372 results found
Snelgrove R, Turnbull A, Pyle C, et al., Abnormal Pro-Gly-Pro pathway and airway neutrophilia in pediatric cystic fibrosis, Journal of Cystic Fibrosis, ISSN: 1569-1993
Palau H, Meng C, Bhargava A, et 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
Bardin EE, Cameron SJS, Perdones-Montero A, et 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.
Paul-Smith M, Pytel K, Gelinas J-F, et 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.
Saleh A, Meng C, Chan M, et 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
Lund-Palau H, Pilou A, Atsumi N, et 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
Clarke N, Saleh A, Meng C, et 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
Turnbull AR, Murphy R, Behrends V, et 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
Thursfield RM, Naderi K, Leaver N, et al., 2018, Children with cystic fibrosis demonstrate no respiratory immunological, infective or physiological, consequences of vitamin D deficiency, Journal of Cystic Fibrosis, 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.
© 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.
Shovlin CL, Nur F, St Prix MS, et al., 2018, Hereditary haemorrhagic telangiectasia and the 100,000 genomes project, Publisher: SPRINGER, Pages: 125-125, ISSN: 0969-6970
Edmondson C, Murphy R, Moffitt K, et 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
Saleh AD, Clarke NK, Meng C, et 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
Atsumi N, Pilou A, Pringle I, et 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
Edmondson C, Murphy R, Moffitt K, et al., 2017, ACTIVE NEUTROPHIL ELASTASE CAN BE DETECTED IN EXHALED BREATH CONDENSATE OF PATIENTS WITH CYSTIC FIBROSIS, Publisher: WILEY, Pages: S316-S316, ISSN: 8755-6863
Coates M, Ito K, Alton E, et 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
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
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
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
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
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
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
Bayfield K, Alton E, Irving S, et al., 2016, Simultaneous SF6 and N-2 gas multiple breath washout (MBW); understanding the difference between test gases, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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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