Daily Respiratory Research Analysis
Three advances span the respiratory spectrum: biomarker-guided biologic therapy in COPD, a platform tRNA approach rescuing CFTR function for cystic fibrosis nonsense mutations, and an engineered mRNA RSV vaccine forming eVLPs that improves antibody durability and dose-sparing in mice. Together, they point to precision therapeutics, genetic code suppression strategies, and next-generation vaccine design for respiratory diseases.
Summary
Three advances span the respiratory spectrum: biomarker-guided biologic therapy in COPD, a platform tRNA approach rescuing CFTR function for cystic fibrosis nonsense mutations, and an engineered mRNA RSV vaccine forming eVLPs that improves antibody durability and dose-sparing in mice. Together, they point to precision therapeutics, genetic code suppression strategies, and next-generation vaccine design for respiratory diseases.
Research Themes
- Biomarker-driven therapy in COPD
- Genetic code suppression for cystic fibrosis nonsense mutations
- Next-generation RSV mRNA vaccine design using eVLPs
Selected Articles
1. Type 2 inflammation biomarkers and their association with response to dupilumab in COPD (BOREAS): an analysis of a randomised, placebo-controlled, phase 3 trial.
In a post-hoc analysis of the phase 3 BOREAS trial in COPD with type 2 inflammation, dupilumab led to greater 52-week reductions in total IgE, FeNO, eotaxin-3, and PARC versus placebo. Higher baseline blood eosinophils and FeNO predicted larger reductions in exacerbation risk, supporting biomarker-guided use of dupilumab.
Impact: This analysis links type 2 biomarkers to clinical response in a large, multicentre RCT, enabling precision selection of COPD patients for dupilumab and supporting longitudinal biomarker monitoring.
Clinical Implications: For COPD patients with eosinophils ≥300/μL, baseline eosinophil count and FeNO can guide dupilumab initiation, and serial biomarker tracking (IgE, FeNO, eotaxin-3, PARC) may help assess response and optimize therapy.
Key Findings
- At week 52, dupilumab achieved greater median percentage reductions than placebo in total IgE (-22.5% vs -0.9%), FeNO (-28.6% vs -6.9%), eotaxin-3 (-8.8% vs -0.4%), and PARC (-14.4% vs -0.8%).
- Higher baseline blood eosinophil counts predicted a greater reduction in exacerbation risk with dupilumab (interaction p=0.0056).
- Higher baseline FeNO also predicted a greater reduction in exacerbation risk with dupilumab (interaction p=0.043).
Methodological Strengths
- Large, multicentre, double-blind RCT parent trial with 939 patients and 52-week follow-up
- Comprehensive biomarker panel (eosinophils, FeNO, IgE, eotaxin-3, PARC) with longitudinal assessment
Limitations
- Post-hoc analysis not prespecified, susceptible to multiplicity and residual confounding
- Biomarker thresholds and generalisability to different inhaled corticosteroid backgrounds require prospective validation
Future Directions: Prospectively validate eosinophil and FeNO thresholds for dupilumab response, integrate biomarker algorithms into COPD care pathways, and assess cost-effectiveness of biomarker-guided biologic therapy.
2. ACE-tRNAs are a platform technology for suppressing nonsense mutations that cause cystic fibrosis.
ACE-tRNAs that recode UGA PTCs to leucine restored CFTR mRNA levels and channel activity across common CF nonsense mutations. A single ACE-tRNA variant rescued function in an airway cell line and two primary CF patient-derived intestinal models, indicating a broadly applicable platform for PTC suppression.
Impact: Demonstrates a genotype-agnostic, codon-level therapeutic strategy with functional rescue across multiple CFTR PTCs, advancing a platform applicable to CF and other nonsense-mediated diseases.
Clinical Implications: If delivery and safety challenges are addressed, ACE-tRNA therapy could offer a mutation-class solution for CF patients with PTCs independent of the original amino acid, complementing or replacing current modulator therapies.
Key Findings
- An ACE-tRNA decoding all UGA PTCs to leucine significantly rescued CFTR transcript abundance and channel function.
- Functional rescue was demonstrated in an immortalized airway cell line and two primary CF patient-derived intestinal cell models.
- Leucine-substituted CFTR variants were highly functional, supporting the feasibility of UGA-to-leucine recoding.
Methodological Strengths
- Multiple complementary model systems, including primary patient-derived cells, to validate functional rescue
- Simultaneous assessment of transcript rescue (NMD avoidance) and channel function
Limitations
- Preclinical in vitro models; in vivo delivery, durability, and immunogenicity not addressed
- Off-target decoding risks and proteome-wide consequences require thorough assessment
Future Directions: Develop safe delivery vehicles for airway epithelia, evaluate in vivo efficacy in CF animal models, and map proteome-wide effects and safety pharmacology for clinical translation.
3. Improved mRNA-based RSV vaccine with PreF forming enveloped virus-like particles.
Engineering PreF mRNA to recruit ESCRT/ALIX and form eVLPs produced higher and more durable neutralizing antibody responses in mice versus conventional PreF mRNA, with dose-sparing efficacy. Transcriptomics implicated TLR and chemokine pathways and platelet-associated signatures in enhanced antibody longevity.
Impact: Introduces a generalizable antigen-engineering strategy to improve durability and potency of mRNA vaccines against respiratory viruses, addressing a core limitation of current RSV vaccines.
Clinical Implications: If translated to humans, eVLP-forming mRNA could improve durability and reduce dose requirements for RSV vaccination, potentially enhancing protection in high-risk populations (infants, elderly).
Key Findings
- PreF-EABR mRNA forming eVLPs elicited higher and more persistent neutralizing antibodies than conventional PreF mRNA in mice.
- A 1 μg dose of PreF-EABR mRNA achieved viral load and pathology suppression comparable to 2.5 μg conventional PreF mRNA (dose-sparing).
- Transcriptomics showed activation of TLR and chemokine pathways and platelet-associated signatures linked to antibody longevity.
Methodological Strengths
- Head-to-head comparison against conventional mRNA with dose-ranging and virologic/pathology endpoints
- Mechanistic immunology readouts (germinal center and memory B cells) and transcriptomics
Limitations
- Murine-only data; human immunogenicity, durability, and safety remain untested
- Long-term persistence and breadth against diverse RSV strains need evaluation
Future Directions: Advance to NHP and early-phase human studies to evaluate safety, durability, and breadth; test eVLP strategy across other respiratory pathogens.