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In vivo gene transduction in hepatoma using monoclonal antibody or specific promotor.

使用单克隆抗体或特异性启动子在肝癌中进行体内基因转导。

基本信息

批准号：
07457282
负责人：
FUJIMOTO Jiro
金额：
$ 4.8万
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：
1995
资助国家：
日本
起止时间：
1995 至 1997
项目状态：
已结题

项目摘要

Most viral vectors are highly immunogenic and are of limited use for somatic gene therapy that requires repetitive administrations. We developed a highly efficient gene transduction procedure useful for repetitive transfection using HVJ-liposome. We revealed that LacZ gene was deliveredto and expressed with high effeciency to rat liver. Antibody response to HVJ-liposome or cytotoxic T lymphocyte were not elicited against autologous rat hepatocyte. Using genetrasduction method, we performed gene therapy for liver cirrhosis using hepatocyte growth factor (HGF) and for hepatocellular carcinoma (HCC) by HSV-TK gene. Established liver cirrhosis rat model which has been induced by dimethy lnitrosamine was treated with muscle directed HGF gene therapy. HGF protein was detected in the plasma of rats, and tyrosine phosphorylation of c-Met/HGF receptor was observed. Fibrous component in the cirrhotic liver disappeared and the mortality was completely abrogated in HGF gene transducted rats. Transgene of HSV-TK gene under the control of alpha-fetoprotein (AFP) promotor achieved tumor regression for AFP-producing human HCC tumor in athymic nude mice. The suicidal gene, HSV-TK,was specifically expressed in the AFP-producing cells but not in normal cells. These results indicated that these gene therapies can be novel molecular approaches for liver cirrhosis and for HCC.

大多数病毒载体具有高度免疫原性，并且对于需要重复施用的体细胞基因治疗的用途有限。我们开发了一种高效的基因转导程序，可用于使用 HVJ 脂质体进行重复转染。我们发现LacZ基因被递送到大鼠肝脏并高效表达。针对自体大鼠肝细胞未引发针对 HVJ 脂质体或细胞毒性 T 淋巴细胞的抗体反应。我们采用基因转导方法，利用肝细胞生长因子（HGF）进行肝硬化的基因治疗，利用HSV-TK基因进行肝细胞癌（HCC）的基因治疗。建立二甲基亚硝胺诱导的肝硬化大鼠模型，采用肌肉定向HGF基因治疗。在大鼠血浆中检测到HGF蛋白，并观察到c-Met/HGF受体酪氨酸磷酸化。在HGF基因转导的大鼠中，肝硬化肝脏中的纤维成分消失并且死亡率完全消除。在甲胎蛋白（AFP）启动子控制下的HSV-TK基因转基因在无胸腺裸鼠中实现了产生AFP的人肝癌肿瘤的肿瘤消退。自杀基因HSV-TK在产生AFP的细胞中特异性表达，但在正常细胞中不表达。这些结果表明这些基因疗法可以成为治疗肝硬化和肝癌的新分子方法。