ベクターに対する生体反応の制御に基づくIn Vivo遺伝子発現の最適化(誌上シンポジウム)

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The spatiotemporal distribution of transgenes determines the therapeutic efficacy of in vivo gene transfer. The important parameters of gene transfer are the level, duration, and cell specificity of expression, and the number of transfected cells. Interaction of vectors with blood cells, antigen-presenting cells, serum proteins, and other biological components affects the tissue distribution of vectors and the profile of transgene expression. Although plasmid DNA is less immunogenic than viral vectors, it can induce inflammatory cytokine release, due mainly to the presence of unmethylated CpG dinucleotides (CpG motifs). It was clearly demonstrated that intravenous injection of a plasmid DNA/cationic liposome complex resulted not only in the induction of inflammatory cytokines, but also in the activation of nuclear factor kB (NF-kB) in the lung. Insertion of additional NF-kB-binding sequences into conventional plasmid DNA resulted in a high transgene expression in the lung, suggesting that the biological response to vectors can be used to increase transgene expression. In a marked contrast to this strategy, long-term transgene expression was achieved by reducing the number of the CpG motifs in plasmid DNA. A plasmid encoding murine interferon (IFN) -β or IFN-γ with reduced numbers of CpG motifs was highly effective in inhibiting metastatic tumor growth in mice. These results clearly demonstrate the importance of the regulation of biological responses to plasmid vectors to optimize plasmid-based in vivo gene transfer.
公益社団法人日本薬学会の論文
2006-11-01

著者

西川元也
京都大学大学院薬学研究科

ベクターに対する生体反応の制御に基づくIn Vivo遺伝子発現の最適化(誌上シンポジウム)

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