Most mutations associated to cystic fibrosis can be classified in different classes according to the mechanisms through which they cause CFTR loss of function. Research has focused on identifying small-molecules, or modulators, that can restore CFTR function. Not all mutations belonging to the same class respond equally to a single agent. Furthermore, many CF patients have poorly characterized mutations, whose responsiveness to pharmacological treatment remains to be established. A personalized approach needs to be strongly considered for the treatment of CF basic defect. Primary cell culture-based models derived from CF patients by a minimally invasive nasal brushing are very important to evaluate CFTR activity and its possible changes due to therapeutic interventions in individual patients. The principal aim of the project is to establish the responsiveness of CF patients to different pharmacological agents applying nasal brushing-derived primary culture models. There are already approved drugs (Ivacaftor, Lumacaftor, Orkambi) that are effective on specific CF mutations. However, many CF patients carry rare mutations with unknown sensitivity to these agents. Moreover, there is an increasing number of CFTR pharmacological modulators that are in preclinical development or in clinical trials. It will be important to test these molecules (among them the new RNF5 inhibitors) in cells from CF patients, particularly those with mutations poorly responsive to approved CFTR modulators.