The pharmacological chaperone N-butyldeoxynojirimycin enhances enzyme replacement therapy in Pompe disease fibroblasts.
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.
Porto
Caterina
C
Department of Pediatrics, Federico II University, Naples, Italy.
Cardone
Monica
M
Fontana
Federica
F
Rossi
Barbara
B
Tuzzi
Maria Rosaria
MR
Tarallo
Antonietta
A
Barone
Maria Vittoria
MV
Andria
Generoso
G
Parenti
Giancarlo
G
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
D004791:Enzyme Inhibitors; D017485:1-Deoxynojirimycin; C059896:miglustat; D000519:alpha-Galactosidase