Anti-sense oligonucleotide therapies for the treatment of hyperlipidaemia

Expert Opinion on Biological Therapy

Volumn 16, Issue 9, 2016, Pages 1125-1134

  Wierzbicki, Anthony S ^a   Viljoen, Adie ^b  

^a GUY'S AND ST THOMAS' NHS FOUNDATION TRUST   (United Kingdom)

^b LISTER HOSPITAL   (United Kingdom)

Author keywords

angiopoietin like protein 3 (ANGPTL3); antisense oligonucleotide; familial chylomcronaemia syndrome; Familial hypercholesterolaemia; lipodystrophy; lipoprotein lipase deficiency; lipoprotein(a); treatment

Indexed keywords

ANGIOPOETIN LIKE PROTEIN 3; ANTISENSE OLIGONUCLEOTIDE; APOLIPOPROTEIN C3; DIACYLGLYCEROL ACYLTRANSFERASE; LIPOPROTEIN A; MIPOMERSEN; PROPROTEIN CONVERTASE SUBTILISIN KEXIN 9; PROTEIN; REGULATOR PROTEIN; SMALL INTERFERING RNA; TRIACYLGLYCEROL; UNCLASSIFIED DRUG; VOLANESORSEN; APOB PROTEIN, HUMAN; APOLIPOPROTEIN B100; HYPOCHOLESTEROLEMIC AGENT; OLIGONUCLEOTIDE;

ANTISENSE THERAPY; CLINICAL TRIAL (TOPIC); DISEASE SEVERITY; DRUG TARGETING; FAMILIAL HYPERCHOLESTEROLEMIA; HUMAN; HYPERLIPIDEMIA; HYPERLIPOPROTEINEMIA TYPE 1; META ANALYSIS (TOPIC); METABOLIC CLEARANCE; NONHUMAN; REVIEW; TRIACYLGLYCEROL BLOOD LEVEL; ANIMAL; HYPERLIPIDEMIAS; HYPERLIPOPROTEINEMIA TYPE I; HYPERLIPOPROTEINEMIA TYPE II; HYPERTRIGLYCERIDEMIA; IMMUNOLOGY; METABOLISM; TREATMENT OUTCOME;

ANIMALS; ANTICHOLESTEREMIC AGENTS; APOLIPOPROTEIN B-100; HUMANS; HYPERLIPIDEMIAS; HYPERLIPOPROTEINEMIA TYPE I; HYPERLIPOPROTEINEMIA TYPE II; HYPERTRIGLYCERIDEMIA; OLIGONUCLEOTIDES; OLIGONUCLEOTIDES, ANTISENSE; TREATMENT OUTCOME;

EID: 84981727611     PISSN: 14712598     EISSN: 17447682     Source Type: Journal    
DOI: 10.1080/14712598.2016.1196182     Document Type: Review

References (73)

1. D.P.Potaczek, H.Garn, S.D.Unger, et al. Antisense molecules:a new class of drugs. J Allergy Clin Immunol. 2016;137:1334–1346. doi:10.1016/j.jaci.2015.12.1344.
2. M.E.Brousseau, E.J.Schaefer, M.L.Wolfe, et al. Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. N Engl J Med. 2004;350:1505–1515. doi:10.1056/NEJMoa031766.
3. E.Blasi, M.Bamberger, D.Knight, et al. Effects of CP-532,623 and torcetrapib, cholesteryl ester transfer protein inhibitors, on arterial blood pressure. J Cardiovasc Pharmacol. 2009;53:507–516.
4. X.Hu, J.D.Dietz, C.Xia, et al. Torcetrapib induces aldosterone and cortisol production by an intracellular calcium-mediated mechanism independently of cholesteryl ester transfer protein inhibition. Endocrinology. 2009;150:2211–2219. doi:10.1210/en.2008-1512.
5. P.J.Barter, M.Caulfield, M.Eriksson, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357:2109–2122. doi:10.1056/NEJMoa0706628.
6. A.S.Wierzbicki, T.C.Hardman, A.Viljoen Inhibition of pro-protein convertase subtilisin kexin-9 (PCSK9) as a treatment for hyperlipidaemia. Expert Opin Investig Drugs. 2012;21:667–676.
7. V.K.Sharma, P.Rungta, A.K.Prasad. Nucleic acid therapeutics:basic concepts and recent developments. RSC Adv. 2014;4:16618. doi:10.1039/c3ra47841f.
8. V.K.Sharma, J.K.Watts. Oligonucleotide therapeutics:chemistry, delivery and clinical progress. Future Med Chem. 2015;7:2221–2242.•• Review of chemical biology of nucleic acid modification to make novel therapeutics.
9. P.C.Zamecnik, M.L.Stephenson. Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide. Proc Natl Acad Sci USA. 1978;75:280–284.
10. M.L.Stephenson, P.C.Zamecnik. Inhibition of Rous sarcoma viral RNA translation by a specific oligodeoxyribonucleotide. Proc Natl Acad Sci USA. 1978;75:285–288.
11. R.M.Crooke, M.J.Graham. Modulation of lipoprotein metabolism by antisense technology:preclinical drug discovery methodology. Methods Mol Biol. 2013;1027:309–324. doi:10.1007/978-1-60327-369-5_14.
12. K.Pelka, T.Shibata, K.Miyake, et al. Nucleic acid-sensing TLRs and autoimmunity:novel insights from structural and cell biology. Immunol Rev. 2016;269:60–75. doi:10.1111/imr.12375.
13. J.A.Engelhardt. Comparative renal toxicopathology of antisense oligonucleotides. Nucleic Acid Ther. 2016. doi:10.1089/nat.2015.0598.
14. V.M.Ruda, R.Chandwani, A.Sehgal, et al. The roles of individual mammalian argonautes in RNA interference in vivo. PLoS One. 2014;9:e101749. doi:10.1371/journal.pone.0101749.
15. C.Baigent, L.Blackwell, J.Emberson, et al. Efficacy and safety of more intensive lowering of LDL cholesterol:a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670–1681. doi:10.1016/S0140-6736(10)61350-5.
16. M.Jun, C.Foote, J.Lv, et al. Effects of fibrates on cardiovascular outcomes:a systematic review and meta-analysis. Lancet. 2010;375:1875–1884. doi:10.1016/S0140-6736(10)60656-3.
17. C.P.Cannon, M.A.Blazing, R.P.Giugliano, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387–2397.
18. M.J.Chapman, H.N.Ginsberg, P.Amarenco, et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease:evidence and guidance for management. Eur Heart J. 2011;32:1345–1361. doi:10.1093/eurheartj/ehr112.
19. S.D.Wiviott, C.P.Cannon, D.A.Morrow, et al. Can low-density lipoprotein be too low? The safety and efficacy of achieving very low low-density lipoprotein with intensive statin therapy:a PROVE IT-TIMI 22 substudy. J Am Coll Cardiol. 2005;46:1411–1416. doi:10.1016/j.jacc.2005.04.064.
20. J.C.Fruchart, F.Sacks, M.P.Hermans, et al. The residual risk reduction initiative:a call to action to reduce residual vascular risk in patients with dyslipidemia. Am J Cardiol. 2008;102:1K–34K. doi:10.1016/j.amjcard.2008.10.002.
21. P.R.Kamstrup, A.Tybjaerg-Hansen, B.G.Nordestgaard. Extreme lipoprotein(a) levels and improved cardiovascular risk prediction. J Am Coll Cardiol. 2013;61:1146–1156. doi:10.1016/j.jacc.2012.12.023.
22. C.Gagne, D.Gaudet, E.Bruckert. Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation. 2002;105:2469–2475.
23. G.R.Thompson. The evidence-base for the efficacy of lipoprotein apheresis in combating cardiovascular disease. Atheroscler Suppl. 2013;14:67–70. doi:10.1016/j.atherosclerosissup.2012.10.001.
24. R.S.Geary, B.F.Baker, S.T.Crooke. Clinical and preclinical pharmacokinetics and pharmacodynamics of mipomersen (kynamro((R))):a second-generation antisense oligonucleotide inhibitor of apolipoprotein B. Clin Pharmacokinet. 2015;54:133–146. doi:10.1007/s40262-014-0224-4.
25. R.Z.Yu, R.Gunawan, Z.Li, et al. No effect on QT intervals of mipomersen, a 2ʹ-O-methoxyethyl modified antisense oligonucleotide targeting ApoB-100 mRNA, in a phase I dose escalation placebo-controlled study, and confirmed by a thorough QT (tQT) study, in healthy subjects. Eur J Clin Pharmacol. 2016;72:267–275. doi:10.1007/s00228-015-1992-y.
26. G.Reyes-Soffer, B.Moon, A.Hernandez-Ono, et al. Complex effects of inhibiting hepatic apolipoprotein B100 synthesis in humans. Sci Transl Med. 2016;8:323ra12.• Lipoprotein turnover study on mechanism of action of mipomersen on lipid fractions.
27. F.J.Raal, R.D.Santos, D.J.Blom, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia:a randomised, double-blind, placebo-controlled trial. Lancet. 2010;375:998–1006. doi:10.1016/S0140-6736(10)60284-X.
28. F.Akdim, D.L.Tribble, J.D.Flaim, et al. Efficacy of apolipoprotein B synthesis inhibition in subjects with mild-to-moderate hyperlipidaemia. Eur Heart J. 2011;32:2650–2659. doi:10.1093/eurheartj/ehr148.
29. R.D.Santos, P.B.Duell, C.East, et al. Long-term efficacy and safety of mipomersen in patients with familial hypercholesterolaemia:2-year interim results of an open-label extension. Eur Heart J. 2015;36:566–575.• Long-term efficacy of mipomersen in the treatment of familial hypercholesterolemia.
30. R.D.Santos, F.J.Raal, J.M.Donovan, et al. Mipomersen preferentially reduces small low-density lipoprotein particle number in patients with hypercholesterolemia. J Clin Lipidol. 2015;9:201–209. doi:10.1016/j.jacl.2014.12.008.
31. R.Panta, K.Dahal, S.Kunwar. Efficacy and safety of mipomersen in treatment of dyslipidemia:a meta-analysis of randomized controlled trials. J Clin Lipidol. 2015;9:217–225.• Meta-analysis of the efficacy and safety of mipomersen in clinical trials.
32. N.Hashemi, R.D.Odze, M.P.McGowan, et al. Liver histology during Mipomersen therapy for severe hypercholesterolemia. J Clin Lipidol. 2014;8:606–611. doi:10.1016/j.jacl.2014.08.002.
33. G.Lambert, B.Sjouke, B.Choque, et al. The PCSK9 decade. J Lipid Res. 2012;53:2515–2524. doi:10.1194/jlr.R026658.
34. E.P.van Poelgeest, M.R.Hodges, M.Moerland, et al. Antisense-mediated reduction of proprotein convertase subtilisin/kexin type 9 (PCSK9):a first-in-human randomized, placebo-controlled trial. Br J Clin Pharmacol. 2015;80:1350–1361.•• Efficacy of an antisense oligonucleotide to PCSK-9 in man.
35. K.Fitzgerald, M.Frank-Kamenetsky, S.Shulga-Morskaya, et al. Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers:a randomised, single-blind, placebo-controlled, phase 1 trial. Lancet. 2014;383:60–68. doi:10.1016/S0140-6736(13)61914-5.
36. M.A.Maier, M.Jayaraman, S.Matsuda, et al. Biodegradable lipids enabling rapidly eliminated lipid nanoparticles for systemic delivery of RNAi therapeutics. Mol Ther. 2013;21:1570–1578. doi:10.1038/mt.2013.124.
37. S.Tsimikas. Lipoprotein(a):novel target and emergence of novel therapies to lower cardiovascular disease risk. Curr Opin Endocrinol Diabetes Obes. 2016;23:157–164. doi:10.1097/MED.0000000000000237.
38. B.G.Nordestgaard, M.J.Chapman, K.Ray, et al. Lipoprotein(a) as a cardiovascular risk factor:current status. Eur Heart J. 2010;31:2844–2853.
39. P.R.Kamstrup, A.Tybjaerg-Hansen, R.Steffensen, et al. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA. 2009;301:2331–2339. doi:10.1001/jama.2009.801.
40. P.R.Kamstrup, A.Tybjaerg-Hansen, B.G.Nordestgaard. Elevated lipoprotein(a) and risk of aortic valve stenosis in the general population. J Am Coll Cardiol. 2014;63:470–477. doi:10.1016/j.jacc.2013.09.038.
41. P.R.Kamstrup. Nordestgaard BG. Elevated lipoprotein(a) levels, LPA risk genotypes, and increased risk of heart failure in the general population. JACC Heart Fail. 2016;4:78–87. doi:10.1016/j.jchf.2015.08.006.
42. P.Willeit, S.Kiechl, F.Kronenberg, et al. Discrimination and net reclassification of cardiovascular risk with lipoprotein(a):prospective 15-year outcomes in the Bruneck Study. J Am Coll Cardiol. 2014;64:851–860. doi:10.1016/j.jacc.2014.03.061.
43. K.G.Parhofer. Lipoprotein(a):medical treatment options for an elusive molecule. Curr Pharm Des. 2011;17:871–876.
44. M.J.Graham, N.Viney, R.M.Crooke, et al. Antisense inhibition of apolipoprotein (a) to lower plasma lipoprotein (a) levels in humans. J Lipid Res. 2016;57:340–351. doi:10.1194/jlr.R052258.
45. R.D.Santos, F.J.Raal, A.L.Catapano, et al. Mipomersen, an antisense oligonucleotide to apolipoprotein B-100, reduces lipoprotein(a) in various populations with hypercholesterolemia:results of 4 phase III trials. Arterioscler Thromb Vasc Biol. 2015;35:689–699.• Efficacy of mipomersen in reducing lipoprotein (a).
46. S.Tsimikas, N.J.Viney, S.G.Hughes, et al. Antisense therapy targeting apolipoprotein(a):a randomised, double-blind, placebo-controlled phase 1 study. Lancet. 2015;386:1472–1483.•• Efficacy of an antisense oligonucleotide to apolipoprotein (a) on lipoprotein (a) levels in man.
47. A.B.Jorgensen, R.Frikke-Schmidt, B.G.Nordestgaard, et al. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med. 2014;371:32–41. doi:10.1056/NEJMoa1308027.
48. A.Viljoen, A.S.Wierzbicki. Diagnosis and treatment of severe hypertriglyceridemia. Expert Rev Cardiovasc Ther. 2012;10:505–514.
49. J.D.Furtado, M.K.Wedel, F.M.Sacks. Antisense inhibition of apoB synthesis with mipomersen reduces plasma apoC-III and apoC-III-containing lipoproteins. J Lipid Res. 2012;53:784–791. doi:10.1194/jlr.P021717.
50. M.J.Graham, R.G.Lee, T.A.Bell, et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ Res. 2013;112:1479–1490. doi:10.1161/CIRCRESAHA.111.300367.
51. D.Gaudet, V.J.Alexander, B.F.Baker, et al. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N Engl J Med. 2015;373:438–447.•• Efficacy of an antisense oligonucleotide to apolipoprotein C3 on triglyceride levels in patients with severe hypertriglyceridemia.
52. X.Yang, S.R.Lee, Y.S.Choi, et al. Reduction in lipoprotein-associated apoC-III levels following volanesorsen therapy:phase 2 randomized trial results. J Lipid Res. 2016;57:706–713. doi:10.1194/jlr.M066399.
53. D.Gaudet, D.Brisson, K.Tremblay, et al. Targeting APOC3 in the familial chylomicronemia syndrome. N Engl J Med. 2014;371:2200–2206.• Efficacy of an antisense oligonucleotide to apolipoprotein C3 on triglyceride levels in patients with lipoprotein lipase deficiency.
54. A.M.Birch, L.K.Buckett, A.V.Turnbull. DGAT1 inhibitors as anti-obesity and anti-diabetic agents. Curr Opin Drug Discov Devel. 2010;13:489–496.
55. V.S.Kamanna, M.L.Kashyap. Nicotinic acid (niacin) receptor agonists:will they be useful therapeutic agents? Am J Cardiol. 2007;100:S53–S61. doi:10.1016/j.amjcard.2007.09.080.
56. X.X.Yu, S.F.Murray, S.K.Pandey, et al. Antisense oligonucleotide reduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia in obese mice. Hepatology. 2005;42:362–371. doi:10.1002/hep.20783.
57. C.S.Choi, D.B.Savage, A.Kulkarni, et al. Suppression of diacylglycerol acyltransferase-2 (DGAT2), but not DGAT1, with antisense oligonucleotides reverses diet-induced hepatic steatosis and insulin resistance. J Biol Chem. 2007;282:22678–22688. doi:10.1074/jbc.M704213200.
58. K.Yamaguchi, L.Yang, S.McCall, et al. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology. 2007;45:1366–1374. doi:10.1002/hep.21655.
59. G.Santulli. Angiopoietin-like proteins:a comprehensive look. Front Endocrinol (Lausanne). 2014;5:4.
60. I.Minicocci, A.Tikka, E.Poggiogalle, et al. Effects of angiopoietin-like protein 3 deficiency on postprandial lipid and lipoprotein metabolism. J Lipid Res. 2016;57:1097–1107. doi:10.1194/jlr.P066183.
61. T.A.Brandt, R.G.Lee, A.Digenio, et al. ISIS-ANGPTL3RX, an antisense inhibitor to angiopoietin-like 3, reduces plasma lipid levels in mouse models and in healthy human volunteers. AtherosclerSuppl. 2015;241:e30–e31. doi:10.1016/j.atherosclerosis.2015.04.115.
62. Y.Wang, V.Gusarova, S.Banfi, et al. Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion. J Lipid Res. 2015;56:1296–1307. doi:10.1194/jlr.M054882.
63. D.Gaudet, D.A.Gipe, R.Pordy, et al. Safety and efficacy of evinacumab, a monoclonal antibody to ANGPTL3, in patients with homozygous familial hypercholesterolemia receiving concomitant lipid-lowering therapies. J Clin Lipidol. 2016;10:715. doi:10.1016/j.jacl.2016.03.091.
64. G.D.Norata, F.Sala, A.L.Catapano, et al. MicroRNAs and lipoproteins:a connection beyond atherosclerosis? Atherosclerosis. 2013;227:209–215. doi:10.1016/j.atherosclerosis.2012.11.019.
65. D.Karunakaran, K.J.Rayner. Macrophage miRNAs in atherosclerosis. Biochim Biophys Acta. 2016. doi:10.1016/j.bbalip.2016.02.006.
66. K.C.Vickers, B.M.Shoucri, M.G.Levin, et al. MicroRNA-27b is a regulatory hub in lipid metabolism and is altered in dyslipidemia. Hepatology. 2013;57:533–542. doi:10.1002/hep.25846.
67. K.J.Rayner, C.C.Esau, F.N.Hussain, et al. Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides. Nature. 2011;478:404–407. doi:10.1038/nature10486.
68. K.J.Rayner, F.J.Sheedy, C.C.Esau, et al. Antagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis. J Clin Invest. 2011;121:2921–2931. doi:10.1172/JCI57275.
69. M.Ouimet, H.N.Ediriweera, U.M.Gundra, et al. MicroRNA-33-dependent regulation of macrophage metabolism directs immune cell polarization in atherosclerosis. J Clin Invest. 2015;125:4334–4348. doi:10.1172/JCI81676.
70. A.S.Wierzbicki, T.Hardman, W.T.Prince. Future challenges for microsomal transport protein inhibitors. Curr Vasc Pharmacol. 2009;7:277–286.
71. A.S.Wierzbicki, A.Viljoen. Alipogene tiparvovec:gene therapy for lipoprotein lipase deficiency. Expert Opin Biol Ther. 2013;13:7–10.
72. S.J.Nicholls, W.H.Tang, H.Scoffone, et al. Lipoprotein(a) levels and long-term cardiovascular risk in the contemporary era of statin therapy. J Lipid Res. 2010;51:3055–3061. doi:10.1194/jlr.M008961.
73. J.Leebmann, E.Roeseler, U.Julius, et al. Lipoprotein apheresis in patients with maximally tolerated lipid-lowering therapy, lipoprotein(a)-hyperlipoproteinemia, and progressive cardiovascular disease:prospective observational multicenter study. Circulation. 2013;128:2567–2576. doi:10.1161/CIRCULATIONAHA.113.002432.