New insights on the pathogenesis of hereditary Cerebral Cavernous Malformations

Cerebral cavernous malformations are a characteristic of a rare genetic disease of brain blood vessels called CCM. These multiple lumen malformations derive from clusters of dilated vessels particularly fragile and leaky. Patients affected by this disease are prone to bleeding which is associated to focal neurological deficits, headache, seizures, paralysis and hemorrhagic stroke. Moreover, these malformations are the main cause of pediatric hemorrhagic stroke. At present, there is no pharmacological therapy available to cure this disease and the only option available is surgical resection. However, surgery is not possible in many cases where malformations are localized in areas of the brain not accessible or with poor benefit/risk balance. The pathology is causes by mutation in three causative genes: CCM1, CCM2 e CCM3. The cells mainly affected are endothelial cells, that form the inner wall of the blood vessels. In our previous work, we have shown that endothelial cells within cerebral malformations have different characteristics compared to normal cells. In particular, they have characteristics of immaturity and high proliferation which are peculiar of stem cells of blood vessels. In the present project, we propose to better identify the molecular and cellular mechanisms through which mutated endothelial cells generate cerebral cavernous malformations. Moreover, we will test, in a preclinical mouse model of the disease, drugs able to target selectively the cells responsible for cavernomas formation. The drugs identified could be used, quite soon, for a pharmacological therapy with immediate positive effects on quality of life of patients affected by this life-threatening disease.