A Novel Pharmacologic Approach to Treat CMT1X

治疗 CMT1X 的新药理学方法

• 批准号: 10481867
• 负责人: Rick T Dobrowsky
• 金额: $ 37.15万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10481867
• 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; 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 goal; translational impact; translational potential; treatment response

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.

总结 新型药物是小分子神经治疗剂，其化学生物学旨在调节神经元的功能。 分子伴侣的活性和表达，例如热休克蛋白90（Hsp 90）和Hsp 70。超过 在过去的十年里，我们发表了严格的临床前数据，表明新药物改善了代谢， 糖尿病周围神经病变（DPN）的临床指标。在药效学上，新药需要Hsp 70用于 因为药物不能改善糖尿病Hsp 70敲除（KO）小鼠的神经功能。KU-596是我们的 大多数临床上先进的新药和广泛的PK/PD和临床前GLP毒理学研究， 已被FDA接受。KU-596的1期试验已经完成，药物显示可接受 PK/PD特征，可忽略的不良事件特征，现在准备进入II期试验。但新 临床前数据支持KU-596的治疗益处也可以扩展到某些遗传性疾病。 神经病Charcot-Marie-Tooth 1X（CMT 1X）是一种X连锁遗传性神经病，可由 连接蛋白32（Cx 32）基因的无效突变。Cx 32缺陷型（Cx 32 def）小鼠是一种可靠的模型， 人类疾病和我们的初步数据支持口服KU-596改善神经肌肉 在Cx 32 def小鼠中以Hsp 70依赖性方式发挥作用。然而，许多CMT 1X患者没有空值， 突变，但表达表现出改变的细胞内运输的Cx 32的突变形式。这些人 开发临床神经病变，如无效突变患者，但目前还不清楚是否有益的药物 应答表型通过错误定位的Cx 32突变体的表达得以维持。因此，这一目标 IGNITE提案旨在验证KU-596在治疗外周和 由错误定位的Cx 32突变引起的CNS症状我们的R61阶段将测试药物 在T55 I-Cx 32 def小鼠中维持了功效，所述小鼠将Cx 32保留在内质网（ER）中。我们将 使用神经传导的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，aim 1将确定轴突损伤标志物的改善是否与神经元损伤相关。 在T55 I-Cx 32 def小鼠中观察到电生理恢复。这些数据将评估预防性治疗是否 治疗可以改善年轻CMT 1X患者的脱髓鞘前轴突病。目标2将测试 假设新疗法减少了周围神经炎症和爆发性CNS功能障碍， Cx 32 def和T55 I-Cx 32 def小鼠。这些研究将评估KU-596的疾病修饰潜力， 减少CMT 1X的外周和中枢症状。目的3将检验药物疗效是 保持高尔基体保留Cx 32。由于Cx 32的ER和高尔基体保留不一定等同， 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促进治疗的进步。 可能对KU-596有反应的CMT 1X患者。重要的是，这项工作具有很高的翻译影响， 缺乏对这种孤儿神经系统疾病的神经治疗选择和药物的第二阶段准备。