Specific inhibition of Huntington's disease gene expression by siRNAs in cultured cells.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an abnormally expanded CAG repeats in exon 1 of HD gene, and consequently its gene product, huntingtin, contains an abnormally long glutamine tract. It is generally accepted that the mutant huntingtin selectively kills striatal neurons. As a first step for the development of a radical therapy toward HD, here we have investigated the effects of siRNAs directed against the HD gene in order to knock down its expression in cultured cells. Results showed that, although efficiencies of three siRNA molecules tested were slightly different from each other with cell types and origins, one siRNA (named siRNA-HDexon1), targeted against a region at immediately upstream of CAG repeats, can efficiently and specifically inhibit the expression of huntingtin exon 1-EGFP fusion construct, whereas the other two had moderate or minor effects. The siRNA-HDexon1 did also efficiently suppress the endogenous huntingtin expression in cells of human origin.