"Each day you see major, significant publications on the roles of microRNAs in regulating pathways of genes involved in disease aetiology," says John Maraganore of Alnylam Pharmaceuticals in Cambridge, Massachusetts. Alongside the research into the mechanisms and roles of microRNA (miRNA) in disease, researchers are now starting to look at the potential of miRNA-based therapeutics.

Regulus Therapeutics in Carlsbad, California, is one of the first companies to be founded entirely for the development of miRNA-based therapeutics. It was formed in September as a joint venture between Alnylam and Isis Pharmaceuticals in Carlsbad. "We recognized that miRNAs were becoming a potential therapeutic opportunity," says Frank Bennett, senior vice-president of research at Isis, "but we also recognized that it was difficult for both companies to input the resources that were warranted." After much discussion, the two firms agreed to supply miRNA assets and core technologies to Regulus.

C. KELLY, B. ORR & M. B. HOLL

Testing of technologies, such as dendrimers, for delivering siRNAs may pave the way for miRNA drugs.

Regulus is taking two approaches to the development of miRNA-based therapeutics. "The most advanced approach is inhibiting the function of an endogenous miRNA in cells," says Bennett. This uses a synthetic oligonucleotide to target the miRNA for silencing.

Although this is different from siRNA, as the miRNA is the target not the therapeutic agent, Bennett thinks that much of the technology developed for targeting mRNAs with siRNA is directly translatable to the targeting of miRNAs with oligonucleotides. And he notes that using oligonucleotides will also minimize any 'off-target' effects. "These oligonucleotides are very specific — even a single base mismatch will cause the oligo to lose activity," he says.

The second approach involves replacing miRNAs in or delivering them to cells, which Bennett says is similar to the current approach for siRNAs. The first applications here might be replacing miRNAs that are missing from disease-associated cells but present in a normal cells, which happens in some cancers, or augmenting naturally occurring miRNAs.

Although experience of siRNAs will help this nascent field, there is one unique issue in miRNA biology that researchers will have to address: miRNAs can inhibit tens to hundreds of genes at a time. Scores of researchers, both inside and outside academia, are now working to understand exactly how this regulation by miRNAs occurs. "You can use specific chemical modifications to the miRNA to limit that potential," says Bennett, "but it is still present."

Many researchers and companies now think miRNA-based therapeutics hold great promise for the future. And although some companies are waiting in the wings for more information on their basic mechanisms of action, others including Merck, Santaris Pharma of H?rsholm, Denmark, Rosetta Genomics in Rehovot, Israel, and Actigenics of Maurens-Scopont, France, are actively involved in miRNA research and development.

N.B.