Cardiovascular and metabolic effects of ANGPTL3 antisense oligonucleotides

New England Journal of Medicine

Volumn 377, Issue 3, 2017, Pages 222-232

  Graham, Mark J ^a   Lee, Richard G ^a   Brandt, Teresa A ^a   Tai, Li Jung ^a   Fu, Wuxia ^a   Peralta, Raechel ^a   Yu, Rosie ^a   Hurh, Eunju ^a   Paz, Erika ^a   McEvoy, Bradley W ^a   Baker, Brenda F ^a   Pham, Nguyen C ^a   Digenio, Andres ^a   Hughes, Steven G ^a   Geary, Richard S ^a   Witztum, Joseph L ^b   Crooke, Rosanne M ^a   Tsimikas, Sotirios ^a,b  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b Akcea Therapeutics   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANGIOPOIETIN LIKE 3 PROTEIN; ANTISENSE OLIGONUCLEOTIDE; APOLIPOPROTEIN B; APOLIPOPROTEIN C3; LIPID; LOW DENSITY LIPOPROTEIN CHOLESTEROL; MESSENGER RNA; PLACEBO; PROTEIN; TRIACYLGLYCEROL; UNCLASSIFIED DRUG; VERY LOW DENSITY LIPOPROTEIN CHOLESTEROL; ANGIOPOIETIN; ANGPTL3 PROTEIN, HUMAN; ANGPTL3 PROTEIN, MOUSE; IONIS-ANGPTL3-LRX; OLIGONUCLEOTIDE;

ADULT; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; ATHEROSCLEROSIS; CARDIOVASCULAR EFFECT; CLINICAL ARTICLE; CONTROLLED STUDY; DIZZINESS; DOSE RESPONSE; DOUBLE BLIND PROCEDURE; DRUG DOSE INCREASE; DRUG EFFECT; FEMALE; HEADACHE; HUMAN; INSULIN SENSITIVITY; LIPID BLOOD LEVEL; MALE; METABOLISM; MOUSE; NONHUMAN; PHASE 1 CLINICAL TRIAL; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; REPEATED DRUG DOSE; SINGLE DRUG DOSE; AGED; ANIMAL; ANTAGONISTS AND INHIBITORS; BLOOD; CLINICAL TRIAL; CORONARY ARTERY DISEASE; DISEASE MODEL; DRUG EFFECTS; DYSLIPIDEMIAS; GENETICS; INBRED MOUSE STRAIN; LIPID METABOLISM; MIDDLE AGED;

ADULT; AGED; ANGIOPOIETINS; ANIMALS; ATHEROSCLEROSIS; CORONARY ARTERY DISEASE; DISEASE MODELS, ANIMAL; DOUBLE-BLIND METHOD; DYSLIPIDEMIAS; FEMALE; HUMANS; LIPID METABOLISM; LIPIDS; MALE; MICE; MICE, INBRED STRAINS; MIDDLE AGED; OLIGONUCLEOTIDES; OLIGONUCLEOTIDES, ANTISENSE; RNA, MESSENGER;

EID: 85025630463     PISSN: 00284793     EISSN: 15334406     Source Type: Journal    
DOI: 10.1056/NEJMoa1701329     Document Type: Article

References (23)

1. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015; 372: 2387-97.
2. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017; 376: 1713-22.
3. Willer CJ, Sanna S, Jackson AU, et al. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet 2008; 40: 161-9.
4. Musunuru K, Pirruccello JP, Do R, et al. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med 2010; 363: 2220-7.
5. Musunuru K, Kathiresan S. Surprises from genetic analyses of lipid risk factors for atherosclerosis. Circ Res 2016; 118: 579-85.
6. Dewey FE, Gusarova V, O'Dushlaine C, et al. Inactivating variants in ANGPTL4 and risk of coronary artery disease. N Engl J Med 2016; 374: 1123-33.
7. Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators. Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease. N Engl J Med 2016; 374: 1134-44.
8. 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 2013; 33: 1706-13.
9. 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: 366-72.
10. Jin W, Wang X, Millar JS, et al. Hepatic proprotein convertases modulate HDL metabolism. Cell Metab 2007; 6: 129-36.
11. Minicocci I, Santini S, Cantisani V, et al. Clinical characteristics and plasma lipids in subjects with familial combined hypolipidemia: a pooled analysis. J Lipid Res 2013; 54: 3481-90.
12. Viney NJ, van Capelleveen JC, Geary RS, et al. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, doseranging trials. Lancet 2016; 388: 2239-53.
13. Wilson DE, Lees RS. Metabolic relationships among the plasma lipoproteins: reciprocal changes in the concentrations of very low and low density lipoproteins in man. J Clin Invest 1972; 51: 1051-7.
14. Lee RG, Fu W, Graham MJ, et al. Comparison of the pharmacological profiles of murine antisense oligonucleotides targeting apolipoprotein B and microsomal triglyceride transfer protein. J Lipid Res 2013; 54: 602-14.
15. Gaudet D, Brisson D, Tremblay K, et al. Targeting APOC3 in the familial chylomicronemia syndrome. N Engl J Med 2014; 371: 2200-6.
16. Gaudet D, Alexander VJ, Baker BF, et al. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N Engl J Med 2015; 373: 438-47.
17. Gordts PL, Nock R, Son NH, et al. ApoC-III inhibits clearance of triglyceride- rich lipoproteins through LDL family receptors. J Clin Invest 2016; 126: 2855-66.
18. Norata GD, Tsimikas S, Pirillo A, Catapano AL. Apolipoprotein C-III: from pathophysiology to pharmacology. Trends Pharmacol Sci 2015; 36: 675-87.
19. Cohen JC, Stender S, Hobbs HH. APOC3, coronary disease, and complexities of Mendelian randomization. Cell Metab 2014; 20: 387-9.
20. 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 2015; 56: 1308-17.
21. Wang Y, Gusarova V, Banfi S, Gromada J, Cohen JC, Hobbs HH. Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion. J Lipid Res 2015; 56: 1296-307.
22. Wallace C, Newhouse SJ, Braund P, et al. Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia. Am J Hum Genet 2008; 82: 139-49.
23. 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 2009; 119: 70-9.