Obeticholic acid as a novel treatment for Alport syndrome

项目总结/摘要 目前Alport综合征的治疗选择非常有限：Alport综合征是一种遗传性疾病， 由胶原IV α3α4α5异源三聚体缺陷引起的孤儿病， 肾病（CKD）。肾移植是Alport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了可用性。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Alport综合征患者CKD的主要药理学药物。 甲基巴多索龙（BdMe）是一种很有前途的研究药物，非常接近于被批准用于治疗 Alport综合征然而，开发Alport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是由胆汁酸内源性激活。奥贝胆酸（OCA） 是一种特定的FXR激动剂，已经被FDA批准。因此，OCA可以重新用于治疗 Alport综合征，如果它被证明是有效的。重要的是，OCA已被证明是保护在许多其他 慢性肾脏疾病的模型。 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的综合征。我们将测试假设，OCA治疗，有或没有 在Alport综合征的小鼠模型中，雷米普利或BdMe的联合给药具有肾保护作用。这些 选择联合用药的部分原因是，其他肾脏疾病模型的证据表明，OCA 可能通过类似的途径发挥作用，如雷米普利和BdMe。因此，OCA可能会增强 的有益效果。这可能独立于OCA的任何其他有益作用。 此外，我们还将研究FXR及其明确的靶基因在肾活检组织中的水平， Alport综合征患者将进行无标记成像以量化纤维化和代谢， 它们与FXR表达的相关性将在同一活检中用空间分辨率进行研究。 还将寻求这些数据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.