Human Molecular Genetics, 2002, Vol. 11, No. 2 175-184
© 2002 Oxford University Press
Rescue of polyglutamine-mediated cytotoxicity by double-stranded RNA-mediated RNA interference
Medical Genetics Branch, National Human Genome Research Institute and 1Neurogenetics Branch, National Institute of Neurological Diseases, National Institutes of Health, Bethesda, MD, USA and 2Carnegie Institution of Washington, Department of Embryology, Baltimore, MD, USA
RNA interference (RNAi) is a mechanism that appears to control unwanted gene expression in a wide range of species. In Drosophila, RNAi is most effectively induced by double-stranded RNAs (dsRNAs) of over ~80 nucleotides (nt) and in mammalian cells an RNAi-like inhibition of gene expression has been shown to be mediated by dsRNAs of 
21–23 nt. To test if RNAi can be used to specifically down-regulate a human disease-related transcript we have used Drosophila and human tissue culture models of the dominant genetic disorder spinobulbar muscular atrophy (SBMA). A variety of different dsRNAs were assessed for the ability to inhibit expression of transcripts that included a truncated human androgen receptor (ar) gene containing different CAG repeat lengths (16–112 repeats). In Drosophila cells, dsRNAs corresponding to non-repetitive sequences mediated a high degree of sequence-specific inhibition, whereas RNA duplexes containing CAG repeat tracts only induced gene-specific inhibition when flanking ar sequences were included; dsRNAs containing various lengths of CAG repeats plus ar sequences were unable to induce allele-specific interference. In mammalian cells we tested sequence-specific small dsRNAs of 22 nt; these rescued the toxicity and caspase-3 activation induced by plasmids expressing a transcript encoding an expanded polyglutamine tract. This study demonstrates the feasibility of targeting a transcript associated with an important group of genetic diseases by RNAi.
+ To whom correspondence should be addressed at: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, 10 Center Drive, 10C103, Bethesda, MD 20892, USA. Tel: +1 301 435 2833; Fax: +1 301 496 7184; Email: ncaplen@nhgri.nih.govPresent address:Richard A. Morgan, Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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