Therapeutic Strategy to slow progression of calcific aortic valve stenosis

血流动力学显著钙化性主动脉瓣狭窄（CAVS）影响3%的人群 65岁以上，甚至中度主动脉瓣狭窄患者（峰值流速3-4 m/sec） 5年无事件生存率低于40%。目前，没有有效的治疗方法 减缓主动脉瓣钙化的进展，主动脉瓣置换术是唯一可用的 治疗晚期CAVS。因此，我们的研究计划的主要目标包括：1）使用 综合方法，以确定有助于CAVS启动和进展的机制， 和2）使用综合方法来确定治疗干预， CAVS的进展而不负面影响体内其他器官系统/组织（例如， 骨骼骨化）。在目前的UH 2/UH 3申请中（提交给NIH- 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新型药物疗法，可以减缓CAVS的进展。期间 UH 2阶段的赠款，我们的目标是提供关键的概念验证数据，这种化合物：1）是 轻度至中度CAVS患者耐受良好，2）以稳健的方式减缓CAVS的进展， 瓣膜钙化和狭窄的小鼠模型，3）减少人中的成骨信号传导 体外的主动脉瓣间质细胞，和4）减弱来自患者的瓣膜中的成骨信号传导 严重的CAVS在补助的UH 2阶段达到适当的里程碑后，我们 我们将迅速进入赠款的UH 3阶段，在那里我们将研究以下方面的影响： 化合物的长期给药对主动脉瓣钙的积累、 主动脉瓣和心室功能障碍，以及轻度至 中度CAVS。总的来说，我们认为拟议的研究不仅有很高的可能性， 为CAVS基因表达调控的基本机制提供了新的见解， 也可能将该化合物确定为一种新型治疗药物，以减缓CAVS的进展， 人类

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.