430 - Examining Neuromuscular Transmission Deficits in Patients with Charcot Marie Tooth disease and the Impact of ClC-1 Inhibition in Preclinical Models

Charcot-Marie-Tooth (CMT) includes a phenotypically and genetically diverse group of inherited neuropathies that result in muscle weakness and fatigue with no treatments currently approved. Preclinical studies suggest that deficits in neuromuscular junction (NMJ) transmission contribute to muscle dysfunction in CMT. This study aimed to assess NMJ function in patients with CMT types 1 and 2 and to investigate whether enhancing NMJ transmission could improve muscle function in preclinical CMT models.

Design:

An observational study was first conducted using single-fiber electromyography (SFEMG) and clinical assessments in patients with CMT types 1 and 2, as well as in healthy controls (HC). Subsequently, preclinical studies were performed to investigate the impact of  partial inhibition of ClC-1 chloride channels using the novel small molecule NMD670 on nerve-stimulated muscle force production.

Results:

The observational study enrolled 21 CMT patients (mean age 46.4±14.4 years) and 10 healthy controls (mean age 43.3±12.7 years). SFEMG jitter, indicating NMJ variability, was significantly higher in CMT patients [median (range): 56µs (35;197µs)] compared to healthy controls [29µs (19;36µs)], (p< 0.05). NMJ blocking (transmission failure) was also elevated in CMT patients (13.4% (0.0;90.9%)) versus controls (0.0% (0.0;4.5%)), (p< 0.05). Among CMT patients, increased jitter and blocking were inversely associated with muscle strength, mobility, balance, and endurance. In CMT 1A and 2D mouse models, NMD670 enhanced both peak muscle force and contractile endurance in vivo.

 

Conclusions: The findings of this study indicate that NMJ dysfunction plays a significant role in muscle impairment in patients with CMT types 1 and 2. Additionally, the preclinical data offer proof-of-mechanism for muscle function recovery through ClC-1 inhibition in CMT mouse models. Together, our findings support that modulating NMJ transmission with ClC-1 inhibitors is a promising approach in the treatment of patients impacted by CMT.