December 2012

Insights into a new therapy for a rare form of cystic fibrosis

Scientists at the Hospital for Sick Children in Toronto have established that VX-770, a drug recently approved by the FDA to treat a form of cystic fibrosis caused by a rare mutation, works through an unconventional mechanism. Their results shed light on the regulation of the cystic fibrosis transmembrane conductance regulator and reveal new possibilities for treating cystic fibrosis caused by various mutations.

Cystic fibrosis is a genetically inherited disease afflicting about 70,000 people around the world. It is caused by various mutations in the CFTR protein, a channel found in the lining of many organs that controls the viscosity of the mucus coating them. A characteristic feature of the disease is thick mucus buildup in the air passages, which causes difficulty breathing and recurring infections.

Recently, the FDA approved the drug VX-770, also known by the trade names Kalydeco and Ivacaftor, for people with cystic fibrosis caused by a particular mutation in CFTR – the G551D mutation – for whom it effectively eases breathing. But exactly how VX-770 works was unknown.

The established mechanism for CFTR regulation requires phosphorylation of the protein and binding of ATP. However, in their recent Journal of Biological Chemistry “Paper of the Week,” Christine Bear and colleagues report that VX-770 opens phosphorylated normal and mutant CFTR channels without ATP. Their results indicate that VX-770 binds to a different site on CTFR than ATP, suggesting that it works through an alternative mechanism. Significantly, this mechanism may be an effective target for treating cystic fibrosis caused by various CFTR mutations that, like the G551D mutation, impair ATP-mediated channel regulation.

Bear’s group determined how VX-770 works via the development of a new assay system. Their results demonstrate the potential of this assay system to discover drugs that target the basic defects caused by CFTR mutations, Bear explains. The assay system is useful to identify candidate compounds that interact with rare mutations, such as G551D as well as the major CFTR mutant F508del, Bear said.

Photo of Danielle GutierrezDanielle Gutierrez ( is a freelance science writer based in Corpus Christi, Texas.

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