Aoki Masashi
(Department of Neurology, Tohoku University School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
Nihon Shinkei Seishin Yakurigaku Zasshi. 2012 Nov;32(5-6):287-92.
Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disorder characterized by the death of upper and lower motor neurons. About 10% of all ALS cases are familial; approximately 20% of familial ALS cases are caused by mutations in the superoxide dismutase 1 (SOD1) gene. We developed rats that express a human SOD1 transgene with ALS-associated mutations, developing striking motor neuron degeneration and paralysis. The larger size of this rat model as compared with the ALS mice, will facilitate studies involving manipulations of spinal fluid and the spinal cord. Hepatocyte growth factor (HGF) is one of the most potent survival-promoting factors for motor neurons. We administered human recombinant HGF (hrHGF) by continuous intrathecal delivery to the transgenic rats at the onset of paralysis for 4 weeks. Intrathecal administration of hrHGF attenuated motor neuron degeneration and prolonged the duration of the disease by 63%. To translate this strategy to human treatment, we induced a contusive cervical spinal cord injury in the common marmoset, a primate, and then administered hrHGF intrathecally. The intrathecal administration of hrHGF promoted functional recovery. These results prompted further clinical trials in ALS using continuous intrathecal administration of hrHGF.
肌萎缩侧索硬化症（ALS）是一种成人发病的神经退行性疾病，其特征是上下运动神经元死亡。所有ALS病例中约10%为家族性；家族性ALS病例中约20%由超氧化物歧化酶1（SOD1）基因突变引起。我们培育出了表达带有ALS相关突变的人类SOD1转基因的大鼠，这些大鼠出现了明显的运动神经元退化和瘫痪。与ALS小鼠相比，这种大鼠模型体型更大，将便于开展涉及脑脊液和脊髓操作的研究。肝细胞生长因子（HGF）是对运动神经元最有效的促存活因子之一。我们在瘫痪发作时通过持续鞘内给药的方式给转基因大鼠注射人重组HGF（hrHGF），持续4周。鞘内注射hrHGF可减轻运动神经元退化，并使疾病持续时间延长63%。为了将这一策略转化为人类治疗方法，我们在灵长类动物普通狨猴身上诱导了挫伤性颈脊髓损伤，然后进行鞘内注射hrHGF。鞘内注射hrHGF促进了功能恢复。这些结果促使人们进一步开展使用持续鞘内注射hrHGF治疗ALS的临床试验。
