Small molecule therapeutic for calcific aortic valve disease

项目总结 在西方世界，主动脉瓣狭窄是瓣膜疾病的主要原因，也是第三大原因。 成人心脏病。这是一种与钙化相关的进行性疾病，随着年龄的增长而恶化，因此 随着全球人口老龄化，患病率不断上升。发展医疗疗法的需求尚未得到满足 对于这种情况，作为钙化性主动脉瓣疾病(CAVD)的唯一治疗方法，需要进行瓣膜置换。一个 钙化性主动脉瓣病(CAVD)的主要危险因素是二尖瓣(BAV)，发生率为1-2%。 涉及形成两个而不是三个小叶瓣膜。约35%的BAV感染者 会随着年龄的增长而发展为CAVD，但一些BAV患者甚至在童年时就会表现出叶面增厚。我们之前已经 据报道，NOTCH1基因功能丧失突变会导致先天性二尖瓣主动脉瓣(BAV)和 早发性CAVD。来自无NOTCH1的CAVD患者的患者特异性IPSCs和原代主动脉瓣细胞 突变揭示了瓣膜细胞向成骨样细胞转化的异常细胞命运是潜在的 CAVD的发病机制。使用基于基因网络的小分子文库筛选和机器学习 算法，我们发现化合物XCT790广泛纠正了NOTCH1单倍体的基因失调 人IPSC来源的内皮细胞。我们推测XCT790可能具有调节细胞命运转换的功能 事件与激发遗传原因无关，因为我们没有筛选NOTCH1激动剂；实际上，在初级 来自无NOTCH1突变证据的移植患者瓣膜内皮细胞， 在绝大多数患者细胞中，失调的基因网络得到了纠正。在小鼠CAVD模型XCT790中， 抑制雌激素相关受体-a(ERRA)，减少瓣膜增厚、狭窄和钙化 在体内，将该化合物定位为CAVD患者治疗干预的有力候选者。一秒钟 ERRA抑制剂，化合物29，也纠正了基因网络，似乎阻止了小鼠的既定疾病。 在这里，我们将测试XCT790通过靶向Errα来阻止CAVD进展的假设，并且 XCT790或口服ERRA抑制剂化合物29具有良好的药代动力学和毒性特性 进一步的药物开发。我们建议通过以下目标来实现这一目标：1)确定 与XCT790/化合物29治疗CAVD活性相关的分子靶点；2)确定最低限度 XCT790和化合物29治疗两个独立模型的剂量和最佳给药途径 3)评价XCT790和化合物29的体内药代动力学和潜在毒性。这些 研究将测试XCT790和化合物29的治疗潜力，并为临床奠定基础 翻译这些药物来治疗一种代表着巨大的未得到满足的医疗需求的疾病，是有特点的 由于死亡率和发病率高，目前的主要治疗方法是侵入性手术。

PROJECT SUMMARY 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 associated with calcification that worsens with aging, thus is rising in prevalence as the worldwide population ages. There is an unmet need to develop medical therapeutics for this condition, as the only treatment for calcific aortic valve disease (CAVD) involves valve 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, leaflet valve. ~35% of individuals with BAV will develop CAVD with age, but some with BAV display leaflet thickening even in childhood. We have previously reported that loss-of-function mutations in the NOTCH1 gene cause congenital bicuspid aortic valve (BAV) and early-onset CAVD. Patient-specific iPSCs and primary aortic valve cells from CAVD patients without NOTCH1 mutations revealed that abnormal cell fate conversion of valve cells into osteoblast-like cells is the underlying pathogenesis of CAVD. Using a gene network-based small molecule library screen and a machine learning algorithm, we found the compound XCT790 broadly corrected gene dysregulation in NOTCH1 haploinsufficient human iPSC-derived endothelial cells. We postulated XCT790 may function to modulate the cell fate conversion event regardless of the inciting genetic cause as we did not screen for a NOTCH1 agonist; indeed, in primary aortic valve endothelial cells from explanted patient valves without evidence of NOTCH1 mutations, the dysregulated gene network was corrected in the vast majority of patient cells. In a mouse CAVD model, XCT790, annotated to inhibit estrogen-related receptor-a (ERRa), reduced valvular thickening, stenosis and calcification in vivo, positing this compound as a strong candidate for therapeutic intervention in CAVD patients. A second ERRa inhibitor, Compound 29, also corrected gene networks and appears to arrest established disease in mice. Here we will test the hypothesis that XCT790 prevents the progression of CAVD by targeting ERRα, and that XCT790 or an oral ERRa inhibitor, Compound 29, has favorable pharmacokinetics and toxicity properties for further drug development. We propose to achieve this by pursuing the following Aims: 1) Identification of the molecular target associated with therapeutic activity of XCT790/Compound 29 for CAVD; 2) Determine minimal dosing and optimal route of administration for XCT790 and Compound 29 for treating two independent models of CAVD; and 3) Evaluate pharmacokinetics and potential toxicities of XCT790 and Compound 29 in vivo. These studies will test the therapeutic potential of XCT790 and Compound 29, and establish the groundwork for clinical translation of these drugs to treat a disease that represents an enormous unmet medical need, is characterized by high mortality and morbidity, and for which the main current remedy is invasive surgery.