Cemdomespib Therapy Slows the Progression of Neuromuscular Weakness and Demyelination in the R75W-Connexin 32 Animal Model of Charcot–Marie–Tooth 1X Disease

Mutations in connexin 32 (Cx32) are a common cause of Charcot-Marie-Tooth 1X (CMT1X) disease, an inherited peripheral neuropathy characterized by progressive neuromuscular weakness and demyelination. There are no approved pharmacologic therapies for CMT1X, and identifying new treatments that slow the onset and severity of neuromuscular decline may aid disease management. Cemdomespib is an orally bioavailable small molecule that improved demyelination and neuromuscular junction (NMJ) morphology in mice lacking Cx32 expression. However, whether a similar efficacy may manifest in models of CMT1X arising from Cx32 mutations that cause the organellar accumulation of the protein was unclear. Additionally, it was unclear whether cemdomespib therapy slowed the rate of demyelination/NMJ degeneration or stabilized nerve and NMJ morphology to levels present at the initiation of drug therapy. To address these issues, 4-month-old R75W-Cx32 mice, which accumulate the mutant Cx32 in golgi, were treated for 0, 10, or 20 weeks with 0 or 3 mg/kg cemdomespib. Grip strength, motor nerve conduction velocity (MNCV), femoral nerve myelination, and NMJ morphology were quantified. Daily drug therapy significantly slowed the decline in grip strength over the course of treatment, while 20 weeks of drug treatment significantly improved MNCV and decreased the g-ratio and the number of thinly myelinated femoral nerve axons. Similarly, 20 weeks of cemdomespib therapy improved the NMJ morphology and the overlap between presynaptic (synaptophysin) and postsynaptic (α-bungarotoxin) markers. These data show that cemdomespib therapy slows the rate of neuromuscular decline and demyelination and may present a disease-modifying approach for patients with gain-of-function Cx32 mutations.