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Articles://dx.doi.org/10.1016/S0140-6736(13)61939-X1Long-termsafetyandtolerabilityofProSavin,alentiviralvector-basedgenetherapyforParkinson’sdisease:adoseescalation,open-label,phase1/2trialStéphanePalfi,JeanMarcGurruchaga*,GScottRalph*,HeleneLepetit*,SoniaLavisse,PhilipCButtery,ColinWatts,JamesMiskin,MichelleKelleher,SarahDeeley,HirokazuIwamuro,JeanPascalLefaucheur,ClaireThiriez,GillesFenelon,CherryLucas,PierreBrugières,InannaGabriel,KouAbhay,XavierDrouot,NaokiTani,AurelieKas,BijanGhaleh,PhilippeLeCorvoisier,PatriceDolphin,DavidPBreen,SarahMason,NatalieValleGuzman,NicholasDMazarakis,PippaARadcliffe,RichardHarrop,SusanMKingsman,OlivierRascol,StuartNaylor,RogerABarker,PhilippeHantraye,PhilippeRemy,PierreCesaro,KyriacosAMitrophanousSummaryBackgroundParkinson’sdiseaseistypicallytreatedwithoraldopaminereplacementtherapies;however,long-termtreatmentleadstomotorcomplicationsand,occasionally,impulsecontroldisorderscausedbyintermittentstimulationofdopaminereceptorsandoff-targeteffects,respectively.Weaimedtoassessthesafety,tolerability,andefficacyofbilateral,intrastriataldeliveryofProSavin,alentiviralvector-basedgenetherapyaimedatrestoringlocalandcontinuousdopamineproductioninpatientswithadvancedParkinson’sdisease.MethodsWeundertookaphase1/2open-labeltrialwith12-monthfollow-upattwostudysites(FranceandUK)toassessthesafetyandefficacyofProSavinafterbilateralinjectionintotheputamenofpatientswithParkinson’sdisease.Allpatientswerethenenrolledinaseparateopen-labelfollow-upstudyoflong-termsafety.Threedoseswereassessedinseparatecohorts:lowdose(1·9×10⁷transducingunits[TU]);middose(4·0×10⁷TU);andhighdose(1×10⁸TU).Inclusioncriteriawereage48–65years,diseaseduration5yearsorlonger,motorfluctuations,and50%orhighermotorresponsetooraldopaminergictherapy.Theprimaryendpointsofthephase1/2studywerethenumberandseverityofadverseeventsassociatedwithProSavinandmotorresponsesasassessedwithUnifiedParkinson’sDiseaseRatingScale(UPDRS)partIII(offmedication)scores,at6monthsaftervectoradministration.BothtrialsareregisteredatClinicalTrials.gov,NCT00627588andNCT01856439.Findings15patientsreceivedProSavinandwerefollowedup(threeatlowdose,sixmiddose,sixhighdose).Duringthefirst12monthsoffollow-up,54drug-relatedadverseeventswerereported(51mild,threemoderate).Mostcommonwereincreasedon-medicationdyskinesias(20events,11patients)andon–offphenomena(12events,ninepatients).Noseriousadverseeventsrelatedtothestudydrugorsurgicalprocedurewerereported.AsignificantimprovementinmeanUPDRSpartIIImotorscoresoffmedicationwasrecordedinallpatientsat6months(meanscore38[SD9]vs26[8],n=15,p=0·0001)and12months(38vs27[8];n=15,p=0·0001)comparedwithbaseline.InterpretationProSavinwassafeandwelltoleratedinpatientswithadvancedParkinson’sdisease.Improvementinmotorbehaviourwasobservedinallpatients.FundingOxfordBioMedica.IntroductionParkinson’sdiseaseisacommonneurodegenerativedisordermainlycharacterisedbymotordysfunctionresultinginbradykinesia,rigidity,tremor,gaitimpairment,andposturalinstability.Thediseasehasaprevalenceofaround1%inpeopleaged60years,affectingaround5millionpeopleworldwide.1SeveralriskfactorsareassociatedwithParkinson’sdiseaseincludinginheritance(5–10%ofpatients)2andexposuretochemicalssuchaspesticides.3Acrucialpathologicalcomponentistheprogressivedegenerationofdopaminergicneuronsinthesubstantianigraparscompactathatprojectaxonstothestriatum,wheredopamineisreleased.Therateofdopaminebiosynthesisislimitedbythreeenzymesthatareexpressedinnigralneurons:tyrosinehydroxylaseandcyclohydrolase1,whichfacilitatetheconversionoftyrosinetolevodopa,andaminoaciddecarboxylase(AADC),whichconvertslevodopatodopamine.4–6CurrenttherapiesforParkinson’sdisease,whicharemainlybasedontheoraldopamineprecursorlevodopa,provideexcellentcontrolofmotorsymptomsintheinitialstagesofthedisease.7However,asthediseaseprogresses,levodopatherapybecomeslesseffectiveasside-effectsemergesuchason–offphenomena(whenthepatienthasimprovedmobility[on]duetolevodopaandwhichisthenfollowedbysuddenunpredictableimpairedmobility[off])anddyskinesias.8PreviousstudieshaveshownthattheintermittentnatureoforallevodopaadministrationandsubsequentirregularstimulationofpostsynapticdopaminereceptorsisatleastpartlyresponsibleforthesemotorPublishedOnlineJanuary10,2014(13)61939-XSeeOnline/Comment(13)62108-X*EqualcontributionAP-HP,GroupeHospitalierHenri-Mondor,DHUPePsy,UFNeurochirurgieFonctionnelle,Neurologie,Neurophysiologie,Anesthésie,Centred’InvestigationClinique006,PlateformedeRessourcesBiologiques,Créteil,France(ProfSPalfiMD,JMGurruchagaMD,HLepetitPhD,HIwamuroMD,JPLefaucheurMD,CThiriezMD,GFenelonMD,PBrugièresMD,IGabrielMD,KAbhayMD,XDrouotMD,NTaniMD,ProfBGhalehMD,PLeCorvoisierMD,PDolphinMSc,ProfPRemyMD,ProfPCesaroMD);UniversitéParis12,FacultédeMédecine,Créteil,France(ProfSPalfi,JMGurruchaga,HLepetit,HIwamuro,JPLefaucheur,CThiriez,GFenelon,PBrugières,IGabriel,KAbhay,XDrouot,NTani,BGhaleh,PLeCorvoisier,PDolphin,PRemy,PCesaro);INSERMU955,E01,Institut