Stem cell-derived sensory neurons modelling inherited erythromelalgia: normalization of excitability
Stem cell-derived sensory neurons modelling inherited erythromelalgia: normalization of excitability
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DOI：
10.1093/brain/awac031
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发表时间：
2022-01-28
期刊：
影响因子：
14.5
通讯作者：
Waxman, Stephen G.
中科院分区：
文献类型：
--
作者：
Alsaloum, Matthew;Labau, Julie I. R.;Waxman, Stephen G.
Alsaloum等人报道，通过动态钳位电生理学重现来自遗传性红斑性肢痛症患者的背根神经节神经元的人干细胞衍生的感觉神经元的超兴奋性可以通过精确减去Na（V）1.7电流来正常化。有效治疗疼痛仍然是一种未满足的医疗保健需求，需要新的有效治疗方法。Na（V）1.7已被遗传和功能验证为疼痛介质。Na（V）1.7-选择性阻断剂的临床前研究已显示出有限的成功，并且转化为临床研究受到限制。减弱神经元兴奋性和改善疼痛所需的Na（V）1.7通道阻断程度是药物发现的重要问题。在这里，我们利用动态钳电生理学和诱导多能干细胞衍生的感觉神经元（iPSC-SN）来回答这个问题，遗传性红斑性肢痛症，一种由Na（v）1.7功能获得性突变引起的疼痛疾病。我们发现，动态钳可以在与两种不同的遗传性红斑性肢痛症突变Na（V）1.7-S241 T和Na（V）1.7-I848 T相关的iPSC-SN中产生过度兴奋。我们进一步表明，阻断约50%的Na（V）1.7电流可以将神经元的过度兴奋性逆转至基线水平。
Alsaloum et al. report that the hyperexcitability of human stem cell-derived sensory neurons, made to recapitulate dorsal root ganglion neurons from patients with inherited erythromelalgia via dynamic clamp electrophysiology, can be normalized by precise subtraction of Na(V)1.7 currents.Effective treatment of pain remains an unmet healthcare need that requires new and effective therapeutic approaches. Na(V)1.7 has been genetically and functionally validated as a mediator of pain. Preclinical studies of Na(V)1.7-selective blockers have shown limited success and translation to clinical studies has been limited. The degree of Na(V)1.7 channel blockade necessary to attenuate neuronal excitability and ameliorate pain is an unanswered question important for drug discovery. Here, we utilize dynamic clamp electrophysiology and induced pluripotent stem cell-derived sensory neurons (iPSC-SNs) to answer this question for inherited erythromelalgia, a pain disorder caused by gain-of-function mutations in Na(v)1.7. We show that dynamic clamp can produce hyperexcitability in iPSC-SNs associated with two different inherited erythromelalgia mutations, Na(V)1.7-S241T and Na(V)1.7-I848T. We further show that blockade of approximately 50% of Na(V)1.7 currents can reverse neuronal hyperexcitability to baseline levels.