Bringing CCM into a dish: cell culture models for cerebral cavernous malformations

Cerebral cavernous malformations (CCMs) are vascular lesions that can cause severe neurological complications due to intracranial hemorrhage. Although the CCM disease genes, , , and , have been known for more than 15 years now, our understanding of CCM pathogenesis is still incomplete. CCM research currently focuses on three main disease mechanisms: (1) clonal expansion of endothelial cells with biallelic inactivation of , , or , (2) recruitment of cells with preserved CCM protein expression into the growing lesion, and (3) disruption of endothelial cell–cell junctions in CCMs. We here describe novel CRISPR/Cas9-based models of CCM and discuss their strengths and limitations in the context of high-throughput drug screening and repurposing approaches.