Strategy for Identifying Repurposed Drugs for the Treatment of Cerebral Cavernous Malformation

Christopher C. Gibson, Weiquan Zhu, Chadwick T. Davis, Jay A. Bowman-Kirigin, Aubrey C. Chan, Jing Ling, Ashley E. Walker, Luca Goitre, Simona Delle Monache, Saverio Francesco Retta, Yan-Ting E. Shiu, Allie H. Grossmann, Kirk R. Thomas, Anthony J. Donato, Lisa A. Lesniewski, Kevin J. Whitehead, Dean Y. Li December 8, 2014
Circulation
Originally Published on December 8, 2014

Background
Cerebral cavernous malformation (CCM) is a hemorrhagic stroke disease affecting up to 0.5% of North Americans with no approved non-surgical treatment. A subset of patients have a hereditary form of the disease due primarily to loss-of-function mutations in KRIT1, CCM2, or PDCD10. We sought to identify known drugs that could be repurposed to treat CCM.

Methods and Results
We developed an unbiased screening platform based on both cellular and animal models of loss-of-function of CCM2. Our discovery strategy consisted of four steps: an automated immunofluorescence and machine-learning-based primary screen of structural phenotypes in human endothelial cells deficient in CCM2; a secondary screen of functional changes in endothelial stability in these same cells; a rapid in vivo tertiary screen of dermal microvascular leak in mice lacking endothelial Ccm2; and finally a quaternary screen of CCM lesion burden in these same mice. We screened 2,100 known drugs and bioactive compounds, and identified two candidates for further study, cholecalciferol (Vitamin D3) and tempol (a scavenger of superoxide). Each drug decreased lesion burden in a mouse model of CCM vascular disease by approximately 50%.