Adenovirus-mediated factor VIII gene expression results in attenuated anti-factor VIII-specific immunity in hemophilia a mice compared with factor VIII protein infusion

Hemophilia A patients are typically treated by factor VIII (FVIII) protein replacement, an expensive therapy that induces FVIII-specific inhibitors in approximately 30% of patients with severe hemophilia. FVIII gene therapy h as the potential to improve the current treatment protocols. In this report , we used a hemophilia A mouse model to compare the humoral and cellular im mune responses between an E1/E2a/E3-deficient adenovirus expressing human F VIII directed by a liver-specific albumin promoter and purified recombinant FVIII protein infusion. Adenovirus-mediated FVIII expression did not elici t detectable CD4(+) or CD8(+) T cell responses and induced a weak antibody immune response to FVIII. In contrast, FVIII protein administration resulte d in a potent anti-FVIII antibody response and moderate CD4(+) T cell respo nse. Furthermore, hemophiliac mice preimmunized with FVIII protein infusion to induce anti-FVIII immunity, and subsequently treated by adenovirus-medi ated FVIII gene therapy, expressed therapeutic levels of FVIII despite the presence of low levels of anti-FVIII antibodies. No FVIII was detected in t he plasma of mice with intermediate or high antibody levels, although anti- FVIII antibody levels in some vector-treated animals declined. The data sup port the hypothesis that liver-specific gene therapy-mediated expression of FVIII may be less immunogenic than traditional protein replacement therapy .