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:
    10315231
  • 负责人:
  • 金额:
    $ 3.33万
  • 依托单位:
  • 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:
    2021-08-27 至 2025-08-26
  • 项目状态:
    未结题

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.
项目摘要/摘要

项目成果

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Bryce Alan Jones其他文献

Bryce Alan Jones的其他文献

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{{ truncateString('Bryce Alan Jones', 18)}}的其他基金

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:
    10491716
  • 财政年份:
    2021
  • 资助金额:
    $ 3.33万
  • 项目类别:
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
  • 财政年份:
    2021
  • 资助金额:
    $ 3.33万
  • 项目类别:

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