The overall objective of the Duke Translational Medicine Institute Center for Thrombotic and Hemostatic Disorders (DTMI-CTHD) is to establish a home for and provide support for investigators focused upon developing novel approaches to treat thrombotic and hemostatic diseases at Duke University. As its name indicates, the DTMI-CTHD will be tightly integrated with the CTSA supported Duke Translational Medicine Institute, which is the home for all translational and clinical research at Duke. The scientific focus of the DTMI-CTHD is on treating thrombotic disease in acute care prothrombotic settings. Profound antithrombotic therapy is critical during both percutaneous and surgical revascularization procedures to prevent deleterious effects of coagulation and platelet aggregation triggered by foreign materials and vascular trauma. Such potent antithrombotic therapy is associated with the common complication of bleeding which makes management of such therapy challenging. To address this challenge, we have established a translational research program that has three research projects and three cores. Each project and core is led by a seasoned investigator(s). Project 1 will evaluate potent, yet antidote controllable combinations of antithrombotic agents in cell and animal based models. Project 2 will translate the first antidote controllable antiplatelet agent, a RNA aptamer against von Willebrand factor (VWF) and its matched antidote oligonucleotide, into phase 1a and 1b studies. Project 3 will employ clinical samples to develop unique laboratory profiles that can be applied to various clinical settings to predict the safety and efficacy of targeted antithrombotic therapy. Collectively these projects will result in 1.) a more thorough basic mechanistic understanding of the prothrombotic environment engendered during common revascularization procedures, 2.) translation of a novel approach to control platelet activity into a phase 1 clinical trial to begin to address a major challenge of antithrombotic therapy, bleeding and 3.) methods to identify and manage the optimal antithrombotic therapy for treatment of individual patients. The molecular, educational and administrative cores will support each of these projects as well as facilitate basic, translational and clinical research on thrombotic and hemostatic disorders across the Duke campus. Each project and core will be briefly discussed below along with the overall research environment at Duke.
We believe that the proposed projects will allow us to identify the approach and agent(s) that result in the highest net therapeutic benefit to limit thrombosis and monitor antithrombotic therapy in a variety of clinically relevant models, and to validate these observations using samples obtained from patients participating in a first-in-human phase 1 clinical trial.
|Soule, Erin E; Bompiani, Kristin M; Woodruff, Rebecca S et al. (2016) Targeting Two Coagulation Cascade Proteases with a Bivalent Aptamer Yields a Potent and Antidote-Controllable Anticoagulant. Nucleic Acid Ther 26:1-9|
|Woodruff, Rebecca S; Sullenger, Bruce A (2015) Modulation of the Coagulation Cascade Using Aptamers. Arterioscler Thromb Vasc Biol 35:2083-91|
|Bompiani, Kristin M; Lohrmann, Jens L; Pitoc, George A et al. (2014) Probing the coagulation pathway with aptamers identifies combinations that synergistically inhibit blood clot formation. Chem Biol 21:935-44|