PubMed · 12087418
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2002. Interfering HIV.. https://doi.org/10.1038/ni0702-609
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RNA silencing, which is termed post-transcriptional gene silencing in plants, is an RNA degradation process through sequence-specific nucleotide interactions induced by double-stranded RNA. In plants, RNA silencing not only serves as a component of the defense mechanism, but also participates in the regulation of endogenous gene expression in a variety of developmental processes. This review elaborates the current progress on the understanding of the molecular basis of RNA silencing including a mechanistic link between the regulation of microRNA and RNA silencing. The practical use of RNA silencing as a reverse genetics approach in plant functional genomics is also discussed.
Progress in the understanding of RNA biology has brought into focus the prospect of using RNA-based therapeutics as a novel approach to treat human disease. In particular, following the discovery of the RNA interference (RNAi) pathway, the emergence of technology based on small interfering RNA (siRNA) now offers a powerful and highly specific tool for therapeutic gene silencing. Many neurological diseases, including neurodegenerative disorders, tumours and retinal disease are likely candidates to benefit from such advances. The challenges ahead will be to identify appropriate disease gene targets and, crucially, to understand the biological parameters that determine safe, precise and effective delivery and function of RNA-based therapeutic molecules within the unique environment of the nervous system.
The type 1 insulin-like growth factor receptor (IGF1R) is often overexpressed by tumors and mediates growth and apoptosis protection. We previously showed that antisense reagents complementary to the IGF1R translation start site enhance radio- and chemosensitivity and impair Atm function. However these agents induce relatively modest IGF1R down-regulation and affect insulin receptor levels. To identify alternative sites for molecular targeting, we utilized scanning oligonucleotide arrays to probe the secondary structure of IGF1R mRNA. This strategy enabled selection of antisense oligonucleotides that generated high heteroduplex yield with IGF1R but not insulin receptor transcripts. Antisense oligonucleotides that hybridized strongly to IGF1R mRNA caused IGF1R down-regulation within intact tumor cells, whereas weakly hybridizing oligonucleotides were inactive. Furthermore, the ability of small interfering RNAs (siRNAs) to block IGF1R expression correlated with the accessibility of the target sequence within the transcript. Thus, siRNAs corresponding to weakly hybridizing oligonucleotides caused minor IGF1R down-regulation, whereas siRNAs homologous to accessible targets induced profound sequence-specific IGF1R gene silencing, blocked IGF signaling, and enhanced tumor cell radiosensitivity. This indicates that secondary structure in the target transcript has a major effect on siRNA efficacy. These findings have implications for siRNA design and suggest that IGF1R-targeting agents incorporating this mode of action have potential as anticancer therapy.