因表达对肝癌生长的影响。作为这些实验的结果，我们得到了许多新的发现，HGF 介导的抗纤维形成被认为是通过 HGF 增强 MMP 表达，而不是通过抑制 TGFβ1。 HVJ-脂质体在Kuppfer细胞中的激活的安全性评估显示了HVJ-脂质体在灵长类动物中的安全性、可行性和治疗潜力，在肝切除术后HGF基因表达避免了肝衰竭，显示出良好的治疗效果。不仅是大鼠，狗的 HGF 基因表达也抑制了肿瘤的生长，而不是肿瘤的生长。这些结果表明 HGF 基因疗法能够治疗人类肝脏。肝硬化。