The central hypothesis being tested in this proposal is that anticoagulant aptamers and their antidotes represent a safe and effective means of controlling coagulation and preventing thrombosis. In the previous funding cycle of this grant, we tested the hypothesis that aptamers are a class of compounds whose activity can be readily reversed by antidotes. We determined that this hypothesis is correct and in the process developed aptamers that can inhibit the activity of several coagulation factors including factors VIIa, IXa, Xa and thrombin, and generated two classes of antidotes, oligonucleotide-based antidotes and universal antidotes, that can rapidly reverse the anticoagulant activity of such aptamers. Furthermore, we also generated aptamer-antidote pairs against the platelet proteins GP IIb/IIIa and VWF and have demonstrated their ability to inhibit platelet function. Thus we now have a set of novel antidote-controllable anticoagulant agents that we will use in this proposal to test the overall hypothesis that such aptamers and antidotes represent a safe and effective approach to control coagulation and platelet function in a variety of clinically relevant settings. Such control is especially valuable in the case of anticoagulant therapy because administration of such therapeutics can induce side effects such as severe bleeding that increase patient morbidity and mortality. Our three specific aims are: 1) to elucidate the mechanism(s) that aptamers utilize to inhibit coagulation factor activity. 2) To assess the net therapeutic benefit of aptamers that inhibit "safe" anticoagulant targets versus aptamer-antidote pairs that reversibly inhibit "validated" anticoagulant targets. 3) To determine which anticoagulant aptamers can effectively inhibit coagulation in the setting of cardiopulmonary bypass surgery and determine if oligonucleotide and universal antidotes can rapidly and safely reverse the effects of such aptamers following surgery.
Antithrombotic aptamers and antidotes 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, as well as dialysis. This therapy is also used as a treatment for a number of thrombotic diseases including acute coronary syndromes (myocardial infarction 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. In this grant application, we propose to develop and test a number of new anticoagulant and antiplatelet agents along with antidote molecules for this new therapeutics. We believe the generation of such antidote controllable therapeutic agents will lead to safer treatment of a number of cardiovascular disorders and improve the overall health and welfare of the public.
|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|
|Woodruff, R S; Xu, Y; Layzer, J et al. (2013) Inhibiting the intrinsic pathway of coagulation with a factor XII-targeting RNA aptamer. J Thromb Haemost 11:1364-73|
|Bompiani, K M; Monroe, D M; Church, F C et al. (2012) A high affinity, antidote-controllable prothrombin and thrombin-binding RNA aptamer inhibits thrombin generation and thrombin activity. J Thromb Haemost 10:870-80|
|Nimjee, Shahid M; Lohrmann, Jens D; Wang, Haichen et al. (2012) Rapidly regulating platelet activity in vivo with an antidote controlled platelet inhibitor. Mol Ther 20:391-7|
|Sullenger, Bruce; Woodruff, Rebecca; Monroe, Dougald M (2012) Potent anticoagulant aptamer directed against factor IXa blocks macromolecular substrate interaction. J Biol Chem 287:12779-86|
|Brandal, Stephanie; Blake, Charlene M; Sullenger, Bruce A et al. (2011) Effects of plasminogen activator inhibitor-1-specific RNA aptamers on cell adhesion, motility, and tube formation. Nucleic Acid Ther 21:373-81|
|Blake, Charlene M; Wang, Haichen; Laskowitz, Daniel T et al. (2011) A reversible aptamer improves outcome and safety in murine models of stroke and hemorrhage. Oligonucleotides 21:11-9|
|Buddai, Sai K; Layzer, Juliana M; Lu, Genmin et al. (2010) An anticoagulant RNA aptamer that inhibits proteinase-cofactor interactions within prothrombinase. J Biol Chem 285:5212-23|
|Oney, Sabah; Lam, Ruby T S; Bompiani, Kristin M et al. (2009) Development of universal antidotes to control aptamer activity. Nat Med 15:1224-8|
|Mi, Zhiyong; Guo, Hongtao; Russell, M Benjamin et al. (2009) RNA aptamer blockade of osteopontin inhibits growth and metastasis of MDA-MB231 breast cancer cells. Mol Ther 17:153-61|
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