Obeticholic acid as a novel treatment for Alport syndrome

项目摘要/摘要 目前治疗Alport综合征的选择极其有限：Alport综合征是一种遗传性疾病 孤儿病是由于IV型胶原α3α4α5异源三聚体缺陷引起的，它总是导致慢性 肾病(CKD)。肾移植是治疗Alport综合征引起的CKD的最终方法，但 对肾脏捐赠者的需求远远超过了可获得性。肾素-血管紧张素-醛固酮系统(RAAS)阻断， 如药物雷米普利，是用于治疗Alport综合征患者CKD的主要药理支柱。 甲基巴度松龙(BdMe)是一种很有前途的研究药物，非常接近被批准用于治疗 阿尔波特综合征。然而，开发治疗Alport综合征的其他疗法是至关重要的。 法尼醇X受体(FXR)：FXR是一种核受体，在肾脏、肝脏、 肾上腺、小肠和血管系统。它由胆汁酸内源性激活。乙酰胆酸(OCA) 是一种已经得到FDA批准的特定FXR激动剂。因此，OCA可以被重新用于治疗 阿波特综合征，如果它被证明是有效的。重要的是，OCA已被证明在许多其他疾病中具有保护作用 慢性肾脏疾病的模型。 这项建议的首要目标是研究OCA作为治疗Alport的新方法 使用转基因小鼠模型的综合症。我们将检验这一假设，即OCA治疗，无论是否有 雷米普利或BdMe联合给药对Alport综合征小鼠的肾脏有保护作用。这些 之所以选择组合，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，亚奥理事会可能会增强 雷米普利和BdMe的有益作用。这可能独立于OCA的任何其他有益影响而发生。 此外，我们还将研究肾活检组织中FXR及其明确定义的靶基因的水平。 阿尔波特综合征患者。将进行无标记成像以量化纤维化和新陈代谢，以及 它们与FXR表达的相关性将在同一活检组织中以空间分辨率进行研究。 还将寻求这些数据和与每次活检相关的临床元数据之间的相关性。

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.