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Development of native and stem cell-derived electrophysiological assays for neurotoxicology screening and translational drug discovery

Neurotoxicological effects now rank second behind cardiovascular events as adverse events impeding the development and safety of new drug candidates. Accordingly, Metrion has developed assays that can be used to predict seizurogenic and neurotoxic compound activity in the peripheral and central nervous system using native neurons, and are now building similar assays with human stem-cell derived neurons. Both approaches provide a translational step for development of anticonvulsant compounds and safe and effective treatments for other central nervous system diseases.

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Monitoring drug-induced cytotoxicity and hepatotoxicity using impedance

A number of different cell-based assays for cytotoxic effects of drugs exist including the lactate dehydrogenase (LDH) leakage assay, the neutral red assay, protein measurement and methyl tetrazolium (MTT) assay. We describe the development and optimization of a cell-based assay for cytotoxicity using impedance measurements. This assay is sensitive and provides reproducible results for safety pharmacology, toxicity screens of adherent, proliferating or non-proliferating cells. Changes in the impedance signal indicate effects on cell contractility, cell morphology and proliferation.

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CiPA update: Refining in vitro cardiac ion channel assays, in silico models and iPSC cardiomyocyte reagents for improved proarrhythmia risk prediction

Metrion is working towards the requirements of the FDA’s Comprehensive in vitro Proarrhythmia (CiPA) initiative (cipaproject.org) which comprises 3 parts: 1) High quality in vitro cardiac ion channel assays, 2) Comprehensive in silico action potential (AP) models, and 3) Predictive assays using induced pluripotent stem cell derived cardiomyocytes (iPSC-CM).

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Human ventricular stem cell cardiomyocytes: validating in vitro assays and screening platforms for proarrhythmia risk prediction

To fulfil the last requirement of the CiPA initiative, the suitability and maturity of ventricular iPSC-CM need to be determined. In the current study, two ventricular iPSC- CM cell lines (LDN-1 and LDN-2) were generated and their molecular and biophysical properties compared with a commercial iPSC-CM cell line (COM-1) using three different methodologies.

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Electrophysiological profiling of Axiogenesis vCor.4U iPSC-derived cardiomyocytes

Here, we have assessed the suitability of Axiogenesis CorV.4U 2nd generation iPSC-CM for cardiotoxicity screening by evaluating their biophysical and pharmacological characteristics using three different methodologies:

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Human stem cell-derived cardiomyocytes: in vitro assays and screening platforms for exploring ventricular and atrial phenotypes

For CiPA, iPSC-CMs expressing a mature ventricular phenotype are required. At Metrion Biosciences we have focused on electrophysiological profiling of Axol Human iPSC-Derived Ventricular Cardiomyocytes (hiPSC-vCMs) by evaluating their biophysical and pharmacological characteristics.

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Profiling endogenous sodium channels in the ND7-23 neuroblastoma cell line: implications for use as a heterologous ion channel expression system and native tissue model suitable for automated patch-clamp screening

Voltage-dependent sodium channels (Nav) are implicated in a wide range of diseases, with their role in triggering and modulating membrane excitability making them key drug discovery targets for cardiac and neurological indications. Neuronal Nav’s are divided into TTX-sensitive (Nav1.1, Nav1.2, Nav1.3, Nav1.6 and Nav1.7) and TTX-resistant channels (Nav1.8 and Nav1.9), with those found in the CNS underlying various types of epilepsy and those expressed in the periphery implicated in many types of pain behaviour such as inflammatory, neuropathic, chemotherapy and cancer-induced pain, as well as visceral pain conditions such as irritable bowel syndrome (IBS). 

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Developing a package of in vitro human cardiac ion channel assays using automated patch-clamp to predict clinical arrhythmia risk

Current cardiac safety testing regimes have successfully prevented new drugs coming to market with unknown proarrhythmic risk. However, they are expensive and time-consuming, and an over-reliance on hERG liability as a marker for proarrhythmia has led to exclusion of useful chemical scaffolds from further drug development. In addition, the focus on hERG ignores the risk posed by potential drug interactions with multiple cardiac ion channels (MICE) that can alter cardiac action potentials.

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Optimising a difficult Nav1.8 cell line assay for automated patch-clamp screening

The TTX-resistant sodium channel Nav1.8 is expressed in peripheral sensory nociceptors and is implicated in a range of inflammatory and visceral pain conditions such as irritable bowel syndrome (IBS)1. Nav1.8 channel function in sensory neurons changes after injury or inflammation, with a redistribution from the soma to axons and upregulated activity through inflammatory mediators and signalling pathways.

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Metrion Biosciences is a contract research organisation (CRO) specialising in high-quality preclinical drug discovery services.
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