MICA: Investigation into the mechanisms that drive cough in health and disease

Lead Research Organisation: Imperial College London
Department Name: National Heart and Lung Institute

Abstract

Coughing is a reflex action started by stimulation of sensory nerves in the lining of the respiratory passages which are the tubes we use to breathe. When a person coughs, there is a short intake of breath and the larynx (the voice box) closes momentarily. The abdominal and chest muscles used for breathing contract, which in turn increases the pressure needed to drive air out the lungs when the larynx re-opens. Cough is a reflex mechanism that helps clear foreign material and secretions from the airways. However, it may also be the first and most persistent symptom of many inflammatory airways diseases, including asthma, COPD, post viral infections, pulmonary fibrosis, bronchiectasis and cough can also be present when a cause cannot be identified. In these situations cough may present as a debilitating symptom and can adversely affect the quality of a patient's life in multiple ways for example by causing exhaustion, self consciousness, insomnia, horseness, musculoskeletal pain, sweating, urinary incontinence and in severe cases patients can break ribs through excessive coughing. Despite these facts, cough is a largely ignored research area and novel anti-tussive agents are lacking. Treatment options are limited and recent meta-analysis concluded that over the counter (OTC) remedies are ineffective plus there is increasing concern about their use in children. Understanding the mechanisms involved in initiating cough will uncover novel therapeutic targets which will impact significantly on patient quality of life and a reduction in associated healthcare costs. The cough reflex is initiated by activation of airway sensory afferent nerves. We hypothesize that agents that inhibit sensory nerve activity will also inhibit the cough reflex. In this proposal we describe pre-clinical data from our laboratory, genetic association data in respiratory disease from the scientific literature and our data from clinical studies implicating certain proteins or ion channels called Transient Receptor Potential (TRP) channels as 'master controllers' of the cough reflex. There are a number of these channels that are expressed in airway sensory nerves and so in this project we will be evaluating their importance using pharmacology (tool compounds that block these targets) or genetically modified mice (which are bred without each of the TRP channels) in isolated nerve experiments (using animal and human tissue) and in animal models of cough. We will investigate their role in the cough response under normal conditions and then in models which are configured to resemble asthma related cough, post-viral cough and that associated with chronic obstructive pulmonary disease (COPD). Finally we will evaluate the role of these channels in patients that demonstrate chronic cough of different aeitiologies (eg. Asthma, COPD, smokers, post-viral, and chronic cough of no known cause).The aim of these studies is to identify possible novel drug targets which can be used as starting points for drug discovery programmes to find novel cough therapies to treat this debilitating symptom. Another output from this grant that we hope to achieve is to establish if the various animal model systems we use to investigate this hypothesis actually represent the human cough and that the systems used to test therapeutics are predictive of anti-tussive activity in patients.

Technical Summary

The goal of this collaboration would be to provide insight into the mechanisms that drive cough in health and disease and to understand the similarities and differences in exaggerated cough that is present in specific patient groups. This would provide novel target validation data and inform a translational and predictive screening pathway from high throughput assays to clinical trial design.

(1) Investigate which endogenous mediators (produced in inflammatory diseases) and environmental irritants are able to elicit cough, which fibre type they activate and evaluate their mechanism of action.
(2) Evaluate the utility of selective ligands in cell lines overexpressing the corresponding target protein. Establish which TRP channels are involved in the activation of airway sensory nerves and evoke a cough reflex under 'normal' conditions using selective ligands and vagal tissue from gene deleted animals (eg. TRPV1, TRPV4, TRPA1). If Ad and C-fibre afferents are involved preferentially evaluate the role of NaV channels (in particular NaV1.7). We will perform pharmacokinetic/pharmacodynamic (PK/PD) modelling integrating compound exposure information with in vitro and in vivo data which will aid in the interpretation of the data sets.
(3) Investigate changes in the function and phenotype of airway specific afferents and cough in disease models (eg. allergen, sensitised and challenged guinea-pigs; CS exposed guinea-pigs) as previously described by our lab and others using selective ligands. Develop a model of post viral cough (mirroring the most appropriate clinical phenotype eg. H1N1, rhinovirus).
(4) Perform clinical studies using ion channel specific tussive stimuli (eg. TRPV1, capsaicin; TRPA1, cinnamaldehyde; TRPV4, investigate appropriate stimuli, our pre-clinical studies suggest hypertonic saline may partially activate through TRPV4) across the relevant patient groups (normal, non-smokers, smokers, asthmatics, COPD, idiopathic coughers).

Planned Impact

Who will benefit from this research and how?

Researchers: Sensory neurobiologists, respiratory physiologists and pharmacologists and respiratory clinicians will benefit from the proposed project through interaction with the PI's and researchers involved in this project. Interactions at meetings and publications in peer review journals will inform research in other laboratories.

Students (basic science and medical): will learn from the wide range of scientists involved in this project who have basic science, clinical and industrial experience. In particular, at Imperial scientists will be able to learn from top class scientists involved in doing complex electrophysiology and in vivo models.The lack of in vivo physiologists and pharmacologists is still apparent in spite of recent initiatives and so it is still essential that those people that possess these skills train young researchers so as to strengthen the UK in vivo skills base. Birrell and Belvisi train their own staff in these methodologies and together with the named scientists (Eric Dubuis, Sarah Maher) also run practical modules in which they are involved in 'hands on' teaching (BSc, MRes, Phd students) thereby contributing to the training of youngsters in the UK and increasing the research capacity in this area. Outside the UK the group always takes holiday experience placements and visiting fellows from across the globe that will benefit from the expertise and skills they can learn. Outreach events have also been hosted.

Patients:Treatment options are limited and recent meta-analysis concluded that over the counter (OTC) remedies are ineffective plus there is increasing concern about their use in children. Understanding the mechanisms involved in initiating cough will uncover novel therapeutic targets which will impact significantly on patient quality of life and a reduction in associated healthcare costs.

Government and NHS funding bodies: Cough is the most frequent reason for consultation with a family doctor, or with a general or respiratory physician. In the UK, over £93 million/year is spent on over the counter anti-tussives of questionable efficacy Cough has a major impact on the UK economy with absenteeism from work, reduced productivity, physician consultations and prescription costs estimated at £1 billion annually. Chronic cough is often associated with an underlying inflammatory condition (eg. lung infections, asthma, COPD, pulmonary fibrosis, bronchiectasis, lung cancer) and can also be iodiopathic in nature with no known cause. Despite these facts, cough is a largely ignored research area and novel anti-tussive agents are lacking.

The European Respiratory Society (ERS) published guidelines on the management of cough. Belvisi and Smith were on this taskforce and Smith is also a member of the American College of Chest Physicians taskforce. The aim was to provide consensus regarding the diagnosis and treatment of cough in both adults and children. In 2004, the ERS produced a practical document, which provides helpful guidance to researchers, clinicians, the pharmaceutical industry and regulatory authorities. This document included recommendations on the following key elements: 1) safe standardised methods of inhalation cough challenge; 2) reliable, reproducible and relevant clinical cough recording and analysis; 3) clinical assessment of cough-related quality of life; 4) appropriate animal models in which to evaluate novel cough treatments; and 5) areas for future research. We believe that this document helped to improved patient care, enhance the quality of cough research and ultimately assist in the development of effective new therapies. Belvisi and Smith remain on these committees and in a key position to influence the field and inform on the cutting edge research they are performing whithin their laboratories. (Eur Respir J. 2004 Sep;24(3):481-92; Eur Respir J. 2007 Jun;29(6):1256-76).

Publications

10 25 50
 
Description Chair of BTS Cough SAG
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description House of Commons Select Committee inquiry into women in STEM careers
Geographic Reach National 
Policy Influence Type Gave evidence to a government review
 
Description Membership of ERS taskforce for update of Cough Guidelines
Geographic Reach Europe 
Policy Influence Type Membership of a guideline committee
 
Description NC3Rs Asthma Advisory Group
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description MRC Industrial CASE Studentship 2015
Amount £214,600 (GBP)
Funding ID MR/N018567/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2016 
End 09/2020
 
Description NC3Rs Infrastructure grant NC/P001041/1 (01/10/2016-30/09/2019) Human Tissue Models for Lung Disease
Amount £497,719 (GBP)
Funding ID NC/P001041/1 
Organisation National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) 
Sector Private
Country United Kingdom
Start 09/2016 
End 08/2019
 
Description NIHR Clinical Research Facility Funding
Amount £12,500,000 (GBP)
Organisation Sheffield Teaching Hospitals NHS Foundation Trust 
Department NIHR Clinical Research Facility
Sector Hospitals
Country United Kingdom
Start 04/2017 
End 03/2022
 
Description NIHR Manchester Biomedical Research Centre Award.
Amount £28,500,000 (GBP)
Organisation National Institute for Health Research 
Department NIHR Biomedical Research Centre
Sector Academic/University
Country United Kingdom
Start 04/2017 
End 03/2022
 
Description RESPIRE3 Marie Sklodowska-Curie fellowship (Global Fellowship)
Amount € 242,700 (EUR)
Organisation European Respiratory Society (ERS) 
Sector Charity/Non Profit
Country European Union (EU)
Start 12/2017 
End 12/2020
 
Description Wellcome Investigator Award in Science
Amount £2,871,430 (GBP)
Funding ID 207504/B/17/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2018 
End 01/2023
 
Title Pharmacodynamic modelling of cough challenge responses 
Description Novel cough challenge methodology that uses pharmacodynamic modelling to define the relationships between tussive agent and concentration and cough responses. Suggests novel endpoint Emax better discriminates health from disease. 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2015 
Provided To Others? Yes  
Impact This cough challenge method better differentiates healthy patients from those with chronic cough, has been utilised in two clinical trials of novel therapies and has been used to demonstrate different phenotypes of neuronal function in asthma patients. 
 
Title RADAR cough recording database 
Description Ethically approved database of cough recordings (anonymised) for the development of cough detection and analysis algorithms. Allows sharing of data with academic and commercial researchers in the field. 
Type Of Material Database/Collection of data 
Year Produced 2016 
Provided To Others? Yes  
Impact No impacts as yet 
 
Description Afferent Pharma 
Organisation Afferent Pharmaceuticals Inc.
Country United States 
Sector Private 
PI Contribution We performed all the research experiments and developed the hypotheses.
Collaborator Contribution Synthesised molecule for proof of concept pre-clinical studies
Impact Joint publication (Bonvini et al., 2016-in publication output list)
Start Year 2014
 
Description AstraZeneca Collaboration 
Organisation AstraZeneca
Department Respiratory, Inflammation and Autoimmunity
Country Sweden 
Sector Private 
PI Contribution Provision of expertise and intellectual input into targets for novel cough therapies, clinical trial design and endpoints. Completion of two RCTs of AZ drug (lesogaberan) as part of AZ/MRC funded mechanisms of disease project grant. Planned provision of clinical samples from chronic cough patients for biomarker analysis.
Collaborator Contribution Match drug (lesogaberan) and placebo and knowledge of drug safety/tolerability. Expertise and cutting edge technology for biomarker measurement and expertise in the development of devices for close-to-patient biomarker measurement.
Impact Completion of two randomised controlled trials, manuscripts in progress.
Start Year 2017
 
Description Collaboration with experts in Transient receptor potential channels 
Organisation University of Leuven
Country Belgium 
Sector Academic/University 
PI Contribution Assessing the role of novel ion channels in respiratory neurons that may be involved in mediating reflex events.
Collaborator Contribution Provision of expertise and novel chemistry
Impact Generation of data that will eventually lead to a joint publication
Start Year 2014
 
Description Dr Kyle Pattinson, Functional Magnetic Resonance Imaging 
Organisation University of Oxford
Department Oxford Centre for Functional MRI of the Brain (FMRIB)
Country United Kingdom 
Sector Academic/University 
PI Contribution Expertise on cough challenge and neurobiology of cough
Collaborator Contribution Expertise in fMRI studies, collaborator on study design for resting state fMRI studies.
Impact Collaborator on Wellcome Trust for Investigator Award, awarded Oct 17 £2.8M. Multi-disciplinary between Respiratory Medicine, Anaesthetics, and MR physicists.
Start Year 2017
 
Description MICA-Almirall-Manchester University 
Organisation Almirall
Country Spain 
Sector Private 
PI Contribution All outlined in the MICA form
Collaborator Contribution All outlined in the MICA form
Impact Multidiciplinary collaborating bringing together Imperial (pre-clinical), Almirall (Industry) and Manchester University (Clinical)
Start Year 2013
 
Description Merck Inc 
Organisation Merck
Country Germany 
Sector Private 
PI Contribution Advice on clinical trial design and cough monitoring in clinical trials in the development of a P2X3 antagonist, chief investigator and recruitment centre for phase 2b study.
Collaborator Contribution Funding of clinical trials towards marketing of a novel therapy for cough
Impact Abstract accepted for oral presentation at American Thoracic Society Meeting 2017
Start Year 2016
 
Description Neuronal Dysfunction in Asthma 
Organisation McMaster University
Country Canada 
Sector Academic/University 
PI Contribution Knowledge and expertise in cough challenge testing Funding of a Clinical fellow studying for a PhD
Collaborator Contribution Knowledge and expertise in allergen challenge techniques
Impact Two publications and James Trust BMA grant award. Third manuscript in preparation; data to be presented at ATS May 2018. Clinical fellow successfully completed PhD and in 2017 was award a European Respiratory Society Longterm Global Fellowship to fund salary for 3 years (2 years in McMaster and 1 year back in Manchester). Collaboration between experts in Respiratory Medicine (Allergy and Cough) with immunology and histopathology (neuronal imaging).
Start Year 2014
 
Description 'Body Experience' organised by Manchester Museum 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact We performed lung function testing and played cough sounds to children and their parents attending this event.
This provoked discussion about lung symptoms, health and research.

Have been invited to participate again next year.
Year(s) Of Engagement Activity 2014
 
Description Annual public engagement Event 'Combat my Cough' 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact A day event consisting of talks about clinical research, basic research (with collaborators attending from Imperial College London) and also talk by a patient with chronic cough. Also included workshops about clinical and research procedures to exchange knowledge and opinions with patients and a question and answer session.
Year(s) Of Engagement Activity 2013,2014,2015,2016,2017
URL https://www.combatmycough.com/events
 
Description Attended a Parlimentary links day (science & diversity) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Attended and discussed with policy makers

Contributed to the British Pharmacological Society response to the House of Commons select committtee inquiry into women in STEM careers
Year(s) Of Engagement Activity 2013
 
Description Cheltenham Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Attend by school children and the public. Increase awareness of medical science and the use of animals in research.

Asked to participate in other events
Year(s) Of Engagement Activity 2013
 
Description Combat my Cough 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact My team and I gave a series of presentations about our research. A specific question and answer session was held and much discussion with patients about their condition was provoked.

Increased patient interest and recruitment to studies.
Requests for further similar events.
Year(s) Of Engagement Activity 2014
URL http://www.combatmycough.com
 
Description Combat my cough website 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact Website describes our clinical service for patients with chronic cough and the research studies we perform.
Year(s) Of Engagement Activity 2015,2016,2017
URL https://www.combatmycough.com/
 
Description Patient Involvement (Manchester) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact Out clinical collaborators (MRC grant partners on this award) in Manchester hold an event each year to keep chronic cough patients up to date with the work they are doing in their clinic and through our research to find a cure for chronic cough. Combat my Cough is an opportunity to listen to and talk to the research team, but also for you to meet and talk to other sufferers with the condition.

http://www.combatmycough.com/#!events/c1k9b
Year(s) Of Engagement Activity 2015,2016
URL http://www.combatmycough.com/#!events/c1k9b
 
Description Press release about P2X3 study 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact A press release via NOCRI describing a phase two clinical trial of a novel cough therapy, on which I was chief investigator. Led to further press coverage, a TV interview and numerous enquiries through our website and email about clinical trial participation.
Year(s) Of Engagement Activity 2016