Start Making Sense - Exon Skipping & Nonsense Suppression
Nonsense suppression
However, this technology now has major competition from a quite unexpected direction - the field of conventional small molecule therapeutics, and a rather remarkable single drug candidate. Nonsense suppression, or stop codon read-through, has been shown as an interesting "side-effect" of certain small molecules, including the marketed antibiotic gentamicin. These compounds can induce ribosomes to override a premature stop codon, and read through to generate a full-length protein, by a mechanism that is not yet fully understood. Commercial R&D has been restricted to a single development candidate, ataluren, from the US company PTC Therapeutics (standing for post-transcriptional control). The entry of this lone candidate compound into commercially-focused R&D would not necessarily attract attention - except that ataluren has now reached as far as Phase III for cystic fibrosis, with Phase II trials in progress for DMD, BMD and both haemophilia-A and -B, and approval for DMD mooted for as soon as 2012. Genzyme has collaborated on this project since 2008, with responsibility for commercialization outside North America.
Although restricted to the smaller subset of genetic diseases caused by premature stop codon mutations, the broad applicability of this single drug cannot be denied. The fact that it is also administered orally (including as a vanilla-flavoured powder mixed with water or milk) increases its marketability. Phase II results so far have shown significant improvements in respiratory symptoms and body weight in cystic fibrosis patients, and reported improvements in muscle strength and endurance levels in DMD patients. Again, more definitive clinical results are awaited before this drug can be hailed as a true breakthrough in treatment - results from the various ongoing Phase II trials are expected throughout 2010, and the Phase III trial is expected to report in early 2012.
