Cerebral Cavernous Malformations (CCM)

Cerebral Cavernous Malformations (CCM; OMIM 116860) are common vascular anomalies of the central nervous system that can cause seizures, focal neurological deficits, or hemorrhagic stroke. Most CCMs are solitary and occur sporadically; however, multiple lesions are a hallmark of autosomal dominant disease. Sporadic lesions are characterized by remarkable genetic heterogeneity and involve somatic mutations in CCM1, CCM2, or CCM3, or, more commonly, somatic activating mutations in the oncogene PIK3CA. Individuals with familial CCM inherit a germline loss-of-function monoallelic mutation in one of three CCM genes, and are thought to acquire a second-hit, somatic mutation that is necessary for lesion formation.

Our work has centered on understanding the biology of CCM3. By generating and characterizing a mouse model that develops vascular lesions, we demonstrated unique functions of CCM3 in neural development and neurovascular unit homeostasis and identified statins as candidate compounds that prevent and reverse the outcomes CCM3 loss. We are currently pursuing studies to uncover the molecular genetic mechanisms underlying familial CCM and to identify candidate pathways that can be exploited as therapeutic targets.