Abstract
Background
Gaucher disease is a common glycolipid storage disease, caused by a deficiency of lysosomal β-glucosidase (glucocerebrosidase). Alglucerase is a form of glucocerebrosidase enriched with terminal mannose moieties, so as to “target” the preparation to the high-affinilty 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 β-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 β-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.
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Acknowledgments
We appreciate the cooperation of our patients in making samples available to us and to Harlan C. Amstutz, MD, C. A. Chalian, MD, and John P. Heiner, MD, for collecting and shipping bone samples to us. This is Manuscript 8967-MEM from The Scripps Research Institute. This work was supported by National Institutes of Health Grants DK36639 and RR00833 and the Stein Endowment Fund.
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Beutler, E., Kuhl, W. & Vaughan, L.M. Failure of Alglucerase Infused into Gaucher Disease Patients to Localize in Marrow Macrophages. Mol Med 1, 320–324 (1995). https://doi.org/10.1007/BF03401556
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DOI: https://doi.org/10.1007/BF03401556