Recombinant adenosine deaminase ameliorates inflammation, vascular disease and fibrosis in preclinical models of systemic sclerosis

Systemic sclerosis (SSc) is characterized by fibrosis, vascular disease and inflammation. Adenosine signaling has been shown to play 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. The effects of PEG-ADA on inflammation, vascular remodeling and tissue fibrosis were analyzed in two mouse models, in Fos-related antigen-2 transgenic (Fra2) mice and in the 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 with forced overexpression of active transforming growth factor-beta receptor I. PEG-ADA effectively inhibited myofibroblast differentiation and reduced pulmonary, dermal and intestinal fibrosis in Fra2 mice. Potent antifibrotic effects of PEG-ADA were also demonstrated in scl cGvHD, and in a human full-thickness skin model. PEG-ADA also decreased inflammation and corrected the M2 / Th2 / ILC2-bias. Moreover, PEG-ADA inhibited proliferation of pulmonary vascular smooth muscle cells, prevented thickening of the vessel walls and occlusions of pulmonary arteries. Treatment with PEG-ADA also inhibited apoptosis of microvascular endothelial cells and blunted the capillary rarefication. RNASeq demonstrated that treatment with PEG-ADA normalized multiple pathways related to fibrosis, vasculopathy and inflammation in Fra2 mice. Treatment with PEG-ADA ameliorates the three cardinal features of SSc, inflammation, vasculopathy and tissue fibrosis 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.