AUTHORS - Giving Compass · Parkinson’s Disease Foundation Anders Björklund, MD, PhD ... In...
Transcript of AUTHORS - Giving Compass · Parkinson’s Disease Foundation Anders Björklund, MD, PhD ... In...
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AUTHORS
LEADAUTHOR
EkeminiA.U.Riley,PhD
CONTRIBUTINGAUTHORS
LaTeseBriggs,PhDYooRiKim,MSErikLontok,PhDMelissaStevens,MBA
PDSCIENTIFICADVISORYGROUP
WegraciouslythankthemembersofandliaisonstothePDScientificAdvisoryGroupfortheirparticipationandcontributiontothePDProjectandGivingSmarterGuide.Theinformativediscussionsbefore,during,andafterthePDRetreatwerecriticaltoidentifyingthekeyunmetneedsandidealphilanthropicopportunitiestobenefitpatientsandadvancePDresearch.
CharlesH.Adler,MD,PhDProfessorofNeurologyMayoClinicCollegeofMedicineMayoClinicArizonaJamesBeck,PhDVicePresident,ScientificAffairsParkinson’sDiseaseFoundationAndersBjörklund,MD,PhDProfessorandHeadofNeurobiologyWallenbergNeuroscienceCenterUniversityofLundPatrikBrundin,MD,PhDDirector,VARICenterforNeurodegenerativeScienceHead,LaboratoryforTranslationalPDResearchAssociateDirectorofResearchJayVanAndelEndowedChairinParkinson’sResearchVanAndelResearchInstitute(VARI)PaulCannon,PhD
Parkinson’sDiseaseProgramManager23andMe
JesseCedarbaum,MDVicePresident,ClinicalDevelopmentMovementandNeuromuscularDisordersBiogen P.JeffreyConn,PhDDirector,VanderbiltCenterforNeuroscienceDrugDiscoveryProfessorofPharmacologyVanderbiltUniversity TedDawson,MD,PhDDirector,InstituteforCellEngineeringDirector,MorrisK.UdallPDResearchCenterProfessor,DepartmentsofNeurology,NeuroscienceandPharmacology&MolecularSciencesJohnsHopkinsUniversitySchoolofMedicineE.RayDorsey,MD,MBADirector,CenterforExperimentalTherapeuticsProfessorofNeurologyUniversityofRochesterMedicalCenterJohnDunlop,PhDHead,NeuroscienceInnovativeMedicinesCo-Director,AstraZenecaTuftsLabforBasicandTranslationalNeuroscience
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StanleyFahn,MDDirector,CenterforParkinson'sDiseaseandOtherMovementDisordersH.HoustonMerrittProfessorofNeurologyColumbiaUniversityMedicalCenter StevenFinkbeiner,MD,PhDDirector,Taube/KoretCenterforNeurodegenerativeDiseaseResearchGladstoneInstituteofNeurologicalDiseaseProfessorofNeurologyandPhysiologyUniversityofCalifornia,SanFranciscoStephenFriend,MD,PhDPresident,Co-Founder,andDirectorSageBionetworksOleIsacson,MDProfessorofNeurologyDirector,NeuroregenerationLaboratoriesandCenterforNeuroregenerationResearchatMcLeanHospitalHarvardMedicalSchoolKarlKieburtz,MD,PhDDirector,ClinicalandTranslationalScienceInstituteProfessorofNeurologyProfessorofCommunityandPreventiveandEnvironmentalMedicineUniversityofRochesterMedicalCenter
WalterKoroshetz,MDDirectorNationalInstituteofNeurologicalDisordersandStroke,NationalInstitutesofHealthAnthonyLang,MDSeniorScientistTorontoWesternResearchInstituteJ.WilliamLangston,MDChiefScientificOfficerandFounderParkinson’sInstitute
PeterLeWitt,MDProfessorofNeurologyWayneStateUniversitySchoolofMedicineDirector,Parkinson'sDiseaseandMovementDisordersProgramHenryFordHospital
IreneLitvan,MD,PhDDirector,MovementDisordersCenterProfessor,Parkinson’sDiseaseResearchUniversityofCalifornia,SanDiegoKennethMarek,MDPresident,Co-Founder,andSeniorScientistInstituteforNeurodegenerativeDisordersHelenMatthewsChiefOperatingOfficerTheCureParkinson’sTrustC.WarrenOlanow,MDProfessorofNeurologyandNeuroscienceMountSinaiSchoolofMedicineSpyrosPapapetropoulos,MD,PhDVicePresident,GlobalHeadClinicalDevelopmentNeurodegenerativeDiseasesTevaPharmaceuticalsAnupamPathak,PhDMechanicalEngineerGoogle[x]R&D,GoogleRachelSaunders-Pullman,MD,MPHAssociateProfessorofNeurologyAttendingNeurologistMountSinaiBethIsraelMedicalCenterDarryleSchoepp,PhDVicePresidentandTherapeuticAreaHead,NeuroscienceMerckResearchLaboratoriesMichaelSchwarzschild,MD,PhDProfessorofNeurology,HarvardMedicalSchoolNeurologist,MassachusettsGeneralHospitalChair,ParkinsonStudyGroupExecutiveCommitteeToddSherer,PhDChiefExecutiveOfficerMichaelJ.FoxFoundationforParkinson'sResearchBeth-AnneSieber,PhDProgramDirector,NeurodegenerationClusterNationalInstituteofNeurologicalDisordersandStroke,NationalInstitutesofHealth
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TanyaSimuni,MDDirector,Parkinson’sDiseaseandMovementDisordersProgramProfessorofNeurologyNorthwesternUniversityAndrewSingleton,PhDSeniorInvestigatorChief,LaboratoryofNeurogeneticsChief,MolecularGeneticsSectionNationalInstituteonAging,NationalInstitutesofHealthDavidSulzer,PhDProfessor,DepartmentsofPsychiatry,Neurology,andPharmacologyColumbiaUniversityMedicalCenterD.JamesSurmeier,PhDProfessorandChair,DepartmentofPhysiologyNorthwesternUniversityCarolineTanner,MD,PhDDirectorParkinson'sDiseaseResearchEducationandClinicalCenterSanFranciscoVeteran'sAffairsMedicalCenterRyanWatts,PhDActingChiefExecutiveOfficerandChiefScientificOfficerDenaliTherapeuticsAllisonWillis,MD,MSCIAssistantProfessorofNeurologyAssistantProfessorofEpidemiology&BiostatisticsUniversityofPennsylvaniaSchoolofMedicine
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CONTENTS
Authors...................................................................................................................................1
PDScientificAdvisoryGroup...................................................................................................1
ExecutiveSummary.................................................................................................................7
Overview................................................................................................................................8
SocietalImpactofParkinson’sDisease.............................................................................................................8
Parkinson’sDiseaseBasics....................................................................................................10
CharacteristicsofParkinson’sDisease............................................................................................................11
RiskFactorsandPrevention...........................................................................................................................12
GeneralRiskFactors...........................................................................................................................................12
GeneticRiskFactors...........................................................................................................................................12
Prevention..........................................................................................................................................................12
Diagnosis..............................................................................................................................13
ClinicalObservationsUsedtoDiagnosePD.....................................................................................................13
TheChallengeofAccuratelyDiagnosingPD....................................................................................................13
Treatment.............................................................................................................................14
PharmacologicalTreatmentOptions..............................................................................................................14
DopaminergicMotorSymptomtherapy............................................................................................................14
Non-DopaminergicMotorSymptomTherapy...................................................................................................15
Non-MotorSymptomTherapy...........................................................................................................................16
Non-PharmacologicalTreatmentOptions.......................................................................................................16
SurgicalTreatmentOptions............................................................................................................................16
MonitoringTreatmentEfficacy.......................................................................................................................17
TheMechanicsofParkinson’sDisease...................................................................................17
HowtheNervousSystemWorks....................................................................................................................17
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TalkingNeurons–HowNerveCellsCommunicate..........................................................................................18
HallmarksofPDPathology...................................................................................................19
IrreversibleSNNeuronalCellDeath..................................................................................................................19
ToxicAlpha-Synuclein-ContainingAggregates...................................................................................................20
OtherDysfunctionalCellularProcessesInvolvedinPD...................................................................................21
MitochondrialDysfunction................................................................................................................................21
Neuroinflammation............................................................................................................................................21
Autophagy–ACellularCleaningProcess...........................................................................................................21
PDGenetics....................................................................................................................................................22
ClinicalTrialsandInvestigationalTherapies..........................................................................23
ClinicalTrials–Overview................................................................................................................................23
Parkinson’sDiseaseClinicalTrials...................................................................................................................23
InvestigationalTherapies...............................................................................................................................25
Alpha-SynucleinTargetingTherapies.................................................................................................................25
LRRK2TargetingTherapies................................................................................................................................26
StemCellTherapy..............................................................................................................................................26
GeneTherapy.....................................................................................................................................................27
DrugRepurposing...........................................................................................................................................27
BarrierstoPDResearchProgressandKeyPhilanthropicOpportunities.................................29
IncompleteUnderstandingofUnderlyingDiseaseBiology................................................................................29
SlowProgressinBiomarkerDiscoveryandDrugDevelopment.........................................................................30
InadequatePreclinicalModels...........................................................................................................................33
LackofDisease-ModifyingTherapies(DMTs)andClinicalTrialFailures...........................................................34
SuboptimalCurrentTreatmentOptionstoManageSymptoms........................................................................36
KeyStakeholdersinthePDCommunity.................................................................................38
DomesticResearchGrant-MakingOrganizations............................................................................................38
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TheMichaelJ.FoxFoundationforParkinson’sResearch(MJFF).......................................................................38
NationalParkinsonFoundation(NPF)................................................................................................................39
AmericanParkinsonDiseaseFoundation(APDA)..............................................................................................39
Parkinson’sDiseaseFoundation(PDF)...............................................................................................................39
OtherKeyGrant-MakingOrganizations..........................................................................................................40
ParkinsonStudyGroup(PSG).............................................................................................................................40
Parkinson’sUK...................................................................................................................................................40
TheCureParkinson’sTrust(CPT).......................................................................................................................40
CollaborativeInitiatives........................................................................................................41
Government-SponsoredPrograms.................................................................................................................41
Parkinson’sDiseaseBiomarkersProgram(PDBP)..............................................................................................41
MorrisK.UdallCentersforExcellenceinParkinson’sDisease..........................................................................41
ConsortiaandStrategicPartnerships..............................................................................................................42
BiomarkersAcrossNeurodegenerativeDiseases(BAND)..................................................................................42
InternationalParkinson’sDiseaseGenomicsConsortium(IPDGC)....................................................................42
NetworkforExcellenceinNeuroscienceCLinicalTrials(NeuroNEXT)...............................................................43
Parkinson'sDiseaseResearchToolsConsortium(PDRTC).................................................................................43
Parkinson’sProgressiveMarkerInitiative..........................................................................................................43
Appendix..............................................................................................................................44
FDA-ApprovedPharmacologicalTreatments..................................................................................................44
Glossary................................................................................................................................46
References............................................................................................................................49
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EXECUTIVESUMMARY
Parkinson’sdisease(PD)isachronic,neurodegenerativemovementdisorderthataffectsthelivesofmorethan1millionAmericans.PDslowlyworsensovertime,increasinglyrobbingpatientsofcoordinatedmovementandinflictinganumbernon-motorsymptomsrangingfromcognitiveimpairmenttogastrointestinalissues.Approximately90percentofPDcasesoccurspontaneously,while10percentofcasesarefamilial.PDmainlyaffectstheelderly,howeverthecauseofPDisunknown.Therearecurrentlynotreatmentsthatcansloworstoptherelentlessprogressionofthedisease.Asthesizeandproportionoftheelderlypopulationgrows,sotoowillthesocietalandeconomicburden.ThecurrentestimatedannualcostofPDisastaggering$14.4billion,whichisprojectedtodoubleby2040.Thisprojectionmaybeevenhigherifnoeffectivetreatmentsarefound.Inadditiontothelackofdisease-modifyingtherapies,therearenoestablishedbiomarkersofdisease.Inotherwords,therearenoobjectivemeasurestodiagnosepatients,trackdiseaseprogressionorresponsetotreatment.Rather,physiciansrelyonimprecise,qualitativeratingscales,ultimatelyhamperingdrugdevelopmenteffortsandclinicaltrialsuccess.MisdiagnosisisalsoaseriousissueduetothedifficultyindistinguishingseveralearlysymptomsofPDfromthenaturaleffectsofagingorotherneurologicaldisorders.Itisoverwhelminglyclearthatprogressisdesperatelyneededtocombatthisdisorder.ThePDfieldisfraughtwithanumberofotherunmetneedsthathamperprogress,including:
• PoorunderstandingofunderlyingPDdiseasebiologyandlackoffundingtosupportbasicresearch• Poorunderstandingoftheunderlyingbiologyofnon-motorandtreatment-inducedsymptoms• Slowprogressinbiomarkerdiscoveryandtheneedforamorepredictivetranslationalpipeline
ThereisrenewedinterestinPDduetorecentbreakthroughsinthegeneticsofthediseaseandindigitalhealth.GeneticdiscoverieshaveexpandedourunderstandingofPDheredityandbroadenedinsightsintospontaneousdisease.Moreover,keytherapeutictargetshavebeenuncovered,whicharedrivingdrugdevelopmentstrategy.Digitalhealthadvancementsinmobileapplicationsandwearabletechnologyareallowinginvestigatorstoamassanunprecedentedamountofpatientdata.ThesenewtechnologieshavethepotentialtobroadenclinicaltrialparticipationandrevolutionizethewayPDsymptomsaremonitoredandquantified.Capitalizingonthismomentumthroughstrategicinvestmentindiscoveryscience,infrastructure,andresearchtoolsareessentialforcontinuedprogress.TheMilkenInstitutePhilanthropyAdvisoryServicehasdevelopedthisGivingSmarterGuideforParkinson’sDiseasewiththeexpresspurposeofempoweringpatients,supporters,andstakeholderstomakestrategicandinformeddecisionswhendirectingtheirphilanthropicinvestmentsandenergyintoresearchanddevelopmentefforts.Readerswillbeabletousethisguidetopinpointresearchsolutionsalignedwiththeirinterests.Thisguidewillhelptoanswerthefollowingquestions:• WhyshouldIinvestinPDresearch? • WhatkeythingsshouldIknowaboutthisdisease?• Whatisthecurrentstandardofcare? • WhatisthecurrentstateofPDresearchefforts?• Whatarethebarrierspreventingdevelopmentofnewtherapeutics?
• HowcanphilanthropyleverageexistinginfrastructuretosupportPDresearchandadvancenewtherapies?
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OVERVIEW
Parkinson’sdisease(PD)isadebilitatingneurodegenerativedisorderthatseverelyaffectsmovementandcoordination.Morethan1millionAmericansarecurrentlysufferingfromPD,anditisestimatedthatnearly60,000newcaseswillbediagnosedthisyearalone.Thisdisordermostcommonlyoccursinpeopleage60andolder;however,thosewithspecificinheritedgeneticmutationslinkedtoPD(referredtoasfamilialPD)canexperiencesymptomsintheir40sorevenearlier.PDcausesavarietyofmotorsymptomsincludingtremors,musclestiffness,posturalinstabilityandothers.Thediseasealsocausesarangeofnon-motorsymptomsthatinclude,butarenotlimitedto,cognitiveimpairment,mooddisordersandgastrointestinalissues.Therearealitanyofchallengesassociatedwithidentifying,understandingandtreatingPD.ItiscurrentlyunclearwhatcausesPD.Inaddition,diagnosingthediseaseisachallengebecausedefinitivediagnosisrequiresautopsy.Finally,andmostimportantly,thereisnocure.Whilecurrenttreatmentshelptomanagesymptoms,theydonotmodifythediseasetosloworhaltitsprogression.Withlongerlifeexpectanciesandanagingpopulation,thesocietalburdenofPDisenormousandisonlyexpectedtoincrease.ConsequentlythereisanurgentneedtoacceleratePDresearchprogresstoidentifynoveltreatmentsthatcanmodifythediseaseratherthanjustmanagesymptoms.
SOCIETALIMPACTOFPARKINSON’SDISEASE
POPULATIONBURDEN
PDisthesecondmostcommonneurodegenerativedisease,followingAlzheimer’sdisease,andthefourteenthleadingcauseofdeathintheUnitedStates.AccordingtotheAmericanParkinsonDiseaseAssociation,anAmericanisdiagnosedwithPDeverynineminutes,culminatingin5,000newcasespermonth.TheprevalenceofPDincreaseswithage,andthusisthreetosixtimeshigherinpeopleovertheageof65,andthirteentosixteentimeshigherinpeopleovertheageof85comparedtothegeneralpopulation(asdepictedinFigure1).
UnfortunatelyastheglobalpopulationcontinuestoageintodemographicswithhigherPDprevalence,thesupplyofneurologists(themedicalspecialiststrainedtodiagnoseandtreatnervoussystemdisorders)areprojectedtofall20percentbelowdemandby2020,accordingtotheAmericanAcademyofNeurology.ThiswillresultinanoverloadedmedicalsystemandwilllikelybecomeamajorimpedimenttoimprovingcareandtreatmentoptionsforParkinson’spatients.
Figure1.PDPrevalencebyAge.About0.3%ofthegeneralpopulationhavePD,whereas1-2%ofpeopleage65andolderand4-5%ofpeopleage85andolderhavePD.
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ECONOMICBURDEN
Theincreasinglydebilitativecourseofthediseasecontributestohighmedicalandnon-medicalcosts.Annually,thetotalnationaleconomicburdenisestimatedtobe$14.4billion($22,800perpatient)accordingtoa2013studypublishedinMovementDisorders(seeFigure2).Thatestimateiscomprisedofdisease-relatedmedicalcostsofapproximately$8.1billion($12,800perpatient)andnon-medicalcostsofapproximately$6.3billion($10,000perpatient).TaxpayersbearthebruntofthemedicalcostofPD,withanestimated48percent($3.8billion)paidforbyMedicare,Medicaidorothergovernmentprograms,asillustratedinFigure3.
Figure2.EconomicBurdenofPD-relatedCare.AstheprevalenceofPDincreaseswithage,sotoodoesthecost.PDpatientsunderage45incurcostsofabout$3,500peryear,whereasPDpatientsage85andoldercanincurcostsrangingfrom$14,000to$41,500peryear.Intotal,PDpatientspayabout$2.7billioninout-of-pocketexpensesannually–anoftentimeshugefinancialstrainonapopulationthatexperiencesareducedabilitytoworkassymptomsworsenovertime.TheannualcostofPDisexpectedtoatleastdoubleby2040andmayincreaseevenmoreifnoprogresstowarddisease-modifyingtherapiesaremade.
Figure3.DistributionofMedicalCostsbyPayer.
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Figure4.BrainAnatomy-PartsoftheMidbrain.Crosssectionofbraindepictingthelocationofthesubstantianigra(SN).SNneuronsproducetheneurotransmitterdopamine,essentialforsmoothmovement.SNneuronsprojectdirectlytothestriatum(alsopicturedabove).ThedeathofSNneuronsaltersthedopaminepathway,havingdirecteffectsonthestriatumandotherbrainstructures.
PARKINSON’SDISEASEBASICS
Parkinson’sdisease(PD)belongstoagroupofconditionscollectivelycalledmovementdisorders.Thereareover20differenttypesofmovementdisorders;someexamplesincludeHuntington’sdisease,cerebralpalsy,andTourette’ssyndrome.Everybodilymovementisacarefulcoordinationbetweenthenervoussystemandmuscles.Nervecells,knownasneurons,communicateinordertofacilitatemovementandvirtuallyallotherbodilyprocesses.
Movementexecutionandcoordinationiscontrolled,inpart,byaverysmallstructuredeepwithinthemidbraincalledthesubstantianigra(SN)asillustratedinFigure4.NeuronsintheSNproducedopamine,achemicalsignal(alsoknownasaneurotransmitter),whichisresponsibleforsmooth,coordinatedmovement.Thedeathofthesedopamine-producingneuronsleadstotheclassicmotorsymptomsseeninPDpatients.
PDprogressionresultsinacontinuouschemicalimbalanceinthebrainthataffectsotherregionsinadditiontotheSN.Ultimatelythiscanleadtothedevelopmentofadditionalmotorandnon-motorsymptoms,aswellastreatmentresistancetothestandardtherapylevodopa.
Unfortunately,itisnotknownwhattriggerstheseneuronstodie.BythetimePDisclinicallydiagnosed,nearly60-80percentofthedopamine-producingneuronsarealreadydead,whichhighlightsthecriticalneedforbetterdiagnosticcriteriaforthisdisease.
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Figure5.ProgressionofPDandAssociatedSymptoms.Symptomsintheprodromalstageareoftentimesindistinguishablefromvariousotherdiseases.The“classic”PDsymptomsarenotseenuntilthetransitionintothenextstageofdiseaseprogression(‘EarlyStage’)andthisisthestagewheretheclinicaldiagnosisismade.Advancedstagesymptomsalsoincludeseverecognitiveimpairmentalongwithworseningofexistingmotorconditions.TheimageabovedepictsthemyriadofsymptomsaccordingtowhentheygenerallyappearduringthenaturalprogressionofPD.
Table1.CommonPDSymptoms.
CHARACTERISTICSOFPARKINSON’SDISEASE
TherearetwotypesofPD,idiopathic(spontaneous)andfamilial(inherited).ThecauseofPDisunknown;however,developmentoffamilialPDisstronglyassociatedwithmutationsincertainPDsusceptibilitygenes(discussedlaterinPDGeneticssectiononpage22).ThemajorityofpatientshaveidiopathicPD,asonly10percentofPDcausesarefamilial.
Tremorsareperhapsthemostwell-knownsymptomassociatedwithPD.Thereareseveralothermotor,non-motorandtreatment-inducedsymptomsthatcontributetothecomplicatednatureofthisdisease.Theseverityandnumberofsymptomsexperiencedcanvarywildlyfrompatienttopatient.Table1highlightsseveralofthe
mostcommonPDsymptoms,althoughthislistisnotexhaustive.
Symptomstypicallyoccuratvaryingtimesduringthediseasecourse,withseveralnon-motorsymptomsappearingbeforemotorsymptomsbecomeapparent.Treatment-inducedsymptomstypicallyoccurafterfourtosevenyears.SincePDisachronic,progressivedisease,virtuallyallPDpatientswillexperiencethesesymptomsandmore.
ThediseasecourseofPDisoftendescribedinphasesasdepictedinFigure5:prodromal,early,andadvanced.PDphasesarebenchmarkedbyclinicallyovertmotorsymptoms;however,bythispoint,significantneurodegenerationhasalreadytakenplaceasnearly60-80percentofSNneuronshavealreadydied.
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MutationsinthefollowinggenesareassociatedwithincreasedriskfordevelopingPD:
GBA–thegreatestgeneticriskfactordevelopingPD.
LRRK2–mostcommoncauseoffamilialPDbutisalsofoundinidiopathicPDcases.
Parkin–commoninyoung-onsetPD.
SNCA–firstgeneassociatedwithfamilialPD.
CommonGeneticRiskFactorsforPD
RISKFACTORSANDPREVENTION
WhilethecauseofPDisunknown,investigatorshaveidentifiedgeneralandgeneticfactorsthatincreasetheriskofdevelopingbothidiopathicandfamilialPD.
GENERALRISKFACTORS
Generalriskfactorsincludebutarenotlimitedto:
• Age–theincidenceandprevalenceofPDincreasessubstantiallywithage(seeFigure1).
• Sex–menare50percentmorelikelytodevelopPDthanwomen.
• Environmentalfactors–exposuretopesticidesandothertoxinsaresuggestedtoincreasetheriskofdevelopingPD.
• Medicalconditions–priorheadinjuryordepressionaresuggestedtoincreasethelikelihoodofdevelopingPD.
GENETICRISKFACTORS
ThereareanumberofgeneticmutationsthatarethoughttocontributetothedevelopmentofPD–knownasgeneticriskfactors.ThesegeneticriskfactorsarediscussedfurtherinthePDGeneticssectiononpage22.
PREVENTION
WhiletherearenoknownwaystopreventdevelopmentofPD,investigatorshaveidentifiedfactorsthatdecreasetheriskofdevelopingPD:
• Exercise–ResearchhasshownthatexerciseisvitalforbothpreventionandmanagementofPD.Recentevidenceshowsthatearly-stagePDpatientswhomaintainedanactivelifestylecoulddelaythestartoftreatmentbyasmuchastwoyears.
• Nicotineexposure
• Caffeineconsumption
• Nonsteroidalanti-inflammatorydrug(NSAIDs)orcalciumchannelblockeruse
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AllcasesofPDdiagnosisinlivingpatientsareconsideredprobableuntilconfirmedbyautopsy.Adefinitivediagnosisrequirespostmortemanalysisofbraintissuetodetectproteinclumps,oraggregates,containingalpha-synuclein–theculpritproteininPD.
DIAGNOSIS
CLINICALOBSERVATIONSUSEDTODIAGNOSEPD
PDiscurrentlydiagnosedbasedontheclinicalpresentationofmotorsymptoms.Todate,thereisnoobjectivediagnosticexamorbiomarkerforPD.Abiomarkerisacharacteristicthatisobjectivelymeasuredandevaluatedasanindicatorofdiseasestateortreatmentefficacy.Abiomarkercanbedetectedinbiofluids(e.g.blood,urine,cerebrospinalfluid),tissues(e.g.skin,brain)oranimagingscanofthebrain.Someexamplesofwidelyusedbiomarkersarebloodsugarlevelfordiabetesorcholesterollevelforcardiovasculardiseases.Withoutabiomarker,aneurologisthastorelyonpatienthistoryandmotorsymptomspresentduringaneurologicalexamtogiveaformalPDdiagnosis.AneurologisttypicallyusesacombinationofthefollowingclinicalobservationsandteststodiagnosePD:
• Primarymotorsymptoms–Restingtremor,rigidity,slownessofmovement(bradykinesia)andimpairedbalance(posturalinstability)arethefourprimarymotorsymptomsofPD.Physicianswilloftenlookfortwoormoreofthesehallmarkmotorsymptomswhenmakingaformaldiagnosis.
• Ratingscales–BecausePDisaprogressivediseasethatbecomesincreasinglydebilitatingovertime,physicianswillemployratingscalestotrackdiseasesymptoms.Theseratingscalesareusedtoaiddiagnosis,asphysiciansoftenneedtotrackpatientsovertimebeforerenderingaPDdiagnosis.Additionally,ratingscalesareusedtotrackpatientresponsetotreatment,andasanevaluationtoolinclinicaltrials.Pointsareassignedforvarioussymptomsandthecompositenumberisusedtocomparepatientstatus.ThemostwidelyusedclinicalratingscaleforPDistheMovementDisorderSociety-sponsoredrevisionoftheUnifiedParkinson’sDiseaseRatingScale(MDS-UPDRS).
• Neuroimagingtechniques–Thepresenceofdopamineisassessedusingbrainimaging.ImagingaloneisnotsufficienttodiagnosePDbecausethereareotheroverlappingparkinsoniansyndromes(suchasprogressivesupranuclearpalsy[PSP]ormultiplesystematrophy[MSA]),whichproducedopaminelossinthebrainaswell.Whilecurrentbrainimagingtechniquesarenotdiagnostic,physicianscanusetheimagestoruleoutotherparkinsoniansyndromes,trackdopaminelossovertimeandtoassesspatienteligibilityforcertainclinicaltrials.
THECHALLENGEOFACCURATELYDIAGNOSINGPD
AccuratelydiagnosingPDisespeciallychallengingfortwokeyreasons:
• Difficultyidentifyingpatientsintheprodromalstage–manynon-motorsymptoms,suchasconstipationordifficultyrecallingtasks,oftenoccurseveralyearsbeforemotorsymptomsareapparentandareoftenattributedtothenaturalcourseofaging;therefore,PDcangoundetectedforseveralyears.ThereisgreatinterestinthefieldtoidentifyprodromalPDpatientssince,theoretically,therapeuticinterventionintheearlyprodromalphasecouldbethecrucialwindowtoslowdiseaseprogressionbeforepatientsexperiencesignificantSNneuronalloss.
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• Overlappingsymptomswithotherdisorders–theclassicPDmotorsymptomscanbepresentinotherneurodegenerativediseases,oftenresultinginmisdiagnosis.
BeingovertlysymptomaticiscentraltoPDdiagnosis;however,studiesdemonstratethatbythetimesymptomsareclinicallypresent,significantdegenerationofSNneuronshasalreadyoccurred,andcontinuousprogressionofthediseaseiseminent.CurrenttherapiesarenotequippedtosloworhalttherelentlessprogressionofPD,andeffortstodosoarehamperedbythelackofbiomarkersavailableto1)identifypatientsintheprodromalphase,2)objectivelydiagnosepatientsand3)tracktreatmentefficacy.Thislackofbiomarkerstosupportclinicalresearchhasbeenakeycontributortofailedclinicaltrialsandalackofoverallprogressioninthespace.
TREATMENT
ThereisnowaytosloworhaltthenaturalprogressionofPD,andcurrentlyavailabletreatmentsonlytreatthesymptomsofPDratherthanmodifytherelentlessprogressionofPD.Moreover,giventheprogressivenatureofPD,eventhemosteffectivesymptomatictherapyhaslimitedefficacyovertime.Patientsreporthavingtotakemedicationuptoonceeveryhoursimplytoalleviatemotorsymptoms,severelycompromisingqualityoflife(QOL).Assuch,thelackofeffectivedisease-modifyingtherapiesisarguablyoneofthelargestunmetneedsforthePDcommunity.ThefollowingmedicationsusedtotreatPDarediscussedbelow:
• Levodopa/Carbidopa• DopamineAgonists• MonoamineoxidaseB(MAO-B)inhibitors• Catechol-O-methlytransferase(COMT)inhibitors• Anticholinergicagents• Amantadine
PHARMACOLOGICALTREATMENTOPTIONS
DOPAMINERGICMOTORSYMPTOMTHERAPY
Thistreatmentstrategyaimstoincreasethedopamineconcentrationinthebrain,whichissignificantlydecreasedduetoneuronalcelldeathintheSN.Figure6illustratesthefollowingwaysthatincreaseddopaminecanbeachieved:
LEVODOPA/CARBIDOPA
Levodopaisadopamineprecursorthatisconvertedtodopamine.Levodopaisadministeredincombinationwithcarbidopa,adrugthatpreventslevodopafrombeingconvertedtodopaminebeforeitcrossesthe
Figure6.DopaminergicMotorSymptomTherapy.Thisfigureillustratesthemechanismofactionforthefollowingdopamine-basedmedications:levodopa,dopamineagonists,MAO-BinhibitorsandCOMTinhibitors.
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blood-brainbarrier(BBB),asemi-permeablefilteringmechanismthatonlyallowscertainmoleculestopassintothecentralnervoussystem(CNS).Levodopawasfirstintroducedintotheclinicin1967,yetmorethan45yearslaterlevodopaisstillthemosteffectivetreatmentforPDmotorsymptoms.However,itsefficacydecreaseswithdiseaseprogression.Levodopacanremainhighlyeffectiveforaboutfourtosevenyears,butassymptomsworsen,patientsmayexperiencelossofbenefitbetweendoses,knownasthe“wearingoff”effect.Theemergenceofmotorfluctuationsandlevodopa-induceddyskinesias(asindicatedinTable1)severelyaffectspatientQOL.ThelimiteddurationoflevodopaefficacyhighlightstheneedformoreeffectivesymptomatictherapiestoincreasetheQOLforPDpatients.U.S.FoodandDrugAdministration(FDA)-approvedlevodopa/carbidopaagentsarelistedintheAppendix.
DOPAMINEAGONISTS
Theseagentsmimictheactionofdopaminebybindingdirectlytoandactivatingdopaminereceptorsinthebrain.Theprolongeduseofdopamineagonistsisassociatedwiththeonsetofimpulsecontroldisorders(seeTable1).FDA-approveddopamineagonistsarelistedintheAppendix.
MONOAMINEOXIDASEB(MAO-B)INHIBITORS
Theseinhibitorsareresponsibleforpreservingexistingdopamineinthesynapse(thejunctionbetweenneurons).TheyselectivelyblocktheactivityoftheenzymeMAO-B,whichmetabolizes(orbreaksdown)existingdopamineinthesynapse.FDA-approvedMAO-BinhibitorsarelistedintheAppendix.
CATECHOL-O-METHLYTRANSFERASE(COMT)INHIBITORS
Theseinhibitorsareresponsibleforincreasingthebioavailabilityoflevodopa.TheyblocktheactivityoftheenzymeCOMT,whichmetabolizes(orbreaksdown)levodopaintheperipherybeforeitcanbeconvertedtodopamine.FDA-approvedCOMTinhibitorsarelistedintheAppendix.
NON-DOPAMINERGICMOTORSYMPTOMTHERAPY
Thesetreatmentoptionsaredesignedtotargetnon-dopaminergicsignalingpathwaysinthebrainandmayhaveaneffectonsome,butnotall,motorsymptoms.FDA-approvednon-dopaminergicagentsarelistedintheAppendix.
ANTICHOLINERGICAGENTS
Acetylcholineisaneurotransmitterthatworksincoordinationwithdopaminetoproducesmoothmovement.InPD,theacetylcholine-dopaminebalanceisdisturbed.Thisdrugclassblockstheactionofacetylcholineandisusedtotreatrestingtremorandrigidity.However,theyarenoteffectiveforbradykinesiaorotherfeaturesofadvancedPD.
AMANTADINE
Thisdrugisanantiviralagentwithwidespreadproperties.Itfunctionstoincreasedopaminereleaseandblockdopaminereuptake.Amantadineisusedtotreattremor,bradykinesia,rigidityandlevodopa-induceddyskinesia.
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NON-MOTORSYMPTOMTHERAPY
Non-motorsymptomsarecommoninPD,withseveralstudiesindicatingthatalmostallPDpatientswillexperienceatleastonenon-motorsymptomduringthecourseoftheirdisease.ThereareFDA-approvedtreatmentsavailableforseveralnon-motorsymptoms,suchasanti-depressants,cognitiveenhancersandagentstotreatarangeofgastrointestinalissues.Dependingonthenon-motorsymptomthatpresents,theneurologistmaycollaboratewithaphysicianthatspecializesinthenon-motorsymptomareatotreatthesymptom.Inthesescenariositisimportanttocarefullyconsiderhowthetreatmentofonesymptommayaffectthetreatmentofanothersoastolimitadverseeffects.
Patientsfindnon-motorsymptomsparticularlydebilitatingandanegativeinfluenceonQOL.Whenpatientexperiencesweresurveyedatrecentmeetings,includingtheFDAPatient-FocusedPDDrugDevelopmentPublicMeeting(September2015inWhiteOak,Md.)andtheGrandChallengesinPDconference(October2015inGrandRapids,Mich.),patientsreportedthatoftentimesnon-motorsymptomsposeevenagreaterchallengetoQOLthanthemotorsymptoms.
NON-PHARMACOLOGICALTREATMENTOPTIONS
ExercisehasbeenshowntohaveanenormousbenefitinhelpingPDpatientsmanagepainandmaintainQOL.DatafromtheNationalParkinsonFoundation-sponsoredParkinson’sOutcomesProjectdemonstratedthatexercisecanslowtherateofdeclineintheQOLexperiencebyPDpatientswhenstartedearlierratherthanlaterinthediseasecourse.Resultsofthestudywerepresentedatthe19thInternationalCongressofParkinson’sDiseaseandMovementDisordersheldinSanDiego,Calif.,inJune2015.
Complementarypracticessuchasmeditation,yogaandtaichiareoftenrecommendedformoodandpainmanagement.Dependingonpainseverity,physicaltherapymayberecommended.Forpatientsexperiencingspeechissues,speechtherapymayberecommended.
SURGICALTREATMENTOPTIONS
Deepbrainstimulation(DBS)isasurgicalprocedureapprovedforthetreatmentofadvancedPDinpatientswhosemotorsymptomsarenotadequatelycontrolledwithmedications.DBSisusedtotreattremor,bradykinesia,rigidityandgaitissues.Approvedinthe1990s,DBSisnotedasthemostimportanttherapeuticadvancementsincelevodopa,withpatientsusuallyreportingmotorsymptomrelief.Whileeffective,DBSisnotsuitableforallPDpatients,andusuallybenefitspatientswhohavepreviouslyrespondedtopharmacologicaltreatment.
TheDBSsystemusesthefollowingcomponents(seeFigure7):
• Electrodes(alsoknownasleadsorprobes)–thesearethin,insulatedwiresthataresurgicallyimplantedinthe
Figure7.DBSSystemComponents.ThethreecomponentsoftheDBSsystemareillustratedabove.ImagereusedunderCreativeCommonslicense(Source).
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brainthroughasmallopeningintheskull.Theelectrodetipsareinsertedintocertainareasdeepwithinthebrain.
• Extensions–thisisaninsulatedwirethatconnectstheelectrodetotheimplantablepulsegenerator.Theextensionslieundertheskinofthehead,neckandshoulder.
• Implantablepulsegenerator(IPG)–thisisthe“batterypack”thatdelivershighfrequencyelectricalstimulationtothebrain,similartoaheartpacemaker.TheIPGisusuallyimplantedundertheskinnearthecollarbone.
MONITORINGTREATMENTEFFICACY
TreatmentefficacyisprimarilymonitoredbypatientdiariestoassessmotorsymptomseverityinthecourseofdailylivingandthroughphysicianassessmentusingtheMDS-UPDRSratingsystem.DependenceonPDpatientdiariespresentschallengesasmanypatientsdealwithbothmotorandcognitiveimpairment;thustheydonotalwayshavethecapacitytoaccuratelyrecordandconveysymptomstotheirphysicians.Also,giventhevariabilityinthepatientperceptionofpainanddegreeofimpairment,itishardtocomparetreatmentefficacyacrosspatientpopulations.
Objectivemeasurementofpatientresponsetotreatment,atamolecularandwholebodymovementlevel,wouldlessentherelianceonself-reportedpatientdiariesandprovidephysicianswithmoreaccurateinformationwithwhichtodeterminetreatmentdecisions,againunderscoringtheneedforbiomarkersinthePDspace.Currentlytheuseoftechnology,suchaswearabledevicesandmobiletechnology,isalsobeingexploredasameanstoprovideobjectivemeasurementofmotorsymptoms.
THEMECHANICSOFPARKINSON’SDISEASE
HOWTHENERVOUSSYSTEMWORKS
InordertofullyappreciatethediseasecourseofPD,itishelpfultounderstandtheanatomyofthenervoussystemandhowneuronsinthenervoussystem(alsoknownasnervecells)communicate.
ThenervoussystemismadeupoftwopartsasseeninFigure8:
• Centralnervoussystem(CNS)–comprisedofthebrainandspinalcord.
• Peripheralnervoussystem(PNS)–comprisedofallthenervesandnervebundles(knownasganglia)outsideoftheCNS.
ThePNSconnectstheCNStoourextremitiesandorgans.Similartothefunctionperformedbyelectricalwiringinahome–carryingelectricalimpulsestooutletstopower
Figure8.TheHumanNervousSystem.TheCNS(pink)containsthebrainandspinalcord.ThePNS(yellow)containsallthenervesandnervebundlesoutsideofbrainandspinalcord.ImagereusedunderCreativeCommonslicense(Source).
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appliances–thenervoussystemexecutesasimilarfunctionbycarryingelectricalimpulsesthroughnervecellstopowermovementandotherfunctions.Nervecells,knownasneurons,arethebasicbuildingblocksofthenervoussystem,andtheirabilitytocommunicateisabsolutelynecessaryfornervoussystemfunction.
TALKINGNEURONS–HOWNERVECELLSCOMMUNICATE
Neuronshaveacellbodywithtwotypesofcellularextensions:dendritesandaxons(seeFigure9,left).Ononeend,dendritesreceiveinformationfromaneighboringneuronandcarrythatinformationtothecellbody.Theinformationthentravelsawayfromthecellbody,intheformofanelectricalimpulse,throughtheaxondowntotheterminalbranchesoftheaxon.
Theelectricalimpulsetriggersthereleaseofchemicalsignalscalledneurotransmitters.Neurotransmittersarereleasedacrossasmallgapinbetweentwoneuronscalledthesynapse(seeFigure9,right).
Thetypeandamountofneurotransmitterreleasedaffectscommunicationbetweentwoneurons.Withouttherightamountofneurotransmitters,communicationislost,andthefunctionthatthoseneuronsgovernwillsuffer.
ThecentralneurotransmitterinPDisdopamine.Dopaminesignalingbetweenneuronsfacilitatessmoothcoordinatedmovement.Aspreviouslymentioned,SNneuronsproduce,releaseandareactivatedbydopamine,thereforetheyaredescribedasbeing“dopaminergic.”AsPDkillsdopaminergicneurons,lessdopamineisavailableforpropercommunicationwithintheSNandotherbrainregions,therebycompromisingtheabilitytoperformsmoothcoordinatedmovements.
Figure9.NeuronalAnatomyandCommunication.(Left)Thepartsofaneuronareillustratedabove.ImageadaptedfromtheNationalInstituteofHealth(Source).
(Right)Aclose-upofthesmallgapbetweentwoneurons,thesynapse,isillustratedabove.ImagesadaptedfromtheNationalInstituteonAging[PublicDomain]viaWikipediaCommons(Source).
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HALLMARKSOFPDPATHOLOGY
ThecauseofPDisunknown;however,PDismarkedbythefollowingcriticalpathologicalfeatures:
• Irreversibleneuronalcelldeathinthesubstantianigra(SN)regionofthebrain
• Accumulationandabnormalaggregationoftheproteinalpha-synuclein
Thereareseveralriskfactors(detailedintheRiskFactorsandPreventionsectionofpage12),suchasgeneticabnormalitiesandexposuretoenvironmentaltoxins,thatareproposedtoacceleratetheprocessesthatleadtotheaforementionedpathologicalfeatures.
IRREVERSIBLESNNEURONALCELLDEATH
Asmentionedpreviously,theirreversiblelossofdopamine-producingneuronsintheSNleadstotheovertmotorsymptomsexperiencedbyPDpatients.BythetimeaPDpatientpresentswiththemotorsymptomsnecessaryforPDdiagnosis,approximately60-80percentofthedopamine-producingSNneuronshavealreadybeenlost.
ThedeathoftheseneuronsleadstoachainreactioninthebrainasdepictedinFigure10.Asexplainedpreviously,neuronsareinterconnectedandcommunicatewitheachotherbysendingchemicalsignalsintheformofneurotransmitters.Theneurotransmitterdopaminestimulatesacollectionofbrainstructurescalledthestriatum,therebyfacilitatingnormalmovements.
Figure10.SequenceofEventsFollowingDopamineLoss.ThedopamineimbalancecausedbythedeathofSNneuronscausesachainreactionfurtheringaffectingotherbrainstructures.
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TOXICALPHA-SYNUCLEIN-CONTAININGAGGREGATES
Alpha-synucleinisaproteinthatisfoundpredominatelyinthebrain,withlesseramountsfoundthroughoutthebody.Proteinsundergoanintricatefoldingprocessuponproductiontoensureappropriatefunctioninthecell;however,someproteinsmisfoldandcanbecometoxictothecell.InPDpatients,alpha-synucleiniscommonlyfoundinthemisfoldedform.Thismisfoldedproteinclumpstogethertoformtoxicaggregates,includingstructurescalledLewybodies.AdefinitivediagnosisofPDisdependentonthepresenceofthesetoxicalpha-synucleinaggregatesatautopsy(seeFigure11).
Itisbelievedthattheabnormalbuild-upofLewybodiesleadstoadysfunctionalneuronalstatethatprecedesSNneuronalcelldeath.Recently,scientistshavediscoveredthatLewybodiesareabletospreadtootherneuronsandinducealpha-synucleinmisfoldingandaggregation,possiblyexplainingtheprogressivenatureofPD.
Becausealpha-synucleinisfoundconsistentlyinthebrainofPDpatients,theabilitytoimagealpha-synucleinwhilepatientswerestillliving,ratherthanatautopsy,coulddecreasemisdiagnosisandfacilitatebetterpatientselectionforclinicaltrials.Thedevelopmentofanalpha-synucleinimagingbiomarkercouldpotentiallyrevolutionizePDdiagnosticsanddrugdevelopment.
Understandingabnormalalpha-synucleindynamicsisanareaunderintenseinvestigationastheyrepresent“druggable”processesthatcanbetargetedpharmacologically.ThehopeisthatPDdiseasemodificationcanbeachievedifeitheralpha-synucleinaggregationand/orspreadcanbepreventedorhalted.
Whilealpha-synuclein-containingLewybodiesareahallmarkofPDpathology,othertypesofproteinaggregates(suchasthecommonproteinaggregatesfoundinAlzheimer’sdisease)arealsofoundinthebrainsofPDpatients.ThissuggeststhatthepathologyofPDisfarmorecomplexthanthecurrentmodelcenteredprimarilyonalpha-synuclein.
Figure11.Alpha-synucleinLewyBody.Microscopicimageofanalpha-synuclein-containingLewybodyintheSN.ImagebySurajRajan(ownwork)viaWikipediaCommons,reusedandmodifiedunderCreativeCommonlicense3.0(Source).
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OTHERDYSFUNCTIONALCELLULARPROCESSESINVOLVEDINPD
DescribedbelowareseveralotherdysfunctionalcellularprocessesbelievedtocontributetoPD.
MITOCHONDRIALDYSFUNCTION
Mitochondrialdysfunctionmakescellssusceptibletodeath,thuspromotingneurodegeneration.Themitochondriaisthecellularstructureresponsibleforgeneratingenergyforallcellularprocessesandisconsideredthepowerhouseofthecell.Italsoplaysakeyroleincellularsurvival.Mitochondrialdysfunctionhasbeenlinkedconsistentlytoseveralneurodegenerativediseases,includingbothsporadicandfamilialPD,therebyrepresentinganattractivedrugtarget.
NEUROINFLAMMATION
Chronicinflammationcanleadtocelldeath.ChronicneuroinflammationhaslongbeenimplicatedinPD,althoughthisareaofstudyhasbeenlargelyneglected.Theinflammatoryresponseisdrivenbytheactivationofmicroglialcells(residentimmunecellsoftheCNS)andinfiltrationofTcells(atypeofimmunecell)intotheSN.Theinflammatoryresponseisalsoactivatedbytheproductionofpro-inflammatorymolecules.RecentresearchsuggeststhatmutatedLRRK2(seeTable2)isimplicatedinneuroinflammation.ResearchinthisareaisexperiencingaresurgenceinthePDfieldbecausecellulareventsthataretriggeredbyneuroinflammationrepresentpossibletherapeutictargets.BothLRRK2-targetingandanti-inflammationtherapiesarebeingactivelyexploredbythepharmaceuticalindustryforpotentialdisease-modifyingbenefit.
AUTOPHAGY–ACELLULARCLEANINGPROCESS
Autophagyisafundamentalcellularcleaningprocessthatisaqualitycontrolmechanismforthecell.Thelysosome,oftentimesreferredtoasthe“garbagecanofthecell,”isresponsiblefordegradingoldordefectivecellularcomponents,andiskeyfortheautophagicprocess.Enhancingtheautophagicprocessiscurrentlybeingexploredasatherapeuticstrategytopromotetheclearanceofalpha-synucleinfromneurons.
Therearealsointerestingconnectionsbetweensomegeneticriskfactorsandautophagy.Forexample,theGBAgene(seeTable2)encodesforaproteinfoundinthelysosome,whichisthekeycellularstructureforautophagy.Further,LRRK2mutationsareimplicatedinautophagicdysfunctionaswell,andrecentresearchsuggeststhatdisruptedautophagycontributestoalpha-synucleinbuildupinneurons–furtherhighlightingtheconnectionbetweenautophagicdysfunctionandPD.
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Table2.GeneticRiskFactorsAssociatedwithPD.
PDGENETICS
RaregeneticmutationsarestronglyassociatedwiththedevelopmentoffamilialPD.Genescodeforproteins,whichinturncarryoutcellularfunctions.Geneticmutationscangiverisetoadysfunctionalprotein(s),therebycontributingtodisease.
WhiletheraregeneticmutationslistedinTable2greatlyincreasetheriskofdevelopingPD,therearealargenumberofcommongeneticchangesthatarealsoseeninidiopathicPDcases.Individuallythesechangesalterriskbyonlyasmallamount;however,researchthatinvestigatestheunderlyingbiologyaffectedbyaparticulargeneticmutationwillshedlightonthebiologicalprocessesthatleadtofamilialandidiopathicPD.Itisimportanttorememberthatinvestigatorsareconstantlydiscoveringnewgeneticriskfactors.Therefore,Table2isnotanexhaustivelist;rather,itcapturessomeofthemostresearchedgenes(listedinalphabeticalorderbyproteinname).
ThescienceofPDisstillunfoldingand,despiteintensestudy,manyunansweredquestionsremain.Nevertheless,PDisnolongerrecognizedasapurelydopaminergicneurodegenerativedisease.Thefieldismovingtowardsamulti-systemviewofthisneurodegenerativediseasewithbothCNSandPNSinvolvement,havingeffectsonbothdopaminergicandnon-dopaminergicneuronsinvariousbrainregions.
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Figure13.CurrentInterventionalPDClinicalTrials.Ofthe138active,interventionalPDclinicaltrials,37(27%)areinPhase3.Dataobtainedfromwww.clinicaltrials.gov.
Figure12.PhasesofClinicalTrials.DuringPhaseI,researcherstestanewdrugortreatmentforthefirsttimeinasmallgroupofpeopletoevaluateitssafety,determineasafedoserangeandidentifypotentialsideeffects.DuringPhaseII,proof-of-conceptstudiesareperformedasthedrugortreatmentisgiventoalargergroupofpeopletodetermineeffectiveandoptimaldose.DuringPhaseIII,thedrugortreatmentisgiventolargegroupsofpeopletoconfirmitseffectiveness,monitorsideeffectsandassessitsimpactcomparedtothecurrentstandardofcare(SOC).SomeclinicaltrialsinvolvemultiplephasestofacilitateseamlesstransitionfromonetoanotherandarewrittenasPhaseI/IIorPhaseII/III.Thesedesignationsarealsousedinadaptivetrials,whereinstudyparametersaremodifiedwithrespecttoongoingtrialresults.
CLINICALTRIALSANDINVESTIGATIONALTHERAPIES
CLINICALTRIALS–OVERVIEW
Clinicalresearch(alsoreferredtoasclinicaldevelopment)isabranchofbiomedicalresearchinvolvinghumansubjects.Thegoalofclinicalresearchistoevaluatesafetyandefficacyofdrugs,medicaldevicesordiagnosticsintendedforuseinhumanpatients.
Clinicaltrialsareanimportantcomponentofclinicalresearchsincetheyareusedtoevaluatethesafetyandefficacyofanexperimentaldrugortherapyinhumansubjects.ClinicaltrialsaredividedintophasesasdescribedinFigure12.Theycanalsobeusedtocollectspecimensfromhumansubjectsforfurtherresearch.Importantly,informationonpotentialsideeffectsaregatheredduringtheclinicaltrialperiodandweighedagainstthepotentialtherapeuticbenefitofthetreatmentunderinvestigation.
Theresearchanddevelopment(R&D)process–theprocessbywhichalaboratorydiscoveryisdevelopedintoacommercialtherapeutic,diagnosticordevice–isverycostlyandtime-intensive.Itisestimatedthat95percentofnewdrugsfailtomakeitintotheclinic.Thisisahighfailurerateforaprocessthatcostsabout$1billioninoverallresearchcostsandupto15yearsoftimeinvested.
PARKINSON’SDISEASECLINICALTRIALS
AsofJanuary2016,thereare138activeinterventionalclinicaltrialsforPD.Figure13illustratesthedistributionofthesetrialsbyphase.PDclinicaltrials–aswithotherneurodegenerativediseases–havebeenfraughtwithfailuresinthepast,whichcausedpharmaceuticalandbiotechnologycompaniestofleethespace.However,thisdynamicisrapidlyshiftingasrecentadvanceshaverenewedinterestandinvestmentinPD.
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Figure14.NIHFundingforPDversusTotalFundingforNeurosciences.AnnualNIHfundingforPD-specificresearchhasconsistentlybeenlessthan3%ofthetotalfundingforallneuroscienceresearchsinceFY2011.ThistrendisforecastedtoremainunchangedforFY2015and2016.DataobtainedfromNIHResearchPortfolioOnlineReportingTools.
PDclinicaltrialsareexpensiveandinherentlyriskyforseveralreasons:
• Timeneededtocompleteastudy–Largepatientpopulationsneedtobefollowedforlongperiodsoftimeinordertocaptureanypossibleeffectsondiseaseprogression.Infact,thetimetoPDclinicaltrialcompletionisprojectedtotakenearly25percentlongerthanclinicaltrialsforothertherapeuticareas.
• Lackofreliablebiomarkerstomonitortreatmentresponse–Theefficacyofanexperimentaldrugortherapycannotbeadequatelyevaluatedwithoutareliablewaytodetermineifthedrugpenetratedthetargetorganandengagedtheintendedmoleculartarget.ThisisakeychallengeinPD,aswithmostneurologicaldiseases,sincethebrainisthemostdifficultorgantopenetrate.
• Heterogeneousnatureofthedisease–Patientheterogeneitycanhavenegativeeffectsonstudyresults.Testingauniformgroupofpatientswouldpreventdilutionoftreatmenteffectandalloweffectivetreatmentstoberecognizedquicker.Thisagainhighlightstheneedforbetterpatientstratificationtoensurethatinvestigationaltreatmentsarebeingappliedtotherightpatients.
Thoughtherisksaregreat,strategicphilanthropicinvestmentisuniquelypoisedtode-riskPDresearchbyprovidingscientistswiththeresourcesthatcanacceleratepromisingsciencefrombasicresearch,throughthecriticaltranslationalresearchphase,andintoclinicaldevelopment.GovernmentfundingforPDismodestatbest,asillustratedinFigure14,withthemajorityoffundsgoingtowardsbasicresearch.PD-specificfundingrepresented2.5percentofthetotalneurosciencesfundingfromtheNationalInstitutesofHealth(NIH)forFY2014–atrendthathasbeenconsistentforthepastfouryears–andisestimatedtoremainunchangedforFY2015and2016.Itisevidentthatfundingfromothersourcesisdesperatelyneeded,andthisiswherephilanthropycanplayapivotalrole.
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Figure15.NewExperimentalAgentsinClinicalDevelopmentforPD.(Left)Newexperimentalagentsarerepresentedbyclinicaltrialphase.Ofthe64newexperimentalagentsindevelopment,9(14%)haveprogressedtoPhase3.
(Right)Newexperimentalagentsarerepresentedbytherapeuticstrategy.
AlldataobtainedfromBioCenturyOnlineIntelligence.
INVESTIGATIONALTHERAPIES
AsofJanuary2016,withinthe138totalactive,interventionalclinicaltrials,thereare64distinctagentsinclinicaldevelopmentforPD.Figure15illustratesthedistributionoftheseagentsbytypeandphaseofdevelopment.
Inthesectionsbelow,selectkeytherapeuticstrategiescurrentlyinclinicaldevelopmentforPDaswellaspromisingtherapiesunderinvestigationarediscussed.
ALPHA-SYNUCLEINTARGETINGTHERAPIES
Therearesixalpha-synucleintargetingagentscurrentlyinclinicaldevelopment.Theoverallgoalofthisstrategyistoclearalpha-synucleinbuild-upinthebraininordertopreventLewybodyformationandtransmissiontootherbrainregions.
Therearetwotherapeuticapproachesbeingtestedtoachievethegoalsstatedabove–smallmoleculeinhibitorsandimmunotherapy.
SMALLMOLECULEINHIBITORS(SMI)
SMIsarelowmolecularweightcompoundsthataresmallenoughtopassivelyenteracell,whichmakesthemamenabletooraldrugformulations.Ofparticularimportanceforneurologicaldrugsistheabilitytopassthebloodbrainbarrier(BBB).Thebrainistheonlyorganprotectedbyitsownselectivelypermeabledefensesystem,theBBB.ThegoalistodevelopSMIsthatcantargetalpha-synucleinbydisruptingthemisfoldedprotein’sabilitytointeractwithothermisfoldedalpha-synucleinproteinstoformaggregates.Thisisachallengebecausetheprotein-proteininterfacestypicallyspanlargesurfaceareas,therebymakingitverydifficulttodeterminewhichportionsoftheinterfacetheSMIshouldtarget.
ALPHA-SYNUCLEINIMMUNOTHERAPY
Inadditiontoexploringsmallmoleculedrugstotargetthealpha-synucleinprotein,researchersarealsotestingwhethertheycanactivatetheimmunesystemtotargetalpha-synuclein.Thisstrategy,referredtoasimmunotherapy,worksbysolicitingeitheranactiveorpassiveimmuneresponse.Activeimmunotherapyinvolves
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administeringasubstance(e.g.,drug,vaccine,etc.)intothebodythatinducesanimmuneresponseleadingtothenaturalproductionofantibodies(proteinsusedbytheimmunesystemtobindandneutralizeothermoleculesinthebody)againsttheintendedtarget(i.e.,alpha-synuclein).Passiveimmunotherapydiffersfromactiveimmunotherapyinthatantibodiesagainstthetargetarecommerciallymanufacturedoutsideofthebodyandadministeredasadrug.Resultsfromearlytrialsusingtheactiveimmunotherapyapproachindicatedthatthevaccinewaswelltoleratedandtherewasearlyevidenceofclinicalbenefit.
Onekeyconsiderationisthemanagementoftheimmuneresponsetoensurethattheimmunotherapeuticapproachesdonotpromoteexcessiveinflammation.Theimmunesystemmustremainincarefulbalanceasunder-orover-stimulationoftheimmunesystemcanleadtodeleteriouseffects.
LRRK2TARGETINGTHERAPIES
LRRK2genemutationsarethemostcommoncauseofgeneticPD(seeTable2).TheLRRK2geneencodesfortheLRRK2protein,whichisakinase,atypeofproteinthatcatalyzesphosphorylation(thetransferofphosphategroupsfromonemoleculetoanother).
SeveralLRRK2mutationsincreaseitskinaseactivity,whichistoxictoneurons.ThisiswhytheoverallgoalofthistherapeuticapproachistoinhibitLRRK2kinaseactivity.WhileLRRK2inhibitorsarenotyetinclinicaltrials,theyarecurrentlyinpreclinicaldevelopmentatPfizer,MerckandGenentech.Recently,toxicityconcernshavesloweddevelopment.However,TheMichaelJ.FoxFoundationforParkinson’sResearchhasconvenedanLRRK2IndustryAdvisoryGrouptopromotepre-competitivecollaborationacrossthesecompaniestosystematicallyaddressconcernsandgetclosertotestinganLRRK2-targetingdruginclinicaltrials.WhilethistherapyhasimmediaterelevanceforPDpatientswithLRRK2mutations,theremaybepotentialapplicationsforidiopathicPDpatientsaswell.
STEMCELLTHERAPY
Therearecurrentlytwostemcelltherapiesinclinicaldevelopment.Stemcellshavetheabilitytobecome(differentiateinto)anycelltypeinthebodygiventheproperbiologicalsignals.ThehypotheticalbasisforthistherapyisthatstemcellscouldberecruitedtoorplacedindamagedregionsandreplaceSNdopaminergicneuronsthatwerelostasaresultofPDandrestorepropersignaling.
Inadditiontoreplacingdamagedcells,stemcellsarebeingexploredasadiseasemodelingsystemtoscreennewPDtherapies.
USINGSTEMCELLSTOMODELPDANDSCREENNEWTHERAPIES
Aspreviouslymentioned,PDsymptomscanvarysignificantlyamongpatients,highlightingdiseaseheterogeneity.Itisimportanttobeabletomodeltheunderlyingbiologicalmechanismsdrivingtheheterogeneityofthediseaseinordertofindacure.Unfortunately,currentanimalmodelsfailtoadequatelyrecapitulatethedisease.Thetremendousprogressinstemcellresearchhasenabledresearcherstousethistechnologytocreatepatient-specificmodelsofPDinapetridish.ThisisdonebytakingskincellsfromaPDpatient(donor)andreprogrammingthemtomakeaninducedpluripotentstemcell(iPSC).TheseiPSCscanbereprogrammedtodevelopintoanycelltype,butforthepurposeofPDresearch,theyarereprogrammedtobecomeneurons.
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Becausethecellsarederiveddirectlyfromapatient,despitebeinggrowninpetridishes,theydisplaythesamemolecularandpathologicalfeaturesidentifiedinthedonorpatient.Thecouplingofthepatient’sclinicalsymptomstothebiologyandbehaviorofthestemcellscouldprovidenewinsightsintothekeymechanismsofPD.Thesepatient-derivediPScellscanalsobeusedtotestnewdrugs.TheuseofiPScellstoscreendrugsthatmaybeeffectiveagainstPDprovidesanadditionalmethodtovalidateresultsobservedinanimalsstudies.Thisisimportantbecauseanimalmodelsareoftenpoorpredictorsoftheclinicalsuccessorfailureofnewdrugs,whichisamajorimpedimenttoclinicaltrialsuccessinPD.
GENETHERAPY
Therearecurrentlyfourgenetherapiesinclinicaldevelopment.Thistherapeuticstrategyinvolvesdeliveringageneasadrug.ForPD,thistreatmentcoulddelivertheenzymethatconvertslevodopatodopamineinanefforttoincreasetheamountofdopamineinthebrainortodeliverfactorsthatpromoteneuronalsurvival.Althoughthetheoryisstraightforward,inpracticeitisconsiderablymorecomplextoachievethisoutcomeasaresultofmultiplevariablesthatcanbedifficulttocontrol.Todate,clinicaltrialstestingthisstrategyinPDaswellasotherneurodegenerativediseaseshavefailedtoshowimprovementaboveplacebo.Effortstoimprovegenetherapyarefocusedontwokeyareas:vectordesignanddeliverymechanism.
DRUGREPURPOSING
DrugrepurposinginvestigateswhetheradrugthatisalreadyFDA-approvedforanotherdiseasemaybeeffectivefortreatinganewdisease.Thetheoryisthatdiseasesthathavecommoncellularpathwaysmaybenefitfromsimilardrugs.FDA-approveddrugshavealreadybeentestedforsafety,meaningthatPhaseIrequirementshavealreadybeenmet.ThereforetestinganFDA-approveddrugforpotentialefficacyinadifferentdiseasecouldgostraighttoPhaseII,therebyreducingtimeandcostoftheclinicaltrial.ThisapproachhasbeenappliedtoPDrecentlywithsomesuccess:
• Metabolicagents–Metabolicagents,suchastypeIIdiabetesdrugs,haveshownefficacyinPDmodels.Abnormalglucosemetabolism(pathologicalfeatureofdiabetes)andabnormalmitochondrialfunction(pathologicalfeatureofPD)areintricatelylinked,givingareasonablebasistoexplorerepurposingmetabolicdrugsforPD.Arecentsmallpilotstudy(“proofofconcept”clinicaltrial)usinganFDA-approvedtypeIIdiabetesdruggeneratedexcitementinthePDfieldduetotheclinicalbenefitexperiencedbypatientstakingthedrug.APhaseIIclinicaltrialhasbeenlaunchedandiscurrentlyongoing.
• Chemotherapeuticagents–Recently,PDpatientsdemonstratedevidenceofmotorandnon-motorimprovementinasmallpilotstudyusinganFDA-approvedchemotherapyagentusedtotreatleukemia.ItisbelievedthattheagentworkstocleartoxicbuildupofLewybodies.ItseffectonPDiscurrentlyunderinvestigation.
• Antioxidantagents–ElevatedlevelsoftheantioxidanturateareassociatedwithalowerriskofdevelopingPDandslowerdiseaseprogressionifdiagnosedwithPD.Antioxidantagentscombatoxidativestress(theimbalancebetweenfreeradicalsandnaturalantioxidantsgeneratedinthecell).MitochondrialDysfunction,describedabove,isamajorcontributortooxidativestress.AnactivePhaseIIIclinicaltrialisinvestigatingwhethertheuseofthenutritionalsupplementinosine(whichthebodynaturallyconvertstotheantioxidanturate),canslowdiseaseprogressioninearly-stagePDpatients.
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• Highbloodpressuremedication–Previousstudiesshowthatcalciumchannelblockers,aparticularclassofhighbloodpressuremedication,mayreducetheriskofdevelopingPDandslowdiseaseprogressionifdiagnosedwithPD.MitochondrialDysfunctionoccursiftoomuchcalciumentersthecell.Calciumchannelblockersaredesignedtopreventthisexcessivecalciuminfluxintothecell.AnactivePhaseIIIclinicaltrialisinvestigatingwhethertherepurposedhighbloodpressuredrug,isradipine,canslowtheprogressionofearlystagePD.
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BARRIERSTOPDRESEARCHPROGRESSANDKEYPHILANTHROPICOPPORTUNITIES
PDisamultifactorialdiseasewithanumberofchallengesandunmetneedsthatstandinthewayofdesperatelyneededprogress.InNovember2015,theMilkenInstitutePhilanthropyAdvisoryServiceconvenedworld-renownedPDexpertstodiscussthestateofsciencerelevanttoPDandthechallengescurrentlyimpedingresearchprogress.Thegoaloftheretreatwastoidentifyhigh-impact,actionablesolutionswherestrategicphilanthropicinvestmentcouldaccelerateprogressinPD.Theexpertsprioritizedthefollowingchallenges:
• Incompleteunderstandingofunderlyingdiseasebiology
• Slowprogressinbiomarkerdiscoveryanddrugdevelopment
• Inadequatepreclinicalmodels
• Lackofdisease-modifyingtherapies(DMTs)andclinicaltrialfailures
• Suboptimalcurrenttreatmentoptionstomanagesymptoms
ThissectionoutlineseachofthekeychallengesalongwithpotentialsolutionsandcorrespondingphilanthropicopportunitiestoaddressthechallengesandacceleratePDresearchprogress.Pleasenotethattheopportunitiespresentedbelowarehigh-levelrepresentationsandshouldbeconsideredcarefullywithrespecttoyourphilanthropicgoalsanddiscussedindetailwithaphilanthropicadvisor.
INCOMPLETEUNDERSTANDINGOFUNDERLYINGDISEASEBIOLOGY
THEPROBLEM
TheunderlyingbiologyofPDisstillpoorlyunderstood,especiallywithrespecttokeyproteinssuchasalpha-synucleinandLRRK2.EvidenceoverwhelminglysuggeststhatPDconvergesontheaberrantprocessingofalpha-synuclein,yetseveralquestionsremainpertainingtohowabnormalalpha-synucleinmechanisticallycontributestoPD.Further,LRRK2mutationsarethemostcommoncauseofhereditaryPDandmayalsoplayaroleinspontaneousPD,yetverylittleisknownaboutthisprotein’snormalbiologicalfunctioninthecellanditsassociatedsignalingpathways.StrategicallyaddressinghighprioritybasicsciencequestionswouldenhanceourunderstandingoftheunderlyingPDdiseasepathologyandthusimprovechancesofidentifyingnewdisease-modifyingtreatments.
FundingtoexplorebasicbiologytypicallycomesfromNIH(thelargestsourceoffundingformedicalresearchintheworld).However,constrainedfederalspendinghascrippledtheNIHbudgetinrecentyears,therebyaffectingPDresearchfunding,whichisalreadyonlyasmallfractionofNIHspendingforallneurosciences(asillustratedinFigure14).AdeeperunderstandingofPDbiologywillinformdrugdevelopmentefforts,asalpha-synucleinandLRRK2representmajordrugtargetsforseveralindustryprograms(seeInvestigationalTherapiessectiononpage25).
POTENTIALSOLUTIONS
• Basicresearchinvestment–WhiletherehasbeenconsiderableinvestmentintranslationalandclinicalPDresearch,basicsciencehasbeenneglected.Betterscientificunderstandingwillinformdrugdevelopmentefforts,selectionofpatients,biomarkersandendpointsforclinicalstudies.Expertssuggestedemployinga
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modelthatallowsinvestigatorstoembarkonhigherriskprojectsthanhavetypicallybeenfundedbythegovernment.Keyprioritiesareastoconsiderare:
o Biologicalmechanismandimpactofalpha-synucleinprotein
o BiologicalmechanismandimpactofLRRK2protein
o BiologicalmechanismandimpactofotherPD-relatedgenes
o Selectivevulnerabilityofneuronaldeath
o Compensatoryneurotransmitterpathways
• Humancapitalinvestment–Thereisaneedtobettersupportexistinginvestigatorsandtoattractnewinvestigatorstothefield.Doingsowillnotonlyacceleratethepaceofresearch,butalsomakeitsustainablebytrainingthenextgenerationofinvestigators.Thereisadearthoffundingforpostdoctoral-levelandearlycareerinvestigators,whoperformthemajorityoftheearlybasicsciencestudies.Thishasthepotentialtonegativelyaffectbothacademicandindustry-ledresearchefforts,asbasicsciencestudiesformthebasisforfuturetranslationalandclinicalresearch.Additionally,decreasedsupportforbothestablishedandnewinvestigatorsincreasesthelikelihoodthatscientistswillleaveresearchinpursuitofothercareeroptions,thusdecreasingthepoolofscientistsavailabletoattackkeyscientificproblems.
EXAMPLESOFCORRESPONDINGPHILANTHROPICOPPORTUNITIES
• Fundbasicscienceresearchinitiativesthatenablebetterunderstandingofdiseasepathology.Thereareseveralmodelstosupportthisapproach,rangingfromfundinginvestigator-initiatedresearchtofundingacollaborativegroupofinvestigators.
• Fundadditionaltrainingprogramsthatinvestinpostdoctoralfellowsandearly-stageinvestigators,whogenerallycannotcompeteformajorgrantsupportastheydonothavethetrackofrecordofestablishedinvestigators.However,theyareimportanttoprovideforthefuturebasisofthefield.
Table3.SummaryofSolutionstoCatalyzeChangeinBasicResearch.
SLOWPROGRESSINBIOMARKERDISCOVERYANDDRUGDEVELOPMENT
THEPROBLEM
Atpresent,therearenobiomarkersavailabletoobjectivelydiagnosePD,assessdiseaseprogressionortotracktreatmentefficacyinpatients.Theprocessofbiomarkerdiscoveryandvalidationiscentraltodrugdevelopment.Effortstoincreaseefficiencyintheprocesshavethepotentialtoreducethetimeandcostofclinicaltrials.Inorderforabiomarkertobeacceptedasatrueobjectivemeasureofdiseasestateortreatmentefficacy,itmustfirstbe
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identified(biomarkerdiscovery),thenconfirmedthroughreplication(biomarkervalidation)andfinallydetectedinclinicallyrelevanttests(assaydevelopment).Alargeamountofbiologicalsamplesisnecessarytosuccessfullyhoneinonthefewcandidatebiomarkersthatpossesstheappropriatesensitivityandselectivitytobeadoptedastruebiomarkers.
Recentlarge-scaleefforts–suchastheParkinson’sDiseaseBiomarkersProgram(PDBP),sponsoredbytheNationalInstituteofNeurologicalDisordersandStroke(NINDS),andtheParkinson’sProgressionMarkersInitiative(PPMI),sponsoredbytheMichaelJ.FoxFoundationforParkinson’sResearch(MJFF)–haveestablishedcriticalinfrastructuretosupportbiomarkerdiscoveryand/orvalidationusingpatientbiologicalsamples(e.g.,blood,urine,cerebrospinalfluid[CSF],DNA,RNA).However,thereispotentialtomaximizetheutilityofthesedata-richresourcestosupportbothbiomarkerdiscoveryandvalidation(asopposedtooneortheother)withintheiralreadyestablishedpatientcohorts.
Asmentioned,biomarkerdiscoveryeffortsnecessitatelargeamountsofbiologicalsamples.Unfortunately,humanbraintissuefromlivingpatientsisnotavailabletostudyinneurodegenerativediseases,likePD,asthebrainisnottypicallybiopsied.WhilePDBPandPPMIcollectawidevarietyofbiologicalsamplesfrompatients,braintissueisnotcollected.Alternativelytherearevariousbrainbanksacrossthecountrythathousepost-mortembraindonationsfrombothpatientswithhealthybrainsandthosethatsufferedfromavarietyofneurodegenerativediseases.Althoughbraintissuefromthesefacilitiescanberequested,obtainingsufficientlylargeamountsoftissueiscostprohibitiveformanyresearchlaboratories.Further,thesebrainbanksareseverelyfragmented,eachhavingtheirownprocessesandhandlingprotocolswhichcancreatedatavariabilitywhenanalyzingsamplesfromvarioussources.Finallythesefacilitiesareoftenunderstaffedandunderfunded,therebycreatingsystemicinefficienciesthatultimatelymakethebraintissueinaccessible.However,ifthesechallengescouldbeovercome,elucidatingdifferencesinthemolecularprofile(e.g.genes,proteins,lipids,metabolicstate)ofPD-diagnosedbrainsversushealthybrainscouldaugmentbiomarkerdiscoveryeffortsandacceleratedrugdiscovery.
POTENTIALSOLUTIONS
• Leverageexistinginfrastructuresforbiomarkerdiscovery–ExistingprogramssuchasPDBPandPPMIhaveextensivesupportinplace,includingstandardizedcollectionandstorageofbiospecimens.However,theiroriginalintendedusewaseithertosupportbiomarkerdiscovery(PDBP)orvalidation(PPMI).Yet,theirutilitycouldbemorepowerfuliftheywereaugmentedtosupportbothbiomarkerdiscoveryandvalidationwithintheirestablishedcohorts.Strategicpatientcohortexpansionwithintheseprogramscouldsupportthedualbiomarkeractivitiesbyextendingstudydurationoverall,re-openingclosedpatientcohortsand/orrecruitingnewpatientcohorts.Theseactionscouldallowformorein-depthanalysisofdiseaseprogressionandheterogeneityinthesearchforcandidatebiomarkers.
• Leverageexistingbrainbankinfrastructuretocatalyzebiomarkerdiscovery–Todatetherehasbeennolarge-scaleefforttoperformdeepmolecularcharacterizationofbraintissueacrossU.S.brainbanks.CoordinatingexistingPDbrainbankingprogramsacrossthecountrytoperformlargescale“-omics”studiescouldincreasetheutilityoftheresourceandinformbiomarkerdiscoveryefforts.
• Createabiomarkervalidationandassaydevelopmentteam–Followingbiomarkerdiscoverywithintheabovementionedinfrastructures,validationteamscouldbeestablishedwiththeoverallgoalofgatheringsufficientdataonatargettomakeitattractiveforindustrytopickup.Onceacandidatebiomarkerisvalidated,amethodtodetectitspresenceintheappropriatebiofluidand/orimagingscanmustbeestablished.Assuch,thisteamcouldalsodevelopstandardized,robustassaystobeusedinclinical
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research.Strategicphilanthropicinvestmenttosupportassaydevelopmentwillincreasetheefficiencyofdrugdiscoveryefforts
EXAMPLESOFCORRESPONDINGPHILANTHROPICOPPORTUNITIES
• Fundongoinglongitudinalassessmentsand/ortheexpansionofprodromalandgeneticcohortswithinexistingPPMIandPDBPinfrastructures.Theseexpandedinfrastructureswouldbeabletosupportbiomarkerdiscoveryduetotheincreasedamountofsamplesavailable.Additionally,fundingalarge-scaleefforttodeeplycharacterizethesamplesbyperforming“-omics”studieswouldexpandtheutilityofthisresource.Suchaneffortwouldalloweachpatient’sentiregenome(genomics),expressedgeneprofile(transcriptomics),proteinprofile(proteomics),lipidprofile(lipidomics),andmetabolicstate(metabolomics)tobestudiedovertime.Thisdatasetcouldthenbemadeopenaccessforthescientificcommunityasaresourcetofuelallstagesofresearch.
• FundthecoordinationofexistingPDbrainbanksaroundthecountrytodevelopaPDbrainbanknetwork.DeepcharacterizationofPDpatientbrainsusinglarge-scale“-omics”studiesandbigdataanalyticscouldlowerthebarrierofdiscoveryandprovideanadditionalplatformforbiomarkerresearch.Thisdataset,assuggestedabove,couldthenbemadeopenaccessforthescientificcommunityasaresourcetofuelallstagesofresearch.
• FundBiomarkerDiscoverySWAT(SpecialWeaponsandTactics)TeamstoutilizePPMIandPDBPinfrastructure.Functionally,theteamswouldproposeabiomarkertarget,peer-reviewedbyscientists,andthenbringtogethergroupsofresearcherstovalidatethetargetanddevelopanassociatedassay.PharmaceuticalanddiagnostickitmanufacturingrepresentativesshouldworkwiththeSWATTeamstoadviseonkeyelementsneededtosuccessfullyvalidateadrugtargetandincreasethelikelihoodofproceedingwithdevelopmenteffortsaroundtheproposedtargetintheirrespectiveindustries.
Table4.SummaryofSolutionstoAcceleratethePaceofBiomarkerDiscovery.
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INADEQUATEPRECLINICALMODELS
THEPROBLEM
NosinglePDpreclinicalmodelfullyrecapitulatesthekeyfeaturesofhumandisease.Animalmodelsareusedtostudydiseasebiologyandtestexperimentaltherapeuticsinordertodemonstratepotentialbenefitbeforetheyareapprovedfortestingonhumansinclinicaltrials(preclinical).Poorreliabilityandpredictivecapabilityofthepreclinicaltranslationalpipelinenegativelyaffectdrugdevelopmentandcontributestothehighcostandfailureofclinicaltrials.
AsdescribedpreviouslyintheStemCellTherapysectiononpage26,thereismomentumacrosstheneurodegenerativespace(e.g.,Alzheimer’sdisease,ALS,PD,etc.)toutilizeinducedpluripotentstemcells(iPSCs),generatedfrompatientskinbiopsiesand/orbloodsamples,asbothabiomarkeranddrugdiscoveryplatform.HumaniPSCshavetheadvantageofretainingeachpatient’smoleculardiseasesignaturesandcanbedifferentiatedintovariouscelltypes(e.g.,neurons,heartcells,livercells,etc.)inadish(invitro),whichresemblethatfunctionalcelltypeinapatient’sbody.Assuch,thistechniquelendsitselftomodelinggeneticriskfactorsofdiseaseparticularlywell.ThisabilitytogeneratemultiplecelllineagesfromiPSCsprovidesinvestigatorswithawaytoevaluatetheeffectofanexperimentaldrugonmultiplecelltypessimultaneously.Forexample,investigatorscanassayforontargeteffectsonneuronsgeneratedfromiPSCsorforpotentialsafetysignalsinheartandlivercellsgeneratedfromiPSCsearlierinthedrugdevelopmentprocess.
POTENTIALSOLUTIONS
• Developamorepredictivepreclinicalpipeline–ThereareseveralpreclinicalmodelsavailablethroughtheParkinson’sDiseaseResearchToolsConsortium(PDRTC)sponsoredbyMJFFandtheiPSCConsortiumsponsoredbyNINDS;however,theycouldbebetterutilizedthroughrationalalignmentwithresearchgoals.Additionally,deepmolecularcharacterizationeffortsthroughlarge-scale“-omics”studies(asrecommendedforsolutionsdescribedintheprevioussection)couldalsoimprovemodelutilitytosupportmorerobusttranslationalresearchefforts.
EXAMPLESOFCORRESPONDINGPHILANTHROPICOPPORTUNITIES
• Fundalarge-scalepatient-derivediPSCeffortthatemploysasystemsbiologyapproachthroughcomprehensivebiologicalanalytics(e.g.,proteomics,transcriptomics,epigenomics,wholegenomesequencing,metabolomics,etc).Thisdatasetcouldthenbeavailableforthescientificcommunityasaresourcetofuelallstagesofresearch.Further,thisiPSCplatformcouldalsobeusedforhigh-throughputdrugscreening.AniPSCeffortcouldbeachievedby:
o CreatingaPDiPSCnetworkwithexistingiPSCbanksacrossthecountry,or
o SpearheadinganewefforttocreateiPSCsfromnewlyrecruitedpatients,or
o ExpandingthePPMIand/orPDBPbiospecimenresourcebycreatingpatient-derivediPSClinesfromenrolledpatients.
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Table5.SummaryofSolutionstoImprovethePreclinicalPipeline.
LACKOFDISEASE-MODIFYINGTHERAPIES(DMTS)ANDCLINICALTRIALFAILURES
THEPROBLEM
OfalltheavailabletreatmentsforPD,noneisproventoslow,haltorreversethenaturalprogressionofthedisease.Moreover,allnewinvestigationaldrugsforPDhavefailedtoshowadisease-modifyingeffectinpivotalclinicaltrials.Clinicaltrialsarecostlyandriskyendeavors,withthemostexpensivefailuresoccurringinlatephaseIIandIIIstudies.WhilethisissueislargelyduetotheincompleteunderstandingoftheunderlyingdiseasebiologythatisdrivingPD,thereareothercontributingfactors,suchas:
• Poorpatientselectionandstratification–Itisextremelydifficulttoselectpatientsintheearlieststagesofdiseaseasthesignsandsymptomsaresubtle,variableandmanyaredistinctfromthemotorsymptomsthatlaterpredominate.ThisprodromalperiodistheoreticallywhenpatientswouldbenefitmostfromaDMT.Theinabilitytostratifypatientsappropriately(i.e.,bydiseaseseverityandsubtype)hasseriousramificationsforsuccessfulclinicaltrialsandultimatelyfordevelopingDMTs.
• Lackofbiomarkers–Again,asmentionedpreviously,theinabilitytoreliablyandobjectivelydiagnosePD,assessdiseaseprogression,assesstargetengagement,ormonitortreatmentresponsehamperstheevaluationofapotentialDMT.Withoutappropriatemeasures,itisnotpossibletoknowwhetherapotentialtherapeuticisactuallyslowingtheprogressionofPD.
Additionally,investigatorsneedtointegratepatientperspectiveandinputintotheclinicaltrialprocess–anemergingimperativeinclinicalresearch.Patientsarerequiredforclinicalresearch,andtheirinputinstudydesign,parametersandoutcomemeasurescaninformtradeoffsbetweendesiredbenefitsandtolerablerisksthatareunaccountedforormisjudgedbyphysiciansandregulators.Poorpatientrecruitmentintoclinicaltrialsisacontributingfactortohighcosts.Infact,manytrialsareterminatedearlyiftheycannotrecruittheappropriatenumberofpatients.Effortstoengagepatientsintheclinicaltrialprocesscanincreaseclinicaltrialsuccessandwillbetterinformproductdevelopment.Forexample,conductingbenefit-riskanalyseswithpatientscouldshedlightonwhattypeandlevelofsideeffects,studyconditions,andburdensthatpatientsthemselvesmaybewillingtoaccept,whichphysiciansmaynothaveexpected.
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POTENTIALSOLUTIONS
• Validatemobileappsandwearable/sensingtechnologyplatforms–Suchobjectivemeasurescouldbebeneficialforcurrentclinicaltreatments(asdescribedinthenextsection)aswellasfutureclinicaltrials.Forclinicaltrialpurposes,thesemeasuresmayallowinvestigatorstoquantifymotorandnon-motorsymptoms,detectsmallerchangesinperformanceandmonitorpatientsremotely.Asaresult,thedatacaninformpatientstratificationandthedevelopmentofdigitalbiomarkers.However,atpresent,thefieldisill-equippedtohandletheenormousamountofdatageneratedbythesenewtechnologicalplatforms.Moreover,thereisnosetofquantitativedatastandardsthatcanbeappliedacrossclinicaltrialsindependentofthetechnologydeveloperand/ortrialsponsor.Thereforevalidationofthesedigitalhealthplatformsisessentialtoaddresslimitationsandfacilitateadoptionoftheseplatformsbyregulatoryagencies.
• Integratepatientperspective–Accountingforthepatient’sexperiencewillenrichclinicaltrialstudydesign,promotestudyaccrualandadherenceandidentifyacceptablerisksthatwerepreviouslynotconsidered.Further,thisisanopportunitytotakeintoaccountwhatbenefitsareactuallyimportanttopatients.Forexample,patientsmayfindthatatreatmentwhichallowsthemmorepredictabilityof“on”timewithina48-hourperiodmorevaluablethananextrahourofunpredictable“on”timewithina48-hourperiod,thusallowingthemthecontroltoplantheirday.Thesepreferencescouldaffectpatientparticipationinonetrialoveranother.Asweareenteringaneraofpatient-centeredcare,itisimportanttoactivelyseekandintegratethepatientvoiceintoclinicaldevelopmentandplanning,asthesetreatmentsareultimatelybeingdevelopedforthebenefitofpatients.
• Drugrepurposingclinicaltrials–Thesetrials,asdescribedpreviouslyintheDrugRepurposingsectiononpage27,offerthebenefitsofdecreasedtimeandcostforclinicaltrialsbyusingcompoundsthatweredevelopedforotherindicationsthatshowevidenceofpossibletherapeuticbenefitinPD.ItisworthnotingthattherearecurrentclinicaltrialsthatareinvestigatingrepurposeddrugsforthetreatmentofPD(e.g.,exenatide,atypeIIdiabetesdrug;isradipine,ahighbloodpressuredrug;nilotinib,acancerdrug).
EXAMPLESOFCORRESPONDINGPHILANTHROPICOPPORTUNITIES
• Fundaprecompetitive,multi-stakeholdermobiletechnologyinitiativetodesignandrunvalidationstudiesforapre-determinedsetofmotor,non-motorandtreatment-inducedsymptoms.Thegoalofthiseffortistoestablishaquantitativeglobalstandardforthedeterminedsymptomsthatcanbeappliedtoanydigitalhealthplatform.
o ThiseffortwillaffectallmembersofthePDresearchcommunity,includingcompetitorsinthepharmaceuticalandmedicaldevicemanufacturingindustries,aswellasacademicandnonprofitpartners.Therefore,precompetitivecollaborationwillallowthesecompetitorstosafelyshareindevelopingthestandardsthatwillbenefitthewholeecosystem.
o Ideally,thisinitiativewillleadtogloballyaccessiblequantitationmeasurementtools,aswellasdatathatareclinicallyactionableandavailabletobothpatientsandinvestigators.
• Fundpatientpreferencestudiestogaininsightintowhatoutcomemeasuresaremeaningfultopatients.Theresultsofthesestudieswouldthenbescaledtoinformtrialdesign,eligibilitycriteria,trialendpointsandsecondarymeasures.Further,patientengagementcouldbeincludedasaconditionofgrantfunding
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forinvestigatorsseekingclinicaltrialfunding.ThiswillensurethatthepatientperspectiveisincorporatedintotrialdesignpriortoInstitutionalReviewBoard(IRB)approval.
• Fundnoveldrugrepurposingefforts.Priortoclinicaltrials,iPSCplatformscouldbeusedasarepurposeddrugscreeningplatform.Additionally,theuseofbioinformatics-guidedapproachestodrugrepurposingcouldprovideamorerobustmethodtoexplorenewtherapies.
Table6.SummaryofSolutionstoSupportDMTResearchandClinicalTrials.
SUBOPTIMALCURRENTTREATMENTOPTIONSTOMANAGESYMPTOMS
THEPROBLEM
WhilefindingatreatmentthatslowsorhaltstheprogressionofPD(disease-modifyingtherapy)isalong-termgoalinthePDfield,effortstomakepatients’livesmoremanageableintheshorttermshouldnotbeignored.Patientsconsistentlyidentifytheprogressivemotorandnon-motorsymptomsasparticularlydebilitating.Therehavebeenrecentimprovementstolevodopaformulations(e.g.,extendedreleasetablets,patchandcontinuousinfusionviaintestinalpump);however,chroniclevodopatherapyleadstomotorfluctuations,themechanismofwhichispoorlyunderstood.Further,progressivemotorsymptoms,suchasfreezingofgaitandfalls,continuetobehugeunmetneedsforthefield,yetnotreatmentexistsforthesesymptoms.Adeeperunderstandingoftheunderlyingbiologyassociatedwithdiseaseprogressionwouldsupporteffortstodevelopmoreeffectivesymptomatictherapies.
Thereisalsonowagreaterappreciationfornon-motorsymptoms,yettheetiologyandunderlyingbiologydrivingthesenon-motorsymptomsarealsopoorlyunderstood.Cognitivedysfunctioninparticularremainsasignificantunmetneed,asthefieldlacksmeasurestoadequatelyassessdegreeofcognitivedecline.Near-termeffortstoimprovetherapeuticoptionsforpatientswouldaidinimprovingthequalityoflifeforpatients,andlongtermeffortstocharacterizePDfeatureswouldcontributetoDMTdevelopment.
POTENTIALSOLUTIONS
• Fundbasicresearchefforts–Anunderstandingofthenon-dopaminergiccompensatorypathwaysinthebraincoulduncovernew“druggable”targetsandsignalingpathwaysthatcouldbeexploitedfortherapeuticbenefit.DBSisasuccessfulexampleofasurgicaltherapythatcamefromthefield’sincreasedunderstandingofnon-dopaminergicpathways.Additionally,theunderlyingbiologyassociatedwithnon-motorsymptomsneedstobeexploredtosupportdevelopmentofrationaltherapeutics.
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• Harmonizeandstandardizelargeclinicaltrialdatabases–Clinicaltrialsaretypicallyperformedindependentofeachotherand,assuch,inconsistenciesinhowdatawere/arecapturedrenderthemajorityofclinicaltrialdatabasesincompatible.Dataaggregation,harmonizationandstandardizationofmultipledatasetswouldallowresearcherstoseamlesslyqueryacrossthewealthofinformationstoredinlargeinterventionalclinicaltrialdatabases.CapitalizingontheseexistingdatabasescoulduncovernewinsightsintoPDregardingthenaturalhistoryofdisease,diseasesubtypesandthebasisoftreatment-resistantfeatures.Thisprocessistimeintensive;however,databaseharmonizationtechnologyisbeingdevelopedtocreateprocessefficiency.
• Datagatheringwithmobileappsandwearable/sensingtechnology–Suchobjectivemeasurescouldallowinvestigatorstoquantifysymptoms,monitorpatientsremotelyandpersonalizecare.PDisaheterogeneousdisease;therefore,employingmethodstoassessthemotorandnon-motorfeaturesofprodromalandtreatment-resistantPDwouldaidDMTdevelopment.Additionally,thiseffortwouldenablepatientstoparticipateinstudiesremotely,thusallowingforlarge-scalenaturalhistorystudiestocharacterizethenaturalprogressionofPD.
EXAMPLESOFCORRESPONDINGPHILANTHROPICOPPORTUNITIES
• Fundbasicscienceresearchinitiativesthatenablebetterunderstandingoftreatment-inducedmotorsymptomsaswellasnon-motorsymptoms.Thereareseveralmodelstosupportthisapproach,rangingfromfundinginvestigator-initiatedresearchtofundingacollaborativegroupofinvestigators.
• FundanefforttoharmonizeandstandardizelargeinterventionalPDclinicaltrialdatabases.Ideally,thiseffortwouldincludeaccesstoandharmonizationacrossbothpublic(typicallygovernment-fundedtrials)andprivate(typicallyindustry-fundedtrials)databases.
• Fundatechnologyinitiativetoencouragesupplementarydatacollectionwithmobileappsandwearabletechnologyinfuturelarge-scalenaturalhistorystudies.Additionally,fundadataanalyticsefforttosupportalgorithmdevelopment,whichwouldtranslatethelargeamountsofdatageneratedfromwearable/sensingtechnologyintofunctionalinformationthatcanbeinterpretedbyphysicianstoinformcaredecisions,suchasdrugclassordosingchanges.
Table7.SummaryofSolutionstoImproveSymptomaticTreatments.
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KEYSTAKEHOLDERSINTHEPDCOMMUNITY
DOMESTICRESEARCHGRANT-MAKINGORGANIZATIONS
ThereareseveralnonprofitorganizationsspecificallyfocusedoncharitablegivingtosupportPDandotherneurodegenerativediseases.ThissectionprovidesabriefoverviewofthenonprofitorganizationsinvolvedinPDresearch.Theirinvolvementcanbethroughdirectlyfundingresearchorsupportingresearch.ThissectiononlyincludesU.S.-basedPDorganizationswitharesearchfocus;organizationsthataresolelyinvolvedinpatientsupport,advocacy,
awarenessorwhosemissionistofundonespecificresearchcenterareexcluded.Table8displaysthetopfournonprofitfundersofPDresearch.Additionalinformationregardingtheirmission,keyresearchfundingmechanismsandclinicaltrialssupportactivitiesisalsoprovidedbelow.
THEMICHAELJ. FOXFOUNDATIONFORPARKINSON’SRESEARCH(MJFF)
MISSION
TheMJFFmissionistofindacureforParkinson'sdiseasethroughanaggressivelyfundedresearchagendaandtoensurethedevelopmentofimprovedtherapiesforthoselivingwithParkinson'stoday.
RESEARCHFUNDINGMECHANISMS
MJFFmainlysupportstranslationalandearlyclinicalresearch.MJFFhasalargefootprintintheglobalPDcommunityastheyhaveinjectedover$450Minresearchfundssincetheirinception.Theyinvestedover$60MinFY2014.MJFFsupportsresearcheffortsinbothacademiaandindustryspanningdrugtargetvalidation,therapeuticdevelopmentforbothDMTandsymptomatictreatments,aswellasresearchtooldevelopmentanddatascience.AsignificantamountoffundingalsogoestosupporttheParkinson’sProgressiveMarkerInitiative(seepage43),MJFF’ssignatureprogramtodevelopdiseaseprogressionbiomarkers.
Formoreinformationaboutavailableawards,pleasevisitMJFF’swebsite.
Table8.TopNonprofitOrganizationFundingPDResearchinFY2014.
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NATIONALPARKINSONFOUNDATION(NPF)
MISSION
NPF’smissionistoimprovethelivesofParkinson’spatientsthroughexpertcareandresearch.
RESEARCHFUNDINGMECHANISMS
NPF’sresearchfundinghasaclearclinicalfocus.Theyhaveinfusedover$180MinresearchfundsintothePDfieldsincetheirinception.Theyawardedover$3MinresearchsupportinFY2014.NPFfundsinvestigator-initiatedresearchthatcoversawiderangeofPD-relevanttopicareas.Additionally,NPFsupportshumancapitalinvestmentintothefieldastheyprovideclinicalfellowshipstotrainneurologistsinthemovementdisorderspecialty.ThisisdesperatelyneededasmostPDpatientsdonotseeamovementdisorderspecialist.Theyalsoprovideresearchgrantstosupportcareerdevelopmentofyounginvestigators.
Formoreinformationaboutavailableawards,pleasevisitNPF’swebsite.
AMERICANPARKINSONDISEASEFOUNDATION(APDA)
MISSION
TheAPDAmissionisto“EasetheBurden–FindtheCureforParkinson’sdisease.”Asthecountry'slargestgrassrootsorganizationservingmorethan1millionAmericanswithParkinson'sdiseaseandtheirfamilies,APDA'senergyisfocusedonresearch,patientservices,educationandraisingpublicawareness.
RESEARCHFUNDINGMECHANISMS
APDAhasastrongfocusonpatientsupport,advocacyandawareness,howevertheydoalsofundPDresearch.Theyhaveawardedover$42Minresearchfundssincetheirinception,includingover$2MtosupportresearchactivitiesinFY2014.APDA’sresearchfundingisprimarilyfocusedonsupportingthecareersofaspiringandearlystagePDscientistsas75percentoftheirfundingmechanismsareintendedforyounginvestigators,postdoctoralfellowsorpracticingneurologists.
Formoreinformationaboutavailableawards,pleasevisitAPDA’swebsite.
PARKINSON’SDISEASEFOUNDATION(PDF)
MISSION
ThePDFmissionistoimprovethelivesandfuturesofpeopletouchedbyPDbyfundingpromisingscientificresearchwhilesupportingpeoplelivingwithParkinson’sthrougheducationalprogramsandservices.
RESEARCHFUNDINGMECHANISMS
PDF’sresearchfundingmainlysupportsbasicandtranslationalresearch.Sincetheirinception,theyhaveawardedover$110Minresearchfunds,includingover$5MduringFY2014.PDFsupportsbothinvestigator-initiatedaswell
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ascollaborative,center-wideresearch.PDFhasaglobalreachastheyfunddomesticallyandinternationally.TrainingandcareerdevelopmentisalsoapriorityforPDFsincetheyactivelyfundresearchandclinicalfellowships.
Formoreinformationaboutavailableawards,pleasevisitPDF’swebsite.
OTHERKEYGRANT-MAKINGORGANIZATIONS
PARKINSONSTUDYGROUP(PSG)
ThePSGisthelongeststanding,largest,not-for-profit,scientificnetworkofPDCentersinNorthAmericaconsistingof132centers.ThePSGaimstoconductclinicaltrialstoadvanceknowledgeaboutthecause(s),diseaseprogressionandtreatmentofPDandrelateddisorders.PSG-sponsoredclinicaltrialshavebeeninstrumentalintheFDAapprovaloffourPDdrugs:Rasagiline,Rotigotine,EntacaponeandPramipexole.PSGprovidesfundingforretrospectivedata-mining,mentoredclinicalresearch,andbiomarkerdiscoveryandvalidation.
Formoreinformationaboutavailableawards,pleasevisitPSG’swebsite.
PARKINSON’SUK
Parkinson’sUK’svisionandultimateambitionaretofindacureandimprovelifeforeveryoneaffectedbyPD.Parkinson’sUKisthelargestcharityfunderofPDresearchintheUK.Parkinson’sUKfundsmulti-yearresearchgrantsacrossalllevelsofresearch(basictoclinical)andresearchexperience(pre-doctoraltoseniorindependentinvestigator).ItprovidesfundingforlargeprojectsandcareerdevelopmentforaspiringPDinvestigators.
Formoreinformationaboutavailableawards,pleasevisitParkinson’sUK’swebsite.
THECUREPARKINSON’STRUST(CPT)
CPTisfocusedonfindingacureforParkinson’s.Itfundsprojectsthatcandemonstratethepotentialtoslow,stoporreversethecondition.CPTactivelyencouragescollaborationamongscientistsandfosterstheserelationshipstoaccelerateprogress.CPTfundsbothpreclinicalresearchandclinicaltrials.MostofthecurrentclinicaltrialssupportedareapartofitsLinkedClinicalTrialsInitiative.CPT’srecentresearchportfoliosupportsregenerativemedicine,mitochondrialfunctionstudies,alpha-synuclein-targetinganddrugdeliverymechanisms.
Formoreinformationaboutavailableawards,pleasevisitCPT’swebsite.
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COLLABORATIVEINITIATIVES
GOVERNMENT-SPONSOREDPROGRAMS
PARKINSON’SDISEASEBIOMARKERSPROGRAM(PDBP)
PDBP,launchedin2012,isaprogramoftheNationalInstituteofNeurologicalDisordersandStroke,whosegoalistosupportPDbiomarkerdiscoveryeffortsbyfundingresearchandresourcedevelopmentusingcollectedpatientsamples.ThePDBPhascollectedthousandsofpatientbiospecimens(e.g.DNA,RNA,CSF,blood)for30monthsin6monthintervals,allowingforlongitudinalstudies.Grantstotalingover$5MhavebeenawardedunderPDBPtodatewithactivefundingannouncementsouttosupportfuturework.
MORRISK.UDALLCENTERSFOREXCELLENCEINPARKINSON’SDISEASE
ThisNINDSprogramwasnamedinhonorofCongressmanMorrisK.UdallofArizona,whowasdiagnosedwithPDin1979.UdallremainedactiveinCongressuntilhisretirementin1991,andpassedawayin1998afteralongbattlewithPD.UdallCentersutilizeamultidisciplinaryresearchapproachtoelucidatethefundamentalcausesofPDaswellastoimprovethediagnosisandtreatmentofpatientswithPDandrelatedneurodegenerativedisorders.UdallCentersarerequiredtosharedataandengagepatientstopromoteknowledgeadvancementinboththePDresearchandpatientcommunities.TherearecurrentlynineUdallCentersacrossthecountry:
• TheBrighamandWomen'sHospital(Boston,MA)• FeinsteinInstituteforMedicalResearch(Manhasset,NY)• JohnsHopkinsUniversitySchoolofMedicine(Baltimore,MD)• MayoClinic,Jacksonville• NorthwesternUniversity(Chicago,IL)• UniversityofMiami• UniversityofMichigan• UniversityofPennsylvaniaSchoolofMedicine• UniversityofWashington
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CONSORTIAANDSTRATEGICPARTNERSHIPS
Consortiaaretemporaryassociationsofstakeholdersfromvarioussectors–academia,industry,government,nonprofits,etc.–thatshareresourcesinordertoachieveacommongoal.AccordingtoFasterCures’Consortia-pediaCatalogue,adatabaseofbiomedicalresearchconsortia,therearecurrentlynearly10consortiaforPD.Table9listsselectconsortiathatarefocusedexclusivelyonPDresearch,resourcebuildingand/ortherapeuticdevelopment.Patientcohortsareexcludedfromthisanalysis.Forafulllist,pleasevisitwww.consortiapedia.fastercures.org.
Table9.PDConsortia.
BIOMARKERSACROSSNEURODEGENERATIVEDISEASES(BAND)
TheBANDconsortiumconsistsoftheAlzheimer’sAssociation,Alzheimer’sResearchUK,MJFFandtheWestonBrainInstitute.ThegoaloftheBANDconsortiumistostimulateanalysesacrosstheAlzheimer’sdiseaseandPDresearchenterprisestoengageinfurtherdataanalysisofexistingcohorts.Dataanalysiswillcontributetobiomarkerdiscovery,standardizationofassays,geneticprofilesandimagingmodalities.Thegoalistoenablepreliminarypilotresearchorproof-of-principlestudiesutilizingdataand/orsamplesfromtwolargebiomarkerstudies–theAlzheimer’sDiseaseNeuroimagingInitiativeandthePPMI–inordertogarnerfurtherresearchsupportfromotherfundingagencies.
INTERNATIONALPARKINSON’SDISEASEGENOMICSCONSORTIUM(IPDGC)
TheIPDGCisamultinationalcollaborativegroup.MembersoftheIPDGChaveledtheefforttodefineandunderstandthegeneticbasisofPD,identifyingthemajorityofknowngeneticriskfactorsforthisdisease.Todate,thelargestgenome-wideassociationanalysisforPDwasperformedbyIPDGCmembers.IPDGCalsospearheadedthecreationofinexpensiveandpowerfulgenotypingtools,suchastheNeuroXchip,throughanindustrycollaborationwithIllumina.Thetoolshavebeenwidelyadoptedforthestudyofmultipleneurodegenerativediseases.
Theirworkisbeingextendedtoincludebiomarkeridentification,riskprediction,diseasesubtyping,andthemolecularbasisofdisease.ThemembersoftheIPDGC,whoarebasedintheUSA,France,England,Wales,Germany,TheNetherlands,andEstonia,meetinpersonbiannually.
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NETWORKFOREXCELLENCEINNEUROSCIENCECLINICALTRIALS(NEURONEXT)
NeuroNEXTwascreatedtoconductstudiesoftreatmentsforneurologicaldiseasesthroughpartnershipswithacademia,privatefoundationsandindustry.ThenetworkisdesignedtoexpandtheNINDS’capabilitytotestpromisingnewtherapies,increasetheefficiencyofclinicaltrialsbeforeembarkingonlargerstudiesandrespondquicklyasnewopportunitiesarisetotestpromisingtreatmentsforpeoplewithneurologicaldisorders.
NeuroNEXTprovidesanestablishedinfrastructure,includingadatacoordinatingcenter(UniversityofIowa),ClinicalCoordinatingCenter(MassachusettsGeneralHospital)andapproximately28studysites.FundedNeuroNEXTstudieswillusethisinfrastructure,whichincludesacentralIRBandpre-establishedcontractualagreementswithallsites.AllbutthreeNeuroNEXTsitesarealsoPSGsites.
PARKINSON'SDISEASERESEARCHTOOLSCONSORTIUM(PDRTC)
ThePDRTCformalizespreviouslyadhocinputandfeedbacktotheMJFFfromtooldevelopersandendusersinpursuitofmorerobusttoolsforthePDresearchcommunity.Thecurrentlandscapeoflaboratorytooldevelopmentisacostlyandtime-consumingpracticewherescientistscreateandvalidatetoolsforspecificexperiments.Theseself-producedtoolscreatechallengesrelatedtolengthymaterialtransferagreementsandintellectualpropertyissuesand,unfortunately,inmanycasescannotbeusedreproduciblyinotherlabs.Since2010,theMJFFToolsProgramhasstrivedtoliberateresearchersfromthesechallengesbycreatingvalidated,characterizedresearchtoolsanddistributingthemtoacademicandindustryresearchersatlittletonocostthroughanexpeditedprocess.MJFFcurrentlyoffers260preclinicalresearchtoolstoscientistsandcounts8,500toolsdistributed.
PARKINSON’SPROGRESSIVEMARKERINITIATIVE
PPMI,sponsoredandcoordinatedbyMJFF,isanobservationalclinicalstudypartnershipinvolvingresearchers,fundersandstudyparticipantsworkingtowardthegoalofidentifyingprogressionbiomarkerstoimprovePDtherapeutics.PPMIwasestablishedsixyearsagoasabiomarkervalidationplatform.Tothatend,PPMIhasestablishedacomprehensive,standardized,longitudinalPDdatabaseandbiologicalsample(biospecimen)repositorythatisavailabletotheresearchcommunity.ThePPMIbiospecimenrepositoryhousesurine,plasma,serum,cerebrospinalfluid,DNAandRNAforeverypatientparticipant.Thedatabaseandbiorepositoryincludeadvancedimagingandbiospecimenanalysiswithclinicalandbehavioralassessments.Over700patientsarecurrentlyenrolledinPPMI,withafewcohortsstillenrollingpatients.PPMIistakingplaceatclinicalsitesintheUnitedStates,Europe,IsraelandAustralia.
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APPENDIX
FDA-APPROVEDPHARMACOLOGICALTREATMENTS
Table10.FDA-ApprovedLevodopa/CarbidopaAgents.
Table11.FDA-ApprovedDopamineAgonists.
Table12.FDA-ApprovedMAO-BInhibitors.
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Table13.FDA-ApprovedCOMTInhibitors.
Table14.FDA-ApprovedNon-DopaminergicAgents.
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GLOSSARY
ACETYLCHOLINE(ACH)Aneurotransmitterthatplaysanimportantroleinmanyneurologicalfunctions,includinglearningandmemory.Acetylcholinealsoworksincoordinationwithdopaminetoproducesmoothmovement.
ACTIVEIMMUNOTHERAPYAdministrationofadrugvaccineintothebodytoinduceanimmuneresponseleadingtothenaturalproductionofantibodiesagainstatarget
ADENO-ASSOCIATEDVIRUSES(AAVS) Acommontypeofviralvector
AKINESIA Slownessofmovementinitiation
ANTIBODIESProteinsusedbytheimmunesystemtobindandneutralizeothermoleculesinthebody
ANTICHOLINERGICAGENTS
Thisdrugclassblockstheactionofacetylcholineandisusedtotreatrestingtremorandrigidity
AUTOPHAGYAfundamentalcellularcleaningprocessthatisaqualitycontrolmechanismforthecell
AXON Theappendageofaneuronthattransmitsimpulsesawayfromthecellbody.BASALGANGLIA OneofthemajorregionsofthebraininvolvedinmotorcontrolBILATERAL Involvingbothsidesofthebody
BIOMARKERMeasurablesubstanceormoleculewhosepresenceisindicativeofdisease,infectionorenvironmentalexposure
BIOPSY Tissueremovedfromalivingbody
BLOOD-BRAINBARRIER
Alayerofcellsliningtheinnersurfaceofbraincapillaries.Itprotectsthebrainfrominfectiousagentsandtoxiccompoundsbylettingnutrientsandoxygeninandwasteproductsout.Becausethebarrierstrictlyregulatesthepassageoflargermoleculesandoftenpreventsdrugmoleculesfromenteringthebrain,ithaslongposedoneofthemostdifficultchallengesindevelopingtreatmentsforbraindisorders.
BRADYKINESIA SlownessofmovementexecutionCATECHOL-O-METHLYTRANSFERASE(COMT)INHIBITORS
Drugsthatareresponsibleforincreasingthebioavailabilityoflevodopa.
CENTRALNERVOUSSYSTEM(CNS) Comprisedofthebrainandspinalcord
CEREBROSPINALFLUID(CSF)
Clear,colorlessbodyfluidthatbathesthebrainandspinalcord.WhiletheprimaryfunctionofCSFistocushionthebrainwithintheskullandserveasashockabsorberforthecentralnervoussystem,CSFalsocirculatesnutrientsandchemicalsfilteredfromthebloodandremoveswasteproductsfromthebrain.
CLINICALRESEARCH Branchofbiomedicalresearchinvolvinghumansubjects
CLINICALTRIALSResearchstudiesonhumansubjectsthataredesignedtoevaluatethesafetyandefficacyofpotentialinterventions,includingdrugs,vaccinesandmedicaldevices
DATAMINING Examininglargedatabasesinordertogeneratenewinformation.DEEPBRAINSTIMULATION(DBS)
AsurgicalprocedureapprovedforthetreatmentofadvancedPDinpatientswhosemotorsymptomsarenotadequatelycontrolledwithmedications
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DENDRITE NeuronalprojectionthatreceiveschemicalmessagesforneuronsDISEASE-MODIFYINGTHERAPY
Drugthatcanmodifyorchangethecourseofadisease
DJ-1GENE EncodesfortheDJ-1proteinDOPAMINE PrimaryneurotransmitterinvolvedinParkinson'sdisease
DOPAMINEAGONISTSThesedrugsmimictheactionofdopaminebybindingdirectlytoandactivatingdopaminereceptorsinthebrain
DYSKINESIASporadicinvoluntarymovementsthattypicallyoccurafterlong-termlevodopatherapy
EFFICACYMeasureoftheabilityofthedrugtotreatwhateverconditionitisindicatedfor.Itisnotastatementaboutthedrug'stolerabilityoreaseofuse.
ENZYME Aproteinoriginatingfromlivingcellsthatcatalyzesaspecificbiochemicalreaction
FAMILIALPD InheritedPDFIBRIL AmolecularcomplexthatconsistsofafewoligomericunitsGBAGENE Encodesfortheβ-glucocerebrosidaseprotein
GENETICMUTATIONPermanentalterationintheDNAsequencethatmakesupagene,suchthatthesequencediffersfromwhatisfoundinmostpeople
GENOME Anorganism'scompletesetofDNAIDIOPATHICPD SpontaneousPD
IMPULSECONTROLDISORDERS(ICDS)
Aclassofpsychiatricdisorderscharacterizedbyfailuretoresistatemptation,urgeorimpulsethatmayharmoneselforothers(e.g.gambling,sexualhyperactivity,etc.)
INDUCEDPLURIPOTENTSTEMCELLS(IPSCELLS)
Stemcellsderivedfromanycellinthebody
INTRAVENOUS(IV) Existingortakingplacewithin,oradministeredinto,aveinorveins
KINASE Anenzymethatcatalyzestheadditionofphosphorousandoxygengroupstoaprotein
LENTIVIRUS Acommontypeofviralvector
LEVODOPA Aprecursortodopamine.PrimarydopaminereplacementtherapeuticagentusedtotreatPD.
LEWYBODIES Accumulationoftoxicproteinclumps(aggregates)LRRK2GENE Encodesfortheleucine-richrepeatkinase2proteinLYSOSOME AhighlyacidifiedcellularstructurethatiskeyforautophagyMETABOLIZE Tobreakdownorconverttoanothermolecule
MICROGLIA Theresidentimmunecellsofthecentralnervoussystemthatrespondtoandremovedamagedneurons
MICROTUBULE Ahollowcylindricalproteinstructureinneuronsthatholdsthecellinitspropershapeandalsohelpstransportnutrientswithinthecell
MITOCHONDRIA Thepowerhouseofthecellresponsibleforgeneratingenergyforallcellularprocesses
MONOAMINEOXIDASEB(MAO-B)INHIBITORS
Drugsthatareresponsibleforpreservingexistingdopamineinthesynapse
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NATIONALINSTITUTESOFHEALTH(NIH)
PrimaryagencyoftheU.S.governmentresponsibleforbiomedicalandhealth-relatedresearch.TheNIHcomprises27separateinstitutesandcentersthatconductresearchindifferentdisciplinesofbiomedicalscience.
NEUROINFLAMMATIONAninnateimmuneresponseinthecentralnervoussystemthatinvolvestheaccumulationofactivatedimmunecellstoasiteofinjuryorforeignsubstances
NEUROLOGISTS Themedicalspecialiststrainedtodiagnoseandtreatnervoussystemdisorders
NEURON Atypeofcellfoundinthenervoussystemthatprocessesandtransmitsinformationtoothercellsthroughelectricalandchemicalsignals.Alsocallednervecell.
NEUROTRANSMITTER Achemicalthattransmitssignalsacrossasynapsefromoneneurontoanothercell
NON-VIRALVECTOR ThesevectorsretainthecircularDNAvectorstructurebutarestrippedoftheviralreplicationfactorspresentinviralvectors
OFF-TARGETEFFECT HavinganeffectonsomethingotherthantheintendedtargetOLIGOMER Amolecularcomplexthatconsistsofafewmonomerunits
OXIDATIVESTRESS Theincreasedgenerationofreactiveoxygenspecies,(ROS)whichmakesthecellmoresusceptibletodeath
PARKINGENE EncodesfortheParkinproteinPASSIVEIMMUNOTHERAPY
Administrationofantibodiesorotherimmunesystemcomponentsthataremadeoutsideofthebody
PERIPHERALNERVOUSSYSTEM(PNS) ComprisedofallthenervesandnervebundlesoutsidetheCNS
PINK1GENE EncodesforthePTEN-inducedputativekinase1proteinPOSTURALINSTABILITY Impairedbalance
PRECLINICALMODEL Stageofresearchbeforeclinicaltrialswherefeasibilityanddrugsafetyarecollected
REPROGRAMMING TheprocessofusingmolecularfactorstocreateiPScellsRESEARCHANDDEVELOPMENT(R&D)
Theprocessbywhichalaboratorydiscoveryisdevelopedintoacommercialtherapeutic,diagnosticordevice
RIGIDITY StiffmusclesSMALLMOLECULEINHIBITORS(SMIS) Lowmolecularweightcompoundsthataresmallenoughtopassivelyenteracell
SNCAGENE Encodesfortheα-synucleinproteinSUBSTANTIANIGRA BrainregionthatcontainsdopamineregionSYMPTOMATICTHERAPY TherapiesthatalleviatesymptomsSYNAPSE SpecializedconnectionsbetweenneuronswhereinformationistransmittedSYNAPTICCLEFT Thespacebetweenneuronsintowhichneurotransmittersarereleased
SYNAPTICTRANSMISSION Processbywhichsignalingmolecules(neurotransmitters)arereleasedbyaneuronandbindtoandactivatetheneuronsofanotherneuron
TAUPROTEIN Aproteinthatbindstoandregulatestheassemblyandstabilityofneuronalmicrotubules,foundinanabnormalforminAlzheimer’sdisease
UNILATERAL Involvingonesideofthebody
VIRALVECTOR Thesevectorsaremodifiedbyremovingviralgenesandreplacingthemwiththedesiredtherapeuticgenesothattheycanbeusedclinically
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