Mucopolysaccharidoses (MPSs) are degenerative genetic diseases linked to an enzymatic defect. In particular, MPSs are caused by the deficiency or the inactivity of lysosomal enzymes which catalyze the gradual metabolism of complex sugar molecules called glycosaminoglycans (GAGs). These enzymatic deficiencies cause an accumulation of GAGs in the cells, the tissues and, in particular, the cell lysosomes of affected subjects, leading to permanent and progressive cell damage which affects the appearance, the physical capacities, the organ function and, in most cases, the mental development of affected subjects.
Eleven distinct enzymatic defects have been identified, corresponding to seven distinct clinical categories of MPS. Each MPS is characterized by a deficiency or inactivity of one or more enzymes which degrade mucopolysaccharides, namely heparan sulfate, dermatan sulfate, chondroitin sulfate and keratin sulfate.
Mucopolysaccharidosis type III (MPS III) or Sanfilippo disease is a lysosomal storage disease, of the mucopolysaccharidosis group, characterized by severe and rapid intellectual degradation. The first symptoms appear between 2 and 6 years old: behavioral problems (hyperkinesia, aggressiveness) and intellectual degradation, and sleeping problems with very moderate dysmorphic signs. The neurological damage becomes more marked around the age of 10 years old, with loss of psychomotor acquisitions and of communication with the entourage. Epilepsy often occurs after the age of 10 years old. The disease is due to the presence of undegraded heparan sulfate owing to the defect in one or other of the four enzymes required for its catabolism, responsible for one of the four types of MPS III: type IIIA (heparan sulfamidase), type IIIB (alpha-N-acetylglucosaminidase), type IIIC (acetylCoA: alpha-glucosaminide-N-acetyltransferase) and type IIID (N-acetylglucosamine-6-sulfate sulfatase). There is at the current time no effective treatment for this disease.
Mucopolysaccharidosis type VI (MPS VI) or Maroteaux-Lamy disease is a lysosomal storage disease, of the mucopolysaccharidosis group, characterized by severe somatic involvement and an absence of psycho-intellectual regression. The prevalence of this rare mucopolysaccharidosis is between 1/250 000 and 1/600 000 births. In the severe forms, the first clinical manifestations occur between 6 and 24 months and are gradually accentuated: facial dysmorphia (macroglossia, mouth constantly half open, thick features), joint limitations, very severe dysostosis multiplex (platyspondyly, kyphosis, scoliosis, pectus carinatum, genu valgum, long bone deformation), small size (less than 1.10 m), hepatomegaly, heart valve damage, cardiomyopathy, deafness, corneal opacities. Intellectual development is usually normal or virtually normal, but the auditory and ophthalmological damage can cause learning difficulties.
The symptoms and the severity of the disease vary considerably from one patient to the other and intermediate forms, or even very moderate forms also exist (spondyloepiphyseal-metaphyseal dysplasia associated with cardiovascular involvement). Like the other mucopolysaccharidoses, Maroteaux-Lamy disease is linked to the defect of an enzyme of mucopolysaccharide metabolism, in the case in point N-acetylgalactosamine-4-sulfatase (also called arylsulfatase B). This enzyme metabolizes the sulfate group of dermatan sulfate (Neufeld et al.: “The mucopolysaccharidoses” The Metabolic Basis of Inherited Diseases, eds. Scriver et al, New York, McGraw-Hill, 1989, p. 1565-1587). This enzymatic defect blocks the gradual degradation of dermatan sulfate, thereby leading to an accumulation of dermatan sulfate in the lysosomes of the storage tissues. At the current time, there is just one medicament authorized for the treatment of this disease: Naglazyme® (recombinant human galsulfase), the cost of which is extremely high (in the United States, it is about $350 000 per year). An alternative to this treatment is bone marrow allograft.
Mucopolysaccharidosis type VII (MPS VII) or Sly disease is a very rare lysosomal storage disease of the mucopolysaccharidosis group. The symptomology is extremely heterogeneous: antenatal forms (nonimmune fetoplacental anasarca), severe neonatal forms (with dysmorphia, hernias, hepatosplenomegaly, club feet, dysostosis, significant hypotonia and neurological problems evolving to retarded growth and a profound intellectual deficiency in the event of survival) and very moderate forms discovered at adolescence or even at adult age (thoracic kyphosis). The disease is due to a defect in beta-D-glucuronidase, responsible for accumulation, in the lysosomes, of various glycosaminoglycans: dermatan sulfate, heparan sulfate and chondroitin sulfate. There is at the current time no effective treatment for this disease.
There is therefore clearly a need to provide subjects suffering from MPS type III, VI and VII with a drug treatment, and in the case of MPS type VI, an alternative treatment not derived from biotechnology.
Odiparcil (4-methyl-2-oxo-2H-1-benzopyran-7-yl-5-thio-β-D-xylopyranoside; CAS 137215-12-4) belongs to the thioxyloside family. This compound, described in patent application EP-A-0 421 829, corresponds to the formula:

This compound was the subject of a clinical development (phases 1 and 2) in the treatment of thrombosis at the end of the 1990s and at the beginning of the 2000s. Its mechanism of action can be summarized in the following way: Odiparcil behaves as a substrate for an enzyme, GT1 (galactosyl transferase 1), which initiates the synthesis of GAG chains toward the dermatan sulfate/chondroitin sulfate pathway. These GAGs are cell constituents as proteoglycans (when they are bonded to proteins on a serine and a first sugar which is xylose) and are also secreted into the extracellular medium. They have varied roles, ranging from the control of coagulation (heparin/heparan and dermatan sulfate secreted into the circulation) to the regulation of growth factors (beta-glycan).
It has now been noted, and this is the subject of the present invention, that Odiparcil makes it possible to increase total GAG synthesis at the extracellular level and, by the same token, will contribute to reducing the intracellular GAG load by acting as a “decoy”, making the residual activity of N-acetylgalactosamine-4-sulfatase more effective. It is thus possible to envision the treatment of MPS type III, VI and VII owing to the decrease in GAG accumulation at the intracellular level.