title: Gene therapy for immune tolerance induction in hemophilia with inhibitors.
abstract: The development of inhibitors, i.e. neutralizing alloantibodies against factor (F) VIII or FIX, is the most significant complication of protein replacement therapy for patients with hemophilia, and is associated with both increased mortality and substantial physical, psychosocial and financial morbidity. Current management, including bypassing agents to treat and prevent bleeding, and immune tolerance induction for inhibitor eradication, is suboptimal for many patients. Fortunately, there are several emerging gene therapy approaches aimed at addressing these unmet clinical needs of patients with hemophilia and inhibitors. Herein, we review the mounting evidence from preclinical hemophilia models that the continuous uninterrupted expression of FVIII or FIX delivered as gene therapy can bias the immune system towards tolerance induction, and even promote the eradication of pre-existing inhibitors. We also discuss several gene transfer approaches that directly target immune cells in order to promote immune tolerance. These preclinical findings also shed light on the immunologic mechanisms that underlie tolerance induction.
authors.affiliation: The Children's Hospital of Philadelphia, Philadelphia, PA, USA.|Perelman Center for Cell and Molecular Therapeutics, Philadelphia, PA, USA.|Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: V R
authors.initials: VR
authors.lastname: Arruda
authors.affiliation: The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Samelson-Jones
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D004285:Dogs; D005164:Factor IX / Q000737:chemistry; D005169:Factor VIII / Q000737:chemistry; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006467:Hemophilia A / Q000235:genetics / Q000276:immunology*; D006470:Hemorrhage / Q000188:drug therapy; D006801:Humans; D007108:Immune Tolerance; D007518:Isoantibodies / Q000737:chemistry; D008297:Male; D051379:Mice
chemical_list: D007518:Isoantibodies; D005169:Factor VIII; D005164:Factor IX
keywords: alloantibodies; factor IX; factor VIII; gene therapy; hemophilia; immune tolerance