Generation of a Kupffer Cell-evading Adenovirus for Systemic and Liver-directed Gene Transfer
Generation of a Kupffer Cell-evading Adenovirus for Systemic and Liver-directed Gene Transfer
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DOI：
10.1038/mt.2011.71
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发表时间：
2011-07-01
影响因子：
12.4
通讯作者：
Barry, Michael A.
中科院分区：
文献类型：
--
作者：
Khare, Reeti;May, Shannon M.;Barry, Michael A.
多达90%的静脉内（i. v.）注射剂量的腺病毒血清型5（Ad 5）被肝枯否细胞吸收和破坏。逃离这些细胞的病毒可以在结合因子X（FX）后感染肝细胞。考虑到与FX和库普弗细胞的相互作用被认为发生在Ad 5六邻体蛋白上，我们用Ad 6的那些替换了其暴露的高变区（HVR）。当在BALB/c小鼠和仓鼠中体内测试时，Ad 5/6嵌合体在肝脏中介导>10倍的转导。这种影响不是由于FX结合的变化。相反，与Ad 5相比，Ad 5/6似乎逃脱了枯否细胞摄取，如通过在体内不产生枯否细胞死亡，不需要在体内预给药，并且在体外被巨噬细胞吞噬的效率较低所证明的。当作为辅助依赖性腺病毒（Ad）载体进行测试时，Ad 5/6比辅助依赖性腺病毒5（HD-Ad 5）或HD-Ad 6载体介导更高的荧光素酶和因子IX转基因表达。这些数据表明，Ad 5/6六邻体嵌合体避开枯否细胞，并可能具有全身和肝脏定向治疗的效用。收稿日期：2010年10月12日;接受日期：2011年3月20日;在线发表日期：2011年4月19日。doi：10.1038/mt.2011.71
As much as 90% of an intravenously (i.v.) injected dose of adenovirus serotype 5 (Ad5) is absorbed and destroyed by liver Kupffer cells. Viruses that escape these cells can then transduce hepatocytes after binding factor X (FX). Given that interactions with FX and Kupffer cells are thought to occur on the Ad5 hexon protein, we replaced its exposed hypervariable regions (HVR) with those from Ad6. When tested in vivo in BALB/c mice and in hamsters, the Ad5/6 chimera mediated >10 times higher transduction in the liver. This effect was not due to changes in FX binding. Rather, Ad5/6 appeared to escape Kupffer cell uptake as evidenced by producing no Kupffer cell death in vivo, not requiring predosing in vivo, and being phagocytosed less efficiently by macrophages in vitro compared to Ad5. When tested as a helper-dependent adenovirus (Ad) vector, Ad5/6 mediated higher luciferase and factor IX transgene expression than either helper-dependent adenoviral 5 (HD-Ad5) or HD-Ad6 vectors. These data suggest that the Ad5/6 hexon-chimera evades Kupffer cells and may have utility for systemic and liver-directed therapies. Received 12 October 2010; accepted 20 March 2011; published online 19 April 2011. doi: 10.1038/mt.2011.71