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1、Articleslong-term,efficientinhibitionofmicrornAfunctioninmiceusingrAAVvectorsJunXie1,2,15,StefanLAmeres3,4,15,RandallFriedline5,6,Jui-HungHung7,8,YuZhang1,9,QingXie1,10,LiZhong1,11,QinSu1,RanHe1,MengxinLi1,2,HuapengLi1,2,XinMu1,12,HongweiZhang1,2,JenniferABroderick3,JasonKKim5,6,ZhipingWeng7
2、,TerenceRFlotte1,2,13,PhillipDZamore3,14&GuangpingGao1,2understandingthefunctionofindividualmicrornA(mirnA)inadultmice.Currently,chemicallymodifiedanti-miRNAoligo-speciesinmicewouldrequiretheproductionofhundredsnucleotides(AMOs)complementarytomaturemiRNAsarewidelyofloss-of-functionstrains.to
3、accelerateanalysisofmirnAusedtoinhibitmiRNAsinvitroandinvivo3–5.EffectiveAMOsbiologyinmammals,wecombinedrecombinantadeno-typicallyhaveexpensiveorproprietarymodificationssuchas2′-associatedvirus(rAAV)vectorswithmirnA‘toughdecoys’O-methyl,2′-O-methoxyethylor2′,4′-methylene(lockednucleic(tuds)t
4、oinhibitspecificmirnAs.intravenousinjectionofacid)andrequirerepeatedadministrationtosuppressexpressionrAAV9expressinganti–mir-122oranti–let-7tudsdepletedofthecognatemiRNA5–8.CurrentchemistriesandformulationsthecorrespondingmirnAandincreaseditsmrnAtargets.donotpermitdeliveryofAMOstomanytissue
5、sororgans.rAAVproducinganti–mir-122tudbutnotanti–let-7tudPlasmidDNAvectorsthatexpressmiRNA‘sponges’,whichcom-reducedserumcholesterolby>30%for25weeksinwild-typeprisemultipletandemmiRNAbindingsitesdesignedtocompeti-mice.high-throughputsequencingoflivermirnAsfromthetivelyinhibitmiRNAfunction,ha
6、vebeenusedinculturedcells9treatedmiceconfirmedthatthetargetedmirnAsweredepletedandinflies10.DepletionofmiR-223usingasponge-expressingandrevealedthattudsinducedmirnAtailingandtrimminglentiviralvectortostablymodifyhematopoieticstemcellsexvivo,invivo.rAAV-mediatedmirnAinhibitionthusprovidesasim
7、plefollowedbybonemarrowreconstitutioninmice,producedapheno-waytostudymirnAfunctioninadultmammalsandapotentialtypesimilartothatobservedinageneticmiRNAknockout11.therapyfordyslipidemiaandotherdiseasescausedbyLentiviralvectorsdeliveredbystereotaxicinj
