Wersquove crossed the Chasm and climbed out of the TroughAdvances and advantages with iPSC-derived cell types in drug

discovery

Blake Anson PhD

Oct 31 2014

2

Technology Hype Cycle

CDI Overview

Sampling of iCell Product use in IndustryToxicity and Drug Discovery

Population Diversity

Wrap-up

Where is stem cell technology as it applies to drug discovery

Particularly iCellreg Products

The Chasm The Trough

3

Company Overview

Cellular Dynamics International (CDI) is the worldrsquos largest producer of human iPS cells

and iPS cell-derived cell types

Headquartered in Madison WI

Currently employs ~138 total staff

~650 yrs human stem cell experience

gt800 patents (owned or licensed) to enable FTO

Core competencies

Creation and culture of human iPS cells

Normal and disease phenotypes

Genetic engineering of iPS cells

Lineage and pathway-specific markers can be introduced

Development of new differentiation protocols

Differentiated cells from all three germ layers

Manufacture of human iPS cell-derived cell types

Scalable production of highly purified cells

Partnership with iPS Academia Japan enables access

and support for CDIrsquos products in Japan

4

Product Portfolio

2009 2010 2011 2012 2013

Essential 8 Medium

Episomal Reprogramming Kit

Vitronectin

iCell Products

iCell Cardiomyocytes

iCell Cardiac Progenitor Cells (New)

iCell Hematopoietic Progenitor Cells

iCell Endothelial Cells

iCell Hepatocytes

iCell Neurons

iCell Astrocytes

iCell DopaNeurons (New)

iCell Skeletal Myoblasts

MyCell Products

iPS Cell Reprogramming

iPS Cell Genetic Engineering

iPS Cell Differentiation

MyCell Disease and Diversity Panel (New)

2014

iCell Cardiomyocytes iCell

Endothelial Cells

MyCell Products

iCell

Hepatocytes

iCell Astrocytes

iCell

Hematopoietic

Progenitor

Cells

iCell Skeletal

Myoblasts

iCell Cardiac

Progenitor CellsiCell

DopaNeurons

iCell Neurons

5

iCell Cardiomyocytes

Human Cardiomyocytes

gt95 pure cryopreserved ready to use

gt4x106 cardiomyocytes per unit

Normal human biology

Broad platform utility for life science research drug

discovery and toxicity testing

Improved workflow with greater predictivity

Full product solution unlimited quantities

6

iCell CardiomyocytesCharacterization

Electrophysiology E-C Coupling Contractility

Enables mechanistic toxicity testing

Whole-Genome Gene Expression

Relevant amp stable over time in culture

------ Adult myocardium____ d28 iCell CM____ d120 iCell CM

____ PromoCell____ Celprogen

-------Myocardium

Babiarz et al 2012 Kattman et al 2011 Rana et al 2012 Ma et al 2011

(For a complete list of iCell Cardiomyocytes publications go to

wwwcellulardynamicscom)

Metabolism

Recapitulates normal human

cardiac function

Protein Expression

Appropriate for interrogating

mitochondrial toxicity

iCell Cardiomyocytes native human biology enables

Mechanistic interrogation of cardiac function

Toxicity testing disruption of normal processes

Disease modeling corruption of normal processes

Well represented in the peer reviewed literature

~40 iCell Cardiomyocytes pubs to-date

More than all other commercial iPSC-CMs combined

7

1 Nakamura Y1 Matsuo J (2014) Assessment of testing methods for

drug-induced repolarization delay and arrhythmias in an iPS cell-

derived cardiomyocyte sheet multi-site validation study J

Pharmacol Sci 124(4)494-501

2 Eldridge S Guo L et al (2014) Examining the Protective Role of

ErbB2 Modulation in Human Induced Pluripotent Stem Cell-

Derived Cardiomyocytes Toxicol Sci 2014 Jul 23 pii kfu150

[Epub ahead of print]

3 Kolaja K (2014) Stem cells and stem cell-derived tissues and their

use in safety assessment J Biol Chem 2014 Feb 21289(8)4555-

61

4 Uesugi M Ojima A et al (2014) Low-density plating is sufficient to

induce cardiac hypertrophy and electrical remodeling in highly

purified human iPS cell-derived cardiomyocytes J Pharmacol

Toxicol Methods 69(2)177-88

5 Cameron BJ Gerry AB et al (2013) Identification of a Titin-

derived HLA-A1-presented peptide as a cross-reactive target for

engineered MAGE A3-directed T cells Sci Transl Med

5(197)197ra103

6 Carlson C Koonce C et al (2013) Phenotypic screening with

human iPS cell-derived cardiomyocytes HTS-compatible assays

for interrogating cardiac hypertrophy J Biomol Screen

18(10)1203-11

7 Doherty K Wappel R et al (2013) Multiparameter in vitro toxicity

testing of crizotinib sunitinib erlotinib and nilotinib in human

cardiomyocytes Toxicol Appl Pharmacol 272(1)245-55

8 Fine M Lu F et al (2013) Human Induced Pluripotent Stem Cell-

derived Cardiomyocytes for Studies of Cardiac Ion Transporters

Am J Physiol Cell Physiol 305(5)C481-91

9 Guo L Coyle l et al (2013) Refining the Human iPSC-

Cardiomyocyte Arrhythmic Risk Assessment Model Toxicol Sci

136(2)581-94

10 Harris K Aylott M et al (2013) Comparison of

Electrophysiological Data from Human Induced Pluripotent Stem

Cell Derived Cardiomyoyctes (hiPSC-CMs) to Functional Pre-

clinical Safety Assays Toxicol Sci 134(2)412-26

11 Ivashchenko CY1 Pipes GC et al (2013) Human-induced

pluripotent stem cell-derived cardiomyocytes exhibit temporal

changes in phenotype Am J Physiol Heart Circ Physiol

305(6)H913-22

12 Jehle J Ficker E et al (2013) Mechanisms of Zolpidem-induced

Long QT Ayndrome Acute Inhibition of Recombinant hERG K+

Channels and Action Potential Prolongation in Human

Cardiomyocytes Derived from Induced Pluripotent Stem Cells

British J Pharm 1681215-29

13 Puppala D Collis LP et al (2013) Comparative Gene Expression

Profiling in Human Induced Pluripotent Stem Cell Derived

Cardiocytes and Human and Cynomolgus Heart Tissue Toxicol

Sci 131292-301

14 Rao C Prodromakis T et al (2013) The effect of microgrooved

culture substrates on calcium cycling of cardiac myocytes

derived from human induced pluripotent stem cells Biomaterials

34(10)2399-411

15 Schweikart K Guo L et al (2013) The Effects of Jaspamide on

Human Cardiomyocyte Function and Cardiac Ion Channel Activity

Toxicol in Vitro 27745-51

16 Sirenko O Crittenden C et al (2013) Multiparameter In Vitro

Assessment of Compound Effects on Cardiomyocyte Physiology

Using iPS Cells J Biomol Screening 1839-53

17 Sirenko O Cromwell EF et al (2013) Assessment of beating

parameters in human induced pluripotent stem cells enables

quantitative in vitro screening for cardiotoxicity Toxicol Appl

Pharmacol 273(3)500-07

18 Babiarz JE Ravon M et al (2012) Determination of the Human

Cardiomyocyte mRNA and miRNA Differentiation Network by

Fine-scale Profiling Stem Cells Dev 211956-65

19 Cerignoli R Charlot D et al (2012) High Throughput Measurement

of Ca2+ Dynamics for Drug Risk Assessment in Human Stem Cell-

derived Cardiomyocytes by Kinetic Image Cytometry

J Pharmacol Toxicol Methods 66246-256

20 Lee P Kloss M et al (2012) Simultaneous Voltage and Calcium

Mapping of Genetically Purified Human Induced Pluripotent Stem

Cell-derived Cardiac Myocyte Monolayers Circ Res 1101556-63

21 Mioulane M Foldes G et al (2012) Development of High Content

Imaging Methods for Cell Death Detection in Human Pluripotent

Stem Cell-derived Cardiomyocytes J of Cardiovasc Trans Res

5593-604

22 Rana P Anson BD et al (2012) Characterization of Human-

induced Pluripotent Stem Cell-derived Cardiomyocytes

Bioenergetics and Utilization in Safety Screening Toxicol Sci

130117-31

23 Reynolds JG Geretti E et al (2012) HER2-targeted Liposomal

Doxorubicin Displays Enhanced Anti-tumorigenic Effects without

Associated Cardiotoxicity Toxicol Appl Pharmacol 2621-10

24 Wei H Zhang G et al (2012) Hydrogen Sulfide Suppresses

Outward Rectifier Potassium Currents in Human Pluripotent Stem

Cell-Derived Cardiomyocytes Plos One 7(11)e50641

25 Zhi D Irvin MR et al (2012) Whole-exome Sequencing and an

iPSC-derived Cardiomyocyte Model Provides a Powerful Platform

for Gene Discovery in Left Ventricular Hypertrophy Frontiers in

Genetics 392

26 Cohen JD Babiarz JE et al (2011) Use of Human Stem Cell-

derived Cardiomyocytes to Examine Sunitinib Mediated

Cardiotoxicity and Electrophysiological Alterations Toxicol Appl

Pharmacol 25774-83

27 Guo L Qian JY et al (2011) The Electrophysiological Effects of

Cardiac Glycosides in Human iPSC-derived Cardiomyocytes and

in Guinea Pig Isolated Hearts Cell Physiol Biochem 27453-462

28 Guo L Abrams RM et al (2011) Estimating the Risk of Drug-

induced Proarrhythmia Using Human Induced Pluripotent Stem

Cell-derived Cardiomyocytes Toxicol Sci 123281-289

29 Jonsson MKB Wang QD et al (2011) Impedance-based Detection

of Beating Rhythm and Proarrhythmic Effects of Compounds on

Stem Cell-derived Cardiomyocytes Assay and Drug Dev Tech 91-

11

30 Ma J Guo L et al (2011) High Purity Human-induced Pluripotent

Stem Cell-derived Cardiomyocytes Electrophysiological

Properties of Action Potentials and Ionic Currents Am J Physiol

Heart Circ Physiol 301H2006-H2017

iCell CardiomyocytesMarket Validation (82014)

~40 Peer-reviewed

Publications (102014)

bull Characterization

bull Toxicity testing

bull Disease modeling

2

Technology Hype Cycle

CDI Overview

Sampling of iCell Product use in IndustryToxicity and Drug Discovery

Population Diversity

Wrap-up

Where is stem cell technology as it applies to drug discovery

Particularly iCellreg Products

The Chasm The Trough

3

Company Overview

Cellular Dynamics International (CDI) is the worldrsquos largest producer of human iPS cells

and iPS cell-derived cell types

Headquartered in Madison WI

Currently employs ~138 total staff

~650 yrs human stem cell experience

gt800 patents (owned or licensed) to enable FTO

Core competencies

Creation and culture of human iPS cells

Normal and disease phenotypes

Genetic engineering of iPS cells

Lineage and pathway-specific markers can be introduced

Development of new differentiation protocols

Differentiated cells from all three germ layers

Manufacture of human iPS cell-derived cell types

Scalable production of highly purified cells

Partnership with iPS Academia Japan enables access

and support for CDIrsquos products in Japan

4

Product Portfolio

2009 2010 2011 2012 2013

Essential 8 Medium

Episomal Reprogramming Kit

Vitronectin

iCell Products

iCell Cardiomyocytes

iCell Cardiac Progenitor Cells (New)

iCell Hematopoietic Progenitor Cells

iCell Endothelial Cells

iCell Hepatocytes

iCell Neurons

iCell Astrocytes

iCell DopaNeurons (New)

iCell Skeletal Myoblasts

MyCell Products

iPS Cell Reprogramming

iPS Cell Genetic Engineering

iPS Cell Differentiation

MyCell Disease and Diversity Panel (New)

2014

iCell Cardiomyocytes iCell

Endothelial Cells

MyCell Products

iCell

Hepatocytes

iCell Astrocytes

iCell

Hematopoietic

Progenitor

Cells

iCell Skeletal

Myoblasts

iCell Cardiac

Progenitor CellsiCell

DopaNeurons

iCell Neurons

5

iCell Cardiomyocytes

Human Cardiomyocytes

gt95 pure cryopreserved ready to use

gt4x106 cardiomyocytes per unit

Normal human biology

Broad platform utility for life science research drug

discovery and toxicity testing

Improved workflow with greater predictivity

Full product solution unlimited quantities

6

iCell CardiomyocytesCharacterization

Electrophysiology E-C Coupling Contractility

Enables mechanistic toxicity testing

Whole-Genome Gene Expression

Relevant amp stable over time in culture

------ Adult myocardium____ d28 iCell CM____ d120 iCell CM

____ PromoCell____ Celprogen

-------Myocardium

Babiarz et al 2012 Kattman et al 2011 Rana et al 2012 Ma et al 2011

(For a complete list of iCell Cardiomyocytes publications go to

wwwcellulardynamicscom)

Metabolism

Recapitulates normal human

cardiac function

Protein Expression

Appropriate for interrogating

mitochondrial toxicity

iCell Cardiomyocytes native human biology enables

Mechanistic interrogation of cardiac function

Toxicity testing disruption of normal processes

Disease modeling corruption of normal processes

Well represented in the peer reviewed literature

~40 iCell Cardiomyocytes pubs to-date

More than all other commercial iPSC-CMs combined

7

1 Nakamura Y1 Matsuo J (2014) Assessment of testing methods for

drug-induced repolarization delay and arrhythmias in an iPS cell-

derived cardiomyocyte sheet multi-site validation study J

Pharmacol Sci 124(4)494-501

2 Eldridge S Guo L et al (2014) Examining the Protective Role of

ErbB2 Modulation in Human Induced Pluripotent Stem Cell-

Derived Cardiomyocytes Toxicol Sci 2014 Jul 23 pii kfu150

[Epub ahead of print]

3 Kolaja K (2014) Stem cells and stem cell-derived tissues and their

use in safety assessment J Biol Chem 2014 Feb 21289(8)4555-

61

4 Uesugi M Ojima A et al (2014) Low-density plating is sufficient to

induce cardiac hypertrophy and electrical remodeling in highly

purified human iPS cell-derived cardiomyocytes J Pharmacol

Toxicol Methods 69(2)177-88

5 Cameron BJ Gerry AB et al (2013) Identification of a Titin-

derived HLA-A1-presented peptide as a cross-reactive target for

engineered MAGE A3-directed T cells Sci Transl Med

5(197)197ra103

6 Carlson C Koonce C et al (2013) Phenotypic screening with

human iPS cell-derived cardiomyocytes HTS-compatible assays

for interrogating cardiac hypertrophy J Biomol Screen

18(10)1203-11

7 Doherty K Wappel R et al (2013) Multiparameter in vitro toxicity

testing of crizotinib sunitinib erlotinib and nilotinib in human

cardiomyocytes Toxicol Appl Pharmacol 272(1)245-55

8 Fine M Lu F et al (2013) Human Induced Pluripotent Stem Cell-

derived Cardiomyocytes for Studies of Cardiac Ion Transporters

Am J Physiol Cell Physiol 305(5)C481-91

9 Guo L Coyle l et al (2013) Refining the Human iPSC-

Cardiomyocyte Arrhythmic Risk Assessment Model Toxicol Sci

136(2)581-94

10 Harris K Aylott M et al (2013) Comparison of

Electrophysiological Data from Human Induced Pluripotent Stem

Cell Derived Cardiomyoyctes (hiPSC-CMs) to Functional Pre-

clinical Safety Assays Toxicol Sci 134(2)412-26

11 Ivashchenko CY1 Pipes GC et al (2013) Human-induced

pluripotent stem cell-derived cardiomyocytes exhibit temporal

changes in phenotype Am J Physiol Heart Circ Physiol

305(6)H913-22

12 Jehle J Ficker E et al (2013) Mechanisms of Zolpidem-induced

Long QT Ayndrome Acute Inhibition of Recombinant hERG K+

Channels and Action Potential Prolongation in Human

Cardiomyocytes Derived from Induced Pluripotent Stem Cells

British J Pharm 1681215-29

13 Puppala D Collis LP et al (2013) Comparative Gene Expression

Profiling in Human Induced Pluripotent Stem Cell Derived

Cardiocytes and Human and Cynomolgus Heart Tissue Toxicol

Sci 131292-301

14 Rao C Prodromakis T et al (2013) The effect of microgrooved

culture substrates on calcium cycling of cardiac myocytes

derived from human induced pluripotent stem cells Biomaterials

34(10)2399-411

15 Schweikart K Guo L et al (2013) The Effects of Jaspamide on

Human Cardiomyocyte Function and Cardiac Ion Channel Activity

Toxicol in Vitro 27745-51

16 Sirenko O Crittenden C et al (2013) Multiparameter In Vitro

Assessment of Compound Effects on Cardiomyocyte Physiology

Using iPS Cells J Biomol Screening 1839-53

17 Sirenko O Cromwell EF et al (2013) Assessment of beating

parameters in human induced pluripotent stem cells enables

quantitative in vitro screening for cardiotoxicity Toxicol Appl

Pharmacol 273(3)500-07

18 Babiarz JE Ravon M et al (2012) Determination of the Human

Cardiomyocyte mRNA and miRNA Differentiation Network by

Fine-scale Profiling Stem Cells Dev 211956-65

19 Cerignoli R Charlot D et al (2012) High Throughput Measurement

of Ca2+ Dynamics for Drug Risk Assessment in Human Stem Cell-

derived Cardiomyocytes by Kinetic Image Cytometry

J Pharmacol Toxicol Methods 66246-256

20 Lee P Kloss M et al (2012) Simultaneous Voltage and Calcium

Mapping of Genetically Purified Human Induced Pluripotent Stem

Cell-derived Cardiac Myocyte Monolayers Circ Res 1101556-63

21 Mioulane M Foldes G et al (2012) Development of High Content

Imaging Methods for Cell Death Detection in Human Pluripotent

Stem Cell-derived Cardiomyocytes J of Cardiovasc Trans Res

5593-604

22 Rana P Anson BD et al (2012) Characterization of Human-

induced Pluripotent Stem Cell-derived Cardiomyocytes

Bioenergetics and Utilization in Safety Screening Toxicol Sci

130117-31

23 Reynolds JG Geretti E et al (2012) HER2-targeted Liposomal

Doxorubicin Displays Enhanced Anti-tumorigenic Effects without

Associated Cardiotoxicity Toxicol Appl Pharmacol 2621-10

24 Wei H Zhang G et al (2012) Hydrogen Sulfide Suppresses

Outward Rectifier Potassium Currents in Human Pluripotent Stem

Cell-Derived Cardiomyocytes Plos One 7(11)e50641

25 Zhi D Irvin MR et al (2012) Whole-exome Sequencing and an

iPSC-derived Cardiomyocyte Model Provides a Powerful Platform

for Gene Discovery in Left Ventricular Hypertrophy Frontiers in

Genetics 392

26 Cohen JD Babiarz JE et al (2011) Use of Human Stem Cell-

derived Cardiomyocytes to Examine Sunitinib Mediated

Cardiotoxicity and Electrophysiological Alterations Toxicol Appl

Pharmacol 25774-83

27 Guo L Qian JY et al (2011) The Electrophysiological Effects of

Cardiac Glycosides in Human iPSC-derived Cardiomyocytes and

in Guinea Pig Isolated Hearts Cell Physiol Biochem 27453-462

28 Guo L Abrams RM et al (2011) Estimating the Risk of Drug-

induced Proarrhythmia Using Human Induced Pluripotent Stem

Cell-derived Cardiomyocytes Toxicol Sci 123281-289

29 Jonsson MKB Wang QD et al (2011) Impedance-based Detection

of Beating Rhythm and Proarrhythmic Effects of Compounds on

Stem Cell-derived Cardiomyocytes Assay and Drug Dev Tech 91-

11

30 Ma J Guo L et al (2011) High Purity Human-induced Pluripotent

Stem Cell-derived Cardiomyocytes Electrophysiological

Properties of Action Potentials and Ionic Currents Am J Physiol

Heart Circ Physiol 301H2006-H2017

iCell CardiomyocytesMarket Validation (82014)

~40 Peer-reviewed

Publications (102014)

bull Characterization

bull Toxicity testing

bull Disease modeling

3

Company Overview

Cellular Dynamics International (CDI) is the worldrsquos largest producer of human iPS cells

and iPS cell-derived cell types

Headquartered in Madison WI

Currently employs ~138 total staff

~650 yrs human stem cell experience

gt800 patents (owned or licensed) to enable FTO

Core competencies

Creation and culture of human iPS cells

Normal and disease phenotypes

Genetic engineering of iPS cells

Lineage and pathway-specific markers can be introduced

Development of new differentiation protocols

Differentiated cells from all three germ layers

Manufacture of human iPS cell-derived cell types

Scalable production of highly purified cells

Partnership with iPS Academia Japan enables access

and support for CDIrsquos products in Japan

4

Product Portfolio

2009 2010 2011 2012 2013

Essential 8 Medium

Episomal Reprogramming Kit

Vitronectin

iCell Products

iCell Cardiomyocytes

iCell Cardiac Progenitor Cells (New)

iCell Hematopoietic Progenitor Cells

iCell Endothelial Cells

iCell Hepatocytes

iCell Neurons

iCell Astrocytes

iCell DopaNeurons (New)

iCell Skeletal Myoblasts

MyCell Products

iPS Cell Reprogramming

iPS Cell Genetic Engineering

iPS Cell Differentiation

MyCell Disease and Diversity Panel (New)

2014

iCell Cardiomyocytes iCell

Endothelial Cells

MyCell Products

iCell

Hepatocytes

iCell Astrocytes

iCell

Hematopoietic

Progenitor

Cells

iCell Skeletal

Myoblasts

iCell Cardiac

Progenitor CellsiCell

DopaNeurons

iCell Neurons

5

iCell Cardiomyocytes

Human Cardiomyocytes

gt95 pure cryopreserved ready to use

gt4x106 cardiomyocytes per unit

Normal human biology

Broad platform utility for life science research drug

discovery and toxicity testing

Improved workflow with greater predictivity

Full product solution unlimited quantities

6

iCell CardiomyocytesCharacterization

Electrophysiology E-C Coupling Contractility

Enables mechanistic toxicity testing

Whole-Genome Gene Expression

Relevant amp stable over time in culture

------ Adult myocardium____ d28 iCell CM____ d120 iCell CM

____ PromoCell____ Celprogen

-------Myocardium

Babiarz et al 2012 Kattman et al 2011 Rana et al 2012 Ma et al 2011

(For a complete list of iCell Cardiomyocytes publications go to

wwwcellulardynamicscom)

Metabolism

Recapitulates normal human

cardiac function

Protein Expression

Appropriate for interrogating

mitochondrial toxicity

iCell Cardiomyocytes native human biology enables

Mechanistic interrogation of cardiac function

Toxicity testing disruption of normal processes

Disease modeling corruption of normal processes

Well represented in the peer reviewed literature

~40 iCell Cardiomyocytes pubs to-date

More than all other commercial iPSC-CMs combined

7

1 Nakamura Y1 Matsuo J (2014) Assessment of testing methods for

drug-induced repolarization delay and arrhythmias in an iPS cell-

derived cardiomyocyte sheet multi-site validation study J

Pharmacol Sci 124(4)494-501

2 Eldridge S Guo L et al (2014) Examining the Protective Role of

ErbB2 Modulation in Human Induced Pluripotent Stem Cell-

Derived Cardiomyocytes Toxicol Sci 2014 Jul 23 pii kfu150

[Epub ahead of print]

3 Kolaja K (2014) Stem cells and stem cell-derived tissues and their

use in safety assessment J Biol Chem 2014 Feb 21289(8)4555-

61

4 Uesugi M Ojima A et al (2014) Low-density plating is sufficient to

induce cardiac hypertrophy and electrical remodeling in highly

purified human iPS cell-derived cardiomyocytes J Pharmacol

Toxicol Methods 69(2)177-88

5 Cameron BJ Gerry AB et al (2013) Identification of a Titin-

derived HLA-A1-presented peptide as a cross-reactive target for

engineered MAGE A3-directed T cells Sci Transl Med

5(197)197ra103

6 Carlson C Koonce C et al (2013) Phenotypic screening with

human iPS cell-derived cardiomyocytes HTS-compatible assays

for interrogating cardiac hypertrophy J Biomol Screen

18(10)1203-11

7 Doherty K Wappel R et al (2013) Multiparameter in vitro toxicity

testing of crizotinib sunitinib erlotinib and nilotinib in human

cardiomyocytes Toxicol Appl Pharmacol 272(1)245-55

8 Fine M Lu F et al (2013) Human Induced Pluripotent Stem Cell-

derived Cardiomyocytes for Studies of Cardiac Ion Transporters

Am J Physiol Cell Physiol 305(5)C481-91

9 Guo L Coyle l et al (2013) Refining the Human iPSC-

Cardiomyocyte Arrhythmic Risk Assessment Model Toxicol Sci

136(2)581-94

10 Harris K Aylott M et al (2013) Comparison of

Electrophysiological Data from Human Induced Pluripotent Stem

Cell Derived Cardiomyoyctes (hiPSC-CMs) to Functional Pre-

clinical Safety Assays Toxicol Sci 134(2)412-26

11 Ivashchenko CY1 Pipes GC et al (2013) Human-induced

pluripotent stem cell-derived cardiomyocytes exhibit temporal

changes in phenotype Am J Physiol Heart Circ Physiol

305(6)H913-22

12 Jehle J Ficker E et al (2013) Mechanisms of Zolpidem-induced

Long QT Ayndrome Acute Inhibition of Recombinant hERG K+

Channels and Action Potential Prolongation in Human

Cardiomyocytes Derived from Induced Pluripotent Stem Cells

British J Pharm 1681215-29

13 Puppala D Collis LP et al (2013) Comparative Gene Expression

Profiling in Human Induced Pluripotent Stem Cell Derived

Cardiocytes and Human and Cynomolgus Heart Tissue Toxicol

Sci 131292-301

14 Rao C Prodromakis T et al (2013) The effect of microgrooved

culture substrates on calcium cycling of cardiac myocytes

derived from human induced pluripotent stem cells Biomaterials

34(10)2399-411

15 Schweikart K Guo L et al (2013) The Effects of Jaspamide on

Human Cardiomyocyte Function and Cardiac Ion Channel Activity

Toxicol in Vitro 27745-51

16 Sirenko O Crittenden C et al (2013) Multiparameter In Vitro

Assessment of Compound Effects on Cardiomyocyte Physiology

Using iPS Cells J Biomol Screening 1839-53

17 Sirenko O Cromwell EF et al (2013) Assessment of beating

parameters in human induced pluripotent stem cells enables

quantitative in vitro screening for cardiotoxicity Toxicol Appl

Pharmacol 273(3)500-07

18 Babiarz JE Ravon M et al (2012) Determination of the Human

Cardiomyocyte mRNA and miRNA Differentiation Network by

Fine-scale Profiling Stem Cells Dev 211956-65

19 Cerignoli R Charlot D et al (2012) High Throughput Measurement

of Ca2+ Dynamics for Drug Risk Assessment in Human Stem Cell-

derived Cardiomyocytes by Kinetic Image Cytometry

J Pharmacol Toxicol Methods 66246-256

20 Lee P Kloss M et al (2012) Simultaneous Voltage and Calcium

Mapping of Genetically Purified Human Induced Pluripotent Stem

Cell-derived Cardiac Myocyte Monolayers Circ Res 1101556-63

21 Mioulane M Foldes G et al (2012) Development of High Content

Imaging Methods for Cell Death Detection in Human Pluripotent

Stem Cell-derived Cardiomyocytes J of Cardiovasc Trans Res

5593-604

22 Rana P Anson BD et al (2012) Characterization of Human-

induced Pluripotent Stem Cell-derived Cardiomyocytes

Bioenergetics and Utilization in Safety Screening Toxicol Sci

130117-31

23 Reynolds JG Geretti E et al (2012) HER2-targeted Liposomal

Doxorubicin Displays Enhanced Anti-tumorigenic Effects without

Associated Cardiotoxicity Toxicol Appl Pharmacol 2621-10

24 Wei H Zhang G et al (2012) Hydrogen Sulfide Suppresses

Outward Rectifier Potassium Currents in Human Pluripotent Stem

Cell-Derived Cardiomyocytes Plos One 7(11)e50641

25 Zhi D Irvin MR et al (2012) Whole-exome Sequencing and an

iPSC-derived Cardiomyocyte Model Provides a Powerful Platform

for Gene Discovery in Left Ventricular Hypertrophy Frontiers in

Genetics 392

26 Cohen JD Babiarz JE et al (2011) Use of Human Stem Cell-

derived Cardiomyocytes to Examine Sunitinib Mediated

Cardiotoxicity and Electrophysiological Alterations Toxicol Appl

Pharmacol 25774-83

27 Guo L Qian JY et al (2011) The Electrophysiological Effects of

Cardiac Glycosides in Human iPSC-derived Cardiomyocytes and

in Guinea Pig Isolated Hearts Cell Physiol Biochem 27453-462

28 Guo L Abrams RM et al (2011) Estimating the Risk of Drug-

induced Proarrhythmia Using Human Induced Pluripotent Stem

Cell-derived Cardiomyocytes Toxicol Sci 123281-289

29 Jonsson MKB Wang QD et al (2011) Impedance-based Detection

of Beating Rhythm and Proarrhythmic Effects of Compounds on

Stem Cell-derived Cardiomyocytes Assay and Drug Dev Tech 91-

11

30 Ma J Guo L et al (2011) High Purity Human-induced Pluripotent

Stem Cell-derived Cardiomyocytes Electrophysiological

Properties of Action Potentials and Ionic Currents Am J Physiol

Heart Circ Physiol 301H2006-H2017

iCell CardiomyocytesMarket Validation (82014)

~40 Peer-reviewed

Publications (102014)

bull Characterization

bull Toxicity testing

bull Disease modeling

4

Product Portfolio

2009 2010 2011 2012 2013

Essential 8 Medium

Episomal Reprogramming Kit

Vitronectin

iCell Products

iCell Cardiomyocytes

iCell Cardiac Progenitor Cells (New)

iCell Hematopoietic Progenitor Cells

iCell Endothelial Cells

iCell Hepatocytes

iCell Neurons

iCell Astrocytes

iCell DopaNeurons (New)

iCell Skeletal Myoblasts

MyCell Products

iPS Cell Reprogramming

iPS Cell Genetic Engineering

iPS Cell Differentiation

MyCell Disease and Diversity Panel (New)

2014

iCell Cardiomyocytes iCell

Endothelial Cells

MyCell Products

iCell

Hepatocytes

iCell Astrocytes

iCell

Hematopoietic

Progenitor

Cells

iCell Skeletal

Myoblasts

iCell Cardiac

Progenitor CellsiCell

DopaNeurons

iCell Neurons

5

iCell Cardiomyocytes

Human Cardiomyocytes

gt95 pure cryopreserved ready to use

gt4x106 cardiomyocytes per unit

Normal human biology

Broad platform utility for life science research drug

discovery and toxicity testing

Improved workflow with greater predictivity

Full product solution unlimited quantities

6

iCell CardiomyocytesCharacterization

Electrophysiology E-C Coupling Contractility

Enables mechanistic toxicity testing

Whole-Genome Gene Expression

Relevant amp stable over time in culture

------ Adult myocardium____ d28 iCell CM____ d120 iCell CM

____ PromoCell____ Celprogen

-------Myocardium

Babiarz et al 2012 Kattman et al 2011 Rana et al 2012 Ma et al 2011

(For a complete list of iCell Cardiomyocytes publications go to

wwwcellulardynamicscom)

Metabolism

Recapitulates normal human

cardiac function

Protein Expression

Appropriate for interrogating

mitochondrial toxicity

iCell Cardiomyocytes native human biology enables

Mechanistic interrogation of cardiac function

Toxicity testing disruption of normal processes

Disease modeling corruption of normal processes

Well represented in the peer reviewed literature

~40 iCell Cardiomyocytes pubs to-date

More than all other commercial iPSC-CMs combined

7

1 Nakamura Y1 Matsuo J (2014) Assessment of testing methods for

drug-induced repolarization delay and arrhythmias in an iPS cell-

derived cardiomyocyte sheet multi-site validation study J

Pharmacol Sci 124(4)494-501

2 Eldridge S Guo L et al (2014) Examining the Protective Role of

ErbB2 Modulation in Human Induced Pluripotent Stem Cell-

Derived Cardiomyocytes Toxicol Sci 2014 Jul 23 pii kfu150

[Epub ahead of print]

3 Kolaja K (2014) Stem cells and stem cell-derived tissues and their

use in safety assessment J Biol Chem 2014 Feb 21289(8)4555-

61

4 Uesugi M Ojima A et al (2014) Low-density plating is sufficient to

induce cardiac hypertrophy and electrical remodeling in highly

purified human iPS cell-derived cardiomyocytes J Pharmacol

Toxicol Methods 69(2)177-88

5 Cameron BJ Gerry AB et al (2013) Identification of a Titin-

derived HLA-A1-presented peptide as a cross-reactive target for

engineered MAGE A3-directed T cells Sci Transl Med

5(197)197ra103

6 Carlson C Koonce C et al (2013) Phenotypic screening with

human iPS cell-derived cardiomyocytes HTS-compatible assays

for interrogating cardiac hypertrophy J Biomol Screen

18(10)1203-11

7 Doherty K Wappel R et al (2013) Multiparameter in vitro toxicity

testing of crizotinib sunitinib erlotinib and nilotinib in human

cardiomyocytes Toxicol Appl Pharmacol 272(1)245-55

8 Fine M Lu F et al (2013) Human Induced Pluripotent Stem Cell-

derived Cardiomyocytes for Studies of Cardiac Ion Transporters

Am J Physiol Cell Physiol 305(5)C481-91

9 Guo L Coyle l et al (2013) Refining the Human iPSC-

Cardiomyocyte Arrhythmic Risk Assessment Model Toxicol Sci

136(2)581-94

10 Harris K Aylott M et al (2013) Comparison of

Electrophysiological Data from Human Induced Pluripotent Stem

Cell Derived Cardiomyoyctes (hiPSC-CMs) to Functional Pre-

clinical Safety Assays Toxicol Sci 134(2)412-26

11 Ivashchenko CY1 Pipes GC et al (2013) Human-induced

pluripotent stem cell-derived cardiomyocytes exhibit temporal

changes in phenotype Am J Physiol Heart Circ Physiol

305(6)H913-22

12 Jehle J Ficker E et al (2013) Mechanisms of Zolpidem-induced

Long QT Ayndrome Acute Inhibition of Recombinant hERG K+

Channels and Action Potential Prolongation in Human

Cardiomyocytes Derived from Induced Pluripotent Stem Cells

British J Pharm 1681215-29

13 Puppala D Collis LP et al (2013) Comparative Gene Expression

Profiling in Human Induced Pluripotent Stem Cell Derived

Cardiocytes and Human and Cynomolgus Heart Tissue Toxicol

Sci 131292-301

14 Rao C Prodromakis T et al (2013) The effect of microgrooved

culture substrates on calcium cycling of cardiac myocytes

derived from human induced pluripotent stem cells Biomaterials

34(10)2399-411

15 Schweikart K Guo L et al (2013) The Effects of Jaspamide on

Human Cardiomyocyte Function and Cardiac Ion Channel Activity

Toxicol in Vitro 27745-51

16 Sirenko O Crittenden C et al (2013) Multiparameter In Vitro

Assessment of Compound Effects on Cardiomyocyte Physiology

Using iPS Cells J Biomol Screening 1839-53

17 Sirenko O Cromwell EF et al (2013) Assessment of beating

parameters in human induced pluripotent stem cells enables

quantitative in vitro screening for cardiotoxicity Toxicol Appl

Pharmacol 273(3)500-07

18 Babiarz JE Ravon M et al (2012) Determination of the Human

Cardiomyocyte mRNA and miRNA Differentiation Network by

Fine-scale Profiling Stem Cells Dev 211956-65

19 Cerignoli R Charlot D et al (2012) High Throughput Measurement

of Ca2+ Dynamics for Drug Risk Assessment in Human Stem Cell-

derived Cardiomyocytes by Kinetic Image Cytometry

J Pharmacol Toxicol Methods 66246-256

20 Lee P Kloss M et al (2012) Simultaneous Voltage and Calcium

Mapping of Genetically Purified Human Induced Pluripotent Stem

Cell-derived Cardiac Myocyte Monolayers Circ Res 1101556-63

21 Mioulane M Foldes G et al (2012) Development of High Content

Imaging Methods for Cell Death Detection in Human Pluripotent

Stem Cell-derived Cardiomyocytes J of Cardiovasc Trans Res

5593-604

22 Rana P Anson BD et al (2012) Characterization of Human-

induced Pluripotent Stem Cell-derived Cardiomyocytes

Bioenergetics and Utilization in Safety Screening Toxicol Sci

130117-31

23 Reynolds JG Geretti E et al (2012) HER2-targeted Liposomal

Doxorubicin Displays Enhanced Anti-tumorigenic Effects without

Associated Cardiotoxicity Toxicol Appl Pharmacol 2621-10

24 Wei H Zhang G et al (2012) Hydrogen Sulfide Suppresses

Outward Rectifier Potassium Currents in Human Pluripotent Stem

Cell-Derived Cardiomyocytes Plos One 7(11)e50641

25 Zhi D Irvin MR et al (2012) Whole-exome Sequencing and an

iPSC-derived Cardiomyocyte Model Provides a Powerful Platform

for Gene Discovery in Left Ventricular Hypertrophy Frontiers in

Genetics 392

26 Cohen JD Babiarz JE et al (2011) Use of Human Stem Cell-

derived Cardiomyocytes to Examine Sunitinib Mediated

Cardiotoxicity and Electrophysiological Alterations Toxicol Appl

Pharmacol 25774-83

27 Guo L Qian JY et al (2011) The Electrophysiological Effects of

Cardiac Glycosides in Human iPSC-derived Cardiomyocytes and

in Guinea Pig Isolated Hearts Cell Physiol Biochem 27453-462

28 Guo L Abrams RM et al (2011) Estimating the Risk of Drug-

induced Proarrhythmia Using Human Induced Pluripotent Stem

Cell-derived Cardiomyocytes Toxicol Sci 123281-289

29 Jonsson MKB Wang QD et al (2011) Impedance-based Detection

of Beating Rhythm and Proarrhythmic Effects of Compounds on

Stem Cell-derived Cardiomyocytes Assay and Drug Dev Tech 91-

11

30 Ma J Guo L et al (2011) High Purity Human-induced Pluripotent

Stem Cell-derived Cardiomyocytes Electrophysiological

Properties of Action Potentials and Ionic Currents Am J Physiol

Heart Circ Physiol 301H2006-H2017

iCell CardiomyocytesMarket Validation (82014)

~40 Peer-reviewed

Publications (102014)

bull Characterization

bull Toxicity testing

bull Disease modeling

5

iCell Cardiomyocytes

Human Cardiomyocytes

gt95 pure cryopreserved ready to use

gt4x106 cardiomyocytes per unit

Normal human biology

Broad platform utility for life science research drug

discovery and toxicity testing

Improved workflow with greater predictivity

Full product solution unlimited quantities

6

iCell CardiomyocytesCharacterization

Electrophysiology E-C Coupling Contractility

Enables mechanistic toxicity testing

Whole-Genome Gene Expression

Relevant amp stable over time in culture

------ Adult myocardium____ d28 iCell CM____ d120 iCell CM

____ PromoCell____ Celprogen

-------Myocardium

Babiarz et al 2012 Kattman et al 2011 Rana et al 2012 Ma et al 2011

(For a complete list of iCell Cardiomyocytes publications go to

wwwcellulardynamicscom)

Metabolism

Recapitulates normal human

cardiac function

Protein Expression

Appropriate for interrogating

mitochondrial toxicity

iCell Cardiomyocytes native human biology enables

Mechanistic interrogation of cardiac function

Toxicity testing disruption of normal processes

Disease modeling corruption of normal processes

Well represented in the peer reviewed literature

~40 iCell Cardiomyocytes pubs to-date

More than all other commercial iPSC-CMs combined

7

1 Nakamura Y1 Matsuo J (2014) Assessment of testing methods for

drug-induced repolarization delay and arrhythmias in an iPS cell-

derived cardiomyocyte sheet multi-site validation study J

Pharmacol Sci 124(4)494-501

2 Eldridge S Guo L et al (2014) Examining the Protective Role of

ErbB2 Modulation in Human Induced Pluripotent Stem Cell-

Derived Cardiomyocytes Toxicol Sci 2014 Jul 23 pii kfu150

[Epub ahead of print]

3 Kolaja K (2014) Stem cells and stem cell-derived tissues and their

use in safety assessment J Biol Chem 2014 Feb 21289(8)4555-

61

4 Uesugi M Ojima A et al (2014) Low-density plating is sufficient to

induce cardiac hypertrophy and electrical remodeling in highly

purified human iPS cell-derived cardiomyocytes J Pharmacol

Toxicol Methods 69(2)177-88

5 Cameron BJ Gerry AB et al (2013) Identification of a Titin-

derived HLA-A1-presented peptide as a cross-reactive target for

engineered MAGE A3-directed T cells Sci Transl Med

5(197)197ra103

6 Carlson C Koonce C et al (2013) Phenotypic screening with

human iPS cell-derived cardiomyocytes HTS-compatible assays

for interrogating cardiac hypertrophy J Biomol Screen

18(10)1203-11

7 Doherty K Wappel R et al (2013) Multiparameter in vitro toxicity

testing of crizotinib sunitinib erlotinib and nilotinib in human

cardiomyocytes Toxicol Appl Pharmacol 272(1)245-55

8 Fine M Lu F et al (2013) Human Induced Pluripotent Stem Cell-

derived Cardiomyocytes for Studies of Cardiac Ion Transporters

Am J Physiol Cell Physiol 305(5)C481-91

9 Guo L Coyle l et al (2013) Refining the Human iPSC-

Cardiomyocyte Arrhythmic Risk Assessment Model Toxicol Sci

136(2)581-94

10 Harris K Aylott M et al (2013) Comparison of

Electrophysiological Data from Human Induced Pluripotent Stem

Cell Derived Cardiomyoyctes (hiPSC-CMs) to Functional Pre-

clinical Safety Assays Toxicol Sci 134(2)412-26

11 Ivashchenko CY1 Pipes GC et al (2013) Human-induced

pluripotent stem cell-derived cardiomyocytes exhibit temporal

changes in phenotype Am J Physiol Heart Circ Physiol

305(6)H913-22

12 Jehle J Ficker E et al (2013) Mechanisms of Zolpidem-induced

Long QT Ayndrome Acute Inhibition of Recombinant hERG K+

Channels and Action Potential Prolongation in Human

Cardiomyocytes Derived from Induced Pluripotent Stem Cells

British J Pharm 1681215-29

13 Puppala D Collis LP et al (2013) Comparative Gene Expression

Profiling in Human Induced Pluripotent Stem Cell Derived

Cardiocytes and Human and Cynomolgus Heart Tissue Toxicol

Sci 131292-301

14 Rao C Prodromakis T et al (2013) The effect of microgrooved

culture substrates on calcium cycling of cardiac myocytes

derived from human induced pluripotent stem cells Biomaterials

34(10)2399-411

15 Schweikart K Guo L et al (2013) The Effects of Jaspamide on

Human Cardiomyocyte Function and Cardiac Ion Channel Activity

Toxicol in Vitro 27745-51

16 Sirenko O Crittenden C et al (2013) Multiparameter In Vitro

Assessment of Compound Effects on Cardiomyocyte Physiology

Using iPS Cells J Biomol Screening 1839-53

17 Sirenko O Cromwell EF et al (2013) Assessment of beating

parameters in human induced pluripotent stem cells enables

quantitative in vitro screening for cardiotoxicity Toxicol Appl

Pharmacol 273(3)500-07

18 Babiarz JE Ravon M et al (2012) Determination of the Human

Cardiomyocyte mRNA and miRNA Differentiation Network by

Fine-scale Profiling Stem Cells Dev 211956-65

19 Cerignoli R Charlot D et al (2012) High Throughput Measurement

of Ca2+ Dynamics for Drug Risk Assessment in Human Stem Cell-

derived Cardiomyocytes by Kinetic Image Cytometry

J Pharmacol Toxicol Methods 66246-256

20 Lee P Kloss M et al (2012) Simultaneous Voltage and Calcium

Mapping of Genetically Purified Human Induced Pluripotent Stem

Cell-derived Cardiac Myocyte Monolayers Circ Res 1101556-63

21 Mioulane M Foldes G et al (2012) Development of High Content

Imaging Methods for Cell Death Detection in Human Pluripotent

Stem Cell-derived Cardiomyocytes J of Cardiovasc Trans Res

5593-604

22 Rana P Anson BD et al (2012) Characterization of Human-

induced Pluripotent Stem Cell-derived Cardiomyocytes

Bioenergetics and Utilization in Safety Screening Toxicol Sci

130117-31

23 Reynolds JG Geretti E et al (2012) HER2-targeted Liposomal

Doxorubicin Displays Enhanced Anti-tumorigenic Effects without

Associated Cardiotoxicity Toxicol Appl Pharmacol 2621-10

24 Wei H Zhang G et al (2012) Hydrogen Sulfide Suppresses

Outward Rectifier Potassium Currents in Human Pluripotent Stem

Cell-Derived Cardiomyocytes Plos One 7(11)e50641

25 Zhi D Irvin MR et al (2012) Whole-exome Sequencing and an

iPSC-derived Cardiomyocyte Model Provides a Powerful Platform

for Gene Discovery in Left Ventricular Hypertrophy Frontiers in

Genetics 392

26 Cohen JD Babiarz JE et al (2011) Use of Human Stem Cell-

derived Cardiomyocytes to Examine Sunitinib Mediated

Cardiotoxicity and Electrophysiological Alterations Toxicol Appl

Pharmacol 25774-83

27 Guo L Qian JY et al (2011) The Electrophysiological Effects of

Cardiac Glycosides in Human iPSC-derived Cardiomyocytes and

in Guinea Pig Isolated Hearts Cell Physiol Biochem 27453-462

28 Guo L Abrams RM et al (2011) Estimating the Risk of Drug-

induced Proarrhythmia Using Human Induced Pluripotent Stem

Cell-derived Cardiomyocytes Toxicol Sci 123281-289

29 Jonsson MKB Wang QD et al (2011) Impedance-based Detection

of Beating Rhythm and Proarrhythmic Effects of Compounds on

Stem Cell-derived Cardiomyocytes Assay and Drug Dev Tech 91-

11

30 Ma J Guo L et al (2011) High Purity Human-induced Pluripotent

Stem Cell-derived Cardiomyocytes Electrophysiological

Properties of Action Potentials and Ionic Currents Am J Physiol

Heart Circ Physiol 301H2006-H2017

iCell CardiomyocytesMarket Validation (82014)

~40 Peer-reviewed

Publications (102014)

bull Characterization

bull Toxicity testing

bull Disease modeling

6

iCell CardiomyocytesCharacterization

Electrophysiology E-C Coupling Contractility

Enables mechanistic toxicity testing

Whole-Genome Gene Expression

Relevant amp stable over time in culture

------ Adult myocardium____ d28 iCell CM____ d120 iCell CM

____ PromoCell____ Celprogen

-------Myocardium

Babiarz et al 2012 Kattman et al 2011 Rana et al 2012 Ma et al 2011

(For a complete list of iCell Cardiomyocytes publications go to

wwwcellulardynamicscom)

Metabolism

Recapitulates normal human

cardiac function

Protein Expression

Appropriate for interrogating

mitochondrial toxicity

iCell Cardiomyocytes native human biology enables

Mechanistic interrogation of cardiac function

Toxicity testing disruption of normal processes

Disease modeling corruption of normal processes

Well represented in the peer reviewed literature

~40 iCell Cardiomyocytes pubs to-date

More than all other commercial iPSC-CMs combined

7

1 Nakamura Y1 Matsuo J (2014) Assessment of testing methods for

drug-induced repolarization delay and arrhythmias in an iPS cell-

derived cardiomyocyte sheet multi-site validation study J

Pharmacol Sci 124(4)494-501

2 Eldridge S Guo L et al (2014) Examining the Protective Role of

ErbB2 Modulation in Human Induced Pluripotent Stem Cell-

Derived Cardiomyocytes Toxicol Sci 2014 Jul 23 pii kfu150

[Epub ahead of print]

3 Kolaja K (2014) Stem cells and stem cell-derived tissues and their

use in safety assessment J Biol Chem 2014 Feb 21289(8)4555-

61

4 Uesugi M Ojima A et al (2014) Low-density plating is sufficient to

induce cardiac hypertrophy and electrical remodeling in highly

purified human iPS cell-derived cardiomyocytes J Pharmacol

Toxicol Methods 69(2)177-88

5 Cameron BJ Gerry AB et al (2013) Identification of a Titin-

derived HLA-A1-presented peptide as a cross-reactive target for

engineered MAGE A3-directed T cells Sci Transl Med

5(197)197ra103

6 Carlson C Koonce C et al (2013) Phenotypic screening with

human iPS cell-derived cardiomyocytes HTS-compatible assays

for interrogating cardiac hypertrophy J Biomol Screen

18(10)1203-11

7 Doherty K Wappel R et al (2013) Multiparameter in vitro toxicity

testing of crizotinib sunitinib erlotinib and nilotinib in human

cardiomyocytes Toxicol Appl Pharmacol 272(1)245-55

8 Fine M Lu F et al (2013) Human Induced Pluripotent Stem Cell-

derived Cardiomyocytes for Studies of Cardiac Ion Transporters

Am J Physiol Cell Physiol 305(5)C481-91

9 Guo L Coyle l et al (2013) Refining the Human iPSC-

Cardiomyocyte Arrhythmic Risk Assessment Model Toxicol Sci

136(2)581-94

10 Harris K Aylott M et al (2013) Comparison of

Electrophysiological Data from Human Induced Pluripotent Stem

Cell Derived Cardiomyoyctes (hiPSC-CMs) to Functional Pre-

clinical Safety Assays Toxicol Sci 134(2)412-26

11 Ivashchenko CY1 Pipes GC et al (2013) Human-induced

pluripotent stem cell-derived cardiomyocytes exhibit temporal

changes in phenotype Am J Physiol Heart Circ Physiol

305(6)H913-22

12 Jehle J Ficker E et al (2013) Mechanisms of Zolpidem-induced

Long QT Ayndrome Acute Inhibition of Recombinant hERG K+

Channels and Action Potential Prolongation in Human

Cardiomyocytes Derived from Induced Pluripotent Stem Cells

British J Pharm 1681215-29

13 Puppala D Collis LP et al (2013) Comparative Gene Expression

Profiling in Human Induced Pluripotent Stem Cell Derived

Cardiocytes and Human and Cynomolgus Heart Tissue Toxicol

Sci 131292-301

14 Rao C Prodromakis T et al (2013) The effect of microgrooved

culture substrates on calcium cycling of cardiac myocytes

derived from human induced pluripotent stem cells Biomaterials

34(10)2399-411

15 Schweikart K Guo L et al (2013) The Effects of Jaspamide on

Human Cardiomyocyte Function and Cardiac Ion Channel Activity

Toxicol in Vitro 27745-51

16 Sirenko O Crittenden C et al (2013) Multiparameter In Vitro

Assessment of Compound Effects on Cardiomyocyte Physiology

Using iPS Cells J Biomol Screening 1839-53

17 Sirenko O Cromwell EF et al (2013) Assessment of beating

parameters in human induced pluripotent stem cells enables

quantitative in vitro screening for cardiotoxicity Toxicol Appl

Pharmacol 273(3)500-07

18 Babiarz JE Ravon M et al (2012) Determination of the Human

Cardiomyocyte mRNA and miRNA Differentiation Network by

Fine-scale Profiling Stem Cells Dev 211956-65

19 Cerignoli R Charlot D et al (2012) High Throughput Measurement

of Ca2+ Dynamics for Drug Risk Assessment in Human Stem Cell-

derived Cardiomyocytes by Kinetic Image Cytometry

J Pharmacol Toxicol Methods 66246-256

20 Lee P Kloss M et al (2012) Simultaneous Voltage and Calcium

Mapping of Genetically Purified Human Induced Pluripotent Stem

Cell-derived Cardiac Myocyte Monolayers Circ Res 1101556-63

21 Mioulane M Foldes G et al (2012) Development of High Content

Imaging Methods for Cell Death Detection in Human Pluripotent

Stem Cell-derived Cardiomyocytes J of Cardiovasc Trans Res

5593-604

22 Rana P Anson BD et al (2012) Characterization of Human-

induced Pluripotent Stem Cell-derived Cardiomyocytes

Bioenergetics and Utilization in Safety Screening Toxicol Sci

130117-31

23 Reynolds JG Geretti E et al (2012) HER2-targeted Liposomal

Doxorubicin Displays Enhanced Anti-tumorigenic Effects without

Associated Cardiotoxicity Toxicol Appl Pharmacol 2621-10

24 Wei H Zhang G et al (2012) Hydrogen Sulfide Suppresses

Outward Rectifier Potassium Currents in Human Pluripotent Stem

Cell-Derived Cardiomyocytes Plos One 7(11)e50641

25 Zhi D Irvin MR et al (2012) Whole-exome Sequencing and an

iPSC-derived Cardiomyocyte Model Provides a Powerful Platform

for Gene Discovery in Left Ventricular Hypertrophy Frontiers in

Genetics 392

26 Cohen JD Babiarz JE et al (2011) Use of Human Stem Cell-

derived Cardiomyocytes to Examine Sunitinib Mediated

Cardiotoxicity and Electrophysiological Alterations Toxicol Appl

Pharmacol 25774-83

27 Guo L Qian JY et al (2011) The Electrophysiological Effects of

Cardiac Glycosides in Human iPSC-derived Cardiomyocytes and

in Guinea Pig Isolated Hearts Cell Physiol Biochem 27453-462

28 Guo L Abrams RM et al (2011) Estimating the Risk of Drug-

induced Proarrhythmia Using Human Induced Pluripotent Stem

Cell-derived Cardiomyocytes Toxicol Sci 123281-289

29 Jonsson MKB Wang QD et al (2011) Impedance-based Detection

of Beating Rhythm and Proarrhythmic Effects of Compounds on

Stem Cell-derived Cardiomyocytes Assay and Drug Dev Tech 91-

11

30 Ma J Guo L et al (2011) High Purity Human-induced Pluripotent

Stem Cell-derived Cardiomyocytes Electrophysiological

Properties of Action Potentials and Ionic Currents Am J Physiol

Heart Circ Physiol 301H2006-H2017

iCell CardiomyocytesMarket Validation (82014)

~40 Peer-reviewed

Publications (102014)

bull Characterization

bull Toxicity testing

bull Disease modeling

7

1 Nakamura Y1 Matsuo J (2014) Assessment of testing methods for

drug-induced repolarization delay and arrhythmias in an iPS cell-

derived cardiomyocyte sheet multi-site validation study J

Pharmacol Sci 124(4)494-501

2 Eldridge S Guo L et al (2014) Examining the Protective Role of

ErbB2 Modulation in Human Induced Pluripotent Stem Cell-

Derived Cardiomyocytes Toxicol Sci 2014 Jul 23 pii kfu150

[Epub ahead of print]

3 Kolaja K (2014) Stem cells and stem cell-derived tissues and their

use in safety assessment J Biol Chem 2014 Feb 21289(8)4555-

61

4 Uesugi M Ojima A et al (2014) Low-density plating is sufficient to

induce cardiac hypertrophy and electrical remodeling in highly

purified human iPS cell-derived cardiomyocytes J Pharmacol

Toxicol Methods 69(2)177-88

5 Cameron BJ Gerry AB et al (2013) Identification of a Titin-

derived HLA-A1-presented peptide as a cross-reactive target for

engineered MAGE A3-directed T cells Sci Transl Med

5(197)197ra103

6 Carlson C Koonce C et al (2013) Phenotypic screening with

human iPS cell-derived cardiomyocytes HTS-compatible assays

for interrogating cardiac hypertrophy J Biomol Screen

18(10)1203-11

7 Doherty K Wappel R et al (2013) Multiparameter in vitro toxicity

testing of crizotinib sunitinib erlotinib and nilotinib in human

cardiomyocytes Toxicol Appl Pharmacol 272(1)245-55

8 Fine M Lu F et al (2013) Human Induced Pluripotent Stem Cell-

derived Cardiomyocytes for Studies of Cardiac Ion Transporters

Am J Physiol Cell Physiol 305(5)C481-91

9 Guo L Coyle l et al (2013) Refining the Human iPSC-

Cardiomyocyte Arrhythmic Risk Assessment Model Toxicol Sci

136(2)581-94

10 Harris K Aylott M et al (2013) Comparison of

Electrophysiological Data from Human Induced Pluripotent Stem

Cell Derived Cardiomyoyctes (hiPSC-CMs) to Functional Pre-

clinical Safety Assays Toxicol Sci 134(2)412-26

11 Ivashchenko CY1 Pipes GC et al (2013) Human-induced

pluripotent stem cell-derived cardiomyocytes exhibit temporal

changes in phenotype Am J Physiol Heart Circ Physiol

305(6)H913-22

12 Jehle J Ficker E et al (2013) Mechanisms of Zolpidem-induced

Long QT Ayndrome Acute Inhibition of Recombinant hERG K+

Channels and Action Potential Prolongation in Human

Cardiomyocytes Derived from Induced Pluripotent Stem Cells

British J Pharm 1681215-29

13 Puppala D Collis LP et al (2013) Comparative Gene Expression

Profiling in Human Induced Pluripotent Stem Cell Derived

Cardiocytes and Human and Cynomolgus Heart Tissue Toxicol

Sci 131292-301

14 Rao C Prodromakis T et al (2013) The effect of microgrooved

culture substrates on calcium cycling of cardiac myocytes

derived from human induced pluripotent stem cells Biomaterials

34(10)2399-411

15 Schweikart K Guo L et al (2013) The Effects of Jaspamide on

Human Cardiomyocyte Function and Cardiac Ion Channel Activity

Toxicol in Vitro 27745-51

16 Sirenko O Crittenden C et al (2013) Multiparameter In Vitro

Assessment of Compound Effects on Cardiomyocyte Physiology

Using iPS Cells J Biomol Screening 1839-53

17 Sirenko O Cromwell EF et al (2013) Assessment of beating

parameters in human induced pluripotent stem cells enables

quantitative in vitro screening for cardiotoxicity Toxicol Appl

Pharmacol 273(3)500-07

18 Babiarz JE Ravon M et al (2012) Determination of the Human

Cardiomyocyte mRNA and miRNA Differentiation Network by

Fine-scale Profiling Stem Cells Dev 211956-65

19 Cerignoli R Charlot D et al (2012) High Throughput Measurement

of Ca2+ Dynamics for Drug Risk Assessment in Human Stem Cell-

derived Cardiomyocytes by Kinetic Image Cytometry

J Pharmacol Toxicol Methods 66246-256

20 Lee P Kloss M et al (2012) Simultaneous Voltage and Calcium

Mapping of Genetically Purified Human Induced Pluripotent Stem

Cell-derived Cardiac Myocyte Monolayers Circ Res 1101556-63

21 Mioulane M Foldes G et al (2012) Development of High Content

Imaging Methods for Cell Death Detection in Human Pluripotent

Stem Cell-derived Cardiomyocytes J of Cardiovasc Trans Res

5593-604

22 Rana P Anson BD et al (2012) Characterization of Human-

induced Pluripotent Stem Cell-derived Cardiomyocytes

Bioenergetics and Utilization in Safety Screening Toxicol Sci

130117-31

23 Reynolds JG Geretti E et al (2012) HER2-targeted Liposomal

Doxorubicin Displays Enhanced Anti-tumorigenic Effects without

Associated Cardiotoxicity Toxicol Appl Pharmacol 2621-10

24 Wei H Zhang G et al (2012) Hydrogen Sulfide Suppresses

Outward Rectifier Potassium Currents in Human Pluripotent Stem

Cell-Derived Cardiomyocytes Plos One 7(11)e50641

25 Zhi D Irvin MR et al (2012) Whole-exome Sequencing and an

iPSC-derived Cardiomyocyte Model Provides a Powerful Platform

for Gene Discovery in Left Ventricular Hypertrophy Frontiers in

Genetics 392

26 Cohen JD Babiarz JE et al (2011) Use of Human Stem Cell-

derived Cardiomyocytes to Examine Sunitinib Mediated

Cardiotoxicity and Electrophysiological Alterations Toxicol Appl

Pharmacol 25774-83

27 Guo L Qian JY et al (2011) The Electrophysiological Effects of

Cardiac Glycosides in Human iPSC-derived Cardiomyocytes and

in Guinea Pig Isolated Hearts Cell Physiol Biochem 27453-462

28 Guo L Abrams RM et al (2011) Estimating the Risk of Drug-

induced Proarrhythmia Using Human Induced Pluripotent Stem

Cell-derived Cardiomyocytes Toxicol Sci 123281-289

29 Jonsson MKB Wang QD et al (2011) Impedance-based Detection

of Beating Rhythm and Proarrhythmic Effects of Compounds on

Stem Cell-derived Cardiomyocytes Assay and Drug Dev Tech 91-

11

30 Ma J Guo L et al (2011) High Purity Human-induced Pluripotent

Stem Cell-derived Cardiomyocytes Electrophysiological

Properties of Action Potentials and Ionic Currents Am J Physiol

Heart Circ Physiol 301H2006-H2017

iCell CardiomyocytesMarket Validation (82014)

~40 Peer-reviewed

Publications (102014)

bull Characterization

bull Toxicity testing

bull Disease modeling

8

Interrogating BiologyElectrical and Mechanical Activity

Cardiomyocyte Activity

Electrical biochemical and mechanical

Electrical

Biochemical

Mechanical

Three main areas need to be

considered for cardiotoxicity

9

Predicting ProarrhythmiaLabel Free Impedance Measurements

iCell Cardiomyocytes provide a more predictive tool for detecting proarrhythmia

Greater Predictivity

~120 Compounds

gt90 -- QT prediction

gt82 -- arrhy prediction

Qualitative Assessment

Guo et al 2011

Guo et al 2013

Relevant biology and metrics leads to

greater predictivity

Expanded dataset

o ~120 compounds

Fine tune metrics

o Include beat rate

atypical beats

onset of IB20

o Use concentration

thresholds or IB20

rank ordering

10

KI-induced Cardiotoxicity

Deconvoluting the problem

S Lamore AstraZeneca

iCell Cardiomyocytes provide a predictive tool for detecting KI toxicity

12

Parameter IonOptix

sensitivity 83

specificity 84

accuracy 82

pos predict 90

neg predict 76

Parameter Impedance3

sensitivity 90

specificity 74

accuracy 84

pos predict 85

neg predict 82

IonOptix

Good to excellent validation parameters

Primary culture from dog heart

Low throughput

Conventional Interrogation

Screening with iCell Cardiomyocytes

1 AR Harmer Tox App Pharm 2012

iCell Cardiomyocytes provide a predictive

model for detecting contractility

2 C Scott (Tox Sci 2014 )

49 compound validation set with actives and inactives

xCelligence RTCA

Good to excellent assay parameters2

Human cardiomyocytes

Medium to high throughput

Detecting Effects on ContractilityMoving to higher throughput predictive detection

13

iCell Cardiomyocytes and xCelligence RTCA Predictive solutions for multi-modal cardiotoxicity

14

Case 1 Cardiac HypertrophyiCellreg Cardiomyocytes

Control

ET-1 (10 nM)

-14 -13 -12 -11 -10 -9 -81000

1100

1200

1300

1400

1500

Log [ET-1] (M)

To

tal A

rea (

m2)

Control

+ET-1 (10 nM)

Control

+ET-1 (10 nM)

Cell SizeCytoskeletal

Rearrangements

Fetal Gene

Expression

iCell Cardiomyocytes exhibit classic hallmarks of cardiac hypertrophy

15

iCell Cardiomyocyte HypertrophyRelevance

Aggarwal et al Plos One 2014

Hypertrophic iCell Cardiomyocytes share similarities with cardiac

samples from LVH patientsiCell Cardiomyocytes are a relevant system for cardiac hypertrophy

16

Case 2 Diabetic Cardiac MyopathyEnvironmental and Innate Induction

Application of a diabetic medium (ET-1 cortisol glucose) to iCell CMs induces a hypertrophic phenotype

Increases in

bull Cell and nuclear size

bull Cytoskeletal disorganization

bull Glycolysis

bull Lipid accumulation

bull ROS Accumulation

Drawnel et al Cell Reports 2014

ROS Production

Diabetic patient iPSC-cardiomyocyte show a hypertrophic phenotype under basal conditions

Cytoskeletal

disorganization

Compounds have been identified that revert the

diabetic phenotype present in the iPSC-CMs

iCell Cardiomyocytes can be used for induced and innate disease modeling

17

iCell Cardiomyocytes were used to verify

a potential therapeutic target for human

dilated cardiomyopathy

Over-expression and knockdown of

target in iCell Cardiomyocytes affected

related proteins

Confocal imaging demonstrates effects of ILK on Ca2+ transients

iCell Cardiomyocytes provided a model

for in-vitro target validation and

subsequent functional screens

Phenotypic screens in iCell Cardiomyocytes were

utilized to show functional effects of target modulation

Impedance measurements show rhythm and contractile phenotype

Over-expression of target increases function

ILK is in a protein scaffold from control but not DCM

cardiac tissue

Does this represent a potential DCM targets

Case 3 Dilated CardiomyopathyTarget verification and functional assays

18

iCell Neurons

iCell Neurons pure functional

human neurons made at scale

Post-thaw Time course (10x Objective)

Morphology

Day 1 Day 8

5 ml Pellet of Pure

Neurons

Phenotype

MAP2 GABA Hoechst

Purity

Identity

Scale

Electrophysiology

19

iCell Neurons

iCell Neurons are a mixed population of cortical GABAergic and Glutamatergic neurons

that enable new in-vitro research efforts

5 ml Pellet of Pure

Neurons = ~4

Billion Neurons

Alzheimerrsquos Research

Autism Investigations

Latent VZV Infection

Botox batch release testing

20

The Power of IPSC Technology

hellippopulations

What abouthellip

21

StandardizationManufacturing Benchmarks

NHLBI Next Generation Genetic

Association Studies(RFA-HL-11-066)

250 patient samples - HyperGEN cohort

GWAS ndash Left Ventricular Hypertrophy (LVH)

Derive iPS cells and cardiomyocytes from

all 250 individuals

Induce hypertrophy phenotype perform

molecular analyses

Correlate GWAS findings with in vitro

phenotype

Scale-Out

Manufacturing

bull 1000rsquos of individuals

bull Billions of cells

Scale-Up

Manufacturing

bull Quality

bull Quantity

bull Purity

CDI Manufacturing Benchmarks (cells per day gt95 purity)

2 billion iPS cells

1 billion cardiomyocytes

1 billion neurons

05 billion endothelial cells

04 billion hepatocytes

22

NHLBI Next Generation Genetic

Association Studies (RFA-HL-11-066)

250 patient samples ndash HyperGEN cohort

GWAS ndash Left Ventricular Hypertrophy (LVH)

Derive iPS cells and cardiomyocytes

Induce hypertrophy perform molecular analyses

Correlate GWAS findings with in vitro phenotype

Progress as of July 2014

250 donors reprogrammed

Differentiation protocol optimized to work robustly across all lines

128 iPS cell lines (1 per donor) are differentiated or in progress

Cardiomyocytes from 89 donors cryopreserved amp all pass QC

20 batches of cardiomyocytes are in currently being tested in

hypertrophy assays

Initial data show Et-1 EC50 correlation with progression of disease (Uli Broeckel MCOW)

Progress ReportPopulation genomics and left ventricular hypertrophy

CDIrsquos iPSC technology is enabling population studies

23

CIRM AwardiPS Cell Manufacture amp Banking

California Institute for Regenerative Medicine (CIRM)

Human iPS Cell Initiative ndash 3 Awards

Sample Collection (7 awardees)

iPS Cell Derivation (CDI)

iPS Cell Banking (Coriell CDI primary subcontractor)

iPS Cell Derivation

3000 donors (healthy amp disease phenotypes)

3 iPS cell clones per donor

Disease categories epilepsy autism cerebral palsy cardiomyopathy Alzheimerrsquos

disease eye diseases hepatitis (HCV) non-alcoholic steatohepatitis (NASH)

pulmonary fibrosis

Derived from peripheral blood (preferred) or skin fibroblasts

Episomal ldquofootprint-freerdquo method

CDI ndash Coriell Partnership

Extensive collaboration to bring together expertise in electronic record-keeping

sample tracking iPS cell derivation amp characterization cell banking amp distribution

Joint facility located within the Buck Institute Novato CA

24

iCell CardiomyocytesDevelopment Regulatory Guidance

Nature Reviews Drug Discovery (Aug Sept 2013)

Product launch regulatory evaluation in 3 years

iPS cell-derived cardiomyocytes are

being evaluated for use in arrhythmia

assessment amp as a replacement for

thorough QT studies

25

bullRight species - human

bull Essential functionality

bull Active use in toxicity testing and drug discovery

bull Scalable and applicable to populations

bull Involved in the changing regulatory landscape

Technology

Trigger

Trough of

Disillusionment

Slope of

Enlightenment

Plateau of

Productivity

Peak of

Inflated

Expectation

Maturity

Vis

ibili

tyGartnercom

Technology Hype CycleWhere are we

M Peters

26

9

Predicting ProarrhythmiaLabel Free Impedance Measurements

iCell Cardiomyocytes provide a more predictive tool for detecting proarrhythmia

Greater Predictivity

~120 Compounds

gt90 -- QT prediction

gt82 -- arrhy prediction

Qualitative Assessment

Guo et al 2011

Guo et al 2013

Relevant biology and metrics leads to

greater predictivity

Expanded dataset

o ~120 compounds

Fine tune metrics

o Include beat rate

atypical beats

onset of IB20

o Use concentration

thresholds or IB20

rank ordering

10

KI-induced Cardiotoxicity

Deconvoluting the problem

S Lamore AstraZeneca

iCell Cardiomyocytes provide a predictive tool for detecting KI toxicity

12

Parameter IonOptix

sensitivity 83

specificity 84

accuracy 82

pos predict 90

neg predict 76

Parameter Impedance3

sensitivity 90

specificity 74

accuracy 84

pos predict 85

neg predict 82

IonOptix

Good to excellent validation parameters

Primary culture from dog heart

Low throughput

Conventional Interrogation

Screening with iCell Cardiomyocytes

1 AR Harmer Tox App Pharm 2012

iCell Cardiomyocytes provide a predictive

model for detecting contractility

2 C Scott (Tox Sci 2014 )

49 compound validation set with actives and inactives

xCelligence RTCA

Good to excellent assay parameters2

Human cardiomyocytes

Medium to high throughput

Detecting Effects on ContractilityMoving to higher throughput predictive detection

13

iCell Cardiomyocytes and xCelligence RTCA Predictive solutions for multi-modal cardiotoxicity

14

Case 1 Cardiac HypertrophyiCellreg Cardiomyocytes

Control

ET-1 (10 nM)

-14 -13 -12 -11 -10 -9 -81000

1100

1200

1300

1400

1500

Log [ET-1] (M)

To

tal A

rea (

m2)

Control

+ET-1 (10 nM)

Control

+ET-1 (10 nM)

Cell SizeCytoskeletal

Rearrangements

Fetal Gene

Expression

iCell Cardiomyocytes exhibit classic hallmarks of cardiac hypertrophy

15

iCell Cardiomyocyte HypertrophyRelevance

Aggarwal et al Plos One 2014

Hypertrophic iCell Cardiomyocytes share similarities with cardiac

samples from LVH patientsiCell Cardiomyocytes are a relevant system for cardiac hypertrophy

16

Case 2 Diabetic Cardiac MyopathyEnvironmental and Innate Induction

Application of a diabetic medium (ET-1 cortisol glucose) to iCell CMs induces a hypertrophic phenotype

Increases in

bull Cell and nuclear size

bull Cytoskeletal disorganization

bull Glycolysis

bull Lipid accumulation

bull ROS Accumulation

Drawnel et al Cell Reports 2014

ROS Production

Diabetic patient iPSC-cardiomyocyte show a hypertrophic phenotype under basal conditions

Cytoskeletal

disorganization

Compounds have been identified that revert the

diabetic phenotype present in the iPSC-CMs

iCell Cardiomyocytes can be used for induced and innate disease modeling

17

iCell Cardiomyocytes were used to verify

a potential therapeutic target for human

dilated cardiomyopathy

Over-expression and knockdown of

target in iCell Cardiomyocytes affected

related proteins

Confocal imaging demonstrates effects of ILK on Ca2+ transients

iCell Cardiomyocytes provided a model

for in-vitro target validation and

subsequent functional screens

Phenotypic screens in iCell Cardiomyocytes were

utilized to show functional effects of target modulation

Impedance measurements show rhythm and contractile phenotype

Over-expression of target increases function

ILK is in a protein scaffold from control but not DCM

cardiac tissue

Does this represent a potential DCM targets

Case 3 Dilated CardiomyopathyTarget verification and functional assays

18

iCell Neurons

iCell Neurons pure functional

human neurons made at scale

Post-thaw Time course (10x Objective)

Morphology

Day 1 Day 8

5 ml Pellet of Pure

Neurons

Phenotype

MAP2 GABA Hoechst

Purity

Identity

Scale

Electrophysiology

19

iCell Neurons

iCell Neurons are a mixed population of cortical GABAergic and Glutamatergic neurons

that enable new in-vitro research efforts

5 ml Pellet of Pure

Neurons = ~4

Billion Neurons

Alzheimerrsquos Research

Autism Investigations

Latent VZV Infection

Botox batch release testing

20

The Power of IPSC Technology

hellippopulations

What abouthellip

21

StandardizationManufacturing Benchmarks

NHLBI Next Generation Genetic

Association Studies(RFA-HL-11-066)

250 patient samples - HyperGEN cohort

GWAS ndash Left Ventricular Hypertrophy (LVH)

Derive iPS cells and cardiomyocytes from

all 250 individuals

Induce hypertrophy phenotype perform

molecular analyses

Correlate GWAS findings with in vitro

phenotype

Scale-Out

Manufacturing

bull 1000rsquos of individuals

bull Billions of cells

Scale-Up

Manufacturing

bull Quality

bull Quantity

bull Purity

CDI Manufacturing Benchmarks (cells per day gt95 purity)

2 billion iPS cells

1 billion cardiomyocytes

1 billion neurons

05 billion endothelial cells

04 billion hepatocytes

22

NHLBI Next Generation Genetic

Association Studies (RFA-HL-11-066)

250 patient samples ndash HyperGEN cohort

GWAS ndash Left Ventricular Hypertrophy (LVH)

Derive iPS cells and cardiomyocytes

Induce hypertrophy perform molecular analyses

Correlate GWAS findings with in vitro phenotype

Progress as of July 2014

250 donors reprogrammed

Differentiation protocol optimized to work robustly across all lines

128 iPS cell lines (1 per donor) are differentiated or in progress

Cardiomyocytes from 89 donors cryopreserved amp all pass QC

20 batches of cardiomyocytes are in currently being tested in

hypertrophy assays

Initial data show Et-1 EC50 correlation with progression of disease (Uli Broeckel MCOW)

Progress ReportPopulation genomics and left ventricular hypertrophy

CDIrsquos iPSC technology is enabling population studies

23

CIRM AwardiPS Cell Manufacture amp Banking

California Institute for Regenerative Medicine (CIRM)

Human iPS Cell Initiative ndash 3 Awards

Sample Collection (7 awardees)

iPS Cell Derivation (CDI)

iPS Cell Banking (Coriell CDI primary subcontractor)

iPS Cell Derivation

3000 donors (healthy amp disease phenotypes)

3 iPS cell clones per donor

Disease categories epilepsy autism cerebral palsy cardiomyopathy Alzheimerrsquos

disease eye diseases hepatitis (HCV) non-alcoholic steatohepatitis (NASH)

pulmonary fibrosis

Derived from peripheral blood (preferred) or skin fibroblasts

Episomal ldquofootprint-freerdquo method

CDI ndash Coriell Partnership

Extensive collaboration to bring together expertise in electronic record-keeping

sample tracking iPS cell derivation amp characterization cell banking amp distribution

Joint facility located within the Buck Institute Novato CA

24

iCell CardiomyocytesDevelopment Regulatory Guidance

Nature Reviews Drug Discovery (Aug Sept 2013)

Product launch regulatory evaluation in 3 years

iPS cell-derived cardiomyocytes are

being evaluated for use in arrhythmia

assessment amp as a replacement for

thorough QT studies

25

bullRight species - human

bull Essential functionality

bull Active use in toxicity testing and drug discovery

bull Scalable and applicable to populations

bull Involved in the changing regulatory landscape

Technology

Trigger

Trough of

Disillusionment

Slope of

Enlightenment

Plateau of

Productivity

Peak of

Inflated

Expectation

Maturity

Vis

ibili

tyGartnercom

Technology Hype CycleWhere are we

M Peters

26

10

KI-induced Cardiotoxicity

Deconvoluting the problem

S Lamore AstraZeneca

iCell Cardiomyocytes provide a predictive tool for detecting KI toxicity

12

Parameter IonOptix

sensitivity 83

specificity 84

accuracy 82

pos predict 90

neg predict 76

Parameter Impedance3

sensitivity 90

specificity 74

accuracy 84

pos predict 85

neg predict 82

IonOptix

Good to excellent validation parameters

Primary culture from dog heart

Low throughput

Conventional Interrogation

Screening with iCell Cardiomyocytes

1 AR Harmer Tox App Pharm 2012

iCell Cardiomyocytes provide a predictive

model for detecting contractility

2 C Scott (Tox Sci 2014 )

49 compound validation set with actives and inactives

xCelligence RTCA

Good to excellent assay parameters2

Human cardiomyocytes

Medium to high throughput

Detecting Effects on ContractilityMoving to higher throughput predictive detection

13

iCell Cardiomyocytes and xCelligence RTCA Predictive solutions for multi-modal cardiotoxicity

14

Case 1 Cardiac HypertrophyiCellreg Cardiomyocytes

Control

ET-1 (10 nM)

-14 -13 -12 -11 -10 -9 -81000

1100

1200

1300

1400

1500

Log [ET-1] (M)

To

tal A

rea (

m2)

Control

+ET-1 (10 nM)

Control

+ET-1 (10 nM)

Cell SizeCytoskeletal

Rearrangements

Fetal Gene

Expression

iCell Cardiomyocytes exhibit classic hallmarks of cardiac hypertrophy

15

iCell Cardiomyocyte HypertrophyRelevance

Aggarwal et al Plos One 2014

Hypertrophic iCell Cardiomyocytes share similarities with cardiac

samples from LVH patientsiCell Cardiomyocytes are a relevant system for cardiac hypertrophy

16

Case 2 Diabetic Cardiac MyopathyEnvironmental and Innate Induction

Application of a diabetic medium (ET-1 cortisol glucose) to iCell CMs induces a hypertrophic phenotype

Increases in

bull Cell and nuclear size

bull Cytoskeletal disorganization

bull Glycolysis

bull Lipid accumulation

bull ROS Accumulation

Drawnel et al Cell Reports 2014

ROS Production

Diabetic patient iPSC-cardiomyocyte show a hypertrophic phenotype under basal conditions

Cytoskeletal

disorganization

Compounds have been identified that revert the

diabetic phenotype present in the iPSC-CMs

iCell Cardiomyocytes can be used for induced and innate disease modeling

17

iCell Cardiomyocytes were used to verify

a potential therapeutic target for human

dilated cardiomyopathy

Over-expression and knockdown of

target in iCell Cardiomyocytes affected

related proteins

Confocal imaging demonstrates effects of ILK on Ca2+ transients

iCell Cardiomyocytes provided a model

for in-vitro target validation and

subsequent functional screens

Phenotypic screens in iCell Cardiomyocytes were

utilized to show functional effects of target modulation

Impedance measurements show rhythm and contractile phenotype

Over-expression of target increases function

ILK is in a protein scaffold from control but not DCM

cardiac tissue

Does this represent a potential DCM targets

Case 3 Dilated CardiomyopathyTarget verification and functional assays

18

iCell Neurons

iCell Neurons pure functional

human neurons made at scale

Post-thaw Time course (10x Objective)

Morphology

Day 1 Day 8

5 ml Pellet of Pure

Neurons

Phenotype

MAP2 GABA Hoechst

Purity

Identity

Scale

Electrophysiology

19

iCell Neurons

iCell Neurons are a mixed population of cortical GABAergic and Glutamatergic neurons

that enable new in-vitro research efforts

5 ml Pellet of Pure

Neurons = ~4

Billion Neurons

Alzheimerrsquos Research

Autism Investigations

Latent VZV Infection

Botox batch release testing

20

The Power of IPSC Technology

hellippopulations

What abouthellip

21

StandardizationManufacturing Benchmarks

NHLBI Next Generation Genetic

Association Studies(RFA-HL-11-066)

250 patient samples - HyperGEN cohort

GWAS ndash Left Ventricular Hypertrophy (LVH)

Derive iPS cells and cardiomyocytes from

all 250 individuals

Induce hypertrophy phenotype perform

molecular analyses

Correlate GWAS findings with in vitro

phenotype

Scale-Out

Manufacturing

bull 1000rsquos of individuals

bull Billions of cells

Scale-Up

Manufacturing

bull Quality

bull Quantity

bull Purity

CDI Manufacturing Benchmarks (cells per day gt95 purity)

2 billion iPS cells

1 billion cardiomyocytes

1 billion neurons

05 billion endothelial cells

04 billion hepatocytes

22

NHLBI Next Generation Genetic

Association Studies (RFA-HL-11-066)

250 patient samples ndash HyperGEN cohort

GWAS ndash Left Ventricular Hypertrophy (LVH)

Derive iPS cells and cardiomyocytes

Induce hypertrophy perform molecular analyses

Correlate GWAS findings with in vitro phenotype

Progress as of July 2014

250 donors reprogrammed

Differentiation protocol optimized to work robustly across all lines

128 iPS cell lines (1 per donor) are differentiated or in progress

Cardiomyocytes from 89 donors cryopreserved amp all pass QC

20 batches of cardiomyocytes are in currently being tested in

hypertrophy assays

Initial data show Et-1 EC50 correlation with progression of disease (Uli Broeckel MCOW)

Progress ReportPopulation genomics and left ventricular hypertrophy

CDIrsquos iPSC technology is enabling population studies

23

CIRM AwardiPS Cell Manufacture amp Banking

California Institute for Regenerative Medicine (CIRM)

Human iPS Cell Initiative ndash 3 Awards

Sample Collection (7 awardees)

iPS Cell Derivation (CDI)

iPS Cell Banking (Coriell CDI primary subcontractor)

iPS Cell Derivation

3000 donors (healthy amp disease phenotypes)

3 iPS cell clones per donor

Disease categories epilepsy autism cerebral palsy cardiomyopathy Alzheimerrsquos

disease eye diseases hepatitis (HCV) non-alcoholic steatohepatitis (NASH)

pulmonary fibrosis

Derived from peripheral blood (preferred) or skin fibroblasts

Episomal ldquofootprint-freerdquo method

CDI ndash Coriell Partnership

Extensive collaboration to bring together expertise in electronic record-keeping

sample tracking iPS cell derivation amp characterization cell banking amp distribution

Joint facility located within the Buck Institute Novato CA

24

iCell CardiomyocytesDevelopment Regulatory Guidance

Nature Reviews Drug Discovery (Aug Sept 2013)

Product launch regulatory evaluation in 3 years

iPS cell-derived cardiomyocytes are

being evaluated for use in arrhythmia

assessment amp as a replacement for

thorough QT studies

25

bullRight species - human

bull Essential functionality

bull Active use in toxicity testing and drug discovery

bull Scalable and applicable to populations

bull Involved in the changing regulatory landscape

Technology

Trigger

Trough of

Disillusionment

Slope of

Enlightenment

Plateau of

Productivity

Peak of

Inflated

Expectation

Maturity

Vis

ibili

tyGartnercom

Technology Hype CycleWhere are we

M Peters

26

12

Parameter IonOptix

sensitivity 83

specificity 84

accuracy 82

pos predict 90

neg predict 76

Parameter Impedance3

sensitivity 90

specificity 74

accuracy 84

pos predict 85

neg predict 82

IonOptix

Good to excellent validation parameters

Primary culture from dog heart

Low throughput

Conventional Interrogation

Screening with iCell Cardiomyocytes

1 AR Harmer Tox App Pharm 2012

iCell Cardiomyocytes provide a predictive

model for detecting contractility

2 C Scott (Tox Sci 2014 )

49 compound validation set with actives and inactives

xCelligence RTCA

Good to excellent assay parameters2

Human cardiomyocytes

Medium to high throughput

Detecting Effects on ContractilityMoving to higher throughput predictive detection

13

iCell Cardiomyocytes and xCelligence RTCA Predictive solutions for multi-modal cardiotoxicity

14

Case 1 Cardiac HypertrophyiCellreg Cardiomyocytes

Control

ET-1 (10 nM)

-14 -13 -12 -11 -10 -9 -81000

1100

1200

1300

1400

1500

Log [ET-1] (M)

To

tal A

rea (

m2)

Control

+ET-1 (10 nM)

Control

+ET-1 (10 nM)

Cell SizeCytoskeletal

Rearrangements

Fetal Gene

Expression

iCell Cardiomyocytes exhibit classic hallmarks of cardiac hypertrophy

15

iCell Cardiomyocyte HypertrophyRelevance

Aggarwal et al Plos One 2014

Hypertrophic iCell Cardiomyocytes share similarities with cardiac

samples from LVH patientsiCell Cardiomyocytes are a relevant system for cardiac hypertrophy

16

Case 2 Diabetic Cardiac MyopathyEnvironmental and Innate Induction

Application of a diabetic medium (ET-1 cortisol glucose) to iCell CMs induces a hypertrophic phenotype

Increases in

bull Cell and nuclear size

bull Cytoskeletal disorganization

bull Glycolysis

bull Lipid accumulation

bull ROS Accumulation

Drawnel et al Cell Reports 2014

ROS Production

Diabetic patient iPSC-cardiomyocyte show a hypertrophic phenotype under basal conditions

Cytoskeletal

disorganization

Compounds have been identified that revert the

diabetic phenotype present in the iPSC-CMs

iCell Cardiomyocytes can be used for induced and innate disease modeling

17

iCell Cardiomyocytes were used to verify

a potential therapeutic target for human

dilated cardiomyopathy

Over-expression and knockdown of

target in iCell Cardiomyocytes affected

related proteins

Confocal imaging demonstrates effects of ILK on Ca2+ transients

iCell Cardiomyocytes provided a model

for in-vitro target validation and

subsequent functional screens

Phenotypic screens in iCell Cardiomyocytes were

utilized to show functional effects of target modulation

Impedance measurements show rhythm and contractile phenotype

Over-expression of target increases function

ILK is in a protein scaffold from control but not DCM

cardiac tissue

Does this represent a potential DCM targets

Case 3 Dilated CardiomyopathyTarget verification and functional assays

18

iCell Neurons

iCell Neurons pure functional

human neurons made at scale

Post-thaw Time course (10x Objective)

Morphology

Day 1 Day 8

5 ml Pellet of Pure

Neurons

Phenotype

MAP2 GABA Hoechst

Purity

Identity

Scale

Electrophysiology

19

iCell Neurons

iCell Neurons are a mixed population of cortical GABAergic and Glutamatergic neurons

that enable new in-vitro research efforts

5 ml Pellet of Pure

Neurons = ~4

Billion Neurons

Alzheimerrsquos Research

Autism Investigations

Latent VZV Infection

Botox batch release testing

20

The Power of IPSC Technology

hellippopulations

What abouthellip

21

StandardizationManufacturing Benchmarks

NHLBI Next Generation Genetic

Association Studies(RFA-HL-11-066)

250 patient samples - HyperGEN cohort

GWAS ndash Left Ventricular Hypertrophy (LVH)

Derive iPS cells and cardiomyocytes from

all 250 individuals

Induce hypertrophy phenotype perform

molecular analyses

Correlate GWAS findings with in vitro

phenotype

Scale-Out

Manufacturing

bull 1000rsquos of individuals

bull Billions of cells

Scale-Up

Manufacturing

bull Quality

bull Quantity

bull Purity

CDI Manufacturing Benchmarks (cells per day gt95 purity)

2 billion iPS cells

1 billion cardiomyocytes

1 billion neurons

05 billion endothelial cells

04 billion hepatocytes

22

NHLBI Next Generation Genetic

Association Studies (RFA-HL-11-066)

250 patient samples ndash HyperGEN cohort

GWAS ndash Left Ventricular Hypertrophy (LVH)

Derive iPS cells and cardiomyocytes

Induce hypertrophy perform molecular analyses

Correlate GWAS findings with in vitro phenotype

Progress as of July 2014

250 donors reprogrammed

Differentiation protocol optimized to work robustly across all lines

128 iPS cell lines (1 per donor) are differentiated or in progress

Cardiomyocytes from 89 donors cryopreserved amp all pass QC

20 batches of cardiomyocytes are in currently being tested in

hypertrophy assays

Initial data show Et-1 EC50 correlation with progression of disease (Uli Broeckel MCOW)

Progress ReportPopulation genomics and left ventricular hypertrophy

CDIrsquos iPSC technology is enabling population studies

23

CIRM AwardiPS Cell Manufacture amp Banking

California Institute for Regenerative Medicine (CIRM)

Human iPS Cell Initiative ndash 3 Awards

Sample Collection (7 awardees)

iPS Cell Derivation (CDI)

iPS Cell Banking (Coriell CDI primary subcontractor)

iPS Cell Derivation

3000 donors (healthy amp disease phenotypes)

3 iPS cell clones per donor

Disease categories epilepsy autism cerebral palsy cardiomyopathy Alzheimerrsquos

disease eye diseases hepatitis (HCV) non-alcoholic steatohepatitis (NASH)

pulmonary fibrosis

Derived from peripheral blood (preferred) or skin fibroblasts

Episomal ldquofootprint-freerdquo method

CDI ndash Coriell Partnership

Extensive collaboration to bring together expertise in electronic record-keeping

sample tracking iPS cell derivation amp characterization cell banking amp distribution

Joint facility located within the Buck Institute Novato CA

24

iCell CardiomyocytesDevelopment Regulatory Guidance

Nature Reviews Drug Discovery (Aug Sept 2013)

Product launch regulatory evaluation in 3 years

iPS cell-derived cardiomyocytes are

being evaluated for use in arrhythmia

assessment amp as a replacement for

thorough QT studies

25

bullRight species - human

bull Essential functionality

bull Active use in toxicity testing and drug discovery

bull Scalable and applicable to populations

bull Involved in the changing regulatory landscape

Technology

Trigger

Trough of

Disillusionment

Slope of

Enlightenment

Plateau of

Productivity

Peak of

Inflated

Expectation

Maturity

Vis

ibili

tyGartnercom

Technology Hype CycleWhere are we

M Peters

26

13

iCell Cardiomyocytes and xCelligence RTCA Predictive solutions for multi-modal cardiotoxicity

14

Case 1 Cardiac HypertrophyiCellreg Cardiomyocytes

Control

ET-1 (10 nM)

-14 -13 -12 -11 -10 -9 -81000

1100

1200

1300

1400

1500

Log [ET-1] (M)

To

tal A

rea (

m2)

Control

+ET-1 (10 nM)

Control

+ET-1 (10 nM)

Cell SizeCytoskeletal

Rearrangements

Fetal Gene

Expression

iCell Cardiomyocytes exhibit classic hallmarks of cardiac hypertrophy

15

iCell Cardiomyocyte HypertrophyRelevance

Aggarwal et al Plos One 2014

Hypertrophic iCell Cardiomyocytes share similarities with cardiac

samples from LVH patientsiCell Cardiomyocytes are a relevant system for cardiac hypertrophy

16

Case 2 Diabetic Cardiac MyopathyEnvironmental and Innate Induction

Application of a diabetic medium (ET-1 cortisol glucose) to iCell CMs induces a hypertrophic phenotype

Increases in

bull Cell and nuclear size

bull Cytoskeletal disorganization

bull Glycolysis

bull Lipid accumulation

bull ROS Accumulation

Drawnel et al Cell Reports 2014

ROS Production

Diabetic patient iPSC-cardiomyocyte show a hypertrophic phenotype under basal conditions

Cytoskeletal

disorganization

Compounds have been identified that revert the

diabetic phenotype present in the iPSC-CMs

iCell Cardiomyocytes can be used for induced and innate disease modeling

17

iCell Cardiomyocytes were used to verify

a potential therapeutic target for human

dilated cardiomyopathy

Over-expression and knockdown of

target in iCell Cardiomyocytes affected

related proteins

Confocal imaging demonstrates effects of ILK on Ca2+ transients

iCell Cardiomyocytes provided a model

for in-vitro target validation and

subsequent functional screens

Phenotypic screens in iCell Cardiomyocytes were

utilized to show functional effects of target modulation

Impedance measurements show rhythm and contractile phenotype

Over-expression of target increases function

ILK is in a protein scaffold from control but not DCM

cardiac tissue

Does this represent a potential DCM targets

Case 3 Dilated CardiomyopathyTarget verification and functional assays

18

iCell Neurons

iCell Neurons pure functional

human neurons made at scale

Post-thaw Time course (10x Objective)

Morphology

Day 1 Day 8

5 ml Pellet of Pure

Neurons

Phenotype

MAP2 GABA Hoechst

Purity

Identity

Scale

Electrophysiology

19

iCell Neurons

iCell Neurons are a mixed population of cortical GABAergic and Glutamatergic neurons

that enable new in-vitro research efforts

5 ml Pellet of Pure

Neurons = ~4

Billion Neurons

Alzheimerrsquos Research

Autism Investigations

Latent VZV Infection

Botox batch release testing

20

The Power of IPSC Technology

hellippopulations

What abouthellip

21

StandardizationManufacturing Benchmarks

NHLBI Next Generation Genetic

Association Studies(RFA-HL-11-066)

250 patient samples - HyperGEN cohort

GWAS ndash Left Ventricular Hypertrophy (LVH)

Derive iPS cells and cardiomyocytes from

all 250 individuals

Induce hypertrophy phenotype perform

molecular analyses

Correlate GWAS findings with in vitro

phenotype

Scale-Out

Manufacturing

bull 1000rsquos of individuals

bull Billions of cells

Scale-Up

Manufacturing

bull Quality

bull Quantity

bull Purity

CDI Manufacturing Benchmarks (cells per day gt95 purity)

2 billion iPS cells

1 billion cardiomyocytes

1 billion neurons

05 billion endothelial cells

04 billion hepatocytes

22

NHLBI Next Generation Genetic

Association Studies (RFA-HL-11-066)

250 patient samples ndash HyperGEN cohort

GWAS ndash Left Ventricular Hypertrophy (LVH)

Derive iPS cells and cardiomyocytes

Induce hypertrophy perform molecular analyses

Correlate GWAS findings with in vitro phenotype

Progress as of July 2014

250 donors reprogrammed

Differentiation protocol optimized to work robustly across all lines

128 iPS cell lines (1 per donor) are differentiated or in progress

Cardiomyocytes from 89 donors cryopreserved amp all pass QC

20 batches of cardiomyocytes are in currently being tested in

hypertrophy assays

Initial data show Et-1 EC50 correlation with progression of disease (Uli Broeckel MCOW)

Progress ReportPopulation genomics and left ventricular hypertrophy

CDIrsquos iPSC technology is enabling population studies

23

CIRM AwardiPS Cell Manufacture amp Banking

California Institute for Regenerative Medicine (CIRM)

Human iPS Cell Initiative ndash 3 Awards

Sample Collection (7 awardees)

iPS Cell Derivation (CDI)

iPS Cell Banking (Coriell CDI primary subcontractor)

iPS Cell Derivation

3000 donors (healthy amp disease phenotypes)

3 iPS cell clones per donor

Disease categories epilepsy autism cerebral palsy cardiomyopathy Alzheimerrsquos

disease eye diseases hepatitis (HCV) non-alcoholic steatohepatitis (NASH)

pulmonary fibrosis

Derived from peripheral blood (preferred) or skin fibroblasts

Episomal ldquofootprint-freerdquo method

CDI ndash Coriell Partnership

Extensive collaboration to bring together expertise in electronic record-keeping

sample tracking iPS cell derivation amp characterization cell banking amp distribution

Joint facility located within the Buck Institute Novato CA

24

iCell CardiomyocytesDevelopment Regulatory Guidance

Nature Reviews Drug Discovery (Aug Sept 2013)

Product launch regulatory evaluation in 3 years

iPS cell-derived cardiomyocytes are

being evaluated for use in arrhythmia

assessment amp as a replacement for

thorough QT studies

25

bullRight species - human

bull Essential functionality

bull Active use in toxicity testing and drug discovery

bull Scalable and applicable to populations

bull Involved in the changing regulatory landscape

Technology

Trigger

Trough of

Disillusionment

Slope of

Enlightenment

Plateau of

Productivity

Peak of

Inflated

Expectation

Maturity

Vis

ibili

tyGartnercom

Technology Hype CycleWhere are we

M Peters

26

14

Case 1 Cardiac HypertrophyiCellreg Cardiomyocytes

Control

ET-1 (10 nM)

-14 -13 -12 -11 -10 -9 -81000

1100

1200

1300

1400

1500

Log [ET-1] (M)

To

tal A

rea (

m2)

Control

+ET-1 (10 nM)

Control

+ET-1 (10 nM)

Cell SizeCytoskeletal

Rearrangements

Fetal Gene

Expression

iCell Cardiomyocytes exhibit classic hallmarks of cardiac hypertrophy

15

iCell Cardiomyocyte HypertrophyRelevance

Aggarwal et al Plos One 2014

Hypertrophic iCell Cardiomyocytes share similarities with cardiac

samples from LVH patientsiCell Cardiomyocytes are a relevant system for cardiac hypertrophy

16

Case 2 Diabetic Cardiac MyopathyEnvironmental and Innate Induction

Application of a diabetic medium (ET-1 cortisol glucose) to iCell CMs induces a hypertrophic phenotype

Increases in

bull Cell and nuclear size

bull Cytoskeletal disorganization

bull Glycolysis

bull Lipid accumulation

bull ROS Accumulation

Drawnel et al Cell Reports 2014

ROS Production

Diabetic patient iPSC-cardiomyocyte show a hypertrophic phenotype under basal conditions

Cytoskeletal

disorganization

Compounds have been identified that revert the

diabetic phenotype present in the iPSC-CMs

iCell Cardiomyocytes can be used for induced and innate disease modeling

17

iCell Cardiomyocytes were used to verify

a potential therapeutic target for human

dilated cardiomyopathy

Over-expression and knockdown of

target in iCell Cardiomyocytes affected

related proteins

Confocal imaging demonstrates effects of ILK on Ca2+ transients

iCell Cardiomyocytes provided a model

for in-vitro target validation and

subsequent functional screens

Phenotypic screens in iCell Cardiomyocytes were

utilized to show functional effects of target modulation

Impedance measurements show rhythm and contractile phenotype

Over-expression of target increases function

ILK is in a protein scaffold from control but not DCM

cardiac tissue

Does this represent a potential DCM targets

Case 3 Dilated CardiomyopathyTarget verification and functional assays

18

iCell Neurons

iCell Neurons pure functional

human neurons made at scale

Post-thaw Time course (10x Objective)

Morphology

Day 1 Day 8

5 ml Pellet of Pure

Neurons

Phenotype

MAP2 GABA Hoechst

Purity

Identity

Scale

Electrophysiology

19

iCell Neurons

iCell Neurons are a mixed population of cortical GABAergic and Glutamatergic neurons

that enable new in-vitro research efforts

5 ml Pellet of Pure

Neurons = ~4

Billion Neurons

Alzheimerrsquos Research

Autism Investigations

Latent VZV Infection

Botox batch release testing

20

The Power of IPSC Technology

hellippopulations

What abouthellip

21

StandardizationManufacturing Benchmarks

NHLBI Next Generation Genetic

Association Studies(RFA-HL-11-066)

250 patient samples - HyperGEN cohort

GWAS ndash Left Ventricular Hypertrophy (LVH)

Derive iPS cells and cardiomyocytes from

all 250 individuals

Induce hypertrophy phenotype perform

molecular analyses

Correlate GWAS findings with in vitro

phenotype

Scale-Out

Manufacturing

bull 1000rsquos of individuals

bull Billions of cells

Scale-Up

Manufacturing

bull Quality

bull Quantity

bull Purity

CDI Manufacturing Benchmarks (cells per day gt95 purity)

2 billion iPS cells

1 billion cardiomyocytes

1 billion neurons

05 billion endothelial cells

04 billion hepatocytes

22

NHLBI Next Generation Genetic

Association Studies (RFA-HL-11-066)

250 patient samples ndash HyperGEN cohort

GWAS ndash Left Ventricular Hypertrophy (LVH)

Derive iPS cells and cardiomyocytes

Induce hypertrophy perform molecular analyses

Correlate GWAS findings with in vitro phenotype

Progress as of July 2014

250 donors reprogrammed

Differentiation protocol optimized to work robustly across all lines

128 iPS cell lines (1 per donor) are differentiated or in progress

Cardiomyocytes from 89 donors cryopreserved amp all pass QC

20 batches of cardiomyocytes are in currently being tested in

hypertrophy assays

Initial data show Et-1 EC50 correlation with progression of disease (Uli Broeckel MCOW)

Progress ReportPopulation genomics and left ventricular hypertrophy

CDIrsquos iPSC technology is enabling population studies

23

CIRM AwardiPS Cell Manufacture amp Banking

California Institute for Regenerative Medicine (CIRM)

Human iPS Cell Initiative ndash 3 Awards

Sample Collection (7 awardees)

iPS Cell Derivation (CDI)

iPS Cell Banking (Coriell CDI primary subcontractor)

iPS Cell Derivation

3000 donors (healthy amp disease phenotypes)

3 iPS cell clones per donor

Disease categories epilepsy autism cerebral palsy cardiomyopathy Alzheimerrsquos

disease eye diseases hepatitis (HCV) non-alcoholic steatohepatitis (NASH)

pulmonary fibrosis

Derived from peripheral blood (preferred) or skin fibroblasts

Episomal ldquofootprint-freerdquo method

CDI ndash Coriell Partnership

Extensive collaboration to bring together expertise in electronic record-keeping

sample tracking iPS cell derivation amp characterization cell banking amp distribution

Joint facility located within the Buck Institute Novato CA

24

iCell CardiomyocytesDevelopment Regulatory Guidance

Nature Reviews Drug Discovery (Aug Sept 2013)

Product launch regulatory evaluation in 3 years

iPS cell-derived cardiomyocytes are

being evaluated for use in arrhythmia

assessment amp as a replacement for

thorough QT studies

25

bullRight species - human

bull Essential functionality

bull Active use in toxicity testing and drug discovery

bull Scalable and applicable to populations

bull Involved in the changing regulatory landscape

Technology

Trigger

Trough of

Disillusionment

Slope of

Enlightenment

Plateau of

Productivity

Peak of

Inflated

Expectation

Maturity

Vis

ibili

tyGartnercom

Technology Hype CycleWhere are we

M Peters

26

15

iCell Cardiomyocyte HypertrophyRelevance

Aggarwal et al Plos One 2014

Hypertrophic iCell Cardiomyocytes share similarities with cardiac

samples from LVH patientsiCell Cardiomyocytes are a relevant system for cardiac hypertrophy

16

Case 2 Diabetic Cardiac MyopathyEnvironmental and Innate Induction

Application of a diabetic medium (ET-1 cortisol glucose) to iCell CMs induces a hypertrophic phenotype

Increases in

bull Cell and nuclear size

bull Cytoskeletal disorganization

bull Glycolysis

bull Lipid accumulation

bull ROS Accumulation

Drawnel et al Cell Reports 2014

ROS Production

Diabetic patient iPSC-cardiomyocyte show a hypertrophic phenotype under basal conditions

Cytoskeletal

disorganization

Compounds have been identified that revert the

diabetic phenotype present in the iPSC-CMs

iCell Cardiomyocytes can be used for induced and innate disease modeling

17

iCell Cardiomyocytes were used to verify

a potential therapeutic target for human

dilated cardiomyopathy

Over-expression and knockdown of

target in iCell Cardiomyocytes affected

related proteins

Confocal imaging demonstrates effects of ILK on Ca2+ transients

iCell Cardiomyocytes provided a model

for in-vitro target validation and

subsequent functional screens

Phenotypic screens in iCell Cardiomyocytes were

utilized to show functional effects of target modulation

Impedance measurements show rhythm and contractile phenotype

Over-expression of target increases function

ILK is in a protein scaffold from control but not DCM

cardiac tissue

Does this represent a potential DCM targets

Case 3 Dilated CardiomyopathyTarget verification and functional assays

18

iCell Neurons

iCell Neurons pure functional

human neurons made at scale

Post-thaw Time course (10x Objective)

Morphology

Day 1 Day 8

5 ml Pellet of Pure

Neurons

Phenotype

MAP2 GABA Hoechst

Purity

Identity

Scale

Electrophysiology

19

iCell Neurons

iCell Neurons are a mixed population of cortical GABAergic and Glutamatergic neurons

that enable new in-vitro research efforts

5 ml Pellet of Pure

Neurons = ~4

Billion Neurons

Alzheimerrsquos Research

Autism Investigations

Latent VZV Infection

Botox batch release testing

20

The Power of IPSC Technology

hellippopulations

What abouthellip

21

StandardizationManufacturing Benchmarks

NHLBI Next Generation Genetic

Association Studies(RFA-HL-11-066)

250 patient samples - HyperGEN cohort

GWAS ndash Left Ventricular Hypertrophy (LVH)

Derive iPS cells and cardiomyocytes from

all 250 individuals

Induce hypertrophy phenotype perform

molecular analyses

Correlate GWAS findings with in vitro

phenotype

Scale-Out

Manufacturing

bull 1000rsquos of individuals

bull Billions of cells

Scale-Up

Manufacturing

bull Quality

bull Quantity

bull Purity

CDI Manufacturing Benchmarks (cells per day gt95 purity)

2 billion iPS cells

1 billion cardiomyocytes

1 billion neurons

05 billion endothelial cells

04 billion hepatocytes

22

NHLBI Next Generation Genetic

Association Studies (RFA-HL-11-066)

250 patient samples ndash HyperGEN cohort

GWAS ndash Left Ventricular Hypertrophy (LVH)

Derive iPS cells and cardiomyocytes

Induce hypertrophy perform molecular analyses

Correlate GWAS findings with in vitro phenotype

Progress as of July 2014

250 donors reprogrammed

Differentiation protocol optimized to work robustly across all lines

128 iPS cell lines (1 per donor) are differentiated or in progress

Cardiomyocytes from 89 donors cryopreserved amp all pass QC

20 batches of cardiomyocytes are in currently being tested in

hypertrophy assays

Initial data show Et-1 EC50 correlation with progression of disease (Uli Broeckel MCOW)

Progress ReportPopulation genomics and left ventricular hypertrophy

CDIrsquos iPSC technology is enabling population studies

23

CIRM AwardiPS Cell Manufacture amp Banking

California Institute for Regenerative Medicine (CIRM)

Human iPS Cell Initiative ndash 3 Awards

Sample Collection (7 awardees)

iPS Cell Derivation (CDI)

iPS Cell Banking (Coriell CDI primary subcontractor)

iPS Cell Derivation

3000 donors (healthy amp disease phenotypes)

3 iPS cell clones per donor

Disease categories epilepsy autism cerebral palsy cardiomyopathy Alzheimerrsquos

disease eye diseases hepatitis (HCV) non-alcoholic steatohepatitis (NASH)

pulmonary fibrosis

Derived from peripheral blood (preferred) or skin fibroblasts

Episomal ldquofootprint-freerdquo method

CDI ndash Coriell Partnership

Extensive collaboration to bring together expertise in electronic record-keeping

sample tracking iPS cell derivation amp characterization cell banking amp distribution

Joint facility located within the Buck Institute Novato CA

24

iCell CardiomyocytesDevelopment Regulatory Guidance

Nature Reviews Drug Discovery (Aug Sept 2013)

Product launch regulatory evaluation in 3 years

iPS cell-derived cardiomyocytes are

being evaluated for use in arrhythmia

assessment amp as a replacement for

thorough QT studies

25

bullRight species - human

bull Essential functionality

bull Active use in toxicity testing and drug discovery

bull Scalable and applicable to populations

bull Involved in the changing regulatory landscape

Technology

Trigger

Trough of

Disillusionment

Slope of

Enlightenment

Plateau of

Productivity

Peak of

Inflated

Expectation

Maturity

Vis

ibili

tyGartnercom

Technology Hype CycleWhere are we

M Peters

26

16

Case 2 Diabetic Cardiac MyopathyEnvironmental and Innate Induction

Application of a diabetic medium (ET-1 cortisol glucose) to iCell CMs induces a hypertrophic phenotype

Increases in

bull Cell and nuclear size

bull Cytoskeletal disorganization

bull Glycolysis

bull Lipid accumulation

bull ROS Accumulation

Drawnel et al Cell Reports 2014

ROS Production

Diabetic patient iPSC-cardiomyocyte show a hypertrophic phenotype under basal conditions

Cytoskeletal

disorganization

Compounds have been identified that revert the

diabetic phenotype present in the iPSC-CMs

iCell Cardiomyocytes can be used for induced and innate disease modeling

17

iCell Cardiomyocytes were used to verify

a potential therapeutic target for human

dilated cardiomyopathy

Over-expression and knockdown of

target in iCell Cardiomyocytes affected

related proteins

Confocal imaging demonstrates effects of ILK on Ca2+ transients

iCell Cardiomyocytes provided a model

for in-vitro target validation and

subsequent functional screens

Phenotypic screens in iCell Cardiomyocytes were

utilized to show functional effects of target modulation

Impedance measurements show rhythm and contractile phenotype

Over-expression of target increases function

ILK is in a protein scaffold from control but not DCM

cardiac tissue

Does this represent a potential DCM targets

Case 3 Dilated CardiomyopathyTarget verification and functional assays

18

iCell Neurons

iCell Neurons pure functional

human neurons made at scale

Post-thaw Time course (10x Objective)

Morphology

Day 1 Day 8

5 ml Pellet of Pure

Neurons

Phenotype

MAP2 GABA Hoechst

Purity

Identity

Scale

Electrophysiology

19

iCell Neurons

iCell Neurons are a mixed population of cortical GABAergic and Glutamatergic neurons

that enable new in-vitro research efforts

5 ml Pellet of Pure

Neurons = ~4

Billion Neurons

Alzheimerrsquos Research

Autism Investigations

Latent VZV Infection

Botox batch release testing

20

The Power of IPSC Technology

hellippopulations

What abouthellip

21

StandardizationManufacturing Benchmarks

NHLBI Next Generation Genetic

Association Studies(RFA-HL-11-066)

250 patient samples - HyperGEN cohort

GWAS ndash Left Ventricular Hypertrophy (LVH)

Derive iPS cells and cardiomyocytes from

all 250 individuals

Induce hypertrophy phenotype perform

molecular analyses

Correlate GWAS findings with in vitro

phenotype

Scale-Out

Manufacturing

bull 1000rsquos of individuals

bull Billions of cells

Scale-Up

Manufacturing

bull Quality

bull Quantity

bull Purity

CDI Manufacturing Benchmarks (cells per day gt95 purity)

2 billion iPS cells

1 billion cardiomyocytes

1 billion neurons

05 billion endothelial cells

04 billion hepatocytes

22

NHLBI Next Generation Genetic

Association Studies (RFA-HL-11-066)

250 patient samples ndash HyperGEN cohort

GWAS ndash Left Ventricular Hypertrophy (LVH)

Derive iPS cells and cardiomyocytes

Induce hypertrophy perform molecular analyses

Correlate GWAS findings with in vitro phenotype

Progress as of July 2014

250 donors reprogrammed

Differentiation protocol optimized to work robustly across all lines

128 iPS cell lines (1 per donor) are differentiated or in progress

Cardiomyocytes from 89 donors cryopreserved amp all pass QC

20 batches of cardiomyocytes are in currently being tested in

hypertrophy assays

Initial data show Et-1 EC50 correlation with progression of disease (Uli Broeckel MCOW)

Progress ReportPopulation genomics and left ventricular hypertrophy

CDIrsquos iPSC technology is enabling population studies

23

CIRM AwardiPS Cell Manufacture amp Banking

California Institute for Regenerative Medicine (CIRM)

Human iPS Cell Initiative ndash 3 Awards

Sample Collection (7 awardees)

iPS Cell Derivation (CDI)

iPS Cell Banking (Coriell CDI primary subcontractor)

iPS Cell Derivation

3000 donors (healthy amp disease phenotypes)

3 iPS cell clones per donor

Disease categories epilepsy autism cerebral palsy cardiomyopathy Alzheimerrsquos

disease eye diseases hepatitis (HCV) non-alcoholic steatohepatitis (NASH)

pulmonary fibrosis

Derived from peripheral blood (preferred) or skin fibroblasts

Episomal ldquofootprint-freerdquo method

CDI ndash Coriell Partnership

Extensive collaboration to bring together expertise in electronic record-keeping

sample tracking iPS cell derivation amp characterization cell banking amp distribution

Joint facility located within the Buck Institute Novato CA

24

iCell CardiomyocytesDevelopment Regulatory Guidance

Nature Reviews Drug Discovery (Aug Sept 2013)

Product launch regulatory evaluation in 3 years

iPS cell-derived cardiomyocytes are

being evaluated for use in arrhythmia

assessment amp as a replacement for

thorough QT studies

25

bullRight species - human

bull Essential functionality

bull Active use in toxicity testing and drug discovery

bull Scalable and applicable to populations

bull Involved in the changing regulatory landscape

Technology

Trigger

Trough of

Disillusionment

Slope of

Enlightenment

Plateau of

Productivity

Peak of

Inflated

Expectation

Maturity

Vis

ibili

tyGartnercom

Technology Hype CycleWhere are we

M Peters

26

17

iCell Cardiomyocytes were used to verify

a potential therapeutic target for human

dilated cardiomyopathy

Over-expression and knockdown of

target in iCell Cardiomyocytes affected

related proteins

Confocal imaging demonstrates effects of ILK on Ca2+ transients

iCell Cardiomyocytes provided a model

for in-vitro target validation and

subsequent functional screens

Phenotypic screens in iCell Cardiomyocytes were

utilized to show functional effects of target modulation

Impedance measurements show rhythm and contractile phenotype

Over-expression of target increases function

ILK is in a protein scaffold from control but not DCM

cardiac tissue

Does this represent a potential DCM targets

Case 3 Dilated CardiomyopathyTarget verification and functional assays

18

iCell Neurons

iCell Neurons pure functional

human neurons made at scale

Post-thaw Time course (10x Objective)

Morphology

Day 1 Day 8

5 ml Pellet of Pure

Neurons

Phenotype

MAP2 GABA Hoechst

Purity

Identity

Scale

Electrophysiology

19

iCell Neurons

iCell Neurons are a mixed population of cortical GABAergic and Glutamatergic neurons

that enable new in-vitro research efforts

5 ml Pellet of Pure

Neurons = ~4

Billion Neurons

Alzheimerrsquos Research

Autism Investigations

Latent VZV Infection

Botox batch release testing

20

The Power of IPSC Technology

hellippopulations

What abouthellip

21

StandardizationManufacturing Benchmarks

NHLBI Next Generation Genetic

Association Studies(RFA-HL-11-066)

250 patient samples - HyperGEN cohort

GWAS ndash Left Ventricular Hypertrophy (LVH)

Derive iPS cells and cardiomyocytes from

all 250 individuals

Induce hypertrophy phenotype perform

molecular analyses

Correlate GWAS findings with in vitro

phenotype

Scale-Out

Manufacturing

bull 1000rsquos of individuals

bull Billions of cells

Scale-Up

Manufacturing

bull Quality

bull Quantity

bull Purity

CDI Manufacturing Benchmarks (cells per day gt95 purity)

2 billion iPS cells

1 billion cardiomyocytes

1 billion neurons

05 billion endothelial cells

04 billion hepatocytes

22

NHLBI Next Generation Genetic

Association Studies (RFA-HL-11-066)

250 patient samples ndash HyperGEN cohort

GWAS ndash Left Ventricular Hypertrophy (LVH)

Derive iPS cells and cardiomyocytes

Induce hypertrophy perform molecular analyses

Correlate GWAS findings with in vitro phenotype

Progress as of July 2014

250 donors reprogrammed

Differentiation protocol optimized to work robustly across all lines

128 iPS cell lines (1 per donor) are differentiated or in progress

Cardiomyocytes from 89 donors cryopreserved amp all pass QC

20 batches of cardiomyocytes are in currently being tested in

hypertrophy assays

Initial data show Et-1 EC50 correlation with progression of disease (Uli Broeckel MCOW)

Progress ReportPopulation genomics and left ventricular hypertrophy

CDIrsquos iPSC technology is enabling population studies

23

CIRM AwardiPS Cell Manufacture amp Banking

California Institute for Regenerative Medicine (CIRM)

Human iPS Cell Initiative ndash 3 Awards

Sample Collection (7 awardees)

iPS Cell Derivation (CDI)

iPS Cell Banking (Coriell CDI primary subcontractor)

iPS Cell Derivation

3000 donors (healthy amp disease phenotypes)

3 iPS cell clones per donor

Disease categories epilepsy autism cerebral palsy cardiomyopathy Alzheimerrsquos

disease eye diseases hepatitis (HCV) non-alcoholic steatohepatitis (NASH)

pulmonary fibrosis

Derived from peripheral blood (preferred) or skin fibroblasts

Episomal ldquofootprint-freerdquo method

CDI ndash Coriell Partnership

Extensive collaboration to bring together expertise in electronic record-keeping

sample tracking iPS cell derivation amp characterization cell banking amp distribution

Joint facility located within the Buck Institute Novato CA

24

iCell CardiomyocytesDevelopment Regulatory Guidance

Nature Reviews Drug Discovery (Aug Sept 2013)

Product launch regulatory evaluation in 3 years

iPS cell-derived cardiomyocytes are

being evaluated for use in arrhythmia

assessment amp as a replacement for

thorough QT studies

25

bullRight species - human

bull Essential functionality

bull Active use in toxicity testing and drug discovery

bull Scalable and applicable to populations

bull Involved in the changing regulatory landscape

Technology

Trigger

Trough of

Disillusionment

Slope of

Enlightenment

Plateau of

Productivity

Peak of

Inflated

Expectation

Maturity

Vis

ibili

tyGartnercom

Technology Hype CycleWhere are we

M Peters

26

18

iCell Neurons

iCell Neurons pure functional

human neurons made at scale

Post-thaw Time course (10x Objective)

Morphology

Day 1 Day 8

5 ml Pellet of Pure

Neurons

Phenotype

MAP2 GABA Hoechst

Purity

Identity

Scale

Electrophysiology

19

iCell Neurons

iCell Neurons are a mixed population of cortical GABAergic and Glutamatergic neurons

that enable new in-vitro research efforts

5 ml Pellet of Pure

Neurons = ~4

Billion Neurons

Alzheimerrsquos Research

Autism Investigations

Latent VZV Infection

Botox batch release testing

20

The Power of IPSC Technology

hellippopulations

What abouthellip

21

StandardizationManufacturing Benchmarks

NHLBI Next Generation Genetic

Association Studies(RFA-HL-11-066)

250 patient samples - HyperGEN cohort

GWAS ndash Left Ventricular Hypertrophy (LVH)

Derive iPS cells and cardiomyocytes from

all 250 individuals

Induce hypertrophy phenotype perform

molecular analyses

Correlate GWAS findings with in vitro

phenotype

Scale-Out

Manufacturing

bull 1000rsquos of individuals

bull Billions of cells

Scale-Up

Manufacturing

bull Quality

bull Quantity

bull Purity

CDI Manufacturing Benchmarks (cells per day gt95 purity)

2 billion iPS cells

1 billion cardiomyocytes

1 billion neurons

05 billion endothelial cells

04 billion hepatocytes

22

NHLBI Next Generation Genetic

Association Studies (RFA-HL-11-066)

250 patient samples ndash HyperGEN cohort

GWAS ndash Left Ventricular Hypertrophy (LVH)

Derive iPS cells and cardiomyocytes

Induce hypertrophy perform molecular analyses

Correlate GWAS findings with in vitro phenotype

Progress as of July 2014

250 donors reprogrammed

Differentiation protocol optimized to work robustly across all lines

128 iPS cell lines (1 per donor) are differentiated or in progress

Cardiomyocytes from 89 donors cryopreserved amp all pass QC

20 batches of cardiomyocytes are in currently being tested in

hypertrophy assays

Initial data show Et-1 EC50 correlation with progression of disease (Uli Broeckel MCOW)

Progress ReportPopulation genomics and left ventricular hypertrophy

CDIrsquos iPSC technology is enabling population studies

23

CIRM AwardiPS Cell Manufacture amp Banking

California Institute for Regenerative Medicine (CIRM)

Human iPS Cell Initiative ndash 3 Awards

Sample Collection (7 awardees)

iPS Cell Derivation (CDI)

iPS Cell Banking (Coriell CDI primary subcontractor)

iPS Cell Derivation

3000 donors (healthy amp disease phenotypes)

3 iPS cell clones per donor

Disease categories epilepsy autism cerebral palsy cardiomyopathy Alzheimerrsquos

disease eye diseases hepatitis (HCV) non-alcoholic steatohepatitis (NASH)

pulmonary fibrosis

Derived from peripheral blood (preferred) or skin fibroblasts

Episomal ldquofootprint-freerdquo method

CDI ndash Coriell Partnership

Extensive collaboration to bring together expertise in electronic record-keeping

sample tracking iPS cell derivation amp characterization cell banking amp distribution

Joint facility located within the Buck Institute Novato CA

24

iCell CardiomyocytesDevelopment Regulatory Guidance

Nature Reviews Drug Discovery (Aug Sept 2013)

Product launch regulatory evaluation in 3 years

iPS cell-derived cardiomyocytes are

being evaluated for use in arrhythmia

assessment amp as a replacement for

thorough QT studies

25

bullRight species - human

bull Essential functionality

bull Active use in toxicity testing and drug discovery

bull Scalable and applicable to populations

bull Involved in the changing regulatory landscape

Technology

Trigger

Trough of

Disillusionment

Slope of

Enlightenment

Plateau of

Productivity

Peak of

Inflated

Expectation

Maturity

Vis

ibili

tyGartnercom

Technology Hype CycleWhere are we

M Peters

26

19

iCell Neurons

iCell Neurons are a mixed population of cortical GABAergic and Glutamatergic neurons

that enable new in-vitro research efforts

5 ml Pellet of Pure

Neurons = ~4

Billion Neurons

Alzheimerrsquos Research

Autism Investigations

Latent VZV Infection

Botox batch release testing

20

The Power of IPSC Technology

hellippopulations

What abouthellip

21

StandardizationManufacturing Benchmarks

NHLBI Next Generation Genetic

Association Studies(RFA-HL-11-066)

250 patient samples - HyperGEN cohort

GWAS ndash Left Ventricular Hypertrophy (LVH)

Derive iPS cells and cardiomyocytes from

all 250 individuals

Induce hypertrophy phenotype perform

molecular analyses

Correlate GWAS findings with in vitro

phenotype

Scale-Out

Manufacturing

bull 1000rsquos of individuals

bull Billions of cells

Scale-Up

Manufacturing

bull Quality

bull Quantity

bull Purity

CDI Manufacturing Benchmarks (cells per day gt95 purity)

2 billion iPS cells

1 billion cardiomyocytes

1 billion neurons

05 billion endothelial cells

04 billion hepatocytes

22

NHLBI Next Generation Genetic

Association Studies (RFA-HL-11-066)

250 patient samples ndash HyperGEN cohort

GWAS ndash Left Ventricular Hypertrophy (LVH)

Derive iPS cells and cardiomyocytes

Induce hypertrophy perform molecular analyses

Correlate GWAS findings with in vitro phenotype

Progress as of July 2014

250 donors reprogrammed

Differentiation protocol optimized to work robustly across all lines

128 iPS cell lines (1 per donor) are differentiated or in progress

Cardiomyocytes from 89 donors cryopreserved amp all pass QC

20 batches of cardiomyocytes are in currently being tested in

hypertrophy assays

Initial data show Et-1 EC50 correlation with progression of disease (Uli Broeckel MCOW)

Progress ReportPopulation genomics and left ventricular hypertrophy

CDIrsquos iPSC technology is enabling population studies

23

CIRM AwardiPS Cell Manufacture amp Banking

California Institute for Regenerative Medicine (CIRM)

Human iPS Cell Initiative ndash 3 Awards

Sample Collection (7 awardees)

iPS Cell Derivation (CDI)

iPS Cell Banking (Coriell CDI primary subcontractor)

iPS Cell Derivation

3000 donors (healthy amp disease phenotypes)

3 iPS cell clones per donor

Disease categories epilepsy autism cerebral palsy cardiomyopathy Alzheimerrsquos

disease eye diseases hepatitis (HCV) non-alcoholic steatohepatitis (NASH)

pulmonary fibrosis

Derived from peripheral blood (preferred) or skin fibroblasts

Episomal ldquofootprint-freerdquo method

CDI ndash Coriell Partnership

Extensive collaboration to bring together expertise in electronic record-keeping

sample tracking iPS cell derivation amp characterization cell banking amp distribution

Joint facility located within the Buck Institute Novato CA

24

iCell CardiomyocytesDevelopment Regulatory Guidance

Nature Reviews Drug Discovery (Aug Sept 2013)

Product launch regulatory evaluation in 3 years

iPS cell-derived cardiomyocytes are

being evaluated for use in arrhythmia

assessment amp as a replacement for

thorough QT studies

25

bullRight species - human

bull Essential functionality

bull Active use in toxicity testing and drug discovery

bull Scalable and applicable to populations

bull Involved in the changing regulatory landscape

Technology

Trigger

Trough of

Disillusionment

Slope of

Enlightenment

Plateau of

Productivity

Peak of

Inflated

Expectation

Maturity

Vis

ibili

tyGartnercom

Technology Hype CycleWhere are we

M Peters

26

20

The Power of IPSC Technology

hellippopulations

What abouthellip

21

StandardizationManufacturing Benchmarks

NHLBI Next Generation Genetic

Association Studies(RFA-HL-11-066)

250 patient samples - HyperGEN cohort

GWAS ndash Left Ventricular Hypertrophy (LVH)

Derive iPS cells and cardiomyocytes from

all 250 individuals

Induce hypertrophy phenotype perform

molecular analyses

Correlate GWAS findings with in vitro

phenotype

Scale-Out

Manufacturing

bull 1000rsquos of individuals

bull Billions of cells

Scale-Up

Manufacturing

bull Quality

bull Quantity

bull Purity

CDI Manufacturing Benchmarks (cells per day gt95 purity)

2 billion iPS cells

1 billion cardiomyocytes

1 billion neurons

05 billion endothelial cells

04 billion hepatocytes

22

NHLBI Next Generation Genetic

Association Studies (RFA-HL-11-066)

250 patient samples ndash HyperGEN cohort

GWAS ndash Left Ventricular Hypertrophy (LVH)

Derive iPS cells and cardiomyocytes

Induce hypertrophy perform molecular analyses

Correlate GWAS findings with in vitro phenotype

Progress as of July 2014

250 donors reprogrammed

Differentiation protocol optimized to work robustly across all lines

128 iPS cell lines (1 per donor) are differentiated or in progress

Cardiomyocytes from 89 donors cryopreserved amp all pass QC

20 batches of cardiomyocytes are in currently being tested in

hypertrophy assays

Initial data show Et-1 EC50 correlation with progression of disease (Uli Broeckel MCOW)

Progress ReportPopulation genomics and left ventricular hypertrophy

CDIrsquos iPSC technology is enabling population studies

23

CIRM AwardiPS Cell Manufacture amp Banking

California Institute for Regenerative Medicine (CIRM)

Human iPS Cell Initiative ndash 3 Awards

Sample Collection (7 awardees)

iPS Cell Derivation (CDI)

iPS Cell Banking (Coriell CDI primary subcontractor)

iPS Cell Derivation

3000 donors (healthy amp disease phenotypes)

3 iPS cell clones per donor

Disease categories epilepsy autism cerebral palsy cardiomyopathy Alzheimerrsquos

disease eye diseases hepatitis (HCV) non-alcoholic steatohepatitis (NASH)

pulmonary fibrosis

Derived from peripheral blood (preferred) or skin fibroblasts

Episomal ldquofootprint-freerdquo method

CDI ndash Coriell Partnership

Extensive collaboration to bring together expertise in electronic record-keeping

sample tracking iPS cell derivation amp characterization cell banking amp distribution

Joint facility located within the Buck Institute Novato CA

24

iCell CardiomyocytesDevelopment Regulatory Guidance

Nature Reviews Drug Discovery (Aug Sept 2013)

Product launch regulatory evaluation in 3 years

iPS cell-derived cardiomyocytes are

being evaluated for use in arrhythmia

assessment amp as a replacement for

thorough QT studies

25

bullRight species - human

bull Essential functionality

bull Active use in toxicity testing and drug discovery

bull Scalable and applicable to populations

bull Involved in the changing regulatory landscape

Technology

Trigger

Trough of

Disillusionment

Slope of

Enlightenment

Plateau of

Productivity

Peak of

Inflated

Expectation

Maturity

Vis

ibili

tyGartnercom

Technology Hype CycleWhere are we

M Peters

26

21

StandardizationManufacturing Benchmarks

NHLBI Next Generation Genetic

Association Studies(RFA-HL-11-066)

250 patient samples - HyperGEN cohort

GWAS ndash Left Ventricular Hypertrophy (LVH)

Derive iPS cells and cardiomyocytes from

all 250 individuals

Induce hypertrophy phenotype perform

molecular analyses

Correlate GWAS findings with in vitro

phenotype

Scale-Out

Manufacturing

bull 1000rsquos of individuals

bull Billions of cells

Scale-Up

Manufacturing

bull Quality

bull Quantity

bull Purity

CDI Manufacturing Benchmarks (cells per day gt95 purity)

2 billion iPS cells

1 billion cardiomyocytes

1 billion neurons

05 billion endothelial cells

04 billion hepatocytes

22

NHLBI Next Generation Genetic

Association Studies (RFA-HL-11-066)

250 patient samples ndash HyperGEN cohort

GWAS ndash Left Ventricular Hypertrophy (LVH)

Derive iPS cells and cardiomyocytes

Induce hypertrophy perform molecular analyses

Correlate GWAS findings with in vitro phenotype

Progress as of July 2014

250 donors reprogrammed

Differentiation protocol optimized to work robustly across all lines

128 iPS cell lines (1 per donor) are differentiated or in progress

Cardiomyocytes from 89 donors cryopreserved amp all pass QC

20 batches of cardiomyocytes are in currently being tested in

hypertrophy assays

Initial data show Et-1 EC50 correlation with progression of disease (Uli Broeckel MCOW)

Progress ReportPopulation genomics and left ventricular hypertrophy

CDIrsquos iPSC technology is enabling population studies

23

CIRM AwardiPS Cell Manufacture amp Banking

California Institute for Regenerative Medicine (CIRM)

Human iPS Cell Initiative ndash 3 Awards

Sample Collection (7 awardees)

iPS Cell Derivation (CDI)

iPS Cell Banking (Coriell CDI primary subcontractor)

iPS Cell Derivation

3000 donors (healthy amp disease phenotypes)

3 iPS cell clones per donor

Disease categories epilepsy autism cerebral palsy cardiomyopathy Alzheimerrsquos

disease eye diseases hepatitis (HCV) non-alcoholic steatohepatitis (NASH)

pulmonary fibrosis

Derived from peripheral blood (preferred) or skin fibroblasts

Episomal ldquofootprint-freerdquo method

CDI ndash Coriell Partnership

Extensive collaboration to bring together expertise in electronic record-keeping

sample tracking iPS cell derivation amp characterization cell banking amp distribution

Joint facility located within the Buck Institute Novato CA

24

iCell CardiomyocytesDevelopment Regulatory Guidance

Nature Reviews Drug Discovery (Aug Sept 2013)

Product launch regulatory evaluation in 3 years

iPS cell-derived cardiomyocytes are

being evaluated for use in arrhythmia

assessment amp as a replacement for

thorough QT studies

25

bullRight species - human

bull Essential functionality

bull Active use in toxicity testing and drug discovery

bull Scalable and applicable to populations

bull Involved in the changing regulatory landscape

Technology

Trigger

Trough of

Disillusionment

Slope of

Enlightenment

Plateau of

Productivity

Peak of

Inflated

Expectation

Maturity

Vis

ibili

tyGartnercom

Technology Hype CycleWhere are we

M Peters

26

22

NHLBI Next Generation Genetic

Association Studies (RFA-HL-11-066)

250 patient samples ndash HyperGEN cohort

GWAS ndash Left Ventricular Hypertrophy (LVH)

Derive iPS cells and cardiomyocytes

Induce hypertrophy perform molecular analyses

Correlate GWAS findings with in vitro phenotype

Progress as of July 2014

250 donors reprogrammed

Differentiation protocol optimized to work robustly across all lines

128 iPS cell lines (1 per donor) are differentiated or in progress

Cardiomyocytes from 89 donors cryopreserved amp all pass QC

20 batches of cardiomyocytes are in currently being tested in

hypertrophy assays

Initial data show Et-1 EC50 correlation with progression of disease (Uli Broeckel MCOW)

Progress ReportPopulation genomics and left ventricular hypertrophy

CDIrsquos iPSC technology is enabling population studies

23

CIRM AwardiPS Cell Manufacture amp Banking

California Institute for Regenerative Medicine (CIRM)

Human iPS Cell Initiative ndash 3 Awards

Sample Collection (7 awardees)

iPS Cell Derivation (CDI)

iPS Cell Banking (Coriell CDI primary subcontractor)

iPS Cell Derivation

3000 donors (healthy amp disease phenotypes)

3 iPS cell clones per donor

Disease categories epilepsy autism cerebral palsy cardiomyopathy Alzheimerrsquos

disease eye diseases hepatitis (HCV) non-alcoholic steatohepatitis (NASH)

pulmonary fibrosis

Derived from peripheral blood (preferred) or skin fibroblasts

Episomal ldquofootprint-freerdquo method

CDI ndash Coriell Partnership

Extensive collaboration to bring together expertise in electronic record-keeping

sample tracking iPS cell derivation amp characterization cell banking amp distribution

Joint facility located within the Buck Institute Novato CA

24

iCell CardiomyocytesDevelopment Regulatory Guidance

Nature Reviews Drug Discovery (Aug Sept 2013)

Product launch regulatory evaluation in 3 years

iPS cell-derived cardiomyocytes are

being evaluated for use in arrhythmia

assessment amp as a replacement for

thorough QT studies

25

bullRight species - human

bull Essential functionality

bull Active use in toxicity testing and drug discovery

bull Scalable and applicable to populations

bull Involved in the changing regulatory landscape

Technology

Trigger

Trough of

Disillusionment

Slope of

Enlightenment

Plateau of

Productivity

Peak of

Inflated

Expectation

Maturity

Vis

ibili

tyGartnercom

Technology Hype CycleWhere are we

M Peters

26

23

CIRM AwardiPS Cell Manufacture amp Banking

California Institute for Regenerative Medicine (CIRM)

Human iPS Cell Initiative ndash 3 Awards

Sample Collection (7 awardees)

iPS Cell Derivation (CDI)

iPS Cell Banking (Coriell CDI primary subcontractor)

iPS Cell Derivation

3000 donors (healthy amp disease phenotypes)

3 iPS cell clones per donor

Disease categories epilepsy autism cerebral palsy cardiomyopathy Alzheimerrsquos

disease eye diseases hepatitis (HCV) non-alcoholic steatohepatitis (NASH)

pulmonary fibrosis

Derived from peripheral blood (preferred) or skin fibroblasts

Episomal ldquofootprint-freerdquo method

CDI ndash Coriell Partnership

Extensive collaboration to bring together expertise in electronic record-keeping

sample tracking iPS cell derivation amp characterization cell banking amp distribution

Joint facility located within the Buck Institute Novato CA

24

iCell CardiomyocytesDevelopment Regulatory Guidance

Nature Reviews Drug Discovery (Aug Sept 2013)

Product launch regulatory evaluation in 3 years

iPS cell-derived cardiomyocytes are

being evaluated for use in arrhythmia

assessment amp as a replacement for

thorough QT studies

25

bullRight species - human

bull Essential functionality

bull Active use in toxicity testing and drug discovery

bull Scalable and applicable to populations

bull Involved in the changing regulatory landscape

Technology

Trigger

Trough of

Disillusionment

Slope of

Enlightenment

Plateau of

Productivity

Peak of

Inflated

Expectation

Maturity

Vis

ibili

tyGartnercom

Technology Hype CycleWhere are we

M Peters

26

24

iCell CardiomyocytesDevelopment Regulatory Guidance

Nature Reviews Drug Discovery (Aug Sept 2013)

Product launch regulatory evaluation in 3 years

iPS cell-derived cardiomyocytes are

being evaluated for use in arrhythmia

assessment amp as a replacement for

thorough QT studies

25

bullRight species - human

bull Essential functionality

bull Active use in toxicity testing and drug discovery

bull Scalable and applicable to populations

bull Involved in the changing regulatory landscape

Technology

Trigger

Trough of

Disillusionment

Slope of

Enlightenment

Plateau of

Productivity

Peak of

Inflated

Expectation

Maturity

Vis

ibili

tyGartnercom

Technology Hype CycleWhere are we

M Peters

26

25

bullRight species - human

bull Essential functionality

bull Active use in toxicity testing and drug discovery

bull Scalable and applicable to populations

bull Involved in the changing regulatory landscape

Technology

Trigger

Trough of

Disillusionment

Slope of

Enlightenment

Plateau of

Productivity

Peak of

Inflated

Expectation

Maturity

Vis

ibili

tyGartnercom

Technology Hype CycleWhere are we

M Peters

26

26