Network-driven drug repurposing in cardiovascular disease: NDRA clinical trial planning

网络驱动的心血管疾病药物再利用：NDRA 临床试验规划

基本信息

批准号：
10195846
负责人：
Chiara Giannarelli
金额：
$ 39.87万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-02 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10195846
关键词：
Adherence Affect Anti-Inflammatory Agents Aorta Architecture Arterial Fatty Streak Atherosclerosis Auranofin Biological Biological Markers Biometry Blood C-reactive protein Cardiovascular Diseases Cardiovascular system Carotid Arteries Cells Cessation of life Characteristics Clinical Clinical Research Clinical Trials Complex Coronary Arteriosclerosis Data Databases Development Disease Dose Drug Targeting Enrollment Ensure Event FDA approved Foam Cells Future Genes Genetic Goals Human Image Imaging Techniques Immunotherapy In Vitro Inflammation Inflammatory Intervention Lesion Life Style Lipids Manuals Measures Modeling Molecular Molecular Profiling Morbidity - disease rate Multi-Institutional Clinical Trial Mus Myocardial Infarction Oryctolagus cuniculus Patients Pharmaceutical Preparations Phase Phenotype Positron-Emission Tomography Preparation Procedures Protocols documentation Publishing Randomized Recording of previous events Regulator Genes Research Design Rheumatoid Arthritis Running Safety Sample Size Selection Criteria Site Statistical Data Interpretation Stroke System Systems Biology Target Populations Testing Therapeutic Tissues Translating Translations Treatment Efficacy Validation Work base biomarker signature cardiovascular imaging cardiovascular risk factor clinical Diagnosis clinical imaging clinical translation cost effective data management design drug discovery drug efficacy drug repurposing efficacy testing experimental study fluorodeoxyglucose fluorodeoxyglucose positron emission tomography functional restoration genetic analysis high risk hypercholesterolemia imaging modality in vivo inhibitor/antagonist innovation macrophage mortality mouse model multimodality non-invasive imaging novel novel therapeutics patient population pre-clinical preclinical efficacy preclinical imaging predictive modeling predictive signature response retention rate screening study population therapeutic development therapeutic target treatment duration treatment optimization

项目摘要

Summary Despite optimized treatments with lipid lowering drugs, such as the well-validated statins or novel PCSK9 inhibitors, cardiovascular disease still remains the main cause of morbidity and mortality worldwide. Inflammation is a known key driver in the development of atherosclerotic plaques at high-risk for causing severe clinical events (such as myocardial infarction and stroke) and represents a promising therapeutic target to further reduce cardiovascular risk. However, up until recently, clinical translation of new therapies, or the repurposing of already FDA-approved drugs that lower cardiovascular risk by targeting inflammation, has proven difficult. Part of the challenge faced by these studies is that these therapeutic compounds have been identified based on single- target drug discovery. However, the biological architecture of common complex disorders, like cardiovascular disease, is better explained by gene regulatory networks (GRN) acting within and across tissues. Identifying new uses for existing drugs to restore the function of GRN in atherosclerotic vessels is a groundbreaking and cost- effective strategy to treat CVD. Using an innovative and rigorous combination of systems genetics and computational drug repurposing analyses, we have previously identified existing compounds predicted to influence the function of four key driver genes in RGN 42, a CVD-causal network acting in the atherosclerotic arterial wall of patients that affect foam cell formation. In previous work (R21TR001739), we rigorously validated the pre-clinical efficacy of Auranofin, the top-hit compound targeting RGN42 using a multimodality approach encompassing in vitro experiments, in vivo mouse work and translational in vivo 18F-FDG PET imaging of inflammation in a rabbit model of atherosclerosis. Our data demonstrates that auranofin alone or in combination with statin effectively reduces atherosclerotic plaque inflammatory cells (macrophages) content and halts the development of plaque inflammation in the rabbit model. Based on these results, we propose to engage in the planning of a clinical trial to test the effects of Auranofin in patients with cardiovascular disease. Our specific aims for this application are i) to identify the optimal target population, as we as treatment dose and duration for Auranofin; ii) to determine the general study design and surrogate imaging endpoints to determine drug efficacy in our patient population; and iii) to identify blood biomarkers and molecular signatures related to drug efficacy, and to ingrate these markers with imaging results. We anticipate that the results of our future clinical trial will represent the basis for future, more extensive Phase III clinical studies to better establish the use of Auranofin in cardiovascular disease.

概括尽管对脂质降低药物进行了优化的治疗，例如验证毒素良好或新颖的PCSK9 抑制剂，心血管疾病仍然是全球发病率和死亡率的主要原因。炎是高危造成严重临床事件的高危动脉粥样硬化斑块开发的主要驱动力（例如心肌梗塞和中风），代表一个有前途的治疗靶标，可以进一步减少心血管风险。但是，直到最近，新疗法的临床翻译或已重新使用事实证明，通过靶向炎症，通过降低心血管风险的FDA批准药物被证明很困难。一部分这些研究面临的挑战是，这些治疗性化合物已根据单一鉴定靶向药物发现。但是，常见复合疾病的生物结构，例如心血管疾病可以通过在组织内部和跨组织内和跨组织内作用的基因调节网络（GRN）更好地解释疾病。识别新的现有药物在动脉粥样硬化血管中恢复GRN功能的用途是一种开创性和成本 - 治疗CVD的有效策略。使用系统遗传学和严格的组合计算药物重新利用分析，我们以前已经确定了预测的现有化合物影响RGN 42中四个关键驱动基因的功能，RGN 42是作用在动脉粥样硬化中影响泡沫细胞形成的患者的动脉壁。在先前的工作（R21TR001739）中，我们对 Auranofin的临床前功效，使用多模式方法的靶向RGN42的最高攻击化合物涵盖体外实验，体内鼠标的工作和体内翻译18f-fdg PET成像动脉粥样硬化模型中的炎症。我们的数据表明，单独或组合单独或组合Auranonofin 他汀类药物有效地减少了动脉粥样硬化斑块炎症细胞（巨噬细胞）的含量并停止兔模型中斑块炎症的发展。基于这些结果，我们建议参与计划一项临床试验，以测试光环素对心血管疾病患者的影响。我们的具体该应用的目的是i）确定最佳目标人群，因为我们作为治疗剂量和持续时间 auranofin; ii）确定一般研究设计和替代成像终点以确定药物疗效在我们的患者人群中； iii）确定与药物疗效有关的血液生物标志物和分子特征并通过成像结果吸引这些标记。我们预计我们未来的临床试验的结果将代表未来，更广泛的III期临床研究的基础，以更好地建立Auranofin的使用在心血管疾病中。