Novel therapeutic interventions for cerebral cavernous malformations

Cerebral Cavernous Malformation (CCM) is a rare genetic disorder characterized by malformations of blood vessels mostly localized in the brain. These malformations are fragile and prone to leak causing a variety of neurological symptoms that severely affect life quality and survival of the patients. For example, CCM is the most frequent cause of hemorrhagic stroke in childhood. No pharmacological therapy is available at present and surgery is often not applicable due to the location of the malformations in un-accessible regions of the brain. Loss of function mutations in any one of three distinct genes, CCM1, CCM2 and CCM3 cause the pathology. The cell type mostly affected by such mutations is the endothelium that forms the internal cover of cerebral blood vessels and faces blood. In previous work we found that endothelial cells lining the CCM cavernomas present abnormal functional responses and that inhibitors of these responses can significantly reduce the malformations. In this project we plan to confirm and extend these observations. We will test a relatively large number of pharmacological inhibitors acting with different mechanism of action. The potential outcome of this project is the identification of one or more compounds to be tested in clinical trials on CCM patients. The goal of finding a cure to a rare genetic disease is relevant to Telethon's mission.