Stem cell therapy targeting skeletal muscles for ALS

针对 ALS 骨骼肌的干细胞疗法

• 批准号: 7532266
• 负责人: Masatoshi Suzuki
• 金额: $ 19.49万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7532266
• 关键词: Age-Years; Amyotrophic Lateral Sclerosis; Animal Disease Models; Bone Marrow; Brain-Derived Neurotrophic Factor; Cell Therapy; Cells; Cessation of life; Clinical Trials; Disease; Engineering; Equus caballus; Familial Amyotrophic Lateral Sclerosis; Genes; Growth Factor; Health; Human; Infection; Insulin-Like Growth Factor I; Mesenchymal; Mesenchymal Stem Cells; Mission; Modeling; Motor Neurons; Mus; Muscle; Muscular Atrophy; Mutation; Neurodegenerative Disorders; Numbers; Onset of illness; Oxides; Paralysed; Pathogenesis; Patients; Point Mutation; Public Health; Rattus; Research; Research Proposals; Role; Site; Skeletal Muscle; Source; Spinal Cord; Testing; Tissues; Transgenic Organisms; Translational Research; United States National Institutes of Health; Vascular Endothelial Growth Factors; Viral Vector; Virus; base; cell growth; gene therapy; glial cell-line derived neurotrophic factor; improved; insight; mutant; neuron loss; novel; novel therapeutics; preclinical study; stem cell therapy

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a progressive disorder that leads to degeneration of upper and lower motor neurons, muscle atrophy, and ultimately death. The onset of disease is usually between 40 and 60 years of age. In 5% of cases, ALS is caused by a point mutation in the super oxide dismutase 1 gene (SOD1) and is referred to as familial ALS. Motor neuron cell death and paralysis result when this mutation is over expressed in mice and rats (SOD1G93A mutants). This translational research proposal will investigate the efficacy of ex vivo cell therapy targeting skeletal muscles to ameliorate motor neuron death in a rat model of ALS. We will focus on human mesenchymal stem cells (hMSC) derived from bone marrow, which can be isolated from normal donors or patients with ALS, easily expanded to large numbers and modified ex vivo with transgenic genes using viral vectors. We propose to use the hMSC as "Trojan horses" to deliver key trophic factors postulated to have a role in ALS pathogenesis: glial cell line-derived neurotrophic factor (GDNF), insulin-like growth factor-I (IGF-I), brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF). We will also determine the potential benefits of this hMSC based approach compared to a viral vector based approach. Furthermore, we will determine if combined delivery of these growth factors using hMSC has any synergistic effects on motor neuron loss in the SOD1G93A rats. These aims will provide highly novel insights into effective approaches using cell and growth factor-based treatments for ALS, and may provide the rationale for novel therapeutic strategies for a neurodegenerative disease with no known cure. Our rationale for using human mesenchymal cells in this project is that they represent a safe viable source of cells that could potentially be used in multiple clinical trials. Thus, any results acquired from the use of these cells in animal models of disease will be directly translatable to pre-clinical studies in ALS. The relevance to the NIH mission of improving health becomes extremely high when using human cells. PROJECT NARRATIVE Amyotrophic lateral sclerosis (ALS) is an incurable disease characterized by rapid loss of muscle control and eventual paralysis. The proposed research will contribute new novel information to effective therapies for neurodegenerative diseases, which is relevant to the NIH mission of improving public health.

描述（由申请人提供）：肌萎缩性侧索硬化症（ALS）是一种进行性疾病，可导致上下运动神经元变性、肌肉萎缩并最终死亡。发病年龄通常在40至60岁之间。在5%的病例中，ALS是由超氧化物歧化酶1基因（SOD 1）的点突变引起的，被称为家族性ALS。当这种突变在小鼠和大鼠中过度表达时（SOD 1G 93 A突变体），会导致运动神经元细胞死亡和瘫痪。这项转化研究提案将研究靶向骨骼肌的离体细胞疗法改善ALS大鼠模型中运动神经元死亡的疗效。我们将专注于来自骨髓的人间充质干细胞（hMSC），它可以从正常供体或ALS患者中分离出来，很容易扩增到大量，并使用病毒载体用转基因基因进行体外修饰。我们建议使用hMSC作为“特洛伊木马”来传递假定在ALS发病机制中起作用的关键营养因子：胶质细胞系源性神经营养因子（GDNF）、胰岛素样生长因子-I（IGF-I）、脑源性神经营养因子（BDNF）和血管内皮生长因子（VEGF）。我们还将确定这种基于hMSC的方法与基于病毒载体的方法相比的潜在益处。此外，我们将确定使用hMSC联合递送这些生长因子是否对SOD 1G 93 A大鼠中的运动神经元损失具有任何协同作用。这些目标将为使用基于细胞和生长因子的治疗ALS的有效方法提供高度新颖的见解，并可能为未知治愈的神经退行性疾病的新治疗策略提供理论基础。我们在这个项目中使用人类间充质细胞的理由是，它们代表了一种安全可行的细胞来源，可能用于多个临床试验。因此，在疾病动物模型中使用这些细胞获得的任何结果将直接转化为ALS的临床前研究。当使用人类细胞时，与NIH改善健康的使命的相关性变得非常高。肌萎缩侧索硬化症（ALS）是一种无法治愈的疾病，其特征是肌肉控制迅速丧失，最终瘫痪。拟议的研究将为神经退行性疾病的有效治疗提供新的新颖信息，这与NIH改善公众健康的使命有关。