The French National Research Agency Projects for science

Voir cette page en français

ANR funded project

JCJC : Sciences de la vie, de la santé et des écosystèmes : Physiologie, métabolisme, physiopathologie, santé publique (JCJC SVSE 1) 2010
Projet THA-MRO

Thalidomide stimulates vessel maturation: new strategy to treat vascular malformations in Hereditary Hemorrhagic Telangiectasia

Background: Bringing a new drug to market typically costs 1 billion euros. The development of new drugs to treat rare diseases is therefore unattractive for the pharmaceutical industry since predicted revenues will by definition be limited. Most research on a rare disease like Hereditary Haemorrhagic Telangiectasia (HHT), characterized by weak vessel walls is therefore carried out within academia. Symptoms include arteriovenous vascular malformations located on mucosal surfaces that are of special clinical relevance because such lesions may cause intense bleeding, which in severe cases can require hundreds of blood transfusions over a period of years. Despite diagnostic improvements, treatment of such patients remains a clinical challenge. Multiple lesions disseminated over the nasal and gastrointestinal mucosal surfaces are frequently present, making local treatment an unfavourable choice or impossible. There are few therapeutic options but, they only offer a haemorrhage-free interval and effective medical treatment of these patients is urgently needed. HHT is caused by mutations in receptors for transforming growth factor ß (TGF-ß? expressed predominantly in vascular endothelial cells (ECs). The mechanisms underlying the vessel phenotype include loss of mural cell coverage due to reduced levels of TGF-ß signalling from endothelial cells to mural cells and pathologic accumulation of Vascular Endothelial Growth Factor (VEGF) and suggest strategies for therapeutic intervention that may include off-label drug use.
Pilot results: we have recently reported that nosebleeds were dramatically reduced in a small group of HHT patients daily treated by thalidomide, but not without side effects. One patient had to stop treatment because of peripheral neuropathies. To investigate its effects in vivo, we first focussed on developmental retinal angiogenesis in Eng+/- or ALK1+/- mice. Mutant mice showed increased vascular density associated with elevated number of vessel sprouts in the peripheral part of the vascular plexus when compared to controls. Interestingly, thalidomide was able to normalize the excessive vessel branching phenotype and importantly to enhance vessel maturation. Furthermore, vessel coverage defects observed in ear and in the subcutis area of skin of mutant mice were rescued by thalidomide injections, although vessel density was unchanged. Whilst the precise mechanisms underlying thalidomide-induced vessel maturation are unknown, thalidomide seems to target both pericytes and endothelial cells. Finally, preliminary evidences indicate that similar mechanisms might occur in human. Taken together, we demonstrate that thalidomide reduces epistaxis in HHT patients by stimulating pericyte/vSMC recruitment. An understanding of the mechanisms underlying thalidomide action may thus lead to new strategies for novel drug design to treat HHT patients. Objectives: we will determine the molecular mechanisms by which thalidomide induces endothelial-mural cells interactions and more generally will validate the concept of vessel stabilization for the treatment of vascular malformations in HHT. Our final objective is to develop an in vitro model for high output screening drugs that stabilize the vasculature. We expect within the scope of the proposal to develop economic feasible options for treating symptoms in patients that most affect their quality of life perception, their chronic nasal and gastrointestinal bleeding that lead to serious anaemia if they are not life threatening.



ANR grant: 280 000 euros
Beginning and duration: - 48 mois


ANR Programme: JCJC : Sciences de la vie, de la santé et des écosystèmes : Physiologie, métabolisme, physiopathologie, santé publique (JCJC SVSE 1) 2010

Project ID: ANR-10-JCJC-1112

Project coordinator:
Monsieur franck lebrin (COLLEGE DE FRANCE)


Back to the previous page


The project coordinator is the author of this abstract and is therefore responsible for the content of the summary. The ANR disclaims all responsibility in connection with its content.