Through close cooperation between European and Brazilian scientists, an EU-funded project is developing and currently testing novel preclinical drug candidates designed to prevent various chronic autoimmune and inflammatory diseases.
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The TARKINAID project is in the process of validating the use of these newly developed anti-inflammatory agents, which inhibit a particular family of signalling molecules. If successful, the team hopes to be able to develop entirely novel small-molecule inhibitors as oral anti-inflammatory therapeutics.
Besides its scientific achievements, the project also brought together scientists from various countries, encouraging the development of a network between European and Brazilian immunologists (two group leaders are from Brazil) and promoting research in Eastern European countries (the coordinator and one SME partner are from Hungary).
Addressing a chronic problem
Autoimmune diseases occur when the immune system mistakes its own tissue as foreign and mounts an attack. The overproduction of certain signalling molecules – produced by cells to carry out specific biological functions – can lead to chronic autoimmune and inflammatory diseases such as rheumatoid arthritis or chronic inflammatory lung diseases. These debilitating conditions can strongly impair quality of life.
“Chronic inflammatory diseases are also a major burden to society, which is why the development of novel therapeutic strategies is a research priority,” says project coordinator Attila Mócsai, Professor at the Semmelweis University School of Medicine in Budapest, Hungary. “However, therapeutic options are still limited, in part because of side effects and very high costs, and because of our limited understanding of the pathological mechanisms involved.”
Testing targeted therapies
This was the motivation for the TARKINAID project. Prior to the start of the project in January 2012, members of the consortium had demonstrated that certain signalling molecules – called Src-family tyrosine kinases – play an important role in certain types of tissue inflammation. “Src-family kinases have recently emerged as major therapeutic targets in malignant diseases, but their suitability as potential targets of inflammatory diseases has not yet received widespread acceptance,” says Mócsai.
Building on this knowledge, three key objectives for the TARKINAID project were identified: to develop novel Src-family kinase inhibitors that effectively address chronic autoimmune and inflammatory diseases; to analyse the effect of known Src-family inhibitors already in use; and to analyse the effect of genetics on inflammation susceptibility. A core part of the TARKINAID project has been pre-clinical analysis of novel Src-family kinase inhibitors in mice, supported by in vitro and in vivo experiments to predict and optimise the most promising inhibitors and to test their safety.
So far, the team has developed and tested a number of novel Src-family inhibitors, which have had a major effect on inflammatory cell function. “We have also identified a number of unexpected effects of an anti-cancer drug on inflammatory cell function, and revealed that having a genetic deficiency of Src-family kinases can cancel out inflammatory processes in mice,” says Mócsai. “Members of the consortium have also obtained genetic evidence showing that Src-family kinases play a key role in autoimmune inflammatory diseases such as rheumatoid arthritis or blistering skin diseases.”
Src-family kinases could hold the key to more effective treatments of chronic immune and inflammatory diseases in the future. Results of the project to date have been presented at various international meetings and in a number of scientific publications.