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半乳糖凝集素-3抑制剂的人类蛋白质，作为一种生物抑制剂