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

• 批准号: 8768834
• 负责人: MAURICE ENRIQUEZ-SARANO
• 金额: $ 68.14万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-18 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8768834
• 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

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.

血流动力学显着的钙化性主动脉瓣狭窄 (CAVS) 影响 3% 的人口 65 岁以上，甚至有中度主动脉瓣狭窄的患者（峰值速度 3-4 m/sec） 5 年无事件生存率低于 40%。目前尚无有效治疗方法 为了减缓主动脉瓣钙化的进展，主动脉瓣置换术是唯一可行的方法 晚期 CAVS 的治疗。因此，我们研究计划的主要目标包括：1）使用 确定导致 CAVS 发生和进展的机制的综合方法， 2）使用综合方法来确定减缓病情的治疗干预措施 CAVS 的进展而不会对体内其他器官系统/组织产生负面影响（例如， 骨骼骨化）。在目前的 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 赛诺菲化合物是一种可以减缓 CAVS 进展的新型药物疗法。期间 在资助的 UH2 阶段，我们的目标是提供该化合物的关键概念验证数据：1) 轻度至中度 CAVS 患者的耐受性良好，2) 可以有效减缓 CAVS 的进展 瓣膜钙化和狭窄的小鼠模型，3) 减少人类成骨信号传导 体外主动脉瓣间质细胞，4) 减弱患者瓣膜中的成骨信号传导 患有严重的 CAVS。在 UH2 拨款阶段达到适当的里程碑后，我们 将迅速进入拨款的 UH3 阶段，我们将在该阶段检查以下项目的影响： 长期服用该化合物会导致主动脉瓣钙积聚， 轻度至心室功能障碍患者的主动脉瓣和心室功能障碍以及炎症细胞因子水平 中度 CAVS。总的来说，我们认为拟议的研究很可能不仅 为调节 CAVS 基因表达的基本机制提供了新的见解，但 也有可能将该化合物确定为一种新型治疗剂，以减缓 CAVS 的进展 人类。