Arthritis Rheumatol: Recombinant adenosine deaminase improves inflammation, vascular disease and fibrosis in preclinical models of systemic sclerosis

Systemic sclerosis (SSc) is characterized by fibrosis, vascular disease and inflammationAdenosine signaling plays an important role in fibroblast activationThe purpose of this study was to assess the therapeutic effects of the use of polyglycol adenosine deaminase (PEG-ADA) depleted adenosine in ssc preclinical modelsanalyzed the effects of PEG-ADA on inflammation, vascular remodeling and tissue fibrosis in the B10.D2-Balb/c (H-2d) model of Fos-related antigen-2 genetically modified (Fra2) mice and sclerestosis-like chronic transplant anti-host disease (scl-cGvHD)disease with hostThe role of PEG-ADA is confirmed in in vitro human full-thickness skin modelsin Fra2 mice was effective in inhibiting the differentiation of myobromal fibroblasts and reducing lung (collagen expression decreased by 34.3%, p.0079, n?6), skin (51.8%, p.0006, n?6) and intestinal fibrosis (17.7%, p.0228, n-6)The anti-fibrosis effect of PEG-ADA is also demonstrated in the skin models of scl-cGvHD (38.4%, p-0.0063, n-8) and human full-thickness skinPEG-ADA reduces inflammation and corrects M2-Th2-ILC2-biasIn addition, PEG-ADA inhibited the proliferation of pulmonary vascular smooth muscle cells (40.5%, p 0.0001, n-6), preventing the thickening of blood vessel walls (39.6%, p-0.0028, n-6) and pulmonary artery blocking (63.9%, p-0.0147, n-6)PEG-ADA treatment inhibits apoptosis of microvascular endothelial cells (65.4%, p-0.0001, n-6) and weakens capillary thinning (32.5%, p-0.0199, n-6)RNASeq has been shown that PEG-ADA therapy normalizes many pathways associated with fibrosis, vascular lesions, and inflammation in Fra2 micePEG-ADA therapy can improve the three main characteristics of SSc, and the dose is pharmacologically correlated and well toleratedThese findings are of direct significance because PEG-ADA has been approved by the FDA for treatment of PATIENTs with ADA deficiency SCID