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

• Published in: International journal of molecular sciences 2019-04, Vol.20 (8), p.2014
• Main Authors: Rigon, Laura, Salvalaio, Marika, Pederzoli, Francesca, Legnini, Elisa, Duskey, Jason Thomas, D'Avanzo, Francesca, De Filippis, Concetta, Ruozi, Barbara, Marin, Oriano, Vandelli, Maria Angela, Ottonelli, Ilaria, Scarpa, Maurizio, Tosi, Giovanni, Tomanin, Rosella
• Format: Article
• Language: English
• Subjects: Albumins; Blood-brain barrier; Brain diseases; brain targeting; central nervous system; Chitosan; enzyme replacement therapy; Enzymes; Fibroblasts; Hunter syndrome; Inorganic materials; Insulin; Ligands; Liver; lysosomal storage disorders; MPS II; mucopolysaccharidosis; Nanoparticles; Parenchyma; Peptides; PLGA; Polyethylene glycol; Polylactide-co-glycolide; Rodents; Silica; Sodium chloride; Transferrin; Transferrins
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20082014

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.