New therapeutic potential for chronic inflammatory diseases

Substances that trigger prolonged immune responses contribute to the development of atherosclerosis. An EU-funded project is identifying these substances and the underlying mechanisms involved, opening the door to new management strategies for chronic inflammatory diseases.

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Countries
Countries
  Algeria
  Argentina
  Australia
  Austria
  Bangladesh
  Belarus
  Belgium
  Benin
  Bolivia
  Bosnia and Herzegovina
  Brazil
  Bulgaria
  Burkina Faso
  Cambodia
  Cameroon
  Canada
  Cape Verde
  Chile
  China
  Colombia
  Costa Rica
  Croatia
  Cyprus
  Czechia
  Denmark
  Ecuador
  Egypt
  Estonia
  Ethiopia
  Faroe Islands
  Finland
  France
  French Polynesia
  Georgia


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Published: 4 February 2019  
Related theme(s) and subtheme(s)
Health & life sciencesMajor diseases  |  Public health
Innovation
International cooperation
Research policyHorizon 2020
SMEs
Countries involved in the project described in the article
Denmark  |  France  |  Germany  |  Italy  |  Netherlands  |  Poland  |  Romania  |  Switzerland  |  United States
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New therapeutic potential for chronic inflammatory diseases

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© 7activestudio, #121921317, 2019 source:stock.adobe.com

Atherosclerosis is a disease defined by the accumulation of fatty deposits called plaques inside the arteries. It is a leading cause of heart attacks and strokes. Despite treatments that address risk factors such as poor diet, up to 70 % of cardiovascular events are not prevented by current therapeutic procedures.

Recent research shows that immune cell responses contribute to atherosclerotic plaque progression. Meanwhile, studies in mice have indicated that poor diet can trigger an inflammatory state of the immune system over long periods due to an epigenetic mechanism. Epigenetics is a change in an organism caused by modifications in gene expression; such changes can be triggered by environmental factors.

The EU-funded REPROGRAM project is examining the epigenetic programming of the immune cells associated with atherosclerosis and other chronic inflammatory diseases. Its results open up a new therapeutic area, in which epigenetic interventions target innate immune cells to reduce the progression of cardiovascular and chronic inflammatory diseases, offering new pharmacological strategies to better manage these conditions.

‘We aim to demonstrate that a persistent pro-inflammatory state of the innate immune system is built up via epigenetic pathways, which contributes to atherosclerosis development,’ says project coordinator Erik Stroes, of the Academic Medical Centre of Amsterdam University in the Netherlands. ‘Identification of the triggers, mediating this epigenetic activation of immune cells, offers exciting and novel targets for pharmacological strategies to lower the residual cardiovascular morbidity and mortality.’

Identifying triggers, revealing mechanisms

The project consortium identified various substances that cause chronic activation of plasma immune cells, leading to persistent pro-inflammatory reactions in a type of white blood cell, or monocyte, in laboratory studies.

Among the substances found to stimulate inappropriate immune responses were the lipid particles LDL-cholesterol and lipoprotein(a). These are both known risk factors contributing to cardiovascular disease. The consortium is also identifying novel inflammatory triggers on which to target pharmacological strategies.

‘We also unravelled a key mechanism mediating this pro-inflammatory reaction, including specific epigenetic and metabolic pathways. This is likely to facilitate the quest for novel therapeutic targets to prevent these inappropriate pro-inflammatory changes in patients,’ explains Stroes.

The project consortium is now using state-of-the-art techniques to elucidate the mechanisms causing the persistent pro-inflammatory state in hospital patients. Building on the results from their in-vitro cell and mice experiments, they are conducting proof-of-concept studies in patients with atherosclerosis. These are targeting specific pathways, with the aim of preventing or slowing down the development of atherosclerotic cardiovascular disease.

New clinical strategies

Cardiovascular disease risk management is currently focused on lowering LDL-cholesterol with expensive new drugs. But, according to Stroes, the project showed that LDL-cholesterol lowering is only one of the mediators inducing a chronic inflammatory state. Epigenetic pathways appear to provide a ‘final common pathway’ controlling inflammatory activation induced by LDL-cholesterol, lipoprotein(a), glucose, hormones and other triggering substances.

‘More importantly, we also identified intracellular pathways, contributing to this inflammatory state,’ he says. ‘Using these novel insights, we hope to be able to identify new targets, allowing us to attenuate the pro-inflammatory activity in patients, eventually contributing to a further reduction of the residual cardiovascular burden.’

Furthermore, the project consortium identified biomarkers that can be used to estimate the arterial wall inflammatory activity in patients with advanced atherosclerosis. These could be valuable for refining disease management where inflammatory activity persists despite potent LDL-cholesterol lowering drug treatments.

Project details

  • Project acronym: REPROGRAM
  • Participants: Netherlands (Coordinator), Germany, Denmark, Romania, Italy, Switzerland, United States, Poland, France
  • Project N°: 667837
  • Total costs: € 6 000 000
  • EU contribution: € 5 250 000
  • Duration: January 2016 to December 2019

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