Therapy Analysis - microRNA
microRNA as a therapeutic target
The function of a cell’s miRNA population may be compared to a ‘master-switch’ – but one involved in fine tuning rather than a crude on-off mechanism. Following transcription, the fate of a nascent mRNA transcript is not just dependent on its stability – it can be prey to one or more of the population of miRNAs within that particular cell, or none. The result is that even highly-transcribed genes may never be translated, their levels may be up- or down-regulated highly precisely, or translation may be allowed to proceed unhindered. Thus, in theory, inhibition of a particular miRNA linked to disease can remove the block against expression of a therapeutic protein – and conversely, administration of a miRNA mimetic can boost the endogenous miRNA population repressing a detrimental gene. However, just to complicate things, one must remember that blocking or boosting one miRNA may impact on expression of many genes rather than just one, some in completely different tissues or affecting entire pathways – giving a whole new dimension to the idea of ‘off-target effects’. Clearly this new branch of drug development requires a radical new way of thinking.
This last fact has not deterred a pioneering group of specialist companies from embracing the new development and tackling the finicky problem of creating viable therapeutic candidates – some miRNA inhibitors and some miRNA mimetics – in fields as diverse as cancer, cardiovascular disease, neurological disorders and viral infection. The drug candidates in question are all DNA-based therapeutics, since no anti-miRNA small molecules are yet on the radar. The new players in this select area have been fired up, maybe, by the high-speed development of therapeutic siRNAs – with the first siRNA candidate (bevasiranib sodium for wet AMD) reaching Phase III within four short years of initial research – and, amazingly, the first miRNA inhibitor has already reached the clinic, with more set to follow (Table 1).
The company with the honour of the first-to-clinic candidate is a Danish company with well-established credentials in the therapeutic DNA field – Santaris Pharma. The company, formed in 2003 by the long-established players Cureon and Pantheco (founded in 1998-99), is focused on the therapeutic applications of its proprietary DNA analogues, particularly its Locked Nucleic Acid (LNA) technology, which produces next-generation antisense oligonucleotide drugs with very high specificity and potency. Adapting this technology to target a miRNA, rather than a conventional gene, is one attractive route to generating miRNA inhibitors. This has resulted in a class of compounds referred to by Santaris as ‘LNA-antimiRs’, which function via an advanced antisense mechanism to block endogenous miRNAs. The lead LNA-antimiR is SPC-3649, which targets the liver-specific miRNA 122. This miRNA has the intriguing effect of binding to hepatitis-C virus (HCV) RNA and stimulating its replication – and thus blocking it opens up a brand-new avenue of HCV treatment. It has not escaped Santaris’ attention that this target miRNA is also involved in regulating genes implicated in hypercholesterolaemia – and indeed in vivo murine studies have confirmed the potential of SPC-3649 as a cholesterol-lowering agent. GlaxoSmithKline has an option on this project, which one presumes it must be monitoring with quite some interest.
Although Santaris can claim to be the first past the post to the clinic, it is by no means the longest-established specialist company in the miRNA arena. This distinction belongs to Rosetta Genomics, based in Israel and established in 2000 at the birth of the miRNA revolution. An early and far-sighted focus on high-throughput discovery and validation of miRNA sequences resulted in the integrated scanning of the entire human genome for miRNAs in 2005, and the company has now validated around 400 of the known human miRNAs. Rosetta has divided its interests between the development of miRNA-based diagnostic systems for cancer, already a lucrative area, and the development of its own pipeline of miRNA-based therapeutics, with both miRNA inhibitors and mimetics under scrutiny as drug candidates. The company has a formidable IP position, covering miRNA validation methodologies, specific sequences and therapeutic applications.
