ex vivo gene delivery for stem cells of clinical interests using
DESCRIPTION
Specific Targeted Research or Innovation Project. Ex vivo gene delivery for stem cells of clinical interests using synthetic processes of cellular and nuclear import and targeted chromosomal integration SyntheGeneDelivery 2006-2008. LEPG. 2.4 M €. Equipe Edward Smith (Suède) - PowerPoint PPT PresentationTRANSCRIPT
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Ex vivo gene delivery for stem cells of clinical interests
using
synthetic processes of cellular and nuclear
import and targeted chromosomal integration
SyntheGeneDelivery2006-2008
Specific Targeted Research or Innovation Project
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LEPG
2.4 M €
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Vecteurs synthétiques : SyntheGene Transfert
Equipe Dominique Wells (Angleterre)
Equipe Ronald Chalmers (Angleterre)
Transfection ex vivo de cellules souches dans un cadre de thérapie génique
Equipe Edward Smith (Suède)
Bioplexe (PNA ciblage au noyau)
Equipe Yves Bigot (France)
Vecteur d’intégration site spécifique
Equipe Bruno Pitard (France)
Vecteur d’administration Lipoplexe-Block copolymère
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SyntheGeneDelivery
Non-viral systems for ex-vivo gene transfer
Transposon-based system
Improved to bypass the biological barriers of the cell
Site directed gene integration
Safety is our leitmotiv…
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SyntheGeneDelivery
Transposon-based system :
Mariner Mos1
Transposase gene5’ITR 3’ITR
?
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Mos1
Mariner
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Mos1
• ITR de 28 pb• 4 différences entre ITR5’ et ITR3’• Gène sans intron codant la Tnp (345 acides aminés)• Autonome
ADN de 1286 pb
ITR5’ ITR3’
UTR5’ UTR3’ORF Transposase TATA
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ATG
Mos1
Transcription du gène codant la Tnp ?
ITR5’ ITR3’UTR5’ UTR3’
ORF Transposase TATA
polyA
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Mos1
Transcription du gène codant la Tnp ?
ITR5’ ITR3’UTR5’ UTR3’
ORF Transposase TATA
polyA
ITRMos1 mRNA
Petit et al. 2006
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Mos1
Traduction du messager codant la Tnp ?
Domaine de liaison à l’ADN
3-D non connue
Domaine Catalytique
3-D connue
HTH
D D 34 D 1 345
MgCl2 ou MnCl2
Hélice
Feuillet
Richardson et al. 2006
La Tpase est nécessaire et suffisante pour la transposition
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Qu’est ce que l’on sait sur HTH et ITR
ITRpalindrome
mirror Site symétrique
33
Liaison
Courbure
CRO, CRP, répresseur
Famille des protéines HTHHomodimère
Hardwidge et al., 2002
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Fonctionnement de la transpositionFonctionnement de la transposition
mirror
palindrome
66
Capacité de courbure
In silico data
http://hydra.icgeb.trieste.it/dna/bend_it.html
ITR seul
Courbé rigide
Point de flexibilité
Méthode aléatoire
Fixation asymétrique du dimère de transposase1/2 site différent ?
ITR + Tnp
1 2 3 4 5 6
Freeprobe
Probes
SEC2SEC1
Permutation circulaire
ITR5’= ITR3’
Angle 90°
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83 kDa
160 kDa
kDa225
100
150
75
WT (1-345)
0 5 15 30 60 C
minutes
MONOMERE dimère
HTH
D D 34 D
cis-dimérisation monomère / dimère
Qu’est ce que l’on sait sur le comportement de Mos1
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Mos1: mécanisme de transposition
5’-TCAGGTGTACAAGTATGAAATGTCGTTT-3’3’-AGTCCACATGTTCATACTTTACAGCAAA-5’
TA
D 34 D D D D 34 DHTHHTH
Et après ??
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Mos1: mécanisme de transposition
Liaison à l’ADN
Complexesynaptique Excision Insertion
TA
« Exciser - réinsérer »« Couper - coller »
Vecteur ??
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Mos1: mécanisme de transposition
Augé-Gouillou et al. 2001
Interaction Tnp/ITR
ITR3’ > ITR5’
Impact sur la transposition ?
Mécanisme améliorable ??
Mécanisme régulé ??
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Mos1: mécanisme de transposition
Test de transposition en bactéries.
Tnpi
• Plasmide source de Tnp• Production inductible
Pseudo-Mos1
• Plasmide donneur de transposon• 3Tet3 versus 5Tet3• Tétracycline sensible avant transposition
Induction
Promoteur « tagging » : Apparition de clones tétra R
= Evénements de transposition
F = Nb bact Tet R / Nb total bactsans Tnp
avec Tnp
5Tet3 0 0
3Tet3 0 10-4
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Mécanisme régulé
Mécanisme améliorable
Mos1: régulations
Régulation ?
Temperature (°C)25 28 32 37
Tra
nsp
osit
ion
fr
eq
uen
cy
10-7
10-4
10-5
10-6
10-2
10-3
Transgene size (bp)
Transposition
efficiency
372 10-3
1 200 10-4
2 500 1.2 10-4
5 000 5 10-6
7 000 3.6 10-8
13 000 < 10-9
+ Tnp
5Tet3 0
3Tet3 10-4
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Mécanisme régulé
Mécanisme améliorable
Mos1: régulations
Régulation ?
1,00E-06
2,10E-05
4,10E-05
6,10E-05
8,10E-05
1,01E-04
0 5 15 30 60
Fré
qu
en
ce d
e
tran
sp
osit
ion
in
vit
ro
minutes
Tnp déPTnp P
Tnp protéine eucaryote.Modifications post-traductionnelles ?
ITR3’
Tnp P
Tnp déP
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Mos1: vecteur de demain…
Transposon• Ubiquiste• Simple• Améliorable
Vecteur !!
SyntheGeneDelivery
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SyntheGeneDelivery
Transposon-based system :
Mariner Mos1
Transposase gene5’ITR 3’ITR
Chromosome
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SyntheGeneDelivery
Transposon-based system :
Mariner mos1
Transposase gene5’ITR 3’ITR
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SyntheGeneDelivery
Transposon-based system :
Mariner mos1
Transposase gene5’ITR 3’ITR
Simple and small DNA molecule (1300 bp)Active in different cell types
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SyntheGeneDelivery
Transposon-based system :
Mariner mos1
Transgene5’ITR 3’ITR
Transposase supplied in transPlasmidmRNAProtein
Transgène = gène médicament / thérapie cellulaire
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SyntheGeneDelivery
1 - Enter into the cell 2 - Enter
into the nucleus
3 - Enter into the chromosome
Ex vivo
All synthetic, non-viral components
+ Transposase
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SyntheGeneDelivery: 1- To enter into the cell
ev-Synthetic gene delivery systems
+ Transposase
BGTC-Dope
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In Cell Art (Bruno Pitard)
FDAStem cells
LipoplexesBGTC-Dope
no yes
Block copolymersyes no
yes yes
SyntheGeneDelivery: 1- To enter into the cell
ev-Synthetic gene delivery systems
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+ Transposase
LEPG - Tours (Yves Bigot)
Bypass the nuclear membrane: NLS
SV40 NLS: on plasmids backbone
DNA-NLS
SyntheGeneDelivery: 2- To enter into the nucleus
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Bypass the nuclear membrane: NLS
SyntheGeneDelivery: 2- To enter into the nucleus
Avaris AB (Elisabeth Törnquist)
Karolinska Institutet (Edvard Smith)
+ Transposase
Bioplex (PNA + NLS): coupled to plasmids backbone
NLS
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+ Transposase
SyntheGeneDelivery: 3- To enter into the chromosome
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+ Transposase
SyntheGeneDelivery: 3- To enter into the chromosome
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+ Transposase
SyntheGeneDelivery: 3- To enter into the chromosome
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Oxford Univ (Ronald Chalmers)
LEPG -Tours (Yves Bigot)
Improve mos1 efficiency
SyntheGeneDelivery: 3- To enter into the chromosome
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Improve mos1 transposition efficiency
TEST: Transfection of human cells (HeLa)
SyntheGeneDelivery: 3- To enter into the chromosome
Analyse des clones résistants à la Néo
Transfection: J1
Composition des complexes transfectés :
- un plasmide donneur de transposon (néo)- un plasmide donneur de transposase (+/-)- un agent transfectant (PEI)
J3
boîte depétri
Sélection en G41815 jours
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Improve mos1 transposition efficiency
Transfection of human cells
SyntheGeneDelivery: 3- To enter into the chromosome
Fischer et al. 2001
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Improve mos1 transposition efficiency
Transfection of human cells
SyntheGeneDelivery: 3- To enter into the chromosome
Wu et al. 2006
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Improve mos1 transposition efficiency
Transfection of human cells
SyntheGeneDelivery: 3- To enter into the chromosome
Keravala et al. 2006
Himar in vitro
Himar en cellules humaines
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Improve mos1 transposition efficiency
Transfection of human cells
SyntheGeneDelivery: 3- To enter into the chromosome
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Improve mos1 transposition efficiency
Transfection of human cells
SyntheGeneDelivery: 3- To enter into the chromosome
Petit et al. 2006
Pas de Tnp = pas de transposition
Régulation négative de la production de Tnp MOS1 ?
Induction RNAi ?
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Improve mos1 transposition efficiency
Engineering the transposase and the
vectorMutagenesis to obtain
hyperactive and/or non-phosphorylable MOS1 Tnp
SyntheGeneDelivery: 3- To enter into the chromosome
0
10
20
30
40
50
60
70
80
90
100
WT(53) E137KT216A
F53YT216A
T216AY237C
E137KY237C
Q91RE137KT216A
F53YQ91R
F53YQ91RE137KT216A
Q91RY237C
F53YY237C
F53YE137KT216A
F53YT216AY237C
F53YE137KT216AY237C
F53YQ91RE137KT216AY237C
Mutant
Facteur d'hyperactivité
X 36
X 24
X 14
X 3
X 17
X 87
X 15X 8
X 21
X 61
X 11
Transposition en bactérie
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Improve mos1 transposition efficiency
Engineering the transposase and the
vectorMutagenesis to obtain
hyperactive transposon sequence
SyntheGeneDelivery: 3- To enter into the chromosome
10-7
10-6
10-5
10-4
10-3
49 51 53 55 57 59 61 63
GC content (%)
Tra
nspo
siti
on f
requ
ency
3T3
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Improve mos1 transposition efficiency
Engineering the transposase and the
vectorMutagenesis to obtain
hyperactive transposon sequence (ITR/UTR)
SyntheGeneDelivery: 3- To enter into the chromosome
TransgeneTranspositi
on efficiency
3Tet3 1
5Tet3 0,03
3Tet33 16
33Tet55 6,2
33Tet33 6
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Improve mos1 transposition efficiency
Engineering the transposase and the
vector
SyntheGeneDelivery: 3- To enter into the chromosome
TransgeneTranspositi
on efficiency
3Tet3 1
5Tet3 0,03
3Tet33 16
33Tet55 6,2
33Tet33 6
+ Tnp hyperactive (X 80)
Amélioration d’un facteur ± 1200
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Improve mos1 transposition efficiency
Target the insertion
SyntheGeneDelivery: 3- To enter into the chromosome
Program the integration site using the DNA binding
specificity of a defined ZFD fused to the transposase.
Insertion aléatoire : qualité des cellules
obtenues ?
Essais de Fisher avec les « enfants bulle »
Leucémies…
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Improve mos1 transposition efficiency
Target the insertion
SyntheGeneDelivery: 3- To enter into the chromosome
ZFD fused Tnp
Principe :
Zing Finger Domain
30 AAStructurés par un ZnLiaison spécifique triplet AcNucl
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Improve mos1 transposition efficiency
Target the insertion
SyntheGeneDelivery: 3- To enter into the chromosome
ZFD fused Tnp
Principe :
Zing Finger Domain
30 AAStructurés par un ZnLiaison spécifique triplet AcNucl
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Improve mos1 transposition efficiency
Target the insertion
SyntheGeneDelivery: 3- To enter into the chromosome
ZFD fused Tnp
4 x 3 pb = 12 pb.Séquence unique.
Choix de la séquence « cible » pour l’intégration du transgène: 12 pb.
Fabrication du ZBS correspondant / fusion avec la Tnp MOS1.
Ciblage de l’intégration
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Imperial College (Dominic Wells)
Muscle stem cellsGenetic muscle disorderIntramuscular graft = Factory cells
Mesenchymal stem cells (hfMSC) First trimester fetal blood - multipotentiality (differentiation)Therapeutic potential in utero transplantationMesenchymal deficiency diseases
SyntheGeneDelivery: 4- Transformation of stem cells
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Analyses of transposition events
SyntheGeneDelivery
Un événement de transposition « vraie » par cellule.
Pas de recombinaison (présence trop ADN ou Tnp)
Disparition du plasmide donneur de transposon.
Disparition de la source de Tnp.
Localisation de l’intégration.Southern blots =
Choix des « bonnes » cellules
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Analyses of transposition events
SyntheGeneDelivery
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Analyses of transposition events
SyntheGeneDelivery
Liu et al. 2005
Transposition = 1 bandeTA au séquençage
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Avoiding recombination
SyntheGeneDelivery
Insertion d’un gène suicide dans le plasmide donneur de transgène et apport de la transposase
sous forme d’ARNm
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Avoiding recombination
SyntheGeneDelivery
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SyntheGeneDelivery
Stem cell clones or population (?)
Purify or select the genetically modified stem cells
Therapeutic gene
Efficiently transfert & integrate the transgene at a specific site Stem cells
Amplify safe stem cells
Control the quality of the cells to warrant safety
Safe stem cell clones or
population (?)
Reimplant safe stem cells in
patient
Patient
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SyntheGeneDelivery
Challenges
To solve the size limitation of mariner based vectors
To target the transgene insertion at a defined “safe”
locus
We are only “tools conceptors”, not clinicians.
To efficiently transform stem cells with a FDA agreed
product
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SyntheGeneDelivery
Un outil pour quoi faire ?
Cellules usines ré-implantées :
Greffe intra-musculaire
Hemophilia A (f VIII)Hemophilia B (f IX)Diabètes insulino-dépendants
Adulte ou enfant
Thérapie cellulaire/génique
DMD (micro-dystrophin)Osteogenesis Imperfecta type
I
Foetus