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

到目前为止，肝硬变被认为是纤维性瘢痕不可逆转的末端，目前还没有有效的治疗方法。我们最近建立了一种新的基因治疗方法，即通过脂质体介导的肌肉导向的肝细胞生长因子(HGF)基因转移来治疗大鼠肝硬变。在这项研究中，我们进行了以下几个实验来应用于人类肝硬变：a)H.GF介导的抗纤维化的详细机制的分析；b)HVJ-脂质体在非人灵长类动物中的安全性评价；c)大鼠肝切除后肝功能衰竭的预防；d)大鼠肝硬变的裸露HGF基因治疗；f)HGF基因表达对肝细胞生长的影响。作为这些实验的结果，我们获得了许多新的发现。肝细胞生长因子介导的抗纤维化作用不是通过激活肝细胞生长因子来抑制转化生长因子β1的表达，而是增强肝细胞生长因子对基质金属蛋白酶的表达。HUJ-脂质体的安全性评价表明，HUJ-脂质体在灵长类动物中的安全性、可行性和治疗潜力。在肝硬变大鼠，肝细胞生长因子基因的表达避免了肝切除后的肝功能衰竭。无论是大鼠还是狗，HGF裸露给药均显示出良好的治疗效果。HGF基因表达抑制肿瘤生长，而不是抑制肿瘤生长。这些结果提示HGF基因治疗是有能力治疗人类肝硬变的。

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.