Recombinant adenosine deaminase ameliorates inflammation, vascular disease and fibrosis in preclinical models of systemic sclerosis
2020
BACKGROUND: Systemic sclerosis (SSc) is characterized by fibrosis, vascular disease and inflammation. Adenosine signaling plays a central role in fibroblast activation. The aim of the present study was to evaluate the therapeutic effects of adenosine depletion with pegylated adenosine deaminase (PEG-ADA) in preclinical models of SSc. METHODS: The effects of PEG-ADA on inflammation, vascular remodeling and tissue fibrosis were analyzed in Fos-related antigen-2 transgenic (Fra2) mice and in the B10.D2-->Balb/c(H-2d) model of sclerodermatous-chronic-graft-versus-host-disease (scl-cGvHD). The effects of PEG-ADA were confirmed in vitro in a human full-thickness-skin-model. RESULTS: PEG-ADA effectively inhibited myofibroblast differentiation and reduced pulmonary (with decreased collagen expression by 34.3%, p=0.0079, n=6), dermal (51.8%, p=0.0006, n=6) and intestinal fibrosis (17.7%, p=0.0228, n=6) in Fra2 mice. Antifibrotic effects of PEG-ADA were also demonstrated in scl-cGvHD (38.4%, p=0.0063, n=8), and in a human full-thickness-skin model. PEG-ADA decreased inflammation and corrected the M2-Th2-ILC2-bias. Moreover, PEG-ADA inhibited proliferation of pulmonary vascular smooth muscle cells (40.5%, p<0.0001, n=6), prevented thickening of the vessel walls (39.6%, p=0.0028, n=6) and occlusions of pulmonary arteries (63.9%, p=0.0147, n=6). Treatment with PEG-ADA inhibited apoptosis of microvascular endothelial cells (65.4%, p=0.0001, n=6) and blunted the capillary rarefication (32.5%, p=0.0199, n=6). RNASeq demonstrated that treatment with PEG-ADA normalized multiple pathways related to fibrosis, vasculopathy and inflammation in Fra2 mice. CONCLUSION: Treatment with PEG-ADA ameliorates the three cardinal features of SSc in pharmacologically relevant and well-tolerated doses. These findings may have direct translational implications as PEG-ADA is already FDA-approved for the treatment of patients with ADA-deficient-SCID.
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