Science Pool

Vanoxerine is a multi-ion channel blocker. For this reason, it was developed as a therapy for atrial fibrillation. However, in Phase III trials, 11.5% of patients developed torsades de pointes. Using MEA and human iPSC-derived cardiomyocytes, it was possible to detect this cardiotoxic liability. 

In this poster, we focus on:

• the use of MEA and human iPSC-derived cardiomyocytes to detect vanoxerine arrhythmias
• the time dependent effect of vanoxerine cardiotoxicity
• the ADME properties of vanoxerine which may impact on its cardiotoxic effect

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TAK-875 (fasiglifam) is a GPR40 agonist which was developed for the treatment of type 2 diabetes. However, TAK-875 was withdrawn from phase III clinical trials due to drug-induced liver injury (DILI).

In this poster, we focus on:

• investigating the mechanism behind the hepatotoxicity of TAK-875
• an in-depth understanding of the effect of TAK-875 on mitochondrial toxicity 
• understanding the impact of plasma protein binding

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Advances in human iPSC-derived neuronal models in conjunction with microelectrode array (MEA) technology has enhanced our understanding of complex burst organisation and network characteristics in humans. This now provides a viable human model for studying drug-induced toxicity and CNS liabilities as well as potential pharmacology effects on the neurones.

In this poster, we focus on:

• investigating co-cultures of human iPSC-derived glutamatergic neurons with astrocytes on the MEA platform
• determining spike activity, burst organisation and network organisation (synchrony) patterns for different types of CNS compounds (GABA_A agonists, potassium channel blockers, opioid receptor agonist, glycine receptor antagonist and cholinergic and muscarinic receptor agonists)
• understanding developmental and pharmacological responses when assessed by MEA

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Drug or chemical-induced nephrotoxicity is responsible for 25% of renal failure in the clinic.

In this poster, we focus on:

• a comparison of 2D and 3D human primary kidney cell-based models for predicting nephrotoxicity
• the use of mono and co-culture kidney models
• using HCS for the simultaneous detection of DNA structure, GSH content, mitochondrial toxicity and phospholipidosis

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Pilocarpine is a muscarinic receptor agonist which is used as a model inducer of epilepsy in the rat. We evaluated the seizurogenic response of pilocarpine using an in vitro MEA platform.

In this poster, we focus on:

• a comparison of pilocarpine response in different neuronal cell types; cryopreserved rat cortical neurons, cryopreserved rat hippocampal neurons and a co-culture of human iPSC-derived glutamatergic neurons with astrocytes
• the impact of DIV and cell maturation on the response
• identifying muscarinic receptor expression over time

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The benefits of 3D cell-based models in the prediction of drug-induced liver injury are now being realised. 

In this poster, we focus on:

• the use of 3D models (cryopreserved human hepatocytes co-cultured with human non-parenchymal cells compared with HepaRG monocultures)
• cytochrome P450 (CYP) activity in the different models
• HCS analysis of DNA structure, GSH content, ROS formation and mitochondrial function
• prediction of DILI potential for a set of DILI-positive and negative compounds

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Drug-induced liver injury (often termed DILI) is a major cause of drug failure. The aetiology of DILI is often complex and multifactorial - meaning a single endpoint is unlikely to be sufficient in predicting this liability. Although 2D DILI models have traditionally been used in he prediction of DILI, the advantages of 3D models are now being realised.

In this poster, we focus on:

• the use of multiparametric confocal high content screening (HCS) in DILI prediction
• comparison of co-cultures of human liver 3D microtissues containing cryopreserved human hepatocytes with human non-parenchymal cells and HepaRG 3D spheroids
• the assessment of a set of DILI-positive and DILI-negative compounds following drug exposure over 14 days
• endpoints for DNA structure, GSH content, ROS formation and mitochondrial function

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Drug-induced mitochondrial toxicity has been implicated in adverse events such as liver failure and cardiotoxicity. There are several in vitro assays used to detect mitochondrial toxicity including the glu/gal cytotoxicity assay, high content screening for mitochondrial membrane potential and the Seahorse flux analyser to detect OCR (cellular oxygen consumption rate), reserve capacity and ECAR (extracellular acidification rate).

In this poster, we focus on:

• an analysis of the different methods for detecting mitochondrial toxicity
• an insight into the mechanism of mitochondrial toxicity using the permeabilised cell assay. 

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Domoic acid is a neurotoxin which was associated with the poisoning of 107 people and 3 subsequent deaths on Prince Edward Island in 1987 following the ingestion of mussels containing this poison. The associated neurotoxic effects of domoic acid are clearly identified at concentrations of ≥ 1µM using neurons analysed on a microelectrode array (MEA) platform. Interestingly, domoic acid had no effect up to 25µM in the neurite outgrowth assay (another common method for detecting neurotoxicity).

In this poster, we focus on:

• a comparison of the neurite outgrowth assay with the MEA platform
• sensitivity of the two methods for detecting neurotoxins and seizurogenic compounds
• a screening strategy for testing neurotoxic compounds 

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Pilocarpine is a muscarinic receptor agonist, originally developed to treat dry mouth and glaucoma. It is also used to induce epilepsy in the rat. 

In this poster, we focus on:

• pilocarpine response in vitro using MEA
• analysis of the neuronal responses of different cell types such as cryopreserved rat cortical neurons, rat hippocampal neurons and human iPSC-derived glutamatergic neurons and astrocytes
• the impact of cell maturation (DIV)

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