Inhibition of Galectin-3 for Therapy of Remodeling After Myocardial Infarction

项目摘要/摘要 这个项目的总体目标是开发一种人类蛋白，它是Galectin-3的抑制剂，作为一种生物 帮助预防和治疗心肌梗死后有害的重塑(MI；心脏病发作)， 从而改善心功能，降低后续心力衰竭的死亡率。MI是最常见的 这是西方世界心脏病发病率和死亡率的主要原因。在美国的发病率为61万 每年发生新的攻击和325 000次反复攻击，大约每34秒发生一次。肝纤维化被触发 通过对损伤或感染的生理反应，导致细胞外基质沉积，并形成 新生结缔组织的形成。由侮辱引起的过度或失调的纤维化可以显著减少 心脏和其他器官的功能。在心脏，过度的间质纤维化会降低收缩能力，ELA- 弹性和扩张性，加剧导致心力衰竭的过程。尽管有治疗药物 目前在心肌梗塞后使用的有效药物，如盐皮质激素受体拮抗剂(MRAs)， 血管紧张素转换酶(ACE)抑制剂和血管紧张素II受体阻滞剂(ARB)，以及 在动物研究中显示了抗纤维化的作用，心肌梗塞造成的健康负担仍然很大。纤维化是受调控的 通过一些炎症细胞因子和生长因子，以及Galectin-3最近被认为是一种 器官纤维化的主要和新的介体。血清Galectin-3水平升高已被批准在 美国和欧盟作为进行性心力衰竭死亡风险的预测指标， 支持Galectin-3是药物开发靶点的假设。基于其作用机制 这种蛋白质是Galectin-3的一种独特的抑制剂，具有传达治疗优势的特性。 我们在大鼠心肌缺血再灌注(I/R)损伤模型上的初步研究显示了非常有希望的疗效。 快车道第一阶段/第二阶段项目的具体目标如下：(第一阶段)目标一是确定 Gal-3C治疗动物模型的疗效：测定Gal-3C的抗肝纤维化潜力 冠状动脉永久结扎所致的损伤，并评价Gal-3C治疗的疗效 ARB和抗纤维化对照药物在大鼠I/R心肌梗死模型中的作用。(第二阶段)目的2是为了更好地了解Gal- 3C动物模型治疗：确定Gal-3C对大鼠I/R心肌梗死的疗效和最佳剂量； Gal-3C与MRA和ARB在大鼠I/R MI模型中的疗效比较；并确定 Gal-3C对心肌梗死小鼠心肌缺血再灌注模型的影响目标3是开发GLP/GMP生产方法和 Gal-3C的配方。目的4是在啮齿动物体内进行药代动力学研究和急性/亚急性毒理学研究。 这些目标的实现有望使MandalMed完成临床前开发 短期内并随后提交研究新药(IND)申请。

PROJECT SUMMARY/ABSTRACT 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 for- mation 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, elas- ticity, 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.