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Optimization of in-vivo gene transfer through regulating biological response to vectors

机译：通过调节对载体的生物反应来优化体内基因转移

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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 kappaB (NF-kappaB) in the lung. Insertion of additional NF-kappaB-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)-beta or IFN-gamma 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.
机译：转基因的时空分布决定了体内基因转移的治疗效果。基因转移的重要参数是表达的水平，持续时间和细胞特异性，以及转染的细胞数量。载体与血细胞，抗原呈递细胞，血清蛋白和其他生物学成分的相互作用影响载体的组织分布和转基因表达的概况。尽管质粒DNA的免疫原性不如病毒载体，但它可以诱导炎性细胞因子释放，这主要是由于未甲基化的CpG二核苷酸（CpG基序）的存在。清楚地证明，静脉内注射质粒DNA /阳离子脂质体复合物不仅导致炎症细胞因子的诱导，而且导致肺中核因子κB（NF-κB）的活化。在常规质粒DNA中插入其他NF-κB结合序列会导致肺中高转基因表达，这表明对载体的生物学反应可用于增加转基因表达。与该策略形成鲜明对比的是，通过减少质粒DNA中CpG基序的数量，实现了长期转基因表达。具有减少的CpG基序数量的编码鼠干扰素（IFN）-β或IFN-γ的质粒在抑制小鼠转移性肿瘤生长方面非常有效。这些结果清楚地证明了调节对质粒载体的生物反应以优化基于质粒的体内基因转移的重要性。

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