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）：人体对损伤的伤口愈合反应涉及诱导纤维化，这是一个动态瘢痕形成过程。当纤维化发生在内部器官时，它无可争议地是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抑制剂作为药物，限制心肌梗死（心脏病发作）后心脏的过度纤维化和不良重塑，从而改善患者预后并降低死亡率。在I期项目中，我们将测试使用显性阴性半乳糖凝集素-3抑制剂（称为半乳糖凝集素-3C（Ga-3C））限制心肌梗死（MI）后不良重塑和改善心脏功能的可行性。MI是西方世界心脏病发病率和死亡率的最常见原因，在美国每年造成1/6例死亡（约400，000例）。半乳糖凝集素-3是凝集素的半乳糖凝集素家族之一，其具有同源的碳水化合物识别结构域和对半乳糖苷的特征性亲和力。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，半乳糖凝集素-3的血浆水平被美国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），其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： 1.确定Gal-3C对TGF-β 1诱导的原代心脏成纤维细胞分化为肌成纤维细胞及其胶原分泌的影响。 2.确定Gal-3C在MI的大鼠缺血/再灌注模型中减少纤维化的有效剂量。Subaim 2A.我们将在手术诱导MI后使用渗透泵向大鼠递送Gal-3C进行初始剂量范围探索研究。心脏中的胶原蛋白水平将作为主要终点进行分析。Subaim 2B.我们将测试MI后1-7天内给予的两种不同剂量的Gal-3C，以确定其对MI后1个月心脏功能的影响。 3.确定立即或延迟Gal-3C治疗是否会改善心脏功能。Subaim 3A.我们将测定在不同时间从Subaim 2B中的大鼠中收集的血清，以建立半乳糖凝集素-3出现的时间过程，以确定Gal-3C递送的时间窗。Subaim 3B.我们将根据我们在Subaim 3A中了解到的情况，重复Aim 2中的Gal-3C递送实验，并延迟治疗时间。 在第二阶段，我们计划测试具有较长循环半衰期的缓释形式或Gal-3C构建体，进行研究以改进动物模型中的MI后治疗，并专注于毒理学，药代动力学和GMP生产，以向FDA提交IND申请并启动I期人体临床试验。