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: 9202835
• 负责人: Constance M John
• 金额: $ 22.47万
• 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 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9202835
• 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; Development; Drug Controls; Drug Kinetics; Elasticity; European Union; Event; Extracellular Matrix; Fibroblasts; Fibrosis; Formulation; Functional disorder; Galactose Binding Lectin; Galectin 3; Goals; Growth; Health; Heart; Heart failure; Human; Immune; Implant; Incidence; Infarction; Infection; Inflammatory; Infusion procedures; Injury; Interleukin-1; Interleukin-13; 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; 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; 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; pre-clinical; preclinical study; prevent; protein structure; response; response to injury

PROJECT SUMMARY/ABSTRACT 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 for- mation 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, elas- ticity, 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.

项目摘要/摘要 该项目的总体目标是开发一种人蛋白，该蛋白是Galectin-3的抑制剂，作为生物学 帮助预防和治疗心肌梗死（MI;心脏病发作）后的有害重塑 从而改善心脏功能并降低死亡率，从随后的心力衰竭中降低死亡率。 Mi是最常见的 西方世界的心脏发病和死亡率的原因。美国的发病率为610,000 每年大约每34秒一次发动新攻击和325,000次反复攻击。触发纤维化 通过对损伤或感染的生理反应，并导致细胞外基质的沉积 新结缔组织的介绍。侮辱过度或失调的纤维化会大大减少 心脏和其他器官的功能。在心脏中，过度的间质纤维化可降低收缩力，elas- 易变性和可扩展性，加剧导致​​心力衰竭的过程。虽然有治疗剂 目前在有效的MI之后使用，例如矿物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），并且具有 显示在动物研究中的抗纤维化作用，MI的健康负担仍然显着。调节纤维化 通过许多炎症性细胞因子和生长因子，以及Galectin-3最近被认为是一种 器官纤维化的主要和新型介体。血清lectectin-3水平升高已在 美国和欧盟是渐进性心力衰竭死亡风险的预后指标， 支持Galectin-3是药物开发的靶标的假设。根据其作用机理 和结构，该蛋白质是galectin-3的独特抑制剂，具有传达治疗优势的特性。 我们在大鼠缺血再灌注（I/R）损伤模型中的初步研究表现出非常有希望的功效。 该快速轨道I/II项目的具体目的是以下：（第I阶段）目标1是确定 GAL-3C治疗在动物模型中的功效：在更大的背景下确定GAL-3C的抗纤维化潜力 由冠状动脉的永久连接造成的伤害，并评估GAL-3C治疗相对于 大鼠I/R MI模型中的ARB和抗纤维化控制药物。 （第二阶段）目标2是更好地了解GAL的功效 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；决定 与MRA相比，GAL-3C的功效与大鼠I/R MI模型中的ARB相比；并确定 GAL-3C在MISWINE I/R模型中的功效。 AIM 3是开发GLP/GMP生产方法和A GAL-3C的配方。目标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。 这些目标的实现有望在 近期，随后提交研究新药（IND）应用。