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Osteoarthritis,adegenerativediseaseopentofuturecell
therapy?
DrYves-MariePERSMCU-PH
ImmunologiecliniqueetThérapeutiqueostéo-articulaireDépartementdeRhumatologie- CHUMontpellier
IRMB-INSERMU1183ympers2000@yahoo.fr
• 17%wholepopulation• 10millionspatientsinFrance• Incidence
Ø KneeOA:240/100.000PAØ HandOA:100/100.000PAØ HipOA:88/100.000PA
• Highburdencost+++Ø 3millionsphysicianvisit/yearØ 14millionsdrugprescribed
• Mainriskfactors:Ø AgeØ SexØ Obesity
Bijlsma JWJetal.Lancet2011
Introduction- OA
synoviocytes
monocyteschondrocytes
osteoclasts
OA,pathophysiology:theplayers
Sellam,J.&Berenbaum,F.(2010) Theroleofsynovitisinpathophysiologyandclinic
OApathophysiology:synovialinflammation
UnmetneedinOA
• 3unmetmedicalneeds• Efficientdiseasemodifyingtreatment• Moreeffectivesymptomatictreatment:NSAIDsimprovelessthan50%WOMACscores
• Safertreatment:NSAIDscarrysignificantGIandCVrisk
FINDNEWTHERAPYWITHVARIOUSTARGETS
Cellulartherapy ofrheumatic diseases.EULARText Book2012
Whatisastemcell?
CharacteristicsofMesenchymalStemCells(MSC)
• MSC are defined by :• Adherence to plastic• Fibroblast like morphology• Differentiation potential : fat, bone, cartilage• Phenotype characteristics :
• Negative : CD11b, CD14, CD34, CD45• Positive : CD90, CD105, CD73, ….
• Enhance hematopoietic stem cell engraftment• Tissue reconstitution• Immuno supressive properties• Self-renewal
Selfrenewal
Differentiation
Migration
Releaseofgrowthfactorsandanti-
inflammatorymolecules
Tissueregeneration
CartilageMuscleBoneAdipose
Functionsofstemcells?
Immunecellshomeostasis
Bone marrowhematopoietic niche
preventapoptosis
preventfibrosis
tissuehomeostasis
Functionsofstemcells?
WherewecanfindMSC– “stromalcells”?
De Girolamo L. Knee Surg Sports Traumatol Arthrosc 2016
McGonagle D. Nat Review Rheum. 2017
WherewecanfindMSC– “stromalcells”?
Jiang and Tuan., Nat Review Rheum. 2015
• Spontaneousrepairofcartilagedefectsafterrealignmentosteotomyorjointdistraction
• Localjointresidentstromalcells?
WherewecanfindMSC– “stromalcells”?
Targetinglocalprogenitorscells?
Johnson K. Science 2012
• Kartogenin promoteschondrocytedifferentiationofMSC• Modelofcartilagerepairstrategy
Maumus M, Biochimie. 2013
WhyMSCmakesensesinOA?
§ Synoviocytes orchondrocyteswereco-culturedinmonolayerwithASCfor7days
§ Synoviocytes:ASCssignificantlydown-modulatetheexpressionofIL1β,IL6andIL8
§ Chondrocytes:ASCsignificantlydecreasedIL1β,IL6,MMP13,MCP-1andMIP-1α
Manferdini et al. Arthritis and Rheumatol. 2013
• EffectofASConsynoviocytes andOAchondrocytes
15
ProofofconceptMSCinOA
Collagen I expression Collagen III expression
Col
I ex
pres
sion
(fol
d ch
ange
)
0.0
0.5
1.0
1.5
2.0
****
ChondrocytesASC
aHGF-AbIsotype control
+ + + + +
+- - - -+ + +- -
+-- - -rhHGF (50ng/mL) -- - - +
Col
III e
xpre
ssio
n(f
old
chan
ge)
0.0
0.5
1.0
1.5
2.0
*** *
ChondrocytesASC
aHGF-AbIsotype control
+ + + + +
+- - - -+ + +- -
+-- - -rhHGF (50ng/mL) -- - - +
Maumus M et al. Stem cell Res. 2013
HG
F co
ncen
tratio
n (p
g/m
L)
0
50
100
150
200
ND
Chalone
ASCalone
Co-culture
HG
F ex
pres
sion
(2-D
CT)
0.00
0.01
0.02
0.03
0.04
0.05
Ch Ch-co
ASC
*
ASC-co
HGF induction
ASCmaintainchondrocytephenotypeandpreventchondrocytehypertrophyHGFisakeyfactorforthisparacrineeffect
• HGF-mediatedparacrineeffectofASCsonchondrocytes
16
ProofofconceptMSCinOA
Luz-Crawford P et al. Stem cells 2015
§ ActivatedMSCexpressIL1RA§MSCdecreasemonocyteactivation
Macrophages MSC WT MSC IL1RA-/-0
500
1000
1500
pg
/ml (
TN
F-α
)
*
Macrophages MSC WT MSC IL1RA-/-0
100
200
300
400
pg/
ml (
IL-1
0 )
*
TNFa IL10
C I A M S C W T M S C I L 1 R A - /-0
5 0
1 0 0
1 5 0
2 0 0
2 5 0
pg
/ml
(IL
-1b)
*
*
IL1b
• MSCswitchmonocytes/macrophagessubsetsthroughIL1RA
ProofofconceptMSCinOA
MSC
monocytes
IL1RA
IL1b M2polarisation
ê TNFaé IL10ê CD4Tcellsê Bcellsurvival
IFNgTNFaIL1b
CD4
§MSCinduceM2polarisationinvitrothroughIL1binhibition§ SupernatantsfromcocultureofmacrophagesandMSCsinhibitstheproliferationofT-cells
Luz-Crawford P et al. Stem cells 2015
• MSCswitchmonocytes/macrophagessubsetsthroughIL1RA
18
ProofofconceptMSCinOA
• SingleinjectionofASCsintotheknee-jointatanearlyorlatetimepointafterinductionofOA(Collagenasemodel)
Collagenase injection ASC
injection
Mice sacrificedfor Histology
d0 d14 d42d-7 d-5
• ASCswereisolatedfromfatsurroundingtheinguinallymphnodes(Toulouse:LouisCasteilla)
• ASCswerecharacterizedonMSC-markers§ ASCsstainedpositiveforCD105,CD44andSca-1§ andnegativeforCD11b,CD34andcKit§ ASCs(2.104)wereunilaterallyinjectedintotheOAknee-jointin6µL
Ter Huurne and Van Lent P et al. Arthritis and Rheumatol. 201219
ProofofconceptMSCinOA
• Collagenase modelinBalb/c• Day-7,ASCtreatmentatday 0
n=10pergroup* p<0.05
0
5
10
15
20
25
Lat Tibia Lat Femur Med Femur
Med Tibia Mean
d42
Ctrl
ASC
* *
0
5
10
15
20
25
Lat Tibia Lat Femur Med Femur
Med Tibia Mean
d14
*
CartilageDestruction
* *
MedFemur
MedTibia
d42Ctrl ASC-treated2independentexperiments
Ter Huurne and Van Lent P et al. Arthritis and Rheumatol. 2012
ProofofconceptMSCinOA
• Collagenase OAmodelatday -7,ASCtreatmentatday 0
*
n= 10 per group* p< 0.05
d14 d42
Synovial activation
Ctrl ASCCtrl ASC
0.0
0.5
1.0
1.5
2.0
2.5
Syno
vial
act
ivat
ion
(arb
itrar
y sc
ore)
*
Day 42
!"#$%&'(")(*)+,-.)'"&()&/$)0"$$)#('"&)1&)213)4)1*&$5)6+)'"27%&'(").7885$..$.)(.&$(8/3&$)*(591&'(")1&)213):;)1*&$5)&5$1&9$"&)
Osteophyte formation
CtrlASCs
0
1000
2000
3000
4000
Ost
eoph
yt s
urfa
ce (
um2)
Day 14 Day 42
F
T
control F
T
ASC
Osteophyte formation in time
* p< 0.05
*
Collagenase-induced OA
Ter Huurne andVanLentPetal.ArthritisandRheumatol.201221
ProofofconceptMSCinOA
ASC ASC
ASC
3T3
24 hrs after injection:105 ASC
ligaments
Draining lymph nodes
JS
JS
ASC
Ter Huurne andVanLentPetal.ArthritisandRheumatol.201222
ProofofconceptMSCinOA
0
4
8
12
16
20
24
CN 2.106ASC 6.106ASC
Follow-up:8 weeks
* ^^L
averty’sscore
*
4%RSA 2x106 ADSC 6x106 ADSC0
4
8
12
16
20
24
4%RSA 2X106ASC 6X106ASC
Follow-up:16weeks
4%RSA 2x106 ADSC 6x106 ADSC
*
*Laverty’sscore
100 μm 100 μm 100 μm 100 μm
2 x10 6 ADSCs4 % RSAOA 6 x10 6 ADSCs
100 μm 100 μm 100 μm 100 μm
F.up= 8 weeks
F.up = 16 weeks
At16weeks:ØIncreasecartilagethickness:
+18.4%group2.106+21%group6.106
ØReductioninLavertyscoreØReductioninostophytevolume:
36± 2group2.10630± 2group6.10659± 2CT
NZWrabbitOAmodelwithASC
Desando Getal.ArthritisRes.Ther.201323
ProofofconceptMSCinOA
Day11
Day29
Day86
DetectionofhumansequencesbyFISHanalysis
Toupetetal.Arthritis andRheumatol.201324
ProofofconceptMSCinOA
Invivomechanisms
Protectioncartilage
Osteophyteformation
Inflammation(TNF-α,MMP-1)
Synovitis
Invitromechanisms
Inflammation(IL-1,IL-6,IL-8,MMP-13)
Apoptosis
Fibrosis
CTR ASC
Pers YM et al. HMBCI 2016
ASCareeffectiveinOA
• RegisteredClinicaltrialsofMSCbasedtherapyonClinicalTrials.gov
Phase I31%
Phase II50%
Phase III 15%
Phase IV 4%
Myocardial infraction 23%
GVHD 16%
Diabetes10%Liver cirrhosis
10%
Spinal Cord injury9%
OA 8%
CDMSRA SLE Others
§ Major stem cell used for cell therapy§ Easily isolated and successfully expanded§ large therapeutical applications§ Development of large scale GMP production
From Xin Wei et al. 2013
MSCbasedtherapyinhumans
MSCbasedtherapyinhumans
GVHDImmunedisorders
- Lupus- Arthritis
- Sjögrensyndrome- SystemicSclerosis- Multiplesclerosis
- IBD- Diabetes
TissueRepair- Bone
- Cartilage- Osteoarthritis
Angiogenesis- Ischemic cardiopathy
- Limb ischemia- Stroke
Trophic effect- Skinhealing- Scleroderma
MSCbasedtherapyinhumans
lipoaspiration
ADSCisolation/expansionGMPconditionsCellviabilityReleasecriteria/toxicology
Intra-articularinjectionsSyringe,differentdoses
Evaluation:phase1trialsafety,doseresponseclinicalevaluation(WOMAC…)MRIGemric,
ADIPOAclinicaltrial
Qualitycontrols:§Sterilitytestday8§Endotoxintestday11§Mycoplasmatestday11§Karyotypeperformedon20cultures.Allarenormal.
Releasecriteria:§Cellviability>80%,§CD45+/CD14+cells<5%,§CD90+orCD73+cells>80%§ AbsenceofexpressionofhTERTandOct-4attheendoftheprimaryculturetoassessgenotypestability.
ADIPOAclinicaltrial:cellproduction
ADIPOAclinicaltrial:fatharvesting
AdiposederivedStromalCellsforOsteoArthritis treatment.Aphase1study,bi-centric(Mtp,Wurzburg),doseescalatingstudy
withautologousASCinseverekneeOA(>3K/L)
MRI
Adiposetissue
collection
ASC injection
Arthroscopy + MRI
– 35d - 14d Baseline W1 M1 M3 M6
Clinical assessment
ADIPOAclinicaltrial:design
Pers YM et al. SCTM 2016
48 patients assessed for eligibility
18 consecutively enrolled to receive autologous ASCs
6 received 2 x 106 cells(Low-Dose)
6 received 10 x 106 cells(Mild-Dose)
6 received 50 x 106 cells(High-Dose)
No patients lost to follow-up
6 patients analysed
No patients lost to follow-up
6 patients analysed
No patients lost to follow-up
6 patients analysed
ADIPOAclinicaltrial:design
Pers YM et al. SCTM 2016
• Primarygoal:safety ofasingleinjectionofautologousadiposederivedstemcellsonpatientswithsevereosteoarthritisoftheknee
• Secondaryobjectives:• shorttermefficacyofasingleinjectionofautologousadiposederivedstemcellsonpatientswithsevereosteoarthritisoftheknee
• Besttolerateddose
ADIPOAclinicaltrial:design
Pers YM et al. SCTM 2016
• n=18• 60%ofpatientswerewomen• Age:64.6years• MeandurationOAwas10.8(± 6)years• MeanstageKL:83.3%stageIVand16.7%stageIII• InitialtotalWOMACscore:48.9(± 18.07)• MeaninitialpainVASscore:61.47(± 12.52)
ADIPOAclinicaltrial:patientscharacteristics
Pers YM et al. SCTM 2016
01020304050607080
Baseline 1 Week 3 Months 6 Months
Low Dose
Mild Dose
High Dose
0102030405060708090
Baseline 1 Week 3 Months 6 Months
Low DoseMild DoseHigh Dose
VAS pain score
KOOS Questionnaire
0
5
10
15
20
25
30
35
Baseline 1 Week 3 Months 6 Months
Low Dose
Mild Dose
High Dose
SAS score
ADIPOAclinicaltrial
Ø Safeprocedure:4localskinreactioninthefirstmonth
Ø Only2patientsunderwentsurgeryTKAafteroneyearfollow-upand55%after4years
36Pers YM et al. SCTM 2016
Ø dGEMRIC indexincreasein3outof6selectedpatients
Ø Suggestapossiblestructuraleffect
ADIPOAclinicaltrial:structuralassessment
Pers YM et al. SCTM 2016
Courtesy F Barry
Functionsofstemcells?
Tyndal A. Nat Review Rheum. 2013
• MSCcoordinateimmunecellssuchasa“maestroconductor”
Functionsofstemcells?
§ HLAG5nonclassicHLAclassImolecule,expressedbytrophoblastandhumanMSC
§ IL10andLIFinduceHLAG5expressionbyMSC
§ MSCaddedtoMLRinducedfunctionalCD25+foxp3+Tcells
§ HLAG5inhibitionpreventedTreg induction§ Cell:cell contactiscriticalastranswellpreventedTreg induction
CD4
CD25
MSCinduceTregs throughHLAG5
Selmani et al, Stem cells, 2008
§ BMMSCpreventedlethalsepsis§ PrimedMSCdecreaselunginflammationthroughmonocytesinteractionö IL10ø TNFa,IL6§MSCactivatedthroughTNFa,TLR4§ InteractionsmediatedthroughPGE2
Nemeth, Nature med 2009
MSCinhibitmacrophagesthroughPGE2
TBTreg
M1
PNNM2
Reduce INFLAMMATIONIMMUNEREGULATION
NO, VEGF, PGE2, TSG6, CCL2, IL-10, PDL-1, HO1,
TGFβ1, HGF, HLA-G5
• Which immune cells populations in blood are affected by MSC treatment ?
o Numbero Activation status
• Is there any effect on « target » cells ?
• Are there any surrogate marker for clinical response ?
ADIPOAclinicaltrial:immunemonitoring
Pers YM et al. Theranostics 2018 (in press)
T 4.Treg induction ?• Number• Activation markers
B 3. Alteration of B cells ontogeny?• Maturation markers•Surface Ig (class switch) • Regulatory B cells
1. Alteration of monocyte compartment ?• Subsets
2. Alteration of DC compartment ?• Subsets
1 platform involved8 colors panels with up to 19 various antibodies in the same tubeCANTO II analyser
Pers YM et al. Theranostics 2018 (in press)
ADIPOAclinicaltrial:immunemonitoring
Phase 1 conducted between March 2012 and December 2014Prospective, single-arm, open-label18 patientsDose escalatingLow dose (n=6): 2x106 ASC IA injection (5 ml)Medium dose (n=6) : 10x106 ASC IA injection (5 ml) High dose (n=6): 50x106 ASC intra-articular injection (5 ml)
Bi centric- Universität Würzburg, GERMANY (7 patients)- CHU Montpellier, France (11 patients)
Pers YM et al. Theranostics 2018 (in press)
ADIPOAclinicaltrial:immunemonitoring
Harmonization of blood collection Harmonization of blood specimen age prior to staining (max 24hrs)SOP for PBMC preparation and cellular staining
Blood specimen are collected before and after MSC therapy (D0, D7, M1, M3)
Pers YM et al. Theranostics 2018 (in press)
ADIPOAclinicaltrial:immunemonitoring
CD25+CD127lowFoxP3+in CD4+CD25+FoxP3+inCD4+
D0 D7 M1 M3 D0 D7 M1 M3
Group 1Group 2Group 3
Pers YM et al. Theranostics 2018 (in press)
ADIPOAclinicaltrial:immunemonitoring
SignificantincreasedinCD25highCD127lowFoxP3+ inCD4
• Treg lymphocytessubsets
• Safety of I.A. injection of ADSCs
• Global switch towards regulatory immune cells
- increased percentage of Treg cells similar results obtained in GVHD and fistulising Crohn disease
- increased percentage of Breg-containing subset
- decreased percentage of classical pro-inflammatory monocytes
• Longer term effect on the immune response?
ADIPOAclinicaltrial:immunemonitoring
ParacrinefactorsproducedbyMSCs
RegulationofimmunecellsfunctionsbyMSC-derivedmiRNAs
IdentificationofmiRNAsinvolvedintheregulationofMSCsuppression
• Firststep:TAC(Taqman ArraysCard)• HumanMSC± PBMC(MLRTranswell)• N=3donors• CellsactivatedbybeadsCD3-CD28• CollectRNAatDay3• 384miRNA ineachcard• 8sampleloadingport(48well)• RT-PCR• SoftwareSDSforanalysis• 2pools
• A=miRNA broadlyexpressed,optimization• B=newmiRNA,lessstudied
IdentificationofmiRNAsinvolvedintheregulationofMSCsuppression
• TACPoolAanalysisØ Volcano-plotwithupregulatedmiRNAingreen
(n=13)anddownregulatedmiRNAinred(n=3)Ø Belowthebluelinep=NSØ Threshold:FoldChange>2
IdentificationofmiRNAsinvolvedintheregulationofMSCsuppression
• Second step: Real Time qPCR validation of the three upregulated miRNAs• Human MSC ± PBMC• N ≥ 4 different donors• Cells activated by BEADS CD3-CD28/PHA• Immunosuppression assay CFSE/ CTV analysis
BM-MSCs
Activated lymphocytes Fresh Blood
Healthy donor
RatiosMSC:PBMC
1:5
Co-culture Day 4Beads
BM-MSC 119Ratio 1:5
BM-MSC 122Ratio 1:5
IdentificationofmiRNAsinvolvedintheregulationofMSCsuppression
TAC
up-
regu
late
d
*p<0,05**p<0,01
IdentificationofmiRNAsinvolvedintheregulationofMSCsuppression
• Second step: Real Time qPCR validation of the three upregulated miRNAs• Human MSC ± PBMC• N ≥ 4 different donors• Cells activated by BEADS CD3-CD28/PHA• Immunosuppression assay CFSE/ CTV analysis
• TransfectionMSCwithpremiR• Ourhypothesis:
EnhancingMSCimmunosuppression
miRNAupregulated
DecreasePBMCproliferation
ValidationofthefunctionalroleofmiRNAsinMSCimmunomodulation
PHAStimulatedPeripheral blood
mononuclear cell (PBMC)
• TransfectionMSCwithpremiR
DAY0CultureofhBM-MSC
DAY1Transfectionwith premiR
orantagomiR
Oligofectamine andpre/antago-miR mix
DAY2Coculture ofhBM-MSCandPBMC
DAY61)Verification oftransfectionbyRT-qPCR2)Determination ofPBMCproliferation
" CellTrace™Violetlabeling&flowcytometryanalysis
Transfected hBM-MSCover/down-expressing a
candidatemiRNA
ValidationofthefunctionalroleofmiRNAsinMSCimmunomodulation
• Transfection MSCwithpremiR (gainoffunction)• Focusonup-regulatedmiRNAs• Oligofectamine• TaqMan premiR-Ctrl,premiR-29a,premiR-146a,premiR-155(50nM)
è Efficacy of MSC Transfection with oligofectamine (500 to 10 000 fold)
ValidationofthefunctionalroleofmiRNAsinMSCimmunomodulation
• TransfectionMSCwithpremiR• CONTACTPHAPBMC/MSC,96-wellplate(Ratio1:10)• ComparisonPBMCproliferationw/womiRNAupregulation
è InhibitionofTcellproliferationissignificantlyhigherafter premiR MSCtransfectionofmiR-29aandmiR-155
*p<0,05
ValidationofthefunctionalroleofmiRNAsinMSCimmunomodulation
• ParacrinefactorsproducedbyMSCafterpremiR-29atransfection• MSCSupernatant(ELISA):Day4co-culture• RT-PCRwith MSC(ARNm):Day4co-culture
èTGBbetapathwayregulation?
ValidationofthefunctionalroleofmiRNAsinMSCimmunomodulation
• ParacrinefactorsproducedbyMSCafterpremiR-155transfection• MSCSupernatant(ELISA):Day4co-culture• RT-PCRwith MSC(ARNm):Day4co-culture
èIL-6andPGE2inhibition
ValidationofthefunctionalroleofmiRNAsinMSCimmunomodulation
• Affymetrix®microarray• TransfectionMSCwithpremiR andantagomiR formicroRNAsupregulated(29a,146aand155)
• MSC=1donor• Aim:identifymRNAsthatarebothupregulatedwithantagomir anddownregulatedwithpremir usingaFCthreshold:
• mRNAdownregulatedwithpremir /pCT (FC<-1.5)• mRNAupregulatedwithantagomir /aCT (FC>1.5) Mergeforanalysis
IdentificationofthemRNAtargetsoftheselectedmiRNAs
IdentificationofthemRNAtargetsoftheselectedmiRNAs
• miR-29aandmiR-155targetsPSAT1?
• PSAT1:targetofmiR-29a?– RT-qPCRwithMSC(ARNm)Day4coculture(n=3MSC)
PSAT1maybeatargetofmiR-29aNosignificantdownexpressionaftertransfectionwithpremiR-146aand-155
IdentificationofthemRNAtargetsoftheselectedmiRNAs
• PSAT1:targetofmiR-29a?– TransfectionsiRNAPSAT1– ReducePBMCproliferation
IdentificationofthemRNAtargetsoftheselectedmiRNAs
PSAT:cellproliferationforSerine/Glycin metabolism
Synthesis
miR-29aandPSAT1arenewfactorsmodulatingMSCimmunosuppressivefunctions
Extracellularvesicles(EVs)derivedfromMSC:afutureoption?
Extracellularvesicles(EVs)derivedfromMSC:afutureoption?
Extracellularvesicles(EVs)derivedfromMSC:afutureoption?
Extracellularvesicles(EVs)derivedfromMSC:afutureoption?
BM-MSC-derived MPs andExosprotected mice from osteoarthritic damagesinthecollagenase-induced OAmodel.
Cosenza S et al. Sci Report 2017
SenescenceandOA
Childs BG et al. Nat Review 2017
SenescenceandOA
McCulloch et al. Aging Cells 2017
ChondrocytesenescenceinOA
Loeser R. et al. OAC 2009
SenescenceandOA
McCulloch et al. Aging Cells 2017
• Chondrocyteskeyplayer• BalanceECMsynthesisanddegradation• Mechanicalstressinducesenescence• Expressionsenescentmarkers• SASP(VEGF,IL1,MMP3,MMP13,IL6)
• Protectiveeffect• Cancer• Skintissuerepair/woundhealing
Senolytics andOA
Hee Jeon O et al. Nat Med 2017
Ganciclovir(selectivekillingofp16-INK4A)reducesOApost-traumaticdevelopment
Senolytics andOA
UBX0101(selectiveclearanceofSNC)attenuatesOApost-traumaticdevelopment
Hee Jeon O et al. Nat Med 2017
Senolytics andOA
Pellets3DhumanchondrocytesUBX0101reduceslevelsofSNCspromotingachondrocytephenotype
Hee Jeon O et al. Nat Med 2017
Senolytics andOA
Childs BG et al. Nat Review 2017
• PreclinicaldatasupportefficiencyofMSCinOA• FirststepforASCbasedtherapyinosteoarthritis• LogisticsvalidatedatEUlevel• Proceduresafe• Optimaldosecloseto2.106 ASC• SystemictoleranceinducedafterlocalIAinjection• Next:ADIPOA2,randomizedcontrolledtrialendin2019
Conclusions
10 CLINICAL CENTRES with 15 patients each / 3 PRODUCTION PLATFORM•1. IRELAND, NUIG (F. Shannon) •2. IRELAND SSC (R. Moran),•3. UK CAM (A. McCaskie)•4. NETHERLANDS RUMC (F. van den Hoogen)
•5. ITALY, IOR (R. Meliconi), •6. ITALY, UHP (R. Ramonda) •7. EWK (U. Nöth) GERMANY
•8. MONTPELLIER, CHUM (C. Jorgensen)•9. TOULOUSE, CHUT (A. Cantagrel),•10. PARIS, APHP (F. Berenbaum) FRANCE
NUIG 40 batches
EFS 30 batches
UULM 30 batches
• AphaseIIb,multi-centre,prospective,randomized,double-blindstudy,comparingculture-expandedautologousASCwithplacebo
• 3armstoatotalof153 patientsandfollowedupfor25months(1monthbeforeand24monthsafterkneeinjection)
• Durationofrecruitmentforeachcentre:12monthsTreatment group Dose Frequency Number of patients
Group 1 2.106 ADSC Single injection 51
Group 2 10.106 ADSC Single injection 51
Group 3 Vehicle Single injection 51
!
• PreclinicaldatasupportefficiencyofMSCinOA• FirststepforASCbasedtherapyinosteoarthritis• LogisticsvalidatedatEUlevel• Proceduresafe• Optimaldosecloseto2.106 ASC• SystemictoleranceinducedafterlocalIAinjection• Next:ADIPOA2,randomizedcontrolledtrialendin2019• Next:Allogeneic,EVs,senolytics ?
Conclusions
ADIPOA
MontpellierRosannaFerreira PascalePlenceMarieMaumus FaridaDjouadKarineToupet ClaireBonyDanièleNoël PLuz-CrawfordChristianJorgensen
GalwayFrankBarry
Würzburg– BerlinUlrichNoeth