Valder Arruda, M.D., Ph.D.
Our laboratory is interested in the development of gene-based strategies for the treatment of bleeding and thrombotic diseases. In a collaborative effort, we, along with others, have carried out 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 translational research studies on the efficacy and safety of intravascular delivery of AAV vectors to skeletal muscle or liver of dogs and mice with severe hemophilia B and hemophilia A (factor VIII deficiency). We are developing novel variants of coagulation factor VIII or factor IX with enhanced biological activity to optimize gene and protein based strategies. We have identified a factor IX variant (FIX Padua) with 8-10-fold higher specific activity, and this molecule is now used for gene therapy in hemophilia B dog models.
Recently the focus of the laboratory has been on the use of gene therapy to treat a major complication of the treatment of hemophilia, the formation of neutralizing antibodies to the infused protein (inhibitors). Our data showed that AAV-mediated liver expression of FVIII is associated with successful eradication of inhibitory antibodies to FVIII in hemophilia A dogs, and in this model we are defining the underlying mechanism of immune tolerance induction.
The protein C anticoagulant pathway plays a major role in the interface between coagulation and inflammatory processes. Venous thrombosis is most commonly the result of defects in the proteins that play a part in the protein C anticoagulant pathway. Activated Protein C (APC) mediates anticoagulant effects and signals cellular responses that are anti-inflammatory in nature. The current notion that occlusive vascular diseases, such as atherosclerosis, are forms of systemic diseases in which underlying inflammatory and thrombotic processes play a critical role, has led us to postulate that APC could offer an alternate therapeutic option. Ongoing studies are aimed at elucidating in vivo functions of APC in a series of animal models for thrombotic and/or inflammatory diseases.
We recently discovered a novel role of APC/PC pathway in modulating tumor metastasis; the PC zymogen proved the most effective modulator in preventing lung metastasis and offers an attractive therapeutic option with minimal risk of bleeding. Together, these studies should improve our understanding of the interface of blood coagulation and inflammation, cancer progression, and identification of novel therapeutic strategies for coagulation disorders and other diseases.
Site Design: Squirrelle | Powered by: -melle.io- | © 2014-2017 Center for Advanced Retinal and Ocular Therapeutics