Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2012
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
_version_ 1782228964159258624
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
work_keys_str_mv AT benjaminelfridar coadministrationwiththepharmacologicalchaperoneat1001increasesrecombinanthumanagalactosidaseatissueuptakeandimprovessubstratereductioninfabrymice
AT khannarichie coadministrationwiththepharmacologicalchaperoneat1001increasesrecombinanthumanagalactosidaseatissueuptakeandimprovessubstratereductioninfabrymice
AT schillingadriane coadministrationwiththepharmacologicalchaperoneat1001increasesrecombinanthumanagalactosidaseatissueuptakeandimprovessubstratereductioninfabrymice
AT flanaganjohnj coadministrationwiththepharmacologicalchaperoneat1001increasesrecombinanthumanagalactosidaseatissueuptakeandimprovessubstratereductioninfabrymice
AT pellegrinoleej coadministrationwiththepharmacologicalchaperoneat1001increasesrecombinanthumanagalactosidaseatissueuptakeandimprovessubstratereductioninfabrymice
AT brignolnastry coadministrationwiththepharmacologicalchaperoneat1001increasesrecombinanthumanagalactosidaseatissueuptakeandimprovessubstratereductioninfabrymice
AT lunyi coadministrationwiththepharmacologicalchaperoneat1001increasesrecombinanthumanagalactosidaseatissueuptakeandimprovessubstratereductioninfabrymice
AT guillendarlene coadministrationwiththepharmacologicalchaperoneat1001increasesrecombinanthumanagalactosidaseatissueuptakeandimprovessubstratereductioninfabrymice
AT ranesbriane coadministrationwiththepharmacologicalchaperoneat1001increasesrecombinanthumanagalactosidaseatissueuptakeandimprovessubstratereductioninfabrymice
AT frascellamichelle coadministrationwiththepharmacologicalchaperoneat1001increasesrecombinanthumanagalactosidaseatissueuptakeandimprovessubstratereductioninfabrymice
AT soskarebecca coadministrationwiththepharmacologicalchaperoneat1001increasesrecombinanthumanagalactosidaseatissueuptakeandimprovessubstratereductioninfabrymice
AT fengjessie coadministrationwiththepharmacologicalchaperoneat1001increasesrecombinanthumanagalactosidaseatissueuptakeandimprovessubstratereductioninfabrymice
AT dunganleo coadministrationwiththepharmacologicalchaperoneat1001increasesrecombinanthumanagalactosidaseatissueuptakeandimprovessubstratereductioninfabrymice
AT youngbrandy coadministrationwiththepharmacologicalchaperoneat1001increasesrecombinanthumanagalactosidaseatissueuptakeandimprovessubstratereductioninfabrymice
AT lockhartdavidj coadministrationwiththepharmacologicalchaperoneat1001increasesrecombinanthumanagalactosidaseatissueuptakeandimprovessubstratereductioninfabrymice
AT valenzanokennethj coadministrationwiththepharmacologicalchaperoneat1001increasesrecombinanthumanagalactosidaseatissueuptakeandimprovessubstratereductioninfabrymice