New Frontiers: MicroRNAs and Human Disease
MicroRNAs are a large class of small RNAs, typically 19-24 nucleotides in length, and are believed to regulate a significant portion of our genes with diverse roles ranging from development to cell signaling. The natural counterparts of therapeutic small RNAs or siRNAs, microRNAs are an abundant class of regulatory RNAs thought to control about one third of our genes.
It is therefore not surprising that during disease, changes in the pattern of microRNAs will occur with some being indicative of treatment outcome and disease progression. Arguably even more exciting than their diagnostic value is the mounting evidence that directly implicates microRNAs in a number of diseases, most notably cancer. There is, consequently, increased interest in manipulating microRNA function for therapeutic purposes.
One approach is to mimic microRNA activity by introducing microRNA "mimics"containing the same genetic information as the natural microRNA. This should be of therapeutic value where the loss of microRNA function contributes to or causes a disease, or where the addition of a "good" microRNA will improve a condition.
For example, by adding more of a microRNA known as let-7, it has been possible to halt cancer cells from further multiplying. Since microRNA mimics in many ways resemble an RNAi therapeutic, their development as a therapeutic modality will be greatly benefitted from progress in the RNAi therapeutics field.
Another complementary approach to using microRNAs for therapy is to inhibit the activity of disease-associated microRNAs. This can be achieved by employing antisense oligonucleotides that, based on sequence complementarity, will bind to and consequently inactivate microRNA function.
Studies from Alnylam and those of others have supported the viability of this strategy by demonstrating efficient and specific microRNA inhibition using "antagomirs" in animal models. Such studies show that inhibiting a highly abundant miRNA in the liver, microRNA-122, not only lowered the level of LDL-cholesterol in the blood, but did so without any adverse effects on the animal. High LDL-cholesterol is a major risk factor for cardiovascular disease and additional strategies to lowering it are urgently needed for patients that do not achieve their cholesterol goals.
MicroRNA-122 inhibition also holds promise for the treatment of Hepatitis C Virus (HCV) infection. Underlining the central importance of non-coding RNAs in many cellular processes, some viruses of major medical importance such as HCV and HIV have learned to make use of and even come to depend on microRNAs found in the host cell. Accordingly, antisense-mediated inhibition of miRNA-122 negatively impacts HCV replication and this result may lay the foundation for novel HCV antivirals. Still other viruses encode and produce their own microRNAs, usually as a means to avoiding recognition by the immune system. Sometimes, as is the case for some Herpes viruses, these microRNAs are the only visible manifestation of an infection and therefore the only therapeutic targets.
Clearly, the exponential growth of knowledge on microRNA function as part of a global research effort combined with the development of potent therapeutic technologies will make drug development centered on miRcroNAs a vibrant field in the years to come. To this end, Alnylam and Isis Pharmaceuticals Inc. have formed Regulus Therapeutics LLC, a joint venture focused on the discovery, development and commercialization of miRNA therapeutics.
