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首页> 外文期刊>The journal of gene medicine >Efficient targeted transduction of primary human endothelial cells with dual-targeted lentiviral vectors
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Efficient targeted transduction of primary human endothelial cells with dual-targeted lentiviral vectors

机译：双重靶向慢病毒载体对人原代内皮细胞的高效靶向转导

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摘要

Angiogenesis is a rate-limiting factor for numerous human diseases. Angiogenic vessels and also the endothelium of certain organs such as the lung display molecular addresses that can be exploited for the selective delivery of gene therapeutics. Lentiviral vectors (LVs) are powerful tools for stable gene delivery but their integration and expression in undesired cell types poses a serious safety concern. We have developed a dual-targeted LV that can specifically target primary endothelial cells (ECs). Cell selectivity is achieved during entry, using a modified Sindbis virus envelope, and during transcription, with an EC-specific promoter. We evaluated four surface markers for EC targeting and seven promoter sequences from genes preferentially expressed in ECs. The efficiency and specificity of the double targeted vector were assayed in a panel of human primary cultures and tumor cell lines. A vector targeted to CD146, an endothelial adhesion molecule, and carrying a derivative of the EC tyrosine kinase Tie2 promoter, increased specificity of transduction up to 50 times and was also effective at selectively transducing ECs in a mixed coculture with human fibroblasts. The vector presented here is a potentially powerful tool that could be used in a variety of human diseases. Copyright (C) 2007 John Wiley & Sons, Ltd.
机译：血管生成是许多人类疾病的限速因素。血管生成血管以及某些器官（例如肺）的内皮细胞显示出可用于选择性递送基因治疗药物的分子地址。慢病毒载体（LVs）是稳定传递基因的强大工具，但它们在不希望的细胞类型中的整合和表达引起了严重的安全隐患。我们已经开发出了一种可以特异性靶向原代内皮细胞（EC）的双重靶向LV。在进入过程中，使用修饰的Sindbis病毒包膜，以及在转录过程中，使用EC特异性启动子可实现细胞选择性。我们评估了EC靶向的四个表面标记和来自EC中优先表达的基因的七个启动子序列。在一组人原代培养物和肿瘤细胞系中测定了双重靶向载体的效率和特异性。靶向内皮粘附分子CD146的载体并带有EC酪氨酸激酶Tie2启动子的衍生物，可将转导的特异性提高多达50倍，并且在与人成纤维细胞的混合共培养中，还可以有效地选择性转导EC。此处介绍的载体是一种潜在强大的工具，可用于多种人类疾病。版权所有（C）2007 John Wiley＆Sons，Ltd.

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