Ataluren’s proposed mechanism of action {credit}PTC Therapeutics{/credit}
A drug in clinical trials for muscular dystrophy and cystic fibrosis might not work through the molecular mechanism that scientists think it does. Although the new findings do not cast doubt on the clinical efficacy of the medication, the new experiments suggest that researchers might need to double-check that therapeutics believed to rescue normal protein production by helping parts of the cell ‘read through’ the genetic sequences actually do just that.
The drug in question, ataluren, was developed by New Jersey’s PTC Therapeutics to treat illnesses caused by nonsense mutations such as Duchenne muscular dystrophy, a disease in which disrupted production of dystrophin, a protein critical to muscle structure and stability, leads to progressive muscle deterioration. The drug has also shown clinical benefit in the 10% of cystic fibrosis patients with a mutation in the CFTR gene that causes truncated proteins and has potential for treating other ailments, including hemophilia.
Overall, about 11% of genetic mutations found in inherited diseases involve changes in the code of messenger RNA that prematurely stop protein translation to produce a dysfunctional or nonexistent protein product. But ataluren, formerly known as PTC124, was thought to work by cozying up to parts of the cell known as ribosomes and allowing them to ‘read through’ these errors and continue to make a normal protein.
The developers of ataluren had conducted experiments in human embryonic kidney cells in which the drug succeeded in reading over a mutation and restoring normal production of the enzyme firefly luciferase (FLuc), which causes cells to glow. However, two subsequent reports found evidence that ataluren boosted production of FLuc without assisting the read-through of the code for the enzyme.
In a new study published today in PLoS Biology, researchers ran additional experiments and came across more data placing the read-through mechanism in doubt. Stuart McElroy, a molecular biologist at the Drug Discovery Unit at the University of Dundee, UK, and his team tested ataluren against G418 activity, a well-documented antibiotic read-through agent, in four non-luciferase assays and found in each case that G418 rescued production of proteins but ataluren did not. Researchers also manipulated the sequence of nonsense mutations in another 12 assays and, again, found no measureable effect of read-through activity with ataluren.
