In cystic fibrosis (CF) an approved therapy exists for patients who have at least one F508del mutation. This therapy comprises a combination of two correctors and a potentiator. Despite this progress, numerous CFTR mutations still lack effective therapeutic interventions, underscoring the pressing necessity for alternative or supportive treatments to complement existing clinical drugs.
Researchers observed that oxidative stress is closely linked to defects in autophagy, a cellular process designated to the removal of damaged cellular organelles. It could be useful to identify molecules capable of restoring CFTR function by balancing the pro-oxidative state in CF models.
To do so, researchers used computational analyses to pinpoint promising compounds, biochemical and cellular studies to validate the mechanisms of action, and functional analyses to assess the efficacy and impact of the identified molecules.
Alternative strategies other than channel targeting were considered, focusing on the study of oxidative imbalance in CF and how restoring it to physiological levels could recover channel activity. Specifically, they explored lipid peroxidation as a phenomenon that, through radical damage to biological membranes, could lead to malfunctions in membrane proteins such as CFTR and inflammation. Additionally, cellular proteins involved in the antioxidant system were investigated as new targets in CF.
It has been demonstrated that cellular models with F508del mutation show an increased level of lipid peroxidation and a decreased level of antioxidant protection. Moreover, molecules capable of trapping specific lipid radicals or enhancing antioxidant defence, such as Nrf2, improve the efficiency of current correctors in restoring CFTR channel activity.
The research will be extended to various CFTR mutations to clarify common traits and divergences; the panel of active molecules will be expanded and tested on different CF models. The ultimate goal is to suggest new therapeutic interventions independent of the CFTR mutation.