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Published on: December 27, 2013
Targeting Brain Disease in MPSII: Preclinical Evaluation of IDS-Loaded PLGA Nanoparticles
Laura Rigon1,2, Marika Salvalaio3,4, Francesca Pederzoli5,6
1Department of Women's and Children's Health, University of Padova, 35128 Padova, Italy. laura.rigon@unipd.it.
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.
Insights
This study introduces brain-targeted nanoparticles to deliver enzyme replacement therapy for Mucopolysaccharidosis type II (MPSII). The nanomedicine approach successfully reduced GAG accumulation and improved brain pathology in MPSII models.
Area of Science:
- Biomedical Engineering
- Nanomedicine
- Lysosomal Storage Disorders
Background:
- Mucopolysaccharidosis type II (MPSII) is a genetic disorder causing glycosaminoglycan (GAG) buildup.
- Current enzyme replacement therapy for MPSII has limited efficacy due to inability to cross the blood-brain barrier.
- Neurological involvement affects a significant portion of MPSII patients.
Purpose of the Study:
- To develop and evaluate a brain-targeted nanomedicine approach for MPSII enzyme replacement therapy.
- To assess the efficacy of enzyme-loaded nanoparticles in reducing GAG accumulation and improving brain pathology in MPSII models.
Main Methods:
- Utilized brain-targeted polymeric nanoparticles (g7-NPs) loaded with iduronate 2-sulfatase (IDS) enzyme.
- Treated MPSII patient fibroblasts in vitro to measure IDS activity and GAG levels.
- Administered g7-NPs-IDS weekly to MPSII mice for a short-term in vivo study.
- Conducted biochemical, histological, and immunohistochemical analyses of liver and brain tissues.
Main Results:
- In vitro: Restored IDS activity and reduced GAG levels in MPSII fibroblasts.
- In vivo: Significantly reduced GAG deposits in liver and brain tissues of MPSII mice.
- Demonstrated reduction in neurological and inflammatory markers (LAMP2, CD68, GFAP) in the brain.
- Indicated a general improvement in brain pathology.
Conclusions:
- Brain-targeted polymeric nanoparticles (g7-NPs) loaded with IDS represent a promising strategy for enzyme replacement therapy in MPSII.
- This nanomedicine approach facilitates enzyme delivery across the blood-brain barrier, addressing a key limitation of conventional therapy.
- Further optimization of NP formulation is warranted to enhance therapeutic efficacy for MPSII neurological complications.
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