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Brain-targeted enzyme-loaded nanoparticles: A breach through the blood-brain barrier for enzyme replacement therapy in Krabbe disease

Lysosomal storage disorders (LSDs) result from an enzyme deficiency within lysosomes. The systemic administration of the missing enzyme, however, is not effective in the case of LSDs with central nervous system (CNS)-involvement. Here, an enzyme delivery system based on the encapsulation of cross-li...

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Autores principales: Del Grosso, Ambra, Galliani, Marianna, Angella, Lucia, Santi, Melissa, Tonazzini, Ilaria, Parlanti, Gabriele, Signore, Giovanni, Cecchini, Marco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6867879/
https://www.ncbi.nlm.nih.gov/pubmed/31799395
http://dx.doi.org/10.1126/sciadv.aax7462
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author Del Grosso, Ambra
Galliani, Marianna
Angella, Lucia
Santi, Melissa
Tonazzini, Ilaria
Parlanti, Gabriele
Signore, Giovanni
Cecchini, Marco
author_facet Del Grosso, Ambra
Galliani, Marianna
Angella, Lucia
Santi, Melissa
Tonazzini, Ilaria
Parlanti, Gabriele
Signore, Giovanni
Cecchini, Marco
author_sort Del Grosso, Ambra
collection PubMed
description Lysosomal storage disorders (LSDs) result from an enzyme deficiency within lysosomes. The systemic administration of the missing enzyme, however, is not effective in the case of LSDs with central nervous system (CNS)-involvement. Here, an enzyme delivery system based on the encapsulation of cross-linked enzyme aggregates (CLEAs) into poly-(lactide-co-glycolide) (PLGA) nanoparticles (NPs) functionalized with brain targeting peptides (Ang2, g7 or Tf2) is demonstrated for Krabbe disease, a neurodegenerative LSD caused by galactosylceramidase (GALC) deficiency. We first synthesize and characterize Ang2-, g7- and Tf2-targeted GALC CLEA NPs. We study NP cell trafficking and capability to reinstate enzymatic activity in vitro. Then, we successfully test our formulations in the Twitcher mouse. We report enzymatic activity measurements in the nervous system and in accumulation districts upon intraperitoneal injections, demonstrating activity recovery in the brain up to the unaffected mice level. Together, these results open new therapeutic perspectives for all LSDs with major CNS-involvement.
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spelling pubmed-68678792019-12-03 Brain-targeted enzyme-loaded nanoparticles: A breach through the blood-brain barrier for enzyme replacement therapy in Krabbe disease Del Grosso, Ambra Galliani, Marianna Angella, Lucia Santi, Melissa Tonazzini, Ilaria Parlanti, Gabriele Signore, Giovanni Cecchini, Marco Sci Adv Research Articles Lysosomal storage disorders (LSDs) result from an enzyme deficiency within lysosomes. The systemic administration of the missing enzyme, however, is not effective in the case of LSDs with central nervous system (CNS)-involvement. Here, an enzyme delivery system based on the encapsulation of cross-linked enzyme aggregates (CLEAs) into poly-(lactide-co-glycolide) (PLGA) nanoparticles (NPs) functionalized with brain targeting peptides (Ang2, g7 or Tf2) is demonstrated for Krabbe disease, a neurodegenerative LSD caused by galactosylceramidase (GALC) deficiency. We first synthesize and characterize Ang2-, g7- and Tf2-targeted GALC CLEA NPs. We study NP cell trafficking and capability to reinstate enzymatic activity in vitro. Then, we successfully test our formulations in the Twitcher mouse. We report enzymatic activity measurements in the nervous system and in accumulation districts upon intraperitoneal injections, demonstrating activity recovery in the brain up to the unaffected mice level. Together, these results open new therapeutic perspectives for all LSDs with major CNS-involvement. American Association for the Advancement of Science 2019-11-20 /pmc/articles/PMC6867879/ /pubmed/31799395 http://dx.doi.org/10.1126/sciadv.aax7462 Text en Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). http://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (http://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Research Articles
Del Grosso, Ambra
Galliani, Marianna
Angella, Lucia
Santi, Melissa
Tonazzini, Ilaria
Parlanti, Gabriele
Signore, Giovanni
Cecchini, Marco
Brain-targeted enzyme-loaded nanoparticles: A breach through the blood-brain barrier for enzyme replacement therapy in Krabbe disease
title Brain-targeted enzyme-loaded nanoparticles: A breach through the blood-brain barrier for enzyme replacement therapy in Krabbe disease
title_full Brain-targeted enzyme-loaded nanoparticles: A breach through the blood-brain barrier for enzyme replacement therapy in Krabbe disease
title_fullStr Brain-targeted enzyme-loaded nanoparticles: A breach through the blood-brain barrier for enzyme replacement therapy in Krabbe disease
title_full_unstemmed Brain-targeted enzyme-loaded nanoparticles: A breach through the blood-brain barrier for enzyme replacement therapy in Krabbe disease
title_short Brain-targeted enzyme-loaded nanoparticles: A breach through the blood-brain barrier for enzyme replacement therapy in Krabbe disease
title_sort brain-targeted enzyme-loaded nanoparticles: a breach through the blood-brain barrier for enzyme replacement therapy in krabbe disease
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6867879/
https://www.ncbi.nlm.nih.gov/pubmed/31799395
http://dx.doi.org/10.1126/sciadv.aax7462
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