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Spinal Subpial Gene Delivery for Treatment of Amyotrophic Lateral Sclerosis

脊髓软膜下基因递送治疗肌萎缩侧索硬化症

基本信息

批准号：
10710405
负责人：
MARTIN MARSALA
金额：
$ 63.67万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-28 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10710405
关键词：
Adult Aftercare Alleles Amyotrophic Lateral Sclerosis Animal Model Animals Appearance Behavior Biodistribution Clinical Clinical Data Data Development Devices Diagnosis Disease Dose Family suidae Future Gastrocnemius Muscle Gene Delivery Gene Expression Gene Silencing Genes Genome Goals Human Inherited Injections Interneurons Leg Length Life Extension Lumbar spinal cord structure Mediating Methods Modeling Motor Neurons Mus Muscle Mutate Nervous System Physiology Organ Organism Patients Peripheral Proteins Rattus Research Design Rodent Safety Siblings Spinal Spinal Cord Study models Testing Therapeutic Effect Toxic effect Transgenic Organisms Vertebral column Work amyotrophic lateral sclerosis therapy autosome clinically relevant cohort effective therapy end stage disease mouse model novel novel therapeutic intervention pre-clinical preclinical development preservation prototype response small hairpin RNA superoxide dismutase 1 therapy development treatment duration treatment effect vector vector genome white matter

项目摘要

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.

项目概要目前的临床数据表明，散发性或任何形式的遗传性肌萎缩症尚无有效治疗方法。侧索硬化。我们之前的工作和初步数据表明，AAV9-的两级脊髓软膜下递送如果治疗有效，shRNA-SOD1 载体可以非常有效地阻止疾病的发生或进展。在成年症状前或早期症状 ALS 小鼠 (SOD1G37R) 或 ALS 大鼠 (SOD1G93A) 中启动。这与高度脊髓 α-运动神经元、中间神经元和白细胞相关的功能定义的保护整个长度中观察到的物质保存和导致 ALS 突变的 SOD1 基因表达的沉默小鼠和大鼠 ALS 模型中的脊髓。目前尚未发现治疗后生存期较长至今尚未系统研究过。在我们提出的研究中，使用 SOD1G93A 大鼠模型，我们将定义： i) 在成人预治疗中软膜下递送 AAV9-shRNA-SOD1 后临床定义的治疗效果的最长持续时间有症状或早期有症状的 SOD1G93A 大鼠。 ii) 在野生型 SD 大鼠和猪的单独队列中，SOD1 沉默载体将用于研究内源性SOD1基因沉默后的毒性阈值。目标，研究设计和方法已开发出来，重点关注突变 SOD1 基因诱导的 ALS，并生成全面的疗效和初始安全性数据，以支持该药物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 SOD1 基因引起的 ALS。