GM1 gangliosidosis is a
glycosphingolipid (GSL)
lysosomal storage disease caused by a genetic deficiency of
acid beta-galactosidase (beta-gal), the
enzyme that catabolyzes GM1 within lysosomes. Accumulation of GM1 and its asialo form (GA1) occurs primarily in the brain, leading to progressive neurodegeneration and brain dysfunction. Substrate reduction
therapy aims to decrease the rate of GSL biosynthesis to counterbalance the impaired rate of catabolism. The imino
sugar N-butyldeoxygalactonojirimycin (
NB-DGJ) is a competitive inhibitor of the
ceramide-specific
glucosyltransferase that catalyzes the first step in GSL biosynthesis. Neonatal C57BL/6J (B6) and beta-gal knockout (-/-) mice were injected daily from post-natal day 2 (p-2) to p-5 with either vehicle or
NB-DGJ at 600 mg or 1200 mg/kg
body weight. These
drug concentrations significantly reduced total brain
ganglioside and GM1 content in the B6 and the beta-gal (-/-) mice.
Drug treatment had no significant effect on viability,
body weight, brain weight, or brain water content in the B6 and beta-gal (-/-) mice. Significant elevations in neutral
lipids (GA1,
ceramide, and
sphingomyelin) were observed in the
NB-DGJ-treated beta-gal (-/-) mice, but were not associated with adverse effects. Also,
NB-DGJ treatment of B6 and beta-gal (-/-) mice from
p-2 to p-5 had no subsequent effect on brain
ganglioside content at p-21. Our results show that
NB-DGJ is effective in reducing total brain
ganglioside and GM1 content at early neonatal ages. These findings suggest that substrate reduction
therapy using
NB-DGJ may be an effective early intervention for
GM1 gangliosidosis and possibly other GSL
lysosomal storage diseases.