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

开发 KCC2 神经调节剂来治疗脊髓损伤后的瘫痪。

基本信息

批准号：
10483094
负责人：
Joanna Stanicka
金额：
$ 77.38万
依托单位：
AXONIS THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10483094
关键词：
Activities of Daily Living Adult Anatomy Animals Autopsy Behavioral Biological Assay Biological Availability Biological Products Body Weight Canis familiaris Cardiovascular Physiology Case Study Cervical spinal cord injury Chemicals Chlorides Chronic Classification Clinical Clinical Chemistry Clinical Pathology Combined Modality Therapy Development Dose Drug Exposure Electric Stimulation Electrocardiogram Enhancers Ensure Evaluation Family Formulation Genetic Goals Hematology Histopathology Home Hour Human In Vitro Individual Injury Lead Lesion Lymphocyte Maximum Tolerated Dose Measurable Methods Modeling Monitor Mus Neuromodulator Neurons No-Observed-Adverse-Effect Level Oral Organ Weight Outcome Pain Paralysed Patients Penetration Permeability Persons Pharmaceutical Preparations Pharmacology Phase Phase I Clinical Trials Plasma Rattus Recovery Rodent Rodent Model Safety Self Care Small Business Innovation Research Grant Societies Solubility Spinal Spinal Cord Spinal Cord Contusions Spinal cord injury Spinal cord injury patients System Testing Therapeutic Tissues Toxic effect Toxicokinetics Toxicology Walking analog analytical method chronic pain management clinical practice commercialization comorbidity cost drug efficacy early phase clinical trial efficacy study feeding first-in-human food consumption functional restoration healthy volunteer improved mobility in vivo in vivo Model medication safety method development micronucleus motor deficit motor function recovery nervous system disorder neuronal circuitry neuroregulation novel painful neuropathy pre-clinical pre-clinical research respiratory response safety study severe injury spasticity symporter telemetering

项目摘要

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.

开发 KCC2 神经调节剂来治疗脊髓损伤。抽象的：尽管大约有 17,000 名患者接受过治疗，但尚无批准的治疗脊髓损伤 (SCI) 后瘫痪的疗法美国每年有 30 万人患有 SCI，其中慢性 SCI 患者约 30 万人。对于绝大多数人来说患者受伤后无法行走，或者如果患有颈椎损伤，则完全依赖他人向其他人寻求从喂养到个人护理的所有日常生活活动的帮助。这些费用对个人和整个社会来说都具有重要意义，因为 SCI 经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 患者中也是如此在临床案例研究中使用硬膜外电刺激。我们正在开发一种非侵入性口腔神经调节药物，可广泛治疗大多数幸存但功能失调的 SCI 患者，脊髓组织。 SCI 后，幸存的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。这种不平衡是由于中枢神经系统功能下降引起的。特定的氯离子转运蛋白称为 KCC2。事实上，通过药理学和遗传手段恢复 KCC2 在幸存的脊髓神经元中的方法可以使严重瘫痪的啮齿动物恢复行走能力。此外，KCC2 增强剂药物可减轻啮齿动物模型中的神经性疼痛和痉挛。在这个申请中，我们建议开展非GLP和GLP IND支持的药物疗效和临床前研究我们的新型 KCC2 增强剂药物 AXN-006 的安全性。完成拟议目标后，AXONIS 的目标是准备好委托 GMP 药品生产、提交 IND 申请并迅速进入人体首例试验在健康志愿者中进行的 1 期临床试验。总体目标是将一流的口服药物商业化 KCC2 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指征。