Elexacaftor/tezacaftor/ivacaftor (ETI) therapy modifies the expression of interferon beta and inflammatory genes in the airways of adult patients with cystic fibrosis: a pilot study

Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies have revolutionized the treatment of cystic fibrosis (CF) by targeting the underlying protein defect. Investigating how elexacaftor/tezacaftor/ivacaftor (ETI) therapy affects interferon (IFN) signalling and inflammatory cytokine production in CF airway epithelial cells may clarify its role in alleviating the dysregulated innate immune response. Clinical efficacy was evaluated in 26 modulator-naive CF patients with at least one F508del mutation before and after 3 and 6 months of ETI treatment. Type I/III IFNs, IFNLR1, IFN-stimulated genes (ISG15, ISG56), interleukin 8 (IL-8) and IL-1 beta mRNA levels were analysed by RT real-time PCR in CF airway samples (n = 74). Patients showed significant improvements in pulmonary function (ppFEV1, 3 months: 12.5%, 6 months: 17.6%), BMI (3 months: 0.9 kg/m2, 6 months: 1.4 kg/m2), and sweat chloride (3 months: - 32.1 mEq/L, 6 months: - 44.4 mEq/L) compared to baseline (all p <= 0.001). The total number of exacerbations was also reduced (p = 0.002). Increased levels of IFN beta (p < 0.001) were found after 6 months of ETI therapy, whilst ISG15 and ISG56 decreased significantly (p = 0.022, p = 0.004). After 3 months, CF patients produced reduced levels of IL-8 and IL-1 beta (p = 0.001, p = 0.011) and even significantly lower levels after 6 months (p < 0.001, p < 0.001). ETI treatment appears to restore IFN beta expression and reduce levels of inflammatory genes (ISGs, IL-8 and IL-1 beta) in the airways, highlighting the potential of ETI to improve the dysregulated inflammatory status in CF.