A Novel Pharmacologic Approach to Treat CMT1X

摘要 诺洛格是一种小分子神经治疗药物，其化学生物学旨在调节 分子伴侣的活性和表达，如热休克蛋白90(Hsp90)和Hsp70。完毕 在过去的十年里，我们已经发布了严格的临床前数据，表明新药可以改善新陈代谢和 糖尿病周围神经病变(DPN)临床指标。药效学方面，新药需要热休克蛋白70 因为这些药物不能改善糖尿病Hsp70基因敲除(KO)小鼠的神经功能。KU-596是我们的 大多数临床晚期新药和广泛的PK/PD和临床前GLP毒理学研究 已被FDA接受。KU-596的一期试验已经完成，药物显示可以接受 PK/PD曲线，可以忽略不计的不良事件曲线，现在正准备进入第二阶段试验。然而，新的 临床前数据支持KU-596的治疗益处也可能延伸到某些遗传性疾病 神经病。Charcot-Marie-Tooth 1X(CMT1X)是一种X连锁遗传性神经病，可由 连接蛋白32(Cx32)基因零突变。Cx32缺陷(Cx32def)小鼠是一种可靠的 人类疾病和我们的初步数据支持口服KU-596可以改善神经肌肉 在Cx32def小鼠中以Hsp70依赖的方式发挥作用。然而，许多CMT1X患者没有NULL 突变，但表达Cx32的突变形式，表现出改变的细胞内运输。这些人 发展为临床神经病变的患者类似于零突变，但目前尚不清楚是否有有益的药物 错误定位的Cx32突变体的表达维持了反应表型。因此，这一计划的目标是 IGNITE提案旨在验证KU-596在治疗外周和外周血中的治疗强度和局限性 错误定位的Cx32突变引起的中枢神经系统症状。我们的R61阶段将测试药物 T55I-Cx32def小鼠的疗效保持不变，它们将Cx32保留在内质网(ER)中。我们会 以神经传导的测量为客观里程碑，确定内质网滞留是否影响药物疗效。 在R33阶段，目标1将确定轴突损伤标志物的改善是否与 观察到T55I-Cx32def小鼠的电生理恢复。这些数据将评估预防措施是否 治疗可改善年轻CMT1X患者的脱髓鞘前轴索病变。目标2将测试 假说新药治疗可减少大鼠周围神经炎症和暴发性中枢神经系统功能障碍 Cx32def和T55I-Cx32def小鼠。这些研究将评估KU-596对疾病的改善潜力 减少CMT1X的外周和中枢症状。目标3将检验药物疗效是 保持Cx32的高尔基保留率。因为Cx32的内质网和高尔基体保留率不一定相等 在他们对治疗的反应中，这些数据将通过扩大治疗的广度来进一步推进治疗 对KU-596可能有反应的CMT1X患者。重要的是，这部作品具有很高的翻译影响力 缺乏对这种孤儿神经疾病的神经治疗选择，以及药物的第二阶段准备就绪。

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.