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Improving treatment options

For around five per cent of people with asthma, current treatments don't work. And for others, they may not be as effective as we would like, or they may cause side effects or be inconvenient to take.

This is why one of the core areas of work within the Centre is improving treatment options for people with asthma.

This research includes: research into immuno therapy to better understand who it may work for, and how we can make it better; using our understanding of viruses from other areas of work within the Centre to develop anti-viral medications that could help people with asthma when they catch a cold or the 'flu; understanding how vitamin D could play a role in improving our immune system, and whether increasing this vitamin could help people; developing treatments to stop airways from closing up when irritated; and other areas of research to work towards new treatments for people with asthma.

 

See the Centre structure for the full list of researchers supporting each research theme.

 

Anti-viral strategies

Johnston will collaborate with Bristol Myers Squibb to develop inhaled interferon-λ (lambda) as a novel therapy for virus-induced asthma exacerbations. Edwards will develop novel macrolides with enhanced anti-viral activity and no anti-bacterial activity, to treat virus-induced airway disease without encouraging development of anti-microbial resistance.

Johnston will work to develop broadly protective cross-serotype anti-rhinovirus vaccines. Openshaw will collaborate with several companies to develop novel vaccines against RSV, and test vaccines in the human respiratory syncytial virus (RSV) challenge model. Solari and Johnston plan to develop two novel anti-rhinovirus approaches via their proposed Imperial spin-out company ViricX Ltd.

 

Allergen Immunotherapy

Durham, Till and Shamji will explore alternative allergen immunotherapy approaches to discover more effective, convenient and safe curative therapies. They will run a trial that compares subcutaneous and sublingual routes head-to-head, with potential for major impact on clinical practice of immunotherapy and a unique opportunity to study antigen-specific tolerance to inform novel therapeutic pathways and biomarkers that predict responders/non-responders to treatment. In another trial Till will study short course intradermal immunotherapy for hay fever. In industrial collaborations Durham and Shamji will study the impact of combining novel adjuvants with conventional subcutaneous immunotherapy to improve efficacy and safety. These include combinations of allergen with strategies against the IL-4 pathway, and with novel immunomodulators that induce immune deviation from Th2 to Th1 responses and the induction of Tregs. Durham and Shamji have set up a long-term placebo-controlled trial of sublingual immunotherapy to explore T cell receptor and B cell antibody repertoires before/after treatment. Historical safety concerns preclude use of subcutaneous immunotherapy for asthma, although house dust mite tablet immunotherapy is licensed for rhinitis and asthma in Europe. Till and Durham plan the first UK in-depth clinical study of sublingual house dust mite immunotherapy in asthma, focusing on local bronchial immune and inflammatory responses.

 

Ion sensing channels and the control of cough, airway hyperresponsiveness, airway inflammation and bronchospasm

Certain families of ion channels (called transient receptor potential channels) are key regulators of airway afferent (sensory) nerves, responding to common asthma triggers. Non-atopic asthma patients are frequently treatment-resistant, and may possess a neuronal hyperresponsiveness phenotype. Belvisi will investigate this in translational pre-clinical models; concepts validated in pre-clinical in vivo models and in cases where clinic-ready assets are available will be tested in a clinical experimental setting.

Calcilytics target a novel molecular target CaSR upstream from the targets of most current therapies, and may prove effective in difficult-to-treat and steroid-resistant asthma. Ward and Corrigan will develop their findings to facilitate translation to a phase 2 trial within 4-5 years, including 1) extension of pre-clinical studies to determine potential steroid-sparing actions in chronic severe, steroid-resistant asthma models; 2) parallel studies to establish most appropriate calcilytics for both efficacy in asthma and formulation for inhaled delivery; 3) in-licensing of lead compound(s) followed by Phase 1b trials. Applications for funding are in progress, with a King’s College London/Cardiff University spin out to facilitate translation to man.

Page will investigate the bifunctional anti-inflammatory and bronchodilator activity drug RPL 554 (a dual PDE3/4 inhibitor), using animal models of asthma, and human systems. Page aims to advance into clinical development novel peptides isolated from a TB mycobacteria-derived chaperonin that has extraordinary potency for disease modification in allergic models.

 

Vitamin D

Vitamin D deficiency is highly prevalent globally and is associated with increased incidence, severity and control of asthma. Hawrylowicz, with Lavender will study the biological mechanisms underlying the steroid-enhancing properties of vitamin D in asthma using isolated peripheral blood populations (T cells, APC-enriched from steroid resistant and sensitive asthma patients pre/post calcitriol and/or prednisolone) available from their completed trial. Preliminary findings highlight significant differences in antimicrobial mediators, Th17-family cytokines and gender, which are the focus of future work. Griffiths, Corrigan and Hawrylowicz plan to compare the steroid-enhancing properties of vitamin D3 supplementation versus treatment with pharmacological 1,25-dihydroxyvitamin D3, in severe asthma.

Mechanisms by which vitamin D promotes respiratory health will be studied using vitamin D-treated airway and peripheral blood cells (Hawrylowicz, with Lavender, Hansel, Corrigan), and transcriptional gene expression arrays. Pathways/mediators of interest will be validated in samples from clinically well-characterised patients, individuals of known vitamin D status, as well as pre/post steroid and/or vitamin D treatment of patients. The serine protease inhibitor alpa-1-antitrypsin is highly upregulated by vitamin D, and Gooptu, with Hawrylowicz, will study how misfolding and secretory deficiency of pathological variants of alpa-1-antitrypsin causes aberrant behaviour of immune cells (monocytes/macrophages, lymphocytes), using subcellular proteomics. Hawrylowicz with Kelly will further test the hypothesis that the immunoregulatory activities of vitamin D counteract the detrimental effects of urban particulate matter on asthma relevant immune functions; and compare the immunoregulatory activities of restoration of vitamin D sufficiency following supplementation versus UVB irradiation. Griffiths, Bush and Grigg, in a collaborative programme with the Asthma UK Centre for Applied Research will determine the translational clinical impact of vitamin D supplementation through two meta-analyses of published supplementation trials, and complete trials of supplementation in children with pre-school wheeze.

 

Anti IgE, small molecular inhibitors

Sutton, Gould, Beavil, McDonnell will study IgE biology in order to understand the mechanisms of IgE-mediated disease and identify new targets with potential to transform the lives of people with asthma through new, affordable and more widely applicable treatment(s). Their structural studies of complexes between IgE-Fc and anti-IgE antibody Fabs will investigate their mode of action and the intrinsic dynamics of IgE. Structural, biophysical, mutagenesis and functional studies of the interaction between IgE and CD23 will aim to elucidate the mechanism of IgE regulation. They will investigate regulation of the IgE B cell receptor, its signalling mechanism, and develop biomarkers in the pathway of B cell development from IgM to IgE. In vivo trafficking of IgE, and the engineering of glycosylation and knocking out of receptor binding sites to investigate this process, will also be pursued.

Corrigan will advance studies of omalizumab in non-atopic asthma into more extensive clinical trials; and with Gould will study the structural basis of action of this anti-IgE based strategy. Staphylococcus aureus enterotoxins may play a role in chronic allergic disease; the role of enterotoxin-specific “superantibodies”, and the potential to develop therapeutic blocking antibodies will be studied. Their work with allergens will build upon their discovery of “superallergen” activity in a grass pollen allergen, and will involve peanut allergens to identify dominant epitopes and markers in the development of allergic sensitivity or tolerance (with Lack, Santos). Studies of IgG4 blocking antibodies in food sensitized children and in immunotherapy studies will investigate whether epitope specificity, bi-specificity and/or their non-inflammatory receptor-mediated activities are key to their beneficial blocking activity. This fundamental work has the potential to lead to the development of permanently disease-modifying therapeutic options.