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BACKGROUND: Gaucher disease is a common glycolipid storage disease, caused by a deficiency of lysosomal beta-glucosidase (glucocerebrosidase). Alglucerase is a form of glucocerebrosidase enriched with terminal mannose moieties, so as to "target" the preparation to the high-affinity macrophage receptor in patients with Gaucher disease. Our earlier in vitro studies indicated that alglucerase was bound by cells other than macrophages by a widely distributed, low-affinity mannose receptor. MATERIALS AND METHODS: Bone was removed at surgery from six patients with Gaucher disease; in three cases, bone was obtainable both when the patient was untreated and after receiving an infusion of alglucerase. Four samples of bone were obtained from patients without Gaucher disease and served as controls. A bone marrow aspirate was obtained from another patient with Gaucher disease immediately after enzyme infusion. Marrow beta-glucosidase activity and chitotriosidase (a macrophage marker) was determined on all samples. RESULTS: Even with the large bolus doses used for the treatment of Gaucher disease by some, scarcely any beta-glucosidase activity was found in marrow samples; the amount of the enzyme was much less than would have been anticipated had the enzyme been evenly distributed to all body cells. CONCLUSIONS: Alglucerase is not targeted to marrow macrophages. Its unquestioned therapeutic effectiveness must be due either to its activity at some site other than marrow macrophages or to the fact that the doses administered are so enormous that even a small fraction is sufficient to achieve a therapeutic effect.