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

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.

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.