Abstract
Mucopolysaccharidoses are a class of lysosomal storage diseases, characterized by enzymatic deficiency in the degradation of specific glycosaminoglycans (GAG). Pathological accumulation of excess GAG leads to multiple clinical symptoms with systemic character, most severely affecting bones, muscles and connective tissues. Current therapies include periodic intravenous infusion of supplementary recombinant enzyme (Enzyme Replacement Therapy–ERT) or bone marrow transplantation. However, ERT has limited efficacy due to poor penetration in some organs and tissues. Here, we investigated the potential of the β-D-xyloside derivative odiparcil as an oral GAG clearance therapy for Maroteaux–Lamy syndrome (Mucopolysaccharidosis type VI, MPS VI). In vitro, in bovine aortic endothelial cells, odiparcil stimulated the secretion of sulphated GAG into culture media, mainly of chondroitin sulphate (CS) /dermatan sulphate (DS) type. Efficacy of odiparcil in reducing intracellular GAG content was investigated in skin fibroblasts from MPS VI patients where odiparcil was shown to reduce efficiently the accumulation of intracellular CS with an EC50 in the range of 1 μM. In vivo, in wild type rats, after oral administrations, odiparcil was well distributed, achieving μM concentrations in MPS VI disease-relevant tissues and organs (bone, cartilage, heart and cornea). In MPS VI Arylsulphatase B deficient mice (Arsb-), after chronic oral administration, odiparcil consistently stimulated the urinary excretion of sulphated GAG throughout the treatment period and significantly reduced tissue GAG accumulation in liver and kidney. Furthermore, odiparcil diminished the pathological cartilage thickening observed in trachea and femoral growth plates of MPS VI mice. The therapeutic efficacy of odiparcil was similar in models of early (treatment starting in juvenile, 4 weeks old mice) or established disease (treatment starting in adult, 3 months old mice). Our data demonstrate that odiparcil effectively diverts the synthesis of cellular glycosaminoglycans into secreted soluble species and this effect can be used for reducing cellular and tissue GAG accumulation in MPS VI models. Therefore, our data reveal the potential of odiparcil as an oral GAG clearance therapy for MPS VI patients.
Highlights
MPS VI (Maroteaux-Lamy syndrome) is caused by deficiency of the enzyme N-acetylgalactosamine-4-sulfatase [1,2,3,4,5]
We investigated the potential of odiparcil, a β-D-xyloside analog [18], as an oral GAG clearance therapy in MPS VI. β-D-xylosides are substrates of galactosyltransferase I (β4GalT7) [19,20,21,22], the enzyme responsible for the attachment of a galactosyl molecule to protein bound xylose that is required for the synthesis of O-glycosylated proteoglycans [23,24]. β-D-xyloside derivatives are found to be more efficient than D-xylose as substrates for β4GalT7, eliminating the need for core protein and xylosyltransferase but still engaging the downstream GAG synthesis machinery [19,20,21,22]
To reduce the pathological GAG content increase in MPS VI disease, we suggest an alternative approach where the levels of intracellular GAG are reduced by odiparcil, a β-D-xyloside analogue, substrate for β4GalT7. β-D-xylosides have been used to manipulate synthesis of proteoglycans and their ability to divert GAG synthesis has been investigated in thrombosis [18,25,41,42], cancer models [43,44] and in tissue regeneration [45,46,47]
Summary
MPS VI (Maroteaux-Lamy syndrome) is caused by deficiency of the enzyme N-acetylgalactosamine-4-sulfatase (arylsulfatase B) [1,2,3,4,5] This enzyme is required for lysosomal degradation of chondroitin sulphate type of GAG (CSGAG) consisting of CS and DS. In recent years tremendous advancements have been made in developing and applying therapies for MPS disease treatment and management [5,13,14] These novel therapies aim to compensate for the lack of endogenous enzyme activity. ERT with galsulfase is more commonly used and consists of the intravenous infusion of exogenous recombinant enzymes to compensate for insufficient endogenous functions [5,15,16] These therapies improve clinical manifestations of the disease (such as reduced mobility, endurance and growth) and are reported to slow down disease progression. Because of low tissue distribution of exogenous recombinant enzymes (in bones, cartilage, eyes) and / or associated risks due to various immune responses or off-target gene effects, there remains a high unmet medical need, requiring further research and development of new therapies for MPS
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