Newly uncovered mechanism could drive next-gen cystic fibrosis treatments

Cystic fibrosis (CF) is a genetic condition that affects the lungs, pancreas and other organs, caused by variations on the cystic fibrosis transmembrane conductance regulator?(CFTR) gene. There are around 700 known variants that cause CF, but current treatments address only a few, and none offer a cure.

"Therapeutics for cystic fibrosis have hit a plateau, demanding that we uncover new ways of looking at the science behind the condition. By studying protein organization, we've uncovered a brand-new avenue for developing therapeutics for cystic fibrosis," says Dr. Jonathon Ditlev, Scientist in the Molecular Medicine and Cell & Systems Biology programs.

Phase separation key to CFTR protein

Rather than looking solely at the function of the CFTR protein, the study, published in Proceedings of the National Academy of Sciences (PNAS), examined how CFTR proteins are organized on the cell membrane. In healthy children, the proteins form clusters, helping to regulate water and salt intake. In people with CF, those clusters are disrupted.

The process that forms the clusters is called phase separation, a well-known process that has recently been appreciated for its role in biological organization and that Dr. Julie Forman-Kay, Program Head and Senior Scientist in the Molecular Medicine program and co-lead author of the paper, proposed might be relevant to CFTR in 2017.

"Our findings establish CFTR as a phase-separating protein, opening up a previously unexplored mode of protein regulation and a new target for future therapies," explains Forman-Kay.

The future of CF therapeutics -- inspired by the past

The research team is already working with other SickKids scientists, including Dr. Christine Bear, Co-Director of the Cystic Fibrosis Centre, to explore ways to advance this research into novel therapies for CF.

"Current therapies for cystic fibrosis are effective for most children, but not all," says Bear, who is also a Senior Scientist in the Molecular Medicine program. "These findings could help us target those for whom current therapies remain ineffective, while also bolstering outcomes for all those affected by CF."

While the study could inform the next generation of CF therapeutics and advance Precision Child Health at SickKids, Ditlev joined SickKids without any thought of researching CF -- but that quickly changed.

"Being a part of the SickKids, with its storied history of research excellence impacting patients with cystic fibrosis, I realized how my experience and tools could contribute to and enhance this legacy."

This research was funded by the Natural Sciences and Engineering Research Council (NSERC), the National Institutes of Health (NIH) and Cystic Fibrosis Canada.