Abstract
The traditional treatment for hemophilia has been by protein replacement. This is complicated by the development of inhibitory antibodies to the infused factor (Factor VIII [FVIII] or Factor IX [FIX]). High-dose infusion of recombinant activated Factor VII (rFVIIa) has a long track record of success in such patients but its short-half life limits its use in prophylaxis. We have developed an alternative strategy by continuous expression of activated FVII from a transgene that is introduced into the host by means of gene transfer. For this, we modified the FVII cDNA to introduce a cleavage site between the light and heavy chain that would generate a FVII molecule secreted in the two-chain, activated form. Using viral-mediated delivery and expression from a liver-specific promoter (or as a transgenic approach) we demonstrated the long-term hemostatic efficacy of this approach in hemophilic mice. Subsequently, we used the canine version of our modified FVII and via gene transfer, showed multi-year phenotypic correction in hemophilic dogs, clearly evident by the absence of spontaneous bleeds that are characteristic in this animal model. No adverse events were observed throughout the study. Remarkably, clinical benefit was also observed in one treated dog despite the lack of hemostatic effect by in vitro assays. Overall, the results in this large animal model of hemophilia indicate the potential of gene-based continuous expression of activated FVII as a therapeutic strategy for hemophilia or other coagulation defects currently treated by rFVIIa.