Wednesday, May 23, 2007

RNAi-related Phenomena and their Relevance for RNAi Therapeutics

Following the discovery of small RNAs as part of RNAi and a growing range of other classes of small RNAs, it soon became clear that RNAi is just one part of a network of small RNA-directed cellular processes. MicroRNAs which are involved in a wide range of post-transcriptional gene regulatory processes are probably best known, but small RNAs have also been found to play roles from chromatin silencing to chromosome rearrangement. The existence and importance of these functions can vary greatly between different organisms. Nevertheless within a given organisms these functions are interconnected by partly making use of overlapping sets of proteins or proteins from the same gene families.

One concern in the development of RNAi Therapeutics for human use would therefore be that small RNAs may engage unwanted small RNA-directed processes. In humans, the microRNA pathway and RNAi-related chromatin silencing are probably the main concerns. The microRNA pathway is actually the main reason for off-targeting in RNAi experiments, and I have outlined potential strategies about how to selectively engage RNAi and not the microRNA pathway in earlier posts. Silencing chromatin through the introduction of small RNAs in human cells, however, is much more controversial. Even if we assume that this pathway does exist, then according to published papers you would probably need more than one small RNA targeting the same gene. Moreover, one would likely have to introduce small RNAs targeted to the promoter region and not the transcribed gene as siRNAs do in RNAi. A possibly related interesting phenomena that was reported recently is RNA activation, or RNAa. In these examples small RNAs targeted to certain promoters actually upregulated gene activity. It is clear, however, that not any small RNA will have this effect, and again siRNAs targeted towards the transcribed genes are not likely to result in promoter activation.

Alone from the fact that there are 4 Argonaute genes and additional related Piwi genes, and new classes of small RNAs being discovered on almost a monthly basis, one can expect the RNAi-related universe to expand ever more. However, largely based on microarray studies, it seems that exogenous small RNAs almost exclusively engage the RNAi machinery and the related microRNA pathway. It is therefore a focus on the microRNA pathway that is most likely to ultimately improve the specificity of RNAi Therapeutics.

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By Dirk Haussecker. All rights reserved.

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