Study establishes roadmap for future research on therapies for cystic fibrosis and other protein trafficking diseases

Photo: National Center for Advancing Translational Sciences (NCATS), National Institutes of Health
Photo: National Center for Advancing Translational Sciences (NCATS), National Institutes of Health

Cystic fibrosis (CF) is the most common fatal genetic disease for Canadian children and young adults, affecting an estimated one in 3,600 children born in Canada according to Cystic Fibrosis Canada. The affliction is caused by mutations in the gene that encodes a protein called “cystic fibrosis transmembrane conductance regulator” (CFTR), which forms a channel in the membrane of cells.  Persistent infections it causes in the lungs leads to loss of lung function, and eventually death in the majority of those with CF. Effective treatments are being sought and this work provides new ways to correct the basic defect causing CF.

Working with collaborators in Italy, researchers from McGill University’s Faculty of Medicine recently participated in the completion of the first-ever systems biology analysis of CF. Using an Italian-designed systems biology tool known as MANTRA, Dr. Fabiana Ciciriello – who is also affiliated with the Telethon Institute of Genetics and Medicine in Italy-,  Dr. David Thomas and Dr. Graeme Carlile, all with the Department of Biochemistry at McGill and the McGill Cystic Fibrosis Translational Research Centre , were able to help measure the effects of correctors of CF by measuring the amounts of messenger RNA produced genome-wide, the results of which were recently published in the journal e-Life.

“The challenge that we had was to analyze the very large dataset and to obtain meaningful predictions of pathways and targets to treat cystic fibrosis,” says Dr. Thomas, one of the study’s co-authors.  “Working with our Italian collaborators, we then took the predicted pathways and targets and validated their significance through a number of biological tests that we have developed.”

The researchers first tested drugs that control how proteins fold and move to the membrane in order to see how they affect gene expression in cells with the most common cystic fibrosis-causing mutation. These drugs were already known to improve the function of the CFTR mutant but do so too weakly to be of immediate clinical interest. The experiments revealed that the expression of a few hundred genes was changed in response to the drugs with many of these genes involved in major signaling pathways that control how CFTR is folded and trafficked within cells.

The group then tested drugs that inhibit these signaling pathways to see if they would improve salt handling in the mutated cells. The experiments demonstrated that these inhibitor drugs efficiently either block the breakdown of misfolded CFTR or boost the likelihood of CFTR making it to the membrane, helping improve salt trafficking in the cells. The inhibitors produced even better results when used in combination with a known CFTR-protecting drug.

“The results show that targeting signaling pathways involved in the folding, trafficking and breakdown of CFTR is a promising way to treat not only cystic fibrosis, but other protein trafficking diseases as well,” notes Dr. Thomas. “There is a huge amount of data to work with and we will take the most promising results we found and work with our international partners  to develop CF therapies.”

This study was made possible with funding from the CIHR and the CFI

January 22, 2016