Anti-inflammatory and phosphorylation effects of CFTR modulator triple therapy in cystic fibrosis

Cystic Fibrosis is an autosomal recessive disorder caused by mutations in the CFTR gene, which encodes a key chloride channel, leading to impaired ion transport and severe progressive respiratory failure. CFTR modulators, such as Trikafta© has improved morbidity in CF, but its systemic effects remain unclear. This study evaluated the clinical outcomes, safety, and cellular mechanisms of Trikafta© in young children (< 11 years) with CF using a multi-omic approach. Seventeen children with CF (median age 8.7 years, 26% female) and 12 healthy controls (median age 9.6 years, 42% female) were included for multi-omic analysis. The analysis included RNA sequencing, proteomics and phosphoproteomics. Baseline pathway enrichment analysis (FDR < 0.05) revealed systemic inflammation, transmembrane transporter deficiencies, reduced protein kinase, and reduced GTPase activity. Three months post-Trikafta© treatment, anti-inflammatory effects, epigenetic modulation, and increased protein kinase activity were observed, indicating partial reversal of cellular abnormalities. Trikafta© improves clinical outcomes and reduces inflammation, epigenetic changes and key phosphorylation pathways in young children with CF, offering insights into CF pathology and potential biomarkers for monitoring treatment.