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

• 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
• 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

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)是心脏病的一种突出表现，病死率很高。尽管 外科手术、血管内介入和溶栓治疗大获成功，心肌梗死死亡率居高不下 相当大比例的心肌梗死幸存者患有心力衰竭。因此，存在着强烈的需求和巨大的 进一步降低死亡率和治疗心肌梗塞后心力衰竭的新药市场。心肌梗塞的治疗需要 及时再通闭塞的冠状动脉和再通缺血的组织。然而，再灌流 其本身可引起心肌缺血/再灌注损伤，增加心脏损伤和死亡率。 结果表明，炎症、随之而来的血管渗漏和微血管血栓形成都起着关键作用。 在心肌缺血再灌注损伤中的作用。抗血小板药物是急性心肌梗死患者的常规用药，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，因此抗 从理论上讲，血小板药物应该具有保护作用。然而，尽管抗血小板治疗改善了心肌梗死的预后 一般来说，在温和和缓慢的基础上使用更有效和起效更快的静脉抗血小板药物-- 作用的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显著更有效 单独使用血小板药物。因为当前抗血小板药物效力的增加与 引起血管渗漏和出血的不良反应，这也是MI/R损伤的重要因素 假设这些不良反应可能会限制抗血小板药物治疗MI/R损伤的疗效。基座 关于我们的新概念(Gong等人2010年《科学》，沈等人，《自然》，2013年)，G13-依赖于自外而内 血小板整合素IIb3(GPIIb-IIIa)信号在阻塞性血栓形成中选择性地重要，但不是 为了止血，我们设计了一种G13-整合素相互作用的多肽抑制剂M3mP6和一种新型的高负荷 用于体内细胞内多肽递送的多肽纳米颗粒(HLPN)制剂。在概念验证研究中， 我们已经证明，M3mP6 HLPN有效地抑制闭塞性血管内血栓形成，而不会导致 在流血。重要的是，M3mP6还通过抑制2-G13结合而发挥抗炎作用。 白细胞，从而降低中性粒细胞的功能。M3mP6对MI/R的治疗作用显著 在小鼠模型上造成损伤。对M3mP6 HLPN进行的初步毒理学研究表明没有毒性。基于 这些令人振奋的新数据，我们建议在这种直接的二期SBIR应用中进一步开发这种新药 从概念验证阶段到IND，用于治疗MI/R损伤和预防MI后心力衰竭。 我们的具体目标是：(1)比较M3mP6 HLPN和目前标准的抗血小板治疗的效果。 以及它们在治疗心肌缺血再灌注损伤和预防心肌梗死后心力衰竭动物模型中的相加作用。(2)至 进一步评价M3mP6 HLPN加用和不加用现有抗菌药物的不良反应和毒性 血小板疗法。(3)开发药物放大方法，为IND提交做准备。如果成功，这一新的 药物在进一步改善心肌梗死存活率和减少心肌梗死后心力衰竭方面应发挥重要作用。