Each mutation has number of effects on the cells of the lungs. New evidence generated in vitro by Vojo Deretic and colleagues at the University of New Mexico School of Medicine, Albuquerque, has provided insight into the mechanisms by which one of these changes impacts both CF and the complications of CF. These data provide support for ongoing clinical trials and raise the possibility of new targets for the development of drugs to treat individuals with CF.

CFTR mutations that cause CF make a compartment of the cell known as the TGN more acidic than it is in cells from healthy individuals. In this study, in vitro analysis revealed that hyperacidification of the TGN causes increased activity of a protein known as furin. Through increased production of a soluble factor known as TGF-beta this augmented the production of collagen (which in situ is associated with tissue fibrosis, a characteristic of damaged lung in individuals with CF) and suppressed the ability of human macrophages to kill the bacterium Pseudomonas aeruginosa, infection with which is a major complication for individuals with CF. This study provides strong support for the use of chloroquine (which counteracts high levels of TGN acidity) to treat CF, something that is currently being tested in clinical trials, and identifies furin inhibitors as potential new therapeutics for the treatment of CF.

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These studies suggest that the middle dose of PTC124 is as effective as the highest dose, at least over the course of a month's treatment.

"DMD is a disorder with a significant need for better treatment options and we are encouraged by the results we have seen to date with PTC124," said Brenda Wong, associate professor of Pediatrics and Neurology at Cincinnati (Ohio) Children's Hospital Medical Center and one of the trial's lead investigators. "Based on the findings from this study, we believe that the safety profile of PTC124 supports continued testing in longer-term studies."

MDA's Hesterlee said the "proof of principle" demonstrated in these DMD studies also implies a wide-ranging potential for PTC124 to treat over 1,800 genetic diseases, including other forms of muscular dystrophy, in cases where the cellular defect results from a premature stop codon.

MDA is a voluntary health organization that funds research and provides services in more than 40 neuromuscular diseases. Duchenne muscular dystrophy is a major focus for MDA.

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