Publications
451 results found
Turnbull A, Lund-Palau H, Murphy R, et al., 2016, The T2R38 bitter taste receptor as a modifier of host response to pseudomonas aeruginosa in cystic fibrosis: does T2R38 genotype impact on clinical infection?, Publisher: BMJ Publishing Group, Pages: A44-A44, ISSN: 0040-6376
Pressler T, Donaldson SH, Davies JC, et al., 2016, A DOUBLE-BLIND, RANDOMISED, PLACEBO-CONTROLLED CROSS-OVER STUDY OF INHALED ALGINATE OLIGOSACCHARIDE (OLIGOG) ADMINISTERED FOR 28 DAYS IN SUBJECTS WITH CYSTIC FIBROSIS, North American Cystic Fibrosis Conference, Publisher: WILEY-BLACKWELL, Pages: 271-271, ISSN: 8755-6863
Turnbull AR, Lund-Palau H, Simbo A, et al., 2016, CHALLENGES CORRECTLY CLASSIFYING <i>PSEUDOMONAS AERUGINOSA</i> INFECTION STATUS IN PATIENTS ON INHALED ANTIBIOTICS: ARE NEGATIVE CULTURES CLINICALLY MEANINGFUL?, PEDIATRIC PULMONOLOGY, Vol: 51, Pages: 323-323, ISSN: 8755-6863
Alton EWFW, Boyd AC, Davies JC, et al., 2016, Genetic Medicines for CF: Hype versus Reality, Pediatric Pulmonology, Vol: 51, Pages: S5-S17, ISSN: 8755-6863
Since identification of the CFTR gene over 25 years ago, gene therapy for cystic fibrosis (CF) has been actively developed. More recently gene therapy has been joined by other forms of “genetic medicines” including mRNA delivery, as well as genome editing and mRNA repair-based strategies. Proof-of-concept that gene therapy can stabilize the progression of CF lung disease has recently been established in a Phase IIb trial. An early phase study to assess the safety and explore efficacy of CFTR mRNA repair is ongoing, while mRNA delivery and genome editing-based strategies are currently at the pre-clinical phase of development. This review has been written jointly by some of those involved in the various CF “genetic medicine” fields and will summarize the current state-of-the-art, as well as discuss future developments. Where applicable, it highlights common problems faced by each of the strategies, and also tries to highlight where a specific strategy may have an advantage on the pathway to clinical translation. We hope that this review will contribute to the ongoing discussion about the hype versus reality of genetic medicine-based treatment approaches in CF.
Turnbull AR, Lund-Palau H, Murphy R, et al., 2016, The T2R38 bitter taste receptor as a modifier of host response to Pseudomonas aeruginosa in cystic fibrosis: does T2R38 genotype impact on clinical infection?, Pediatric Pulmonology, Vol: 51, Pages: 323-323, ISSN: 8755-6863
Pseudomonas aeruginosa (Pa) utilises quorum sensing (QS) to mediate several virulence factors including growth in biofilms. Intriguing in vitro data suggests QS signalling molecules can be “sensed” at the epithelial surface via the T2R38 (bitter taste) receptor expressed on air-way cilia (Lee RJ, et al. J Clin Invest. 2012;122:4145-59). Activation of this receptor is predicted to lead to changes in ciliary beat frequency and nitric oxide production, which may enhance bacterial clearance. Three common polymorphisms exist in the gene coding for this receptor, altering the amino acid sequence at positions 49, 262, and 296 and correlating with receptor function; the functional allele has proline-alanine-valine (PAV) whereas the non-functional allele has alanine-valine-isoleucine (AVI) at these residues. In vitro response to QS molecules has been shown to be greatest in cells with the PAV/PAV genotype. We hypothesised that the T2R38 receptor may be important in host defence against Pa in people with cystic fibrosis (CF) and that T2R38 genotype may therefore modify infection status and clinical outcomes.
McNally PG, O'Rourke J, Fantino E, et al., 2016, POOLING OF BRONCHOALVEOLAR LAVAGE IN CHILDREN WITH CYSTIC FIBROSIS DOES NOT AFFECT THE MICROBIOLOGICAL YIELD AND MAY ALLOW EARLIER DETECTION OF PULMONARY INFLAMMATION, PEDIATRIC PULMONOLOGY, Vol: 51, Pages: 288-288, ISSN: 8755-6863
Farrant K, Davies JC, Williams H, 2016, IDENTIFICATION OF HYPOCHLOROUS ACID (HOCL) PROTECTIVE MECHANISMS IN PSEUDOMONAS AERUGINOSA AND THE IMPORTANCE OF HOCL IN THE CYSTIC FIBROSIS LUNG, PEDIATRIC PULMONOLOGY, Vol: 51, Pages: 305-305, ISSN: 8755-6863
Collins N, Steele L, Irving S, et al., 2016, CLINICAL UTILITY OF SPUTUM INDUCTION TO DETECT INFECTION AND ASSESS SUCCESS OF ERADICATION IN NONEXPECTORATING CHILDREN WITH CYSTIC FIBROSIS, PEDIATRIC PULMONOLOGY, Vol: 51, Pages: 362-362, ISSN: 8755-6863
De Boeck C, Heijerman H, Davies JC, et al., 2016, CLINICAL BENEFITS OF ATALUREN IN CYSTIC FIBROSIS PATIENTS WITH A CFTR NONSENSE MUTATION NOT RECEIVING CHRONIC INHALED TOBRAMYCIN, PEDIATRIC PULMONOLOGY, Vol: 51, Pages: 273-273, ISSN: 8755-6863
Ahmed B, Cox MJ, Cuthbertson L, et al., 2016, EARLY DEVELOPMENT OF THE AIRWAY MICROBIOTA IN INFANTS WITH CF, PEDIATRIC PULMONOLOGY, Vol: 51, Pages: 328-328, ISSN: 8755-6863
Bardin E, Bolt F, Cameron S, et al., 2016, Metabolomic characterization of Pseudomonas aeruginosa isolates from cystic fibrosis patients using rapid evaporative ionisation mass spectrometry, Pediatric Pulmonology, Vol: 51, Pages: S194-S485, ISSN: 8755-6863
Rapid evaporative ionization mass spectrometry (REIMS) is a new technique that has been shown to accurately classify yeast and bacteria. Thermal stress is applied onto bacterial colonies which results in evaporation and ionisation of metabolites and structural lipids. The mass spectrometer detects and identifies analytes through spectral database comparison (Strittmatter N, et al. Anal Chem. 2014;86:6555-62). We describe the application of REIMS to cystic fibrosis (CF)-related pathogens and show that the technology can identify P. aeruginosa with 100% accuracy. Differences were observed in the phospholipid and rhamnolipid range; derivatives of quorum sensing molecules (QSM) were also detected. These may provide useful biomarkers for a non-invasive diagnostic tool using ambient mass spectrometric (MS) approaches currently in development.
Griesenbach U, Davies JC, Alton E, 2016, Cystic fibrosis gene therapy: a mutation-independent treatment, Current Opinion in Pulmonary Medicine, Vol: 22, Pages: 602-609, ISSN: 1531-6971
PURPOSE OF THE REVIEW: Since cloning of the disease-causing gene 27 years ago, the development of cystic fibrosis (CF) gene therapy has been pursued. Here, we will summarize key findings with a particular focus on recent developments. RECENT FINDINGS: Almost 3 decades of research have highlighted the complexity of lung gene transfer and have generated a body of data that has recently led to the completion of a large phase IIB study. This trial has, for the first time, shown that nonviral gene transfer can, albeit modestly, stabilize lung function in CF and provides the impetus for further development of more potent gene transfer agents. Lentiviral vectors, specifically pseudotyped to enable entry into airway epithelial cells have most recently been developed. Persistent expression after a single dose and the ability to be administered repeatedly suggest that these viral vectors hold promise for the treatment of CF; a first-in-man clinical trial will shortly be initiated. SUMMARY: Although the development of CF gene therapy has been slower than initially anticipated, recent progress has been encouraging and has renewed the interest of academics and industry to pursue lung gene therapy.
Lund-Palau H, Turnbull AR, Bush A, et al., 2016, Pseudomonas aeruginosa infection in cystic fibrosis: pathophysiological mechanisms and therapeutic approaches, Expert Review of Respiratory Medicine, Vol: 10, Pages: 685-697, ISSN: 1747-6348
Pseudomonas aeruginosa is a remarkably versatile environmental bacterium with an extraordinary capacity to infect the cystic fibrosis (CF) lung. Infection with P. aeruginosa occurs early, and although eradication can be achieved following early detection, chronic infection occurs in over 60% of adults with CF. Chronic infection is associated with accelerated disease progression and increased mortality. Extensive research has revealed complex mechanisms by which P. aeruginosa adapts to and persists within the CF airway. Yet knowledge gaps remain, and prevention and treatment strategies are limited by the lack of sensitive detection methods and by a narrow armoury of antibiotics. Further developments in this field are urgently needed in order to improve morbidity and mortality in people with CF. Here, we summarize current knowledge of pathophysiological mechanisms underlying P. aeruginosa infection in CF. Established treatments are discussed, and an overview is offered of novel detection methods and therapeutic strategies in development.
Griesenbach U, Alton EWFW, Beekman JM, et al., 2016, Preparation for a First-in-Man Lentivirus Trial in Cystic Fibrosis Patients, 19th Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT), Publisher: Nature Publishing Group, Pages: S214-S214, ISSN: 1525-0024
Edmondson C, Davies JC, 2016, Current and future treatment options for cystic fibrosis lung disease: latest evidence and clinical implications, Therapeutic Advances in Chronic Disease, Vol: 7, Pages: 170-183, ISSN: 2040-6231
Treatment for cystic fibrosis (CF) has conventionally targeted downstream consequences of the defect such as mucus plugging and infection. More recently, significant advances have been made in treating the root cause of the disease, namely a defective CF transmembrane conductance regulator (CFTR) gene. This review summarizes current pulmonary treatment options and highlights advances in research and development of new therapies.
Turnbull AR, Davies JC, 2016, New drug developments in the management of cystic fibrosis lung disease, Expert Opinion on Pharmacotherapy, Vol: 17, Pages: 1103-1112, ISSN: 1744-7666
Introduction: Therapies for cystic fibrosis (CF) pulmonary disease have, until recently, all targeted downstream manifestations rather than the root cause of the disease. A step-change in our approach has been achieved in the last few years, with novel small-molecule CFTR modulating drugs entering the clinic.Areas covered: In this article, we will discuss the field of drug development for CF lung disease. The case will be made for the potential benefits of basic defect-targeted strategies, which will be described in detail. Novel therapies directed at the downstream pulmonary manifestations of CF – infection, inflammation, and mucus impaction – will be reviewed. Finally, we will speculate on future directions and challenges.Expert opinion: CF drug development is in an exciting phase, catalysed by the impressive results seen in patients with ivacaftor-responsive CFTR mutations. The research field is active with trials of novel therapies targeting the basic defect, alongside drugs targeting downstream effects. In order to detect potentially small improvements due to novel therapies, especially in the context of treating young patients with early disease, sensitive outcome measures and the coordinated efforts of collaborative research networks are crucial.
Vermeulen F, Le Camus C, Davies JC, et al., 2016, Variability of sweat chloride concentration in subjects with cystic fibrosis and G551D mutations, Journal of Cystic Fibrosis, Vol: 16, Pages: 36-40, ISSN: 1569-1993
Introduction:Sweat chloride concentration, a biomarker of CFTR function, is an appropriate outcome parameter in clinical trials aimed at correcting the basic CF defect. Although there is consensus on a cut-off value to diagnose CF, we have only limited information on the within subject variability of sweat chloride over time. Such information would be useful for sample size calculations in clinical trials. Therefore, we retrospectively analyzed repeated sweat chloride values obtained in patients with G551D mutation(s) assigned to placebo in an ivacaftor interventional trial.Methods:In subjects with G551D at least 12 years of age, a pilocarpine sweat test using Macroduct collector was taken on both arms at 8 time points over 48 weeks. We explored 1062 pilocarpine sweat test values obtained in 78 placebo patients of the VX08-770-102 trial.Results:Mean overall sweat chloride value (all patients, all tests, n = 1062) was 100.8 mmol/L (SD 12.7 mmol/L). Using a multilevel mixed model, the between-subject standard deviation (SD) for sweat chloride was 8.9 mmol/L (95% CI 7.4–10.6) and within-subject SD was 8.1 mmol/L (95% CI 7.5–8.7). Limits of repeatability for repeat measurements were − 19.7 to + 21.6 mmol/L using values from one arm, and − 13.3 to 11.8 mmol/L using mean of values obtained at 4 test occasions. Sample size calculations showed that the minimal treatment effect on sweat chloride concentration that can be demonstrated for a group of 5 patients is around 15 mmol/L, using a cross-over design and combinations of 4 tests for each phase of the trial. Conclusion:Although the sweat test is considered a robust measure, sweat chloride measurements in patients with CF and a G551D mutation had an inherent biological variability that is higher than commonly considered. Further analyses of placebo group data are crucial to learn more about the natural variability of this outcome parameter.
Stuart Elborn J, Davies J, Bell S, et al., 2016, The effect of CFTR modulation on the disease progression of cystic fibrosis in the era of precision medicine, Journal of Cystic Fibrosis, Vol: 15, ISSN: 1569-1993
This educational activity is based from a live satellite symposium from the 38th European Cystic Fibrosis Conference held in Brussels, Belgium (Online access: http://www.elseviercme.com/591e). The expert faculty for this CME activity will present a comprehensive review of the effects of CFTR modulation therapeutics on cystic fibrosis disease progression. The new era of precision medicine has arrived and many patients can now be managed on the basis of phenotypes where very good healthcare outcomes can be achieved. Cystic fibrosis patients on treatment show new progress on lung function, BMI, exercise ability, infectious complications, life expectancy, and co-morbid conditions such as diabetes, liver failure, bone disease, and overall quality of life. This clinically relevant activity also includes panel discussions with case presentations to advance your skills in caring for cystic fibrosis patients.
Hippolyte S, Pabary R, Waller M, et al., 2016, Clinical Trials of Novel Treatments for Cystic Fibrosis, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 193, Pages: 569-571, ISSN: 1073-449X
Pabary R, Huang J, Kumar S, et al., 2016, Does mass spectrometric breath analysis detect Pseudomonas aeruginosa in cystic fibrosis?, European Respiratory Journal, Vol: 47, Pages: 994-997, ISSN: 1399-3003
Detecting P. aeruginosa infection is problematic; breath analysis shows promise but requires optimisation http://ow.ly/WE1H2
Davies JC, Cunningham S, Harris WT, et al., 2016, Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study, The Lancet Respiratory Medicine, Vol: 4, Pages: 107-115, ISSN: 2213-2600
BackgroundIvacaftor has been shown to be a safe, effective treatment for cystic fibrosis in patients aged 6 years or older with a CFTR gating mutation. We aimed to assess the safety, pharmacokinetics, and pharmacodynamics of ivacaftor in children aged 2–5 years.MethodsIn the two-part KIWI study, we enrolled children aged 2–5 years weighing 8 kg or more with a confirmed diagnosis of cystic fibrosis and a CFTR gating mutation on at least one allele from 15 hospitals in the USA, UK, and Canada. Participants received oral ivacaftor 50 mg (if bodyweight <14 kg) or 75 mg (if bodyweight ≥14 kg) every 12 h for 4 days in part A (to establish the short-term safety of doses for subsequent assessment in part B), and then for 24 weeks in part B (to assess safety and longer-term pharmacodynamics). Children could participate in both or just one part of the study. Primary outcomes were pharmacokinetics and safety, analysed in all patients who received at least one dose of ivacaftor. Secondary outcomes were absolute change from baseline in sweat chloride concentrations and bodyweight, body-mass index (BMI), and height Z scores, and pharmacokinetic parameter estimation of ivacaftor. This study is registered with ClinicalTrials.gov, number NCT01705145.FindingsBetween Jan 8, 2013, and March 1, 2013, nine patients were enrolled onto part A of the study, all of whom completed the 4 day treatment period, and eight of whom took part in part B. Between June 28, 2013, and Sept 26, 2013, 34 patients were enrolled in part B, 33 of whom completed the 24 week treatment period. All patients received at least one dose of ivacaftor. Results of ivacaftor pharmacokinetics suggested that exposure was similar to that reported in adults (median Cmin were 536 ng/mL for the 50 mg dose; 580 ng/mL for the 75 mg dose; median ivacaftor AUC values were 9840 ng × h/mL and 10 200 ng × h/mL, respectively). Common adverse events in part B included cough (in 19 [56%] of 34 patients) an
Griesenbach U, Alton EWFW, Boyd AC, et al., 2015, A Phase I/IIa safety and efficacy study of nebulized liposome-mediated gene therapy for cystic fibrosis supports a multidose trial, American Journal of Respiratory and Critical Care Medicine, Vol: 192, Pages: 1389-1392, ISSN: 1535-4970
Davies JC, Cunningham S, Southern KW, et al., 2015, IVACAFTOR TREATMENT IN PRESCHOOL CHILDREN WITH CYSTIC FIBROSIS AND A CFTR GATING MUTATION: EXTENDED EVALUATION, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A14-A14, ISSN: 0040-6376
Khoo V, Pabary R, Palau HL, et al., 2015, VARIABILITY IN SUSCEPTIBILITY TO ANTIBIOTICS AND BACTERIOPHAGES BETWEEN INDIVIDUAL COLONIES OF PSEUDOMONAS AERUGINOSA FROM CYSTIC FIBROSIS SPUTUM SAMPLES: IMPLICATIONS FOR FUTURE CLINICAL TRIAL DESIGN, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A64-A65, ISSN: 0040-6376
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Grillo L, Irving S, Hansell DM, et al., 2015, The reproducibility and responsiveness of the lung clearance index in bronchiectasis, European Respiratory Journal, Vol: 46, Pages: 1645-1653, ISSN: 1399-3003
Lung clearance index (LCI) is a potential clinical outcome marker in bronchiectasis. Its responsiveness to therapeutic intervention has not been determined. This study evaluates its responsiveness to a session of physiotherapy and intravenous antibiotic treatment of an exacerbation.32 stable and 32 exacerbating bronchiectasis patients and 26 healthy controls were recruited. Patients had LCI and lung function performed before and after physiotherapy on two separate occasions in the stable patients and at the beginning and end of an intravenous antibiotic course in the exacerbating patients.LCI was reproducible between visits in 25 stable patients, with an intraclass correlation of 0.978 (0.948, 0.991; p<0.001). There was no significant difference in LCI (mean±sd) between stable 11.91±3.39 and exacerbating patients 12.76±3.47, but LCI was significantly higher in both bronchiectasis groups compared with healthy controls (7.36±0.99) (p<0.001). Forced expiratory volume in 1 s improved after physiotherapy, as did alveolar volume after intravenous antibiotics, but LCI did not change significantly.LCI is reproducible in stable bronchiectasis but unlike conventional lung function tests, is unresponsive to two short-term interventions and hence is unlikely to be a useful clinical tool for short-term acute assessment in these patients. Further evaluation is required to establish its role in milder disease and in the evaluation of long-term interventions.
Ahmad F, Irving S, Alton E, et al., 2015, Multiple breath washouts in children can be shortened without compromising quality, European Respiratory Journal, Vol: 46, Pages: 1814-1816, ISSN: 1399-3003
Pabary R, Singh C, Morales S, et al., 2015, Anti-Pseudomonal Bacteriophage Reduces Infective Burden and Inflammatory Response in Murine Lung, Antimicrobial Agents and Chemotherapy, Vol: 60, Pages: 744-751, ISSN: 1098-6596
As antibiotic resistance increases, there is a need for new therapies to treat infection, particularly in cystic fibrosis (CF), where Pseudomonas aeruginosa is a ubiquitous pathogen associated with increased morbidity and mortality. Bacteriophages are an attractive alternative treatment, as they are specific to the target bacteria and have no documented side effects. The efficacy of phage cocktails was established in vitro. Two P. aeruginosa strains were taken forward into an acute murine infection model with bacteriophage administered either prophylactically, simultaneously, or postinfection. The infective burden and inflammation in bronchoalveolar lavage fluid (BALF) were assessed at various times. With low infective doses, both control mice and those undergoing simultaneous phage treatment cleared P. aeruginosa infection at 48 h, but there were fewer neutrophils in BALF of phage-treated mice (median, 73.2 × 104/ml [range, 35.2 to 102.1 × 104/ml] versus 174 × 104/ml [112.1 to 266.8 × 104/ml], P < 0.01 for the clinical strain; median, 122.1 × 104/ml [105.4 to 187.4 × 104/ml] versus 206 × 104/ml [160.1 to 331.6 × 104/ml], P < 0.01 for PAO1). With higher infective doses of PAO1, all phage-treated mice cleared P. aeruginosa infection at 24 h, whereas infection persisted in all control mice (median, 1,305 CFU/ml [range, 190 to 4,700 CFU/ml], P < 0.01). Bacteriophage also reduced CFU/ml in BALF when administered postinfection (24 h) and both CFU/ml and inflammatory cells in BALF when administered prophylactically. A reduction in soluble inflammatory cytokine levels in BALF was also demonstrated under different conditions. Bacteriophages are efficacious in reducing both the bacterial load and inflammation in a murine model of P. aeruginosa lung infection. This study provides proof of concept for future clinical trials in patients with CF.
Davies JC, 2015, The future of CFTR modulating therapies for cystic fibrosis, CURRENT OPINION IN PULMONARY MEDICINE, Vol: 21, Pages: 579-584, ISSN: 1070-5287
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Rosenfeld M, Robertson S, Green Y, et al., 2015, EXTENDED EVALUATION OF IVACAFTOR TREATMENT IN PEDIATRIC PATIENTS WITH CYSTIC FIBROSIS AND A <i>CFTR</i> GATING MUTATION, PEDIATRIC PULMONOLOGY, Vol: 50, Pages: 284-285, ISSN: 8755-6863
Griesenbach U, Alton E, Beekman J, et al., 2015, MOVING LENTIVIRAL-BASED GENE THERAPY INTO A FIRST-IN-MAN CF TRIAL, PEDIATRIC PULMONOLOGY, Vol: 50, Pages: 283-283, ISSN: 8755-6863
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