CCM (Cerebral Cavernous Malformations) is a common cerebrovascular disease characterized by the presence of vascular lesions in the CNS and retina, for which pharmacological therapies are currently lacking. The objective of this application is to test whether sustained inhibition of the mevalonate pathway by HMG-CoA reductase and prenylation inhibitors, respectively fluvastatin and zoledronic acid, represents a pharmacological therapy that can be applied to all genetic forms of familial CCM disease in pre-clinical models. Recent work in our laboratory identified these two medicines via a high-throughput screen of FDA-approved drugs and validated them in vitro and in vivo assays, demonstrating their efficacy in reversing outcomes of CCM3 loss in chronic and acute mouse models, reducing lesion burden, and extending survival. We now propose to test the generality of these findings across all genetic forms of CCM disease, by applying similar validation methodologies in the context of CCM1 and CCM2 protein loss. This work will establish fluvastatin and zoledronic acid for consideration as pharmacological options for familial, and possibly sporadic, CCM disease in patients.
The proposed work examines the efficacy of combined drug treatment in animal models of CCM disease. CCM is a common disease that leads to vascular malformations in the brain, causing headache, seizures, neurological problems, and, on occasion, brain bleeds with catastrophic consequences, including death. Pharmacological treatment options for CCM disease are not available. Our proposed work will examine if two drugs, which we recently found to be efficient in a mouse model of CCM disease, are also efficient in two additional mouse models of the disease, each representing one of three forms of hereditary CCM in patients. The proposed studies will determine if the two drugs can be used for all forms of disease in animal models. If successful, they will open up new avenues for future studies aiming to evaluate the drugs for use in patients.
