The pharmacological chaperone 1-deoxygalactonojirimycin increases α-galactosidase A levels in Fabry patient cell lines

@article{Benjamin2009ThePC,
  title={The pharmacological chaperone 1-deoxygalactonojirimycin increases $\alpha$-galactosidase A levels in Fabry patient cell lines},
  author={Elfrida R. Benjamin and John J. Flanagan and Adriane Schilling and H. H. Chang and L. Agarwal and Evan Katz and X. Wu and Corey W Pine and Brandon A. Wustman and R. J. Desnick and David J Lockhart and Kenneth J. Valenzano},
  journal={Journal of Inherited Metabolic Disease},
  year={2009},
  volume={32},
  pages={424-440}
}
SummaryFabry disease is an X-linked lysosomal storage disorder caused by mutations in the gene encoding α-galactosidase A (α-Gal A), with consequent accumulation of its major glycosphingolipid substrate, globotriaosylceramide (GL-3). Over 500 Fabry mutations have been reported; approximately 60% are missense. The iminosugar 1-deoxygalactonojirimycin (DGJ, migalastat hydrochloride, AT1001) is a pharmacological chaperone that selectively binds α-Gal A, increasing physical stability, lysosomal… 
The pharmacological chaperone 1-deoxygalactonojirimycin reduces tissue globotriaosylceramide levels in a mouse model of Fabry disease.
TLDR
It is indicated that oral administration of DGJ increases mutant alpha-Gal A activity and reduces GL-3 in disease-relevant tissues in Tg/KO mice, and thus merits further evaluation as a treatment for Fabry disease.
Synergy between the pharmacological chaperone 1-deoxygalactonojirimycin and the human recombinant alpha-galactosidase A in cultured fibroblasts from patients with Fabry disease
TLDR
This study provides additional evidence for a synergistic effect between ERT and pharmacological chaperone therapy and supports the idea that the efficacy of combination protocols may be superior to ERT alone.
Misfolding of Lysosomal α-Galactosidase a in a Fly Model and Its Alleviation by the Pharmacological Chaperone Migalastat
TLDR
When expressed in the fly’s dopaminergic cells, misfolding of α-Gal A and UPR activation led to death of these cells and to a shorter life span, which could be improved, in a mutation-dependent manner, by migalastat.
Co-administration With the Pharmacological Chaperone AT1001 Increases Recombinant Human α-Galactosidase A Tissue Uptake and Improves Substrate Reduction in Fabry Mice
TLDR
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, thus warranting clinical investigation.
Coformulation of a Novel Human α-Galactosidase A With the Pharmacological Chaperone AT1001 Leads to Improved Substrate Reduction in Fabry Mice
  • Su Xu, Y. Lun, +22 authors R. Khanna
  • Chemistry, Medicine
    Molecular therapy : the journal of the American Society of Gene Therapy
  • 2015
TLDR
Investigation of the effects of coformulating AT1001 with a proprietary recombinant human α-galactosidase A (ATB100) into a single intravenous formulation indicates that intravenous administration of ATB100 coformulated with AT1001 may provide an improved therapy for Fabry disease and thus warrants further investigation.
Glucosylceramide synthase inhibition with lucerastat lowers globotriaosylceramide and lysosome staining in cultured fibroblasts from Fabry patients with different mutation types
TLDR
Investigation of the ability of lucerastat to lower Gb3, globotriaosylsphingosine and lysosomal staining in cultured fibroblasts from 15 different Fabry patients found it provides a viable mechanism to reduce Gb 3 accumulation andLysosome volume, suitable for all Fabry Patients regardless of genotype.
DLHex-DGJ, a novel derivative of 1-deoxygalactonojirimycin with pharmacological chaperone activity in human G(M1)-gangliosidosis fibroblasts.
TLDR
It is demonstrated that a novel iminosugar, DLHex-DGJ, has potent effects as competitive inhibitor of human acid beta-galactosidase in vitro, and its effects on activity, protein expression, maturation and intracellular transport in vivo in 13 fibroblasts lines with GLB1 mutations are described.
Functional Characterisation of Alpha-Galactosidase A Mutations as a Basis for a New Classification System in Fabry Disease
TLDR
In order to predict the metabolic consequence of a given mutation, in vitro enzyme activity with in vivo biomarker data is combined with the pharmacological chaperone 1-deoxygalactonojirimycin (DGJ) to provide information for the clinical relevance of PC therapy for a given mutant.
α-Galactosidase Aggregation Is a Determinant of Pharmacological Chaperone Efficacy on Fabry Disease Mutants*
TLDR
The observations reinforce the idea that treatment of aggregation-associated loss of function observed for the more severe α-galactosidase mutants could be enhanced by combining pharmacological chaperone treatment with the suppression of mutant aggregation, e.g. via proteostatic regulator compounds that increase cellular chaper one expression.
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TLDR
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