Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China; Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States.
Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States.
Virology. 2018 May;518:95-102. doi: 10.1016/j.virol.2018.02.007. Epub 2018 Feb 16.
It has been demonstrated that human serum albumin (HSA) directly interacts with AAV virions and enhances AAV transduction. Several other proteins have also been identified a potential for enhancing AAV8 liver transduction. In our study, LDL or transferrin could enhance transduction in vitro and in vivo. We also found that any combination of two or three of these proteins (HSA, LDL, and transferrin) increased AAV8 transduction in Huh7 cells and in mice liver, which was similar to albumin alone. Pre-incubation of HSA with AAV8 virions prevented AAV8 virions from binding to other proteins. Furthermore, these serum protein receptors didn't impact AAV8 transduction but blocked the transduction enhancement from AAV8-serum protein complexes. These results indicate that serum proteins are hijacked by AAV8 vectors to increase hepatocyte binding, which shares same binding site. Importantly, the results could help us design an optimal formulation for effective AAV vector delivery in future clinical trials.
已经证实，人血清白蛋白（HSA）可直接与 AAV 病毒粒子相互作用，从而增强 AAV 转导。还有其他几种蛋白质也被鉴定出具有增强 AAV8 肝脏转导的潜力。在我们的研究中，LDL 或转铁蛋白可在体外和体内增强转导。我们还发现，这三种蛋白（HSA、LDL 和转铁蛋白）中的任意两种或三种组合均可增加 Huh7 细胞和小鼠肝脏中的 AAV8 转导，其效果与单独使用白蛋白相似。HSA 与 AAV8 病毒粒子预孵育可防止 AAV8 病毒粒子与其他蛋白结合。此外，这些血清蛋白受体不会影响 AAV8 转导，但可阻止 AAV8-血清蛋白复合物的转导增强。这些结果表明，血清蛋白被 AAV8 载体劫持以增加肝细胞结合，它们共享相同的结合位点。重要的是，这些结果可帮助我们在未来的临床试验中设计有效的 AAV 载体传递的最佳配方。
