Treatment of Acute Coronary Syndromes with Recombinant LCAT Infusion

重组 LCAT 输注治疗急性冠脉综合征

基本信息

批准号：
8000271
负责人：
Brian Robert Krause
金额：
$ 102.28万
依托单位：
ALPHACORE PHARMA, LLC
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8000271
关键词：
Achievement Acute Adenoviruses American Animal Model Animals Antiatherogenic Arterial Fatty Streak Arteries Atherosclerosis Bile Acids Bile fluid Biliary Blood flow CETP gene Cardiovascular system Carrier Proteins Cholesterol Cholesterol Esters Chronic Clinical Clinical Trials Collaborations Collagen Complex Cooperative Research and Development Agreement Coronary Coronary heart disease Data Development Diet Dose Enzymes Esterification Event Excision Excretory function Fatty acid glycerol esters Feces Funding Gene Transfer Genes Goals Hamsters Heart Diseases High Density Lipoprotein Cholesterol High Density Lipoproteins Hour Human Immune Individual Infarction Inflammation Infusion procedures Injection of therapeutic agent Intramuscular Intramuscular Injections Intravenous Investigation Investigational Drugs Investments Lead Lesion Lipids Lipoproteins Liver Low-Density Lipoproteins Mediating Membrane Metabolism Methodology Monkeys Mus Myocardial Infarction Oryctolagus cuniculus Patients Peripheral Pharmaceutical Preparations Phase Phase I Clinical Trials Phenotype Phosphatidylcholine-Sterol O-Acyltransferase Physiological Plasma Process Production Proteins Publishing Reaction Recombinants Recurrence Reporting Risk Route Rupture Safety Saimiri Self Administration Small Business Innovation Research Grant Staging Testing Tissues Toxic effect Toxicology Transgenic Organisms United States National Institutes of Health Vascular Diseases Woman Work acute coronary syndrome arterial lesion effective therapy feeding high risk lecithin cholesterol acyltransferase deficiency macrophage men mouse model nonhuman primate novel therapeutics particle pre-beta high-density lipoprotein public health relevance receptor research study response reverse cholesterol transport subcutaneous therapeutic protein uptake

项目摘要

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.

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聚，形成斑块，从而导致心脏病发作（心肌梗塞（MI））。过量的胆固醇会引起炎症，促进斑块不稳定，并在后期缩小血管腔以阻碍血流。通常，胆固醇通过称为“反向胆固醇转运”(RCT) 的多步骤过程从动脉中去除并输送到肝脏排泄到胆汁中。在 RCT 的第一步中，称为“前β”HDL 的小高密度脂蛋白 (HDL) 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HDL中携带的胆固醇量。最近的观察发现，患有心脏病的个体具有较高的前β HDL 水平和较低的 LCAT 活性，这表明 LCAT 是 RCT 的关键组成部分，并且可能是 RCT 的限速组成部分。此外，通过基因转移，或者最近通过注射重组LCAT，在动物模型中增强LCAT，已知可以增加HDL-C，增强RCT并减少动脉粥样硬化。因此，增加 MI 患者 LCAT 的量将迅速刺激 RCT，稳定斑块，从而减少另一次不良临床事件的可能性，这是合理的。 AlphaCore Pharma 的长期商业目标是获得 FDA 批准重组人 LCAT (rhLCAT) 作为降低 MI 后患者再次（继发性）MI 风险的疗法。该项目第一阶段非常成功。 SBIR 资金用于活性 rhLCAT 的实验室规模生产，并在小鼠中进行初步概念验证研究。在三个相关小鼠模型中单次注射 rhLCAT 会增加 HDL 胆固醇（主要是 LCAT 衍生的胆固醇酯）和大小。此外，HDL-C 保持升高状态超过 48 小时，这增加了人类每周一次给药的可能性。无论注射途径是血管内、肌内还是皮下，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。几天内多次注射 rhLCAT 可使 HDL-C 产生更大的增加，并导致参与胆汁酸产生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 是否会引起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研究性新药提交的数据； 4) 证明rhLCAT在注射后与HDL结合并且具有功能。这些具体目标的实现将能够向 FDA 申请批准测试 rhLCAT 在人体中的安全性和有效性。最终目标是使 rhLCAT 成为一种独特且有效的疗法，以减少梗塞后患者不可接受的复发性心血管事件的数量。公共卫生相关性：冠心病是动脉粥样硬化最常见的表现，仍然是美国男性和女性的最大杀手。 AlphaCore Pharma 提出，注射卵磷脂：胆固醇酰基转移酶将导致血管和外周胆固醇快速动员为 HDL，从而稳定动脉，从而降低至少遭受过一次心脏病发作的患者重复事件的风险。