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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2015
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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. |
format | Online Article Text |
id | pubmed-4585660 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
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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