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Effect of Cemdomespib in Improving Neuromuscular Junction Innervation and Nerve Axon Myelination in Charcot-Marie-Tooth Disease mouse model
Chawla, Riddhi
Chawla, Riddhi
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Abstract
Charcot-Marie-Tooth disease type 1X (CMT1X) is a hereditary neuropathy resulting from mutations in the GJB1 gene, which encodes connexin 32 (Cx32), a protein essential for the homeostasis of myelinated axons. Cemdomespib, a C-terminal heat shock protein 90 (Hsp90) modulator currently in phase 2 clinical trials, has shown potential in previous studies to enhance motor nerve conduction velocity (MNCV), grip strength, and neuromuscular junction (NMJ) innervation following five months of treatment in Cx32def and T55I-Cx32def mouse models of CMTX. In this study, we investigate the efficacy of cemdomespib in a different CMTX disease mouse model, the R75W-Cx32 model. This model mirrors a common human Cx32 mutation, which leads to its accumulation in the Golgi body. We assessed the effect of cemdomespib on improving grip strength, nerve conduction velocity, neuromuscular junction (NMJ) innervation, and nerve axon myelination. We conducted a comprehensive assessment over 2.5-month and 5-month treatment periods to evaluate both the early and long-term effects of the drug. The results demonstrated significant improvements in grip strength in the cemdomespib-treated groups compared to the vehicle-treated controls at both time points, as well as enhanced motor nerve conduction velocity (MNCV) after 20 weeks of cemdomespib treatment. These findings underscore the drug's role in mitigating neuropathic deficits. Histological analyses revealed better-preserved axonal and myelin integrity, with lower g-ratios indicating enhanced myelination. Additionally, immunohistochemistry analysis of NMJs in cemdomespib-treated mice showed structural preservation and sustained pre-synaptic and post-synaptic marker colocalization, indicating improved NMJ integrity. These findings suggest that cemdomespib effectively slows the progression of CMT1X by preserving nerve structure and function starting at 10 weeks of treatment, with more pronounced effects observed at 20 weeks, offering a promising therapeutic approach for managing this debilitating disease.
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2024-08-31
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University of Kansas
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Chawla_ku_0099M_19697.pdf
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Neurosciences, Health sciences, Medicine, Cemdomespib, Charcot-Marie-Tooth Disease, Heat Shock Protein Modulator, KU-596, Myelination, Neuromuscular Junction