Depletion of globosides and isoglobosides fully reverts the morphologic phenotype of Fabry disease.

[fabry disease]

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 .