A nanoparticle-based vaccine targeting PCSK9

项目总结 美国超过30%的成年人低密度脂蛋白胆固醇水平升高 (低密度脂蛋白-C)，这是一种与冠心病和中风风险增加相关的疾病。生活方式 他汀类药物的修饰和治疗足以治疗轻度升高的低密度脂蛋白，但 服用他汀类药物的患者中有相当大比例未能达到推荐的低密度脂蛋白胆固醇目标。因此，新的方法 是控制低密度脂蛋白胆固醇所必需的。枯草杆菌前蛋白转换酶9(PCSK9)是一种 调节低密度脂蛋白受体(LDL-R)的表达。自然发生的突变会降低酶的活性 PCSK9与低密度脂蛋白水平降低和心血管疾病风险降低有关。更多 最近的临床试验表明，PCSK9靶向的单抗可以 显著降低低密度脂蛋白水平。这项提议目标是制定一项积极的疫苗接种战略，以针对 PCSK9，作为单抗治疗的替代方案。为此，我们将使用病毒样颗粒(VLP)纳米颗粒 平台，我们以前曾用它来诱导针对PCSK9和其他自身的高效价抗体反应 抗原靶标。在目标1中，我们将针对PCSK9中的不同表位设计基于VLP的疫苗，以及 比较它们的免疫原性和降低小鼠血脂水平的能力。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和 我们的领先PCSK9-VLP疫苗在非人类灵长类动物中的功能性，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产针对人类PCSK9的有效疫苗，并减少 低密度脂蛋白-C作为一种新型的以疫苗为基础的心脏病治疗方法。

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.