Publications
451 results found
Hyde SC, Alton E, Boyd A, et al., 2015, PRODUCTION OF SIV.F/HN: A NEW LENTIVIRUS VECTOR FOR CF GENE THERAPY, PEDIATRIC PULMONOLOGY, Vol: 50, Pages: 291-291, ISSN: 8755-6863
Coates M, Brookes D, Ito K, et al., 2015, RESPIRATORY SYNCYTIAL VIRUS LEADS TO MORE RAPID CELL DEATH IN PHE508DEL BRONCHIAL EPITHELIAL CELLS, PEDIATRIC PULMONOLOGY, Vol: 50, Pages: 314-315, ISSN: 8755-6863
Sonneveld N, Stanojevic S, Amin R, et al., 2015, Lung clearance index in cystic fibrosis subjects treated for pulmonary exacerbations, EUROPEAN RESPIRATORY JOURNAL, Vol: 46, Pages: 1055-1064, ISSN: 0903-1936
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- Citations: 51
Alton EWFW, Armstrong DK, Ashby D, 2015, Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial, The Lancet Respiratory Medicine, Vol: 3, Pages: 684-691, ISSN: 2213-2600
BackgroundLung 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.MethodsWe 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.FindingsBetween 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.InterpretationMonthly application of the pGM169/GL67A gene therapy formulation was associated with a significant, albeit modest, benefit in FEV1 compared with placebo at 1 yea
Bayfield K, Saunders C, Alton E, et al., 2015, Comparison of CF and non CF FRC and LCI values measured with Exhalyzer D and Innocor™ devices, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Alton EWFW, Armstrong DK, Ashby D, 2015, Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fi brosis: a randomised, double-blind, placebo-controlled, phase 2b trial (vol 3, pg 684, 2015), LANCET RESPIRATORY MEDICINE, Vol: 3, Pages: E33-E33, ISSN: 2213-2600
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- Citations: 2
Wainwright CE, Elborn JS, Ramsey BW, et al., 2015, Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR, New England Journal of Medicine, Vol: 373, Pages: 220-231, ISSN: 1533-4406
BACKGROUNDCystic fibrosis is a life-limiting disease that is caused by defective or deficient cystic fibrosis transmembrane conductance regulator (CFTR) protein activity. Phe508del is the most common CFTR mutation.METHODSWe conducted two phase 3, randomized, double-blind, placebo-controlled studies that were designed to assess the effects of lumacaftor (VX-809), a CFTR corrector, in combination with ivacaftor (VX-770), a CFTR potentiator, in patients 12 years of age or older who had cystic fibrosis and were homozygous for the Phe508del CFTR mutation. In both studies, patients were randomly assigned to receive either lumacaftor (600 mg once daily or 400 mg every 12 hours) in combination with ivacaftor (250 mg every 12 hours) or matched placebo for 24 weeks. The primary end point was the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1) at week 24.RESULTSA total of 1108 patients underwent randomization and received study drug. The mean baseline FEV1 was 61% of the predicted value. In both studies, there were significant improvements in the primary end point in both lumacaftor–ivacaftor dose groups; the difference between active treatment and placebo with respect to the mean absolute improvement in the percentage of predicted FEV1 ranged from 2.6 to 4.0 percentage points (P<0.001), which corresponded to a mean relative treatment difference of 4.3 to 6.7% (P<0.001). Pooled analyses showed that the rate of pulmonary exacerbations was 30 to 39% lower in the lumacaftor–ivacaftor groups than in the placebo group; the rate of events leading to hospitalization or the use of intravenous antibiotics was lower in the lumacaftor–ivacaftor groups as well. The incidence of adverse events was generally similar in the lumacaftor–ivacaftor and placebo groups. The rate of discontinuation due to an adverse event was 4.2% among patients who received lumacaftor–ivacaftor versus 1.6% among those who
Gielen V, Sykes A, Zhu J, et al., 2015, Increased nuclear suppressor of cytokine signaling 1 in asthmatic bronchial epithelium suppresses rhinovirus induction of innate interferons, Journal of Allergy and Clinical Immunology, Vol: 136, Pages: 177-188e.11, ISSN: 1097-6825
BackgroundRhinovirus infections are the dominant cause of asthma exacerbations, and deficient virus induction of IFN-α/β/λ in asthmatic patients is important in asthma exacerbation pathogenesis. Mechanisms causing this interferon deficiency in asthmatic patients are unknown.ObjectiveWe sought to investigate the expression of suppressor of cytokine signaling (SOCS) 1 in tissues from asthmatic patients and its possible role in impaired virus-induced interferon induction in these patients.MethodsWe assessed SOCS1 mRNA and protein levels in vitro, bronchial biopsy specimens, and mice. The role of SOCS1 was inferred by proof-of-concept studies using overexpression with reporter genes and SOCS1-deficient mice. A nuclear role of SOCS1 was shown by using bronchial biopsy staining, overexpression of mutant SOCS1 constructs, and confocal microscopy. SOCS1 levels were also correlated with asthma-related clinical outcomes.ResultsWe report induction of SOCS1 in bronchial epithelial cells (BECs) by asthma exacerbation–related cytokines and by rhinovirus infection in vitro. We found that SOCS1 was increased in vivo in bronchial epithelium and related to asthma severity. SOCS1 expression was also increased in primary BECs from asthmatic patients ex vivo and was related to interferon deficiency and increased viral replication. In primary human epithelium, mouse lung macrophages, and SOCS1-deficient mice, SOCS1 suppressed rhinovirus induction of interferons. Suppression of virus-induced interferon levels was dependent on SOCS1 nuclear translocation but independent of proteasomal degradation of transcription factors. Nuclear SOCS1 levels were also increased in BECs from asthmatic patients.ConclusionWe describe a novel mechanism explaining interferon deficiency in asthmatic patients through a novel nuclear function of SOCS1 and identify SOCS1 as an important therapeutic target for asthma exacerbations.
Alton E, Griesenbach U, Davies JC, et al., 2015, A randomised, double-blind, placebo-controlled trial of repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis, Lancet Respiratory Medicine, ISSN: 2213-2619
Subbarao P, Milla C, Aurora P, et al., 2015, Multiple-Breath Washout as a Lung Function Test in Cystic Fibrosis A Cystic Fibrosis Foundation Workshop Report, ANNALS OF THE AMERICAN THORACIC SOCIETY, Vol: 12, Pages: 932-939, ISSN: 1546-3222
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- Citations: 86
Harman KML, Irving SJ, Bayfield K, et al., 2014, CHANGES IN INDICES DERIVED FROM MULTIBREATH WASHOUT (MBW) FOLLOWING TREATMENT WITH IVACAFTOR IN PATIENTS WITH CYSTIC FIBROSIS, Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A167-A167, ISSN: 0040-6376
Collins N, Robson K, Nagakumar P, et al., 2014, SPUTUM INDUCTION REDUCES THE NEED FOR BRONCHOSCOPY IN SCHOOL-AGED CHILDREN WITH CYSTIC FIBROSIS, Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A123-A124, ISSN: 0040-6376
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- Citations: 1
Bayfield KJ, McGovern M, Simpson AJ, et al., 2014, RELIABILITY OF MEASUREMENTS USING INNOCOR BREATH BY BREATH ANALYSER DURING A MAXIMAL EXERCISE TEST IN CYSTIC FIBROSIS PATIENTS, Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A167-A168, ISSN: 0040-6376
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- Citations: 1
Griesenbach U, Alton EWFW, Armstrong DK, et al., 2014, Assessment of immune responses to single and repeat dose aeroslisation of the non-viral formualtion PGM169/GL67A in cystic fibrosis patients, ESGCT and NVGCT Collaborative Congress, Publisher: MARY ANN LIEBERT, INC, Pages: A110-A111, ISSN: 1043-0342
Davies JC, Ebdon A-M, Orchard C, 2014, Recent advances in the management of cystic fibrosis, ARCHIVES OF DISEASE IN CHILDHOOD, Vol: 99, Pages: 1033-1036, ISSN: 0003-9888
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- Citations: 32
McKone EF, Borowitz D, Drevinek P, et al., 2014, Long-term safety and efficacy of ivacaftor in patients with cystic fibrosis who have the Gly551Asp-<i>CFTR</i> mutation: a phase 3, open-label extension study (PERSIST), LANCET RESPIRATORY MEDICINE, Vol: 2, Pages: 902-910, ISSN: 2213-2600
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- Citations: 162
Ahmed B, Bush A, Davies JC, 2014, How to use: bacterial cultures in diagnosing lower respiratory tract infections in cystic fibrosis, ARCHIVES OF DISEASE IN CHILDHOOD-EDUCATION AND PRACTICE EDITION, Vol: 99, Pages: 181-187, ISSN: 1743-0585
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- Citations: 13
Nair C, Shoemark A, Chan M, et al., 2014, Cyanide levels found in infected cystic fibrosis sputum inhibit airway ciliary function, European Respiratory Journal, ISSN: 0903-1936
Griesenbach U, Alton EW, Boyd A, et al., 2014, IMMUNE RESPONSES TO SINGLE AND REPEATED ADMINISTRATION OF PGM169/GL67A: THE UK CF GENE THERAPY CONSORTIUM CLINICAL TRIALS, PEDIATRIC PULMONOLOGY, Vol: 49, Pages: 297-297, ISSN: 8755-6863
Thursfield RM, Bush A, Alton EW, et al., 2014, VITAMIN D DEFICIENCY IS NOT ASSOCIATED WITH <i>PSEUDOMONAS AERUGINOSA</i> OR <i>STAPHYLOCOCCUS AUREUS</i> INFECTION IN CHILDREN WITH CYSTIC FIBROSIS, PEDIATRIC PULMONOLOGY, Vol: 49, Pages: 346-347, ISSN: 8755-6863
Waller MD, Harman KM, Boyd A, et al., 2014, MEASUREMENT OF CFTR FUNCTION IN CYSTIC FIBROSIS PATIENTS IN RESPONSE TO MULTIDOSE CFTR GENE THERAPY, PEDIATRIC PULMONOLOGY, Vol: 49, Pages: 249-250, ISSN: 8755-6863
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- Citations: 2
Thursfield RM, Bush A, Alton EW, et al., 2014, BALF LEVELS OF LL37 CORRELATE WITH BALF CELLULAR AND SOLUBLE MARKERS OF INFLAMMATION IN CHILDREN WITH CYSTIC FIBROSIS, PEDIATRIC PULMONOLOGY, Vol: 49, Pages: 304-304, ISSN: 8755-6863
Harman KM, Irving SJ, Bayfield KJ, et al., 2014, EXPLORING INDICES DERIVED FROM MULTIBREATH WASHOUT (MBW) FOLLOWING TREATMENT WITH IVACAFTOR, PEDIATRIC PULMONOLOGY, Vol: 49, Pages: 267-268, ISSN: 8755-6863
Irving SJ, Davies JC, Alton EWF, et al., 2014, Lung Clearance Index in Primary Ciliary Dyskinesia and Bronchiectasis, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 189, Pages: 1147-1148, ISSN: 1073-449X
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- Citations: 5
Armstrong DK, Cunningham S, Davies JC, et al., 2014, Gene therapy in cystic fibrosis, ARCHIVES OF DISEASE IN CHILDHOOD, Vol: 99, Pages: 465-468, ISSN: 0003-9888
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- Citations: 34
Kent L, Reix P, Innes JA, et al., 2014, Lung clearance index: Evidence for use in clinical trials in cystic fibrosis, JOURNAL OF CYSTIC FIBROSIS, Vol: 13, Pages: 123-138, ISSN: 1569-1993
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- Citations: 146
Alton EWFW, Boyd AC, Cheng SH, et al., 2014, Toxicology study assessing efficacy and safety of repeated administration of lipid/DNA complexes to mouse lung, GENE THERAPY, Vol: 21, Pages: 89-95, ISSN: 0969-7128
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- Citations: 33
Naehrlich L, Ballmann M, Davies J, et al., 2014, Nasal potential difference measurements in diagnosis of cystic fibrosis: An international survey, JOURNAL OF CYSTIC FIBROSIS, Vol: 13, Pages: 24-28, ISSN: 1569-1993
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- Citations: 31
Pabary R, Kumar S, Huang J, et al., 2013, SIFT-MS ANALYSIS AS A NON-INVASIVE DETERMINANT OF PSEUDOMONAS AERUGINOSA INFECTION IN PATIENTS WITH CYSTIC FIBROSIS, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A8-A8, ISSN: 0040-6376
Alton EWFW, Baker A, Baker E, et al., 2013, The safety profile of a cationic lipid-mediated cystic fibrosis gene transfer agent following repeated monthly aerosol administration to sheep, BIOMATERIALS, Vol: 34, Pages: 10267-10277, ISSN: 0142-9612
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- Citations: 32
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