Cystic fibrosis is caused by a mutation in the gene that encodes a particular protein, known as the cystic fibrosis transmembrane conductance regulator (or CFTR). Although this discovery was made 25 years ago and the lives of those with the disease have been extended, there is still no effective cure for the disease. Now new information about the nature of the most common form of mutation in the CFTR gene, gathered by a research team led by Dr. Gergely Lukacs of the Department of Physiology at McGill University, offers exciting new avenues for improving the treatment of the disease.

To better understand the difficulty of looking for a cure, or even effective treatment, one must understand the large and complex nature of the CFTR protein. It is made up of 1,480 amino acids strung together in five three-dimensional strands (called domains) that spin together and fold to act as building blocks for the CFTR protein.

“Looking for a treatment or cure for the disease is like trying to repair a tear in a braided rag rug,” says Lukacs. “We need both to figure out where the tear originates in an individual coil of cloth, and then we need to discover how best to reattach this individual coil to the larger rug in order to make a solid whole. It’s a monumental task.”

Scientists already have part of the information needed to move ahead with this work. Although there are about 2,000 mutations associated with the CFTR gene, the most common mutation, known as F508del, found in 90 per cent of patients with the disease, involves the deletion of a single amino acid at position 508 in the CFTR protein.  Like a single missing stitch in the carpet, this single absence weakens the whole protein structure and renders it non-functional.

The best hope for treating symptoms of cystic fibrosis at the moment is a drug called Vertex VX-809, which is currently under clinical trial. However, this experimental drug is ineffective for the vast majority of those who suffer from the disease. That is because VX-809 seems only to restore inter-domain communication within the protein (i.e. to continue with the rug analogy, it can help reattach the coils of rags to one another) but the domains within the protein remain weak (i.e. each individual braided strand in the rug still has tears in it).

In their previous research, Dr. Lukacs and his colleagues have been able to show in cell cultures that the F508del structural effect is not restricted to the domain where it is found. The mutation has negative effects on the other four domains of the protein as well, which compromises the appearance of CFTR at the cell surface. It’s as though the weakness or break in a single strand of braided rug affected not just the strength of the strand next to it but that of the rug as a whole.

Lukacs and his team then tried combining Vertex VX-809 with other chemical compounds that target two major structural defects in the protein at the same time. The results were startling. By combining Vertex VX-809 with chemical compounds that act as correctors on the domain containing the F508del mutation, the efficiency of the combination of drugs went up from 15 per cent to 60-80 per cent in cell culture models.

“These findings offer a rational way of choosing drug candidates with distinct mechanisms of action,” says Lukacs. “What is even more crucial is that they also suggest the importance of combining drugs which target complementary structural defects in order to overcome the limited success of individual corrector molecules that are currently under clinical trial. 

To read the full paper in Nature Chemical Biology: 

The research was funded jointly by Cystic Fibrosis Canada, The Cystic Fibrosis Foundation Therap. Inc., the Canadian Institutes for Health Research (CIHR), the Canada Research Chair (CRC) program, and the Canada Foundation for Innovation (CFI).