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Cellules souches embryonnaires humaines
(hES)Blastocyste
Embryon surnuméraire(diagnostic préimplantatoire)
Fécondation in vitro
Cellules souchespluripotentes induites
(hiPS)
Reprogrammation
Biopsie de donneur adulte
Gènes
Cellules de biopsie
3
Modélisation pathologique et pharmacologie
Cellules souches pluripotentes humaines mutées
Thérapie cellulaire de substitution
Cellules souches pluripotentes humaines saines
4
5
NCT Principal Investigator Sponsor Product Phase Indication Design Primary
ObjectiveStatus as in
Q1 17 Start End est. subect nbr
Countries / Centers
JPRN-UMIN000011929UMIN000011929
Masayo TAKAHASHIi
RIKEN Center for the development Biology
Kobe Institute
Monolayer of autologous iPS derived RPE cells in
a sheetI Exudative age-related
macular degeneration
Non-RandomizedSingle group Assignment
Open labelDose escalation in sequential cohort
Safety Discontinued Aug-13 2 JapanMonocentric
Masayo TAKAHASHIi
RIKEN Center for the development Biology
Kobe Institute
Monolayer of alogenic iPS derived RPE cells in
a sheetI Exudative age-related
macular degeneration
Non-RandomizedSingle group Assignment
Open labelDose escalation in sequential cohort
Safety Recruiting Apr-171er patient
implanté en avril 2016
JapanMonocentric
iPS
Essais cliniques de thérapie cellulaire fondés sur des dérivés de cellules souches pluripotentes
humaines
6
NCT Principal Investigator Sponsor Product Phase Indication Type Design Primary Objective Status Start End Subec
t nbrCountries /
Centers
NCT02239354 ViaCyte
VC-01 =- PEC-01
pancreatic Beta cell precursors- Encaptra drug delivery system
I/IIType I
Diabetes Mellitus
Interventional
Non-randomizedSigle group assignment
Open lael
Recruiting Sep-14 Aug-17 (est) 40
USA, California, San Diego
(multicentric)
NCT02057900 Philipppe MÉNASCHÉ APHP
hES cell-derived DC15+ Isl 1+ progenitors
IIschemic
Heart Disease
Interventional
Single group assignmentOpen Label
- Number and nature of adverse events within the first year after surgery- Evidence for new clinical/biological abnormalities, occurrence of arrhytmias or development of a cardiac or extra-cardiac tumor
Jun-13 Jun-18 (est) 6 France
Single center
NCT01344993Medical Directoir Astellas
Astellas hESC-RPEMA09-hRPE I/II
Dry Age Related Macular
Degeneration
Interventional
Single group assignmentOpen Label
Safety of hESC derived RPE cells Published Apr-11 Apr-15 13 USAMulticentric
NCT01345006 SCHWARTZ Astellas hESC-RPEMA09-hRPE I/II
Stargardt's Macular
Dystrophy
Interventional
Single group assignmentOpen Label
- Safety and tolerence of transplantation Published Apr-11 Apr-15 13 USAMulticentric
NCT01469832 Astellas hESC-RPEMA09-hRPE I/II
Stargardt's Macular
Dystrophy
Interventional
Single group assignmentOpen Label
- Safety and tolerence of transplantation Published Nov-15 Sep-15 12 UKMulticentric
NCT02122159 OCATA Therapeutics
hESC-RPEMA09-hRPE I/II
Myopic Macular
Degeneration
Interventional
Single group assignmentOpen Label
The transplantation of hESC-derived RPE cells MA09-hRPE will be considered safe and tolerated in the absence of:- Any grade 2 (NCI grading system) or greater adverse event related to the cell product- Any evidence that the cells are contaminated with an infectious agent- Any evidence that the cells show tumorigenic potential
Mar-13 Jul-16USA
UCLA
NCT01674829CHABiotech CO = filiale Ocata Ther
hESC-RPEMA09-hRPE I/II AMD Interventi
onal
Single group assignmentOpen Label
- Safety of hES cell derived RPE cellsThe transplantation of hESC-derived RPE cells will be consider safe in the absence of:- Any Grade 2 or greater event related to the cell product- Any evidence that cells are contaminated with an infectious agent- Any evidence that the cells show tumorigenic potential
Aborted Sep-12 Avortée aug-12 12
Republic of Korea
Single center
NCT02286089Cell Cure
Neurosciences Ltd
hESC-RPEOpRegen I/Iia Progressive
dry-AMDInterventi
onal
Single group assignmentOpen Label
Safety and tolerability of OpRegen Apr-15 Sep-17 15 IsraelSingle center
NCT01691261 Peter COFFEY Pfizer
PF-05206388: hESC-RPE on a
polyester membrane
I/Iia Progressive Wet AMD
Interventional
Single group assignmentOpen Label
- Incidence and severity of adverse events- Change in baseline in ETDRS best corrected visual acuity (BCVA) - Proportion of subjects with an improvement of 15 letters or more at Week 24
May-15 Mar-17 supended 2/10
UK University colllege London
Moorfields
NCT02302157
Asterias Biopharmace
utics (ex-Geron)
AST-OPC1 I/II
Cervical Sensorimotor
Complete Spinal Cord
Injury
Interventional
Non-RandomizedSingle group AssignmentOpen label
Dose escalation in sequential cohort
Safety Finished Oct-10Jul-13
Discontinued
5/15 USA multicentric
NCT02590692
Regeneraive Patch
Technologies LLC
CPCB-RPE1 (hESC-RPE on a
parylene membrane)
I/IIa
Advanced Dry AMD w/
geographic atrophy
Interventional
Open label, 2 successive cohorts
safety: adverses event, comparison of both eyes (product,procedure,
immunosuppression)Recruiting Oct-15 sept-22 10+10 USA (CA)
multicentric
ES
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Current production of primary adult keratinocytes epidermis
Stem Cells, 2010Christine Baldeschi’s team
8
hESC Functional epidermis
Novembre 2009
Keratinocytes
Tout commence par une recherche fondamentale qui débouche sur un résultat exploitable
9The Lancet, 2009
Immunodeficient miceArtificial Skin
Graft
10
Protocols (in vitro)
Clinical grade
protocol
Cell biology (in vitro)
Function (in vivo)
Safety
11
Bulk cellproduction
Banking
Differentiation
Regenerativemedicine
QC
Olivier Chose/Pauline Georges
12
13
ES/iPS cell lines
PGD embryo / donor
Adapted from Vogel, Science 2010
Un paradigme expérimental qui commence à porter ses fruits
14
Un exemple à I-Stem : la myotoniedystrophique (Steinert)
Foci and MBNL1 colocalization
DAPI
(CUG)n MBNL1
DAPI / (CUG)n / MBNL1
Insulin receptor α-subunit splicing
IR-B (+ex11)
IR-A (-ex11)
WT DM1
MPCs
Marteyn et al. Cell Stem Cells 2011
foci
INSRTNNT2CLCN1 ….
Splicing defects
Cécile Martinat’s team
Des mécanismes pathologiques connus sont retrouvésdans les cellules dérivées de cellules souches
15
L’exploration des cellules souches permet de révéler des mécanismes pathologiques ignorés
Gene under expressed in VUB03_DM1
Gene Title Gene
Symbol
Chr
Number
Fold
change
hES NPC MPC
zinc finger protein 37a (KOX21) ZNF37A chr10 3,78 11,85 10,71PSMD5 chr9 8,34 3,21ZNF248 chr10 54,62
SLITRK4 chrX 20,84EPHA5 chr4 22,36
PRRX1 chr1 9,22NAPRT1 chr8 7,72RPL31 chr2 6,17
Fold
change
Fold
change
Proteasome 26S subunit, non ATPase
zinc finger protein 248
SLIT and NTRK-like family, member 4
EPH receptor A5
Paired related homeobox 1
Nicotinate phosphoribosyltransferase 1
Ribosomal protein L31
Gene over expressed in VUB03_DM1
Gene Title Gene
Symbol
Chr
Number
Fold
change
hES NPC MPC
Fold
change
Fold
change
trafficking protein particle complex 3 TRAPPC3 chr1 2,61 3,20
cathepsin B CTSB chr8 2,09 3,17
maternally expressed 3 gene MEG3 chr14 8,79 90,57
NAD(P)H dehydrogenase, quinone 2 NQO2 chr6 5,16 3,08
interleukin 13 receptor, alpha 1 IL13RA1 chrX 5,41
EIF2S3 chr12 2,57
PRICKLE1 chr12 2,92
Eukaryotic translation initiation factor 2
Prickle-like 1 (Drosophila)
a
a
aa
a
SLITRK DM1normal
L’extinction du gène SLITRK dans un neurone normal provoque une pousse
aberrante des prolongements…
… et diminue le nombre de contacts synaptiques
16
17
Un exemple à I-Stem: Progeria
Xavier Nissan’s team
18
Explorer l’action de médicaments connus
*
*
Des traitements agissent sur certaines anomalies, d’autres sur d’autres
Blondel et al., Stem Cells Trans Med 2013
19
Confirmer l’intérêt de composés identifiés sur la base d’hypothèses mécanistiques
1824C>T
SRSF1
Metformin
En agissantindirectement sur la maturation de l’ARN, la metformine réduitla production de protéine toxique
Egesipe et al., Aging and Mech Dis 2016
20
Réaliser “à l’aveugle” des criblages à haut débitde chimiothèques de composés
Johana Tournois/Gurvan Mahé
21
Viser une altération moléculaire: e.g. la farnésylation de la prélamine A
Les aminopyrimidines inhibent la farnésylation
Blondel et al., 2015 Cell Death Dis
22
Tipifarnib 3µM
Positive Control
DMSO 0.1%
Negative Control
ATRA 13Cys Ret
L’acide rétinoïque régularise le rythme de formation du tissu osseux
Lo Cicero et al., Scientific Rep 2016
Ou encore viser une altération fonctionnelle: e.g. l’ostéogenèse prématurée
23
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