Repurposing esomeprazole for the treatment of scleroderma

重新利用埃索美拉唑治疗硬皮病

基本信息

批准号：
10250666
负责人：
Yohannes T Ghebre
金额：
$ 35.2万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-10 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10250666
关键词：
3-Dimensional Acidity Affect Animal Disease Models Animal Model Animals Anti-Inflammatory Agents Antioxidants Appearance Binding Sites Biological Bleomycin Blood Vessels Breeding Cell Nucleus Cells Cessation of life Chronic Chronic Disease Coin Collagen Connective Tissue Diseases Cutaneous Involvement Data Deposition Dermal Development Diffuse Scleroderma Disease Distant Environmental Risk Factor Esomeprazole Etiology Extracellular Matrix FDA approved Family Fibroblasts Fibronectins Fibrosis Genetic Grant Human Immune Immune System Diseases In Vitro Incidence Inflammation Inflammatory Knock-out Knockout Mice Lung Lung Inflammation Mediating Mitogen-Activated Protein Kinases Modeling Molecular Multiple Organ Failure Mus Nuclear Translocation Organ Oxidative Stress Parents Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Preparation Process Promoter Regions Proton Pump Inhibitors Publishing Pulmonary Fibrosis Radiation Reducing Agents Regulation Research Scleroderma Skin Stomach Systemic Scleroderma Testing Tissues Topical application United States Universities Up-Regulation Visceral analog base curative treatments fibrogenesis heme oxygenase-1 high throughput screening in vivo innovation insight knockout animal member mouse model novel novel therapeutics nuclear factor-erythroid 2 reduce symptoms skin disorder small molecule standard of care targeted treatment therapeutic evaluation transcription factor

项目摘要

PROJECT SUMMARY Systemic sclerosis (scleroderma) is a deadly connective tissue disorder of unknown etiology affecting the skin, lungs and other visceral organs. The disease is characterized by immune dysfunction, vascular pathology, chronic inflammation, fibroblast overproliferation and collagen buildup. Current estimates of disease incidence are 20 cases per million and include about 100,000 cases in the United States. Although there are limited treatment options including immunosuppressive drugs, these therapies only alleviate symptoms but are unable to reverse established fibrosis and cure scleroderma. Thus, there is an opportunity to develop novel antifibrotic therapies that target chief drivers of the disease: fibroblast overproliferation and collagen accumulation. According to our new study, the parent compound esomeprazole and its topically-formulated analog (coined Dermaprazole) might be novel therapy to halt progression of scleroderma. This understanding is based on our extended studies of high throughput screening (HTS) 130,000 small molecules to discover and validate compounds that regulate processes involved in tissue inflammation and fibrosis. Our published molecular, cell biological and in vivo data demonstrate that systemic administration of esomeprazole inhibits bleomycin- induced lung inflammation and fibrosis by 50%. The study also showed that esomeprazole is anti-proliferative with profound effect on fibroblast proliferation. Encouraged by these, we recently reformulated esomeprazole into Dermaprazole for the treatment of scleroderma with limited cutaneous involvement, while the systemically administered esomeprazole is being developed for severe forms of scleroderma. Our data using human 3D skin model, dermal fibroblasts isolated from scleroderma patients, and mouse model of scleroderma revealed that both forms of the drug are effective in blocking collagen buildup and restoring normal skin appearance. Our molecular studies indicate that esomeprazole/Dermaprazole simultaneously modulates oxidative stress, inflammation and fibrosis through upregulation of the master antioxidant and cytoprotective pathway: nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO1), and suppression of key extracellular matrix (ECM) components such as collagen and fibronectin. Accordingly, we plan to test our central hypothesis “the antioxidant and antifibrotic actions of esomeprazole are able to slow or halt established fibrosis in scleroderma”. To test this, we propose the following Specific Aims: i) Understand the mechanism(s) by which esomeprazole activates HO1 to control inflammatory and fibrotic processes in scleroderma. In this Aim, we will evaluate the mechanistic interaction between esomeprazole and Nrf2 to activate HO1 and its effectors, as well as investigate whether activation of Nrf2/HO1 by esomeprazole is required in the regulation of scleroderma fibroblast proliferation and collagen deposition. ii) Evaluate the efficacy of esomeprazole/Dermaprazole in modulating dermal and lung fibrosis in vivo using wildtype and Nrf2 knockout mouse models of scleroderma. This is an innovative project proposing to repurpose a promising drug to effectively slow or halt scleroderma.

项目概要系统性硬化症（硬皮病）是一种病因不明的致命结缔组织疾病，影响皮肤，该疾病的特点是免疫功能障碍、血管病理、慢性炎症、成纤维细胞过度增殖和胶原蛋白积聚目前对疾病发病率的估计。每百万例中有 20 例，其中美国约有 10 万例。治疗选择包括免疫抑制药物，这些疗法只能缓解症状，但无法逆转已形成的纤维化并治愈硬皮病，因此有机会开发新型抗纤维化药物。针对疾病主要驱动因素的疗法：成纤维细胞过度增殖和胶原蛋白积累。根据我们的新研究，母体化合物埃索美拉唑及其外用制剂类似物（创造德马普拉唑）可能是阻止硬皮病进展的新疗法。这种理解是基于我们的。对 130,000 个小分子进行高通量筛选 (HTS) 的扩展研究以发现和验证我们发表的分子、细胞调节过程的化合物。生物学和体内数据表明，全身施用埃索美拉唑可抑制博莱霉素- 诱发肺部炎症和纤维化 50% 研究还表明，埃索美拉唑具有抗增殖作用。受这些因素的鼓舞，我们最近重新配制了埃索美拉唑。德马拉唑用于治疗皮肤受累有限的硬皮病，而全身治疗我们正在开发用于治疗严重硬皮病的埃索美拉唑，我们使用人体 3D 数据。皮肤模型、从硬皮病患者分离的真皮成纤维细胞和硬皮病小鼠模型揭示这两种形式的药物都能有效阻止胶原蛋白堆积并恢复正常皮肤外观。我们的分子研究表明埃索美拉唑/德马拉唑同时调节氧化应激，通过上调主要抗氧化和细胞保护途径：核红细胞因子 2 相关因子 2 (Nrf2)/血红素加氧酶 1 (HO1)，以及关键细胞外基质的抑制（ECM）成分，例如胶原蛋白和纤连蛋白，我们计划检验我们的中心假设“ 埃索美拉唑的抗氧化和抗纤维化作用能够减缓或阻止已形成的纤维化为了测试这一点，我们提出以下具体目标： i) 了解其机制。埃索美拉唑激活 HO1 来控制硬皮病的炎症和纤维化过程。评估埃索美拉唑和 Nrf2 之间激活 HO1 及其效应子的机制相互作用研究硬皮病的调节是否需要埃索美拉唑激活 Nrf2/HO1 成纤维细胞增殖和胶原沉积 ii) 评估埃索美拉唑/德马拉唑的功效。使用硬皮病野生型和 Nrf2 敲除小鼠模型调节体内真皮和肺纤维化。这是一个创新项目，旨在重新利用一种有前途的药物来有效减缓或阻止硬皮病。