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rAAV-mediated shRNA ameliorated neuropathology in Huntington disease model mouse
Yoko Machida1, Takashi Okada, Masaru Kurosawa
1Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
Insights
RNA interference (RNAi) therapy delivered via recombinant adeno-associated virus (rAAV) successfully reduced mutant huntingtin (htt) protein and neuronal aggregates in a mouse model of Huntington disease (HD) after symptom onset.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Huntington disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (htt) gene.
- RNA interference (RNAi) offers a potential therapeutic strategy by reducing htt expression.
- The efficacy of post-symptomatic RNAi treatment in HD models requires further investigation.
Purpose of the Study:
- To investigate the effects of RNAi-mediated htt reduction in the striatum of HD model mice after disease onset.
- To assess the therapeutic potential of recombinant adeno-associated virus (rAAV)-delivered RNAi for Huntington disease.
Main Methods:
- Delivery of RNAi using rAAV into the striatum of HD model mice post-symptomatic onset.
- Evaluation of neuropathological markers, including insoluble protein accumulation and DARPP-32 expression.
- Assessment of neuronal aggregate reduction following RNAi transduction.
Main Results:
- RNAi transduction successfully ameliorated HD-associated neuropathological abnormalities.
- Insoluble protein accumulation and DARPP-32 down-regulation were improved by RNAi treatment.
- A significant reduction in striatal neuronal aggregates was observed after RNAi transduction compared to pre-treatment levels.
Conclusions:
- Direct inhibition of mutant huntingtin gene expression using rAAV-mediated RNAi is a promising therapeutic approach for Huntington disease.
- This strategy shows potential for treating Huntington disease even after the onset of symptoms.
- Post-symptomatic RNAi therapy could offer a viable treatment option for Huntington disease patients.
Abstract:
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.
