Publications
600 results found
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.
Leoni G, Wasowicz MY, Chan M, et al., 2015, Ex Vivo and In Vivo Lentivirus-Mediated Transduction of Airway Epithelial Progenitor Cells., Current Gene Therapy, Vol: 15, Pages: 581-590, ISSN: 1875-5631
A key challenge in pulmonary gene therapy for cystic fibrosis is to provide long-term correction of the genetic defect. This may be achievable by targeting airway epithelial stem/progenitor cells with an integrating vector. Here, we evaluated the ability of a lentiviral vector, derived from the simian immunodeficiency virus and pseudotyped with F and HN envelope proteins from Sendai virus, to transduce progenitor basal cells of the mouse nasal airways. We first transduced basal cell-enriched cultures ex vivo and confirmed efficient transduction of cytokeratin-5 positive cells. We next asked whether progenitor cells could be transduced in vivo. We evaluated the transduction efficiency in mice pretreated by intranasal administration of polidocanol to expose the progenitor cell layer. Compared to control mice, polidocanol treated mice demonstrated a significant increase in the number of transduced basal cells at 3 and 14 days post vector administration. At 14 days, the epithelium of treated mice contained clusters (4 to 8 adjacent cells) of well differentiated ciliated, as well as basal cells suggesting a clonal expansion. These results indicate that our lentiviral vector can transduce progenitor basal cells in vivo, although transduction required denudation of the surface epithelium prior to vector administration.
Gill DR, Alton EW, Armstrong DK, et al., 2015, A Phase 2b clinical trial of non-viral gene therapy in Cystic Fibrosis patients: randomized, double-blind, placebo-controlled repeated aerosol delivery to the lungs., Collaborative Congress of the European-Society-of-Gene-and-Cell-Therapy (ESGCT) and Finnish-Society-of-Gene-Therapy (FSGT), Publisher: MARY ANN LIEBERT, INC, Pages: A18-A18, ISSN: 1043-0342
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
Griesenbach U, Alton E, Armstrong D, et al., 2015, REPEATED ADMINISTRATION OF THE NON-VIRAL GENE TRANSFER AGENT PGM169/GL67A DOES NOT INDUCE ANTI-CFTR OR ANTI-PLASMID IMMUNE RESPONSES, Publisher: WILEY-BLACKWELL, Pages: 283-283, 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
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
Paul-Smith M, Gelinas J-F, Pytel K, et al., 2015, Therapeutic levels of alpha-1-antitrypsin following gene therapy with F/HN pseudotyped simian immunodeficiency virus, Annual Conference of the British-Society-for-Gene-and-Cell-Therapy, Publisher: MARY ANN LIEBERT, INC, Pages: A12-A12, ISSN: 1043-0342
Pytel KM, Smith MP, McIntosh J, et al., 2015, Production of FVIII in the lungs, Annual Conference of the British-Society-for-Gene-and-Cell-Therapy, Publisher: MARY ANN LIEBERT, INC, Pages: A7-A7, ISSN: 1043-0342
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
- Author Web Link
- Cite
- Citations: 2
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
Hyde SC, Davies LA, Pringle IA, et al., 2015, Scalable, Animal-Free, Suspension-Based Production of Siv Lentiviral Vectors, 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT), Publisher: NATURE PUBLISHING GROUP, Pages: S35-S36, ISSN: 1525-0016
- Author Web Link
- Cite
- Citations: 1
Paul-Smith MC, Gelinas J-F, Pytel K, et al., 2015, F/HN Pseudotyped Lentivirus Generates Therapeutically Relevant and Long-Lasting Alpha-1-Antitrypsin Expression in Mouse Lung, 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT), Publisher: NATURE PUBLISHING GROUP, Pages: S147-S147, ISSN: 1525-0016
Pytel KM, 2015, Production of therapeutically relevant levels of FVIII after transduction of lungs with F/HN-pseudotyped lentivirus, American Society for Gene and Cell Therapy, 18th Annual Meeting
Griesenbach U, Pytel K, Alton EWFW, 2015, Cystic Fibrosis gene therapy in the UK and elsewhere, Human Gene Therapy, Vol: 26, Pages: 226-275, ISSN: 1043-0342
The cystic fibrosis transmembrane conductance regulator (CFTR) gene was identified in 1989. This opened the door for the development of cystic fibrosis (CF) gene therapy, which has been actively pursued for the last 20 years. Although 26 clinical trials involving approximately 450 patients have been carried out, the vast majority of these trials were short and included small numbers of patients; they were not designed to assess clinical benefit, but to establish safety and proof-of-concept for gene transfer using molecular end points such as the detection of recombinant mRNA or correction of the ion transport defect. The only currently published trial designed and powered to assess clinical efficacy (defined as improvement in lung function) administered AAV2-CFTR to the lungs of patients with CF. The U.K. Cystic Fibrosis Gene Therapy Consortium completed, in the autumn of 2014, the first nonviral gene therapy trial designed to answer whether repeated nonviral gene transfer (12 doses over 12 months) can lead to clinical benefit. The demonstration that the molecular defect in CFTR can be corrected with small-molecule drugs, and the success of gene therapy in other monogenic diseases, is boosting interest in CF gene therapy. Developments are discussed here.
Griesenbach U, Alton E, 2015, Update on preclinical and clinical gene therapy for the treatment of cystic fibrosis, Gene and Cell Therapy: Therapeutic Mechanisms and Strategies, Fourth Edition, Pages: 925-933, ISBN: 9781466571990
The first gene-therapy-based drug in Europe, an AAV carrying the lipoprotein lipase gene, also known as Glybera, obtained European marketing authorization for the treatment of patients with severe lipoprotein lipase deficiency in 2012. Through advances in recombinant DNA technology, gene therapy is being developed for a large number of inherited and acquired diseases. Although cystic fibrosis (CF) gene therapy has been at the forefront of gene therapy research since cloning of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 1989 (see Table 36.1 for key publications), other disease targets including immune deficiencies, degenerative eye disorders [1], and hemophilia [2] have provided a greater degree of clinical efficacy. This is in part due to the lung being a more difficult target organ to treat than originally anticipated. In addition, conclusive phase IIB clinical trials are expensive and difficult to perform because of the large surface area to be treated. This realization has, over the last 10 years, led to a waning enthusiasm for CF gene therapy, which is currently only being performed by a small number of committed mainly academic groups.
Griesenbach U, Alton EWFW, 2015, Recent advances in understanding and managing cystic fibrosis transmembrane conductance regulator dysfunction., F1000Prime Rep, Vol: 7, ISSN: 2051-7599
Cystic fibrosis is the most common autosomal recessive genetic disease in Caucasians and has been extensively studied for many decades. The cystic fibrosis transmembrane conductance regulator gene was identified in 1989. It encodes a complex protein which has numerous cellular functions. Our understanding of cystic fibrosis pathophysiology and genetics is constantly expanding and being refined, leading to improved management of the disease and increased life expectancy in affected individuals.
Griesenbach U, Boyd AC, Calcedo R, et al., 2014, IMMUNE RESPONSES TO SINGLE AND REPEATED ADMINISTRATION OF PGM169/GL67A: THE UK CF GENE THERAPY CONSORTIUM CLINICAL TRIALS, Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A166-A166, ISSN: 0040-6376
Armstrong DK, Bayfield KJ, Alton EWFW, et al., 2014, STANDARDISATION OF LUNG CLEARANCE INDEX IN A MULTICENTRE CLINICAL TRIAL, Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A168-A169, ISSN: 0040-6376
- Author Web Link
- Cite
- Citations: 1
Hyde SC, Alton E, Boyd AC, et al., 2014, DEVELOPMENT OF AN OPTIMAL F/HN PSEUDOTYPED SIV VECTOR FOR CF GENE THERAPY, Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A165-A166, ISSN: 0040-6376
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
- Author Web Link
- Cite
- Citations: 1
Gill DR, Alton EW, Connolly MM, et al., 2014, Development of F/HN pseudotyped Lentivirus for airway gene transfer, ESGCT and NVGCT Collaborative Congress, Publisher: MARY ANN LIEBERT, INC, Pages: A43-A43, ISSN: 1043-0342
Griesenbach U, Alton EWFW, Armstrong DK, et al., 2014, Results of a Phase IIb non-viral gene therapy trial from the UK CF Gene Therapy Consortium, ESGCT and NVGCT Collaborative Congress, Publisher: MARY ANN LIEBERT, INC, Pages: A51-A51, ISSN: 1043-0342
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
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
Alton E, 2014, THE UK GENE THERAPY TRIAL, PEDIATRIC PULMONOLOGY, Vol: 49, Pages: 153-154, ISSN: 8755-6863
- Author Web Link
- Cite
- Citations: 2
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
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.