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

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机构: [1]Program in Molecular Medicine [2]Department of Bioengineering [3]Department of Medicine [4]Department of Human Genetics [5]Department of Oncological Sciences [6]Division of Geriatrics, Department of Medicine [7]Division of Nephrology and Hypertension, Department of Medicine [8]Department of Pathology [9]Division of Cardiology, and Department of Medicine University of Utah, Salt Lake City, UT [10]Recursion Pharmaceuticals, LLC, Salt Lake City, UT [11]CCM Italia, Department of Clinical and Biological Sciences, University of Torino, Orbassano, Torino, Italy [12]CCM Italia, Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy [13]Geriatrics Research Education and Clinical Center, Veteran’s Affairs Medical Center, Salt Lake City, UT [14]The Key Laboratory for Human Disease Gene Study of Sichuan Province, Institute of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China [15]Cardiology Section, VA Salt Lake City Health Care System, Salt Lake City, UT
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关键词: cerebrovascular disorders endothelium genetics hemorrhage stroke

摘要:
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-ased 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 approximate to 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.

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出版当年[2015]版:
大类 | 1 区 医学
小类 | 1 区 心脏和心血管系统 1 区 外周血管病
最新[2025]版:
大类 | 1 区 医学
小类 | 1 区 心脏和心血管系统 1 区 外周血管病
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出版当年[2015]版:
Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Q1 PERIPHERAL VASCULAR DISEASE
最新[2024]版:
Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Q1 PERIPHERAL VASCULAR DISEASE

影响因子: 最新[2024版] 最新五年平均 出版当年[2015版] 出版当年五年平均 出版前一年[2014版] 出版后一年[2016版]

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第一作者机构: [1]Program in Molecular Medicine [2]Department of Bioengineering [3]Department of Medicine [10]Recursion Pharmaceuticals, LLC, Salt Lake City, UT
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通讯机构: [1]Program in Molecular Medicine [3]Department of Medicine [5]Department of Oncological Sciences [9]Division of Cardiology, and Department of Medicine University of Utah, Salt Lake City, UT [10]Recursion Pharmaceuticals, LLC, Salt Lake City, UT [14]The Key Laboratory for Human Disease Gene Study of Sichuan Province, Institute of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China [15]Cardiology Section, VA Salt Lake City Health Care System, Salt Lake City, UT [*1]University of Utah, Salt Lake City, Bldg 533, Room 4220, 15 N 2030 E, Salt Lake City, UT 84112
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