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1©TheAuthor2015.PublishedbyOxfordUniversityPress.Allrightsreserved.ForPermissions,pleaseemail:journals.permissions@oup.comPerinatalGjb2genetransferrescueshearinginamousemodelofhereditarydeafnessTakashiIizuka1,KazusakuKamiya1,SatoruGotoh2,YoshinobuSuginani2,MasaakiSuzuki3,TetsuoNoda2,4,OsamuMinowa2,4andKatsuhisaIkeda1,*1DepartmentofOtorhinolaryngology,JuntendoUniversityFacultyofMedicine,Tokyo113-84212DepartmentofCellBiology,JapaneseFoundationforCancerResearch,CancerInstitute,Tokyo135-85503DepartmentofOtolaryngology,TeikyoUniversityChibaMedicalCenter,Ichihara299-01114TeamforAdvancedDevelopmentandEvaluationofHumanDiseaseModels,RIKENBioResourceCenter,Tsukuba305-0074,Japan*Towhomcorrespondenceshouldbeaddressedto(ike@juntendo.ac.jp),DepartmentofOtorhinolaryngology,JuntendoUniversityFacultyofMedicine,2-1-1Hongo,Bunkyo-ku,Tokyo113-8421,Japan.Tel:+81-3-5802-1094;Fax:+81-3-5689-0547;Email:ike@juntendo.ac.jpHMGAdvanceAccesspublishedMarch23,2015atChinaUniversityofGeosciencesWuhanCampusonMay18,2015http://hmg.oxfordjournals.org/Downloadedfrom2ABSTRACTHearinglossisthemostwidespreadsensorydisorder,withanincidenceofcongenitalgeneticdeafnessof1in1,600children.Formanyethnicpopulations,themostprevalentformofgeneticdeafnessiscausedbyrecessivemutationsinthegenegapjunctionprotein,beta2,26kDa(GJB2),whichisalsoknownasconnexin26(Cx26).Despitethisknowledge,existingtreatmentstrategiesdonotcompletelyrecoverspeechperception.HereweusedagenedeliverysystemtorescuehearinginamousemodelofGjb2deletion.MicelackingCx26arecharacterizedbyprofounddeafnessfrombirthandimproperdevelopmentofcochlearcells.CochleardeliveryofGjb2usinganadeno-associatedvirus(AAV)significantlyimprovedtheauditoryresponsesanddevelopmentofthecochlearstructure.UsinggenereplacementtorestorehearinginanewmousemodelofGjb2-relateddeafnessmayleadtothedevelopmentoftherapiesforhumanhereditarydeafness.atChinaUniversityofGeosciencesWuhanCampusonMay18,2015http://hmg.oxfordjournals.org/Downloadedfrom3INTRODUCTIONSeveretoprofoundgenetichearinglossaffectsapproximatelyonein1,600children(1).Althoughearlymanagementofhearingimpairmentwithhearingaidsandcochlearimplantsoftenimprovesspeechperception,profoundlydeafchildrencannotcompletelyacquiretheabilitytodevelopspokenlanguage,andthusintelligiblespeechisseverelyrestricted(2).Genetherapymaybecomeapowerfultechnologythatcouldfundamentallycorrectthediseasephenotypeofgeneticdeafness.However,genereplacementapproachesforanimalmodelsofinheriteddeafnesshavebeenextremelylimited(3-7).Currently160lociforthemonogenicformsofhumandeafnesshavebeenreported,and60geneshavebeenidentified(seehttp://hereditaryhearingloss.org/).Themostprevalentformofgenetichearinglossinmanyethnicpopulationsisduetodefectsinthegeneencodingconnexin26(GJB2),whichisexpressedinthenon-sensorycellsofthecochlea.TheGJB2mutationscausebetweenonethirdand50%ofprelingualgeneticnon-syndromichearingloss,includingdominantandrecessivemutations(1).Intheinnerearofmice,bothaspatially-specificapproachthattargetedthedeletionoftheGjb2inthecochlearsensoryepitheliumresultedinthedeathofdifferenttypesintheinnerearafteronsetofhearing(8).Ontheotherhand,adominant-negativeGjb2R75Wtransgenicmousecreatedinourlaboratoriesclearlyshowedincompletedevelopmentofthecochlearsupportingcells,resultinginprofounddeafnessfrombirth(9,10).TheouterhaircellsfromatChinaUniversityofGeosciencesWuhanCamp...