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Antithrombotic Aptamers and Antidotes

项目来源

美国卫生和人类服务部基金(HHS)

项目主持人

KINDZELSKI, ANDREI L.

项目受资助机构

DUKE UNIVERSITY

项目编号

5R01HL065222-17

立项年度

2018

立项时间

未公开

项目级别

国家级

研究期限

未知 / 未知

受资助金额

465035.00美元

学科

Biotechnology; Cardiovascular; Clinical Research; Heart Disease; Heart Disease - Coronary Heart Disease; Hematology; Women's Health;

学科代码

未公开

基金类别

Non-SBIR/STTR RPGs

关键词

未公开

参与者

SULLENGER, BRUCE ALAN

参与机构

NATIONAL HEART, LUNG, AND BLOOD INSTITUTE

项目标书摘要：? DESCRIPTION (provided by applicant): 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.

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  • 1. Hernandez, T. Wilder, L, Kuehn,D and Rubotsky, K.,"Portion Perception: The Missing Link", 2003 submitted for presentation, 5th International Food Data Conference, Washington, DC

  • 2.Therapeutic Aptamers: Evolving to Find their Clinical Niche

    • 关键词：
    • Aptamer; DNA; RNA; therapeutic; clinical trial; ligonucleotides;VON-WILLEBRAND-FACTOR; TRANSCRIPTION FACTOR DECOY; VEIN GRAFT FAILURE;GENE-THERAPY; PHASE-II; ARC1779; TRIAL; GROWTH; OLIGONUCLEOTIDE;SELECTION

    Background: The discovery that short oligonucleotides, termed aptamers, can fold into three-dimensional structures that allow them to selectively bind and inhibit the activity of pathogenic proteins is now over 25 years old. The invention of the SELEX methodology heralded in an era in which such nucleic acid-based ligands could be generated against a wide variety of therapeutic targets.Results: A large number of aptamers have now been identified by combinatorial chemistry methods in the laboratory and moreover, an increasing number have been discovered in nature. The affinities and activities of such aptamers have often been compared to that of antibodies, yet only a few of these agents have made it into clinical studies compared to a large and increasing number of therapeutic antibodies. One therapeutic aptamer targeting VEGF has made it to market, while 3 others have advanced as far as phase III clinical trials.Conclusion: In this manuscript, we hope the reader appreciates that the success of aptamers becoming a class of drugs is less about nucleic acid biochemistry and more about target validation and overall drug chemistry.

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