Sex-dependent modulation of acute respiratory distress syndrome by Bacteroides acidifaciens: gut microbiome impact on lung inflammation

Bacteroides acidifaciens (BA), a common gut commensal, is known to modulate immune responses, but its role in acute respiratory distress syndrome (ARDS) and potential sex-specific effects remain poorly understood. To investigate this, male and female mice were colonized with BA prior to induction of ARDS using dual doses of staphylococcal enterotoxin B (SEB), a potent superantigen that triggers cytokine storm–driven lung injury. Clinical parameters, histopathology, gene expression, ELISA, flow cytometry, and gut barrier assessments were used to evaluate outcomes. BA pre-treatment significantly improved lung function, and attenuated pulmonary inflammation in male mice, correlating with increased IL-22, expansion of γδ T cells, and upregulation of colonic tight junction proteins. In contrast, BA exacerbated ARDS symptoms in females, increasing Th17 responses, neutrophil infiltration, and IgA-associated immune activation while impairing gut barrier integrity. These findings reveal that BA exerts divergent, sex-dependent effects in ARDS, highlighting the critical need to consider sex as a biological variable in microbiome-based therapies targeting inflammatory lung disease

Safety and Efficacy of Ixoberogene Soroparvovec in Neovascular Age-Related Macular Degeneration in the United States (OPTIC): A Prospective, Two-Year, Multicentre Phase 1 Study

Background Gene therapy, successfully used in rare, monogenetic disorders, may prove to be a durable management approach for common, polygenetic conditions, including neovascular age-related macular degeneration (nAMD). Repeated injections, oftentimes monthly, and possibly for decades, of vascular endothelial growth factor antagonists (anti-VEGF), is the standard for nAMD. We hypothesised that an in-office, intravitreal administration of ixoberogene soroparvovec (ixo-vec, formerly ADVM-022), a single-dose gene therapy encoding for the proven anti-VEGF protein, aflibercept, would transform retinal cells to continually produce aflibercept to minimise treatment burden in nAMD. Methods In this two-year, open-label, prospective, multicentre phase 1 study, patients with nAMD responding to antiVEGF were assigned to four cohorts differing by ixo-vec dose (2 × 1011 vs 6 × 1011 vector genomes (vg/eye)) and prophylactic steroids (oral prednisone vs topical difluprednate). The primary outcome was the type, severity, and incidence of ocular and systemic adverse events (AEs); secondary endpoints included vision, central subfield thickness (CST), and the number of supplemental injections. This study was registered with ClinicalTrials.gov, NCT03748784. Findings Thirty patients with nAMD were enrolled between November 14, 2018 and June 30, 2020 at nine study sites in the United States. No systemic ixo-vec related AEs were noted. Across both dose groups the most common adverse event was anterior chamber cell, which was reported in 11 participants in the 6 × 1011 dose group and in 7 participants in the 2 × 1011 dose group; intraocular inflammation was responsive to topical corticosteroids, with no anterior chamber cells or vitreous cells observed in 2 × 1011 vg/eye patients at the end of the study. Vision and CST remained stable throughout two years with annualised anti-VEGF injections reduced by 80% (10.0 mean annualised anti-VEGF injections to 1.9) in 2 × 1011 vg/eye and 98% (9.8 mean annualised anti-VEGF injections to 0.2) in 6 × 1011 vg/eye cohorts. Interpretation Ixo-vec was generally well-tolerated, maintained vision, and improved anatomical outcomes in nAMD, with a substantial reduction in anti-VEGF injections. A single administration of an in-office gene therapy, with vectorised protein with an already established clinical benefit, has the potential to revolutionise the management of common ocular disorders requiring ongoing, frequent therapeutic interventions