STEM CELLS EMBRYONIC STEM CELLS/INDUCED PLURIPOTENT STEM CELLS
Induced pluripotent stem cells for drug discovery and
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Induced pluripotent stem cells for drug discovery and “personalized” therapy Peter Sartipy, PhD Cellectis Stem Cells ESC Congress 2012 , Aug 27, Munich, Germany Declaration of interest: Peter Sartipy is employed by Cellectis Stem Cells / Cellartis AB
Transcript of Induced pluripotent stem cells for drug discovery and
Induced pluripotent stem cells for drug discovery and “personalized” therapy
Peter Sartipy, PhD
Cellectis Stem Cells
ESC Congress 2012 , Aug 27, Munich, Germany
Declaration of interest: Peter Sartipy is employed by Cellectis Stem Cells / Cellartis AB
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Cellectis group: Pioneering genome engineering
Therapeutics
Agrobiotech
Production tools
Research tools
Stem cells
The potential of human pluripotent stem cells
Jensen, Hyllner, and Björquist
J Cell Physiol. 2009 hESC/hiPSC
Endoderm
Mesoderm
Ectoderm
Germ cells
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Frontloading human relevant toxicity testing
in pre-clinical drug discovery
Sartipy and Björquist
Stem Cells, 2011
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Evidence, prevalence, and occurrence of safety liabilities
relating to the cardiovascular and hepatic systems
From: Laverty et al British Journal of Pharmacology (2011) 163 675–693 675
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Genetic diversity for drug development and therapeutics
Subjects/patients
iPS
Reproducible and robust
processing
Somatic cells
Samples
Differentiation
Choice of genotypes
Choice of phenotypes
Single cell type with many genotypes
in vitro models Source of grafts
Genome Engineering
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Medical applications for patient specific iPSC
Robinton & Daley Nature 2012
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Examples of patient specific iPSC
Hepatology 2012
J Clin Invest 2012
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Minimizing variation – Stem cell banking
Characterization
and Safety Testing
Master Cell Bank
Adult Cells
IPS Cell
Colony
Stem Cells
Seed Bank
Expanded Cultures
Working
Cell Banks Applications
Reprogramming
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Established quality control criteria for iPSC
Colony characterization Morphology
Post thaw viability
Sterility Mycoplasma, bacteria, fungi
Human viral pathogens (HIV, hepatitis B and C)
Viral silence/Non integration of episome TaqMan analysis of expression of viral transgenes
and endogenous pluripotency genes
TaqMan analysis to confirm absence of episomes
Identity DNA fingerprinting; STR
Genetic characterization Karyotyping,
Stemness Alkaline phosphatase
Oct 4, Sox2, NANOG, SSEA 4, TRA-1-60 or TRA-
1-81
Pluripotency Embryoid body differentiation into cell lineages of
ectoderm, mesoderm and endoderm
Teratoma formation
In vitro directed differentiation
Oct4 Sox2
NANOG SSEA4
TRA-1-60 Control
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Processes governed by industry standard QA system
• Donation
• Procurement
• Traceability
• Testing/Quality control
• Processing/Manufacturing
• Preservation
• Storage
• Distribution
• Release criteria
• SOPs
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Gene targeting of human pluripotent stem cells
Nat Biotechnol 2011
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Gene correction of disease-causing mutation in hiPSC
Blood 2011
βA → βs mutation in
both alleles of the β-
globin gene results in
a defective form of
adult hemoglobin
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Gene correction of disease-causing mutation in hiPSC
Nature 2011
α1-antitrypsin deficiency (A1ATD):
• Autosomal recessive disorder
• Most common inherited metabolic
disease of the liver
• Single point mutation in the A1AT gene
→ ordered polymers within the
endoplasmic reticulum of hepatocytes
• Causes cirrhosis → liver transplantation
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Conclusions
• Human iPSC allow the creation of cell banks representing genetic diversity
• Rapid progress in the field of human disease modeling in vitro
• Future medical use of hiPSC involves drug discovery (in vitro tools) and
regenerative medicine (cell replacement therapy)
• Standardization of procedures and QC for hiPSC research is needed to
implement the technology in large industrial scale
• Novel tools for genome engineering will contribute to the development of
improved models for drug screening, disease modeling, and gene correction
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Cellectis
8 rue de la Croix-Jarry
75013 Paris
France
http://www.cellectis.com/
Tel. : +33 (0) 1 81 69 16 00
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