Machida Yoko, Okada Takashi, Kurosawa Masaru, Oyama Fumitaka, Ozawa Keiya, Nukina Nobuyuki
Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
Biochem Biophys Res Commun. 2006 Apr 28;343(1):190-7. doi: 10.1016/j.bbrc.2006.02.141. Epub 2006 Mar 3.
Huntington disease (HD) is a fatal progressive neurodegenerative disorder associated with expansion of a CAG repeat in the first exon of the gene coding the protein huntingtin (htt). Although the feasibility of RNA interference (RNAi)-mediated reduction of htt expression to attenuate HD-associated symptoms is suggested, the effects of post-symptomatic RNAi treatment in the HD model mice have not yet been certified. Here we show the effects of recombinant adeno-associated virus (rAAV)-mediated delivery of RNAi into the HD model mouse striatum after the onset of disease. Neuropathological abnormalities associated with HD, such as insoluble protein accumulation and down-regulation of DARPP-32 expression, were successfully ameliorated by the RNAi transduction. Importantly, neuronal aggregates in the striatum were reduced after RNAi transduction in the animals comparing to those at the time point of RNAi transduction. These results suggest that the direct inhibition of mutant gene expression by rAVV would be promising for post-symptomatic HD therapy.
亨廷顿舞蹈症（HD）是一种致命的进行性神经退行性疾病，与编码亨廷顿蛋白（htt）的基因第一外显子中CAG重复序列的扩增有关。尽管有研究表明RNA干扰（RNAi）介导的htt表达降低以减轻HD相关症状具有可行性，但HD模型小鼠出现症状后的RNAi治疗效果尚未得到证实。在此，我们展示了在疾病发作后，重组腺相关病毒（rAAV）介导的RNAi导入HD模型小鼠纹状体的效果。与HD相关的神经病理学异常，如不溶性蛋白质积累和DARPP - 32表达下调，通过RNAi转导成功得到改善。重要的是，与RNAi转导时间点相比，RNAi转导后动物纹状体中的神经元聚集体减少。这些结果表明，rAVV对突变基因表达的直接抑制对于HD症状出现后的治疗具有前景。
