Mannose-terminal glucocerebrosidase

M. K. Bijsterbosch, W. Donker, H. Van de Bilt, S. Van Weely, T. J. Van Berkel, and J. M. Aerts, Quantitative analysis of the targeting of mannose-terminal glucocerebrosidase. Predominant uptake by liver endothelial cells, Eur. J. Biochem., 237 (1996) 344-349. 

Grabowski, G.A., N.W. Barton, G. Pastores, J.M. Dambrosia, T.K. Banerjee, M.A. McKee, C. Parker, R. Schiffmann, S.C. HiU, and R.O. Brady, Enzyme therapy in type 1 Gaucher disease comparative efficacy of mannose-terminated glucocerebrosidase... 

Medicine in New York using glucocerebrosidase that had been produced lecont-binantly in Chinese hamster ovary cells. The enzyme obtained from these cells was modified by exposure to the- same these cxogtycosidases used previously to produce mannose-terminal placental glucoceiebrosidase (Kg, 2). The clinical effectiveness of the recombinant macrophage-targeted enzyme was found to be... 

The clinical effects of mannose-terminal glucocerebrosidase were initially examined in eight patients with non-neuronopathic, type 1 Gaucher disease. Seven of the patients were either adolescents or adults, and one was a 4-year-old boy. A total dose of 190 U of enzyme was administered intravenously to each of these patients weekly over a 6-month period. A beneficial effect was clearly evident only in the youngest of the recipients [26]. A dramatic increase in... 

Figure 2 Production of mannose-terminal glucocerebrosidase by sequential deglycosylation of the native placental enzyme with exoglycosidases. Abbreviations as in Figure 1. (From Ref. 10.)...

Figure 3 Bar graph showing uptake of glucocerebrosidase by hepatocytes and non-parenchymal cells isolated from rat liver after infusion of 6.7 U of native or 5.0 U of mannose-terminal enzyme. (Adapted from Ref. 22.)...

Figure 4 Immunogold localization of mannose-terminal glucocerebrosidase in rat liver Kupffer cells 30 minutes after enzyme infusion. Gold particles are concentrated in the lysosomes. Lys = Lysosome M = mitochondrion Nuc = nucleus PM = plasma membrane. Original magnifications (A) x10,000 (B) x33,000. Bars = 1 pm. (From Ref. 24.)...

Figure 6 Effect of weekly intravenous infusions of mannose-terminal glucocerebrosidase on serum acid phosphatase activity. Enzyme was administered as described in Figure 5. Shaded areas represent the mean values observed during the entire low-dose period and after 2 years of uninterrupted high-dose treatment ( 1 SD). Normal range 0-0.4 U/L.

Figure 9 Effect of mannose-terminal glucocerebrosidase on the bone marrow. Right posterior iliac crest biopsy specimens were obtained before (Pre) and after (Post) 3-1/2 years of treatment with high-dose enzyme supplementation. Marked clearing of the Gaucher cell infiltrate is evident in the posttreatment specimen. Original magnification x8. (From Ref. 28.)...

Figure 11 Enzymatic activity profile of mannose-terminal glucocerebrosidase in plasma of a boy with Gaucher disease. Enzyme was infused over 4 hours at a constant rate of 12.25 U/kg. A steady-state value of 10.6 mU/mL was achieved during the first hour. When the infusion was terminated at 240 minutes, enzyme was cleared from the plasma by a first-oider process with an elimination half-life of 6.3 minutes. The dashed line represents the activity profile calculated from the observed kinetic constants.

Y. Sato and E. Beutler. Binding, internalization, and degradation of mannose-terminated glucocerebrosidase by macrophages. J. Clin. Invest. 97 1909 (1993). 

G. J. Murray and F. S. Jin. Immunoelectron microscopic localization of mannose-terminal glucocerebrosidase in lysosomes of rat liver Kupffer cells. J. Histochem. Cytochem. 43 149 (1995). 

G. J. Murray, K. D. Howard, S. M. Richards, N. W. Barton, and R. O. Brady. Gaucher s disease lack of antibody response in 12 patients following repeated intravenous infusions of mannose-terminal glucocerebrosidase. J. Immunol. Methods 137 113(1991). 

Native placental glucocerebrosidase contains four oligosaccharide chains, all of which terminate with sialic acid (Fig. 16-9). To optimize glucocerebrosidase uptake by macrophages, the enzyme must be treated sequentially with neuraminidase, P-galactosidase, and fS-iV-acetylglucosaminidase, a process that results in the exposure of mannose residues. 

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