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

BONDAR, CONSTANZA; SCHUCHMAN, EDWARD; CRIVARO, ANDREA; MUCCI, JUAN MARCOS; ROZENFELD, PAULA; ORMAZABAL, MAXIMILIANO; SIMONARO, CALOGERA

San Diego

Simposio; World Symposium 2018; 2018

Lysosomal diseases (LDs) are genetic disorders caused by pathogenicmutations in genes associated with lysosomal proteins. The majority ofthem produce enzyme deficiencies, leading to substrate accumulationmainly in lysosomes. An association between LDs and immune systemactivation has been found. In particular, a chronic proinflammatory stateis a hallmark of several lysosomal disorders. Enzyme ReplacementTreatment (ERT) is one specific therapy. ERT ameliorates clinicalmanifestations, however, in some patients the proinflammatory statecannot be reverted. The aim of our study was to analyze the effectof pentosan polysulfate (PPS) treatment on cytokine production inan in vitro model of Fabry disease, and on PBMCs from Fabry andGaucher patients. To determine the concentration and time of PPStreatment, a dose response and a kinetics experiment were performedin an in vitro model of Fabry disease. Macrophages were differentiatedfrom Buffy Coat and treated with Gb3 (20uM) and DGJ (200uM). After24hrs PPS was added at 2, 5 and 10 μg/ml for 24, 48 and 72 hrs. Levels ofIL-1β and TNF-α were evaluated by ELISA. Treatment with 5 μg/ml for72 hrs reduced both cytokines to control levels. In addition, PBMCs fromboth 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 quantifiedin the culture supernatants. Levels of IL-4, IL-1β and TNF-α weresignificantly decreased at 72 hrs for both diseases when cells weretreated with PPS. In conclusion, we observed that treatment with PPSreduced production of proinflammatory cytokines in vitro. Althoughmore studies are needed, these results suggest that PPS could beconsidered as possible adjuvant therapy for Fabry and Gaucher patients