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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：
10325868
负责人：
Randal A Skidgel
金额：
$ 85.69万
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 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10325868
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 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 base design drug production efficacy testing heart damage improved improved outcome in vivo inhibitor/antagonist 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）是心脏病的主要表现，具有非常高的死亡率。尽管尽管手术和血管内介入以及溶栓治疗取得了巨大成功，但MI死亡率仍然很高并且很大比例的MI幸存者患有心力衰竭。因此，有强烈的需求和巨大的市场的新药，以进一步降低死亡率和治疗心肌梗死后心力衰竭。MI的治疗需要及时重新开放阻塞的冠状动脉和缺血组织的再灌注。然而，再灌注其本身可引起心肌缺血/再灌注（MI/R）损伤，这增加了心脏损伤和死亡率。结果表明，炎症反应、血管渗漏和微血管血栓形成都是影响血管功能的重要因素在MI/R损伤中的作用。抗血小板药物常规用于急性MI患者，主要用于预防继发性血栓形成或支架血栓形成。由于微血管血栓形成是MI/R损伤的关键因素，抗- 血小板药物理论上应该是有保护作用的。然而，尽管抗血小板治疗可改善MI结局，一般来说，更有效和快速起效的静脉抗血小板药物，当使用温和和缓慢的顶部- 口服抗血小板药物在改善心肌梗死预后方面并不比口服抗血小板药物更有效。单独使用血小板药物。由于目前抗血小板药物的效力增加与血小板聚集增加有关，血管渗漏和出血也是MI/R损伤的重要因素，假设这些副作用可能限制抗血小板药物治疗MI/R损伤的疗效。基于基于我们的新概念（Gong et al Science 2010，Shen et al，Nature 2013），即G β 13依赖于由外向内血小板整合素GPIIb-IIIa信号传导在闭塞性血栓形成中选择性重要，止血，我们设计了一种G β 13-整联蛋白相互作用的肽抑制剂M3 mP 6，和一种新的高载量的用于体内细胞内肽递送的肽纳米颗粒（HLPN）制剂。在概念验证研究中，我们已经证明M3 mP 6 HLPN有效地抑制闭塞性血管内血栓形成，而不引起流血了重要的是，M3 mP 6还具有抗炎作用，这是通过抑制炎症细胞中的β 2-G β 13结合来介导的。白细胞，从而降低中性粒细胞功能。M3 mP 6对MI/R有显著的治疗作用小鼠模型中的损伤。使用M3 mP 6 HLPN进行的初步毒理学研究显示无毒性。基于这些令人兴奋的新数据，我们建议在这个直接的II期SBIR应用中进一步开发这种新药从概念验证阶段到IND治疗MI/R损伤和预防MI后心力衰竭。我们的具体目的是（1）比较M3 mP 6 HLPN与当前标准抗血小板治疗的效果，以及它们在动物模型中治疗MI/R损伤和预防MI后心力衰竭的累加作用。(2)到进一步评估M3 mP 6 HLPN在有和没有当前抗- 血小板治疗(3)开发药物放大方法，准备IND申报。如果成功，新药物应该在进一步改善MI存活率和减少MI后心力衰竭方面具有重要影响。