Ivacaftor partially corrects airway inflammation in a humanized G551D rat

Abstract

Animal models have been highly informative for understanding the pathogenesis and progression of cystic fibrosis (CF) lung disease. In particular, the CF rat models recently developed have addressed mechanistic causes of the airway mucus defect characteristic of CF, and how these may change when CFTR activity is restored using new modulator therapies. We hypothesized that inflammatory changes to the airway would develop spontaneously and progressively, and that these changes would be resolved with modulator therapy. To test this, we used a humanized-CFTR rat expressing the G551D variant that responds to the CFTR modulator ivacaftor. Markers typically found in the CF lung were assessed, including neutrophil influx, small airway histopathology, and inflammatory cytokine concentration. Young hG551D rats did not express inflammatory cytokines at baseline but did upregulate these in response to inflammatory trigger. As the hG551D rats aged, histopathology worsened, accompanied by neutrophil influx into the airway and increasing concentrations of TNF-α, IL-1α, and IL-6 in the airways. Ivacaftor administration reduced concentrations of these cytokines when administered to the rats at baseline but was less effective in the rats that had also received inflammatory stimulus. Therefore, we conclude that administration of ivacaftor resulted in an incomplete resolution of inflammation when rats received an external trigger, suggesting that CFTR activation may not be enough to resolve inflammation in the lungs of patients with CF.

Muc5b Contributes to Mucus Abnormality in Rat Models of Cystic Fibrosis

“…which leaves patients with a burden of morbidity that continues to require additional therapies. Mechanistically it is not yet understood why HEMT regimens fail to completely restore lung health, although recently published data from our group indicates that ivacaftor restores inflammatory metrics incompletely following inflammatory trigger ( Green et al, 2021 ). The data presented in the present study indicate that Muc5b in the hG551D rat is restored to WT following ivacaftor administration, but that potentiator therapy is less effective at reducing Muc5ac.…”

Revisiting Host-Pathogen Interactions in Cystic Fibrosis Lungs in the Era of CFTR Modulators

“…The findings indicate that early therapy prevents perinatal disease and the maintenance of therapy is necessary to prevent disease reoccurrence. The effect of ivacaftor has also been tested on G551D humanized rats regarding age-dependent abnormalities of the airway mucus [201] and inflammation [202]. Additional animal studies also confirm that MCC improves with CFTR modulator therapy.…”

The rat takes the cheese: a novel model of CFTR-dependent chronic bacterial airway infection

“…An important future direction of this study will be to use biologically relevant CFTR mutations (e.g. F508del), or mutations sensitive to pharmacological (G551D [14,15],) or genetic [16] correction, as the genetic background.…”