Review

*Author for correspondence: Tel.: +61 08 92240248;

https://orcid.org/0000-0003-2276-1524

School of Medicine, University of Western Australia, Perth, Australia

Department of Cardiology & Internal Medicine, Lipid Disorders Clinic, Royal Perth Hospital, Perth, Australia

Search for more papers by this author

Frederick J Raal

https://orcid.org/0000-0002-9170-7938

Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, Gauteng, South Africa

Search for more papers by this author

Dick C Chan

https://orcid.org/0000-0001-7658-5197

School of Medicine, University of Western Australia, Perth, Australia

Search for more papers by this author

Published Online:15 Oct 2021https://doi.org/10.2217/fca-2021-0096

View article

Abstract

Angiopoietin-like protein 3 (ANGPTL3) is a key physiological regulator of plasma lipid and lipoprotein metabolism that involves the control of enzymes, lipoprotein and endothelial lipases. Inhibition of ANGPTL3 offers a new approach for correcting the health risks of dyslipidemia, including familial hypercholesterolemia, mixed hyperlipidemia, metabolic syndrome and/or severe hypertriglyceridemia. ANGPTL3 inhibition with nucleic acid-based antisense oligonucleotide and siRNA can correct dyslipidemia chiefly by reducing production and increasing catabolism of triglyceride-rich lipoprotein and LDL particles. Early clinical trials have demonstrated that these agents can safely and effectively lower plasma triglyceride and LDL-cholesterol levels by up to 70 and 50%, respectively. However, the long-term safety and cost–effectiveness of these agents await to be confirmed in an ongoing and future clinical trials.

Lay abstract

Angiopoietin-like protein 3 (ANGPTL3) is a protein that is produced by the liver. ANGPTL3 plays an important role in controlling the blood levels of fats, such as cholesterol. Inhibition of ANGPTL3 is a new approach to improve the health in people with abnormal blood fat levels. Treatments that inhibits ANGPTL3, such as nucleic acids that reduce products of genes called RNA, can safely and significantly lower blood fat levels. The safety and value of this new treatment in preventing heart disease in people needs further research.

Keywords:

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

1. Mach F, Baigent C, Catapano AL et al. 2019 ESC/EAS Eur. Heart J. 41(1), 111–188 (2020).
MedlineGoogle Scholar
2. Borén J, Chapman MJ, Krauss RM et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur. Heart J. 41(24), 2313–2330 (2020).
Medline CASGoogle Scholar
3. Davidson MH. Reducing residual cardiovascular risk with novel therapies. Curr. Opin. Lipidol. 31(2), 108–110 (2020).
Medline CASGoogle Scholar
4. Laufs U, Parhofer KG, Ginsberg HN, Hegele RA. Clinical review on triglycerides. Eur. Heart J. 41(1), 99–109 (2020). •• An excellent review of the biology of hypertriglyceridemia and the novel and emerging treatment for triglycerides.
Medline CASGoogle Scholar
5. Reeskamp LF, Tromp TR, Stroes ESG. The next generation of triglyceride-lowering drugs: will reducing apolipoprotein C-III or angiopoietin like protein 3 reduce cardiovascular disease? Curr. Opin. Lipidol. 31(3), 140–146 (2020).
Medline CASGoogle Scholar
6. Musunuru K. Treating coronary artery disease: beyond statins, ezetimibe, and PCSK9 inhibition. Annu. Rev. Med. 72, 447–458 (2021).
Medline CASGoogle Scholar
7. Kersten S. Angiopoietin-like 3 in lipoprotein metabolism. Nat. Rev. Endocrinol. 13(12), 731–739 (2017).
Medline CASGoogle Scholar
8. Wu SA, Kersten S, Qi L. Lipoprotein lipase and its regulators: an unfolding story. Trends Endocrinol. Metab. 32(1), 48–61 (2021). • Most recent review on the role of lipoprotein lipase in the regulation of lipid and lipoprotein metabolism.
Medline CASGoogle Scholar
9. Dewey FE, Gusarova V, Dunbar RL et al. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. N. Engl. J. Med. 377(3), 211–221 (2017).
Medline CASGoogle Scholar
10. Lupo MG, Ferri N. Angiopoietin-like 3 (ANGPTL3) and atherosclerosis: lipid and non-lipid related effects. J. Cardiovasc. Dev. Dis. 5(3), 39 (2018). •• Focuses on metabolic actions and potential mechanisms by which ANGPLT3 and its specific inhibitors contribute to the pathogenesis of cardiovascular diseases.
CASGoogle Scholar
11. Arca M, D'Erasmo L, Minicocci I. Familial combined hypolipidemia: angiopoietin-like protein-3 deficiency. Curr. Opin. Lipidol. 31(2), 41–48 (2020).
Medline CASGoogle Scholar
12. Gusarova V, Alexa CA, Wang Y et al. ANGPTL3 blockade with a human monoclonal antibody reduces plasma lipids in dyslipidemic mice and monkeys. J. Lipid Res. 56(7), 1308–1317 (2015).
Medline CASGoogle Scholar
13. Robciuc MR, Maranghi M, Lahikainen A et al. Angptl3 deficiency is associated with increased insulin sensitivity, lipoprotein lipase activity, and decreased serum free fatty acids. Arterioscler. Thromb. Vasc. Biol. 33(7), 1706–1713 (2013).
Medline CASGoogle Scholar
14. Christopoulou E, Elisaf M, Filippatos T. Effects of angiopoietin-like 3 on triglyceride regulation, glucose homeostasis, and diabetes. Dis. Markers 2019, 6578327 (2019).
MedlineGoogle Scholar
15. Graham MJ, Lee RG, Brandt TA et al. Cardiovascular and metabolic effects of ANGPTL3 antisense oligonucleotides. N. Engl. J. Med. 377(3), 222–232 (2017).
Medline CASGoogle Scholar
16. Stitziel NO, Khera AV, Wang X et al. ANGPTL3 deficiency and protection against coronary artery disease. J. Am. Coll. Cardiol. 69(16), 2054–2063 (2017).
Medline CASGoogle Scholar
17. Romeo S, Yin W, Kozlitina J et al. Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans. J. Clin. Invest. 119(1), 70–79 (2009).
Medline CASGoogle Scholar
18. Musunuru K, Pirruccello JP, Do R et al. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N. Engl. J. Med. 363(23), 2220–2227 (2010).
Medline CASGoogle Scholar
19. Tromp TR, Stroes ESG, Hovingh GK. Gene-based therapy in lipid management: the winding road from promise to practice. Expert. Opin. Investig. Drugs 29(5), 483–493 (2020).
Medline CASGoogle Scholar
20. Tsimikas S. RNA-targeted therapeutics for lipid disorders. Curr. Opin. Lipidol. 29(6), 459–466 (2018).
Medline CASGoogle Scholar
21. Macchi C, Sirtori CR, Corsini A, Santos RD, Watts GF, Ruscica M. A new dawn for managing dyslipidemias: the era of RNA-based therapies. Pharmacol. Res. 150, 104413 (2019). •• A comprehensive review on the development of RNA-based therapies for lipid disorders.
Medline CASGoogle Scholar
22. Katzmann JL, Packard CJ, Chapman MJ, Katzmann I, Laufs U. Targeting RNA with antisense oligonucleotides and small interfering RNA. J. Am. Coll. Cardiol. 76(5), 563–579 (2020).
Medline CASGoogle Scholar
23. Landmesser U, Poller W, Tsimikas S, Most P, Paneni F, Lüscher TF. From traditional pharmacological towards nucleic acid-based therapies for cardiovascular diseases. Eur. Heart J. 41(40), 3884–3899 (2020).
Medline CASGoogle Scholar
24. Levin AA. Treating disease at the RNA level with oligonucleotides. N. Engl. J. Med. 380(1), 57–70 (2019).
MedlineGoogle Scholar
25. Janas MM, Harbison CE, Perry VK et al. The nonclinical safety profile of GalNAc-conjugated RNAi therapeutics in subacute studies. Toxicol. Pathol. 46(7), 735–745 (2018).
Medline CASGoogle Scholar
26. Gaudet D, Gipe DA, Pordy R et al. ANGPTL3 inhibition in homozygous familial hypercholesterolemia. N. Engl. J. Med. 377(3), 296–297 (2017). •• Key study shows the benefit of ANGPTL3 inhibition in the management of homozygous familial hypercholesterolemia.
MedlineGoogle Scholar
27. Watts GF, Schwabe C, Scott R et al. RNA interference targeting hepatic angiopoietin-like protein 3 results in prolonged reductions in plasma triglycerides and LDL-C in human subjects. Circulation 140, e987–988 (2019).
Google Scholar
28. Watts GF, Schwabe C, Scott R et al. Pharmacodynamic effect of ARO-ANG3, an investigational RNA interference targeting hepatic angiopoietin-like protein 3, in patients with hypercholesterolemia. Circulation 142, A15751 (2020). •• This preliminary study demonstrates that ARO-ANG3 results in potent and durable reductions of plasma LDL-cholesterol (LDL-C) and triglyceride levels in patients with hypertriglyceridemia or hypercholesterolemia.
Google Scholar
29. Watts GF, Schwabe C, Scott R et al. RNAi inhibition of angiopoietin-like protein 3 (ANGPTL3) with ARO-ANG3 mimics the lipid and lipoprotein profile of familial combined hypolipidemia. Eur. Heart J. 41(Suppl. 2), 3331 (2020). •• This preliminary study shows that ARO-ANG3, an investigational ligand-conjugated siRNA therapy, is safe and efficacious in lowering plasma LDL-C and triglyceride concentrations in normal volunteers.
Google Scholar
30. Gaudet D, Karwatowska-Prokopczuk E, Baum SJ et al. Vupanorsen, an N-acetyl galactosamine-conjugated antisense drug to ANGPTL3 mRNA, lowers triglycerides and atherogenic lipoproteins in patients with diabetes, hepatic steatosis, and hypertriglyceridaemia. Eur. Heart J. 41(40), 3936–3945 (2020). •• Demonstrates that targeting of hepatic ANGPTL3 mRNA with vupanorsen results in decreased levels of triglycerides and apoB-containing atherogenic lipoproteins, in patients with Type 2 diabetes, hepatic steatosis and hypertriglyceridemia.
Medline CASGoogle Scholar
31. Minicocci I, Tikka A, Poggiogalle E et al. Effects of angiopoietin-like protein 3 deficiency on postprandial lipid and lipoprotein metabolism. J. Lipid Res. 57(6), 1097–1107 (2016).
Medline CASGoogle Scholar
32. Mohamed F, Botha TC, Raal FJ. Inhibition of angiopoietin-like 3 for the management of severe hypercholesterolemia. Curr. Opin. Lipidol. 32(4), 213–218 (2021).
Medline CASGoogle Scholar
33. Adam RC, Mintah IJ, Alexa-Braun CA et al. Angiopoietin-like protein 3 governs LDL-C levels through endothelial lipase-dependent VLDL clearance. J. Lipid Res. 61(9), 1271–1286 (2020). • This mechanistic study indicates that ANGPTL3 inhibition with evinacumab promotes very low LDL clearance and reduces LDL-C production via an endothelial lipase-dependent pathway in patients with null LDL receptor mutations.
Medline CASGoogle Scholar
34. Reeskamp LF, Millar JS, Wu L et al. ANGPTL3 inhibition with evinacumab results in faster clearance of IDL and LDL apoB in patients with homozygous familial hypercholesterolemia. Arterioscler. Thromb. Vasc. Biol. 41(5), 1753–1759 (2021).
Medline CASGoogle Scholar
35. Raal FJ, Rosenson RS, Reeskamp LF et al. Evinacumab for homozygous familial hypercholesterolemia. N. Engl. J. Med. 383(8), 711–720 (2020). • Demonstrates that evinacumab decreases atherogenic lipoprotein levels, including LDL-C, non-LDL-C, HDL-C and apoB in patients with homozygous familial hypercholesterolemia independent of LDL receptor activity.
Medline CASGoogle Scholar
36. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ. Res. 118(4), 547–563 (2016).
Medline CASGoogle Scholar
37. Goldberg RB, Chait A. A comprehensive update on the chylomicronemia syndrome. Front. Endocrinol. 11, 593931 (2020).
MedlineGoogle Scholar
38. Rosenson RS, Gaudet D, Ballantyne CM et al. A Phase II trial of the efficacy and safety of evinacumab in patients with severe hypertriglyceridemia. Atherosclerosis. 331, e293 (2021).
Google Scholar
39. Witztum JL, Gaudet D, Freedman SD et al. Volanesorsen and triglyceride levels in familial chylomicronemia syndrome. N. Engl. J. Med. 381(6), 531–542 (2019).
Medline CASGoogle Scholar
40. Gouni-Berthold I, Alexander VJ, Yang Q et al. Efficacy and safety of volanesorsen in patients with multifactorial chylomicronaemia (COMPASS): a multicentre, double-blind, randomised, placebo-controlled, Phase III trial. Lancet Diabetes Endocrinol. 9(5), 264–275 (2021).
Medline CASGoogle Scholar
41. Ruhanen H, Haridas PAN, Jauhiainen M, Olkkonen VM. Angiopoietin-like protein 3, an emerging cardiometabolic therapy target with systemic and cell-autonomous functions. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1865(12), 158791 (2020).
Medline CASGoogle Scholar

Vol. 18, No. 2

Metrics

Downloaded 199 times

History

Received 20 July 2021

Accepted 1 October 2021

Published online 15 October 2021

Published in print February 2022

Information

Keywords

Author contributions

GF Watts, FJ Raal and DC Chan contributed to the conception, design and writing of the article.

Financial & competing interests disclosure

GF Watts has received honoraria for lectures and advisory boards or research grants from Amgen Inc., Arrowhead, AstraZeneca, Esperion, Kowa, Novartis, Regeneron and Sanofi. FJ Raal has received research grants, honoraria or consulting fees for professional input and/or delivered lectures from Sanofi, Amgen, Regeneron, Novartis and The Medicines Company. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

PDF download

Transcriptomic therapy for dyslipidemias utilizing nucleic acids targeted at ANGPTL3

Abstract

Lay abstract

References