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A VLP-based vaccine targeting ANGPTL3 lowers plasma triglycerides in mice
Alexandra Fowler1, Maureen Sampson2, Alan T Remaley2
1Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, MSC08-4660, Albuquerque, NM 87131, USA.
Abstract:
Elevated triglycerides (TGs) are an important risk factor for the development of coronary heart disease (CHD) and in acute pancreatitis. Angiopoietin-like proteins 3 (ANGPTL3) and 4 (ANGPTL4) are critical regulators of TG metabolism that function by inhibiting the activity of lipoprotein lipase (LPL), which is responsible for hydrolyzing triglycerides in lipoproteins into free fatty acids. Interestingly, individuals with loss-of-function mutations in ANGPTL3 and ANGPTL4 have low plasma TG levels, have a reduced risk of CHD, and are otherwise healthy. Consequently, interventions targeting ANGPTL3 and ANGPTL4 have emerged as promising new approaches for reducing elevated TGs. Here, we developed virus-like particle (VLP) based vaccines that target the LPL binding domains of ANGPTL3 and ANGPTL4. ANGPTL3 VLPs and ANGPTL4 VLPs are highly immunogenic in mice and vaccination with ANGPTL3 VLPs, but not ANGPTL4 VLPs, was associated with reduced steady state levels of TGs. Immunization with ANGPTL3 VLPs rapidly cleared circulating TG levels following an oil gavage challenge and enhanced plasma LPL activity. These data indicate that targeting ANGPTL3 by active vaccination is a potential alternative to other ANGPTL3-inhibiting therapies.
Insights
New vaccines targeting Angiopoietin-like protein 3 (ANGPTL3) reduce triglyceride levels. ANGPTL3 vaccines show potential for treating high triglycerides and reducing coronary heart disease risk.
Area of Science:
- Biochemistry
- Immunology
- Cardiovascular Disease
Background:
- Elevated triglycerides (TGs) are a significant risk factor for coronary heart disease (CHD) and acute pancreatitis.
- Angiopoietin-like proteins 3 (ANGPTL3) and 4 (ANGPTL4) regulate TG metabolism by inhibiting lipoprotein lipase (LPL).
- Loss-of-function mutations in ANGPTL3/ANGPTL4 are associated with lower TGs, reduced CHD risk, and good health.
Purpose of the Study:
- To develop novel virus-like particle (VLP) based vaccines targeting the LPL binding domains of ANGPTL3 and ANGPTL4.
- To assess the immunogenicity and efficacy of ANGPTL3 and ANGPTL4 VLPs in modulating TG levels.
Main Methods:
- Development of ANGPTL3 and ANGPTL4 virus-like particle (VLP) based vaccines.
- Vaccination of mice with ANGPTL3 VLPs and ANGPTL4 VLPs.
- Measurement of steady-state TG levels, response to oil gavage challenge, and plasma LPL activity.
Main Results:
- Both ANGPTL3 and ANGPTL4 VLPs were highly immunogenic in mice.
- Vaccination with ANGPTL3 VLPs, but not ANGPTL4 VLPs, led to reduced steady-state TG levels.
- ANGPTL3 VLP immunization accelerated clearance of circulating TGs after an oil challenge and enhanced plasma LPL activity.
Conclusions:
- Targeting ANGPTL3 through active vaccination using ANGPTL3 VLPs is a viable strategy for reducing elevated TGs.
- This approach offers a potential alternative to existing ANGPTL3-inhibiting therapies for managing hypertriglyceridemia and associated cardiovascular risks.
