Grønnebæk Thomas Skjærlund, Haahr-Lillevang Helga, Skov Martin, Kelly Kristina, Kerr Nathan R, Viteri Jose A, Jaworek Andrea, Bartlett Amy, Bold Jane, Hutchison John, Quiroz Jorge, Tankisi Hatice, Pedersen Thomas Holm, Andersen Henning, Arnold William David
NMD Pharma A/S, Aarhus, Denmark.
Department of Neurology, Aarhus University Hospital, Aarhus, Denmark.
Ann Clin Transl Neurol. 2025 Feb;12(2):320-331. doi: 10.1002/acn3.52252. Epub 2024 Dec 13.
Charcot-Marie Tooth (CMT) is a hereditary neuropathy characterized by muscle weakness and fatigue with no approved therapies. Preclinical studies implicate neuromuscular junction (NMJ) transmission deficits in muscle dysfunction in CMT. This study aimed to evaluate NMJ function in patients with CMT types 1 and 2, and to determine whether enhancing NMJ transmission can improve muscle function in preclinical CMT models.
First, an observational study involving single fiber electromyography (SFEMG) and clinical testing in patients with CMT 1 and 2 and healthy controls (HC) was conducted. Next, preclinical studies examined muscle function, specifically nerve-stimulated muscle force after partially inhibiting ClC-1 chloride channels with the novel small molecule NMD670.
Twenty-one CMT patients (46.4 ± 14.4 years) and 10 HC (43.3 ± 12.7 years) were enrolled. SFEMG jitter (NMJ variability) was higher [median (range)] in the CMT patients [56 μs (35; 197 μs)] vs. HC [29 μs (19; 36 μs)], (p < 0.05). Blocking (NMJ failure) was higher in the CMT patients (13.4% (0.0; 90.9%)) vs. HC (0.0% (0.0; 4.5%)), (p < 0.05). In CMT, jitter and blocking correlated inversely with muscle strength, mobility, balance, and endurance. In CMT 1A and 2D mice, NMD670 increased both peak force and contractile endurance in vivo.
Our study suggests that NMJ dysfunction contributes to muscle dysfunction in patients with CMT 1 and 2. Furthermore, our preclinical data provide proof-of-mechanism for recovery of muscle function with ClC-1 inhibition in CMT mouse models. Collectively, these findings suggest that targeting NMJ dysfunction with ClC-1 inhibitors could enhance muscle function in CMT patients, warranting further clinical trials.
夏科-马里-图斯病（CMT）是一种遗传性神经病变，其特征为肌肉无力和疲劳，目前尚无获批的治疗方法。临床前研究表明，神经肌肉接头（NMJ）传递缺陷与CMT患者的肌肉功能障碍有关。本研究旨在评估1型和2型CMT患者的NMJ功能，并确定增强NMJ传递是否能改善临床前CMT模型的肌肉功能。
首先，对CMT 1型和2型患者及健康对照（HC）进行了一项涉及单纤维肌电图（SFEMG）和临床测试的观察性研究。接下来，进行临床前研究，检测肌肉功能，特别是用新型小分子NMD670部分抑制ClC-1氯通道后神经刺激的肌肉力量。
纳入了21例CMT患者（46.4±14.4岁）和10例HC（43.3±12.7岁）。CMT患者的SFEMG抖动（NMJ变异性）更高[中位数（范围）]，为56μs（35；197μs），而HC为29μs（19；36μs），（p<0.05）。CMT患者的阻滞（NMJ衰竭）更高，为13.4%（0.0；90.9%），而HC为0.0%（0.0；4.5%），（p<0.05）。在CMT中，抖动和阻滞与肌肉力量、活动能力、平衡和耐力呈负相关。在CMT 1A和2D小鼠中，NMD670增加了体内的峰值力量和收缩耐力。
我们的研究表明，NMJ功能障碍导致CMT 1型和2型患者的肌肉功能障碍。此外，我们的临床前数据为CMT小鼠模型中通过抑制ClC-1恢复肌肉功能提供了机制证据。总体而言，这些发现表明，用ClC-1抑制剂靶向NMJ功能障碍可增强CMT患者的肌肉功能，值得进一步开展临床试验。
