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Biological Chemistry

Doubt Cast On Muscle Disorder Drug Candidate’s Mechanism

Study suggests that an experimental drug to treat muscular dystrophy doesn’t work in the way scientists originally proposed

by Stu Borman
July 1, 2013 | A version of this story appeared in Volume 91, Issue 26

An experimental drug in human clinical trials for muscular dystrophy doesn’t work in the way scientists had originally proposed, a study finds. In 2007, PTC Therapeutics developed the small molecule ataluren as a readthrough agent, a molecule that restores protein levels in cells with mutations that block production of those proteins. In cells and in mice with a muscular dystrophy mutation, ataluren boosts levels of the disease-related protein and improves muscle function, respectively. Ataluren is in a Phase III trial for muscular dystrophy, and a cystic fibrosis trial is planned. In the new study, Stuart P. McElroy of the University of Dundee, in Scotland, and coworkers find that the assay used to identify ataluren as a readthrough agent gave a false-positive indication, because it interacts with the assay’s luciferase reporter enzyme instead of the protein translation process (PLoS Biol. 2013, DOI: 10.1371/journal.pbio.1001593). McElroy’s team used other assays to show that ataluren has no readthrough activity, suggesting that any efficacy it has is the result of some other bioactivity. PTC Therapeutics maintains that ataluren readthrough has also been confirmed in nonluciferase assays and that it shows activity in cells, animals, and people.


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