Mitigating oxidative damage: novel therapeutic approaches for cystic fibrosis

Cystic Fibrosis (CF) is a genetic disorder caused by mutations in the CFTR gene. There are over 2000 known CFTR mutations, with the most prevalent being F508del. Current therapy (Trikafta®) works on a limited number of mutations, and new adverse effects are emerging. Hence, there is a need for new therapeutic strategies. In CF, a pro-oxidative and pro-inflammatory environment has been described, which contributes to disease outcome. The onset of inflammation and oxidative stress in patients happens early in life resulting from a complex interplay of various factors. These include the overproduction of reactive oxygen species (ROS), NF-E2-related factor 2 (Nrf2) and glutathione (GSH) depletion, and lipid peroxidation (LPO) of membrane lipids. In this thesis, I have exploited cellular models of CF to test Nrf2 activators as possible therapeutic agents to improve the current therapy. The idea is that recovering the derailed CF intracellular environment might improve proteostasis and functional rescue of mutated CFTR. Preliminary Ussing chamber data on Nrf2 activators combined with CFTR correctors support the initial hypothesis. Specifically, the collected data unveil new therapeutic alternatives that could be translated to orphan mutations. Moreover, I identified and characterized the antioxidant properties of the potentiator VX770. The identification of a CFTR-independent mechanism acting in parallel with the function for which the compound had been approved in CF represents an absolute novelty and offers a therapeutic opportunity for diseases associated with oxidative stress.