iCell® and MyCell® human iPSC-derived products were featured in many presentations and workshops at SOT 2017. Topics covered included (but were not limited to):
- Expanding cardiomyocyte functionality and analytical techniques
- Detecting seizurogenic activity with glutamatergic neurons
- Improving hepatocyte function with 3D culturing techniques
- Developing population-based approaches for cardiotoxicity testing
CDI also featured a recently launched iPSC-derived cell line: iCell® GlutaNeurons – a human excitatory neuronal model.
Cellular Dynamics Sponsored Exhibitor Workshops
Squeezing More Out of iPSC-derived Cardiomyocytes: Providing Better Solutions through Increased Functionality and Integrative Analyses
Wednesday, March 15 | 12:00 – 1:00 pm | Room 337
Presented by: ACEA Biosciences, Cellular Dynamics International and Charles River Labs
Abstract: This forum showcases practical advances in xCELLigence® CardioECR and iPSC-cardiomyocyte-based solutions for toxicity studies. Specifically, data will be presented illustrating increased cardiomyocyte functionality and how integrating electrical and mechanical responses provides mechanistic and translatable results from a variety of chemical classes including small molecule kinase inhibitors and inotropic compounds.
Wednesday, March 15 | 1:30 – 2:30 pm | Room 338
Presented by: Cellular Dynamics International and Cyprotex
Abstract: iCell® GlutaNeurons are human excitatory neurons that form spontaneously bursting networks modulated by pro-convulsant and neuroactive molecules, thus adding a new dimension to the toxicologist’s toolbox. This workshop will illustrate the attributes of these neurons, provide case studies highlighting their use, and illustrate potential analyses for pro-seizurogenic investigations.
Human-on-a-Chip Systems for Mechanistic Toxicology Investigations
Wednesday, March 15 | 10:20 am | Room 321
Speaker: J. J. Hickman, University of Central Florida, Orlando, FL
Abstract: The pharmaceutical industry would benefit greatly from better pre-clinical screening technologies for mechanistic toxicology to reduce the attrition rate during clinical trials as well as to begin to pre-select specific genetic sub-populations for optimal drug efficacy with limited distribution. A promising technology to help reduce the cost and time of this process are body-on-a-chip or human-on-a-chip systems either at the single organ level, or more importantly, advanced systems, where multiple organ mimics are integrated in a flow system with a serum-free defined medium to allow organ to organ communication and interaction for mechanistic determinations for safety and efficacy as well. The idea is to integrate microsystems fabrication technology and surface modifications with protein and cellular components, for initiating and maintaining self-assembly and growth into biologically, mechanically, and electronically interactive functional multi-component systems. Cardiac systems have been developed that allow independent evaluation of electrical conduction and force generation in cardiac muscle for mechanistic studies for both iPSC and embryonic stem cells. The cardiac tissues have also been combined with liver systems in the same platform that are shown to provide metabolic capabilities demonstrated with 4 different drug/metabolic pairs. In addition, a functional neuromuscular junction model composed of human stem cell-derived motoneurons and muscle was shown to produce dose response curves for synaptic cleft toxins. Recently, a 4-organ system with recirculating medium was developed in collaboration with an industry partner, and the system was used to test the toxicity profiles of 5 drugs administered to the organ systems over 28 days. These studies resulted in drug-induced multiorgan toxicity that reproduced results typically seen in vivo. Overall, we have demonstrated outstanding potential to apply these new human-on-a-chip systems to understand mechanistic toxicology.
An Industry Perspective on New and Emerging In Vitro Models for Assessing Hepatotoxicity Risk in Drug Discovery
Wednesday, March 15 | 11:20 am | Room 321
Speaker: Will Proctor, Head of Investigative Toxicology, Genentech
Abstract: Drug-induced liver injury (DILI) is still a major source of clinical attrition and post market withdrawal of drugs. This is due to the many different etiologies of DILI, the relatively low incidence rate (<1%) often observed, poor understanding of the drivers for patient susceptibility, and a general insensitivity of preclinical animal models to detect most human hepatotoxicants. Extensive efforts are made to evaluate more physiologically relevant in vitro models for assessing hepatotoxicity risk in drug discovery. New commercially available 3D/organotypic hepatic models present several advantages over traditional in vitro hepatocyte models, including but not limited to long-term treatment durations, sustained and stable metabolic activity, and added complexity (e.g. inclusion of Nonparenchymal cells (NPCs)). In collaboration with AstraZeneca, we evaluated spheroid human liver microtissues (hLiMT) comprised of both primary hepatocytes and NPCs (e.g. Kupffer cells). With a test set of 110 drugs (60% DILI positive and 40% DILI negative), we measured cytotoxicity in long-term (14-day treatment) treatment in hLiMT and acute (48h) treatment in primary human hepatocytes (PHH) from the same donor used to prepare the hLiMT. Using this test set and correcting for clinical exposure (Cmax), hLiMT had increased predictive value (71% sensitivity and 92% specificity) in identifying human hepatotoxicants in comparison to PHH (61% sensitivity and 83% specificity). hLiMT prepared from multiple lots of hepatocytes and NPCs demonstrated reproducibility comparable to that of PHH. Lastly, we employed hLiMTs for assessing mechanisms of potential hepatotoxicity for a proprietary compound associated with clinical transaminase increases and for a panel of antibody drug conjugates that caused liver injury in preclinical species. In both studies, hLiMT were more sensitive to detect drug-induced cytotoxicity than PHH and provided mechanistic information that PHH could not. In conclusion, new microphysiologic in vitro systems, in particular hLiMT, appear promising tools for DILI risk assessment in drug discovery.