Development of oral KCC2 enhancer drug for treatment of painful diabetic neuropathy

开发用于治疗疼痛性糖尿病神经病变的口服 KCC2 增强剂药物

• 批准号: 10699218
• 负责人: Shane Hegarty
• 金额: $ 29.98万
• 依托单位: AXONIS THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2025-06-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10699218
• 关键词: Acute; Address; Affect; Analgesics; Animal Model; Biological Assay; Biological Availability; Biological Markers; Blood - brain barrier anatomy; Chlorides; Chronic; Clinic; Clinical; Collaborations; Data; Development; Diabetes Mellitus; Diabetic Neuralgia; Diabetic Neuropathies; Diagnostic; Disease; Disinhibition; Dorsal; Dose; Down-Regulation; Drug Kinetics; Electrophysiology (science); Enhancers; Equilibrium; Female; Functional disorder; Future; Goals; H-Reflex; Homeostasis; Hyperalgesia; Hypersensitivity; Impairment; Measurement; Measures; Membrane; Mental Depression; Modeling; Mus; Neurons; Oral; Oral Administration; Pain; Painless; Pathologic; Pathology; Patients; Persons; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phase; Posterior Horn Cells; Potassium; Process; Prodrugs; Property; Quality of life; Rattus; Secondary to; Small Business Innovation Research Grant; Spinal; Spinal Cord; Spinal cord injury; Spinal cord posterior horn; Streptozocin; Tactile; Testing; Therapeutic; Time; Toxicology; Translations; Treatment Efficacy; Vertebral column; Work; allodynia; biomarker validation; candidate identification; clinical candidate; diabetic; diabetic patient; diabetic rat; drug action; drug clearance; drug development; drug efficacy; drug metabolism; efficacy study; efficacy testing; gene therapy; global health; improved; improved mobility; in vivo; in-vivo diagnostics; male; mechanical allodynia; neurotransmission; pain model; pain patient; pain reduction; pain relief; pain signal; painful neuropathy; pharmacodynamic biomarker; pharmacokinetics and pharmacodynamics; pregabalin; professor; response; restoration; sedative; side effect; small molecule; spasticity; standard of care; symporter; translational potential; treatment effect; treatment group

Development of oral KCC2 enhancer drug for treatment of painful diabetic neuropathy. Abstract: There is a need for more effective drug treatments for diabetic neuropathic pain (DNP), which affects one-third of people with diabetes. Current analgesics have unpredictable efficacy and debilitating side effects that can outweigh pain relief. Despite its impact on quality of life, there are no disease-modifying treatments for DNP. In recent years, growing evidence shows that neuropathic pain in diabetic neuropathy and other disorders is caused by spinal disinhibition secondary to hypofunction of KCC2, a CNS-specific chloride transporter that is essential for neuronal responses to inhibitory neurotransmission. KCC2-enhancing treatments are effective in animal models of neuropathic pain, including diabetic rats, with analgesic effects in both males and females. Therefore, treatments that restore KCC2 function and neuronal chloride homeostasis within dorsal spinal cord could directly address central pathological mechanisms of DNP, therapy alleviating neuropathic pain and improving quality of life of DNP patients. AXONIS Therapeutics is advancing a first-in- class oral KCC2 enhancer drug, AXN-006-01-3, towards clinic with GLP-toxicology studies planned for Q4 2022. In this Phase 1 SBIR application, we aim to complete key proof of concept studies to show that AXN- 006-01-3 can treat neuropathic pain in a DNP model. Additionally, impaired HRDD is a biomarker of spinal disinhibition, and correlates with drug analgesic efficacy, in both DNP models and patients. Because HRDD impairments reflect KCC2 hypofunction and respond to KCC2 treatments, we will examine HRDD as a translational, electrophysiological biomarker of our KCC2-enhancing small molecule drug for DNP. Finally, we will investigate PK/PD relationships using a confocal-based neuronal KCC2 biomarker.

开发口服KCC 2增强剂药物治疗疼痛性糖尿病神经病变。 摘要： 糖尿病神经性疼痛（DNP）需要更有效的药物治疗， of people with diabetes糖尿病.目前的止痛药具有不可预测的疗效和使人衰弱的副作用， 比止痛更重要尽管其对生活质量的影响，但DNP没有疾病修饰治疗。 近年来，越来越多的证据表明，糖尿病性神经病变和其他神经病变中的神经性疼痛， 这种疾病是由继发于KCC 2功能减退的脊髓去抑制引起的，KCC 2是CNS特异性氯化物 是神经元对抑制性神经传递的反应所必需的转运蛋白。KCC 2增强 治疗在神经性疼痛的动物模型（包括糖尿病大鼠）中有效， 无论是男性还是女性。因此，恢复KCC 2功能和神经元氯稳态的治疗， 脊髓背角内注射能直接解决DNP的中枢病理机制， 神经病理性疼痛和改善DNP患者的生活质量。AXONIS Therapeutics正在推进一项 类口服KCC 2增强剂药物AXN-006-01-3，计划于第4季度进行临床GLP毒理学研究 2022.在第一阶段SBIR应用中，我们的目标是完成关键的概念验证研究，以证明AXN- 006-01-3可以治疗DNP模型中的神经性疼痛。此外，受损的HRDD是脊髓损伤的生物标志物。 在DNP模型和患者中，与药物镇痛功效相关。因为人权捍卫与发展署 损伤反映了KCC 2功能减退，并对KCC 2治疗有反应，我们将检查HRDD作为一种 我们的KCC 2增强小分子药物DNP的翻译，电生理生物标志物。最后我们 将使用基于共焦的神经元KCC 2生物标志物研究PK/PD关系。