Infusion of α-galactosidase A reduces tissue globotriaosylceramide storage in patients with Fabry disease

摘要

Fabry disease is a lysosomal storage disorder caused by a deficiency of the Iysosomal enzyme α-galactosidase A (α-gal A). This enzy- matic defect results in the accumulation of the glycosphingolipid globotriaosylceramide (Gb3: also referred to as ceramidetrihexo- side) throughout the body. To investigate the effects of purified α-gal A. 10 patients with Fabry disease received a single i.v. infusion of one of five escalating dose levels of the enzyme. The objectives of this study were: (i) to evaluate the safety of admin- istered α-gal A, (ii) to assess the pharmacokinetics of i.v.-adminis- tered α-gal A in plasma and liver, and (iii) to determine the effect of this replacement enzyme on hepatic, urine sediment and plasma concentrations of Gb3. α-Gal A infusions were well tolerated in all patients. lmmunohistochemical staining of liver tissue approxi- mately 2 days after enzyme infusion identified α-gal A in several cell types, including sinusoidal endothelial cells, Kupffer cells, and hepatocytes, suggesting diffuse uptake via the mannose 6-phos- phate receptor. The tissue half-life in the liver was greater than 24 hr. After the single dose of α-gal A, nine of the 10 patients had significantly reduced Gb3 levels both in the liver and shed renal tubular epithelial cells in the urine sediment. These data demon- strate that single infusions of α-gal A prepared from transfected human fibroblasts are both safe and biochemically active in pa- tients with Fabry disease. The degree of substrate reduction seen in the study is potentially clinically significant in view of the fact that Gb3 burden in Fabry patients increases gradually over decades. Taken together, these results suggest that enzyme replacement is likely to be an effective therapy for patients with this metabolic disorder.