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Brief overview: The incidence of asthma in the UK adults is 5-10%, the highest in the developed world. Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death, as well as one of the most common causes of acute hospital admissions, contributing significantly to the annual winter acute bed squeeze. Annual healthcare costs attributable to asthma and COPD are around £2 billion.  Unlike many other chronic health conditions, morbidity and mortality rates have not improved over the last 10 years, and there have been few genuine therapeutic advances. Current investment in clinical and basic research in lung and airway diseases is inadequate and strikingly disproportionate to the high levels of morbidity and mortality, representing only 2% of total UK research funding. Progress in this area is an important priority for British pharmaceutical companies as they dominate the market for asthma and COPD treatments.

Strengths in basic/discovery science relevant to the proposed Research Theme: The Oxford BRC has made a significant investment in academic respiratory medicine to build capacity in early translational research. The team have led research into the stratification of airway disease based on biomarkers of airway inflammation rather than traditional measures of symptoms and lung function. This approach led to a proof-of-concept study showing mepolizumab (anti-IL-5) provides clinical benefit specifically in severe eosinophilic airway disease, the first entirely new class of treatment for 15 years. Furthermore, blood eosinophil count was identified as a biomarker associated with risk of attacks of airway disease and likely response to corticosteroid treatment. Biomarker-directed management is now recommended by guideline groups and is entering mainstream clinical medicine. It has led to a clearer focus on additional tractable mechanisms and has shown the potential gains from better stratification.

Aims and Strategy for translation into benefits for patients and the health system

Sub-theme 1. Basic mechanisms in inflammarory arway disease: Patients with severe eosinophilic asthma often have a marked response to anti-IL-5 and anti-IL-13. This establishes a clear link between the disease manifestation and a defined pathophysiological process involving abnormal airway production of the type 2 cytokines IL-5 and 13. We will, in collaboration with Atopix, test the hypothesis that this dysregulated process involves a novel and tractable pathway involving type 2 innate lymphoid cells, PGD2 and the CRTH2 receptor.  Our identification of eosinophilic disease has led to a sharper focus on patients with non-eosinophilic patterns of airway inflammation. Haemophilus Influenzae- associated  neutrophilic airway inflammation as the most important potential treatable aspect in patients with this pattern of disease. We will develop novel and specific methods to identify it; determine whether it is partly a consequence of high dose inhaled corticosteroid treatment (the standard of care in patients with severe airways disease); and identify better, non-antimicrobial methods to treat it. Finally, we have discovered that human epithelial cell lines profoundly inhibit histamine release by mast cells and IL-13 production by Th2 cells. Initial characterization suggests that a non-prostanoid lipid mediator is responsible for this effect.  Inhibition by airway epithelial cells cultured from patients with asthma is significantly less than that from healthy controls. We will identify the mediator involved and test the hypothesis that deficiency in airway epithelial inhibition is a key driving factor in the pathogenesis of asthma.

Subtheme 2. New methods for stratification: We are uniquely placed through previous BRC investment  to make significant progress in this area. Two major, highly novel, technologies have been developed. The opportunity that arises now over the period of the next BRC is to integrate these technologies so as to provide completely unparalleled approaches to stratification in lung disease. Our prior experience in immunological stratification means we are in a strong position to do this. The technologies are: 1) Hyperpolarised xenon (HPX) imaging (Prof Gleeson, Dr Kyle Pattinson). The HPX imaging group working with Computational Biologists and Physicists has developed novel methods for image data analysis. These enable analysis of: ventilation, airways and areas of gas exchange using apparent diffusion coefficient ADC imaging, and the alveolar epithelium and pulmonary interstitium  using dissolved phase imaging. The use of xenon to provide detail on the sites of disease and their relative contributions to the clinical phenotype, alongside its detection of early disease response will enable more targeted and cost effective therapies. 2) Physiological phenotyping (Prof Robbins, Prof Whiteley, Prof Ritchie). We have pioneered the use of in-airway molecular flow sensing using the method of laser absorption spectroscopy and have developed a low order model of the lung’s heterogeneity. Combined, these now give us the ability to measure various characteristics of the lung which have never before been possible.These techniques will now be investigated in the following situations: patients studied during and after an exacerbation; patients undergoing major complex surgery; and patients with proven burnt out, non-progressive airflow limitation. Our goal will be to determine whether

Theme 3. Experimental medicine network (Najib Rahman): We plan to increase capacity in interventional trials in BRC3. Our ambition is to build on our successes and carry out more early phase trials in highly characterised patients using reliable surrogate biological measures, enabling industry to make early and robust development plans. Differential outcomes to shared interventions will also be investigated to improve understanding of disease mechanisms, for example anti-IL-23 (GI/skin/musculoskeletal) and CRTH2 antagonists (respiratory/skin).