Liver-targeted Angptl4 silencing by antisense oligonucleotide treatment attenuates hyperlipidaemia and atherosclerosis development in APOE*3-Leiden.CETP mice

Cardiovasc Res. 2024 Dec 31;120(17):2179-2190. doi: 10.1093/cvr/cvae195.

Abstract

Aims: Angiopoietin-like 3 (ANGPTL3) and 4 (ANGPTL4) inhibit lipoprotein lipase to regulate tissue fatty acid (FA) uptake from triglyceride (TG)-rich lipoproteins such as very low density lipoproteins (VLDL). While pharmacological inhibition of ANGPTL3 is being evaluated as a lipid-lowering strategy, systemic ANGPTL4 inhibition is not pursued due to adverse effects. This study aims to compare the therapeutic potential of liver-specific Angptl3 and Angptl4 silencing to attenuate hyperlipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice, a well-established humanized model for lipoprotein metabolism.

Methods and results: Mice were subcutaneously injected twice per week with saline or liver-targeted antisense oligonucleotides against Angptl3, Angptl4, both, or a scrambled oligonucleotide. Plasma lipid levels, VLDL clearance, and hepatic VLDL production were determined, and atherosclerosis development was assessed. For toxicological evaluation, cynomolgus monkeys were treated with three dosages of liver-targeted ANGPTL4-silencing oligonucleotides. Liver-targeted Angptl4 silencing reduced plasma TGs (-48%) and total cholesterol (-56%), explained by higher VLDL-derived FA uptake by brown adipose tissue and lower VLDL production by the liver. Accordingly, Angptl4 silencing reduced atherosclerotic lesion size (-86%) and improved lesion stability. Hepatic Angptl3 silencing similarly attenuated hyperlipidemia and atherosclerosis development. While Angptl3 and Angptl4 silencing lowered plasma TGs in the refed and fasted state, respectively, combined Angptl3/4 silencing lowered plasma TGs independent of the nutritional state. In cynomolgus monkeys, anti-ANGPTL4 ASO treatment was well tolerated without adverse effects.

Conclusion: Liver-targeted Angptl4 silencing potently attenuates hyperlipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice, and liver-targeted ANGPTL4 silencing is well tolerated in non-human primates. These data warrant further clinical development of liver-targeted ANGPTL4 silencing.

Keywords: Angptl3; Angptl4; Antisense oligonucleotides; Atherosclerosis; Hyperlipidaemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiopoietin-Like Protein 3*
  • Angiopoietin-Like Protein 4* / genetics
  • Angiopoietin-Like Protein 4* / metabolism
  • Angiopoietin-like Proteins / genetics
  • Angiopoietin-like Proteins / metabolism
  • Angiopoietins / genetics
  • Angiopoietins / metabolism
  • Animals
  • Apolipoprotein E3* / genetics
  • Apolipoprotein E3* / metabolism
  • Atherosclerosis* / drug therapy
  • Atherosclerosis* / genetics
  • Atherosclerosis* / metabolism
  • Atherosclerosis* / pathology
  • Atherosclerosis* / prevention & control
  • Cholesterol Ester Transfer Proteins* / antagonists & inhibitors
  • Cholesterol Ester Transfer Proteins* / genetics
  • Cholesterol Ester Transfer Proteins* / metabolism
  • Disease Models, Animal*
  • Humans
  • Hyperlipidemias* / drug therapy
  • Hyperlipidemias* / genetics
  • Hyperlipidemias* / metabolism
  • Lipoproteins, VLDL / blood
  • Lipoproteins, VLDL / metabolism
  • Liver* / drug effects
  • Liver* / metabolism
  • Liver* / pathology
  • Macaca fascicularis
  • Male
  • Mice
  • Mice, Transgenic
  • Oligonucleotides, Antisense* / pharmacology
  • Plaque, Atherosclerotic
  • Triglycerides / blood

Substances

  • Angiopoietin-Like Protein 4
  • Oligonucleotides, Antisense
  • Angiopoietin-Like Protein 3
  • Apolipoprotein E3
  • Angptl4 protein, mouse
  • Cholesterol Ester Transfer Proteins
  • Angptl3 protein, mouse
  • apolipoprotein E3 (Leidein)
  • Lipoproteins, VLDL
  • Angiopoietin-like Proteins
  • ANGPTL3 protein, human
  • Angiopoietins
  • CETP protein, human
  • ANGPTL4 protein, human
  • Triglycerides