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。

• 批准号: 10580091
• 负责人: Joanna Stanicka
• 金额: $ 142.69万
• 依托单位: AXONIS THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580091
• 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; Dryness; Electric Stimulation; Electrocardiogram; Enhancers; Ensure; Equilibrium; Evaluation; Family; Formulation; Genetic; Goals; Hematology; Histopathology; Home; Hour; Human; In Vitro; Individual; Injury; Lead; Lesion; Lymphocyte; Maximum Tolerated Dose; Methods; Modeling; Monitor; Mus; Neuromodulator; Neurons; No-Observed-Adverse-Effect Level; Oral; Oral Administration; Organ Weight; Outcome Measure; 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; Vertebral column; Walking; analog; analytical method; chronic pain management; clinical practice; commercialization; comorbidity; cost; drug action; 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; manufacture; medication safety; method development; micronucleus; motor deficit; motor function recovery; nervous system disorder; neuronal circuitry; neuroregulation; novel; ophthalmic examination; painful neuropathy; pharmacologic; pre-clinical; pre-clinical research; respiratory; response; safety study; severe injury; spasticity; symporter; telemetering

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神经调节剂以治疗脊髓损伤。 抽象的： 尽管大约17,000 每年患有SCI的人，大约有30万人在美国患有慢性SCI。对于绝大多数 患者，受伤使他们无法步行，或者，如果他们遭受了宫颈科学的痛苦，则完全依赖 从喂养到个人护理的所有日常生活活动中，请其他人提供帮助。这些成本 个人以及整个社会都很重要，因为SCI经常在成年人获得高峰期间发生 年。 SCI后神经调节具有恢复功能的潜力，如慢性SCI患者所示 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口头 神经调节药物可以广泛治疗大多数幸免但功能失调的SCI患者 脊髓组织。 SCI之后，在保存的脊髓组织中存在激发/抑制失衡 导致瘫痪，痉挛和神经性疼痛。这种不平衡是由CNS-的减少引起的 特定的氯化物转运蛋白称为KCC2。实际上，通过药理和遗传恢复KCC2 保存的脊髓神经元中的方法会导致严重瘫痪的啮齿动物以恢复步进能力。 此外，KCC2增强剂药物减少了啮齿动物模型中的神经性疼痛和痉挛。在这个 应用，我们建议对药物疗效和 我们新颖的KCC2增强剂药物的安全性AXN-006。提出的目标完成后，Axonis目标是 准备委托GMP药物制造，提交IND并迅速进入人类 健康志愿者的1阶段临床试验。总体目标是一流的口头商业化 KCC2增强剂药物可治疗SCI中的瘫痪，疼痛和痉挛以及其他相关神经系统 无序指示。