Roberts Sean A, Dong Biao, Firrman Jenni A, Moore Andrea R, Sang Nianli, Xiao Weidong
Sol Sherry Thrombosis Research Center, Philadelphia PA 19140, USA.
J Genet Syndr Gene Ther. 2011 Dec 21;1. doi: 10.4172/2157-7412.S1-006.
Current treatment of hemophilia A by intravenous infusion of factor VIII (fVIII) concentrates is very costly and has a potential adverse effect of developing inhibitors. Gene therapy, on the other hand, can potentially overcome these limitations associated with fVIII replacement therapy. Although hemophilia B gene therapy has achieved promising outcomes in human clinical trials, hemophilia A gene therapy lags far behind. Compared to factor IX, fVIII is a large protein which is difficult to express at sustaining therapeutic levels when delivered by either viral or non-viral vectors. To improve fVIII gene delivery, numerous strategies have been exploited to engineer the fVIII molecule and overcome the hurdles preventing long term and high level expression. Here we reviewed these strategies, and discussed their pros and cons in human gene therapy of hemophilia A.
目前通过静脉输注凝血因子VIII（fVIII）浓缩物治疗甲型血友病成本非常高，并且存在产生抑制剂的潜在不良反应。另一方面，基因疗法有可能克服这些与fVIII替代疗法相关的局限性。尽管乙型血友病基因疗法在人体临床试验中取得了令人鼓舞的成果，但甲型血友病基因疗法却远远落后。与凝血因子IX相比，fVIII是一种大蛋白，当通过病毒或非病毒载体递送时，难以在维持治疗水平上表达。为了改善fVIII基因递送，人们已经采用了多种策略来改造fVIII分子，并克服阻碍长期和高水平表达的障碍。在此我们综述了这些策略，并讨论了它们在甲型血友病基因治疗中的优缺点。
