Therapeutic Strategy to slow progression of calcific aortic valve stenosis

血流动力学显着钙化性主动脉瓣狭窄(CAVS)影响3%的人群 65岁以上，甚至患有中度主动脉瓣狭窄(峰值速度为3-4米/秒)的患者 5年无事件存活率低于40%。目前还没有有效的治疗方法。 为了减缓主动脉瓣钙化的进展，而主动脉瓣置换术是唯一可用的 晚期骑士队的治疗。因此，我们研究计划的主要目标包括：1)使用 确定促进CAV启动和进展的机制的综合方法， 2)使用综合方法来确定减缓的治疗干预措施 在不对体内其他器官系统/组织产生负面影响的情况下进行CAV进展(例如， 骨骼骨化)。在本UH2/UH3申请中(应美国国立卫生研究院的要求提交- 行业试点项目：发现现有分子的新治疗用途)，我们建议 赛诺菲的一种化合物是一种新型的药物疗法，可以减缓骑士队的进展。在.期间 UH2阶段的赠款，我们的目标是提供关键的概念验证数据，该化合物：1) 轻度到中度CAV的患者耐受性良好，2)在强健的 瓣膜钙化和狭窄的小鼠模型，3)减少人的成骨信号 体外培养的主动脉瓣间质细胞，4)减弱患者瓣膜成骨信号 与严厉的骑士队。在赠款的UH2阶段达到适当的里程碑后，我们 将迅速进入赠款的UH3阶段，在那里我们将审查 慢性给药对主动脉瓣钙蓄积、血管病变进展的影响 轻度至中度高血压患者的主动脉瓣和心功能不全及炎性细胞因子水平 中等骑士队。总的来说，我们认为拟议的研究很有可能不仅是 提供了对CAV基因表达调控的基本机制的新见解，但 也有可能将该化合物确定为一种减缓CAV进展的新型治疗剂 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.