Development of Antisense Drugs for Dyslipidemia

Abnormal elevation of low-density lipoprotein (LDL) and triglyceride-rich lipoproteins in plasma as well as dysfunction of anti-atherogenic high-density lipoprotein (HDL) have both been recognized as essential components of the pathogenesis of atherosclerosis and are classified as dyslipidemia. This review describes the arc of development of antisense oligonucleotides for the treatment of dyslipidemia. Chemically-armed antisense candidates can act on various kinds of transcripts, including mRNA and miRNA, via several different endogenous antisense mechanisms, and have exhibited potent systemic anti-dyslipidemic effects. Here, we present specific cutting-edge technologies have recently been brought into antisense strategies, and describe how they have improved the potency of antisense drugs in regard to pharmacokinetics and pharmacodynamics. In addition, we discuss perspectives for the use of armed antisense oligonucleotides as new clinical options for dyslipidemia, in the light of outcomes of recent clinical trials and safety concerns indicated by several clinical and preclinical studies.

[1]  S. Obika,et al.  Evaluation of the effects of chemically different linkers on hepatic accumulations, cell tropism and gene silencing ability of cholesterol-conjugated antisense oligonucleotides. , 2016, Journal of Controlled Release.

[2]  S. Crooke,et al.  RNA cleavage products generated by antisense oligonucleotides and siRNAs are processed by the RNA surveillance machinery , 2016, Nucleic acids research.

[3]  Christopher E. Hart,et al.  Hepatotoxicity of high affinity gapmer antisense oligonucleotides is mediated by RNase H1 dependent promiscuous reduction of very long pre-mRNA transcripts , 2015, Nucleic acids research.

[4]  Emma L. Koppe,et al.  In silico and in vitro evaluation of exonic and intronic off-target effects form a critical element of therapeutic ASO gapmer optimization , 2015, Nucleic acids research.

[5]  H. Soifer,et al.  A cytoplasmic pathway for gapmer antisense oligonucleotide-mediated gene silencing in mammalian cells , 2015, Nucleic acids research.

[6]  T. P. Prakash,et al.  Solid-phase synthesis of 5'-triantennary N-acetylgalactosamine conjugated antisense oligonucleotides using phosphoramidite chemistry. , 2015, Bioorganic & medicinal chemistry letters.

[7]  S. Obika,et al.  XRN2 is required for the degradation of target RNAs by RNase H1-dependent antisense oligonucleotides. , 2015, Biochemical and biophysical research communications.

[8]  K. Kataoka,et al.  DNA/RNA heteroduplex oligonucleotide for highly efficient gene silencing , 2015, Nature Communications.

[9]  C. Bennett,et al.  Pharmacokinetics, biodistribution and cell uptake of antisense oligonucleotides. , 2015, Advanced drug delivery reviews.

[10]  S. Obika,et al.  Ca2+ enrichment in culture medium potentiates effect of oligonucleotides , 2015, Nucleic acids research.

[11]  T. P. Prakash,et al.  Efficient Synthesis and Biological Evaluation of 5'-GalNAc Conjugated Antisense Oligonucleotides. , 2015, Bioconjugate chemistry.

[12]  Jian‐Jun Li,et al.  PCSK9: A key factor modulating atherosclerosis. , 2015, Journal of atherosclerosis and thrombosis.

[13]  S. Obika,et al.  Amido-bridged nucleic acids with small hydrophobic residues enhance hepatic tropism of antisense oligonucleotides in vivo. , 2015, Organic & biomolecular chemistry.

[14]  Yi Jing,et al.  Analysis of 13 cell types reveals evidence for the expression of numerous novel primate- and tissue-specific microRNAs , 2015, Proceedings of the National Academy of Sciences.

[15]  Madelyn Light,et al.  Identification of the endosomal sorting complex required for transport-I (ESCRT-I) as an important modulator of anti-miR uptake by cancer cells , 2014, Nucleic acids research.

[16]  D. Gaudet,et al.  Targeting APOC3 in the familial chylomicronemia syndrome. , 2014, The New England journal of medicine.

[17]  S. Obika,et al.  Evaluation of multiple-turnover capability of locked nucleic acid antisense oligonucleotides in cell-free RNase H-mediated antisense reaction and in mice. , 2014, Nucleic acid therapeutics.

[18]  Shuling Guo,et al.  Targeted delivery of antisense oligonucleotides to hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in mice , 2014, Nucleic acids research.

[19]  S. Crooke,et al.  TCP1 complex proteins interact with phosphorothioate oligonucleotides and can co-localize in oligonucleotide-induced nuclear bodies in mammalian cells , 2014, Nucleic acids research.

[20]  A. Burdick,et al.  Comparison of hepatic transcription profiles of locked ribonucleic acid antisense oligonucleotides: evidence of distinct pathways contributing to non-target mediated toxicity in mice. , 2014, Toxicological sciences : an official journal of the Society of Toxicology.

[21]  M. Lindow,et al.  A Kinetic Model Explains Why Shorter and Less Affine Enzyme-recruiting Oligonucleotides Can Be More Potent , 2014, Molecular therapy. Nucleic acids.

[22]  Takeshi Kimura,et al.  MicroRNAs and Lipoprotein Metabolism. , 2014, Journal of atherosclerosis and thrombosis.

[23]  S. Obika,et al.  Locked nucleic acid antisense inhibitor targeting apolipoprotein C-III efficiently and preferentially removes triglyceride from large very low-density lipoprotein particles in murine plasma. , 2014, European journal of pharmacology.

[24]  R. Santos,et al.  Long-term efficacy and safety of mipomersen in patients with familial hypercholesterolaemia: 2-year interim results of an open-label extension , 2013, European heart journal.

[25]  E. Flowers,et al.  MicroRNA associated with dyslipidemia and coronary disease in humans. , 2013, Physiological genomics.

[26]  Shuling Guo,et al.  Characterization of target mRNA reduction through in situ RNA hybridization in multiple organ systems following systemic antisense treatment in animals. , 2013, Nucleic acid therapeutics.

[27]  A. Levin,et al.  Acute kidney injury during therapy with an antisense oligonucleotide directed against PCSK9. , 2013, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[28]  M. Lindow,et al.  Hepatotoxic potential of therapeutic oligonucleotides can be predicted from their sequence and modification pattern. , 2013, Nucleic acid therapeutics.

[29]  C. Ramírez,et al.  Therapeutic Silencing of MicroRNA-33 Inhibits the Progression of Atherosclerosis in Ldlr−/− Mice—Brief Report , 2013, Arteriosclerosis, thrombosis, and vascular biology.

[30]  Soo-Ho Choi,et al.  MCP-1 binds to oxidized LDL and is carried by lipoprotein(a) in human plasma , 2013, Journal of Lipid Research.

[31]  Richard G. Lee,et al.  Antisense Oligonucleotide Inhibition of Apolipoprotein C-III Reduces Plasma Triglycerides in Rodents, Nonhuman Primates, and Humans , 2013, Circulation research.

[32]  A. Lusis,et al.  Anti-miR-33 Therapy Does Not Alter the Progression of Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice , 2013, Arteriosclerosis, thrombosis, and vascular biology.

[33]  A. von Eckardstein,et al.  Altered Activation of Endothelial Anti- and Proapoptotic Pathways by High-Density Lipoprotein from Patients with Coronary Artery Disease: Role of High-Density Lipoprotein–Proteome Remodeling , 2013, Circulation.

[34]  V. Gebski,et al.  Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. , 2012, JAMA.

[35]  Y. Hari,et al.  Amido‐Bridged Nucleic Acids (AmNAs): Synthesis, Duplex Stability, Nuclease Resistance, and in Vitro Antisense Potency , 2012, Chembiochem : a European journal of chemical biology.

[36]  A. Jazayeri,et al.  Structure Activity Relationships of α-L-LNA Modified Phosphorothioate Gapmer Antisense Oligonucleotides in Animals , 2012, Molecular therapy. Nucleic acids.

[37]  S. Tsimikas,et al.  Lipoprotein(a) as a potential causal genetic risk factor of cardiovascular disease: a rationale for increased efforts to understand its pathophysiology and develop targeted therapies. , 2012, Journal of the American College of Cardiology.

[38]  R. Collins,et al.  The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. , 2012, Lancet.

[39]  Z. Yao,et al.  Apolipoprotein C-III and hepatic triglyceride-rich lipoprotein production , 2012, Current opinion in lipidology.

[40]  G. Labbadia,et al.  Mutations in the ANGPTL3 gene and familial combined hypolipidemia: a clinical and biochemical characterization. , 2012, The Journal of clinical endocrinology and metabolism.

[41]  Sander Kersten,et al.  Regulation of triglyceride metabolism by Angiopoietin-like proteins. , 2012, Biochimica et biophysica acta.

[42]  T. Yamaoka,et al.  Cholesterol-lowering Action of BNA-based Antisense Oligonucleotides Targeting PCSK9 in Atherogenic Diet-induced Hypercholesterolemic Mice , 2012, Molecular therapy. Nucleic acids.

[43]  M. Lindholm,et al.  PCSK9 LNA antisense oligonucleotides induce sustained reduction of LDL cholesterol in nonhuman primates. , 2012, Molecular therapy : the journal of the American Society of Gene Therapy.

[44]  J. Stenvang,et al.  Inhibition of microRNA function by antimiR oligonucleotides , 2012, Silence.

[45]  A. Krieg.  Targeting LDL Cholesterol With LNA , 2012, Molecular Therapy: Nucleic Acids.

[46]  K. Moore,et al.  Inhibition of miR-33a/b in non-human primates raises plasma HDL and reduces VLDL triglycerides , 2011, Nature.

[47]  Aaron N. Chang,et al.  Antagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis. , 2011, The Journal of clinical investigation.

[48]  Moshe Levi,et al.  Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. , 2011, Circulation.

[49]  K. Moore,et al.  miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling , 2011, Proceedings of the National Academy of Sciences.

[50]  P. Willeit,et al.  Antisense oligonucleotide lowers plasma levels of apolipoprotein (a) and lipoprotein (a) in transgenic mice. , 2011, Journal of the American College of Cardiology.

[51]  Satoshi Obika,et al.  Antisense drug discovery and development. , 2011, Future medicinal chemistry.

[52]  M. Manoharan,et al.  Mechanisms of single-stranded phosphorothioate modified antisense oligonucleotide accumulation in hepatocytes , 2011, Nucleic acids research.

[53]  E. Izaurralde,et al.  Gene silencing by microRNAs: contributions of translational repression and mRNA decay , 2011, Nature Reviews Genetics.

[54]  R. Collins,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 , 2010, The Lancet.

[55]  M. Gnant,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 , 2010 .

[56]  A. Siwkowski,et al.  Configuration of the 5'-methyl group modulates the biophysical and biological properties of locked nucleic acid (LNA) oligonucleotides. , 2010, Journal of medicinal chemistry.

[57]  M. Egli,et al.  An exocyclic methylene group acts as a bioisostere of the 2'-oxygen atom in LNA. , 2010, Journal of the American Chemical Society.

[58]  W. Filipowicz,et al.  The widespread regulation of microRNA biogenesis, function and decay , 2010, Nature Reviews Genetics.

[59]  Tanya M. Teslovich,et al.  Biological, Clinical, and Population Relevance of 95 Loci for Blood Lipids , 2010, Nature.

[60]  S. Yokoyama,et al.  Impact of statin treatment on the clinical fate of heterozygous familial hypercholesterolemia. , 2010, Journal of atherosclerosis and thrombosis.

[61]  M. Lindholm,et al.  Short locked nucleic acid antisense oligonucleotides potently reduce apolipoprotein B mRNA and serum cholesterol in mice and non-human primates , 2010, Nucleic acids research.

[62]  Leaf Huang,et al.  Targeted intracellular delivery of antisense oligonucleotides via conjugation with small-molecule ligands. , 2010, Journal of the American Chemical Society.

[63]  D. Rader,et al.  Angiopoietin-like Protein 3 Inhibits Lipoprotein Lipase Activity through Enhancing Its Cleavage by Proprotein Convertases* , 2010, The Journal of Biological Chemistry.

[64]  Daniel S. Ory,et al.  miR-33 links SREBP-2 induction to repression of sterol transporters , 2010, Proceedings of the National Academy of Sciences.

[65]  K. Moore,et al.  MiR-33 Contributes to the Regulation of Cholesterol Homeostasis , 2010, Science.

[66]  T. Shioda,et al.  MicroRNA-33 and the SREBP Host Genes Cooperate to Control Cholesterol Homeostasis , 2010, Science.

[67]  N. Seidah,et al.  A Locked Nucleic Acid Antisense Oligonucleotide (LNA) Silences PCSK9 and Enhances LDLR Expression In Vitro and In Vivo , 2010, PloS one.

[68]  D. Gaudet,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 , 2010, The Lancet.

[69]  A. Siwkowski,et al.  Antisense oligonucleotides containing conformationally constrained 2',4'-(N-methoxy)aminomethylene and 2',4'-aminooxymethylene and 2'-O,4'-C-aminomethylene bridged nucleoside analogues show improved potency in animal models. , 2010, Journal of medicinal chemistry.

[70]  H. Kloer,et al.  Severe hypertriglyceridemia: an indication for apheresis? , 2009, Atherosclerosis. Supplements.

[71]  H. Soifer,et al.  Efficient gene silencing by delivery of locked nucleic acid antisense oligonucleotides, unassisted by transfection reagents , 2009, Nucleic acids research.

[72]  Stephen Kaptoge,et al.  Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. , 2009, JAMA.

[73]  U. Navaneethan,et al.  Hypertriglyceridemic Pancreatitis: Presentation and Management , 2009, The American Journal of Gastroenterology.

[74]  Kyung-Hyun Cho,et al.  Synthesis of reconstituted high density lipoprotein (rHDL) containing apoA-I and apoC-III: the functional role of apoC-III in rHDL , 2009, Molecules and cells.

[75]  P. White,et al.  Overcoming biological barriers to in vivo efficacy of antisense oligonucleotides , 2009, Expert Reviews in Molecular Medicine.

[76]  K. Rye,et al.  Molecular basis of PCSK9 function. , 2009, Atherosclerosis.

[77]  G. Utermann,et al.  Longitudinal cohort study on the effectiveness of lipid apheresis treatment to reduce high lipoprotein(a) levels and prevent major adverse coronary events , 2009, Nature Clinical Practice Cardiovascular Medicine.

[78]  D. Bartel.  MicroRNAs: Target Recognition and Regulatory Functions , 2009, Cell.

[79]  Y. Hari,et al.  A bridged nucleic acid, 2′,4′-BNACOC: synthesis of fully modified oligonucleotides bearing thymine, 5-methylcytosine, adenine and guanine 2′,4′-BNACOC monomers and RNA-selective nucleic-acid recognition , 2009, Nucleic acids research.

[80]  J. O’Connell,et al.  A Null Mutation in Human APOC3 Confers a Favorable Plasma Lipid Profile and Apparent Cardioprotection , 2008, Science.

[81]  C. Burge,et al.  Most mammalian mRNAs are conserved targets of microRNAs. , 2008, Genome research.

[82]  Nikolaus Marx,et al.  The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia. , 2008, The American journal of cardiology.

[83]  Mark J Graham,et al.  Antisense Oligonucleotide Directed to Human Apolipoprotein B-100 Reduces Lipoprotein(a) Levels and Oxidized Phospholipids on Human Apolipoprotein B-100 Particles in Lipoprotein(a) Transgenic Mice , 2008, Circulation.

[84]  G. Watts,et al.  Apolipoprotein C-III: understanding an emerging cardiovascular risk factor. , 2008, Clinical science.

[85]  S. Kauppinen,et al.  LNA-mediated microRNA silencing in non-human primates , 2008, Nature.

[86]  M. Bergström,et al.  Biodistribution of 68Ga-labeled LNA-DNA mixmer antisense oligonucleotides for rat chromogranin-A. , 2008, Oligonucleotides.

[87]  R. Collins,et al.  Newly identified loci that influence lipid concentrations and risk of coronary artery disease , 2008, Nature Genetics.

[88]  Dolores Corella,et al.  Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans , 2008, Nature Genetics.

[89]  A. Silahtaroglu,et al.  Antagonism of microRNA-122 in mice by systemically administered LNA-antimiR leads to up-regulation of a large set of predicted target mRNAs in the liver , 2007, Nucleic acids research.

[90]  K. Miyashita,et al.  N-Methyl substituted 2',4'- BNANC: a highly nuclease-resistant nucleic acid analogue with high-affinity RNA selective hybridization. , 2007, Chemical communications.

[91]  T. Kooistra,et al.  Mouse models for atherosclerosis and pharmaceutical modifiers. , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[92]  S. Crooke.  Antisense Drug Technology : Principles, Strategies, and Applications, Second Edition , 2007 .

[93]  B. Monia,et al.  Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice Published, JLR Papers in Press, January 22, 2007. , 2007, Journal of Lipid Research.

[94]  R. Yu,et al.  Cross-Species Pharmacokinetic Comparison from Mouse to Man of a Second-Generation Antisense Oligonucleotide, ISIS 301012, Targeting Human Apolipoprotein B-100 , 2007, Drug Metabolism and Disposition.

[95]  J. Danesh,et al.  Triglycerides and the Risk of Coronary Heart Disease: 10 158 Incident Cases Among 262 525 Participants in 29 Western Prospective Studies , 2007, Circulation.

[96]  B. Monia,et al.  Antisense oligonucleotides containing locked nucleic acid improve potency but cause significant hepatotoxicity in animals , 2006, Nucleic acids research.

[97]  Y. Hari,et al.  Synthesis and properties of 2'-O,4'-C-methyleneoxymethylene bridged nucleic acid. , 2006, Bioorganic & medicinal chemistry.

[98]  Mark Graham,et al.  miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. , 2006, Cell metabolism.

[99]  N. Rajewsky,et al.  Silencing of microRNAs in vivo with ‘antagomirs’ , 2005, Nature.

[100]  R. Collins,et al.  Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins , 2005, The Lancet.

[101]  L. Havekes,et al.  ApoC-III deficiency prevents hyperlipidemia induced by apoE overexpression Published, JLR Papers in Press, May 1, 2005. DOI 10.1194/jlr.M400479-JLR200 , 2005, Journal of Lipid Research.

[102]  M. Graham,et al.  An apolipoprotein B antisense oligonucleotide lowers LDL cholesterol in hyperlipidemic mice without causing hepatic steatosis Published, JLR Papers in Press, February 16, 2005. DOI 10.1194/jlr.M400492-JLR200 , 2005, Journal of Lipid Research.

[103]  S. Crooke,et al.  Determination of the Role of the Human RNase H1 in the Pharmacology of DNA-like Antisense Drugs* , 2004, Journal of Biological Chemistry.

[104]  S. Crooke.  Progress in antisense technology. , 2004, Annual review of medicine.

[105]  M. Westergaard,et al.  Expanding the design horizon of antisense oligonucleotides with alpha-L-LNA. , 2003, Nucleic acids research.

[106]  M. Boffa,et al.  Inhibition of Plasminogen Activation by Lipoprotein(a) , 2003, Journal of Biological Chemistry.

[107]  Jonathan D. Cohen,et al.  Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. , 2003, The Journal of clinical investigation.

[108]  J. Weissenbach,et al.  Mutations in PCSK9 cause autosomal dominant hypercholesterolemia , 2003, Nature Genetics.

[109]  Gustav Schonfeld,et al.  Familial hypobetalipoproteinemia Published, JLR Papers in Press, March 16, 2003. DOI 10.1194/jlr.R300002-JLR200 , 2003, Journal of Lipid Research.

[110]  V. Erdmann,et al.  Design of antisense oligonucleotides stabilized by locked nucleic acids. , 2002, Nucleic acids research.

[111]  T. V. van Berkel,et al.  Apolipoprotein C-III deficiency accelerates triglyceride hydrolysis by lipoprotein lipase in wild-type and apoE knockout mice. , 2001, Journal of lipid research.

[112]  A. Levin,et al.  Absolute bioavailability of 2'-O-(2-methoxyethyl)-modified antisense oligonucleotides following intraduodenal instillation in rats. , 2001, The Journal of pharmacology and experimental therapeutics.

[113]  E. Lesnik,et al.  Pharmacokinetic properties of 2'-O-(2-methoxyethyl)-modified oligonucleotide analogs in rats. , 2001, The Journal of pharmacology and experimental therapeutics.

[114]  I. Goldberg.  Diabetic Dyslipidemia: Causes and Consequences , 2001 .

[115]  H. Princen,et al.  Lack of predictability of classical animal models for hypolipidemic activity: a good time for mice? , 1998, Atherosclerosis.

[116]  J. Wengel,et al.  Synthesis of Novel Bicyclo[2.2.1] Ribonucleosides: 2'-Amino- and 2'-Thio-LNA Monomeric Nucleosides. , 1998, The Journal of organic chemistry.

[117]  Poul Nielsen,et al.  LNA (Locked Nucleic Acids): Synthesis of the adenine, cytosine, guanine, 5-methylcytosine, thymine and uracil bicyclonucleoside monomers, oligomerisation, and unprecedented nucleic acid recognition , 1998 .

[118]  Toshimasa Ishida,et al.  Synthesis of 2′-O,4′-C-methyleneuridine and -cytidine. Novel bicyclic nucleosides having a fixed C3, -endo sugar puckering , 1997 .

[119]  A. Levin,et al.  Pharmacokinetics and metabolism in mice of a phosphorothioate oligonucleotide antisense inhibitor of C-raf-1 kinase expression. , 1997, Drug metabolism and disposition: the biological fate of chemicals.

[120]  S. Crooke,et al.  Binding affinity and specificity of Escherichia coli RNase H1: impact on the kinetics of catalysis of antisense oligonucleotide-RNA hybrids. , 1997, Biochemistry.

[121]  R. Griffey,et al.  Kinetic characteristics of Escherichia coli RNase H1: cleavage of various antisense oligonucleotide-RNA duplexes. , 1995, The Biochemical journal.

[122]  J. Fruchart,et al.  Modulation of lipoprotein B binding to the LDL receptor by exogenous lipids and apolipoproteins CI, CII, CIII, and E. , 1995, Arteriosclerosis, thrombosis, and vascular biology.

[123]  S. Eisenberg,et al.  Mechanisms of inhibition by apolipoprotein C of apolipoprotein E-dependent cellular metabolism of human triglyceride-rich lipoproteins through the low density lipoprotein receptor pathway. , 1991, The Journal of biological chemistry.

[124]  J. Breslow,et al.  Hypertriglyceridemia as a result of human apo CIII gene expression in transgenic mice. , 1990, Science.

[125]  C. Ehnholm,et al.  Effect of serum and C‐apoproteins from very low density lipoproteins on human postheparin plasma hepatic lipase , 1976, FEBS letters.

[126]  J. Larosa,et al.  A specific apoprotein activator for lipoprotein lipase. , 1970, Biochemical and biophysical research communications.

[127]  S. Obika,et al.  Serial incorporation of a monovalent GalNAc phosphoramidite unit into hepatocyte-targeting antisense oligonucleotides. , 2016, Bioorganic & medicinal chemistry.

[128]  E. Flowers,et al.  MicroRNA regulation of lipid metabolism. , 2013, Metabolism: clinical and experimental.

[129]  S. Yamashita,et al.  Guidelines for the management of familial hypercholesterolemia. , 2012, Journal of atherosclerosis and thrombosis.

[130]  R Bailén Almorox,et al.  [Effect of a monoclonal antibody to PCSK9 on LDL cholesterol]. , 2012, Revista clinica espanola.

[131]  G. Moneta.  Antagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis , 2012 .

[132]  Ryan E. Temel,et al.  Inhibition of miR-33 a / b in non-human primates raises plasma HDL and lowers VLDL triglycerides , 2011 .

[133]  J. Stockman.  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 , 2011 .

[134]  L. N. Valenti,et al.  Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. , 2010, The New England journal of medicine.

[135]  I. Goldberg,et al.  Clinical review 124: Diabetic dyslipidemia: causes and consequences. , 2001, The Journal of clinical endocrinology and metabolism.

[136]  J. Wengel,et al.  Universality of LNA-mediated high-affinity nucleic acid recognition , 1998 .

[137]  T. Farag,et al.  Familial hypercholesterolemia. , 1988, Journal of the Royal Society of Medicine.