New Cystic Fibrosis Medications Also Help Recover Dysfunction in Other Inflammatory Pathways
Published August 2019 | Journal of Clinical Investigation
Cystic fibrosis (CF) is a genetic disease that impacts multiple organs and is known to be caused by loss of function of the gene CFTR. The disease causes chronic inflammation that contributes to many pathologies, including potentially fatal lung tissue damage. Now, a research team at Cincinnati Children’s reports that medications recently approved to compensate for the loss of CFTR function also impact pathways related to inflammation.
Using multiple models and primary cells from 12 CF patients and six non-CF control subjects, the researchers became the first to identify a direct relationship between CFTR and Nrf2, an important regulator of antioxidant and anti-inflammatory signaling. Using super-clinical doses of approved pharmaceuticals for CFTR, researchers found dysfunction in Nrf2 can also be corrected in a CFTR-dependent fashion.
“Multiple approaches were used and all pointed to a relationship between the primary defect in CF and a major regulator of inflammatory signaling, a very strong and novel finding both in the fields of cystic fibrosis and redox biology, where Nrf2 is more of a focus of study,” says lead author Assem Ziady, PhD, Division of Pulmonary Medicine.
The work also identified the mechanisms involved when correcting loss of CFTR influences inflammatory signaling. Since publication, new drugs have been approved that better correct CFTR than those available at the time of the original research.
“We are interested in whether, at clinical doses, new and improved therapies correct sufficient levels of CFTR to correct anti-inflammatory and anti-oxidant responses in CF,” says Matthew Siefert, co-first author on the study.
The lab is evaluating whether these newer therapies are more efficient at correcting Nrf2 dysfunction and dysregulated inflammatory signaling in CF. They also are looking at CFTR-independent Nrf2 activators as potential co-therapies for CF.
