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

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2025-05-25 DOI:10.1002/ctm2.70339

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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Abstract

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.
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 Na_V 1.7 channel for targeted analgesia.

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筛选候选镇痛药使用患者衍生的人类iPSC模型伤害感觉确定推定的化合物治疗治疗

背景与目的在本研究中，我们应用基于诱导多能干细胞（iPSC）的遗传性红斑性肢痛症（IEM）模型筛选281个小分子文库，旨在鉴定候选的疼痛调节化合物。利用全细胞膜片钳和微电极阵列（MEA）技术对人类ipsc衍生的感觉神经元样细胞进行了评估，这些细胞在有害刺激下表现出动作电位。来自IEM个体的感觉神经元样细胞表现出遗传性疼痛疾病的自发电活动特征。药物筛选发现4种化合物（AZ106、AZ129、AZ037和AZ237）能显著降低自燃，毒性最小。计算出的IC50值表明了这些化合物的潜在功效。电生理分析证实，这些化合物能够减少IEM患者特异性ipsc来源的感觉神经元样细胞的动作电位产生。结论和意义我们的筛选方法证明了人类神经元疾病模型的可重复性和有效性，为发现新的镇痛药提供了一条有希望的途径。这些发现解决了目前全身性和神经性疼痛治疗策略的关键空白，值得进一步研究。这项研究强调了患者来源的iPSC感觉神经元模型在疼痛研究中的创新应用，并强调了个性化药物在开发靶向镇痛药方面的潜力。利用人类多能干细胞向感觉神经元样细胞的有效分化为研究疼痛机制提供了一种新的策略。IEM感觉神经元样细胞表现出关键的生物标志物，并对有害刺激产生动作电位。IEM感觉神经元样细胞显示自发电活动，提供了相关的伤害模型。筛选281种化合物，确定了4种候选化合物，它们显著降低了自发放电，具有低细胞毒性。所选化合物的电生理分析揭示了其作用机制的有希望的见解，特别是调节靶向镇痛的NaV 1.7通道。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

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.