A Retrospective Study of the Cytokine Profile Changes in Mice with FVIII Inhibitor Development After Adeno-Associated Virus–Mediated Gene Therapy in a Hemophilia A Mouse Model

The development of inhibitory autoantibodies to the infused clotting factor VIII (FVIII) is a major complication for severe hemophilia A management. Novel therapy options for hemophilia have significantly progressed in the last decade, and a gene therapy cure for hemophilia is becoming a reality. However, mechanistic studies of FVIII autoantibodies (FVIII inhibitors) have lagged behind and remain a challenge for both protein replacement and gene therapy. FVIII inhibitor formation is assumed to be a classical T cell–dependent immune response in which cytokines/chemokines play an important role. The study of cytokine profile changes during FVIII inhibitor development may be helpful to understand the mechanism of inhibitor development and to explore potential novel approaches that will minimize the risk. After FVIII–/– mice were treated with intravenous administration of an adeno-associated virus 8 vector encoding human FVIII, FVIII expression peaked at week 2 (W2), and FVIII inhibitor was thoroughly develop...