Our laboratory is interested in the molecular basis of bleeding and thrombotic disorders, and development of novel therapies for these debilitating diseases. A major focus of our research is on translational studies in large animal models of hemophilia. This work forms the basis for early-phase clinical studies on adeno-associated viral (AAV) vectors for the treatment of severe hemophilia B (factor IX deficiency). Current projects are focused on studies of the efficacy and safety of intravascular delivery of vectors to skeletal muscle or liver of hemophilia dogs. Recent findings from our laboratory also demonstrate that gene therapy has the potential to induce immune tolerance to therapeutic transgenes. In hemophilia A (factor VIII deficiency) dogs with inhibitory antibodies to FVIII protein, we discovered that continuous expression of FVIII by AAV-mediated gene transfer to the liver has the potential to eradicate FVIII-specific antibodies with consequent improvement of the disease phenotype. These studies indicate a novel application of gene therapy as a strategy for immune tolerance induction in several diseases complicated by the presence of antibody to the therapeutic protein. Finally, we are interested in exploring in vivo functions of activated protein C (APC) using animal models for thrombotic and/or inflammatory diseases. APC mediates anticoagulant effects and signals cellular responses that are anti-inflammatory in nature. The current notion that occlusive vascular diseases, inflammatory and thrombotic processes play and cancer metastasis, led us to postulate that APC/PC could offer an alternative therapeutic option.