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

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Fibrotic diseases are characterized by excessive deposition of extracellular matrix with perturbation of the physiological tissue architecture and impairment of the physiological function of the affected organs. Fibrotic tissue remodeling imposes a major burden on modern societies and has been estimated to contribute to up to 45% of deaths in the developed world. In addition to fibrosis, Systemic sclerosis (SSc) patients are also suffering from inflammatory manifestations and vascular alterations affecting either the pulmonary arteries resulting in pulmonary arterial hypertension (PAH) or smaller vessels at the extremities manifesting as Raynaud´s syndrome and ischemic ulcers, which contribute to the high morbidity and mortality of SSc patients. Thus, there is a huge medical need for effective disease modifying therapies that simultaneously target the vascular alterations, inflammation and tissue fibrosis in SSc.In the preliminary results, we demonstrate that treatment with PEGylated adenosine deaminase (pegADA) inhibited proliferation of pulmonary vascular smooth muscle cells and apoptosis of microvascular endothelial cells in Fra2-transgenic mice, thereby ameliorating PAH and microangiopathic features in this preclinical model. pegADA also effectively blocked myofibroblast differentiation and reduced pulmonary, dermal and myocardial fibrosis in Fra2-transgenic mice and in experimental sclerodermatous chronic graft-versus-host diseases (cGvHD). Treatment with pegADA decreased inflammation with reduced ILC2 numbers, impaired M2 / Th2-polarization and reduced production of profibrotic cytokines. In the proposed project, we will use a comprehensive collection of state-of-the-art in vitro and in in vivo preclinical models, to profile the intracellular pathways that are modulated by adenosine in target cells, to compare the efficacy of pegADA with individual or combined inhibition of adenosine receptors or CD73 and to investigate the efficacy of treatment with pegADA in preclinical models of other fibrotic diseases.