On Thursday 6 December the King Baudouin Foundation presented to Prof. Miikka Vikkula of the UCLouvain de Duve Institute the €500,000 Generet Award for Rare Diseases for his research on genetic vascular abnormalities.
Such a sum is rarely allocated for research on rare diseases. The King Baudouin Foundation awarded €500,000 to Prof. Miikka Vikkula's team for its research on vascular abnormalities. This is thanks to the Generet Fund, which decided to launch this new award and renew it after two years if the researchers' progress report is convincing.
‘Our project was selected by an international jury and is based on what we demonstrated over the last 20 years in the field of vascular malformation genetics’, says Prof. Vikkula, who heads the Human Genetics Group at the UCLouvain de Duve Institute, which he co-directs.
Vascular abnormalities are relatively rare lesions consisting of malformed blood vessels. They are localised but can be anywhere in the body. Often causing chronic pain, bleeding, ulceration, muscle weakness or disabling functional disorders, the lesions greatly affect quality of life. Prof. Vikkula's team is working to find new ways to treat patients for whom sclerotherapy and surgery to eliminate abnormal vessels are not possible or cannot achieve satisfactory results.
Over the last 20 years, de Duve Institute researchers have in particular demonstrated a genetic mutation present in the injured tissues of people with a non-hereditary form of venous malformation. ‘When we looked at the genome of patients who had no family history of this type of malformation, we found that 60% had a “tissue” mutation’, the professor says. ‘This discovery opened new avenues for research in the field and in genetics in general because until then we were looking at blood to find the mutations responsible for diseases rather than at the tissues in question. But these mutations are only present in the lesions and are therefore not hereditary’.
In vitro studies of cultured cells that followed this discovery allowed researchers to see the effect of tissue mutations in the cells that carry them: they over-activate a signalling pathway, that is, they cause a cascade of excessive reactions within the cell. It is also thanks to cell culture that scientists have been able to develop the first animal model for the study of venous malformations. ‘We had the mutation and the cells that contained it’, Prof. Vikkula says. ‘We injected these cells under the skin of mice to generate the same type of lesions as those observed in patients’.
How to stop the mutation’s effect in patients? By preventing the over-activation of the signalling pathway that the mutation causes. ‘We have identified one of the actors in these cascading reactions’, he says. ‘It’s a protein that can be inhibited, at least partially, with a molecule called rapamycin, which is already available on the market to treat other diseases. So we gave this medicine to our mouse model. In a few days, lesion growth stopped’. Since rapamycin is already commercially available and its side effects defined, its effect could be quickly tested in six patients who had been treated with all possible means for vascular malformations without obtaining satisfactory results that improved their quality of life. The result? ‘Thanks to rapamycin, their pain decreased significantly’. In 2018, a study of about 20 patients confirmed these very promising results.
Using the funds provided by the Generet Award for Rare Diseases, Prof. Vikkula intends to carry out the same research loop for other vascular abnormalities: identify mutations through high throughput sequencing and bioinformatics; create cellular and animal models to understand which cascading reactions are involved within cells; search for molecules already commercialised or in development capable of modifying cascading reactions so as to improve patients’ quality of life. ‘We’re going to explore what mutations patients present through our unique biobank containing hundreds of tissue samples taken during surgical treatments’, he says. Researchers will use zebrafish as a model. ‘It reproduces quickly and its embryos especially are completely transparent and thus allow for observation of the vascular system without performing invasive techniques on the body.’
Interestingly, the majority of mutations identified as causing vascular abnormalities also play a role in various cancers. ‘This means there’s already a wide range of molecules on the market to counter the effect of these mutations in cancer treatments that we can test on our models to explore effects on abnormalities’, Prof. Vikkula says.
Rare diseases are still the subject of great ignorance. Due to this lack of knowledge, the correct diagnosis is often not made (in time). In many cases, there is no adequate treatment or patients cannot access it. Not to mention the scant scientific research on rare diseases. In recent years, the King Baudouin Foundation has become a key player in the field. It is responsible for the preparation of the Belgian Plan for Rare Diseases and now manages ten research-focused funds that address a specific rare disease.
In October, Prof. Miikka Vikkula’s team, along with six other universities and two European companies, obtained €3.8 million in H2020 funding to recruit and train PhD students in the field of vascular biology and the study vascular abnormalities. Brought together via the V.A. Cure Network, the seven partners have a research and training programme that spans four years and is coordinated at UCLouvain. This is the first time an international collaborative research project of this magnitude has explored the mechanisms underlying vascular abnormalities. Fourteen PhD students in total, two of whom are at the de Duve Institute, will join the network, which will start its activities in March 2019. (A.B.)
A glance at Miikka Vikkula's bio
Born in Espoo, Finland, Miikka Vikkula graduated from the University of Helsinki in 1992 with a degree in medicine and completed a PhD in molecular genetics in 1993 . From 1993 to 1997, he joined Harvard Medical School as part of a postdoctorate. It was there that he began to take an interest in vascular and lymphatic abnormalities. He moved to Brussels in 1997 and joined UCLouvain’s de Duve Institute, where he developed his own research laboratory on human genetics. He has been on the de Duve Institute’s management staff since 2004. In 2009, his team discovered the genetic cause of a group of vascular abnormalities and in 2015 demonstrated the effectiveness of a drug treatment that improves the quality of life of patients with certain vascular abnormalities. In October 2018, with six other universities and two companies, Prof. Vikkula won €3.8 million in H2020 funding from the European Commission to recruit and train PhD students in the field of vascular abnormality studies. The following December he was awarded the King Baudouin Foundation’s Generet Award for Rare Diseases, a renewable €500,000 prize.