Development of KCC2 neuromodulators to treat paralysis after spinal cord injury.

KCC2神经调节剂治疗脊髓损伤的研究进展 摘要： 目前还没有被批准的治疗脊髓损伤(SCI)后瘫痪的方法，尽管大约有17,000 在美国，每年遭受脊髓损伤的人和大约30万慢性脊髓损伤患者。对于绝大多数人来说 患者，受伤使他们不能行走，或者，如果他们遭受了颈椎脊髓损伤，则完全依赖 在日常生活的所有活动中，从喂食到个人护理，向其他人提供帮助。这些产品的成本 个人和整个社会意义重大，因为脊髓损伤通常发生在成年人的收入高峰期。 好几年了。脊髓损伤后的神经调节有可能恢复功能，即使在慢性脊髓损伤患者中也显示出这一点。 硬膜外电刺激在临床病例研究中的应用。我们正在开发一种非侵入性的口腔 一种神经调节药物，可以广泛治疗大多数幸免但功能障碍的脊髓损伤患者， 脊髓组织。脊髓损伤后，备用脊髓组织中存在兴奋/抑制失衡， 导致瘫痪、痉挛和神经病理性疼痛。这种不平衡是由于中枢神经系统的减少- 一种称为KCC2的特殊氯离子转运体。的确，通过药理和遗传手段恢复KCC2 方法在备用脊髓神经元中，使严重瘫痪的啮齿动物恢复行走能力。 此外，KCC2增强剂药物减少了啮齿动物模型中的神经病理性疼痛和痉挛。在这 应用，我们建议开展非GLP和GLP IND-Enabling药物疗效和临床前研究 我们的新型KCC2增强剂AXN-006的安全性。在完成提出的目标后，AXONIS的目标是 准备好委托GMP药品生产，提交IND并迅速进入人类第一 健康志愿者的1期临床试验。首要目标是将一流的口语商业化。 用于治疗脊髓损伤中的瘫痪、疼痛和痉挛以及其他相关神经疾病的KCC2增强剂 精神障碍的迹象。

Development of KCC2 neuromodulators to treat spinal cord injury. Abstract: There are no approved therapies for treating paralysis after spinal cord injury (SCI), despite roughly 17,000 people suffering SCI per year and about 300,000 people living with chronic SCI in US. For the vast majority of patients, injury leaves them incapable of walking or, if they have suffered a cervical SCI, entirely dependent upon others for assistance in all of their activities of daily living from feeding to personal care. The cost to these individuals, and to society as a whole, are significant as SCI often occurs in adults during their peak earning years. Neuromodulation after SCI has the potential to restore functions, as shown even in chronic SCI patients using epidural electrical stimulation in clinical case studies. We are developing a non-invasive, oral neuromodulating drug that can widely treat the majority of SCI patients who have spared, but dysfunctional, spinal cord tissue. After SCI there is an excitation/inhibition imbalance in the spared spinal cord tissue that leads to paralysis, spasticity and neuropathic pain. This imbalance is caused by a decrease in the CNS- specific chloride transporter called KCC2. Indeed, restoring KCC2 by both pharmacological and genetic methods in spared spinal cord neurons leads severely paralyzed rodents to regain stepping ability. Furthermore, KCC2 enhancer drugs reduce neuropathic pain and spasticity in rodent models. In this application, we propose to carry out non-GLP and GLP IND-enabling preclinical research on drug efficacy and safety of our novel KCC2 enhancer drug, AXN-006. After completion of the proposed aims, AXONIS goal is to be ready to commission GMP drug product manufacturing, file an IND and move rapidly into a first-in-human Phase 1 clinical trial in healthy volunteers. The overarching goal is the commercialization of a first-in-class oral KCC2 enhancer drug to treat paralysis, pain and spasticity in SCI, as well as other relevant neurological disorder indications.