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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
Coformulation of a Novel Human α-Galactosidase A With the Pharmacological Chaperone AT1001 Leads to Improved Substrate Reduction in Fabry Mice
- Source :
- Molecular Therapy
- Publication Year :
- 2015
- Publisher :
- Elsevier BV, 2015.
-
Abstract
- 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.
- Subjects :
- Cell type
Globotriaosylceramide
Pharmacology
law.invention
Substrate Specificity
chemistry.chemical_compound
Mice
law
Drug Discovery
medicine
Genetics
Animals
Humans
Enzyme Replacement Therapy
Molecular Biology
chemistry.chemical_classification
Enzyme replacement therapy
Fibroblasts
medicine.disease
Fabry disease
In vitro
Pharmacological chaperone
Disease Models, Animal
Drug Combinations
Enzyme
Biochemistry
chemistry
alpha-Galactosidase
Mutation
Recombinant DNA
Fabry Disease
Molecular Medicine
Original Article
Oligopeptides
medicine.drug
Molecular Chaperones
Subjects
Details
- ISSN :
- 15250016
- Volume :
- 23
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- Molecular Therapy
- Accession number :
- edsair.doi.dedup.....5db797d492b47f1734acc9db7156d0d8
- Full Text :
- https://doi.org/10.1038/mt.2015.87