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Development of an RNA-based anticoagulant and antidote for precise on/off coagulation control during cardiovascular procedures

开发基于 RNA 的抗凝剂和解毒剂，用于心血管手术期间精确的开/关凝血控制

基本信息

批准号：
10603072
负责人：
Abhichart Krissanaprasit
金额：
$ 98.36万
依托单位：
HELIXOMER, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10603072
关键词：
Acute Address Affect Affinity American Anaphylaxis Animal Model Anticoagulants Anticoagulation Antidotes Appearance Base Pairing Binding Biodistribution Biological Biological Assay Blood Blood Coagulation Factor Canis familiaris Cardiac Surgery procedures Cardiovascular system Cessation of life Clinical Clinical Trials Coagulation Process DNA Data Deep Vein Thrombosis Deposition Detection Development Dialysis procedure Dose Endotoxins Enzyme-Linked Immunosorbent Assay Enzymes Euthanasia Event Extracorporeal Membrane Oxygenation Family suidae Fibrin Future Genetic Transcription Hemorrhage Hemostatic Agents Heparin Hospitalization Hour Human Hypersensitivity Immune response In Vitro Industry Standard Intravenous Ischemia Kinetics Lead Life Liquid substance Maximum Tolerated Dose Medical Medication Errors Methods Mus Myocardial Infarction Operative Surgical Procedures Overdose Patients Pharmaceutical Preparations Phase Plasma Polynucleotides Postoperative Period Preparation Procedures Production Protamines Pulmonary Embolism RNA Rattus Reaction Resistance Risk Safety Saline Shapes Single-Stranded DNA Small Business Innovation Research Grant Stroke Therapeutic Thrombin Thrombosis Time Tissues Toxic effect Toxicology Work analytical method aptamer assay development clinical practice detection assay experience first-in-human heart valve replacement heparin-induced thrombocytopenia immunotoxicity in vivo innovation large scale production manufacture manufacturing scale-up meetings nano novel novel therapeutics patient variability porcine model preclinical development preclinical study prevent response safety assessment side effect

项目摘要

PROJECT SUMMARY Each year, approximately one-third of all hospitalized patients in the US (corresponding to about 12 million Americans) receive unfractionated heparin (UFH) to prevent clotting during surgical and invasive medical procedures, such as open-heart surgery and transcatheter heart valve replacement, and to prevent postoperative clotting issues, such as deep vein thrombosis, and major ischemic events, such as pulmonary embolism, heart attack, and stroke. UFH is a fast-acting, reversible, and inexpensive anticoagulant drug that indirectly inhibits several clotting factors, including thrombin and Xa. However, UFH is associated with serious acute side effects, including hypersensitivity reactions. The non-linear dose response to UFH and a high degree of patient-to-patient and batch-to-batch variability lead to medication errors related to improper dosing, and these errors are among the most common and serious in clinical practice. An estimated 1-5% of patients who receive UFH experience an immune response known as heparin-induced thrombocytopenia (HIT), which is considered life threatening or results in death in 20-30% of affected patients. Additionally, up to 26% of cardiac surgery patients experience “heparin resistance,” where achieving therapeutic anticoagulation requires excessive doses of UFH. As with any anticoagulant, treatment with UFH carries the risk of excessive bleeding, which can be fatal. UFH is reversed by protamine, which is also associated with serious side effects, including anaphylaxis and toxicity. Accurate determination of the dosing ratio of protamine to UFH is challenging, putting patients at risk for protamine overdose. In the context of medical procedures that require precise (i.e., immediate and titratable) hemostatic control, such as transcatheter heart valve replacement, these shortcomings are particularly challenging. Thus, there is a recognized, unmet medical need for new anticoagulant/reversal agent combinations that are safe and fast acting with a predictable dose response to enable more precise hemostatic control during medical procedures. Helixomer, Inc. is developing a novel polynucleotide-based anticoagulant/antidote combination for intravenous anticoagulation. In vitro and in vivo data have demonstrated that Helixomer’s anticoagulant drug, Hex01, and its antidote, Hex02, are highly specific and fast acting, with clear, predictable dose responses. Hex01 specifically binds to and directly inhibits thrombin, the enzyme responsible for fibrin deposition and clot formation. Hex02 base-pairs with and deactivates Hex01, reversing the anticoagulant effect by releasing thrombin. In this Direct-to-Phase II SBIR project, Helixomer will advance the preclinical development of Hex01 and Hex02 by i) validating bioanalytical assays for Hex01 and Hex02 in plasma to support preclinical development, ii) establishing scale-up manufacturing methods for Hex01, iii) determining a dosing strategy for Hex01 and Hex02 in a porcine large-animal model, and iv) defining safety and toxicity profiles for Hex01 and Hex02 and identifying the maximum tolerated dose through non-GLP dose range finding studies in rats and dogs. Successful completion of these critical preclinical studies will support subsequent pivotal GLP toxicology studies and IND submission.

项目总结