神經(jīng)退行性疾病干細(xì)胞移植治療目前研究現(xiàn)狀與未來展望演示文稿

神經(jīng)退行性疾病干細(xì)胞移植治療目前研究現(xiàn)狀與未來展望演示文稿目前一頁\總數(shù)三十四頁\編于十八點(diǎn)（優(yōu)選）神經(jīng)退行性疾病干細(xì)胞移植治療目前研究現(xiàn)狀與未來展望目前二頁\總數(shù)三十四頁\編于十八點(diǎn)胎兒神經(jīng)干細(xì)胞治療帕金森氏病臨床研究發(fā)展歷程EvansJR,MasonSL,BarkerRA.ProgBrainRes.2012;200:169-98目前三頁\總數(shù)三十四頁\編于十八點(diǎn)LindvallO,etal，NatMed.2008May;14(5):501-3THSynucleinOverlayTransplantedfetalmesencephalicdopaminergicneurons(11-16years)developedalpha-synuclein-positiveLewybodiesingraftedneurons目前四頁\總數(shù)三十四頁\編于十八點(diǎn)Synuclein-HostUbiquintin-HostSynuclein-GraftedNeuronsUbiquintin-GraftedNeuronsGraftednigralneuronswerefoundtohaveLewybody-likeinclusions14yearsaftertransplantationintothestriatumofanindividualwithPDOlanowCW.etalNatMed.2008May;14(5):504-6.目前五頁\總數(shù)三十四頁\編于十八點(diǎn)TransplanteddopamineneuronsinpeoplewithPDdonotcontainLewybodiesMendez,Isacsonetal,,NATUREMEDICINEVOLUME14(5):507-509,2008目前六頁\總數(shù)三十四頁\編于十八點(diǎn)FreedCR,JNuclMed.2010Jan;51(1):7-15-LongtermStudy-33oftheoriginaltrialparticipantswhowerefollowedfor2yearsaftertransplantationand15ofthesesubjectswhowerefollowedfor2additionalyears.-Theseresultssuggestthatclinicalbenefitandgraftviabilityaresustainedupto4yaftertransplantation.

FreedCR,Neurotherapeutics(2011)8:549–561目前七頁\總數(shù)三十四頁\編于十八點(diǎn)人體胚胎干細(xì)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(yùn)動障礙22/29DECEMBER2011|VOL480|NATURE|547，LorenzStuder，etal

MemorialSloan-KetteringCancerCenter目前八頁\總數(shù)三十四頁\編于十八點(diǎn)ImprovedCellTherapyProtocolforParkinson’sDiseaseBasedonDifferentiationEfficiencyandSafetyofhESC-,HipscandNon-HumanPrimateiPSC-DerivedDANeuronsIsacsonetal,,StemCells.2013;31(8):1548-62.目前九頁\總數(shù)三十四頁\編于十八點(diǎn)DopaminereleasefromtransplantedneuralstemcellsinParkinsonianratstriatuminvivo.

Zhouz,etal,ProcNatlAcadSciUSA.2014Nov4;111(44):15804-9目前十頁\總數(shù)三十四頁\編于十八點(diǎn)iPSC-DerivedDopamineNeuronsfunctionafterTransplantationinaNon-HumanPrimateModelofParkinson’sDiseaseCellStemCell.2015Mar5;16(3):269-74.

OleIsacsonetal，HarvardStemCellInstitute目前十一頁\總數(shù)三十四頁\編于十八點(diǎn)Stemcell-basedClinicalTrialsfor(ALS)Nuralstem,Inc.thefirstPhaseIclinicaltrialforastemcell-basedtreatmentofALS.Initiatedin2010andcompletedin2013,involvedthetransplan-tationofhumanspinalcord-derivedNSCsintothespinalcordof15latetomid-stageALSpatients目前十二頁\總數(shù)三十四頁\編于十八點(diǎn)Glass,Feldman,E.L.,2012.Lumbarintraspinalinjectionofneuralstemcellsinpatientswithamyotrophiclateralsclerosis:resultsofaphaseItrialin12patients.StemCells30(6),1144–1151.Riley,J.,Feldman,E.L.,2014.“IntraspinalstemcelltransplantationinALS:aphaseItrial,cervicalmicroinjectionandfinalsurgicalsafetyoutcomes”.Neurosurgery74(1),77–87目前十三頁\總數(shù)三十四頁\編于十八點(diǎn)RESULTS:Unilateralcervical(groupD,n=3)andcervicalplusthoracolumbar(groupE,n=3)microinjectionstotheventralhornhavebeencompletedinambulatorypatients.Onepatientdevelopedapostoperativekyphoticdeformitypromptingcompletionofalaminoplastyinsubsequentpatients.Anotherrequiredreoperationforwounddehiscenceandinfection.Thesolitarypatientwithbulbaramyotrophiclateralsclerosisrequiredperioperativereintubation.CONCLUSION:Deliveryofacellularpayloadtothecervicalorthoracolumbarspinalcordwaswelltoleratedbythespinalcordinthisvulnerablepopulation.Thisencouragingfindingsupportsconsiderationofthisdeliveryapproachforneurodegenerative,oncologic,andtraumaticspinalcordafflictions.IntraspinalstemcelltransplantationinALS:aphaseItrial,2014目前十四頁\總數(shù)三十四頁\編于十八點(diǎn)iPSCellsWereGeneratedfromPDpatientsandNormalControls目前十五頁\總數(shù)三十四頁\編于十八點(diǎn)6-OHDA-inducedRatPDModel目前十六頁\總數(shù)三十四頁\編于十八點(diǎn)HumaniPScellsIntegratedtotheHostBrainof6-OHDA-inducedRatPDModelHanF,WangW,ChenC,DuanJ,etalCytotherapy2015目前十七頁\總數(shù)三十四頁\編于十八點(diǎn)分化的胎腦神經(jīng)干細(xì)胞移植治療PD目前十八頁\總數(shù)三十四頁\編于十八點(diǎn)建立大鼠SCI損傷模型A.暴露和部分橫切脊髓外科手術(shù)。B.T7橫斷損傷產(chǎn)生后肢癱瘓。C.無脊髓損傷的正常大鼠。目前十九頁\總數(shù)三十四頁\編于十八點(diǎn)RT-PCRtoDetecttheMicroRNAExpressioninRatSCIModelMiR-124MiR-124MiR-124MiR-127MiR-127MiR-127MiR-127MiR-124MiR-133aMiR-133aMiR-133aMiR-181aMiR-181aMiR-181a目前二十頁\總數(shù)三十四頁\編于十八點(diǎn)Real-TimeRT-PCRtoDetecttheMicroRNAExpressioninSCI目前二十一頁\總數(shù)三十四頁\編于十八點(diǎn)干細(xì)胞移植修復(fù)脊髓神經(jīng)損傷目前二十二頁\總數(shù)三十四頁\編于十八點(diǎn)移植神經(jīng)干細(xì)胞分化的神經(jīng)軸索與宿主脊髓神經(jīng)細(xì)胞及其樹突形成突觸連接LuPetal，Cell.2012September14;150(6):1264–1273目前二十三頁\總數(shù)三十四頁\編于十八點(diǎn)BoneMarrowStromalCellIntraspinalTransplantsFailtoImproveMotorOutcomesinaSevereModelof

SCIJournalofNeurotrauma2015，TuszynskiMHTodeterminewhetherlocalmechanismsmediateBMSCneuroprotectiveactionsgraftedallogeneicBMSCstositesofsevere,compressive

spinalcordinjury

(SCI)inSpragueDawleyrats.

Cells

wereadministered48hoursaftertheoriginal

injury.AdditionalanimalsreceivedallogeneicMSCsthatweregeneticallymodifiedtosecreteBDNF,tofurtherdeterminewhetheralocallyadministeredneurotrophicfactorprovidesorextendsneuroprotection.twomonthspost-injury

inaclinicallyrelevantmodelofsevereSCI,BMSCgraftswithorwithoutBDNFsecretionfailedtoimprovemotoroutcomes.Thus,allogeneicgraftsofBMSCsdonotappeartoactthroughlocalmechanisms,andfuture

clinicaltrials

thatacutelydeliverBMSCstoactualsitesof

injury

withindaysareunlikelytobebeneficial.目前二十四頁\總數(shù)三十四頁\編于十八點(diǎn)IntraspinalStemCellTransplantationinAmyotrophicLateralSclerosis:APhaseISafetyTrial,TechnicalNote,andLumbarSafetyOutcomesNEUROSURGERYVOLUME71|NUMBER2|AUGUST2012DepartmentofNeurosurgery,EmoryUniversity,Atlanta,Georgia;DepartmentofNeurology,EmoryUniversity,Atlanta,Georgia;DepartmentofNeurology,UniversityofMichigan,AnnArbor,Michigan目前二十五頁\總數(shù)三十四頁\編于十八點(diǎn)神經(jīng)干細(xì)胞移植方法Eachmicroinjectionseriescomprised5injections(10mL/injection)separatedby4mm.Eachinjection:100000neuralstemcellsderivedfromafetalspinalcord.Twelvepatientsweretreatedwitheitherunilateralorbilateralinjections.Patientsarefollowedclinicallyandradiologicallytoassesspotentialtoxicityoftheprocedure.目前二十六頁\總數(shù)三十四頁\編于十八點(diǎn)LumbarLaminectomy目前二十七頁\總數(shù)三十四頁\編于十八點(diǎn)Microinjectionplatformapplication目前二十八頁\總數(shù)三十四頁\編于十八點(diǎn)Postoperativeimagingprogression目前二十九頁\總數(shù)三十四頁\編于十八點(diǎn)Riley,J.,Feldman,E.L.,2014.“IntraspinalstemcelltransplantationinALS:aphaseItrial,cervicalmicroinjectionandfinalsurgicalsafetyoutcomes”.Neurosurgery74(1),77–87

目前三十頁\總數(shù)三十四頁\編于十八點(diǎn)ClinicalTrialsusingESCsandiPSCs目前三十一頁\總數(shù)三十四頁\編于十八點(diǎn)ThereisalsoareportofoneJapanesepatientwhoreceivedatransplantofasheetofiPSC-derivedRPE目前三十二頁\總數(shù)三十四頁\編于十八點(diǎn)SummaryonMolecularMechanismofStemCellTransplantationforNeurologicalDiseasesTransplantedcellssurvive，differentiatetoneurons,astrocytes,oligodendrocyteprecursors(hESC,hiPSC,NSC)andreleaseneurologicaltransmittorssuchasdopamine,Ach.Releaseofneurotrophicfactors(GDNF,GDNE,IGF,)toincreasethefunctionsoftheendogenousneuralstemcellsReleaseofimmuno-regulatoryfactorssuchasIL-2,6,8,10toplayimmuno-modulationandattenuationoftheinflammatoryprocess,suchasMSC.Thetransplantedcellsformedsynapsewithhostcells.OtherssuchasdelayingtheonsetandprolongingsurvivalofSOD1ratsIncreasinghostneurogenesis目前三十三頁\總數(shù)三十四頁\編于十八點(diǎn)今后干細(xì)胞治療神經(jīng)退行性疾病的臨床研究

需要考慮的問題1.CellSources：Neuralprojenitors，MSC，hEScells，iPScells2.SCgrafti