Abstract 1459 Cemdomespib Therapy Improves Neuromuscular Function and Axon Morphology in a Mouse Model of Human Charcot Marie Tooth 1X Disease

Charcot-Marie-Tooth (CMT) disease encompasses a group of disorders that result in damage to the peripheral nervous system (PNS). X-linked Charcot-Marie-Tooth (CMT1X), which stems from mutations in the gene that encodes for the protein connexin 32 (Cx32), is the second most common type of CMT and causes symptoms including muscle weakness, high arched feet, and clawed hands. Cx32 is important in proper myelination of Schwann cells and appears to play a role in the formation of gap junctions between regions of myelin to provide pathways of diffusion between the abaxonal and adaxonal layers of myelin. Essentially, this mutation interrupts the ability of the axons in the peripheral nervous system to efficiently send signals throughout the body, leading to a peripheral neuropathy. While recent studies show gene replacement therapy can provide benefits in the Cx32 deficient (Cx32def) mouse model of CMT1X, this method of treatment has many hurdles to overcome and may not be accessible to all patients, highlighting the need for a more accessible treatment method. Our lab has been testing the efficacy of a therapeutic drug called cemdomespib in treating neuropathic symptomatology in R75W-Cx32 mice, an authentic model of CMT1X caused by the R75W point mutation in Cx32 that blocks Cx32 trafficking to the plasma membrane due to its accumulation in the golgi. Overall, these mice allow us to test the efficacy of the drug under the same genetic conditions that would be present in a human CMT1X patient with the R75W-Cx32 mutation. CMT1X is characterized by a reduced nerve conduction velocity, neuromuscular weakness, demyelination, and axonal loss. The goal of the experiment was to develop a dynamic assessment of how cemdomespib improves neuropathic symptomatology by assessing the effect of drug therapy on neuromuscular strength and axon morphology over a 20-week period. We observed that daily treatment of R75W-Cx32 mice with 3 mg/kg of cemdomespib for 20 weeks significantly slowed the rate of decline in grip strength, improved motor nerve conduction velocity and reduced myelin loss in femoral nerve axons as indicated by a lower G-ratio. Furthermore, analysis of axon morphology indicated that treatment with cemdomespib reduced the amount of abnormal axons present. In summary, these data support that cemdomespib therapy may slow the decline of neuromuscular weakness and afford a possible pharmacologic approach to treat human CMT1X.