transients in human ips-derived cardiomyocytes as a predictive … · 2014. 12. 17. · generation...
TRANSCRIPT
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HTS of Ca2+ Transients in Human iPS-derived Cardiomyocytes as a Predictive and Cost
Effective Assay Early on in Drug Development
Dr. Ralf Kettenhofen!Axiogenesis AG, Cologne, Germany
Hamamatsu 10th European Functional Drug Screening Symposium!Actelion, Allschwil, Switzerland
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Content
2
• Introduction into the production of Cor.4U cardiomyocytes
• Overview of established applications with Cor.4U cardiomyocytes
• HTS calcium transient assay in the Hamamatsu FDSS/µCell
• Compound screening
• Data analysis
• Outlook
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Generation of Cor.4U human iPS derived Cardiomyocytes
3
• iPS generated according to Yamanaka (licensed from iPS Academia)
• Production system by Axiogenesis enables large lot sizes
• Tightly controlled differentiation results in minimal lot to lot variations
• Selection based purification technology results in pure cardiomyocytes
• Cryopreserved in various formats
• GFP positive and colourless varieties will be available
• Complete FTO for commercial use on the limited use label license
• Cryopreserved
• Fresh cultures on different substrates (cell culture flasks, 96/384 well plates)
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4
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Introduction
Recording of Calcium Transients in Cor.4U Cardiomyocytes
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Excitation-Contraction Coupling
Time Am
plitud
e
Currents
Action Potential
Na+ Ca2+ L-type Ca2+ T-type Na+/Ca2+-exchanger K+ Ito
K+ IKs
K+ IKr
K+ IKur
Calcium is the messenger that integrates the electrochemcial signals of the action potential with the molecular signaling pathways that regulate contraction
Many Channel Types contribute to the Action Potential
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Hamamatsu FDSS/µCell
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Plating Efficiency on 384 Well Plates Fluo-4 Assay
Data was kindly provided by Dr. Thomas Licher, Sanofi Germany
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FDSS Parameters Analysed by the CalDio/Wave Checker Software
(6)
A
M
P
(5) RMP=Fluorescence
intensity at the bottom
peak
(1)Peak Number
Bottom
(3) P-P duration time
(7)Max_slope[Fluorescence counts/ms]
same as upstroke slope
(but bottom to peak)
(8) MaxNeg_slope[Fluorescence
counts/ms] same as downstroke slope
(but peak to bottom)
AMP= Peak Fluorescence count- RMP
(4)RATIO = AMP/RMP
(2)P rate(BPM)
A
M
P
APD10
APD50(Peak Width, FWHM)
APD90
(9) APD 10 to 90
PWD 90
(1) Peak number (total, BPM)
(2) P-P time [ms] (Ave, Std, Max, Min)
(3) Ratio (Ave, Std) ! Ratio = (AMP+RMP)/RMP
(4) AMP (Ave, Std)
(5) RMP (Ave, Std)
(6) Slope (Ave, Std)! Rising Slope: Slope from bottom to peak! Falling Slope: Slope from peak to bottom!0% - 10%, 10% - 90%, 20% - 80%, 30% - 70%
(7) Integration (Ave, Std)
(8) - (16) PWD (10% - 90%) [ms] (Ave, Std)
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hERG/IKr blocker
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Astemizole hERG Blocker
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FDSS µCell - Astemizole
vehicle control
370 nM
41 nM
5 min
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FDSS µCell - Astemizole 30 min
vehicle control
4.57 nM
13.7 nM
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FDSS µCell - Astemizole
41 nM
123 nM
370 nM
30 min
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Data Analysis with the Wave Checker Module
Astemizole
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FDSS µCell - Astemizole
Wave Checker Module
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FDSS µCell - Astemizole
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FDSS µCell - Astemizole
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FDSS µCell - Astemizole
export of text file format
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FDSS µCell - Astemizole
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FDSS µCell - Astemizole
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FDSS µCell - Astemizole
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FDSS µCell - Astemizole
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Dofetilide hERG Blocker
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FDSS µCell - Dofetilide 5 min
vehicle control
24.7 nM
222 nM
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FDSS µCell - Dofetilide 30 min
vehicle control
24.7 nM
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FDSS µCell - Dofetilide
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8.23#
24.69#
74.07#
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2000.00#
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FDSS µCell - Dofetilide
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Confidential
FDSS µCell - Clustering of Compounds
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Outlook
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Outlook - Hamamatsu FDSS 7000EX
Camera for fast recording of fluorescence and luminescence.
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Outlook
Evaluation of different kinds of fluorescent calcium and membrane potential dyes for the Cor.4U Cardiomyocytes
Establishment of cardiac cytotoxicity/viability assay
Combination of different luminescence assays
viability
cell death detection
apoptosis
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Dopaminergic and Sensory Neurons
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Patch Clamp of hiPS-derived Dopamineric Neurons
0 2 4 6 8 10 12-0.08
-0.06
-0.04
-0.02
0.00
0.02
0.04
0.06
U[V]
T[s]
Manual current clamp recording of spontaneous action potentials
Manual voltage clamp recording of sodium currents
Data was kindly provided by PoreGenic GmbH, Rostock, Germany
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Patch Clamp of hiPS-derived Peripheral Neurons
Manual voltage clamp recording of sodium currents
Data was kindly provided by PoreGenic GmbH, Rostock, Germany
-0.06 -0.04 -0.02 0.00 0.02 0.04 0.06 0.08
-4.00E-009
-3.00E-009
-2.00E-009
-1.00E-009
0.00E+000
1.00E-009
I[A]
U[V]
raw data I/V diagram
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Health and Environmental Science Institute (HESI) Initiative
!
CiPA Initiative (Comprehensive in vitro Pro-Arrhythmia Assay)
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HESI - Initiative
Stem Cell Working Groups - Newly Initiated
Following the workshop, the Cardiac Stem Cell Working Group formed and three subteams were created:
Cytotoxicity
Contractility,
Electrophysiology to explore issues of sensitivity, reproducibility, and predictivity for safety endpoints.
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4Q 2013 1-‐2Q 2014 2-‐3Q 2014 2015
•Subteam goals and objec1ves dra4ed •Data collec1on ini1ated •Link to CIPA project
•Manuscript(s) dra4ing and submission
•Laboratory study ini1ated •Manuscript(s) dra4ing
•Literature search conducted •Laboratory study protocol planning
Cardiac Stem Cell Working Group: Timeline
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Thanks to:
• Axiogenesis AG Anika Duenbostell
• HamamatsuJean Marc D'AngeloThomas NiedereichholzCyril GuerinotThibault PoissingerHirofumi Horai
• Sanofi, Frankfurt Dr. Thomas Licher