2013 New Treatments, Target Identification
Molecular Basis and Novel Therapy of Systemic Lupus-Associated Thrombosis
The Study and What It Means to Patients
"Blood clots triggered by autoantibodies that stick to blood cells are a major complication of lupus. We are seeking to discover how lupus blood clots occur and testing whether a natural chemical found in certain foods, rutin, may be able to prevent clots in lupus mice. If so, we will start testing in humans as rutin is already approved as a food supplement by the FDA."
Why lupus autoantibodies stick to blood cells causing potentially fatal blood clots is not known. As a hematologist and new to lupus, I am working with my brother, a leading rheumatologist to combine my experience in clotting disorders with his expertise in lupus, to discover how blood clots occur in lupus patients and how to prevent them. First, we are using cutting-edge imaging techniques to visualize the formation of clots in the blood vessels of live mice to work out which blood cell type and which protein on the surface of blood cells is targeted by the clot-causing autoantibodies. Second, we recently found that a chemical (rutin) that occurs naturally in certain fruits and vegetables can prevent clots forming in mice with lupus autoantibodies. We are testing rutin in mouse models of lupus thrombosis. If it proves to be effective we anticipate moving quickly to clinical trials in patients, as the drug has already been deemed safe as a food supplement by the US Food and Drug Administration.
Intravital videomicroscopy and our thrombosis model will be used in mice to determine the target cell and receptor of beta2GP1 human autoantibodies important in lupus-associated thrombosis and the anti-phospholipid syndrome. These autoantibodies enhance thrombus size by over 100-fold (Arad, 2011), but the mechanism by which the anti-beta2GP1 autoantibody-beta2GP1 complex activates vascular cells is unknown. Using fluorescent anti-beta2GP1 autoantibodies and beta2GP1, we will identify the cells targeted by these antibodies during thrombus formation. Knockout mice lacking specific receptors will be used to identify the receptors required for thrombus enhancement by anti-beta2GP1 autoantibodies. We discovered the requirement for protein disulfide isomerase (PDI) during thrombus formation. Inhibition of PDI activity blocks thrombus development. Therefore, PDI represents a novel antithrombotic target in lupus. By high throughput screening, we identified a natural product (quercetin-3-rutinoside) that inhibits PDI activity and is approved by the FDA as safe. We will perform pre-clinical studies with this agent using our mouse model to evaluate whether this agent, used prophylactically, will prevent thrombosis induced by beta2GP1 autoantibodies. These are novel approaches to lupus-associated thrombosis, and have never been applied to explore the mechanism of thrombus formation in lupus. Furthermore, quercetin-3-rutinoside offers a new therapeutic approach to the prophylaxis of thrombosis in lupus.