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

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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.