Pseudotyped AAV Vector-Mediated Gene Transfer in a Human Fetal Trachea Xenograft Model Implications for In Utero Gene Therapy for Cystic Fibrosis 英文参考文献.docVIP

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Pseudotyped AAV Vector-Mediated Gene Transfer in a Human Fetal Trachea Xenograft Model Implications for In Utero Gene Therapy for Cystic Fibrosis 英文参考文献.doc

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Pseudotyped AAV Vector-Mediated Gene Transfer in a Human Fetal Trachea Xenograft Model Implications for In Utero Gene Therapy for Cystic Fibrosis 英文参考文献

PseudotypedAAVVector-MediatedGeneTransferina HumanFetalTracheaXenograftModel:Implicationsfor InUteroGeneTherapyforCysticFibrosis SundeepG.Keswani1,2*.,SwathiBalaji1.,LouisLe1.,AliceLeung1,AnnaB.Katz2,Foong-YenLim1,2, MouniraHabli1,HelenN.Jones1,JamesM.Wilson3,TimothyM.Crombleholme1,2 1Center for Molecular Fetal Therapy, Division of Pediatric, General, Thoracic and Fetal Surgery, Cincinnati Children’s Hospital Medical Center and The University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America, 2The Children’s Institute for Surgical Science, The Children’s Hospital of Philadelphia, Philadelphia,Pennsylvania,UnitedStatesofAmerica,3GeneTherapyProgram,DepartmentofPathologyandLaboratoryMedicine,UniversityofPennsylvaniaSchoolof Medicine,Philadelphia,Pennsylvania,UnitedStatesofAmerica Abstract Background: Lung disease including airway infectionand inflammation currently causesthe majority of morbidities and mortalitiesassociatedwithcysticfibrosis(CF),makingtheairwayepitheliumandthesubmucosalglands(SMG)noveltarget cellsforgenetherapyinCF.Thesetargetcellsarerelativelyinaccessibletopostnatalgenetransferlimitingthesuccessof genetherapy.Ourpreviousworkinahuman-fetaltracheaxenograftmodelsuggeststhepotentialbenefitfortreatingCFin utero.In this study, we aim to validate adeno-associated virus serotype 2 (AAV2) gene transfer in ahuman fetal trachea xenograftmodelandtocomparetransductionefficienciesofpseudotypingAAV2vectorsinfetalxenograftsandpostnatal xenograftcontrols. Methodology/Principal Findings: Human fetal trachea or postnatal bronchus controls were xenografted onto immunocompromisedSCIDmiceforafour-weekengraftmentperiod.AfterinjectionofAAV2/2,2/1,2/5,2/7or2/8with aLacZreporterintobothtypesofxenografts,weanalyzedfortransgeneexpressionintherespiratoryepitheliumandSMGs. At1month,transductionbyAAV2/2andAAV2/8inrespiratoryepitheliumandSMGcellswassignificantlygreaterthanthat ofAAV2/1,2/5,and2/7inxenografttracheas.EfficiencyinSMGtransductionwassigni