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Co-administration With the Pharmacological Chaperone AT1001 Increases Recombinant Human α-Galactosidase A Tissue Uptake and Improves Substrate Reduction in Fabry Mice
Fabry disease is an X-linked lysosomal storage disorder (LSD) caused by mutations in the gene (GLA) that encodes the lysosomal hydrolase α-galactosidase A (α-Gal A), and is characterized by pathological accumulation of the substrate, globotriaosylceramide (GL-3). Regular infusion of recombinant huma...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321591/ https://www.ncbi.nlm.nih.gov/pubmed/22215019 http://dx.doi.org/10.1038/mt.2011.271 |
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author | Benjamin, Elfrida R Khanna, Richie Schilling, Adriane Flanagan, John J Pellegrino, Lee J Brignol, Nastry Lun, Yi Guillen, Darlene Ranes, Brian E Frascella, Michelle Soska, Rebecca Feng, Jessie Dungan, Leo Young, Brandy Lockhart, David J Valenzano, Kenneth J |
author_facet | Benjamin, Elfrida R Khanna, Richie Schilling, Adriane Flanagan, John J Pellegrino, Lee J Brignol, Nastry Lun, Yi Guillen, Darlene Ranes, Brian E Frascella, Michelle Soska, Rebecca Feng, Jessie Dungan, Leo Young, Brandy Lockhart, David J Valenzano, Kenneth J |
author_sort | Benjamin, Elfrida R |
collection | PubMed |
description | Fabry disease is an X-linked lysosomal storage disorder (LSD) caused by mutations in the gene (GLA) that encodes the lysosomal hydrolase α-galactosidase A (α-Gal A), and is characterized by pathological accumulation of the substrate, globotriaosylceramide (GL-3). Regular infusion of recombinant human α-Gal A (rhα-Gal A), termed enzyme replacement therapy (ERT), is the primary treatment for Fabry disease. However, rhα-Gal A has low physical stability, a short circulating half-life, and variable uptake into different disease-relevant tissues. We hypothesized that coadministration of the orally available, small molecule pharmacological chaperone AT1001 (GR181413A, 1-deoxygalactonojirimycin, migalastat hydrochloride) may improve the pharmacological properties of rhα-Gal A via binding and stabilization. AT1001 prevented rhα-Gal A denaturation and activity loss in vitro at neutral pH and 37 °C. Coincubation of Fabry fibroblasts with rhα-Gal A and AT1001 resulted in up to fourfold higher cellular α-Gal A and ~30% greater GL-3 reduction compared to rhα-Gal A alone. Furthermore, coadministration of AT1001 to rats increased the circulating half-life of rhα-Gal A by >2.5-fold, and in GLA knockout mice resulted in up to fivefold higher α-Gal A levels and fourfold greater GL-3 reduction than rhα-Gal A alone. Collectively, these data highlight the potentially beneficial effects of AT1001 on rhα-Gal A, thus warranting clinical investigation. |
format | Online Article Text |
id | pubmed-3321591 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-33215912012-04-09 Co-administration With the Pharmacological Chaperone AT1001 Increases Recombinant Human α-Galactosidase A Tissue Uptake and Improves Substrate Reduction in Fabry Mice Benjamin, Elfrida R Khanna, Richie Schilling, Adriane Flanagan, John J Pellegrino, Lee J Brignol, Nastry Lun, Yi Guillen, Darlene Ranes, Brian E Frascella, Michelle Soska, Rebecca Feng, Jessie Dungan, Leo Young, Brandy Lockhart, David J Valenzano, Kenneth J Mol Ther Original Article Fabry disease is an X-linked lysosomal storage disorder (LSD) caused by mutations in the gene (GLA) that encodes the lysosomal hydrolase α-galactosidase A (α-Gal A), and is characterized by pathological accumulation of the substrate, globotriaosylceramide (GL-3). Regular infusion of recombinant human α-Gal A (rhα-Gal A), termed enzyme replacement therapy (ERT), is the primary treatment for Fabry disease. However, rhα-Gal A has low physical stability, a short circulating half-life, and variable uptake into different disease-relevant tissues. We hypothesized that coadministration of the orally available, small molecule pharmacological chaperone AT1001 (GR181413A, 1-deoxygalactonojirimycin, migalastat hydrochloride) may improve the pharmacological properties of rhα-Gal A via binding and stabilization. AT1001 prevented rhα-Gal A denaturation and activity loss in vitro at neutral pH and 37 °C. Coincubation of Fabry fibroblasts with rhα-Gal A and AT1001 resulted in up to fourfold higher cellular α-Gal A and ~30% greater GL-3 reduction compared to rhα-Gal A alone. Furthermore, coadministration of AT1001 to rats increased the circulating half-life of rhα-Gal A by >2.5-fold, and in GLA knockout mice resulted in up to fivefold higher α-Gal A levels and fourfold greater GL-3 reduction than rhα-Gal A alone. Collectively, these data highlight the potentially beneficial effects of AT1001 on rhα-Gal A, thus warranting clinical investigation. Nature Publishing Group 2012-04 2012-01-03 /pmc/articles/PMC3321591/ /pubmed/22215019 http://dx.doi.org/10.1038/mt.2011.271 Text en Copyright © 2012 The American Society of Gene & Cell Therapy http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/ |
spellingShingle | Original Article Benjamin, Elfrida R Khanna, Richie Schilling, Adriane Flanagan, John J Pellegrino, Lee J Brignol, Nastry Lun, Yi Guillen, Darlene Ranes, Brian E Frascella, Michelle Soska, Rebecca Feng, Jessie Dungan, Leo Young, Brandy Lockhart, David J Valenzano, Kenneth J Co-administration With the Pharmacological Chaperone AT1001 Increases Recombinant Human α-Galactosidase A Tissue Uptake and Improves Substrate Reduction in Fabry Mice |
title | Co-administration With the Pharmacological Chaperone AT1001 Increases Recombinant Human α-Galactosidase A Tissue Uptake and Improves Substrate Reduction in Fabry Mice |
title_full | Co-administration With the Pharmacological Chaperone AT1001 Increases Recombinant Human α-Galactosidase A Tissue Uptake and Improves Substrate Reduction in Fabry Mice |
title_fullStr | Co-administration With the Pharmacological Chaperone AT1001 Increases Recombinant Human α-Galactosidase A Tissue Uptake and Improves Substrate Reduction in Fabry Mice |
title_full_unstemmed | Co-administration With the Pharmacological Chaperone AT1001 Increases Recombinant Human α-Galactosidase A Tissue Uptake and Improves Substrate Reduction in Fabry Mice |
title_short | Co-administration With the Pharmacological Chaperone AT1001 Increases Recombinant Human α-Galactosidase A Tissue Uptake and Improves Substrate Reduction in Fabry Mice |
title_sort | co-administration with the pharmacological chaperone at1001 increases recombinant human α-galactosidase a tissue uptake and improves substrate reduction in fabry mice |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321591/ https://www.ncbi.nlm.nih.gov/pubmed/22215019 http://dx.doi.org/10.1038/mt.2011.271 |
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