Small RNA: can RNA interference be exploited for therapy?

Context RNA interference (RNAi) is the sequence specific gene-silencing induced by double-stranded: RNA (dsRNA), and gives information about gene function quickly, easily, and inexpensively. The use of RNAi for genetic-based therapies is widely studied, especially in viral infections,, cancers, and inherited genetic disorders. RNAi has been used to make tissue-specific knockdown mice for studying,gene function in a whole animal. Combined with genomics data, RNAi-directed gene-silencing could allow functional determination of any gene expressed in a cell or pathway. The term RNAi came from the discovery that the injection of dsRNAs into Caenorhabditis elegans interferes with the expression of specific genes containing a complementary region to the delivered dsRNA. Although stalled for a time by the non-gene-specific interferon; response elicited by dsRNA molecules longer than about 30-nucleotides in mammalian cells, Tom Tuschl's group found that, transfection of synthetic 21-nucleotide small-interfering RNA, (siRNA) duplexes were highly selective and sequence-specific inhibitors of endogenous genes. Starting point siRNA expression has been studied with siRNA from plasmid and viral vectors that efficiently deliver siRNAs into both dividing and non-dividing cells, stem cells, zygotes, and their differentiated progeny. A collection of RNA interference vectors that suppress 50 human de-ubiquitinating enzymes allowed Thijn Brummelkamp and colleagues to study this gene family and to-identify de-ubiquitinating enzymes in cancer-relevant pathways (Nature 2003; 424: 797-801). These researchers found that the familial cylindromatosis tumour suppressor gene, (CYLD), previously of unknown function, could enhance the activation of the transcription factor NF-kappaB, leading to increased resistance to apoptosis. They have now started to-investigate the use of CYLD inhibitors in clinical trials. Where next The ability to efficiently and stably produce and deliver sufficient amounts of siRNA to the proper target; tissues require refinement before this new technology can be tried clinically. Initial in-vivo studies reported effective trans gene suppression in adult mice by chemically synthesised siRNAs. More recently many researchers have used plasmid and viral vectors for transcription of short-hairpin RNAs, both in vitro and in vivo. With these expression systems, gene expression was more stably inhibited than with the transient; knockdown recorded with chemically synthesised siRNA. Human trials exploiting these latest findings are likely to soon follow.