Future Uses Of siRNAS

In the 6 years since the first published report of RNAi in C. elegans, researchers have used siRNA-based technology to remove or decrease gene function in a large number of developmental systems. The ability to quickly identify what happens when gene function is removed or decreased in model systems is immensely important to our understanding of how the human body functions from early development through death. In the near future, researchers will begin to explore the feasibility of analyzing loss-of-function phenotypes upon the removal of multiple genes using siRNAs. It is clear that many genes have homologs within an organism's genome. Removal of a single member of a gene family very often produces either a milder phenotype than expected or no phenotype at all. Researchers in C. elegans have successfully used RNAi to remove multiple members of a large gene family of > 20 genes.20 In this analysis, the removal of multiple family members was required to produce a visible phenotype. This study would have been very time-consuming and difficult to reproduce if compound genetic mutations between multiple family members had been required to uncover phenotypes.

The ability to remove or decrease a specific target gene using siRNAs has been exploited in C. elegans to create a siRNA library that can be used to analyze the phenotypes of almost every gene in C. elegans. C. elegans undergo RNAi when fed bacteria producing dsRNA.97 Julie Ahringer's laboratory has created an RNAi feeding library of bacterial strains that produce dsRNA against >86% of the C. elegans genome (~16,500 individual bacterial strains, each producing dsRNA against one specific gene).9899 A number of laboratories have used this RNAi feeding library to systematically analyze the represented genes for loci that are involved in numerous aspects of development. For example, this library has been used to screen the C. elegans genome for genes involved in fat regulation, chromosome stability, longevity, and embryonic development.98 100-103 The ability to quickly screen through a large portion of the entire genome of an organism for a specific phenotype is extremely powerful. Other developmental systems have not been reported to undergo RNAi upon ingestion of dsRNA; however, libraries of siRNAs could be used to knock down gene function in a systemic manner in tissue culture or in other developmental systems (e.g., Drosophila).

Another use for RNAi lies in drug target validation. While the sequencing of the human genome has provided many novel candidate drug targets, it is often difficult to decide which target(s) to pursue. This is an important point because it is time-consuming and expensive to develop a drug that blocks a target, and then evaluate it in animal models and humans. In addition, it is clear that drugs could be developed for many additional candidate drug targets. Because of these facts, the selection of valid drug targets is a huge rate-limiting step in the development of new drugs.

RNAi provides a means to speed up the process for selecting valid drug targets among many potential targets, and it may greatly reduce the cost of drug development. Many industries are seizing RNAi as a technology and using it to test large numbers of potential drug targets. This is being done on a genome-level scale, with literally thousands of siRNAs/RNAi vectors organized in large libraries. Such libraries may be used in conjunction with robots and high-throughput screening assays, lowering the cost and the number of "failed" drugs that successfully block the target protein, but do not alleviate the disease state. This accounts for the majority of the cost in drug development, and in the end RNAi may help to lower the cost of new pharmaceuticals.

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