Respiratory Research Analysis
October’s respiratory research converged on three sustained directions: mechanism-guided repair of alveolar injury, pharmacologic therapy for obstructive sleep apnoea (OSA), and pandemic vaccine platform readiness. mTOR–IL-6–Edn1–FoxO1 signaling was linked to AT2 senescence in LAM with reversal using approved agents, charting a repurposing path. A multicentre phase 2 RCT showed clinically meaningful, dose-dependent benefits of sultiame for OSA, opening a new therapeutic class beyond devices. Rep
Summary
October’s respiratory research converged on three sustained directions: mechanism-guided repair of alveolar injury, pharmacologic therapy for obstructive sleep apnoea (OSA), and pandemic vaccine platform readiness. mTOR–IL-6–Edn1–FoxO1 signaling was linked to AT2 senescence in LAM with reversal using approved agents, charting a repurposing path. A multicentre phase 2 RCT showed clinically meaningful, dose-dependent benefits of sultiame for OSA, opening a new therapeutic class beyond devices. Replicating RNA H5N1 vaccines protected nonhuman primates, including cross-protection from historical antigens, informing flexible stockpile and rapid-response strategies. Note: Only one weekly dataset was available this month, so rankings reflect a truncated top list from that interval.
Selected Articles
1. mTOR dysregulation induces IL-6 and paracrine AT2 cell senescence impeding lung repair in lymphangioleiomyomatosis.
Human LAM lungs, organoids, precision-cut lung slices, and transgenic mice reveal that LAM-cell mTOR dysregulation drives IL‑6→Edn1→FoxO1 signaling, enforcing AT2 senescence and blocking alveolar repair. Rapamycin plus IL‑6R blockade reversed senescence signatures and improved epithelial repair across models.
Impact: Defines a tractable pathway from dysregulated growth signaling to alveolar senescence with reversal using approved agents, enabling immediate mechanism-based repurposing.
Clinical Implications: Supports proof-of-concept trials of combined mTOR inhibition and IL‑6R blockade in LAM using AT2 senescence and repair metrics as biomarkers.
Key Findings
- AT2 senescence markers (p16/p21, SenMayo) are elevated and colocalize with dysfunction in LAM.
- LAM-derived IL‑6 induces Edn1 and FoxO1 sequestration in AT2 cells, enforcing senescence and impaired repair.
- Rapamycin and IL‑6R blockade reduce AT2 senescence and improve epithelial repair in organoids and in vivo.
2. Sultiame once per day in obstructive sleep apnoea (FLOW): a multicentre, randomised, double-blind, placebo-controlled, dose-finding, phase 2 trial.
In a 28-site, phase 2 RCT (n=298), once-daily sultiame reduced AHI3a and improved sleep outcomes in a dose-dependent fashion at 15 weeks, with dose-related sensory adverse events.
Impact: Provides rare, well-powered randomized evidence for pharmacologic OSA treatment, inaugurating carbonic anhydrase inhibition as a therapeutic class beyond device-based care.
Clinical Implications: Potential adjunct or alternative to CPAP; dosing must balance efficacy and sensory adverse effects while phase 3 data refine indications.
Key Findings
- Placebo-subtracted AHI3a relative reductions at 15 weeks: −16.4% (100 mg), −30.2% (200 mg), −34.6% (300 mg).
- Improvements extended to nocturnal hypoxia and patient-reported sleep quality.
- Dose-related adverse events included paresthesia and headache.
3. A replicating RNA vaccine protects cynomolgus macaques against lethal clade 2.3.4.4b influenza A H5N1 virus challenge.
repRNA vaccines encoding contemporary or historical H5 HA protected macaques from lethal H5N1 challenge, lowered viral loads, and reduced respiratory illness; historical HA conferred cross-protection.
Impact: Validates a flexible vaccine platform with cross-protective potential in a stringent nonhuman primate model, informing stockpiling and rapid-response policies.
Clinical Implications: Supports phase 1/2 evaluation of repRNA H5 constructs and assessment of using stockpiled historical antigens during antigenic drift.
Key Findings
- Both contemporary 2.3.4.4b HA and historical H5 HA repRNA vaccines protected against lethal H5N1.
- Vaccination reduced viral load and clinical respiratory illness.
- Historical antigen elicited cross-protection, suggesting stockpile flexibility.