Vaccine targeting ANGPTL3 ameliorates dyslipidemia and associated diseases in mouse models of obese dyslipidemia and familial hypercholesterolemia

Fukami H, Morinaga J, Nakagami H, Hayashi H, Okadome , Matsunaga E, Kadomatsu T, Horiguchi H, Sato M, Sugizaki T, Kuwabara T, Miyata K, Mukoyama M, Morishita R, Oike Y

doi:10.1530/ey.19.12.13

Reports Medicine 2021;2(11):100446. doi: 10.1016/j.xcrm.2021.100446

Brief Summary: This mouse study validated a novel, safe treatment with ANGPTL3 peptide vaccine. It was effective to improve obesity-induced dyslipidemia and fatty liver in mice, and also improved dyslipidemia and atherosclerosis in a mouse model of familial hypercholesterolemia, with no reported toxicity.

Comment: Mounting evidence from human genetic studies indicate that elevated plasma TG are a risk factor, in addition to LDL-C, for atherosclerotic CVD.

Angiopoietin-like 3 protein (ANGPTL3) is an inhibitor of both lipoprotein lipase and endothelial lipase in humans. Loss of function mutations in ANGPTL3 are associated with reductions in TG and in non-high-density lipoprotein cholesterol, and reduced risk of coronary artery disease. Therefore, it is logical that ANGPTL3 inhibition could serve as a promising therapeutic strategy to improve lipid levels and lower the risk of CVD. Indeed, anti-ANGPTL3 antibodies, antisense oligonucleotides and siRNAs targeting ANGPTL3 have been developed, and have shown favorable effects on lipid profiles in homozygous familial hyperlipidemia.

These Japanese scientists developed a peptide vaccine that targets ANGPTL3. To this end, they firstly designed a number of ANGPTL3 epitopes as candidate antigens for immunization. They then used these epitope candidates to produce specific antibodies, and selected the one with the best specificity. Next, they explored the effect of ANGPTL3 vaccination on lipid metabolism in ob/ob mice with dyslipidemia. Six weeks after the first immunization, serum TG levels in non-fasting conditions decreased relative to controls. TG accumulation was also lower in the liver of vaccinated ob/ob mice; and steatosis, lobular inflammation and hepatocyte ballooning were alleviated in immunized relative to control mice. ANGPTL3 vaccination showed anti-dyslipidemia effects such as decreasing circulating levels of LDL-C and TG, and anti-atherosclerotic effects, in a severe FH mouse model fed a high-cholesterol diet. The durability of vaccine treatment based on antibody titers against ANGPTL3 persisted until week 30.

As the mouse epitope of the ANGPTL3 sequence is identical to the corresponding human sequence, the vaccine could potentially be investigated in clinical studies in humans. Given that the vaccination is effective for up to 6 months, it may be an outstanding solution.

ESPE Yearbook of Paediatric Endocrinology

12.13

12.13. Vaccine targeting ANGPTL3 ameliorates dyslipidemia and associated diseases in mouse models of obese dyslipidemia and familial hypercholesterolemia

Fukami H , Morinaga J , Nakagami H , Hayashi H , Okadome Y , Matsunaga E , Kadomatsu T , Horiguchi H , Sato M , Sugizaki T , Kuwabara T , Miyata K , Mukoyama M , Morishita R & Oike Y

Volume 19

Yearbook of Paediatric Endocrinology 2022

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