Fabry disease: Preclinical studies demonstrate the effectiveness of alpha-galactosidase A replacement in enzyme-deficient mice

Preclinical studies of enzyme-replacement therapy for Fabry disease (defici ent alpha -galactosidase A [alpha -Gal A] activity) were performed in alpha -Gal A-deficient mice. The pharmacokinetics and biodistributions were dete rmined for four recombinant human alpha -Gal A glycoforms, which differed i n sialic acid and mannose-6-phosphate content. The plasma half-lives of the glycoforms were similar to2-5 min, with the more sialylated glycoforms cir culating longer. After intravenous doses of 1 or 10 mg/kg body weight were administered, each glycoform was primarily recovered in the liver, with det ectable activity in other tissues but not in the brain. Normal or greater a ctivity levels were reconstituted in various tissues after repeated doses ( 10 mg/kg every other day for eight doses) of the highly sialylated AGA-1 gl ycoform; 4 d later, enzyme activity was retained in the liver and spleen at levels that were, respectively, 30% and 10% of that recovered 1 h postinje ction. Importantly, the globotriaosylceramide (GL-3) substrate was depleted in various tissues and plasma in a dose-dependent manner. A single or repe ated doses (every 48 h for eight doses) of AGA-1 at 0.3-10.0 mg/kg cleared hepatic GL-3, whereas higher doses were required for depletion of GL-3 in o ther tissues. After a single dose of 3 mg/kg, hepatic GL-3 was cleared for greater than or equal to4 wk, whereas cardiac and splenic GL-3 reaccumulate d at 3 wk to similar to 30% and similar to 10% of pretreatment levels, resp ectively. Ultrastructural studies demonstrated reduced GL-3 storage posttre atment. These preclinical animal studies demonstrate the dose-dependent cle arance of tissue and plasma GL-3 by administered alpha -Gal A, thereby prov iding the in vivo rationale-and the critical pharmacokinetic and pharmacody namic data-for the design of enzyme-replacement trials in patients with Fab ry disease.