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The Use of LCAT Infusion to Treat Acute Coronary Syndromes

使用 LCAT 输注治疗急性冠状动脉综合征

基本信息

批准号：
7537318
负责人：
Brian Robert Krause
金额：
$ 24.01万
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 2009-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7537318
关键词：
Activase Acute Affect Alteplase American Animal Model Animals Apolipoprotein A-I Apolipoproteins Apolipoproteins A Arterial Fatty Streak Arteries Atherosclerosis Bile fluid Biological Assay Blood Vessels Blood flow Body Weight Bolus Infusion Cardiac Cardiovascular Agents Cardiovascular Diseases Carrier Proteins Cause of Death Cholesterol Cholesterol Esters Clinical Clinical Trials Coagulation Process Communicable Diseases Cornea Coronary Coronary heart disease Country Data Development Diet Disease Disease Progression Disease regression Disruption Dose Dyslipidemias Elevation Enzymes Esterification Event Excision Excretory function Exhibits Fatty Acids Fill-It Foundations Frequencies Funding Genes Genetic Genetic Engineering Goals Hamsters Heart Diseases High Density Lipoprotein Cholesterol High Density Lipoproteins Human Immune response Immunologics Individual Inflammation Infusion procedures Inherited Injection of therapeutic agent Intramuscular Intravenous Investigational Drugs Investigational New Drug Application Kidney Diseases Kinetics Knowledge Lead Lecithin Lesion Lipids Lipoprotein (a)Lipoprotein (a-)Lipoproteins Liver Macaca fascicularis Mammalian Cell Measures Membrane Metabolism Methods Modality Modeling Mus Myocardial Infarction Numbers Oral Administration Organ Orphan Drugs Participant Particle Size Patients Peptides Peripheral Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Pharmacology Phase Phase II Clinical Trials Phosphatidylcholine-Sterol O-Acyltransferase Plasma Population Positioning Attribute Preparation Process Production Protein Overexpression Proteins Protocols documentation Public Health Rate Rattus Recombinants Research Risk Rodent Route Rupture Safety Scientist Signal Transduction Small Business Funding Mechanisms Small Business Innovation Research Grant Solutions Somatic Cell Staging Staining method Stains Stenosis Sterility Stroke Survivors System Technology Therapeutic Thrombus Toxic effect Toxicology Transgenic Animals Transgenic Mice United States Food and Drug Administration Vascular Diseases Vendor Viral Woman World Health Organization acute coronary syndrome concept critical developmental period day design drug market enzyme replacement therapy experience gene delivery system gene therapy genetic manipulation intraperitoneal intravenous administration lecithin cholesterol acyltransferase deficiency mature animal men neutralizing antibody nonhuman primate novel pre-clinical prevent receptor reconstitution research clinical testing response reverse cholesterol transport size small molecule subcutaneous technological innovation therapeutic protein tool transacylation viral gene delivery

项目摘要

DESCRIPTION (provided by applicant): Coronary heart disease, the most prevalent manifestation of atherosclerosis, remains the single largest killer of American men and women. The "hallmark" of vascular disease or atherosclerosis is the accumulation of cholesterol in arteries, which can lead to heart attack (coronary heart disease), stroke or peripheral artery disease. The excess cholesterol causes stenosis and disruptions of signaling cascades leading to instability within the plaque. Therefore, a method to rapidly remove cholesterol from the atheromas and reduce the peripheral cholesterol burden may stabilize the plaque. Normally, cholesterol is removed from arteries and delivered to the liver for excretion in bile by a multistage process known as "Reverse Cholesterol Transport" (RCT). In the first stage, high-density lipoprotein (HDL) acquires cholesterol from artery walls. In the second stage, the enzyme lecithin:cholesterol acyltransferase (LCAT) increases the amount of cholesterol carried in HDL by the conversion of cholesterol to cholesteryl ester. The observation that individuals with reduced LCAT function exhibit reduced HDL cholesterol (HDL-C) and increased vascular disease suggests that LCAT function is protective. Moreover, enhancement of LCAT in animal models by gene over-expression is known to increase HDL-C and reduces atherosclerosis. AlphaCore Pharma proposes that the injection of active LCAT will result in the rapid mobilization of vessel and peripheral cholesterol to HDL, and consequent stabilization of arterial atheromas, thereby reducing the risk of primary or secondary vascular events in the patient. The Phase I specific aims are 1) Develop a mammalian cell expression system to produce sufficient quantities of recombinant, active, human LCAT (rhLCAT) and 2) Characterize the pharmacodynamics of rhLCAT infusion in mice expressing human apolipoprotein AI (apoA-ITG). The principle measures will be plasma cholesterol, HDL-C, human apoA-I, plasma LCAT activity and plasma content of rhLCAT. The kinetics of these parameters will be determined following a single infusion. Additionally, a comparison between routes of administration (intravenous, intraperitoneal and intra-muscular) will be performed. The data obtained from these studies will demonstrate the kinetics and magnitudes of HDL-C changes in response to a bolus rhLCAT infusion, which is unprecedented. The results will help define the dose sizes and dose frequency needed to obtain significant elevations in HDL-C. This information will be the foundation for a subsequent study of the effects of rhLCAT infusion on atherosclerosis development in an animal model. The ultimate goal of AlphaCore Pharma is to develop LCAT infusion as an acute therapy for unstable plaque and atherosclerosis. 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）：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。血管疾病或动脉粥样硬化的“标志”是胆固醇在动脉中积聚，这可能导致心脏病发作（冠心病）、中风或外周动脉疾病。过量的胆固醇会导致信号级联的狭窄和破坏，从而导致斑块内不稳定。因此，快速去除粥样斑块中的胆固醇并减少外周胆固醇负担的方法可能会稳定斑块。正常情况下，胆固醇通过称为“反向胆固醇转运”(RCT) 的多阶段过程从动脉中清除并输送到肝脏，通过胆汁排泄。在第一阶段，高密度脂蛋白（HDL）从动脉壁获取胆固醇。在第二阶段，卵磷脂：胆固醇酰基转移酶 (LCAT) 通过将胆固醇转化为胆固醇酯来增加 HDL 中携带的胆固醇量。 LCAT 功能降低的个体表现出高密度脂蛋白胆固醇 (HDL-C) 降低和血管疾病增加的观察结果表明，LCAT 功能具有保护作用。此外，已知在动物模型中通过基因过表达增强 LCAT 可以增加 HDL-C 并减少动脉粥样硬化。 AlphaCore Pharma 提出，注射活性 LCAT 将导致血管和外周胆固醇快速动员为 HDL，从而稳定动脉粥样硬化，从而降低患者发生原发性或继发性血管事件的风险。第一阶段的具体目标是 1) 开发哺乳动物细胞表达系统，以产生足够数量的重组、有活性的人 LCAT (rhLCAT)，以及 2) 表征表达人载脂蛋白 AI (apoA-ITG) 的小鼠中 rhLCAT 输注的药效学。主要测量指标为血浆胆固醇、HDL-C、人apoA-I、血浆LCAT活性和rhLCAT血浆含量。这些参数的动力学将在单次输注后确定。此外，还将对给药途径（静脉内、腹膜内和肌肉内）进行比较。从这些研究中获得的数据将证明 HDL-C 因推注 rhLCAT 输注而变化的动力学和幅度，这是前所未有的。结果将有助于确定获得 HDL-C 显着升高所需的剂量大小和剂量频率。该信息将为后续研究 rhLCAT 输注对动物模型动脉粥样硬化发展的影响奠定基础。 AlphaCore Pharma 的最终目标是开发 LCAT 输注作为不稳定斑块和动脉粥样硬化的急性疗法。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。