rAAV-mediated shRNA ameliorated neuropathology in Huntington disease model mouse
rAAV-mediated shRNA ameliorated neuropathology in Huntington disease model mouse
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DOI：
10.1016/j.bbrc.2006.02.141
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发表时间：
2006-04-28
影响因子：
3.1
通讯作者：
Nukina, N
中科院分区：
文献类型：
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作者：
Machida, Y;Okada, T;Nukina, N
亨廷顿病（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（hit）的基因的第一外显子中CAG重复序列的扩增有关。尽管提出了RNA干扰（RNAi）介导的hit表达减少以减轻HD相关症状的可行性，但尚未证实HD模型小鼠中症状后RNAi治疗的效果。在这里，我们显示了重组腺相关病毒（rAAV）介导的RNAi递送到HD模型小鼠纹状体发病后的效果。与HD相关的神经病理学异常，如不溶性蛋白积累和DARPP-32表达下调，通过RNAi转导成功地改善。重要的是，与RNAi转导的时间点相比，在动物中RNAi转导后纹状体中的神经元聚集体减少。这些结果表明，通过rAVV直接抑制突变基因表达将有望用于症状后HD治疗。(c)2006年爱思唯尔公司All rights reserved.
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 (hit). Although the feasibility of RNA interference (RNAi)-mediated reduction of hit 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. (c) 2006 Elsevier Inc. All rights reserved.