Preclinical Development of a Novel Plaque-Regressing Therapy For Atherosclerosis

新型斑块消退疗法治疗动脉粥样硬化的临床前开发

基本信息

批准号：
8394110
负责人：
MICHAEL W FANGER
金额：
$ 67.59万
依托单位：
CELDARA MEDICAL, LLC
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-15 至 2014-08-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8394110
关键词：
Adult Adverse effects Americas Animals Arterial Fatty Streak Arteries Atherosclerosis Biological Markers Blood flow Caliber Cardiovascular Diseases Carotid Artery Diseases Cause of Death Chronic Clinic Coronary Data Dependence Development Disease Dose Economic Burden Endothelium Excision Free Radicals Future Goals Grant Growth Health Heart Diseases Human Hypertension Industry Inflammatory Response Investments Legal patent Life Lipids Low-Density Lipoproteins Marketing Medical Monitor Mus Operative Surgical Procedures Patients Peripheral Pharmaceutical Preparations Pharmacotherapy Phase Plasmin Plasminogen Activator Inhibitor 1 Powder dose form Process Production Protein Isoforms Proteins Protocols documentation Regulatory Pathway Rupture Small Business Innovation Research Grant Staging Stress Stroke Therapeutic Thrombosis Time Toxic effect United States Vascular Diseases Work angiogenesis apolipoprotein B-48 base cardiovascular disorder therapy economic impact effective therapy in vivo interest meetings mortality mouse model novel novel therapeutics peripheral blood pre-clinical preclinical study prevent programs protein expression response scale up stoichiometry success therapeutic target vasa vasorum

项目摘要

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is the leading cause of death in the world. The staggering mortality rate is expected to increase significantly in the next ten years. In the U.S., an estimated 81 million adults will have one or more types of cardiovascular disease with an estimated total annual direct and indirect economic burden of $400 billion. Atherosclerosis is the leading cause of coronary, peripheral and carotid artery disease which are the leading causes of death in the United States. A dysfunctional endothelium is one of the initial signatures of early atherosclerosis. Its development is stimulated by multiple factors including elevated and modified low density lipoproteins (LDL), sheer stress, free radicals and hypertension. The altered endothelium induces an inflammatory response that results in formation of plaque in large and medium sized arteries. As the disease progresses, the plaque obstructs blood flow. Eventually the plaque can become unstable leading to potential life-threatening rupture and thrombosis. Current therapeutics for atherosclerotic disease generally prevent progression. A molecule that promotes plaque regression through a clearly defined novel mechanism would provide profound medical advancement in treatment of atherosclerosis. The goal of these studies is to advance such a new therapeutic toward the clinic for patients with atherosclerosis. Recently, we demonstrated that rPAI-123, a truncated isoform of plasminogen activator inhibitor-1, has anti-angiogenic activity and promotes plaque regression in hypercholesterolemic LDLR-/- ApoB48 deficient mice. The objectives of the proposed studies are: (1) to confirm, in a mouse model of atherosclerosis, that rPAI-123 stimulates plaque regression in a dose-dependent manner through the novel plasmin regulatory pathway, thereby identifying the optimal rPAI-123 dosing for future pre-clinical studies; and 2) to examine potential in vivo toxicity and side-effects associated with rPAI-123 treatment, providing the first data that optimal dosing concentrations demonstrate no or minimal side effects. PUBLIC HEALTH RELEVANCE: Current therapies for cardiovascular disease generally prevent plaque progression. This project aims to develop a therapeutic product that promotes plaque regression through a novel mechanism. Success would ultimately provide a profound medical advancement in treatment of atherosclerosis, a significant benefit to human health, and a dramatic reduction in the economic impact of the number one killer in America.

描述（由申请人提供）：心血管疾病（CVD）是世界上主要的死亡原因。预计未来死亡率将大幅上升十年。在美国，估计有 8100 万成年人患有一种或多种心血管疾病，估计每年直接和间接经济负担总额为 4000 亿美元。动脉粥样硬化是冠状动脉、外周动脉和颈动脉疾病的主要原因，而这些疾病是美国主要的死亡原因。功能失调的内皮细胞是早期动脉粥样硬化的最初特征之一。它的发展受到多种因素的刺激，包括升高和修饰的低密度脂蛋白（LDL）、纯粹的压力、自由基和高血压。改变的内皮会引起炎症反应，导致大中型动脉中斑块的形成。随着疾病的进展，斑块会阻碍血液流动。最终，斑块可能变得不稳定，导致潜在的危及生命的破裂和血栓形成。目前动脉粥样硬化疾病的治疗方法通常可以防止进展。通过明确定义的新机制促进斑块消退的分子将为动脉粥样硬化的治疗带来深远的医学进步。这些研究的目标是将这种新的治疗方法推向动脉粥样硬化患者的临床。最近，我们证明 rPAI-123（纤溶酶原激活剂抑制剂-1 的截短亚型）具有抗血管生成活性，并促进高胆固醇血症 LDLR-/- ApoB48 缺陷小鼠的斑块消退。拟议研究的目的是：(1) 在动脉粥样硬化小鼠模型中，确认 rPAI-123 通过新型纤溶酶调节途径以剂量依赖性方式刺激斑块消退，从而确定 rPAI-123 的最佳剂量。未来的临床前研究； 2) 检查与 rPAI-123 治疗相关的潜在体内毒性和副作用，提供最佳剂量浓度没有副作用或副作用最小的第一批数据。公共卫生相关性：目前心血管疾病的治疗方法通常可以预防斑块进展。该项目旨在开发一种通过新机制促进斑块消退的治疗产品。成功最终将为动脉粥样硬化的治疗带来深远的医学进步，对人类健康产生重大益处，并大幅减少美国头号杀手的经济影响。