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Synergy between the pharmacological chaperone 1‐deoxygalactonojirimycin and the human recombinant alpha‐galactosidase A in cultured fibroblasts from patients with Fabry disease
Author(s) -
Porto Caterina,
Pisani Antonio,
Rosa Margherita,
Acampora Emma,
Avolio Valeria,
Tuzzi Maria Rosaria,
Visciano Bianca,
Gagliardo Cristina,
Materazzi Serena,
Marca Giancarlo,
Andria Generoso,
Parenti Giancarlo
Publication year - 2012
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/s10545-011-9424-3
Subject(s) - globotriaosylceramide , fabry disease , alpha galactosidase , enzyme replacement therapy , recombinant dna , enzyme , intracellular , alpha (finance) , cardiomyopathy , lysosomal storage disease , pharmacology , medicine , biology , chemistry , biochemistry , disease , heart failure , surgery , construct validity , patient satisfaction , gene
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.