Development of neuromodulating AAV-KCC2 gene therapy to treat paralysis, spasticity and neuropathic pain after spinal cord injury.

开发神经调节 AAV-KCC2 基因疗法来治疗脊髓损伤后的瘫痪、痉挛和神经性疼痛。

• 批准号: 10384710
• 负责人: Amanda Leah Zimmerman
• 金额: $ 33.57万
• 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: 2022-09-24 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10384710
• 关键词: Activities of Daily Living; Acute; Anatomy; Animals; Applications Grants; Axon; Behavior; Biodistribution; Blood - brain barrier anatomy; Cerebrospinal Fluid; Cervical spinal cord injury; Chlorides; Chronic; Clinical; Clinical Research; Contusions; Cross-Over Studies; Data; Development; Dose; Down-Regulation; Electric Stimulation; Equilibrium; H-Reflex; Human; Hypersensitivity; Injections; Injury; Intravenous; Ions; Lead; Left; Leg; Lesion; Ligation; Mammals; Measurement; Measures; Membrane; Modality; Modeling; Motor; Motor Neurons; Mus; Muscle; Neurons; Pain; Pain Measurement; Paralysed; Persons; Pharmaceutical Preparations; Pharmacology; Phase; Phenotype; Pre-Clinical Model; Process; Property; Publishing; Quality of life; Rattus; Recovery; Recovery of Function; Reflex action; Research Personnel; Rodent; Rodent Model; Route; Safety; Self Care; Serotyping; Small Business Innovation Research Grant; Spinal Cord; Spinal Cord Contusions; Spinal cord injury; Spinal cord injury patients; Spinal nerve structure; Synapsins; Testing; Thoracic spinal cord structure; Time; Tissues; Toxic effect; Translating; Traumatic CNS injury; United States; Walking; Western Blotting; Work; adeno-associated viral vector; arm movement; base; chronic pain; clinically relevant; comorbidity; drug withdrawal; efficacy study; feeding; gene therapy; improved; improved mobility; in vivo; injured; kinematics; mechanical allodynia; motor deficit; motor function recovery; neuroregulation; novel therapeutics; pain behavior; pain model; pain reduction; painful neuropathy; prevent; promoter; restoration; severe injury; small molecule; spasticity; spontaneous pain; symporter; vector

Summary There are no approved therapies for spinal cord injury. There are about 300,000 people living with chronic spinal cord injury in US. For the vast majority of them, the injury left 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. We are developing a neuromodulating gene therapy for treating both acute and chronic SCI patients that will be delivered as a single injection to spinal cord. Neuromodulation after injury has the potential to restore functional recovery, as shown by a number of different investigators. After SCI there is an electrochemical imbalance that prevents motor neurons from eliciting normal muscle actions that are critical for movement of arms and legs. This imbalance is partly caused by a decrease in the chloride transporter called KCC2. It has been shown that by restoring normal levels of this transporter in spared spinal cord neurons, paralyzed mice regain walking ability. Furthermore, enhancement of KCC2 reduces pain and spasticity in rodent models. This grant application aims to examine a new therapy that has the potency and properties to be translated towards human clinical studies, by testing them in preclinical models.

概括 目前尚无批准的脊髓损伤疗法。大约有 300,000 人患有慢性病 美国脊髓损伤。对于他们中的绝大多数人来说，受伤使他们无法行走，或者如果他们 患有颈椎脊髓损伤，日常活动完全依赖他人的帮助 生活从喂养到个人护理。我们正在开发一种神经调节基因疗法来治疗这两种疾病 急性和慢性 SCI 患者将通过脊髓单次注射进行注射。 大量研究表明，损伤后的神经调节有可能恢复功能恢复 不同的调查员。 SCI 后会出现电化学失衡，阻止运动神经元 引发对手臂和腿部运动至关重要的正常肌肉活动。这种不平衡的部分原因是 由称为 KCC2 的氯离子转运蛋白减少引起。事实证明，通过恢复正常 如果这种转运蛋白在幸存的脊髓神经元中的水平升高，瘫痪的小鼠就会恢复行走能力。此外， KCC2 的增强可减轻啮齿动物模型的疼痛和痉挛。该拨款申请旨在审查 一种新疗法，具有可转化为人类临床研究的效力和特性 在临床前模型中测试它们。