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(申请人提供)：人体对损伤的伤口愈合反应包括诱导纤维化，这是一个动态的疤痕形成过程。当内脏发生纤维化时，它无疑是世界范围内发病率和死亡率的主要原因。这项拟议研究的总体目标是开发一种Galectin-3的抑制剂，作为一种药物，将限制心肌梗死(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。在第一阶段项目中，我们将测试使用显性-负性Galectin-3抑制剂Galectin-3C(Ga-3C)的可行性，以限制心肌梗死(MI)后的不良重构和改善心功能。心肌梗死是西方世界心脏发病率和死亡率的最常见原因，每年美国每6例死亡中就有1例(约40万人)死于心肌梗死。Galectin-3是Galectin凝集素家族的一员，具有同源的碳水化合物识别结构域和与β-半乳糖苷的亲和力。有令人信服的体外和动物数据表明，Galectin-3在器官纤维化，特别是心脏纤维化中起关键作用。在人类中，血浆Galectin-3水平被美国FDA和欧洲批准为慢性心力衰竭患者死亡风险的生物标记物(www.galectin-3.com)，与心力衰竭或肾功能障碍的严重程度无关。第一阶段的具体目标如下： 1.研究Gal-3C对转化生长因子-β1诱导的原代心脏成纤维细胞向肌成纤维细胞分化及胶原分泌的影响。 2.确定Gal-3C在大鼠心肌缺血再灌注模型中抗纤维化的有效剂量。苏巴伊姆2号楼。我们将进行一项初步的剂量-范围发现研究，在外科手术诱导心肌梗死后，使用渗透泵将Gal-3C输送给大鼠。心脏中的胶原蛋白水平将被分析为主要终点。苏巴伊姆2B。我们将在心肌梗死后1-7天测试两种不同剂量的Gal-3C，以确定其对心肌梗死后1个月心功能的影响。 3.确定Gal-3C立即或延迟治疗是否能改善心功能。苏巴伊姆3A。我们将测定不同时间采集的苏巴伊姆2B大鼠血清，以确定Galectin-3出现的时间进程，以确定Gal-3C交付的时间窗口。苏巴伊姆3B。我们将根据我们在Subaim 3A中学到的知识，重复目标2中的Gal-3C递送实验，延迟治疗时间。 在第二阶段，我们计划测试具有更长循环半衰期的缓释形式或Gal-3C结构，进行研究以改进动物模型的MI后治疗，并将重点放在毒理学、药动学和GMP生产方面，以便向FDA提交IND申请并启动第一阶段人体临床试验。