Investigating the Pathogenesis and Response to Therapy of Cerebral Cavernous Malformations Using Transgenic Murine Models

Cerebral cavernous malformations (CCMs), also known as cavernous angiomas, are clusters of sinusoidal capillary-venous vessels that develop in the approximately 1 in 200 individuals. With a gross appearance likened to a mulberry, CCMs have a disrupted endothelial barrier that can lead to patients presenting with focal neurologic deficits, seizures, headaches, and recurrent hemorrhages. Current therapy for CCMs consists of surgical removal in select cases and symptom management. There is no medical therapy to treat the underlying pathology in this disease. CCMs develop following biallelic loss-of-function mutations in CCM1, CCM2, or CCM3. These malformations develop sporadically, often presenting as a solitary lesion, or in an autosomal dominant pattern of inheritance in which individuals develop 10 to 100s of CCMs. How a single mutant endothelial cell leads to the formation of large, multicellular malformation is not known. My doctoral work utilized transgenic murine models of CCM to investigate 1) the early events of CCM formation and 2) the ability of proposed drugs to treat CCMs. We discovered that mutant endothelial cells undergo clonal expansion and incorporate wild-type endothelial cells as the malformation grows. We also developed novel murine models that recapitulate the chronic and acute CCM hemorrhage seen in patients. These new insights and transgenic tools further our understanding of this disease and advance the research community’s efforts to identify a medical treatment for CCMs.