>> Box 1 | The many faces of antisense therapy
FROM THE FOLLOWING ARTICLE:
The long march of antisense
Dan Jones
Nature Reviews Drug Discovery 10, 401-402 (June 2011)
doi:10.1038/nrd3474
Antisense is often used broadly to describe all approaches that use RNA or DNA to block gene expression as a result of complementary base pairing with a target RNA molecule in the cell. Yet, this broad definition actually covers a range of mechanisms and activities. 'Classic antisense' molecules — such as Isis Pharmaceuticals' mipomersen, Genta's oblimersen and OncoGenix/Teva's OGX-011 — bind to target mRNAs, induce ribonuclease H (RNaseH)-dependent degradation and block protein translation, explains Agrawal.
Other antisense agents, however, can work through various other mechanisms. AVI BioPharma, for instance, works with phosphorodiamidate morpholino oligomers (PMOs). Although PMOs can prevent the expression of target mRNAs (but without induction of RNaseH degradation), they can also be used to alter the splicing of pre-mRNAs. AVI BioPharma is using such splice-switching oligomers to achieve exon skipping to create functional proteins in Duchenne muscular dystrophy, and their lead candidate, eteplirsen (AVI-4658), has completed Phase I/II trials in this indication.
Santaris Pharma, meanwhile, is working with locked nucleic acids (LNAs), which are synthetic chemical analogues of RNA that can bind to different types of RNA targets. LNAs can inhibit expression of target mRNAs via induction of RNaseH activity, but Santaris's most advanced LNA compound instead targets microRNA; miravirsen, which is due to enter Phase II trials for hepatitis C virus (HCV) in September 2011, inhibits miR-122, a liver-specific microRNA that is essential for HCV replication.
Idera Pharmaceuticals has also recently reported the creation of a novel class of compounds they call gene-silencing oligonucleotides (GSOs; J. Med. Chem.54, 3027–3036; 2011) — single-stranded DNA or RNA molecules that can target mRNAs and microRNAs, and seem to modulate gene expression via RNA interference (RNAi) activity. Whereas most RNAi-inducing agents are double-stranded, the fact that GSOs are single-stranded may be advantageous in terms of their delivery.
Altman, meanwhile, is working on morpholino oligonucleotides that bind to target mRNAs and activate degradation via RNaseP rather than RNaseH. << |
