Grant: Project Grant

The cystic fibrosis (CF) protein (CFTR) resides at the cell surface and ensures normal water and ion composition of the liquid that lines the airway. CF mutations impair CFTR function and the composition of the airway surface liquid layer. This leads to lung infection and uncontrolled inflammation, the primary cause of premature death in CF. Robust correction of these defects has been achieved for only 9 rare mutations, by ivacaftor, representing a small subset of >2000 mutations, corresponding to ~5% of the CF patient population. The recently approved FDA drug combination of lumacaftor and ivacaftor (Orkambi) targets the most common mutation with variable clinical benefit: 50% of patients gained >5% (FEV1) lung function, while the others showed no or only very modest benefit, indicating a substantial variability of responsiveness. Importantly, the drug susceptibility of most other CFTR mutations, which may be correctable, is still unexplored. To overcome the limited efficacy of the available drugs, there is unmet need for authentic and validated model systems for preclinical investigations. We will implement novel "primary" cell based models derived from noninvasively collected nasal epithelial cells. Based on our preliminary data, this model will maintain patient specific hallmarks of airways cells expressing rare CF mutations. To complement this approach, we will generate 60 of the rare mutations in respiratory epithelial cell lines and use these models for testing approved drugs and optimizing novel combinations of investigational CF drugs in functional and biochemical assays. Promising combinations will be validated in human airway cells and their effect will be compared to their clinical benefit to identify mutation and patient specific treatment protocols.