MICA - DEfining MechanIsms Shared across mulTI-organ FIbrosis to prevent the development of long-term multi-morbidity DEMISTIFI-Multi Morbidity

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

Abstract

Amended lay summary: Scarring ("fibrosis") of the internal organs occurs in many common diseases, including diabetes (scarring in the pancreas), high blood pressure (blood vessels), chronic kidney disease (kidney), cirrhosis (liver) and pulmonary fibrosis (lungs). Scarring of the internal organs can stop these organs working properly and causes about one third of all deaths world-wide. People can be affected by scarring in more than one organ.

Factors believed to contribute to scarring include smoking, alcohol, obesity and infections such as COVID-19. These external factors are known as "environmental" factors. There are also a number of genetic factors (known as genetic mutations or 'variants') that can run in families with people affected more likely to have scarring in different organs, at a younger age.

Genetic factors that cause scarring are often seen in short telomere syndrome, a form of accelerated aging, which leads to scarring throughout the body. In severe cases, this can start in childhood, with scarring affecting different parts of the body. It often starts with the bone marrow, causing severe anaemia, infections and bleeding, and later in the liver leading to cirrhosis or the lung leading to death.

Other people could have milder genetic problems that they may not know about. These might be quite common and cause scarring only in old age or if triggered by external (environmental) factors such as smoking, obesity or drinking too much alcohol. It is likely that both genetic and environmental/external risk factors cause scarring of different organs and may happen at different times.

If patterns of scarring can be identified when young, development of more extensive scarring, in multiple organs in later life, could be prevented. This could be done by identifying groups of people at risk of scarring and working out which specific treatments or medications will work best for each group. Having identified these groups of people, targeted therapies would be used to encourage people to change their lifestyle or to take the medicines that are most likely to be effective for each particular person.

The aim of our research is to identify patterns of scarring in different organs, which we have termed Fibrotic Multi-Morbidity (FMM). We will use new technology such as Magnetic Resonance Imaging (MRI) scans to measure the extent of scarring in different organs, in order to generate a "Fibrotic Multi-Morbidity" Score (i.e., to measure the severity of the scarring). This will enable us to ascertain the full extent of scarring, provide an early warning and detect the spread of scarring from one organ to another. We will map the genetic and environmental/external triggers of scarring in different organs and investigate the underlying biological causes of the scarring so that we can find the treatments to prevent or cure it. We suspect that many medications that are already in use could help prevent or treat scarring but before we can recommend them, we need to prove that these medicines work.

In this way, we hope to provide the right treatment to the right person to stop scarring from destroying the organ in which it is found and to prevent it spreading to other organs. These treatments could involve lifestyle changes, such as weight loss and exercise, and/or medications. We hope that by treating and preventing scarring- 'fibrosis', we may be able to help a lot of people stay healthy and live longer, healthier lives.

Technical Summary

Ammended Technical Summary: Organ fibrosis accounts for one third of all deaths world-wide. It is associated with aging and metabolic abnormalities that occur in response to many genetic and environmental factors. Understanding shared pathogenic mechanisms may identify clusters of disease that will respond to repurposing of available therapies. Common genetic, environmental, lifestyle and socioeconomic factors or biological pathways linking these clusters aren't readily recognised by conventional disease centred approaches. Focusing on the mechanistic basis of fibrosis offers a unique opportunity to recognise early disease, identify disrupted mechanisms and repurpose drugs which target the underlying pathological process.

Our vision is to identify clusters of multi-organ fibrotic diseases, referred to as Fibrotic Multi-Morbidity (FMM), with common pathogenic mechanisms that will benefit from shared management strategies, reducing the burden of treatment through therapeutic rationalisation, early identification of secondary organ involvement, and appropriate risk reduction strategies to increase the health-span of this group of patients.

We will achieve this vision by using Magnetic Resonance Imaging to identify clusters of FMM and measure total body fibrosis to generate a Fibrotic Multi Morbidity Score (FMMS) for use in observational and interventional clinical trials. We will analyse large longitudinal datasets such as UK Biobank and the Clinical Practice Research Datalink as well as in a range of deeply phenotyped organ specific cohorts to identify genetic risks and environmental factors that predispose to FMM, and associate these factors with important clinical outcomes such as disability and premature death.

Through understanding the clusters of Fibrotic Multi-Morbidity and mapping them to the mechanisms of available therapies, the DEMISTIFI consortium will aim to prevent the development of long term Fibrotic Multi-Morbidity.

Publications

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Massen G (2023) Response to: Consensus and agreements on the classification of fibrotic diseases in QJM: An International Journal of Medicine

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Massen GM (2023) Classifying the unclassifiable-a Delphi study to reach consensus on the fibrotic nature of diseases. in QJM : monthly journal of the Association of Physicians

 
Description Defining the anti-fibrotic mechanisms of prostacyclin drugs in pulmonary fibrosis
Amount £289,656 (GBP)
Funding ID MR/X001814/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 03/2023 
End 04/2026
 
Description Multi-Modal
Amount £1,000,000 (GBP)
Funding ID MR/W031469/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2022 
End 09/2025
 
Title DEMISTIFI datasets LUNG, LIVER, PANCREAS and INTESTINE 
Description LUNG, LIVER, PANCREAS and INTESTINE datasets have been added to the HDR Gateway 
Type Of Material Database/Collection of data 
Year Produced 2024 
Provided To Others? No  
Impact Some of the datasets that make up the DEMISTIFI dataset have lead to published outputs but the joint assessment is currently underway 
 
Title PROFILE Study database 
Description We have a collection of over 330 biological samples with matched clinical data from patients with incident IPF 
Type Of Material Database/Collection of data 
Year Produced 2013 
Provided To Others? Yes  
Impact First paper is under review at Lancet and further papers are planned. A number of lectures describing the PROFILE cohort have been delivered and two articles have cited the development of the PROFILE cohort. 
 
Description DEMISTIFI Consortium 
Organisation AstraZeneca
Department MedImmune
Country United Kingdom 
Sector Private 
PI Contribution I established the development of a multi-organ fibrosis consortium to try and prevent the development of multi morbidity.
Collaborator Contribution There are a number of partners involved in this consortium including genetic epidemiologist, MRI physicists, clinicians, fundamental biologists and data scientists as well as patient public representatives and also industry partners. These partners bring a wealth of expertise and resources to the collaboration.
Impact DEMISTIFI collaboration bid submitted.
Start Year 2020
 
Description DEMISTIFI Consortium 
Organisation Bristol-Myers Squibb
Country United States 
Sector Private 
PI Contribution I established the development of a multi-organ fibrosis consortium to try and prevent the development of multi morbidity.
Collaborator Contribution There are a number of partners involved in this consortium including genetic epidemiologist, MRI physicists, clinicians, fundamental biologists and data scientists as well as patient public representatives and also industry partners. These partners bring a wealth of expertise and resources to the collaboration.
Impact DEMISTIFI collaboration bid submitted.
Start Year 2020
 
Description DEMISTIFI Consortium 
Organisation Genentech, Inc
Country United States 
Sector Private 
PI Contribution I established the development of a multi-organ fibrosis consortium to try and prevent the development of multi morbidity.
Collaborator Contribution There are a number of partners involved in this consortium including genetic epidemiologist, MRI physicists, clinicians, fundamental biologists and data scientists as well as patient public representatives and also industry partners. These partners bring a wealth of expertise and resources to the collaboration.
Impact DEMISTIFI collaboration bid submitted.
Start Year 2020
 
Description DEMISTIFI Consortium 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution I established the development of a multi-organ fibrosis consortium to try and prevent the development of multi morbidity.
Collaborator Contribution There are a number of partners involved in this consortium including genetic epidemiologist, MRI physicists, clinicians, fundamental biologists and data scientists as well as patient public representatives and also industry partners. These partners bring a wealth of expertise and resources to the collaboration.
Impact DEMISTIFI collaboration bid submitted.
Start Year 2020
 
Description DEMISTIFI Consortium 
Organisation University of Exeter
Country United Kingdom 
Sector Academic/University 
PI Contribution I established the development of a multi-organ fibrosis consortium to try and prevent the development of multi morbidity.
Collaborator Contribution There are a number of partners involved in this consortium including genetic epidemiologist, MRI physicists, clinicians, fundamental biologists and data scientists as well as patient public representatives and also industry partners. These partners bring a wealth of expertise and resources to the collaboration.
Impact DEMISTIFI collaboration bid submitted.
Start Year 2020
 
Description DEMISTIFI Consortium 
Organisation University of Manchester
Country United Kingdom 
Sector Academic/University 
PI Contribution I established the development of a multi-organ fibrosis consortium to try and prevent the development of multi morbidity.
Collaborator Contribution There are a number of partners involved in this consortium including genetic epidemiologist, MRI physicists, clinicians, fundamental biologists and data scientists as well as patient public representatives and also industry partners. These partners bring a wealth of expertise and resources to the collaboration.
Impact DEMISTIFI collaboration bid submitted.
Start Year 2020
 
Description DEMISTIFI Consortium 
Organisation University of Nottingham
Country United Kingdom 
Sector Academic/University 
PI Contribution I established the development of a multi-organ fibrosis consortium to try and prevent the development of multi morbidity.
Collaborator Contribution There are a number of partners involved in this consortium including genetic epidemiologist, MRI physicists, clinicians, fundamental biologists and data scientists as well as patient public representatives and also industry partners. These partners bring a wealth of expertise and resources to the collaboration.
Impact DEMISTIFI collaboration bid submitted.
Start Year 2020
 
Description DEMISTIFI Consortium 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution I established the development of a multi-organ fibrosis consortium to try and prevent the development of multi morbidity.
Collaborator Contribution There are a number of partners involved in this consortium including genetic epidemiologist, MRI physicists, clinicians, fundamental biologists and data scientists as well as patient public representatives and also industry partners. These partners bring a wealth of expertise and resources to the collaboration.
Impact DEMISTIFI collaboration bid submitted.
Start Year 2020
 
Description Matrix Neo-epitope analysis 
Organisation Nordic Bioscience
Country Denmark 
Sector Private 
PI Contribution We provided samples and phenotypic know-how to help sample analysis
Collaborator Contribution Partner brought scientific and biomarker expertise to assay biomarkers in our patients.
Impact This collaboration has lead to a number of publications in high impact journals and continued analysis of samples from our patients.
Start Year 2013
 
Description Clinical Lecture: Scar Wars: A New Hope 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Clinical grand rounds at the Mayo Clinic
Year(s) Of Engagement Activity 2024
 
Description DEMISTIFI Collaboration day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Approximately 60 partners of the DEMISTIFI consortium attended a day long meeting to update the consortium on progress that had been made. This included short research talks and talks from people with lived experience. This sparked discussions throughout the day and lead to inclusion of fibrotic MultiMorbidity in an Imperial College London application for Centre of Research Excellence application.
Year(s) Of Engagement Activity 2023
 
Description Snyder Endowed Seminar, University of Calgary 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A visit to the University of Calgary which sparked considerable questions and discussion afterwards
Year(s) Of Engagement Activity 2023