Wednesday, March 5, 2008

MicroRNA Mimicry: Not All Triggers are Created Equal

In the online version of Science, Viswanathan and colleagues report on the post-transcriptionally regulated processing of the let-7 microRNA during embryonic stem cell differentiation (Viswanathan et al.: “Selective Blockade of microRNA Processing by Lin-28.” 10.1126/science.1154040). Here, they show that the RNA-binding protein Lin-28 specifically delays the maturation of the let-7 microRNA family until later stages of differentiation. This not only provides an intriguing link between the microRNA and stem cell research areas, it also further supports the role of let-7 in cell differentiation and an additional rationalization for the use of let-7 mimicry as a cancer therapeutic.

With regards to microRNA mimicry as a therapeutic in general, this and an increasing number of other studies reporting on the post-transcriptional regulation of microRNA/small RNA function, including subcellular localization, the sorting into different small RNA effector complexes, and microRNA/small RNA maturation, however also raise the question about the critical role of the choice of the right microRNA mimic in order to achieve the desired therapeutic effect.

This may be a real problem if one assumed that in order to obtain the therapeutic benefit such a microRNA mimick would have to regulate more or less the same set of target genes as its endogenous counterpart. The introduction of a synthetic siRNA-like microRNA duplex e.g. may not sufficiently recapitulate the normal sorting mechanism if this was linked to its biogenesis. Moreover, such a synthetic small RNA would likely have to be modified for pharmacological reasons, something we know may profoundly affect, and ideally reduce the off-target spectrum of an siRNA, but in the case of a microRNA mimick may be undesirable. It is also becoming increasingly clear that even a small difference in the level of a microRNA may have profound effects on its biological output.

While this represents significant scientific challenges and calls for the use of optimal models of human disease as part of the pre-clinical validation process, it also represents IP opportunities for the increasing number of microRNA therapeutics companies. It will be interesting to see whether such companies will soon try to differentiate themselves based on the specific chemistry of microRNA mimicry or a particular gene therapy approach. More so than for RNAi Therapeutics, gene therapy may enjoy here a number of unique advantages, and it would make sense for companies like Benitec, Oxford Biomedia, or Nucleonics to consider a microRNA therapeutics program.

[see also my blog on microRNA sponges for a gene therapy approach to inhibiting microRNA function]

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By Dirk Haussecker. All rights reserved.

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