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-alphaGal 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.

Respiratory manifestations in patients with inherited metabolic diseases

“…The past decade has witnessed extraordinary innovation in the treatment of several inherited metabolic diseases with different approaches now available in pre-clinical and clinical testing, including enzyme replacement therapy (ERT), substrate reduction and haematopoietic stem cells transplantation [1]. More innovative strategies, such as pharmacological chaperone therapy and gene therapy, are under investigation for selected inherited metabolic diseases [135][136][137].…”

“…Some studies from our group demonstrated that the pharmacological chaperones improve the efficacy of ERT with recombinant a-glucosidase in Pompe disease, and with recombinant a-galactosidase A in Fabry disease [135,137,152,153]. Improving the efficacy of ERT has great clinical relevance in Pompe disease, as it is becoming increasingly evident that a synergistic effect of these treatments may result useful in patients responding poorly to ERT, but at present there are no studies on the effects on respiratory manifestations.…”

Enzyme replacement therapy in patients with Fabry disease: State of the art and review of the literature

“…Recent studies have shown that chemical chaperones can improve the efficacy of ERT also in FD [137][138][139]. One GLA inhibitor 1-deoxgalactonojirimycin (DGJ marked as amigal by Amicus Therapeutics, Inc) is currently being studied in a phase 3 clinical trial [140].…”

New strategies for the treatment of lysosomal storage diseases (Review)

“…Although pharmacological chaperone therapy (PCT) has been developed as a strategy to rescue mutant enzymes from degradation, recent studies showed that chaperones are also able to enhance physical stability and potentiate the therapeutic action of the enzymes used for ERT (40)(41)(42)(43). These studies, performed in cell systems and in the animal models of Pompe and Fabry disease, suggested a major change in the use of PCT.…”

“…First, the therapeutic effect is directed toward the exogenous wild-type enzyme used for ERT, it is mutationindependent, and may thus be exploited in any patient on ERT (37,41). Second, while the enhancement of endogenous defective enzymes by chaperones in most cases results in minor changes in terms of residual activity (possibly with a modest impact on patient outcome), the synergy between chaperones and ERT apparently induces, at least in cellular models, notable increases in specific activity with complete or near-complete correction of the enzymatic defect.…”