Asthma models

Asthma affects around 5.4 million people in the UK and 300 million people globally. A number of species including mice, rats, guinea pigs, dogs and non-human primates are used to study asthma and develop new drugs. The majority of these are rodents and are used to explore basic mechanisms of asthma and in early drug discovery/target identification. Few new drugs have made it to the market in the last 50 years. The failure to translate promising drug candidates into safe and effective asthma treatments has led to questions about the utility of current animal models of asthma and demand for more predictive models and tools based on the latest technologies.

We have developed a broad programme of work to develop alternative approaches to replace the use of animals and provide a better understanding of human asthma. We are focusing on:

• Human tissue and tissue engineering approaches
• Using non-mammalian model systems
• Applying mathematical modelling

This work is supported by an expert working group from industry and academia. We also fund research on applying the 3Rs to asthma models through our research funding schemes.

Human tissues and tissue engineering

The use of human tissue for asthma research could reduce reliance on animal models. Working with Asthma UK, the UK Respiratory Research Collaborative and the UK Human Tissue Authority we have surveyed the UK asthma research community to better understand the extent of human tissue use and the potential barriers to use.

The survey results are available to download, along with an analysis of the findings.

A Chest Clinic article published in Thorax describes the findings of the survey.

In 2016 we invested £400k in an infrastructure award to support the development of a process to provide fully ethically consented, post-mortem human normal and diseased lung tissue to the UK scientific community thereby reducing the need for animal tissue. The award is unique in that it includes a strategic partnership with NHS Blood and Transplant Tissue and Eye Services, the organisation responsible for coordinating, collecting, banking and providing tissue for transplant within the NHS. This partnership could truly transform access to human tissue for research purposes and although the initial focus is on asthma, the principles developed during this award will extend to other disease areas.

Using non-mammalian model systems

The use of non-mammalian models (C. elegans, Drosophila, Dictyostelium discoideum and zebrafish) in respiratory disease research is almost non-existent. They have, however, been used to understand the molecular mechanisms of diseases in other organ systems, suggesting that they may be useful alternatives for asthma research. Working with the British Thoracic Society Difficult Asthma Network we have hosted a workshop to explore the feasibility of using non-mammalian models to provide a pathways approach for studying severe asthma.

The output of the workshop also led to a strategic call where we invested £0.5 million in 2014, and made four awards:

• Developing a non-animal model system to investigate bitter tastants as new treatments for asthma
  Professor Robin Williams, Royal Holloway, University of London
• A non-mammalian model to study innate immune modulation of airways remodelling in asthma
  Professor Stephen Renshaw, University of Sheffield
• Use of Drosophila models to explore the function of asthma susceptibility genes
  Professor Donna Davies, University of Southampton
• Developing a model for the study of respiratory inflammation in the zebrafish
  Professor Margaret Dallman, Imperial College London

Applying mathematical modelling

We have provided opportunities for the asthma community to engage with mathematicians in developing new mathematical models to deliver new insights to improve understanding of the disease. These models offer new tools to better analyse existing data and inform future experimental approaches with reduced reliance on animal models.

Specific activities have focused on modelling:

• Airway smooth muscle turnover in asthma.
• Steroid responsiveness in severe asthma and COPD.
• The regulation of immunoglobulin class switching to IgE and IgG in human B cells.

Research funding

We have invested approximately £1.5 million in grants to develop human tissue models of the normal and asthmatic lungs which bridge the gap between traditional cell cultures and animal or human studies. Professor Donna Davies (University of Southampton) and Dr Felicity Rose (University of Nottingham) were both awarded strategic funding to develop microfluidic devices to better understand the dynamic interplay between cells in asthmatic airways; and to examine how environmental factors (e.g. tobacco smoke, air pollution, drugs and other chemicals, diet, and infection) interact with asthma susceptibility genes. These are key features of the human condition which are not adequately replicated in current animal models. Professor Davies’ work builds on previous NC3Rs-funded research to develop a tissue engineered model of the asthmatic airway.

We also awarded a David Sainsbury fellowship to Dr Amanda Tatler (University of Nottingham) to integrate primary human tissue studies with mouse lung slice models and state of the art in vivo imaging. This will improve understanding of the biochemical mechanisms leading to structural changes in the airways of patients with severe asthma, whilst minimising animal use and improving the welfare of those still required.

We have funded research beyond the asthma field to other human and animal respiratory diseases, including pulmonary fibrosis, influenza, pulmonary embolism and tuberculosis.