Models of Motor Neuron Disease: Stem Cell Therapies

描述(申请人提供)：运动神经元疾病，包括肌萎缩侧索硬化症和肌萎缩侧索硬化症，以低位运动神经元的变性和死亡为特征。遗传学的重大进步使得构建壮观的转基因模型成为可能，但这些疾病的基本致病机制仍不清楚，也没有改变疾病的治疗方法。预防细胞死亡的策略，包括使用营养因子和小神经保护分子，在临床上取得的成功非常有限。也许最有希望的是细胞替代策略，基于我们的初步发现，外源性神经干细胞(NSCs)可以被大量植入成年大鼠的脊髓，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，以确保将啮齿动物和人类神经干细胞移植到兴奋性毒性作用后大鼠脊髓运动神经元变性的部位和表现出ALS临床特征的转基因动物的腹角内，即SOD1转基因啮齿动物，以确保其分化为神经元和神经胶质细胞。我们感兴趣的是，我们的初步发现表明，神经干细胞来源的神经元能够接受兴奋性和抑制性神经支配，并将轴突向肌肉靶点延伸到腹根。我们预计，通过对电动设备的行为测试评估，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。同时，我们建议检查基本的临床前参数，以考虑将神经干细胞作为运动神经元疾病的治疗工具。

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.