Screening of candidate analgesics using a patient‐derived human iPSC model of nociception identifies putative compounds for therapeutic treatment

TL;DR

Researchers used patient-derived stem cells to find four new pain-relief compounds that could help treat inherited erythromelalgia and other pain disorders.

Contribution

The study introduces a novel iPSC-based screening method for identifying analgesic compounds targeting pain mechanisms in patient-specific models.

Findings

Four compounds (AZ106, AZ129, AZ037, AZ237) significantly reduced spontaneous firing in IEM patient-derived sensory neurons.

The compounds showed minimal toxicity and potential efficacy based on calculated IC50 values.

Electrophysiological analysis confirmed their ability to modulate the NaV 1.7 channel for targeted analgesia.

Abstract

In this study, we applied an induced pluripotent stem cell (iPSC)‐based model of inherited erythromelalgia (IEM) to screen a library of 281 small molecules, aiming to identify candidate pain‐modulating compounds.

Human iPSC‐derived sensory neuron‐like cells, which exhibit action potentials in response to noxious stimulation, were evaluated using whole‐cell patch‐clamp and microelectrode array (MEA) techniques.

Sensory neuron‐like cells derived from individuals with IEM showed spontaneous electrical activity characteristic of genetic pain disorders. The drug screen identified four compounds (AZ106, AZ129, AZ037 and AZ237) that significantly decreased spontaneous firing with minimal toxicity. The calculated IC50 values indicate the potential efficacy of these compounds. Electrophysiological analysis confirmed the compounds’ ability to reduce action potential generation in IEM patient‐specific iPSC‐derived sensory neuron‐like cells.

Our screening approach demonstrates the reproducibility and effectiveness of human neuronal disease modelling offering a promising avenue for discovering new analgesics. These findings address a critical gap in current therapeutic strategies for both general and neuropathic pain, warranting further investigation. This study highlights the innovative use of patient‐derived iPSC sensory neuronal models in pain research and emphasises the potential for personalised medicine in developing targeted analgesics.

Utilisation of human iPSCs for efficient differentiation into sensory neuron‐like cells offers a novel strategy for studying pain mechanisms.IEM sensory neuron‐like cells exhibit key biomarkers and generate action potentials in response to noxious stimulation.IEM sensory neuron‐like cells display spontaneous electrical activity, providing a relevant nociceptive model.Screening of 281 compounds identified four candidates that significantly reduced spontaneous firing with low cytotoxicity.Electrophysiological profiling of selected compounds revealed promising insights into their mechanisms of action, specifically modulating the NaV 1.7 channel for targeted analgesia.

Utilisation of human iPSCs for efficient differentiation into sensory neuron‐like cells offers a novel strategy for studying pain mechanisms.

IEM sensory neuron‐like cells exhibit key biomarkers and generate action potentials in response to noxious stimulation.

IEM sensory neuron‐like cells display spontaneous electrical activity, providing a relevant nociceptive model.

Screening of 281 compounds identified four candidates that significantly reduced spontaneous firing with low cytotoxicity.

Electrophysiological profiling of selected compounds revealed promising insights into their mechanisms of action, specifically modulating the NaV 1.7 channel for targeted analgesia.

In this study, Thornton and colleagues utilised an induced pluripotent stem cell (iPSC)‐based model of inherited erythromelalgia (IEM) to screen a library of 295 small molecules in search of potential pain‐modulating compounds. Their screening identified four compounds that significantly reduced spontaneous firing in iPSC‐derived nociceptor‐like cells, with minimal associated toxicity
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