Spinal Subpial Gene Delivery for Treatment of Amyotrophic Lateral Sclerosis

项目摘要 目前的临床资料显示，目前尚无有效治疗散发性或任何形式的遗传性肌营养不良的方法。 侧索硬化症。我们以前的工作和初步数据表明，AAV9的两个水平的脊髓软膜下递送- 如果治疗是，shRNA-SOD1载体在阻止疾病的发展或进展方面非常有效 起始于症状前或症状早期的ALS成年小鼠(SOD1G37R)或ALS大鼠(SOD1G93A)。这 功能性保护与脊髓α运动神经元、中间神经元和白质的高度相关 物质保存和沉默引起的肌萎缩侧索硬化症突变的SOD1基因的表达在整个长度 小鼠和大鼠ALS模型的脊髓。目前，治疗后的存活期并不长 到目前为止还没有系统地研究过。在我们提出的研究中，使用SOD1G93A大鼠模型，我们将定义：i) 硬膜下注射AAV9-shRNA-SOD1后临床确定的治疗效果的最长持续时间 有症状或早期症状的SOD1G93A大鼠。Ii)在野生型SD大鼠和猪的单独队列中，SOD1 利用沉默载体研究内源性SOD1基因沉默后的毒性阈值。目标是， 研究设计和方法已经发展到专注于突变的SOD1基因诱导的ALS，并 生成全面的疗效和初步安全性数据，以支持该技术未来的临床前开发 治疗方法，作为一种新的治疗策略，以增强突变的SOD1基因引起的ALS。

Project Summary Current clinical data show that there is no effective treatment of sporadic or any form of hereditary amyotrophic lateral sclerosis. Our previous work and preliminary data show that two-level spinal subpial delivery of AAV9- shRNA-SOD1 vector is highly effective in blocking the disease development or progression if treatment is initiated in adult pre-symptomatic or early-symptomatic ALS mouse (SOD1G37R) or ALS rat (SOD1G93A). This functionally-defined protection correlated with a high degree of spinal α-motoneuron, interneuron and white matter preservation, and silencing of ALS-causing mutated SOD1 gene expression seen in the entire length of the spinal cord in both mouse and rat ALS models. At present no long post-treatment survival periods have been systemically studied as yet. In our proposed studies, using the SOD1G93A rat model, we will define: i) The maximum duration of clinically defined treatment effect after subpial delivery of AAV9-shRNA-SOD1 in adult pre- symptomatic or early symptomatic SOD1G93A rats. ii) In a separate cohort of wild-type SD rats and pigs, a SOD1 silencing vector will be used to study the toxicity threshold after endogenous SOD1 gene silencing. The aims, research design, and methods have been developed to focus on mutated SOD1 gene-induced ALS, and to generate comprehensive efficacy and initial safety data to support future pre-clinical development of this treatment approach, as a novel therapeutic strategy for augmenting mutated SOD1 gene-caused ALS.