Journal article
Strategy for identifying repurposed drugs for the treatment of cerebral cavernous malformation
Circulation (New York, N.Y.), Vol.131(3), pp.289-299
01/20/2015
DOI: 10.1161/CIRCULATIONAHA.114.010403
PMCID: PMC4356181
PMID: 25486933
Abstract
Cerebral cavernous malformation (CCM) is a hemorrhagic stroke disease affecting up to 0.5% of North Americans that has no approved nonsurgical 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.
We developed an unbiased screening platform based on both cellular and animal models of loss of function of CCM2. Our discovery strategy consisted of 4 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 2100 known drugs and bioactive compounds and identified 2 candidates, cholecalciferol (vitamin D3) and tempol (a scavenger of superoxide), for further study. Each drug decreased lesion burden in a mouse model of CCM vascular disease by ≈50%.
By identifying known drugs as potential therapeutics for CCM, we have decreased the time, cost, and risk of bringing treatments to patients. Each drug also prompts additional exploration of biomarkers of CCM disease. We further suggest that the structure-function screening platform presented here may be adapted and scaled to facilitate drug discovery for diverse loss-of-function genetic vascular disease.
Details
- Title: Subtitle
- Strategy for identifying repurposed drugs for the treatment of cerebral cavernous malformation
- Creators
- Christopher C Gibson - University of UtahWeiquan Zhu - University of UtahChadwick T Davis - University of UtahJay A Bowman-Kirigin - University of UtahAubrey C Chan - University of UtahJing Ling - University of UtahAshley E Walker - University of UtahLuca Goitre - University of TurinSimona Delle MonacheSaverio Francesco Retta - University of TurinYan-Ting E Shiu - University of UtahAllie H Grossmann - University of UtahKirk R Thomas - University of UtahAnthony J Donato - University of UtahLisa A Lesniewski - University of UtahKevin J Whitehead - University of UtahDean Y Li - University of Utah
- Resource Type
- Journal article
- Publication Details
- Circulation (New York, N.Y.), Vol.131(3), pp.289-299
- DOI
- 10.1161/CIRCULATIONAHA.114.010403
- PMID
- 25486933
- PMCID
- PMC4356181
- NLM abbreviation
- Circulation
- ISSN
- 0009-7322
- eISSN
- 1524-4539
- Publisher
- Lippincott Williams & Wilkins
- Grant note
- R01 NS075168 / NINDS NIH HHS K02 HL069774 / NHLBI NIH HHS R01 NS080893 / NINDS NIH HHS T32 HL007576 / NHLBI NIH HHS R01 HL065648 / NHLBI NIH HHS R01 CA163970 / NCI NIH HHS 8UL1TR000105 / NCATS NIH HHS S10 RR027506 / NCRR NIH HHS UL1RR025764 / NCRR NIH HHS I01 BX002976 / BLRD VA UL1 RR025764 / NCRR NIH HHS U54 AI065357 / NIAID NIH HHS K02 AG045339 / NIA NIH HHS R01 HL084516 / NHLBI NIH HHS U01 NS083573 / NINDS NIH HHS R01 AR064788 / NIAMS NIH HHS R01 HL077671 / NHLBI NIH HHS R21 AG043952 / NIA NIH HHS R01 AG040297 / NIA NIH HHS UL1 TR000105 / NCATS NIH HHS R01 HL068873 / NHLBI NIH HHS UL1 TR001067 / NCATS NIH HHS
- Language
- English
- Date published
- 01/20/2015
- Academic Unit
- Psychiatry; Internal Medicine
- Record Identifier
- 9984280835402771
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