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Developing a new drug for treating myocardial ischemia/reperfusion injury

开发治疗心肌缺血/再灌注损伤的新药

基本信息

批准号：
10491205
负责人：
Randal A Skidgel
金额：
$ 114.17万
依托单位：
DUPAGE MEDICAL TECHNOLOGY, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10491205
关键词：
Acute Acute myocardial infarction Adverse effects Affect Animal Model Anti-Inflammatory Agents Antiinflammatory Effect Antiplatelet Drugs Arteries Aspirin Binding Blood Blood Platelets Blood Vessels Cardiac Cardiac Myocytes Cardiovascular Diseases Cause of Death Cells Clinical Treatment Coagulation Process Coronary artery Data Drug Delivery Systems Edema Effectiveness Extravasation Family suidae Fibrinolytic Agents Formulation GTP-Binding Proteins Heart Heart Diseases Heart failure Hemorrhage Hemostatic function Incidence Inflammation Inflammatory Inflammatory Response Integrins Intervention Intravenous Leukocytes Mediating Methods Molecular Morbidity - disease rate Myocardial Infarction Myocardial Ischemia Myocardial Reperfusion Nature Neutrophil Infiltration Operative Surgical Procedures Oral Outcome Patients Pattern Peptide Transport Peptides Pharmaceutical Preparations Phase Play Preparation Prevention Property Protein Subunits Reperfusion Injury Reperfusion Therapy Reporting Research Personnel Rodent Role Safety Science Secondary Prevention Signal Transduction Small Business Innovation Research Grant Stroke Survivors Therapeutic Effect Therapeutic Intervention Thrombolytic Therapy Thrombosis Time Tissues Toxic effect Toxicology Vascular blood supply acute toxicity antagonist base design drug production efficacy testing heart damage improved improved outcome in vivo inhibitor injury prevention method development mortality mouse model nanoparticle nanoparticle drug neutrophil novel novel therapeutics percutaneous coronary intervention porcine model preclinical study prevent scale up side effect stent thrombosis success theories thrombotic

项目摘要

Myocardial infarction (MI) is a prominent manifestation of heart disease with very high mortality. Despite the great success of surgical and intravascular interventions and thrombolytic therapies, MI mortality remains high and a significant percentage of MI survivors suffer from heart failure. Thus, there is a strong need and large market for new drugs to further reduce mortality and to treat post-MI heart failure. Treatment of MI requires timely reopening of the blocked coronary artery and reperfusion of the ischemic tissue. However, reperfusion itself may induce myocardial ischemia/reperfusion (MI/R) injury, which increases cardiac damage and mortality. It was shown that inflammation, consequent vascular leakage and microvascular thrombosis all play critical roles in MI/R injury. Anti-platelet drugs are routinely used in acute MI patients, mainly for the prevention of secondary thromboses or stent thrombosis. As microvascular thrombosis is a key factor in MI/R injury, anti- platelet drugs, in theory, should be protective. However, although anti-platelet treatment improves MI outcome in general, the more potent and fast-onset intravenous anti-platelet drugs, when used on top of mild and slow- acting oral anti-platelet drugs, are not significantly more effective in improving MI outcome than oral anti- platelet drugs alone. As the increased potency of the current anti-platelet drugs is associated with increased adverse effect of causing vascular leakage and bleeding, which are also important factors in MI/R injury, we hypothesize that these adverse effects may limit the efficacy of anti-platelet drugs in treating MI/R injury. Based on our new concept (Gong et al Science 2010, Shen et al, Nature 2013) that G13-dependent outside-in signaling of the platelet integrin IIb3 (GPIIb-IIIa) is selectively important in occlusive thrombosis but not hemostasis, we designed a peptide inhibitor of the G13-integrin interaction, M3mP6, and a novel high-loading peptide nanoparticle (HLPN) formulation for in vivo intracellular peptide delivery. In proof-of-concept studies, we have demonstrated that M3mP6 HLPN potently inhibits occlusive intravascular thrombosis without causing bleeding. Importantly, M3mP6 also has anti-inflammatory effects mediated by inhibition of 2-G13 binding in leukocytes, thereby reducing neutrophil function. M3mP6 had a striking therapeutic effect in treating MI/R injury in a mouse model. Pilot toxicology studies carried out with M3mP6 HLPN showed no toxicity. Based on these exciting new data, we propose in this direct Phase II SBIR application to further develop this novel drug from the proof-of-concept stage to IND for the treatment MI/R injury and prevention of post-MI heart failure. Our specific aims are (1) to compare the effect of M3mP6 HLPN to current standard anti-platelet therapy as well as their additive effects in treating MI/R injury and preventing post-MI heart failure in animal models. (2) to further evaluate the adverse effect of bleeding and toxicity of M3mP6 HLPN with and without current anti- platelet therapy. (3) Develop drug scale-up methods and prepare for IND submission. If successful, this new drug should have a major impact in further improving MI survival and reducing post-MI heart failure.

心肌梗死（MI）是心脏病的突出表现，死亡率很高。尽管