Four interrelated but independent hypotheses are being tested in this proposal. A) Aptamers can serve as molecular probes to identify functionally important exosites on coagulation factor proteases, B) Exosite-binding aptamers that inhibit coagulation factors in the contact pathway can limit thrombosis without increasing bleeding, C) Combinations of two exosite-binding aptamers and combinations of an aptamer and small molecule active site inhibitor represent potent, yet rapidly reversible anticoagulation strategies that can support cardiopulmonary bypass surgery and D). The exosite binding Factor IX/IXa aptamer targeting a contact pathway factor will limit factor Xa and thrombin generation and inflammation more effectively than targeting common pathway factors in patients undergoing PCI. Each of these lines of investigation rationally build upon important results obtained in the current funding cycle of this award.
Our specific aims are:
Aim 1 : To utilize aptamers to identify exosites on coagulation factors XIIa, XIa, IXa, Xa, VIIa and Kallikrein.
Aim 2 : To evaluate the ability of aptamers targeting exosites on contact pathway factors to act as potent yet safe antithrombotic agents.
Aim 3 : To elucidate the mechanism by which combinations of A) aptamer-based inhibitors and B) aptamer-based exosite and active site inhibitors of Factor Xa and thrombin synergize and determine if such combinations can produce rapid and safe anticoagulation for cardiopulmonary bypass (CPB) and if antidotes can produce rapid and safe neutralization of anticoagulation following discontinuation of CPB.
Aim 4 : To determine if our factor IXa aptamer limits thrombin and factor Xa generation more effectively than bivalirudin in ACS patients undergoing PCI and if this results in a reduction in inflammation in such patients.
The long-term objective of this project is and has been to create safe and effective, rapid onset anticoagulants (ROAs) to improve clinical outcomes for the millions of Americans requiring such therapeutics each year. With the support of this award, we have made significant progress toward addressing this important medical need. Our factor IXa aptamer and its antidote, made possible by this award, is currently being evaluated in a phase 3 clinical trial in 13,200 acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) and was recently awarded Fast Track Development status by the United States Food and Drug Administration (FDA) as this novel ROA strategy was deemed by the FDA to address an unmet medical need for treating patients undergoing PCI. Nevertheless, our recent studies indicate that aptamer-mediated factor IXa inhibition alone will not be sufficient for other indications requiring ROA. Therefore, herein we propose studies focused upon developing a more thorough mechanistic understanding of anticoagulant aptamers and their inhibitory effects to serve as the basis for developing aptamer-based ROA for other indications.
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| Kahsai, Alem W; Wisler, James W; Lee, Jungmin et al. (2016) Conformationally selective RNA aptamers allosterically modulate the ?2-adrenoceptor. Nat Chem Biol 12:709-16 |
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