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

开发KCC 2神经调节剂治疗脊髓损伤。 摘要： 目前还没有被批准的治疗脊髓损伤（SCI）后瘫痪的疗法，尽管大约有17000种。 在美国，每年约有300，000人患有SCI，约有300，000人患有慢性SCI。对于绝大多数 患者，受伤使他们无法行走，或者，如果他们遭受了颈椎脊髓损伤，完全依赖 在日常生活的所有活动中，从喂养到个人护理，都需要他人的帮助。这些人的代价 对于个人和整个社会来说，这是非常重要的，因为SCI通常发生在成年人的收入高峰期 年SCI后的神经调节有可能恢复功能，即使在慢性SCI患者中也显示出这一点 在临床病例研究中使用硬膜外电刺激。我们正在开发一种非侵入性的， 神经调节药物，可以广泛治疗大多数脊髓损伤患者谁幸免，但功能失调， 脊髓组织SCI后，在备用脊髓组织中存在兴奋/抑制失衡， 导致瘫痪、痉挛和神经性疼痛。这种不平衡是由中枢神经系统的减少引起的。 一种叫做KCC 2的氯离子转运蛋白。事实上，通过药理学和遗传学恢复KCC 2 方法在备用脊髓神经元导致严重瘫痪的啮齿动物恢复行走能力。 此外，KCC 2增强剂药物在啮齿动物模型中减少神经性疼痛和痉挛。在这 申请，我们建议开展非GLP和GLP IND使能的药物疗效临床前研究， 我们的新型KCC 2增强剂药物AXN-006的安全性。在完成拟议目标后，AXONIS的目标是 准备委托GMP药品生产，提交IND并迅速进入首次人体试验 在健康志愿者中进行的I期临床试验。首要目标是商业化的一流的口头 KCC 2增强剂药物，用于治疗SCI中的瘫痪，疼痛和痉挛，以及其他相关的神经系统疾病 紊乱的迹象。

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.