Current treatment of hemophilia A by intravenous infusion of factor VIII (fVIII) concentrates is very costly and has\r\na potential adverse effect of developing inhibitors. Gene therapy, on the other hand, can potentially overcome these\r\nlimitations associated with fVIII replacement therapy. Although hemophilia B gene therapy has achieved promising\r\noutcomes in human clinical trials, hemophilia A gene therapy lags far behind. Compared to factor IX, fVIII is a\r\nlarge protein which is difficult to express at sustaining therapeutic levels when delivered by either viral or non-viral\r\nvectors. To improve fVIII gene delivery, numerous strategies have been exploited to engineer the fVIII molecule\r\nand overcome the hurdles preventing long term and high level expression. Here we reviewed these strategies, and\r\ndiscussed their pros and cons in human gene therapy of hemophilia A.
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