Novel insights into the role of oxidative stress in CCM pathogenesis

Cerebral Cavernous Malformation (CCM) is a major cerebrovascular disease affecting 0.1-0.5% of the general population. It is characterized by abnormally enlarged and leaky capillaries that predispose to seizures, focal neurological deficits and intracerebral hemorrhage. To date there are no direct therapeutic approaches, besides surgical removal of accessible CCM lesions in patients with recurrent hemorrhage or intractable seizures. However, the characterization of molecular mechanisms underlying CCM disease has provided fundamental insights into the development of novel therapeutic strategies. Previously, we found that KRIT1 (CCM1), one of the three CCM disease-associated genes, plays a major role in preventing ROS-mediated oxidative cellular dysfunctions through the modulation of master regulators of cell responses to oxidative stress, including FoxO1, SOD2 and c-Jun, suggesting a novel mechanism for CCM disease pathogenesis. More recently, using coordinated, collaborative and integrative research approaches involving several groups of the CCM_Italia multidisciplinary research network (http://www.ccmitalia.unito.it/) and international collaborators, we obtained further insights into the role of oxidative stress in CCM pathogenesis, identified genetic risk factors associated with the severity of CCM disease, including polymorphisms of oxidative stress-related genes, and tested the effectiveness of distinct antioxidant compounds in cellular and animal models of CCM disease. In particular, we found that a novel phenolic compound of the oat avenanthramide family, produced by genetically engineered yeast, and two repurposed drugs were effective in rescuing phenotypes associated with the loss-of-function of CCM genes, suggesting potential therapeutic benefits for CCM disease.