Aoki Masashi, Warita Hitoshi, Suzuki Naoki, Kato Masaaki, Itoyama Yasuto
Department of Neurology, Tohoku University School of Medicine.
Rinsho Shinkeigaku. 2011 Nov;51(11):1195-8. doi: 10.5692/clinicalneurol.51.1195.
Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disorder characterized by the death of upper and lower motor neurons. Approximately 20% of familial ALS cases are caused by mutations in the superoxide dismutase 1 (SOD1) gene. We have developed rats that express a human SOD1 transgene with two different ALS-associated mutations develop 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 (implantation of intrathecal catheters for chronic therapeutic studies; CSF sampling) and spinal cord (e.g., direct administration of viral- and cell-mediated therapies). Hepatocyte growth factor (HGF) is one of the most potent survival-promoting factors for motor neurons. To examine both its protective effect on motor neurons and its therapeutic potential, 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 attenuates motor neuron degeneration and prolonged the duration of the disease by 63%. Our results indicated the therapeutic efficacy of continuous intrathecal administration of hrHGF in ALS rats. These results should prompt 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。约20%的家族性ALS病例由超氧化物歧化酶1（SOD1）基因突变引起。我们培育出了表达带有两种不同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操作（植入鞘内导管进行慢性治疗研究；脑脊液采样）和脊髓操作（例如，直接给予病毒介导和细胞介导的疗法）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。为了研究其对运动神经元的保护作用及其治疗潜力，我们在瘫痪发作时通过鞘内持续给药的方式，对转基因大鼠给予人重组HGF（hrHGF），持续4周。鞘内给予hrHGF可减轻运动神经元退化，并使疾病持续时间延长63%。我们的结果表明，在ALS大鼠中持续鞘内给予hrHGF具有治疗效果。这些结果应促使在ALS患者中进一步开展使用持续鞘内给予hrHGF的临床试验。
