rAAV-mediated shRNA ameliorated neuropathology in Huntington disease model mouse.
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.
Machida
Yoko
Y
Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
Okada
Takashi
T
Kurosawa
Masaru
M
Oyama
Fumitaka
F
Ozawa
Keiya
K
Nukina
Nobuyuki
N
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D003342:Corpus Striatum / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D015316:Genetic Therapy / Q000379:methods*; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000473:pathology / Q000628:therapy*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D015854:Up-Regulation
D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering