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Coformulation of a Novel Human α-Galactosidase A With the Pharmacological Chaperone AT1001 Leads to Improved Substrate Reduction in Fabry Mice
Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the gene that encodes α-galactosidase A and is characterized by pathological accumulation of globotriaosylceramide and globotriaosylsphingosine. Earlier, the authors demonstrated that oral coadministration of the pharmaco...
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/PMC4817779/ https://www.ncbi.nlm.nih.gov/pubmed/25915924 http://dx.doi.org/10.1038/mt.2015.87 |
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author | Xu, Su Lun, Yi Brignol, Nastry Hamler, Rick Schilling, Adriane Frascella, Michelle Sullivan, Sean Boyd, Robert E Chang, Kate Soska, Rebecca Garcia, Anadina Feng, Jessie Yasukawa, Hidehito Shardlow, Carole Churchill, Alison Ketkar, Amol Robertson, Nicola Miyamoto, Masahito Mihara, Kazutoshi Benjamin, Elfrida R Lockhart, David J Hirato, Tohru Fowles, Susie Valenzano, Kenneth J Khanna, Richie |
author_facet | Xu, Su Lun, Yi Brignol, Nastry Hamler, Rick Schilling, Adriane Frascella, Michelle Sullivan, Sean Boyd, Robert E Chang, Kate Soska, Rebecca Garcia, Anadina Feng, Jessie Yasukawa, Hidehito Shardlow, Carole Churchill, Alison Ketkar, Amol Robertson, Nicola Miyamoto, Masahito Mihara, Kazutoshi Benjamin, Elfrida R Lockhart, David J Hirato, Tohru Fowles, Susie Valenzano, Kenneth J Khanna, Richie |
author_sort | Xu, Su |
collection | PubMed |
description | Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the gene that encodes α-galactosidase A and is characterized by pathological accumulation of globotriaosylceramide and globotriaosylsphingosine. Earlier, the authors demonstrated that oral coadministration of the pharmacological chaperone AT1001 (migalastat HCl; 1-deoxygalactonojirimycin HCl) prior to intravenous administration of enzyme replacement therapy improved the pharmacological properties of the enzyme. In this study, the authors investigated the effects of coformulating AT1001 with a proprietary recombinant human α-galactosidase A (ATB100) into a single intravenous formulation. AT1001 increased the physical stability and reduced aggregation of ATB100 at neutral pH in vitro, and increased the potency for ATB100-mediated globotriaosylceramide reduction in cultured Fabry fibroblasts. In Fabry mice, AT1001 coformulation increased the total exposure of active enzyme, and increased ATB100 levels in cardiomyocytes, cardiac vascular endothelial cells, renal distal tubular epithelial cells, and glomerular cells, cell types that do not show substantial uptake with enzyme replacement therapy alone. Notably, AT1001 coformulation also leads to greater tissue globotriaosylceramide reduction when compared with ATB100 alone, which was positively correlated with reductions in plasma globotriaosylsphingosine. Collectively, these data indicate that intravenous administration of ATB100 coformulated with AT1001 may provide an improved therapy for Fabry disease and thus warrants further investigation. |
format | Online Article Text |
id | pubmed-4817779 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-48177792016-04-15 Coformulation of a Novel Human α-Galactosidase A With the Pharmacological Chaperone AT1001 Leads to Improved Substrate Reduction in Fabry Mice Xu, Su Lun, Yi Brignol, Nastry Hamler, Rick Schilling, Adriane Frascella, Michelle Sullivan, Sean Boyd, Robert E Chang, Kate Soska, Rebecca Garcia, Anadina Feng, Jessie Yasukawa, Hidehito Shardlow, Carole Churchill, Alison Ketkar, Amol Robertson, Nicola Miyamoto, Masahito Mihara, Kazutoshi Benjamin, Elfrida R Lockhart, David J Hirato, Tohru Fowles, Susie Valenzano, Kenneth J Khanna, Richie Mol Ther Original Article Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the gene that encodes α-galactosidase A and is characterized by pathological accumulation of globotriaosylceramide and globotriaosylsphingosine. Earlier, the authors demonstrated that oral coadministration of the pharmacological chaperone AT1001 (migalastat HCl; 1-deoxygalactonojirimycin HCl) prior to intravenous administration of enzyme replacement therapy improved the pharmacological properties of the enzyme. In this study, the authors investigated the effects of coformulating AT1001 with a proprietary recombinant human α-galactosidase A (ATB100) into a single intravenous formulation. AT1001 increased the physical stability and reduced aggregation of ATB100 at neutral pH in vitro, and increased the potency for ATB100-mediated globotriaosylceramide reduction in cultured Fabry fibroblasts. In Fabry mice, AT1001 coformulation increased the total exposure of active enzyme, and increased ATB100 levels in cardiomyocytes, cardiac vascular endothelial cells, renal distal tubular epithelial cells, and glomerular cells, cell types that do not show substantial uptake with enzyme replacement therapy alone. Notably, AT1001 coformulation also leads to greater tissue globotriaosylceramide reduction when compared with ATB100 alone, which was positively correlated with reductions in plasma globotriaosylsphingosine. Collectively, these data indicate that intravenous administration of ATB100 coformulated with AT1001 may provide an improved therapy for Fabry disease and thus warrants further investigation. Nature Publishing Group 2015-07 2015-06-02 /pmc/articles/PMC4817779/ /pubmed/25915924 http://dx.doi.org/10.1038/mt.2015.87 Text en Copyright © 2015 American Society of Gene & Cell Therapy http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 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-nc-nd/4.0/ |
spellingShingle | Original Article Xu, Su Lun, Yi Brignol, Nastry Hamler, Rick Schilling, Adriane Frascella, Michelle Sullivan, Sean Boyd, Robert E Chang, Kate Soska, Rebecca Garcia, Anadina Feng, Jessie Yasukawa, Hidehito Shardlow, Carole Churchill, Alison Ketkar, Amol Robertson, Nicola Miyamoto, Masahito Mihara, Kazutoshi Benjamin, Elfrida R Lockhart, David J Hirato, Tohru Fowles, Susie Valenzano, Kenneth J Khanna, Richie Coformulation of a Novel Human α-Galactosidase A With the Pharmacological Chaperone AT1001 Leads to Improved Substrate Reduction in Fabry Mice |
title | Coformulation of a Novel Human α-Galactosidase A With the Pharmacological Chaperone AT1001 Leads to Improved Substrate Reduction in Fabry Mice |
title_full | Coformulation of a Novel Human α-Galactosidase A With the Pharmacological Chaperone AT1001 Leads to Improved Substrate Reduction in Fabry Mice |
title_fullStr | Coformulation of a Novel Human α-Galactosidase A With the Pharmacological Chaperone AT1001 Leads to Improved Substrate Reduction in Fabry Mice |
title_full_unstemmed | Coformulation of a Novel Human α-Galactosidase A With the Pharmacological Chaperone AT1001 Leads to Improved Substrate Reduction in Fabry Mice |
title_short | Coformulation of a Novel Human α-Galactosidase A With the Pharmacological Chaperone AT1001 Leads to Improved Substrate Reduction in Fabry Mice |
title_sort | coformulation of a novel human α-galactosidase a with the pharmacological chaperone at1001 leads to improved substrate reduction in fabry mice |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817779/ https://www.ncbi.nlm.nih.gov/pubmed/25915924 http://dx.doi.org/10.1038/mt.2015.87 |
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