Fabry disease is an X-linked lysosomal storage disorder that results from the deficient activity of the lysosomal hydrolase α-galactosidase A(α-Gal A). The progressive accumulation of its major glycolipid substrate, globotriaosylceramide (GL-3), leads to premature death due to vascular disease of the kidney, heart or brain. The recent availability of mice with α-Gal A deficiency, generated by gene targeting, permits evaluation of the potential therapeutic effectiveness of α-Gal A replacement. Studies were conducted in the enzyme deficient mice to determine the plasma clearance and biodistribution of four different α-Gal A recombinant glycoforms which varied in their levels of sialylation. The plasma half-lives for all four glycoforms were about 3-5 min, with the most highly sialylated glycoform having the longest half-life. All four glycoforms were primarily taken up by the liver, with a small amount present in kidney and spleen 1 hr after intravenous administration of 1mg/kg. Significant hepatic activity was recovered 96 hr after a single dose (10% and 5% of that recovered at 1 hr after injection, respectively), indicating the in vivo stability of sialylated and non-sialylated glycoforms. Subsequent dosing studies revealed that eight intraveneous doses (1mg/kg every 48 hr), depleted that accumulated GL-3 in plasma, liver, and heart and reduced the renal GL-3 by 30-50%. Ultrastructural examination of liver revealed empty vacuoles indicating that the administered enzyme gained access to and hydrolyzed the accumulated substrate in lysosomes. These preclinical results in the α-Gal A deficient mice provide the rationale for enzyme replacement in Fabry disease.
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(Spon by: Robert J Desnick)
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Ioannou, Y., Zeidner, K., Friedman, B. et al. Fabry disease: Effective tissue substrate depletion following enzyme replacement in α-galactosidase A deficient mice. • 607. Pediatr Res 41 (Suppl 4), 104 (1997). https://doi.org/10.1203/00006450-199704001-00627
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DOI: https://doi.org/10.1203/00006450-199704001-00627