Metabolic protein may lead to cure … – Information Centre – Research & Innovation

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Currently, there is no cure for multiple sclerosis or MS, an extremely debilitating neurodegenerative disease that affects more than 2.3 million people worldwide, mostly between 20 and 40 years of age. The costly treatments that do exist have limited efficacy in preventing progressive neurodegeneration, are complex to administer and can cause severe side effects.

In a series of EU-funded projects supported by the European Research Council – DIDO, DIDO-MS and continuing in ENHANCIDO – a team led by Ursula Grohmann at the University of Perugia in Italy have gained unprecedented insights into indoleamine 2,3-dioxygenase 1 (IDO1), a protein that plays an important role in immune response.

Their work is opening up entirely new therapeutic pathways for treating MS, other autoimmune diseases in which the immune system mistakenly attacks the body’s own cells and tissues, and cancer.

‘The molecules we identified for potential MS treatment are capable of inducing long-term immune tolerance, thereby dampening the autoimmune response significantly in a durable fashion. This unique mechanism has never been used before,’ Grohmann says.

‘We believe that strengthening the activity of immunoregulatory IDO1 may reset the physiologic mechanisms that maintain immune system tolerance towards our cells and tissues, thus creating an opportunity for a definitive cure for MS and possibly other autoimmune diseases.’

Grohmann predicts IDO1-based treatments would potentially not only be more effective, but also cheap to produce in terms of manufacturing and formulation and could be administered orally.

A messenger or catalyst?

IDO1 is a so-called ‘moonlighting’ protein – an ancestral metabolic molecule which, during evolution, acquired the dynamic ability to change functions. It can act as a messenger, providing the initial signal that triggers a chain of events leading to the genetic reprogramming of the cell, or it can act as a catalyst, speeding up metabolic reactions.

In the DIDO and DIDO-MS projects, the researchers explored how the signalling function could be enhanced to better regulate autoimmune response. They developed novel compounds capable of increasing the capacity of IDO1 to interact with other proteins and thereby improve the signalling performance.

The compounds were tested in mice with relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE), a model of relapsing-remitting multiple sclerosis (RR-MS) that is the most common form of MS in humans.

‘The main innovations of DIDO consisted in demonstrating the feasibility of our main hypothesis, i.e. that the signalling activity of IDO1 can be modulated by small compounds that bind directly to the IDO1 protein and either increase or decrease its level of signalling and consequently its interaction with other proteins. Laboratory tests were promising but not as good as we expected. So because of the low therapeutic effects of IDO1 signalling enhancers, we chose to change the class of our novel compounds,’ Grohmann recounts.

As a result, while working in the DIDO-MS project, the team switched focus to the catalytic function of IDO1, specifically investigating positive allosteric modulators that were also developed in the DIDO project. Positive allosteric modulators, or PAMs, are molecules that bind to receptors or enzymes in a cell and intensify how it functions.

‘We realised that PAMs of IDO1 capable of increasing catalytic activity were more effective in preliminary experiments on RR-EAE than compounds capable of increasing IDO1 signalling activity,’ the project coordinator says. ‘Therefore, thanks to a follow-up ERC project called ENHANCIDO, we are now focusing on IDO1 PAMs as first-in-class drugs for MS. Our goal is to address the urgent unmet clinical need for MS treatment caused by the current lack of effective and cost-effective therapeutics.’

In addition, Grohmann points out that with further research, IDO1-based treatments could prove effective against other autoimmune diseases, such as autoimmune diabetes, thyroiditis, Crohn’s disease or rheumatoid arthritis.

The Italian Association for Cancer Research is also backing a separate project involving Grohmann’s team to explore applications for cancer treatment, focused on drugs capable of inhibiting IDO1 signalling rather than catalytic activity.