权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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单一最大杀手。血管疾病或动脉粥样硬化的“标志”是胆固醇在动脉中的积累，这可能导致心脏病发作（冠心病）、中风或外周动脉疾病。过量的胆固醇导致狭窄和信号级联的中断，导致斑块内的不稳定性。因此，从动脉粥样硬化中快速去除胆固醇并降低外周胆固醇负荷的方法可以稳定斑块。正常情况下，胆固醇从动脉中排出，并通过称为“胆固醇逆向转运”（RCT）的多阶段过程输送到肝脏，以胆汁形式排泄。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，酶卵磷脂：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中携带的胆固醇的量。LCAT功能降低的个体表现出降低的HDL胆固醇（HDL-C）和增加的血管疾病的观察表明LCAT功能是保护性的。此外，已知通过基因过表达增强动物模型中的LCAT可增加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。I期的具体目标是：1）开发哺乳动物细胞表达系统，以生产足量的重组活性人LCAT（rhLCAT）; 2）表征rhLCAT输注在表达人载脂蛋白AI（apoA-ITG）的小鼠中的药效学。主要指标为血浆胆固醇、HDL-C、人apoA-I、血浆LCAT活性和血浆rhLCAT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、腹膜内和肌内）进行比较。从这些研究中获得的数据将证明HDL-C响应于推注rhLCAT输注的动力学和幅度变化，这是前所未有的。结果将有助于确定获得HDL-C显著升高所需的剂量大小和剂量频率。这些信息将为后续研究rhLCAT输注对动物模型中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，注射酶卵磷脂：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，降低至少患有一次心脏病的患者重复事件的风险。