A nanoparticle-based vaccine targeting PCSK9

项目摘要 超过30%的美国成年人低密度脂蛋白胆固醇水平升高 低密度脂蛋白胆固醇（LDL-C），一种与冠心病和中风风险增加相关的疾病。生活方式 调整和他汀类药物治疗足以治疗轻度升高的LDL-C，但 接受他汀类药物治疗的患者中有相当大比例未能达到推荐的LDL-C目标。因此，新方法 来控制LDL-C。前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（PCSK 9）是一种分子， 调节LDL受体（LDL-R）的表达。自然发生的突变降低了 PCSK 9与LDL-C水平降低和心血管疾病风险降低相关。更 最近，临床试验显示靶向PCSK 9的单克隆抗体（mAb）可以 显著降低LDL-C水平。该提案的目标是制定一项积极的疫苗接种战略， PCSK 9，作为mAb治疗的替代方案。为此，我们将使用病毒样颗粒（VLP）纳米颗粒 平台，我们以前曾使用它来引发针对PCSK 9和其他自身抗体的高滴度抗体应答。 抗原靶点。在目标1中，我们将设计针对PCSK 9中不同表位的VLP疫苗， 比较它们的免疫原性和降低小鼠脂质水平的能力。在目标2中，我们将测试候选疫苗 在高胆固醇血症和动脉粥样硬化小鼠模型中。在目标3中，我们将评估免疫原性， 我们的主要PCSK 9-VLP疫苗在非人灵长类动物中的功能，并测试其与他汀类药物的相容性。 这项研究的长期目标是产生针对人PCSK 9的有效疫苗， LDL-C，作为一种新的基于疫苗的心脏病治疗方法。

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.