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ALS和SMA，以下运动神经元变性和死亡为特征。遗传学的重大进展已经允许构建壮观的转基因模型，但是这些疾病的基本致病机制仍然未知，并且没有疾病修饰治疗。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（NSC）可以被移植到成年大鼠脊髓中，并产生具有临床相关表型的细胞，即神经元和成鞘细胞。受这些研究结果的鼓舞，我们提出了一种逐步的方法，以确保啮齿动物和人类神经干细胞分化成神经元和神经胶质细胞时，移植在兴奋性毒性应用后，在大鼠脊髓中的退化运动神经元的网站，并在转基因动物的腹角显示ALS的临床特征，即SOD1转基因啮齿动物。我们感兴趣的神经干细胞衍生的神经元的能力，我们的初步研究结果，接受兴奋性和抑制性神经支配，并延长轴突腹根对肌肉的目标。我们预计，退化的神经肌肉单位的恢复将提高SOD1转基因动物的肌肉力量，通过电动设备上的行为测试进行评估。在演唱会上，我们建议检查的基本临床前参数的考虑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.