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

CRIVARO, A.; BONDAR, C.; ORMAZABAL, M.; J.M. MUCCI; SCHUCHMAN, E.; SIMONARO, C.; ROZENFELD, P.

San Diego

Congreso; 14th Annual Lysosomal Disease Network WORLDSymposium; 2018

Lysosomal diseases are genetic pathologies caused by pathogenic mutations in genes associated to lysosomal proteins. The majority of them cause enzyme deficienciesdeficiencies in enzymes leading to substrate accumulation mainly in lysosomes and an association with 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 amelioreates clinical manifestations however in some patients the proinflammatory state can not 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 and DGJ. After 24hs PPS was added at 2, 5 and 10 µg/ml for 24, 48 and 72 hs. Levels of IL-1β and TNF-α were evaluated by ELISA. Treatment with 5 µg/ml for 72 hs 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 hs 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 decreased significantly at 72 hs for both diseases when cells were treated with PPS.In conclusion, we observed that treatment with PPS reduced proinflammatory cytokines in vitro. Although more studies have to be done, these results might suggest that PPS could be considered as possible adjuvant therapy in Fabry and Gaucher patients.