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

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 EC 50 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.

Oral treatment for mucopolysaccharidosis VI: Outcomes of the first phase IIa study with odiparcil

“…Study patients, investigators, study site personnel, sponsor, and contract research personnel remained blinded to study assignment. A 500 mg twice‐daily dose was selected based on preclinical studies, 15 and a clinical pharmacology study, which identified significant clearance of GAGs outside of the cells demonstrated via the increase of plasma GAG concentrations 14 …”

“…5,[10][11][12][13] Odiparcil is an orally available small molecule previously studied at doses up to 1000 mg/day for prevention of venous thrombosis with no safety findings observed in >1900 subjects/patients. 14,15 By acting as a substrate for galactosyltransferase I, odiparcil diverts the synthesis of endogenous and soluble dermatan sulfate (DS) and chondroitin sulfate (CS) GAG bound to odiparcil, excreted from the cells, bypassing lysosomal degradation, reducing GAG load, and eliminated via the urine as shown in in vitro and in vivo models. 15,16 Odiparcil clears CS and DS, which accumulate in tissues of patients with MPS VI.…”

“…14,15 By acting as a substrate for galactosyltransferase I, odiparcil diverts the synthesis of endogenous and soluble dermatan sulfate (DS) and chondroitin sulfate (CS) GAG bound to odiparcil, excreted from the cells, bypassing lysosomal degradation, reducing GAG load, and eliminated via the urine as shown in in vitro and in vivo models. 15,16 Odiparcil clears CS and DS, which accumulate in tissues of patients with MPS VI. Odiparcil has the potential to address the unmet need for a broader range of improvement in patients with MPS VI.…”

Avaliação do centro de gravidade de crianças e adolescentes com Mucopolissacaridose tipo VI

“…A mucopolissacaridose tipo VI (MPS VI) ou síndrome de Maroteaux-Lamy é uma doença metabólica rara, hereditária, conhecida como uma doença de depósito lisossomal (Akyol et al 2019;Entchev et al 2020). Causada pela deficiência da enzima lisossômica N-acetilgalactosamina-4-sulfatase ou arilsufatase B, responsável pela degradação dos glicosaminoglicanos (GAG) sulfato de dermatina e sulfato de condroitina (Turtelli, 2002;Pereira, Garbeli & Palazzo et al 2011;Medeiros, Silva, Queiroz, Cattuzzo & Soares, 2015).…”

“…O risco de queda nesta população pode vir a debilitá-los ainda mais. Esses achados devem estar relacionados às alterações do centro de gravidade (CG), visto que estas alterações estão relacionadas com diversas características físicas individuais, como estatura, percentual de massa muscular, distribuição de massa corporal, comprimento dos segmentos corporais, entre outras (Narciso et al 2010;Entchev et al 2020).…”