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

治疗痛性糖尿病神经病变的口服KCC2增强剂的研制。 摘要： 需要对影响三分之一的糖尿病神经病理性疼痛(DNP)进行更有效的药物治疗 糖尿病患者的健康状况。目前的止痛药具有不可预测的疗效和令人衰弱的副作用，这些副作用可以 比止痛更重要。尽管DNP对生活质量有影响，但目前还没有改善疾病的治疗方法。 近年来，越来越多的证据表明，神经病理性疼痛在糖尿病神经病变等 疾病是由中枢神经系统特异性氯化物KCC2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是必不可少的。KCC2增强剂 治疗对神经病理性疼痛的动物模型有效，包括糖尿病大鼠，在 无论是雄性还是雌性。因此，恢复KCC2功能和神经元氯稳态的治疗 脊髓背侧可直接解决DNP的中枢病理机制，治疗缓解 神经病理性疼痛与改善DNP患者的生活质量。AXONIS治疗公司正在推进一项 口服KCC2类增强剂AXN-006-01-3，计划于第四季度进行GLP毒理学研究 2022年在此第一阶段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模型中的神经病理性疼痛。此外，HRDD受损是脊柱的一个生物标志物 在DNP模型和患者中，去抑制，并与药物止痛效果相关。因为HRDD 损伤反映KCC2功能减退和对KCC2治疗的反应，我们将检查HRDD作为 我们的KCC2增强型小分子药物用于DNP的翻译、电生理生物标记物。最后，我们 将使用基于共聚焦的神经元KCC2生物标记物来研究PK/PD关系。

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.