Development of a PCSK9-targeted nanoparticle vaccine to effectively decrease the hypercholesterolemia

Area of Science:

• Cardiovascular Research
• Immunology
• Nanomedicine

Background:

• Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role in regulating low-density lipoprotein receptor (LDLR) degradation, leading to elevated LDL cholesterol.
• Elevated LDL cholesterol is a major risk factor for atherosclerosis and cardiovascular disease.
• PCSK9 has emerged as a significant therapeutic target for managing hypercholesterolemia.

Purpose of the Study:

• To develop and evaluate a novel nanoparticle (NP) vaccine targeting PCSK9.
• To assess the vaccine's efficacy in reducing serum lipids and mitigating atherosclerosis in preclinical models.
• To elucidate the immunological and cellular mechanisms underlying the vaccine's therapeutic effects.

Main Methods:

• Conjugation of the catalytic domain of PCSK9 to self-assembled 24-mer ferritin NPs to create the PCSK9 NP vaccine.
• Evaluation of the vaccine in high-fat diet-induced and AAV-hPCSK9-induced hypercholesterolemia mouse models.
• Assessment of atherosclerotic plaque burden and macrophage infiltration in a relevant mouse model.
• Investigation of the roles of T follicular helper cells and LDLR in vaccine efficacy.

Main Results:

• The PCSK9 NP vaccine successfully induced interfering antibodies against PCSK9.
• Significant reductions in serum lipid levels were observed in both hypercholesterolemia models.
• The vaccine markedly decreased atherosclerotic plaque areas and macrophage infiltration in the aorta.
• Vaccine efficacy was demonstrated to be dependent on T follicular help cells and LDLR.

Conclusions:

• The developed PCSK9 NP vaccine is a promising immunotherapeutic strategy for hypercholesterolemia.
• This novel vaccine effectively reduces atherosclerosis progression in preclinical models.
• The findings support the potential of PCSK9 NP vaccines as a novel treatment for cardiovascular diseases.