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Strategy for Identifying Repurposed Drugs for the Treatment of Cerebral Cavernous Malformation
Strategy for Identifying Repurposed Drugs for the Treatment of Cerebral Cavernous Malformation
- Publication Year :
- 2014
-
Abstract
- Background— 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. 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 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 D 3 ) and tempol (a scavenger of superoxide), for further study. Each drug decreased lesion burden in a mouse model of CCM vascular disease by ≈50%. Conclusions— 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.
- Subjects :
- Central Nervous System
Pathology
Hemangioma, Cavernous, Central Nervous System
Cerebrovascular disorders
Disease
Drug Screening Assays
Transgenic
Central Nervous System Neoplasms
Mice
Endothelium
Genetics
Hemorrhage
Stroke
Animals
Cells, Cultured
Cholecalciferol
Drug Repositioning
Drug Screening Assays, Antitumor
Endothelial Cells
Free Radical Scavengers
Humans
Mice, Knockout
Mice, Transgenic
Treatment Outcome
Disease Models, Animal
Physiology (medical)
Cardiology and Cardiovascular Medicine
Cultured
Phenotype
Drug repositioning
medicine.anatomical_structure
Cavernous
medicine.symptom
Hemangioma
medicine.medical_specialty
Cells
Knockout
Article
Lesion
In vivo
medicine
Loss function
business.industry
Animal
Antitumor
medicine.disease
Disease Models
business
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....57aa063045e046120547ed1aa017eec6