Huntington's disease is a dominantly inherited neurodegenerative disorder that results from expanded polyglutamine (polyQ) repeats in the huntingtin protein (HTT). This leads to progressive striatal and cortical neurodegeneration and associated motor, cognitive and behavioural disturbances. Reducing the expression of the mutant HTT gene using RNA interference (RNAi) has emerged as a promising treatment for this fatal neurodegenerative disorder, according to a new report in the Proceedings of the National Academy of Sciences USA.

Previous attempts to develop therapeutic interventions for Huntington's disease have focused on targeting the downstream effectors of HTT expression. However, until now, there have been no efforts to directly target the underlying mutant gene.

Davidson and colleagues injected vectors that encode short hairpin RNA sequences into a transgenic mouse model of Huntington's disease. This resulted in reduced expression of mutant human HTT in the striatum and marked improvements in motor and neuropathological abnormalities. The authors suggest that the hairpin sequence could be further optimized according to more recently issued guidelines, which might lead to greater therapeutic benefit.

In this study, RNAi affected the expression of mutant human HTT but not normal mouse Htt owing to differences in the mouse and human genes. However, if this method were used in human patients, the expression of both the normal and the mutated copies of the gene would be reduced, which raises the interesting question of whether reduced expression of both normal and mutated HTT could be tolerated in humans. This question needs to be tackled before RNAi can be tested therapeutically in humans with Huntington's disease. Nevertheless, these results provide encouraging evidence that gene silencing techniques could be developed to directly target the underlying genetic abnormality in Huntington's disease, and, potentially, other neurodegenerative disorders.