ERA-Net E-Rare

Effective drugs for the treatment of Cystic Fibrosis (CF) patients with trafficking mutations are not yet available, and associated lung and liver pathologies remain untreatable with current interventions limited to organ transplantation. Novel compounds have to be identified, and in combination with known CFTR correctors, potentiators, and other small molecules, tailored to specific CFTR mutations, or even to the individual patient. Immortalized cell lines that overexpress mutant CFTR variants are typically used to screen candidate molecules but have proven to be poor predictors of clinical efficacy. The complexity of the mutant CFTR maturation and turnover kinetics requires the use of advanced cellular models that closely recapitulate the specific properties of the most clinically affected organs. To address these unmet needs we propose to generate a collection of primary bronchial epithelial cells and induced pluripotent stem cell (iPSC) lines from patients with common (F508del) and rare trafficking mutations, incl. known intragenic haplotypes with mild & severe phenotypes. The iPSC lines will be genetically corrected to generate adequate isogenic controls, and transgenic reporters will be introduced to facilitate high throughput (HT) screening. Compounds will be identified through HT screening followed by functional validation and identification of mechanism of action. Testing compound combinations in personalized surrogate models of CF lung and liver disease up to the pre-clinical stage will provide new treatment options for CF patients with different CFTR mutations.