ReviewKeynoteAnimal models of asthma: value, limitations and opportunities for alternative approaches
Introduction
The Global Initiative in Asthma (2009) defines asthma as ‘…a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. The chronic inflammation is associated with airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread, but variable, airflow obstruction within the lung that is often reversible either spontaneously or with treatment’ [1]. It is considered one of the most common respiratory diseases worldwide, with almost 5.4 million people in the UK (http://www.asthma.org.uk) and 300 million people globally currently receiving treatment for the disease. The economic burden this represents is significant, costing the UK National Health Service £996 million per year, with global economic costs exceeding those of TB and HIV/AIDS combined (https://apps.who.int/inf-fs/en/fact206.html). With prevalence rates increasing globally by 50% every decade [2], these numbers and the global economic burden of asthma are set to keep rising.
The past 20 years have seen considerable advances in understanding of the pathological basis of asthma at the cellular, molecular and genetic levels; however, the fundamental causes of the disease and the reasons for increased prevalence rates remain unclear. What was once considered a single disease is now recognised as a complex and heterogeneous syndrome made up of a collection of sub-phenotypes (e.g. viral-induced, allergic, non-allergic, intrinsic, extrinsic, occupational, persistent, seasonal, exercise-induced, nocturnal and steroid-resistant) with differing immunology, pathology, clinical expression, response to treatments and long-term outcomes [3]. The severity of the disease can also be affected by the patient's age, genetic background and environmental factors. More recently, cluster analysis applied to asthma of varying severity has led to further disease substratification 4, 5, 6.
Asthma has traditionally been considered an atopic disease, in which allergen sensitisation and continued exposure result in the clinical signs of the disease: airway inflammation, bronchial hyperresponsiveness and reversible airflow obstruction. However, atopy affects half the adult population, yet most do not develop asthma [7], thus signifying that other factors must have a role in the development and progression of the disease. Recent epidemiological data suggest that environmental and lifestyle factors (e.g. pollution, exposure to tobacco smoke, diet and infections) have a more prominent role in the aetiology of asthma than was previously thought 8, 9, 10, 11. This is supported by the increased prevalence of the disease observed in low and middle income countries as they become more westernised 12, 13, 14, suggesting that environmental factors related to ‘modern lifestyle’ are driving changes in disease prevalence. The realisation that factors other than atopy are implicit in asthma has significant implications for disease modelling and drug development.
Despite better understanding of the pathology and pathophysiology of asthma (reviewed in 15, 16), there are still considerable gaps in knowledge that have made it difficult to develop entirely new classes of therapeutic agent to treat the disease. The extent of the problem was summed up in a 2008 Lancet editorial: ‘Progress in understanding asthma and its underlying mechanisms is slow; treatment can be difficult and response unpredictable; and prevention or cure is still a pipedream. Asthma, one of the most important chronic diseases, remains a genuine mystery’ [17].
Most patients with asthma have mild to moderate forms of the disease, and are well controlled with the mainstay of available therapy: anti-inflammatory drugs especially inhaled glucocorticosteroids, leukotriene modifiers and bronchodilators, such as the short and long-acting β2-adrenoceptor-selective agonists (β2-agonists). Nevertheless, 5–10% of the asthma population experience more severe forms of the disease, which remain symptomatic despite high doses of conventional inhaled and oral anti-inflammatory drugs [18]. This represents a relatively small subset of the total population of asthma sufferers, but severe asthmatics account for almost half of the total healthcare costs associated with the disease, and the majority of asthma-related deaths 19, 20. Since the introduction of β2-agonists (1969) and corticosteroids (1974) for the treatment of asthma, therapies directed to only two new asthma targets [cysteinyl leukotrienes and immunoglobulin E (IgE)] have been identified that have translated into clinical use, both of which have restricted indications. The removal from the market of xanthines (dose-limiting adverse effects) and chromones (efficacy) as asthma therapies during this time emphasises the need for new therapeutics that provide more than symptomatic relief for patients with asthma.
This poses considerable challenges for the asthma research community that need to be overcome if safe and effective new therapies that go beyond improving the profile of those drugs that already exist, are to be developed.
Section snippets
Unmet medical need
Despite substantial effort, asthma remains an area of considerable unmet medical need [21]. The UK research councils and research charities invest in excess of £64 million in respiratory research each year, of which a significant proportion is spent on asthma (http://www.ukti.gov.uk/download/108059_100608/Asthma%20and%20COPD%20research.html). This investment has resulted in greater insight into disease mechanisms and progression, but as yet has translated into only a few new effective
Innovation in model development
The lack of translation from preclinical to clinical studies of new asthma compounds and biologics is of particular importance to the severe and/or therapy-resistant asthma group, where new effective therapies for improved asthma control are crucial. The challenge is to develop models that more accurately recapitulate the asthmatic airway for mechanistic studies, target identification and validation, and efficacy and safety testing. Addressing this will require a multidisciplinary,
Conclusions
Asthma is a complex, heterogeneous disease, much of the pathophysiology of which remains unknown despite considerable investigation over the past century. This is reflected in the number of new therapies that have reached the market during the past 50 years, and the complete lack of any drug that can provide long-lasting remission from symptoms or a cure. Many novel compounds directed at new and existing targets have entered human trials on the basis of positive preclinical animal data and
Conflicts of interest
AMH is employed by the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs). The authors state no other conflicts of interest.
Acknowledgements
The National Centre for the Replacement, Refinement and Reduction of Animals in Research expresses its sincere thanks to all speakers and delegates at the workshop. Particular thanks to Stephen Holgate (University of Southampton) for chairing the workshop and to Donna Davies (University of Southampton) for her assistance in putting the workshop together. The authors thank Vicky Robinson and Kathryn Chapman (NC3Rs) for help developing the concepts in this review.
Dr Anthony Holmes is a Programme Manager at the UK NC3Rs with responsibility for the work of the Centre at the interface of academia and industry. He works with the scientific community to develop new research tools and approaches that minimise animal use and to translate these across sectors to address common problems associated with animal models. He obtained his PhD from Cambridge University in 2004 in molecular cell biology and went on to do post-doctoral research at the Babraham Institute
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Dr Anthony Holmes is a Programme Manager at the UK NC3Rs with responsibility for the work of the Centre at the interface of academia and industry. He works with the scientific community to develop new research tools and approaches that minimise animal use and to translate these across sectors to address common problems associated with animal models. He obtained his PhD from Cambridge University in 2004 in molecular cell biology and went on to do post-doctoral research at the Babraham Institute in Cambridge, studying the role of calcium signalling in the development and death of hippocampal neurons.
Dr Roberto Solari is a cell biologist/immunologist and heads the Allergic Inflammation Discovery Performance Unit at GlaxoSmithKline. He obtained his PhD from Nottingham University in 1981 in Mucosal Immunology and went on to do post-doctoral research in Lausanne and Liverpool on the transepithelial transport of immunoglobulins. Since then, he has worked in the both pharmaceutical and biotechnology industries and was recently the CEO of Medical Research Council Technology (MRCT). His current role spans the discovery and validation of new drug targets through to proof-of-concept studies in humans.
Professor Stephen Holgate is Medical Research Council Clinical Professor of Immunopharmacology at the School of Medicine, Southampton, UK. After completing his medical training in London, he spent 2 years at Harvard Medical School to acquire skills in allergic disease mechanisms. On returning to Southampton in 1980, he established a research group focused on the mechanisms of asthma. He has used many approaches to study this disease, including epidemiology, genetics, pathology and immunology, pharmacology and experimental medicine. This research has informed guidelines on asthma management and has identified and validated novel therapeutic targets. His work has resulted in over 920 peer-reviewed publications.