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Development of the Treatment of Amyotrophic Lateral Sclerosis (ALS) with Neural Stem Cells

神经干细胞治疗肌萎缩侧索硬化症（ALS）的进展

基本信息

批准号：
14570598
负责人：
NAGANO Isao
金额：
$ 1.92万
依托单位：
Okayama University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570598/
关键词：
ALS SOD1 VEGF hypoxia Flk-1 IGF-1 neural precursor cell motor neuron G93A transgenic mouse stem cell PI3-K Akt ERK Pl3-K Ref-1

项目摘要

At first, we examined the induction of vascular endothelial growth factor (VEGF) in the G93A SOD1-mutant mice exposed to systemic hypoxia. Baseline expression of VEGF was increased in the SOD1-mutant mice compared with wild-type littermates. VEGF expression in the mutant mice was hardly induced by hypoxia, in contrast to the wild-type littermates where approximately nine-fold increase in VEGF expression was observed, indicating that the response of VEGF to hypoxia is impaired in the SOD1-mutant mice. We next investigated whether reduction of Flk-1, one of VEGF receptors, could induce motor neuron loss by inhibiting the Flk-1 expression using antisense oligodeoxynucleotides (AS-ODNs). Intrathecal infusion of AS-ODNs for 7 days suppressed almost completely Flk-1 expression in the lumbar segment, and was followed by a hypoxic challenge for 1 hour that was repeated for 7 more days. We observed that reduced Flk-1 expression and hypoxic challenge for 7 days resulted in 〜50% loss of motor neurons, in which the activation of Akt and ERK, that is increased levels of phosphorylated-Akt and of phosphorylated-ERK by hypoxia, was markedly inhibited. These results suggest that VEGF exerts its protective effect on motor neurons against hypoxia-induced toxicity by the Flk-1 receptor.To examine the possible effectiveness of IGF-1 in a mouse model of familial ALS, the G93A SOD1-mutant mice were treated by continuous IGF-1 delivery into the intrathecal space of the lumbar spinal cord. We found that the intrathecal administration of IGF-1 improved motor performance, delayed the onset of clinical disease, and extended survival in the G93A transgenic mice. Next, we performed a double blind clinical trial to assess the effect of intrathecal administration of IGF-1 on disease progression in patients with ALS. We found that the intrathecal administration of IGF-1 had a modest but significant beneficial effect in ALS patients without any serious adverse effects.

首先，我们研究了血管内皮生长因子（VEGF）在G93 A SOD 1突变小鼠暴露于全身缺氧的诱导。与野生型同窝小鼠相比，SOD 1突变小鼠的VEGF基线表达增加。突变小鼠中的VEGF表达几乎不受缺氧诱导，与野生型同窝小鼠相反，在野生型同窝小鼠中观察到VEGF表达增加约9倍，表明VEGF对缺氧的反应在SOD 1突变小鼠中受损。接下来，我们研究了VEGF受体之一Flk-1的减少是否可以通过使用反义寡核苷酸（AS-ODN）抑制Flk-1表达来诱导运动神经元损失。鞘内注射AS-ODNs 7天几乎完全抑制了Flk-1在腰段的表达，然后进行低氧攻击1小时，重复7天。我们观察到，Flk-1表达减少和缺氧攻击7天导致运动神经元损失约50%，其中Akt和ERK的激活，即缺氧引起的磷酸化Akt和磷酸化ERK水平的增加，被显著抑制。这些结果表明，VEGF发挥其对运动神经元对缺氧诱导的毒性的Flk-1 receptor.To检查IGF-1在家族性ALS的小鼠模型中的可能的有效性，G93 A SOD 1突变小鼠治疗的持续IGF-1交付到鞘内空间的腰椎脊髓。我们发现鞘内注射IGF-1改善了G93 A转基因小鼠的运动表现，延迟了临床疾病的发作，并延长了存活时间。接下来，我们进行了一项双盲临床试验，以评估鞘内注射IGF-1对ALS患者疾病进展的影响。我们发现，鞘内注射IGF-1对ALS患者有适度但显著的有益作用，没有任何严重的不良反应。