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RTB Lectin: a novel receptor-independent delivery system for lysosomal enzyme replacement therapies

Enzyme replacement therapies have revolutionized patient treatment for multiple rare lysosomal storage diseases but show limited effectiveness for addressing pathologies in “hard-to-treat” organs and tissues including brain and bone. Here we investigate the plant lectin RTB as a novel carrier for hu...

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Autores principales: Acosta, Walter, Ayala, Jorge, Dolan, Maureen C., Cramer, Carole L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4585660/
https://www.ncbi.nlm.nih.gov/pubmed/26382970
http://dx.doi.org/10.1038/srep14144
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author Acosta, Walter
Ayala, Jorge
Dolan, Maureen C.
Cramer, Carole L.
author_facet Acosta, Walter
Ayala, Jorge
Dolan, Maureen C.
Cramer, Carole L.
author_sort Acosta, Walter
collection PubMed
description Enzyme replacement therapies have revolutionized patient treatment for multiple rare lysosomal storage diseases but show limited effectiveness for addressing pathologies in “hard-to-treat” organs and tissues including brain and bone. Here we investigate the plant lectin RTB as a novel carrier for human lysosomal enzymes. RTB enters mammalian cells by multiple mechanisms including both adsorptive-mediated and receptor-mediated endocytosis, and thus provides access to a broader array of organs and cells. Fusion proteins comprised of RTB and human α-L-iduronidase, the corrective enzyme for Mucopolysaccharidosis type I, were produced using a tobacco-based expression system. Fusion products retained both lectin selectivity and enzyme activity, were efficiently endocytosed into human fibroblasts, and corrected the disease phenotype of mucopolysaccharidosis patient fibroblasts in vitro. RTB-mediated delivery was independent of high-mannose and mannose-6-phosphate receptors, which are exploited for delivery of currently approved lysosomal enzyme therapeutics. Thus, the RTB carrier may support distinct in vivo pharmacodynamics with potential to address hard-to-treat tissues.
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spelling pubmed-45856602015-09-29 RTB Lectin: a novel receptor-independent delivery system for lysosomal enzyme replacement therapies Acosta, Walter Ayala, Jorge Dolan, Maureen C. Cramer, Carole L. Sci Rep Article Enzyme replacement therapies have revolutionized patient treatment for multiple rare lysosomal storage diseases but show limited effectiveness for addressing pathologies in “hard-to-treat” organs and tissues including brain and bone. Here we investigate the plant lectin RTB as a novel carrier for human lysosomal enzymes. RTB enters mammalian cells by multiple mechanisms including both adsorptive-mediated and receptor-mediated endocytosis, and thus provides access to a broader array of organs and cells. Fusion proteins comprised of RTB and human α-L-iduronidase, the corrective enzyme for Mucopolysaccharidosis type I, were produced using a tobacco-based expression system. Fusion products retained both lectin selectivity and enzyme activity, were efficiently endocytosed into human fibroblasts, and corrected the disease phenotype of mucopolysaccharidosis patient fibroblasts in vitro. RTB-mediated delivery was independent of high-mannose and mannose-6-phosphate receptors, which are exploited for delivery of currently approved lysosomal enzyme therapeutics. Thus, the RTB carrier may support distinct in vivo pharmacodynamics with potential to address hard-to-treat tissues. Nature Publishing Group 2015-09-18 /pmc/articles/PMC4585660/ /pubmed/26382970 http://dx.doi.org/10.1038/srep14144 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Acosta, Walter
Ayala, Jorge
Dolan, Maureen C.
Cramer, Carole L.
RTB Lectin: a novel receptor-independent delivery system for lysosomal enzyme replacement therapies
title RTB Lectin: a novel receptor-independent delivery system for lysosomal enzyme replacement therapies
title_full RTB Lectin: a novel receptor-independent delivery system for lysosomal enzyme replacement therapies
title_fullStr RTB Lectin: a novel receptor-independent delivery system for lysosomal enzyme replacement therapies
title_full_unstemmed RTB Lectin: a novel receptor-independent delivery system for lysosomal enzyme replacement therapies
title_short RTB Lectin: a novel receptor-independent delivery system for lysosomal enzyme replacement therapies
title_sort rtb lectin: a novel receptor-independent delivery system for lysosomal enzyme replacement therapies
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4585660/
https://www.ncbi.nlm.nih.gov/pubmed/26382970
http://dx.doi.org/10.1038/srep14144
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