Inhibition of Galectin-3 for Therapy of Remodeling After Myocardial Infarction

半乳糖凝集素3抑制治疗心肌梗死后重构

• 批准号: 9453176
• 负责人: Constance M John
• 金额: $ 80.86万
• 依托单位: MANDALMED, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9453176
• 关键词: Achievement; Acute; Acute myocardial infarction; Adverse effects; Anesthetics; Angiotensin II Receptor; Angiotensin Receptor; Angiotensin-Converting Enzyme Inhibitors; Animal Model; Animals; Arteries; Cancer Patient; Cardiac; Cessation of life; Cicatrix; Cleaved cell; Collagen; Collagen Fiber; Connective Tissue; Continuous Infusion; Coronary; Coronary artery; Deposition; Drug Controls; Drug Kinetics; Drug Targeting; Elasticity; European Union; Event; Extracellular Matrix; Fibroblasts; Fibrosis; Formulation; Functional disorder; Galactose Binding Lectin; Galectin 3; Goals; Growth Factor; Health; Heart; Heart failure; Human; Immune; Implant; Incidence; Infarction; Infection; Inflammatory; Injury; Interleukin-13; Intravenous; Intravenous infusion procedures; Investigational New Drug Application; Ischemia; Lead; Lectin; Left; Left Ventricular Ejection Fraction; Ligation; Losartan; Malignant neoplasm of prostate; Measurement; Mediator of activation protein; Medical; Methods; Mineralocorticoid Receptor; Miniature Swine; Modeling; Morbidity - disease rate; Myocardial Infarction; Myocardial Reperfusion; Myocardium; Myofibroblast; Organ; Patients; Pharmaceutical Preparations; Phase; Physiological; Platelet-Derived Growth Factor; Positioning Attribute; Prevention; Process; Procollagen; Production; Prognostic Marker; Property; Prostate-Specific Antigen; Proteins; Pump; Rattus; Recurrence; Reperfusion Injury; Reperfusion Therapy; Risk; Rodent; Serum; Small Business Innovation Research Grant; Structure; TNF gene; Testing; Therapeutic; Therapeutic Agents; Time; Toxicology; United States; Ventricular; Ventricular End-Systolic Volumes; Ventricular Function; Western World; base; chemotherapy; clinical application; cost; crosslink; cytokine; dosage; drug development; elastomeric; experience; heart function; hemodynamics; improved; in vivo; inhibitor/antagonist; interstitial; mortality; novel; novel therapeutics; preclinical development; preclinical study; prevent; response; response to injury

The overall goal of this project is to develop a human protein that is an inhibitor of galectin-3, as a biologic to aid in the prevention and treatment of harmful remodeling after myocardial infarction (MI; heart attack) and, thereby, improve cardiac function and reduce mortality from subsequent heart failure. MI is the most common cause of cardiac morbidity and mortality in the Western world. The incidence in the United States is 610,000 new attacks and 325,000 recurrent attacks annually, approximately one every 34 seconds. Fibrosis is triggered by the physiological response to injury or infection and leads to the deposition of extracellular matrix and formation of new connective tissue. Excessive or dysregulated fibrosis from insults can dramatically reduce the functioning of the heart and other organs. In the heart, excessive interstitial fibrosis reduces contractility, elasticity, and distensibility, exacerbating processes that lead to heart failure. Although there are therapeutic agents currently used after MI that are efficacious, such as the mineralocorticoid receptor antagonists (MRAs), angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs), and that have shown anti-fibrotic effects in animal studies, the health burden from MI remains significant. Fibrosis is regulated by a number of inflammatory cytokines and growth factors, and galectin-3 has recently been implicated as a major and novel mediator of organ fibrosis. Increased serum levels of galectin-3 have been approved in the United States and the European Union as prognostic indicators of risk of death from progressive heart failure, supporting the hypothesis that galectin-3 is a target for drug development. Based on its mechanism of action and structure, the protein is a unique inhibitor of galectin-3 with properties that convey therapeutic advantage. Our preliminary studies in a rat ischemia reperfusion (I/R) injury model of MI showed very promising efficacy. The Specific Aims for this Fast Track Phase I/II project are the following: (Phase I) Aim 1 is to determine efficacy of Gal-3C therapy in animal models: Determine antifibrotic potential of Gal-3C in the context of greater injury caused by permanent ligation of the coronary artery, and evaluate efficacy of Gal-3C therapy relative to ARB and antifibrotic control drugs in a rat I/R MI model. (Phase II) Aim 2 is to better understand efficacy of Gal- 3C therapy in animal models: Determine efficacy and optimal dosage of Gal-3C in rat I/R MI; determine efficacy of Gal-3C in comparison to a MRA and in combination with an ARB in rat I/R MI model; and determine efficacy of Gal-3C in miniswine I/R model of MI. Aim 3 is to develop GLP/GMP production methods and a formulation for Gal-3C. Aim 4 is to perform pharmacokinetic studies and acute/subacute toxicology in rodents. Achievement of these aims is expected to position MandalMed to complete pre-clinical development in the near-term and to subsequently file an Investigational New Drug (IND) application.

该项目的总体目标是开发一种人类蛋白质，它是半乳糖凝集素-3的抑制剂，作为生物制剂， 有助于预防和治疗心肌梗塞（MI;心脏病发作）后的有害重塑， 从而改善心脏功能并降低随后心力衰竭的死亡率。MI是最常见的 心脏病发病率和死亡率的原因在西方世界。美国的发病率为61万 每年发生325 000起新的攻击和经常性攻击，大约每34秒发生一起。纤维化被触发 通过对损伤或感染的生理反应，并导致细胞外基质的沉积和形成 新的结缔组织。由损伤引起的过度或失调的纤维化可以显著减少 心脏和其他器官的功能。在心脏中，过度的间质纤维化降低了收缩力，弹性， 和膨胀性，加剧导致心力衰竭的过程。虽然有治疗药物 目前用于MI后的有效药物，如盐皮质激素受体拮抗剂（MRA）， 血管紧张素转换酶（ACE）抑制剂和血管紧张素II受体阻滞剂（ARB）， 尽管在动物研究中显示了抗纤维化作用，但MI的健康负担仍然很大。纤维化受到调节 由许多炎症细胞因子和生长因子，和半乳糖凝集素-3最近被牵连作为一个 器官纤维化的主要和新介质。半乳糖凝集素-3的血清水平的增加已经在 美国和欧盟作为进展性心力衰竭死亡风险的预后指标， 支持了半乳糖凝集素-3是药物开发的靶点的假设。根据其作用机制 和结构，该蛋白质是一种独特的半乳糖凝集素-3抑制剂，具有传递治疗优势的特性。 我们在大鼠心肌缺血再灌注（I/R）损伤模型中的初步研究显示了非常有希望的疗效。 快速通道第一/第二阶段项目的具体目标如下：（第一阶段）目标1是确定 Gal-3C治疗在动物模型中的功效：在更大的肝纤维化背景下确定Gal-3C的抗纤维化潜力。 永久结扎冠状动脉引起的损伤，并评估Gal-3C治疗相对于 大鼠I/R MI模型中的ARB和抗纤维化对照药物。（II期）目的2是更好地了解Gal的疗效， 动物模型中的3C治疗：确定Gal-3C在大鼠I/R MI中的功效和最佳剂量; 在大鼠I/R MI模型中Gal-3C与MRA相比以及与ARB组合的功效;并确定 Gal-3C在MI小型猪I/R模型中功效。目的3是开发GLP/GMP生产方法， 用于Gal-3C的制剂。目的4是在啮齿动物中进行药代动力学研究和急性/亚急性毒理学研究。 这些目标的实现预计将使MandalMed能够在全球范围内完成临床前开发。 近期，并随后提交研究性新药（IND）申请。