Miglustat is a drug currently under phase 2 clinical trials on patients suffering from cystic fibrosis (1). Its potential for treating the disease was discovered in 2006 thanks to the work of Frédéric Becq's team at the Institute of Cell Physiology and Biology (CNRS/Université de Poitiers), funded by the associations Vaincre la Mucoviscidose, MucoVie66, La Pierre Le Bigaut and ABCF2.
In new work to be published on 1 August 2009 in the American Journal of Respiratory Cell and Molecular Biology, the researchers show that daily, long-term treatment of human cystic fibrosis cells with low doses of miglustat corrects the main pathological abnormalities. They are therefore extremely hopeful that miglustat will prove effective with patients, and become the first drug able to treat the disease rather than the symptoms.
Cystic fibrosis is a genetic disease, transmitted jointly by both parents, and affects around 6000 people in France. It is caused by the dysfunction of a membrane protein (CFTR), present especially in the epithelial cells in the lungs, which controls exchange of water and mineral salts between the cell and the exterior. On the cell level, the disease manifests itself by the absence of chloride secretion, sodium hyperabsorption, deregulation of calcium homeostasis, and heightened inflammatory response. This results in thickening of the mucus that lines the bronchial tubes and the pancreatic ducts, leading to lung infections and digestive disorders. At the current time, there is no treatment that cures cystic fibrosis. In order to alleviate the symptoms, extremely strict daily treatment is necessary.
In 2006, Frédéric Becq's team at the Institute of Cell Physiology and Biology (CNRS/Université de Poitiers) showed that a drug called miglustat restored the activity of the CFTR protein and could thus temporarily correct the specific phenotype characteristic of cystic fibrosis. Used to treat two rare diseases (Gaucher's disease and Niemann-Pick type C disease), its safety and tolerance had already been assessed, and clinical trials could be rapidly begun in September 2007.
In the new study published in American Journal of Respiratory Cell and Molecular Biology, the researchers show that daily treatment of human respiratory cells that are homozygous for the F508del mutation with low concentrations of miglustat leads to progressive, sustained and reversible correction of the diseased phenotype. The researchers cultured diseased human respiratory cells in the presence of miglustat for two months. The correction observed in the cells takes place after 3-4 days, and then stabilizes. When the treatment is stopped, the cells revert to the diseased phenotype. The low doses used (3 micromolars) mean that they can be administered to patients and that their presence in the bloodstream causes no problems.
This study is the first that shows that a cystic fibrosis cell can acquire a sustained non-diseased phenotype when treated daily with a pharmacological agent. The researchers are therefore very optimistic about the results of the clinical trials under way.
(1) The clinical study is being carried out by the Actelion pharmaceutical laboratory on 15 patients suffering from cystic fibrosis and carrying the delta F508 mutation (F508del), which is the most common and the most serious of the mutations affecting children with cystic fibrosis. The results will be known in the coming weeks.
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