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1、微环载体介导肝再生增强因子的肝纤维化的治疗RESEARCHARTICLESAugmenterofLiverRegenerationGeneTherapyUsingaNovelMinicircleDNAVectorAlleviatesLiverFibrosisinRats1,221,21,223XinWu,GuangzeLiu,MaoMu,YutingPeng’XiumeiLi丄isiDeng,221,*andXiangpingKong2?*ZhenweiZhang’MeijuanChen’SongYou,InstituteofLifeScienceandBio・Pharmaceutics
2、^ShenyangPharmaceuticalUniversity,Shenyang,China;2KeyLaboratoryofLiverDiseasezCentreoflnfectiousDiseases,458thHospitalofPLA,Guangzhou,China;3TheFifthAf?liatedHospital,SunYat-SenUniversity,Zhuhai,China.1Liver?brosisresultsincirrhosis,livercancer’andliverfailur巳whichisamajorcauseofmortalityworldwid
3、e.Genetherapyisarelativelynewparadigminmedicine^withenormoustherapeuticpotential.Thedevelopmentofanef?cientandsafedeliverysystemisessentialforclinicalgenetherapy.lnthepresentstudy’weevaluatedaugmenterofliverregeneration/growthfactorERVl・like(ALR/GFER)genethera・peuticeffectmediatedbyanovelminicirc
4、levector(MC-hALR).Theresultsinliver?broticratsthatreceivedMC-hALRthroughhydrodynamics-basedtransfection(HBT)for8weeksindicatedthattheminicircleDNAvectorproducedamoreeffectivegenetherapyeffectthantraditionalplasmids(pcDNA3.1・hALR).EvenwhenwereducedthetreatmentdoseofMC-hALRto30%(w/w)andthetreatment
5、frequencyfromweeklytobiweekly,theinvitroandinvivoresultsstilldemonstratedthathigherALRgeneexpressionsigni?・cantlyblockedincreasesintransforminggrowthfactor・bl(TGF・bl),plateletderivedgrowthfactor-BB(PDGF-BB)/anda-smoothmuscleaorta(a-SMA)levels;effectivelysuppressedtheproductionofcollagens’especial
6、lycollagenl;andeffectivelyalleviatedliverinjuryand?brosisinrats^herebyimprovingthesurvivalrateofliver?broticrats.ltispreliminarilyconcludedthattherelativeoverexpressionofMC・hALRinhibitstheactivationofhepaticstellatecells(HSCs),therebyalleviatingliver?brosisinrats・Keywords:minicircleDNAvector,high
7、-levelexpression,augmenterofliverregeneration(ALR),genetherapy川ver?brosis,hydrodynamics-basedtransfection(HBT)INTRODUCTIONLIVERFIBROSISRESULTSFROMchronicdamagetotheliverinconjunctionwiththeexcessiveaccumulationofextrac