The 2019 Scientific Program features a diverse range of scientific sessions organized into two concurrent themed tracks covering issues such as Cardiac Safety Concerns, New Models: In Vitro, Hot Topics in CNS, Immune Related Adverse Events, Thoughts on Translation, Personalized Medicine, Clinician Perspectives on Safety Pharmacology, Artificial Intelligence/In Silico, Biomarkers—The Far Reaching Value, Early Derisking Strategy and Techniques, Strategies for Getting to FIH and Beyond—Efficiently and Safely, Revisiting S7A and S7B and much more! This will ensure attendees can stay abreast of new content and developments in key areas of interest.
Come visit us at Booth # 406.
FCDI Poster Presentation
Poster #: 152
Integrated Analysis of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in Diversity and Disease Modeling
David Majewski, Jing Liu, Souameng Lor, Giorgia Salvagiotto, Simon Hilcove, Eugenia Jones
FUJIFILM Cellular Dynamics, Inc., Madison, WI
Abstract: Human cell types differentiated from induced pluripotent stem cells (hiPSC) offer an attractive human cellular platform for safety and efficacy testing. Here, we present data demonstrating the utility of hiPSC-derived cardiomyocytes (hiPSC-CMs) in safety assessment and cardiac disease modeling. Clinically-defined Type I cancer therapeutics-related cardiac dysfunction (CTRCD) may be associated with cellular death, structural changes, and permanent damage while Type II CTRCD may be associated with cellular dysfunction, no structural changes, and reversible damage. In this study, we include a comprehensive assessment of CTRCD compounds doxorubicin (type I) and sunitinib (type II) across a panel of hiPSC-CMs derived from 6 apparently healthy donors (DIV 14) at three concentrations [0.1, 1.0, and 10 µM]. Doxorubicin induced type I CTRCD as measured by reduced cell index and altered beat rate, while Sunitiib induced type II CTRCD as measured by maintained cell index with altered beat rate. Both kinetics and concentration-dependent response varies across the panel of 6 apparently healthy donors indicating how iPSC-derived cardiomyocytes might be used to study sensitivities to cardio-oncology liabilities across different genetic backgrounds. Subsequently, we examined basic functional characterization data from several hiPSC-CM disease models, including hypertrophic cardiomyopathy (HCM) MYH7 (R403Q), LMNA-related dilated cardiomyopathy (DCM) LMNA (L35P), and Brugada syndrome (BrS) type 3 CACNA1C (G490R) each with its respective isogenic control at DIV 14. We further identify the functional consequences of each mutation and demonstrate that each model recapitulates classical hallmarks of the disease phenotype. In short, HCM cardiomyocytes display prolonged field potential duration, slowed beat rate, increased spike amplitued and contractility (impedance). DCM cardiomyocytes display reduced contraction amplitude and increased beat rate. BrS cardiomyocytes display increased sensitivity to the calcium channel blocker Isradipine, as measured by increase in beat rate and reduction in FPD. These data illustrate how hiPSC-CMs provide an excellent model system for assessing compound effects across multiple donors and disease models. Taken together, these examples help to create new avenues for safety assessment and efficacy studies, as well as serve as a template for future opportunities in cardiac disease modeling with hiPSC-CMs.
Poster Presentation | Tuesday, Sep. 24
Poster #: 148
Enhancing Stem Cell‐based Toxicity Assays by Engineering the Culture Niche in a High‐throughput, Assay‐agnostic Manner
Sponsored Presentations | Tuesday, Sep. 24
Room 119 | 7:00–8:00 am
Maturation of iPSC-CM Function for Improved Predictivity of In Vitro CM-MEA Assays
iPSC-CMs have significantly advanced in vitro assays for cardiac safety, but remain an immature representation of the human heart. In this seminar, attendees will learn how to mature cardiomyocytes for use in functional assays of the action potential, conduction, and contractility.
Room 120 | 12:30 – 1:30 pm
Using hiPSC-derived Tissues for Cardiac Risk Assessment: Translational Considerations
Translational fidelity is a key consideration when selecting the appropriate model for cardiac risk assessment. Such fidelity requires a platform that reproducibly recapitulates key structural and functional features of adult human cardiac tissue. We will discuss data demonstrating the translational relevance of TARA’s in vitro iPSC-derived Cardiotype tissues including structural toxicity data.
Room 119 | 6:00 –7:00 pm
Are Functionally Mature hiPSC-Cardiomyocytes More Predictive for Safety Assessment?
ACEA Biosciences, Inc. – A part of Agilent
As the field determines how to improve the predictivity of cardiomyocyte models, the questions being raised are: What constitutes CM maturation and is it more a predictive model? To address these questions, we explored the role of electrical pacing using ACEA’s high-throughput ePacer platform and retested a subset of Phase II CiPA compounds. We will discuss our results in this presentation.
Sponsored Presentations | Wednesday, Sep. 25
Room 119 | 12:30–1:30 pm
Leveraging Structurally Matured iPSC-derived Cardiomyocytes for Predictive High-throughput Screening
iPSC-CMs hold great potential for assessing various cardiotoxicity mechanisms in vitro; however their full potential is limited by their expression of fetal and embryonic phenotypes. Learn how structural maturation can improve the predictive power of these cells in a variety of cell-based assays, and how this approach can be easily integrated into most industry-standard high-throughput assays.