Publications
600 results found
Shoemark A, Frost E, Harman K, et al., 2017, Nasal cavity inflammation in patients with primary ciliary dyskinesia (PCD) is associated with bacterial infection, European-Respiratory-Society (ERS) International Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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Edmondson C, Murphy R, Moffitt K, et al., 2017, ACTIVE NEUTROPHIL ELASTASE CAN BE DETECTED IN EXHALED BREATH CONDENSATE OF PATIENTS WITH CYSTIC FIBROSIS, North American Cystic Fibrosis Conference, Publisher: WILEY, Pages: S316-S316, ISSN: 8755-6863
Meng C, Alton E, Boyd C, et al., 2017, QUANTIFICATION OF VECTOR SHEDDING AFTER LENTIVIRUS GENE TRANSFER TO MOUSE LUNG, Publisher: WILEY, Pages: S268-S269, ISSN: 8755-6863
Coates M, Ito K, Alton E, et al., 2017, RSV INFECTION LEADS TO INCREASED BINDING OF <i>PSEUDOMONAS AERUGINOSA</i> TO PHE508DEL CFTR EXPRESSING RESPIRATORY EPITHELIAL CELLS, Publisher: WILEY, Pages: S375-S375, ISSN: 8755-6863
Paul-Smith MC, Pytel KM, Gelinas J-F, et al., 2017, The lung as a factory to produce secreted intrapulmonary and circulatory proteins, Annual Conference of the British-Society-for-Gene-and-Cell-Therapy / Joint UK-Regenerative-Medicine-Platform Meeting, Publisher: MARY ANN LIEBERT, INC, Pages: A11-A12, ISSN: 1043-0342
Meng C, Alton E, Boyd C, et al., 2017, Quantification of vector shedding after transduction of murine lungs with F/HN-pseudotyped lentivirus, Annual Conference of the British-Society-for-Gene-and-Cell-Therapy / Joint UK-Regenerative-Medicine-Platform Meeting, Publisher: MARY ANN LIEBERT, INC, Pages: A12-A12, ISSN: 1043-0342
Smith WD, Bardin E, Cameron L, et al., 2017, Current and future therapies for Pseudomonas aeruginosa infection in patients with cystic fibrosis, FEMS Microbiology Letters, Vol: 364, ISSN: 0378-1097
Pseudomonas aeruginosa opportunistically infects the airways of patients with cystic fibrosis and causes significant morbidity and mortality. Initial infection can often be eradicated though requires prompt detection and adequate treatment. Intermittent and then chronic infection occurs in the majority of patients. Better detection of P. aeruginosa infection using biomarkers may enable more successful eradication before chronic infection is established. In chronic infection P. aeruginosa adapts to avoid immune clearance and resist antibiotics via efflux pumps, β-lactamase expression, reduced porins and switching to a biofilm lifestyle. The optimal treatment strategies for P. aeruginosa infection are still being established, and new antibiotic formulations such as liposomal amikacin, fosfomycin in combination with tobramycin and inhaled levofloxacin are being explored. Novel agents such as the alginate oligosaccharide OligoG, cysteamine, bacteriophage, nitric oxide, garlic oil and gallium may be useful as anti-pseudomonal strategies, and immunotherapy to prevent infection may have a role in the future. New treatments that target the primary defect in cystic fibrosis, recently licensed for use, have been associated with a fall in P. aeruginosa infection prevalence. Understanding the mechanisms for this could add further strategies for treating P. aeruginosa in future.
Coates MS, Alton EWFW, Brookes DW, et al., 2016, INCREASED RESPIRATORY SYNCYTIAL VIRUS BURDEN LEADS TO MORE RAPID CELL DEATH IN PHE508DEL BRONCHIAL EPITHELIAL CELLS, THORAX, Vol: 71, Pages: A44-A44, ISSN: 0040-6376
Alton EW, Beekman JM, Boyd AC, et al., 2016, Preparation for a first-in-man lentivirus trial in patients with cystic fibrosis, Thorax, Vol: 72, Pages: 137-147, ISSN: 0040-6376
We have recently shown that non-viral gene therapy can stabilise the decline of lung function in patients with cystic fibrosis (CF). However, the effect was modest, and more potent gene transfer agents are still required. Fuson protein (F)/Hemagglutinin/Neuraminidase protein (HN)-pseudotyped lentiviral vectors are more efficient for lung gene transfer than non-viral vectors in preclinical models. In preparation for a first-in-man CF trial using the lentiviral vector, we have undertaken key translational preclinical studies. Regulatory-compliant vectors carrying a range of promoter/enhancer elements were assessed in mice and human air-liquid interface (ALI) cultures to select the lead candidate; cystic fibrosis transmembrane conductance receptor (CFTR) expression and function were assessed in CF models using this lead candidate vector. Toxicity was assessed and 'benchmarked' against the leading non-viral formulation recently used in a Phase IIb clinical trial. Integration site profiles were mapped and transduction efficiency determined to inform clinical trial dose-ranging. The impact of pre-existing and acquired immunity against the vector and vector stability in several clinically relevant delivery devices was assessed. A hybrid promoter hybrid cytosine guanine dinucleotide (CpG)- free CMV enhancer/elongation factor 1 alpha promoter (hCEF) consisting of the elongation factor 1α promoter and the cytomegalovirus enhancer was most efficacious in both murine lungs and human ALI cultures (both at least 2-log orders above background). The efficacy (at least 14% of airway cells transduced), toxicity and integration site profile supports further progression towards clinical trial and pre-existing and acquired immune responses do not interfere with vector efficacy. The lead rSIV.F/HN candidate expresses functional CFTR and the vector retains 90-100% transduction efficiency in clinically relevant delivery devices. The data support the progression of the F/HN-pseudotype
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
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.
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.
Harman K, Crowley S, Waller M, et al., 2016, Is there a secondary defect in CFTR in the nasal epithelium of patients with primary ciliary dyskinesia?, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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Bayfield K, Alton E, Irving S, et al., 2016, Simultaneous SF<sub>6</sub> and N<sub>2</sub> gas multiple breath washout (MBW); understanding the difference between test gases, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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Bayfield K, Alton E, Irving S, et al., 2016, Comparison of functional residual capacity (FRC) from two multiple breath washout (MBW) systems and body plethysmography, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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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.
Pytel KM, Chan M, Meng C, et al., 2016, Pre-existing immunity to human parainfluenza virus (hPIV) does not affect rSIV.F/HN-mediated transduction efficiency., Annual Conference of the British Society for Gene and Cell Therapy, Publisher: Mary Ann Liebert, Pages: A19-A19, ISSN: 1557-7422
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.
Paul-Smith MC, Bell RV, Alton WE, et al., 2016, Gene therapy for cystic fibrosis: recent progress and current aims, Expert Opinion on Orphan Drugs, Vol: 4, Pages: 649-658, ISSN: 2167-8707
Introduction: Since identification of the disease causing gene over 25 years ago, cystic fibrosis (CF) has been at the forefront of gene therapy research. Despite initial optimism, CF gene therapy has proven considerably more challenging than initially anticipated. However, research conducted over the past two decades has clarified the strength and weaknesses of viral and non-viral gene transfer agents for CF gene therapy.Areas covered: The older literature related to CF gene therapy has been reviewed in many publications and we will, therefore, restrict this review to a brief description and discussion of the key lessons learnt, instead focusing on more recent progress in the field which was identified through literature searches. This review will summarize research leading up to the recent pivotal proof-of-concept study showing that non-viral gene therapy can stabilize the decline of lung function in CF patients and also highlight recent advances in viral vector development which may overcome problems related to loss of efficacy on repeated administration.Expert opinion: The demonstration that gene therapy can stabilize CF lung disease is an important milestone in gene therapy.
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
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
Pytel KM, Paul-Smith MC, McIntosh J, et al., 2015, F/HN-mediated gene therapy enables lungs to produce therapeutically relevant levels of FVIII, Winter Meeting of the British Thoracic Society, Publisher: BMJ Publishing Group, Pages: A67-A67, ISSN: 0040-6376
We have previously shown that lung when treated with Sendai virus-mediated gene transfer can produce secreted proteins and release them into the circulation (Griesenbach et al., Mol Therapy 2002). Despite the high levels of transduction efficiency the gene expression is transient and repeated administration is not feasible due to induction of immune responses. To overcome these barriers we developed a lentiviral vector specifically pseudotyped with the Sendai virus envelope proteins F and HN (rSIV. F/HN) to allow efficient transduction of the airways. Stable expression for >20 months after a single dose and efficient transduction after repeated administration despite detection of anti-rSIV. F/HN neutralising antibodies make the vector an attractive candidate for a large range of disease indications. Here, we first transduced mouse lung with rSIV. F/HN carrying the secreted reporter gene Gaussia luciferase (GLux) or a control virus by nasal instillation (1e6 transduction units (TU)/mouse, n = 5 –6/group). Persistent levels of GLux expression were detectable in lung (3 logs above control) and broncho-alveolar lavage fluid (BALF, 4 logs above control) for at least 12 months. Importantly, even this modest dose of virus lead to significant (p < 0.01) levels of GLux in serum (274 ± 72 RLU/ul, control: 41 ± 6 RLU/ul) which persisted for at least 12 months further supporting the hypothesis that the lung is a suitable, non-invasive factory for production of secreted proteins. Gene therapy strategies for haemophilia have focussed on intravenous or intramuscular delivery of the gene transfer agent. Here, we treated the murine lung with rSIV. F/HN carrying the FVIII cDNA (1.6e8–3.4e8 TU/mouse,) or placebo and assessed whether therapeutically relevant levels of FVIII can be produced. Significant (p < 0.05) and dose-related levels of FVIII were detectable in lungs and BALF 10 and 28 days post-transduction. Dose-related levels of FVIII were also
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
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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Paul-Smith MC, Gelinas JF, Pytel K, et al., 2015, GENE THERAPY FOR ALPHA-1-ANTITRYPSIN DEFICIENCY USING A PSEUDOTYPED LENTIVIRUS VECTOR, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A72-A73, ISSN: 0040-6376
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Bayfield KJ, Saunders C, Alton EWFW, et al., 2015, COMPARISON OF CF AND NON CF LCI RESULTS USING THE EXHALYZER D AND INNOCORTM DEVICES, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A115-A115, ISSN: 0040-6376
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Griesenbach U, Alton EWFW, Beekman JM, et al., 2015, MOVING LENTIVIRAL-BASED GENE THERAPY INTO A FIRST-IN-MAN CF TRIAL, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A34-A34, ISSN: 0040-6376
Pabary R, Alegro A, Alton EWFW, et al., 2015, TOWARDS THE CLINICAL APPLICATION OF ANTI-PSEUDOMONAL BACTERIOPHAGE: ACTIVITY IS RETAINED FOLLOWING NEBULISATION WITH A RANGE OF COMMERCIALLY AVAILABLE NEBULISER SYSTEMS, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A34-A34, ISSN: 0040-6376
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Turnbull A, Shoemark A, Lund-Palau H, et al., 2015, DEVELOPMENT OF AN IN VITRO ASSAY TO DETECT CHEMICALLY-INDUCED CHANGES IN CILIARY BEAT FREQUENCY, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A40-A41, ISSN: 0040-6376
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