Repurposing esomeprazole for the treatment of scleroderma

重新利用埃索美拉唑治疗硬皮病

• 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
• 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

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.

项目摘要 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， 肺和其他内脏器官。该疾病的特征是免疫功能障碍，血管病理， 慢性炎症、成纤维细胞过度增殖和胶原蛋白积聚。目前疾病发病率估计数 是每百万人中有20例，包括美国的大约10万例。虽然有限 治疗选择包括免疫抑制药物，这些疗法只能缓解症状，但不能 逆转已形成的纤维化并治愈硬皮病。因此，有机会开发新的抗纤维化药物 针对疾病主要驱动因素的治疗：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局部配制的类似物（ 德马拉唑）可能是阻止硬皮病进展的新疗法。这一理解是基于我们的 高通量筛选（HTS）的扩展研究130，000小分子，以发现和验证 调节组织炎症和纤维化过程的化合物。我们发表的分子，细胞 生物学和体内数据证明全身施用埃索美拉唑抑制博来霉素， 诱导肺部炎症和纤维化的50%。该研究还表明，埃索美拉唑是抗增殖 对成纤维细胞增殖有显著影响。受此鼓舞，我们最近重新制定了埃索美拉唑 进入Dermaprazole治疗硬皮病与有限的皮肤参与，而全身 正在开发用于严重形式的硬皮病的艾美拉唑给药。我们的数据使用人体3D 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了 这两种形式的药物都能有效地阻止胶原蛋白的积累，恢复正常的皮肤外观。 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， 炎症和纤维化通过上调主抗氧化剂和细胞保护途径：核 红系2因子相关因子2（Nrf 2）/血红素加氧酶1（HO 1），以及抑制关键细胞外基质 (ECM)胶原蛋白和纤连蛋白等成分。因此，我们计划测试我们的中心假设“ 埃索美拉唑的抗氧化和抗纤维化作用能够减缓或停止已建立的纤维化， 硬皮病”。为了验证这一点，我们提出了以下具体目标：i）了解 埃索美拉唑激活HO 1以控制硬皮病中的炎症和纤维化过程。在这个目标中，我们将 评价埃索美拉唑和Nrf 2之间激活HO 1及其效应物的机制相互作用，以及 作为研究在硬皮病的调节中是否需要埃索美拉唑激活Nrf 2/HO 1 成纤维细胞增殖和胶原蛋白沉积。ii）评价埃索美拉唑/德马拉唑在以下患者中的功效： 使用硬皮病的野生型和Nrf 2敲除小鼠模型体内调节真皮和肺纤维化。 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停止硬皮病。