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: 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
• 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

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.

项目摘要 /摘要 Alport综合征的当前治疗选择极为有限：ALPORT综合征是遗传 胶原蛋白IVα3α4α5异三聚体中缺陷引起的孤儿疾病，并且总是导致慢性 肾脏疾病（CKD）。肾脏移植是由Alport综合征引起的CKD的确定治疗方法，但 对肾脏捐赠者的需求远远超过了可用性。肾素 - 血管紧张素 - 醛固酮系统（RAAS）封锁， 例如药物雷普里（Ramipril）是用于治疗Alport综合征患者CKD的药物中流tay柱。 Bardoxolone甲基（BDME）是一种有前途的研究药物，非常接近被批准以治疗 ALPORT综合征。然而，开发针对Alport综合征的其他疗法至关重要。 Farnesoid X受体（FXR）：FXR是一种核接收器，在孩子，肝脏， 肾上腺，小肠和脉管系统。它被胆汁酸内源性激活。 Obeticholic Acid（OCA） 是FDA已经批准的特定FXR激动剂。那就是可以重新使用OCA来治疗 Alport综合征如果证明是有效的。重要的是，已经证明OCA受到许多其他保护 慢性肾脏疾病的模型。 该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的综合征。我们将检验以下假设：OCA治疗有或没有 Ramipril或BDME的共同给药在Alport综合征的小鼠模型中是肾脏保护性的。这些 选择组合部分是因为其他肾脏疾病模型中的证据表明OCA 可以通过与Ramipril和BDME相似的途径。这是合理的，OCA可能有潜力 Ramipril和BDME的有益影响。这可能与OCA的任何其他有益作用无关。 此外，我们将研究FXR的水平及其在肾脏活检中定义明确的靶基因 Alport综合征患者。将进行无标签成像以量化纤维化和代谢，并 它们与FXR表达的相关性将在同一活检中以空间分辨率进行研究。 这些数据与与每个活检相关的临床元数据之间也将感觉到相关性。