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Journal articleMoiseenko A, Sinadinos A, Sergijenko A, et al., 2025,
Pharmacological and pre-clinical safety profile of rSIV.F/HN, a hybrid lentiviral vector for cystic fibrosis gene therapy
, European Respiratory Journal, Vol: 65, ISSN: 0903-1936Rationale and objectiveCystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. CFTR modulators offer significant improvements, but ∼10% of patients remain nonresponsive or are intolerant. This study provides an analysis of rSIV.F/HN, a lentiviral vector optimised for lung delivery, including CFTR protein expression, functional correction of CFTR defects and genomic integration site analysis in preparation for a first-in-human clinical trial.MethodsAir–liquid interface cultures of primary human bronchial epithelial cells (HBECs) from CF patients (F508del/F508del), as well as a CFTR-deficient immortalised human lung epithelial cell line mimicking class I (CFTR-null) homozygous mutations, were used to assess transduction efficiency. Quantification methods included a novel proximity ligation assay for CFTR protein expression. For assessment of CFTR channel activity, Ussing chamber studies were conducted. The safety profile was assessed using integration site analysis and in vitro insertional mutagenesis studies.ResultsrSIV.F/HN expressed CFTR and restored CFTR-mediated chloride currents to physiological levels in primary F508del/F508del HBECs as well as in a class I cells. In contrast, the latter could not be achieved by small-molecule CFTR modulators, underscoring the potential of gene therapy for this mutation class. Combination of rSIV.F/HN-CFTR with the potentiator ivacaftor showed a greater than additive effect. The genomic integration pattern showed no site predominance (frequency of occurrence ≤10%), and a low risk of insertional mutagenesis was observed in an in vitro immortalisation assay.ConclusionsThe results underscore rSIV.F/HN as a promising gene therapy vector for CF, providing a mutation-agnostic treatment option.
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Journal articleFenn J, Madon K, Conibear E, et al., 2025,
An ultra-early, transient interferon-associated innate immune response associates with protection from SARS-CoV-2 infection despite exposure
, eBioMedicine, Vol: 111, ISSN: 2352-3964BackgroundA proportion of individuals exposed to respiratory viruses avoid contracting detectable infection. We tested the hypothesis that early innate immune responses associate with resistance to detectable infection in close contacts of COVID-19 cases.Methods48 recently-exposed household contacts of symptomatic COVID-19 cases were recruited in London, UK between May 2020 and March 2021 through a prospective, longitudinal observational study. Blood and nose and throat swabs were collected during the acute period of index case viral shedding and longitudinally thereafter. Magnitude of SARS-CoV-2 exposure was quantified, and serial PCR and serological assays used to determine infection status of contacts. Whole-blood RNA-seq was performed and analysed to identify transcriptomic signatures of early infection and resistance to infection.Findings24 highly-exposed household contacts became PCR-positive and seropositive whilst 24 remained persistently PCR-negative and seronegative. A 96-gene transcriptomic signature of early SARS-CoV-2 infection was identified using RNA-seq of longitudinal blood samples from PCR-positive contacts. This signature was dominated by interferon-associated genes and expression correlated positively with viral load. Elevated expression of this 96-gene signature was also observed during exposure in 25% (6/24) of persistently PCR-negative, seronegative contacts. PCR-negative contacts with elevated signature expression had higher-magnitude SARS-CoV-2 exposure compared to those with low signature expression. We validated this signature in SARS-CoV-2-infected individuals in two independent cohorts. In naturally-exposed healthcare workers (HCWs) we found that 7/58 (12%) PCR-negative HCWs exhibited elevated signature expression. Comparing gene-signature expression in SARS-CoV-2 Controlled Human Infection Model (CHIM) volunteers pre- and post-inoculation, we observed that 14 signature genes were transiently upregulated as soon as 6 hr post-inoculation
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Journal articleCallaby H, Olver J, Emery K, et al., 2025,
Monkeypox virus isolation from longitudinal samples in 11 hospitalised patients
, Lancet Infectious Diseases, Vol: 25, Pages: e4-e5, ISSN: 1473-3099 -
Journal articleKristensen M, Piters WAADS, Wildenbeest J, et al., 2024,
The respiratory microbiome is linked to the severity of RSV infections and the persistence of symptoms in children
, CELL REPORTS MEDICINE, Vol: 5, ISSN: 2666-3791- Cite
- Citations: 3
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Journal articleDavies JC, Polineni D, Boyd AC, et al., 2024,
Lentiviral gene therapy for cystic fibrosis: a promising approach and first-in-human trial
, American Journal of Respiratory and Critical Care Medicine, Vol: 210, Pages: 1398-1408, ISSN: 1073-449XCystic fibrosis (CF) is a genetic disease caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene. Although CF is a multiorgan disease, the leading causes of morbidity and mortality are related to progressive lung disease. Current understanding of the effects of the broad spectrum of CFTR mutations on CFTR function has allowed for the development of CFTR modulator therapies. Despite the remarkable impact that these therapies have had, there remains a significant proportion of people with CF (estimated at 10–15% of the global CF population) who are genetically ineligible for, or intolerant of, current CFTR-targeting therapies and whose therapeutic needs remain unmet. Inhaled genetic therapies offer the prospect of addressing the unmet pulmonary treatment need in people with CF, with several approaches, including gene addition therapy (the focus of this review), RNA-based therapies, antisense oligonucleotides, and gene editing, being explored. Various nonviral and viral vectors have been investigated for CF gene addition therapy for mutation-agnostic restoration of CFTR function in the lungs. Lentiviral vectors offer the prospect of highly efficient and long-lasting gene expression, and the potential to be safely and, in contrast to other commonly used viral vectors, effectively redosed. A third-generation lentiviral vector pseudotyped with Sendai virus F and HN envelope proteins (rSIV.F/HN) has been developed for the treatment of CF. Promising preclinical results support the progression of this vector carrying a full-length CFTR transgene (BI 3720931) into a first-in-human clinical trial expected to begin in 2024.
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Thesis dissertationMcMillan M, 2024,
Understanding the interactions and clinical impact of Pseudomonas aeruginosa and Staphylococcus aureus (co-)infections in cystic fibrosis
I nfections are the primary cause of morbidity and mortality among people with cystic fibrosis (CF). Traditionally, Pseudomonas aeruginosa (PA) has been considered the dominant pathogen in CF, with Staphylococcus aureus (SA) mainly cultured in children. Once co-infections were identified as common, research suggested they may cause greater harm to patients than single-species infections. Despite this, no criteria currently exist to assess co-infection severity. This study demonstrates that, by applying the Leeds chronicity criteria to both pathogens, chronic SA/PA co- infections are associated with better pulmonary function and fewer days on intravenous antibiotics compared to chronic PA mono-infections.To investigate the dynamics of chronic co-infections, paired SA and PA isolates from ten individuals with the longest-recorded co-infections in our bacterial repository were selected. Their ability to coexist using a synthetic CF media (SCFM2) model was assessed, and both culture- based and non-culture-based methods to quantify each species within mixed-species biofilms were evaluated. While studies report that isolates cultured from the same patient can coexist in vitro, we found evidence of both coexistence and competition within our pairings.Furthermore, differential cell wall staining of SA and PA revealed that many SA cells grown within SCFM2 lost their cell wall, which did not occur in these same isolates in rich media, leading to the identification of a cell wall-deficient (CWD) phenotype. This phenotype developed after 24 hr growth and was mainly triggered by DNA and egg yolk components within the media. Importantly, it was also observed in laboratory strains, suggesting it is not specific to respiratory isolates and may be an adaptive mechanism to counteract cell wall-targeted stress.Further research is needed to understand why chronic isolates from the same patient display varied interaction phenotypes and to elucidate the role and prevalence of the CWD SA
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Journal articleEllis HR, Allsopp LP, 2024,
Respiratory Epithelial Cell Surface Decoration Provides Defense against Bacterial Damage during Infection
, AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, Vol: 71, Pages: 625-627, ISSN: 1044-1549 -
Journal articleOwen AR, Farias A, Levins A-M, et al., 2024,
Exposure to bacterial PAMPs before RSV infection exacerbates innate inflammation and disease via IL-1a and TNF-a
, Mucosal Immunology, Vol: 17, Pages: 1184-1198, ISSN: 1933-0219Respiratory syncytial virus (RSV) can cause severe lower respiratory tract infections. Understanding why some individuals get more serious disease may help with diagnosis and treatment. One possible risk factor underlying severe disease is bacterial exposure before RSV infection. Bacterial exposure has been associated with increased respiratory viral-induced disease severity but the mechanism remains unknown. Respiratory bacterial infections or exposure to their pathogen associated molecular patterns (PAMPs) trigger innate immune inflammation, characterised by neutrophil and inflammatory monocyte recruitment and the production of inflammatory cytokines. We hypothesise that these changes to the lung environment alter the immune response and disease severity during subsequent RSV infection. To test this, we intranasally exposed mice to LPS, LTA or Acinetobacter baumannii (an airway bacterial pathogen) before RSV infection and observed an early induction of disease, measured by weight loss, at days 1–3 after infection. Neutrophils or inflammatory monocytes were not responsible for driving this exacerbated weight loss. Instead, exacerbated disease was associated with increased IL-1α and TNF-α, which orchestrated the recruitment of innate immune cells into the lung. This study shows that exposure to bacterial PAMPs prior to RSV infection increases the expression of IL-1α and TNF-α, which dysregulate the immune response resulting in exacerbated disease.
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Journal articleDrysdale SB, Thwaites RS, Price J, et al., 2024,
What have we learned from animal studies of immune responses to respiratory syncytial virus infection?
, Journal of Clinical Virology, Vol: 175, ISSN: 1386-6532Respiratory syncytial virus (RSV) is a common cause of severe respiratory tract infection at the extremes of age and in vulnerable populations. However, it is difficult to predict the clinical course and most infants who develop severe disease have no pre-existing risk factors. With the recent licencing of RSV vaccines and monoclonal antibodies, it is important to identify high-risk individuals in order to prioritise those who will most benefit from prophylaxis. The immune response to RSV and the mechanisms by which the virus prevents the establishment of immunological memory have been extensively investigated but remain incompletely characterised. In animal models, beneficial and harmful immune responses have both been demonstrated. While only chimpanzees are fully permissive for human RSV replication, most research has been conducted in rodents, or in calves infected with bovine RSV. Based on these studies, components of innate and adaptive immune systems, cytokines, chemokines and metabolites, and specific genetic and transcriptomic signatures are identified as potential predictive indicators of RSV disease severity. These findings may inform the development of future human studies and contribute to the early identification of patients at high risk of severe infection. This narrative review summarises the factors involved in the immune response to RSV infection in these models and highlights the relationship between potential biomarkers and disease severity.
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Journal articleFelton I, Downes A, Bokobza I, et al., 2024,
“Shifting sands in cystic fibrosis”: impacts of CFTR modulators on reproductive health in people with cystic fibrosis and challenges related to in utero exposure
, Expert Opinion on Pharmacotherapy, Vol: 25, Pages: 2243-2252, ISSN: 1465-6566IntroductionMutation-specific disease modifying drugs such as the triple combination Elexacaftor/Tezacaftor/Ivacaftor (ETI), are associated with significant improvements in physical health. Reproductive health and a pursuit of parenthood are of increased relevance; a dramatic increase in childbirth rates for females with CF has already been observed.Areas coveredFertility in males and females with CF, and any subsequent impact of CFTR modulator therapy, is reviewed. The potential impacts of maternal use of CFTR modulator drugs on offspring health are considered, as constituent components have been found in fetal circulation in animals and humans, and the implications for maternal continuation or cessation of treatment. Clinical data are reassuring, although cases of lens opacities, and missed CF diagnoses due to false negative newborn screening results have been reported.Expert opinionMore research and high-quality evidence are needed to characterize maternal, fetal and long-term offspring outcomes following CFTR modulator therapy use during pregnancy and breastfeeding. There is a potential therapeutic impact of targeting CFTR-related organ dysfunction in CF-fetuses via maternal-administration of CFTR modulators. Additionally, any consequences of CFTR-modulation in heterozygote carrier infant warrants urgent and collective consensus regarding ethical and clinical research programs to evaluate this discrete population.
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