Antisense oligonucleotide therapy for neurodegenerative disease
Antisense oligonucleotide therapy for neurodegenerative disease
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DOI：
10.1172/jci25424
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发表时间：
2006-08-01
影响因子：
15.9
通讯作者：
Cleveland, Don W.
中科院分区：
文献类型：
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作者：
Smith, Richard A.;Miller, Timothy M.;Cleveland, Don W.
错误折叠/突变蛋白的积累造成的神经毒性被认为是神经退行性疾病的致病原因。由于降低导致这种堆积的蛋白质水平可能会改善疾病，因此已经开发出一种治疗策略，以下调中枢神经系统中几乎任何基因的表达。修饰的反义寡核苷酸被证明广泛分布于啮齿动物和灵长类动物的中枢神经系统，包括主要神经退行性疾病的影响区域。使用这种给药途径，我们发现超氧化物歧化酶1(SOD1)的反义寡核苷酸降低了整个大脑和脊髓的SOD1蛋白和mRNA水平。超氧化物歧化酶1是大脑中含量最丰富的蛋白质之一。在由SOD1突变引起的肌萎缩侧索硬化症(ALS)模型中，在接近发病时开始的治疗显著减缓了疾病的进展。这表明，在已知适当的靶蛋白的情况下，直接递送反义寡核苷酸可能是治疗包括ALS在内的神经退行性疾病的一种有效的、剂量可控的方法。
Neurotoxicity from accumulation of misfolded/mutant proteins is thought to drive pathogenesis in neurodegenerative diseases. Since decreasing levels of proteins responsible for such accumulations is likely to ameliorate disease, a therapeutic strategy has been developed to downregulate almost any gene in the CNS. Modified antisense oligonucleotides, continuously infused intraventricularly, have been demonstrated to distribute widely throughout the CNS of rodents and primates, including the regions affected in the major neurodegenerative diseases. Using this route of administration, we found that antisense oligonucleotides to superoxide dismutase 1 (SOD1), one of the most abundant brain proteins, reduced both SOD1 protein and mRNA levels throughout the brain and spinal cord. Treatment initiated near onset significantly slowed disease progression in a model of amyotrophic lateral sclerosis (ALS) caused by a mutation in SOD1. This suggests that direct delivery of antisense oligonucleotides could be an effective, dosage-regulatable means of treating neurodegenerative diseases, including ALS, where appropriate target proteins are known.