神经退行性疾病干细胞移植治疗 ppt课件.ppt

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 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 LindvallO etal NatMed 2008May 14 5 501 3 TH Synuclein Overlay Transplantedfetalmesencephalicdopaminergicneurons 11 16years developedalpha synuclein positiveLewybodiesingraftedneurons Synuclein Host Ubiquintin Host Synuclein GraftedNeurons Ubiquintin GraftedNeurons GraftednigralneuronswerefoundtohaveLewybody likeinclusions14yearsaftertransplantationintothestriatumofanindividualwithPD OlanowCW etalNatMed 2008May 14 5 504 6 TransplanteddopamineneuronsinpeoplewithPDdonotcontainLewybodies Mendez Isacsonetal NATUREMEDICINEVOLUME14 5 507 509 2008 FreedCR JNuclMed 2010Jan 51 1 7 15 LongtermStudy 33oftheoriginaltrialparticipantswhowerefollowedfor2yearsaftertransplantationand15ofthesesubjectswhowerefollowedfor2additionalyears Theseresultssuggestthatclinicalbenefitandgraftviabilityaresustainedupto4yaftertransplantation FreedCR Neurotherapeutics 2011 8 549 561 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 etalMemorialSloan KetteringCancerCenter ImprovedCellTherapyProtocolforParkinson sDiseaseBasedonDifferentiationEfficiencyandSafetyofhESC HipscandNon HumanPrimateiPSC DerivedDANeurons Isacsonetal StemCells 2013 31 8 1548 62 DopaminereleasefromtransplantedneuralstemcellsinParkinsonianratstriatuminvivo Zhouz etal ProcNatlAcadSciUSA 2014Nov4 111 44 15804 9 iPSC DerivedDopamineNeuronsfunctionafterTransplantationinaNon HumanPrimateModelofParkinson sDisease CellStemCell 2015Mar5 16 3 269 74 OleIsacsonetal HarvardStemCellInstitute Stemcell basedClinicalTrialsfor ALS Nuralstem Inc thefirstPhaseIclinicaltrialforastemcell basedtreatmentofALS Initiatedin2010andcompletedin2013 involvedthetransplan tationofhumanspinalcord derivedNSCsintothespinalcordof15latetomid stageALSpatients Glass Feldman E L 2012 Lumbarintraspinalinjectionofneuralstemcellsinpatientswithamyotrophiclateralsclerosis resultsofaphaseItrialin12patients StemCells30 6 1144 1151 Riley J Feldman E L 2014 IntraspinalstemcelltransplantationinALS aphaseItrial cervicalmicroinjectionandfinalsurgicalsafetyoutcomes Neurosurgery74 1 77 87 RESULTS Unilateralcervical groupD n 3 andcervicalplusthoracolumbar groupE n 3 microinjectionstotheventralhornhavebeencompletedinambulatorypatients Onepatientdevelopedapostoperativekyphoticdeformitypromptingcompletionofalaminoplastyinsubsequentpatients Anotherrequiredreoperationforwounddehiscenceandinfection Thesolitarypatientwithbulbaramyotrophiclateralsclerosisrequiredperioperativereintubation CONCLUSION Deliveryofacellularpayloadtothecervicalorthoracolumbarspinalcordwaswelltoleratedbythespinalcordinthisvulnerablepopulation Thisencouragingfindingsupportsconsiderationofthisdeliveryapproachforneurodegenerative oncologic andtraumaticspinalcordafflictions IntraspinalstemcelltransplantationinALS aphaseItrial 2014 iPSCellsWereGeneratedfromPDpatientsandNormalControls 6 OHDA inducedRatPDModel HumaniPScellsIntegratedtotheHostBrainof6 OHDA inducedRatPDModel HanF WangW ChenC DuanJ etalCytotherapy2015 分化的胎脑神经干细胞移植治疗PD 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 RT PCRtoDetecttheMicroRNAExpressioninRatSCIModel Real TimeRT PCRtoDetecttheMicroRNAExpressioninSCI 干细胞移植修复脊髓神经损伤 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 BoneMarrowStromalCellIntraspinalTransplantsFailtoImproveMotorOutcomesinaSevereModelofSCI JournalofNeurotrauma2015 TuszynskiMHTodeterminewhetherlocalmechanismsmediateBMSCneuroprotectiveactionsgraftedallogeneicBMSCstositesofsevere compressivespinalcordinjury SCI inSpragueDawleyrats Cellswereadministered48hoursaftertheoriginalinjury AdditionalanimalsreceivedallogeneicMSCsthatweregeneticallymodifiedtosecreteBDNF tofurtherdeterminewhetheralocallyadministeredneurotrophicfactorprovidesorextendsneuroprotection twomonthspost injuryinaclinicallyrelevantmodelofsevereSCI BMSCgraftswithorwithoutBDNFsecretionfailedtoimprovemotoroutcomes Thus allogeneicgraftsofBMSCsdonotappeartoactthroughlocalmechanisms andfutureclinicaltrialsthatacutelydeliverBMSCstoactualsitesofinjurywithindaysareunlikelytobebeneficial IntraspinalStemCellTransplantationinAmyotrophicLateralSclerosis APhaseISafetyTrial TechnicalNote andLumbarSafetyOutcomesNEUROSURGERYVOLUME71 NUMBER2 AUGUST2012DepartmentofNeurosurgery EmoryUniversity Atlanta Georgia DepartmentofNeurology EmoryUniversity Atlanta Georgia DepartmentofNeurology UniversityofMichigan AnnArbor Michigan 神经干细胞移植方法 Eachmicroinjectionseriescomprised5injections 10mL injection separatedby4mm Eachinjection 100000neuralstemcellsderivedfromafetalspinalcord Twelvepatientsweretreatedwitheitherunilateralorbilateralinjections Patientsarefollowedclinicallyandradiologicallytoassesspotentialtoxicityoftheprocedure LumbarLaminectomy Microinjectionplatformapplication Postoperativeimagingprogression Riley J Feldman E L 2014 IntraspinalstemcelltransplantationinALS aphaseItrial cervicalmicroinjectionandfinalsurgicalsafetyoutcomes Neurosurgery74 1 77 87 ClinicalTrialsusingESCsandiPSCs ThereisalsoareportofoneJapanesepatientwhoreceivedatransplantofasheetofiPSC derivedRPE SummaryonMolecularMechanismofStemCellTransplantationforNeurologicalDiseases Transplantedcellssurvive differentiatetoneurons astrocytes oligodendrocyteprecursors hESC hiPSC NSC andreleaseneurologicaltransmittorssuchasdopamine Ach Releaseofneurotrophicfactors GDNF GDNE IGF toincreasethefunctionsoftheendogenousneuralstemcellsReleaseofimmuno regulatoryfactorssuchasIL 2 6 8 10toplayimmuno modulationandattenuationoftheinflammatoryprocess suchasMSC Thetransplantedcellsformedsynapsewithhostcells OtherssuchasdelayingtheonsetandprolongingsurvivalofSOD1ratsIncreasinghostneurogenesis 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 SCgraftsshouldexhibitregulatedreleaseofdopamineinlinewiththatofendogenousdopaminergicneurons 4 Byreestablishingthestriataldopaminergicsystem graftsshould