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AUTHORS LEADAUTHOR EkeminiA.U.Riley,PhD CONTRIBUTINGAUTHORS LaTeseBriggs,PhD YooRiKim,MS ErikLontok,PhD MelissaStevens,MBA PDSCIENTIFICADVISORYGROUP WegraciouslythankthemembersofandliaisonstothePDScientificAdvisoryGroupfortheirparticipationand contributiontothePDProjectandGivingSmarterGuide.Theinformativediscussionsbefore,during,andafterthe PDRetreatwerecriticaltoidentifyingthekeyunmetneedsandidealphilanthropicopportunitiestobenefit patientsandadvancePDresearch. CharlesH.Adler,MD,PhD ProfessorofNeurology MayoClinicCollegeofMedicine MayoClinicArizona JamesBeck,PhD VicePresident,ScientificAffairs Parkinson’sDiseaseFoundation AndersBjörklund,MD,PhD ProfessorandHeadofNeurobiology WallenbergNeuroscienceCenter UniversityofLund PatrikBrundin,MD,PhD Director,VARICenterforNeurodegenerativeScience Head,LaboratoryforTranslationalPDResearch AssociateDirectorofResearch JayVanAndelEndowedChairinParkinson’s Research VanAndelResearchInstitute(VARI) PaulCannon,PhD Parkinson’sDiseaseProgramManager 23andMe ! JesseCedarbaum,MD VicePresident,ClinicalDevelopment MovementandNeuromuscularDisorders Biogen P.JeffreyConn,PhD Director,VanderbiltCenterforNeuroscienceDrug Discovery ProfessorofPharmacology VanderbiltUniversity TedDawson,MD,PhD Director,InstituteforCellEngineering Director,MorrisK.UdallPDResearchCenter Professor,DepartmentsofNeurology,Neuroscience andPharmacology&MolecularSciences JohnsHopkinsUniversitySchoolofMedicine E.RayDorsey,MD,MBA Director,CenterforExperimentalTherapeutics ProfessorofNeurology UniversityofRochesterMedicalCenter JohnDunlop,PhD Head,NeuroscienceInnovativeMedicines Co-Director,AstraZenecaTuftsLabforBasicand TranslationalNeuroscience StanleyFahn,MD Director,CenterforParkinson'sDiseaseandOther MovementDisorders H.HoustonMerrittProfessorofNeurology ColumbiaUniversityMedicalCenter StevenFinkbeiner,MD,PhD Director,Taube/KoretCenterforNeurodegenerative DiseaseResearch GladstoneInstituteofNeurologicalDisease ProfessorofNeurologyandPhysiology UniversityofCalifornia,SanFrancisco StephenFriend,MD,PhD President,Co-Founder,andDirector SageBionetworks OleIsacson,MD ProfessorofNeurology Director,NeuroregenerationLaboratoriesandCenter forNeuroregenerationResearchatMcLeanHospital HarvardMedicalSchool KarlKieburtz,MD,PhD Director,ClinicalandTranslationalScienceInstitute ProfessorofNeurology ProfessorofCommunityandPreventiveand EnvironmentalMedicine UniversityofRochesterMedicalCenter WalterKoroshetz,MD Director NationalInstituteofNeurologicalDisordersand Stroke,NationalInstitutesofHealth AnthonyLang,MD SeniorScientist TorontoWesternResearchInstitute J.WilliamLangston,MD ChiefScientificOfficerandFounder Parkinson’sInstitute PeterLeWitt,MD ProfessorofNeurology WayneStateUniversitySchoolofMedicine Director,Parkinson'sDiseaseandMovement DisordersProgram HenryFordHospital ! IreneLitvan,MD,PhD Director,MovementDisordersCenter Professor,Parkinson’sDiseaseResearch UniversityofCalifornia,SanDiego KennethMarek,MD President,Co-Founder,andSeniorScientist InstituteforNeurodegenerativeDisorders HelenMatthews ChiefOperatingOfficer TheCureParkinson’sTrust C.WarrenOlanow,MD ProfessorofNeurologyandNeuroscience MountSinaiSchoolofMedicine SpyrosPapapetropoulos,MD,PhD VicePresident,GlobalHeadClinicalDevelopment NeurodegenerativeDiseases TevaPharmaceuticals AnupamPathak,PhD MechanicalEngineer [x] Google R&D,Google RachelSaunders-Pullman,MD,MPH AssociateProfessorofNeurology AttendingNeurologist MountSinaiBethIsraelMedicalCenter DarryleSchoepp,PhD VicePresidentandTherapeuticAreaHead, Neuroscience MerckResearchLaboratories MichaelSchwarzschild,MD,PhD ProfessorofNeurology,HarvardMedicalSchool Neurologist,MassachusettsGeneralHospital Chair,ParkinsonStudyGroupExecutiveCommittee ToddSherer,PhD ChiefExecutiveOfficer MichaelJ.FoxFoundationforParkinson'sResearch Beth-AnneSieber,PhD ProgramDirector,NeurodegenerationCluster NationalInstituteofNeurologicalDisordersand Stroke,NationalInstitutesofHealth TanyaSimuni,MD Director,Parkinson’sDiseaseandMovementDisordersProgram ProfessorofNeurology NorthwesternUniversity AndrewSingleton,PhD SeniorInvestigator Chief,LaboratoryofNeurogenetics Chief,MolecularGeneticsSection NationalInstituteonAging,NationalInstitutesofHealth DavidSulzer,PhD Professor,DepartmentsofPsychiatry,Neurology,andPharmacology ColumbiaUniversityMedicalCenter D.JamesSurmeier,PhD ProfessorandChair,DepartmentofPhysiology NorthwesternUniversity CarolineTanner,MD,PhD Director Parkinson'sDiseaseResearchEducationandClinicalCenter SanFranciscoVeteran'sAffairsMedicalCenter RyanWatts,PhD ActingChiefExecutiveOfficerandChiefScientificOfficer DenaliTherapeutics AllisonWillis,MD,MSCI AssistantProfessorofNeurology AssistantProfessorofEpidemiology&Biostatistics UniversityofPennsylvaniaSchoolofMedicine ! 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 ! 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 ! 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 ! EXECUTIVESUMMARY Parkinson’sdisease(PD)isachronic,neurodegenerativemovementdisorderthataffectsthelivesofmorethan1 millionAmericans.PDslowlyworsensovertime,increasinglyrobbingpatientsofcoordinatedmovementand inflictinganumbernon-motorsymptomsrangingfromcognitiveimpairmenttogastrointestinalissues. Approximately90percentofPDcasesoccurspontaneously,while10percentofcasesarefamilial.PDmainly affectstheelderly,howeverthecauseofPDisunknown.Therearecurrentlynotreatmentsthatcansloworstop therelentlessprogressionofthedisease. Asthesizeandproportionoftheelderlypopulationgrows,sotoowillthesocietalandeconomicburden.The currentestimatedannualcostofPDisastaggering$14.4billion,whichisprojectedtodoubleby2040.This projectionmaybeevenhigherifnoeffectivetreatmentsarefound.Inadditiontothelackofdisease-modifying therapies,therearenoestablishedbiomarkersofdisease.Inotherwords,therearenoobjectivemeasuresto diagnosepatients,trackdiseaseprogressionorresponsetotreatment.Rather,physiciansrelyonimprecise, qualitativeratingscales,ultimatelyhamperingdrugdevelopmenteffortsandclinicaltrialsuccess.Misdiagnosisis alsoaseriousissueduetothedifficultyindistinguishingseveralearlysymptomsofPDfromthenaturaleffectsof agingorotherneurologicaldisorders.Itisoverwhelminglyclearthatprogressisdesperatelyneededtocombatthis disorder. ThePDfieldisfraughtwithanumberofotherunmetneedsthathamperprogress,including: • PoorunderstandingofunderlyingPDdiseasebiologyandlackoffundingtosupportbasicresearch • Poorunderstandingoftheunderlyingbiologyofnon-motorandtreatment-inducedsymptoms • Slowprogressinbiomarkerdiscoveryandtheneedforamorepredictivetranslationalpipeline ThereisrenewedinterestinPDduetorecentbreakthroughsinthegeneticsofthediseaseandindigitalhealth. GeneticdiscoverieshaveexpandedourunderstandingofPDheredityandbroadenedinsightsintospontaneous disease.Moreover,keytherapeutictargetshavebeenuncovered,whicharedrivingdrugdevelopmentstrategy. Digitalhealthadvancementsinmobileapplicationsandwearabletechnologyareallowinginvestigatorstoamass anunprecedentedamountofpatientdata.Thesenewtechnologieshavethepotentialtobroadenclinicaltrial participationandrevolutionizethewayPDsymptomsaremonitoredandquantified.Capitalizingonthis momentumthroughstrategicinvestmentindiscoveryscience,infrastructure,andresearchtoolsareessentialfor continuedprogress. TheMilkenInstitutePhilanthropyAdvisoryServicehasdevelopedthisGivingSmarterGuideforParkinson’s Diseasewiththeexpresspurposeofempoweringpatients,supporters,andstakeholderstomakestrategicand informeddecisionswhendirectingtheirphilanthropicinvestmentsandenergyintoresearchanddevelopment efforts.Readerswillbeabletousethisguidetopinpointresearchsolutionsalignedwiththeirinterests.Thisguide willhelptoanswerthefollowingquestions: • WhyshouldIinvestinPDresearch? • WhatkeythingsshouldIknowaboutthisdisease? • Whatisthecurrentstandardofcare? • WhatisthecurrentstateofPDresearchefforts? • Whatarethebarrierspreventingdevelopment • Howcanphilanthropyleverageexistinginfrastructure ofnewtherapeutics? tosupportPDresearchandadvancenewtherapies? ! OVERVIEW Parkinson’sdisease(PD)isadebilitatingneurodegenerativedisorderthatseverelyaffectsmovementand coordination.Morethan1millionAmericansarecurrentlysufferingfromPD,anditisestimatedthatnearly60,000 newcaseswillbediagnosedthisyearalone.Thisdisordermostcommonlyoccursinpeopleage60andolder; however,thosewithspecificinheritedgeneticmutationslinkedtoPD(referredtoasfamilialPD)canexperience symptomsintheir40sorevenearlier. PDcausesavarietyofmotorsymptomsincludingtremors,musclestiffness,posturalinstabilityandothers.The diseasealsocausesarangeofnon-motorsymptomsthatinclude,butarenotlimitedto,cognitiveimpairment, mooddisordersandgastrointestinalissues.Therearealitanyofchallengesassociatedwithidentifying, understandingandtreatingPD.ItiscurrentlyunclearwhatcausesPD.Inaddition,diagnosingthediseaseisa challengebecausedefinitivediagnosisrequiresautopsy.Finally,andmostimportantly,thereisnocure. Whilecurrenttreatmentshelptomanagesymptoms,theydonotmodifythediseasetosloworhaltits progression.Withlongerlifeexpectanciesandanagingpopulation,thesocietalburdenofPDisenormousandis onlyexpectedtoincrease.ConsequentlythereisanurgentneedtoacceleratePDresearchprogresstoidentify noveltreatmentsthatcanmodifythediseaseratherthanjustmanagesymptoms. SOCIETALIMPACTOFPARKINSON’SDISEASE POPULATIONBURDEN PDisthesecondmostcommonneurodegenerative disease,followingAlzheimer’sdisease,andthe fourteenthleadingcauseofdeathintheUnited States.AccordingtotheAmericanParkinsonDisease Association,anAmericanisdiagnosedwithPDevery nineminutes,culminatingin5,000newcasesper month.TheprevalenceofPDincreaseswithage,and thusisthreetosixtimeshigherinpeopleoverthe ageof65,andthirteentosixteentimeshigherin peopleovertheageof85comparedtothegeneral population(asdepictedinFigure1). Figure1.PDPrevalencebyAge. Unfortunatelyastheglobalpopulationcontinuesto About0.3%ofthegeneralpopulationhavePD,whereas12%ofpeopleage65andolderand4-5%ofpeopleage85 ageintodemographicswithhigherPDprevalence, andolderhavePD. thesupplyofneurologists(themedicalspecialists trainedtodiagnoseandtreatnervoussystem disorders)areprojectedtofall20percentbelowdemandby2020,accordingtotheAmericanAcademyof Neurology.Thiswillresultinanoverloadedmedicalsystemandwilllikelybecomeamajorimpedimentto improvingcareandtreatmentoptionsforParkinson’spatients. ! ECONOMICBURDEN Theincreasinglydebilitativecourseofthediseasecontributestohighmedicalandnon-medicalcosts.Annually,the totalnationaleconomicburdenisestimatedtobe$14.4billion($22,800perpatient)accordingtoa2013study publishedinMovementDisorders(seeFigure2).Thatestimateiscomprisedofdisease-relatedmedicalcostsof approximately$8.1billion($12,800perpatient)andnon-medicalcostsofapproximately$6.3billion($10,000per patient).TaxpayersbearthebruntofthemedicalcostofPD,withanestimated48percent($3.8billion)paidforby Medicare,Medicaidorothergovernmentprograms,asillustratedinFigure3. Figure2.EconomicBurdenofPD-relatedCare. AstheprevalenceofPDincreaseswithage,sotoodoesthecost.PDpatientsunderage45incurcostsofabout $3,500peryear,whereasPDpatientsage85andoldercanincurcostsrangingfrom$14,000to$41,500peryear. Intotal,PDpatientspayabout$2.7billioninout-of-pocketexpensesannually–anoftentimeshugefinancialstrain onapopulationthatexperiencesareducedabilitytoworkassymptomsworsenovertime.TheannualcostofPD isexpectedtoatleastdoubleby2040andmayincreaseevenmoreifnoprogresstowarddisease-modifying therapiesaremade. Figure3.DistributionofMedicalCostsbyPayer. ! PARKINSON’SDISEASEBASICS Parkinson’sdisease(PD)belongstoagroupofconditions collectivelycalledmovementdisorders.Thereareover20 differenttypesofmovementdisorders;someexamples includeHuntington’sdisease,cerebralpalsy,and Tourette’ssyndrome.Everybodilymovementisacareful coordinationbetweenthenervoussystemandmuscles. Nervecells,knownasneurons,communicateinorderto facilitatemovementandvirtuallyallotherbodily processes. Movementexecutionandcoordinationiscontrolled,in part,byaverysmallstructuredeepwithinthemidbrain calledthesubstantianigra(SN)asillustratedinFigure4. NeuronsintheSNproducedopamine,achemicalsignal (alsoknownasaneurotransmitter),whichisresponsiblefor smooth,coordinatedmovement.Thedeathofthese dopamine-producingneuronsleadstotheclassicmotor symptomsseeninPDpatients. Figure4.BrainAnatomy-PartsoftheMidbrain. Crosssectionofbraindepictingthelocationofthe substantianigra(SN).SNneuronsproducethe neurotransmitterdopamine,essentialforsmooth movement.SNneuronsprojectdirectlytothestriatum (alsopicturedabove).ThedeathofSNneuronsaltersthe dopaminepathway,havingdirecteffectsonthestriatum andotherbrainstructures. PDprogressionresultsinacontinuouschemicalimbalance inthebrainthataffectsotherregionsinadditiontotheSN.Ultimatelythiscanleadtothedevelopmentof additionalmotorandnon-motorsymptoms,aswellastreatmentresistancetothestandardtherapylevodopa. Unfortunately,itisnotknownwhattriggerstheseneuronstodie.BythetimePDisclinicallydiagnosed,nearly 60-80percentofthedopamine-producingneuronsarealreadydead,whichhighlightsthecriticalneedforbetter diagnosticcriteriaforthisdisease. !" CHARACTERISTICSOFPARKINSON’SDISEASE TherearetwotypesofPD,idiopathic(spontaneous)andfamilial(inherited).ThecauseofPDisunknown;however, developmentoffamilialPDisstronglyassociatedwithmutationsincertainPDsusceptibilitygenes(discussedlater inPDGeneticssectiononpage22).ThemajorityofpatientshaveidiopathicPD,asonly10percentofPDcauses arefamilial. Tremorsareperhapsthemostwell-knownsymptomassociatedwithPD.Thereareseveralothermotor,nonmotorandtreatment-inducedsymptomsthatcontributetothecomplicatednatureofthisdisease.Theseverity andnumberofsymptomsexperiencedcanvarywildlyfrompatienttopatient.Table1highlightsseveralofthe Table1.CommonPDSymptoms. mostcommonPDsymptoms, althoughthislistisnot exhaustive. Symptomstypicallyoccurat varyingtimesduringthe diseasecourse,withseveral non-motorsymptoms appearingbeforemotor symptomsbecomeapparent. Treatment-induced symptomstypicallyoccur afterfourtosevenyears. SincePDisachronic, progressivedisease,virtually allPDpatientswillexperience thesesymptomsandmore. ThediseasecourseofPDis oftendescribedinphasesas depictedinFigure5: prodromal,early,and advanced.PDphasesare benchmarkedbyclinically overtmotorsymptoms; however,bythispoint, significant neurodegenerationhas alreadytakenplaceas nearly60-80percentofSN neuronshavealreadydied. Figure5.ProgressionofPDandAssociatedSymptoms. Symptomsintheprodromalstageareoftentimesindistinguishablefromvariousother diseases.The“classic”PDsymptomsarenotseenuntilthetransitionintothenextstageof diseaseprogression(‘EarlyStage’)andthisisthestagewheretheclinicaldiagnosisismade. Advancedstagesymptomsalsoincludeseverecognitiveimpairmentalongwithworseningof existingmotorconditions.Theimageabovedepictsthemyriadofsymptomsaccordingto whentheygenerallyappearduringthenaturalprogressionofPD. !! RISKFACTORSANDPREVENTION WhilethecauseofPDisunknown,investigatorshaveidentified generalandgeneticfactorsthatincreasetheriskofdevelopingboth idiopathicandfamilialPD. GENERALRISKFACTORS Generalriskfactorsincludebutarenotlimitedto: • Age–theincidenceandprevalenceofPDincreases substantiallywithage(seeFigure1). CommonGeneticRisk FactorsforPD Mutationsinthefollowing genesareassociatedwith increasedriskfordevelopingPD: GBA–thegreatestgeneticrisk factordevelopingPD. LRRK2–mostcommoncauseof familialPDbutisalsofoundin idiopathicPDcases. • Sex–menare50percentmorelikelytodevelopPDthan women. • Environmentalfactors–exposuretopesticidesandother toxinsaresuggestedtoincreasetheriskofdevelopingPD. Parkin–commoninyoungonsetPD. • Medicalconditions–priorheadinjuryordepressionare suggestedtoincreasethelikelihoodofdevelopingPD. SNCA–firstgeneassociated withfamilialPD. GENETICRISKFACTORS ThereareanumberofgeneticmutationsthatarethoughttocontributetothedevelopmentofPD–knownas geneticriskfactors.ThesegeneticriskfactorsarediscussedfurtherinthePDGeneticssectiononpage22. PREVENTION WhiletherearenoknownwaystopreventdevelopmentofPD,investigatorshaveidentifiedfactorsthatdecrease theriskofdevelopingPD: • Exercise–ResearchhasshownthatexerciseisvitalforbothpreventionandmanagementofPD.Recent evidenceshowsthatearly-stagePDpatientswhomaintainedanactivelifestylecoulddelaythestartof treatmentbyasmuchastwoyears. • Nicotineexposure • Caffeineconsumption • Nonsteroidalanti-inflammatorydrug(NSAIDs)orcalciumchannelblockeruse !" DIAGNOSIS CLINICALOBSERVATIONSUSEDTODIAGNOSEPD AllcasesofPDdiagnosisinliving PDiscurrentlydiagnosedbasedontheclinicalpresentationof patientsareconsideredprobableuntil motorsymptoms.Todate,thereisnoobjectivediagnostic confirmedbyautopsy.Adefinitive examorbiomarkerforPD.Abiomarkerisacharacteristicthat diagnosisrequirespostmortemanalysis isobjectivelymeasuredandevaluatedasanindicatorofdisease ofbraintissuetodetectproteinclumps, stateortreatmentefficacy.Abiomarkercanbedetectedin biofluids(e.g.blood,urine,cerebrospinalfluid),tissues(e.g. oraggregates,containingalpha- skin,brain)oranimagingscanofthebrain.Someexamplesof synuclein–theculpritproteininPD. widelyusedbiomarkersarebloodsugarlevelfordiabetesor cholesterollevelforcardiovasculardiseases.Withouta biomarker,aneurologisthastorelyonpatienthistoryandmotorsymptomspresentduringaneurologicalexamto giveaformalPDdiagnosis.Aneurologisttypicallyusesacombinationofthefollowingclinicalobservationsand teststodiagnosePD: • Primarymotorsymptoms–Restingtremor,rigidity,slownessofmovement(bradykinesia)andimpaired balance(posturalinstability)arethefourprimarymotorsymptomsofPD.Physicianswilloftenlookfor twoormoreofthesehallmarkmotorsymptomswhenmakingaformaldiagnosis. • Ratingscales–BecausePDisaprogressivediseasethatbecomesincreasinglydebilitatingovertime, physicianswillemployratingscalestotrackdiseasesymptoms.Theseratingscalesareusedtoaid diagnosis,asphysiciansoftenneedtotrackpatientsovertimebeforerenderingaPDdiagnosis. Additionally,ratingscalesareusedtotrackpatientresponsetotreatment,andasanevaluationtoolin clinicaltrials.Pointsareassignedforvarioussymptomsandthecompositenumberisusedtocompare patientstatus.ThemostwidelyusedclinicalratingscaleforPDistheMovementDisorderSocietysponsoredrevisionoftheUnifiedParkinson’sDiseaseRatingScale(MDS-UPDRS). • Neuroimagingtechniques–Thepresenceofdopamineisassessedusingbrainimaging.Imagingaloneis notsufficienttodiagnosePDbecausethereareotheroverlappingparkinsoniansyndromes(suchas progressivesupranuclearpalsy[PSP]ormultiplesystematrophy[MSA]),whichproducedopaminelossin thebrainaswell.Whilecurrentbrainimagingtechniquesarenotdiagnostic,physicianscanusethe imagestoruleoutotherparkinsoniansyndromes,trackdopaminelossovertimeandtoassesspatient eligibilityforcertainclinicaltrials. THECHALLENGEOFACCURATELYDIAGNOSINGPD AccuratelydiagnosingPDisespeciallychallengingfortwokeyreasons: • Difficultyidentifyingpatientsintheprodromalstage–manynon-motorsymptoms,suchasconstipation ordifficultyrecallingtasks,oftenoccurseveralyearsbeforemotorsymptomsareapparentandareoften attributedtothenaturalcourseofaging;therefore,PDcangoundetectedforseveralyears.Thereisgreat interestinthefieldtoidentifyprodromalPDpatientssince,theoretically,therapeuticinterventioninthe earlyprodromalphasecouldbethecrucialwindowtoslowdiseaseprogressionbeforepatients experiencesignificantSNneuronalloss. !" • Overlappingsymptomswithotherdisorders–theclassicPDmotorsymptomscanbepresentinother neurodegenerativediseases,oftenresultinginmisdiagnosis. BeingovertlysymptomaticiscentraltoPDdiagnosis;however,studiesdemonstratethatbythetimesymptoms areclinicallypresent,significantdegenerationofSNneuronshasalreadyoccurred,andcontinuousprogressionof thediseaseiseminent.CurrenttherapiesarenotequippedtosloworhalttherelentlessprogressionofPD,and effortstodosoarehamperedbythelackofbiomarkersavailableto1)identifypatientsintheprodromalphase,2) objectivelydiagnosepatientsand3)tracktreatmentefficacy.Thislackofbiomarkerstosupportclinicalresearch hasbeenakeycontributortofailedclinicaltrialsandalackofoverallprogressioninthespace. TREATMENT ThereisnowaytosloworhaltthenaturalprogressionofPD,andcurrentlyavailabletreatmentsonlytreatthe symptomsofPDratherthanmodifytherelentlessprogressionofPD.Moreover,giventheprogressivenatureof PD,eventhemosteffectivesymptomatictherapyhaslimitedefficacyovertime.Patientsreporthavingtotake medicationuptoonceeveryhoursimplytoalleviatemotorsymptoms,severelycompromisingqualityoflife (QOL).Assuch,thelackofeffectivedisease-modifyingtherapiesisarguablyoneofthelargestunmetneedsfor thePDcommunity.ThefollowingmedicationsusedtotreatPDarediscussedbelow: • • • • • • Levodopa/Carbidopa DopamineAgonists MonoamineoxidaseB(MAO-B)inhibitors Catechol-O-methlytransferase(COMT)inhibitors Anticholinergicagents Amantadine PHARMACOLOGICALTREATMENTOPTIONS DOPAMINERGICMOTORSYMPTOM THERAPY Thistreatmentstrategyaimstoincreasethe dopamineconcentrationinthebrain,whichis significantlydecreasedduetoneuronalcell deathintheSN.Figure6illustratesthe followingwaysthatincreaseddopaminecanbe achieved: LEVODOPA/CARBIDOPA Levodopaisadopamineprecursorthatis convertedtodopamine.Levodopais administeredincombinationwithcarbidopa,a drugthatpreventslevodopafrombeing convertedtodopaminebeforeitcrossesthe !" Figure6.DopaminergicMotorSymptomTherapy. Thisfigureillustratesthemechanismofactionforthefollowing dopamine-basedmedications:levodopa,dopamineagonists,MAO-B inhibitorsandCOMTinhibitors. blood-brainbarrier(BBB),asemi-permeablefilteringmechanismthatonlyallowscertainmoleculestopassinto thecentralnervoussystem(CNS).Levodopawasfirstintroducedintotheclinicin1967,yetmorethan45years laterlevodopaisstillthemosteffectivetreatmentforPDmotorsymptoms.However,itsefficacydecreaseswith diseaseprogression.Levodopacanremainhighlyeffectiveforaboutfourtosevenyears,butassymptomsworsen, patientsmayexperiencelossofbenefitbetweendoses,knownasthe“wearingoff”effect.Theemergenceof motorfluctuationsandlevodopa-induceddyskinesias(asindicatedinTable1)severelyaffectspatientQOL.The limiteddurationoflevodopaefficacyhighlightstheneedformoreeffectivesymptomatictherapiestoincrease theQOLforPDpatients.U.S.FoodandDrugAdministration(FDA)-approvedlevodopa/carbidopaagentsarelisted intheAppendix. DOPAMINEAGONISTS Theseagentsmimictheactionofdopaminebybindingdirectlytoandactivatingdopaminereceptorsinthebrain. Theprolongeduseofdopamineagonistsisassociatedwiththeonsetofimpulsecontroldisorders(seeTable1). FDA-approveddopamineagonistsarelistedintheAppendix. MONOAMINEOXIDASEB(MAO-B)INHIBITORS Theseinhibitorsareresponsibleforpreservingexistingdopamineinthesynapse(thejunctionbetweenneurons). TheyselectivelyblocktheactivityoftheenzymeMAO-B,whichmetabolizes(orbreaksdown)existingdopaminein thesynapse.FDA-approvedMAO-BinhibitorsarelistedintheAppendix. CATECHOL-O-METHLYTRANSFERASE(COMT)INHIBITORS Theseinhibitorsareresponsibleforincreasingthebioavailabilityoflevodopa.Theyblocktheactivityofthe enzymeCOMT,whichmetabolizes(orbreaksdown)levodopaintheperipherybeforeitcanbeconvertedto dopamine.FDA-approvedCOMTinhibitorsarelistedintheAppendix. NON-DOPAMINERGICMOTORSYMPTOMTHERAPY Thesetreatmentoptionsaredesignedtotargetnon-dopaminergicsignalingpathwaysinthebrainandmayhave aneffectonsome,butnotall,motorsymptoms.FDA-approvednon-dopaminergicagentsarelistedinthe Appendix. ANTICHOLINERGICAGENTS Acetylcholineisaneurotransmitterthatworksincoordinationwithdopaminetoproducesmoothmovement.In PD,theacetylcholine-dopaminebalanceisdisturbed.Thisdrugclassblockstheactionofacetylcholineandisused totreatrestingtremorandrigidity.However,theyarenoteffectiveforbradykinesiaorotherfeaturesofadvanced PD. AMANTADINE Thisdrugisanantiviralagentwithwidespreadproperties.Itfunctionstoincreasedopaminereleaseandblock dopaminereuptake.Amantadineisusedtotreattremor,bradykinesia,rigidityandlevodopa-induceddyskinesia. !" NON-MOTORSYMPTOMTHERAPY Non-motorsymptomsarecommoninPD,withseveralstudiesindicatingthatalmostallPDpatientswillexperience atleastonenon-motorsymptomduringthecourseoftheirdisease.ThereareFDA-approvedtreatmentsavailable forseveralnon-motorsymptoms,suchasanti-depressants,cognitiveenhancersandagentstotreatarangeof gastrointestinalissues.Dependingonthenon-motorsymptomthatpresents,theneurologistmaycollaboratewith aphysicianthatspecializesinthenon-motorsymptomareatotreatthesymptom.Inthesescenariositis importanttocarefullyconsiderhowthetreatmentofonesymptommayaffectthetreatmentofanothersoasto limitadverseeffects. Patientsfindnon-motorsymptomsparticularlydebilitatingandanegativeinfluenceonQOL.Whenpatient experiencesweresurveyedatrecentmeetings,includingtheFDAPatient-FocusedPDDrugDevelopmentPublic Meeting(September2015inWhiteOak,Md.)andtheGrandChallengesinPDconference(October2015inGrand Rapids,Mich.),patientsreportedthatoftentimesnon-motorsymptomsposeevenagreaterchallengetoQOLthan themotorsymptoms. NON-PHARMACOLOGICALTREATMENTOPTIONS ExercisehasbeenshowntohaveanenormousbenefitinhelpingPDpatientsmanagepainandmaintainQOL.Data fromtheNationalParkinsonFoundation-sponsoredParkinson’sOutcomesProjectdemonstratedthatexercisecan slowtherateofdeclineintheQOLexperiencebyPDpatientswhenstartedearlierratherthanlaterinthedisease course.Resultsofthestudywerepresentedatthe19thInternationalCongressofParkinson’sDiseaseand MovementDisordersheldinSanDiego,Calif.,inJune2015. Complementarypracticessuchasmeditation,yogaandtaichiareoftenrecommendedformoodandpain management.Dependingonpainseverity,physicaltherapymayberecommended.Forpatientsexperiencing speechissues,speechtherapymayberecommended. SURGICALTREATMENTOPTIONS Deepbrainstimulation(DBS)isasurgicalprocedureapprovedfor thetreatmentofadvancedPDinpatientswhosemotorsymptoms arenotadequatelycontrolledwithmedications.DBSisusedto treattremor,bradykinesia,rigidityandgaitissues.Approvedin the1990s,DBSisnotedasthemostimportanttherapeutic advancementsincelevodopa,withpatientsusuallyreporting motorsymptomrelief.Whileeffective,DBSisnotsuitableforall PDpatients,andusuallybenefitspatientswhohavepreviously respondedtopharmacologicaltreatment. TheDBSsystemusesthefollowingcomponents(seeFigure7): • Electrodes(alsoknownasleadsorprobes)–theseare thin,insulatedwiresthataresurgicallyimplantedinthe !" Figure7.DBSSystemComponents. ThethreecomponentsoftheDBSsystemare illustratedabove.ImagereusedunderCreative Commonslicense(Source). brainthroughasmallopeningintheskull.Theelectrodetipsareinsertedintocertainareasdeepwithin thebrain. • Extensions–thisisaninsulatedwirethatconnectstheelectrodetotheimplantablepulsegenerator.The extensionslieundertheskinofthehead,neckandshoulder. • Implantablepulsegenerator(IPG)–thisisthe“batterypack”thatdelivershighfrequencyelectrical stimulationtothebrain,similartoaheartpacemaker.TheIPGisusuallyimplantedundertheskinnear thecollarbone. MONITORINGTREATMENTEFFICACY Treatmentefficacyisprimarilymonitoredbypatientdiariestoassessmotorsymptomseverityinthecourseof dailylivingandthroughphysicianassessmentusingtheMDS-UPDRSratingsystem.DependenceonPDpatient diariespresentschallengesasmanypatientsdealwithbothmotorandcognitiveimpairment;thustheydonot alwayshavethecapacitytoaccuratelyrecordandconveysymptomstotheirphysicians.Also,giventhevariability inthepatientperceptionofpainanddegreeofimpairment,itishardtocomparetreatmentefficacyacrosspatient populations. Objectivemeasurementofpatientresponsetotreatment,atamolecularandwholebodymovementlevel,would lessentherelianceonself-reportedpatientdiariesandprovidephysicianswithmoreaccurateinformationwith whichtodeterminetreatmentdecisions,againunderscoringtheneedforbiomarkersinthePDspace.Currently theuseoftechnology,suchaswearabledevicesandmobiletechnology,isalsobeingexploredasameansto provideobjectivemeasurementofmotorsymptoms. THEMECHANICSOFPARKINSON’SDISEASE HOWTHENERVOUSSYSTEMWORKS InordertofullyappreciatethediseasecourseofPD,itishelpful tounderstandtheanatomyofthenervoussystemandhow neuronsinthenervoussystem(alsoknownasnervecells) communicate. ThenervoussystemismadeupoftwopartsasseeninFigure8: • • Centralnervoussystem(CNS)–comprisedofthebrain andspinalcord. Peripheralnervoussystem(PNS)–comprisedofallthe nervesandnervebundles(knownasganglia)outsideof theCNS. Figure8.TheHumanNervousSystem. ThePNSconnectstheCNStoourextremitiesandorgans. Similartothefunctionperformedbyelectricalwiringina home–carryingelectricalimpulsestooutletstopower !" TheCNS(pink)containsthebrainandspinalcord.ThePNS (yellow)containsallthenervesandnervebundlesoutsideof brainandspinalcord.ImagereusedunderCreativeCommons license(Source). appliances–thenervoussystemexecutesasimilarfunctionbycarryingelectricalimpulsesthroughnervecellsto powermovementandotherfunctions.Nervecells,knownasneurons,arethebasicbuildingblocksofthenervous system,andtheirabilitytocommunicateisabsolutelynecessaryfornervoussystemfunction. TALKINGNEURONS–HOWNERVECELLSCOMMUNICATE Neuronshaveacellbodywithtwotypesofcellularextensions:dendritesandaxons(seeFigure9,left).Onone end,dendritesreceiveinformationfromaneighboringneuronandcarrythatinformationtothecellbody.The informationthentravelsawayfromthecellbody,intheformofanelectricalimpulse,throughtheaxondownto theterminalbranchesoftheaxon. Figure9.NeuronalAnatomyandCommunication. (Left)Thepartsofaneuronareillustratedabove.ImageadaptedfromtheNationalInstituteofHealth(Source). (Right)Aclose-upofthesmallgapbetweentwoneurons,thesynapse,isillustratedabove.Imagesadaptedfromthe NationalInstituteonAging[PublicDomain]viaWikipediaCommons(Source). Theelectricalimpulsetriggersthereleaseofchemicalsignalscalledneurotransmitters.Neurotransmittersare releasedacrossasmallgapinbetweentwoneuronscalledthesynapse(seeFigure9,right). Thetypeandamountofneurotransmitterreleasedaffectscommunicationbetweentwoneurons.Withoutthe rightamountofneurotransmitters,communicationislost,andthefunctionthatthoseneuronsgovernwillsuffer. ThecentralneurotransmitterinPDisdopamine.Dopaminesignalingbetweenneuronsfacilitatessmooth coordinatedmovement.Aspreviouslymentioned,SNneuronsproduce,releaseandareactivatedbydopamine, thereforetheyaredescribedasbeing“dopaminergic.”AsPDkillsdopaminergicneurons,lessdopamineis availableforpropercommunicationwithintheSNandotherbrainregions,therebycompromisingtheabilityto performsmoothcoordinatedmovements. !" HALLMARKSOFPDPATHOLOGY ThecauseofPDisunknown;however,PDismarkedbythefollowingcriticalpathologicalfeatures: • Irreversibleneuronalcelldeathinthesubstantianigra(SN)regionofthebrain • Accumulationandabnormalaggregationoftheproteinalpha-synuclein Thereareseveralriskfactors(detailedintheRiskFactorsandPreventionsectionofpage12),suchasgenetic abnormalitiesandexposuretoenvironmentaltoxins,thatareproposedtoacceleratetheprocessesthatleadto theaforementionedpathologicalfeatures. IRREVERSIBLESNNEURONALCELLDEATH Asmentionedpreviously, theirreversiblelossof dopamine-producing neuronsintheSNleadsto theovertmotor symptomsexperiencedby PDpatients.Bythetimea PDpatientpresentswith themotorsymptoms necessaryforPD diagnosis,approximately 60-80percentofthe dopamine-producingSN neuronshavealready beenlost. Figure10.SequenceofEventsFollowingDopamineLoss. ThedopamineimbalancecausedbythedeathofSNneuronscausesachainreaction Thedeathoftheseneurons leadstoachainreactioninthe furtheringaffectingotherbrainstructures. brainasdepictedinFigure10.Asexplainedpreviously,neuronsareinterconnectedandcommunicatewitheach otherbysendingchemicalsignalsintheformofneurotransmitters.Theneurotransmitterdopaminestimulatesa collectionofbrainstructurescalledthestriatum,therebyfacilitatingnormalmovements. !" TOXICALPHA-SYNUCLEIN-CONTAININGAGGREGATES Alpha-synucleinisaproteinthatisfoundpredominatelyinthebrain, withlesseramountsfoundthroughoutthebody.Proteinsundergoan intricatefoldingprocessuponproductiontoensureappropriate functioninthecell;however,someproteinsmisfoldandcanbecome toxictothecell.InPDpatients,alpha-synucleiniscommonlyfoundin themisfoldedform.Thismisfoldedproteinclumpstogethertoform toxicaggregates,includingstructurescalledLewybodies.Adefinitive diagnosisofPDisdependentonthepresenceofthesetoxicalphasynucleinaggregatesatautopsy(seeFigure11). Itisbelievedthattheabnormalbuild-upofLewybodiesleadstoa dysfunctionalneuronalstatethatprecedesSNneuronalcelldeath. Recently,scientistshavediscoveredthatLewybodiesareableto spreadtootherneuronsandinducealpha-synucleinmisfoldingand aggregation,possiblyexplainingtheprogressivenatureofPD. Figure11.Alpha-synucleinLewyBody. Microscopicimageofanalpha-synucleincontainingLewybodyintheSN.ImagebySuraj Rajan(ownwork)viaWikipediaCommons, reusedandmodifiedunderCreativeCommon license3.0(Source). Becausealpha-synucleinisfoundconsistentlyinthebrainofPD patients,theabilitytoimagealpha-synucleinwhilepatientswerestillliving,ratherthanatautopsy,coulddecrease misdiagnosisandfacilitatebetterpatientselectionforclinicaltrials.Thedevelopmentofanalpha-synuclein imagingbiomarkercouldpotentiallyrevolutionizePDdiagnosticsanddrugdevelopment. Understandingabnormalalpha-synucleindynamicsisanareaunderintenseinvestigationastheyrepresent “druggable”processesthatcanbetargetedpharmacologically.ThehopeisthatPDdiseasemodificationcanbe achievedifeitheralpha-synucleinaggregationand/orspreadcanbepreventedorhalted. Whilealpha-synuclein-containingLewybodiesareahallmarkofPDpathology,othertypesofproteinaggregates (suchasthecommonproteinaggregatesfoundinAlzheimer’sdisease)arealsofoundinthebrainsofPDpatients. ThissuggeststhatthepathologyofPDisfarmorecomplexthanthecurrentmodelcenteredprimarilyonalphasynuclein. !" OTHERDYSFUNCTIONALCELLULARPROCESSESINVOLVEDINPD DescribedbelowareseveralotherdysfunctionalcellularprocessesbelievedtocontributetoPD. MITOCHONDRIALDYSFUNCTION Mitochondrialdysfunctionmakescellssusceptibletodeath,thuspromotingneurodegeneration.Themitochondria isthecellularstructureresponsibleforgeneratingenergyforallcellularprocessesandisconsideredthe powerhouseofthecell.Italsoplaysakeyroleincellularsurvival.Mitochondrialdysfunctionhasbeenlinked consistentlytoseveralneurodegenerativediseases,includingbothsporadicandfamilialPD,therebyrepresenting anattractivedrugtarget. NEUROINFLAMMATION Chronicinflammationcanleadtocelldeath.ChronicneuroinflammationhaslongbeenimplicatedinPD,although thisareaofstudyhasbeenlargelyneglected.Theinflammatoryresponseisdrivenbytheactivationofmicroglial cells(residentimmunecellsoftheCNS)andinfiltrationofTcells(atypeofimmunecell)intotheSN.The inflammatoryresponseisalsoactivatedbytheproductionofpro-inflammatorymolecules.Recentresearch suggeststhatmutatedLRRK2(seeTable2)isimplicatedinneuroinflammation.Researchinthisareais experiencingaresurgenceinthePDfieldbecausecellulareventsthataretriggeredbyneuroinflammation representpossibletherapeutictargets.BothLRRK2-targetingandanti-inflammationtherapiesarebeingactively exploredbythepharmaceuticalindustryforpotentialdisease-modifyingbenefit. AUTOPHAGY–ACELLULARCLEANINGPROCESS Autophagyisafundamentalcellularcleaningprocessthatisaqualitycontrolmechanismforthecell.The lysosome,oftentimesreferredtoasthe“garbagecanofthecell,”isresponsiblefordegradingoldordefective cellularcomponents,andiskeyfortheautophagicprocess.Enhancingtheautophagicprocessiscurrentlybeing exploredasatherapeuticstrategytopromotetheclearanceofalpha-synucleinfromneurons. Therearealsointerestingconnectionsbetweensomegeneticriskfactorsandautophagy.Forexample,theGBA gene(seeTable2)encodesforaproteinfoundinthelysosome,whichisthekeycellularstructureforautophagy. Further,LRRK2mutationsareimplicatedinautophagicdysfunctionaswell,andrecentresearchsuggeststhat disruptedautophagycontributestoalpha-synucleinbuildupinneurons–furtherhighlightingtheconnection betweenautophagicdysfunctionandPD. !" PDGENETICS Raregeneticmutationsare stronglyassociatedwiththe developmentoffamilialPD. Genescodeforproteins, whichinturncarryout cellularfunctions.Genetic mutationscangiverisetoa dysfunctionalprotein(s), therebycontributingto disease. Table2.GeneticRiskFactorsAssociatedwithPD. Whiletheraregenetic mutationslistedinTable2 greatlyincreasetheriskof developingPD,therearea largenumberofcommongeneticchangesthatarealsoseeninidiopathicPDcases.Individuallythesechanges alterriskbyonlyasmallamount;however,researchthatinvestigatestheunderlyingbiologyaffectedbya particulargeneticmutationwillshedlightonthebiologicalprocessesthatleadtofamilialandidiopathicPD.Itis importanttorememberthatinvestigatorsareconstantlydiscoveringnewgeneticriskfactors.Therefore,Table2is notanexhaustivelist;rather,itcapturessomeofthemostresearchedgenes(listedinalphabeticalorderby proteinname). ThescienceofPDisstillunfoldingand,despiteintensestudy,manyunansweredquestionsremain.Nevertheless, PDisnolongerrecognizedasapurelydopaminergicneurodegenerativedisease.Thefieldismovingtowardsa multi-systemviewofthisneurodegenerativediseasewithbothCNSandPNSinvolvement,havingeffectsonboth dopaminergicandnon-dopaminergicneuronsinvariousbrainregions. !! CLINICALTRIALSANDINVESTIGATIONALTHERAPIES CLINICALTRIALS–OVERVIEW Clinicalresearch(alsoreferredtoas clinicaldevelopment)isabranchof biomedicalresearchinvolvinghuman subjects.Thegoalofclinicalresearchisto evaluatesafetyandefficacyofdrugs, medicaldevicesordiagnosticsintended foruseinhumanpatients. Clinicaltrialsareanimportantcomponent ofclinicalresearchsincetheyareusedto evaluatethesafetyandefficacyofan experimentaldrugortherapyinhuman subjects.Clinicaltrialsaredividedinto phasesasdescribedinFigure12.Theycan alsobeusedtocollectspecimensfrom humansubjectsforfurtherresearch. Importantly,informationonpotentialside effectsaregatheredduringtheclinical trialperiodandweighedagainstthe potentialtherapeuticbenefitofthe treatmentunderinvestigation. Figure12.PhasesofClinicalTrials. DuringPhaseI,researcherstestanewdrugortreatmentforthefirsttimeina smallgroupofpeopletoevaluateitssafety,determineasafedoserangeand identifypotentialsideeffects.DuringPhaseII,proof-of-conceptstudiesare performedasthedrugortreatmentisgiventoalargergroupofpeopleto determineeffectiveandoptimaldose.DuringPhaseIII,thedrugortreatment isgiventolargegroupsofpeopletoconfirmitseffectiveness,monitorside effectsandassessitsimpactcomparedtothecurrentstandardofcare(SOC). Someclinicaltrialsinvolvemultiplephasestofacilitateseamlesstransition fromonetoanotherandarewrittenasPhaseI/IIorPhaseII/III.These designationsarealsousedinadaptivetrials,whereinstudyparametersare modifiedwithrespecttoongoingtrialresults. Theresearchanddevelopment(R&D)process–theprocessbywhichalaboratorydiscoveryisdevelopedintoa commercialtherapeutic,diagnosticordevice–isverycostlyandtime-intensive.Itisestimatedthat95percentof newdrugsfailtomakeitintotheclinic.Thisisahighfailurerateforaprocessthatcostsabout$1billioninoverall researchcostsandupto15yearsoftimeinvested. PARKINSON’SDISEASECLINICALTRIALS AsofJanuary2016,thereare138activeinterventional clinicaltrialsforPD.Figure13illustratesthe distributionofthesetrialsbyphase.PDclinicaltrials– aswithotherneurodegenerativediseases–havebeen fraughtwithfailuresinthepast,whichcaused pharmaceuticalandbiotechnologycompaniestoflee thespace.However,thisdynamicisrapidlyshiftingas recentadvanceshaverenewedinterestand Figure13.CurrentInterventionalPDClinicalTrials. investmentinPD. Ofthe138active,interventionalPDclinicaltrials,37(27%)are inPhase3.Dataobtainedfromwww.clinicaltrials.gov. !" PDclinicaltrialsareexpensiveandinherentlyriskyforseveralreasons: • Timeneededtocompleteastudy–Largepatientpopulationsneedtobefollowedforlongperiodsof timeinordertocaptureanypossibleeffectsondiseaseprogression.Infact,thetimetoPDclinicaltrial completionisprojectedtotakenearly25percentlongerthanclinicaltrialsforothertherapeuticareas. • Lackofreliablebiomarkerstomonitortreatmentresponse–Theefficacyofanexperimentaldrugor therapycannotbeadequatelyevaluatedwithoutareliablewaytodetermineifthedrugpenetratedthe targetorganandengagedtheintendedmoleculartarget.ThisisakeychallengeinPD,aswithmost neurologicaldiseases,sincethebrainisthemostdifficultorgantopenetrate. • Heterogeneousnatureofthedisease– Patientheterogeneitycanhavenegative effectsonstudyresults.Testingauniform groupofpatientswouldpreventdilutionof treatmenteffectandalloweffective treatmentstoberecognizedquicker.This againhighlightstheneedforbetterpatient stratificationtoensurethatinvestigational treatmentsarebeingappliedtotheright patients. Thoughtherisksaregreat,strategicphilanthropic investmentisuniquelypoisedtode-riskPDresearch byprovidingscientistswiththeresourcesthatcan Figure14.NIHFundingforPDversusTotalFundingfor acceleratepromisingsciencefrombasicresearch, Neurosciences. throughthecriticaltranslationalresearchphase, AnnualNIHfundingforPD-specificresearchhasconsistently andintoclinicaldevelopment.Governmentfunding beenlessthan3%ofthetotalfundingforallneuroscience researchsinceFY2011.Thistrendisforecastedtoremain forPDismodestatbest,asillustratedinFigure14, unchangedforFY2015and2016.DataobtainedfromNIH withthemajorityoffundsgoingtowardsbasic ResearchPortfolioOnlineReportingTools. research.PD-specificfundingrepresented2.5 percentofthetotalneurosciencesfundingfromtheNationalInstitutesofHealth(NIH)forFY2014–atrendthat hasbeenconsistentforthepastfouryears–andisestimatedtoremainunchangedforFY2015and2016.Itis evidentthatfundingfromothersourcesisdesperatelyneeded,andthisiswherephilanthropycanplayapivotal role. !" INVESTIGATIONALTHERAPIES AsofJanuary2016,withinthe138totalactive,interventionalclinicaltrials,thereare64distinctagentsinclinical developmentforPD.Figure15illustratesthedistributionoftheseagentsbytypeandphaseofdevelopment. Inthesectionsbelow,selectkeytherapeuticstrategiescurrentlyinclinicaldevelopmentforPDaswellas promisingtherapiesunderinvestigationarediscussed. Figure15.NewExperimentalAgentsinClinicalDevelopmentforPD. (Left)Newexperimentalagentsarerepresentedbyclinicaltrialphase.Ofthe64newexperimentalagentsindevelopment,9 (14%)haveprogressedtoPhase3. (Right)Newexperimentalagentsarerepresentedbytherapeuticstrategy. AlldataobtainedfromBioCenturyOnlineIntelligence. ALPHA-SYNUCLEINTARGETINGTHERAPIES Therearesixalpha-synucleintargetingagentscurrentlyinclinicaldevelopment.Theoverallgoalofthisstrategyis toclearalpha-synucleinbuild-upinthebraininordertopreventLewybodyformationandtransmissiontoother brainregions. Therearetwotherapeuticapproachesbeingtestedtoachievethegoalsstatedabove–smallmoleculeinhibitors andimmunotherapy. SMALLMOLECULEINHIBITORS(SMI) SMIsarelowmolecularweightcompoundsthataresmallenoughtopassivelyenteracell,whichmakesthem amenabletooraldrugformulations.Ofparticularimportanceforneurologicaldrugsistheabilitytopasstheblood brainbarrier(BBB).Thebrainistheonlyorganprotectedbyitsownselectivelypermeabledefensesystem,the BBB.ThegoalistodevelopSMIsthatcantargetalpha-synucleinbydisruptingthemisfoldedprotein’sabilityto interactwithothermisfoldedalpha-synucleinproteinstoformaggregates.Thisisachallengebecausetheproteinproteininterfacestypicallyspanlargesurfaceareas,therebymakingitverydifficulttodeterminewhichportionsof theinterfacetheSMIshouldtarget. ALPHA-SYNUCLEINIMMUNOTHERAPY Inadditiontoexploringsmallmoleculedrugstotargetthealpha-synucleinprotein,researchersarealsotesting whethertheycanactivatetheimmunesystemtotargetalpha-synuclein.Thisstrategy,referredtoas immunotherapy,worksbysolicitingeitheranactiveorpassiveimmuneresponse.Activeimmunotherapyinvolves !" administeringasubstance(e.g.,drug,vaccine,etc.)intothebodythatinducesanimmuneresponseleadingtothe naturalproductionofantibodies(proteinsusedbytheimmunesystemtobindandneutralizeothermoleculesin thebody)againsttheintendedtarget(i.e.,alpha-synuclein).Passiveimmunotherapydiffersfromactive immunotherapyinthatantibodiesagainstthetargetarecommerciallymanufacturedoutsideofthebodyand administeredasadrug.Resultsfromearlytrialsusingtheactiveimmunotherapyapproachindicatedthatthe vaccinewaswelltoleratedandtherewasearlyevidenceofclinicalbenefit. Onekeyconsiderationisthemanagementoftheimmuneresponsetoensurethattheimmunotherapeutic approachesdonotpromoteexcessiveinflammation.Theimmunesystemmustremainincarefulbalanceasunder- orover-stimulationoftheimmunesystemcanleadtodeleteriouseffects. LRRK2TARGETINGTHERAPIES LRRK2genemutationsarethemostcommoncauseofgeneticPD(seeTable2).TheLRRK2geneencodesforthe LRRK2protein,whichisakinase,atypeofproteinthatcatalyzesphosphorylation(thetransferofphosphate groupsfromonemoleculetoanother). SeveralLRRK2mutationsincreaseitskinaseactivity,whichistoxictoneurons.Thisiswhytheoverallgoalofthis therapeuticapproachistoinhibitLRRK2kinaseactivity.WhileLRRK2inhibitorsarenotyetinclinicaltrials,theyare currentlyinpreclinicaldevelopmentatPfizer,MerckandGenentech.Recently,toxicityconcernshaveslowed development.However,TheMichaelJ.FoxFoundationforParkinson’sResearchhasconvenedanLRRK2Industry AdvisoryGrouptopromotepre-competitivecollaborationacrossthesecompaniestosystematicallyaddress concernsandgetclosertotestinganLRRK2-targetingdruginclinicaltrials.Whilethistherapyhasimmediate relevanceforPDpatientswithLRRK2mutations,theremaybepotentialapplicationsforidiopathicPDpatientsas well. STEMCELLTHERAPY Therearecurrentlytwostemcelltherapiesinclinicaldevelopment.Stemcellshavetheabilitytobecome (differentiateinto)anycelltypeinthebodygiventheproperbiologicalsignals.Thehypotheticalbasisforthis therapyisthatstemcellscouldberecruitedtoorplacedindamagedregionsandreplaceSNdopaminergicneurons thatwerelostasaresultofPDandrestorepropersignaling. Inadditiontoreplacingdamagedcells,stemcellsarebeingexploredasadiseasemodelingsystemtoscreennew PDtherapies. USINGSTEMCELLSTOMODELPDANDSCREENNEWTHERAPIES Aspreviouslymentioned,PDsymptomscanvarysignificantlyamongpatients,highlightingdiseaseheterogeneity. Itisimportanttobeabletomodeltheunderlyingbiologicalmechanismsdrivingtheheterogeneityofthedisease inordertofindacure.Unfortunately,currentanimalmodelsfailtoadequatelyrecapitulatethedisease.The tremendousprogressinstemcellresearchhasenabledresearcherstousethistechnologytocreatepatientspecificmodelsofPDinapetridish.ThisisdonebytakingskincellsfromaPDpatient(donor)andreprogramming themtomakeaninducedpluripotentstemcell(iPSC).TheseiPSCscanbereprogrammedtodevelopintoanycell type,butforthepurposeofPDresearch,theyarereprogrammedtobecomeneurons. !" Becausethecellsarederiveddirectlyfromapatient,despitebeinggrowninpetridishes,theydisplaythesame molecularandpathologicalfeaturesidentifiedinthedonorpatient.Thecouplingofthepatient’sclinicalsymptoms tothebiologyandbehaviorofthestemcellscouldprovidenewinsightsintothekeymechanismsofPD.These patient-derivediPScellscanalsobeusedtotestnewdrugs.TheuseofiPScellstoscreendrugsthatmaybe effectiveagainstPDprovidesanadditionalmethodtovalidateresultsobservedinanimalsstudies.Thisis importantbecauseanimalmodelsareoftenpoorpredictorsoftheclinicalsuccessorfailureofnewdrugs,whichis amajorimpedimenttoclinicaltrialsuccessinPD. GENETHERAPY Therearecurrentlyfourgenetherapiesinclinicaldevelopment.Thistherapeuticstrategyinvolvesdeliveringa geneasadrug.ForPD,thistreatmentcoulddelivertheenzymethatconvertslevodopatodopamineinaneffortto increasetheamountofdopamineinthebrainortodeliverfactorsthatpromoteneuronalsurvival.Althoughthe theoryisstraightforward,inpracticeitisconsiderablymorecomplextoachievethisoutcomeasaresultof multiplevariablesthatcanbedifficulttocontrol.Todate,clinicaltrialstestingthisstrategyinPDaswellasother neurodegenerativediseaseshavefailedtoshowimprovementaboveplacebo.Effortstoimprovegenetherapyare focusedontwokeyareas:vectordesignanddeliverymechanism. DRUGREPURPOSING DrugrepurposinginvestigateswhetheradrugthatisalreadyFDA-approvedforanotherdiseasemaybeeffective fortreatinganewdisease.Thetheoryisthatdiseasesthathavecommoncellularpathwaysmaybenefitfrom similardrugs.FDA-approveddrugshavealreadybeentestedforsafety,meaningthatPhaseIrequirementshave alreadybeenmet.ThereforetestinganFDA-approveddrugforpotentialefficacyinadifferentdiseasecouldgo straighttoPhaseII,therebyreducingtimeandcostoftheclinicaltrial.ThisapproachhasbeenappliedtoPD recentlywithsomesuccess: • Metabolicagents–Metabolicagents,suchastypeIIdiabetesdrugs,haveshownefficacyinPDmodels. Abnormalglucosemetabolism(pathologicalfeatureofdiabetes)andabnormalmitochondrialfunction (pathologicalfeatureofPD)areintricatelylinked,givingareasonablebasistoexplorerepurposing metabolicdrugsforPD.Arecentsmallpilotstudy(“proofofconcept”clinicaltrial)usinganFDA-approved typeIIdiabetesdruggeneratedexcitementinthePDfieldduetotheclinicalbenefitexperiencedby patientstakingthedrug.APhaseIIclinicaltrialhasbeenlaunchedandiscurrentlyongoing. • Chemotherapeuticagents–Recently,PDpatientsdemonstratedevidenceofmotorandnon-motor improvementinasmallpilotstudyusinganFDA-approvedchemotherapyagentusedtotreatleukemia.It isbelievedthattheagentworkstocleartoxicbuildupofLewybodies.ItseffectonPDiscurrentlyunder investigation. • Antioxidantagents–Elevatedlevelsoftheantioxidanturateareassociatedwithalowerriskof developingPDandslowerdiseaseprogressionifdiagnosedwithPD.Antioxidantagentscombatoxidative stress(theimbalancebetweenfreeradicalsandnaturalantioxidantsgeneratedinthecell).Mitochondrial Dysfunction,describedabove,isamajorcontributortooxidativestress.AnactivePhaseIIIclinicaltrialis investigatingwhethertheuseofthenutritionalsupplementinosine(whichthebodynaturallyconvertsto theantioxidanturate),canslowdiseaseprogressioninearly-stagePDpatients. !" • Highbloodpressuremedication–Previousstudiesshowthatcalciumchannelblockers,aparticularclass ofhighbloodpressuremedication,mayreducetheriskofdevelopingPDandslowdiseaseprogressionif diagnosedwithPD.MitochondrialDysfunctionoccursiftoomuchcalciumentersthecell.Calcium channelblockersaredesignedtopreventthisexcessivecalciuminfluxintothecell.AnactivePhaseIII clinicaltrialisinvestigatingwhethertherepurposedhighbloodpressuredrug,isradipine,canslowthe progressionofearlystagePD. !" BARRIERSTOPDRESEARCHPROGRESSANDKEYPHILANTHROPICOPPORTUNITIES PDisamultifactorialdiseasewithanumberofchallengesandunmetneedsthatstandinthewayofdesperately neededprogress.InNovember2015,theMilkenInstitutePhilanthropyAdvisoryServiceconvenedworldrenownedPDexpertstodiscussthestateofsciencerelevanttoPDandthechallengescurrentlyimpedingresearch progress.Thegoaloftheretreatwastoidentifyhigh-impact,actionablesolutionswherestrategicphilanthropic investmentcouldaccelerateprogressinPD.Theexpertsprioritizedthefollowingchallenges: • Incompleteunderstandingofunderlyingdiseasebiology • Slowprogressinbiomarkerdiscoveryanddrugdevelopment • Inadequatepreclinicalmodels • Lackofdisease-modifyingtherapies(DMTs)andclinicaltrialfailures • Suboptimalcurrenttreatmentoptionstomanagesymptoms Thissectionoutlineseachofthekeychallengesalongwithpotentialsolutionsandcorrespondingphilanthropic opportunitiestoaddressthechallengesandacceleratePDresearchprogress.Pleasenotethattheopportunities presentedbelowarehigh-levelrepresentationsandshouldbeconsideredcarefullywithrespecttoyour philanthropicgoalsanddiscussedindetailwithaphilanthropicadvisor. INCOMPLETEUNDERSTANDINGOFUNDERLYINGDISEASEBIOLOGY THEPROBLEM TheunderlyingbiologyofPDisstillpoorlyunderstood,especiallywithrespecttokeyproteinssuchasalphasynucleinandLRRK2.EvidenceoverwhelminglysuggeststhatPDconvergesontheaberrantprocessingofalphasynuclein,yetseveralquestionsremainpertainingtohowabnormalalpha-synucleinmechanisticallycontributesto PD.Further,LRRK2mutationsarethemostcommoncauseofhereditaryPDandmayalsoplayarolein spontaneousPD,yetverylittleisknownaboutthisprotein’snormalbiologicalfunctioninthecellandits associatedsignalingpathways.Strategicallyaddressinghighprioritybasicsciencequestionswouldenhanceour understandingoftheunderlyingPDdiseasepathologyandthusimprovechancesofidentifyingnewdiseasemodifyingtreatments. FundingtoexplorebasicbiologytypicallycomesfromNIH(thelargestsourceoffundingformedicalresearchin theworld).However,constrainedfederalspendinghascrippledtheNIHbudgetinrecentyears,therebyaffecting PDresearchfunding,whichisalreadyonlyasmallfractionofNIHspendingforallneurosciences(asillustratedin Figure14).AdeeperunderstandingofPDbiologywillinformdrugdevelopmentefforts,asalpha-synucleinand LRRK2representmajordrugtargetsforseveralindustryprograms(seeInvestigationalTherapiessectiononpage 25). POTENTIALSOLUTIONS • Basicresearchinvestment–WhiletherehasbeenconsiderableinvestmentintranslationalandclinicalPD research,basicsciencehasbeenneglected.Betterscientificunderstandingwillinformdrugdevelopment efforts,selectionofpatients,biomarkersandendpointsforclinicalstudies.Expertssuggestedemployinga !" modelthatallowsinvestigatorstoembarkonhigherriskprojectsthanhavetypicallybeenfundedbythe government.Keyprioritiesareastoconsiderare: • o Biologicalmechanismandimpactofalpha-synucleinprotein o BiologicalmechanismandimpactofLRRK2protein o BiologicalmechanismandimpactofotherPD-relatedgenes o Selectivevulnerabilityofneuronaldeath o Compensatoryneurotransmitterpathways Humancapitalinvestment–Thereisaneedtobettersupportexistinginvestigatorsandtoattractnew investigatorstothefield.Doingsowillnotonlyacceleratethepaceofresearch,butalsomakeit sustainablebytrainingthenextgenerationofinvestigators.Thereisadearthoffundingforpostdoctorallevelandearlycareerinvestigators,whoperformthemajorityoftheearlybasicsciencestudies.Thishas thepotentialtonegativelyaffectbothacademicandindustry-ledresearchefforts,asbasicsciencestudies formthebasisforfuturetranslationalandclinicalresearch.Additionally,decreasedsupportforboth establishedandnewinvestigatorsincreasesthelikelihoodthatscientistswillleaveresearchinpursuitof othercareeroptions,thusdecreasingthepoolofscientistsavailabletoattackkeyscientificproblems. EXAMPLESOFCORRESPONDINGPHILANTHROPICOPPORTUNITIES • Fundbasicscienceresearchinitiativesthatenablebetterunderstandingofdiseasepathology.Thereare severalmodelstosupportthisapproach,rangingfromfundinginvestigator-initiatedresearchtofundinga collaborativegroupofinvestigators. • Fundadditionaltrainingprogramsthatinvestinpostdoctoralfellowsandearly-stageinvestigators,who generallycannotcompeteformajorgrantsupportastheydonothavethetrackofrecordofestablished investigators.However,theyareimportanttoprovideforthefuturebasisofthefield. Table3.SummaryofSolutionstoCatalyzeChangeinBasicResearch. SLOWPROGRESSINBIOMARKERDISCOVERYANDDRUGDEVELOPMENT THEPROBLEM Atpresent,therearenobiomarkersavailabletoobjectivelydiagnosePD,assessdiseaseprogressionortotrack treatmentefficacyinpatients.Theprocessofbiomarkerdiscoveryandvalidationiscentraltodrugdevelopment. Effortstoincreaseefficiencyintheprocesshavethepotentialtoreducethetimeandcostofclinicaltrials.Inorder forabiomarkertobeacceptedasatrueobjectivemeasureofdiseasestateortreatmentefficacy,itmustfirstbe !" identified(biomarkerdiscovery),thenconfirmedthroughreplication(biomarkervalidation)andfinallydetectedin clinicallyrelevanttests(assaydevelopment).Alargeamountofbiologicalsamplesisnecessarytosuccessfullyhone inonthefewcandidatebiomarkersthatpossesstheappropriatesensitivityandselectivitytobeadoptedastrue biomarkers. Recentlarge-scaleefforts–suchastheParkinson’sDiseaseBiomarkersProgram(PDBP),sponsoredbythe NationalInstituteofNeurologicalDisordersandStroke(NINDS),andtheParkinson’sProgressionMarkersInitiative (PPMI),sponsoredbytheMichaelJ.FoxFoundationforParkinson’sResearch(MJFF)–haveestablishedcritical infrastructuretosupportbiomarkerdiscoveryand/orvalidationusingpatientbiologicalsamples(e.g.,blood,urine, cerebrospinalfluid[CSF],DNA,RNA).However,thereispotentialtomaximizetheutilityofthesedata-rich resourcestosupportbothbiomarkerdiscoveryandvalidation(asopposedtooneortheother)withintheiralready establishedpatientcohorts. Asmentioned,biomarkerdiscoveryeffortsnecessitatelargeamountsofbiologicalsamples.Unfortunately,human braintissuefromlivingpatientsisnotavailabletostudyinneurodegenerativediseases,likePD,asthebrainisnot typicallybiopsied.WhilePDBPandPPMIcollectawidevarietyofbiologicalsamplesfrompatients,braintissueis notcollected.Alternativelytherearevariousbrainbanksacrossthecountrythathousepost-mortembrain donationsfrombothpatientswithhealthybrainsandthosethatsufferedfromavarietyofneurodegenerative diseases.Althoughbraintissuefromthesefacilitiescanberequested,obtainingsufficientlylargeamountsoftissue iscostprohibitiveformanyresearchlaboratories.Further,thesebrainbanksareseverelyfragmented,eachhaving theirownprocessesandhandlingprotocolswhichcancreatedatavariabilitywhenanalyzingsamplesfromvarious sources.Finallythesefacilitiesareoftenunderstaffedandunderfunded,therebycreatingsystemicinefficiencies thatultimatelymakethebraintissueinaccessible.However,ifthesechallengescouldbeovercome,elucidating differencesinthemolecularprofile(e.g.genes,proteins,lipids,metabolicstate)ofPD-diagnosedbrainsversus healthybrainscouldaugmentbiomarkerdiscoveryeffortsandacceleratedrugdiscovery. POTENTIALSOLUTIONS • Leverageexistinginfrastructuresforbiomarkerdiscovery–ExistingprogramssuchasPDBPandPPMIhave extensivesupportinplace,includingstandardizedcollectionandstorageofbiospecimens.However,their originalintendedusewaseithertosupportbiomarkerdiscovery(PDBP)orvalidation(PPMI).Yet,their utilitycouldbemorepowerfuliftheywereaugmentedtosupportbothbiomarkerdiscoveryand validationwithintheirestablishedcohorts.Strategicpatientcohortexpansionwithintheseprograms couldsupportthedualbiomarkeractivitiesbyextendingstudydurationoverall,re-openingclosedpatient cohortsand/orrecruitingnewpatientcohorts.Theseactionscouldallowformorein-depthanalysisof diseaseprogressionandheterogeneityinthesearchforcandidatebiomarkers. • Leverageexistingbrainbankinfrastructuretocatalyzebiomarkerdiscovery–Todatetherehasbeenno large-scaleefforttoperformdeepmolecularcharacterizationofbraintissueacrossU.S.brainbanks. CoordinatingexistingPDbrainbankingprogramsacrossthecountrytoperformlargescale“-omics” studiescouldincreasetheutilityoftheresourceandinformbiomarkerdiscoveryefforts. • Createabiomarkervalidationandassaydevelopmentteam–Followingbiomarkerdiscoverywithinthe abovementionedinfrastructures,validationteamscouldbeestablishedwiththeoverallgoalofgathering sufficientdataonatargettomakeitattractiveforindustrytopickup.Onceacandidatebiomarkeris validated,amethodtodetectitspresenceintheappropriatebiofluidand/orimagingscanmustbe established.Assuch,thisteamcouldalsodevelopstandardized,robustassaystobeusedinclinical !" research.Strategicphilanthropicinvestmenttosupportassaydevelopmentwillincreasetheefficiencyof drugdiscoveryefforts EXAMPLESOFCORRESPONDINGPHILANTHROPICOPPORTUNITIES • Fundongoinglongitudinalassessmentsand/ortheexpansionofprodromalandgeneticcohortswithin existingPPMIandPDBPinfrastructures.Theseexpandedinfrastructureswouldbeabletosupport biomarkerdiscoveryduetotheincreasedamountofsamplesavailable.Additionally,fundingalarge-scale efforttodeeplycharacterizethesamplesbyperforming“-omics”studieswouldexpandtheutilityofthis resource.Suchaneffortwouldalloweachpatient’sentiregenome(genomics),expressedgeneprofile (transcriptomics),proteinprofile(proteomics),lipidprofile(lipidomics),andmetabolicstate (metabolomics)tobestudiedovertime.Thisdatasetcouldthenbemadeopenaccessforthescientific communityasaresourcetofuelallstagesofresearch. • FundthecoordinationofexistingPDbrainbanksaroundthecountrytodevelopaPDbrainbanknetwork. DeepcharacterizationofPDpatientbrainsusinglarge-scale“-omics”studiesandbigdataanalyticscould lowerthebarrierofdiscoveryandprovideanadditionalplatformforbiomarkerresearch.Thisdataset,as suggestedabove,couldthenbemadeopenaccessforthescientificcommunityasaresourcetofuelall stagesofresearch. • FundBiomarkerDiscoverySWAT(SpecialWeaponsandTactics)TeamstoutilizePPMIandPDBP infrastructure.Functionally,theteamswouldproposeabiomarkertarget,peer-reviewedbyscientists, andthenbringtogethergroupsofresearcherstovalidatethetargetanddevelopanassociatedassay. PharmaceuticalanddiagnostickitmanufacturingrepresentativesshouldworkwiththeSWATTeamsto adviseonkeyelementsneededtosuccessfullyvalidateadrugtargetandincreasethelikelihoodof proceedingwithdevelopmenteffortsaroundtheproposedtargetintheirrespectiveindustries. Table4.SummaryofSolutionstoAcceleratethePaceofBiomarkerDiscovery. !" INADEQUATEPRECLINICALMODELS THEPROBLEM NosinglePDpreclinicalmodelfullyrecapitulatesthekeyfeaturesofhumandisease.Animalmodelsareusedto studydiseasebiologyandtestexperimentaltherapeuticsinordertodemonstratepotentialbenefitbeforetheyare approvedfortestingonhumansinclinicaltrials(preclinical).Poorreliabilityandpredictivecapabilityofthe preclinicaltranslationalpipelinenegativelyaffectdrugdevelopmentandcontributestothehighcostandfailureof clinicaltrials. AsdescribedpreviouslyintheStemCellTherapysectiononpage26,thereismomentumacrossthe neurodegenerativespace(e.g.,Alzheimer’sdisease,ALS,PD,etc.)toutilizeinducedpluripotentstemcells(iPSCs), generatedfrompatientskinbiopsiesand/orbloodsamples,asbothabiomarkeranddrugdiscoveryplatform. HumaniPSCshavetheadvantageofretainingeachpatient’smoleculardiseasesignaturesandcanbe differentiatedintovariouscelltypes(e.g.,neurons,heartcells,livercells,etc.)inadish(invitro),whichresemble thatfunctionalcelltypeinapatient’sbody.Assuch,thistechniquelendsitselftomodelinggeneticriskfactorsof diseaseparticularlywell.ThisabilitytogeneratemultiplecelllineagesfromiPSCsprovidesinvestigatorswithaway toevaluatetheeffectofanexperimentaldrugonmultiplecelltypessimultaneously.Forexample,investigators canassayforontargeteffectsonneuronsgeneratedfromiPSCsorforpotentialsafetysignalsinheartandliver cellsgeneratedfromiPSCsearlierinthedrugdevelopmentprocess. POTENTIALSOLUTIONS • Developamorepredictivepreclinicalpipeline–Thereareseveralpreclinicalmodelsavailablethroughthe Parkinson’sDiseaseResearchToolsConsortium(PDRTC)sponsoredbyMJFFandtheiPSCConsortium sponsoredbyNINDS;however,theycouldbebetterutilizedthroughrationalalignmentwithresearch goals.Additionally,deepmolecularcharacterizationeffortsthroughlarge-scale“-omics”studies(as recommendedforsolutionsdescribedintheprevioussection)couldalsoimprovemodelutilitytosupport morerobusttranslationalresearchefforts. EXAMPLESOFCORRESPONDINGPHILANTHROPICOPPORTUNITIES • Fundalarge-scalepatient-derivediPSCeffortthatemploysasystemsbiologyapproachthrough comprehensivebiologicalanalytics(e.g.,proteomics,transcriptomics,epigenomics,wholegenome sequencing,metabolomics,etc).Thisdatasetcouldthenbeavailableforthescientificcommunityasa resourcetofuelallstagesofresearch.Further,thisiPSCplatformcouldalsobeusedforhigh-throughput drugscreening.AniPSCeffortcouldbeachievedby: o CreatingaPDiPSCnetworkwithexistingiPSCbanksacrossthecountry,or !! o SpearheadinganewefforttocreateiPSCsfromnewlyrecruitedpatients,or o ExpandingthePPMIand/orPDBPbiospecimenresourcebycreatingpatient-derivediPSClines fromenrolledpatients. Table5.SummaryofSolutionstoImprovethePreclinicalPipeline. LACKOFDISEASE-MODIFYINGTHERAPIES(DMTS)ANDCLINICALTRIALFAILURES THEPROBLEM OfalltheavailabletreatmentsforPD,noneisproventoslow,haltorreversethenaturalprogressionofthe disease.Moreover,allnewinvestigationaldrugsforPDhavefailedtoshowadisease-modifyingeffectinpivotal clinicaltrials.Clinicaltrialsarecostlyandriskyendeavors,withthemostexpensivefailuresoccurringinlatephase IIandIIIstudies.Whilethisissueislargelyduetotheincompleteunderstandingoftheunderlyingdiseasebiology thatisdrivingPD,thereareothercontributingfactors,suchas: • Poorpatientselectionandstratification–Itisextremelydifficulttoselectpatientsintheearlieststagesof diseaseasthesignsandsymptomsaresubtle,variableandmanyaredistinctfromthemotorsymptoms thatlaterpredominate.Thisprodromalperiodistheoreticallywhenpatientswouldbenefitmostfroma DMT.Theinabilitytostratifypatientsappropriately(i.e.,bydiseaseseverityandsubtype)hasserious ramificationsforsuccessfulclinicaltrialsandultimatelyfordevelopingDMTs. • Lackofbiomarkers–Again,asmentionedpreviously,theinabilitytoreliablyandobjectivelydiagnosePD, assessdiseaseprogression,assesstargetengagement,ormonitortreatmentresponsehampersthe evaluationofapotentialDMT.Withoutappropriatemeasures,itisnotpossibletoknowwhethera potentialtherapeuticisactuallyslowingtheprogressionofPD. Additionally,investigatorsneedtointegratepatientperspectiveandinputintotheclinicaltrialprocess–an emergingimperativeinclinicalresearch.Patientsarerequiredforclinicalresearch,andtheirinputinstudydesign, parametersandoutcomemeasurescaninformtradeoffsbetweendesiredbenefitsandtolerablerisksthatare unaccountedforormisjudgedbyphysiciansandregulators.Poorpatientrecruitmentintoclinicaltrialsisa contributingfactortohighcosts.Infact,manytrialsareterminatedearlyiftheycannotrecruittheappropriate numberofpatients.Effortstoengagepatientsintheclinicaltrialprocesscanincreaseclinicaltrialsuccessandwill betterinformproductdevelopment.Forexample,conductingbenefit-riskanalyseswithpatientscouldshedlight onwhattypeandlevelofsideeffects,studyconditions,andburdensthatpatientsthemselvesmaybewillingto accept,whichphysiciansmaynothaveexpected. !" POTENTIALSOLUTIONS • Validatemobileappsandwearable/sensingtechnologyplatforms–Suchobjectivemeasurescouldbe beneficialforcurrentclinicaltreatments(asdescribedinthenextsection)aswellasfutureclinicaltrials. Forclinicaltrialpurposes,thesemeasuresmayallowinvestigatorstoquantifymotorandnon-motor symptoms,detectsmallerchangesinperformanceandmonitorpatientsremotely.Asaresult,thedata caninformpatientstratificationandthedevelopmentofdigitalbiomarkers.However,atpresent,thefield isill-equippedtohandletheenormousamountofdatageneratedbythesenewtechnologicalplatforms. Moreover,thereisnosetofquantitativedatastandardsthatcanbeappliedacrossclinicaltrials independentofthetechnologydeveloperand/ortrialsponsor.Thereforevalidationofthesedigitalhealth platformsisessentialtoaddresslimitationsandfacilitateadoptionoftheseplatformsbyregulatory agencies. • Integratepatientperspective–Accountingforthepatient’sexperiencewillenrichclinicaltrialstudy design,promotestudyaccrualandadherenceandidentifyacceptablerisksthatwerepreviouslynot considered.Further,thisisanopportunitytotakeintoaccountwhatbenefitsareactuallyimportantto patients.Forexample,patientsmayfindthatatreatmentwhichallowsthemmorepredictabilityof“on” timewithina48-hourperiodmorevaluablethananextrahourofunpredictable“on”timewithina48hourperiod,thusallowingthemthecontroltoplantheirday.Thesepreferencescouldaffectpatient participationinonetrialoveranother.Asweareenteringaneraofpatient-centeredcare,itisimportant toactivelyseekandintegratethepatientvoiceintoclinicaldevelopmentandplanning,asthese treatmentsareultimatelybeingdevelopedforthebenefitofpatients. • Drugrepurposingclinicaltrials–Thesetrials,asdescribedpreviouslyintheDrugRepurposingsectionon page27,offerthebenefitsofdecreasedtimeandcostforclinicaltrialsbyusingcompoundsthatwere developedforotherindicationsthatshowevidenceofpossibletherapeuticbenefitinPD.Itisworth notingthattherearecurrentclinicaltrialsthatareinvestigatingrepurposeddrugsforthetreatmentofPD (e.g.,exenatide,atypeIIdiabetesdrug;isradipine,ahighbloodpressuredrug;nilotinib,acancerdrug). EXAMPLESOFCORRESPONDINGPHILANTHROPICOPPORTUNITIES • • Fundaprecompetitive,multi-stakeholdermobiletechnologyinitiativetodesignandrunvalidation studiesforapre-determinedsetofmotor,non-motorandtreatment-inducedsymptoms.Thegoalof thiseffortistoestablishaquantitativeglobalstandardforthedeterminedsymptomsthatcanbeapplied toanydigitalhealthplatform. ThiseffortwillaffectallmembersofthePDresearchcommunity,includingcompetitorsinthe pharmaceuticalandmedicaldevicemanufacturingindustries,aswellasacademicandnonprofit partners.Therefore,precompetitivecollaborationwillallowthesecompetitorstosafelysharein developingthestandardsthatwillbenefitthewholeecosystem. o Ideally,thisinitiativewillleadtogloballyaccessiblequantitationmeasurementtools,aswellas datathatareclinicallyactionableandavailabletobothpatientsandinvestigators. Fundpatientpreferencestudiestogaininsightintowhatoutcomemeasuresaremeaningfultopatients. Theresultsofthesestudieswouldthenbescaledtoinformtrialdesign,eligibilitycriteria,trialendpoints andsecondarymeasures.Further,patientengagementcouldbeincludedasaconditionofgrantfunding !" o forinvestigatorsseekingclinicaltrialfunding.Thiswillensurethatthepatientperspectiveisincorporated intotrialdesignpriortoInstitutionalReviewBoard(IRB)approval. • Fundnoveldrugrepurposingefforts.Priortoclinicaltrials,iPSCplatformscouldbeusedasarepurposed drugscreeningplatform.Additionally,theuseofbioinformatics-guidedapproachestodrugrepurposing couldprovideamorerobustmethodtoexplorenewtherapies. Table6.SummaryofSolutionstoSupportDMTResearchandClinicalTrials. SUBOPTIMALCURRENTTREATMENTOPTIONSTOMANAGESYMPTOMS THEPROBLEM WhilefindingatreatmentthatslowsorhaltstheprogressionofPD(disease-modifyingtherapy)isalong-term goalinthePDfield,effortstomakepatients’livesmoremanageableintheshorttermshouldnotbeignored. Patientsconsistentlyidentifytheprogressivemotorandnon-motorsymptomsasparticularlydebilitating.There havebeenrecentimprovementstolevodopaformulations(e.g.,extendedreleasetablets,patchandcontinuous infusionviaintestinalpump);however,chroniclevodopatherapyleadstomotorfluctuations,themechanismof whichispoorlyunderstood.Further,progressivemotorsymptoms,suchasfreezingofgaitandfalls,continuetobe hugeunmetneedsforthefield,yetnotreatmentexistsforthesesymptoms.Adeeperunderstandingofthe underlyingbiologyassociatedwithdiseaseprogressionwouldsupporteffortstodevelopmoreeffective symptomatictherapies. Thereisalsonowagreaterappreciationfornon-motorsymptoms,yettheetiologyandunderlyingbiologydriving thesenon-motorsymptomsarealsopoorlyunderstood.Cognitivedysfunctioninparticularremainsasignificant unmetneed,asthefieldlacksmeasurestoadequatelyassessdegreeofcognitivedecline.Near-termeffortsto improvetherapeuticoptionsforpatientswouldaidinimprovingthequalityoflifeforpatients,andlongterm effortstocharacterizePDfeatureswouldcontributetoDMTdevelopment. POTENTIALSOLUTIONS • Fundbasicresearchefforts–Anunderstandingofthenon-dopaminergiccompensatorypathwaysinthe braincoulduncovernew“druggable”targetsandsignalingpathwaysthatcouldbeexploitedfor therapeuticbenefit.DBSisasuccessfulexampleofasurgicaltherapythatcamefromthefield’sincreased understandingofnon-dopaminergicpathways.Additionally,theunderlyingbiologyassociatedwithnonmotorsymptomsneedstobeexploredtosupportdevelopmentofrationaltherapeutics. !" • Harmonizeandstandardizelargeclinicaltrialdatabases–Clinicaltrialsaretypicallyperformed independentofeachotherand,assuch,inconsistenciesinhowdatawere/arecapturedrenderthe majorityofclinicaltrialdatabasesincompatible.Dataaggregation,harmonizationandstandardizationof multipledatasetswouldallowresearcherstoseamlesslyqueryacrossthewealthofinformationstoredin largeinterventionalclinicaltrialdatabases.Capitalizingontheseexistingdatabasescoulduncovernew insightsintoPDregardingthenaturalhistoryofdisease,diseasesubtypesandthebasisoftreatmentresistantfeatures.Thisprocessistimeintensive;however,databaseharmonizationtechnologyisbeing developedtocreateprocessefficiency. • Datagatheringwithmobileappsandwearable/sensingtechnology–Suchobjectivemeasurescouldallow investigatorstoquantifysymptoms,monitorpatientsremotelyandpersonalizecare.PDisa heterogeneousdisease;therefore,employingmethodstoassessthemotorandnon-motorfeaturesof prodromalandtreatment-resistantPDwouldaidDMTdevelopment.Additionally,thiseffortwould enablepatientstoparticipateinstudiesremotely,thusallowingforlarge-scalenaturalhistorystudiesto characterizethenaturalprogressionofPD. EXAMPLESOFCORRESPONDINGPHILANTHROPICOPPORTUNITIES • Fundbasicscienceresearchinitiativesthatenablebetterunderstandingoftreatment-inducedmotor symptomsaswellasnon-motorsymptoms.Thereareseveralmodelstosupportthisapproach,ranging fromfundinginvestigator-initiatedresearchtofundingacollaborativegroupofinvestigators. • FundanefforttoharmonizeandstandardizelargeinterventionalPDclinicaltrialdatabases.Ideally,this effortwouldincludeaccesstoandharmonizationacrossbothpublic(typicallygovernment-fundedtrials) andprivate(typicallyindustry-fundedtrials)databases. • Fundatechnologyinitiativetoencouragesupplementarydatacollectionwithmobileappsandwearable technologyinfuturelarge-scalenaturalhistorystudies.Additionally,fundadataanalyticseffortto supportalgorithmdevelopment,whichwouldtranslatethelargeamountsofdatageneratedfrom wearable/sensingtechnologyintofunctionalinformationthatcanbeinterpretedbyphysicianstoinform caredecisions,suchasdrugclassordosingchanges. Table7.SummaryofSolutionstoImproveSymptomaticTreatments. !" KEYSTAKEHOLDERSINTHEPDCOMMUNITY DOMESTICRESEARCHGRANT-MAKINGORGANIZATIONS ThereareseveralnonprofitorganizationsspecificallyfocusedoncharitablegivingtosupportPDandother neurodegenerativediseases.ThissectionprovidesabriefoverviewofthenonprofitorganizationsinvolvedinPD research.Theirinvolvementcanbethroughdirectlyfundingresearchorsupportingresearch.Thissectiononly includesU.S.-basedPDorganizationswitharesearchfocus;organizationsthataresolelyinvolvedinpatient support,advocacy, Table8.TopNonprofitOrganizationFundingPDResearchinFY2014. awarenessorwhose missionistofundone specificresearchcenter areexcluded.Table8 displaysthetopfour nonprofitfundersofPD research.Additional informationregarding theirmission,key researchfunding mechanismsandclinical trialssupportactivities isalsoprovidedbelow. THEMICHAELJ.FOXFOUNDATIONFORPARKINSON’SRESEARCH(MJFF) MISSION TheMJFFmissionistofindacureforParkinson'sdiseasethroughanaggressivelyfundedresearchagendaandto ensurethedevelopmentofimprovedtherapiesforthoselivingwithParkinson'stoday. RESEARCHFUNDINGMECHANISMS MJFFmainlysupportstranslationalandearlyclinicalresearch.MJFFhasalargefootprintintheglobalPD communityastheyhaveinjectedover$450Minresearchfundssincetheirinception.Theyinvestedover$60Min FY2014.MJFFsupportsresearcheffortsinbothacademiaandindustryspanningdrugtargetvalidation, therapeuticdevelopmentforbothDMTandsymptomatictreatments,aswellasresearchtooldevelopmentand datascience.AsignificantamountoffundingalsogoestosupporttheParkinson’sProgressiveMarkerInitiative (seepage43),MJFF’ssignatureprogramtodevelopdiseaseprogressionbiomarkers. Formoreinformationaboutavailableawards,pleasevisitMJFF’swebsite. !" NATIONALPARKINSONFOUNDATION(NPF) MISSION NPF’smissionistoimprovethelivesofParkinson’spatientsthroughexpertcareandresearch. RESEARCHFUNDINGMECHANISMS NPF’sresearchfundinghasaclearclinicalfocus.Theyhaveinfusedover$180MinresearchfundsintothePDfield sincetheirinception.Theyawardedover$3MinresearchsupportinFY2014.NPFfundsinvestigator-initiated researchthatcoversawiderangeofPD-relevanttopicareas.Additionally,NPFsupportshumancapitalinvestment intothefieldastheyprovideclinicalfellowshipstotrainneurologistsinthemovementdisorderspecialty.Thisis desperatelyneededasmostPDpatientsdonotseeamovementdisorderspecialist.Theyalsoprovideresearch grantstosupportcareerdevelopmentofyounginvestigators. Formoreinformationaboutavailableawards,pleasevisitNPF’swebsite. AMERICANPARKINSONDISEASEFOUNDATION(APDA) MISSION TheAPDAmissionisto“EasetheBurden–FindtheCureforParkinson’sdisease.”Asthecountry'slargest grassrootsorganizationservingmorethan1millionAmericanswithParkinson'sdiseaseandtheirfamilies,APDA's energyisfocusedonresearch,patientservices,educationandraisingpublicawareness. RESEARCHFUNDINGMECHANISMS APDAhasastrongfocusonpatientsupport,advocacyandawareness,howevertheydoalsofundPDresearch. Theyhaveawardedover$42Minresearchfundssincetheirinception,includingover$2Mtosupportresearch activitiesinFY2014.APDA’sresearchfundingisprimarilyfocusedonsupportingthecareersofaspiringandearly stagePDscientistsas75percentoftheirfundingmechanismsareintendedforyounginvestigators,postdoctoral fellowsorpracticingneurologists. Formoreinformationaboutavailableawards,pleasevisitAPDA’swebsite. PARKINSON’SDISEASEFOUNDATION(PDF) MISSION ThePDFmissionistoimprovethelivesandfuturesofpeopletouchedbyPDbyfundingpromisingscientific researchwhilesupportingpeoplelivingwithParkinson’sthrougheducationalprogramsandservices. RESEARCHFUNDINGMECHANISMS PDF’sresearchfundingmainlysupportsbasicandtranslationalresearch.Sincetheirinception,theyhaveawarded over$110Minresearchfunds,includingover$5MduringFY2014.PDFsupportsbothinvestigator-initiatedaswell !" ascollaborative,center-wideresearch.PDFhasaglobalreachastheyfunddomesticallyandinternationally. TrainingandcareerdevelopmentisalsoapriorityforPDFsincetheyactivelyfundresearchandclinicalfellowships. Formoreinformationaboutavailableawards,pleasevisitPDF’swebsite. OTHERKEYGRANT-MAKINGORGANIZATIONS PARKINSONSTUDYGROUP(PSG) ThePSGisthelongeststanding,largest,not-for-profit,scientificnetworkofPDCentersinNorthAmericaconsisting of132centers.ThePSGaimstoconductclinicaltrialstoadvanceknowledgeaboutthecause(s),disease progressionandtreatmentofPDandrelateddisorders.PSG-sponsoredclinicaltrialshavebeeninstrumentalinthe FDAapprovaloffourPDdrugs:Rasagiline,Rotigotine,EntacaponeandPramipexole.PSGprovidesfundingfor retrospectivedata-mining,mentoredclinicalresearch,andbiomarkerdiscoveryandvalidation. Formoreinformationaboutavailableawards,pleasevisitPSG’swebsite. PARKINSON’SUK Parkinson’sUK’svisionandultimateambitionaretofindacureandimprovelifeforeveryoneaffectedbyPD. Parkinson’sUKisthelargestcharityfunderofPDresearchintheUK.Parkinson’sUKfundsmulti-yearresearch grantsacrossalllevelsofresearch(basictoclinical)andresearchexperience(pre-doctoraltoseniorindependent investigator).ItprovidesfundingforlargeprojectsandcareerdevelopmentforaspiringPDinvestigators. Formoreinformationaboutavailableawards,pleasevisitParkinson’sUK’swebsite. THECUREPARKINSON’STRUST(CPT) CPTisfocusedonfindingacureforParkinson’s.Itfundsprojectsthatcandemonstratethepotentialtoslow,stop orreversethecondition.CPTactivelyencouragescollaborationamongscientistsandfosterstheserelationshipsto accelerateprogress.CPTfundsbothpreclinicalresearchandclinicaltrials.Mostofthecurrentclinicaltrials supportedareapartofitsLinkedClinicalTrialsInitiative.CPT’srecentresearchportfoliosupportsregenerative medicine,mitochondrialfunctionstudies,alpha-synuclein-targetinganddrugdeliverymechanisms. Formoreinformationaboutavailableawards,pleasevisitCPT’swebsite. !" COLLABORATIVEINITIATIVES GOVERNMENT-SPONSOREDPROGRAMS PARKINSON’SDISEASEBIOMARKERSPROGRAM(PDBP) PDBP,launchedin2012,isaprogramoftheNationalInstituteofNeurologicalDisordersandStroke,whosegoalis tosupportPDbiomarkerdiscoveryeffortsbyfundingresearchandresourcedevelopmentusingcollectedpatient samples.ThePDBPhascollectedthousandsofpatientbiospecimens(e.g.DNA,RNA,CSF,blood)for30monthsin 6monthintervals,allowingforlongitudinalstudies.Grantstotalingover$5MhavebeenawardedunderPDBPto datewithactivefundingannouncementsouttosupportfuturework. MORRISK.UDALLCENTERSFOREXCELLENCEINPARKINSON’SDISEASE ThisNINDSprogramwasnamedinhonorofCongressmanMorrisK.UdallofArizona,whowasdiagnosedwithPD in1979.UdallremainedactiveinCongressuntilhisretirementin1991,andpassedawayin1998afteralongbattle withPD.UdallCentersutilizeamultidisciplinaryresearchapproachtoelucidatethefundamentalcausesofPDas wellastoimprovethediagnosisandtreatmentofpatientswithPDandrelatedneurodegenerativedisorders.Udall CentersarerequiredtosharedataandengagepatientstopromoteknowledgeadvancementinboththePD researchandpatientcommunities.TherearecurrentlynineUdallCentersacrossthecountry: • • • • • • • • • TheBrighamandWomen'sHospital(Boston,MA) FeinsteinInstituteforMedicalResearch(Manhasset,NY) JohnsHopkinsUniversitySchoolofMedicine(Baltimore,MD) MayoClinic,Jacksonville NorthwesternUniversity(Chicago,IL) UniversityofMiami UniversityofMichigan UniversityofPennsylvaniaSchoolofMedicine UniversityofWashington !" CONSORTIAANDSTRATEGICPARTNERSHIPS Consortiaaretemporaryassociationsofstakeholdersfromvarioussectors–academia,industry,government, nonprofits,etc.–thatshareresourcesinordertoachieveacommongoal.AccordingtoFasterCures’ Consortia-pediaCatalogue,adatabaseofbiomedicalresearchconsortia,therearecurrentlynearly10consortiafor PD.Table9listsselectconsortiathatarefocusedexclusivelyonPDresearch,resourcebuildingand/ortherapeutic development.Patientcohortsareexcludedfromthisanalysis.Forafulllist,pleasevisit www.consortiapedia.fastercures.org. Table9.PDConsortia. BIOMARKERSACROSSNEURODEGENERATIVEDISEASES(BAND) TheBANDconsortiumconsistsoftheAlzheimer’sAssociation,Alzheimer’sResearchUK,MJFFandtheWeston BrainInstitute.ThegoaloftheBANDconsortiumistostimulateanalysesacrosstheAlzheimer’sdiseaseandPD researchenterprisestoengageinfurtherdataanalysisofexistingcohorts.Dataanalysiswillcontributeto biomarkerdiscovery,standardizationofassays,geneticprofilesandimagingmodalities.Thegoalistoenable preliminarypilotresearchorproof-of-principlestudiesutilizingdataand/orsamplesfromtwolargebiomarker studies–theAlzheimer’sDiseaseNeuroimagingInitiativeandthePPMI–inordertogarnerfurtherresearch supportfromotherfundingagencies. INTERNATIONALPARKINSON’SDISEASEGENOMICSCONSORTIUM(IPDGC) TheIPDGCisamultinationalcollaborativegroup.MembersoftheIPDGChaveledtheefforttodefineand understandthegeneticbasisofPD,identifyingthemajorityofknowngeneticriskfactorsforthisdisease.Todate, thelargestgenome-wideassociationanalysisforPDwasperformedbyIPDGCmembers.IPDGCalsospearheaded thecreationofinexpensiveandpowerfulgenotypingtools,suchastheNeuroXchip,throughanindustry collaborationwithIllumina.Thetoolshavebeenwidelyadoptedforthestudyofmultipleneurodegenerative diseases. Theirworkisbeingextendedtoincludebiomarkeridentification,riskprediction,diseasesubtyping,andthe molecularbasisofdisease.ThemembersoftheIPDGC,whoarebasedintheUSA,France,England,Wales, Germany,TheNetherlands,andEstonia,meetinpersonbiannually. !! NETWORKFOREXCELLENCEINNEUROSCIENCECLINICALTRIALS(NEURONEXT) NeuroNEXTwascreatedtoconductstudiesoftreatmentsforneurologicaldiseasesthroughpartnershipswith academia,privatefoundationsandindustry.ThenetworkisdesignedtoexpandtheNINDS’capabilitytotest promisingnewtherapies,increasetheefficiencyofclinicaltrialsbeforeembarkingonlargerstudiesandrespond quicklyasnewopportunitiesarisetotestpromisingtreatmentsforpeoplewithneurologicaldisorders. NeuroNEXTprovidesanestablishedinfrastructure,includingadatacoordinatingcenter(UniversityofIowa), ClinicalCoordinatingCenter(MassachusettsGeneralHospital)andapproximately28studysites.Funded NeuroNEXTstudieswillusethisinfrastructure,whichincludesacentralIRBandpre-establishedcontractual agreementswithallsites.AllbutthreeNeuroNEXTsitesarealsoPSGsites. PARKINSON'SDISEASERESEARCHTOOLSCONSORTIUM(PDRTC) ThePDRTCformalizespreviouslyadhocinputandfeedbacktotheMJFFfromtooldevelopersandendusersin pursuitofmorerobusttoolsforthePDresearchcommunity.Thecurrentlandscapeoflaboratorytool developmentisacostlyandtime-consumingpracticewherescientistscreateandvalidatetoolsforspecific experiments.Theseself-producedtoolscreatechallengesrelatedtolengthymaterialtransferagreementsand intellectualpropertyissuesand,unfortunately,inmanycasescannotbeusedreproduciblyinotherlabs.Since 2010,theMJFFToolsProgramhasstrivedtoliberateresearchersfromthesechallengesbycreatingvalidated, characterizedresearchtoolsanddistributingthemtoacademicandindustryresearchersatlittletonocost throughanexpeditedprocess.MJFFcurrentlyoffers260preclinicalresearchtoolstoscientistsandcounts8,500 toolsdistributed. PARKINSON’SPROGRESSIVEMARKERINITIATIVE PPMI,sponsoredandcoordinatedbyMJFF,isanobservationalclinicalstudypartnershipinvolvingresearchers, fundersandstudyparticipantsworkingtowardthegoalofidentifyingprogressionbiomarkerstoimprovePD therapeutics.PPMIwasestablishedsixyearsagoasabiomarkervalidationplatform.Tothatend,PPMIhas establishedacomprehensive,standardized,longitudinalPDdatabaseandbiologicalsample(biospecimen) repositorythatisavailabletotheresearchcommunity.ThePPMIbiospecimenrepositoryhousesurine,plasma, serum,cerebrospinalfluid,DNAandRNAforeverypatientparticipant.Thedatabaseandbiorepositoryinclude advancedimagingandbiospecimenanalysiswithclinicalandbehavioralassessments.Over700patientsare currentlyenrolledinPPMI,withafewcohortsstillenrollingpatients.PPMIistakingplaceatclinicalsitesinthe UnitedStates,Europe,IsraelandAustralia. !" APPENDIX FDA-APPROVEDPHARMACOLOGICALTREATMENTS Table10.FDA-ApprovedLevodopa/CarbidopaAgents. Table11.FDA-ApprovedDopamineAgonists. Table12.FDA-ApprovedMAO-BInhibitors. !! Table13.FDA-ApprovedCOMTInhibitors. Table14.FDA-ApprovedNon-DopaminergicAgents. !" GLOSSARY ACETYLCHOLINE(ACH) Aneurotransmitterthatplaysanimportantroleinmanyneurologicalfunctions, includinglearningandmemory.Acetylcholinealsoworksincoordinationwith dopaminetoproducesmoothmovement. ACTIVEIMMUNOTHERAPY Administrationofadrugvaccineintothebodytoinduceanimmuneresponse leadingtothenaturalproductionofantibodiesagainstatarget ADENO-ASSOCIATED VIRUSES(AAVS) Acommontypeofviralvector AKINESIA Slownessofmovementinitiation ANTIBODIES Proteinsusedbytheimmunesystemtobindandneutralizeothermoleculesinthe body ANTICHOLINERGIC AGENTS Thisdrugclassblockstheactionofacetylcholineandisusedtotreatrestingtremor andrigidity AUTOPHAGY Afundamentalcellularcleaningprocessthatisaqualitycontrolmechanismforthe cell AXON BASALGANGLIA BILATERAL Theappendageofaneuronthattransmitsimpulsesawayfromthecellbody. Oneofthemajorregionsofthebraininvolvedinmotorcontrol Involvingbothsidesofthebody BIOMARKER Measurablesubstanceormoleculewhosepresenceisindicativeofdisease,infection orenvironmentalexposure BIOPSY Tissueremovedfromalivingbody BLOOD-BRAINBARRIER Alayerofcellsliningtheinnersurfaceofbraincapillaries.Itprotectsthebrainfrom infectiousagentsandtoxiccompoundsbylettingnutrientsandoxygeninandwaste productsout.Becausethebarrierstrictlyregulatesthepassageoflargermolecules andoftenpreventsdrugmoleculesfromenteringthebrain,ithaslongposedoneof themostdifficultchallengesindevelopingtreatmentsforbraindisorders. BRADYKINESIA CATECHOL-OMETHLYTRANSFERASE (COMT)INHIBITORS CENTRALNERVOUS SYSTEM(CNS) Slownessofmovementexecution Drugsthatareresponsibleforincreasingthebioavailabilityoflevodopa. Comprisedofthebrainandspinalcord CEREBROSPINALFLUID (CSF) Clear,colorlessbodyfluidthatbathesthebrainandspinalcord.Whiletheprimary functionofCSFistocushionthebrainwithintheskullandserveasashockabsorber forthecentralnervoussystem,CSFalsocirculatesnutrientsandchemicalsfiltered fromthebloodandremoveswasteproductsfromthebrain. CLINICALRESEARCH Branchofbiomedicalresearchinvolvinghumansubjects CLINICALTRIALS Researchstudiesonhumansubjectsthataredesignedtoevaluatethesafetyand efficacyofpotentialinterventions,includingdrugs,vaccinesandmedicaldevices DATAMINING Examininglargedatabasesinordertogeneratenewinformation. DEEPBRAINSTIMULATION AsurgicalprocedureapprovedforthetreatmentofadvancedPDinpatientswhose (DBS) motorsymptomsarenotadequatelycontrolledwithmedications !" DENDRITE DISEASE-MODIFYING THERAPY DJ-1GENE DOPAMINE Neuronalprojectionthatreceiveschemicalmessagesforneurons Drugthatcanmodifyorchangethecourseofadisease EncodesfortheDJ-1protein PrimaryneurotransmitterinvolvedinParkinson'sdisease DOPAMINEAGONISTS Thesedrugsmimictheactionofdopaminebybindingdirectlytoandactivating dopaminereceptorsinthebrain DYSKINESIA Sporadicinvoluntarymovementsthattypicallyoccurafterlong-termlevodopa therapy EFFICACY Measureoftheabilityofthedrugtotreatwhateverconditionitisindicatedfor.Itis notastatementaboutthedrug'stolerabilityoreaseofuse. ENZYME Aproteinoriginatingfromlivingcellsthatcatalyzesaspecificbiochemicalreaction FAMILIALPD FIBRIL GBAGENE InheritedPD Amolecularcomplexthatconsistsofafewoligomericunits Encodesfortheβ-glucocerebrosidaseprotein GENETICMUTATION PermanentalterationintheDNAsequencethatmakesupagene,suchthatthe sequencediffersfromwhatisfoundinmostpeople GENOME IDIOPATHICPD Anorganism'scompletesetofDNA SpontaneousPD IMPULSECONTROL DISORDERS(ICDS) Aclassofpsychiatricdisorderscharacterizedbyfailuretoresistatemptation,urge orimpulsethatmayharmoneselforothers(e.g.gambling,sexualhyperactivity,etc.) INDUCEDPLURIPOTENT STEMCELLS(IPSCELLS) Stemcellsderivedfromanycellinthebody INTRAVENOUS(IV) Existingortakingplacewithin,oradministeredinto,aveinorveins KINASE Anenzymethatcatalyzestheadditionofphosphorousandoxygengroupstoa protein LENTIVIRUS Acommontypeofviralvector LEVODOPA Aprecursortodopamine.Primarydopaminereplacementtherapeuticagentusedto treatPD. LEWYBODIES LRRK2GENE LYSOSOME METABOLIZE Accumulationoftoxicproteinclumps(aggregates) Encodesfortheleucine-richrepeatkinase2protein Ahighlyacidifiedcellularstructurethatiskeyforautophagy Tobreakdownorconverttoanothermolecule MICROGLIA Theresidentimmunecellsofthecentralnervoussystemthatrespondtoand removedamagedneurons MICROTUBULE Ahollowcylindricalproteinstructureinneuronsthatholdsthecellinitsproper shapeandalsohelpstransportnutrientswithinthecell MITOCHONDRIA Thepowerhouseofthecellresponsibleforgeneratingenergyforallcellular processes MONOAMINEOXIDASEB (MAO-B)INHIBITORS Drugsthatareresponsibleforpreservingexistingdopamineinthesynapse !" NATIONALINSTITUTESOF HEALTH(NIH) PrimaryagencyoftheU.S.governmentresponsibleforbiomedicalandhealthrelatedresearch.TheNIHcomprises27separateinstitutesandcentersthatconduct researchindifferentdisciplinesofbiomedicalscience. NEUROINFLAMMATION Aninnateimmuneresponseinthecentralnervoussystemthatinvolvesthe accumulationofactivatedimmunecellstoasiteofinjuryorforeignsubstances NEUROLOGISTS Themedicalspecialiststrainedtodiagnoseandtreatnervoussystemdisorders NEURON Atypeofcellfoundinthenervoussystemthatprocessesandtransmitsinformation toothercellsthroughelectricalandchemicalsignals.Alsocallednervecell. NEUROTRANSMITTER Achemicalthattransmitssignalsacrossasynapsefromoneneurontoanothercell NON-VIRALVECTOR ThesevectorsretainthecircularDNAvectorstructurebutarestrippedoftheviral replicationfactorspresentinviralvectors OFF-TARGETEFFECT OLIGOMER Havinganeffectonsomethingotherthantheintendedtarget Amolecularcomplexthatconsistsofafewmonomerunits OXIDATIVESTRESS Theincreasedgenerationofreactiveoxygenspecies,(ROS)whichmakesthecell moresusceptibletodeath PARKINGENE EncodesfortheParkinprotein PASSIVE IMMUNOTHERAPY Administrationofantibodiesorotherimmunesystemcomponentsthataremade outsideofthebody PERIPHERALNERVOUS SYSTEM(PNS) ComprisedofallthenervesandnervebundlesoutsidetheCNS PINK1GENE POSTURALINSTABILITY EncodesforthePTEN-inducedputativekinase1protein Impairedbalance PRECLINICALMODEL Stageofresearchbeforeclinicaltrialswherefeasibilityanddrugsafetyarecollected REPROGRAMMING TheprocessofusingmolecularfactorstocreateiPScells RESEARCHAND DEVELOPMENT(R&D) Theprocessbywhichalaboratorydiscoveryisdevelopedintoacommercial therapeutic,diagnosticordevice RIGIDITY Stiffmuscles SMALLMOLECULE INHIBITORS(SMIS) Lowmolecularweightcompoundsthataresmallenoughtopassivelyenteracell SNCAGENE SUBSTANTIANIGRA SYMPTOMATICTHERAPY SYNAPSE SYNAPTICCLEFT Encodesfortheα-synucleinprotein Brainregionthatcontainsdopamineregion Therapiesthatalleviatesymptoms Specializedconnectionsbetweenneuronswhereinformationistransmitted Thespacebetweenneuronsintowhichneurotransmittersarereleased SYNAPTICTRANSMISSION Processbywhichsignalingmolecules(neurotransmitters)arereleasedbyaneuron andbindtoandactivatetheneuronsofanotherneuron TAUPROTEIN Aproteinthatbindstoandregulatestheassemblyandstabilityofneuronal microtubules,foundinanabnormalforminAlzheimer’sdisease UNILATERAL Involvingonesideofthebody VIRALVECTOR !" 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