All are examples of gene mutations in which pathology results from the deficiency of a single lysosomal hydrolase. ![]() The potential for ERT to be an effective treatment modality for MPS disorders is high. Clinical trials of ERT in several lysosomal storage disorders are also currently underway (abstracts of the Fifth International Symposium on MPS and Related Diseases, unpublished proceedings). Joint movement is also progressively limited ( 1, 2).Įnzyme replacement therapy (ERT) is currently in clinical use for at least two genetically transmitted disorders: Gaucher's disease and severe combined immunodeficiency/adenosine deaminase deficiency ( 4– 6). For severely affected children this involves short stature and bone radiographic changes (dysostosis multiplex). Children with MPS VI present with a range of clinical symptoms, most notably skeletal abnormalities. A reduction in the level of 4S results in the accumulation of undegraded glycosaminoglycans within the lysosomes of many tissues ( 3). This enzyme is required for the lysosomal degradation of dermatan sulfate and chondroitin sulfate glycosaminoglycan chains. Mucopolysaccharidosis VI (MPS VI, Maroteaux-Lamy syndrome) results from the deficiency of the lysosomal hydrolase N-acetylgalactosamine-4-sulphatase (4S EC 3.1.6.1). The mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders that have in common an inability to degrade glycosaminoglycan chains ( 1, 2). To optimize therapy and improve the amount of enzyme reaching cartilage and other tissues demonstrating poor uptake, it may be necessary to bypass the liver or prolong plasma half-life so that proportionately more enzyme is delivered to other tissues. ![]() Distribution experiments indicated the majority of enzyme is taken up by the liver irrespective of modification. However, in vivo ERT studies demonstrated that response to therapy was not significantly improved by either the enzyme modifications or change to the dosing regimen, when compared with ERT with unmodified enzyme. Modification resulted in active 4S that maintained its ability to correct MPS storage and increased the partitioning coefficient of 4S into cartilage by 77% and 50% for ethylene diamine and poly-L-lysine, respectively. To alter the tissue distribution of 4S, the enzyme was coupled to ethylene diamine or poly-L-lysine, increasing its overall charge and diffusion into cartilage, and the dosing frequency of unmodified 4S was increased. administered enzyme does not distribute significantly into articular cartilage in vivo. In vitro, the penetration of 4S into articular cartilage is low (partitioning coefficient = 0.06) and i.v. In this study, we demonstrate that recombinant human N-acetylgalactosamine-4-sulphatase (4S) is taken up by chondrocytes via a mannose-6-phosphate-dependent mechanism and is effective at removing MPS storage. ![]() One exception is that cartilage and chondrocytes remained distended with extensive lysosomal vacuolation after long-term, high-dose ERT. Enzyme replacement therapy (ERT) in the MPS VI cat is effective at reducing or eliminating pathology in most connective tissues.
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