2017-SOT-posters-presentations
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SOT / ToxExpo 2017 Presentations and Posters

Cyprotex showcased the following research at the Annual Society of Toxicology Meeting (SOT) and ToxExpo. Posters presented by Cyprotex are available for download below.

Poster Presentations

Paul Walker, PhD Predicting DILI using Multi-donor Type Human Liver Microtissues, Confocal High Content Screening (HCS) Data and Normalisation to Therapeutically Relevant Tissue Specific Concentrations
Donald Keller Development of a Model for Assessment of Blue Light Activated Toxicity in EpiGingival™ and EpiGingival™-FT Tissues
Paul Walker, PhD Kidney In Vitro Models for The Improved Prediction of Chemical-Induced Nephrotoxicity
Paul Walker, PhD Cardiac Microtissue Models for the Improved Prediction of Drug-Induced Cardiac Hypertrophy
Christopher Strock, PhD Human-Induced Pluripotent Stem Cell-Derived Neurons: Evaluating Maturation and Neurotoxic Predictability in the Presence or Absence of GABAergic Neurons and Astrocytes Using a Microelectrode Array Platform
Christopher Strock, PhD Evaluating the Arrhythmic Potential of Vanoxerine in Human iPSC Derived Cardiomyocytes on a Multiwell MEA

Research Partner Poster Presentations

J.L. Woodhouse
DILIsym Services
Quantitative Systems Toxicology Analysis of In Vitro Mechanistic Assays Reveals Importance of Bile Acid Accumulation TAK-875-Induced Liver Injury
An Van Rompay, PhD
VITO NV
CON4EI: Consortium for In Vitro Eye Irritation Testing Strategy
H. Kandarova
MatTek
CON4EI: EpiOcular Eye Irritation Tests (OECD TG 492 and ET-50 Protocols)
W.H. De Jong, PhD
RIVM
Round Robin Study to Evaluate the Reconstructed Human Epidermis (RhE) Model as In Vitro Skin Irritation Test for Detection of Irritant Activity in Medical Device Extracts
Brian Hess
LaunchPad Medical
Assessment of the Biocompatibility of Various Bone Graft Substitutes Using Primary Human Osteoblasts and Mesenchymal Stem Cells Isolated from Bone Marrow
Paul Fowler, PhD
Unilever
A Mechanistic Safety Assessment Framework from In Vitro Human Liver Models Treated with Doxorubicin

Poster Presentations

Predicting DILI using Multi-donor Type Human Liver Microtissues, Confocal High Content Screening (HCS) Data and Normalisation to Therapeutically Relevant Tissue Specific Concentrations

Presented by: Paul Walker, PhD

In this study, human Liver Microtissues (hLiMTs) were formed from primary human hepatocytes and donor matched or unmatched non-parenchymal cells. The microtissues consistently displayed uniform size, shape, ATP content and longevity beyond 21 days in culture; however, hLiMTs derived from different patient cohorts show markedly different cytochrome P450 (CYP) activity.

29 compounds (20 DILI-positive, 9 DILI-negative) were evaluated in this study, which sought to assess hLiMTs’ utility in DILI detection using reduced glutathione content (GSH), reactive oxygen species (ROS) formation, and mitochondrial dysfunction as endpoints. Multiplexed confocal images were acquired and cellular ATP measurement was used to evaluate cytotoxicity. Using the minimum effective concentration (MEC) in conjunction with the liver tissue Cmax, DILI prediction was significantly improved. The study demonstrates that 3D cell models can be a cost effective component in an in vitro toxicology cascade, especially when used in conjunction with in silico tissue specific Cmax modelling.

Development of a Model for Assessment of Blue Light Activated Toxicity in EpiGingival™ and EpiGingival™-FT Tissues

Presented by: Donald Keller

The use of blue light is becoming more common in therapeutic applications. However, like UV light, lower energy blue light can activate certain chemicals which can lead to adverse outcomes.

In this study, EpiGingival™-FT (MatTek) was used to evaluate the resultant toxicity of several compounds following blue light exposure. After dosing, exposure and a recovery period, tissue viability was assessed using MTT. Viability was unaffected by blue light on its own, however, blue-light dependent toxicity was observed in the presence of certain known reference compounds.

Kidney in vitro Models for the Improved Prediction of Chemical Induced Nephrotoxicity

Presented by: Paul Walker, PhD

The kidneys play an essential role in the elimination of chemicals and their metabolites from the body, and are therefore a common site for toxicity. Three in vitro kidney models were evaluated for their potential to predict nephrotoxicity. These included two 3D microtissue models (one cultured exclusively with renal proximal tubular epithelial cells (RPTEC), and the other a tri-culture model utilising RPTEC, renal fibroblasts (RF) and endothelia cells (EC)), and a 2D RPTEC model. Exposure to known nephrotoxicants was followed by HCS analysis of mitochondrial dysfunction, glutathione content, and reactive oxygen species, which was combined with a measurement of cellular ATP content, over 72 hr or over repeat dosing regimens of 9 and 14 days. The results indicate that 3D microtissues improve the in vitro to in vivo extrapolation for chemical induced nephrotoxicity.

Cardiac Microtissue Models for the Improved Prediction of Drug-induced Cardiac Hypertrophy

Presented by: Paul Walker, PhD

Repeat dose drug exposures can lead to morphological damage of myocardial tissue such as hypertrophy. 3D cell-based models offer improved viability and so are more suitable for repeat dose exposure. In this study, we evaluate three types of cardiac microtissues (MTs) and their utility in detecting cardiac hypertrophy. The MTs assessed were formed as either monocultures (cardiomyocytes alone), co-cultures (cardiomyocytes with endothelial cells or fibroblasts), or tri-cultures (cardiomyocytes, endothelial cells and fibroblasts). MTs were exposed to a panel of 16 compounds (10 known hypertrophy inducing cardiotoxins, 4 other structural cardiotoxins and two negative controls), and fluorescent HCS analysis was used to measure calcium homeostasis and mitochondrial dysfunction. This data was combined with cellular ATP measurements to determine structural cardiotoxicity. Hypertrophy was assessed by measuring an increase in B-Type Natriuretic Peptide (BNP). Overall, the results showed promise in using single organotypic human derived 3D cardiac microtissues in combination with multiplexed HCS to enhance in vitro to in vivo translation of the potential for drug-induced hypertrophy.

Human-Induced Pluripotent Stem Cell-Derived Neurons: Evaluating Maturation and Neurotoxic Predictability in the Presence or Absence of GABAergic Neurons and Astrocytes Using a Microelectrode Array Platform

Presented by: Christopher Strock, PhD

Early electrophysiological neuronal models using human induced Pluripotent Stem Cell-derived (hiPSC) neurons lacked complex burst organisation, resulting in incomplete neurotoxicity data when used in conjunction with a microelectrode array (MEA) platform. Rodent-derived models have proven to be an adequate stand in, but lack the physiological relevancy that human models can provide. In single culture, glutamatergic hiPSC neurons show robust firing rates, burst organisation and network characteristics, which constitute an advancement from previous hiPSC models.

Known seizurogenic compounds were used to elicit electrophysiological responses in glutamatergic hiPSCs plated alone, and in the presence of different ratios of GABAergic neurons and astrocytes. Together, these cultures present a robust platform that can not only assess neuronal development patterns, but responses to certain neurotoxic/seizurogenic compounds as well.

Evaluating the Arrhythmic Potential of Vanoxerine in Human iPSC-Derived Cardiomyocytes on a Multiwell MEA

Presented by: Christopher Strock, PhD

The investigation of vanoxerine as a dopamine transporter antagonist to treat cocaine addiction was halted when the compound was shown to be a potent hERG blocker. It was also found to be a multichannel inhibitor, blocking Cav1.2 and Nav1.5, which appeared to counteract the hERG effects, and demonstrated significant potential to treat atrial fibrillation. While vanoxerine was found to successfully treat 69% of patients in a Phase III study, 11.5% developed torsades de pointes (TdP), thus halting the trial.

CiPA (Comprehensive In Vitro Proarrhythmia Assay) is a consortium established to evaluate a range of in vitro and in silico tools to be used in a tiered approach for the prediction of cardiotoxicity. Vanoxerine was shown to be safe in in vitro ion channel testing and in silico modelling – the first two tiers of CIPA. However, in the third tier of testing, vanoxerine extended Field Potential Duration (FPD) at all concentrations when assessed in the MEA assay with iPSC-derived cardiomyocytes. With the exception of Na amplitude, negative effects were maximal for all endpoints including arrhythmia at 0.316µM. Moreover, the compound has found to have a relatively slower action than many hERG inhibitors, with maximal responses and arrhythmias occurring three hours after treatment.

Research Partner Poster Presentations

Quantitative Systems Toxicology Analysis of In Vitro Mechanistic Assays Reveals Importance of Bile Acid Accumulation in TAK-875-Induced Liver Injury

Presented by: J.L. Woodhouse, DILIsym Services

CON4EI: Consortium for In Vitro Eye Irritation Testing Strategy

Presented by: An Van Rompay, PhD, VITO NV

CON4EI: EpiOcular Eye Irritation Tests (OECD TG 492 and ET-50 Protocols)

Presented by: H. Kandarova, PhD, MatTek

Assessment of the Biocompatibility of Various Bone Graft Substitutes Using Primary Human Osteoblasts and Mesenchymal Stem Cells Isolated from Bone Marrow

Presented by: Brian Hess, LaunchPad Medical

Round Robin Study to Evaluate the Reconstructed Human Epidermis (RhE) Model as In Vitro Skin Irritation Test for Detection of Irritant Activity in Medical Device Extracts

Presented by: W.H. De Jong, PhD, RIVM

A Mechanistic Safety Assessment Framework from In Vitro Human Liver Models Treated with Doxorubicin

Presented by: Paul Fowler, PhD, Unilever

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