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Maroteaux-Lamy disease/mucopolysaccharidosis VI/N-acetylgalactosamine-4-sulfatase deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
N-acetylgalactosamine-4-sulfatase catalyzes the hydrolysis of the sulfate from moieties of N-acetylgalactosamine-4-sulfate which occur in dermatan sulfate. The moieties are also found in chondroitin-4-sulfate. Defective activity in this hydrolysis may account for some of the abnormalities in the joints, but chondroitin sulfate is not found in the urine because it can be degraded by hyaluronidase. The enzyme is also known as arylsulfatase B. The human enzyme has been purified [37, 38]. Its biosynthesis and processing involve the phosphorylation of mannose moieties and proteolysis in the classic lysosomal enzyme pattern [39, 40].
Chemistry
Published in Stephen P. Coburn, The Chemistry and Metabolism of 4′-Deoxypyridoxine, 2018
We94 also found some unexpected neighboring group effects which misled Shane and Snell446 in their examination of the metabolism of 5′-deoxypyridoxine. First, 2,6 dimethyl substitution around the phenol group almost completely inhibited arylsulfatases from limpet, Helix pomatia, abalone entrails, and Aerobaeter aerogenes. Thus, the 3-sulfate derivatives of 4′- and 5-deoxypyridoxines were not hydrolyzed even though they are aryl sulfates.
What’s next in gene therapy for Crigler-Najjar syndrome?
Published in Expert Opinion on Biological Therapy, 2023
Sem J Aronson, Giuseppe Ronzitti, Piter J Bosma
A second limitation to be addressed is the use of AAV-mediated gene therapy in neonates or children suffering from this disease. The rapid loss of episomal AAV vectors upon hepatocyte proliferation hampers long-term treatment efficacy in the fast-growing liver of neonatal and juvenile animals [10]. In addition, treatment with AAV vectors results in the formation of a strong, neutralizing antibody response, rendering subsequent hepatocyte transduction ineffective. This underscores that treatment early after birth may not provide long-term correction. In contrast to rodents, in which the liver growth occurs in a very limited period of 6 weeks, the slower liver growth in humans may lead to lower vector dilution. Interestingly, a recent report indicated persistent expression of the transgene in a 4-year-old MPS VI patient treated with an AAV8 vector expressing arylsulfatase B, suggesting that AAV treatment of young children may provide sustained correction [15].
Novel chorioretinal findings in two siblings with mucopolysaccharidosis type VI
Published in Ophthalmic Genetics, 2022
Tanya Kowalski, Sarah Donoghue, Gerard de Jong, Heather G. Mack
The Mucopolysaccharidoses are a collection of clinically distinct syndromes grouped together under this nomenclature as they each result from specific genetically defined alterations in the biochemical processing of glycosaminoglycans (GAG). Mucopolysaccharidosis type VI (MPS VI, Maroteaux-Lamy syndrome, OMIM # 253,200) is an autosomal recessive lysosomal storage disorder caused by genetic variants in the arylsulfatase B (ARSB) gene on chromosome 5q14. The arylsulfatase B enzyme is responsible for processing the residues at the ends of dermatan sulfate and chondroitin 4-sulfate by hydrolysing the C4 ester linkage in the N-acetylgalactosamine 4-sulfate residues at the non-reducing end of the GAG (1). Deficiency of ARSB enzyme activity in MPS VI patients leads to the accumulation of partially degraded GAGs dermatan sulfate and chondroitin-4 sulfate. Accumulation of these intermediate breakdown products in the lysosomes of tissues in multiple organ systems causes cellular and structural damage by a number of mechanisms including inflammatory cascades through the activation of the Toll-like receptor-4 (2).
Nanoparticles as carriers for drug delivery of macromolecules across the blood-brain barrier
Published in Expert Opinion on Drug Delivery, 2020
Giovanni Tosi, J. T. Duskey, Jörg Kreuter
One of these diseases is metachromatic leukodystrophy (MLD). This LSD is caused by the accumulation of the sulfated glycosphingolipid 3-O-sulfogalactosylceramide (sulfatide), a main lipid component of myelin [81,82], resulting in the demyelination of the CNS, progressive neurological symptoms, and premature death of patients [31]. The deficient enzyme in this disease is the lysosomal enzyme arylsulfatase A the lysosomal enzyme arylsulfatase A (ASA), which is required for the degradation of the sulfatide. In order to enable the transport of this enzyme across the BBB, Schuster et al. investigated three different strategies to bind ASA to the NPs surfaces, i.e. adsorption, high-affinity binding via the neutravidin-biotin system, and covalent binding [31]. The authors employed four types of nanoparticle polymers PBCA, poly-lactic acid, PLGA, and crosslinked HSA. The sizes of all these preparations were between 100 and 310 nm. Although adsorption led to a high loading of ASA, after contact with saline or serum the enzyme was rapidly desorbed, whereas negligible ASA release was achieved by the high-affinity and by the covalent binding. In the context of this review it has to be noted that adsorption of the biochemically similar arylsulfatase B was more stable under the same conditions [83]. ASA bound by PLGA nanoparticles via the neutravidin-biotin system as well as ASA bound via the crosslinker MALHEX-NH-PEG-O-C3H6-CONHS to HSA nanoparticles were administered by tail-vein injections into ASA−/− mice, an animal model of MLD. Compared to free ASA, injected as a control, the biodistribution of nanoparticle-bound ASA was altered in peripheral organs, but no increase of brain levels was detectable. This failure to improve brain delivery suggests that due to the peculiarities of ASA, this glycoprotein may interfere with processes required to direct the nanoparticles to the respective receptors of the brain capillary endothelial cells or prevents a receptor-mediated transcytosis of the nanoparticles across the BBB [31].