Weekly Respiratory Research Analysis
This week’s respiratory literature prioritized translationally actionable biology and near-term clinical impact. A multi-omics Mendelian randomization and translational study nominates SERPING1 (a complement regulator) as a causal COPD modulator with biomarker and therapeutic potential. A high-resolution single-nucleus/spatial COPD atlas maps pathological cell states and plasma biomarkers that enable patient stratification and target discovery. Finally, a multicountry phase 2b RCT shows oral nal
Summary
This week’s respiratory literature prioritized translationally actionable biology and near-term clinical impact. A multi-omics Mendelian randomization and translational study nominates SERPING1 (a complement regulator) as a causal COPD modulator with biomarker and therapeutic potential. A high-resolution single-nucleus/spatial COPD atlas maps pathological cell states and plasma biomarkers that enable patient stratification and target discovery. Finally, a multicountry phase 2b RCT shows oral nalbuphine ER meaningfully reduces objective cough in IPF, offering a symptom-directed therapy ready for phase 3 validation.
Selected Articles
1. Multiomics Mendelian randomization identifies serpin family G member 1 as a chronic obstructive pulmonary disease modulator.
Integrated multi-omics Mendelian randomization, longitudinal cohort analyses, and AAV-mediated overexpression in smoke-exposed mice nominate SERPING1 as a causal COPD modulator. Higher circulating SERPING1 associated with slower early FEV1 decline in UK Biobank and ECOPD cohorts, and SERPING1 overexpression improved lung function and alveolar integrity in mice.
Impact: Bridges genetic causality to mechanistic and in vivo validation, proposing a tractable complement-regulatory target with immediate biomarker utility for COPD risk stratification.
Clinical Implications: SERPING1 could be developed as a predictive biomarker for early FEV1 decline and explored as a host-directed therapeutic target (complement modulation) in ancestry-stratified early-phase trials.
Key Findings
- pQTL/eQTL-integrated MR identifies SERPING1 as causally associated with reduced COPD risk and better lung function metrics.
- Higher circulating SERPING1 linked to slower early FEV1 decline in UK Biobank and ECOPD longitudinal analyses.
- AAV-mediated SERPING1 overexpression in smoke-exposed mice improved lung function, reduced alveolar destruction, and upregulated elastic-fiber genes.
2. Aberrant cellular communities underlying disease heterogeneity in chronic obstructive pulmonary disease.
A large single-nucleus RNA-seq (1.5M nuclei) study integrated with spatial transcriptomics and plasma proteomics across 141 lungs maps emergent cell states linked to lung function, emphysema and symptoms. It defines spatial pathological niches, nominates plasma biomarkers of cell states, and uncovers intercellular networks that can inform stratified therapeutics.
Impact: Provides a high-resolution cellular atlas that links tissue pathology to accessible plasma biomarkers and therapeutic hypotheses, enabling biomarker-driven trials in COPD.
Clinical Implications: Supports development of blood-based panels for patient stratification and trial enrichment, and prioritizes interventions targeting profibrotic/remodeling niches and their signaling.
Key Findings
- Single-nucleus RNA-seq identified stage-linked emergent cell states correlating with lung function and symptoms.
- Spatial transcriptomics revealed localized pathological niches with co-occurring cell communities.
- Plasma proteomics nominated circulating biomarkers tied to extracellular matrix remodeling and pathological cell states.
3. Oral Nalbuphine in Idiopathic Pulmonary Fibrosis-Associated Cough: The CORAL Randomized Clinical Trial.
In a 52-site, double-blind phase 2b RCT (n=165 randomized, 160 analyzed), nalbuphine ER (27/54/108 mg twice daily) reduced 24-hour objective cough frequency in IPF over 6 weeks with dose-response; the two higher doses also improved patient-reported cough frequency. Safety and longer-term efficacy remain to be established in phase 3.
Impact: High-quality randomized evidence for a symptom-directed pharmacotherapy in IPF addresses an important unmet need and sets the stage for definitive phase 3 evaluation with objective digital endpoints.
Clinical Implications: Pending phase 3 confirmation, nalbuphine ER could become the first approved, objectively measured symptomatic treatment for IPF cough; clinicians and trialists should incorporate digital cough monitoring into designs.
Key Findings
- All three nalbuphine doses reduced 24-hour cough counts versus placebo at 6 weeks with dose-response (relative decreases 47.9%, 53.4%, 60.2% vs 16.9%).
- 54 mg and 108 mg doses improved patient-reported cough frequency; trial was randomized, double-blind, multicenter with digital monitoring.