AIRWAY MUCINS AS DETERMINANTS AND THERAPEUTIC TARGETS OF MUCUS DYSFUNCTION IN ASTHMA

Abstract

Airway mucus serves as a highly effective first line of defense, protecting the airways from environmental pathogens and particulate matter. Mucus is a hydrogel made up of two gel-forming mucins, MUC5B and MUC5AC, with MUC5B being the predominant mucin in healthy airways. Particles trapped in mucus are cleared through coordinated ciliary movement, a process known as mucociliary clearance. However, in asthma, mucus is sticky and viscous, impairing mucociliary clearance and leading to muco-obstruction in diseased airways. Evidence from biochemical analysis of the patients’ sputum revealed a shift from MUC5B to MUC5AC as the predominant mucin. The effect of this shift in mucin composition on mucus dysfunction in diseased airways remains poorly understood. This dissertation aims i) to explore how mucin imbalances lead to abnormal mucus properties and impaired transport, and ii) to evaluate whether targeting mucins could be a viable therapeutic strategy in airway diseases. To study the first aim, we systematically varied mucin composition to form mucus gels. We found that gels with elevated MUC5AC, as seen in asthma, exhibited increased viscoelasticity and impaired transportability. To study the second aim of mucins as therapeutic targets, we used an adeno-associated virus as a gene delivery vector to transduce airway epithelial cells and reduce MUC5AC expression via siRNA delivery. When used as a prophylactic, we observed effective transduction in vitro, decreased MUC5AC mRNA and protein levels, and consistent mucociliary transport despite asthma challenge. In an in vivo fungal allergen model, we observed successful transduction and reduced MUC5AC-rich mucus plugs in treated mice. Together, this work highlights the role of mucins in airway dysfunction and provides a long-term gene-therapeutic solution targeting MUC5AC in asthma to restore normal airway clearance