About a third of Italian patients with cystic fibrosis is lacking approved CFTR modulators. Using findings in intestinal organoids (from rectal biopsies) and nasal cells (from nasal brushing), individual CF patients carrying rare CFTR mutations are proposed for treatment. Measurements of CFTR function are performed in intestinal and nasal cells to evaluate the efficacy of already approved CFTR modulators for other mutations (tezacaftor, lumacaftor, elexacaftor, ivacaftor) or not (ELX-02, PTC-124, others in preclinical phase) in 3D (FIS assay) and 2D (Ussing chambers). For the CFTR stop mutations and splicing mutations we evaluate the presence of transcripts (CFTR-mRNA), necessary for the therapeutic effect. Evaluation of the transport of bicarbonate in addition to chloride was set up in intestinal cells. Cells with at least one CFTR stop mutation after treatment with PTC-124 or ELX-02 alone showed no significant effect, the addition of ivacaftor at least doubled their chloride secretion which was further increased by adding tezacaftor/elexacaftor. Various CFTR mutations treated with tezacaftor/lumacaftor/elexacaftor/ivacaftor combinations showed significant recovery of CFTR function (up to fourfold). Similar results were obtained in intestinal and nasal cells from various patients with specific limitations/advantages of the two different potentially complementary models. When the drug was made available for therapy, the clinical effects in individual patients proved to be consistent with previously obtained laboratory results. These assays could indeed predict patient response to drugs and thus support authorization for CFTR modulator therapy of patients with rare mutations for whom classic experimental studies are impossible.