A substantial number of people with cystic fibrosis (CF) carry in their CFTR gene nonsense mutations that lead to the production of a non-functional truncated CFTR protein.  So far, there are no pharmacological therapies to correct the basic defect in such patients. Such mutations can potentially be addressed with gene therapy, but several challenges still need to be overcome before they can be applied to CF. An interesting alternative is represented by small molecules, discovered in scientific laboratories, that show activity on nonsense mutations. These molecules act through different mechanisms to promote the synthesis of a full length CFTR protein.

The general goal of this project is the demonstration that a pharmacological approach for the correction of nonsense mutations in CF is feasible.

The researchers will evaluate in vitro different combinations of molecules active on nonsense mutations. They will also analyse the effect of inflammatory stimuli based on the cytokines IL-4 and IL-17A that, from preliminary results, seem to favour the correction of these mutations.

The experiments will be conducted on bronchial and nasal epithelial cells from people with CF (obtained through FFC Research’s Primary Culture Service) with stop mutations, in particular G542X and W1282X. Using these cells, epithelial tissue models will be generated that can reproduce the characteristics of the tissue in vivo and on which the restoration of CFTR activity after treatment will be measured. 

With this study, it will be possible to identify the best combinations of molecules active on nonsense mutations, endowed with maximum efficacy and minimum undesired effects. Furthermore, analysing the effects of inflammatory stimuli may reveal new therapeutic targets.