Shi Q, Wilcox DA, Fahs SA, et al. Factor VIII ectopically targeted to platelets is therapeutic in hemophilia A with high-titer inhibitory antibodies. J Clin Invest 2006;116:1974-1982.

Hemophilia A remains a vexing clinical problem in spite of our detailed molecular understanding of its pathogenesis. Factor VIII (FVIII) infusion has been the mainstay of therapy for 40 years — initially with partially purified plasma proteins, and more recently with recombinant human FVIII produced with its carrier protein, vWF. Hemophilia has been a darling of experimental gene therapists impressed by the seriousness of the disease and the potential for cure. Relatively modest production of the missing factor provides clear clinical benefit, and there are appropriate animal models for pre-clinical studies. However, although recombinant FVIII protein is effective whether produced in cultured cells or in vivo, up to 30 percent of patients develop inhibitory antibodies that limit its therapeutic potential. In this report, Shi and colleagues report a clever new gene transfer approach, to deliver FVIII to sites of bleeding while keeping it carefully hidden from the immune system.

This paper builds on previous studies showing that hooking up a modified FVIII gene to the glycoprotein Ib alpha (GPIbα) promoter forces the expression of FVIII in platelets, where vWF is already produced1 . That strategy corrected bleeding in transgenic mice that lacked FVIII. Shi and colleagues confirmed the earlier results and went several steps further. They showed that platelets engineered to express FVIII could correct hemophilia when transfused into FVIII-null mice. The platelet-produced FVIII even worked in mice that produced high-titer inhibitor antibodies against FVIII, indicating that storage of the factor in platelet alpha granules shields it from the immune system and allows it to be released upon platelet activation at the site of vascular injury. In fact, almost none of the transgenic FVIII protein could be detected in plasma, even though it was clearly effective at preventing bleeding. The authors speculate that this strategy might be used in hemophilia patients, by introducing the GPIbα-FVIII transgene into autologous hematopoietic stem cells, transplanting them back, and relying on expression in mature platelets. The proof-of-concept experiments in mice are very encouraging. But there are still substantial issues to be overcome in human subjects, as discussed in a commentary that accompanied the article2 .

1.
Yarovoi HV, Kufrin D, Eslin DE, et al. Factor VIII ectopically expressed in platelets: efficacy in hemophilia A treatment. Blood 2003;102:4006-
2.
High KA. The leak stops here: platelets as delivery vehicles for coagulation factors. J Clin Invest 2006;116:1840-

Competing Interests

Dr. Andrews indicated no relevant conflicts of interest.