Background/Purpose: Systemic sclerosis (SSc) is a complex and heterogeneous condition characterized by progressive fibrosis in multiple organs. Currently, there is no known cure for SSc, and treatment aims to manage symptoms, slow disease progression, and improve quality of life. Recent studies have implicated plasminogen activator inhibitor 1 (PAI-1, gene SERPINE1) in the pathogenesis of SSc, and PAI-1 is considered a prognostic biomarker for disease progression.

Methods: PAI-1 expression is evaluated in clinical dermal samples from SSc patients, using single-cell RNA-seq analyses.  Additionally, dermal fibroblasts collected from diffuse cutaneous (dc)SSc patients were evaluated for PAI-1 expression as well as changes in pro-fibrotic biomarkers after PAI-1 inhibition. Finally, a causal role for PAI-1 in fibrosis progression was examined in a preclinical model of SSc where bleomycin was administered subcutaneously via an osmotic pump for 7 days to induce systemic fibrosis followed by treatment for 21 days with the potent PAI-1 inhibitor MDI-2517.

Results: Single-cell RNA-seq analysis of skin biopsies from 18 healthy controls and 22 SSc patients revealed a marked overlap between genes involved in extracellular matrix remodeling associated biological processes and SERPINE1 expression in myofibroblasts from scleroderma skin samples. Treatment of dermal fibroblasts from SSc patients with the small molecule PAI-1 inhibitor MDI-2517 reduced the expression of the profibrotic markers ColA1 and ACTA2. To investigate the therapeutic potential of MDI-2517, we evaluated the efficacy of this drug in reducing both skin and lung fibrosis in a preclinical mouse model of SSc. Treatment with MDI-2517 significantly reduced fibrosis in both the skin and lungs, and was superior to treatment with either pirfenidone or mycophenolate mofetil (MMF). Additionally, MDI-2517 significantly reduced the expression of key profibrotic biomarkers and attenuated weight loss. Compared to another PAI-1 inhibitor, tiplaxtinin, previously shown to be effective in a model of SSc, MDI-2517 was found to have superior efficacy at a 10-fold lower dose.

Conclusion: These findings highlight the role of PAI-1 in the pathogenesis of SSc, and the potential of MDI-2517 for the treatment of SSc. Based on these promising preclinical studies and standard non-clinical toxicology and safety pharmacology studies a Phase 1 first in human clinical study evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of MDI-2517 is currently underway. The results of the phase 1 study will inform the continued development of MDI-2517 for the potential treatment of SSc and interstitial lung disease, and will also support the potential evaluation of MDI-2517 in other chronic fibrotic and inflammatory diseases that are associated with excessive PAI-1 activity.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-potent-inhibitor-of-pai-1-mdi-2517-mitigates-disease-severity-in-preclinical-models-of-systemic-sclerosis/