Myasthenia gravis (MG) is a neuromuscular disease that results in compromised transmission of electrical signals at the neuromuscular junction (NMJ) from motor neurons to skeletal muscle fibers. As a result, patients with MG have reduced skeletal muscle function and present with symptoms of severe muscle weakness and fatigue. ClC-1 is a skeletal muscle specific chloride (Cl − ) ion channel that plays important roles in regulating neuromuscular transmission and muscle fiber excitability during intense exercise. Here, we show that partial inhibition of ClC-1 with an orally bioavailable small molecule (NMD670) can restore muscle function in rat models of MG and in patients with MG. In severely affected MG rats, ClC-1 inhibition enhanced neuromuscular transmission, restored muscle function, and improved mobility after both single and prolonged administrations of NMD670. On this basis, NMD670 was progressed through nonclinical safety pharmacology and toxicology studies, leading to approval for testing in clinical studies. After successfully completing phase 1 single ascending dose in healthy volunteers, NMD670 was tested in patients with MG in a randomized, placebo-controlled, single-dose, three-way crossover clinical trial. The clinical trial evaluated safety, pharmacokinetics, and pharmacodynamics of NMD670 in 12 patients with mild MG. NMD670 had a favorable safety profile and led to clinically relevant improvements in the quantitative myasthenia gravis (QMG) total score. This translational study spanning from single muscle fiber recordings to patients provides proof of mechanism for ClC-1 inhibition as a potential therapeutic approach in MG and supports further development of NMD670.

中文翻译：

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ClC-1 氯离子通道抑制剂 NMD670 可改善大鼠模型和重症肌无力患者的骨骼肌功能

重症肌无力 (MG) 是一种神经肌肉疾病，会导致神经肌肉接头 (NMJ) 从运动神经元到骨骼肌纤维的电信号传输受损。因此，重症肌无力患者的骨骼肌功能下降，并出现严重的肌肉无力和疲劳症状。 ClC-1 是一种骨骼肌特异性氯化物 (Cl-）离子通道，在剧烈运动时调节神经肌肉传递和肌纤维兴奋性中发挥重要作用。在这里，我们证明用口服生物可利用的小分子（NMD670）部分抑制 ClC-1 可以恢复 MG 大鼠模型和 MG 患者的肌肉功能。在严重受影响的 MG 大鼠中，单次和长期施用 NMD670 后，ClC-1 抑制增强了神经肌肉传递，恢复了肌肉功能并改善了活动能力。在此基础上，NMD670通过非临床安全药理学和毒理学研究取得进展，并获准进入临床研究。在健康志愿者中成功完成第一阶段单剂量递增后，NMD670 在一项随机、安慰剂对照、单剂量、三向交叉临床试验中在 MG 患者中进行了测试。该临床试验在 12 名轻度 MG 患者中评估了 NMD670 的安全性、药代动力学和药效学。 NMD670 具有良好的安全性，并导致定量重症肌无力 (QMG) 总分的临床相关改善。这项从单肌纤维记录到患者的转化研究提供了 ClC-1 抑制机制作为 MG 潜在治疗方法的证据，并支持 NMD670 的进一步开发。