The Pharmacological Chaperone N-butyldeoxynojirimycin Enhances Enzyme Replacement Therapy in Pompe Disease Fibroblasts

Abstract

In spite of the progress in the treatment of lysosomal storage diseases (LSDs), in some of these disorders the available therapies show limited efficacy and a need exists to identify novel therapeutic strategies. We studied the combination of enzyme replacement and enzyme enhancement by pharmacological chaperones in Pompe disease (PD), a metabolic myopathy caused by the deficiency of the lysosomal acid α-glucosidase. We showed that coincubation of Pompe fibroblasts with recombinant human α-glucosidase and the chaperone N-butyldeoxynojirimycin (NB-DNJ) resulted in more efficient correction of enzyme activity. The chaperone improved α-glucosidase delivery to lysosomes, enhanced enzyme maturation, and increased enzyme stability. Improved enzyme correction was also found in vivo in a mouse model of PD treated with coadministration of single infusions of recombinant human α-glucosidase and oral NB-DNJ. The enhancing effect of chaperones on recombinant enzymes was also observed in fibroblasts from another lysosomal disease, Fabry disease, treated with recombinant α-galactosidase A and the specific chaperone 1-deoxygalactonojirimycin (DGJ). These results have important clinical implications, as they demonstrate synergy between pharmacological chaperones and enzyme replacement. A synergistic effect of these treatments may result particularly useful in patients responding poorly to therapy and in tissues in which sufficient enzyme levels are difficult to obtain.

New insights into therapeutic options for Pompe disease

“…These observations highlighted the fact that the nature and location of amino acid substitutions play a determinant role in the response of GAA variants to pharmacological chaperones. Furthermore, a synergistic effect of N-butyl-DNJ and rhGAA was observed in Pompe disease fibroblasts, resulting in a higher enzymatic correction due to an improved enzyme maturation and delivery to the lysosome (65). These results have important clinical implications, because the association of ERT and chaperonemediated therapy may be particularly useful in patients poorly responding to therapy.…”

Biochemical and structural study on a S529V mutant acid α-glucosidase responsive to pharmacological chaperones

“…13,14 However, mutant GAAs responsive to these imino sugars are restricted to a limited group with specific amino acid substitutions, and the enhancing effects of the imino sugars available are not so strong. [13][14][15] For further improvement of pharmacological chaperone therapy for Pompe disease, detailed information on mutant GAAs responsive to small molecules is required.…”

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.…”