Stem cell therapy targeting skeletal muscles for ALS

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（SOD1）的点突变引起的，被称为家族性ALS。当该突变在小鼠和大鼠（SOD1G93A突变体）中过度表达时，会导致运动神经元细胞死亡和瘫痪。这项转化研究计划将研究针对骨骼肌的体外细胞治疗改善肌萎缩侧索硬化症大鼠模型运动神经元死亡的功效。我们将专注于从骨髓中提取的人间充质干细胞（hMSC），它可以从正常供体或ALS患者中分离出来，很容易大量扩增，并使用病毒载体用转基因基因在体外修饰。我们建议使用hMSC作为“特洛伊木马”来传递在ALS发病机制中起作用的关键营养因子：胶质细胞系来源的神经营养因子（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）。我们还将确定与基于病毒载体的方法相比，这种基于hMSC的方法的潜在益处。此外，我们将确定使用hMSC联合递送这些生长因子是否对SOD1G93A大鼠的运动神经元丢失有任何协同作用。这些目标将为利用细胞和生长因子治疗ALS的有效方法提供高度新颖的见解，并可能为尚无治愈方法的神经退行性疾病的新治疗策略提供基本原理。我们在这个项目中使用人类间充质细胞的基本原理是，它们代表了一种安全可行的细胞来源，可以潜在地用于多个临床试验。因此，在动物疾病模型中使用这些细胞获得的任何结果都将直接转化为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。肌萎缩性侧索硬化症（ALS）是一种无法治愈的疾病，其特征是迅速失去肌肉控制并最终瘫痪。该研究将为神经退行性疾病的有效治疗提供新的新信息，这与NIH改善公众健康的使命有关。

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.