Reduction of globotriaosylceramide in Fabry disease mice by substrate deprivation

We used a potent inhibitor of glucosylceramide synthase to test whether sub strate deprivation could lower globotriaosylceramide levels in alpha-galact osidase A (alpha-galA) knockout mice, a model of Fabry disease. C57BL/6 mic e treated twice daily for 3 days with D-threo- 1-ethylendioxyphenyl-2-palmi toylamino-3-pyrrolidino-propanol (D-t-EtDO-P4) showed a concentration-depen dent decrement in glucpsylceramide levels in kidney, liver, and spleen. A s ingle intraperitoneal injection of D-t-EtDO-P4 resulted in a 55% reduction in renal glucosylceramide, consistent with rapid renal glucosylceramide met abolism. A concentration-dependent decrement in renal and hepatic globotria osylceramide levels was observed in alpha-GalA(-) males treated for 4 weeks with D-t-EtDO-P4. When S-week-old alpha-Gal A(-) males were treated for 8 weeks with 10 mg/kg twice daily, renal globotriaosylceramide fell to below starting levels, consistent with an a-galactosidase A-independent salvage p athway for globotriaosylceramide degradation. Complications observed with a nother glucosylceramide synthase inhibitor, N-butyldeoxynojirimycin, includ ing weight loss and acellularity of lymphatic organs, were not observed wit h D-t-EtDO-P4. These data suggest that Fabry disease may be amenable to sub strate deprivation therapy.