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

基本信息

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
项目类别：
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

项目摘要

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.

开发用于治疗疼痛性糖尿病神经病变的口服 KCC2 增强剂药物。抽象的：糖尿病神经性疼痛 (DNP) 影响着三分之一的患者，因此需要更有效的药物治疗糖尿病患者。目前的镇痛药具有不可预测的功效和令人衰弱的副作用，胜过缓解疼痛。尽管 DNP 会影响生活质量，但尚无缓解疾病的治疗方法。近年来，越来越多的证据表明，糖尿病性神经病和其他疾病中的神经性疼痛该疾病是由 KCC2（一种中枢神经系统特异性氯化物）功能减退继发的脊髓去抑制引起的转运蛋白对于神经元对抑制性神经传递的反应至关重要。 KCC2-增强治疗对神经病理性疼痛的动物模型（包括糖尿病大鼠）有效，并具有镇痛作用男性和女性。因此，恢复 KCC2 功能和神经元氯稳态的治疗背脊髓内的药物可以直接解决 DNP 的中枢病理机制，缓解治疗神经病理性疼痛并改善 DNP 患者的生活质量。 AXONIS Therapeutics 正在推进一项首创的类口服 KCC2 增强剂药物 AXN-006-01-3，计划在第四季度进行 GLP 毒理学研究，用于临床 2022 年。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，以表明 AXN- 006-01-3 可以治疗 DNP 模型中的神经性疼痛。此外，受损的 HRDD 是脊柱疾病的一个生物标志物。在 DNP 模型和患者中，去抑制作用与药物镇痛功效相关。因为HRDD 损伤反映了 KCC2 功能低下并对 KCC2 治疗有反应，我们将检查 HRDD 作为我们的 KCC2 增强小分子药物 DNP 的转化电生理生物标志物。最后，我们将使用基于共聚焦的神经元 KCC2 生物标志物研究 PK/PD 关系。