Preclinical Development of a Novel Plaque-Regressing Therapy For Atherosclerosis

描述(申请人提供)：心血管疾病(CVD)是世界上最主要的死亡原因。令人震惊的死亡率预计将在接下来的几年里大幅上升。 十年了。在美国，估计有8100万成年人将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、外周和颈动脉疾病的主要原因，而这些疾病在美国是主要的死亡原因。内皮功能障碍是早期动脉粥样硬化的最初标志之一。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)、纯粹的应激、自由基和高血压。内皮细胞的改变会引起炎症反应，导致大中型动脉斑块的形成。随着疾病的发展，斑块会阻碍血液流动。最终，斑块可能会变得不稳定，导致潜在的危及生命的破裂和血栓形成。目前动脉粥样硬化性疾病的治疗方法通常可以阻止病情的发展。通过明确定义的新机制促进斑块消退的分子将在治疗动脉粥样硬化方面提供深刻的医学进步。这些研究的目标是将这种新的治疗方法推向临床，治疗动脉粥样硬化患者。最近，我们证明了RPAI-123，纤溶酶原激活物抑制物-1的截短亚型，在高胆固醇血症LDLR-/-ApoB48缺陷小鼠中具有抗血管生成活性和促进斑块消退的作用。拟议研究的目的是：(1)在动脉粥样硬化的小鼠模型上，证实RPAI-123通过新的纤溶酶调节途径以剂量依赖的方式刺激斑块消退，从而确定用于未来临床前研究的最佳RPAI-123剂量；以及2)检测与RPAI-123治疗相关的潜在体内毒性和副作用，提供最优剂量组无副作用或副作用最小的数据。 公共卫生相关性：目前心血管疾病的治疗方法通常可以防止斑块的进展。该项目旨在开发一种通过一种新的机制促进斑块消退的治疗产品。成功最终将在治疗动脉粥样硬化方面带来深刻的医学进步，对人类健康有重大好处，并显著减少美国头号杀手对经济的影响。

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.