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動態-発現相関の解析に基づくin vivo遺伝子導入キャリアーシステムの分子設計

基于动力学-表达关系分析的体内基因转移载体系统分子设计

基本信息

批准号：
10470492
负责人：
HASHIDA Mitsuru
金额：
$ 8.38万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

项目摘要

In vivo gene therapy is increasingly attractive as one of advanced therapeutic methodologies against various diseases. For successful gene therapy, it is necessary to develop the carriers delivering gene to the target in a selective and effective manner. In this study, we analyzed relationship between pharmacokinetics and gene expression of plasmid DNA complexed with macromolecular and particulate carriers, and developed some strategies for controlling gene delivery using macromolecular and particulate carriers bearing specific ligands. In vitro gene transfection experiments found glycosylated cationic macromolecules and liposomes effective for specific delivery via sugar recognition mechanisms. The pharmacokinetics and in vivo gene transfection of plasmid DNA complexes were also investigated. When plasmid DNA complexed with glycosylated carriers was intraportally injected, it selectively accumulated and exhibited transfection activity in the liver. Membrane-fusogenic peptides were introduced to glycosylated cationic poly (amino acids), to control an intracellular trafficking of plasmid DNA complexes. The complexes were highly effective and liver-specific even when intravenously injected. Throughout this study, we demonstrated that in vivo expression of exogenous genes was much improved by controlling their pharmacokinetics, and developed the prototypes of gene delivery systems towards various diseases such as hepatic disorders.

体内基因治疗作为针对各种疾病的先进治疗方法之一越来越有吸引力。为了成功的基因治疗，有必要开发以选择性和有效的方式将基因递送至靶点的载体。在这项研究中，我们分析了与大分子和颗粒载体复合的质粒DNA的药代动力学和基因表达之间的关系，并开发了一些使用带有特定配体的大分子和颗粒载体来控制基因传递的策略。体外基因转染实验发现，糖基化阳离子大分子和脂质体可有效通过糖识别机制进行特异性递送。还研究了质粒DNA复合物的药代动力学和体内基因转染。当与糖基化载体复合的质粒DNA被注射到肝脏时，它选择性地在肝脏中积累并表现出转染活性。将膜融合肽引入糖基化阳离子聚氨基酸中，以控制质粒 DNA 复合物的细胞内运输。即使静脉注射，该复合物也非常有效且具有肝脏特异性。在整个研究中，我们证明了通过控制外源基因的药代动力学可以大大改善其体内表达，并开发了针对各种疾病（例如肝病）的基因递送系统的原型。