Treatment of Acute Coronary Syndromes with Recombinant LCAT Infusion

重组 LCAT 输注治疗急性冠脉综合征

• 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
• 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

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"是胆固醇在动脉中的积聚，导致斑块，斑块可导致心脏病发作（心肌梗死（MI））。过量的胆固醇引起炎症，促进斑块不稳定，并在后期阶段，使血管腔变窄以阻碍血液流动。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）的多步骤过程输送到肝脏，排泄到胆汁中。在随机对照试验的第一步中，称为"前β" HDL的小高密度脂蛋白（HDL）颗粒从动脉壁获得胆固醇。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中携带的胆固醇的量。最近的观察表明，心脏病患者的前β HDL水平较高，LCAT活性降低，这表明LCAT是RCT的一个关键组成部分，可能是限速组成部分。此外，已知通过基因转移或最近通过注射重组LCAT增强动物模型中的LCAT可增加HDL-C，增强RCT并减少动脉粥样硬化。因此，增加MI患者的LCAT量将快速刺激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后患者重复（继发性）MI风险的疗法。该项目的第一阶段非常成功。SBIR资金用于实验室规模生产活性rhLCAT，并在小鼠中进行初步概念验证研究。在三种相关小鼠模型中单次注射rhLCAT增加了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的反应都相似，这表明在人体中可能存在不同的给药选择，包括自我给药。在几天内多次注射rhLCAT产生HDL-C的更大增加，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递送增强。II期的具体目的是1）证明注射rhLCAT后巨噬细胞特异性RCT的增强，2）确定rhLCAT是否会诱导家兔动脉粥样硬化病变的快速变化，3）在非人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）证明注射后rhLCAT与HDL相关，并且具有功能性。这些具体目标的实现将使申请FDA批准测试rhLCAT在人体中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，用于减少梗死后患者中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。