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 α-
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.