A Novel Pharmacologic Approach to Treat CMT1X

治疗 CMT1X 的新药理学方法

基本信息

批准号：
10043231
负责人：
Rick T Dobrowsky
金额：
$ 38.72万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10043231
关键词：
Adverse event Affect Animal Model Biochemical Biology Charcot-Marie-Tooth Disease Chemicals Clinical Clinical Data Code Data Demyelinations Disease Disease model Dose Electrophysiology (science)Endoplasmic Reticulum Exhibits FDA approved Female Fiber Functional disorder Future Gap Junctions Gene Mutation Genes Goals Golgi Apparatus Heat-Shock Proteins 90 Human Immune Individual Inflammation Investigation Ions Knock-in Knockout Mice Lead Link Measures Medical Medication Management Metabolic Modeling Molecular Chaperones Motor Movement Mus Mutation Nerve Nerve Degeneration Neural Conduction Neuropathy No-Observed-Adverse-Effect Level Oral Orphan Outcome Pathway interactions Patients Peripheral Peripheral Nerves Peripheral Nervous System Diseases Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Pharmacological Treatment Pharmacology Phase Phenotype Physiological Point Mutation Proteins Publishing Readiness Recovery S Phase Safety Symptoms Testing Therapeutic Toxicology Transgenic Organisms Validation Variant Work axon injury axonopathy clinically relevant comparative connexin 32 diabetic drug efficacy functional loss hereditary neuropathy human disease human subject improved in vivo indexing loss of function loss of function mutation male motor function improvement mutant nervous system disorder neuroinflammation neuromuscular neuromuscular function novel novel strategies null mutation pharmacokinetics and pharmacodynamics phase I trial phase II trial pre-clinical preservation prophylactic response small molecule small molecule therapeutics success trafficking translational impact

项目摘要

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.

概括 Novologues 是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，例如热休克蛋白 90 (Hsp90) 和 Hsp70。在过去的十年中，我们发表了严格的临床前数据，表明 novologies 可以改善代谢和糖尿病周围神经病变 (DPN) 的临床指标在药效学上需要 Hsp70。我们的药物不能改善糖尿病 Hsp70 敲除 (KO) 小鼠的神经功能，因此疗效不佳。大多数临床先进的新药和广泛的 PK/PD 和临床前 GLP 毒理学研究已 KU-596 的 1 期试验已获得 FDA 接受，并且该药物显示可接受。 PK/PD 概况，不良事件概况可以忽略不计，现在准备进入 2 期试验。临床前数据支持 KU-596 的治疗益处也可能扩展到某些遗传性疾病腓骨肌萎缩症 1X (CMT1X) 是一种 X 连锁遗传性神经病，可能由以下疾病引起：连接蛋白 32 (Cx32) 基因缺失突变 (Cx32def) 小鼠是真实的模型。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 Cx32def 小鼠中以 Hsp70 依赖性方式发挥功能然而，许多 CMT1X 患者不具有 null 功能。突变，但表达 Cx32 的突变形式，这些个体表现出细胞内运输的改变。出现像无效突变患者一样的临床神经病，但尚不清楚有益的药物是否通过错误定位的 Cx32 突变体的表达来维持反应表型，因此，这是该研究的目标。 IGNITE 提案旨在验证 KU-596 在治疗外周和神经系统疾病方面的治疗优势和局限性由错误定位的 Cx32 突变引起的中枢神经系统症状我们的 R61 阶段将检验药物的假设。 T55I-Cx32def 小鼠中保留了 Cx32 的功效，我们将在内质网 (ER) 中保留 Cx32。使用神经传导测量作为客观里程碑来确定 ER 保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轴突损伤相关在 T55I-Cx32def 小鼠中观察到的电生理恢复这些数据将评估是否具有预防性。治疗可能会改善年轻 CMT1X 患者的脱髓鞘前轴突病，目标 2 将测试该治疗。假设 novologue 疗法可减少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 改变疾病的潜力。减少 CMT1X 的外周和中枢症状将检验药物疗效的假设。由于 ER 和高尔基体保留 Cx32 不一定相同。在他们对治疗的反应中，这些数据将通过扩大治疗范围来进一步推动治疗进步可能对 KU-596 产生反应的 CMT1X 患者重要的是，鉴于这项工作具有很高的转化影响。这种孤儿神经系统疾病缺乏神经治疗选择以及该药物的 2 期准备情况。