Wang Yu-Lai, Liu Wanzhao, Wada Etsuko, Murata Miho, Wada Keiji, Kanazawa Ichiro
Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo 187-8502, Japan.
Neurosci Res. 2005 Nov;53(3):241-9. doi: 10.1016/j.neures.2005.06.021. Epub 2005 Aug 10.
Huntington's disease (HD) is an autosomal dominant inheritable neurodegenerative disorder currently without effective treatment. It is caused by an expanded polyglutamine (poly Q) tract in the corresponding protein, huntingtin (htt), and therefore suppressing the huntingtin expression in brain neurons is expected to delay the onset and mitigate the severity of the disease. Here, we have used small interfering RNAs (siRNAs) directed against the huntingtin gene to repress the transgenic mutant huntingtin expression in an HD mouse model, R6/2. Results showed that intraventricular injection of siRNAs at an early postnatal period inhibited transgenic huntingtin expression in brain neurons and induced a decrease in the numbers and sizes of intranuclear inclusions in striatal neurons. Treatments using this siRNA significantly prolonged model mice longevity, improved motor function and slowed down the loss of body weight. This work suggests that siRNA-based therapy is promising as a future treatment for HD.
亨廷顿舞蹈症（HD）是一种常染色体显性遗传的神经退行性疾病，目前尚无有效治疗方法。它由相应蛋白质亨廷顿蛋白（htt）中多聚谷氨酰胺（poly Q）序列的扩增引起，因此抑制脑神经元中亨廷顿蛋白的表达有望延缓疾病的发作并减轻其严重程度。在此，我们使用针对亨廷顿基因的小干扰RNA（siRNA）来抑制HD小鼠模型R6/2中的转基因突变亨廷顿蛋白表达。结果显示，在出生后早期经脑室注射siRNA可抑制脑神经元中的转基因亨廷顿蛋白表达，并使纹状体神经元内核内包涵体的数量和大小减少。使用这种siRNA进行治疗可显著延长模型小鼠的寿命，改善运动功能并减缓体重减轻。这项研究表明，基于siRNA的疗法有望成为未来治疗HD的方法。
