Daily Respiratory Research Analysis

BACKGROUND: A raised blood eosinophil count (≥300 cells per μL), a marker of type 2 inflammation, can identify patients with chronic obstructive pulmonary disease (COPD) with higher exacerbation risk. Dupilumab reduced exacerbations in patients with COPD and type 2 inflammation in the BOREAS trial. In this post-hoc analysis, we evaluated the predictive value and longitudinal changes in type 2 inflammatory biomarkers in patients with COPD and type 2 inflammation from the BOREAS trial who received dupilumab treatment. METHODS: BOREAS, a phase 3, multicentre, double-blind, randomised trial was conducted at 275 sites in 24 countries and included patients with COPD and type 2 inflammation (screening blood eosinophils ≥300 cells per μL). Patients were randomly assigned (1:1) to receive 300 mg of dupilumab every 2 weeks for 52 weeks or matching placebo. Randomisation was stratified by country and inhaled corticosteroid dose at baseline. This post-hoc analysis assessed blood eosinophil counts, fractional exhaled nitric oxide (FeNO), serum eotaxin-3, total plasma immunoglobulin E (IgE), and serum pulmonary and activation-regulated chemokine (PARC) concentrations in the safety population. The study was registered at ClinicalTrials.gov, NCT03930732 and is complete. FINDINGS: BOREAS was conducted between April 15, 2019, and May 2, 2023, and included 939 patients with COPD and type 2 inflammation. 468 patients were randomly assigned to receive 300 mg of dupilumab every 2 weeks for 52 weeks and 471 were randomly assigned to receive matching placebo. 319 (34%) participants were female and 620 (66%) were male. 657 (70%) were former smokers and 282 (30%) were current smokers. At week 52, greater median percentage reductions were observed in dupilumab versus placebo for most biomarkers (total IgE: -22·5% [IQR -30·4 to -16·5] vs -0·9% [-6·5 to 4·8]; FeNO: -28·6% [-57·1 to 0] vs -6·9% [-35·7 to 25·0]; eotaxin-3: -8·8% [-15·6 to -2·9] vs -0·4% [-5·6 to 5·0]; and PARC: -14·4% [-29·2 to 2·1] vs -0·8% [-13·9 to 17·2]). Reductions were similar across treatment groups by blood eosinophil counts. Exacerbation risk overall was reduced, with a greater magnitude of reduction in those with higher baseline blood eosinophil count (p=0·0056) and baseline FeNO (p=0·043). INTERPRETATION: Patients with COPD and type 2 inflammation who were given dupilumab showed reduced type 2 inflammatory biomarkers, with elevated blood eosinophil count and FeNO predicting greater treatment response. These findings support biomarker-driven treatment strategies to optimise therapy. FUNDING: Sanofi and Regeneron Pharmaceuticals.

Nonsense mutations arise from single nucleotide substitutions that result in premature termination codons (PTCs). PTCs result in little to no full-length protein production and decreased mRNA stability due to the nonsense-mediated mRNA decay (NMD) pathway. We provide evidence that anticodon-edited (ACE-) tRNAs efficiently suppress the most prevalent cystic fibrosis (CF)-causing PTCs, promoting significant rescue of endogenous cystic fibrosis transmembrane conductance regulator (CFTR) transcript abundance and channel function in different model systems. We show that our best-performing ACE-tRNA, which decodes all UGA PTCs to a leucine amino acid, markedly rescues CFTR function from the most prevalent CF-causing PTCs, all of which arose from nonleucine encoding codons. Using this single ACE-tRNA variant, we demonstrate significant rescue of CFTR function in an immortalized airway cell line and two different primary CF patient-derived intestinal cell models with CFTR nonsense mutations. Further, we demonstrate that leucine substitution CFTR variants are highly functional. Thus, ACE-tRNAs have promise as a platform therapeutic for CF and other nonsense-associated diseases.

Respiratory syncytial virus (RSV) causes severe respiratory disease in infants and the elderly. However, natural infection fails to induce durable immune protection, and existing mRNA vaccines for older adults exhibit limited long-term efficacy. We developed an antigen engineering strategy inserting ESCRT/ALIX-binding region (EABR) into truncated RSV prefusion F (PreF) cytoplasmic tails to form enveloped virus-like particles (eVLPs). In murine models, PreF-EABR mRNA vaccines elicited higher, more persistent neutralizing antibodies than conventional PreF mRNA, correlating with enhanced germinal center B cell and memory B cell responses. A lower dose of PreF-EABR mRNA (1 μg) suppressed viral load and pathology comparable to higher-dose PreF mRNA (2.5 μg). Transcriptomic analysis showed PreF-EABR mRNA activated toll-like receptor and chemokine signaling pathways, enhancing antibody longevity via platelet-associated signatures. This study explores the development and possible mechanism of long-lasting RSV mRNA vaccines by eVLPs technology, which also suggest its potential application in other vaccines.