Odiparcil, a potential glycosaminoglycans clearance therapy in mucopolysaccharidosis VI—Evidence from in vitro and in vivo models

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...

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Veröffentlicht in:	PloS one Jg. 15; H. 5; S. e0233032
Hauptverfasser:	Entchev, Eugeni, Jantzen, Ingrid, Masson, Philippe, Bocart, Stephanie, Bournique, Bruno, Luccarini, Jean-Michel, Bouchot, Andre, Lacombe, Olivier, Junien, Jean-Louis, Broqua, Pierre, Tallandier, Mireille
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States Public Library of Science 15.05.2020 Public Library of Science (PLoS)
Schlagworte:	Accumulation Antibodies Anticoagulants Aorta Bioaccumulation Biology and Life Sciences Biopharmaceuticals Bone marrow Bone marrow transplantation Cartilage Cell culture Chloride Chondroitin Connective tissues Cornea Culture media Diseases Drug therapy Endothelial cells Endothelium Enzyme therapy Enzymes Ethanol Fibroblasts Genetic disorders Glycosaminoglycans Growth plate Health services Inborn errors of metabolism Intracellular Intravenous administration Intravenous infusion Kidneys Life Sciences Lysosomal storage diseases Maroteaux-Lamy syndrome Medical treatment Medicine and Health Sciences Metabolic disorders Mice Mucopolysaccharides Mucopolysaccharidoses Mucopolysaccharidosis Muscles Oral administration Organs Patients Pharmaceutical sciences Pharmacology Physiological aspects R&D Research & development Research and Analysis Methods Signs and symptoms Skin Sodium Sulfates Surgery Therapy Thickening Tissues Trachea Transplantation France
ISSN:	1932-6203, 1932-6203
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Zusammenfassung:	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.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 PMCID: PMC7228089 Competing Interests: I have read the journal’s policy and the authors of this manuscript have financial competing interests: PB is a co-founder and CSO of Inventiva; EE, IJ, OL, and MT are employees of Inventiva; JLJ is the Chairman of the Scientific Advisory Board and consultant for Inventiva and receives financial compensation from Inventiva; PM, SB, BB and JML were employees of Inventiva while the study was conducted; PM and JLJ are co-inventors on a patent for the use of odiparcil in the treatment of Mucopolysaccharidosis (FR1359657A); Inventiva affiliated authors (EE, IJ, PM, SB, BB, JML, OL, JLJ, PB and MT) have received stocks and shares from Inventiva; Odiparcil is being developed as a product for treatment of Mucopolysaccharidosis by Inventiva. AB is an employee of a company (DimaCell) that provided services on behalf of Inventiva. The authors confirm that “These do not alter our adherence to PLOS ONE policies on sharing data and materials”.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0233032