Science Pool

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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Microelectrode array (MEA) is a powerful technique for the prediction of proarrhythmic liability. One of the main advantages of MEA is its ability to predict unexpected cardiac liabilities and long term chronic effects in vitro. 

In this poster, we focus on:

• the ability of the MEA platform to predict chronic long term effects including hERG trafficking
• predicting the cardiotoxicity of BMS-986094 (INX-08189), a hepatitis C therapy which caused death in its clinical trial after multiple weeks

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The mitochondria are a common target of drug-induced toxicity. A number of approaches are used to detect mitochondrial toxicity but how do we know which to use?

In this poster, we focus on:

• a comparison of the different methods including the glucose/galactose (glu/gal) cytotoxicity assay, high content screening (HCS) method for mitochondrial membrane potential and cytotoxicity, and the Seahorse flux analyser
• the ability of the different methods to predict mitochondrial toxicity through sensitivity, specificity and accuracy assessment
• an insight into the mechanism of mitochondrial toxicity through the Seahorse flux analyser and permeabilised cell assay.

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Cardiac left ventricular hypertrophy is a risk factor for heart failure. Morphological (structural) effects such as cardiac hypertrophy can be drug-induced therefore it is important to identify these liabilities at an early stage of drug discovery and development.

In this poster, we focus on:

• using HCS to detect cardiac hypertrophy
• the comparison of single cell, co-culture and triculture microtissues models for predicting cardiac hypertrophy

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Genotoxicity is a key concern during drug discovery and development. Clastogens and aneugens are two types of mutagens which result in chromosomal aberrations. Clastogens directly damage the chromosome causing sections of the DNA being deleted, added or rearranged (structural chromosomal aberrations). Aneugens cause an abnormal number of chromosomes (numerical chromosomal aberrations). Early stage screening of genotoxicity potential along with identification of the mechanism of action of the genotoxicity is important in reducing late stage failure.

In this poster, we focus on:

• a modified HCS assay for detecting genotoxins
• the incorporation of S9 fraction to identify metabolically activated genotoxins
• distinguishing between clastogens and aneugens

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Mitochondria are a common target for drug-induced toxicity. Several different in vitro methods exist for investigating drug-induced mitochondrial toxicity. 

In this poster, we focus on:

• a comparison of three different in vitro assays for detecting mitochondrial toxicity (Glu/Gal cytotoxicity assay, Seahorse Flux Analyser and high content imaging of mitochondrial membrane potential)
• the effect of protein binding on the mitochondrial toxicity
• recommendations for a tiered screening approach

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In vitro 3D cell-based models are more representative of the complex in vivo microenvironment than traditional 2D monolayers. Furthermore, these models allow for long term compound exposures - more closely replicating clinical dosing strategies.

In this poster, we focus on:

• 3D human liver microtissues formed from multiple donors co-cultured with human non-parenchymal cells
• exposure of the cells to multiple doses of hepatotoxins and non-hepatotoxins
• HCS analysis of DNA structure, GSH content, ROS formation and mitochondrial function
• the impact of correcting for therapeutically relevant tissue C_max 

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BMS-986094 (INX-08189) is a prodrug of a guanosine nucleotide analogue which was developed to treat hepatitis C virus but was discontinued during clinical trials due to cardiotoxic effects.

In this poster, we focus on:

• the mechanism of BMS-986094 cardiotoxicity 
• the impact of chronic dosing over multiple time points
• evaluation of data from an MEA platform, a cardiac mitochondrial protein biogenesis assay, a calcium flux assay and a cardiac cytotoxicity assay 

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BMS-986094 (INX-08189) is a guanosine nucleotide analogue prodrug which was developed to treat hepatitis C virus (HCV). However, BMS-986094 was discontinued in Phase III clinical trials with 1 death and 8 people hospitalised with significantly reduced left ventricular ejection fraction (LVEF). Cardiotoxic effects were observed in 14 out of the 34 patients with left ventricular dysfunction, with ST depressions, T-wave inversions or loss of T-wave amplitude.

In this poster, we focus on:

• investigating the mechanism behind the cardiotoxicity of BMS-986094
• the use of MEA and human iPSC-derived cardiomyocytes in long term incubations with BMS-986094

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