With our research project we aimed to investigate the effect of the lipid environment on the rescue of F508del CFTR. Indeed, several lines of evidence suggest an important role of cell lipids in cystic fibrosis (CF), particularly for their involvement in the stabilization of CFTR channel within the plasma membrane. CF cells carrying the mutation F508del are in fact characterized by alteration in lipid content, especially regarding sphingolipids and cholesterol.
Interestingly, we found that when CF cells are treated with the new drug combination Kaftrio, the rescue of CFTR is accompanied by an increase of a particular class of sphingolipids, gangliosides. In particular, we observed an increase in GM1, a ganglioside we demonstrated to directly interact with CFTR and be defective in CF cells.
We already demonstrated that the additional administration of GM1 improves the stability and activity of F508del CFTR rescued by Orkambi (lumacaftor/ivacaftor) and, with the present project, we observed that the treatment with GM1 enhances the plasma membrane stability of the mutated CFTR also in cells treated with Kaftrio. Unfortunately, in CF the beneficial effects of CFTR modulators is compromised by Pseudomonas aeruginosa (Pa) infections. However, the exogenous administration of the ganglioside GM1 decreases the negative effect of Pa infection, increasing the plasma membrane stability of rescued channel and reducing its turnover.

Furthermore, with the aim to increase the cellular levels of cholesterol, we treated F508del cells with Kaftrio in combination with human lipoproteins (HDL or LDL). These particles, especially LDL, seem to exhibit an adjuvant role to Kaftrio for the CFTR rescue. Based on these data, the co-administration of GM1 and/or cholesterol and CFTR modulators could be considered as an innovative strategy to ameliorate the effectiveness of the CF drugs on the plasma membrane stability of mutated CFTR, even when Pa infections are present.