Targeting PCSK9 for hypercholesterolemia

Annual Review of Pharmacology and Toxicology

Volumn 54, Issue , 2014, Pages 273-293

  Norata, Giuseppe Danilo ^a,b   Tibolla, Gianpaolo ^a,c   Catapano, Alberico Luigi ^a,c  

^a UNIVERSITY OF MILAN   (Italy)

^b Bassini Hospital   (Italy)

^c IRCCS MULTIMEDICA   (Italy)

Author keywords

LDL cholesterol; LDL receptor; LDLR; MAbs; Monoclonal antibodies

Indexed keywords

APOLIPOPROTEIN B; LOW DENSITY LIPOPROTEIN CHOLESTEROL; MONOCLONAL ANTIBODY; PEGDINETANIB; PROPROTEIN CONVERTASE SUBTILISIN KEXIN TYPE 9; SERINE PROTEINASE; UNCLASSIFIED DRUG;

ADD ON THERAPY; BLOOD LEVEL; CLINICAL PRACTICE; DIGESTIVE TRACT PARAMETERS; GENE SILENCING; HEPATIC OUTPUT; HUMAN; HYPERCHOLESTEROLEMIA; LIVER CLEARANCE; MODULATION; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN STRUCTURE; REGULATORY MECHANISM; REVIEW; VALIDATION PROCESS;

ANIMALS; ANTIBODIES, MONOCLONAL; CHOLESTEROL, LDL; DISEASE MODELS, ANIMAL; GENE EXPRESSION REGULATION; HYPERCHOLESTEROLEMIA; MOLECULAR TARGETED THERAPY; PROPROTEIN CONVERTASES; RANDOMIZED CONTROLLED TRIALS AS TOPIC; SERINE ENDOPEPTIDASES;

EID: 84891883866     PISSN: 03621642     EISSN: 15454304     Source Type: Book Series    
DOI: 10.1146/annurev-pharmtox-011613-140025     Document Type: Review

References (112)

1. Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin SB, et al. 2003. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc. Natl. Acad. Sci. USA 100:928-33
2. Abifadel M, Varret M, Rabes JP, Allard D, Ouguerram K, et al. 2003. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet. 34:154-56
3. Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH. 2005. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat. Genet. 37:161-65
4. Norata GD, Garlaschelli K, Grigore L, Raselli S, Tramontana S, et al. 2010. Effects of PCSK9 variants on common carotid artery intima media thickness and relation to ApoE alleles. Atherosclerosis 208:177-82
5. Abifadel M, Rabes JP, Devillers M, Munnich A, Erlich D, et al. 2009. Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease. Hum. Mutat. 30:520-29
6. Davignon J, Dubuc G, Seidah NG. 2010. The influence of PCSK9 polymorphisms on serum low-density lipoprotein cholesterol and risk of atherosclerosis. Curr. Atheroscler. Rep. 12:308-15
7. Benjannet S, Rhainds D, Essalmani R, Mayne J, Wickham L, et al. 2004. NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol. J. Biol. Chem. 279:48865-75
8. Seidah NG. 2011. The proprotein convertases, 20 years later. Methods Mol. Biol. 768:23-57
9. Piper DE, Jackson S, Liu Q, Romanow WG, Shetterly S, et al. 2007. The crystal structure of PCSK9: a regulator of plasma LDL-cholesterol. Structure 15:545-52
10. Cunningham D, Danley DE, Geoghegan KF, Griffor MC, Hawkins JL, et al. 2007. Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia. Nat. Struct. Mol. Biol. 14:413-19
11. Hampton EN, Knuth MW, Li J, Harris JL, Lesley SA, Spraggon G. 2007. The self-inhibited structure of full-length PCSK9 at 1.9 Å reveals structural homology with resistin within the C-terminal domain. Proc. Natl. Acad. Sci. USA 104:14604-9
12. Du F, Hui Y, Zhang M, Linton MF, Fazio S, Fan D. 2011. Novel domain interaction regulates secretion of proprotein convertase subtilisin/kexin type 9 (PCSK9) protein. J. Biol. Chem. 286:43054-61
13. Benjannet S, Hamelin J, Chretien M, Seidah NG. 2012. Loss- and gain-of-function PCSK9 variants: cleavage specificity, dominant negative effects, and low density lipoprotein receptor (LDLR)degradation. J. Biol. Chem. 287:33745-55
14. Fan D, Yancey PG, Qiu S, Ding L, Weeber EJ, et al. 2008. Self-association of human PCSK9 correlates with its LDLR-degrading activity. Biochemistry 47:1631-39
15. Kosenko T, Golder M, Leblond G, Weng W, Lagace TA. 2013. Low density lipoprotein binds to proprotein convertase subtilisin/kexin type-9 (PCSK9) in human plasma and inhibits PCSK9-mediated low density lipoprotein receptor degradation. J. Biol. Chem. 288:8279-88
16. Qian YW, Schmidt RJ, Zhang Y, Chu S, Lin A, et al. 2007. Secreted PCSK9 downregulates low density lipoprotein receptor through receptor-mediated endocytosis. J. Lipid Res. 48:1488-98
17. Nassoury N, Blasiole DA, Tebon Oler A, Benjannet S, Hamelin J, et al. 2007. The cellular trafficking of the secretory proprotein convertase PCSK9 and its dependence on the LDLR. Traffic 8:718-32
18. McNutt MC, Lagace TA, Horton JD. 2007. Catalytic activity is not required for secreted PCSK9 to reduce low density lipoprotein receptors in HepG2 cells. J. Biol. Chem. 282:20799-803
19. Lagace TA, Curtis DE, Garuti R, McNutt MC, Park SW, et al. 2006. Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabioticmice. J. Clin. Investig. 116:2995-3005
20. Zhang DW, Lagace TA, Garuti R, Zhao Z, McDonald M, et al. 2007. Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J. Biol. Chem. 282:18602-12
21. Bottomley MJ, Cirillo A, Orsatti L, Ruggeri L, Fisher TS, et al. 2009. Structural and biochemical characterization of the wild type PCSK9-EGF(AB) complex and natural familial hypercholesterolemia mutants. J. Biol. Chem. 284:1313-23
22. Zhang DW, Garuti R, Tang WJ, Cohen JC, Hobbs HH. 2008. Structural requirements for PCSK9-mediated degradation of the low-density lipoprotein receptor. Proc. Natl. Acad. Sci. USA 105:13045-50
23. Yamamoto T, Lu C, Ryan RO. 2011. A two-step binding model of PCSK9 interaction with the low density lipoprotein receptor. J. Biol. Chem. 286:5464-70
24. Saavedra YG, Day R, Seidah NG. 2012. The M2module of the Cys-His-rich domain (CHRD) of PCSK9 protein is needed for the extracellular low-density lipoprotein receptor (LDLR) degradation pathway. J. Biol. Chem. 287:43492-501
25. Holla OL, Cameron J, Tveten K, Strom TB, Berge KE, et al. 2011. Role of the C-terminal domain of PCSK9 in degradation of the LDL receptors. J. Lipid Res. 52:1787-94
26. Maxwell KN, Fisher EA, Breslow JL. 2005. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Proc. Natl. Acad. Sci. USA 102:2069-74
27. Poirier S, Mayer G, Poupon V, McPherson PS, Desjardins R, et al. 2009. Dissection of the endogenous cellular pathways of PCSK9-induced low density lipoprotein receptor degradation: evidence for an intracellular route. J. Biol. Chem. 284:28856-64
28. Ferri N, Tibolla G, Pirillo A, Cipollone F, Mezzetti A, et al. 2012. Proprotein convertase subtilisin kexin type 9 (PCSK9) secreted by cultured smooth muscle cells reduces macrophages LDLR levels. Atherosclerosis 220:381-86
29. Rousselet E, Marcinkiewicz J, Kriz J, Zhou A, Hatten ME, et al. 2011. PCSK9 reduces the protein levels of the LDL receptor in mouse brain during development and after ischemic stroke. J. Lipid Res. 52:1383-91
30. Mayer G, Poirier S, Seidah NG. 2008. Annexin A2 is aC-terminal PCSK9-binding protein that regulates endogenous low density lipoprotein receptor levels. J. Biol. Chem. 283:31791-801
31. Zhao Z, Tuakli-Wosornu Y, Lagace TA, Kinch L, Grishin NV, et al. 2006. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am. J. Hum. Genet. 79:514-23
32. Hooper AJ, Marais AD, Tanyanyiwa DM, Burnett JR. 2007. The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population. Atherosclerosis 193:445-48
33. Sun XM, Eden ER, Tosi I, Neuwirth CK, Wile D, et al. 2005. Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia. Hum. Mol. Genet. 14:1161-69
34. Herbert B, Patel D, Waddington SN, Eden ER, McAleenan A, et al. 2010. Increased secretion of lipoproteins in transgenic mice expressing human D374Y PCSK9 under physiological genetic control. Arterioscler. Thromb. Vasc. Biol. 30:1333-39
35. Ouguerram K, Chetiveaux M, Zair Y, Costet P, Abifadel M, et al. 2004. Apolipoprotein B100 metabolism in autosomal-dominant hypercholesterolemia related to mutations in PCSK9. Arterioscler. Thromb. Vasc. Biol. 24:1448-53
36. Lalanne F, Lambert G, Amar MJ, Chetiveaux M, Zair Y, et al. 2005. Wild-type PCSK9 inhibits LDL clearance but does not affect apoB-containing lipoprotein production in mouse and cultured cells. J. Lipid Res. 46:1312-19
37. Lambert G, Jarnoux AL, Pineau T, Pape O, Chetiveaux M, et al. 2006. Fasting induces hyperlipidemia in mice overexpressing proprotein convertase subtilisin kexin type 9: lack of modulation of very-low-density lipoprotein hepatic output by the low-density lipoprotein receptor. Endocrinology 147:4985-95
38. Sun H, Samarghandi A, Zhang N, Yao Z, Xiong M, Teng BB. 2012. Proprotein convertase subtilisin/kexin type 9 interacts with apolipoprotein B and prevents its intracellular degradation, irrespective of the low-density lipoprotein receptor. Arterioscler. Thromb. Vasc. Biol. 32:1585-95
39. Sullivan S, Fabbrini E, Horton JD, Korenblat K, Patterson BW, Klein S. 2011. Lack of a relationship between plasma PCSK9 concentrations and hepatic lipoprotein kinetics in obese people. Transl. Res. 158:302-6
40. Jeong HJ, Lee HS, Kim KS, Kim YK, Yoon D, Park SW. 2008. Sterol-dependent regulation of proprotein convertase subtilisin/kexin type 9 expression by sterol-regulatory element binding protein-2. J. Lipid Res. 49:399-409
41. Horton JD, Shah NA, Warrington JA, Anderson NN, Park SW, et al. 2003. Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc. Natl. Acad. Sci. USA 100:12027-32
42. Maxwell KN, Soccio RE, Duncan EM, Sehayek E, Breslow JL. 2003. Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice. J. Lipid Res. 44:2109-19
43. Dubuc G, Chamberland A, Wassef H, Davignon J, Seidah NG, et al. 2004. Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler. Thromb. Vasc. Biol. 24:1454-59
44. Li H, Liu J. 2012. The novel function of HINFP as a co-activator in sterol-regulated transcription of PCSK9 in HepG2 cells. Biochem. J. 443:757-68
45. Li H, Dong B, Park SW, Lee HS, Chen W, Liu J. 2009. Hepatocyte nuclear factor 1αplays a critical role in PCSK9 gene transcription and regulation by the natural hypocholesterolemic compound berberine. J. Biol. Chem. 284:28885-95
46. Dong B, Wu M, Li H, Kraemer FB, Adeli K, et al. 2010. Strong induction of PCSK9 gene expression through HNF1α and SREBP2: mechanism for the resistance to LDL-cholesterol lowering effect of statins in dyslipidemic hamsters. J. Lipid Res. 51:1486-95
47. Ai D, Chen C, Han S, Ganda A, Murphy AJ, et al. 2012. Regulation of hepatic LDL receptors by mTORC1 and PCSK9 in mice. J. Clin. Investig. 122:1262-70
48. Essalmani R, Susan-Resiga D, Chamberland A, Abifadel M, Cremers JW, et al. 2011. In vivo evidence that furin from hepatocytes inactivates PCSK9. J. Biol. Chem. 286:4257-63
49. Lipari MT, Li W, Moran P, Kong-Beltran M, Sai T, et al. 2012. Furin-cleaved proprotein convertase subtilisin/kexin type 9 (PCSK9) is active and modulates low density lipoprotein receptor and serum cholesterol levels. J. Biol. Chem. 287:43482-91
50. Lakoski SG, Lagace TA, Cohen JC, Horton JD, Hobbs HH. 2009. Genetic and metabolic determinants of plasma PCSK9 levels. J. Clin. Endocrinol. Metab. 94:2537-43
51. Baass A, Dubuc G, Tremblay M, Delvin EE, O'Loughlin J, et al. 2009. Plasma PCSK9 is associated with age, sex, and multiple metabolic markers in a population-based sample of children and adolescents. Clin. Chem. 55:1637-45
52. Cui Q, Ju X, Yang T, Zhang M, Tang W, et al. 2010. Serum PCSK9 is associated with multiple metabolic factors in a large Han Chinese population. Atherosclerosis 213:632-36
53. Dubuc G, Tremblay M, Pare G, Jacques H, Hamelin J, et al. 2010. A new method for measurement of total plasma PCSK9: clinical applications. J. Lipid Res. 51:140-49
54. Huijgen R, Boekholdt SM, Arsenault BJ, Bao W, Davaine JM, et al. 2012. Plasma PCSK9 levels and clinical outcomes in the TNT (Treating to New Targets) trial: a nested case-control study. J. Am. Coll. Cardiol. 59:1778-84
55. Persson L, Cao G, Stahle L, Sjoberg BG, Troutt JS, et al. 2010. Circulating proprotein convertase subtilisin kexin type 9 has a diurnal rhythm synchronous with cholesterol synthesis and is reduced by fasting in humans. Arterioscler. Thromb. Vasc. Biol. 30:2666-72
56. Careskey HE, Davis RA, Alborn WE, Troutt JS, Cao G, Konrad RJ. 2008. Atorvastatin increases human serum levels of proprotein convertase subtilisin/kexin type 9. J. Lipid Res. 49:394-98
57. Awan Z, Seidah NG, MacFadyen JG, Benjannet S, Chasman DI, et al. 2012. Rosuvastatin, proprotein convertase subtilisin/kexin type 9 concentrations, and LDL cholesterol response: the JUPITER trial. Clin. Chem. 58:183-89
58. Welder G, Zineh I, Pacanowski MA, Troutt JS, Cao G, Konrad RJ. 2010. High-dose atorvastatin causes a rapid sustained increase in human serum PCSK9 and disrupts its correlation with LDL cholesterol. J. Lipid Res. 51:2714-21
59. Davignon J, Dubuc G. 2009. Statins and ezetimibe modulate plasma proprotein convertase subtilisin kexin-9 (PCSK9) levels. Trans. Am. Clin. Climatol. Assoc. 120:163-73
60. Nilsson LM, Abrahamsson A, Sahlin S, Gustafsson U, Angelin B, et al. 2007. Bile acids and lipoprotein metabolism: effects of cholestyramine and chenodeoxycholic acid on human hepatic mRNA expression. Biochem. Biophys. Res. Commun. 357:707-11
61. Lambert G, Ancellin N, Charlton F, Comas D, Pilot J, et al. 2008. Plasma PCSK9 concentrations correlate with LDL and total cholesterol in diabetic patients and are decreased by fenofibrate treatment. Clin. Chem. 54:1038-45
62. Troutt JS, Alborn WE, Cao G, Konrad RJ. 2010. Fenofibrate treatment increases human serum proprotein convertase subtilisin kexin type 9 levels. J. Lipid Res. 51:345-51
63. Costet P, Hoffmann MM, Cariou B, Guyomarc'h Delasalle B, Konrad T, Winkler K. 2010. Plasma PCSK9 is increased by fenofibrate and atorvastatin in a non-additive fashion in diabetic patients. Atherosclerosis 212:246-51
64. Browning JD, Horton JD. 2010. Fasting reduces plasma proprotein convertase, subtilisin/kexin type 9 and cholesterol biosynthesis in humans. J. Lipid Res. 51:3359-63
65. Le May C, Kourimate S, Langhi C, Chetiveaux M, Jarry A, et al. 2009. Proprotein convertase subtilisin kexin type 9 null mice are protected from postprandial triglyceridemia. Arterioscler. Thromb. Vasc. Biol. 29:684-90
66. Langhi C, Le May C, Gmyr V, Vandewalle B, Kerr-Conte J, et al. 2009. PCSK9 is expressed in pancreatic δ-cells and does not alter insulin secretion. Biochem. Biophys. Res. Commun. 390:1288-93
67. Poirier S, Mayer G, Benjannet S, Bergeron E, Marcinkiewicz J, et al. 2008. The proprotein convertase PCSK9 induces the degradation of low density lipoprotein receptor (LDLR) and its closest family members VLDLR and ApoER2. J. Biol. Chem. 283:2363-72
68. Lan H, Pang L, Smith MM, Levitan D, Ding W, et al. 2010. Proprotein convertase subtilisin/kexin type 9 (PCSK9) affects gene expression pathways beyond cholesterol metabolism in liver cells. J. Cell. Physiol. 224:273-81
69. Ranheim T, Mattingsdal M, Lindvall JM, Holla OL, Berge KE, et al. 2008. Genome-wide expression analysis of cells expressing gain of function mutant D374Y-PCSK9. J. Cell. Physiol. 217:459-67
70. Kysenius K, Muggalla P, Matlik K, Arumae U, Huttunen HJ. 2012. PCSK9 regulates neuronal apoptosis by adjusting ApoER2 levels and signaling. Cell. Mol. Life Sci. 69:1903-16
71. Casserly IP, Topol EJ. 2004. Convergence of atherosclerosis and Alzheimer's disease: cholesterol, inflammation, and misfolded proteins. Discov. Med. 4:149-56
72. Mahley RW, Weisgraber KH, Huang Y. 2006. Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer's disease. Proc. Natl. Acad. Sci. USA 103:5644-51
73. Jonas MC, Costantini C, Puglielli L. 2008. PCSK9 is required for the disposal of non-acetylated intermediates of the nascent membrane protein BACE1. EMBO Rep. 9:916-22
74. Liu M, Wu G, Baysarowich J, Kavana M, Addona GH, et al. 2010. PCSK9 is not involved in the degradation of LDL receptors and BACE1 in the adult mouse brain. J. Lipid Res. 51:2611-18
75. Postmus I, Trompet S, de Craen AJ, Buckley BM, Ford I, et al. 2012. PCSK9 SNP rs11591147 is associated with low cholesterol levels but not with cognitive performance or noncardiovascular clinical events in an elderly population. J. Lipid Res. 54:561-66
76. Sharotri V, Collier DM, Olson DR, Zhou R, Snyder PM. 2012. Regulation of epithelial sodium channel trafficking by proprotein convertase subtilisin/kexin type 9 (PCSK9). J. Biol. Chem. 287:19266-74
77. Kwakernaak AJ, Lambert G, Slagman MC, Waanders F, Laverman GD, et al. 2013. Proprotein convertase subtilisin-kexin type 9 is elevated in proteinuric subjects: relationship with lipoprotein response to antiproteinuric treatment. Atherosclerosis 226:459-65
78. Levy E, Ouadda AB, Spahis S, Sane AT, Garofalo C, et al. 2013. PCSK9 plays a significant role in cholesterol homeostasis and lipid transport in intestinal epithelial cells. Atherosclerosis 227:297-306
79. Cariou B, Ouguerram K, Zair Y, Guerois R, Langhi C, et al. 2009. PCSK9 dominant negative mutant results in increased LDL catabolic rate and familial hypobetalipoproteinemia. Arterioscler. Thromb. Vasc. Biol. 29:2191-97
80. Cariou B, Langhi C, Le Bras M, Bortolotti M, Le KA, et al. 2013. Plasma PCSK9 concentrations during an oral fat load and after short term high-fat, high-fat high-protein and high-fructose diets. Nutr. Metab. 10:4
81. Mbikay M, Sirois F, Mayne J, Wang GS, Chen A, et al. 2010. PCSK9-deficient mice exhibit impaired glucose tolerance and pancreatic islet abnormalities. FEBS Lett. 584:701-6
82. Roubtsova A, Munkonda MN, Awan Z, Marcinkiewicz J, Chamberland A, et al. 2011. Circulating proprotein convertase subtilisin/kexin 9 (PCSK9) regulates VLDLR protein and triglyceride accumulation in visceral adipose tissue. Arterioscler. Thromb. Vasc. Biol. 31:785-91
83. Kwakernaak AJ, Lambert G, Dullaart RP. 2012. Relationship of proprotein convertase subtilisin-kexin type 9 levels with resistin in lean and obese subjects. Clin. Biochem. 45:1522-24
84. Melone M, Wilsie L, Palyha O, Strack A, Rashid S. 2012. Discovery of a new role of human resistin in hepatocyte low-density lipoprotein receptor suppression mediated in part by proprotein convertase subtilisin/kexin type 9. J. Am. Coll. Cardiol. 59:1697-705
85. Denis M, Marcinkiewicz J, Zaid A, Gauthier D, Poirier S, et al. 2012. Gene inactivation of proprotein convertase subtilisin/kexin type 9 reduces atherosclerosis in mice. Circulation 125:894-901
86. Huijgen R, Fouchier SW, Denoun M, Hutten BA, Vissers MN, et al. 2012. Plasma levels of PCSK9 and phenotypic variability in familial hypercholesterolemia. J. Lipid Res. 53:979-83
87. Lee CJ, Lee YH, Park SW, Kim KJ, Park S, et al. 2013. Association of serum proprotein convertase subtilisin/kexin type 9 with carotid intima media thickness in hypertensive subjects. Metabolism 62:845-50
88. Bassi DE, Fu J, Lopez de Cicco R, Klein-Szanto AJ. 2005. Proprotein convertases: "master switches" in the regulation of tumor growth and progression. Mol. Carcinog. 44:151-61
89. Sun X, Essalmani R, Day R, Khatib AM, Seidah NG, Prat A. 2012. Proprotein convertase subtilisin/kexin type 9 deficiency reduces melanoma metastasis in liver. Neoplasia 14:1122-31
90. Tibolla G, Norata GD, Artali R, Meneghetti F, Catapano AL. 2011. Proprotein convertase subtilisin/kexin type 9 (PCSK9): from structure-function relation to therapeutic inhibition. Nutr. Metab. Cardiovasc. Dis. 21:835-43
91. Norata GD, Ballantyne CM, Catapano AL. 2013. New therapeutic principles in dyslipidaemia: focus on LDL and Lp(a) lowering drugs. Eur. Heart J. 34:1783-89
92. Norata GD, Tibolla G, Catapano AL. 2013. Gene silencing approaches for the management of dyslipidaemia. Trends Pharmacol. Sci. 34:198-205
93. Stein EA, Mellis S, Yancopoulos GD, Stahl N, Logan D, et al. 2012. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N. Engl. J. Med. 366:1108-18
94. McKenney JM, Koren MJ, Kereiakes DJ, Hanotin C, Ferrand AC, Stein EA. 2012. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J. Am. Coll. Cardiol. 59:2344-53
95. Stein EA, Gipe D, Bergeron J, Gaudet D, Weiss R, et al. 2012. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet 380:29-36
96. Roth EM, McKenney JM, Hanotin C, Asset G, Stein EA. 2012. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N. Engl. J. Med. 367:1891-900
97. Dias CS, Shaywitz AJ, Wasserman SM, Smith BP, Gao B, et al. 2012. Effects of AMG145 on low-density lipoprotein cholesterol levels: results from 2 randomized, double-blind, placebo-controlled, ascendingdose phase 1 studies in healthy volunteers and hypercholesterolemic subjects on statins. J. Am. Coll. Cardiol. 60:1888-98
98. Giugliano RP, Desai NR, Kohli P, Rogers WJ, Somaratne R, et al. 2012. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, doseranging, phase 2 study. Lancet 380:2007-17
99. Koren MJ, Scott R, Kim JB, Knusel B, Liu T, et al. 2012. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study. Lancet 380:1995-2006
100. Raal F, Scott R, Somaratne R, Bridges I, Li G, et al. 2012. Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the reduction of LDL-C with PCSK9 inhibition in heterozygous familial hypercholesterolemia disorder (RUTHERFORD) randomized trial. Circulation 126:2408-17
101. Sullivan D, Olsson AG, Scott R, Kim JB, Xue A, et al. 2012. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA 308:2497-506
102. Chan JC, Piper DE, Cao Q, Liu D, King C, et al. 2009. A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates. Proc. Natl. Acad. Sci. USA 106:9820-25
103. Ni YG, Di Marco S, Condra JH, Peterson LB, Wang W, et al. 2011. A PCSK9-binding antibody that structurally mimics the EGF(A) domain of LDL-receptor reduces LDL cholesterol in vivo. J. Lipid Res. 52:78-86
104. Gumbiner B. 2012. Effects of 12 weeks of treatment with RN316 (PF-04950615), a humanized IgG2Δa monoclonal antibody binding proprotein convertase subtilisin kexin type 9, in hypercholesterolemic subjects on high and maximal dose statins. Presented at Am. Heart Assoc. Sci. Sess., Los Angeles
105. Labonte P, Begley S, Guevin C, Asselin MC, Nassoury N, et al. 2009. PCSK9 impedes hepatitis C virus infection in vitro and modulates liver CD81 expression. Hepatology 50:17-24
106. Stein EA. 2013. Trial evaluating AMG145, a PCSK9 antibody, in patients with homozygous FH: results of an initial dose-scheduling study. Presented at 81st Eur. Atheroscler. Soc. Congr., June 2-5, Lyon, France
107. Bloom L, Calabro V. 2009. FN3: a new protein scaffold reaches the clinic. Drug Discov. Today 14:949-55
108. Crunkhorn S. 2012. Trial watch: PCSK9 antibody reduces LDL cholesterol. Nat. Rev. Drug Discov. 11:11
109. Frank-Kamenetsky M, Grefhorst A, Anderson NN, Racie TS, Bramlage B, et al. 2008. Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proc. Natl. Acad. Sci. USA 105:11915-20
110. Graham MJ, Lemonidis KM, Whipple CP, Subramaniam A, Monia BP, et al. 2007. Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice. J. Lipid Res. 48:763-67
111. Gupta N, Fisker N, Asselin MC, Lindholm M, Rosenbohm C, et al. 2010. A locked nucleic acid antisense oligonucleotide (LNA) silences PCSK9 and enhances LDLR expression in vitro and in vivo. PLoS ONE 5:e10682
112. Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S, Liebow A, Bettencourt BR, et al. 2013. 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. In press. doi: 10.1016/S0140-6736(13) 61914-5