EBioMedicine最新文献

{"title":"Viral and non-viral vectors in gene therapy: current state and clinical perspectives.","authors":"Guannan Geng, Yixin Xu, Ziying Hu, Hui Wang, Xiaoyun Chen, Wei Yuan, Yilai Shu","doi":"10.1016/j.ebiom.2025.105834","DOIUrl":"10.1016/j.ebiom.2025.105834","url":null,"abstract":"<p><p>Advancements in gene therapy have achieved significant milestones in treating human diseases, offering renewed hope to patients with limited options. Key to this progress are vectors, which include both viral and non-viral methodologies that impact the success of gene therapy. Over the past two decades, three widely used viral vectors-lentiviruses (LV), adenoviruses (Ad), and adeno-associated viruses (AAV)-have enabled notable preclinical and clinical successes, including the approval of Luxturna for a genetic retinal disease and CAR-T therapies for blood cancers. Recently, the first-in-human dual AAV therapy for hereditary hearing loss, which overcomes large gene delivery, has showcased the restoration of auditory function for patients. Additionally, non-viral vectors such as lipid nanoparticles (LNP) and N-acetylgalactosamine (GalNAc) have led to successful gene therapy products. This review focuses on both viral and non-viral delivery systems in gene therapy, highlighting their current state and future perspectives in treating human diseases.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"118 ","pages":"105834"},"PeriodicalIF":10.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12271757/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144552600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identifying common disease trajectories of Alzheimer's disease with electronic health records.","authors":"Mingzhou Fu, Sriram Sankararaman, Bogdan Pasaniuc, Keith Vossel, Timothy S Chang","doi":"10.1016/j.ebiom.2025.105831","DOIUrl":"10.1016/j.ebiom.2025.105831","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is a leading cause of dementia and an escalating public health concern. Although recent research has identified multiple AD risk factors, most studies examine isolated comorbidities rather than complex, sequential progressions. In this study, we sought to identify multi-step trajectories culminating in AD by analysing longitudinal electronic health records (EHRs).</p><p><strong>Methods: </strong>We analysed data from 24,473 patients in the University of California Health Data Warehouse (UCHDW). A Fine-Gray subdistribution hazard model identified temporally associated diagnoses, from which we constructed diagnostic trajectories. We employed dynamic time warping and k-means clustering to group similar trajectories, and network analyses to characterize their common structures. Causal inferences were explored using the Greedy Equivalence Search algorithm. Validation in the UCHDW included association tests and comparison to control groups. We further validated our findings in the All of Us Research Program, a diverse, nationally representative cohort.</p><p><strong>Findings: </strong>After filtering, 5762 patients contributed 6794 unique AD progression trajectories, revealing four major trajectory clusters: mental health, encephalopathy, mild cognitive impairment, and vascular disease. These clusters differed significantly in demographic and clinical features. Approximately 26% of edges showed consistent directional ordering (e.g., hypertension → depressive episode → AD). In an independent population, these multi-step trajectories conferred greater AD risk than single diagnoses alone. Our validation in the All of Us cohort confirmed the reproducibility of these trajectory patterns in a more diverse population.</p><p><strong>Interpretation: </strong>Our findings demonstrate the value of examining sequential diagnostic patterns in AD pathogenesis. Multi-step progressions reveal potential latent contributors to AD, offering pathways for risk stratification, early detection, and targeted interventions.</p><p><strong>Funding: </strong>This study was supported by the National Institutes of Health, National Institute on Aging, the National Science Foundation, the Hillblom and Fineberg Foundations, and the California Department of Public Health.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"118 ","pages":"105831"},"PeriodicalIF":10.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12266379/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exposure to per- and poly-fluoroalkyl substances in association to later occurrence of type 2 diabetes and metabolic pathway dysregulation in a multiethnic US population.","authors":"Vishal Midya, Meizhen Yao, Elena Colicino, Dinesh Barupal, Xiangping Lin, Chris Gennings, Leda Chatzi, Veronica Wendy Setiawan, Ruth J F Loos, Ryan W Walker, Douglas I Walker, Damaskini Valvi","doi":"10.1016/j.ebiom.2025.105838","DOIUrl":"10.1016/j.ebiom.2025.105838","url":null,"abstract":"<p><strong>Background: </strong>Growing evidence suggests that exposure to per- and polyfluoroalkyl substances (PFAS) are linked to an increased risk of type 2 diabetes (T2D); however, the effect of PFAS mixtures and underlying mechanisms are not well understood. We examined the associations between exposure to PFAS mixture with later T2D diagnosis and underlying metabolic dysregulations.</p><p><strong>Methods: </strong>We conducted a nested case-control study within BioMe, an electronic health record-linked biobank of >65,000 patients seeking primary care at Mount Sinai Hospital, New York, since 2007. After excluding prevalent T2D cases at baseline, we selected 180 incident T2D cases (33% African Americans, 33% Hispanics, 33% Whites) and 180 age, sex, and ancestry-matched T2D-free controls. In prediagnostic plasma collected at baseline (∼6 years before diagnosis), we quantified seven PFAS and untargeted metabolomic profiles. We used Weighted Quantile Sum regression to evaluate the PFAS mixture association with the odds for incident T2D. We analysed the associations between ∼650 annotated metabolites and the PFAS mixture or T2D odds using Hierarchical Bayesian Weighted Quantile Sum and logistic regression, respectively, adjusting for matching factors and other confounders. Pathway enrichment analyses were performed using Mummichog.</p><p><strong>Findings: </strong>Each tertile increase in the PFAS mixture was associated with higher odds of incident T2D (OR [95% CI] = 1.31 [1.01, 1.70]), with Perfluorooctane Sulfonate (PFOS) having the highest contribution to this association. Metabolites associated with both the PFAS mixture and T2D odds were 5-hydroxytryptophan, glucoheptulose, and sulfolithocholylglycine; the associations with sulfolithocholylglycine survived multiple testing corrections. Pathways associated with both the PFAS mixture and T2D were glutamate metabolism, arginine and proline metabolism, and drug metabolism-cytochrome p450.</p><p><strong>Interpretation: </strong>Exposure to PFAS mixtures may be associated with increased odds for T2D in multiethnic populations via dysregulations in amino acid and drug metabolism. Larger investigations in multiethnic populations are required to elucidate the potential PFAS contribution to metabolic alterations and T2D risk.</p><p><strong>Funding: </strong>National Institutes of Health (R01ES033688, P30ES023515, R21ES035148, R35ES030435, R01ES032242, R01ES034521, R01ES029944, R01ES030364, U01HG013288, R21ES037112 and P30ES007048).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":" ","pages":"105838"},"PeriodicalIF":10.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12368339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144689573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative immune analysis in patients with leprosy reveals host factors associated with mycobacterial control.","authors":"Anouk van Hooij, Krista E van Meijgaarden, Marufa Khatun, Santosh Soren, Kimberley Walburg, Khorshed Alam, Abu Sufian Chowdhury, Colette L M van Hees, Jan Hendrik Richardus, Annemieke Geluk","doi":"10.1016/j.ebiom.2025.105855","DOIUrl":"10.1016/j.ebiom.2025.105855","url":null,"abstract":"<p><strong>Background: </strong>Leprosy is a debilitating, chronic infectious disease, ranking second after tuberculosis in the order of severe human mycobacterial diseases. If timely treatment is not initiated, infection with its causative agent, Mycobacterium leprae, can result in severe nerve damage leading to life-long disabilities. Host immunity largely dictates the spectral disease presentation, ranging from multi- to paucibacillary. Studying the host response to M. leprae is, however, complicated by the inability to culture this mycobacterium in vitro. Immune correlates of protection in persons at risk of leprosy are, therefore, essentially unknown.</p><p><strong>Methods: </strong>To identify host factors related to mycobacterial control, functional mycobacterial growth inhibition assays combined with extensive immunophenotyping by spectral flow cytometry were performed for patients with leprosy and their contacts. This integrative approach merged sampling of peripheral blood mononuclear cells in low resource areas with immune-analysis using cutting edge technology.</p><p><strong>Findings: </strong>In contrast to the current dogma, no intrinsic differences in mycobacterial control in vitro between patients with high and low bacillary loads were observed. Immunophenotyping at consecutive levels revealed a significant link between the induction of chemokines to mycobacterial antigens and expression of CXCR3 and CCR4 on adaptive immune cells in contacts controlling M. leprae infection.</p><p><strong>Interpretation: </strong>These results offer more detailed insights into protective immunity against M. leprae and define host factors associated with bacterial control, fuelling improved diagnosis and treatment of leprosy.</p><p><strong>Funding: </strong>Q.M. Gastmann-Wichers Foundation, the Leprosy Research Initiative & the Turing Foundation (ILEP#: 707.19.02), R2STOP; the Leprosy Mission Great Britain.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"118 ","pages":"105855"},"PeriodicalIF":10.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12296519/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tandem CD19/CD22 CAR T-cells as potential therapy for children and young adults with high-risk r/r B-ALL.","authors":"Berta González-Martínez, Víctor Galán-Gómez, Alfonso Navarro-Zapata, Isabel Mirones-Aguilar, Marta Cobo, Alicia Pernas-Sánchez, Susana Vallejo, Elena Sánchez-Zapardiel, Odelaisy León-Triana, Carlos Echecopar, Isabel Martínez-Romera, Pilar Guerra-García, Sonsoles San Román-Pacheco, Adela Escudero, Elisa Izquierdo, Manuel Izquierdo, Sara Naharro, Alicia Martín-Ayuso, Halin Bareke, Andrés París-Muñoz, Peirong Hu, Dina Schneider, Rimas J Orentas, Jordi Minguillón, Antonio Pérez-Martínez","doi":"10.1016/j.ebiom.2025.105872","DOIUrl":"10.1016/j.ebiom.2025.105872","url":null,"abstract":"<p><strong>Background: </strong>Chimeric antigen receptor (CAR) T-cells targeting CD19 have shown impressive outcomes in refractory/relapsed B-cell acute lymphoblastic leukaemia (r/r B-ALL); however, frequent relapse demands multi-targeted approaches.</p><p><strong>Methods: </strong>We report Spanish clinical data on the safety and efficacy of tandem anti-CD19/CD22 CAR T-cells administered on a compassionate use basis in a cohort of 10 heavily pretreated paediatric, adolescent, and young adult (AYA) patients with r/r B-ALL.</p><p><strong>Findings: </strong>Most (9/10) of the patients had relapsed B-ALL, 7 having received previous anti-CD19 CAR T-cell therapy and 6 haematopoietic stem cell transplantation (HSCT). Two patients had Down syndrome. Increased high-grade CRS/ICANS and proinflammatory markers (IL-6, LDH and ferritin) correlated with patients with a high tumour burden (TB) before lymphodepletion. Complete remission on day +28 post-infusion was achieved in 8/10 patients (7 with MRD-), and 5/7 patients received HSCT as consolidative therapy within three months post-infusion. Two patients with early relapse after tandem anti-CD19/CD22 CAR received rescue therapy and HSCT. At the 18-month follow up, overall survival (OS) was 70% (95% CI, 47%-100%).</p><p><strong>Interpretation: </strong>Tandem anti-CD19/CD22 CAR T-cell administration combined with consolidative HSCT is a promising therapeutic approach, though managing bridging therapy and reducing the TB prior to infusion remain key challenges (REALL_CART trial, NCT06709469, EudraCT 2023-509723-41-01).</p><p><strong>Funding: </strong>This work was supported by a grant from the Instituto de Salud Carlos III to APM PI22/01226, two grants from CRIS Cancer Foundation to Beat Cancer as part of the projects \"Advanced Cell Therapy Unit Hospital Universitario La Paz\" and JM \"Proyecto Mateo: CAR T-cell therapy for juvenile myelomonocytic leukaemia\" and \"Terapia avanzada CAR-T CD19/CD22\", Ayuda Nominativa de la Consejería de Investigación, Comunidad de Madrid, Spain. Work in MI lab was funded by a grant from the Spanish Ministry of Science and Innovation (PID2020-114148RB-I00). VGG was granted with Río Hortega (AES 2022 exp. Nº. CM22/00078) and Juan Rodés (AES 2024 exp. Nº. JR24/00003) contracts from the Carlos III Health Institute (ISCIII) through the European Funds of the Recovery, Transformation and Resilience Plan and financed by the European Union NextGenerationEU.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"118 ","pages":"105872"},"PeriodicalIF":10.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12341234/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144774940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Post COVID 19 resurgence of diphtheria in Kano, Nigeria: analysis of 18,320 cases.","authors":"Muhammad Adamu Abbas, Abubakar Labaran Yusuf, Hassan Adam Murtala, Aisha Adam Abdullahi, Adam Muhammad Murtala, Jordi Bertran Torrelles, Muktar Hassan Aliyu, Hamisu Mohammed Salihu","doi":"10.1016/j.ebiom.2025.105877","DOIUrl":"10.1016/j.ebiom.2025.105877","url":null,"abstract":"<p><strong>Background: </strong>The COVID 19 pandemic led to significant disruptions in health services, including immunisation programs, which contributed to a major post-pandemic diphtheria outbreak in Kano State, Nigeria. This region accounted for 85% of the nation's documented diphtheria cases.</p><p><strong>Methods: </strong>This study examined the epidemiology, clinical characteristics, and mortality outcomes of cases diagnosed between February 2022 and April 2024. Data were collected through the Surveillance Outbreak Response Management and Analysis System (SORMAS), and case definitions followed WHO guidelines. Case fatality rate (CFR) was calculated, and a logistic regression model was used to assess mortality-related risk factors, reporting adjusted odds ratios (AOR).</p><p><strong>Findings: </strong>A total of 18,320 cases were analysed, with the outbreak showing a bimodal distribution. The primary peak occurred in August 2023, followed by a smaller secondary peak in early 2024. The case fatality rate (CFR) was 4.5%. Patients who were not vaccinated had more than double the likelihood of death compared to fully vaccinated individuals (AOR 2.45; 95% CI: 2.05, 2.94, p < 0.0001; logistic regression). Similarly, patients without vaccination documentation also had greater odds, with more than 87% increase likelihood of mortality compared to fully vaccinated individuals (AOR 1.87, 95% CI: 1.27, 2.68, p < 0.0001; logistic regression).</p><p><strong>Interpretation: </strong>Our study reinforces previous reports of the weakening preventive health delivery systems in resource constrained settings, particularly after the disruptions caused by the COVID 19 pandemic leading to the resurgence of vaccine preventable diseases, such as diphtheria. These highlight the need for improved vaccination coverage and surveillance systems.</p><p><strong>Fundings: </strong>This research did not receive any external funding.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"118 ","pages":"105877"},"PeriodicalIF":10.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12314330/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction notice to R-spondin 2-LGR4 system regulates growth, migration and invasion, epithelial-mesenchymal transition and stem-like properties of tongue squamous cell carcinoma via Wnt/β-catenin signaling [eBioMedicine 44, June 2019 (year) 275-288].","authors":"Liping Zhang, Yan Song, Zihang Ling, Yuanyuan Li, Xianyue Ren, Jing Yang, Zhi Wang, Juan Xia, Weizhen Zhang, Bin Cheng","doi":"10.1016/j.ebiom.2025.105702","DOIUrl":"10.1016/j.ebiom.2025.105702","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":" ","pages":"105702"},"PeriodicalIF":10.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12368288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated virologic analysis of resistance to nirmatrelvir/ritonavir in individuals across four phase 2/3 clinical studies for the treatment of COVID-19.","authors":"Mary Lynn Baniecki, Shunjie Guan, Devendra K Rai, Qingyi Yang, Jonathan T Lee, Li Hao, Edward Weinstein, Craig Hyde, Rhonda D Cardin, Holly Soares, Jennifer Hammond","doi":"10.1016/j.ebiom.2025.105819","DOIUrl":"10.1016/j.ebiom.2025.105819","url":null,"abstract":"<p><strong>Background: </strong>SARS-CoV-2 resistance to nirmatrelvir/ritonavir (NMV/r) surveillance is essential to identify emergence and track treatment-resistance.</p><p><strong>Methods: </strong>This integrative virologic analysis across EPIC (Evaluation of Protease Inhibition of COVID-19) phase 2/3 clinical studies (-High Risk [HR], -Standard Risk [SR], -Immunocompromised [IC], -Retreatment) used next-generation sequencing to identify SARS-CoV-2 variants and M^pro or cleavage site emergent substitutions (ES). Treatment ES (TES) and ES in patients experiencing COVID-19‒related hospitalisation or viral RNA rebound were evaluated for in vitro NMV resistance, structure analysis, and global incidence via GISAID EpiCoV SARS-CoV-2 database.</p><p><strong>Findings: </strong>Sequences were evaluated in 1605 NMV/r, 1216 placebo (PBO), and 114 PBO/r-treated participants. NMV/r M^pro TES were observed in EPIC-HR/SR (pooled) (T98I/R/del [n = 4], E166V [n = 3], W207L/R/del [n = 4]), cleavage (A5328 S/V [n = 7], S6799 A/P/Y [n = 4]). PBO cleavage ES were observed (A5328T [n = 1], S6799F [n = 1]). Among hospitalised NMV/r-treated participants (EPIC-HR [n = 10], -SR [n = 5], -IC [n = 2], -Retreatment [n = 0]), 2 M^pro ES were observed: A260T (EPIC-HR [n = 1]), K269R (EPIC-SR [n = 1]). In EPIC-IC, 3 M^pro ES (T98S, A191V, T201I) and 2 cleavage site ES (A4136V, S4145N) were observed with rebound. E166V was the only TES associated with resistance (NMV/r: HR [n = 3]; PBO/r: -Retreatment [n = 1]), but not in participants experiencing hospitalisation or with immunocompromising conditions. Global E166V incidence was rare (<0.001% in pre- and post-NMV/r emergency use authorization) by GISAID (December 1, 2019-June 30, 2024).</p><p><strong>Interpretation: </strong>In EPIC, NMV-resistance mutations were infrequent. E166V was the only resistance-associated substitution but was not identified in participants experiencing hospitalisation or with immunocompromising conditions. NCT04960202, NCT05011513, NCT05438602, NCT05567952.</p><p><strong>Funding: </strong>Pfizer Inc.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"118 ","pages":"105819"},"PeriodicalIF":10.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12266373/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genotype and transcript processing of the tumour necrosis factor receptor TNFRSF1A in epithelial cells: implications for survival in cystic fibrosis.","authors":"Alexander Uden, Inga Dunsche, Sabina Janciauskiene, Simon Gräber, Longhua Feng, Stephanie Tamm, Silke Hedtfeld, Gesa Stege, Kirsten Jahn, Julia Kontsendorn, Nadine Alfeis, Iris Kühbandner, Rebecca Minso, Christian Dopfer, Matthias Griese, Olaf Sommerburg, Felix C Ringshausen, Lutz Nährlich, Gesine Hansen, Tobias Welte, Peter Braubach, Marcus A Mall, Burkhard Tümmler, Anna-Maria Dittrich, Frauke Stanke","doi":"10.1016/j.ebiom.2025.105848","DOIUrl":"10.1016/j.ebiom.2025.105848","url":null,"abstract":"<p><strong>Background: </strong>Cystic fibrosis is caused by mutations of the cystic fibrosis transmembrane conductance regulator, CFTR, an epithelial anion transport protein, responsible for, inter alia, sputum viscoelasticity in the lung. We previously identified the TNF receptor superfamily 1A TNFRSF1A (TNFR1) as a genetic modifier of CFTR function and disease severity in the CF twin and sibling study population. We aimed to replicate our findings in independent cohorts, assess the role of TNFR1 for patient survival and identify functional changes associated with TNFR1 polymorphisms.</p><p><strong>Methods: </strong>We incorporated data from three independent long-term mono- and multicentric cohorts of people with cystic fibrosis (pwCF) to confirm the previously described association of TNFR1 with CFTR function and to extend our study to include survival data for our local cohort and a pan-European cohort of pwCF. We studied TNFR1 transcripts obtained from primary airway epithelia grown as air-liquid interface cultures to address possible mechanisms involved in up-stream and down-stream effects of TNFR1.</p><p><strong>Findings: </strong>Survival differed by more than a decade when comparing carriers of contrasting TNFR1 genotypes among unrelated pwCF as well as among CF siblings pairs. The presence of the TNFR1 transcript variant TNFR1delEx2 in primary airway epithelia was associated with TNFR1 genotype.</p><p><strong>Interpretation: </strong>The association of the TNFR1 transcript variant TNFR1delEx2 associates with the TNFR1 genotype, possibly mediating the genotype-survival association we found regarding TNFR1 genotype and patient survival in cystic fibrosis.</p><p><strong>Funding: </strong>Supported by the German Ministry for Education and Research (BMBF) (82DZL009B1 to MAM and 82DZL002A1, to GH, BT, AMD, FS) and the Mukoviszidose Institut gGmbH (MI-2002, to LN, AMD, FS).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"118 ","pages":"105848"},"PeriodicalIF":10.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12275981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144616869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effectorless Fc-fusion improves FLT3L drug-like properties for cancer immunotherapy combinations.","authors":"Jérémie Decalf, Evangeline Toy, Dongping He, Radhika Kenkre, Amy M Berkley, Devon Wong, Mandy Kwong, Yee-Seir Kee, Yue Sun, Srividya Myneni, Xiangdan Wang, Ahmad Ebtikar, Anthony Ancheta, Yanli Yang, Hok Seon Kim, Nga Tang, Debarko Banerji, Elaine Mai, Pranay Dogra, Meredith McLerie, Alan G Gutierrez, Geraldine Strasser, Gautham K Rao, Matt Betzenhauser, Wilson Phung, Peter Day, Wendy Sandoval, Ayse Meric Ovacik, Pamela Chan, Shomyseh Sanjabi, Laetitia Comps-Agrar, Sivan Cohen, James A Ernst, Greg A Lazar, Christopher C Kemball, Iraj Hosseini, Yichin Liu, Jill M Schartner, Travis W Bainbridge, Christine Moussion","doi":"10.1016/j.ebiom.2025.105822","DOIUrl":"10.1016/j.ebiom.2025.105822","url":null,"abstract":"<p><strong>Background: </strong>Conventional dendritic cells (cDCs), are central to antitumour immunity, but their low prevalence in tumours limits the efficacy of immunotherapies. FLT3L is a key growth factor regulating cDCs development in the bone marrow. It expands cDCs when administered exogenously, favouring antitumour T cell priming and tumour control. Currently, FLT3L pharmacokinetic (PK) and pharmacodynamic (PD) properties require daily dosing for up to 14 days, which may limit its clinical use. In the present study, we developed and characterised a therapeutic modality named FLT3L-Fc NG2LH.</p><p><strong>Methods: </strong>We improved human FLT3L PK properties by fusing it with a modified fragment crystallisable (Fc) domain of IgG1. To prevent Fc gamma receptor (FcγR) mediated effector function, we engineered an effectorless Fc format called NG2LH, consisting of the aglycosylation substitution N297G, combined with a graft of the lower hinge region of IgG2 onto an otherwise IgG1 Fc.</p><p><strong>Findings: </strong>FLT3L-Fc NG2LH had limited binding to FcγRs and failed to elicit antibody dependent cellular cytotoxicity (ADCC) and cellular phagocytosis (ADCP). PK/PD studies using a mouse effectorless equivalent, mFLT3L-Fc, showed that a single injection of mFLT3L-Fc leads to sustained expansion of cDCs in blood, spleen, and B16F10 tumours. When combined with polyI:C and anti-PD-L1, a single mFLT3L-Fc injection delays the growth of B16F10 tumours and reinvigorates CD8+ T cell immunity.</p><p><strong>Interpretation: </strong>The improved properties of FLT3L-Fc NG2LH are expected to mitigate the practical limitations of FLT3L usage in the clinic, and constitute an asset for future cancer immunotherapy combination regimens leveraging cDC biology in situ.</p><p><strong>Funding: </strong>This work was performed at, and funded by Genentech Inc. South San Francisco, CA 94080, USA.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"118 ","pages":"105822"},"PeriodicalIF":10.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12272481/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144575068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}