Researchers find new targets for cystic fibrosis therapy

Cystic fibrosis causes lung damage and a loss of lung function which eventually leads to death in the majority of patients.

Dave Yasvinski 3 minute read February 15, 2022
Challenge concept

Researchers identified a group of overlooked membrane proteins, including some that may factor into cystic fibrosis. GETTY

Canadian researchers have zeroed in on hundreds of new proteins that could play a part in cystic fibrosis and help explain why patients with the same genetic mutation often have very different responses to therapy.

The study, published in the journal Molecular Systems Biology, examined the relationship between these new proteins and the cystic fibrosis transmembrane conductance regulator (CFTR) — a protein that helps maintain the balance of salt and water on surfaces of the body, including the lungs. Mutations to the gene underlying this protein can disrupt its ability to function properly and give rise to the accumulation of mucous in the lungs and other organs that typifies cystic fibrosis.

“We identified more than 400 proteins associated with either healthy or mutant CFTR and have shown that some of them could predict the variability seen in patient symptoms and treatment responses,” said Igor Stagljar, principal investigator of the study and a professor in the Donnelly Centre for Cellular and Biomolecular Research at the University of Toronto’s Temerty Faculty of Medicine. “With a more comprehensive view of the CFTR protein interaction network, we can identify novel drug targets that should enable more patient-specific therapies.”

Cystic fibrosis is a fatal genetic disease

Cystic fibrosis is a fatal, genetic disease that affects roughly one in every 3,600 children in the country, according to Cystic Fibrosis Canada. The disease, which can occur when a child inherits an abnormal CFTR gene from each parent, targets the digestive system and lungs, with the persistence and severity of infection varying from patient to patient.

The multi-system disorder results in symptoms that include a persistent cough with thick mucus, wheezing and shortness of breath, salty tasting sweat and frequent chest infections. Sustained damage and a loss of lung function caused by these infections eventually leads to death in the majority of patients.

With around 2,000 known mutations of the CFTR gene leading to cystic fibrosis, treatment of the disease is often tailored to a specific patient’s profile. While some of these therapies have been remarkably successful at restoring the proper function of the CFTR protein, they do not always achieve the same results in other patients.

To better understand the mechanisms underlying cystic fibrosis, researchers built on technology they designed in 2014 that allowed them to screen a vast amount of membrane proteins that interact with the CFTR protein. “The earlier design was array-based, and we could only screen about 200 proteins at a time,” Stagljar said. “With this new technology, we’ve introduced several changes that allow us to screen thousands of protein targets simultaneously, in a pooled manner.”

This helped them identify a group of overlooked membrane proteins, including some that may factor into CFTR function and cystic fibrosis. One protein in particular, which is believed to play a role in hepatitis, liver disease and immune function, caught their attention. Downregulation of this protein, known as Fibrinogen-like 2 protein — resulted in the increased expression of CFTR in 3D in vitro models used by researchers.

“We think Fibrinogen-like 2 protein is a valuable drug target for cystic fibrosis and we’re now working with our collaborators to validate other proteins that turned up in this study and in genome-wide association studies,” Stagljar said.

Dave Yasvinski is a writer with Healthing.ca

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