Development and Analysis of Aptamer-Antidote Pairs

Duke University, Durham NC

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Anticoagulant and/or antithrombotic therapy is required to perform a number of clinical procedures including percutaneous coronary interventions (PCI, "angioplasties"), coronary artery bypass graft (CABG) surgery and other surgeries, and dialysis; and is also used as a treatment for a number of thrombotic diseases including acute coronary syndromes (heart attacks and unstable angina), deep vein thrombosis, pulmonary embolism, and peripheral vascular disease. The major toxicity and limitation of anticoagulant and antithrombotic therapy is serious drug-induced bleeding. For example, transfusions due to blood loss are required in upwards of 50% of CABG surgeries and 10-15% of PCI procedures. Thus, a critical need exists for the development of safer anticoagulant and antithrombotic agents, particularly ones whose activity can be readily controlled, to reduce the number and magnitude of such bleeding events. To begin to address this clinical need, we have worked toward developing a strategy for generating matched drug-antidote pairs. We have demonstrated that novel anticoagulant aptamers can be isolated against clotting factors and that antidotes can be rationally designed to neutralize the activity of one such anticoagulant aptamer that targets factor IXa. Herein we propose to extend these studies to determine if this strategy can be utilized to create matched aptamer-antidote pairs targeting other coagulation proteins as well as the platelet receptor glycoprotein IIb/IIIa (gplIb/IIIa). Our specific aims are: 1.) To develop aptamer-antidote pairs targeting clotting factors VIIa, Xa and thrombin and evaluate the activity of the aptamers and antidotes in vitro, 2.) To evaluate the activity of anticoagulant and antithrombotic aptamers in animal models and evaluate the ability of the antidotes to neutralize aptamer activity in vivo and 3.) To develop aptamer-antidote pairs targeting the platelet receptor gplIb/IIIa and evaluate the activity of these aptamers and antidotes in vitro. These studies will yield a strategy for rationally designing antidotes to aptamer-based therapeutics and thus lead to the development of safer therapeutic agents. [unreadable] [unreadable] [unreadable]