Models of Motor Neuron Disease: Stem Cell Therapies

描述（由申请人提供）：运动神经元疾病，包括肌萎缩侧索硬化症（ALS）和肌萎缩侧索硬化症（SMA），以下运动神经元变性和死亡为特征。遗传学的重大进展使构建引人注目的转基因模型成为可能，但这些疾病的基本致病机制仍然未知，也没有改善疾病的治疗方法。细胞死亡预防策略，包括使用营养因子和小神经保护分子，临床成功非常有限。也许最大的希望在于细胞替代策略，基于我们的初步发现，外源性神经干细胞（NSCs）可以被大量移植到成年大鼠脊髓中，并产生具有临床相关表型的细胞，即神经元和鞘细胞。受这些发现的鼓舞，我们提出了一种循序渐进的方法，以确保鼠类和人的NSCs在兴奋毒性应用后移植到大鼠脊髓退行性运动神经元的部位，以及移植到具有ALS临床特征的转基因动物（即SOD1转基因啮齿动物）的腹角时，能够分化为神经元和胶质细胞。根据我们的初步研究结果，我们对nsc来源的神经元接受兴奋性和抑制性神经支配的能力感兴趣，并将轴突延伸到腹侧根，朝向肌肉目标。我们期望通过在电动装置上的行为测试来评估，退化的神经肌肉单位的恢复将改善SOD1转基因动物的肌肉力量。因此，我们建议研究将NSCs作为运动神经元疾病治疗工具的基本临床前参数。

DESCRIPTION (provided by applicant): Motor neuron diseases, including ALS and SMA, are featured by degeneration and death of lower motor neurons. Significant progress in genetics has allowed for the construction of spectacular transgenic models, but the basic pathogenic mechanisms of these illnesses remain unknown and there are no disease-modifying treatments. Cell death prevention strategies, including the use of trophic factors and small neuroprotective molecules, have had very limited clinical success. Perhaps the greatest promise lies in cell replacement strategies, based on our preliminary findings that exogenous neural stem cells (NSCs) can become avidly engrafted in the adult rat spinal cord and give rise to cells with clinically relevant phenotypes, i.e. neurons and ensheathing cells. Encouraged by these findings, we propose a stepwise approach to ensure that rodent and human NSCs differentiate into neurons and glia when transplanted at the sites of degenerated motor neurons in rat spinal cord after excitotoxic applications and in the ventral horn of transgenic animals which show the clinical features of ALS, i.e. SOD1 transgenic rodents. We are interested in the ability of NSC-derived neurons, suggested by our preliminary findings, to receive excitatory and inhibitory innervation and extend axons to ventral roots towards muscle targets. We expect that the restitution of the degenerating neuromuscular units will improve muscle strength in SOD1 transgenic animals, as assessed by behavioral testing on motorized devices. In concert, we propose to examine the essential preclinical parameters for the consideration of NSCs as therapeutic tools for motor neuron disease.