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RNAi Still Has Far to Go

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RNA interference has generated great excitement within the global research community as well as the biotech business sector due to its potential applications in functional genomics, drug screening, target validation, and therapeutic development. I have no doubt that within 10 years RNAi will emerge as a routine technique to study the problems in biomolecular medicine and potentially to treat diseases. But there is much to understand about the technology before that happens.

RNAi has already been used successfully in a variety of experiments, for both gene function analysis and for therapeutic development.

For instance, RNAi has been applied to inhibit the replication of viruses including Hepatitis B, Hepatitis C, HIV, SARS, RSV, Dengue, influenza, respiratory syncytial virus, and poliovirus. RNAi has also been used to study cardiovascular and neuronal diseases.

In addition, there is great promise in marrying RNAi with microarray technology to obtain snapshots of gene expression within cells — a powerful means of analyzing biological cellular pathways. RNAi results could be combined with data obtained from a robust microarray analysis to further validate gene expression followed by real-time PCR.

In a recent study of asbestos-induced mesothelioma, scientists identified an upregulated proto-oncogene (fra-1) by microarray analysis, and its functional validation using RNAi helped them to identify genes that are causally linked to fra-1 with genes governing cell motility and tumor invasion. Inhibition of fra-1 signaling pathways may be an emerging therapeutic strategy for malignant mesothelioma. This particular strategy can be extended to identify linking molecules in the signaling pathways, which could in turn lead to the discovery of drug or therapeutic molecules.

In fact, combining microarray analysis with RNAi provides an excellent means to identify, define, and characterize the role of specific genes that are upregulated in disease states. Beyond the ability to silence individual genes, it is necessary to determine the effect of knockdowns on a particular pathway. Gene, protein, and phenotype profiling are of great importance in establishing the effects of knockdown of a specific gene. RNAi may complement standard knockout approaches and accelerate studies of gene function in living mammals.

Genome-wide microarrays containing 43,000 DNA elements or 36,000 genes that have been adopted recently have been shown to be highly specific when used with RNAi at relatively low concentrations. But we know that higher concentrations of siRNAs induce non-specific changes in gene expression levels, and improperly designed siRNAs may cross-react with targets of limited sequence similarity. In fact, before we go on, we need to understand more fundamentally how RNA interference works. There is still too much mystery surrounding the design of siRNAs, their specificity and efficacy, and how they are delivered into cells.

Only once all of these issues are addressed will the vision of those who promote RNAi as a target validation tool and those seeking to steer RNAi down therapeutic avenues be realized. With these rate-limiting factors solved, RNAi will be a nice complementary technique to microarrays for validating the results obtained from massive genome-wide and high-throughput screenings.

Opposite Strand is a forum for readers to express opinions and ideas about trends and issues in genomics.

 

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