A Novel Pharmacologic Approach to Treat CMT1X

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SUMMARY Novologues are small molecule neurotherapeutics whose chemical biology is directed at modulating the activity and expression of molecular chaperones, such as heat shock protein 90 (Hsp90) and Hsp70. Over the last decade we have published rigorous pre-clinical data showing that novologues improve metabolic and clinical indices of diabetic peripheral neuropathy (DPN). Pharmacodynamically, novologues require Hsp70 for efficacy since the drugs cannot improve nerve function in diabetic Hsp70 knockout (KO) mice. KU-596 is our most clinically advanced novologue and extensive PK/PD and pre-clinical GLP toxicology studies have been accepted by the FDA. A Phase 1 trial of KU-596 has been completed and the drug showed acceptable PK/PD profiles, a negligible adverse event profile and is now poised to enter to Phase 2 trials. However, new pre-clinical data supports that the therapeutic benefit of KU-596 may also extend to certain inherited neuropathies. Charcot-Marie-Tooth 1X (CMT1X) is an X-linked inherited neuropathy that can result from a null mutation in the gene for connexin 32 (Cx32). Cx32 deficient (Cx32def) mice are an authentic model of the human disease and our preliminary data supports that oral dosing of KU-596 improves neuromuscular function in Cx32def mice in an Hsp70-dependent manner. However, many CMT1X patients do not have a null mutation but express mutant forms of Cx32 that exhibit altered intracellular trafficking. These individuals develop a clinical neuropathy like patients with null mutations, but it is unclear whether the beneficial drug response phenotype is maintained with expression of mis-localized Cx32 mutants. Thus, the goals of this IGNITE proposal are to validate the therapeutic strengths and limitations of KU-596 in treating peripheral and CNS symptoms arising from mis-localized Cx32 mutations. Our R61 Phase will test the hypothesis that drug efficacy is maintained in T55I-Cx32def mice, which retain Cx32 in the endoplasmic reticulum (ER). We will determine if ER retention affects drug efficacy using measures of nerve conduction as the objective milestone. In the R33 phase aim 1 will identify whether improvements in markers of axonal damage correlate with the electrophysiologic recovery observed in the T55I-Cx32def mice. These data will assess whether prophylactic therapy may improve the predemyelinating axonopathy in young CMT1X patients. Aim 2 will test the hypothesis that novologue therapy decreases peripheral nerve inflammation and fulminant CNS dysfunction in Cx32def and T55I-Cx32def mice. These studies will assess the disease modifying potential of KU-596 toward reducing peripheral and central symptoms in CMT1X. Aim 3 will test the hypothesis that drug efficacy is maintained with golgi retention of Cx32. Since ER and golgi retention of Cx32 are not necessarily equivalent in their response to therapies, these data will further therapeutic advancement by broadening the breadth of CMT1X patients that may respond to KU-596. Importantly, this work has high translational impact given the lack of neurotherapeutic options for this orphan neurologic disorder and the drug’s Phase 2 readiness.