Research led by the University of Toronto has identified a large group of proteins that interact with the function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein.
The researchers think their findings could clarify why some patients with the inherited condition cystic fibrosis, caused by mutations in the CFTR gene, respond better to gene modulating therapies than others and think their findings could also help identify new drug targets for the genetic condition.
“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 on the study and a professor in the Donnelly Centre for Cellular and Biomolecular Research at the University of Toronto, in a press statement.
“With a more comprehensive view of the CFTR protein interaction network, we can identify novel drug targets that should enable more patient-specific therapies,” he added.
As described in a paper outlining the study published in the journal Molecular Systems Biology, the researchers used updated technology based on a platform they designed in 2014 known as a mammalian membrane two-hybrid system. The earlier system was also able to scan for protein-protein interactions, but on a smaller scale. The upgraded version allows for higher throughput.
“The earlier design was array-based, and we could only screen about 200 proteins at a time,” said Stagljar. “With this new technology, we’ve introduced several changes that allow us to screen thousands of protein targets simultaneously, in a pooled manner.”
Some of the proteins that the team identified as interacting with CFTR, were previously overlooked in the pathology of cystic fibrosis. For example, they found that down regulation of the protein fibrinogen-like 2 led to higher expression of the CFTR protein in organoids.
In cystic fibrosis patients, inherited recessive mutations in the gene encoding CFTR cause the protein to be dysfunctional, which leads to thick and sticky sweat, digestive fluids and mucus, causing many problems around the body.
“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.
The researchers also think the study could explain why some patients treated with CFTR modulating drugs such as ivacaftor, elexacaftor and tezacaftor, among others, have differing responses. These therapies have been very effective at improving outcomes for some patients with cystic fibrosis, but less so for others.
Researchers suspected this could be due to environmental and secondary genetic effects. The current study findings suggest that proteins physically interacting with CFTR are one of those factors
