Kaftrio (ETI) modifies the content of natural fats (or lipids) in cells, in particular by inducing the accumulation of a specific class of lipids, called dihydroceramides, which play a very important role in cell life. 
Deepening knowledge about these effects of the therapy can help to put into context some of the known side effects detected during use in the clinic and to monitor others that may arise at a later time. Furthermore, expanding the knowledge base on the action of modulators helps to design other, even more effective and safer molecules.  

In this project, continuation of the previous FFC#1/2021, the researchers treated bronchial cells from people with cystic fibrosis (CF) and healthy subjects with the drugs that make up Kaftrio (elexacaftor, tezacaftor and ivacaftor) for 15 days and then measured the levels of dihydroceramides. They then repeated the experiment on human liver cells and subsequently understood the mechanism using further experiments.

The experiments showed that tezacaftor slows down the activity of an important human enzyme called DEGS, thus inducing an accumulation of dihydroceramides. This effect was shown to be related to the drug itself, and not to CFTR or its recovery.
An animal model was then used to confirm the observations made in vitro: non-CF mice were treated with ETI for 5 days and the levels of dihydroceramides in their brains were measured. The same observations made on the cells in vitro were repeated on mice treated with ETI for 5 days. 

The work will continue over the next three years, also thanks to the support of FFC Ricerca, with further experiments on mice, to understand whether these observations have practical relevance from the point of view of the safety of Kaftrio.

Publications

• Ciobanu DZ, Liessi N et al. Tezacaftor is a direct inhibitor of sphingolipid delta-4 desaturase enzyme (DEGS). Journal of Cystic Fibrosis. 2024; 23(6):1167-1172.