title: Synergy between the pharmacological chaperone 1-deoxygalactonojirimycin and the human recombinant alpha-galactosidase A in cultured fibroblasts from patients with Fabry disease.
abstract: Fabry disease (FD) is an X-linked inherited disease due to alpha-galactosidase A (alpha-Gal A) deficiency and characterized by lysosomal storage of globotriaosylceramide (Gb3) and related neutral glycosphingolipids. Storage of these substrates results in multisystem manifestations, including renal failure, cardiomyopathy, premature myocardial infarctions, stroke, chronic neuronopathic pain, gastrointestinal disturbances, and skin angiokeratoma. Enzyme replacement therapy (ERT) with recombinant human alpha-galactosidase A (rh-alpha-Gal A) is now available for the treatment of FD and in most patients results in clinical improvement or stabilization. However, ERT efficacy may vary in different tissues and its long-term effects remain to be defined. As a strategy to improve the efficacy of ERT, we tested the combination of rh-alpha-Gal A with the chaperone molecule 1-deoxynojirimycin (DGJ) in cultured FD fibroblasts with negligible residual enzyme activity. Compared to the effects of rh-alpha-Gal A alone, co-administration of DGJ and rh-alpha-Gal A resulted in better correction (4.8 to 16.9-fold) of intracellular alpha-Gal A activity, and increased amounts of the enzyme within the lysosomal compartment. The clearance of lyso-Gb3, one of the substrates stored in FD and a potent inhibitor of alpha-Gal A, was also significantly improved with the co-administration of DGJ and rh-alpha-Gal A. 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.
authors.affiliation: Department of Pediatrics, Federico II University, Via S. Pansini 5, 80131 Naples, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Porto
authors.forename: Antonio
authors.initials: A
authors.lastname: Pisani
authors.forename: Margherita
authors.initials: M
authors.lastname: Rosa
authors.forename: Emma
authors.initials: E
authors.lastname: Acampora
authors.forename: Valeria
authors.initials: V
authors.lastname: Avolio
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Tuzzi
authors.forename: Bianca
authors.initials: B
authors.lastname: Visciano
authors.forename: Cristina
authors.initials: C
authors.lastname: Gagliardo
authors.forename: Serena
authors.initials: S
authors.lastname: Materazzi
authors.forename: Giancarlo
authors.initials: G
authors.lastname: la Marca
authors.forename: Generoso
authors.initials: G
authors.lastname: Andria
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Parenti
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D016022:Case-Control Studies; D005091:Exons; D000795:Fabry Disease / Q000201:enzymology* / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D005838:Genotype; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal / Q000379:methods; D008856:Microscopy, Fluorescence / Q000379:methods; D009154:Mutation; D011994:Recombinant Proteins / Q000378:metabolism*; D014281:Trihexosylceramides / Q000737:chemistry; D000519:alpha-Galactosidase / Q000378:metabolism*
chemical_list: D011994:Recombinant Proteins; D014281:Trihexosylceramides; D017485:1-Deoxynojirimycin; C018549:globotriaosylceramide; C090092:migalastat; D000519:alpha-Galactosidase