1mpeschanski@istem.fr

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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

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Modélisation pathologique et pharmacologie

Cellules souches pluripotentes humaines mutées

Thérapie cellulaire de substitution

Cellules souches pluripotentes humaines saines

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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

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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

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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

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Protocols (in vitro)

Clinical grade

protocol

Cell biology (in vitro)

Function (in vivo)

Safety

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Bulk cellproduction

Banking

Differentiation

Regenerativemedicine

QC

Olivier Chose/Pauline Georges

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13

ES/iPS cell lines

PGD embryo / donor

Adapted from Vogel, Science 2010

Un paradigme expérimental qui commence à porter ses fruits

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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

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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

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Un exemple à I-Stem: Progeria

Xavier Nissan’s team

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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

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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

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Réaliser “à l’aveugle” des criblages à haut débitde chimiothèques de composés

Johana Tournois/Gurvan Mahé

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Viser une altération moléculaire: e.g. la farnésylation de la prélamine A

Les aminopyrimidines inhibent la farnésylation

Blondel et al., 2015 Cell Death Dis

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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

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