Retargeted delivery of adenoviral vectors through fibroblast growth factor receptors involves unique cellular pathways
Retargeted delivery of adenoviral vectors through fibroblast growth factor receptors involves unique cellular pathways
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DOI：
10.1096/fasebj.13.11.1459
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发表时间：
1999-08-01
期刊：
影响因子：
4.8
通讯作者：
Sosnowski, BA
中科院分区：
文献类型：
--
作者：
Doukas, J;Hoganson, DK;Sosnowski, BA
基因治疗的一个主要目标是通过替代细胞受体递送载体来提高靶特异性。我们以前报道过腺病毒载体通过碱性成纤维细胞生长因子（FGF2）受体传递增强细胞转导和体内疗效。我们现在提出的研究解决这些事件背后的细胞通路和机制。腺病毒的细胞受体对于通过FGF 2再靶向载体的转导是不需要的。此外，α（V）整联蛋白可以拮抗FGF 2重靶向，这与它们在非重靶向载体递送中的强制性作用相反。相比之下，高亲和力FGF受体，其在潜在的肿瘤靶点上过表达，是FGF2重新靶向转导所必需的。然而，低亲和力硫酸乙酰肝素蛋白聚糖相互作用不是先决条件，与其在FGF2促有丝分裂信号传导中的强制性作用形成鲜明对比。通过比较受体表达和配体结合与转基因表达，我们还证明了FGF2重靶向增强转导的机制，而不是增加靶细胞的数量。相反，替代靶向配体的使用支持特定受体相互作用和细胞内事件用于增强转基因表达的结论。总之，这些研究突出了FGF2重靶向腺病毒使用的独特递送和转导途径，并有助于确定其增强体内功效的基础。
A major goal of gene therapy is to improve target specificity by delivering vectors through alternative cellular receptors. We previously reported that adenoviral vector delivery through basic fibroblast growth factor (FGF2) receptors enhances both cellular transduction and in vivo efficacy. We now present studies addressing the cellular pathways and mechanisms underlying these events. Cellular receptors for adenoviruses are not required for transduction by FGF2-retargeted vectors. Moreover, alpha(v) integrins can antagonize FGF2 retargeting, in contrast to their obligatory role in non-retargeted vector delivery. By contrast, high-affinity FGF receptors, which are overexpressed on potential tumor targets, are required for FGF2-retargeted transduction. Low-affinity heparan sulfate proteoglycan interactions, however, are not a prerequisite, in marked contrast to their obligatory role in FGF2 mitogenic signaling. By comparing receptor expression and Ligand binding with transgene expression, we also demonstrate that FGF2 retargeting enhances transduction by mechanisms other than increasing the number of targeted cells. Rather, the use of alternative targeting Ligands supports the conclusion that specific receptor interactions and intracellular events serve to enhance transgene expression. Together, these studies highlight the unique delivery and transduction pathways used by FGF2-retargeted adenoviruses, and help define the basis for their enhanced in vivo efficacy.