Hemophilia A is a recessive X-linked bleeding disorder resulting from a factor VIII (FVIII) deficiency.1 Although protein replacement therapy is effective for patients with hemophilia A, it is expensive and requires frequently accessing blood vessels, which limits its universal availability.2,3 Furthermore, up to 30% of patients with severe hemophilia A will develop inhibitory antibodies after protein infusion.4–۶ These inhibitory antibodies, referred to as inhibitors, will inactivate functional FVIII activity, rendering routine protein replacement therapy useless for bleeding episodes in patients with hemophilia A.7–۹ Gene therapy has the promise of treating hemophilia A but, in addition, has brought up a question about the importance of its relation to the biosynthesis of its carrier protein von Willebrand factor (VWF). This paper reviews site-specific FVIII expression in platelets, which are one of the two cell types synthesizing and storing VWF in the body, for gene therapy of hemophilia A and hemophilia B.

Platelet-Specific Gene Therapy of Hemophilia A and Hemophilia A with Inhibitors

Directing FVIII expression to the cells that synthesize VWF (platelets or endothelial cells) in vivo could potentially result in the formation of an intracellular VWF/FVIII complex and enhance the stability of FVIII compared to targeting cells, which do not synthesize VWF (e.g., stromal cells or hepatocytes). Targeting FVIII expression to platelets could be especially beneficial for gene therapy of hemophilia A because FVIII will be delivered together with VWF to the site of injury. This is particularly important for hemophilia A with inhibitors because FVIII would be sequestered by platelets, avoiding inhibitor inactivation in the circulation. Furthermore, a substantial amount of FVIII may be released from platelets at hemostatic sites, where aggregated platelets become activated at sites of injury, thus circumventing the time-dependent inactivation by inhibitors and achieving improved hemostasis. Several groups have been devoting efforts to develop unique gene therapy protocols using platelets as a target to deliver therapeutics for hemophilia A treatment. Various platelet lineage-specific promoters have been utilized to direct FVIII expression to platelets, including the platelet glycoprotein (GP) IIb (aIIb) promoter, GPIb promoter, and platelet factor-4 (PF4) promoter. Both transgenesis- and lentivirus-mediated gene delivery have been used to introduce platelet-specific FVIII expression. A schematic diagram of platelet-specific gene therapy of hemophilia A is depicted in Figure 1.