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神經(jīng)退行性疾病干細胞移植治療目前研究現(xiàn)狀與未來展望(優(yōu)選)神經(jīng)退行性疾病干細胞移植治療目前研究現(xiàn)狀與未來展望胎兒神經(jīng)干細胞治療帕金森氏病臨床研究發(fā)展歷程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人體胚胎干細胞分化的多巴胺神經(jīng)元移植
改善小鼠,大鼠和猴子帕金森氏病的運動障礙22/29DECEMBER2011|VOL480|NATURE|547,LorenzStuder,etal
MemorialSloan-KetteringCancerCenterImprovedCellTherapyProtocolforParkinson’sDiseaseBasedonDifferentiationEfficiencyandSafetyofhESC-,HipscandNon-HumanPrimateiPSC-DerivedDANeuronsIsacsonetal,,StemCells.2013;31(8):1548-62.DopaminereleasefromtransplantedneuralstemcellsinParkinsonianratstriatuminvivo.Twelvepatientsweretreatedwitheitherunilateralorbilateralinjections.6OHDAinducedRatPDModel分化的胎腦神經(jīng)干細胞移植治療PDIncreasinghostneurogenesis“IntraspinalstemcelltransplantationinALS:aphaseItrial,cervicalmicroinjectionandfinalsurgicalsafetyoutcomes”.TodeterminewhetherlocalmechanismsmediateBMSCneuroprotectiveactionsetalNatMed.(優(yōu)選)神經(jīng)退行性疾病干細胞移植治療目前研究現(xiàn)狀與未來展望胎兒神經(jīng)干細胞治療帕金森氏病臨床研究發(fā)展歷程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.暴露和部分橫切脊髓外科手術。University,Atlanta,Georgia;DepartmentofNeurology,EmoryUniversity,Atlanta,Georgia;DepartmentofNeurology,UniversityofMichigan,AnnArbor,MichiganGlass,Feldman,E.RTPCRtoDetecttheMicroRNAExpressioninRatSCIModelPatientsarefollowedclinicallyandradiologicallytoassesspotentialtoxicityoftheprocedure.Cells
wereadministered48hoursaftertheoriginal
injury.SCgraftsshouldexhibitregulatedreleaseofdopamineinlinewiththatofendogenousdopaminergicneurons.-LongtermStudy神經(jīng)退行性疾病干細胞移植治療目前研究現(xiàn)狀與未來展望Isacsonetal,,StemCells.神經(jīng)退行性疾病干細胞移植治療目前研究現(xiàn)狀與未來展望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分化的胎腦神經(jīng)干細胞移植治療PD建立大鼠SCI損傷模型A.暴露和部分橫切脊髓外科手術。B.T7橫斷損傷產(chǎn)生后肢癱瘓。C.無脊髓損傷的正常大鼠。RTPCRtoDetecttheMicroRNAExpressioninRatSCIModelMiR-124MiR-124MiR-124MiR-127MiR-127MiR-127MiR-127MiR-124MiR-133aMiR-133aMiR-133aMiR-181aMiR-181aMiR-181aRealTimeRTPCRtoDetecttheMicroRNAExpressioninSCI干細胞移植修復脊髓神經(jīng)損傷移植神經(jīng)干細胞分化的神經(jīng)軸索與宿主脊髓神經(jīng)細胞及其樹突形成突觸連接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神經(jīng)干細胞移植方法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干細胞移植修復脊髓神經(jīng)損傷AmyotrophicLateralSclerosis:OleIsacsonetal,HarvardStemCellInstituteIntraspinalstemcelltransplantationinALS:aphaseItrial,2014“IntraspinalstemcelltransplantationinALS:aphaseItrial,cervicalmicroinjectionandfinalsurgicalsafetyoutcomes”.神經(jīng)退行性疾病干細胞移植治療目前研究現(xiàn)狀與未來展望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.分化的胎腦神經(jīng)干細胞移植治療PDiPSCellsWereGeneratedfromPDpatientsandNormalControlstoincreasethefunctionsoftheendogenousneuralstemcells6OHDAinducedRatPDModel2010Jan;51(1):7-15“IntraspinalstemcelltransplantationinALS:aphaseItrial,cervicalmicroinjectionandfinalsurgicalsafetyoutcomes”.ThereisalsoareportofoneJapanesepatientwhoreceivedatransplantofa-LongtermStudyThereisalsoareportofoneJapanesepatientwhoreceivedatransplantofaPatientsarefollowedclinicallyandradiologicallytoassesspotentialtoxicityoftheprocedure.Patientsarefollowedclinicallyandradiologicallytoassesspotentialtoxicityoftheprocedure.SCgraftsshouldexhibitregulatedreleaseofdopamineinlinewiththatofendogenousdopaminergicneurons.APhase
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