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Journal articleRosenheim J, Bender B, Gilmour J, et al., 2026,
Conference report: airway mucosal sampling and immune analysis.
, Vaccine, Vol: 88Respiratory pathogens cause substantial global morbidity, mortality, and pandemic risk. While parenteral vaccines can effectively reduce severe disease for some respiratory infections, they are often less effective at preventing infection and onward transmission. Vaccines delivered directly to the airways have the potential to induce protective mucosal immunity at the site of pathogen entry. However, progress in mucosal vaccine development has been constrained by limited understanding of airway immune mechanisms, the technical challenges of sampling respiratory tissues, and the lack of standardised, validated immunological assays capable of defining mucosal correlates of protection. To address these challenges, the Novo Nordisk Foundation and Wellcome Trust convened a workshop on airway mucosal sampling and immunological assays, bringing together researchers, clinicians, funders, and representatives from major research consortia. Participants reviewed approaches to sampling the upper and lower respiratory tract, assay technologies, and regulatory considerations for integrating mucosal endpoints into vaccine development. Discussions highlighted major barriers including variability in sampling techniques, low and inconsistent cell yields, limited assay standardisation, and insufficient cross-study comparability. The workshop produced a set of recommendations in four priority areas (i.e., Collaboration, Communication, Consistency and Conduct of research) to share knowledge, accelerate standardisation and validation, and generate evidence supporting mucosal vaccine development. Together, these advances will help strengthen the scientific and regulatory foundations needed to realize the full potential of airway-delivered vaccines for the prevention of respiratory diseases.
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Journal articleOzoh O, Owusu SK, Nantanda R, et al., 2026,
Prevalence of asthma among African children and adolescents: findings from the chronic respiratory disease observatory for Africa (CHEST-Africa)
, Thorax, ISSN: 0040-6376 -
Journal articleKnox-Brown B, Sylvester K, Amaral A, 2026,
Physiological quotients for discriminating mortality and respiratory outcomes: a UK biobank cohort study
, ERJ Open Research, ISSN: 2312-0541BackgroundSpirometry is traditionally interpreted using reference-based metrics derived from equations such as those from the Global Lung Function Initiative (GLI). Physiological quotients, which express lung function relative to a lower physiological boundary, have been proposed as an alternative approach. We aimed to compare the prognostic performance of physiological quotients with conventional reference-based metrics including both the GLI 2012 ethnicity-specific and the GLI 2023 Global equations, in a large population-based cohort.MethodsWe analysed data from 270,599 UK Biobank participants aged 40–69 years with baseline spirometry. Physiological quotients were calculated for FEV₁, FVC, and FEV₁/FVC using previously established first percentile boundaries. Associations with all-cause and cause-specific mortality, respiratory hospitalisation, respiratory symptoms, and self-reported respiratory diagnoses were examined using Cox proportional hazards and logistic regression models.ResultsOver a median follow-up of 15.7 years, 26,197 (10%) participants died. Lower physiological quotients were consistently associated with adverse outcomes. Each 1-SD decrement in FEV₁Q, FVCQ, and FEV₁/FVCQ was associated with higher all-cause mortality (HRs 1.06–1.09), cardiovascular mortality (HRs 1.06–1.20), respiratory mortality (HRs 1.28–1.77), and respiratory hospitalisation (HRs 1.04–1.41). Discrimination for all-cause mortality was modest (C-statistics 0.64–0.65), moderate for cardiovascular mortality (0.72–0.73), and good for respiratory mortality (0.76–0.79). Discrimination of respiratory hospitalisation was modest but slightly higher for FEV₁Q and FVCQ (0.65) than for percent predicted values and z-scores (0.61–0.62). Across mortality outcomes, discriminative performance was similar between physiological quotients, percent predicted values, and z-scores. ConclusionPhysiological quotients demonstrated prognostic performanc
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Journal articleShah A, 2026,
PRESIDE protocol: a global registry of antimicrobial resistance in chronic lung disease
, ERJ Open Research, ISSN: 2312-0541Antimicrobial resistance (AMR) is an escalating global health threat. Chronic lung diseases (CLDs) represent a key area in which AMR poses unique and often underestimated challenges, yet high-quality epidemiological data remain scarce. To address this gap, the European Respiratory Society Clinical Research Collaboration on AMR in Lung Infections (AMR-Lung CRC) has developed PRESIDE, an international prospective observational registry designed to evaluate the prevalence and burden of AMR in patients with CLD. PRESIDE is a global, multicentre study recruiting paediatrics and adults with CLD who have undergone respiratory microbiological testing as part of routine clinical care within the year prior to data collection. Participating centres enroll patients during two-week recruitment periods, held twice yearly over five years from 2025 to 2030. The registry captures a comprehensive set of core variables, including demographics and smoking history, CLD type and aetiology, microbiological history, comorbidities, clinical characteristics, therapeutic exposures, and respiratory microbiology results.This registry aims to generate robust, prospective, real-world evidence on AMR epidemiology in CLD, enabling comparison across regions and disease phenotypes. Findings are expected to inform clinical decision-making, support antimicrobial stewardship, and guide the development of context-specific guidelines and public health strategies. Ultimately, PRESIDE seeks to strengthen global efforts to address AMR in chronic respiratory infections and improve outcomes for patients with CLD.
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Journal articleBurney P, Knox-Brown B, Amaral A, 2026,
The use of spirometry to define airflow obstruction and diagnose COPD
, European Respiratory Journal, ISSN: 0903-1936 -
Journal articleSaralaya D, Mustapa MN, Ferreira J, et al., 2026,
A phase 2a, double-blind, randomised, placebo-controlled trial of the myeloperoxidase inhibitor, mitiperstat, in participants with chronic obstructive pulmonary disease.
, Eur Respir JBACKGROUND: Neutrophilic inflammation is a common feature of chronic obstructive pulmonary disease (COPD). Mitiperstat, an inhibitor of myeloperoxidase expressed in neutrophils, may have potential as a COPD treatment. METHODS: This phase 2a, randomised, placebo-controlled, double-blind, parallel-arm, event-driven trial evaluated the efficacy and safety of mitiperstat 5 mg daily up to 24 weeks (NCT05492877). Adults (40-80 years) with moderate-to-severe COPD, at high risk of exacerbation, and receiving dual or triple inhaled therapy were included. The primary endpoint was time to first composite endpoint for exacerbations in COPD (COPDCompEx) event. Secondary endpoints included time to first moderate-to-severe COPD exacerbation, post-bronchodilator forced expiratory volume in 1 s (post-BD FEV1) change at Week 12, respiratory symptoms, disease impact and safety. RESULTS: Overall, 381 participants (mean age, 66.0 years; 39.6% female) were randomised to mitiperstat (n=189) or placebo (n=192). In total, 125 (66.1%) mitiperstat-treated versus 125 (65.1%) placebo-treated participants experienced COPDCompEx events over 24 weeks. There was no improvement in time to first COPDCompEx event (hazard ratio [HR] 1.07 [90% confidence interval (CI) 0.87, 1.32]; p=0.599) or time to first moderate-to-severe COPD exacerbation (HR 1.23 [90% CI 0.88, 1.73]) with mitiperstat versus placebo. Improvements in post-BD FEV1, respiratory symptoms or disease impact were not seen with mitiperstat. A similar proportion of participants in both groups reported adverse events; seven mitiperstat-treated participants and two placebo-treated participants had pneumonia during the study. CONCLUSION: These results indicate that the risks outweigh the benefits of mitiperstat as a treatment for COPD.
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Journal articleWedzicha JA, Finney LJ, Martinez FJ, 2026,
Every exacerbation counts: shifting the dial for future exacerbation risk.
, Am J Respir Crit Care Med, Vol: 212, Pages: 1675-1676 -
Journal articleDvorscek AR, Kushnir AS, Dibben O, et al., 2026,
Mucosal immunity as a vaccine-induced correlate of protection against influenza.
, Mucosal Immunol, Vol: 19Licensure of influenza vaccines relies on serum hemagglutination inhibition (HAI) titers, a correlate of protection (CoP) that was developed more than 50 years ago and which is only poorly predictive of protection. This is especially true of immunity induced by intranasal live attenuated influenza vaccines (LAIVs). Unlike intramuscular inactivated influenza vaccines (IIVs), LAIV and natural infection selectively stimulate mucosal immunity. Developments in mucosal immunology now enable measurement of diverse aspects of mucosal immunity, including the frequencies and functions of nasal antibodies, T cells, and B cells. This review assesses the potential of new sampling and assay approaches that may overcome inconsistent findings from previous methodologies. Standardization of the collection and assessment of mucosal samples is essential in developing new CoPs for vaccine development and licensure of novel vaccines that induce nasal protection and are more effective in prevention of viral transmission.
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Journal articleQuintero Santofimio V, Ma J, Potts J, et al., 2026,
Association of respiratory health with occupational exposures in the Burden of Obstructive Lung Disease (BOLD) cohort: a multinational longitudinal study
, BMJ Open Respiratory Research, Vol: 31, ISSN: 2052-4439Background: Occupational exposures are contributors to chronic respiratory diseases, particularly in low- and middle-income countries (LMICs), where regulatory policies are limited. We investigated associations between occupational exposures and respiratory outcomes using longitudinal data from the Burden of Obstructive Lung Disease study.Methods: We analysed data from 4,237 participants across 17 sites, mostly in LMICs. Occupational exposures were assessed by self-report (never vs ever) and the ALOHA+ Job Exposure Matrix for vapours, gases, dusts, fumes (VGDF), pesticides, solvents, and metals (cumulative exposure). Respiratory outcomes included: forced expiratory volume-in-1-second (FEV₁), forced vital capacity (FVC), the FEV₁/FVC, and respiratory symptoms. Associations were examined using multilevel linear and logistic regression models adjusted for age, sex, smoking, pack-years, education, body mass index, and baseline FVC. We further explored sex differences and non-linear relationships for symptoms.Results: Over a median 10 years of follow-up, FEV₁/FVC decline was associated with moderate (β=–1.34; 95%CI: –2.32, –0.35) and high (β=–1.79; 95%CI: –3.33, –0.20) exposure to VGDF and low (β=–1.11; 95%CI: –2.11, –0.08) and high (β =–2.16; 95%CI: –4.08, –0.24) exposure to pesticides. Increased risk of wheeze was associated with moderate (RR=1.45; 95%CI: 1.05-2.15) and high (RR=1.89; 95%CI: 1.100-3.26) exposure to pesticides. Associations did not differ by sex. There was weak evidence of non-linear exposure–response relationships, and no associations with solvents or metals.Conclusions: A significant decline in FEV1/FVC was associated with exposure to VGDF and pesticides. Increased risk wheeze was also associated with exposure to pesticides. These findings underscore the need for continued monitoring in high-exposure settings, particularly in LMICs.
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Journal articleHowlett P, Durairaj A, Gan J, et al., 2026,
Adjusting for the diagnostic accuracy of CXR in the dose-response relationship between cumulative silica exposure and silicosis in miners.
, Occup Environ MedINTRODUCTION: A recent meta-analysis confirmed that chest X-ray (CXR) has low sensitivity for diagnosing silicosis. We re-estimated previously published dose-response relationships between cumulative respirable crystalline silica (RCS) exposure and silicosis risk, under the assumptions that sensitivity was either fixed or relative to the population proportion of severe silicosis. METHODS: We combined unpublished logistic regression models from Scottish coal miners with meta-analysis results to model how CXR sensitivity changed according to cumulative RCS exposure. We assumed specificity was 0.95. Among mining cohorts, we calculated the difference in the cumulative risk of silicosis between the unadjusted and fixed and relative scenarios. Finally, we re-estimated a published dose-response meta-analysis and associated absolute risk reductions (ARR). RESULTS: The cumulative risk of silicosis was substantially higher in both the fixed and relative sensitivity scenarios compared with the unadjusted estimate in all mining cohorts. This was most pronounced in the relative scenario and when cumulative RCS exposures were below approximately 6 mg/m³-years. A reduction in cumulative RCS exposure from 4 to 2mg/m³-years corresponded to larger ARRs in the fixed and relative scenarios than the unadjusted scenario; 382 (95% CI 361 to 399) and 529 (95% CI 353 to 592) cases per 1000 miners compared with 313 (95% CI 288 to 333) cases per 1000 miners, respectively. DISCUSSION: We relied on a single estimate of the proportion of severe disease to link sensitivity and cumulative RCS exposure. Nevertheless, adjusting for the reduced diagnostic accuracy of CXR for silicosis suggests the burden of silicosis is underestimated in published mining cohorts.
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Journal articleMeghji J, 2026,
The ITARA research programme: investigating Integrated Tuberculosis and Respiratory care in Africa using transdisciplinary methods
, BMJ Open, ISSN: 2044-6055IntroductionPulmonary tuberculosis (PTB) and chronic respiratory diseases (CRDs) are closely linked. Affected groups present with similar symptoms, and share many risk factors (E.g. Poverty related factors, smoking, occupational exposures). PTB is itself an independent risk factor for chronic lung disease. However, in many high TB-incidence settings health services for these conditions are provided separately, with little integration of prevention, diagnosis, or care.Methods and analysisWe describe a transdisciplinary programme of research investigating strategies for integrated TB-CRD care in Arusha, Tanzania, Nairobi, Kenya and Lagos, Nigeria, using clinical, health economic, health systems, and qualitative research methods. A prospective clinical cohort study will describe the burden and impact of non-TB respiratory disease (E.g. Asthma, COPD, post-TB lung disease) amongst adolescents and adults presenting to primary and secondary health facilities with chronic cough, who would normally be managed via TB care pathways. Health economics methods will explore patient costs of non-TB respiratory disease, facility-level costs of integrated TB/respiratory diagnostics, and will develop a modelling framework to estimate the costs and consequences of integration more broadly. In-depth interviews, focus group discussions, observations and participatory methods will be used to explore lived experiences of chronic respiratory symptoms, disease and exposures amongst patients and providers, and to identify and address challenges around respiratory health and care. Lastly, existing TB and CRD health care services and systems in our three research sites will be described, and local, national, and policy level understandings of ‘integration’ of TB and CRD care will be explored. Together, the findings of this work will be used to develop context informed model(s) of integrated TB-CRD care, and a theory of change and framework for evaluation in future implementation st
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Journal articleBisson GP, Allwood B, Byrne A, et al., 2026,
Post-tuberculosis lung disease: a case definition for use in research studies.
, Lancet Infect Dis, Vol: 26, Pages: e315-e325Despite growing awareness of the substantial burden of long-term pulmonary impairment among tuberculosis survivors, marked variability in how post-tuberculosis lung disease is defined across research studies limits the comparison of findings and synthesis of evidence. To facilitate greater harmonisation within the field, we propose a case definition for post-tuberculosis lung disease for use in research studies. Conceptual aspects of this case definition were initially developed with input from a broad group of stakeholders at the 2nd International Post-Tuberculosis Symposium and were refined by the authors after the Symposium. Guiding principles for the definition include specificity, feasibility in settings with high tuberculosis disease burdens, probable relevance to long-term health outcomes, and applicability across the lifespan. The definition is designed to be used alongside, rather than instead of, study-specific definitions used to explore primary study hypotheses, and is accompanied by a reporting framework. The case definition has three components: that the individual had previous pulmonary or pleural tuberculosis disease and does not have tuberculosis disease at the time of evaluation; that the individual has, at the time of assessment, evidence of pulmonary disease with abnormalities in at least two of three clinical domains of lung function, respiratory symptoms, and chest imaging; and that the pulmonary disease manifestations should be attributable at least in part to previous tuberculosis disease. This definition is developed in the absence of data on long-term patient outcomes and will need to evolve over time in response to emerging evidence. However, we believe this proposed definition will lead to greater consistency and rigor across studies of post-tuberculosis lung disease with the goal of improving care and quality of life for millions of tuberculosis survivors worldwide.
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Journal articleMeme H, Matu S, Orina F, et al., 2026,
Lung function across the life course in Kenya: a series of cross-sectional surveys.
, ERJ Open Res, Vol: 12, ISSN: 2312-0541BACKGROUND: The high prevalence of COPD in sub-Saharan Africa is poorly understood. In high-income countries, COPD is the consequence of suboptimal lung growth during childhood and/or accelerated lung function decline in adult life. We have conducted cross-sectional studies to measure the lung function of children and adults in Kenya and to identify associations with age. METHODS: We performed spirometry in three groups in Kenya: a random sample of schoolchildren in two districts of urban Nairobi and age/sex-stratified representative community samples of adults in Nairobi and rural Machakos. Forced expiratory volume in 1 s (FEV1) and forced vital capacity were expressed as z-scores using race-neutral GLI-Global reference equations. RESULTS: The mean (95% CI) FEV1 z-score in Nairobi schoolchildren (n=2373, median age 10 years (IQR 8-13) 52% girls) was -0.60 (-0.64- -0.55); in Nairobi adults (n=2936, median age 32 years (24-43), 62% female) -0.49 (-0.53- -0.45); and in Machakos adults (n=1607, median age 46 years (35-59), 65% female) -0.67 (-0.72- -0.61). In adults, FEV1 was negatively associated with age (FEV1 z-score regression coefficient β -0.005/year (95% CI -0.009- -0.002) p=0.005, and there was a negative interaction between residence in Nairobi and age, β -0.006/year (95% CI -0.011- -0.001), p=0.020. CONCLUSION: The lung function of children and adults in Kenya was lower than predicted by race-neutral Global Lung Function Initiative (GLI)-Global reference equations. In adults, a negative association between lung function and age was greater in urban, than in rural, settings. Further work is required to identify and mitigate relevant influences.
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Journal articleDavies JC, Bakkeheim E, Chansard A, et al., 2026,
Perspective of the European Cystic Fibrosis Society on Improving Global Cystic Fibrosis Care.
, Pediatr Pulmonol, Vol: 61INTRODUCTION: Outcomes for people with the inherited disease, cystic fibrosis, have improved greatly over the last few decades, but one result of this is a widening gap between regions with high income and well-resourced healthcare systems and low/middle income countries. The gap stretches from newborn screening programs, provision of standard diagnostics and genetic testing through to access to standard of care therapies. METHODS AND RESULTS: This paper describes the various initiatives of the European Cystic Fibrosis Society: our Patient Registry, a Twinning Program linking centers from different regions and our Educational Program. CONCLUSIONS: The European Cystic Fibrosis Society recognizes this as a major issue and seeks through these programs to support colleagues, patients and families in low/middle income countries.
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Journal articleDe Boeck K, Burgel P-R, Bierlaagh M, et al., 2026,
ECFS statement on theratyping and theranostics in the context of rare and ultrarare CFTR variants in people with CF.
, J Cyst Fibros, Vol: 25, Pages: 584-593Genotype-based drug development has yielded highly effective therapies, notably the triple combinations elexacaftor/tezacaftor/ivacaftor (ETI) and vanzacaftor/tezacaftor/deutivacaftor (VTD), now approved in Europe for people with CF having at least one non-class I variant. However not all these people with CF will respond to ETI or VTD, and a few not under the label may respond. Facilitating opportunities to access for patients with rare variants has required a shift in paradigm toward functional testing-based access. This approach assesses the potential benefit of modulator therapy using in vitro functional assays, either in engineered systems expressing defined CFTR variants (theratyping) or in patient-derived tissues (theranostics). We review theranostics as a critical tool for personalized medicine in CF, highlighting its validation in in vitro models derived from patients' own cells such as human intestinal organoids and human nasal epithelial cells. We discuss the current regulatory landscape regarding modulator approval and propose strategies for improving equitable access to effective treatments for all people with CF. Importantly, we advocate for functional assays to be accepted as standalone evidence of drug efficacy for patients with rare variants. Theranostic approaches remain critical when theratyping has not been achieved, and genetic data is not available or clearly interpretable. Indeed, theranostics has emerged as an essential pillar of CF drug access, complementing genotype-driven strategies. As the field advances, continued validation, standardization, and regulatory integration of in vitro functional assays will be key to ensuring that every person with CF-regardless of their genotype-has the opportunity to benefit from precision therapies.
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Journal articleThorarinsdottir E, Benediktsdóttir B, Aspelund T, et al., 2026,
Screening for obstructive sleep apnoea in the general population in Iceland and uptake of positive airway pressure treatment: a prospective cohort study
, BMJ Open, ISSN: 2044-6055Objectives: To estimate uptake of obstructive sleep apnoea (OSA) screening and initiation and long-term use of positive airway pressure (PAP) treatment in a middle-aged and older general population cohort.Design: Prospective population-based cohort study.Setting: Icelandic arm of the multinational Burden of Obstructive Lung Disease follow-up study II (2019 - 2021)Participants: 378 non-institutionalised adults aged 54 to 91 years were invited from a general population cohort. Twenty-six with prior OSA diagnosis were excluded. Of the remaining participants, 334 (88.4%) completed a technically adequate home sleep apnoea test (HSAT).Interventions: Those with an apnoea–hypopnoea index (AHI) ≥15 events/hour were invited for clinical evaluation and when appropriate, referred for PAP treatment. Adherence was assessed two years after PAP initiation. Main outcome measures: Primary outcomes were screening uptake and PAP initiation. Secondary outcomes included long-term PAP use and objective adherence two years after referral.Results: AHI ≥15 was identified in 132/334 participants (39.5%). Of these, 123 (93.2%) attended clinical evaluation and 99 (75.0%) were referred for PAP treatment. Of those not referred, six declined PAP and the remainder were advised alternative management or reassessment. At two-year follow-up, 53/99 (53.5%) were long-term PAP users, 43/99 (43.4%) had discontinued, and 3/99 (3.0%) never initiated PAP. Objective adherence data were available for 47/53 long-term users; 21/47 (44.7%) met adherence criteria (≥4 hours/night on ≥70% of nights in the preceding 30 days). Conclusions: Most adults accepted OSA screening when offered. Among those with moderate-to-severe OSA identified through population screening, most accepted evaluation and PAP treatment, with approximately half becoming long-term users. These findings suggest that population-based detection of OSA followed by routine clinical management is feasible. Future studies should identi
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Journal articleFinney LJ, Conway FM, Sethi DK, 2026,
COPD Biologics: Right Patient, Right Pathway, Right Time.
, Pulm TherChronic obstructive pulmonary disease (COPD) is a heterogeneous disease that is entering a new era in precision medicine. Advances in disease endotyping have challenged the traditional view of COPD as a uniformly neutrophilic disorder and revealed biologically distinct subgroups in whom targeted immunomodulation may be effective. Reproducible signatures of type 2 (T2) inflammation and epithelial-derived alarmin activation have emerged as actionable pathways, reshaping therapeutic development in COPD. This narrative review synthesises mechanistic insights and clinical trial evidence for biologic therapies targeting key T2 cytokines such as interleukin-5 (IL-5) IL-4/IL-13 and upstream epithelial alarmins, including interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP). We examine why earlier approaches targeting neutrophilic inflammation failed, and how biomarker-driven trial design has enabled success in selected populations. Across these programmes, therapeutic efficacy has depended not only on the pathway targeted but also on patient selection, disease stage and timing of intervention. We propose that the future of biologics in COPD lies in integrating biomarkers, treatable traits and longitudinal phenotyping to align the right patient with the right pathway at the right time, closing persistent treatment gaps in this common, overlooked and burdensome disease.
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Journal articleGandhi SA, Liu GY, Fazio JC, et al., 2026,
Silicosis in the Artificial Stone Countertop Industry: An Official American Thoracic Society Workshop Report.
, Ann Am Thorac SocArtificial stone-associated silicosis (AS silicosis) has emerged over the past decade as a severe, rapidly progressive, and preventable occupational lung disease affecting workers who manufacture, fabricate, and install artificial stone countertops. Characterized by short latency, accelerated progression, and high morbidity and mortality, AS silicosis disproportionately affects young workers employed in precarious conditions. In response to the growing global burden of disease, this American Thoracic Society workshop was convened in 2025 to review the current state of knowledge regarding AS silicosis, synthesize the current evidence, and identify priorities for research, clinical care, public health surveillance, and prevention. Workshop participants reviewed data spanning exposure science, epidemiology, clinical manifestations, health equity, and policy responses. Evidence demonstrates that artificial stone (AS) dust is highly toxic, containing high concentrations of respirable crystalline silica, resin-derived volatile compounds, and trace metals, resulting in exposures that routinely exceed occupational exposure limits. Despite widespread implementation of wet methods, ventilation, and respiratory protection, hazardous exposures persist across diverse settings globally, highlighting fundamental limitations of existing control strategies. Clinically, AS silicosis is associated with high rates of progressive massive fibrosis, autoimmune disease, infection, respiratory failure, and increasing need for lung transplantation. Treatment options remain limited, underscoring the importance of early detection and exposure cessation. The workshop identified critical gaps in medical screening and public health surveillance worldwide, with inconsistent regulatory frameworks, low compliance, underreporting, and delayed diagnoses. Case detection is often dependent on symptomatic presentation rather than proactive screening, exacerbating disease severity and inequities in care.
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Journal articleBell RV, Faulkner NB, Sinadinos A, et al., 2026,
Assessment of F/HN-pseudotyped lentiviral vector following intravenous delivery to mice.
, Gene TherIn pursuit of a gene transfer agent with efficient pulmonary transduction, the UK Respiratory Gene Therapy Consortium has developed a lentiviral vector pseudotyped with the envelope proteins, F and HN from Sendai virus (rSIV.F/HN). In contrast to other viral vectors, pulmonary rSIV.F/HN delivery achieves sustained gene expression ( ~ 2 years in mice) in the lungs and systemic circulation following a single dose. Here, we investigate the application of the rSIV.F/HN vector-platform for wider indications, including systemic disorders that require serum expression of therapeutic proteins. To assess the potential for rSIV.F/HN to produce systemic proteins, intravenous vector delivery was characterised and compared against intrapulmonary administration, achieved via 'nasal sniffing'. Both delivery routes achieved sustained (at least 1 year) systemic expression of the secreted reporter protein Gaussia luciferase. Systemic rSIV.F/HN delivery resulted in widespread protein expression across multiple organs, accompanied by the generation of significant anti-vector neutralising antibodies limiting vector readministration. Conversely, localised airway transduction was observed following pulmonary administration, which we have previously shown is not an impediment to efficient vector readministration. These data support intrapulmonary rSIV.F/HN delivery for systemic protein production, with sustained high-level transgene expression and feasible readministration.
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Journal articleSinadinos A, Bell R, Juarez-Molina CI, et al., 2026,
Using the nose as a factory to secrete proteins into the lungs or circulation
, Molecular Therapy Advances, Vol: 34, ISSN: 3117-387XTargeting of the nasal epithelium for sustained therapeutic protein secretion represents a potential non-invasive lentiviral vector application strategy. Using reporter imaging, molecular, and radiopharmaceutical tracing methods in mice, we have developed an intranasal (nose-only) dosing strategy with a Sendai-virus envelope glycoprotein pseudotyped lentiviral vector (rSIV.F/HN). Using multiple (up to 10) small volume (5 μL) intranasal bolus applications, technetium radiotracer showed >90% liquid retention in the murine head and <1% in the lung. Following vector administration, transgene expression was dose-related in the nose with minimal lung expression. No acute nasal toxicity was associated with nose-only delivery. Next, we compared levels of a secreted protein, Gaussia luciferase (Gluc), in the airways and serum after nose-only and intravenous administration of rSIV.F/HN-Gluc (2e8 TU/mouse). Gluc expression in the nose and lungs was higher following nose-only versus intravenous administration. Serum levels were similar after either route of administration. Finally, nose-only delivery of rSIV.F/HN encoding GM-CSF, led to sufficient lung levels of this therapeutic protein to correct disease biomarkers in a mouse model of pulmonary alveolar proteinosis. We conclude that non-invasive administration of a lentiviral vector to the nasal epithelium provides a safe and convenient route for secreted protein production and is readily translatable into humans.
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