Figure 1.

Schematic Diagram of Platelet-Specific Gene Therapy of Hemophilia A

Lentiviral vectors harboring FVIII expression cassette under control of a platelet-specific promoter (αIIb, Ib, or PF4 promoter) are used to transduce hematopoietic stem cells (HSCs). Transduced HSCs undergo self-renewal as well as differentiation into megakaryocytes, where FVIII transgene protein will be made and stored in α-granules, which will be shed into platelets circulating in blood. Platelet-sequestered FVIII will be protected from anti-FVIII inhibitory antibody inactivation. At the site of injury, FVIII (together with its carrier protein VWF) will be released from activated platelets, and thus time-dependent inhibitor activation may be circumvented, achieving improved hemostasis. Figure was used by permission of Q. Shi.