Abstract
Mucopolysaccharidosis type II (MPSII) is a lysosomal storage disorder due to the deficit of the enzyme iduronate 2-sulfatase (IDS), which leads to the accumulation of glycosaminoglycans in most organ-systems, including the brain, and resulting in neurological involvement in about two-thirds of the patients. The main treatment is represented by a weekly infusion of the functional enzyme, which cannot cross the blood-brain barrier and reach the central nervous system. In this study, a tailored nanomedicine approach based on brain-targeted polymeric nanoparticles (g7-NPs), loaded with the therapeutic enzyme, was exploited. Fibroblasts from MPSII patients were treated for 7 days with NPs loaded with the IDS enzyme; an induced IDS activity like the one detected in healthy cells was measured, together with a reduction of GAG content to non-pathological levels. An in vivo short-term study in MPSII mice was performed by weekly administration of g7-NPs-IDS. Biochemical, histological, and immunohistochemical evaluations of liver and brain were performed. The 6-weeks treatment produced a significant reduction of GAG deposits in liver and brain tissues, as well as a reduction of some neurological and inflammatory markers (i.e., LAMP2, CD68, GFAP), highlighting a general improvement of the brain pathology. The g7-NPs-IDS approach allowed a brain-targeted enzyme replacement therapy. Based on these positive results, the future aim will be to optimize NP formulation further to gain a higher efficacy of the proposed approach.
Highlights
Mucopolysaccharidosis type II (MPSII, MIM #309900) is a rare, inherited disorder belonging to the group of mucopolysaccharidoses, a subgroup of the lysosomal storage disorders (LSDs)
enzyme replacement therapy (ERT) has shown some peripheral efficacy in patients [2,5,6,7], it cannot help the brain disease due to the inability of iduronate 2-sulfatase (IDS), like other lysosomal enzymes, to cross the blood-brain barrier (BBB) and reach the brain tissue
As this data was confirmed in at least three different batches of NPs, we assumed that this difference could be due to amphiphilic properties of the g7 peptide linked to PLGA, which could act as a bridge between the oil and water phases and could compete with IDS site within the hydrophilic environment inside the polymeric matrix
Summary
Mucopolysaccharidosis type II (MPSII, MIM #309900) is a rare, inherited disorder belonging to the group of mucopolysaccharidoses, a subgroup of the lysosomal storage disorders (LSDs). ERT has shown some peripheral efficacy in patients [2,5,6,7], it cannot help the brain disease due to the inability of IDS, like other lysosomal enzymes, to cross the blood-brain barrier (BBB) and reach the brain tissue. Another approach, hematopoietic stem cell transplantation, has shown in MPSII an almost complete inefficacy on brain disease, and a quite high risk to benefits ratio; the procedure is scarcely applied [8]
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