Aberrant activation of adenosine-dependent signalling has been implicated in a number of fibrotic diseases, including systemic sclerosis (SSc). The results of a new study indicate that adenosine depletion with recombinant pegylated adenosine deaminase (PEG-ADA) improves the three cardinal features of SSc, namely fibrosis, inflammation and vasculopathy, in preclinical models of the disease.
PEG-ADA is currently used as enzyme replacement therapy for patients with adenosine deaminase severe combined immunodeficiency (ADA-SCID). “As PEG-ADA is already used for the treatment of ADA-SCID and is well tolerated even with long-term application, our findings could have clinical implications and stimulate clinical trials with PEG-ADA in SSc,” notes Yun Zhang, first author of the study.
Targeting adenosine signalling in SSc has been attempted before, primarily by inactivation of CD73 (an ectonucleotidase important in adenosine production) or by targeting individual adenosine receptors. However, neither approach has yielded an effective treatment for SSc.
In the present study, Zhang and colleagues investigated the effects of PEG-ADA in two mouse models of SSc: Fra2-transgenic mice and the sclerodermatous chronic graft-versus-host disease (Scl-GVHD) mouse model. In both models, treatment with PEG-ADA inhibited myofibroblast differentiation and ameliorated fibrosis in the skin, lungs and intestines, organ systems commonly affected in SSc. “The antifibrotic effects in the mouse models were also translated to the human context using a full-thickness skin model,” notes Zhang.
treatment with PEG-ADA inhibited myofibroblast differentiation and ameliorated fibrosis in the skin, lungs and intestines
Treatment with PEG-ADA also prevented vascular manifestations in Fra2-transgenic mice and dampened the inflammatory response in both the Scl-GVHD and Fra2-transgenic mouse models. RNA-Seq analysis demonstrated that PEG-ADA treatment normalized the expression of several genes related to fibrosis, vasculopathy and inflammation in Fra2-transgenic mice.
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Zhang, Y. et al. Recombinant adenosine deaminase ameliorates inflammation, vascular disease and fibrosis in preclinical models of systemic sclerosis. Arthritis Rheumatol. https://doi.org/10.1002/art.41259 (2020)
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Onuora, S. Targeting adenosine in SSc. Nat Rev Rheumatol 16, 298 (2020). https://doi.org/10.1038/s41584-020-0435-z
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DOI: https://doi.org/10.1038/s41584-020-0435-z
