Multi-Organ and Species-Specific Safety Profiling using Transcriptomics
Presented by: Paul Walker PhD Date: March 29, 2022 Time: 10:30 AM - 11:30 AM PDT Room: 23C
We present cutting-edge research in the field of transcriptomics and how this technology can be used to improve multi-organ safety profiling in human and preclinical species. In addition, there is a demonstration of how this platform can provide an additional in-depth mechanistic understanding of toxicological pathways.
Cyprotex Poster Presentations
Identifying Seizures with MEA: Complementary Human and Rat Neuronal Models Enhance Predictivity
Presented by: Chris Strock PhD Date: March 28, 2022 Time: 2:30 PM- 4:15 PM PDT Abstract Number/Poster number: 3289/P439
The microelectrode array (MEA) platform is an important tool for the prediction of seizurogenic and neurotoxic potential in test compounds, though work using rat cortical neurons revealed key targets that have not responded as reliably as expected. In this poster, we present an alternative screening method using human iPSC-derived glutamatergic neurones co-cultured with human iPSC-derived astrocytes (FCDI) which is highly effective in identifying compounds with CNS liabilities. In addition, this model can successfully identify chemical agents targeting the muscarinic receptor, which is not definitively identified by the rat cortical neuron model. Because the human model does not reliably identify GABAA antagonists, which are consistently identified in the rat models, we recommend a combined screening approach to provide a more robust and accurate in vitro prediction of CNS liabilities using the MEA platform.
Development of In Vitro Assays to Predict Potential Immunotoxicological Liabilities of Candidate Drugs using Human Peripheral Blood Mononuclear Cells
Presented by: Stephen Madden PhD Date: March 29, 2022 Time: 9 AM- 10:45 AM PDT Abstract Number/Poster number: 4121/P825
Drug hypersensitivity is an immunological adverse drug reaction (ADR) which, typically, targets the skin, liver, blood and kidneys. It is currently not possible to accurately predict which individuals will be hypersensitive to new drugs during early development. This is partly due to the majority of the susceptibility factors being genetic and idiosyncratic, which makes them difficult to recapitulate in vivo and in existing in vitro assays. In addition, the immunoregulatory system that preserves tolerance to neoantigens varies between individuals and can be further influenced by disease and environmental factors.
The research presented in this poster explores the cytotoxicity profiles of 27 reference compounds known to target the liver, skin or blood via immune-mediated mechanisms involving drug-specific lymphocytes. We demonstrate that in vitro immunotoxicity assays developed using primary immune cells isolated from multiple donors have the potential to improve the safety of drugs, chemicals, cosmetics and biologics.
Evaluating Functional and Structural Cardiotoxicants using Calcium Flux, HCI and High Throughput Transcriptomics
Presented by: Stephen Madden PhD Date: March 30, 2022 Time: 9 AM - 10:45 AM PDT Abstract Number/Poster number: 4377/P331
Cardiotoxicity is a major cause of drug attrition during drug development. Drug-induced functional changes can be defined as an acute alteration in the mechanical function of the myocardium, or structural in nature as defined by morphological damage to cardiomyocytes and/or loss of cell viability. In vitro strategies have developed to utilise high throughput assessment of functional cardiomyocyte changes through kinetic monitoring of calcium transients, while structural morphology can be monitored in a high throughput manner using high content imaging (HCI).
Within this poster, we describe a combined risk assessment method to allow the morphological analysis of cardiomyocytes alongside calcium transient assessment in a single assay. Together with whole genome high throughput (HT) RNA-sequencing (RNA-seq), this method provides defined functional and structural cardiotoxicity events.
High Throughput RNA-Seq Profiling of 3D Liver Organoids to Predict Drug-Induced Liver Injury (DILI)
Presented by: Paul Walker PhD Date: March 30, 2022 Time: 10:45 AM- 12:30 PM PDT Abstract Number/Poster number: 4449/P449
Drug-induced organ toxicity remains a major reason for drug attrition and a primary concern in the development of new drugs. A variety of in vitro liver models have been developed to de-risk DILI in earlier drug discovery. One such approach is the use of organotypic three-dimensional (3D) microtissues combined with High-Content Imaging (HCI). By combining the most predictive and physiologically relevant in vitro models with analysis of the cellular transcriptome, an enhanced mechanistic understanding of off-target cellular effects can be gained.
In this poster, we show how predictive toxicogenomics (TGx) combined with organotypic liver models and machine learning can be used to profile novel chemical entities to determine DILI risk, providing a valuable insight in to the potential mode of action implicated in a drug’s toxicity.
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