A nanoparticle-based vaccine targeting PCSK9

一种针对 PCSK9 的纳米颗粒疫苗

• 批准号: 9413459
• 负责人: Bryce C Chackerian
• 金额: $ 34.74万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9413459
• 关键词: Active Immunization; Adult; Adverse effects; Adverse reactions; Alzheimer' s Disease; Animal Model; Antibodies; Antibody Response; Antibody titer measurement; Antigen Targeting; Antigens; Atherosclerosis; Autoantigens; B-Lymphocytes; Bacteriophages; Biological Models; Blocking Antibodies; Cardiovascular Diseases; Cardiovascular system; Cholesterol; Cholesterol Homeostasis; Chronic Disease; Clinical Trials; Coronary heart disease; Data; Development; Disease; Disease model; Engineering; Epitopes; Event; FDA approved; Goals; HIV Infections; Heart Diseases; Human; Incidence; Individual; LDL Cholesterol Lipoproteins; Lead; Life Style; Life Style Modification; Lipids; Low Density Lipoprotein Receptor; Macaca; Modeling; Monoclonal Antibodies; Monoclonal Antibody Therapy; Mus; Mutation; Passive Immunization; Patient risk; Patients; Peptides; Pharmaceutical Preparations; Population; Price; Proprotein Convertases; Proteins; Recombinants; Regulation; Research; Rheumatoid Arthritis; Risk; Serum; Stroke; Subtilisins; Surface; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Monoclonal Antibodies; Therapeutic Uses; Treatment Failure; United States; Vaccination; Vaccines; Virus-like particle; antibody inhibitor; autoreactive T cell; base; cardiovascular disorder risk; chemical conjugate; cholesterol control; efficacy study; gain of function mutation; humanized monoclonal antibodies; hypercholesterolemia; immunogenicity; in vivo; innovation; interest; lifetime risk; loss of function mutation; mouse model; nanoparticle; nonhuman primate; novel; novel strategies; novel vaccines; secretory protein; therapeutic target; vaccination strategy; vaccine candidate; virus identification

PROJECT SUMMARY Over 30% of the adult population of the United States has elevated levels of low-density lipoprotein cholesterol (LDL-C), a condition that is correlated with an increased risk of coronary heart disease and stroke. Lifestyle modifications and treatment with statins can be sufficient for the treatment of mildly elevated LDL-C, but a substantial percentage of patients on statins fail to meet recommended LDL-C goals. Thus, new approaches are needed to control LDL-C. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a molecule that modulates expression of the LDL receptor (LDL-R). Naturally occurring mutations that reduce the activity of PCSK9 are associated with decreased LDL-C levels and reduced risk of cardiovascular disease. More recently, it has been shown in clinical trials that PCSK9-targeted monoclonal antibodies (mAbs) can dramatically reduce LDL-C levels. The goal of this proposal is develop an active vaccination strategy to target PCSK9, as an alternative to mAb therapy. To do this we will use a virus-like particle (VLP) nanoparticle platform, which we have used previously to elicit high-titer antibody responses against PCSK9 and other self- antigen targets. In Aim 1 we will engineer VLP-based vaccines targeting different epitopes in PCSK9, and compare their immunogenicity and ability to reduce lipid levels in mice. In Aim 2 we will test candidate vaccine in hypercholesterolemic and atherosclerotic mouse models. In Aim 3 we will assess the immunogenicity and functionality of our lead PCSK9-VLP vaccine in non-human primates, and test its compatibility with statins. The long-term goal of this research is to generate effective vaccines that target human PCSK9 and reduce LDL-C, as a novel vaccine-based therapeutic treatment for heart disease.

项目摘要 超过30％的美国成年人口的低密度脂蛋白胆固醇水平升高 （LDL-C），这种疾病与冠心病和中风的风险增加有关。生活方式 他汀类药物的修饰和治疗足以治疗轻度升高的LDL-C，但 他汀类药物的大量患者无法满足建议的LDL-C目标。因此，新方法 需要控制LDL-C。普罗蛋白转化酶枯草蛋白/KEXIN 9型（PCSK9）是一个分子 调节LDL受体（LDL-R）的表达。自然发生的突变，以减少 PCSK9与LDL-C水平降低和心血管疾病风险降低有关。更多的 最近，在临床试验中已显示PCSK9靶向的单克隆抗体（mAb）可以 大大降低LDL-C水平。该提案的目的是制定一种积极的疫苗接种策略来针对目标 PCSK9，作为MAB治疗的替代方法。为此，我们将使用病毒样粒子（VLP）纳米颗粒 平台，我们以前用来引起针对PCSK9和其他自我的高速抗体反应 抗原靶标。在AIM 1中，我们将设计基于VLP的疫苗，以PCSK9中的不同表位和 比较它们的免疫原性和降低小鼠脂质水平的能力。在AIM 2中，我们将测试候选疫苗 在高胆固醇和动脉粥样硬化小鼠模型中。在AIM 3中，我们将评估免疫原性和 非人类灵长类动物中铅PCSK9-VLP疫苗的功能，并测试其与他汀类药物的兼容性。 这项研究的长期目标是生成针对人PCSK9的有效疫苗并减少 LDL-C是一种基于疫苗的新型心脏病治疗。