Effects of ivacaftor on systemic inflammation and the plasma proteome in people with CF and G551D

• Published in: Journal of cystic fibrosis 2022-11, Vol.21 (6), p.950-958
• Main Authors: Hoppe, Jordana E., Wagner, Brandie D., Kirk Harris, J., Rowe, Steven M., Heltshe, Sonya L, DeBoer, Emily M., Sagel, Scott D.
• Format: Article
• Language: English
• Subjects: Aminophenols - therapeutic use; Calreticulin - genetics; Calreticulin - metabolism; CFTR modulation; Cystic Fibrosis - drug therapy; Cystic Fibrosis - genetics; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism; Extrapulmonary; Granulocyte Colony-Stimulating Factor; HMGB Proteins - genetics; HMGB Proteins - metabolism; Humans; Inflammation; Inflammation - drug therapy; Insulin-Like Growth Factor I - genetics; Insulin-Like Growth Factor I - metabolism; Leptin - genetics; Leptin - metabolism; Leukocyte L1 Antigen Complex - genetics; Leukocyte L1 Antigen Complex - metabolism; Lipids; Mutation; Proteome - genetics; Proteome - metabolism; Proteomics; Respiratory System Agents - therapeutic use
• ISSN: 1569-1993; 1873-5010
• DOI: 10.1016/j.jcf.2022.03.012

•Ivacaftor led to sustained reductions in serum HMGB-1 and calprotectin.•SAA and G-CSF decreased and IGF-1 increased 1 month after treatment initiation.•Proteomic analyses identified 9 proteins that changed significantly with ivacaftor.•Ivacaftor altered lipid digestion/transport and extracellular matrix organization proteins.•These changes lend insight into the extrapulmonary effects of CFTR modulation. Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator for people with CF and the G551D mutation. We aimed to investigate the biology of CFTR modulation and systemic effects of CFTR restoration by examining changes in circulating measurements of inflammation and growth and novel proteins with ivacaftor treatment. Blood samples from 64 CF subjects with G551D-CFTR were analyzed for inflammatory and growth-related proteins at baseline, 1 and 6 months after ivacaftor initiation. In 30 subjects, plasma was assayed for 1,322 proteins using the SomaScan proteomic platform at baseline and 6 months post-ivacaftor. Correlations with clinical outcomes were assessed. Significant reductions in high mobility group box-1 protein (HMGB-1), calprotectin, serum amyloid A, and granulocyte colony-stimulating factor (G-CSF), and an increase in insulin-like growth factor (IGF-1) occurred 1 month after ivacaftor. This treatment effect was sustained at 6 months for HMGB-1 and calprotectin. Correcting for multiple comparisons in the proteomic analysis, 9 proteins (albumin, afamin, leptin, trypsin, pancreatic stone protein [PSP], pituitary adenylate cyclase-activating polypeptide-38, repulsive guidance molecule A [RGMA], calreticulin, GTPase KRas) changed significantly with ivacaftor. Proteins changing with treatment are involved in lipid digestion and transport and extracellular matrix organization biological processes. Reductions in calprotectin and G-CSF and increases in calreticulin, and RGMA correlated with improved lung function, while increasing IGF-1, leptin and afamin and decreasing PSP correlated with increased weight. Ivacaftor led to changes in inflammatory, lipid digestion, and extracellular matrix proteins, lending insights into the extrapulmonary effects of CFTR modulation.