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

肝硬化被认为是纤维性瘢痕不可逆转的终点，至今尚无有效的治疗方法。我们最近建立了一种新的基因治疗方法，通过hvj脂质体介导肝细胞生长因子（HGF）的肌肉定向基因转移治疗大鼠肝硬化。在本研究中，我们进行了几项实验，将这种新方法应用于人类肝硬化：a) H.GF介导的抗纤维化的详细机制分析b)非人类灵长类动物hvj -脂质体的安全性评价c)大鼠肝硬化肝切除术后肝功能衰竭的预防d)大鼠肝硬化裸HGF基因治疗e)狗肝硬化裸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。在Kuppfer细胞中，HGF介导的抗纤维生成被认为是通过HGF增强MMP的表达，而不是通过激活HGF抑制tgf - β1。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，HGF基因表达可避免肝衰竭。裸给药HGF对大鼠和犬均有良好的治疗效果。HGF基因表达抑制肿瘤生长，而非抑制肿瘤生长。这些结果提示HGF基因疗法能够治疗人类肝硬化。

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.