Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model
Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model
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DOI：
10.1038/nm1205
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发表时间：
2005-04-01
期刊：
影响因子：
82.9
通讯作者：
Azzouz, M
中科院分区：
文献类型：
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作者：
Ralph, GS;Radcliffe, PA;Azzouz, M
肌萎缩侧索硬化症(ALS)是一种致命的神经退行性疾病，导致大脑和脊髓运动神经元的选择性死亡。一些家族性肌萎缩侧索硬化症家族性病例是由编码超氧化物歧化酶(SOD1)(2-4)基因的显性突变引起的。针对特定基因沉默的干扰RNA(RNAi)的出现可能对此类显性遗传性疾病的治疗有益(5-7)。我们构建了一个慢病毒载体来介导针对人SOD1基因(SOD1)的RNAi分子的表达。将该载体注射到基因工程过表达突变形式的人SOD1(G93A)的小鼠的不同肌肉组中，可以有效和特异地降低SOD1的表达，并改善脑干和脊髓中脆弱运动神经元的存活率。此外，SOD1沉默改善了这些动物的运动能力，导致ALS症状的出现明显延迟了100%以上，并延长了它们正常寿命的近80%。这些数据首次显示，在使用RNAi的致命的、以遗传为主的神经退行性疾病的动物模型中，存活率显著延长，并提供了该领域迄今观察到的最高治疗效果。
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease resulting in the selective death of motor neurons in the brain and spinal cord(1). Some familial cases of ALS are caused by dominant mutations in the gene encoding superoxide dismutase (SOD1)(2-4). The emergence of interfering RNA (RNAi) for specific gene silencing could be therapeutically beneficial for the treatment of such dominantly inherited diseases(5-7). We generated a lentiviral vector to mediate expression of RNAi molecules specifically targeting the human SOD1 gene ( SOD1). Injection of this vector into various muscle groups of mice engineered to overexpress a mutated form of human SOD1 (SOD1(G93A)) resulted in an efficient and specific reduction of SOD1 expression and improved survival of vulnerable motor neurons in the brainstem and spinal cord. Furthermore, SOD1 silencing mediated an improved motor performance in these animals, resulting in a considerable delay in the onset of ALS symptoms by more than 100% and an extension in survival by nearly 80% of their normal life span. These data are the first to show a substantial extension of survival in an animal model of a fatal, dominantly inherited neurodegenerative condition using RNAi and provide the highest therapeutic efficacy observed in this field to date.