Targeting Brain Disease in MPSII: Preclinical Evaluation of IDS-Loaded PLGA Nanoparticles

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.

Mucopolysaccharidosis Type II: One Hundred Years of Research, Diagnosis, and Treatment

“…Brain-targeted PLGA-nanoparticles were reported to be able to carry a high molecular weight model drug (albumin) across the blood-brain barrier in MPS I and MPS II mouse models [184]. Recently, the same nanoparticles were demonstrated to be able to transport the human recombinant IDS enzyme into the central nervous system, leading to a reduction of GAG storage and neuroinflammation in the MPS II mouse model [185].…”

“…From then on, fibroblasts have become a basic tool for studying the disease, from a diagnostic and therapeutic point of view, and for understanding the disease itself. Since the late '90s, fibroblasts have also been used to test the therapeutic activity of IDS enzymes released and purified from IDS-overexpressing cells [204,205], as well as in all the in vitro tests conducted as a preliminary analysis in the development of new therapeutic options, for instance, genistein [188,206], new recombinant human IDS enzymes [103], anti-human transferrin receptor antibody IDS fusion proteins [135], and brain-targeted nanoparticles loaded with IDS enzymes [185].…”

“…In the last twenty years, all these Ids-ko mouse models have been widely used for preclinical studies on different types of treatments. Among these are different dosages and routes of administration of ERT [103,125,222,229,[231][232][233][234][235], microcapsules enclosing myoblasts over-expressing IDS [183], different gene-therapy approaches [164][165][166]171,172,223,236], genistein [188], brain-penetrating IgG-Iduronate 2-sulphatase fusion protein [134], HSCT [234,237,238], ZFN-mediated in vivo genome editing [239], engineered nanoparticles for IDS enzyme brain-targeting [184,185], anti-human transferrin receptor antibody fusion protein [135], and chloroquine [230]. They were also useful for testing new methods of GAG analysis, aimed at improving their use as biomarkers in pre-clinical studies and successively in patients [125,223,240,241].…”

Mucopolysaccharidosis IVA: Diagnosis, Treatment, and Management

“…[140,141]. One of the advantages of nanomedicine is the capacity of some nanostructures to cross the biological barrier as the blood-brain barrier [142][143][144][145], where the main barrier for the effective treatment of MPS was due to neurological complications. In 2019, Donida et al reported the capacity of nanoparticles to cross BBB feasibly [146].…”

Investigating Novel Syntheses of a Series of Unique Hybrid PLGA-Chitosan Polymers for Potential Therapeutic Delivery Applications

“…(3) capable of producing both nanosystems or polymeric scaffolds; (4) chemically modifiable to include stealthing moieties (polyethylene glycol, PEG) and/or targeting ligands. All of these aspects have been widely exploited in production of PLGA nanoparticles (NPs) for the possible cure of a plethora of diseases [13][14][15][16][17][18].…”