Jack R. Thornton, Alberto Capurro, Sally Harwood, Thomas C Henderson, Adrienne Unsworth, Franziska Görtler, Sushma Nagaraja-Grellscheid, Vsevolod Telezhkin, Majlinda Lako, Evelyne Sernagor, Lyle Armstrong
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Thornton, Alberto Capurro, Sally Harwood, Thomas C Henderson, Adrienne Unsworth, Franziska Görtler, Sushma Nagaraja-Grellscheid, Vsevolod Telezhkin, Majlinda Lako, Evelyne Sernagor, Lyle Armstrong","doi":"10.1002/ctm2.70339","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background and purpose</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> Experimental approach</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> Key results</h3>\n \n <p>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 IC<sub>50</sub> 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.</p>\n </section>\n \n <section>\n \n <h3> Conclusions and implications</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> Key points</h3>\n \n <div>\n <ul>\n \n <li>Utilisation of human iPSCs for efficient differentiation into sensory neuron-like cells offers a novel strategy for studying pain mechanisms.</li>\n \n <li>IEM sensory neuron-like cells exhibit key biomarkers and generate action potentials in response to noxious stimulation.</li>\n \n <li>IEM sensory neuron-like cells display spontaneous electrical activity, providing a relevant nociceptive model.</li>\n \n <li>Screening of 281 compounds identified four candidates that significantly reduced spontaneous firing with low cytotoxicity.</li>\n \n <li>Electrophysiological profiling of selected compounds revealed promising insights into their mechanisms of action, specifically modulating the Na<sub>V</sub> 1.7 channel for targeted analgesia.</li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9000,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70339","citationCount":"0","resultStr":"{\"title\":\"Screening of candidate analgesics using a patient-derived human iPSC model of nociception identifies putative compounds for therapeutic treatment\",\"authors\":\"Jack R. 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Screening of candidate analgesics using a patient-derived human iPSC model of nociception identifies putative compounds for therapeutic treatment
Background and purpose
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.
Experimental approach
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.
Key results
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.
Conclusions and implications
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.
Key points
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.
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.
期刊介绍：
Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.
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