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演示文稿

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演示文稿目前一页\总数三十四页\编于十八点（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目前二页\总数三十四页\编于十八点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;200:169-98目前三页\总数三十四页\编于十八点LindvallO,etal，NatMed.2008May;14(5):501-3THSynucleinOverlayTransplantedfetalmesencephalicdopaminergicneurons(11-16years)developedalpha-synuclein-positiveLewybodiesingraftedneurons目前四页\总数三十四页\编于十八点Synuclein-HostUbiquintin-HostSynuclein-GraftedNeuronsUbiquintin-GraftedNeuronsGraftednigralneuronswerefoundtohaveLewybody-likeinclusions14yearsaftertransplantationintothestriatumofanindividualwithPDOlanowCW.etalNatMed.2008May;14(5):504-6.目前五页\总数三十四页\编于十八点TransplanteddopamineneuronsinpeoplewithPDdonotcontainLewybodiesMendez,Isacsonetal,,NATUREMEDICINEVOLUME14(5):507-509,2008目前六页\总数三十四页\编于十八点FreedCR,JNuclMed.2010Jan;51(1):7-15-LongtermStudy-33oftheoriginaltrialparticipantswhowerefollowedfor2yearsaftertransplantationand15ofthesesubjectswhowerefollowedfor2additionalyears.-Theseresultssuggestthatclinicalbenefitandgraftviabilityaresustainedupto4yaftertransplantation.

FreedCR,Neurotherapeutics(2011)8:549–561目前七页\总数三十四页\编于十八点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-KetteringCancerCenter目前八页\总数三十四页\编于十八点ImprovedCellTherapyProtocolforParkinson’sDiseaseBasedonDifferentiationEfficiencyandSafetyofhESC-,HipscandNon-HumanPrimateiPSC-DerivedDANeuronsIsacsonetal,,StemCells.2013;31(8):1548-62.目前九页\总数三十四页\编于十八点DopaminereleasefromtransplantedneuralstemcellsinParkinsonianratstriatuminvivo.

Zhouz,etal,ProcNatlAcadSciUSA.2014Nov4;111(44):15804-9目前十页\总数三十四页\编于十八点iPSC-DerivedDopamineNeuronsfunctionafterTransplantationinaNon-HumanPrimateModelofParkinson’sDiseaseCellStemCell.2015Mar5;16(3):269-74.

OleIsacsonetal，HarvardStemCellInstitute目前十一页\总数三十四页\编于十八点Stemcell-basedClinicalTrialsfor(ALS)Nuralstem,Inc.thefirstPhaseIclinicaltrialforastemcell-basedtreatmentofALS.Initiatedin2010andcompletedin2013,involvedthetransplan-tationofhumanspinalcord-derivedNSCsintothespinalcordof15latetomid-stageALSpatients目前十二页\总数三十四页\编于十八点Glass,Feldman,E.L.,2012.Lumbarintraspinalinjectionofneuralstemcellsinpatientswithamyotrophiclateralsclerosis:resultsofaphaseItrialin12patients.StemCells30(6),1144–1151.Riley,J.,Feldman,E.L.,2014.“IntraspinalstemcelltransplantationinALS:aphaseItrial,cervicalmicroinjectionandfinalsurgicalsafetyoutcomes”.Neurosurgery74(1),77–87目前十三页\总数三十四页\编于十八点RESULTS:Unilateralcervical(groupD,n=3)andcervicalplusthoracolumbar(groupE,n=3)microinjectionstotheventralhornhavebeencompletedinambulatorypatients.Onepatientdevelopedapostoperativekyphoticdeformitypromptingcompletionofalaminoplastyinsubsequentpatients.Anotherrequiredreoperationforwounddehiscenceandinfection.Thesolitarypatientwithbulbaramyotrophiclateralsclerosisrequiredperioperativereintubation.CONCLUSION:Deliveryofacellularpayloadtothecervicalorthoracolumbarspinalcordwaswelltoleratedbythespinalcordinthisvulnerablepopulation.Thisencouragingfindingsupportsconsiderationofthisdeliveryapproachforneurodegenerative,oncologic,andtraumaticspinalcordafflictions.IntraspinalstemcelltransplantationinALS:aphaseItrial,2014目前十四页\总数三十四页\编于十八点iPSCellsWereGeneratedfromPDpatientsandNormalControls目前十五页\总数三十四页\编于十八点6-OHDA-inducedRatPDModel目前十六页\总数三十四页\编于十八点HumaniPScellsIntegratedtotheHostBrainof6-OHDA-inducedRatPDModelHanF,WangW,ChenC,DuanJ,etalCytotherapy2015目前十七页\总数三十四页\编于十八点分化的胎脑神经干细胞移植治疗PD目前十八页\总数三十四页\编于十八点建立大鼠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。目前十九页\总数三十四页\编于十八点RT-PCRtoDetecttheMicroRNAExpressioninRatSCIModelMiR-124MiR-124MiR-124MiR-127MiR-127MiR-127MiR-127MiR-124MiR-133aMiR-133aMiR-133aMiR-181aMiR-181aMiR-181a目前二十页\总数三十四页\编于十八点Real-TimeRT-PCRtoDetecttheMicroRNAExpressioninSCI目前二十一页\总数三十四页\编于十八点干细胞移植修复脊髓神经损伤目前二十二页\总数三十四页\编于十八点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):1264–1273目前二十三页\总数三十四页\编于十八点BoneMarrowStromalCellIntraspinalTransplantsFailtoImproveMotorOutcomesinaSevereModelof

SCIJournalofNeurotrauma2015，TuszynskiMHTodeterminewhetherlocalmechanismsmediateBMSCneuroprotectiveactionsgraftedallogeneicBMSCstositesofsevere,compressive

spinalcordinjury

(SCI)inSpragueDawleyrats.

Cells

wereadministered48hoursaftertheoriginal

injury.AdditionalanimalsreceivedallogeneicMSCsthatweregeneticallymodifiedtosecreteBDNF,tofurtherdeterminewhetheralocallyadministeredneurotrophicfactorprovidesorextendsneuroprotection.twomonthspost-injury

inaclinicallyrelevantmodelofsevereSCI,BMSCgraftswithorwithoutBDNFsecretionfailedtoimprovemotoroutcomes.Thus,allogeneicgraftsofBMSCsdonotappeartoactthroughlocalmechanisms,andfuture

clinicaltrials

thatacutelydeliverBMSCstoactualsitesof

injury

withindaysareunlikelytobebeneficial.目前二十四页\总数三十四页\编于十八点IntraspinalStemCellTransplantationinAmyotrophicLateralSclerosis:APhaseISafetyTrial,TechnicalNote,andLumbarSafetyOutcomesNEUROSURGERYVOLUME71|NUMBER2|AUGUST2012DepartmentofNeurosurgery,EmoryUniversity,Atlanta,Georgia;DepartmentofNeurology,EmoryUniversity,Atlanta,Georgia;DepartmentofNeurology,UniversityofMichigan,AnnArbor,Michigan目前二十五页\总数三十四页\编于十八点神经干细胞移植方法Eachmicroinjectionseriescomprised5injections(10mL/injection)separatedby4mm.Eachinjection:100000neuralstemcellsderivedfromafetalspinalcord.Twelvepatientsweretreatedwitheitherunilateralorbilateralinjections.Patientsarefollowedclinicallyandradiologicallytoassesspotentialtoxicityoftheprocedure.目前二十六页\总数三十四页\编于十八点LumbarLaminectomy目前二十七页\总数三十四页\编于十八点Microinjectionplatformapplication目前二十八页\总数三十四页\编于十八点Postoperativeimagingprogression目前二十九页\总数三十四页\编于十八点Riley,J.,Feldman,E.L.,2014.“IntraspinalstemcelltransplantationinALS:aphaseItrial,cervicalmicroinjectionandfinalsurgicalsafetyoutcomes”.Neurosurgery74(1),77–87

目前三十页\总数三十四页\编于十八点ClinicalTrialsusingESCsandiPSCs目前三十一页\总数三十四页\编于十八点ThereisalsoareportofoneJapanesepatientwhoreceivedatransplantofasheetofiPSC-derivedRPE目前三十二页\总数三十四页\编于十八点SummaryonMolecularMechanismofStemCellTransplantationforNeurologicalDiseasesTransplantedcellssurvive，differentiatetoneurons,astrocytes,oligodendrocyteprecursors(hESC,hiPSC,NSC)andreleaseneurologicaltransmittorssuchasdopamine,Ach.Releaseofneurotrophicfactors(GDNF,GDNE,IGF,)toincreasethefunctionsoftheendogenousneuralstemcellsReleaseofimmuno-regulatoryfactorssuchasIL-2,6,8,10toplayimmuno-modulationandattenuationoftheinflammatoryprocess,suchasMSC.Thetransplantedcellsformedsynapsewithhostcells.OtherssuchasdelayingtheonsetandprolongingsurvivalofSOD1ratsIncreasinghostneurogenesis目前三十三页\总数三十四页\编于十八点今后干细胞治疗神经退行性疾病的临床研究

需要考虑的问题1.CellSources：Neuralprojenitors，MSC，hEScells，iPScells2.SCgrafti