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.
Scleroderma is a chronic disease of the connective tissue that is characterized by excessive accumulation of fibrous material (i.e. collagen) in the skin and ultimately in the lungs and other internal organs leading to multiple organ failure and death. Although there is no cure for this disease, research progress in animals and humans has led to better understanding of the disease process, and possible treatment options that can halt or reverse the disease are on the horizon. Recently, our research identified that an FDA-approved drug (for other disease) might be effective for scleroderma, and we now propose to conduct additional studies to develop the drug, as well as understand the mechanism(s) by which it blocks collagen overproduction in cells obtained from scleroderma patients, and in animal models of the disease.