Patrick Shearer

Severe asthma is a heterogenous and multifactorial condition, which remains a major clinical challenge. Recent treatment strategies have shifted from symptom control towards mechanism-guided approaches, such as biologic therapies [1]. However, a large proportion of patients do not respond to treatment, and research is needed to define mechanistically informative biomarkers which can guide personalized therapy. Extracellular vesicles (EVs) are lipid-bilayer enclosed nanoparticles secreted by all cell types. They contain a variety of cargo, including proteins, lipids, and metabolites. EVs are involved in immune surveillance, tissue repair, and inflammation, and the structure of EVs enhances their stability [2]. Thus, they can be isolated from archived, cell-free clinical biofluids, such as plasma, bronchioalveolar lavage fluid (BALF) or urine. Furthermore, EV cargo is protected from degradation, and can reflect the state of the cell of origin, making EVs promising candidates for biomarker discovery. Eicosanoids are a diverse group of bioactive lipid mediators derived from membrane lipids such as arachidonic acid. They include prostaglandins, leukotrienes (LTs), thromboxanes, and lipoxins, and many of them play central roles in the pathogenesis of asthma by regulating bronchoconstriction, vascular permeability, and immune cell recruitment [3]. Clinically, eicosanoids have been used as markers of disease severity and subtype. For example, urinary LTE4 is associated with more severe disease and type 2 airway inflammation. EVs isolated from BALF of healthy controls and mild asthmatic patients were shown to contain biologically active enzymes for LT biogenesis, [4] but the abundance and significance of the eicosanoid biosynthesis machinery in EVs from severe asthmatics has not been investigated. To address these questions, particularly during biologics treatment, this project aims to produce pilot data for further grant applications through the isolation and analysis of EVs from a cohort of severe asthmatics receiving Mepolizumab or Dupilumab biologics therapy as part of the Biocross study [5].