Aortic Valve Disease: Mechanisms and Therapeutic Approaches

主动脉瓣狭窄是西方世界瓣膜疾病的主要原因，也是成人心脏病的第三大原因。这是一种进行性疾病，随着年龄的增长而恶化。主动脉瓣增厚后会发生钙化，导致进一步狭窄，最终需要手术置换。钙化主动脉瓣疾病（CAVD）的主要危险因素是二尖瓣主动脉瓣（BAV），存在于1-2%的人群中，涉及形成两个瓣而不是三个瓣的小叶。~35%的BAV患者会随着年龄的增长而发展为CAVD，但有些BAV患者甚至在儿童时期就有增厚，需要干预。CAVD患者没有药物治疗，唯一的临床选择是手术瓣膜置换术。我们报道了NOTCH1 （N1）转录因子的杂合无意义突变导致先天性双尖瓣主动脉瓣（BAV）和严重的CAVD，证据表明N1在瓣膜内皮细胞（ECs）中是单倍体不足的。诱导多能干细胞（iPSC）衍生的内皮细胞来自一些CAVD和N1单倍功能不全的患者，显示出促成骨和炎症信号的表达增加。网络分析揭示了导致大部分基因失调的关键节点。通过靶向rna测序对恢复120个失调基因表达能力的化学筛选显示，几种药物可以恢复人类ipsc - ec中接近N1+/+状态的网络，其中一种药物XCT790在小鼠模型中显示出对主动脉瓣增厚、钙化和狭窄的体内疗效。XCT790被认为是雌激素相关受体α (ERRα)的抑制剂。我们现在提议测试XCT790通过抑制ERRα活性来预防主动脉瓣疾病的假设，可以治疗已建立的疾病，并且可以在没有N1突变的CAVD患者细胞亚群中发挥作用。目的是：1)确定XCT790纠正疾病相关基因表达和预防主动脉瓣疾病的作用机制；2)确定XCT790是否可以治疗已建立的CAVD或预防新生儿瓣膜狭窄；3)确定具有或不具有NOTCH1通路基因变异的散发性CAVD患者原发性主动脉瓣内皮细胞基因失调是否对XCT790有反应。这些研究将推动一种潜在的治疗方法来治疗一种疾病，这种疾病代表着巨大的未满足的医疗需求，其特点是高死亡率和发病率，目前唯一的治疗方法是高侵入性手术。

Aortic valve stenosis is the major cause of valve disease in the Western world, and the third leading cause of adult heart disease. It is a progressive disorder that worsens with age. Thickening of the aortic valve is followed by calcification that results in further stenosis that ultimately necessitates surgical replacement. A major risk factor for calcific aortic valve disease (CAVD) is bicuspid aortic valve (BAV), which is present in 1–2% of the population, and involves formation of a two- rather than three-valve leaflet. ~35% of individuals with BAV will develop CAVD with age, but some with BAV have thickening even in childhood, requiring intervention. There are no medical treatments available for CAVD patients, and the only clinical option is surgical valve replacement. We reported that heterozygous nonsense mutations in the NOTCH1 (N1) transcription factor cause congenital biscuspid aortic valve (BAV) and severe CAVD and evidence suggests N1 is haploinsufficient in valve endothelial cells (ECs). Induced pluripotent stem cell (iPSC)-derived ECs from several patients with CAVD and N1 haploinsufficiency showed increased expression of pro-osteogenic and inflammatory signaling. Network analysis revealed key nodes that were responsible for much of the gene dysregulation. A chemical screen for the ability to restore expression of 120 dysregulated genes by targeted RNA-sequencing revealed several drugs that restored the network close to the N1+/+ state in human iPSC-ECs, with one, XCT790, showing efficacy in vivo for aortic valve thickening, calcification and stenosis in a mouse model. XCT790 is annotated to function as an inhibitor of estrogen-related receptor alpha (ERRα). We now propose to test the hypotheses that XCT790 prevents aortic valve disease by inhibiting ERRα activity, can treat established disease, and can function in a subset of CAVD patient cells without N1 mutations. The aims are 1) to determine the mechanism of action by which XCT790 corrects disease-associated gene expression and prevents aortic valve disease; 2) to determine if XCT790 can treat established CAVD or prevent neonatal valve stenosis; and 3) to determine if gene dysregulation in primary aortic valve endothelial cells from sporadic CAVD patients with or without genetic variants in NOTCH1 pathway genes is responsive to XCT790. These studies will advance a potential therapeutic to treat a disease that represents an enormous unmet medical need, is characterized by high mortality and morbidity, and for which the only current remedy is a highly invasive surgery.