434 results found
The prospect of gene therapy for inherited and acquired respiratory disease has energized the research community since the 1980s, with cystic fibrosis, as a monogenic disorder, driving early efforts to develop effective strategies. The fact that there are still no approved gene therapy products for the lung, despite many early phase clinical trials, illustrates the scale of the challenge: in the 1990s, first generation non-viral and viral vector systems demonstrated proof-of-concept but low efficacy. Since then, there has been steady progress towards improved vectors with the capacity to overcome at least some of the formidable barriers presented by the lung. In addition, the inclusion of features such as codon optimisation and promoters providing long-term expression have improved the expression characteristics of therapeutic transgenes. Early approaches were based on gene addition, where a new DNA copy of a gene is introduced to complement a genetic mutation: however, the advent of RNA-based products that can directly express a therapeutic protein or manipulate gene expression, together with the expanding range of tools for gene editing, has stimulated the development of alternative approaches. This review discusses the range of vector systems being evaluated for lung delivery; the variety of cargoes they deliver, including DNA, antisense oligonucleotides, mRNA, siRNA and peptide nucleic acids; and exemplifies progress in selected respiratory disease indications.
Alton E, Lund-Palau H, Juarez-Molina C, et al., 2022, Correction of a chronic pulmonary disease through lentiviral vector-mediated protein expression, Molecular Therapy - Methods and Clinical Development, Vol: 25, Pages: 382-391, ISSN: 2329-0501
We have developed a novel lentiviral vector, pseudotyped with the F and HN proteins from Sendai virus (rSIV.F/HN), which produces long-lasting, high efficiency transduction of the respiratory epithelium. Here, we addressed whether this platform technology can secrete sufficient levels of a therapeutic protein into the lung to ameliorate a fatal pulmonary disease, as an exemplar of its translational capability. Pulmonary Alveolar Proteinosis (PAP) results from alveolar GM-CSF insufficiency, resulting in abnormal surfactant homeostasis and consequent ventilatory problems. Lungs of GM-CSF knockout mice were transduced with a single dose of rSIV.F/HN expressing murine (m)GM-CSF (1e5-92e7 TU/mouse); mGM-CSF expression was dose-related and persisted for at least 11 months. PAP disease biomarkers were rapidly and persistently corrected, but we noted a narrow toxicity/efficacy window. rSIV.F/HN may be a useful platform technology to deliver therapeutic proteins for lung diseases requiring long-lasting and stable expression of secreted proteins.
Clarke NK, Sergijenko A, Pineault K, et al., 2022, Ex Vivo Transduced Macrophages Engraft in the Lung Following Transplantation and Produce Therapeutic Levels of Secreted Proteins, American Society of Cell and Gene Therapy, Publisher: CELL PRESS, Pages: 405-405, ISSN: 1525-0016
Bell R, Clarke NK, Isalan M, et al., 2022, Regulated Expression of LentiviralVectors Following Administration of anInducing Molecule, 2022 ASGCT Annual Meeting, Publisher: Cell Press, Pages: 419-419, ISSN: 1525-0016
Hickmott JW, Prasertsuk P, Bell RV, et al., 2022, Heterologous Signal Peptides Enhance Protein Secretion for Respiratory Gene Therapy, Publisher: CELL PRESS, Pages: 417-418, ISSN: 1525-0016
Bell RV, Clarke NK, Isalan M, et al., 2022, Regulated Expression of Lentiviral Vectors Following Administration of an Inducing Molecule, Publisher: CELL PRESS, Pages: 419-419, ISSN: 1525-0016
Sergijenko A, Pineault KM, Moiseenko A, et al., 2022, Development of Molecular Assays to Determine Lentiviral Vector-Mediated Transduction Efficiency in Airway Epithelial Cells, Publisher: CELL PRESS, Pages: 419-419, ISSN: 1525-0016
Balachandar S, Graves TJ, Shimonty A, et al., 2022, 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, Vol: 188, Pages: 959-964, 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.
Edmondson C, Westrupp N, Seddon P, et al., 2022, The feasibility of home monitoring of young people with cystic fibrosis: results from CLIMB-CF, Journal of Cystic Fibrosis, Vol: 21, Pages: 70-77, 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.
Clarke N, Sinadinos A, Meng C, et al., 2021, Ex vivo transduced macrophages produce therapeutic levels of secreted protein when transplanted to the lung, ESGCT Collaborative Virtual Congress, Publisher: Mary Ann Liebert, ISSN: 1043-0342
Bell R, Faulkner N, Griesenbach U, et al., 2021, Intravenous administration of F/HN pseudotyped lentiviral vector, ESGCT Collaborative Virtual Congress, Publisher: Mary Ann Liebert, ISSN: 1043-0342
Bell RV, Isalan M, Alton EWFW, et al., 2021, Regulation of lentivirus‐mediated expression in a human airway model, ESGCT Collaborative Virtual Congress, Publisher: Mary Ann Liebert, ISSN: 1043-0342
, 2021, ESGCTCollaborative Virtual Congress19–22 October 2021Abstracts, Human Gene Therapy, Vol: 32, Pages: A1-A152, ISSN: 1043-0342
Moiseenko A, Pineault K, Sergijenko A, et al., 2021, Functional characterisation of an engineered next generation lentivirus vector for the treatment of cystic fibrosis, Publisher: MARY ANN LIEBERT, INC, Pages: A39-A39, ISSN: 1043-0342
Juarez-Molina CI, Lund-Palau H, Meng C, et al., 2021, Lentiviral vector/GM-CSF Gene Therapy for Autoimmune Pulmonary Alveolar Proteinosis, Publisher: MARY ANN LIEBERT, INC, Pages: A38-A38, ISSN: 1043-0342
Hickmott JW, Prasertsuk P, Bell RV, et al., 2021, Modifying signal peptides for respiratory gene therapy with secreted proteins, Publisher: MARY ANN LIEBERT, INC, Pages: A39-A40, ISSN: 1043-0342
Hickmott JW, Sinadinos AJ, Sergijenko A, et al., 2021, Single cell tools for measuring mRNA and protein expression for gene therapy, Publisher: MARY ANN LIEBERT, INC, Pages: A39-A39, ISSN: 1043-0342
Faulkner N, Alton EW, Griesenbach U, et al., 2021, Reducing anti-vector humoral immunity through modulation of surface glycoprotein density, Publisher: MARY ANN LIEBERT, INC, Pages: A108-A109, ISSN: 1043-0342
Hickmott JW, Alton EWFW, Griesenbach U, et al., 2021, Signal peptides
Juarez-Molina CI, Lund-Palau H, Meng C, et al., 2021, Gene Therapy for Autoimmune Pulmonary Alveolar Proteinosis, Publisher: CELL PRESS, Pages: 256-257, ISSN: 1525-0016
Clarke NK, Sinadinos A, Meng C, et al., 2021, Production of Recombinant Protein after Transplantation of Ex Vivo Transduced Macrophages, Publisher: CELL PRESS, Pages: 378-378, ISSN: 1525-0016
Bell RV, Faulkner N, Alton EWFW, et al., 2021, Assessment of F/HN Pseudotyped Lentiviral Vector Following Intravenous Delivery to Mice, 24th Annual Meeting of the American Society of Gene & Cell Therapy, Publisher: CELL PRESS, Pages: 138-139, ISSN: 1525-0016
Sergijenko A, Moiseenko A, Pineault K, et 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
Hickmott JW, Prasertsuk P, Bell RV, et 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
Sinadinos A, Sergijenko A, Meng C, et 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
Sinadinos A, Pineault K, Saleh A, et al., 2021, Computational Tools for Airway-Image and Multidimensional-Data Analysis, Publisher: CELL PRESS, Pages: 257-257, ISSN: 1525-0016
Pineault KM, Meng C, Alton EWFW, et 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
MacSweeney R, Reddy K, Davies J, et 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.
Martin I, Kenna D, Morales S, et 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.
Sinadinos AJ, Sergijenko A, Saleh AD, et 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
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