Spinal Subpial Gene Delivery for Treatment of Amyotrophic Lateral Sclerosis

项目摘要 目前的临床资料显示，对于散发性或任何形式的遗传性肌萎缩性肌萎缩症， 侧索硬化我们以前的工作和初步数据表明，两个水平的脊髓软膜下递送AAV 9- shRNA-SOD 1载体在阻断疾病发展或进展方面是高度有效的，如果治疗是有效的， 在成年症状前或早期症状ALS小鼠（SOD 1G 37 R）或ALS大鼠（SOD 1G 93 A）中开始。这 功能确定的保护与脊髓α运动神经元、中间神经元和白色高度相关 物质保存，并沉默ALS引起突变的SOD 1基因表达，在整个长度的 在小鼠和大鼠ALS模型中的脊髓。目前，治疗后存活期不长， 系统研究至今。在我们提出的研究中，使用SOD 1G 93 A大鼠模型，我们将定义： 在成年学龄前儿童中软膜下递送AAV 9-shRNA-SOD 1后临床定义的治疗效果的最长持续时间 症状或早期症状的SOD 1G 93 A大鼠。ii）在野生型SD大鼠和猪的单独队列中， 沉默载体将用于研究内源性SOD 1基因沉默后的毒性阈值。目标， 研究设计和方法已经发展到关注突变的SOD 1基因诱导的ALS， 生成全面的疗效和初始安全性数据，以支持未来的临床前开发 治疗方法，作为一种新的治疗策略，用于增强突变的SOD 1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.