Lung-Targeted HGF mRNA Restores Alveolar Structure in Experimental Emphysema.

Summary

Using a clinical-stage SM102 LNP platform, intratracheal and nebulized delivery of HGF mRNA restored lung function and reduced alveolar destruction in elastase- and cigarette-smoke-induced emphysema models. scRNA-seq and human organoid data supported increased AT2 cell proliferation/differentiation, consistent with lung regeneration.

Key Findings

• HGF expression shows a biphasic pattern: upregulated in milder emphysema and reduced in advanced disease.
• Intratracheal HGF mRNA LNPs improved lung function and attenuated alveolar destruction in elastase-induced emphysema.
• Nebulized HGF mRNA achieved broad pulmonary distribution and efficacy in cigarette-smoke models, reducing inflammation and apoptosis.
• scRNA-seq and human organoids indicated enhanced AT2 cell proliferation and differentiation with HGF mRNA therapy.

Clinical Implications

While preclinical, this supports early-phase trials of nebulized HGF mRNA in emphysema, with AT2-cell metrics and inflammation/apoptosis markers as mechanistic endpoints and pulmonary function as clinical endpoints.

Limitations

• Preclinical animal and organoid data; human safety, dose, and durability are unknown.
• Quantitative sample sizes and long-term outcomes were not detailed in the abstract.

Future Directions

Conduct phase 1 trials of nebulized HGF mRNA in emphysema; define optimal dosing, safety, and durability; incorporate AT2 lineage markers and functional imaging as mechanistic endpoints.