AUTHORS - Giving Compass · Parkinson’s Disease Foundation Anders Björklund, MD, PhD ... In addition to the lack of disease-modifying therapies, there are no established biomarkers

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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


• 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.


• 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).


• 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.


• 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.


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.


APDAhasastrongfocusonpatientsupport,advocacyandawareness,howevertheydoalsofundPDresearch.Theyhaveawardedover$42Minresearchfundssincetheirinception,includingover$2MtosupportresearchactivitiesinFY2014.APDA’sresearchfundingisprimarilyfocusedonsupportingthecareersofaspiringandearlystagePDscientistsas75percentoftheirfundingmechanismsareintendedforyounginvestigators,postdoctoralfellowsorpracticingneurologists.

Formoreinformationaboutavailableawards,pleasevisitAPDA’swebsite.

PARKINSON’SDISEASEFOUNDATION(PDF)

MISSION

ThePDFmissionistoimprovethelivesandfuturesofpeopletouchedbyPDbyfundingpromisingscientificresearchwhilesupportingpeoplelivingwithParkinson’sthrougheducationalprogramsandservices.


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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AUTHORS - Giving Compass · Parkinson’s Disease Foundation Anders Björklund, MD, PhD ... In addition to the lack of disease-modifying therapies, there are no established biomarkers