基因疗法为治疗慢性疼痛开辟了新的可能性

诸平

据英国牛津大学(University of Oxford, UK)2023年10月5日提供的消息，牛津大学与英国剑桥大学（University of Cambridge, UK）以及英国巴茨和伦敦医学和牙科学院（Barts and the London School of Medicine and Dentistry, London, UK）的研究人员合作，利用基因疗法为治疗慢性疼痛开辟了新的可能性（Gene therapy opens new possibilities for treating chronic pain）。相关研究结果于2023年10月4日已经在《科学转化医学》（Science Translational Medicine）杂志网站发表——Jimena Perez-Sanchez, Steven J. Middleton, Luke A. Pattison, Helen Hilton, Mosab Ali Awadelkareem, Sana R. Zuberi, Maria B. Renke, Huimin Hu, Xun Yang, Alex J. Clark, Ewan St. John Smith, David L. Bennett. A humanized chemogenetic system inhibits murine pain-related behavior and hyperactivity in human sensory neurons. Science Translational Medicine, 2023, 15（716）. DOI: 10.1126/scitranslmed.adh3839. ePub. 4 Oct 2023. https://www.science.org/doi/10.1126/scitranslmed.adh3839

牛津大学纳菲尔德临床神经科学系（Nuffield Department of Clinical Neurosciences at the University of Oxford）的研究人员与剑桥大学以及英国巴茨和伦敦医学和牙科学院的同事一起，展示了一种新的基因治疗方法沉默人类感觉神经元（神经细胞）的潜力作为治疗持续性疼痛的一种手段。目前许多治疗慢性疼痛的药物具有高度累加性，因此发现新的替代备选方案非常重要。

化学遗传学（Chemogenetics）是一个过程，其中控制神经元兴奋（刺激）的分子被设计成只有在无毒药物存在时才会变得活跃。在涉及动物的研究中，这一过程已经显示出作为抑制这种兴奋性的一种手段的前景。纳菲尔德临床神经科学系的博士后研究科学家西梅纳·佩雷斯-桑切斯（Jimena Perez-Sanchez）和斯蒂文·米德尔顿（Steven Middleton）是这项研究的共同作者，她和她的同事现在已经证明，有一种适合人类应用的化学遗传学方法。

首先，研究小组在小鼠感觉神经元（sensory neurons）中表达了 PSAM4-GlyR 基因，这是一种基于人类蛋白质受体烟碱乙酰胆碱（nicotinic acetylcholine）和甘氨酸（glycine）的化学遗传系统。他们用临床批准的药物伐尼克兰（varenicline）激活 PSAM4-GlyR，该药物可以抑制感觉神经元（sensory neurons），还可以减轻通常与小鼠关节炎或神经损伤相关的疼痛超敏反应（pain hypersensitivity）。

然后，研究人员继续激活来自红斑性肢痛症（erythromelalgia）患者的感觉神经元中的 PSAM4-GlyR系统，红斑性肢痛症是一种以灼痛为特征的疾病。他们发现这会抑制感觉神经元并使多动症（hyperactivity）恢复正常。

纳菲尔德临床神经科学系神经学和神经生物学教授大卫·班尼特（David Bennett）和博士后研究科学家西梅纳·佩雷斯-桑切斯评论道：“整个团队很高兴展示了基因治疗方法治疗慢性疼痛的潜力，仍然是未满足的巨大健康需求之一。这是通过关闭过度活跃的神经纤维来实现的。通过瞄准疼痛回路的这个初始组成部分，我们可以避免现有止痛药如阿片类药物（opioids）的成瘾潜力。

尽管需要在人类疼痛模型中进行进一步验证，但结果表明感觉神经元过度兴奋导致关节炎或神经系统损伤引起的持续性疼痛。研究人员已经展示了改造人类蛋白质受体用于治疗疼痛的转化潜力。

本研究得到了惠康（Wellcome: 102645/Z/13/Z, 202747/Z/16/Z, 109116/Z/15/Z, 223149/Z/21/Z）、英国生物科技及生物科学研究委员会（Biotechnology and Biological Sciences Research Council: BB/V509528/1）以及加拿大医学研究理事会（Medical Research Council Canada: MR/T020113/1，MR/W002426/1）的资助。

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Editor’s summary

The current opioid crisis emphasizes the need for nonaddictive pain treatments. Here Perez-Sanchez and colleagues evaluated whether direct inhibition of pain-related hyperactivity in sensory neurons could be such a targeted pain treatment strategy. The authors expressed PSAM4-GlyR, a chemogenetic system based on the human nicotinic acetylcholine and glycine receptors, in mouse sensory neurons. PSAM⁴-GlyR activation with the FDA-approved drug varenicline inhibited sensory neurons and improved acute, inflammatory, and neuropathic pain-related behaviors in mice. PSAM⁴-GlyR activation also inhibited human-derived sensory neurons and normalized hyperactivity in sensory neurons derived from a patient with erythromelalgia, a condition characterized by burning pain. Although further validation in human pain models is needed, these results suggest the potential of PSAM⁴-GlyR in gene therapy for pain treatment. —Daniela Neuhofer

Abstract

Hyperexcitability in sensory neurons is known to underlie many of the maladaptive changes associated with persistent pain. Chemogenetics has shown promise as a means to suppress such excitability, yet chemogenetic approaches suitable for human applications are needed. PSAM⁴-GlyR is a modular system based on the human α7 nicotinic acetylcholine and glycine receptors, which responds to inert chemical ligands and the clinically approved drug varenicline. Here, we demonstrated the efficacy of this channel in silencing both mouse and human sensory neurons by the activation of large shunting conductances after agonist administration. Virally mediated expression of PSAM⁴-GlyR in mouse sensory neurons produced behavioral hyposensitivity upon agonist administration, which was recovered upon agonist washout. Stable expression of the channel led to similar reversible suppression of pain-related behavior even after 10 months of viral delivery. Mechanical and spontaneous pain readouts were also ameliorated by PSAM⁴-GlyR activation in acute and joint pain inflammation mouse models. Furthermore, suppression of mechanical hypersensitivity generated by a spared nerve injury model of neuropathic pain was also observed upon activation of the channel. Effective silencing of behavioral hypersensitivity was reproduced in a human model of hyperexcitability and clinical pain: PSAM⁴-GlyR activation decreased the excitability of human-induced pluripotent stem cell–derived sensory neurons and spontaneous activity due to a gain-of-function Na_V1.7 mutation causing inherited erythromelalgia. Our results demonstrate the contribution of sensory neuron hyperexcitability to neuropathic pain and the translational potential of an effective, stable, and reversible humanized chemogenetic system for the treatment of pain.