Nisha Limaye’s work on the signalling pathway involved in 80% of venous malformation cases not only won her a prize but has created new treatment possibilities.
Every four years the Prix Lambertine Lacroix recognises successful translational research on cardiovascular diseases. In 2016, Nisha Limaye, an FNRS research associate, was rewarded for discovering more about the causes of venous malformation and proposing an innovative treatment approach for severe cases.
When veins develop abnormally
As a member of the team of Prof. Miikka Vikkula of the UCL de Duve Institute, Dr Limaye became interested in venous malformation, particularly its non-hereditary form. ‘It’s the abnormal development of veins,’ she explains, ‘they’re larger and aren’t round, among other abnormalities. This has repercussions for the organs in which they appear. Pain, bleeding and coagulation problems occur. So it’s a very debilitating disease.’
One of the causes: the TEK gene
By analysing afflicted tissue, the team noticed that in certain cases venous malformations originated in endothelial cells, which drive blood vessel formation. ‘The TEK gene was mutated among 60% of afflicted patients,’ Dr Limaye explains, ‘and it’s this gene that codes the TIE2 protein in endothelial cells.’ Dr Limaye tried to understand how this mutation could induce a malformation. ‘In persons with this mutation, the TIE2-PI3K-AKT signalling pathway is constantly activated, causing a communication defect between cells involved in vein formation. The result is abnormal formation.’
Rapamycin: a genuine treatment approach
Having identified this mechanism, the team experimented successfully with rapamycin, an immunosuppressant used in cancer treatment. ‘This molecule can inhibit the PI3K-AKT cellular pathway’, Dr Limaye said. ‘In other words, it blocks the action of the mutated TEK gene and stops the progression of malformations. It doesn’t eliminate them, but it does stop them from developing further – in both mice and humans – and reduces symptoms considerably. The six patients treated during the first testing phase led by Profs Laurence Boon and Emmanuel Seront of Saint-Luc University Hospital experienced significantly reduced pain and bleeding and improved coagulation and mobility.’ The added advantage of rapamycin is that it is already used in cancer treatment and has thus already passed tests for toxicity. Researchers can proceed directly to clinical trials and concentrate on its effectiveness.
A treatment option for all patients?
Dr Limaye explains, ‘If clinical studies confirm our results, the first choice in case of venous malformation will still be surgery, because rapamycin is a chronic treatment and therefore indicated when surgery fails. To avoid recurrence, the entire malformation must be removed, which is not always possible and it’s precisely in this case that rapamycin can make a difference. Finally, even more encouraging, we recently identified another mutated gene in 20% of venous malformations: PIK3CA. These mutations activate the same cellular pathway, which means its inhibition would be effective in the great majority of venous malformations.’
Elise Dubuisson
A glance at Nisha Limaye's bio
1995 Bachelor of Arts Degree in Psychology, English Literature and Journalism, Mount Carmel College, Bangalore University, India
1998 Bachelor of Science Degree in Psychology, University of Texas at Arlington, Arlington, Texas, USA
2005 PhD in Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
2010 Research Associate, FNRS