LAUSR

RATIONALE Animal models have been highly informative for understanding characteristics, onset, and progression of cystic fibrosis (CF) lung disease. In particular, the CFTR-/- rat has revealed insights into the airway mucus defect characteristic of CF, but does not replicate a human-relevant CFTR variant. OBJECTIVE We hypothesized that a rat expressing a humanized version of CFTR, harboring the ivacaftor-sensitive variant G551D, could be used to test the impact of CFTR modulators on pathophysiologic development and correction. METHODS In this study, we describe a humanized-CFTR rat expressing the G551D variant, obtained by zinc finger nuclease editing of a human cDNA super-exon, spanning exon 2-27, with a 5' insertion site into the rat gene just beyond intron 1. This targeted insertion takes advantage of the endogenous rat promoter, resulting in appropriate expression compared to wild-type. MEASUREMENTS AND MAIN RESULTS The bioelectric phenotype of the epithelia recapitulates the expected absence of CFTR activity, which was restored with ivacaftor. Large airway defects, including depleted airway surface liquid and periciliary layers, delayed mucus transport rates, and increased mucus viscosity were normalized following administration of ivacaftor. CONCLUSIONS This model is useful to understand mechanisms of disease and the extent of pathology reversal with CFTR modulators.