Obeticholic acid as a novel treatment for Alport syndrome

奥贝胆酸作为阿尔波特综合征的新型治疗方法

• 批准号: 10315231
• 负责人: Bryce Alan Jones
• 金额: $ 3.33万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-27 至 2025-08-26
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10315231
• 关键词: Acids; Adrenal Glands; Age; Agonist; Arginine; Bile Acids; Binding; Biochemical; Biopsy; Blood Pressure; Chronic Kidney Failure; Clinical; Clinical Trials; Collagen; Collagen Type IV; Data; Defect; Diabetic Nephropathy; Diet; Disease Progression; Etiology; FDA approved; Female; Fibrosis; Fluorescein-5-isothiocyanate; Gene Activation; Generations; Genes; Genetic Transcription; Genotype; Glomerular Filtration Rate; Glycolysis; Goals; Hereditary Disease; Hereditary nephritis; Human; Image; Immune response; Immunohistochemistry; Inflammation; Inherited; Investigational Drugs; Kidney; Kidney Diseases; Kidney Transplantation; Label; Left; Liver; Measures; Mediating; Metabolic; Metabolism; Metadata; Microscope; Modeling; Mus; NADH; Nitric Oxide Synthetase Inhibitor; Nuclear Receptors; Nuclear Translocation; Organ; Oxidative Stress; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Primary biliary cirrhosis; Proteolysis; Ramipril; Rare Diseases; Receptor Activation; Recovery; Renin-Angiotensin-Aldosterone System; Resolution; Risk Factors; Serum; Severities; Slide; Small Intestines; Techniques; Testing; Tissues; Transactivation; Transgenic Mice; Urine; Work; biological adaptation to stress; dimethylargininase; drug repurposing; effective therapy; fluorescence lifetime imaging; kidney biopsy; kidney fibrosis; lipid biosynthesis; male; mouse model; multi-photon; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; prevent; promoter; receptor; receptor expression; second harmonic; transcription factor; treatment duration

PROJECT SUMMARY / ABSTRACT Current treatment options for Alport syndrome are extremely limited: Alport syndrome is a hereditary orphan disease arising from defects in the collagen IV α3α4α5 heterotrimer, and it invariably results in chronic kidney disease (CKD). A kidney transplant is the definitive cure for CKD arising from Alport syndrome, but the need for kidney donors far exceeds the availability. Renin-angiotensin-aldosterone system (RAAS) blockade, such as the drug ramipril, is the pharmacological mainstay used to treat CKD in patients with Alport syndrome. Bardoxolone methyl (BdMe) is a promising investigational drug that is very close to being approved to treat Alport syndrome. Nevertheless, developing additional therapies for Alport syndrome is critically important. Farnesoid X receptor (FXR): FXR is a nuclear receptor that is highly expressed in the kidneys, liver, adrenals, small intestines, and vasculature. It is endogenously activated by bile acids. Obeticholic acid (OCA) is a specific FXR agonist that is already approved by the FDA. Thus, OCA could be repurposed to treat Alport syndrome if it is shown to be effective. Importantly, OCA has been shown to be protective in many other models of chronic kidney disease. The OVERARCHING GOAL OF THIS PROPOSAL is to investigate OCA as a novel treatment for Alport syndrome using a transgenic mouse model. We will test the hypothesis that OCA treatment, with or without coadministration of either ramipril or BdMe, is nephroprotective in a mouse model of Alport syndrome. These combinations were chosen in part because evidence in other models of kidney disease suggests that OCA may work through similar pathways as ramipril and BdMe. Thus, it is plausible that OCA could potentiate the beneficial effects of ramipril and BdMe. This may occur independently of any other beneficial effects of OCA. In addition, we will investigate levels of FXR and its well-defined target genes in renal biopsies from patients with Alport syndrome. Label-free imaging will be performed to quantify fibrosis and metabolism, and their correlation with FXR expression will be investigated with spatial resolution within the same biopsy. Correlations will also be sought between these data and the clinical metadata associated with each biopsy.

项目概要/摘要 目前阿尔波特综合征的治疗选择极其有限：阿尔波特综合征是一种遗传性疾病 孤儿病是由 IV 型胶原蛋白 α3α4α5 异三聚体缺陷引起的，它总是会导致慢性 肾脏疾病（CKD）。肾移植是阿尔波特综合征引起的 CKD 的最终治愈方法，但 对肾脏捐赠者的需求远远超过其供应量。肾素-血管紧张素-醛固酮系统（RAAS）阻断， 例如药物雷米普利，是用于治疗阿尔波特综合征患者慢性肾病的主要药理学药物。 Bardoxolonemethyl (BdMe) 是一种很有前途的研究药物，非常接近被批准用于治疗 奥尔波特综合症。尽管如此，开发针对阿尔波特综合征的其他疗法至关重要。 法尼醇 X 受体 (FXR)：FXR 是一种核受体，在肾脏、肝脏、 肾上腺、小肠和脉管系统。它被胆汁酸内源性激活。奥贝胆酸 (OCA) 是一种特定的 FXR 激动剂，已获得 FDA 批准。因此，OCA 可以重新用于治疗 奥尔波特综合症（如果被证明有效）。重要的是，OCA 已被证明在许多其他方面具有保护作用 慢性肾病模型。 本提案的总体目标是研究 OCA 作为 Alport 的新型治疗方法 使用转基因小鼠模型研究综合症。我们将检验以下假设：OCA 治疗（无论有或没有） 雷米普利或 BdMe 的共同给药对阿尔波特综合征小鼠模型具有肾保护作用。这些 选择组合的部分原因是其他肾脏疾病模型的证据表明 OCA 可能通过与雷米普利和 BdMe 类似的途径发挥作用。因此，OCA 可能会增强 雷米普利和 BdMe 的有益作用。这可能独立于 OCA 的任何其他有益作用而发生。 此外，我们将研究肾活检中 FXR 及其明确目标基因的水平 阿尔波特综合征患者。将进行无标记成像来量化纤维化和代谢，以及 它们与 FXR 表达的相关性将在同一活检中通过空间分辨率进行研究。 还将寻找这些数据和与每次活检相关的临床元数据之间的相关性。