current state of stem cell treatments for cerebral …current state of stem cell treatments for...
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CurrentStateofStemCellTreatmentsforCerebralPalsy:AGuideforPatients,Families,andServiceProviders
StephanieBeldickMichaelG.Fehlings
KrembilResearchInstitute,UniversityHealthNetworkInstituteofMedicalSciences,UniversityofToronto
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GlossaryPerinatal–Aroundthetimeofbirth
Centralnervoussystem—Thebrainandspinalcord
Neurons–Cellsinthebrainthatsendsignalsinordertocommunicatewithotherregionsofthebrainandthebody.
Axons–Longprocessesattachedtoneuronsthatrelayelectricalsignals.Analogoustowiresinanelectricalcircuit.
Oligodendrocytes–Producemyelin,afatthatinsulatesneuronalaxonssothatneuronscansendsignalsquickly.
Whitemattertract–Abundleofaxonsconnectingtwodifferentregionsofthecentralnervoussystem.
Regenerativetherapy—Atherapythatseekstorestoretheintegrityofdamagedtissue.Regenerativetherapiesusingstemcellsoftenseektoreplacedeadcellsandsupporttheremainingcells.
Differentiate—Theabilitytotransformintospecializedcelltypesfoundinthebody.Oncedifferentiated,thecellscannotgobacktotheirpreviousstate.
Pluripotent–Atermusedtodescribecertainstemcellsthatcandifferentiateintoallthedifferentcelltypesfoundinthehumanbody.
Somaticcell–Afullydifferentiatedcellfoundinthehumanbody(forexample,askincell).
Directlyreprogrammedcell–Asomaticcellthathasbeendirectlytransformedintothedesiredcelltype.Thiscellhasby-passedthepluripotentstatethatisrequiredwhenmakingiPSC-derivedcells(seesectiononinducedpluripotentstemcells).
Multipotent—Stemcellsthatcanonlydifferentiateintospecificcelltypes.Forexample,aneuralprecursorcellcanonlydifferentiateintothecelltypesfoundinthebrainandspinalcordandnotintocelltypesfoundintheskin.
Allogeneicstemcelltransplantation–Stemcellsthataretakenfromadonorandgiventoapatient.Posesahighriskofimmunerejection.
Autologousstemcelltransplantation–Stemcellsthataretakenfromapatientandafterculturing,aretransplantedbackintothepatient.Minimalriskofimmunerejection,butthepreparationofthecellstakesalongtime.
Endogenous–Residingwithinatissue.Thisisopposedto“exogenous”,whichmeansfrom“outside”thetissue.
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StemCellsandCerebralPalsy
Cerebralpalsy(CP)isanumbrellatermusedtodescribeadisorderthatresultsfromperinatalbraininjury.CPcanbecausedbyamultitudeoffactors,includingprematurebirth,infectionintheuterus,lackofnutritionalsupportduringdevelopment,lackofoxygenatthetimeofbirth,andgeneticaberrations.WhilethecauseofCPismultifactorial,theinjuryconsistentlyleadstovariousneuro-motordeficits,oftenaccompaniedbyothersymptoms,suchasvisualandcognitiveimpairments.
Whenaninsultoccurstothebrainduringthesensitiveperinatalperiod,theresidentbraincellsareunabletopromotepropergrowthanddevelopmentofthebrain.Neuronsandoligodendrocytesdieand/orfailtomature,andthewhitemattertractsthatconnectvariousbrainregionsbecomedamaged.Importantly,thecorticospinaltract(CST),whichconnectsthemotorregionsofthebraintothespinalcordandhelpscontrolmovement,isoftendamaged.WithoutfunctionalCSTconnections,motordeficitsensue.
Stemcelltransplantationisaregenerativetherapythathasthepotentialtoreplacethedamagedandnon-functionalcellsinthebrainsofCPpatients,aswellastoprovidesupporttotheremainingneuronsandoligodendrocytes.Therearemanykindsofstemcells,eachwithdifferentanduniquecharacteristics.
Asresearchhasadvanced,wehavediscoveredthatstemcellscanbeinducedtobecomemorespecializedcelltypes,andwhentransplantedintothebody,theycanprovidesupporttoadamagedenvironment.Inaddition,wecanmodifythesestemcellstoexpresscertainfactorsthatcanenhancethisability.Wecanalsomodifythecellstoexpressscar-degradingfactorsthatcanhelptoreducescarringinthebrainandpromoterecovery.
ThereisaplethoraofresearchinthefieldofstemcelltransplantationforCP,andthiswillbediscussedbelowinthecontextofbothpreclinicalanimalresearchandclinicaltrials.
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WhatAreStemCells?
Therearetwocharacteristicsthatmakestemcellsuniquefromothercellsinthebody.First,theyhavetheabilitytodivideandmakecopiesofthemselvesoverextendedperiodsoftime.Second,theycandifferentiateintomorespecifiedfunctionalcelltypes.Thismeanstheycantransformintospecializedcelltypesofthebodysuchasheart,lung,orbraincells.Thetwocharacteristicsoflong-termcelldivisionanddifferentiationcapacityhavesomeveryimportantimplicationsforregenerativetherapeuticstrategies.Theabilityofstemcellstocreatecopiesofthemselvesoverlongperiodsmeansthattheirsupplyistheoreticallylimitless;underoptimalconditions,astemcellcanbegrowninaculturedishandendupformingcoloniesofstemcells.Aftergeneratingalargepoolofstemcells,theycanbedirectedtotransformintomorespecializedcelltypes,assumingthescientistknowsthecorrectfactorsthatwillleadtothedesiredchange.Below,wewilldiscusssomeofthemostimportantstemcelltypesrelevanttothetreatmentofCP,aswellastheirprosandconsforuseinresearchandtheclinic.
Embryonicstemcells(ESCs)arefoundinthedevelopingembryo.Thesecellsareknownaspluripotent,meaningtheyhavethepotentialtodifferentiateintoallthecelltypesfoundinthehumanbody.ESCshavebeenstudiedextensivelyinordertounderstandthemolecularpathwaysthatregulatetheir“stemcell-ness”,alongwiththosepathwaysthatguidedifferentiationtomorespecializedcelltypes(forexample,howdoesoneESCbecomeaneuronandanotheraskincell?).ESCshaveuniquepotentialforrepairingdamagedtissuebecauseof
theirversatiledifferentiationcapacity.ThismeansthatESCscouldbeusedtotreatavastnumberofdisorders.However,scientistsarestillworkingtopiecetogetherthecorrectbiologicalcodesthatcanfullydifferentiateanESC
intothedesiredcelltype.AconsequenceofnotyetunderstandingthefullmolecularpictureisthatESC-derivedcellscansometimesrevertbackintopluripotentcellsandformtumours.AnotherdrawbackisthatthederivationofESCsrequirestheuseofcellsfromtheembryo,thusraisingmoralandethicaldilemmas.
In2008,ProfessorShinyaYamanakawontheNobelPrizefordiscoveringfourbiologicalfactorsthatcouldbeusedtoturnanysomatic(fullydifferentiated)cellintoapluripotentstemcell.Thesenew,ESC-likecellsweretermedinducedpluripotentstemcells(iPSCs).Followingthisdiscovery,therewasagreatexcitementinthescientificcommunity.Beingabletocreatepluripotentstemcellsessentiallyeliminatestheneedforembryonictissueinordertoobtainpluripotentstemcells.Thiswasnottheendoftheexcitementthough;Normally,ifapatientis
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toreceiveastemcelltransplantation,adonorforthesecellsisrequired(allogeneictransplantation).iPSCs,however,canbederivedfromthepatient’sownsomaticcells.First,abiopsyofsomaticcells(e.g.skincells)wouldbetaken;thecellswouldthenbeinducedintoiPSCsinaculturedishandallowedtodivide.Followingdivision,theiPSCscouldbedifferentiatedintoanycelltypeandthenplacedbackintothepatient(autologoustransplantation)Notneedingadonortoacquirethecellssignificantlyreducestheriskofrejectionfollowingtransplantationintothepatient.Despitetheenthusiasmsurroundingthesecells,iPSC-derivedcellsstillpresentariskoftumourformation,similartoESCs.Furtherresearchisneededtobetterunderstandthemolecularpathwaysunderlying“stemcell-ness”anddifferentiationprocessessothatthesafetyandefficacyofthesecellscanbeoptimizedforregenerativetherapies.Interestingly,inrecentyears,newtechnologyhasallowedfortheinvestigationofdirectlyreprogrammedcells.Inthiscase,somaticcellscanbedirectlytransformedintothedesiredcelltype,essentiallyby-passingthepluripotentstagethatisrequiredwhenusingiPSCtechnology.Onebenefitofthesedirectlyreprogrammedcellsisthereducedriskfortumourformation;however,furtherresearchisneededinordertofully
understandhowwecangeneratethesecellsinasafeandefficientway.
WhileESCsandiPSCsareexcellentsourcesforversatilecells,theyarenotconvenientfortransplantationontheirown(duetotumourformation),andsotheyarenearlyalwaysinducedtodifferentiateintomorespecializedcelltypesbeforetransplantation.
Neuralprecursorcells(NPCs)arestemcellsthatarefoundinhumanswithinthecentralnervoussystem(CNS).Thesestemcellsaremoredifferentiatedthanpluripotentstemcells,inthattheycanonlydifferentiateintothecellsthatarefoundintheCNS.Accordingly,theyarecalledmultipotentstemcells.NPCscanbetakenfromadonororthepatient,growninaculturedishandthentransplantedintothepatient.NPCshaveauniquebenefitoverothercelltypestotreatCP;theirabilitytodifferentiateintobraincellsprovidesthemwiththegreatestpotentialtoappropriatelyintegrateintotheinjuredbrainandreplacethedamagedandnon-functionalcells.However,thedrawbacktousingNPCsisthatthereisalimitedsupplyofthesecells,andwhiletheycanbegrowninculture,themethodofretrievalfromthebrainorspinalcordisveryinvasive.Inaddition,thesecellsareincrediblycomplexandthereislimitedresearchontheirusefortreatingCP.Conversely,somebenefitsinclude:noethicaldilemmaswiththeirderivation,theycanbetakenfromthepatientsotheriskofrejectionisminimizedupontransplantation,andthetimerequiredtoculturethecellsisshorterthanforpluripotentstemcells,sincetheyarealreadyinthedesiredformat.
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Mesenchymalstromalcells(MSCs)areanotherkindofstemcellthathavebeenusedinresearchsurroundingCP.Thesecellshavetwomainorigins,eitherfromthebonemarrow(BM-MSCs)orfromtheumbilicalcordblood(UC-MSCs).LikeNPCs,MSCsaremultipotent,andtheyhavethepotentialtodifferentiateintovariouscelltypesthatplaystructuralandimmunerolesinthebody.MSCshavebeenusedinresearchandtheclinicfordecades.Theirbenefitslieintheireasyaccessibilityandtheirimmune-modulationproperties.However,MSCslackthefullpotentialtofullydifferentiateintofunctionalcellsoftheCNS,andforthisreason,theyareunlikelytobethemajorfocusoffuturemultipotentstemcellresearchforCP.
SourcesofStemCellsforTransplantation
Whendiscussingtransplantationstrategies,allstemcells,regardlessoftheirtype,caneitherbeclassifiedasallogeneicorautologous.Allogeneiccellsarethosetakenfromadonorandgiventoapatient,whereasautologouscellsarederivedfromthepatient.Allogeneicstemcellshavebenefitsinthatlargestemcellbankscanbecreatedthatcanfreezeandstorestemcelldonationsforextendedperiodsoftime.Whenneeded,thecellscanbethawedandgiventothepatientinashortamountoftime.Adownsidetoallogeneiccells,however,isthatthereisahighriskofimmunerejectionupontransplantation,sincethecellscomefromadonor.Conversely,autologousstemcellsposeminimalriskforimmunerejection,sincetheycomefromthepatient.However,theprocessforextractingthecells,andculturingthemcanbelengthy,andifcellsareneededwithinashorttimeframe,thismethodisinconvenient.
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PreclinicalStemCellResearch
CPresearchershavebeenutilizingvariouscelltypes,includingESC-andiPSC-derivedNPCs,MSCs,aswellasmultipotentNPCsfoundinthebrain.Resultshavebeenpromisinginthatstemcelltransplantationhasresultedinmodestfunctionalimprovementsandpositiveanatomicalchangeswithinthebrain.
AsapartoftheKidsBrainHealthNetworkpreclinicalresearchteam,Dr.MichaelFehlingsandhislaboratory(KrembilResearchInstitute,UniversityHealthNetworkandUniversityofToronto)arecurrentlyinvestigatingNPCsandhumaniPSC-derivedNPCsforthetreatmentofCP.TheteamisdevelopingreproducibleanimalmodelsofCPandinjectingthesestemcellsintothebrain.Importantly,thefocusofthisresearchistousestemcellsasatreatmentinachronicinjurycontext.Thismeansthatwearedesigningstemcelltherapiesthatwillbeefficaciouslongafterthebraininjuryhasoccurred.
Inpreclinicalmodelsafewofthehurdlesthatneedtobeovercomeare:improvingcellsurvivalinthebrainfollowingtransplantation,reducingtheriskoftumourformation(inthecontextofpluripotent-derivedcells),andunderstandinghowwecanforceourtransplantedcellstointegratebetterintotheexistingneuronalpathways.Despitethesechallenges,theknowledgegleanedfromhowstemcellsfunctionandincorporateintothedamagedCNSisincrediblyuseful.Thisinformationhashelpedresearcherstoadvancetheirstrategiesforcelltransplantation,aswellastobetterunderstandtherolesofendogenousNPCs(stemcellsfoundwithinthebrain)followingbraininjury.
StemCellTherapyClinicalTrials
Currentlythereare12clinicaltrialsaroundtheworldusingstemcellstotreatCP.Fourofthesearerecruiting,oneisactivebutnotrecruiting,andsevenhavebeencompleted.Manyofthesetrialsaremakinguseofbonemarrow/blood-derivedmononuclearcells(acombinationofcellsoriginallyfoundinthebonemarrowthatcontainhematopoieticstemcells(stemcellsthatgiverisetoredandwhitebloodcells,alsotermedHSCs)andBM-MSCs).OthersareusingpurifiedHSCs,orumbilicalcordbloodcontainingUC-MSCsandHSCs.Manyofthesetrialshavepassedtheinitialphasesofclinicaltrialsthatonlyseektoevaluatethecorrectdosageandsafetyoftheintervention.ThesetrialsareactuallybeginningtotesttheefficacyofthesestemcellsastreatmentsforCP.
Todate,thefindingsofonlyonestudyhavebeenpublished.Thisstudyhadthreegroupsofchildparticipants:Thosereceivingconventionalrehabilitationtherapyonly,thosereceivingadrugcallederythropoietin(showntohavepromiseintreatingCP)alongwithconventionalrehabilitationtherapy,orthosereceivingumbilicalcordblood(containingstemcells)+erythropoietin+conventionalrehabilitationtherapy.Thestudyfoundthatthegroupwhoreceivedstemcellsshowedgreaterimprovementsoncognitiveandmotorassessmentswhencomparedtotheothertreatmentarms.
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Whilethegrowthinthenumberofclinicaltrialssincethelasteditionofthismanuscriptin2011(4vs.thecurrent12)isexcitingandholdspromiseforthefutureofstemcelltherapiesforCP,thereisstillalongwaytogo.NoneoftheclinicaltrialstodatehaveusedNPCsoriPSC-sourcedcells,which,asdiscussedabove,haveuniqueadvantages.NPCshavethegreatestpotentialtointegrateintothedamagedbrain,andbeingabletouseiPSC-derivedcellswillheavilyreducetheneedforstemcelldonors,therebyminimizingtheriskofrejectionupontransplantationintothepatient.iPSCsalsoholdthepotentialtobedifferentiatedintoanycelltype.ThisversatilitywillbequiteusefulasmoreresearchisconductedondifferentcelltypesforthetreatmentofCP.However,learninghowtofullycontrolbothNPCsandiPSCsandmaximizetheirpotentialisanongoingareaofresearchthatrequiresalotoftimeandmoney.Researchershavebeenworkinghardthough,andwiththehelpofextensivecollaborations,funding,anddedication,theworld’sfirstiPSCclinicaltrial(RIKENtrialforage-relatedmaculardegeneration),putonholdinearly2015,hasresumed.
ManufacturingandRegulatoryIssues
Despitetheprogressseenwithclinicaltrialsinrecentyears,therearesomehurdlesthatneedtobeovercomeinorderforstemcellstobecomeawidelyaccessibletreatment.Oneofthemajorissuescurrentlyfacingthestemcellcommunityistheproblemof“scaleup”.Inthelaboratory,stemcellsareculturedinPetridishes.Itisfeasibletousethisapproachtotreatoneortwopatients,butasstemcelltherapiescomeclosertotheclinicthereisanincreasingneedtodevelopstrategiestomanufacturecellsonalargescale.Toolscalledbioreactorsareapromisingapproachtosolvethisproblem,however,withnewlarge-scaleproductionstrategies,theprotocolsforcellproductionwillneedtobere-evaluatedandtheefficienciesofcell
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productionwillchange.Moreresearchisneededinordertobetterunderstandhowwecanproduceourdesiredstemcellsinmassquantities.
Theotherproblemisthatregulatoryagencies,suchastheFDAandHealthCanadaarehavingdifficultydevelopingstandardizedguidelinesfortheproductionanduseofstemcells.Notonlywillindividualregulationsberequiredforeachuniquecelltype,butalsocellsareacompletelydifferentbiologicaltherapeuticwhencomparedtoconventionaldrugs.Cellsarelivingentitiesandtheireffectsonthehumanbodywillnotbeaswelldefined.Thereisanurgentneedtobetterestablishtheseguidelines,aswellastostandardizethemanufacturingprocessinordertoreducevariabilityamongthecellsduringproduction.Atthebasicsciencelevel,someofthesechallengeswillbeovercomebyimprovingourunderstandingofthemechanismsunderlyinghowthecellswork.Basicscientists,clinicians,industrypartners,regulatoryagencies,andpatientadvocatesallneedtoworktogethertohelpstemcelltherapiesmoveforward.
StemCellTourism
WhiletheNorthAmericanmedicalcommunityisworkingtobetterestablishstemcelltherapiesforCP,itisimportanttobecautiousofunregulatedoverseasstemcellclinics.Theactofgoingtotheseunregulatedclinicsiscalled“stemcelltourism”.Whileitmayseemtemptingtodoso,andthetestimonialsontheseclinics’websiteslookpromising,takeheed;Stemcelltransplantationisstillanunproventreatmentandwhiletherearecertainlycasesofreportedrecovery,therearealsomanyincidencesofincreasingdisability.Manyoftheclinicsusethesametypesofstemcellstotreatahostofdifferentdisordersdespitethelackofevidencetosupporttheiruse.Thetreatmentsarecostlyandtherisktopatientsisenormous.Ifyouareinterestedinstemcelltherapiesforyourselforalovedone,itisstronglyadvisedtogothroughreputableroutesandaccessregisteredclinicaltrials.
RisksandLimitationsofStemCellTherapy
ItmustbecautionedthatstemcelltherapyisstillanexperimentaltechniquethatisnotreadytobeadoptedasthestandardofcareforpatientswithCP.Asmentionedpreviously,theriskoftumourformationisahurdlethatmustbeovercome.Thisisanimportantissuetoaddress,becauseonceinjectedintothebody,stemcellscannotberemoved.Atpresentitisstillnotwellknownastowhetherornotthe“reprogrammingprocess”ofESCsandiPSCstomoredifferentiatedcelltypesisaleadingcauseoftumourformation.Severalresearchprojectsarecurrentlyunderwaytoreduceandifpossibleeliminatethegenerationofroguestemcellsthatcouldbetumour-forming.Theissuesof“scale-up”andcreatingwell-definedregulatoryguidelinesfortheuseofstemcellsintheclinicmustalsobeaddressed.
Thepromiseofstemcelltherapyisgreatandheraldsapotentialrevolutioninmedicinebyprovidingnewtherapiesforpreviouslyuntreatableconditions.However,itisunlikelytoprovideaone-stopmagicbullettoalleviateallclinicalsymptoms.InthecaseofCP,stemcelltherapyislikelytoresultinsmallincrementalimprovementsinfunctionthatinturnwillleadtonoticeableimprovementsinthequalityoflifeformostpatients.Additionally,atpresentitisnotknownfor
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howlongthebeneficialeffectsofstemcelltransplantationwilllast,andifmultipletransplantationsofstemcellsoverseveralyearswillberequiredtoimproveormaintainfunctionalrecovery.
Asacommunity,itisimportantthatwemanageourexpectationsofstemcelltherapies.Asmentionedabove,thistreatmentisstillundergoingdevelopmentandisnotyetwidelyacceptedintheclinic.WhilestemcelltherapieshavehugepotentialforthefuturetreatmentofCP,thestudyofthesecellsisalengthyprocessthatrequiresextensiveinvestmentoftimeandmoney.Supportoftheresearchthatismovingstemcelltherapiesforwardwillhelptofast-trackthistherapeutictotheforefrontofmedicinewithinthenext20years.
NextSteps
Nowthatyouhaveabasicunderstandingofthestateofstemcelltherapiesinthelaboratoryandclinic,wewouldliketoprovideyouwithsomereputablesourcestohelpyoulearnmore.Formoredetailsonstemcelltherapies,pleaseseethefollowinglinks:
Basicsofstemcells:http://stemcellfoundation.ca/en/;https://stemcells.nih.gov/info/basics/1.htm
StemcellsinCP:http://stemcellfoundation.ca/en/diseases/cerebral-palsy/
Informationonclinicaltrials:https://clinicaltrials.gov/;http://stemcellfoundation.ca/en/toward-treatments/clinical-trials/
Stemcelltourism:http://stemcellfoundation.ca/en/tag/stem-cell-tourism/;https://www.cirm.ca.gov/patients/stem-cell-tourism;http://www.nytimes.com/2016/06/23/health/a-cautionary-tale-of-stem-cell-tourism.html
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Table1:TheProsandConsofDifferentStemCellTypes
Pros ConsESC-DerivedCells • Candifferentiateinto
anycelltypetheuserdesires
• Well-studied
• Destructionofanembryo
• Riskoftumourformation
• Longprocesstoobtaindesiredcelltype
iPSC-DerivedCells • Candifferentiateintoanycelltypetheuserdesires
• Canbederivedfrompatient’sowncellssothereisminimalriskofrejectionupontransplantation
• Riskoftumourformation
• Longprocesstoobtaindesiredcelltype
MultipotentStemCells(e.g.NPCs,MSCs,HSCs)
• Alreadyexistinthedesiredformatwithinthebody
• Lowriskoftumourformation
• Potentiallyinvasiveprocesstoretrievethecells
• Limitedsupply• Ifthepatienthas
geneticriskfactors,thesegeneswillpersistinthesecellsiftakenfromthepatient.Canbeovercomebyusingadonor,butthisincreasestheriskofrejection
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