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

417 results found

Balachandar S, Graves TJ, Shimonty A, Kerr K, Kilner J, Xiao S, Slade R, Sroya M, Alikian M, Curetean E, Thomas E, McConnell VPM, McKee S, Boardman-Pretty F, Devereau A, Fowler TA, Caulfield MJ, Alton EW, Ferguson T, Redhead J, McKnight AJ, Thomas GA, Aldred MA, Shovlin CLet al., 2021, Identification and validation of a novel pathogenic variant in GDF2 (BMP9) responsible for hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations, American Journal of Medical Genetics Part A, ISSN: 0148-7299

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant multisystemic vascular dysplasia, characterized by arteriovenous malformations (AVMs), mucocutaneous telangiectasia and nosebleeds. HHT is caused by a heterozygous null allele in ACVRL1, ENG, or SMAD4, which encode proteins mediating bone morphogenetic protein (BMP) signaling. Several missense and stop-gain variants identified in GDF2 (encoding BMP9) have been reported to cause a vascular anomaly syndrome similar to HHT, however none of these patients met diagnostic criteria for HHT. HHT families from UK NHS Genomic Medicine Centres were recruited to the Genomics England 100,000 Genomes Project. Whole genome sequencing and tiering protocols identified a novel, heterozygous GDF2 sequence variant in all three affected members of one HHT family who had previously screened negative for ACVRL1, ENG, and SMAD4. All three had nosebleeds and typical HHT telangiectasia, and the proband also had severe pulmonary AVMs from childhood. In vitro studies showed the mutant construct expressed the proprotein but lacked active mature BMP9 dimer, suggesting the mutation disrupts correct cleavage of the protein. Plasma BMP9 levels in the patients were significantly lower than controls. In conclusion, we propose that this heterozygous GDF2 variant is a rare cause of HHT associated with pulmonary AVMs.

Journal article

Edmondson C, Westrupp N, Seddon P, Olden C, Wallis C, Dawson C, Brodlie M, Baxter F, McCormick J, MacFarlane S, Rice D, Macleod A, Brooker R, Connon M, Ghayyda S, Blaikie L, Thursfield R, Brown L, Price A, Fleischer E, Itterman J, Hughes D, Barrett P, Surette M, Donnelly C, Mateos-Corral D, Padley G, Wallenburg J, Brownlee K, Alton EWFW, Bush A, Davies JCet al., 2021, The feasibility of home monitoring of young people with cystic fibrosis: results from CLIMB-CF, Journal of Cystic Fibrosis, ISSN: 1569-1993

BACKGROUND: CF is traditionally assessed in clinic. It is unclear if home monitoring of young people with CF is feasible or acceptable. The COVID-19 pandemic has made home monitoring more of a necessity. We report the results of CLIMB-CF, exploring home monitoring's feasibility and potential obstacles. METHODS: We designed a mobile app and enrolled participants with CF aged 2-17 years and their parents for six months. They were asked to complete a variety of measures either daily or twice a week. During the study, participants and their parents completed questionnaires exploring depression, anxiety and quality of life. At the end of the study parents and participants completed acceptability questionnaires. RESULTS: 148 participants were recruited, 4 withdrew prior to starting the study. 82 participants were female with median (IQR) age 7.9 (5.2-12 years). Median data completeness was 40.1% (13.6-69.9%) for the whole cohort; when assessed by age participants aged ≥ 12 years contributed significantly less (15.6% [9.8-30%]). Data completeness decreased over time. There was no significant difference between parental depression and anxiety scores at the start and the end of the study nor in CFQ-R respiratory domain scores for participants ≥ 14 years. The majority of participants did not feel the introduction of home monitoring impacted their daily lives. CONCLUSIONS: Most participants felt home monitoring did not negatively impact their lives and it did not increase depression, anxiety or decrease quality of life. However, uptake was variable, and not well sustained. The teenage years pose a particular challenge and further work is required.

Journal article

Hickmott JW, Alton EWFW, Griesenbach U, Prasertsuk Pet al., 2021, Signal peptides

Patent

Sinadinos A, Sergijenko A, Meng C, Gamlin T, Hyde S, Gill DR, Griesenbach U, Alton EWFWet al., 2021, Development of Lentiviral Vector Respiratory Tract Dosing Methods in Anticipation of Rodent GLP Toxicology Assessment, Publisher: CELL PRESS, Pages: 220-221, ISSN: 1525-0016

Conference paper

Sinadinos A, Pineault K, Saleh A, Griesenbach U, Alton EWFWet al., 2021, Computational Tools for Airway-Image and Multidimensional-Data Analysis, Publisher: CELL PRESS, Pages: 257-257, ISSN: 1525-0016

Conference paper

Pineault KM, Meng C, Alton EWFW, Griesenbach Uet al., 2021, Biosafety Risk Assessment: Biodistribution and Environmental Shedding of Topically Administered Lentiviral Vector to the Murine Airway, Publisher: CELL PRESS, Pages: 259-260, ISSN: 1525-0016

Conference paper

Clarke NK, Sinadinos A, Meng C, Alton EWFW, Griesenbach Uet al., 2021, Production of Recombinant Protein after Transplantation of Ex Vivo Transduced Macrophages, Publisher: CELL PRESS, Pages: 378-378, ISSN: 1525-0016

Conference paper

Bell RV, Faulkner N, Alton EWFW, Griesenbach Uet al., 2021, Assessment of F/HN Pseudotyped Lentiviral Vector Following Intravenous Delivery to Mice, Publisher: CELL PRESS, Pages: 138-139, ISSN: 1525-0016

Conference paper

Sergijenko A, Moiseenko A, Pineault K, Nafchi NAM, Chan M, Gamlen T, Gill DR, Hyde SC, Kreuz S, Griesenbach U, Alton EWFWet al., 2021, Assessment of the Air-Liquid Interface Culture Model as a Tool to Validate Efficacy of a rSIV.F/HN-CFTR Vector, Publisher: CELL PRESS, Pages: 260-260, ISSN: 1525-0016

Conference paper

Juarez-Molina CI, Lund-Palau H, Meng C, Gill D, Hyde S, Alton E, Griesenbach Uet al., 2021, Gene Therapy for Autoimmune Pulmonary Alveolar Proteinosis, Publisher: CELL PRESS, Pages: 256-257, ISSN: 1525-0016

Conference paper

Hickmott JW, Prasertsuk P, Bell RV, Chan M, Griesenbach U, Alton EWFWet al., 2021, Towards Enhancing Signal Peptides for Respiratory Gene Therapy with Secreted Proteins, American Society of Gene and Cell Therapy, Publisher: CELL PRESS, Pages: 139-139, ISSN: 1525-0016

Conference paper

MacSweeney R, Reddy K, Davies J, Parker M, Kelly B, Elborn JS, Conlon J, Verghis RM, Calfee CS, Matthay MA, Alton EWFW, McAuley Det al., 2021, Trans-epithelial nasal potential difference in patients with, and at risk of acute respiratory distress syndrome, Thorax, Vol: 76, Pages: 1099-1107, ISSN: 0040-6376

Background: Impaired alveolar fluid clearance, determined in part by alveolar sodium transport, is associated with acute respiratory distress syndrome (ARDS). Nasal sodium transport may reflect alveolar transport. The primary objective of this prospective, observational study was to determine if reduced nasal sodium transport, as measured by nasal potential difference (NPD), was predictive of the development of and outcome from ARDS.Methods: NPD was measured in 15 healthy controls and in 88 patients: 40 mechanically ventilated patients defined as ‘at-risk’ for ARDS, 61 mechanically ventilated patients with ARDS (13 who were previously included in the ‘at-risk’ group) and 8 ARDS survivors on the ward.Results: In at-risk subjects, maximum NPD (mNPD) was greater in those who developed ARDS (difference –8.4 mV; 95% CI –13.8 to –3.7; p=0.005) and increased mNPD predicted the development of ARDS before its onset (area under the curve (AUC) 0.75; 95% CI 0.59 to 0.89). In the ARDS group, mNPD was not significantly different for survivors and non-survivors (p=0.076), and mNPD was a modest predictor of death (AUC 0.60; 95% CI 0.45 to 0.75). mNPD was greater in subjects with ARDS (−30.8 mV) than in at-risk subjects (−24.2 mV) and controls (−19.9 mV) (p<0.001). NPD values were not significantly different for survivors and controls (p=0.18).Conclusions: Increased NPD predicts the development of ARDS in at-risk subjects but does not predict mortality. NPD increases before ARDS develops, is greater during ARDS, but is not significantly different for controls and survivors. These results may reflect the upregulated sodium transport necessary for alveolar fluid clearance in ARDS. NPD may be useful as a biomarker of endogenous mechanisms to stimulate sodium transport. Larger studies are now needed to confirm these associations and predictive performance.

Journal article

Martin I, Kenna D, Morales S, Alton EWFW, Davies Jet al., 2021, Variability in bacteriophage and antibiotic sensitivity in serial Pseudomonas aeruginosa isolates from cystic fibrosis airway cultures over 12 months, Mircoorganisms, Vol: 9, ISSN: 2076-2607

Antibiotic treatment for Pseudomonas aeruginosa (Pa) in cystic fibrosis is limited in efficacy and may lead to multi-drug resistance (MDR). Alternatives such as bacteriophages are being explored but well designed, and controlled trials are crucial. The rational selection of patients with bacteriophage susceptible infections is required for both safety and efficacy monitoring. We questioned whether bacteriophage susceptibility profiles were constant or variable over time, variability having been reported with antibiotics. Serial Pa isolates (n = 102) from 24 chronically infected cystic fibrosis (CF) patients over one year were investigated with plaque and antibiotic disc diffusion assays. Variable number tandem repeat (VNTR) analysis identified those patients with >1 isolate. A median (range) of 4 (3–6) isolates/patient were studied. Twenty-one (87.5%) individuals had a single VNTR type; three (12.5%) had two VNTR types at different times. Seventy-five percent of isolates were sensitive to bacteriophage at ≥ 1 concentration; 50% of isolates were antibiotic multidrug resistant. Serial isolates, even when representing a single VNTR type, varied in sensitivity to both bacteriophages and antibiotics. The rates of sensitivity to bacteriophage supports the development of this therapy; however, the variability in response has implications for the selection of patients in future trials which must be on the basis of current, not past, isolate testing.

Journal article

Sinadinos AJ, Sergijenko A, Saleh AD, Nafchi NAM, Hickmott JW, Gamlen T, Gill DR, Hyde SC, Alton EWFW, Griesenbach Uet al., 2021, QUANTIFICATION OF MRNA AND PROTEIN FROM SINGLE CELLS FOR CYSTIC FIBROSIS GENE THERAPY, Publisher: BMJ PUBLISHING GROUP, Pages: A50-A50, ISSN: 0040-6376

Conference paper

Coates M, Alton E, Rapeport W, Davies J, Ito Ket al., 2021, Pseudomonas aeruginosa induces p38MAP kinase-dependent IL-6 and CXCL8 release from bronchial epithelial cells via a Syk kinase pathway, PLoS One, Vol: 16, ISSN: 1932-6203

Pseudomonas aeruginosa (Pa) infection is a major cause of airway inflammation in immunocompromised and cystic fibrosis (CF) patients. Mitogen-activated protein (MAP) and tyrosine kinases are integral to inflammatory responses and are therefore potential targets for novel anti-inflammatory therapies. We have determined the involvement of specific kinases in Pa-induced inflammation. The effects of kinase inhibitors against p38MAPK, MEK 1/2, JNK 1/2, Syk or c-Src, a combination of a p38MAPK with Syk inhibitor, or a novel narrow spectrum kinase inhibitor (NSKI), were evaluated against the release of the proinflammatory cytokine/chemokine, IL-6 and CXCL8 from BEAS-2B and CFBE41o- epithelial cells by Pa. Effects of a Syk inhibitor against phosphorylation of the MAPKs were also evaluated. IL-6 and CXCL8 release by Pa were significantly inhibited by p38MAPK and Syk inhibitors (p<0.05). Phosphorylation of HSP27, but not ERK or JNK, was significantly inhibited by Syk kinase inhibition. A combination of p38MAPK and Syk inhibitors showed synergy against IL-6 and CXCL8 induction and an NSKI completely inhibited IL-6 and CXCL8 at low concentrations. Pa-induced inflammation is dependent on p38MAPK primarily, and Syk partially, which is upstream of p38MAPK. The NSKI suggests that inhibiting specific combinations of kinases is a potent potential therapy for Pa-induced inflammation.

Journal article

Sinadinos A, Sergijenko A, Meng C, Gamlen T, Hyde S, Gill DR, Griesenbach U, Alton EWFWet al., 2021, DEVELOPMENT OF PROTOCOLS FOR MOUSE GLP-TOXICOLOGY STUDIES, Publisher: BMJ PUBLISHING GROUP, Pages: A32-A32, ISSN: 0040-6376

Conference paper

Alton EWFW, Boyd AC, Davies JC, Gill DR, Griesenbach U, Harman TE, Hyde SC, McLachlan Get al., 2021, TOWARDS A FIRST-IN-HUMAN TRIAL WITH A PSEUDOTYPED LENTIVIRUS, Publisher: BMJ PUBLISHING GROUP, Pages: A42-A42, ISSN: 0040-6376

Conference paper

Sergijenko A, Moiseenko A, Pineault K, Nafchi NAM, Chan M, Gamlen T, Gill DR, Hyde SC, Kreuz S, Griesenbach U, Alton EWFWet al., 2021, LOW LEVELS OF LENTIVIRUS-MEDIATED CFTR GENE TRANSFER ARE SUFFICIENT TO GENERATE ION TRANSPORT CORRECTION IN AIR-LIQUID INTERFACE CULTURES FROM CYSTIC FIBROSIS PATIENTS, Publisher: BMJ PUBLISHING GROUP, Pages: A42-A42, ISSN: 0040-6376

Conference paper

Sinadinos A, Sergijenko A, Meng C, Gamlen T, Hyde S, Gill DR, Griesenbach U, Alton EWet al., 2020, DEVELOPMENT OF PROTOCOLS FOR MOUSE GLP-TOXICOLOGY STUDIES, Publisher: WILEY, Pages: S196-S196, ISSN: 8755-6863

Conference paper

Edmondson C, Westrupp N, Wallenburg J, Brownlee K, Alton EW, Bush A, Davies JCet al., 2020, MONITORING LUNG FUNCTION OF YOUNG PEOPLE WITH CF AT HOME: IS IT RELIABLE? RESULTS FROM THE CLIMB-CF STUDY, Publisher: WILEY, Pages: S290-S290, ISSN: 8755-6863

Conference paper

Edmondson C, Westrupp N, Wallenburg J, Brownlee K, Alton EW, Bush A, Davies JCet al., 2020, WHAT IS FEASIBLE WHEN IT COMES TO MONITORING YOUNG PEOPLE WITH CYSTIC FIBROSIS AT HOME? THE RESULTS OF THE CLIMB-CF STUDY, Publisher: WILEY, Pages: S297-S297, ISSN: 8755-6863

Conference paper

Sinadinos A, Sergijenko A, Saleh A, Pineault KM, Nafchi NA, Hickmott JW, Choudhary TR, Mclaughlin CL, Gamlen T, Gill DR, Hyde S, McLachlan G, Alton EW, Griesenbach Uet al., 2020, SINGLE-CELL ASSAYS FOR QUANTIFYING MRNA AND PROTEIN DURING CYSTIC FIBROSIS GENE THERAPY TRIALS, North American Cystic Fibrosis Conference, Publisher: WILEY, Pages: S203-S203, ISSN: 8755-6863

Conference paper

Alton EW, Boyd A, Davies JC, Gill DR, Griesenbach U, Harman TE, Hyde S, McLachlan Get al., 2020, TOWARDS A FIRST-IN-HUMAN TRIAL WITH A PSEUDOTYPED LENTIVIRUS, Publisher: WILEY, Pages: S224-S224, ISSN: 8755-6863

Conference paper

Sergijenko A, Moiseenko A, Pineault KM, Nafchi NA, Chan M, Gamlen T, Gill DR, Hyde S, Kreuz S, Griesenbach U, Alton EWet al., 2020, LOW LEVELS OF CFTR GENE TRANSFER WITH F/HN PSEUDOTYPED LENTIVIRUS ARE SUFFICIENT TO GENERATE ION TRANSPORT CORRECTION IN AIRWAY CELL CULTURES FROM CYSTIC FIBROSIS PATIENTS, Publisher: WILEY, Pages: S73-S73, ISSN: 8755-6863

Conference paper

Pineault KM, Meng C, Griesenbach U, Alton EWet al., 2020, BIODISTRIBUTION AND ENVIRONMENTAL SHEDDING OF LENTIVIRAL VECTORS FOLLOWING TOPICAL ADMINISTRATION TO MURINE LUNGS, Publisher: WILEY, Pages: S240-S240, ISSN: 8755-6863

Conference paper

Alton EWFW, Boyd AC, Davies JC, Gill DR, Griesenbach U, Harman TE, Hyde S, McLachlan Get al., 2020, Gene Therapy for Respiratory Diseases: Progress and a Changing Context, HUMAN GENE THERAPY, Vol: 31, Pages: 911-916, ISSN: 1043-0342

Journal article

Morris-Rosendahl DJ, Edwards M, McDonnell MJ, John S, Alton EWFW, Davies JC, Simmonds NJet al., 2020, Whole-gene sequencing of CFTR reveals a high prevalence of the intronic variant c.3874-4522A>G in cystic fibrosis., American Journal of Respiratory and Critical Care Medicine, Vol: 201, Pages: 1438-1441, ISSN: 1073-449X

Journal article

Bayfield KJ, Alton E, Irving S, Bush A, Davies JCet al., 2020, “Nitrogen offset in N2 multiple washout method”. Katie J. Bayfield, Eric Alton, Samantha Irving, Andrew Bush, Jane C. Davies. ERJ Open Res 2019; 6: 00043-2020, ERJ Open Research, Vol: 6, Pages: 1-1, ISSN: 2312-0541

This article was originally published with the sentence “Thank you for the opportunity to respond to the correspondence by J.G. Nielsen from Innovision about our recent paper”. The authors have since been made aware that J.G. Nielsen sold Innovision ApS (Glamsbjerg, Denmark) prior to the submission of his correspondence and, at the time of writing, has no financial interests in any business relating to lung clearance index technologies. This sentence has now been changed to “Thank you for the opportunity to respond to the correspondence by J.G. Nielsen about our recent paper” in the article itself.

Journal article

Bayfield KJ, Alton E, Irving S, Bush A, Davies JCet al., 2020, Nitrogen offset in N-2 multiple washout method, ERJ Open Research, Vol: 6, Pages: 1-2, ISSN: 2312-0541

Journal article

Davies J, Bayfield K, Alton E, Bush A, Irving Set al., 2020, Letter to the ERJ OPEN reply 24th January 2020

Journal article

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