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，也是第三大主要原因 成人心脏病。这是一种与计算有关的进行性障碍，随着衰老而恶化，因此 随着全球人口年龄的增长，患病率上升。不需要开发医学治疗剂 对于这种情况，作为钙化主动脉瓣疾病（CAVD）的唯一治疗方法涉及瓣膜置换。一个 钙化主动脉瓣疾病（CAVD）的主要危险因素是双质主动脉瓣（BAV），它以1-2％的形式存在 人口的形成，涉及两个而不是三个传单阀。 〜35％的BAV个人 会随着年龄的增长而发展的CAVD，但有些人即使在童年时期也会显示出传单增厚。我们以前有 报道Notch1基因的功能丧失突变导致先天性双刺主动脉瓣（BAV）和 早期发作的CAVD。来自没有Notch1的CAVD患者的患者特异性IPSC和原发性主动脉瓣细胞 突变表明，瓣膜细胞异常细胞命运转化为成骨细胞样细胞是基础 CAVD的发病机理。使用基于基因网络的小分子库屏幕和机器学习 算法，我们发现Notch1单倍弹性的化合物XCT790广泛校正的基因失调 人IPSC衍生的内皮细胞。我们假设XCT790可能会起作用以调节细胞脂肪的转化 事件不管是煽动遗传原因，因为我们没有筛选Notch1激动剂；确实，在主要 主动脉瓣内皮细胞来自外植的患者瓣膜，没有Notch1突变的证据， 在绝大多数患者细胞中校正了失调的基因网络。在鼠标CAVD模型中，XCT790， 注释以抑制与中核相关的接收器-A（ERRA），瓣膜增厚，狭窄和钙化减少 在体内，将这种化合物作为对CAVD患者的治疗干预的有力候选者。第二 ERRA抑制剂，化合物29，也纠正了基因网络，似乎阻止了小鼠已建立的疾病。 在这里，我们将测试XCT790的假设，可以通过靶向ERRα来防止CAVD的进展，并且 XCT790或口服ERRA抑制剂，化合物29具有有利的药代动力学和毒性特性 进一步的药物开发。我们建议通过追求以下目的来实现这一目标：1）确定 与CAVD的XCT790/化合物29的治疗活性相关的分子靶标； 2）确定最小 XCT790和化合物29的剂量和最佳给药途径用于治疗两个独立模型 卡夫德; 3）评估XCT790和化合物29体内的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，并为临床建立基础 这些药物的翻译以治疗代表巨大未满足医学需求的疾病的特征 通过高死亡率和发病率，主要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