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

摘要 目前还没有批准的治疗脊髓损伤的方法。大约有30万人患有慢性阻塞性肺病 美国的脊髓损伤。对于绝大多数人来说，受伤使他们无法行走，或者，如果他们 患有颈椎脊髓损伤，在日常生活中的所有活动都完全依赖他人的帮助 从进食到个人护理。我们正在开发一种神经调节基因疗法来治疗这两种疾病 急性和慢性脊髓损伤患者，将作为一次脊髓注射。 损伤后的神经调节有可能恢复功能恢复，如一些 不同的调查员。脊髓损伤后有一种电化学失衡，阻止运动神经元 引发对手臂和腿的运动至关重要的正常肌肉动作。这种失衡在一定程度上是 这是由名为KCC2的氯离子转运蛋白减少引起的。已经证明，通过恢复正常 在瘫痪的小鼠恢复行走能力的情况下，脊髓神经元中这种转运蛋白的水平。此外， KCC2的增强减轻了啮齿动物模型中的疼痛和痉挛。这项拨款申请旨在审查 一种新的疗法，具有转化为人类临床研究的效力和特性，通过 在临床前模型中对它们进行测试。

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.