About the Meeting
On October 25 and 26, 2016, in Arlington, Virginia, SOT hosted a Contemporary Concepts in Toxicology (CCT) meeting focused on human stem cell-derived cardiomyocytes (hiPSC-CMs).
The organizing committee was comprised of Douglas Keller, Chair, Sanofi, Bridgewater, NJ, USA; Jane Bai, Chair, US FDA, Silver Spring, MD, USA; Yvonne Will, Chair, Pfizer, Groton, CT, USA; Gary Gintant, Abbvie, North Chicago, IL, USA; Brian Guth, Boehringer-Ingelheim, Biberach, Germany; Jennifer B. Pierson, ILSI Health and Environmental Science Institute, Washington DC, USA; Ajay Pillai, NIH, Bethesda, MD, USA; Ruth Roberts, Council Contact, Apconix, Cheshire, United Kingdom; Norman Stockbridge, US FDA, Silver Spring, MD, USA; and York Tomita, US FDA, Silver Spring, MD, USA.
In addition to SOT, the meeting was supported by the American College of Toxicology, AxioGenesis, HESI, Pfizer, Safety Pharmacology Society, Sanofi, Society of Toxicologic Pathology, and The Teratology Society.
Vision and Background
Human stem cell-derived cardiomyocytes (hiPSC-CMs) are increasingly used in drug discovery, toxicity assessment, and cell-based disease treatment. In vitro screening assays also are used to make decisions about which drug candidates to progress into development. From the public health perspective, assessing the cardiovascular toxicity potential of any new drug product or environmental toxicant is important. Comprehensive in vitro proarrhythmia (CiPA) assay is a new risk assessment paradigm proposed to replace the current thorough QT study which is currently needed for each new drug application. One of the proposals included in CiPA is to use hiPSC-CM to test drug-induced effects on the myocardial action potential to confirm the outcome of in silico modeling of drug-induced effects. The in silico modeling is based on the blocking activity of a given drug on the most important human myocardial ion channels involved in myocardial depolarization and repolarization. It is therefore important to understand the functional, morphological, and biochemical hallmarks of hiPSC-CMs and how this may relate to factors including the maturity of the hiPSC-CMs used and the specific conditions used to culture the cells. We need to understand how these cells behave in comparison to adult human ventricular or atrial CMs. Only when this is understood can we determine if they will provide a useful model for predicting in vivo activity. In addition, the acceptable translation of effects in stem cell-derived CM tested with environmental chemicals to human environmental exposure levels requires a thorough understanding of these same parameters.
In light of the potential utility of this emergent technology, this workshop will engage experts in presenting and discussing various aspects of the phenotype of these cells (functional, proteins, biochemical) and comparing them to adult ventricular CMs, as a basis for assessing their potential uses in drug and chemical safety testing. Topics covered include description of cell phenotypes from different sources, in vitro culture conditions and quality assessment, assay methods and validation, in vitro/in vivo correlation, current experience and challenges, and outlining and prioritizing the further work needed. This workshop included domestic and international scientists from government agencies, pharmaceutical industry, and academia to discuss the current state of the art and the path forward.
The specific objectives of the workshop included:
- Sharing of experiences using stem cell-derived cardiomyocytes (SC-CMs) including hiPSC-CMs and embryonic stem cells-derived cardiomyocytes (hESC-CMs) for the testing of electrophysiological effects and the assessment of resultant proarrhythmic risk or other drug-induced safety risks (e.g., contractility or calcium homeostasis).
- Defining the cell characteristics needed for use in a given assay system.
- Discussing in vitro assay methods and markers needed to standardize the defined phenotype of hiPSC-CM and ensure quality.
- Discussing the role of electrophysiological studies of cardiac myocytes to predict the proarrhythmic potential of drugs.
- Identifying advanced uses of hiPSC-CM that can be used to identify potential cardiovascular risk.
Some conference materials are restricted and only may be accessed by individuals who registered to attend “The Use of Cardiomyocytes for the Assessment of Proarrhythmic Risk.”
Abstracts for Poster and Invited Speaker Presentations