Repurposing esomeprazole for the treatment of scleroderma

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PROJECT SUMMARY Scleroderma is a 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. 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, esomeprazole and its topically-formulated analog (coined Dermaprazole) might halt progression of scleroderma. This understanding is based on our extended studies of high throughput screening (HTS) 130,000 small molecules to discover compounds that regulate processes involved in tissue inflammation and fibrosis. Our molecular, cell biological and in vivo data demonstrate that systemic administration of esomeprazole inhibits lung inflammation and fibrosis by 50%. The study also showed that esomeprazole is anti-proliferative with profound effect on fibroblast proliferation, and differentiation into myofibroblasts. Encouraged by these, we recently reformulated esomeprazole into Dermaprazole for the treatment of scleroderma with limited cutaneous involvement, while the systemic esomeprazole is being developed for severe forms of the disease. Our data using human 3D skin model, dermal fibroblasts isolated from scleroderma patients, and mouse models of scleroderma demonstrated that both forms of the drug are effective in inhibiting fibrosis and restoring normal skin appearance. In addition, systemic esomeprazole was found to suppress lung fibrosis secondary to skin fibrosis in a model of systemic sclerosis. Our molecular studies indicate that esomeprazole/Dermaprazole modulate fibrosis through nuclear translocation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) to activate heme oxygenase 1 (HO1), and suppress key extracellular matrix (ECM) proteins. Molecular studies also show that activation of HO1 by esomeprazole involves phosphorylation of the Mitogen-Activated Protein Kinase (MAPK) pathway. Accordingly, we plan to test our central hypothesis: esomeprazole/Dermaprazole is able to slow or halt established fibrosis in scleroderma in MAPK/Nrf2/HO1 dependent manner. 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, MAPK 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, Nrf2, and MAPK knockout mouse models of scleroderma.