By Kevin Davies
July 22, 2009 | Twenty years after the sensational discovery of the mutated gene in cystic fibrosis (CF), researchers are still searching for a true cure for the deadly recessively inherited disease, which affects about 1 in 2000 live births in people of European descent. But new findings from French researchers suggest that a drug called miglustat could restore function to the most commonly mutated form of the CF protein. The French team says that its study is the first to show that CF cells can be essentially corrected with the daily treatment of a standard pharmacological agent.
CF patients harbor mutations in the gene that encodes a large membrane protein, the cystic fibrosis transmembrane regulator (CFTR). The protein is found in the cells lining the lung, where it controls the flux of water and salt between the cells and the airways. CF cells are unable to secrete chloride, resulting in a debilitating thickening of the mucus that lines the airway passages (and other sites), leading to often untreatable lung infections by Pseudomonas bacteria. New drugs, including molecules in clinical trials developed by Vertex Pharmaceuticals, show promise, while more effective antibiotic and palliative treatments have significantly improved the quality of life for CF patients over the past two decades. But a cure for CF remains elusive.
Now, French researchers are reporting success in treating the symptoms of CF cells with a drug called miglustat, which is primarily used to treat rare inborn errors of metabolism such as Gaucher disease and Niemann-Pick type C. In 2006, Frédéric Becq's team at the Institute of Cell Physiology and Biology (CNRS) showed that miglustat applied to CF cells restored the transport and activity of CFTR and could thus temporarily correct the specific phenotype characteristic of cystic fibrosis. Because of its prior use in treating other diseases, clinical trials for CF were quickly initiated in September 2007.
In a new study published in the American Journal of Respiratory Cell and Molecular Biology (August 1 2009), the CNRS team found that daily administration of low doses of miglustat on human respiratory cells that are homozygous for the delta F508 CFTR mutation results in a sustained and reversible correction of the CF phenotype. The cellular correction takes place after 3-4 days, and then stabilizes. The low doses used in the study suggest that the drug could be safely administered to patients.
Last year, the Swiss company Actelion Pharmaceuticals initiated a Phase IIa proof-of-concept clinical trial with miglustat in 15 CF patients with the delta F508 mutation, which is the most common and most serious of the 1500 or so documented CFTR mutations. Many studies have shown that the delta F508 CFTR mutation does not rob the protein of its crucial chloride transport activity, but prevents the protein from folding properly and traveling through the cell to reach its proper destination in the outer membrane.
The trial looked at the nasal potential difference, a standard measure of CFTR activity. The investigators were hopeful that miglustat could become the first drug able to treat the CF disease rather than the symptoms. After reviewing the results of the Phase IIa study, Actelion decided not tocontinue clinical development for the time being. But in light of the French team's results, Actelion has decided to conduct further preclinical evaluation of the drug in CF before making any final decisions.
Miglustat (Zavesca) is a small-molecule inhibitor of glucosylceramide synthase and α-glucosidase. The drug is widely approved for the treatment of some forms of Gaucher disease, and in Europe for the treatment of patients with Niemann-Pick type C disease, a rare disorder also known as “childhood Alzheimer’s.”