Lead Inventors: Thomas Diacovo, Jianchun Chen Problem or Unmet Need: One major hurdle hindering antithrombotic drug development is the lack of an appropriate small animal model of thrombosis to test promising therapies, as in vitro models of thrombosis...

Lead Inventors: Thomas Diacovo, Jianchun Chen Problem or Unmet Need: One major hurdle hindering antithrombotic drug development is the lack of an appropriate small animal model of thrombosis to test promising therapies, as in vitro models of thrombosis do not accurately recapitulate the hemodynamic conditions, cell-cell interactions, or cell-protein interactions that occur at sites of vascular injury in a living animal. Thus, the development of a "humanized" mouse model of hemostasis and thrombosis would potentially expedite drug discovery and testing against human platelets under physiologically relevant conditions. The technology: A genetically altered mouse that expresses a mutated form of von Willebrand Factor (VWF), which is able to support adhesion of human platelets to a level observed for its human counterpart. As a result, the technology provides a unique animal model to perform pre-clinical testing of anti-thrombotic agents and targeted molecular imaging agents directed against human platelets in vivo, and to study the molecular mechanisms governing human platelet binding at sites of vascular injury. Details of the Invention: The invention provides for a "humanized" mouse model that comprises a mouse expressing VWF that contains a mutation or combination of mutations in its Al domain that change the mouse protein's binding specificity from being specific for mouse platelets to being specific for human platelets. Thus, the mutant Al domain contained within mouse plasma VWF particularly supports the binding of human platelets in vivo and ex-vivo. In one embodiment, the mouse model is infused with human platelets. In another embodiment, human platelets are labeled ex-vivo or in vivo so as to be detected while in the animal using intravital microscopy. Applications: • Methods for identifying and evaluating potential antithrombotic reagents and compounds • Methods for testing for undesirable thrombotic or bleeding side effects of reagents in the clinical testing • In vivo model to test the efficacy of potential anti-thrombotic drugs directed against receptors, ligands, intracellular signaling pathways in human platelets Advantages: • The technology provides a great advantage of being able to test directly compounds that target human platelets in an in vivo system • The technology combined with contrast agent, provides a method to visualize and monitor human platelets at sites of thrombosis Patent Status: Patent Pending (WO/2008/005290) Licensing Status: Available for Sponsored Research Support and Fee for Service

Pat. Title: Screening Anti-thrombotic Compounds using Vwf-A1 Protein METHODS FOR TESTING ANTI-THROMBOTIC AGENTS METHODS FOR TESTING ANTI-THROMBOTIC AGENTS

Publication #: WO/2008/005290

App. #: 60/817,600 US07/015043 12/345,363

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