We are investigating the biology of Ccm3, one of three genes implicated in the pathogenesis of CCM, a monogenic cerebrovascular disorder. We have generated a mouse model that develops vascular lesions highly similar to human cavernomas; its study has led to the identification of cell autonomous as well as cell non-autonomous functions of CCM3 in vascular and neural development, and has unraveled an important role of this protein in the neurovascular unit. Using high-throughput screening we recently discovered that fluvastatin and zoledronate, two drugs already approved for clinical use for other indications, act synergistically to reverse outcomes of CCM3 loss in primary cells and animal models of CCM in vivo. Our studies suggest that combined therapy targeting the mevalonate pathway might have therapeutic effects in CCM disease.
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