Problems Plague PTC Therapeutics Drug, Ataluren

A paper just out in PLOS Biology is unable to confirm that the drug Ataluren is able to read through premature stop codons (nonsense mutations, for example 255X, 168X). The drug is already in clinical trials for Cystic Fibrosis and Duchenne's muscular dystrophy. The new data highlights not only the difficulties in drug development and the importance of rigorous clinical trials but also the need for independent confirmation of data. This drug is currently being tested in a mouse model of Rett Syndrome with a 168X mutation.

Drug Mechanism Questioned
A study fails to confirm that the small molecule PTC124, in development for multiple genetic disorders, aids in read-through of premature stop codons.
By Kate Yandell

An in vitro study of PTC124, a drug in clinical trials for the treatment of cystic fibrosis and several other genetic disorders, has some scientists wondering whether the molecule works the way its developers say it does.

PTC124 is intended to treat disorders, including some cases of cystic fibrosis and Duchenne muscular dystrophy, that stem from mutations that cause stop codons to erroneously appear in critical gene transcripts, thereby inhibiting translation of vital proteins. The new study, published today (June 25) in PLOS Biology, demonstrates that PTC124 does not promote read-through of such premature stop codons, or “nonsense” mutations, in several reporter assays done using a human cell line.

“The paper is well designed and carefully executed, and the dataset is unambiguous,” said Bryan Roth, a professor of pharmacology at the University of North Carolina at Chapel Hill who was not involved in the work, in an email to The Scientist. “I think these are important findings which cast doubt on the role of nonsense suppression on the actions of PTC124.”

“From a basic mechanistic standpoint, it doesn’t look like translational read-through, certainly in our assays,” said Stuart McElroy, a molecular pharmacologist at the University of Dundee in Scotland and an author of the paper.

But representatives from PTC Therapeutics, the New Jersey biotech company that is developing the drug, said that it has produced strong evidence that PTC124, also called ataluren, does encourage the translation of complete proteins despite the nonsense mutations. “Numerous independent laboratories have provided confirmation of our results, demonstrating ataluren’s read-through activity in studies using reporters as well as multiple animal and cell-based nonsense mutation disease models,” the company said in an emailed response to questions sent by The Scientist.