Protein inhibitor of galectin-3 to limit fibrosis after myocardial infarction

Galectin-3 蛋白抑制剂可限制心肌梗死后纤维化

• 批准号: 8597803
• 负责人: Constance M John
• 金额: $ 30万
• 依托单位: MANDALMED, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-04 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8597803
• 关键词: Acute myocardial infarction; Adrenal Cortex Hormones; Affinity; Allergic Reaction; Althaea; Amino Acids; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Appearance; Architecture; Arteries; Azathioprine; Binding; Biological Assay; Biological Availability; Biological Markers; Carbohydrates; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cessation of life; Characteristics; Chimeric Proteins; Chronic; Cicatrix; Clinical Trials; Colchicine; Collagen; Coronary; Development; Diagnostic; Digestion; Dominant-Negative Mutation; Dose; Drug Formulations; Drug Kinetics; Europe; Event; Family; Fibroblasts; Fibrosis; Functional disorder; Galactose Binding Lectin; Galactosides; Galectin 3; Glycoconjugates; Goals; Half-Life; Heart; Heart failure; Hour; Human; Human body; Immune; In Vitro; Incidence; Inflammation; Injury; Ischemia; Kidney; Lead; Learning; Lectin; Ligands; Marketing; Mediating; Mediator of activation protein; Modeling; Morbidity - disease rate; Mus; Mutant Strains Mice; Myocardial Infarction; Myofibroblast; Operative Surgical Procedures; Oral; Organ; Organ Transplantation; Organ failure; Outcome; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Phase; Plasma; Process; Production; Prostate-Specific Antigen; Proteins; Pump; Rattus; Reperfusion Therapy; Research; Risk; Serum; Severities; Subcutaneous Injections; Testing; Therapeutic; Time; Tissues; Toxic effect; Toxicology; Western World; Wound Healing; adverse outcome; angiogenesis; animal data; base; commercialization; effective therapy; improved; in vivo; inhibitor/antagonist; mortality; public health relevance; research study; response

DESCRIPTION (provided by applicant): The wound-healing response of the human body to injuries involves induction of fibrosis, which is a dynamic scarring process. When fibrosis occurs in internal organs, it is indisputably a major cause of morbidity and mortality worldwide. The overall goal of the proposed research is to develop an inhibitor of galectin-3 as a drug that will limit excess fibrosis and adverse remodeling of the heart after myocardial infarction (heart attack) and, thereby, improve patient outcomes and reduce mortality. In the Phase I project, we will test the feasibility of using a dominant-negative galectin-3 inhibitor, termed galectin-3C (Ga-3C), to limit adverse remodeling and improve cardiac function after myocardial infarction (MI). MI is the most common cause of cardiac morbidity and mortality in the western world, and is responsible for 1 in 6 deaths (~400,000) in the US per year. Galectin- 3 is one of the galectin family of lectins that has homologous carbohydrate recognition domains and characteristic affinity for ¿-galactosides. There are compelling in vitro and animal data showing that galectin-3 is critical for organ fibrosis and specifically fibrosis in the heart. In humans, plasma levels of galectin-3 are approved by the US FDA and in Europe as a biomarker for risk of mortality in those with chronic heart failure (www.galectin-3.com) that is independent of severity of heart failure or renal dysfunction. The Phase I Specific Aims are as follows: 1. To determine the effect of Gal-3C on the TGF- ¿1-induced differentiation of primary cardiac fibroblasts to myofibroblasts and on their resulting collagen secretion. 2. To determine an effective dose of Gal-3C to reduce fibrosis in a rat ischemia/reperfusion model of MI. Subaim 2A. We will perform an initial dose-range finding study using osmotic pumps to deliver Gal-3C to rats after surgical induction of MI. Levels of collagen in the heart wil be analyzed as the main endpoint. Subaim 2B. We will test two different doses of Gal-3C administered over days 1-7 post-MI to determine its effect on 1 month post-MI cardiac function. 3. To determine if immediate or delayed treatment with Gal-3C leads to better cardiac function. Subaim 3A. We will assay serum collected at different times from the rats in Subaim 2B to establish the time-course of galectin-3 appearance, to determine the time window for Gal-3C delivery. Subaim 3B. We will repeat the Gal-3C delivery experiment from Aim 2 with delayed treatment timing based on what we learn in Subaim 3A. In Phase II, we plan to test a sustained-release form or a Gal-3C construct with a longer circulating half-life, conduct studies to refine post-MI treatment in animal models, and focus on toxicology, pharmacokinetics, and GMP production towards filing an IND application with the FDA and initiation of Phase I human clinical trials.

描述（由申请人提供）：人体对损伤的创面愈合反应涉及到纤维化的诱导，这是一个动态的瘢痕形成过程。当纤维化发生在内脏器官时，它是无可争议的世界范围内发病率和死亡率的主要原因。拟议研究的总体目标是开发一种半乳糖凝集素-3抑制剂，作为一种药物，可以限制心肌梗死（心脏病发作）后过度纤维化和心脏不良重构，从而改善患者预后并降低死亡率。在一期项目中，我们将测试使用一种优势阴性半乳糖凝集素-3抑制剂的可行性，称为半乳糖凝集素- 3c (Ga-3C)，以限制心肌梗死（MI）后的不良重塑和改善心功能。心肌梗死是西方世界心脏发病和死亡的最常见原因，在美国每年有六分之一的死亡（约40万人）是心肌梗死造成的。凝集素- 3是凝集素家族中的一员，具有同源碳水化合物识别结构域和对-半乳糖苷的特征亲和力。有令人信服的体外和动物数据表明半乳糖凝集素-3对器官纤维化，特别是心脏纤维化至关重要。在人类中，血浆半乳糖凝集素-3水平已被美国FDA和欧洲批准作为慢性心力衰竭患者死亡风险的生物标志物（www.galectin-3.com），与心力衰竭或肾功能不全的严重程度无关。第一阶段的具体目标如下：