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

StemCellSourcesforTreatmentofNeurologicalDiseases(AD,PD,ALS,MS,Stroke,SCI)FabinHan,etal,JournalofNeurorestoratology2015:31–12本文檔共35頁；當前第1頁；編輯于星期二\4點26分胎兒神經(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;200:169-98本文檔共35頁；當前第2頁；編輯于星期二\4點26分LindvallO,etal，NatMed.2008May;14(5):501-3THSynucleinOverlayTransplantedfetalmesencephalicdopaminergicneurons(11-16years)developedalpha-synuclein-positiveLewybodiesingraftedneurons本文檔共35頁；當前第3頁；編輯于星期二\4點26分Synuclein-HostUbiquintin-HostSynuclein-GraftedNeuronsUbiquintin-GraftedNeuronsGraftednigralneuronswerefoundtohaveLewybody-likeinclusions14yearsaftertransplantationintothestriatumofanindividualwithPDOlanowCW.etalNatMed.2008May;14(5):504-6.本文檔共35頁；當前第4頁；編輯于星期二\4點26分TransplanteddopamineneuronsinpeoplewithPDdonotcontainLewybodiesMendez,Isacsonetal,,NATUREMEDICINEVOLUME14(5):507-509,2008本文檔共35頁；當前第5頁；編輯于星期二\4點26分FreedCR,JNuclMed.2010Jan;51(1):7-15-LongtermStudy-33oftheoriginaltrialparticipantswhowerefollowedfor2yearsaftertransplantationand15ofthesesubjectswhowerefollowedfor2additionalyears.-Theseresultssuggestthatclinicalbenefitandgraftviabilityaresustainedupto4yaftertransplantation.

FreedCR,Neurotherapeutics(2011)8:549–561本文檔共35頁；當前第6頁；編輯于星期二\4點26分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-KetteringCancerCenter本文檔共35頁；當前第7頁；編輯于星期二\4點26分ImprovedCellTherapyProtocolforParkinson’sDiseaseBasedonDifferentiationEfficiencyandSafetyofhESC-,HipscandNon-HumanPrimateiPSC-DerivedDANeuronsIsacsonetal,,StemCells.2013;31(8):1548-62.本文檔共35頁；當前第8頁；編輯于星期二\4點26分DopaminereleasefromtransplantedneuralstemcellsinParkinsonianratstriatuminvivo.

Zhouz,etal,ProcNatlAcadSciUSA.2014Nov4;111(44):15804-9本文檔共35頁；當前第9頁；編輯于星期二\4點26分iPSC-DerivedDopamineNeuronsfunctionafterTransplantationinaNon-HumanPrimateModelofParkinson’sDiseaseCellStemCell.2015Mar5;16(3):269-74.

OleIsacsonetal，HarvardStemCellInstitute本文檔共35頁；當前第10頁；編輯于星期二\4點26分Stemcell-basedClinicalTrialsfor(ALS)Nuralstem,Inc.thefirstPhaseIclinicaltrialforastemcell-basedtreatmentofALS.Initiatedin2010andcompletedin2013,involvedthetransplan-tationofhumanspinalcord-derivedNSCsintothespinalcordof15latetomid-stageALSpatients本文檔共35頁；當前第11頁；編輯于星期二\4點26分Glass,Feldman,E.L.,2012.Lumbarintraspinalinjectionofneuralstemcellsinpatientswithamyotrophiclateralsclerosis:resultsofaphaseItrialin12patients.StemCells30(6),1144–1151.Riley,J.,Feldman,E.L.,2014.“IntraspinalstemcelltransplantationinALS:aphaseItrial,cervicalmicroinjectionandfinalsurgicalsafetyoutcomes”.Neurosurgery74(1),77–87本文檔共35頁；當前第12頁；編輯于星期二\4點26分RESULTS:Unilateralcervical(groupD,n=3)andcervicalplusthoracolumbar(groupE,n=3)microinjectionstotheventralhornhavebeencompletedinambulatorypatients.Onepatientdevelopedapostoperativekyphoticdeformitypromptingcompletionofalaminoplastyinsubsequentpatients.Anotherrequiredreoperationforwounddehiscenceandinfection.Thesolitarypatientwithbulbaramyotrophiclateralsclerosisrequiredperioperativereintubation.CONCLUSION:Deliveryofacellularpayloadtothecervicalorthoracolumbarspinalcordwaswelltoleratedbythespinalcordinthisvulnerablepopulation.Thisencouragingfindingsupportsconsiderationofthisdeliveryapproachforneurodegenerative,oncologic,andtraumaticspinalcordafflictions.IntraspinalstemcelltransplantationinALS:aphaseItrial,2014本文檔共35頁；當前第13頁；編輯于星期二\4點26分iPSCellsWereGeneratedfromPDpatientsandNormalControls本文檔共35頁；當前第14頁；編輯于星期二\4點26分6-OHDA-inducedRatPDModel本文檔共35頁；當前第15頁；編輯于星期二\4點26分HumaniPScellsIntegratedtotheHostBrainof6-OHDA-inducedRatPDModelHanF,WangW,ChenC,DuanJ,etalCytotherapy2015本文檔共35頁；當前第16頁；編輯于星期二\4點26分分化的胎腦神經(jīng)干細胞移植治療PD本文檔共35頁；當前第17頁；編輯于星期二\4點26分建立大鼠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。本文檔共35頁；當前第18頁；編輯于星期二\4點26分RT-PCRtoDetecttheMicroRNAExpressioninRatSCIModelMiR-124MiR-124MiR-124MiR-127MiR-127MiR-127MiR-127MiR-124MiR-133aMiR-133aMiR-133aMiR-181aMiR-181aMiR-181a本文檔共35頁；當前第19頁；編輯于星期二\4點26分Real-TimeRT-PCRtoDetecttheMicroRNAExpressioninSCI本文檔共35頁；當前第20頁；編輯于星期二\4點26分干細胞移植修復脊髓神經(jīng)損傷本文檔共35頁；當前第21頁；編輯于星期二\4點26分移植神經(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):1264–1273本文檔共35頁；當前第22頁；編輯于星期二\4點26分BoneMarrowStromalCellIntraspinalTransplantsFailtoImproveMotorOutcomesinaSevereModelof

SCIJournalofNeurotrauma2015，TuszynskiMHTodeterminewhetherlocalmechanismsmediateBMSCneuroprotectiveactionsgraftedallogeneicBMSCstositesofsevere,compressive

spinalcordinjury

(SCI)inSpragueDawleyrats.

Cells

wereadministered48hoursaftertheoriginal

injury.AdditionalanimalsreceivedallogeneicMSCsthatweregeneticallymodifiedtosecreteBDNF,tofurtherdeterminewhetheralocallyadministeredneurotrophicfactorprovidesorextendsneuroprotection.twomonthspost-injury

inaclinicallyrelevantmodelofsevereSCI,BMSCgraftswithorwithoutBDNFsecretionfailedtoimprovemotoroutcomes.Thus,allogeneicgraftsofBMSCsdonotappeartoactthroughlocalmechanisms,andfuture

clinicaltrials

thatacutelydeliverBMSCstoactualsitesof

injury

withindaysareunlikelytobebeneficial.本文檔共35頁；當前第23頁；編輯于星期二\4點26分IntraspinalStemCellTransplantationinAmyotrophicLateralSclerosis:APhaseISafetyTrial,TechnicalNote,andLumbarSafetyOutcomesNEUROSURGERYVOLUME71|NUMBER2|AUGUST2012DepartmentofNeurosurgery,EmoryUniversity,Atlanta,Georgia;DepartmentofNeurology,EmoryUniversity,Atlanta,Georgia;DepartmentofNeurology,UniversityofMichigan,AnnArbor,Michigan本文檔共35頁；當前第24頁；編輯于星期二\4點26分神經(jīng)干細胞移植方法Eachmicroinjectionseriescomprised5injections(10mL/injection)separatedby4mm.Eachinjection:100000neuralstemcellsderivedfromafetalspinalcord.Twelvepatientsweretreatedwitheitherunilateralorbilateralinjections.Patientsarefollowedclinicallyandradiologicallytoassesspotentialtoxicityoftheprocedure.本文檔共35頁；當前第25頁；編輯于星期二\4點26分LumbarLaminectomy本文檔共35頁；當前第26頁；編輯于星期二\4點26分Microinjectionplatformapplication本文檔共35頁；當前第27頁；編輯于星期二\4點26分Postoperativeimagingprogression本文檔共35頁；當前第28頁；編輯于星期二\4點26分Riley,J.,Feldman,E.L.,2014.“IntraspinalstemcelltransplantationinALS:aphaseItrial,cervicalmicroinjectionandfinalsurgicalsafetyoutcomes”.Neurosurgery74(1),77–87

本文檔共35頁；當前第29頁；編輯于星期二\4點26分ClinicalTrialsusingESCsandiPSCs本文檔共35頁；當前第30頁；編輯于星期二\4點26分ThereisalsoareportofoneJapanesepatientwhoreceivedatransplantofasheetofiPSC-derivedRPE本文檔共35頁；當前第31頁；編輯于星期二\4點26分SummaryonMolecularMechanismofStemCellTransplantationforNeurologicalDiseasesTransplantedcellssurvive，differentiatetoneurons,astrocytes,oligodendrocyteprecursors(hESC,hiPSC,NSC)andreleaseneurologicaltransmittorssuchasdopamine,Ach.Releaseofneurotrophicfactors(GDNF,GDNE,IGF,)toincreasethefunctionsoftheendogenousneuralstemcellsReleaseofimmuno-regulatoryfactorssuchasIL-2,6,8,10toplayimmuno-modulationandattenuationoftheinflammatoryprocess,suchasMSC.Thetransplantedcellsformedsynapsewithhostcells.OtherssuchasdelayingtheonsetandprolongingsurvivalofSOD1ratsIncreasinghostneurogenesis本文檔共35頁；當前第32頁；編輯于星期二\4點26分今后干細胞治療神經(jīng)退行性疾病的臨床研究

需要考慮的問題1.CellSources：Neuralprojenitors，MSC，hEScells，iPScells2.SCgraftingshouldbeconductedtoensure>100,000dopaminergicneurons（PD）survivepertransplantationsite.3.SCgraftsshouldexh