Therapeutic Strategy to slow progression of calcific aortic valve stenosis

减缓钙化性主动脉瓣狭窄进展的治疗策略

基本信息

批准号：
8598594
负责人：
MAURICE ENRIQUEZ-SARANO
金额：
$ 98.78万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-18 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8598594
关键词：
2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole Affect Age Animal Model Antioxidants Aortic Valve Stenosis Apolipoproteins Area Attenuated Biological Assay Biological Markers Biological Process Blood Bone Density Calcified Calcium Cardiovascular system Cells Chronic Clinical Cross-Over Studies Data Development Diet Disease Disease-Free Survival Dose Double-Blind Method Elderly Event Experimental Models Functional disorder Gene Expression Grant Hour Human In Vitro Individual Industry Inflammatory Intervention Left Ventricular Function Measurement Measures Medical Mus Nitric Oxide Nitric Oxide Synthase Operative Surgical Procedures Oxidative Stress Patients Pharmaceutical Preparations Pharmacotherapy Phase Pilot Projects Placebos Plasma Population Pre-Clinical Model Randomized Recruitment Activity Research Research Design Risk Schedule Sclerosis Signal Transduction Soluble Guanylate Cyclase Staging Stenosis Testing Therapeutic Therapeutic Agents Therapeutic Intervention Therapeutic Uses Time Tissues Titrations Treatment Efficacy United States National Institutes of Health Ventricular Dysfunction aortic valve aortic valve disorder aortic valve replacement body system calcification cofactor cytokine design drug efficacy effective therapy efficacy evaluation feeding in vivo insight interstitial cell meetings mouse model novel novel therapeutics osteogenic oxidation pre-clinical programs protective effect response secondary outcome skeletal valve replacement

项目摘要

Hemodynamically significant calcific aortic valve stenosis (CAVS) affects 3% of the population over age 65, and patients with even moderate aortic valve stenosis (peak velocity of 3-4 m/sec) have a 5 year event-free survival of less than 40%. Presently, there are no effective treatments to slow progression of aortic valve calcification, and aortic valve replacement is the only available treatment for advanced CAVS. Thus, major aims of our research program include: 1) the use of integrative approaches to identify mechanisms contributing to initiation and progression of CAVS, and 2) the use of integrative approaches to identify therapeutic interventions that slow progression of CAVS without negatively impacting other organ systems/tissues in vivo (e.g., skeletal ossification). In the present UH2/UH3 application (submitted in response to the NIH- Industry Pilot Project: Discovering New Therapeutic Uses for Existing Molecules), we propose that a Sanofi compound is a novel pharmacotherapy that can slow progression CAVS. During the UH2 phase of the grant, we aim to provide key proof-of-concept data that this compound: 1) is well tolerated by patients with mild to moderate CAVS, 2) slows progression of CAVS in a robust mouse model of valvular calcification and stenosis, 3) reduces osteogenic signaling in human aortic valve interstitial cells in vitro, and 4) attenuates osteogenic signaling in valves from patients with severe CAVS. Upon meeting appropriate milestones during the UH2 phase of the grant, we will rapidly move towards the UH3 phase of the grant, where we will examine the effects of chronic administration of the compound on accumulation of aortic valve calcium, progression of aortic valve and ventricular dysfunction, and inflammatory cytokine levels in patients with mild to moderate CAVS. Collectively, we believe the proposed studies have a high likelihood of not only providing new insight into fundamental mechanisms regulating gene expression in CAVS, but are also likely to identify the compound as a novel therapeutic agent to slow progression of CAVS in humans.

血液动力学意义上的钙化主动脉瓣狭窄（CAVS）影响3％的人群超过65岁，甚至中度主动脉瓣狭窄的患者（峰值速度为3-4 m/sec） 5年的无活动生存率不到40％。目前，没有有效的治疗减慢主动脉瓣钙化和主动脉瓣更换的进展是唯一可用的晚期骑士的处理。因此，我们的研究计划的主要目的包括：1）识别有助于骑士的启动和进展的机制的综合方法， 2）使用综合方法来识别缓慢的治疗干预措施骑士的进展而没有负面影响其他器官系统/组织体内的进展（例如，骨骼骨化）。在当前的UH2/UH3申请中（响应NIH-提交行业试点项目：发现现有分子的新治疗用途），我们建议 SANOFI化合物是一种新型的药物疗法，可以减慢进展为Cavs。在赠款的UH2阶段，我们旨在提供该化合物的关键概念证明数据：1）轻度至中度骑士的患者耐受良好的耐受性，2）在强大的瓣膜钙化和狭窄的小鼠模型，3）降低了人类的成骨信号传导主动脉瓣在体外的间隙细胞，4）患者的瓣膜中的成骨信号传导减弱有严重的骑士。在赠款的UH2阶段达到适当的里程碑后，我们将迅速朝着赠款的UH3阶段迈进，我们将研究长期给予化合物主动脉瓣钙积累的化合物，进展温和的患者的主动脉瓣和心室功能障碍以及炎症性细胞因子水平中度骑士。总的来说，我们认为所提出的研究不仅很有可能提供有关调节基因表达基因表达的基本机制的新见解，但是还可能将化合物识别为一种新型的治疗剂，以减慢骑士的进展人类。