Developing a rational basis for pharmacological correction of the D508-CFTR folding–trafficking defects

Cystic fibrosis is a genetic disease that affects 1 in 3,200 live births in the Caucasian population. This disease is caused by mutations in the gene that encodes a protein that is necessary to maintain the fluid balance in the lungs, pancreas and testis. These mutations lead to improper fluid balance, which itself leads to thickened mucus in these organs. This thickened mucus is difficult to clear and results in enhanced infection of the lungs. Cystic fibrosis patients generally die because of respiratory problems, usually around the age of 30-35 years. Currently there are no curative therapies available for cystic fibrosis, and disease management is usually restricted to symptomatic therapy. There are some curative drugs in clinical trials that show promise, although their effects are modest, and their modes of action are not known. Here, we propose to investigate and define the modes of action of these drugs using systems biology approaches. We believe that an understanding of their modes of action would help us to deliver better and more efficient curative therapies that are lacking at present. Indeed, our preliminary results have already given indications as to the mode of action of some of these drugs, and our initial predicted beneficial drugs have shown curative effects in laboratory studies that are equivalent to those of the drugs that are already in clinical trials. We would like to further improve on these curative effects by understanding the molecular pathways of the drug actions, and by introducing novel drugs or combinations of drugs that can potently improve curative therapies for patients with cystic fibrosis.