Porcine Model of Hemophilia A 英文参考文献.docVIP

PorcineModelofHemophiliaA YujiKashiwakura1.,JunMimuro1*.,AkiraOnishi2.,MasakiIwamoto2,3.,SeijiMadoiwa1, DaiichiroFuchimoto2,ShunichiSuzuki2,MisaeSuzuki2,ShoichiroSembon2,AkiraIshiwata1, AtsushiYasumoto1,AsukaSakata1,TsukasaOhmori1,MichikoHashimoto3,SatokoYazaki3, YoichiSakata1 1ResearchDivisionofCellandMolecularMedicine,CenterforMolecularMedicine,JichiMedicalUniversity,Shimotsuke,Tochigi-ken,Japan,2TransgenicAnimalResearch Center,NationalInstituteofAgrobiologicalSciences,Tsukuba,Ibaraki-ken,Japan,3AdvancedTechnologyDevelopmentTeam,PrimeTechLtd.,Tsuchiura,Ibaraki-ken, Japan Abstract Hemophilia Ais acommonX chromosome-linked geneticbleeding disorder caused by abnormalities in thecoagulation factorVIIIgene(F8).HemophiliaApatientssufferfromableedingdiathesis,suchaslife-threateningbleedinginthebrain and harmful bleeding in joints and muscles. Because it could potentially be cured by gene therapy, subhuman animal modelshavebeensought.CurrentmousehemophiliaAmodelsgeneratedbygenetargetingoftheF8havedifficultiesto extrapolatehumandiseaseduetodifferencesinthecoagulationandimmunesystemsbetweenmiceandhumans.Here,we generatedaporcinemodelofhemophiliaAbynucleartransfercloningfromF8-targetedfibroblasts.ThehemophiliaApigs showedaseverebleedingtendencyuponbirth,similartohumanseverehemophiliacs,butincontrasttohemophiliaAmice whichrarelybleedunderstandardbreedconditions.InfusionofhumanfactorVIIIwaseffectiveinstoppingbleedingand reducingthebleedingfrequencyofahemophiliaApigletbutwasblockedbytheinhibitoragainsthumanfactorVIII.These datasuggestthatthehemophiliaApigisaseverehemophiliaAanimalmodelforstudyingnotonlyhemophiliaAgene therapybutalsothenextgenerationrecombinantcoagulationfactors,suchasrecombinantfactorVIIIvariantswithaslower clearancerate. Citation: Kashiwakura Y, Mimuro J, Onishi A, Iwamoto M, Madoiwa S, et al. (2012) Porcine Model of Hemophilia A. PLoS ONE 7(11): e49450. doi:10.1371/ journal.pone.0049450 Editor:ChristopherB.Doering,EmoryUniversitySchoolofMedicine,UnitedStat