Cystic fibrosis gene modifier SLC26A9 modulates airway response to CFTR-directed therapeutics.

Cystic fibrosis is realizing the promise of personalized medicine. Recent advances in drug development that target the causal CFTR directly result in lung function improvement, but variability in response is demanding better prediction of outcomes to improve management decisions. The genetic modifier SLC26A9 contributes to disease severity in the CF pancreas and intestine at birth and here we assess its relationship with disease severity and therapeutic response in the airways. SLC26A9 association with lung disease was assessed in individuals from the Canadian and French CF Gene Modifier consortia with CFTR-gating mutations and in those homozygous for the common Phe508del mutation. Variability in response to a CFTR-directed therapy attributed to SLC26A9 genotype was assessed in Canadian patients with gating mutations. A primary airway model system determined if SLC26A9 shows modification of Phe508del CFTR function upon treatment with a CFTR corrector. In those with gating mutations that retain cell surface-localized CFTR we show that SLC26A9 modifies lung function while this is not the case in individuals homozygous for Phe508del where cell surface expression is lacking. Treatment response to ivacaftor, which aims to improve CFTR-channel opening probability in patients with gating mutations, shows substantial variability in response, 28% of which can be explained by rs7512462 in SLC26A9 (P = 0.0006). When homozygous Phe508del primary bronchial cells are treated to restore surface CFTR, SLC26A9 likewise modifies treatment response (P = 0.02). Our findings indicate that SLC26A9 airway modification requires CFTR at the cell surface, and that a common variant in SLC26A9 may predict response to CFTR-directed therapeutics.

Effects of positive end-expiratory pressure on oscillated volume during high frequency chest compression in children with cystic fibrosis.

OBJECTIVE: To investigate the effects of positive end-expiratory pressure (PEEP) on end-expiratory lung volume (EELV) and mean oscillated volume (V(osc)) during high frequency chest compression (HFCC). DESIGN: A clinic-based prospective intervention study. SETTING: Pulmonary function laboratory, University of Alberta, Edmonton, Alberta. POPULATION: Nine children with cystic fibrosis with little or no obstructive airway disease who were selected from the outpatient Cystic Fibrosis and Pediatric Pulmonary Clinics at the University of Alberta Hospital, Edmonton, Alberta. METHODS: Each child received HFCC alone (at 10 Hz with chest wall pressure of 8 cm H2O) and HFCC plus PEEP. A closed circuit spirometry system was used to measure HFCC- and PEEP-induced changes in EELV, expressed as per cent baseline functional residual capacity (FRC) measured using helium dilution. An isothermic chamber permitted measurement of V(osc). RESULTS: HFCC caused a significant 9% decrease in EELV. Adding 2.0 +/- 0.3 cm H2O of PEEP increased EELV back to at least the FRC level. With HFCC alone, Vosc was significantly lower during spontaneous expiration than during spontaneous inspiration, but adding PEEP to HFCC increased V(osc), especially during spontaneous expiration. CONCLUSIONS: Adding PEEP during HFCC prevents the decrease in EELV and increases V(osc). Therefore, PEEP may improve HFCC-induced mucus clearance in children with cystic fibrosis.