Small molecule therapeutic for calcific aortic valve disease

钙化性主动脉瓣疾病的小分子治疗

• 批准号: 10735711
• 负责人: DEEPAK SRIVASTAVA
• 金额: $ 79.81万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735711
• 关键词: Abnormal Cell; Adult; Age; Aging; Agonist; Aortic Valve Stenosis; Biological Availability; Cells; Characteristics; Childhood; Clinical; Disease; Disease Progression; Disease model; Dose; Drug Delivery Systems; Drug Kinetics; Drug Targeting; ERR1 protein; Eligibility Determination; Endothelial Cells; Estrogen Antagonists; Event; Family suidae; Future; Genes; Genetic; Heart Diseases; Human; Individual; Intervention; Laboratories; Loss of Heterozygosity; Mechanics; Mediating; Medical; Modeling; Molecular Target; Morbidity - disease rate; Mus; Mutation; NOTCH1 gene; Network-based; Operative Surgical Procedures; Oral; Organ; Osteoblasts; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Population; Prevalence; Property; Receptor Inhibition; Reporting; Risk Factors; Route; Stenosis; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Toxic effect; United States; Western World; aortic valve; aortic valve disorder; aortic valve replacement; bicuspid aortic valve; calcification; clinical development; clinical translation; comparative; dosage; drug development; early onset; efficacy evaluation; estrogen-related receptor; gene correction; gene network; in vivo; induced pluripotent stem cell; inhibitor; intraperitoneal; loss of function mutation; machine learning algorithm; mortality; mouse model; pharmacologic; prevent; small molecule; small molecule libraries; small molecule therapeutics; therapeutic candidate; therapeutic evaluation; translational study; valve replacement

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.

项目摘要 主动脉瓣狭窄是西方世界瓣膜疾病的主要原因，也是心脏病的第三大原因。 成人心脏病它是一种与钙化有关的进行性疾病，与衰老有关，因此， 随着全球人口老龄化，患病率不断上升。有一个未满足的需要，发展医疗 对于这种情况，因为钙化性主动脉瓣疾病（CAVD）的唯一治疗方法包括瓣膜置换术。一 钙化性主动脉瓣疾病（CAVD）的主要风险因素是二叶式主动脉瓣（BAV），其存在于1-2% 并且涉及形成两个而不是三个瓣叶瓣膜。约35%的BAV患者 随着年龄的增长，会发生CAVD，但有些BAV患者甚至在儿童时期就显示瓣叶增厚。我们先前已经 报道了NOTCH 1基因的功能缺失突变导致先天性二叶主动脉瓣（BAV）， 早发性CAVD来自无NOTCH 1的CAVD患者的患者特异性iPSC和原代主动脉瓣细胞 突变揭示了瓣膜细胞向成骨细胞样细胞的异常细胞命运转换是导致骨缺损的潜在原因。 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XCT 790广泛纠正了NOTCH 1单倍不足的基因失调， 人iPSC衍生的内皮细胞。我们推测XCT 790可能具有调节细胞命运转换的功能 由于我们没有筛查NOTCH 1激动剂，因此无论诱发遗传原因如何，原发性高血压患者中均未发生此类事件;事实上， 没有NOTCH 1突变证据的移植患者瓣膜的主动脉瓣内皮细胞， 失调的基因网络在绝大多数患者细胞中得到纠正。在小鼠CAVD模型XCT 790中， 注释为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，假定该化合物是CAVD患者治疗干预的强有力候选物。第二 ERRa抑制剂，化合物29，也纠正了基因网络，并似乎阻止了小鼠中已建立的疾病。 在此，我们将检验XCT 790通过靶向ERRα阻止CAVD进展的假设， XCT 790或口服ERRa抑制剂化合物29对于治疗癌症具有有利的药代动力学和毒性性质。 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XCT 790/化合物29对CAVD的治疗活性相关的分子靶标; 2）确定最小的 用于治疗两个独立模型的XCT 790和化合物29的剂量和最佳给药途径 和3）评估XCT 790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XCT 790和化合物29的治疗潜力，并为临床应用奠定基础。 将这些药物转化为治疗代表巨大未满足的医疗需求的疾病，其特征在于 高死亡率和发病率，目前主要的治疗方法是侵入性手术。

项目成果

Sodium Bicarbonate Treatment and Vascular Function in CKD: A Randomized, Double-Blind, Placebo-Controlled Trial.

CKD 中的碳酸氢钠治疗和血管功能：一项随机、双盲、安慰剂对照试验。

• DOI: 10.1681/asn.0000000000000161
• 发表时间: 2023
• 期刊: Journal of the American Society of Nephrology : JASN
• 作者: Kendrick,Jessica;You,Zhiying;Andrews,Emily;Farmer-Bailey,Heather;Moreau,Kerrie;Chonchol,Michel;Steele,Cortney;Wang,Wei;Nowak,KristenL;Patel,Nayana
• 通讯作者: Patel,Nayana