Network-driven drug repurposing approaches to treat coronary artery disease

网络驱动的药物再利用方法治疗冠状动脉疾病

• 批准号: 9205566
• 负责人: JOHAN M BJORKEGREN
• 金额: $ 33.9万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9205566
• 关键词: Affect; Alzheimer' s Disease; Animal Model; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Auranofin; Binding; Cholesterol Esters; Clinical; Clinical Trials; Complex; Coronary; Coronary Arteriosclerosis; Data; Data Analyses; Data Set; Diet; Disease; Drug Targeting; FDA approved; Foam Cells; Functional disorder; Gene Expression; Genes; Genetic; Goals; High Fat Diet; Human; Hybrids; Image; Imaging Techniques; In Vitro; Incubated; Inflammation; Inherited; Lead; Lipids; Magnetic Resonance Imaging; Measures; Microvascular Permeability; Modeling; Molecular Models; Morbidity - disease rate; Mus; New Zealand; Oryctolagus cuniculus; Patients; Pharmaceutical Preparations; Phase; Phenotype; Placebos; Positron-Emission Tomography; Preventive; Processed Genes; Protocols documentation; Public Health; RNA; RNA Processing; Randomized; Regimen; Regulator Genes; Residual state; Risk; Severity of illness; Specificity; Speed; Staging; System; Systems Analysis; Systems Biology; Testing; Translating; Translations; Treatment Efficacy; Vitamin D; Work; acetyl-LDL; clinical efficacy; disability; drug efficacy; efficacy testing; feeding; genetic analysis; genetic approach; genome wide association study; genomic data; imaging modality; in vivo; innovation; macrophage; male; molecular drug target; molecular modeling; mortality; mouse model; non-invasive imaging; novel; novel strategies; novel therapeutics; oxidized low density lipoprotein; pre-clinical; prevent; screening; standard of care; trait

PROJECT SUMMARY Coronary artery disease (CAD) is the leading cause of mortality and disability worldwide. Even in patients treated with optimized standard-of-care regimens, residual morbidity and mortality remain high. New strategies that directly target atherosclerosis—the main cause of CAD—are urgently needed. One innovative approach is to find drugs that target the molecular dysfunctions that drive atherosclerosis in the arterial wall. Systems genetics is a new approach that models molecular dysfunctions of complex traits like CAD in the form of regulatory gene networks (RGNs). Combined with network-driven computational approaches to repurpose existing drugs targeting networks in complex diseases, systems genetics can speed up the discovery of powerful strategies to treat CAD. In our previous work, using a systems genetics approach, we have identified RGN42—a CAD-causal network consisting of RNA-processing genes acting in the atherosclerotic arterial wall of CAD patients of the Stockholm Atherosclerosis Gene Expression (STAGE) study. As a proof-of-concept, we silenced the four key drivers genes of RGN42 and found that cholesterol-ester accumulation in foam-cells in vitro was markedly affected. Next we applied a rigorous combination of systems biology and computational drug repurposing analyses and we identified several compounds predicted to influence the four key drivers in RGN42 that affect foam cell formation. Preliminary phenotypic screening revealed that two of our top-hit compounds strongly inhibit foam-cell formation in vitro. Given these findings, we hypothesize that RGN42-targeted compound(s) will show anti- atherosclerotic efficacy. We propose to rigorously validate the pre-clinical efficacy of either FDA approved or phase 2a-ready test compound(s), with the goal of translating the findings into human clinical trials. In specific Aim 1, we will identify the most effective RGN42-targeted compounds for their ability to prevent foam-cell formation in vitro and atherosclerosis in vivo. In Specific Aim 2, we will measure compound(s) therapeutic efficacy in vivo using translational pre- clinical imaging in a well-validated rabbit model of atherosclerosis that recapitulates the complexity of human atherosclerotic plaques better than mouse models. The use of sophisticated, non-invasive imaging modalities to measure the efficacy of compounds targeting RGN42 in a validated large animal model of atherosclerosis will provide robust evidence for the translation of our findings to clinical trials. This study will set the stage for a translational platform to speed the repurposing of existing drugs with new indications identified by network strategies to treat CAD.

项目总结