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 没有批准的脊髓损伤疗法。大约有300,000人患有慢性 我们的脊髓损伤。对于绝大多数人来说，伤害使他们无法走路或 已经遭受了宫颈科学的痛苦，完全依赖他人在每日活动中的所有活动中的帮助 从喂养到个人护理生活。我们正在开发一种神经调节基因治疗，以治疗 急性和慢性SCI患者将作为单一注射到脊髓。 受伤后的神经调节有可能恢复功能恢复，如许多 不同的研究人员。 SCI之后，有一种电化学失衡，可防止运动神经元 引发对胳膊和腿运动至关重要的正常肌肉动作。这种失衡部分是 由称为KCC2的氯化物转运蛋白减少引起。已经表明，通过恢复正常 该转运蛋白的水平在保存的脊髓神经元中，瘫痪的小鼠恢复了步行能力。此外， KCC2的增强可减少啮齿动物模型中的疼痛和痉挛。该赠款申请旨在检查 通过 在临床前模型中测试它们。