There is ample evidence that PTC Therapeutics Inc.'s lead compound ataluren promotes premature stop codon readthrough in vivo, but at least two academic groups have found that the Duchenne muscular dystrophy and cystic fibrosis therapy has no activity in in vitro assays used to measure readthrough.1,2 Resolving the discrepancy will require a better understanding of ataluren's mechanism of action and could help inform the development of next-generation therapeutics.
Many genetically inherited diseases are caused by nonsense mutations that give rise to premature termination codons (PTCs), which reduce or eliminate the production of full-length, functional protein. These include about 5%-10% of cystic fibrosis (CF) cases and 10%-15% of Duchenne muscular dystrophy (DMD) cases. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), and DMD is caused by mutations in dystrophin (DMD).
Proof of concept