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

StemCellSourcesforTreatmentofNeurologicalDiseases(AD,PD,ALS,MS,Stroke,SCI)FabinHan,etal,JournalofNeurorestoratology2015:31–12第一页，共三十五页。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第二页，共三十五页。LindvallO,etal，NatMed.2008May;14(5):501-3THSynucleinOverlayTransplantedfetalmesencephalicdopaminergicneurons(11-16years)developedalpha-synuclein-positiveLewybodiesingraftedneurons第三页，共三十五页。Synuclein-HostUbiquintin-HostSynuclein-GraftedNeuronsUbiquintin-GraftedNeuronsGraftednigralneuronswerefoundtohaveLewybody-likeinclusions14yearsaftertransplantationintothestriatumofanindividualwithPDOlanowCW.etalNatMed.2008May;14(5):504-6.第四页，共三十五页。TransplanteddopamineneuronsinpeoplewithPDdonotcontainLewybodiesMendez,Isacsonetal,,NATUREMEDICINEVOLUME14(5):507-509,2008第五页，共三十五页。FreedCR,JNuclMed.2010Jan;51(1):7-15-LongtermStudy-33oftheoriginaltrialparticipantswhowerefollowedfor2yearsaftertransplantationand15ofthesesubjectswhowerefollowedfor2additionalyears.-Theseresultssuggestthatclinicalbenefitandgraftviabilityaresustainedupto4yaftertransplantation.

FreedCR,Neurotherapeutics(2011)8:549–561第六页，共三十五页。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第七页，共三十五页。ImprovedCellTherapyProtocolforParkinson’sDiseaseBasedonDifferentiationEfficiencyandSafetyofhESC-,HipscandNon-HumanPrimateiPSC-DerivedDANeuronsIsacsonetal,,StemCells.2013;31(8):1548-62.第八页，共三十五页。DopaminereleasefromtransplantedneuralstemcellsinParkinsonianratstriatuminvivo.

Zhouz,etal,ProcNatlAcadSciUSA.2014Nov4;111(44):15804-9第九页，共三十五页。iPSC-DerivedDopamineNeuronsfunctionafterTransplantationinaNon-HumanPrimateModelofParkinson’sDiseaseCellStemCell.2015Mar5;16(3):269-74.

OleIsacsonetal，HarvardStemCellInstitute第十页，共三十五页。Stemcell-basedClinicalTrialsfor(ALS)Nuralstem,Inc.thefirstPhaseIclinicaltrialforastemcell-basedtreatmentofALS.Initiatedin2010andcompletedin2013,involvedthetransplan-tationofhumanspinalcord-derivedNSCsintothespinalcordof15latetomid-stageALSpatients第十一页，共三十五页。Glass,Feldman,E.L.,2012.Lumbarintraspinalinjectionofneuralstemcellsinpatientswithamyotrophiclateralsclerosis:resultsofaphaseItrialin12patients.StemCells30(6),1144–1151.Riley,J.,Feldman,E.L.,2014.“IntraspinalstemcelltransplantationinALS:aphaseItrial,cervicalmicroinjectionandfinalsurgicalsafetyoutcomes”.Neurosurgery74(1),77–87第十二页，共三十五页。RESULTS:Unilateralcervical(groupD,n=3)andcervicalplusthoracolumbar(groupE,n=3)microinjectionstotheventralhornhavebeencompletedinambulatorypatients.Onepatientdevelopedapostoperativekyphoticdeformitypromptingcompletionofalaminoplastyinsubsequentpatients.Anotherrequiredreoperationforwounddehiscenceandinfection.Thesolitarypatientwithbulbaramyotrophiclateralsclerosisrequiredperioperativereintubation.CONCLUSION:Deliveryofacellularpayloadtothecervicalorthoracolumbarspinalcordwaswelltoleratedbythespinalcordinthisvulnerablepopulation.Thisencouragingfindingsupportsconsiderationofthisdeliveryapproachforneurodegenerative,oncologic,andtraumaticspinalcordafflictions.IntraspinalstemcelltransplantationinALS:aphaseItrial,2014第十三页，共三十五页。iPSCellsWereGeneratedfromPDpatientsandNormalControls第十四页，共三十五页。6-OHDA-inducedRatPDModel第十五页，共三十五页。HumaniPScellsIntegratedtotheHostBrainof6-OHDA-inducedRatPDModelHanF,WangW,ChenC,DuanJ,etalCytotherapy2015第十六页，共三十五页。分化的胎脑神经干细胞移植治疗PD第十七页，共三十五页。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。第十八页，共三十五页。RT-PCRtoDetecttheMicroRNAExpressioninRatSCIModelMiR-124MiR-124MiR-124MiR-127MiR-127MiR-127MiR-127MiR-124MiR-133aMiR-133aMiR-133aMiR-181aMiR-181aMiR-181a第十九页，共三十五页。Real-TimeRT-PCRtoDetecttheMicroRNAExpressioninSCI第二十页，共三十五页。干细胞移植修复脊髓神经损伤第二十一页，共三十五页。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第二十二页，共三十五页。BoneMarrowStromalCellIntraspinalTransplantsFailtoImproveMotorOutcomesinaSevereModelof

SCIJournalofNeurotrauma2015，TuszynskiMHTodeterminewhetherlocalmechanismsmediateBMSCneuroprotectiveactionsgraftedallogeneicBMSCstositesofsevere,compressive

spinalcordinjury

(SCI)inSpragueDawleyrats.

Cells

wereadministered48hoursaftertheoriginal

injury.AdditionalanimalsreceivedallogeneicMSCsthatweregeneticallymodifiedtosecreteBDNF,tofurtherdeterminewhetheralocallyadministeredneurotrophicfactorprovidesorextendsneuroprotection.twomonthspost-injury

inaclinicallyrelevantmodelofsevereSCI,BMSCgraftswithorwithoutBDNFsecretionfailedtoimprovemotoroutcomes.Thus,allogeneicgraftsofBMSCsdonotappeartoactthroughlocalmechanisms,andfuture

clinicaltrials

thatacutelydeliverBMSCstoactualsitesof

injury

withindaysareunlikelytobebeneficial.第二十三页，共三十五页。IntraspinalStemCellTransplantationinAmyotrophicLateralSclerosis:APhaseISafetyTrial,TechnicalNote,andLumbarSafetyOutcomesNEUROSURGERYVOLUME71|NUMBER2|AUGUST2012DepartmentofNeurosurgery,EmoryUniversity,Atlanta,Georgia;DepartmentofNeurology,EmoryUniversity,Atlanta,Georgia;DepartmentofNeurology,UniversityofMichigan,AnnArbor,Michigan第二十四页，共三十五页。神经干细胞移植方法Eachmicroinjectionseriescomprised5injections(10mL/injection)separatedby4mm.Eachinjection:100000neuralstemcellsderivedfromafetalspinalcord.Twelvepatientsweretreatedwitheitherunilateralorbilateralinjections.Patientsarefollowedclinicallyandradiologicallytoassesspotentialtoxicityoftheprocedure.第二十五页，共三十五页。LumbarLaminectomy第二十六页，共三十五页。Microinjectionplatformapplication第二十七页，共三十五页。Postoperativeimagingprogression第二十八页，共三十五页。Riley,J.,Feldman,E.L.,2014.“IntraspinalstemcelltransplantationinALS:aphaseItrial,cervicalmicroinjectionandfinalsurgicalsafetyoutcomes”.Neurosurgery74(1),77–87

第二十九页，共三十五页。ClinicalTrialsusingESCsandiPSCs第三十页，共三十五页。ThereisalsoareportofoneJapanesepatientwhoreceivedatransplantofasheetofiPSC-derivedRPE第三十一页，共三十五页。SummaryonMolecularMechanismofStemCellTransplantationforNeurologicalDiseasesTransplantedcellssurvive，differentiatetoneurons,astrocytes,oligodendrocyteprecursors(hESC,hiPSC,NSC)andreleaseneurologicaltransmittorssuchasdopamine,Ach.Releaseofneurotrophicfactors(GDNF,GDNE,IGF,)toincreasethefunctionsoftheendogenousneuralstemcellsReleaseofimmuno-regulatoryfactorssuchasIL-2,6,8,10toplayimmuno-modulationandattenuationoftheinflammatoryprocess,suchasMSC.Thetransplantedcellsformedsynapsewithhostcells.OtherssuchasdelayingtheonsetandprolongingsurvivalofSOD1ratsIncreasinghostneurogenesis第三十二页，共三十五页。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.SCgraftingshouldbeconductedtoensure>100,000dopaminergicneurons（PD）survivepertransplantationsite.3.SCgraftsshouldexhibitregul