The project belongs to the international line of research for development of diagnostic systems to test the CFTR modulators’ efficacy in the cells of each CF patient, particularly if they are carrying rare and orphan mutations. Researchers will implement the study in nasal cells (from mucosal brushing) and in intestinal cells (from rectal biopsy) of CF patients with rare and orphan CFTR mutations, in order to propose and monitor specific treatments with CFTR modulators. The study plans to enroll 65 CF patients (90% of which have participated in the first part of the European multicenter study HIT-CF, hitcf.org); the CFTR function in intestinal organoids and nasal cells will be analyzed in response to both available potentiators and correctors (Ivacaftor, Lumacaftor, Tezacaftor, Elexacaftor), and to other experimental drugs, such as those potentially effective on stop mutations. The follow-up will be carried out in two Italian centers (CF Center, Azienda Ospedaliera Verona; CF Center, Ospedale Bambino Gesù Roma) and it will allow to verify to what extent the experimental tests can predict the effectiveness of the drugs, both on the basis of clinical parameters and of CFTR functionality in vivo (sweat test, nasal potentials, intestinal short circuit current). The study could provide support to the patients who are not eligible for the currently available CFTR modulating drugs.