Oxidative stress and Cerebral Cavernous Malformations (CCM): from disease mechanisms toward prevention and treatment

Cerebral cavernous malformations (CCM) consist of abnormally enlarged and leaky capillary cavities (caverns) that predispose to seizures, neurological deficits, and intracerebral hemorrhage. Their surgical removal is necessary for patients with recurrent hemorrhage or intractable seizures, since direct pharmacological treatments are not available so far. Magnetic Resonance Imaging is the diagnostic modality of choice. It has been estimated that this disease affects 0.5% of the general population, although only 20-30% of affected individuals develop clinical symptoms; these typically occur in the third through fifth decades of life, although lesions have been described in all age groups. CCM is a disease of proven genetic origin with three known associated genes. At least 47% of the hereditary forms of CCMs are caused by mutation in the KRIT1 gene. Previously, we found that this gene is involved in preventing cellular oxidative damage, raising the possibility that CCM lesions may result from reduced cellular defense against local oxidative stress events in cerebrovascular districts of genetically predisposed individuals (Goitre et al., 2010, 2014) and leading to promising therapeutic perspectives (Gibson et al., in press). Consistently, experiments in animal models showed that KRIT1 loss is not sufficient to induce CCM lesions, suggesting that microenvironmental stress factors occurring locally contribute crucially to the onset of CCM disease. To further characterize CCM disease mechanisms and address our working hypothesis, we will take advantage of ongoing collaborations within the CCM_Italia multidisciplinary research network (www.ccmitalia.unito.it). In particular, using an integrated research approach based on studies in cellular and animal models of CCM disease, and surgical samples of CCM lesions, the three research Units mainly involved in this project should provide novel insights into CCM pathogenetic mechanisms and their translational implementation.