Abstract Background Airway mucus serves as the first line of defense against inhaled pathogens and toxins. The major structural components of airway mucus are the gel-forming mucins MUC5AC and MUC5B. In muco-obstructive diseases such as asthma, COPD, NCFB, and CF, mucins are overexpressed due to goblet cell hyperplasia, and MUC5AC/MUC5B ratio becomes elevated. This imbalance leads to viscous mucus accumulation, airway obstruction, chronic infections, and persistent inflammation. Elevated MUC5AC levels in patients have been shown to correlate with disease severity, including reduced FEV1 and increased exacerbation frequency. SPL5AC is an antisense oligonucleotide (ASO) therapy developed by Splisense, designed to specifically reduce MUC5AC expression in patients with muco-obstructive diseases. By lowering MUC5AC levels, SPL5AC aims to enhance mucus clearance and alleviate airway obstruction and inflammation. Splisense is a platform technology company developing transformative RNA-based therapies for pulmonary diseases. The favorable safety and efficacy profile demonstrated in the company’s lead cystic fibrosis program provides clinical validation of the Splisense platform. Methods SPL5AC effect, durability and pharmacodynamics were tested in-vitro in IL-13 induced primary HBEs and in-vivo in three industry standard disease mouse models. The effects on RNA , and protein were analyzed using RT-qPCR and Western Blot. Clinical translational endpoints were also evaluated including mucus plug staining, inflammation profile assessment and mice lung function. Results SpliSenes clinical lead candidate, SPL5AC, effect and durability were tested in different in-vitro and in-vivo disease models. In-vitro in IL-13 induced HBEs, SPL5AC was demonstrated to reduce MUC5AC RNA and protein levels with a durable effect for at least 3 weeks. Importantly, when administered on top of the mucus layer, SPL5AC migrated freely through the induced thick mucus layer penetrating into the cells, reducing MUC5AC levels. In vivo, SPL5AC was shown to efficiently reduce Muc5ac expression across multiple disease mouse models, preventing mucus plug formation, attenuating airway inflammation, and inhibiting airway hyperresponsiveness (AHR). Pharmacodynamic analyses demonstrated the high potency and stability of SPL5AC in a disease-relevant model. Weekly administration of low doses of SPL5AC resulted in a significant reduction in Muc5ac levels and goblet cell hyperplasia. Consistent with the in vitro findings, the effect of SPL5AC was durable for at least four weeks. Conclusions Restoring proper mucus viscoelasticity and clearance in the lungs of patients with muco-obstructive diseases remains a major goal. Collectively, the presented studies support the potential of SPL5AC as prophylactic therapy for muco-obstructive patients with the objective to advance to first in Human in 2026. This abstract is funded by: None
G Hart (Fri,) studied this question.