A Locked Nucleic Acid Antisense Oligonucleotide (LNA) Silences PCSK9 and Enhances LDLR Expression In Vitro and In Vivo 英文参考文献.docVIP

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A Locked Nucleic Acid Antisense Oligonucleotide (LNA) Silences PCSK9 and Enhances LDLR Expression In Vitro and In Vivo 英文参考文献.doc

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A Locked Nucleic Acid Antisense Oligonucleotide (LNA) Silences PCSK9 and Enhances LDLR Expression In Vitro and In Vivo 英文参考文献

ALockedNucleicAcidAntisenseOligonucleotide(LNA) SilencesPCSK9andEnhancesLDLRExpressionInVitro andInVivo NidhiGupta1.,NielsFisker2.,Marie-ClaudeAsselin1,MarieLindholm2,ChristophRosenbohm2 ,Henrik ?rum2,JoacimElme′n2,NabilG.Seidah1*,EllenMarieStraarup2 1LaboratoryofBiochemicalNeuroendocrinology,ClinicalResearchInstituteofMontreal,Montreal,Quebec,Canada,2SantarisPharmaA/S,H?rsholm,Denmark Abstract Background: The proprotein convertase subtilisin/kexin type 9 (PCSK9) is an important factor in the etiology of familial hypercholesterolemia(FH)andisalsoanattractivetherapeutictargettoreducelowdensitylipoprotein(LDL)cholesterol. PCSK9 accelerates the degradation of hepatic low density lipoprotein receptor (LDLR) and low levels of hepatic PCSK9 activityareassociatedwithreducedlevelsofcirculatingLDL-cholesterol. Methodology/Principal Findings: The present study presents the first evidence for the efficacy of a locked nucleic acid (LNA)antisenseoligonucleotide(LNAASO)thattargetsbothhumanandmousePCSK9.Weemployedhumanhepatocytes derivedcelllinesHepG2andHuH7andapancreaticmouseb-TC3celllineknowntoexpresshighendogenouslevelsof PCSK9.LNAASOefficientlyreducedthemRNAandproteinlevelsofPCSK9withaconcomitantincreaseinLDLRprotein levelsaftertransfectioninthesecells.InvivoefficacyofLNAASOwasfurtherinvestigatedinmicebytailveinintravenous administrationofLNAASOinsalinesolution.ThelevelofPCSK9mRNAwasreducedby,60%,aneffectlastingmorethan 16days.HepaticLDLRproteinlevelsweresignificantlyup-regulatedby2.5–3foldsforatleast8daysand,2foldfor16 days. Finally, measurement of liver alanine aminotransferase (ALT) levels revealed that long term LNA ASO treatment (7 weeks)doesnotcausehepatotoxicity. Conclusion/Significance: LNA-mediated PCSK9 mRNA inhibition displayed potent reduction of PCSK9 in cell lines and mouseliver.OurdataclearlyrevealedtheefficacyandsafetyofLNAASOinreducingPCSK9levels,anapproachthatisnow readyfortestinginprimates.Themajorsignificanceandtakehomemessageofthisworkisthedevelopmentofa