Vigant Frédéric, Descamps Delphyne, Jullienne Betsy, Esselin Stéphanie, Connault Elisabeth, Opolon Paule, Tordjmann Thierry, Vigne Emmanuelle, Perricaudet Michel, Benihoud Karim
CNRS UMR 8121, Vectorologie et Transfert de Gènes, Institut Gustave Roussy, Villejuif Cedex, France.
Mol Ther. 2008 Aug;16(8):1474-80. doi: 10.1038/mt.2008.132. Epub 2008 Jun 17.
Liver tropism potentially leading to massive hepatocyte transduction and hepatotoxicity still represents a major drawback to adenovirus (Ad)-based gene therapy. We previously demonstrated that substitution of the hexon hypervariable region 5 (HVR5), the most abundant capsid protein, constituted a valuable platform for efficient Ad retargeting. The use of different mouse strains revealed that HVR5 substitution also led to dramatically less adenovirus liver transduction and associated toxicity, whereas HVR5-modified Ad were still able to transduce different cell lines efficiently, including primary hepatocytes. We showed that HVR5 modification did not significantly change Ad blood clearance or liver uptake at early times. However, we were able to link the lower liver transduction to enhanced HVR5-modified Ad liver clearance and impaired use of blood factors. Most importantly, HVR5-modified vectors continued to transduce tumors in vivo as efficiently as their wild-type counterparts. Taken together, our data provide a rationale for future design of retargeted vectors with a safer profile.
肝脏嗜性可能导致大量肝细胞转导和肝毒性，这仍然是基于腺病毒（Ad）的基因治疗的一个主要缺点。我们之前证明，替换六邻体高变区5（HVR5），即最丰富的衣壳蛋白，构成了一个用于高效腺病毒重靶向的有价值平台。使用不同的小鼠品系表明，HVR5替换还导致腺病毒肝脏转导和相关毒性显著降低，而HVR5修饰的腺病毒仍能够有效地转导不同的细胞系，包括原代肝细胞。我们表明，HVR5修饰在早期并没有显著改变腺病毒的血液清除率或肝脏摄取。然而，我们能够将较低的肝脏转导与增强的HVR5修饰的腺病毒肝脏清除率以及血液因子利用受损联系起来。最重要的是，HVR5修饰的载体在体内转导肿瘤的效率与野生型载体一样高。综上所述，我们的数据为未来设计具有更安全特性的重靶向载体提供了理论依据。
