Changes in fecal microbiota with CFTR modulator therapy: A pilot study.

Studies have demonstrated that people with CF with pancreatic insufficiency (PI) have fecal dysbioses. Evidence suggests the causes of these dysbioses are multifactorial, and that important drivers include antibiotic exposure, dietary intake, and CF gastrointestinal tract dysfunction, including nutrient malabsorption. In this pilot study, we tested whether initiation of the CFTR modulator treatments ivacaftor (in a cohort of pancreatic sufficient (PS) people with CF and an R117H CFTR variant) or lumacaftor/ivacaftor (in a cohort of PI people with CF and an F508del variant) changed fecal measures of malabsorption or fecal microbiomes. While we identified no statistically significant fecal changes with either treatment, we detected trends in the PI cohort when initiating lumacaftor/ivacaftor towards decreased fecal fat content and towards fecal microbiomes that more closely resembled the fecal microbiota of people without PI. While these findings support a model in which nutrient malabsorption resulting from CF-induced PI drives fecal dysbiosis, they must be validated in future, larger studies of fecal microbiome and malabsorption outcomes with highly effective CFTR modulator therapies.

Targeting the PI3K/Akt/mTOR signalling pathway in Cystic Fibrosis.

Deletion of phenylalanine 508 of the cystic fibrosis transmembrane conductance regulator (ΔF508 CFTR) is a major cause of cystic fibrosis (CF), one of the most common inherited childhood diseases. ΔF508 CFTR is a trafficking mutant that is retained in the endoplasmic reticulum (ER) and unable to reach the plasma membrane. Efforts to enhance exit of ΔF508 CFTR from the ER and improve its trafficking are of utmost importance for the development of treatment strategies. Using protein interaction profiling and global bioinformatics analysis we revealed mammalian target of rapamycin (mTOR) signalling components to be associated with ∆F508 CFTR. Our results demonstrated upregulated mTOR activity in ΔF508 CF bronchial epithelial (CFBE41o-) cells. Inhibition of the Phosphatidylinositol 3-kinase/Akt/Mammalian Target of Rapamycin (PI3K/Akt/mTOR) pathway with 6 different inhibitors demonstrated an increase in CFTR stability and expression. Mechanistically, we discovered the most effective inhibitor, MK-2206 exerted a rescue effect by restoring autophagy in ΔF508 CFBE41o- cells. We identified Bcl-2-associated athanogene 3 (BAG3), a regulator of autophagy and aggresome clearance to be a potential mechanistic target of MK-2206. These data further link the CFTR defect to autophagy deficiency and demonstrate the potential of the PI3K/Akt/mTOR pathway for therapeutic targeting in CF.

Ivacaftor as salvage therapy in a patient with cystic fibrosis genotype F508del/R117H/IVS8-5T.

Ivacaftor is a novel CFTR potentiator that increases CFTR activity and improves clinical outcomes in cystic fibrosis (CF) patients with at least one copy of CFTR-G551D. Clinical trials have shown an improvement in lung function, weight and CF pulmonary exacerbation in adults with CFTR-G551D leading to the approval of ivacaftor as a novel CF therapy [1]. In vitro studies of ivacaftor have also shown significant improvements in CFTR chloride channel opening time in other non-G551D CFTR mutations suggesting that ivacaftor may be of benefit to patients with mutations other than gating mutations [2]. R117H-CFTR is a relatively common CFTR mutation that demonstrates an in-vitro response to ivacaftor [2,3]. A clinical trial has suggested that there may be a role for ivacaftor in older patients with R117H-CFTR although this trial did not include patients with very severe CF lung disease [4]. In 2014, ivacaftor was approved in the United States as a treatment for CF subjects aged greater than 6 years old with a copy of R117H-CFTR. We present a case demonstrating a substantial therapeutic effect of ivacaftor in a CF patient with genotype F508del/R117H and advanced lung disease.

Experience using centralized spirometry in the phase 2 randomized, placebo-controlled, double-blind trial of denufosol in patients with mild to moderate cystic fibrosis.

BACKGROUND: Centralized spirometry may significantly improve quality of spirometry and reduce variability of this outcome measure in clinical trials in cystic fibrosis (CF). METHODS: Spirometry was performed during the phase 2 randomized, placebo-controlled, double-blind clinical trial of denufosol in patients with mild to moderate CF using American Thoracic Society guidelines. Uniform spirometers were used with electronic data transmission of all the data to a reading center. Spirometry was evaluated for quality by a central reader based on start of test, cough during the test, and evidence of a plateau. RESULTS: A total of 1418 spirometry values were assessed in 89 subjects during the trial. In only 5 instances did the central reading center need to give feedback to sites regarding the quality of spirometry. The study site data matched the central reading center's data for all but 78 (6%) spirometry values in 33 patients. Many of these differences were small with only 35 (3%) values differing by more than 50 mL in 26 patients. CONCLUSION: Spirometry in this clinical trial was of high quality with low rate of significant centralized over-read.

The role of supplemental oxygen during submaximal exercise in patients with cystic fibrosis.

Repeated bouts of submaximal exercise are an important part of most pulmonary rehabilitation programmes. Patients with moderate-to-severe cystic fibrosis (CF) often demonstrate oxygen desaturation during submaximal exercise, which may limit their ability to participate in these programmes. This study examines whether arterial desaturation contributes to submaximal exercise limitation by testing whether supplemental O2 improves submaximal exercise capacity. Eight patients with CF (mean forced expiratory volume in one second 41% predicted) each underwent two submaximal exercise tests on a bicycle ergometer at 80% of maximal workload. The two tests were identical except for the addition of supplemental O2 (inspiratory O2 fraction 39%) during one of the tests. Exercise duration was significantly longer in the supplemental O2 study versus control (673+/-63 s versus 835+/-99 s). Arterial O2 saturation was also higher in the supplemental O2 study than the control exercise test (96+/-0.3% versus 86+/-1.5%). There was no statistical difference at end exercise between O2 consumption, minute ventilation and heart rate. There was a significant relationship between improvement in exercise capacity and the amount of desaturation during the control exercise test. Results indicate that supplemental oxygen improves submaximal exercise capacity in patients with moderate-to-severe cystic fibrosis. Oxygen therapy may be an important intervention to improve participation and maximise the benefits of pulmonary exercise rehabilitation programmes.

Reproducibility of maximal exercise ergometer testing in patients with cystic fibrosis.

OBJECTIVES: Exercise testing in patients with cystic fibrosis (CF) has become an important tool in assessing disease severity and predicting overall outcome. The reproducibility of maximal exercise testing was examined in adult subjects with stable CF. METHODS: Nine subjects with CF underwent a total of three maximal exercise tests carried out under identical circumstances over a 28-day period. Oxygen uptake (VO2), minute ventilation (VE), respiratory frequency (f), heart rate (HR), and arterial oxygen saturation (SaO2) were measured at rest, at end exercise, and at 40% and 70% of maximum workload. RESULTS: There were no significant differences in these measurements among the three tests. Reproducibility of exercise performance was assessed using the coefficient of variation. The mean within-subject coefficient of variation for test variables at end exercise are as follows: VO2, 6.9%; VE, 6.2%; f, 5.8%; IIR, 3.0%; and SaO2, 1.1%. The mean within-subject coefficient of variation for test variables at 40% and 70% of maximal work rates are as follows: VO2, 5.2% and 4.6%; SaO2, 0.3% and 0.9%; HR, 4.0% and 3%; VE, 5.7% and 6.5%; and f, 5.8% and 7.2%, respectively. CONCLUSIONS: Variables measured during clinical cycle ergometer exercise testing in adult patients with stable CF are reproducible. No learning effect was found on repeated testing.