In Vivo Screening for Cystic Fibrosis Drugs: Transfer of Clinical Read‐Out Parameters in CF Patients to the delF508 CFTR CF Mice

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Background and Objectives Cystic fibrosis (CF) is a life threating disease with no approved, disease modifying therapy for the most common delF508 CFTR mutation. We aim to identify new drugs able to correct delF508 CFTR. Therefore, we established in vivo read outs in CF mice, which reflect the basic characteristics as decreased sweat secretion, increased sweat chloride concentration and decreased nasal potential difference (NPD) of CF patients. Study design & Measurements: Use of CFTR knockout mice (CFTRtm1Unc), two delF508 CFTR mice strains (CFTRtm1Kth and CFTRtm1Eur) and wild type (WT) mice. Establishment of the measurements for: A) the isoprenaline-stimulated salivary secretion in the presence of atropine B) the pilocarpine-stimulated salivary chloride concentration and C) the forskolin-stimulated nasal potential difference (NPD) in the presence of amiloride and zero-chloride. Results & Conclusion We found a) a decrease in salivary secretion, b) a decrease in salivary chloride concentration and c) a decrease in nasal potential difference of delF508 CF mice. These changes correlate with a) a decrease in sweat production, b) a decrease in sweat chloride concentration and c) a decrease in nasal potential difference in delF508 CF patients. Therefore, the good correlation of our preclinical read outs in CF mice to the validated clinical read-out parameters, could help to identify new and effective causal treatment options for delF508 CF patients.