Publications
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Morris-Rosendahl DJ, Edwards M, McDonnell MJ, et al., 2020, Whole-gene sequencing of CFTR reveals a high prevalence of the intronic variant c.3874-4522A>G in cystic fibrosis., American Journal of Respiratory and Critical Care Medicine, Vol: 201, Pages: 1438-1441, ISSN: 1073-449X
Bayfield KJ, Alton E, Irving S, et al., 2020, “Nitrogen offset in N2 multiple washout method”. Katie J. Bayfield, Eric Alton, Samantha Irving, Andrew Bush, Jane C. Davies. ERJ Open Res 2019; 6: 00043-2020, ERJ Open Research, Vol: 6, Pages: 1-1, ISSN: 2312-0541
This article was originally published with the sentence “Thank you for the opportunity to respond to the correspondence by J.G. Nielsen from Innovision about our recent paper”. The authors have since been made aware that J.G. Nielsen sold Innovision ApS (Glamsbjerg, Denmark) prior to the submission of his correspondence and, at the time of writing, has no financial interests in any business relating to lung clearance index technologies. This sentence has now been changed to “Thank you for the opportunity to respond to the correspondence by J.G. Nielsen about our recent paper” in the article itself.
Bayfield KJ, Alton E, Irving S, et al., 2020, Nitrogen offset in N-2 multiple washout method, ERJ Open Research, Vol: 6, Pages: 1-2, ISSN: 2312-0541
Davies J, Bayfield K, Alton E, et al., 2020, Letter to the ERJ OPEN reply 24th January 2020
Turnbull A, Pyle C, Patel D, et al., 2020, Abnormal pro-gly-pro pathway and airway neutrophilia in pediatric cystic fibrosis, Journal of Cystic Fibrosis, Vol: 19, Pages: 40-48, ISSN: 1569-1993
BackgroundProline–glycine–proline (PGP) is a bioactive fragment of collagen generated by the action of matrix metalloproteinase-9 (MMP-9) and prolylendopeptidase (PE), and capable of eliciting neutrophil chemotaxis and epithelial remodelling. PGP is normally then degraded by leukotriene A4 hydrolase (LTA4H) to limit inflammation and remodelling. This study hypothesized that early and persistent airway neutrophilia in Cystic Fibrosis (CF) may relate to abnormalities in the PGP pathway and sought to understand underlying mechanisms.MethodsBroncho-alveolar lavage (BAL) fluid was obtained from 38 CF (9 newborns and 29 older children) and 24 non-CF children. BAL cell differentials and levels of PGP, MMP-9, PE and LTA4H were assessed.ResultsWhilst PGP was present in all but one of the older CF children tested, it was absent in non-CF controls and the vast majority of CF newborns. BAL levels of MMP-9 and PE were elevated in older children with CF relative to CF newborns and non-CF controls, correlating with airway neutrophilia and supportive of PGP generation. Furthermore, despite extracellular LTA4H commonly being greatly elevated concomitantly with inflammation to promote PGP degradation, this was not the case in CF children, potentially owing to degradation by neutrophil elastase.ConclusionsA striking imbalance between PGP-generating and -degrading enzymes enables PGP accumulation in CF children from early life and potentially supports airway neutrophilia.
Shovlin CL, Morris-Rosendahl DJ, Copeland F, et al., 2019, DELIVERING THE 100,000 GENOMES PROJECT TO ESTABLISH THE FUNCTIONAL ROLE OF DNA SEQUENCE VARIANTS IN RESPIRATORY RARE DISEASES, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A44-A45, ISSN: 0040-6376
Saleh AD, Durham SR, Shamji MH, et al., 2019, PEAK NASAL INSPIRATORY FLOW AND NASAL CYTOKINES ARE USEFUL BIOMARKERS OF NASAL INFLAMMATION IN CYSTIC FIBROSIS GENE THERAPY, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A13-A13, ISSN: 0040-6376
Davies J, Alton E, Simbo A, et al., 2019, Training dogs to differentiate Pseudomonas aeruginosa from other cystic fibrosis bacterial pathogens: not to be sniffed at?, European Respiratory Journal, Vol: 54, ISSN: 0903-1936
Bayfield KJ, Horsley A, Alton E, et al., 2019, Simultaneous sulfur hexafluoride and nitrogen multiple-breath washout (MBW) to examine inherent differences in MBW outcomes, ERJ Open Research, Vol: 5, ISSN: 2312-0541
Multiple-breath washout (MBW) can be performed with different gases (sulfur hexafluoride (SF6-) and nitrogen (N2)) and different devices, all of which give discrepant results. This study aimed to confirm previously reported differences and explore factors influencing discrepant results; equipment factors or the physical properties of gases used. Methods: Healthy controls (HCs) and participants with cystic fibrosis (CF) completed MBW trials on two commercially available devices (Exhalyzer D (N2) and Innocor (SF6)). Simultaneous washout of both gases at the same time on the commercial equipment and simultaneous washouts using a respiratory mass spectrometer (RMS) were completed in subsets. Primary outcomes were lung clearance index (LCI), breath number and time required to washout. Results: Breath number was higher with N2 washout than SF6 in both HCs and patients with CF, whether washouts were completed individually or simultaneously. The difference was greater in more advanced disease, largely caused by differences in the final part of the washout. Results from commercial devices were similar to those obtained with the RMS. Conclusions: N2 MBW results were higher than SF6 MBW, with some of the largest differences reported to date being observed. The biggest impact was at the end of the washout and this was even the case when gases were washed out simultaneously. N2 and SF6 MBW results are inherently different and should be considered as independent measurements.
Waller MD, Harman K, Bayfield KJ, et al., 2019, OPPORTUNISTIC ASSESSMENT OF UPPER AND LOWER AIRWAY ELECTROPHYSIOLOGY AND LUNG FUNCTION IN CYSTIC FIBROSIS, North American Cystic Fibrosis Conference, Publisher: WILEY, Pages: S163-S163, ISSN: 8755-6863
Edmondson C, Westrupp N, Brownlee K, et al., 2019, ENGAGEMENT (OR NOT) OF TEENAGERS WITH CF IN HEALTH MONITORING AT HOME: RESULTS FROM THE CLIMB-CF FEASABILITY STUDY, Publisher: WILEY, Pages: S430-S430, ISSN: 8755-6863
Saleh A, Griesenbach U, Alton E, et al., 2019, ASSAY DEVELOPMENT FOR A FIRST-IN-MAN LENTIVIRUS GENE THERAPY TRIAL FOR CYSTIC FIBROSIS, Publisher: WILEY, Pages: S358-S358, ISSN: 8755-6863
Edmondson C, Westrupp N, Brownlee K, et al., 2019, DOES HOME MONITORING OF CHILDREN WITH CF IMPACT DEPRESSION AND ANXIETY LEVELS IN THEIR PARENTS? RESULTS FROM THE CLIMB-CF FEASIBILITY STUDY, Publisher: WILEY, Pages: S405-S405, ISSN: 8755-6863
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Bell RV, McKinnon TAJ, Alton EWFW, et al., 2019, Gene therapy for thrombotic thrombocytopaenic purpura, Annual Conference of the British Society for Gene and Cell Therapy, Publisher: Mary Ann Liebert, Pages: A14-A14, ISSN: 1043-0342
Thrombotic Thrombocytopaenic Purpura (TTP) is a rare (∼1/200,000 people) but life‐threatening disease caused by inherited or acquired deficiencies in ADAMTS13; a metalloprotease responsible for cleavage of large von Willebrand factor (VWF) multimers in the plasma. Reduced cleavage of thrombogenic VWF multimers through deficient ADAMTS13 can lead to spontaneous, wide‐spread accumulation of platelet‐rich thrombi. Without treatment, thrombi accumulation within the microvasculature causes organ failure and death in 90% of acute events. Individuals with TTP receive regular plasma infusions to restore ADAMTS13 levels. Despite current treatments reducing mortality rates, high treatment burden and morbidity associated with donor‐derived plasma warrants the development of a novel therapy for TTP. Gene therapy offers an alternative treatment which could prevent the onset of life‐threatening acute TTP episodes. The UK Cystic Fibrosis Gene Therapy Consortium, has developed a lentivirus pseudotyped with the Sendai virus envelope proteins F and HN for efficient lung gene transfer. Here, we assess whether lungs can be used as ‘factories’ for efficient and persistent ADAMTS13 production. We first cloned ADAMTS13 cDNA into a lentivirus producer plasmid and demonstrated proteolytic activity against VWF following co‐expression in HEK293T cells and subsequent detection of cleaved VWF by SDS‐PAGE. Vector is currently being manufactured using GMP‐compliant production methods. Next, ADAMTS13 knockout mice were characterised to determine suitable biomarkers (e.g. ADAMTS13 plasma levels and VWF cleavage activity) for assessing efficacy of pulmonary gene transfer. Future work will assess the restoration of plasma ADAMTS13 function in knockout mice and protection against TTP‐like symptoms.
Palau H, Meng C, Bhargava A, et al., 2019, Lentivirus Gene Therapy for Autoimmune Pulmonary Alveolar Proteinosis, 22nd Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT), Publisher: CELL PRESS, Pages: 43-44, ISSN: 1525-0016
Davies G, Griesenbach U, Alton E, et al., 2019, 53 - Molecular Therapies for Cystic Fibrosis, Kendig's Disorders of the Respiratory Tract in Children, Pages: 800-811.e3, ISBN: 9780323448871
This chapter describes the therapeutic strategies for cystic fibrosis which are based on targeting cystic fibrosis transmembrane conductance regulator (CFTR), either at the gene or protein level. We provide updates on small molecule CFTR modulators and gene therapy, focusing on clinical development and evaluation. The field has seen significant progress over recent years, particularly with the CFTR potentiator, ivacaftor, in patients with class III mutations. Increased understanding of the abnormalities in the structure and function of CFTR protein will help optimize the approaches required for normalizing function and, in doing so, aid the rational design of clinical trials-both in terms of the development of more efficacious drugs and the selection of appropriate patient populations. While progress with gene therapy remains some way behind, potential benefits (including being mutation agnostic and a nonsystemic route of delivery) remain significant. It may be that future optimal approaches will harness the benefits of more than one of these approaches and lead to considerable synergy. The ultimate goal for molecular and advanced therapies in cystic fibrosis is to find drugs or combinations of drugs capable of restoring CFTR function, applicable to patients with any genetic mutation.
Davies G, Griesenbach U, Alton E, et al., 2019, Molecular Therapies for Cystic Fibrosis, Kendig's Disorders of the Respiratory Tract in Children, Publisher: Elsevier, Pages: 800-811.e3
Lund-Palau H, Meng C, Pilou A, et al., 2018, LENTIVIRUS GM-CSF GENE THERAPY AMELIORATES AUTOIMMUNE PULMONARY ALVEOLAR PROTEINOSIS, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A1-A2, ISSN: 0040-6376
Simmonds NJ, Pabary R, Kohlhaufl J, et al., 2018, THE ADDED VALUE OF NASAL POTENTIAL DIFFERENCE MEASUREMENT WHEN FIRST-LINE CYSTIC FIBROSIS (CF) INVESTIGATIONS ARE NON-DIAGNOSTIC, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A84-A85, ISSN: 0040-6376
Thursfield RM, Naderi K, Leaver N, et al., 2018, Children with cystic fibrosis demonstrate no respiratory immunological, infective or physiological, consequences of vitamin D deficiency, Journal of Cystic Fibrosis, Vol: 17, Pages: 657-665, ISSN: 1569-1993
BACKGROUND: Vitamin D has health benefits in many respiratory diseases but the evidence in CF is unclear. Induction of the antimicrobial peptides cathelicidin (LL37) and human-beta-defensin-2 (HBD-2) may be the mechanism of any benefit. We hypothesised that antimicrobial peptide levels would be decreased, and airway infection and inflammation greater, in CF children with vitamin D deficiency. The objective of the study was to explore relationships between vitamin D, LL37 and HBD-2, and airway infection, inflammation and physiology in children with CF. METHODS: Bronchoalveolar lavage (BALF) and blood were obtained from children undergoing fibreoptic bronchoscopy. Serum vitamin D, BALF HBD-2 and LL37, cultured bacteria and inflammatory markers were measured. Clinical parameters were recorded. RESULTS: 113 patients with CF, 23 with non-CF chronic suppurative lung disease (CSLD) and 6 healthy controls were included. We found no relationship between serum vitamin D and BALF HBD-2 or LL-37. There were no differences in infective or inflammatory markers between vitamin D sufficient and deficient groups. Vitamin D deficient patients (<50 nmol/L) did not have a worse FEV1 (CF: 66 (58-71)% vs. 71.5 (61-76)%, ns; non-CF CSLD: 69 (36-88)% vs. 70 (62-95)%, ns). CONCLUSIONS: In the first bronchoscopic study exploring this question, we demonstrate that vitamin D deficiency is not associated with immunological, infective or clinical markers of disease severity in patients with CF or CSLD.
Bardin EE, Cameron SJS, Perdones-Montero A, et al., 2018, Metabolic phenotyping and strain characterisation of pseudomonas aeruginosa Isolates from cystic fibrosis patients using rapid evaporative ionisation mass spectrometry, Scientific Reports, Vol: 8, ISSN: 2045-2322
Rapid evaporative ionisation mass spectrometry (REIMS) is a novel technique for the real-time analysis of biological material. It works by conducting an electrical current through a sample, causing it to rapidly heat and evaporate, with the analyte containing vapour channelled to a mass spectrometer. It was used to characterise the metabolome of 45 Pseudomonas aeruginosa (P. aeruginosa) isolates from cystic fibrosis (CF) patients and compared to 80 non-CF P. aeruginosa. Phospholipids gave the highest signal intensity; 17 rhamnolipids and 18 quorum sensing molecules were detected, demonstrating that REIMS has potential for the study of virulence-related metabolites. P. aeruginosa isolates obtained from respiratory samples showed a higher diversity, which was attributed to the chronic nature of most respiratory infections. The analytical sensitivity of REIMS allowed the detection of a metabolome that could be used to classify individual P. aeruginosa isolates after repeated culturing with 81% accuracy, and an average 83% concordance with multilocus sequence typing. This study underpins the capacities of REIMS as a tool with clinical applications, such as metabolic phenotyping of the important CF pathogen P. aeruginosa, and highlights the potential of metabolic fingerprinting for fine scale characterisation at a sub-species level.
Paul-Smith M, Pytel K, Gelinas J-F, et al., 2018, The murine lung as a factory to produce secreted intrapulmonary and circulatory proteins, Gene Therapy, Vol: 25, Pages: 345-358, ISSN: 0969-7128
We have shown that a lentiviral vector (rSIV.F/HN) pseudotyped with the F and HN proteins from Sendai virus generates high levels of intracellular proteins after lung transduction. Here, we evaluate the use of rSIV.F/HN for production of secreted proteins. We assessed whether rSIV.F/HN transduction of the lung generates therapeutically relevant levels of secreted proteins in the lung and systemic circulation using 1-anti-trypsin (hAAT) and factor VIII (hFVIII) as exemplars. Sedated mice were transduced with rSIV.F/HN carrying either the secreted reporter gene Gaussia luciferase (GLux) or the hAAT or hFVIII cDNAs by nasal sniffing.rSIV.F/HN-hAAT transduction lead to therapeutically relevant hAAT levels (70 g/ml) in ELF, with stable expression persisting for at least 19 months from a single application. Secreted proteins produced in the lung were released into the circulation and stable expression was detectable in blood. The levels of hFVIII in murine blood approached therapeutically relevant targets. rSIV.F/HN was also able to produce secreted hAAT and hFVIII in transduced human primary airway cells.rSIV.F/HN transduction of the murine lungs leads to long-lasting and therapeutically relevant levels of secreted proteins in the lung and systemic circulation. These data broaden the use of this vector platform for a large range of disease indications.
Saleh A, Meng C, Chan M, et al., 2018, RNA in-situ hybridisation is able to quantify lentiviral transduction of respiratory epithelium, Annual Conference of the British-Society-for-Gene-and-Cell-Therapy, Publisher: MARY ANN LIEBERT, INC, Pages: A7-A7, ISSN: 1043-0342
Lund-Palau H, Pilou A, Atsumi N, et al., 2018, Lentivirus GM-CSF gene therapy for autoimmune pulmonary alveolar proteinosis, Annual Conference of the British-Society-for-Gene-and-Cell-Therapy, Publisher: MARY ANN LIEBERT, INC, Pages: A2-A2, ISSN: 1043-0342
Clarke N, Saleh A, Meng C, et al., 2018, Validation of a PCR-based assay to quantify lentiviral vector shedding in human body fluids, Annual Conference of the British-Society-for-Gene-and-Cell-Therapy, Publisher: MARY ANN LIEBERT, INC, Pages: A11-A11, ISSN: 1043-0342
Turnbull AR, Murphy R, Behrends V, et al., 2018, Impact of T2R38 receptor polymorphisms on pseudomonas aeruginosa infection in cystic fibrosis, American Journal of Respiratory and Critical Care Medicine, Vol: 197, Pages: 1635-1638, ISSN: 1073-449X
Shovlin CL, Nur F, St Prix MS, et al., 2018, Hereditary haemorrhagic telangiectasia and the 100,000 genomes project, Publisher: SPRINGER, Pages: 125-125, ISSN: 0969-6970
Edmondson C, Murphy R, Moffitt K, et al., 2017, IT IS POSSIBLE TO DETECT ACTIVE NEUTROPHIL ELASTASE IN EXHALED BREATH CONDENSATE OF PATIENTS WITH CYSTIC FIBROSIS, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A219-A219, ISSN: 0040-6376
Saleh AD, Clarke NK, Meng C, et al., 2017, DEVELOPMENT OF ASSAYS TO ASSESS SAFETY AND EFFICACY OF LENTIVIRAL GENE THERAPY FOR CYSTIC FIBROSIS, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A57-A57, ISSN: 0040-6376
Atsumi N, Pilou A, Pringle I, et al., 2017, GENE THERAPY FOR PULMONARY ALVEOLAR PROTEINOSIS, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A72-A73, ISSN: 0040-6376
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