Efficacy of Pentosan Polysulfate in in vitro models of lysosomal storage disorders: Fabry and Gaucher Disease

CRIVARO, A.; MUCCI JM; BONDAR C; ORMAZABAL, M.; CECI R; SIMONARO C; ROZENFELD PA

PLOS ONE

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2019

1932-6203

Gaucher and Fabry diseases are the most prevalent sphingolipidoses. Chronic inflammationis activated in those disorders, which could play a role in pathogenesis. Significant degreesof amelioration occur in patients upon introduction of specific therapies; however, restorationto complete health status is not always achieved. The idea of an adjunctive therapy thattargets inflammation may be a suitable option for patients. PPS is a mixture of semisyntheticsulfated polyanions that have been shown to have anti-inflammatory effects in mucopolysaccharidosistype I and II patients and animal models of type I, IIIA and VI. We hypothesizedPPS could be a useful adjunctive therapy to inflammation for Gaucher and Fabrydiseases. The objective of this work is to analyze the in vitro effect of PPS on inflammatorycytokines in cellular models of Gaucher and Fabry diseases, and to study its effect inGaucher disease associated in vitro bone alterations. Cultures of peripheral blood mononuclearcells from Fabry and Gaucher patients were exposed to PPS. The secretion of proinflammatorycytokines was significantly reduced. Peripheral blood cells exposed to PPS fromGaucher patients revealed a reduced tendency to differentiate to osteoclasts. Osteoblastsand osteocytes cell lines were incubated with an inhibitor of glucocerebrosidase, and conditionedmedia was harvested in order to analyze if those cells secrete factors that induceosteoclastogenesis. Conditioned media from this cell cultures exposed to PPS producedlower numbers of osteoclasts. We could demonstrate PPS is an effective molecule toreduce the production of proinflammatory cytokines in in vitro models of Fabry and Gaucherdiseases. Moreover, it was effective at ameliorating bone alterations of in vitro models ofGaucher disease. These results serve as preclinical supportive data to start clinical trials inhuman patients to analyze the effect of PPS as a potential adjunctive therapy for Fabry andGaucher diseases.