Start Making Sense - Exon Skipping & Nonsense Suppression
Further prospects
Hot on the heels of this Phase II project is a rival Phase Ib/II project, from a well-established US company with strong credentials in the antisense field, AVI BioPharma. AVI has had a long and chequered history, having been founded at the dawn of the biotechnology industry in 1980, and somehow surviving over the years despite never yet having brought a drug to market. AVI has recently focused its resources on developing antisense oligonucleotides directed against both mRNA and precursor mRNA, for precise control of targeted gene expression; the advent of this new application of antisense oligonucleotides could not have come at a better time for the company's fortunes. AVI is one of the few established antisense companies to have jumped on the exon skipping bandwagon, especially as its propriety splice switching oligomer (SSO) technology seems supremely well-suited for this purpose.
AVI's lead anti-DMD project is AVI-4658, an SSO which, like PRO-051, targets exon-51 of the dystrophin gene. Preliminary results from the current Phase Ib/II trial involving systemic administration of AVI-4658 in 16 patients have shown no major drug-related adverse events, and previous Phase I trials with localised delivery detected robust increases in dystrophin expression following treatment. As with the Prosensa drug, success or failure of the strategy will depend on the true efficacy against DMD on a systemic basis, so the forthcoming results of Phase II trials for both products will be crucial.
Further commercial development in exon skipping is still thin on the ground. Aside from follow-up projects from both Prosensa and AVI, only Amsterdam Molecular Therapeutics (AMT) has disclosed an exon skipping R&D project - this one using a gene therapy vector expressing an antisense small nuclear RNA (snRNA), rather than a synthetic oligonucleotide. AMT expects to enter the clinic with this candidate, AMT-080, in 2012.
A side-effect of the rapid pace of these therapeutic candidates has been a belated and rather unexpected mini-renaissance in the previously flagging field of antisense therapeutics. Since the launch of a lone antisense drug by ISIS Pharmaceuticals over a decade ago (Vitravene for cytomegalovirus infection in 1998, recently withdrawn from the market for strategic reasons), only a handful of antisense therapies have struggled as far as Phase III trials, despite a huge research input over the years. It was beginning to look as though the advent of the generally more robust and controllable technology of RNA interference was likely to supersede antisense technology in the long run, both in the research laboratory and in therapeutics. However, the advent of exon skipping, which so far has been entirely dependent on antisense technology, gives perhaps the strongest chance yet of success from this sector.
