Susa Benseler: Rare Disease Day 2016 Conference

BuildingonCanada’sRareExper4se:Inflamma4on

SusaBenselerSec&onChiefRheumatologyDeputyHeadResearchAlbertaChildren’sHospitalDepartmentofPaediatricsCummingSchoolofMedicineUniversityofCalgary

CORD-CanadianOrganiza4onforRareDisorders-RareDiseasesDay2016

Inflammatorydiseases

•  Singleormul&-organdiseases•  Monogenic,polygenic,mul&factorial•  Earlyonset,rapidprogression,slowcourse•  Trigger:infec&on,cold,stress,other

•  Symptomsoffather•  Arthri&s•  Migraine•  Ur&caria-likerash•  Conjunc&vi&s•  Sensorineuralhearingloss

•  Symptomsofdaughter•  Ur&caria-likerash•  Arthri&s

CryopyrinAssociatedPeriodicSyndromesCAPS

Courtesy:RonLaxer,SickkidsFather

Daughter


•  Singleormul&-organdiseases•  Monogenic,polygenic,mul&factorial•  Earlyonset,rapidprogression,slowcourse•  Trigger:infec&on,cold,stress,other

Reversibleorgan

irrita&on

Irreversibleorganinjury/

damage

InflammatoryBrainDiseases

Seizurestatus

Brainvesselinflamma4on


Reversibleorgan

irrita&on


damage


Reversibleorgan

irrita&on

Healingandorgan

recovery

Recovery

TheInterna4onalInves4gatorNetworkforChildhood

InflammatoryBrainDiseases….preven/ngbraininjuryfrom

inflamma/on…


•  InterdisciplinaryprogramclinicsacrossCanada,theUSandbeyond;model:SickkidsToronto


•  InterdisciplinaryprogramclinicsacrossCanada,theUSandbeyond;model:SickkidsToronto

•  Inves&gatornetworkandvirtualcohortBrainWorksenablingustolearnfromeverysinglechild

•  Interna&onal,interdisciplinaryweb-basedprospec4ve,observa&onalcohortstudy

•  Online,password-secureddatacollec&on,hostedatCCB,Toronto,ownershipofdatawithcenters.

Right

Right


•  InterdisciplinaryprogramclinicsacrossCanada,theUSandbeyond


•  Tools/pathwaystoevaluateandprotocolstotreatchildrensafelyandeffec&vely

Twilt,NatureReviews2012;Graus,LancetNeurology2016

Howtoevaluatebrainbiopsies?

TowardsahistologicaldiagnosisofcPACNS

30SVcPACNScases10epilepsycontrols10inflammatorycontrols

http://www.sickkids.ca/Research/Brainworks/Welcome/Welcome.html …or google childhood CNS vasculitis

BrainWorks

VersionNov2015

http://www.sickkids.ca/Research/Brainworks/Welcome/Welcome.html …or google childhood CNS vasculitis

BrainWorks

Outcome

Hutchinson, Lancet Neurology 2010

An&-TNFαTherapyinrefractorySVcPACNS

Bhattish, 2012, J Rheumatology

Rehabilita4onstrategies

Titulaer,LancetNeurology2014

Interna4onalPartnerships:RelapsesinNMDAREncephali4s





•  Effec&veknowledgetransla&on

BrainWorkswebsite





•  Effec&veknowledgetransla&on•  Transla&onalresearchbedside-to-benchandback:Bridgingthegap

CIHRTeamgrantfunding

Siterecruitment–  48sitesfrom10countriescollec&ngclinicaldata–  21sitesfrom7countrieswithethicsforbiosampling

Clinicaldata–  381systemicvasculi&spa&ents–  406primaryCNSvasculi&spa&ents(Approx90%havefollow-updataupto12months)

Biologicalsamples–  93pa&entscontributed(RNA,DNA,serum,plasma,urine)

BiomarkerdiscoveryBio-plexbeadtechnology

EGF: epidermal growth factor

Eotaxin FGF-2(basic) Fractalkine GM-CSF IFNalpha2 and IFNgamma IL-1alpha, IL-1beta, IL-1Ra IL-2,IL-3, IL-5, IL-6, IL-7,

IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17

IP-10 MCP-3 MDC MIP1alpha PDGF-AA/AB/BB CD40L (CD154) sIL-2Ralpha TGFalpha TNFbeta ENA-78 SDF-1alpha + beta

InflammatoryBiomarkerProfiles

Mineyko, 2012

Nowbiomarkers:S100A9/A12proteins

Foell,2016submided

GeneExpressionProfiling

•  AffymetrixHumanGene2.0STArray– >33,500codingtranscripts– >11,000longintergenicnon-codingtranscripts

HierarchicalClustering

Candidatepathways

CanadianAutoInflamma4onNetworkInauguralNa4onalMee4ng-inpersonandweb-based-Calgary,February08,2016

CANFlameInnova4onforInflamma4onI4I

TypicalPa&entFlowandDiagnosisforPa&entswithAutoinflammatoryDiseases

Timeline

3years 4years2years 6years 7years5years ≥8years1year

Mostpa&entshavefrequentcoursesofan&bio&csbyage

10

SInternist

Familyphysician/Pediatrician

Dermatologist

Nephrologist

Rheumatologist

Ophthalmologist

Neurologist Otolaryngologist

Allergist

GI

PneumologistPa4ent

Urologist

Audiologist


Reversibleorgan

irrita&on


damage

Innova&on4Inflamma&on

•  InterdisciplinaryprogramclinicsacrossCanada

•  Inves&gatornetworkandvirtualcohortCANFLAMEenablingustolearnfromeverysinglechild

•  Na4onalnetworkofpartnersforadvanceddiagnos4cevalua4on


•  Effec&veknowledgetransla&on

Newtasks…

•  Facilitatorofknowledgeexchange– Researchfundingopportuni&es,buildinginterna&onalfundingpartnerships

– Diagnos&cnetworks–genes,pathways,imaging,func&onaltests(hearing,vision)

– Treatmentnetworks–protocols,outcome,measures,safety

– Drugaccessstrategies

Thankyou…

Susa Benseler: Rare Disease Day 2016 Conference

Government & Nonprofit

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