PPS beyond MPS: efficacy in Fabry and Gaucher in vitro studies

BONDAR C; SCHUCHMAN E; ORMAZABAL MAXIMILIANO; SIMONARO C; CRIVARO A; MUCCI JM; ROZENFELD PA

Congreso; Lysosomal Disease Network-14th Annual WORLD Symposium; 2018

Lysosomal diseases (LDs) are genetic disorders caused by pathogenic mutations in genes associated with lysosomal proteins. The majority of them produce enzyme deficiencies, leading to substrate accumulation mainly in lysosomes. An association between LDs and immune system activation has been found. In particular, a chronic proinflammatory state is a hallmark of several lysosomal disorders. Enzyme Replacement Treatment (ERT) is one specific therapy. ERT ameliorates clinical manifestations, however, in some patients the proinflammatory state cannot be reverted. The aim of our study was to analyze the effect of pentosan polysulfate (PPS) treatment on cytokine production in an in vitro model of Fabry disease, and on PBMCs from Fabry and Gaucher patients. To determine the concentration and time of PPS treatment, a dose response and a kinetics experiment were performed in an in vitro model of Fabry disease. Macrophages were differentiated from Buffy Coat and treated with Gb3 (20uM) and DGJ (200uM). After 24hrs PPS was added at 2, 5 and 10 µg/ml for 24, 48 and 72 hrs. Levels of IL-1β and TNF-α were evaluated by ELISA. Treatment with 5 µg/ml for 72 hrs reduced both cytokines to control levels. In addition, PBMCs from both Fabry and Gaucher patients were incubated with PPS (5 µg/ml) for 48 and 72 hrs and IL-4, IL-1β, IL-10, IL-6 and TNF-α were quantified in the culture supernatants. Levels of IL-4, IL-1β and TNF-α were significantly decreased at 72 hrs for both diseases when cells were treated with PPS. In conclusion, we observed that treatment with PPS reduced production of proinflammatory cytokines in vitro. Although more studies are needed, these results suggest that PPS could be considered as possible adjuvant therapy for Fabry and Gaucher patients.