Pharmacological correction of CFTR improves systemic inflammation and lung disease in Cystic Fibrosis but does not correct a basic defect in lung repair

BackgroundCystic Fibrosis (CF) is a lethal genetic condition affecting over 100,000 people worldwide, characterised by multi-organ dysfunction and a progressive lethal lung disease. The disease occurs due to faulty cystic fibrosis transmembrane conductance regulator (CFTR) ion channels effecting flow of chloride, bicarbonate and water out of cells. This causes thick mucus with repeated bacterial infections, systemic inflammation and a decrease in lung function. CFTR modulator therapies have shown variable improvements in lung function and reduction in exacerbation frequency. Basal cells within the lung act as a stem cell for repair following injury and can repopulate the epithelial layer. This process is dysfunctional in CF causing progressive damage. Spontaneous lung repair is well described but not well characterised. Nothing is known about the effects of CFTR modulator therapy on these cells, but this could be of major consequence for people with CF (pwCF). AimsTo determine the effects of CFTR modulator therapy on the activity of CF basal cells and relate this to progenitor function and to study the effects of CFTR modulators on systemic inflammation and clinical outcomes. MethodsClinical information, blood and nasal brushes were obtained from pwCF prior to commencing modulator therapy and at multiple time points up until 1 year of treatment. 10 pwCF were recruited to undertake thoracic CT scans pre-treatment and at 1 year of therapy. Nasal samples were used to isolate basal cells and serum to study systemic markers of inflammation. RNA sequencing of basal cells was undertaken by Ilumina Novoseq to a depth of 20 million read pairs and gene ontology analysis was performed. Functional assays of basal cell activity were carried out. Proteomic analysis and ELISAs were undertaken to determine changes in inflammatory cytokines within the serum across the first year of treatment. Quantitative results were generated by Lung Quantification (LungQ) analysis with qualitative reports from independent radiologists. Results were compared with clinical outcomes. Results110 pwCF were recruited in total who commenced a commercially available CFTR modulator therapy. Serum samples were collected from 77pwCF, nasal brushes obtained from 40 pwCF and 10 completed their CT scans following 1 year of highly effective CFTR modulator therapy. Systemic IL-6, CRP and calprotectin (a biomarker of CF exacerbation) were all significantly reduced with highly effective CFTR modulator treatment. Clinical results were in keeping with those seen in published CFTR modulator clinical trials with improvement in lung function, weight, and exacerbation frequency. Subjective improvements were seen in all 10 CT scans following 1 year of modulator therapy. Significant reductions were seen in airway wall thickening and reduction in thoracic lymphadenopathy were also observed. Basal cell RNA sequencing showed that the relative expression of 2570 genes were significantly different following treatment with CFTR modulators. Ontology analysis showed enrichment in multiple pathways including cilliagenesis and Notch signalling, a key pathway in lung tissue development and homeostasis. Functional assays exhibited a deficit in repair mechanisms of the CF basal cell compared to healthy controls, and reduction in progenitor function. ConclusionsAlthough CFTR modulators improve multiple clinical and radiological outcomes, they also have impacts on basal cell function. There are however, limited impacts on systemic inflammation and more work is needed in this area to understand the disease process.