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1.  Airway remodelling in children with cystic fibrosis 
Thorax  2007;62(12):1074-1080.
Background
The relationship between airway structural changes and inflammation is unclear in early cystic fibrosis (CF) lung disease. A study was undertaken to determine changes in airway remodelling in children with CF compared with appropriate disease and healthy controls.
Methods
Bronchoalveolar lavage and endobronchial biopsy were performed in a cross‐sectional study of 43 children with CF (aged 0.3–16.8 years), 7 children with primary ciliary dyskinesia (PCD), 26 with chronic respiratory symptoms (CRS) investigated for recurrent infection and/or cough and 7 control children with no lower airway symptoms. Inflammatory cells, cytokines, proteases and matrix constituents were measured in bronchoalveolar lavage fluid (BALF). Reticular basement membrane (RBM) thickness was measured on biopsy specimens using light microscopy.
Results
Increased concentrations of elastin, glycosaminoglycans and collagen were found in BALF from children with CF compared with the CRS group and controls, each correlating positively with age, neutrophil count and proteases (elastase activity and matrix metalloproteinase‐9 (MMP‐9) concentration). There were significant negative correlations between certain of these and pulmonary function (forced expiratory volume in 1 s) in the CF group (elastin: r = −0.45, p<0.05; MMP‐9:TIMP‐1 ratio: r = −0.47, p<0.05). Median RBM thickness was greater in the CF group than in the controls (5.9 μm vs 4.0 μm, p<0.01) and correlated positively with levels of transforming growth factor‐β1 (TGF‐β1; r = 0.53, p = 0.01), although not with other inflammatory markers or pulmonary function.
Conclusions
This study provides evidence for two forms of airway remodelling in children with CF: (1) matrix breakdown, related to inflammation, proteolysis and impaired pulmonary function, and (2) RBM thickening, related to TGF‐β1 concentration but independent of other markers of inflammation.
doi:10.1136/thx.2006.074641
PMCID: PMC2094274  PMID: 17526676
2.  Gene therapy for the treatment of cystic fibrosis 
Gene therapy is being developed as a novel treatment for cystic fibrosis (CF), a condition that has hitherto been widely-researched yet for which no treatment exists that halts the progression of lung disease. Gene therapy involves the transfer of correct copies of cystic fibrosis transmembrane conductance regulator (CFTR) DNA to the epithelial cells in the airways. The cloning of the CFTR gene in 1989 led to proof-of-principle studies of CFTR gene transfer in vitro and in animal models. The earliest clinical trials in CF patients were conducted in 1993 and used viral and non-viral gene transfer agents in both the nasal and bronchial airway epithelium. To date, studies have focused largely on molecular or bioelectric (chloride secretion) outcome measures, many demonstrating evidence of CFTR expression, but few have attempted to achieve clinical efficacy. As CF is a lifelong disease, turnover of the airway epithelium necessitates repeat administration. To date, this has been difficult to achieve with viral gene transfer agents due to host recognition leading to loss of expression. The UK Cystic Fibrosis Gene Therapy Consortium (Imperial College London, University of Edinburgh and University of Oxford) is currently working on a large and ambitious program to establish the clinical benefits of CF gene therapy. Wave 1, which has reached the clinic, uses a non-viral vector. A single-dose safety trial is nearing completion and a multi-dose clinical trial is shortly due to start; this will be powered for clinically-relevant changes. Wave 2, more futuristically, will look at the potential of lentiviruses, which have long-lasting expression. This review will summarize the current status of translational research in CF gene therapy.
doi:10.2147/TACG.S8873
PMCID: PMC3681190  PMID: 23776378
cystic fibrosis transmembrane conductance regulator (CFTR) gene; gene expression; gene transfer agents (GTAs); outcome measures
3.  Bronchoscopy following diagnosis with cystic fibrosis 
Archives of Disease in Childhood  2006;92(10):898-899.
We recently changed our practice to perform bronchoscopy following diagnosis with cystic fibrosis. On a retrospective review of 25 children, Pseudomonas aeruginosa was detected in bronchoalveolar lavage for the first time in five children (20%) and Staphylococcus aureus in four (16%). Lavage culture was positive in eight of 18 children without respiratory symptoms. This highlights the potential of bronchoscopy following diagnosis, even in asymptomatic children.
doi:10.1136/adc.2006.105825
PMCID: PMC2083238  PMID: 17088336
4.  Assessment of F/HN-Pseudotyped Lentivirus as a Clinically Relevant Vector for Lung Gene Therapy 
Rationale: Ongoing efforts to improve pulmonary gene transfer thereby enabling gene therapy for the treatment of lung diseases, such as cystic fibrosis (CF), has led to the assessment of a lentiviral vector (simian immunodeficiency virus [SIV]) pseudotyped with the Sendai virus envelope proteins F and HN.
Objectives: To place this vector onto a translational pathway to the clinic by addressing some key milestones that have to be achieved.
Methods: F/HN-SIV transduction efficiency, duration of expression, and toxicity were assessed in mice. In addition, F/HN-SIV was assessed in differentiated human air–liquid interface cultures, primary human nasal epithelial cells, and human and sheep lung slices.
Measurements and Main Results: A single dose produces lung expression for the lifetime of the mouse (∼2 yr). Only brief contact time is needed to achieve transduction. Repeated daily administration leads to a dose-related increase in gene expression. Repeated monthly administration to mouse lower airways is feasible without loss of gene expression. There is no evidence of chronic toxicity during a 2-year study period. F/HN-SIV leads to persistent gene expression in human differentiated airway cultures and human lung slices and transduces freshly obtained primary human airway epithelial cells.
Conclusions: The data support F/HN-pseudotyped SIV as a promising vector for pulmonary gene therapy for several diseases including CF. We are now undertaking the necessary refinements to progress this vector into clinical trials.
doi:10.1164/rccm.201206-1056OC
PMCID: PMC3530223  PMID: 22955314
lentivirus; cystic fibrosis; gene therapy; lung; gene transfer
5.  The Th17 Pathway in Cystic Fibrosis Lung Disease 
Rationale
Cystic fibrosis (CF) is characterized by bronchoalveolar neutrophilia and submucosal lymphocytosis. We hypothesized that Th17 lymphocytes are part of this submucosal infiltrate.
Objectives
Quantification and phenotyping of the lymphocytic infiltrate in the bronchial submucosa of patients with CF (n=53, of which 20 were newly diagnosed), non-CF bronchiectasis (n = 17), and healthy control subjects (n = 13).
Methods
We measured IL-17 levels in bronchoalveolar lavage and CD4+, CD8+, and IL-17+ cell counts in endobronchial biopsies. Correlations were made with infection status and other inflammatory markers. Potential cellular sources of IL-17 were determined by double staining.
Measurements and Main Results
IL-17+ cell counts (median [interquartile range] cells/mm2) were significantly higher in patients with established CF (205 [115–551]) and non-CF bronchiectasis (245 [183–436]) than in control subjects (53 [12–82]) (P<0.01 for both). Patients with newly diagnosed CF had intermediate counts (171 [91–252]). IL-17–positive CD4+ T cells, γδT cells, natural killer T cells, and neutrophils were identified. Bronchoalveolar lavage IL-17 levels (pg/ml) were highest in established CF (14.6 [2.2–38.4]), low in newly diagnosed CF and control subjects (1.7 [1.7–1.74]; 1.7 [1.7–3]), and intermediate in non-CF bronchiectasis (9.1 [1.7–34] pg/ml) (Kruskal-Wallis P = 0.001). There was a significant correlation between IL-17 and neutrophil counts (P < 0.001, R = 0.6) as well as IL-4 (P < 0.001, R = 0.84).
Conclusions
Th17 lymphocytes are present in the airway submucosa in CF, even in a young, newly diagnosed group. Other IL-17+ cells include neutrophils, γδ T cells, and natural killer T cells.
doi:10.1164/rccm.201102-0236OC
PMCID: PMC3381840  PMID: 21474644
Th17 cells; cystic fibrosis; inflammation
6.  Cystic fibrosis 
BMJ : British Medical Journal  2007;335(7632):1255-1259.
doi:10.1136/bmj.39391.713229.AD
PMCID: PMC2137053  PMID: 18079549

Results 1-7 (7)