Speaker at International Conference and Expo on Toxicology and Applied Pharmacology Conference  2022 - Sukhmanjit Kaur
University of Kansas, United States
Title : Modulating Molecular Chaperones: A Potential Therapeutic To Treat X-Linked Charcot-Marie-Tooth (CMT1X) Disease


Introduction: CMT1X is an inherited peripheral neuropathy caused by mutations in the GJB-1 gene that encodes for connexin 32 (Cx32). Despite being the second most common form of CMT neuropathies, there are no pharmacologic treatments for CMT1X. We have developed “novologues” as orally bio­available novobiocin analogues that manifest neuroprotective activity by modulating the expression of heat shock protein 70 (Hsp70). The novologue, KU-596, is in clinical trials for treating a metabolic neuropathy and we examined if it may improve neuropathic symptoms in Cx32 deficient (Cx32def) mice and T55I x Cx32def mice, authentic mouse models of human CMT1X.

Methods: 4-month-old Cx32def and T55I x Cx32def mice were treated with either vehicle or KU-596 (0.3 mg/kg, 1mg/kg or 3 mg/kg) daily for 5 months. We measured grip strength (alternate weeks) and nerve electrophysiology as parameters for peripheral neuropathy in CMT1X mouse models.

Results: Cx32def and T55I x Cx32def mice develop a significant reduction in grip strength (~0.8N), motor nerve conduction velocity (MNCV, ~45-50m/sec) and compound muscle action potential (CMAP, ~ 20-25mV) compared to wild-type mice (grip strength, ~1.6N; MNCV, ~60m/sec; CMAP, ~ 40mV). KU-596 therapy in Cx32def mice significantly improved grip strength (~1.5N), MNCV (~ 55-60 m/sec) and CMAP (~ 30mV). Treatment with KU-596 in T55I x Cx32def mice improved grip strength (~1.4N) and MNCV (~ 60m/sec) but did not significantly improve CMAP. To investigate whether these effects were Hsp70 dependent, Cx32def x Hsp70 knockout mice were treated with KU-596. While the deletion of Hsp70 did not affect the development of peripheral neuropathy, the therapeutic efficacy of KU-596 was Hsp70 dependent since, there was no improvement in MNCV or CMAP.

Conclusion: Our data suggests that modulating Hsp70 with KU-596 may be beneficial for treating CMT1X and that efficacy may not be limited by the nature of the underlying genetic mutation in the GJB-1 gene.


Ms. Sukhmanjit Kaur studied Pharmacy in Punjabi University, India, and got her bachelor’s degree in 2016. She joined Dr. Nancy Muma’s lab at the University of Kansas as a MS student and worked on a project entitled “A FRET-based Approach to study SUMOylation in Serotonin 1A Receptors”. Later in 2018, she joined Dr. Rick Dobrowsky’s lab as a PhD student. Her work involves assessing the efficacy of a molecular chaperone modulator (KU-596) in improving motor and myelin deficits associated with X-Linked Charcot-Marie-Tooth Disease, the second most common cause of hereditary peripheral neuropathies.