Treatment of Acute Coronary Syndromes with Recombinant LCAT Infusion

描述（由申请人提供）：动脉粥样硬化的“标志”是胆固醇在动脉中积累，导致斑块，可导致心脏病发作（心肌梗死（MI））。过量的胆固醇会引起炎症，促进斑块不稳定，并在后期使血管腔变窄，阻碍血液流动。正常情况下，胆固醇从动脉中被移除，并通过一个被称为“逆向胆固醇转运”（RCT）的多步骤过程被运送到肝脏排泄成胆汁。在随机对照试验的第一步，被称为“前β”的高密度脂蛋白（HDL）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）通过将胆固醇酯化成胆固醇酯来增加HDL中携带的胆固醇量。最近的观察表明，患有心脏病的个体有较高的β - HDL水平和较低的LCAT活性，这表明LCAT是RCT的一个关键因素，可能是限制率的因素。此外，通过基因转移或最近通过注射重组LCAT来增强动物模型中的LCAT，已知可以增加HDL-C，增强RCT并减少动脉粥样硬化。因此，在心肌梗死患者中增加LCAT的量将迅速刺激RCT，稳定斑块，从而降低另一不良临床事件的可能性是合理的。AlphaCore Pharma的长期商业目标是获得FDA批准重组人LCAT （rhLCAT）作为降低心肌梗死后患者重复（继发性）心肌梗死风险的治疗方法。该项目的第一期非常成功。SBIR资金用于活性rhLCAT的实验规模生产，并在小鼠中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会增加高密度脂蛋白胆固醇（主要是lcat衍生的胆固醇酯）和体型。此外，高密度脂蛋白c升高超过48小时，这增加了在人类中实现每周一次剂量的可能性。无论注射途径是血管内、肌肉内还是皮下注射，对rhLCAT的反应都是相似的，这表明人类可能有不同的给药选择，包括自我给药。在数天内多次注射rhLCAT会产生更大的HDL-C增加，并导致与胆汁酸产生有关的肝脏基因表达增强，表明胆固醇向肝脏的输送增强。II期的具体目标是1)证明注射rhLCAT后巨噬细胞特异性RCT的增强，2)确定rhLCAT是否会诱导兔子动脉粥样硬化病变的快速变化，3)在非人类灵长类动物中进行毒理学研究，以获得新药研究申报的数据；4)证明rhLCAT在注射后与HDL相关并具有功能性。这些具体目标的实现将使FDA批准rhLCAT在人体中的安全性和有效性测试成为可能。最终目标是使rhLCAT成为一种独特而有效的治疗方法，以减少梗死后患者不可接受的心血管事件复发数量。

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.