One size does not fit all when it comes to cystic fibrosis patients’ symptoms, despite the commonality of a mutated gene. Some patients endure severe life-long airway infections while others are relatively unaffected by their condition. Michael Knowles, MD, professor of pulmonary and critical care medicine at the University of North Carolina School of Medicine, has been working to solve this mystery.
“Right now, there are drugs being developed to fix the function of the CFTR protein that is disrupted in cystic fibrosis, but even then, some patients will respond very well to therapy and some won’t,” said Dr. Knowles in a press release from UNC Health Care. “Why is that? We think it’s the genetic background — the pathways that we identified contain genes that likely interact with the main CFTR gene mutation.”
In Dr. Knowles’ laboratory, researchers are studying clusters of genes that are involved in cellular signaling pathways that may affect cystic fibrosis severity. Some of their major findings were published in American Journal of Human Genetics, entitled “Gene Expression in Transformed Lymphocytes Reveals Variation in Endomembrane and HLA Pathways Modifying Cystic Fibrosis Pulmonary Phenotypes.”
In this study, Dr. Knowles, lead author Wanda K. O’Neal, PhD, and collaborators showed that when certain gene clusters are highly active, cystic fibrosis symptoms are less severe. Alternatively, when the clusters are less active, patients are more likely to be hospitalized as a result of their disease.
“Now that we’ve found these pathways, we need to dig into the biology to see how specific genes within them influence disease severity,” said Dr. O’Neal. “This could help us not only to predict which patients will respond to a given therapy but it may also provide drug targets to lessen the severity of disease for all patients.” In fact, it may even result in a new era of personalized medicine to lessen the severity of pulmonary symptoms.
Drs. Knowles and O’Neal used gene expression data from 750 cystic fibrosis patients’ cells that had been collected from 40 centers across the United States. These data represented over 4,000 cell signaling pathways, and some were associated with severe cystic fibrosis symptoms. Two gene clusters made up the most notable differences between severe and less severe symptoms: endomembrane pathways (which regulate protein folding and transport the DF508 protein from the nucleus to the membrane) and HLA pathways (which are important for protecting against Pseudomonas and other pathogens).
These gene clusters may also explain why some patients respond to treatments for cystic fibrosis and why others do not. For the 70% of patients with the DF508 mutation, no FDA-approved drugs are able to correct the mutation, although there are some studies that are combining two new drugs with modest results.
“Now, we’d like to continue to evaluate the response of patients to new treatments,” said Dr. Knowles. “We want to know if people who respond well have higher expression of these genetic pathways. If so, then we’re really on the heels of personalized approaches to treating CF patients at the level of their genes to lessen the severity of often debilitating symptoms.”