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（由适用提供）：人体对损伤的伤口治疗反应涉及纤维化的诱导，这是一个动态的疤痕过程。当内部器官发生纤维化时，它无疑是全球发病率和死亡率的主要原因。拟议的研究的总体目标是开发lectectin-3的抑制剂作为一种药物，该药物将限制心肌梗塞后心脏（心脏病发作）的过量纤维化和心脏不良重塑，从而改善患者的结局并降低死亡率。在第一阶段项目中，我们将测试使用称为galectin-3c（GA-3C）的显性阴性乳糖素3抑制剂的可行性，以限制不良重塑并改善心肌梗塞（MI）后的心脏功能。 MI是西方世界中心脏发病率和死亡率的最常见原因，每年美国造成6分（约400,000）中有1人。 Galectin -3是甲状腺元元素的一家，具有同源的碳水识别域和对 - 半乳糖苷的特征亲和力。有令人信服的体外和动物数据，表明甲状腺素3对于器官纤维化，特定于心脏的纤维化至关重要。在人类中，血浆lectectin-3的水平得到了美国FDA和欧洲的批准，作为慢性心力衰竭患者死亡风险（www.galectin-3.com）的生物标志物，这些风险与心力衰竭或肾功能障碍的严重程度无关。第一阶段的特定目标如下： 1。确定GAL-3C对TGF-»1诱导的原发性心脏成纤维细胞对肌纤维细胞的分化以及其所得胶原蛋白的秘密。 2。确定有效剂量的GAL-3C以减少MI缺血/再灌注模型的纤维化。 Subaim 2a。我们将使用渗透泵进行初始剂量范围的发现研究，以在MI手术诱导后向大鼠提供GAL-3C。心脏中的胶原蛋白水平将被分析为主要终点。 Subaim 2b。我们将测试MI后第1-7天施用的两种不同剂量的GAL-3C，以确定其对MI心脏功能后1个月的影响。 3。确定立即或延迟使用GAL-3C治疗会导致心脏功能更好。 Subaim 3a。我们将在Subaim 2b的大鼠不同时间分析血清，以确定Galectin-3外观的时间顺序，以确定GAL-3C传递的时间窗口。 Subaim 3b。我们将根据我们在Subaim 3A中学到的内容，重复AIM 2的GAL-3C交付实验，并延迟处理时间。 在第二阶段，我们计划测试持续释放的形式或GAL-3C构建体，其循环较长的半衰期，进行研究以完善动物模型中的MI后治疗，并专注于毒理学，药代动力学和GMP的生产，以对使用FDA和I期人类临床试验进行IND应用。