神经退行性疾病干细胞移植治疗目前研究现状与未来展望培训讲义课件

神经退行性疾病干细胞移植治疗目前研究现状与未来展望（优选）神经退行性疾病干细胞移植治疗目前研究现状与未来展望胎儿神经干细胞治疗帕金森氏病临床研究发展历程EvansJR,MasonSL,BarkerRA.ProgBrainRes.2012;200:169-98LindvallO,etal，NatMed.2008May;14(5):501-3THSynucleinOverlayTransplantedfetalmesencephalicdopaminergicneurons(11-16years)developedalpha-synuclein-positiveLewybodiesingraftedneuronsSynuclein-HostUbiquintin-HostSynuclein-GraftedNeuronsUbiquintin-GraftedNeuronsGraftednigralneuronswerefoundtohaveLewybody-likeinclusions14yearsaftertransplantationintothestriatumofanindividualwithPDOlanowCW.etalNatMed.2008May;14(5):504-6.TransplanteddopamineneuronsinpeoplewithPDdonotcontainLewybodiesMendez,Isacsonetal,,NATUREMEDICINEVOLUME14(5):507-509,2008FreedCR,JNuclMed.2010Jan;51(1):7-15-LongtermStudy-33oftheoriginaltrialparticipantswhowerefollowedfor2yearsaftertransplantationand15ofthesesubjectswhowerefollowedfor2additionalyears.-Theseresultssuggestthatclinicalbenefitandgraftviabilityaresustainedupto4yaftertransplantation.

FreedCR,Neurotherapeutics(2011)8:549–561人体胚胎干细胞分化的多巴胺神经元移植

改善小鼠，大鼠和猴子帕金森氏病的运动障碍22/29DECEMBER2011|VOL480|NATURE|547，LorenzStuder，etal

MemorialSloan-KetteringCancerCenterImprovedCellTherapyProtocolforParkinson’sDiseaseBasedonDifferentiationEfficiencyandSafetyofhESC-,HipscandNon-HumanPrimateiPSC-DerivedDANeuronsIsacsonetal,,StemCells.2013;31(8):1548-62.DopaminereleasefromtransplantedneuralstemcellsinParkinsonianratstriatuminvivo.Twelvepatientsweretreatedwitheitherunilateralorbilateralinjections.6OHDAinducedRatPDModel分化的胎脑神经干细胞移植治疗PDIncreasinghostneurogenesis“IntraspinalstemcelltransplantationinALS:aphaseItrial,cervicalmicroinjectionandfinalsurgicalsafetyoutcomes”.TodeterminewhetherlocalmechanismsmediateBMSCneuroprotectiveactionsetalNatMed.（优选）神经退行性疾病干细胞移植治疗目前研究现状与未来展望胎儿神经干细胞治疗帕金森氏病临床研究发展历程Releaseofimmuno-regulatoryfactorssuchasIL-2,6,8,10toplayimmuno-modulationandattenuationoftheinflammatoryprocess,suchasMSC.2012;200:169-98ImprovedCellTherapyProtocolforParkinson’sDiseaseBasedonDifferentiationEfficiencyandSafetyofhESC-,HipscandNon-HumanPrimateiPSC-DerivedDANeuronsIntraspinalstemcelltransplantationinALS:aphaseItrial,2014Anotherrequiredreoperationforwounddehiscenceandinfection.usingESCsandiPSCsiPSCellsWereGeneratedfromPDpatientsandNormalControlsUbiquintin-GraftedNeuronsIncreasinghostneurogenesisgraftedallogeneicBMSCstositesofsevere,compressive

spinalcordinjury

(SCI)inSpragueDawleyrats.DopaminereleasefromtransplantedneuralstemcellsinParkinsonianratstriatuminvivo.

Zhouz,etal,ProcNatlAcadSciUSA.2014Nov4;111(44):15804-9iPSCDerivedDopamineNeuronsfunctionafterTransplantationinaNonHumanPrimateModelofParkinson’sDiseaseCellStemCell.2015Mar5;16(3):269-74.

OleIsacsonetal，HarvardStemCellInstituteStemcellbasedClinicalTrialsfor(ALS)Nuralstem,Inc.thefirstPhaseIclinicaltrialforastemcell-basedtreatmentofALS.Initiatedin2010andcompletedin2013,involvedthetransplan-tationofhumanspinalcord-derivedNSCsintothespinalcordof15latetomid-stageALSpatients“IntraspinalstemcelltransplantationinALS:aphaseItrial,cervicalmicroinjectionandfinalsurgicalsafetyoutcomes”.SummaryonMolecularMechanismofStemCellTransplantationforNeurologicalDiseasestoincreasethefunctionsoftheendogenousneuralstemcellsThisencouragingfindingsupportsconsiderationofthisdeliveryapproachforneurodegenerative,oncologic,andtraumaticspinalcordafflictions.暴露和部分横切脊髓外科手术。University,Atlanta,Georgia;DepartmentofNeurology,EmoryUniversity,Atlanta,Georgia;DepartmentofNeurology,UniversityofMichigan,AnnArbor,MichiganGlass,Feldman,E.RTPCRtoDetecttheMicroRNAExpressioninRatSCIModelPatientsarefollowedclinicallyandradiologicallytoassesspotentialtoxicityoftheprocedure.Cells

wereadministered48hoursaftertheoriginal

injury.SCgraftsshouldexhibitregulatedreleaseofdopamineinlinewiththatofendogenousdopaminergicneurons.-LongtermStudy神经退行性疾病干细胞移植治疗目前研究现状与未来展望Isacsonetal,,StemCells.神经退行性疾病干细胞移植治疗目前研究现状与未来展望RealTimeRTPCRtoDetecttheMicroRNAExpressioninSCIiPSCellsWereGeneratedfromPDpatientsandNormalControlsGlass,Feldman,E.Thus,allogeneicgraftsofBMSCsdonotappeartoactthroughlocalmechanisms,andfuture

clinicaltrials

thatacutelydeliverBMSCstoactualsitesof

injury

withindaysareunlikelytobebeneficial.Ubiquintin-GraftedNeurons“IntraspinalstemcelltransplantationinALS:aphaseItrial,cervicalmicroinjectionandfinalsurgicalsafetyoutcomes”.Thisencouragingfindingsupportsconsiderationofthisdeliveryapproachforneurodegenerative,oncologic,andtraumaticspinalcordafflictions.IntraspinalstemcelltransplantationinALS:aphaseItrial,2014Glass,Feldman,E.L.,2012.Lumbarintraspinalinjectionofneuralstemcellsinpatientswithamyotrophiclateralsclerosis:resultsofaphaseItrialin12patients.StemCells30(6),1144–1151.Riley,J.,Feldman,E.L.,2014.“IntraspinalstemcelltransplantationinALS:aphaseItrial,cervicalmicroinjectionandfinalsurgicalsafetyoutcomes”.Neurosurgery74(1),77–87RESULTS:Unilateralcervical(groupD,n=3)andcervicalplusthoracolumbar(groupE,n=3)microinjectionstotheventralhornhavebeencompletedinambulatorypatients.Onepatientdevelopedapostoperativekyphoticdeformitypromptingcompletionofalaminoplastyinsubsequentpatients.Anotherrequiredreoperationforwounddehiscenceandinfection.Thesolitarypatientwithbulbaramyotrophiclateralsclerosisrequiredperioperativereintubation.CONCLUSION:Deliveryofacellularpayloadtothecervicalorthoracolumbarspinalcordwaswelltoleratedbythespinalcordinthisvulnerablepopulation.Thisencouragingfindingsupportsconsiderationofthisdeliveryapproachforneurodegenerative,oncologic,andtraumaticspinalcordafflictions.IntraspinalstemcelltransplantationinALS:aphaseItrial,2014iPSCellsWereGeneratedfromPDpatientsandNormalControls6OHDAinducedRatPDModelHumaniPScellsIntegratedtotheHostBrainof6OHDAinducedRatPDModelHanF,WangW,ChenC,DuanJ,etalCytotherapy2015分化的胎脑神经干细胞移植治疗PD建立大鼠SCI损伤模型A.暴露和部分横切脊髓外科手术。B.T7横断损伤产生后肢瘫痪。C.无脊髓损伤的正常大鼠。RTPCRtoDetecttheMicroRNAExpressioninRatSCIModelMiR-124MiR-124MiR-124MiR-127MiR-127MiR-127MiR-127MiR-124MiR-133aMiR-133aMiR-133aMiR-181aMiR-181aMiR-181aRealTimeRTPCRtoDetecttheMicroRNAExpressioninSCI干细胞移植修复脊髓神经损伤移植神经干细胞分化的神经轴索与宿主脊髓神经细胞及其树突形成突触连接LuPetal，Cell.2012September14;150(6):1264–1273BoneMarrowStromalCellIntraspinalTransplantsFailtoImproveMotorOutcomesinaSevereModelof

SCIJournalofNeurotrauma2015，TuszynskiMHTodeterminewhetherlocalmechanismsmediateBMSCneuroprotectiveactionsgraftedallogeneicBMSCstositesofsevere,compressive

spinalcordinjury

(SCI)inSpragueDawleyrats.

Cells

wereadministered48hoursaftertheoriginal

injury.AdditionalanimalsreceivedallogeneicMSCsthatweregeneticallymodifiedtosecreteBDNF,tofurtherdeterminewhetheralocallyadministeredneurotrophicfactorprovidesorextendsneuroprotection.twomonthspost-injury

inaclinicallyrelevantmodelofsevereSCI,BMSCgraftswithorwithoutBDNFsecretionfailedtoimprovemotoroutcomes.Thus,allogeneicgraftsofBMSCsdonotappeartoactthroughlocalmechanisms,andfuture

clinicaltrials

thatacutelydeliverBMSCstoactualsitesof

injury

withindaysareunlikelytobebeneficial.IntraspinalStemCellTransplantationinAmyotrophicLateralSclerosis:APhaseISafetyTrial,TechnicalNote,andLumbarSafetyOutcomesNEUROSURGERYVOLUME71|NUMBER2|AUGUST2012DepartmentofNeurosurgery,EmoryUniversity,Atlanta,Georgia;DepartmentofNeurology,EmoryUniversity,Atlanta,Georgia;DepartmentofNeurology,UniversityofMichigan,AnnArbor,Michigan神经干细胞移植方法Eachmicroinjectionseriescomprised5injections(10mL/injection)separatedby4mm.Eachinjection:100000neuralstemcellsderivedfromafetalspinalcord.Twelvepatientsweretreatedwitheitherunilateralorbilateralinjections.Patientsarefollowedclinicallyandradiologicallytoassesspotentialtoxicityoftheprocedure.LumbarLaminectomyMicroinjectionplatformapplicationPostoperativeimagingprogressionRiley,J.,Feldman,E.L.,2014.“IntraspinalstemcelltransplantationinALS:aphaseItrial,cervicalmicroinjectionandfinalsurgicalsafetyoutcomes”.Neurosurgery74(1),77–87

ClinicalTrialsusingESCsandiPSCsThereisalsoareportofoneJapanesepatientwhoreceivedatransplantofasheetofiPSC-derivedRPESummaryonMolecularMechanismofStemCellTransplantationforNeurologicalDiseasesTransplantedcellssurvive，differentiatetoneurons,astrocytes,oligodendrocyteprecursors(hESC,hiPSC,NSC)andreleaseneurologicaltransmittorssuchasdopamine,Ach.Releaseofneurotrophicfactors(GDNF,GDNE,IGF,)toincreasethefunctionsoftheendogenousneuralstemcellsReleaseofimmuno-regulatoryfactorssuchasIL-2,6,8,10toplayimmuno-modulationandattenuationoftheinflammatoryprocess,suchasMSC.Thetransplantedcellsformedsynapsewithhostcells.OtherssuchasdelayingtheonsetandprolongingsurvivalofSOD1ratsIncreasinghostneurogenesisOleIsacsonetal，HarvardStemCellInstituteEachinjection:100000neuralstemcellsderivedfromafetalspinalcord.Cells

wereadministered48hoursaftertheoriginal

injury.sheetofiPSC-derivedRPEOtherssuchasdelayingtheonsetandprolongingsurvivalofSOD1ratsEachmicroinjectionseriescomprised5injections(10mL/injection)separatedby4mm.“IntraspinalstemcelltransplantationinALS:aphaseItrial,cervicalmicroinjectionandfinalsurgicalsafetyoutcomes”.SummaryonMolecularMechanismofStemCellTransplantationforNeurologicalDiseasesIntraspinalstemcelltransplantationinALS:aphaseItrial,2014Glass,Feldman,E.University,Atlanta,Georgia;DepartmentofNeurology,EmoryUniversity,Atlanta,Georgia;DepartmentofNeurology,UniversityofMichigan,AnnArbor,MichiganAmyotrophicLateralSclerosis:Cells

wereadministered48hoursaftertheoriginal

injury.ThereisalsoareportofoneJapanesepatientwhoreceivedatransplantofa,Feldman,E.AmyotrophicLateralSclerosis:2008May;14(5):504-6.“IntraspinalstemcelltransplantationinALS:aphaseItrial,cervicalmicroinjectionandfinalsurgicalsafetyoutcomes”.Twelvepatientsweretreatedwitheitherunilateralorbilateralinjections.Mendez,Isacsonetal,,NATUREMEDICINEVOLUME14(5):507-509,2008干细胞移植修复脊髓神经损伤AmyotrophicLateralSclerosis:OleIsacsonetal，HarvardStemCellInstituteIntraspinalstemcelltransplantationinALS:aphaseItrial,2014“IntraspinalstemcelltransplantationinALS:aphaseItrial,cervicalmicroinjectionandfinalsurgicalsafetyoutcomes”.神经退行性疾病干细胞移植治疗目前研究现状与未来展望Patientsarefollowedclinicallyandradiologicallytoassesspotentialtoxicityoftheprocedure.OleIsacsonetal，HarvardStemCellInstituteThisincludestheabsenceoftumorformationandGIDs（graft-induceddyskinesia）throughoutlong-termfollow-upperiods.2012September14;150(6):1264–1273Ubiquintin-GraftedNeuronsIncreasinghostneurogenesisEvaluationSystem（Symptoms,Dopaminerelease,Levodopa-response),UnifiedParkinson’sDiseaseRatingScale(UPDRS)，BiomarkersTrial,TechnicalNote,andLumbarSafetyOutcomes“IntraspinalstemcelltransplantationinALS:aphaseItrial,cervicalmicroinjectionandfinalsurgicalsafetyoutcomes”.,Feldman,E.Adverseeffectsmustbeminimal.GraftednigralneuronswerefoundtohaveLewybody-likeinclusions14yearsaftertransplantationintothestriatumofanindividualwithPD“IntraspinalstemcelltransplantationinALS:aphaseItrial,cervicalmicroinjectionandfinalsurgicalsafetyoutcomes”.“IntraspinalstemcelltransplantationinALS:aphaseItrial,cervicalmicroinjectionandfinalsurgicalsafetyoutcomes”.DopaminereleasefromtransplantedneuralstemcellsinParkinsonianratstriatuminvivo.分化的胎脑神经干细胞移植治疗PDiPSCellsWereGeneratedfromPDpatientsandNormalControlstoincreasethefunctionsoftheendogenousneuralstemcells6OHDAinducedRatPDModel2010Jan;51(1):7-15“IntraspinalstemcelltransplantationinALS:aphaseItrial,cervicalmicroinjectionandfinalsurgicalsafetyoutcomes”.ThereisalsoareportofoneJapanesepatientwhoreceivedatransplantofa-LongtermStudyThereisalsoareportofoneJapanesepatientwhoreceivedatransplantofaPatientsarefollowedclinicallyandradiologicallytoassesspotentialtoxicityoftheprocedure.Patientsarefollowedclinicallyandradiologicallytoassesspotentialtoxicityoftheprocedure.SCgraftsshouldexhibitregulatedreleaseofdopamineinlinewiththatofendogenousdopaminergicneurons.APhase