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Pharmacological enhancement of mutated alpha-glucosidase activity in fibroblasts from patients with Pompe disease

Parenti, G
•
Zuppaldi, A
•
Pittis, MG
altro
Andria G.
2007
  • journal article

Periodico
MOLECULAR THERAPY
Abstract
We investigated the use of pharmacological chaperones for the therapy of Pompe disease, a metabolic myopathy due to mutations of the gene encoding the lysosomal hydrolase alpha-glucosidase (GAA) and characterized by generalized glycogen storage in cardiac and skeletal muscle. We studied the effects of two imino sugars, deoxynojirimycin (DNJ) and N-butyldeoxynojirimycin (NB-DNJ), on residual GAA activity in fibroblasts from eight patients with different forms of Pompe disease (two classic infantile, two non-classic infantile onset, four late-onset forms), and with different mutations of the GAA gene. We demonstrated a significant increase of GAA activity (1.3-7.5-fold) after imino sugar treatment in fibroblasts from patients carrying the mutations L552P (three patients) and G549R (one patient). GAA enhancement was confirmed in HEK293T cells where the same mutations were overexpressed. No increase of GAA activity was observed for the other mutations. Western blot analysis showed that imino sugars increase the amount of mature GAA molecular forms. Immunofluorescence studies in HEK293T cells overexpressing the L552P mutation showed an improved trafficking of the mutant enzyme to lysosomes after imino sugar treatment. These results provide a rationale for an alternative treatment, other than enzyme replacement, to Pompe disease.
DOI
10.1038/sj.mt.6300074
WOS
WOS:000244405700014
Archivio
http://hdl.handle.net/11368/2847806
info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-33847220777
http://dx.medra.org/10.1038/sj.mt.6300074
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metadata only access
Soggetti
  • Pompe disease, lysoso...

Web of Science© citazioni
96
Data di acquisizione
Mar 19, 2024
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Data di acquisizione
Apr 19, 2024
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