Science Pool

Seizure Prediction using MEA: Importance of Receptor Expression, Cell Type, and Maturity

The fourth webinar in this series on New Approaches in Toxicology was presented by Christopher Strock PhD from Cyprotex.

About the Webinar

For the prediction of seizurogenic and neurotoxic compounds, microelectrode array (MEA) technology has proven to be a very powerful tool. Early human induced potent stem cell (hiPSC) derived neuronal models lacked complex burst organization, making electrophysiological neurotoxic prediction challenging when utilizing an MEA platform. However, advancements in hiPSC neuronal models have addressed these challenges. In this presentation, we learn more about how maturation of the hiPSC model is critical for neuronal characteristics such as bursting and synchrony, we demonstrate how time dependent receptor expression plays a role in this maturation process, and we understand the impact of different cell types and co-culture models on the sensitivity and robustness of the neuronal and seizurogenic activity.

About the Speaker

Christopher Strock PhD Director of Scientific Operations | Cyprotex Chris Strock received his BS in Chemistry from Gannon University in Erie, PA. He worked as an organic chemist for DuPont Ag for a few years before getting his PhD in Biochemistry and Molecular Biology from the University of Maryland, Baltimore where he determined the calcium binding sites on the SR Calcium. Following his PhD, Chris was a Postdoctoral Fellow and Research Associate in the Oncology Department at Johns Hopkins University School of Medicine under Barry Nelkin, PhD where he identified CDK5, a protein important in migration of cells in neural development, as an essential molecule for metastasis in numerous cancer models. He then joined Cellumen where he developed his expertise in High Content Screening technology. While there, he specialized in assay development and was responsible for the design and development of High Content HTS Protein: Protein Interaction biosensor assays. He also worked in the HCS toxicology group, developing and optimizing assays for the in vitro toxicology assay, CellCiphr®. After Cyprotex acquired Cellumen, Chris joined Cyprotex US in Watertown, MA where he has brought his expertise for the last 10 years in the area of HCS assay development, electrophysiology and toxicology. He is the co- chairman of the HesI NeuTox Group for prediction of Seizures using Microelectrode Array. He currently is the Watertown Site Head and the Head of the in vitro Toxicology group and has more than 30 peer reviewed publications.

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Development of an In Vitro T-cell Assay to Assess the Intrinsic Immunogenicity of Drugs and Chemicals

The third webinar in this series on New Approaches in Toxicology was presented by Monday Ogese PhD from University of Liverpool.

About the Webinar

The prediction of drug hypersensitivity is difficult due to the lack of appropriate models and an incomplete understanding of risk factors/mechanisms of immune tolerance. Our research at the MRC centre of Drug Safety Science, University of Liverpool combine aspects of genetics, cell biology and chemistry in order to study the fundamental principles of immunological drug reactions. We have recently developed an in vitro naïve T-cell priming assay with the potential to screen immunogenic drug candidates during preclinical drug development and the application of the assay will be discussed during my presentation.

About the Speaker

Monday Ogese PhD Postdoctoral Scientist at the MRC Centre for Drug Safety Science | University of Liverpool Monday O. Ogese is a postdoctoral scientist at the MRC Centre for Drug Safety Science, University of Liverpool. He was awarded his PhD (Pharmacology) in 2014 at the University of Liverpool. His first postdoctoral fellowship with AstraZeneca R&D, UK focused on drug-specific signalling between primary human hepatocytes and immune cells, and the role of hepatocyte-derived exosomes in drug-induced liver injury. His current research interest focuses on the development of screening assay systems to predict intrinsic immunogenicity of candidate drugs and chemicals. Monday has published 23 peer reviewed articles on various aspects of drug hypersensitivity reactions. In 2021, Monday joined Cyprotex as a Principal Scientist in the UK Toxicology team.

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Understanding the Applicability and Limitations of In Silico and In Vitro Safety Models Towards the Design and Selection of the Safest Drug Candidates

The second webinar in this series on New Approaches in Toxicology was presented by Takafumi Takai PhD from Takeda.

About the Webinar

A variety of in silico and in vitro safety assays are widely used in lead optimization in order to capture the safety-related liability as early as possible. Understanding the applicability and limitation of each assay based on the chemical space/chemotype is important for the effective usage. Several case studies of the applicability analysis including in silico phototoxicity prediction and low-dose in vivo toxicity prediction by cytotoxicity assay will be presented.

About the Speaker

Takafumi Takai PhD Senior Scientist | Takeda Takafumi has more than 15 years of industry experience in drug discovery. He currently manages safety assessments mainly during compound optimization at Takeda California by using his expertise in medicinal and computational chemistry. Prior to joining the drug safety department, he led drug discovery projects as a medicinal chemist at Takeda in Japan. He holds a Ph.D. from Okayama University, Japan as well as a Master’s Degree from Tohoku University, Japan.

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Drug Discovery and Development:  Challenges and Opportunities in Toxicology

The first webinar in this series on new approaches in toxicology was presented by Professor Ruth Roberts from ApconiX.

About the Webinar

Ruth will present lessons learned from >20 years’ experience in the pharmaceutical industry focusing on attrition, prediction and the challenges posed by non-clinical to clinical concordance. Several case studies that focus on science-driven design will be shared for discussion. Chemical liabilities should be eliminated early in discovery while there are still options in chemistry. Equally important is a thorough understanding of potential target-related risks and their likelihood of occurrence. The triple challenge of attrition, concordance and the 3Rs should drive us to take a longer term, strategic approach to drug discovery and safety testing. New technologies such as micro physiological systems (MPS), artificial intelligence and big data all offer opportunities to do things differently. But are we ready for change?  These issues and potential solutions will be presented for discussion.

About the Speaker

Professor Ruth Roberts PhD, ATS, FBTS, ERT, FRSB, FR CPath Director and Co-founder | ApconiX Ruth is chair of drug discovery at Birmingham University, UK and Co-founder of ApconiX, an integrated toxicology and ion channel company that brings together a team of world-renowned nonclinical safety experts with over 300 years of drug discovery and development experience.  Before that Ruth was Global Head of Regulatory Safety at AstraZeneca and Director of Toxicology for Aventis in Paris, France. With >150 publications in peer reviewed journals, she is interested in developing and implementing new models to increase success rates in drug discovery and development. Ruth is former president of EUROTOX, former past president of the Academy of Toxicological Sciences and was recently elected to vice-chair of the Board of Trustees of the Health and Environmental Sciences Institute (HESI), based in Washington, DC. She was the recipient of the SOT Achievement award in 2002, the EUROTOX Bo Holmstedt Award in 2009 and the SOT 2018 Founders award, given in recognition of outstanding leadership in fostering the role of toxicological sciences in safety decision making.

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Learn more about our ligand binding assays and how they can support biological drug testing in a regulated environment, including:

• Regulated bioanalysis
• Immunogenicity
• Immunotoxicity
• Biomarkers (safety and efficacy)
• Clinical Pathology
• Sample Management
• Additional activities

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This article forms a book chapter in Artificial Intelligence in Drug Design.

In this review article, we discuss the use of machine learning approaches in large omics studies

The chapter includes:

• an overview of the typical analysis of an omics dataset using machine learning
• demonstration of how to build a model predicting drug-induced liver injury (DILI) using transcriptomics data
• best practices and pitfalls to consider during initial data exploration and model training through to validation and analysis of the final model

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Learn more about our chronic exposure nephrotoxicity assay including:

• Background information
• Assay details and protocol summary
• Data generated in the chronic exposure nephrotoxicity assay

Learn more about our apoptosis and necrosis assay including:

• Background information
• Assay details and protocol summary
• Data generated in the apoptosis and necrosis assay

Learn more about our 3D combined hypertrophy and cardiotoxicity assay including:

• Background information
• Assay details and protocol summary
• Data generated in the3D combined hypertrophy and cardiotoxicity assay

Learn more about the GreenScreen HC genotoxicity assay including:

• Background information
• Assay details and protocol summary
• Data generated in the GreenScreen HC genotoxicity assay