C70-05 Pulmonary Administration of Antisense Oligonucleotide (ASO) and Feldan Shuttle Delivery Peptide Decreases Mucin Gene Expression in Models of Muco-obstructive Lung Diseases

Abstract Rationale Mucus hypersecretion is a hallmark of muco-obstructive lung diseases, including chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), cystic fibrosis (CF), and primary ciliary dyskinesia (PCD). The accumulation of mucus within the airways promotes chronic inflammation, sustains infection, and drives disease progression. Reducing mucus abundance by inhibiting mucin gene expression represents a potential therapeutic strategy to alleviate mucus burden in these patients. Antisense oligonucleotides (ASOs) offer a promising approach to downregulate mucin gene expression in mucus-secreting cells; however, their clinical utility is limited by the formidable respiratory epithelial barrier and the inherently low intracellular uptake of ASOs. The Feldan Shuttle, a peptide-based intracellular delivery system, has demonstrated high efficacy in delivering biomolecules to airway epithelial cells, including mucin-producing cells, following pulmonary administration in animal models. Methods Here, we developed and evaluated a therapeutic strategy comprising a Feldan Shuttle delivery peptide and an ASO targeting a mucin gene. Treatment effect was evaluated in different muco-obstructive lung disease-related models. Results In a well-differentiated primary human bronchial epithelial cell model, apical treatment with the ASO and Feldan Shuttle achieved ∼85% gene knockdown by RT-qPCR and an ∼80% reduction in Periodic acid-Schiff (PAS)-positive cells by histological analysis. In a house dust mite (HDM)-induced mucus hypersecretion mouse model, treatment resulted in a ∼90% reduction of mucin mRNA in total lung RNA extracts, accompanied by a significant decrease in Th2 inflammatory cytokine expression. Conclusion Collectively, these results indicate that ASO-mediated inhibition of mucin synthesis, enabled by the Feldan Shuttle delivery system, represents a promising therapeutic strategy to reduce mucus burden and improve inflammatory outcomes in patients with muco-obstructive lung diseases. This abstract is funded by: CQDM