Lentiviral vectors (LV) are efficient vehicles for in vivo gene delivery to the liver. LV integration into the chromatin of target cells ensures their transmission upon proliferation, thus allowing potentially life-long gene therapy following a single administration, even to young individuals. The glycoprotein of the vesicular stomatitis virus (VSV.G) is widely used to pseudotype LV, as it confers broad tropism and high stability. The baculovirus-derived GP64 envelope protein has been proposed as an alternative for in vivo liver-directed gene therapy. Here, we perform a detailed comparison of VSV.G- and GP64-pseudotyped LV in vitro and in vivo. We report that VSV.G-LV transduced hepatocytes better than GP64-LV, however the latter showed improved transduction of liver sinusoidal endothelial cells (LSEC). Combining GP64-pseudotyping with the high surface content of the phagocytosis inhibitor CD47 further enhanced LSEC transduction. Coagulation factor VIII (FVIII), the gene mutated in hemophilia A, is naturally expressed by LSEC, thus we exploited GP64-LV to deliver a FVIII transgene under the control of the endogenous FVIII promoter and achieved therapeutic amounts of FVIII and correction of hemophilia A mice.

中文翻译：

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GP64假型慢病毒载体靶向肝内皮细胞并纠正A型血友病小鼠。


慢病毒载体（LV）是将体内基因递送至肝脏的有效载体。慢病毒整合到靶细胞的染色质中，确保它们在增殖时传播，从而允许在单次给药后进行潜在的终生基因治疗，甚至对年轻人来说也是如此。水疱性口炎病毒 (VSV.G) 的糖蛋白广泛用于假型 LV，因为它具有广泛的趋向性和高稳定性。杆状病毒衍生的 GP64 包膜蛋白已被提议作为体内肝脏定向基因治疗的替代方案。在这里，我们对 VSV.G 和 GP64 假型 LV 的体外和体内进行了详细比较。我们报告 VSV.G-LV 转导肝细胞优于 GP64-LV，但后者显示肝窦内皮细胞 (LSEC) 的转导得到改善。将 GP64 假型与吞噬抑制剂 CD47 的高表面含量相结合，进一步增强了 LSEC 转导。凝血因子 VIII (FVIII) 是甲型血友病中突变的基因，由 LSEC 天然表达，因此我们利用 GP64-LV 在内源性 FVIII 启动子的控制下传递 FVIII 转基因，并实现了治疗量的 FVIII 和血友病 A 的校正老鼠。