A New Modality in Dyslipidemia Treatment: Antisense Oligonucleotide Therapy
1
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
There are unmet needs for pharmacologic agents beyond current medications, such as statins, to effectively lower low-density lipoprotein cholesterol levels to target goals, especially in patients with very high or extremely high risk. Pharmacological targeting of mRNA represents an emerging, innovative approach with the potential to expand upon current therapies. In RNA-targeted therapeutics, a novel approach is the use of chemically modified oligonucleotides to inhibit the production of target proteins at their sites of gene coding. There are two main classes of RNA-targeted therapeutics: single-stranded antisense oligonucleotides (ASOs) and double-stranded small inhibiting RNAs. ASOs are synthetic molecules with a length of 15-30 nucleotides that are designed specifically to bind to a target mRNA in a sequence-specific manner. Using these agents to inhibit the translation of key regulatory proteins, such as apolipoprotein CIII, apolipoprotein(a), and angiopoietin-like protein 3, has demonstrated treatment efficacy for dyslipidemia. Many cardiovascular outcome trials with ASOs are ongoing. As clinicians, we must carefully monitor the long-term safety and efficacy of this new modality through large clinical trials in the future.
Abstract
There are unmet needs for pharmacologic agents beyond current medications, such as statins, to effectively lower low-density lipoprotein cholesterol levels to target goals, especially in patients with very high or extremely high risk. Pharmacological targeting of mRNA represents an emerging, innovative approach with the potential to expand upon current therapies. In RNA-targeted therapeutics, a novel approach is the use of chemically modified oligonucleotides to inhibit the production of target proteins at their sites of gene coding. There are two main classes of RNA-targeted therapeutics: single-stranded antisense oligonucleotides (ASOs) and double-stranded small inhibiting RNAs. ASOs are synthetic molecules with a length of 15-30 nucleotides that are designed specifically to bind to a target mRNA in a sequence-specific manner. Using these agents to inhibit the translation of key regulatory proteins, such as apolipoprotein CIII, apolipoprotein(a), and angiopoietin-like protein 3, has demonstrated treatment efficacy for dyslipidemia. Many cardiovascular outcome trials with ASOs are ongoing. As clinicians, we must carefully monitor the long-term safety and efficacy of this new modality through large clinical trials in the future.
참고문헌 (50)
- Ference BA, "Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel", Eur Heart J, 38, pp.2459~2472 (2017)
- 안창호, "New Drugs for Treating Dyslipidemia: Beyond Statins", Diabetes and Metabolism Journal, 39(2), pp.87~94 (2015), 대한당뇨병학회
- Baigent C, "Efficacy and safety of cholesterol-lowering treatment : prospective meta-analysis of data from 90, 056 participants in 14 randomised trials of statins", Lancet, 366, pp.1267~1278 (2005)
- Cholesterol Treatment Trialists’ Collaboration, "Efficacy and safety of statin therapy in older people : a meta-analysis of individual participant data from 28 randomised controlled trials", Lancet, 393, pp.407~415 (2019)
- Mach F, "2019 ESC", EAS Guidelines for the management of dyslipidaemias : lipid modification to reduce cardiovascular risk, 2020, pp.41, 111~188
- Grundy SM, "2018 AHA", ACC, AAPA, pp.ABC, ACPM[DOI]
- Kim K, "Stroke revisited: dyslipidemia in stroke", pp.203~219 (2021), Springer Singapore
- Stancu C, "Statins : mechanism of action and effects", J Cell Mol Med, 5, pp.378~387 (2001)
- Staels B, "Mechanism of action of fibrates on lipid and lipoprotein metabolism", Circulation, 98, pp.2088~2093 (1998)
- Tsimikas S, "RNA-targeted therapeutics for lipid disorders", Curr Opin Lipidol, 29, pp.459~466 (2018)
- Crooke ST, "RNA-targeted therapeutics", Cell Metab, 27, pp.714~739 (2018)
- Levin AA, "Treating disease at the RNA level with oligonucleotides", N Engl J Med, 380, pp.57~70 (2019)
- Crooke ST, "Phosphorothioate modified oligonucleotide-protein interactions", Nucleic Acids Res, 48, pp.5235~5253 (2020)
- Shen X, "Chemistry, mechanism and clinical status of antisense oligonucleotides and duplex RNAs", Nucleic Acids Res, 46, pp.1584~1600 (2018)
- Nordestgaard BG, "Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women", JAMA, 298, pp.299~308 (2007)
- Varbo A, "Remnant cholesterol as a causal risk factor for ischemic heart disease", J Am Coll Cardiol, 61, pp.427~436 (2013)
- Ginsberg HN, "Triglyceride-rich lipoproteins and their remnants : metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European Atherosclerosis Society", Eur Heart J, 42, pp.4791~4806 (2021)
- Borén J, "The roles of apoC-III on the metabolism of triglyceride-rich lipoproteins in humans", Front Endocrinol(Lausanne), 11, pp.474~ (2020)
- Sacks FM, "VLDL, apolipoproteins B, CIII, and E, and risk of recurrent coronary events in the Cholesterol and Recurrent Events(CARE)trial", Circulation, 102, pp.1886~1892 (2000)
- van Capelleveen JC, "Apolipoprotein C-III levels and incident coronary artery disease risk : the EPIC-Norfolk prospective population study", Arterioscler Thromb Vasc Biol, 37, pp.1206~1212 (2017)
- Jørgensen AB, "Loss-of-function mutations in APOC3 and risk of ischemic vascular disease", N Engl J Med, 371, pp.32~41 (2014)
- TG, "Loss-of-function mutations in APOC3, triglycerides, and coronary disease", N Engl J Med, 371, pp.22~31 (2014)
- Marston NA, "Association between triglyceride lowering and reduction of cardiovascular risk across multiple lipid-lowering therapeutic classes : a systematic review and meta-regression analysis of randomized controlled trials", Circulation, 140, pp.1308~1317 (2019)
- Graham MJ, "Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans", Circ Res, 112, pp.1479~1490 (2013)
- Witztum JL, "Volanesorsen and triglyceride levels in familial chylomicronemia syndrome", N Engl J Med, 381, pp.531~542 (2019)
- Alexander VJ, "N-acetyl galactosamine-conjugated antisense drug to APOC3 mRNA, triglycerides and atherogenic lipoprotein levels", Eur Heart J, 40, pp.2785~2796 (2019)
- Gaudet D, "Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia", N Engl J Med, 373, pp.438~447 (2015)
- Gaudet D, "Targeting APOC3 in the familial chylomicronemia syndrome", N Engl J Med, 371, pp.2200~2206 (2014)
- Gouni-Berthold I, "Efficacy and safety of volanesorsen in patients with multifactorial chylomicronaemia(COMPASS) : a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial", Lancet Diabetes Endocrinol, 9, pp.264~275 (2021)
- Paik J, "Volanesorsen : first global approval", Drugs, 79, pp.1349~1354 (2019)
- Tardif JC, "Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk", Eur Heart J, 43, pp.1401~1412 (2022)
- Boffa MB, "Oxidized phospholipids as a unifying theory for lipoprotein(a)and cardiovascular disease", Nat Rev Cardiol, 16, pp.305~318 (2019)
- Emerging Risk Factors Collaboration, "Lipoprotein(a)concentration and the risk of coronary heart disease, stroke, and nonvascular mortality", JAMA, 302, pp.412~423 (2009)
- Kamstrup PR, "Elevated lipoprotein(a)and risk of aortic valve stenosis in the general population", J Am Coll Cardiol, 63, pp.470~477 (2014)
- Clarke R, "Genetic variants associated with Lp(a)lipoprotein level and coronary disease", N Engl J Med, 361, pp.2518~2528 (2009)
- Kamstrup PR, "Genetically elevated lipoprotein(a)and increased risk of myocardial infarction", JAMA, 301, pp.2331~2339 (2009)
- Burgess S, "Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies : a mendelian randomization analysis", JAMA Cardiol, 3, pp.619~627 (2018)
- Tsimikas S, "A test in context : lipoprotein(a) : diagnosis, prognosis, controversies, and emerging therapies", J Am Coll Cardiol, 69, pp.692~711 (2017)
- Tsimikas S, "Antisense therapy targeting apolipoprotein(a) : a randomised, double-blind, placebo-controlled phase 1 study", Lancet, 386, pp.1472~1483 (2015)
- Viney NJ, "Antisense oligonucleotides targeting apolipoprotein(a)in people with raised lipoprotein(a) : two randomised, double-blind, placebo-controlled, dose-ranging trials", Lancet, 388, pp.2239~2253 (2016)
- Tsimikas S, "Lipoprotein(a)reduction in persons with cardiovascular disease", N Engl J Med, 382, pp.244~255 (2020)
- Shimizugawa T, "ANGPTL3 decreases very low density lipoprotein triglyceride clearance by inhibition of lipoprotein lipase", J Biol Chem, 277, pp.33742~33748 (2002)
- Shimamura M, "Angiopoietin-like protein3 regulates plasma HDL cholesterol through suppression of endothelial lipase", Arterioscler Thromb Vasc Biol, 27, pp.366~372 (2007)
- Adam RC, "Angiopoietin-like protein 3 governs LDL-cholesterol levels through endothelial lipase-dependent VLDL clearance", J Lipid Res, 61, pp.1271~1286 (2020)
- Romeo S, "Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans", J Clin Invest, 119, pp.70~79 (2009)
- Musunuru K, "Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia", N Engl J Med, 363, pp.2220~2227 (2010)
- Dewey FE, "Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease", N Engl J Med, 377, pp.211~221 (2017)
- Stitziel NO, "ANGPTL3 deficiency and protection against coronary artery disease", J Am Coll Cardiol, 69, pp.2054~2063 (2017)
- Graham MJ, "Cardiovascular and metabolic effects of ANGPTL3 antisense oligonucleotides", N Engl J Med, 377, pp.222~232 (2017)
- Gaudet D, "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, pp.3936~3945 (2020)