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

基本信息

批准号：
10693277
负责人：
Bryce Alan Jones
金额：
$ 5.27万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-30 至 2025-08-26
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10693277
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 Disinhibition 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 Phase Primary biliary cirrhosis Proteolysis Ramipril Rare Diseases Receptor Activation Recovery Renin-Angiotensin-Aldosterone System Repression 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 pharmacologic prevent promoter receptor receptor expression second harmonic transcription factor treatment duration

项目摘要

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病（CKD）是阿尔波特综合征引起的 CKD 的最终治疗方法，但对肾脏捐献者的需求远远超过肾素-血管紧张素-醛固酮系统（RAAS）阻断的可用性，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、它由胆汁酸 (OCA) 内源性激活。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。阿尔波特综合征（如果被证明有效）重要的是，OCA 已被证明对许多其他疾病具有保护作用。慢性肾病模型。本提案的总体目标是研究 OCA 作为 Alport 的新型治疗方法我们将使用转基因小鼠模型来测试 OCA 治疗（无论有或没有）的假设。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。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 可能会增强这种作用。雷米普利和 BdMe 的有益作用可能独立于 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患有阿尔波特综合征的患者将进行无标记成像以量化纤维化和代谢，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。