We ve crossed the Chasm and climbed out of the Trough. Advances and advantages with ipsc-derived cell types in drug discovery.
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1 We ve crossed the Chasm and climbed out of the Trough. Advances and advantages with ipsc-derived cell types in drug discovery. Blake Anson Ph.D. Oct 31, 2014
2 Technology Hype Cycle The Chasm The Trough Where is stem cell technology as it applies to drug discovery? Particularly icell Products CDI Overview Sampling of icell Product use in Industry Toxicity and Drug Discovery Population Diversity Wrap-up
3 Company Overview Cellular Dynamics International (CDI) is the world s 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 >800 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 CDI s products in Japan
4 Product Portfolio icell Cardiomyocytes icell Endothelial Cells icell Neurons icell Hepatocytes icell Astrocytes icell Cardiac Progenitor Cells icell DopaNeurons 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) MyCell Products Essential 8 Medium Episomal Reprogramming Kit Vitronectin icell Hematopoietic Progenitor Cells icell Skeletal Myoblasts
5 icell Cardiomyocytes Human Cardiomyocytes >95% pure, cryopreserved, ready to use >4x10 6 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 Cardiomyocytes Characterization Whole-Genome Gene Expression Protein Expression Metabolism Myocardium PromoCell Celprogen Adult myocardium d28 icell CM d120 icell CM Relevant & stable over time in culture Recapitulates normal human cardiac function Electrophysiology, E-C Coupling, Contractility 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 Enables mechanistic toxicity testing 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
7 icell Cardiomyocytes Market Validation (8//2014) 1. Nakamura Y 1, Matsuo J (2014) Assessment of testing methods for drug-induced repolarization delay and arrhythmias in an ips cellderived cardiomyocyte sheet: multi-site validation study. J Pharmacol Sci. 124(4): Eldridge S, Guo L, et al. (2014) Examining the Protective Role of ErbB2 Modulation in Human Induced Pluripotent Stem Cell- Derived Cardiomyocytes. Toxicol Sci 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 Feb 21;289(8): 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): Cameron BJ, Gerry AB, et al. (2013) Identification of a Titinderived HLA-A1-presented peptide as a cross-reactive target for engineered MAGE A3-directed T cells. Sci Transl Med. 5(197):197ra 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): 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): Fine M, Lu F, et al. (2013) Human Induced Pluripotent Stem Cellderived Cardiomyocytes for Studies of Cardiac Ion Transporters. Am J Physiol Cell Physiol. 305(5):C Guo L, Coyle l, et al. (2013) Refining the Human ipsc- Cardiomyocyte Arrhythmic Risk Assessment Model. Toxicol Sci 136(2): Harris K, Aylott M, et al. (2013) Comparison of Electrophysiological Data from Human Induced Pluripotent Stem Cell Derived Cardiomyoyctes (hipsc-cms) to Functional Preclinical Safety Assays. Toxicol Sci. 134(2): Ivashchenko CY 1, 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):H 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 168: 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 131: 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): Schweikart K, Guo L, et al. (2013) The Effects of Jaspamide on Human Cardiomyocyte Function and Cardiac Ion Channel Activity. Toxicol in Vitro 27: Sirenko O, Crittenden C, et al. (2013) Multiparameter In Vitro Assessment of Compound Effects on Cardiomyocyte Physiology Using ips Cells. J Biomol Screening 18: 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): Babiarz JE, Ravon M, et al. (2012). Determination of the Human Cardiomyocyte mrna and mirna Differentiation Network by Fine-scale Profiling. Stem Cells Dev 21: Cerignoli R, Charlot D, et al. (2012) High Throughput Measurement of Ca2+ Dynamics for Drug Risk Assessment in Human Stem Cellderived Cardiomyocytes by Kinetic Image Cytometry. J Pharmacol Toxicol Methods 66: 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 110: 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 5: Rana P, Anson BD, et al. (2012) Characterization of Humaninduced Pluripotent Stem Cell-derived Cardiomyocytes: Bioenergetics and Utilization in Safety Screening. Toxicol Sci 130: Reynolds JG, Geretti E, et al. (2012) HER2-targeted Liposomal Doxorubicin Displays Enhanced Anti-tumorigenic Effects without Associated Cardiotoxicity. Toxicol Appl Pharmacol 262: 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):e 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 3: Cohen JD, Babiarz JE, et al. (2011) Use of Human Stem Cellderived Cardiomyocytes to Examine Sunitinib Mediated Cardiotoxicity and Electrophysiological Alterations. Toxicol Appl Pharmacol 257: 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 27: Guo L, Abrams RM, et al. (2011) Estimating the Risk of Druginduced Proarrhythmia Using Human Induced Pluripotent Stem Cell-derived Cardiomyocytes. Toxicol Sci 123: 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 9: 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 301:H2006-H2017. ~40 Peer-reviewed Publications (10/2014): Characterization Toxicity testing Disease modeling
8 Interrogating Biology Electrical and Mechanical Activity Electrical Cardiomyocyte Activity Electrical, biochemical, and mechanical Biochemical Mechanical Three main areas need to be considered for cardiotoxicity
9 Predicting Proarrhythmia Label Free Impedance Measurements Relevant biology and metrics leads to greater predictivity Qualitative Assessment 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 Guo et al., 2013 Guo et al., 2011 Greater Predictivity ~120 Compounds >90% -- QT prediction >82% -- arrhy. prediction icell Cardiomyocytes provide a more predictive tool for detecting proarrhythmia
10 KI-induced Cardiotoxicity Deconvoluting the problem S. Lamore AstraZeneca icell Cardiomyocytes provide a predictive tool for detecting KI toxicity
11 Detecting Effects on Contractility Moving to higher throughput predictive detection Conventional Interrogation IonOptix Good to excellent validation parameters Primary culture from dog heart Low throughput 1 AR Harmer. Tox App Pharm 2012 Screening with icell Cardiomyocytes xcelligence RTCA Good to excellent assay parameters 2 Human cardiomyocytes Medium to high throughput Parameter IonOptix sensitivity 83% specificity 84% accuracy 82% pos predict 90% neg predict 76% Parameter Impedance 3 sensitivity 90% specificity 74% accuracy 84% pos predict 85% neg predict 82% 49 compound validation set with actives and inactives 2 C. Scott (Tox Sci, 2014 ) icell Cardiomyocytes provide a predictive model for detecting contractility
12 icell Cardiomyocytes and xcelligence RTCA: Predictive solutions for multi-modal cardiotoxicity
13 Case #1: Cardiac Hypertrophy icell Cardiomyocytes Cell Size Cytoskeletal Rearrangements Fetal Gene Expression Control ET-1 (10 nm) Control +ET-1 (10 nm) Control +ET-1 (10 nm) 1500 Total Area ( m 2 ) Log [ET-1] (M) icell Cardiomyocytes exhibit classic hallmarks of cardiac hypertrophy
14 icell Cardiomyocyte Hypertrophy Relevance Aggarwal et al., Plos One 2014 Hypertrophic icell Cardiomyocytes icell Cardiomyocytes are a relevant system share for similarities cardiac hypertrophy with cardiac samples from LVH patients
15 Case #2: Diabetic Cardiac Myopathy Environmental and Innate Induction Application of a diabetic medium (ET-1, cortisol, glucose) to icell CMs induces a hypertrophic phenotype Increases in; Cell and nuclear size Cytoskeletal disorganization Glycolysis Lipid accumulation ROS Accumulation Diabetic patient ipsc-cardiomyocyte show a hypertrophic phenotype under basal conditions Cytoskeletal disorganization ROS Production Compounds have been identified that revert the diabetic phenotype present in the ipsc-cms Drawnel, et al., Cell Reports 2014 icell Cardiomyocytes can be used for induced and innate disease modeling
16 Case #3: Dilated Cardiomyopathy Target verification and functional assays icell Cardiomyocytes were used to verify a potential therapeutic target for human dilated cardiomyopathy Confocal Over-expression imaging demonstrates of target increases effects of ILK function Ca 2+ transients ILK is in a protein scaffold from control, but not DCM cardiac tissue. Does this represent a potential DCM targets? Impedance measurements show rhythm and contractile phenotype Phenotypic screens in icell Cardiomyocytes were utilized to show functional effects of target modulation Over-expression and knockdown of target in icell Cardiomyocytes affected related proteins icell Cardiomyocytes provided a model for in-vitro target validation and subsequent functional screens
17 icell Neurons Morphology Electrophysiology Identity Day 1 Day 8 Post-thaw Time course (10x Objective) Purity Phenotype Scale MAP2 / GABA / Hoechst icell Neurons; pure, functional, human neurons made at scale 5 ml Pellet of Pure Neurons
18 icell Neurons Alzheimer s Research 5 ml Pellet of Pure Neurons = ~4 Billion Neurons Latent VZV Infection Autism Investigations Botox batch release testing icell Neurons are a mixed population of cortical GABAergic and Glutamatergic neurons that enable new in-vitro research efforts
19 The Power of IPSC Technology What about. populations?
20 Standardization Manufacturing Benchmarks Scale-Up Manufacturing Quality Quantity Purity CDI Manufacturing Benchmarks (cells per day, >95% purity) 2 billion ips cells 1 billion cardiomyocytes 1 billion neurons 0.5 billion endothelial cells 0.4 billion hepatocytes Scale-Out Manufacturing 1000 s of individuals Billions of cells NHLBI Next Generation Genetic Association Studies (RFA-HL ) 250 patient samples - HyperGEN cohort GWAS 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
21 Progress Report Population genomics and left ventricular hypertrophy NHLBI Next Generation Genetic Association Studies (RFA-HL ) 250 patient samples HyperGEN cohort GWAS 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 & 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) CDI s ipsc technology is enabling population studies
22 CIRM Award ips Cell Manufacture & Banking California Institute for Regenerative Medicine (CIRM) Human ips Cell Initiative 3 Awards Sample Collection (7 awardees) ips Cell Derivation (CDI) ips Cell Banking (Coriell; CDI primary subcontractor) ips Cell Derivation 3000 donors (healthy & disease phenotypes) 3 ips cell clones per donor Disease categories: epilepsy, autism, cerebral palsy, cardiomyopathy, Alzheimer s disease, eye diseases, hepatitis (HCV), non-alcoholic steatohepatitis (NASH), pulmonary fibrosis Derived from peripheral blood (preferred) or skin fibroblasts Episomal footprint-free method CDI Coriell Partnership Extensive collaboration to bring together expertise in electronic record-keeping, sample tracking, ips cell derivation & characterization, cell banking & distribution Joint facility located within the Buck Institute, Novato, CA
23 icell Cardiomyocytes Development Regulatory Guidance Product launch regulatory evaluation in 3 years ips cell-derived cardiomyocytes are being evaluated for use in arrhythmia assessment & as a replacement for thorough QT studies Nature Reviews Drug Discovery (Aug, Sept 2013)
24 Visibility Technology Hype Cycle Where are we? Gartner.com Peak of Inflated Expectation Slope of Enlightenment Plateau of Productivity Trough of Disillusionment Technology Trigger Maturity M. Peters Right species - human Essential functionality Active use in toxicity testing and drug discovery Scalable and applicable to populations Involved in the changing regulatory landscape
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