Lipid metabolism and the targeting of angiopoietin-like 3: Experimental drugs under development

References

• Burks KH, Basu D, Goldberg IJ, et al. Angiopoietin-like 3: an important protein in regulating lipoprotein levels. Best Pract Res Clin Endocrinol Metab. 2022 Aug;12:101688. Epub ahead of print
   Google Scholar
• Shimizugawa T, Ono M, Shimamura M, et al. ANGPTL3 decreases very low density lipoprotein triglyceride clearance by inhibition of lipoprotein lipase. J Biol Chem. 2002;277:33742–33748.
   PubMed Web of Science ®Google Scholar
• Shimamura M, Matsuda M, Yasumo H, et al. Angiopoietin-like protein3 regulates plasma HDL cholesterol through suppression of endothelial lipase. Arterioscler Thromb Vasc Biol. 2007;27:366–372.
   PubMed Web of Science ®Google Scholar
• Dewey FE, Gusarova V, Dunbar RL, et al. Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease. N Engl J Med. 2017;377:211–221. •• An important mendelian randomization study showing that subjects with heterozygous loss-of-function variants in ANGPTL3 have lower levels of triglycerides, HDL-C and LDL-C than participants without these variants and also have lower risk for coronary heart disease.
   PubMed Web of Science ®Google Scholar
• Stitziel NO, Khera AV, Wang X, et al. PROMIS and myocardial infarction genetics consortium investigators. ANGPTL3 deficiency and protection against coronary artery disease. J Am Coll Cardiol. 2017;69:2054–2063. • Another mendelian randomization study also showing that subjects with heterozygous loss-of-function variants in ANGPTL3 have lower levels of triglycerides, HDL-C and LDL-C than participants without these variants and also have lower risk for coronary heart disease.
   PubMed Web of Science ®Google Scholar
• Watts GF, Raal FJ, Chan DC. Transcriptomic therapy for dyslipidemias utilizing nucleic acids targeted at ANGPTL3. Future Cardiol. 2022;18:143–153.
   PubMed Web of Science ®Google Scholar
• Mohamed F, Mansfield BS, Raal FJ. ANGPTL3 as a drug target in hyperlipidemia and atherosclerosis. Curr Atheroscler Rep. 2022 Nov;(11):1–9. Epub ahead of print
   Google Scholar
• Reeskamp LF, Tromp TR, Huijgen R, et al. Statin therapy reduces plasma angiopoietin-like 3 (ANGPTL3) concentrations in hypercholesterolemic patients via reduced liver X receptor (LXR) activation. Atherosclerosis. 2020;315:68–75.
   PubMed Web of Science ®Google Scholar
• Rosenson RS, Burgess LJ, Ebenbichler CF, et al. Evinacumab in Patients with Refractory Hypercholesterolemia. N Engl J Med. 2020;383:2307–2319.
   PubMed Web of Science ®Google Scholar
• Raal FJ, Rosenson RS, Reeskamp LF, et al., ELIPSE HoFH Investigators. Evinacumab for Homozygous Familial Hypercholesterolemia. N Engl J Med. 2020;383(8): 711–720.
   PubMed Web of Science ®Google Scholar
• https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-add-therapy-patients-genetic-form-severely-high-cholesterol-0 Accessed 10 oct 2022
   Google Scholar
• https://www.ema.europa.eu/en/medicines/human/EPAR/evkeeza#product-information-section Accessed 10 oct 2022
   Google Scholar
• Ahmad Z, Banerjee P, Hamon S, et al. Inhibition of Angiopoietin-Like Protein 3 With a Monoclonal Antibody Reduces Triglycerides in Hypertriglyceridemia. Circulation. 2019;140(6):470–486.
   PubMed Web of Science ®Google Scholar
• https://clinicaltrials.gov/ct2/show/NCT04233918 Accessed 10 oct 2022
   Google Scholar
• Graham MJ, Lee RG, Brandt TA, et al. Cardiovascular and Metabolic Effects of ANGPTL3 Antisense Oligonucleotides. N Engl J Med. 2017;377(3):222–232.
   PubMed Web of Science ®Google Scholar
• Shemesh CS, Yu RZ, Gaus HJ, et al. Elucidation of the Biotransformation Pathways of a Galnac3-conjugated Antisense Oligonucleotide in Rats and Monkeys. Mol Ther Nucleic Acids. 2016;5:e319.
   PubMedGoogle Scholar
• Bergmark BA, Marston NA, Bramson CR, et al., Effect of Vupanorsen on Non–High-Density Lipoprotein Cholesterol Levels in Statin-Treated Patients With Elevated Cholesterol: TRANSLATE-TIMI 70. Circulation. 2022;145(18): 1377–1386.
   PubMed Web of Science ®Google Scholar
• Gaudet D, Karwatowska-Prokopczuk E, Baum SJ, et al. Vupanorsen Study Investigators. 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. 2020;41:3936–3945.
   PubMed Web of Science ®Google Scholar
• Watts GF, Schwabe C, Scott C, 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. 2020;41(Suppl.2):3331.
   Google Scholar
• 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. Pharmacodynamic Effect of ARO-ANG3, an Investigational RNA Interference Targeting Hepatic Angiopoietin-like Protein 3, in Patients With Hypercholesterolemia. Circulation. 2020;142(Suppl.3):A15751.
   Google Scholar
• https://clinicaltrials.gov/ct2/show/NCT04832971 Accessed 10 dec 2022
   Google Scholar
• https://clinicaltrials.gov/ct2/show/NCT05217667 Accessed 10 dec 2022
   Google Scholar
• Fowler A, Sampson M, Remaley AT, et al. A VLP-based vaccine targeting ANGPTL3 lowers plasma triglycerides in mice. Vaccine. 2021;39:5780–5786.
   PubMed Web of Science ®Google Scholar
• Fukami H, Morinaga J, Nakagami H, et al. Vaccine targeting ANGPTL3 ameliorates dyslipidemia and associated diseases in mouse models of obese dyslipidemia and familial hypercholesterolemia. Cell Rep Med. 2021;2:100446.
   PubMedGoogle Scholar
• Chadwick AC, Evitt NH, Lv W, et al. Reduced Blood Lipid Levels With In Vivo CRISPR-Cas9 Base Editing of ANGPTL3. Circulation. 2018;137:975–977.
   PubMed Web of Science ®Google Scholar
• Qiu M, Glass Z, Chen J, et al. Lipid nanoparticle-mediated codelivery of Cas9 mRNA and single-guide RNA achieves liver-specific in vivo genome editing of Angptl3. Proc of the Nat Aca of Sci. 2021;118:e2020401118.
   PubMed Web of Science ®Google Scholar