A potent inhibitor of PAI-1, MDI-2517, mitigates disease severity in a preclinical systemic sclerosis model
Enming J. Su, Pei-Suen Tsou, Mark Warnock, Natalya Subbotina, Kris Mann, Sirapa Vichaikul, Alyssa Rosek, Lisa Leung, Xianying Xing, Enze Xing, Olesya Plazyo, Rachael Bogle, Lam C. Tsoi, Cory D. Emal, Dinesh Khanna, John Varga, Thomas H. Sisson, Johann E. Gudjonsson, Daniel A. Lawrence
Enming J. Su, Pei-Suen Tsou, Mark Warnock, Natalya Subbotina, Kris Mann, Sirapa Vichaikul, Alyssa Rosek, Lisa Leung, Xianying Xing, Enze Xing, Olesya Plazyo, Rachael Bogle, Lam C. Tsoi, Cory D. Emal, Dinesh Khanna, John Varga, Thomas H. Sisson, Johann E. Gudjonsson, Daniel A. Lawrence
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Research Article Pulmonology

A potent inhibitor of PAI-1, MDI-2517, mitigates disease severity in a preclinical systemic sclerosis model

Abstract

Systemic sclerosis (SSc) is a complex and heterogeneous condition characterized by progressive fibrosis in multiple organs. Recent studies implicate plasminogen activator inhibitor-1 (PAI-1) in the pathogenesis of SSc, and PAI-1 is considered as a potential target for therapy. Here, using single-cell and spatial RNA-seq analysis of skin biopsies from 18 healthy individuals and 22 SSc patients, we found elevated PAI-1 colocalizing to myofibroblasts with enriched extracellular matrix–associated biological processes. Treatment of SSc dermal fibroblasts with the small-molecule PAI-1 inhibitor MDI-2517 reduced the expression of the profibrotic markers COL1A1 and ACTA2. To investigate the therapeutic potential of MDI-2517, we evaluated its efficacy in reducing fibrosis in a preclinical model of SSc. Treatment of mice with MDI-2517 significantly reduced both skin and lung fibrosis and was superior to treatment with either pirfenidone or mycophenolate mofetil. Additionally, MDI-2517 attenuated weight loss and significantly reduced the expression of key profibrotic markers. Compared with tiplaxtinin, another PAI-1 inhibitor previously shown to be effective in a model of SSc, MDI-2517 was found to have superior efficacy at a 10-fold lower dose. These findings highlight the role of PAI-1 in the pathogenesis of SSc, and the potential of MDI-2517 for the treatment of SSc.

Authors

Enming J. Su, Pei-Suen Tsou, Mark Warnock, Natalya Subbotina, Kris Mann, Sirapa Vichaikul, Alyssa Rosek, Lisa Leung, Xianying Xing, Enze Xing, Olesya Plazyo, Rachael Bogle, Lam C. Tsoi, Cory D. Emal, Dinesh Khanna, John Varga, Thomas H. Sisson, Johann E. Gudjonsson, Daniel A. Lawrence

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Figure 3

Target engagement of MDI-2517.

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Target engagement of MDI-2517. Twelve-week-old male C57BL/6J mice were s...
Twelve-week-old male C57BL/6J mice were subcutaneously implanted with osmotic pumps that delivered 100 U/kg (total) of bleomycin over 7 days. The pumps were then removed, and at that time the mice were placed on chow containing 0 mg/kg (Vehicle) or MDI-2517 at 500 mg/kg chow. On day 28, skin tissue and plasma and were collected. PAI-1 antigen in skin was quantified by immunofluorescence microscopy; images were acquired using the same settings and taken in comparable regions for each skin sample. For quantification, 5 areas of interest per skin sample were analyzed (n = 4 mice per treatment group), and the area of antibody immunoreactivity above a set threshold was measured and averaged for each animal using ImageJ. (A) Immunofluorescent staining of PAI-1 (red) and DAPI nuclear stain (blue), hematoxylin and eosin (H&E), and Picrosirius red staining. (B) Quantification of the relative PAI-1 antigen in skin of the untreated and MDI-2517–treated mice. (C) Active and total PAI-1 in plasma. Scale bars: 100 μm. Data are shown as mean ± SD; n is indicated in each figure by the individual data points (4 to 5); *P < 0.05 in B, **P < 0.01 in C, by 2-tailed t test.