Fabry disease is a monogenic X-linked
lysosomal storage disease caused by α-
galactosidase A (αGalA) deficiency.
Enzyme replacement therapy through administration of the missing αGalA is currently the only accepted therapeutic option. However, this treatment is connected to high costs, has ill-defined indication criteria and its efficacy is controversially discussed. Our aim was to explore the possibility of a novel targeted substrate reduction
therapy for
Fabry disease. Owing to the fact that αGalA-deficient humans and mice accumulate the same
glycosphingolipids (i.e.
globosides,
galabiosylceramide and isoglobosides), αGalA-deficient mice were crossed with mice deficient in
enzymes synthesizing these classes of
glycosphingolipids (i.e.
globotrihexosylceramide and
isoglobotrihexosylceramide synthase, respectively). Functional heart and kidney tests were performed together with an extensive biochemical analysis of urine and serum in aged mice. Lysosomal storage was assessed by thin layer chromatography and electron microscopy. We showed that depletion of
globosides was sufficient to fully abolish the storage of
glycosphingolipids in heart, kidney and liver and was paralleled by a complete restoration of lysosomal morphology in these organs. In contrast, in dorsal root ganglia, a depletion of both
globosides and isoglobosides was necessary to fully counteract the lysosomal storage. The deficiency in
globosides and/or isoglobosides did not cause any adverse effects. We conclude that substrate reduction
therapy through inhibition of the synthesis of
globosides and isoglobosides represents a valuable therapeutic option for
Fabry disease, all the more as
globosides and isoglobosides seem to be dispensable.