Exploring the relationship between loss of CFTR protein function and markers of disease severity in chronic suppurative lung disease

Cystic fibrosis (CF) and Primary Ciliary Dyskinesia (PCD) are chronic suppurative lung diseases (CSLD). CF is characterised by inherited mutations affecting the cystic fibrosis transmembrane regulator (CFTR) protein, which is thought to be normal in PCD, however the role of CFTR in disease is incompletely understood. This thesis investigates the relationship between CFTR, inflammation and airway health, firstly in the context of the CF gene therapy Multidose trial followed by contrasting CF, PCD and control patients. The first study explored the relationship between lower airway potential difference (LAPD) measurements performed in the Multidose trial as a measure of CFTR function, and physiological, radiographic and inflammatory markers of disease severity. At baseline, FEV1 correlated with basal LAPD measurements, however not between restored chloride secretion and change in airway disease following treatment; implicating the role of sodium transport, not chloride in disease pathogenesis. As no direct correlation was seen, I went on to explore an alternative theory that a bi-directional relationship exists between CFTR and inflammation; CFTR dysfunction triggers a hyper-inflammatory state and inflammation causes secondary CFTR dysfunction. Cell cultures were cultivated from the nasal epithelium of patients with CF, PCD and controls. Both at baseline and following stimulation with common respiratory pathogens, the levels of inflammatory mediators in the supernatant from each group of cells were comparable. The numbers involved with this study were small, however did not indicate that CF cells cultured in these conditions (in vitro) were hyper-inflammatory. The final study explored in vivo whether inflammation causes secondary CFTR dysfunction. Nasal potential difference (NPD) measurements were compared with localised levels of inflammation in subjects with CF, PCD and controls. PCD traces showed reduced chloride secretion, however it was not possible to differentiate secondary CFTR dysfunction from damage to epithelial cell integrity. Elevated levels of inflammatory mediators were detected in PCD nasal fluid, however the results were variable and these levels did not correlate with NPD measurements of ion channel function. These studies did not support the hypothesis that there is a direct relationship between CFTR function and airway disease, that in vitro CF cells are hyperinflammatory, or in vivo that inflammation leads to secondary CFTR dysfunction. The experiments performed in this thesis provide a basis for future work exploring this relationship, and may help guide future trials for novel therapies in CF.Open Acces

Political geographies of the object

This paper examines the role of objects in the constitution and exercise of state power, drawing on a close reading of the acclaimed HBO television series The Wire, an unconventional crime drama set and shot in Baltimore, Maryland. While political geography increasingly recognizes the prosaic and intimate practices of stateness, we argue that objects themselves are central to the production, organization, and performance of state power. Specifically, we analyze how three prominent objects on The Wire—wiretaps, cameras, and standardized tests—arrange and produce the conditions we understand as ‘stateness’. Drawing on object-oriented philosophy, we offer a methodology of power that suggests it is generalized force relations rather than specifically social relations that police a population—without, of course, ever being able to fully capture it. We conclude by suggesting The Wire itself is an object of force, and explore the implications of an object-oriented approach for understanding the nature of power, and for political geography more broadly

Proceedings of the 3rd BEAT-PCD Conference and 4th PCD Training School

Abstract Primary ciliary dyskinesia (PCD) is a chronic suppurative airways disease that is usually recessively inherited and has marked clinical phenotypic heterogeneity. Classic symptoms include neonatal respiratory distress, chronic rhinitis since early childhood, chronic otitis media, recurrent airway infections leading to bronchiectasis, chronic sinusitis, laterality defects with and without congenital heart disease including abnormal situs in approximately 50% of the cases, and male infertility. Lung function deteriorates progressively from childhood throughout life. ‘Better Experimental Approaches to Treat Primary Ciliary Dyskinesia’ (BEAT-PCD) is a network of scientists and clinicians coordinating research from basic science through to clinical care with the intention of developing treatments and diagnostics that lead to improved long-term outcomes for patients. BEAT-PCD activities are supported by EU funded COST Action (BM1407). The third BEAT-PCD conference and fourth PCD training school were held jointly in February 2018 in Lisbon, Portugal. Presentations and workshops focussed on advancing the knowledge and skills relating to PCD in: basic science, epidemiology, diagnostic testing, clinical management and clinical trials. The multidisciplinary conference provided an interactive platform for exchanging ideas through a program of lectures, poster presentations, breakout sessions and workshops. Three working groups met to plan consensus statements. Progress with BEAT-PCD projects was shared and new collaborations were fostered. In this report, we summarize the meeting, highlighting developments made during the meeting

Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis:a randomised, double-blind, placebo-controlled, phase 2b trial

Background: Lung delivery of plasmid DNA encoding the CFTR gene complexed with a cationic liposome is a potential treatment option for patients with cystic fibrosis. We aimed to assess the efficacy of non-viral CFTR gene therapy in patients with cystic fibrosis. Methods: We did this randomised, double-blind, placebo-controlled, phase 2b trial in two cystic fibrosis centres with patients recruited from 18 sites in the UK. Patients (aged ≥12 years) with a forced expiratory volume in 1 s (FEV1) of 50–90% predicted and any combination of CFTR mutations, were randomly assigned, via a computer-based randomisation system, to receive 5 mL of either nebulised pGM169/GL67A gene–liposome complex or 0·9% saline (placebo) every 28 days (plus or minus 5 days) for 1 year. Randomisation was stratified by % predicted FEV1 (<70 vs ≥70%), age (<18 vs ≥18 years), inclusion in the mechanistic substudy, and dosing site (London or Edinburgh). Participants and investigators were masked to treatment allocation. The primary endpoint was the relative change in % predicted FEV1. The primary analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT01621867. Findings: Between June 12, 2012, and June 24, 2013, we randomly assigned 140 patients to receive placebo (n=62) or pGM169/GL67A (n=78), of whom 116 (83%) patients comprised the per-protocol population. We noted a significant, albeit modest, treatment effect in the pGM169/GL67A group versus placebo at 12 months' follow-up (3·7%, 95% CI 0·1–7·3; p=0·046). This outcome was associated with a stabilisation of lung function in the pGM169/GL67A group compared with a decline in the placebo group. We recorded no significant difference in treatment-attributable adverse events between groups. Interpretation: Monthly application of the pGM169/GL67A gene therapy formulation was associated with a significant, albeit modest, benefit in FEV1 compared with placebo at 1 year, indicating a stabilisation of lung function in the treatment group. Further improvements in efficacy and consistency of response to the current formulation are needed before gene therapy is suitable for clinical care; however, our findings should also encourage the rapid introduction of more potent gene transfer vectors into early phase trials