Development of a PCSK9-targeted nanoparticle vaccine to effectively decrease the hypercholesterolemia
Qiannan Fang, Xinyu Lu, Yuanqiang Zhu, Xi Lv, Fei Yu, Xiancai Ma, Bingfeng Liu, Hui Zhang
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low-density lipoprotein receptor (LDLR) and mediates its internalization and degradation, resulting in an increase in LDL cholesterol levels. Recently, PCSK9 emerged as a therapeutic target for hypercholesterolemia and atherosclerosis. In this study, we develop a PCSK9 nanoparticle (NP) vaccine by covalently conjugating the catalytic domain (aa 153-aa 454, D374Y) of PCSK9 to self-assembled 24-mer ferritin NPs. We demonstrate that the PCSK9 NP vaccine effectively induces interfering antibodies against PCSK9 and reduces serum lipids levels in both a high-fat diet-induced hypercholesterolemia model and an adeno-associated virus-hPCSK9 D374Y -induced hypercholesterolemia model. Additionally, the vaccine significantly reduces plaque lesion areas in the aorta and macrophages infiltration in an atherosclerosis mouse model. Furthermore, we discover that the vaccine’s efficacy relied on T follicular help cells and LDLR. Overall, these findings suggest that the PCSK9 NP vaccine holds promise as an effective treatment for hypercholesterolemia and atherosclerosis. • The PCSK9 nanoparticle vaccine exerts robust immunogenicity in vivo • The PCSK9 nanoparticle vaccine effectively decreases the hypercholesterolemia • The PCSK9 nanoparticle vaccine’s efficacy relies on T follicular helper cells • The PCSK9 nanoparticle vaccine exhibits a good safety profile in vivo Fang et al. develop a ferritin-based NP vaccine that conjugates human PCSK9 as an antigen. This PCSK9 NP vaccine elicits a potent antibody response that interferes with PCSK9 activity and shows promise as a cholesterol-lowering vaccine.