title: Effects of FVIII immunity on hepatocyte and hematopoietic stem cell-directed gene therapy of murine hemophilia A.
abstract: Immune responses to coagulation factors VIII (FVIII) and IX (FIX) represent primary obstacles to hemophilia treatment. Previously, we showed that hematopoietic stem cell (HSC) retroviral gene therapy induces immune nonresponsiveness to FVIII in both naive and preimmunized murine hemophilia A settings. Liver-directed adeno-associated viral (AAV)-FIX vector gene transfer achieved similar results in preclinical hemophilia B models. However, as clinical immune responses to FVIII and FIX differ, we investigated the ability of liver-directed AAV-FVIII gene therapy to affect FVIII immunity in hemophilia A mice. Both FVIII naive and preimmunized mice were administered recombinant AAV8 encoding a liver-directed bioengineered FVIII expression cassette. Naive animals receiving high or mid-doses subsequently achieved near normal FVIII activity levels. However, challenge with adjuvant-free recombinant FVIII induced loss of FVIII activity and anti-FVIII antibodies in mid-dose, but not high-dose AAV or HSC lentiviral (LV) vector gene therapy cohorts. Furthermore, unlike what was shown previously for FIX gene transfer, AAV-FVIII administration to hemophilia A inhibitor mice conferred no effect on anti-FVIII antibody or inhibitory titers. These data suggest that functional differences exist in the immune modulation achieved to FVIII or FIX in hemophilia mice by gene therapy approaches incorporating liver-directed AAV vectors or HSC-directed LV.
authors.affiliation: Graduate Program in Molecular and Systems Pharmacology, Emory University , Atlanta, Georgia, USA.
authors.forename: Allison M
authors.initials: AM
authors.lastname: Lytle
authors.affiliation: Graduate Program in Molecular and Systems Pharmacology, Emory University , Atlanta, Georgia, USA.
authors.forename: Harrison C
authors.initials: HC
authors.lastname: Brown
authors.affiliation: Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine , Atlanta, Georgia, USA.
authors.forename: Na Yoon
authors.initials: NY
authors.lastname: Paik
authors.affiliation: Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine , Atlanta, Georgia, USA.
authors.forename: Kristopher A
authors.initials: KA
authors.lastname: Knight
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: J Fraser
authors.initials: JF
authors.lastname: Wright
authors.affiliation: Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine , Atlanta, Georgia, USA.
authors.forename: H Trent
authors.initials: HT
authors.lastname: Spencer
authors.affiliation: Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine , Atlanta, Georgia, USA.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Doering