Grant: Foundation Grant

The two most common inherited bleeding disorders, von Willebrand disease (VWD) and hemophilia A (HA), are the result of deficiencies and/or dysfunction of two critical proteins in the human blood clotting system - von Willebrand factor (VWF) and factor VIII (FVIII). These two proteins circulate together in the blood and regulate key stages in the development of a normal blood clot. We will continue studies that have been ongoing in our group for the past 25 years aimed at understanding basic and translational aspects of VWF and FVIII. Although most of the proposed studies employ molecular and animal model strategies, there are obvious connections to clinical care that have the potential to enhance the quality of life of VWD and HA patients. The research program encompasses three interrelated themes exploring the normal and pathologic biology of VWF and FVIII. First, we will conduct studies to better understand the genetic basis, structure and function of VWF. We will use genetic approaches to determine the basis for the 35% of type 1 VWD patients in whom mutations in the VWF gene have not been identified, and will investigate whether the VWF propeptide has an independent clotting function. The second area of focus will evaluate risk factors for the development of an adverse immune response to FVIII therapy in HA, a complication of treatment in ~30% of these patients. We will determine the influence of VWF on FVIII immunity, and will explore the role of the host gut microbiome as a risk factor for FVIII antibody development. In the final phase of this proposal, we will conduct two complementary series of experiments that address the safety and efficacy of gene therapy approaches for the treatment of HA. Using our unique canine hemophilia resource, we will first determine the vector integration patterns following long-term adeno-associated viral vector gene transfer, and will then compare these outcomes with a novel foamy viral vector-based approach.