In the previous project FFC#1/2021, the researchers have collected data suggesting that the three molecules of Kaftrio (elexacaftor/tezacaftor/ivacaftor, ETI) might have an additional effect, never reported before, besides (and not related to) its ability to rescue CFTR. The hypothesis is that the drug might modulate the metabolism of an important class of natural fats (or lipids), named sphingolipids.

Human bronchial epithelial cells treated with ETI exhibited an increase in the amount of specific molecules called dihydroceramides. These are similar to ceramides (whose role in CF disease was already investigated in the past), but with significantly different properties. Since this secondary effect of ETI has never been described before, the researchers propose to extend their studies to confirm and address its biological significance, if any. By using well-established biochemical techniques, they will first investigate if and how ETI impacts on the enzymes that control the synthesis of sphingolipids, with a particular focus on liver function. 

By refining the understanding of the sphingolipid modulation by ETI, the project aims to: 

1. assess and evaluate the clinical relevance of a potential accumulation of dihydroceramides
2. pave the way to the design of new drugs that will exploit ceramide modulation to enhance the beneficial effects of the rescue of CFTR. 

The data collected will help the clinicians in outlining an even safer way to administer the drug to the patients and anticipating any potential future health issues.