title: Adenovirus-mediated factor VIII gene expression results in attenuated anti-factor VIII-specific immunity in hemophilia A mice compared with factor VIII protein infusion.
abstract: 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 has the potential to improve the current treatment protocols. In this report, we used a hemophilia A mouse model to compare the humoral and cellular immune responses between an E1/E2a/E3-deficient adenovirus expressing human FVIII directed by a liver-specific albumin promoter and purified recombinant FVIII protein infusion. Adenovirus-mediated FVIII expression did not elicit detectable CD4+ or CD8+ T cell responses and induced a weak antibody immune response to FVIII. In contrast, FVIII protein administration resulted in a potent anti-FVIII antibody response and moderate CD4+ T cell response. Furthermore, hemophiliac mice preimmunized with FVIII protein infusion to induce anti-FVIII immunity, and subsequently treated by adenovirus-mediated FVIII gene therapy, expressed therapeutic levels of FVIII despite the presence of low levels of anti-FVIII antibodies. No FVIII was detected in the plasma of mice with intermediate or high antibody levels, although anti-FVIII antibody levels in some vector-treated animals declined. The data support the hypothesis that liver-specific gene therapy-mediated expression of FVIII may be less immunogenic than traditional protein replacement therapy.
authors.affiliation: DNA Viral Vectors Unit, Genetic Therapy, Inc., A Novartis Company, 9 West Watkins Mill Road, Gaithersburg, MD 20878, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Bristol
authors.forename: A
authors.initials: A
authors.lastname: Gallo-Penn
authors.forename: J
authors.initials: J
authors.lastname: Andrews
authors.forename: N
authors.initials: N
authors.lastname: Idamakanti
authors.forename: M
authors.initials: M
authors.lastname: Kaleko
authors.forename: S
authors.initials: S
authors.lastname: Connelly
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000418:Albumins / Q000235:genetics; D000818:Animals; D000906:Antibodies / Q000276:immunology; D004195:Disease Models, Animal; D005169:Factor VIII / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology* / Q000627:therapeutic use; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006467:Hemophilia A / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D006801:Humans; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis / Q000276:immunology; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009928:Organ Specificity; D010047:Ovalbumin / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D013997:Time Factors
chemical_list: D000418:Albumins; D000906:Antibodies; D007132:Immunoglobulin Isotypes; D005169:Factor VIII; D010047:Ovalbumin