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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性瘢痕形成的不可逆终点，目前尚无有效的治疗方法，本研究采用HVJ脂质体介导的肌肉介导的肝细胞生长因子（hepatocyte growth factor，HGF）基因转移技术，建立了一种新的大鼠肝硬化基因治疗方法。在这项研究中，我们进行了以下几个实验，将这种新方法应用于人类肝硬化：a）HGF介导的抗纤维化发生的详细机制分析B）HVJ-脂质体在非人灵长类动物中的安全性评价c）大鼠肝硬化中肝切除术后肝衰竭的预防d）大鼠肝硬化中的裸HGF基因治疗e）犬肝硬化中的裸HGF基因治疗f）HGF基因表达对肝癌生长的影响，这些实验结果，我们得到了许多新的发现。认为HGF介导的抗肝纤维化作用是通过激活Kuppfer细胞中MMP的表达而不是通过抑制TGFβ1的表达。HVJ脂质体的安全性评价显示了HVJ脂质体在灵长类动物中的安全性、可行性和治疗潜力。肝硬化大鼠肝切除术后肝细胞生长因子基因表达可避免肝衰竭。裸肝细胞生长因子给药不仅对大鼠而且对犬均有良好的治疗效果。HGF基因表达抑制肿瘤生长，而不是抑制肿瘤生长。提示HGF基因治疗可用于肝硬化的治疗。