MicroRNAs as Therapeutic Targets

MicroRNAs are another class of endogenous cellular small RNAs that like siRNA in RNAi down-regulate target genes. Unlike siRNAs in mammalian cells, these mostly recognise their targets by incomplete base-pair complementarity. Consequently, each of the maybe 1000 microRNAs in humans has the potential to regulate a large number of target genes, with some estimates pegging that number upwards of 100. Together, these microRNAs regulate genes involved in almost all aspects of a cell’s life and some of them have been found to be involved in the pathogenesis of many diseases such as cancer and neurodegenerative conditions. It is therefore hoped that the targeting of microRNAs by antisense techniques or their over-expression in the form of siRNA-based microRNA mimics can be exploited for therapeutic purposes.

When the underlying cause or contributing factor (e.g. viral microRNAs) for a disease is a microRNA, then targeting it should stand a good chance in being an effective treatment as long as loss-of-function of that microRNA in the target cells does not have other undesirable side-effects. It appears to be, however, much more complicated when the idea is to target a microRNA as the regulator of a complex phenotype. One example of this approach is targeting microRNA-122, a highly expressed microRNA in the liver, for treating hypercholesterolemia. Down-regulation of this microRNA has been achieved in the liver in rodents and was shown to result in lower cholesterol levels. It needs to be questioned, however, if this approach is viable for chronic treatment given the importance of microRNAs in general for cell viability and the fact that microRNA-122 in particular makes up about 70% of liver microRNAs. It is interesting to note that targeting microRNAs as modulators of complex phenotypes versus RNAi Therapeutics approaches are derived from quite contrary drug development philosophies. The one philosophy (RNAi Therapeutics) holds that the best treatment with the least side-effect focuses on as few causative genes as possible. The other philosophy, however, proposes that single-gene targeting will only be successful in few instances and the best drugs are those that affect multiple targets. As such many of the small molecule inhibitors on the market today are now known to be actually much less specific than intended and their off-target effects contribute to the therapeutic outcome.

Four investing purposes, four companies that stand to benefit from the development of microRNA-based therapeutics come to mind: Alnylam (ticker: Alny), ISIS (ticker: Isis), Rosetta Genomics (ticker: Rosg), and Asuragen (privately held). Although many more microRNAs exist, Alnylam’s co-founder Tuschl identified the first 120 microRNAs in humans, and these are therefore likely to be amongst the most important in human biology. Alnylam partnered these microRNAs with ISIS Pharmaceuticals which owns many of the fundamental antisense patents required for the targeting of microRNAs. In addition to developing similar microRNA-based therapeutics, Rosetta and Asuragen (a privately-held company that was spun off from Ambion when it was acquired by ABI) are two companies that both expect to generate early revenues through the development of microRNA-based diagnostics, e.g. for the classification of cancers. In addition to their own discovered and characterised microRNAs, they will therefore have to pursue a prudent licensing policy to secure their freedom to operate.

While it is already obvious that microRNAs are extremely important for human gene regulation, much more work remains to be done to confidently identify suitable targets. Fortunately, much of this work is already being undertaken due to the immense interest in microRNAs in biology. In the meantime, let-7 in cancer and microRNA-122 for the treatment of HCV and hypercholesterolemia may lead the way in showing the promise of microRNA-based therapeutics.