advances through stem cells
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Predictive toxicology advances through stem cells презентация
Содержание
- 1. Predictive toxicology advances through stem cells
- 2. Drug development & cardiotoxicity Need for earlier
- 3. Predicting drug toxicity Where can we do better? businessreview webinar | 19 March 2014
- 4. Human stem cell derived models A way
- 5. Stem cell derived human heart cells Industrial
- 6. CytivaTM Plus Cardiomyocytes Differentiated human cells for
- 7. Electrophysiology hERG block
- 8. Assessing effects in context Cardiac action potential
- 9. Assessing pro-arrhythmic potential Whole cell patch clamp
- 10. Comparative pharmacology Species variation in sensitivity of
- 11. Increasing throughput of electrophysiological tests businessreview webinar
- 12. FPD (‘QT’) prolongation & contractility Effect of
- 13. Electrophysiology hERG block
- 14. Functional integrity High Content Analysis (HCA) businessreview
- 15. High Content Analysis (HCA) & screening businessreview
- 16. Why choose High Content Analysis? Cellular detail
- 17. High content analysis solutions Automated microscopy and
- 18. CytivaTM HCA kits: cell health & integrity
- 19. Cardiotoxic potential of selective kinase inhibitors Using
- 20. Cancer & cardiotoxicity Tyrosine kinase inhibitors Data
- 21. Cardiotoxicity of anticancer drugs Overlapping cardiac signalling
- 22. Cardiotoxicity study compounds Panel of 134 compounds,
- 23. Cardiotoxicity screen workflow High content analysis (HCA)
- 24. Data analysis & interpretation Multi-parameter high content
- 25. PD 325901 (MEK1) Δ [Ca2+] only businessreview
- 26. Entinostat (HDAC) Mitochondrial count and Δ [Ca2+]
- 27. Imatinib/Gleevec (TK) Mitochondrial count & morphology, Δ
- 28. Profile clustering Self organizing maps businessreview webinar | 19 March 2014
- 29. Clustering results businessreview webinar | 19 March 2014 See tutorial regarding confidentiality disclosures. *
- 30. Stem cell models in toxicology businessreview webinar
- 31. Stem cell models in toxicology Vision for
- 32. Learn more at the Drug Discovery Knowledge
- 33. CytivaTM Cardiomyocytes are sold under licence from
Drug development & cardiotoxicity
Need for earlier toxicity testing and improved prediction businessreview webinar | 19 March 2014 Data from: Wilke et al. Nature Reviews Drug Discovery (2007) 6:904-916
Слайд 1Applications of human stem cell derived cardiomyocytes for predictive toxicology
Predictive toxicology
Слайд 2Drug development & cardiotoxicity
Need for earlier toxicity testing and improved prediction
businessreview
webinar | 19 March 2014
Data from: Wilke et al. Nature
Reviews Drug Discovery (2007) 6:904-916
Слайд 4Human stem cell derived models A way forward for more predictive toxicity
testing
businessreview webinar | 19 March 2014
Self-renewing
Scalable
Pluripotent
Reproducible
Convenient
Слайд 5Stem cell derived human heart cells
Industrial production of cardiomyocytes (CytivaTM Plus)
businessreview
webinar | 19 March 2014
Слайд 6CytivaTM Plus Cardiomyocytes
Differentiated human cells for safety & efficacy testing
businessreview webinar
| 19 March 2014
DNA Troponin I α-Actinin
Spontaneous contractility
Слайд 7Electrophysiology
hERG block
Na+ & Ca2+ channels QT prolongation contractility
Cardiomyocytes in drug safety testing
Integrated surveillance across platforms & assays
businessreview webinar | 19 March 2014
Patch Clamp
Impedance
High Content Imaging
Respiration
Biochemical Analysis
Functional Integrity
mitochondrial function membrane integrity Ca2+ homeostasis morphology
Слайд 8Assessing effects in context
Cardiac action potential reflects net ion channel function
businessreview
webinar | 19 March 2014
Planar patch clamp
Voltage clamped whole cell currents
Verapamil
Слайд 9Assessing pro-arrhythmic potential
Whole cell patch clamp to assess cardiac AP modulation
businessreview
webinar | 19 March 2014
Terfenadine
Antihistamine
Cisapride
GI motility
AP Prolongation 3 – 100 nM
AP Prolongation
3 – 30 nM
EAD
100nM
Verapamil
Arrhythmia
Mixed effects
IKr and ICa,L
Safe in clinical use
Слайд 10Comparative pharmacology
Species variation in sensitivity of model systems
businessreview webinar | 19
March 2014
Relative Sensitivity
Positive response defined as a change in APD90 >10%
Peng, S. et.al., Journal of Pharmacological and Toxicological Methods 61 (2010) 277–286
Слайд 11Increasing throughput of electrophysiological tests
businessreview webinar | 19 March 2014
Higher throughput
Multi-well formats >> screening
‘ECG-like’ traces, data-rich FPD (“QT”), beat rate, amplitude & slope, conduction velocity, etc.
Non-disruptive label-free recording Preserves cell function and cellular connectivity. Chronic vs. acute effects
Multiple recording sites in parallel Action potential propagation
Ease of use Less skill required compared to manual patch clamp
‘ECG-like’ traces, data-rich FPD (“QT”), beat rate, amplitude & slope, conduction velocity, etc.
Non-disruptive label-free recording Preserves cell function and cellular connectivity. Chronic vs. acute effects
Multiple recording sites in parallel Action potential propagation
Ease of use Less skill required compared to manual patch clamp
Monolayer culture
High success rate
Spontaneous &
Consistent beat rate
Expected shape & pharmacology
Multi-Electrode Arrays (MEA)
Cardiomyocyte requirements
Слайд 12FPD (‘QT’) prolongation & contractility
Effect of quinidine assessed by multi-electrode arrays
businessreview
webinar | 19 March 2014
[Quinidine]
0.0 μM
0.3 μM
1.0 μM
3.0 μM
FPD (“QT”) Prolongation
Contractility Changes
Q
T
Слайд 13Electrophysiology
hERG block
Na+ & Ca2+ channels QT prolongation contractility
Cardiomyocytes in drug safety testing
Integrated surveillance across platforms & assays
businessreview webinar | 19 March 2014
Patch Clamp
Impedance
High Content Imaging
Respiration
Biochemical Analysis
25%
Functional Integrity
mitochondria plasma membrane intracellular calcium morphology
Слайд 14Functional integrity
High Content Analysis (HCA)
businessreview webinar | 19 March 2014
Membrane Integrity
Dissipation
of gradients, organelle disruption, loss of homeostasis
Biochemical Integrity
Disruption of signal transduction, synthesis, metabolism, cytoskeletal machinery
75%
Слайд 15High Content Analysis (HCA) & screening
businessreview webinar | 19 March 2014
Extracting
and interpreting multi-parameter data obtained from high-throughput sub-cellular imaging
[cells + sensors]
[images + data]
[information + knowledge]
Слайд 16Why choose High Content Analysis? Cellular detail extracted rapidly in situ and
in context
businessreview webinar | 19 March 2014
Слайд 17High content analysis solutions
Automated microscopy and analysis for high throughput, high
content cell imaging
businessreview webinar | 19 March 2014
IN Cell Analyzer 2200
Faster, Brighter, Better
IN Cell Analyzer 6000
Cell analysis redefined
Flexible modular wide field imaging
On-board image restoration
7-wavelength solid state illumination
Scientific grade CMOS camera
Laser based confocal imaging
Iris variable aperture technology
405, 488, 561 & 642 nm laser illumination
Scientific grade CMOS camera
Слайд 18CytivaTM HCA kits: cell health & integrity Live interrogation of multiple cell
health markers
businessreview webinar | 19 March 2014
Слайд 19Cardiotoxic potential of selective kinase inhibitors Using stem cell derived cardiomyocytes &
High Content Analysis (HCA)
businessreview webinar | 19 March 2014
In collaboration with
Hirdesh Uppal
Ariel Kauss
Слайд 20Cancer & cardiotoxicity
Tyrosine kinase inhibitors
Data from: Orphanos G.S. et.al. Cardiotoxicity induced
by tyrosine kinase inhibitors 2009; Acta Oncologica, 48: 964-970
Слайд 21Cardiotoxicity of anticancer drugs
Overlapping cardiac signalling & oncology targets
Hypertrophic Stimuli
Physiological Stimuli
Energy
Stress
Growth Factors
Cell Proliferation
Hypertrophy
Autophagy
Cell Death
AKT
GSK3
ERK
RAS
RAF
AKT
BAD
AKT
LKB
AMPK
Pathological Stimuli
[Ca2+]
PLK
JNK
GSK3
NFAT
RTK
RTK
PI3K
PI3K
mTOR
MEK1
Adapted from; Force T & Kolaja K.L. Nature Reviews Drug Discovery (2011) 10, 111-126
Слайд 22Cardiotoxicity study compounds Panel of 134 compounds, kinase inhibitor focus, range of
classes
businessreview webinar | 19 March 2014
Nifedipine Neg Control
Amiodarone Pos Control
Слайд 23Cardiotoxicity screen workflow
High content analysis (HCA)
384-well format, 7-point dose curves
24h, 48h,
72h time points
n=3 wells per treatment condition, 4 images per well
n=3 wells per treatment condition, 4 images per well
businessreview webinar | 19 March 2014
Cells
Imaging
Image Analysis
Data Analysis
Compounds
Fluorescent
probes
Слайд 24Data analysis & interpretation
Multi-parameter high content data
businessreview webinar | 19 March
2014
Pharmacodynamics
Phenotypic profiling
Слайд 27Imatinib/Gleevec (TK)
Mitochondrial count & morphology, Δ [Ca2+], viability
businessreview webinar | 19
March 2014
Слайд 29Clustering results
businessreview webinar | 19 March 2014
See tutorial regarding confidentiality disclosures.
*
Слайд 30Stem cell models in toxicology
businessreview webinar | 19 March 2014
Stem cell
technology offers a way forward for abundant
and reproducible supply of human cell models
and reproducible supply of human cell models
Assessing drug effects in electrophysiological context may
reduce likelihood of false negative & positive results
hESC-Cardiomyocytes (CytivaTM Plus) provide a relevant
model for integrated cardiotoxicity assessment
Complementary high content imaging approaches yield mechanistic insights that aid informed decision making
Слайд 31Stem cell models in toxicology
Vision for future development
businessreview webinar | 19
March 2014
Connectivity in cell models
Integration of interrogation methods
Comprehensive liability surveillance
Слайд 32Learn more at the Drug Discovery Knowledge Center
The Drug Discovery
Knowledge Center gives you access to a wide variety of information to help you achieve deeper insights at every stage of drug discovery from target identification to lead optimization
Слайд 33CytivaTM Cardiomyocytes are sold under licence from Geron Corporation and Wisconsin
Alumni Research Foundation under US patent and publication numbers : US 7,425,448, US 2009/0017465, US 6,800,480, US 5,843,780, US 6,200,806, US 7,029,913, US 7,582,479, US 7,413,902, US 7,297,539, US 2009/0047739 and US 2007/0010012 and equivalent patent and patent applications in other countries.
The IN Cell Analyzer system and the IN Cell Investigator software are sold under use license from Cellomics Inc. under US patent numbers US 5989835, 6365367, 6416959, 6573039, 6620591, 6671624, 6716588, 6727071, 6759206, 6875578, 6902883, 6917884, 6970789, 6986993, 7060445, 7085765, 7117098, 7160687, 7235373, 7476510 ; Canadian patent numbers CA 2282658, 2328194, 2362117, 2381344; Australian patent number AU 730100; European patent numbers EP 0983498, 1095277, 1155304, 1203214, 1348124, 1368689; Japanese patent numbers JP 3466568, 3576491, 3683591, 4011936 and equivalent patents and patent applications in other countries.
Notice to purchaser: Important license information.
© 2014 General Electric Company – All rights reserved.
www.gelifesciences.com, GE Healthcare UK Limited. Amersham Place, Little Chalfont, Buckinghamshire, HP7 9NA UK
Presented as a businessreview webinar, Predictive toxicology advances through stem cells, 19 March 2014.
The IN Cell Analyzer system and the IN Cell Investigator software are sold under use license from Cellomics Inc. under US patent numbers US 5989835, 6365367, 6416959, 6573039, 6620591, 6671624, 6716588, 6727071, 6759206, 6875578, 6902883, 6917884, 6970789, 6986993, 7060445, 7085765, 7117098, 7160687, 7235373, 7476510 ; Canadian patent numbers CA 2282658, 2328194, 2362117, 2381344; Australian patent number AU 730100; European patent numbers EP 0983498, 1095277, 1155304, 1203214, 1348124, 1368689; Japanese patent numbers JP 3466568, 3576491, 3683591, 4011936 and equivalent patents and patent applications in other countries.
Notice to purchaser: Important license information.
© 2014 General Electric Company – All rights reserved.
www.gelifesciences.com, GE Healthcare UK Limited. Amersham Place, Little Chalfont, Buckinghamshire, HP7 9NA UK
Presented as a businessreview webinar, Predictive toxicology advances through stem cells, 19 March 2014.
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