Intrathecal delivery of hepatocyte growth factor from amyotrophic lateral sclerosis onset suppresses disease progression in rat amyotrophic lateral sclerosis model
Intrathecal delivery of hepatocyte growth factor from amyotrophic lateral sclerosis onset suppresses disease progression in rat amyotrophic lateral sclerosis model
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DOI：
10.1097/nen.0b013e318159886b
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发表时间：
2007-11-01
影响因子：
3.2
通讯作者：
Itoyama, Yasuto
中科院分区：
文献类型：
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作者：
Ishigaki, Aya;Aoki, Masashi;Itoyama, Yasuto
肝细胞生长因子（HGF）是运动神经元最有效的促存活因子之一。我们发现，将HGF基因导入G93A转基因小鼠的神经元，可以减轻运动神经元的退化，延长小鼠的寿命。目前，使用重组蛋白的治疗方案比基因治疗更接近临床应用。为了研究其对运动神经元的保护作用和治疗潜力，我们分别在100日龄（脊髓出现病理变化的年龄，但动物没有表现出临床虚弱）和115日龄（开始瘫痪）时，通过鞘内连续递送人重组HGF （hrHGF）给药，剂量为40或200 μ g和200 μ g，各4周。即使从麻痹开始给药，鞘内给药hrHGF也能减轻运动神经元退行性变，并使疾病持续时间延长63%。我们的研究结果表明，持续鞘内给药hrHGF对转基因大鼠的治疗效果，并应考虑进一步使用持续鞘内给药hrHGF治疗肌萎缩性侧索硬化症的临床试验。
Hepatocyte growth factor (HGF) is one of the most potent survival-promoting factors for motor neurons. We showed that introduction of the HGF gene into neurons of G93A transgenic mice attenuates motor neuron degeneration and increases the lifespan of these mice. Currently, treatment regimens using recombinant protein are closer to clinical application than gene therapy. To examine its protective effect on motor neurons and therapeutic potential we administered human recombinant HGF (hrHGF) by continuous intrathecal delivery to G93A transgenic rats at doses of 40 or 200 mu g and 200 mu g at 100 days of age (the age at which pathologic changes of the spinal cord appear, but animals show no clinical weakness) and at 115 days (onset of paralysis), respectively, for 4 weeks each. Intrathecal administration of hrHGF attenuates motor neuron degeneration and prolonged the duration of the disease by 63%, even with administration from the onset of paralysis. Our results indicated the therapeutic efficacy of continuous intrathecal administration of hrHGF in transgenic rats and should lead to the consideration for further clinical trials in amyotrophic lateral sclerosis using continuous intrathecal administration of hrHGF.