A myeloid cell-binding adenovirus efficiently targets gene transfer to the lung and escapes liver tropism
A myeloid cell-binding adenovirus efficiently targets gene transfer to the lung and escapes liver tropism
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DOI：
10.1038/gt.2012.91
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发表时间：
2013-07-01
期刊：
影响因子：
5.1
通讯作者：
Roth, J. C.
中科院分区：
文献类型：
--
作者：
Alberti, M. O.;Deshane, J. S.;Roth, J. C.
腺病毒血清型5 （Ad5）载体的肝隔离阻碍了特异性和高效的基因传递到肺。Ad5肝向性的复杂性已经在很大程度上被解开，从而提高了Ad5基因传递的功效。然而，库普弗细胞（KC）清除和消除Ad5仍然是肺基因传递策略的主要障碍。KC摄取大大降低了Ad5在靶组织中的生物利用度，代偿性剂量增加导致急性肝毒性和强效先天免疫反应。在这里，我们报告了一种新的肺靶向策略，通过重定向Ad5结合到肺微血管内的浓缩白细胞池。我们证明，这种白细胞结合方法将Ad5特异性地重新靶向肺内皮细胞，并阻止KC摄取和肝细胞转导，与Ad5相比，肺靶向性增强了16.5万倍。此外，骨髓细胞特异性结合在单细胞肺悬液中被保留，只有Ad。mbp包被的髓细胞在体外实现了有效的内皮细胞转导。这些发现表明，通过在靶组织中更有效地摄取病毒粒子，可以阻止KC对Ad5的隔离，并表明内皮转导是通过白细胞介导的Ad的“交接”实现的。
Specific and efficient gene delivery to the lung has been hampered by liver sequestration of adenovirus serotype 5 (Ad5) vectors. The complexity of Ad5 liver tropism has largely been unraveled, permitting improved efficacy of Ad5 gene delivery. However, Kupffer cell (KC) scavenging and elimination of Ad5 still represent major obstacles to lung gene delivery strategies. KC uptake substantially reduces bioavailability of Ad5 for target tissues and compensatory dose escalation leads to acute hepatotoxicity and a potent innate immune response. Here, we report a novel lung-targeting strategy through redirection of Ad5 binding to the concentrated leukocyte pool within the pulmonary microvasculature. We demonstrate that this leukocyte-binding approach retargets Ad5 specifically to lung endothelial cells and prevents KC uptake and hepatocyte transduction, resulting in 165 000-fold enhanced lung targeting, compared with Ad5. In addition, myeloid cell-specific binding is preserved in single-cell lung suspensions and only Ad.MBP-coated myeloid cells achieved efficient endothelial cell transduction ex vivo. These findings demonstrate that KC sequestration of Ad5 can be prevented through more efficient uptake of virions in target tissues and suggest that endothelial transduction is achieved by leukocyte-mediated 'hand-off' of Ad.