Imperial College London

ProfessorEricAlton

Faculty of MedicineNational Heart & Lung Institute

Chair in Gene Therapy
 
 
 
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Contact

 

+44 (0)20 7594 7937e.alton

 
 
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Assistant

 

Miss Samia Soussi +44 (0)20 7594 7980

 
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Location

 

Emmanuel Kaye BuildingRoyal Brompton Campus

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Summary

 

Publications

Publication Type
Year
to

381 results found

Davies J, Alton E, Simbo A, Murphy R, Ishani S, Williams K, Somerville M, Jolly L, Morant S, Guest Cet 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

Journal article

Waller MD, Harman K, Bayfield KJ, Saunders C, Simmonds N, Davies JC, Alton Eet al., 2019, OPPORTUNISTIC ASSESSMENT OF UPPER AND LOWER AIRWAY ELECTROPHYSIOLOGY AND LUNG FUNCTION IN CYSTIC FIBROSIS, Publisher: WILEY, Pages: S163-S163, ISSN: 8755-6863

Conference paper

Bayfield KJ, Horsley A, Alton E, Irving S, Bush A, Davies JCet 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.

Journal article

Edmondson C, Westrupp N, Brownlee K, Wallenburg J, Alton E, Bush A, Davies JCet 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

Conference paper

Edmondson C, Westrupp N, Brownlee K, Wallenburg J, Alton E, Bush A, Davies JCet 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

Conference paper

Saleh A, Griesenbach U, Alton E, Sinadinos A, Meng Cet al., 2019, ASSAY DEVELOPMENT FOR A FIRST-IN-MAN LENTIVIRUS GENE THERAPY TRIAL FOR CYSTIC FIBROSIS, Publisher: WILEY, Pages: S358-S358, ISSN: 8755-6863

Conference paper

Bell RV, McKinnon TAJ, Alton EWFW, Griesenbach Uet al., 2019, Gene therapy for thrombotic thrombocytopaenic purpura, Annual Conference of the British-Society-for-Gene-and-Cell-Therapy, Publisher: MARY ANN LIEBERT, INC, Pages: A14-A14, ISSN: 1043-0342

Conference paper

Turnbull A, Pyle C, Patel D, Jackson P, Hilliard T, Regamey N, Tan H-L, Brown S, Thursfield R, Short C, Mc Fie M, Alton E, Gaggar A, Blalock JE, Lloyd C, Bush A, Davies J, Snelgrove Ret al., 2019, Abnormal pro-gly-pro pathway and airway neutrophilia in pediatric cystic fibrosis, Journal of Cystic Fibrosis, 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.

Journal article

Palau H, Meng C, Bhargava A, Pilou A, Atsumi N, Byrne A, Pringle I, Ashworth R, Chan M, Gill D, Hyde S, Morgan C, Alton E, Griesenbach Uet 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

Conference paper

Davies G, Griesenbach U, Alton E, Davies JCet al., 2019, 53 - Molecular Therapies for Cystic Fibrosis, Kendig's Disorders of the Respiratory Tract in Children, Pages: 800-811.e3, ISBN: 9780323448871

© 2019 Elsevier Inc. All rights reserved. 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.

Book chapter

Lund-Palau H, Meng C, Pilou A, Atsumi N, Bhargava A, Chan M, Byrne A, Pringle I, Ashworth R, Gill D, Hyde S, Morgan C, Alton E, Griesenbach Uet 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

Conference paper

Simmonds NJ, Pabary R, Kohlhaufl J, Waller MD, Alton EA, Davies JDet 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

Conference paper

Thursfield RM, Naderi K, Leaver N, Rosenthal M, Alton EWFW, Bush A, Davies JCet 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.

Journal article

Bardin EE, Cameron SJS, Perdones-Montero A, Hardiman K, Bolt F, Alton EWFW, Bush A, Davies JC, Takats Zet 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.

Journal article

Paul-Smith M, Pytel K, Gelinas J-F, McIntosh J, Pringle I, Davies L, Chan M, Meng C, Bell R, Cammack L, Moran C, Cameron L, Inoue M, Tsugumine S, Hironaka T, Gill D, Hyde S, Nathwani A, Alton E, Griesenbach Uet 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.

Journal article

Saleh A, Meng C, Chan M, Alton EWFW, Griesenbach Uet 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

Conference paper

Lund-Palau H, Pilou A, Atsumi N, Pringle I, Ashworth RC, Meng C, Chan M, Gill D, Hyde S, Morgan C, Alton EWFW, Griesenbach Uet 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

Conference paper

Clarke N, Saleh A, Meng C, Griesenbach U, Alton Eet 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

Conference paper

Turnbull AR, Murphy R, Behrends V, Lund-Palau H, Simbo A, Mariveles M, Alton EW, Bush A, Shoemark A, Davies JCet 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

Journal article

Shovlin CL, Nur F, St Prix MS, Redhead J, Alton EA, Bernabeu-Herrero ME, Fowler T, Caulfield M, Thomas E, Boardman-Pretty F, McDonagh E, Devereau A, Scott Ret al., 2018, Hereditary haemorrhagic telangiectasia and the 100,000 genomes project, Publisher: SPRINGER, Pages: 125-125, ISSN: 0969-6970

Conference paper

Edmondson C, Murphy R, Moffitt K, Ribeiro D, Alton EWFW, Davies JCet 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

Conference paper

Saleh AD, Clarke NK, Meng C, Jacobson MR, Davies JC, Durham SR, Alton EWFW, Griesenbach Uet 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

Conference paper

Atsumi N, Pilou A, Pringle I, Ashworth RC, Meng C, Chan M, Gill DR, Hyde S, Morgan C, Alton EWFW, Griesenbach Uet 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

Conference paper

Edmondson C, Murphy R, Moffitt K, Riberio D, Alton E, Davies JCet 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

Conference paper

Coates M, Ito K, Alton E, Davies JCet al., 2017, RSV INFECTION LEADS TO INCREASED BINDING OF PSEUDOMONAS AERUGINOSA TO PHE508DEL CFTR EXPRESSING RESPIRATORY EPITHELIAL CELLS, Publisher: WILEY, Pages: S375-S375, ISSN: 8755-6863

Conference paper

Shoemark A, Frost E, Harman K, Crowley S, Ives A, Donovan J, Tan H-L, Alton EW, Bush A, Hogg C, Davies JCet 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

Conference paper

Meng C, Alton E, Boyd C, Davies JC, Higgins T, Gill D, Hyde S, Griesenbach Uet al., 2017, QUANTIFICATION OF VECTOR SHEDDING AFTER LENTIVIRUS GENE TRANSFER TO MOUSE LUNG, Publisher: WILEY, Pages: S268-S269, ISSN: 8755-6863

Conference paper

Meng C, Alton E, Boyd C, Davies J, Higgins T, Gill D, Hyde S, Griesenbach Uet 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

Conference paper

Paul-Smith MC, Pytel KM, Gelinas J-F, McIntosh J, Pringle I, Davies L, Bell R, Cammack L, Moran C, Cameron L, Inoue M, Tsugumine S, Hironaka T, Gill D, Hyde SC, Nathwani A, Alton E, Griesenbach Uet 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

Conference paper

Smith WD, Bardin E, Cameron L, Edmondson CL, Farrant KV, Martin I, Murphy RA, Soren O, Turnbull AR, Wierre-Gore N, Alton EW, Bundy JG, Bush A, Connett GJ, Faust SN, Filloux A, Freemont PS, Jones AL, Takats Z, Webb JS, Williams HD, Davies JCet 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.

Journal article

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