Treatment of Acute Coronary Syndromes with Recombinant LCAT Infusion

描述(由申请人提供)：动脉粥样硬化的“特征”是胆固醇在动脉中积累，导致斑块，从而导致心脏病发作(心肌梗死)。过量的胆固醇会引起炎症，促进斑块的不稳定，并在后期使血管管腔变窄，阻碍血流。正常情况下，胆固醇从动脉中排出，并通过一个称为“反向胆固醇运输”(RCT)的多步骤过程被输送到肝脏，排入胆汁中。在随机对照试验的第一步，被称为“前β”高密度脂蛋白的小颗粒从动脉壁获取胆固醇。在第二步中，血浆酶卵磷脂：胆固醇酰基转移酶(LCAT)通过将胆固醇酯化为胆固醇酯来增加高密度脂蛋白中携带的胆固醇的量。最近的观察表明，心脏病患者的前β-高密度脂蛋白水平较高，而LCAT活性降低，这表明LCAT是RCT的一个关键的、可能是限速的组成部分。此外，在动物模型中，通过基因转移或最近通过注射重组LCAT来增强LCAT，已知可以增加高密度脂蛋白-C，增强RCT和减少动脉粥样硬化。因此，在心肌梗死患者中增加LCAT的量是合理的，它将迅速刺激RCT，稳定斑块，从而降低另一种不良临床事件的可能性。AlphaCore Pharma的长期商业目标是使FDA批准重组人LCAT(RhLCAT)作为一种治疗方法，用于降低心肌梗死后患者重复(二次)心肌梗死的风险。该项目的第一阶段非常成功。SBIR资金用于实验室规模的活性重组人LCAT的生产和在小鼠身上进行初步的概念验证研究。在三个相关的小鼠模型中单次注射rhLCAT增加了高密度脂蛋白胆固醇(主要是LCAT衍生的胆固醇酯)和大小。此外，高密度脂蛋白-C持续升高超过48小时，这增加了在人类身上每周给药一次的可能性。无论注射途径是血管内、肌肉内还是皮下，对rhLCAT的反应都是相似的，这表明人类可能有不同的剂量选择，包括自我给药。在几天内多次注射重组人LCAT后，高密度脂蛋白-C的升高幅度更大，并导致与胆汁酸产生有关的肝脏基因表达增强，这表明胆固醇向肝脏的输送增加。第二阶段的具体目标是1)展示注射rhLCAT后巨噬细胞特异性RCT的增强，2)确定rhLCAT是否会导致兔动脉粥样硬化病变的快速变化，3)在非人类灵长类动物身上进行毒理学研究，以获得研究新药提交的数据；4)证明注射后rhLCAT与高密度脂蛋白相关并具有功能。这些特定目标的实现将使向FDA申请批准在人体上测试rhLCAT的安全性和有效性成为可能。最终目标是使rhLCAT成为一种独特而有效的治疗方法，用于减少梗塞后患者不可接受的复发心血管事件数量。 与公共卫生相关：冠心病是动脉粥样硬化最常见的表现形式，仍然是美国男性和女性的最大杀手。AlphaCore Pharma公司建议，注射卵磷脂：胆固醇酰基转移酶将导致血管和外周胆固醇迅速转化为高密度脂蛋白，从而稳定动脉，降低至少经历过一次心脏病发作的患者反复发作的风险。

DESCRIPTION (provided by applicant): The "hallmark" of atherosclerosis is the accumulation of cholesterol in arteries, resulting in plaque which can lead to a heart attack (myocardial infarction (MI)). The excess cholesterol causes inflammation, promotes plaque instability, and in later stages, narrows the vessel lumen to obstruct blood flow. Normally, cholesterol is removed from arteries and delivered to the liver for excretion into bile by a multistep process known as "Reverse Cholesterol Transport" (RCT). In the first step of RCT, small high-density lipoprotein (HDL) particles called "pre-beta" HDL acquire cholesterol from artery walls. In the second step, the plasma enzyme lecithin:cholesterol acyltransferase (LCAT) increases the amount of cholesterol carried in HDL by the esterification of cholesterol to cholesteryl ester. The recent observation that individuals with heart disease have high pre-beta HDL levels and reduced LCAT activity suggests that LCAT is a critical and perhaps rate-limiting component of RCT. Moreover, enhancement of LCAT in animal models by gene transfer, or more recently by the injection of recombinant LCAT, is known to increase HDL-C, enhance RCT and reduce atherosclerosis. Therefore, it is reasonable that increasing the amount of LCAT in patients who have suffered an MI will rapidly stimulate RCT, stabilize the plaque, and consequently, reduce the likelihood of another adverse clinical event. The long-term commercial objective of AlphaCore Pharma is to gain FDA approval for recombinant human LCAT (rhLCAT) as a therapy for reducing the risk of a repeat (secondary) MI in post-MI patients. Phase I of this project was highly successful. SBIR funding was used for bench-scale production of active rhLCAT and to conduct initial proof-of-concept studies in mice. A single injection of rhLCAT in three relevant mouse models increased HDL cholesterol (principally LCAT-derived cholesteryl esters) and size. Moreover, HDL-C remained elevated for more than 48 hours, which increases the possibility that once-weekly dosing may be achievable in humans. The response to rhLCAT was similar whether the injection route was intravascular, intramuscular or subcutaneous, which suggests different dosing options may be possible in humans, including self- administration. Multiple injections of rhLCAT over several days produced even greater increases in HDL-C, and resulted in enhanced expression of liver genes involved in bile acid production, suggesting enhanced delivery of cholesterol to the liver. The Phase II specific aims are 1) to demonstrate enhancement of macrophage specific RCT after rhLCAT injection, 2) to determine if rhLCAT will induce rapid changes in atherosclerotic lesions in rabbits, 3) to conduct a toxicology study in non-human primates to obtain the data for an Investigational New Drug submission; 4) to demonstrate that rhLCAT becomes associated with HDL after injection and is functional. Achievement of these specific aims will enable application to the FDA for approval to test rhLCAT safety and efficacy in humans. The ultimate goal is to make rhLCAT a unique and effective therapy for reducing the unacceptable number of recurrent cardiovascular events in post-infarct patients. PUBLIC HEALTH RELEVANCE: Coronary heart disease, the most prevalent manifestation of atherosclerosis, remains the single largest killer of American men and women. AlphaCore Pharma proposes that the injection of the enzyme lecithin:cholesterol acyltransferase will result in the rapid mobilization of vessel and peripheral cholesterol to HDL, and consequent stabilization of the arteries, reducing the risk of repeated events in patients who have suffered at least one heart attack.