title: 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 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.
authors.affiliation: Department of Pediatrics, Federico II University, Naples, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Porto
authors.forename: Monica
authors.initials: M
authors.lastname: Cardone
authors.forename: Federica
authors.initials: F
authors.lastname: Fontana
authors.forename: Barbara
authors.initials: B
authors.lastname: Rossi
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Tuzzi
authors.forename: Antonietta
authors.initials: A
authors.lastname: Tarallo
authors.forename: Maria Vittoria
authors.initials: MV
authors.lastname: Barone
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* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D015153:Blotting, Western; D002460:Cell Line; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005347:Fibroblasts / Q000187:drug effects* / Q000473:pathology; D006009:Glycogen Storage Disease Type II / Q000188:drug therapy*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D000519:alpha-Galactosidase / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D004791:Enzyme Inhibitors; D017485:1-Deoxynojirimycin; C059896:miglustat; D000519:alpha-Galactosidase