A nanoparticle-based vaccine targeting PCSK9

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Principal Investigator: Bryce C Chackerian
Organization: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
Fiscal Year: 2020
Award: $513,123
Funding agency: National Heart Lung and Blood Institute

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.

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