PCSK9 LNA antisense oligonucleotides induce sustained reduction of LDL cholesterol in nonhuman primates

Molecular Therapy

Volumn 20, Issue 2, 2012, Pages 376-381

  Lindholm, Marie W ^a   Elmén, Joacim ^a   Fisker, Niels ^a   Hansen, Henrik F ^a   Persson, Robert ^a   Møller, Marianne R ^a   Rosenbohm, Christoph ^a   Ørum, Henrik ^a   Straarup, Ellen M ^a   Koch, Troels ^a  

^a Santaris Pharma AS   (Denmark)

Author keywords

[No Author keywords available]

Indexed keywords

ALANINE AMINOTRANSFERASE; ANTISENSE OLIGONUCLEOTIDE; APOLIPOPROTEIN B; ASPARTATE AMINOTRANSFERASE; CREATININE; GLUCOSE; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE; LOCKED NUCLEIC ACID; LOW DENSITY LIPOPROTEIN CHOLESTEROL; LOW DENSITY LIPOPROTEIN RECEPTOR; MESSENGER RNA; PROPROTEIN CONVERTASE SUBTILISIN KEXIN TYPE 9; PROTEINASE K; SPC 4061; SPC 5001; TRIACYLGLYCEROL; UNCLASSIFIED DRUG; UREA;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ANTISENSE THERAPY; ARTICLE; CHOLESTEROL BLOOD LEVEL; CONTROLLED STUDY; DRUG EFFICACY; DRUG HALF LIFE; DRUG LIVER LEVEL; DRUG POTENCY; DRUG SAFETY; DRUG TARGETING; DRUG TOLERABILITY; EXPERIMENTAL MONKEY; GENE EXPRESSION; HISTOPATHOLOGY; KIDNEY; LIPID LIVER LEVEL; LIPOPROTEIN BLOOD LEVEL; LIVER HISTOLOGY; LOADING DRUG DOSE; MAINTENANCE DRUG DOSE; MULTIPLE DRUG DOSE; NONHUMAN; PROTEIN BLOOD LEVEL; SINGLE DRUG DOSE;

PRIMATES;

EID: 84856517940     PISSN: 15250016     EISSN: 15250024     Source Type: Journal    
DOI: 10.1038/mt.2011.260     Document Type: Article

References (25)

1. Seidah, NG, Benjannet, S, Wickham, L, Marcinkiewicz, J, Jasmin, SB, Stifani, S 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: 928-933. (Pubitemid 36183932)
2. Abifadel, M, Varret, M, Rabès, JP, Allard, D, Ouguerram, K, Devillers, M et al. (2003). Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 34: 154-156. (Pubitemid 36666925)
3. Horton, JD, Cohen, JC and Hobbs, HH (2007). Molecular biology of PCSK9: its role in LDL metabolism. Trends Biochem Sci 32: 71-77. (Pubitemid 46199197)
4. Zhang, DW, Lagace, TA, Garuti, R, Zhao, Z, McDonald, M, Horton, JD et al. (2007). Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factorlike repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J Biol Chem 282: 18602-18612. (Pubitemid 47100234)
5. Cariou, B, Le May, C and Costet, P (2011). Clinical aspects of PCSK9. Atherosclerosis 216: 258-265.
6. Abifadel, M, Rabès, JP, Devillers, M, Munnich, A, Erlich, D, Junien, C et al. (2009). Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease. Hum Mutat 30: 520-529.
7. Horton, JD, Cohen, JC and Hobbs, HH (2009). PCSK9: a convertase that coordinates LDL catabolism. J Lipid Res 50 (suppl.): S172-S177.
8. Kotowski, IK, Pertsemlidis, A, Luke, A, Cooper, RS, Vega, GL, Cohen, JC et al. (2006). A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Am J Hum Genet 78: 410-422. (Pubitemid 43291224)
9. The global burden of disease: 2004 update.http://www.who.int/healthinfo/ global-burden-disease/2004-report-update/en/.2008 .
10. Abifadel, M, Rabès, JP, Jambart, S, Halaby, G, Gannagé-Yared, MH, Sarkis, A et al. (2009). The molecular basis of familial hypercholesterolemia in Lebanon: spectrum of LDLR mutations and role of PCSK9 as a modifier gene. Hum Mutat 30: E682-E691.
11. Peterson, AS, Fong, LG and Young, SG (2008). PCSK9 function and physiology. J Lipid Res 49: 1152-1156.
12. Zhao, Z, Tuakli-Wosornu, Y, Lagace, TA, Kinch, L, Grishin, NV, Horton, JD et al. (2006). Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet 79: 514-523. (Pubitemid 44384260)
13. Welder, G, Zineh, I, Pacanowski, MA, Troutt, JS, Cao, G and 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: 2714-2721.
14. Graham, MJ, Lemonidis, KM, Whipple, CP, Subramaniam, A, Monia, BP, Crooke, ST et al. (2007). Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice. J Lipid Res 48: 763-767. (Pubitemid 46557881)
15. Gupta, N, Fisker, N, Asselin, MC, Lindholm, M, Rosenbohm, C, Ørum, H 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.
16. Frank-Kamenetsky, M, Grefhorst, A, Anderson, NN, Racie, TS, Bramlage, B, Akinc, A 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: 11915-11920.
17. Chan, JC, Piper, DE, Cao, Q, Liu, D, King, C, Wang, W 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: 9820-9825.
18. Ni, YG, Condra, JH, Orsatti, L, Shen, X, Di Marco, S, Pandit, S et al. (2010). A proprotein convertase subtilisin-like/kexin type 9 (PCSK9) C-terminal domain antibody antigen-binding fragment inhibits PCSK9 internalization and restores low density lipoprotein uptake. J Biol Chem 285: 12882-12891.
19. Ni, YG, Di Marco, S, Condra, JH, Peterson, LB, Wang, W, Wang, F 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.
20. Palmer-Smith, H and Basak, A (2010). Regulatory effects of peptides from the pro and catalytic domains of proprotein convertase subtilisin/kexin 9 (PCSK9) on low-density lipoprotein receptor (LDL-R). Curr Med Chem 17: 2168-2182.
21. Hansen, JB, Fisker, N, Westergaard, M, Kjaerulff, LS, Hansen, HF, Thrue, CA et al. (2008). SPC3042: a proapoptotic survivin inhibitor. Mol Cancer Ther 7: 2736-2745.
22. Straarup, EM, Fisker, N, Hedtjärn, M, Lindholm, MW, Rosenbohm, C, Aarup, V et al. (2010). Short locked nucleic acid antisense oligonucleotides potently reduce apolipoprotein B mRNA and serum cholesterol in mice and non-human primates. Nucleic Acids Res 38: 7100-7111.
23. Lakoski, SG, Lagace, TA, Cohen, JC, Horton, JD and Hobbs, HH (2009). Genetic and metabolic determinants of plasma PCSK9 levels. J Clin Endocrinol Metab 94: 2537-2543.
24. Dubuc, G, Tremblay, M, Paré, G, Jacques, H, Hamelin, J, Benjannet, S et al. (2010). A new method for measurement of total plasma PCSK9: clinical applications. J Lipid Res 51: 140-149.
25. Mbikay, M, Sirois, F, Mayne, J, Wang, GS, Chen, A, Dewpura, T et al. (2010). PCSK9-deficient mice exhibit impaired glucose tolerance and pancreatic islet abnormalities. FEBS Lett 584: 701-706.