Peptide Ligands Incorporated into the Threefold Spike Capsid Domain to Re-Direct Gene Transduction of AAV8 and AAV9 In Vivo 英文参考文献.docVIP

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Peptide Ligands Incorporated into the Threefold Spike Capsid Domain to Re-Direct Gene Transduction of AAV8 and AAV9 In Vivo 英文参考文献.doc

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Peptide Ligands Incorporated into the Threefold Spike Capsid Domain to Re-Direct Gene Transduction of AAV8 and AAV9 In Vivo 英文参考文献

PeptideLigandsIncorporatedintotheThreefoldSpike CapsidDomaintoRe-DirectGeneTransductionofAAV8 andAAV9InVivo StefanMichelfelder1,KarlVaradi3,ChristinaRaupp4,AgnesHunger1,JakobKo¨rbelin1 ,Christiane Pahrmann2,SonjaSchrepfer2,OliverJ.Mu¨ller3,Ju¨rgenA.Kleinschmidt4,MartinTrepel1* 1DepartmentofOncologyandHematology,HubertusWaldCancerCenter,UniversityMedicalCenterHamburg-Eppendorf,Hamburg,Germany,2TransplantandStem Cell Immunobiology Lab, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, 3Internal Medicine III, University Medical Center Heidelberg, Im NeuenheimerFeld10,Heidelberg,Germany,4DeutschesKrebsforschungszentrum,ImNeuenheimerFeld242,Heidelberg,Germany Abstract Efficiency and specificity of viral vectors are vital issues in gene therapy. Insertion of peptide ligands into the adeno- associatedviral(AAV)capsidatreceptorbindingsitescanre-targetAAV2-derivedvectorstoalternativecelltypes.Also,the use of serotypes AAV8 and -9 is more efficient than AAV2 for gene transfer to certain tissues in vivo. Consequently, re- targetingoftheseserotypesbyligandinsertioncouldbeapromisingapproachbuthasnotbeenexploredsofar.Here,we generatedAAV8and-9vectorsdisplayingpeptidesinthethreefoldspikecapsiddomain.Thesepeptideshadbeenselected frompeptidelibrariesdisplayedoncapsidsofAAVserotype2tooptimizesystemicgenedeliverytomurinelungtissueand tobreastcancertissueinPymTtransgenicmice(PymT).Suchpeptideinsertionsatposition590oftheAAV8capsidand position589oftheAAV9capsidchangedthetransductionpropertiesofbothserotypes.However,bothpeptidesinsertedin AAV8didnotresultinthesamechangesoftissuetropismastheydidinAAV2.WhiletheAAV2peptidesselectedonmurine lungtissuedidnotaltertropismofserotypes8and-9,insertionoftheAAV2-derived peptideselectedonbreastcancer tissueaugmentedtumorgenedeliveryinbothserotypes.Further,thispeptidemediatedastrongbutunspecificinvivo genetransferforAAV8andabrogatedtransductionofvariouscontroltissuesforAAV9.Ourfindingsindicatethatpeptide insertionintodefinedsites