The Pharmacological Chaperone N-butyldeoxynojirimycin Enhances Enzyme Replacement Therapy in Pompe Disease Fibroblasts
In: Molecular Therapy, Jg. 17 (2009), Heft 6, S. 964-971
Online
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Zugriff:
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 alpha-glucosidase. We showed that coincubation of Pompe fibroblasts with recombinant human alpha-glucosidase and the chaperone N-butyldeoxynojirimycin (NB-DNJ) resulted in more efficient correction of enzyme activity. The chaperone improved alpha-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 alpha-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 alpha-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.
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The Pharmacological Chaperone N-butyldeoxynojirimycin Enhances Enzyme Replacement Therapy in Pompe Disease Fibroblasts
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Autor/in / Beteiligte Person: | Porto, Caterina ; Maria Vittoria Barone ; Parenti, Giancarlo ; Rossi, Barbara ; Cardone, Monica ; Maria Rosaria Tuzzi ; Tarallo, Antonietta ; Andria, Generoso ; Fontana, Federica ; Porto, C ; Cardone, M ; Fontana, F ; Rossi, B ; Tuzzi, Mr ; Tarallo, A ; Barone, MARIA VITTORIA |
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Zeitschrift: | Molecular Therapy, Jg. 17 (2009), Heft 6, S. 964-971 |
Veröffentlichung: | Nature Publishing Group, 2009 |
Medientyp: | unknown |
ISSN: | 1525-0024 (print) |
DOI: | 10.1038/mt.2009.53 |
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