Charcot-Marie-Tooth (CMT) is a hereditary neuropathy characterized by muscle weakness and fatigue with no approved therapies. Several preclinical studies implicate neuromuscular junction (NMJ) transmission deficits in muscle dysfunction in CMT. We aimed to determine if NMJ dysfunction is evident in patients with CMT and whether therapeutic modulation via ClC-1 inhibition can improve muscle function in animal models of CMT.
First, we conducted an observational study where single fiber electromyography (SFEMG) and standardized clinical tests were used in patients with CMT type 1 and 2 and age, gender matched healthy controls (HC). Then, two preclinical studies examined muscle function, specifically nerve-stimulated muscle force before and after administering the novel small molecule, NMD670, that inhibits ClC-1 chloride channels, specifically in muscle. Clinically, twenty-one CMT patients and 10 HC were enrolled in the observational study; SFEMG jitter (NMJ variability) was higher [median (range)] in the CMT patients [56s (35;197s)] vs. HC [29s (19;36s)], (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 addition, jitter and blocking correlated inversely with muscle strength, mobility, balance, and endurance in CMT patients. Preclinically, CMT 1A and 2D mice displayed reduced strength and muscle function with inability to sustain muscle contraction and administration of NMD670 increased both peak force and contractile endurance in vivo. Our study suggests that NMJ dysfunction exemplified by increased jitter and blocking contributes to muscle dysfunction in patients with CMT 1 and 2. Furthermore, our preclinical data provides proof-of-mechanism for recovery of muscle function, both strength and ability to maintain force during stimulation with ClC-1 inhibition in CMT mouse models. Together, these findings suggest that targeting NMJ dysfunction with ClC-1 inhibitors could enhance muscle function in CMT patients, warranting clinical trials.