Summary
Gaucher disease is caused by a deficiency of glucocerebrosidase. It is the first lysosomal storage disorder for which effective enzyme-supplementation therapy has become available. The enzyme, alglucerase, is glucocerebrosidase derived from human placental tissue; its oligosaccharide chain has been modified to expose terminal mannose residues, facilitating uptake in macrophages.
Many patients have been shown to benefit from treatment with the enzyme. Spleen and liver volumes decrease and cytopenia improves. Over a longer period of time, bone involvement can also be diminished, although severe pre-existing bone abnormalities do not change. The safety profile of alglucerase seems excellent, with only few adverse events and approximately 12% of patients developing antibodies.
Because long term safety is unknown and the enzyme is very expensive, studies have focused on the determination of the optimum individual dosage. Different dosages have shown to be effective, but so far the identification of patients who need a high or a low dosage is unclear. Other issues that deserve attention are the selection criteria for the initiation of treatment and the place of prophylactic treatment. Diversity in the course of the disease, which in many cases cannot be predicted by genotyping, hampers the establishment of strict rules. Multicentre studies, in which comparison of data is made possible by the use of standardised measurements of disease manifestations, may be needed to solve these issues.
Similar content being viewed by others
References
Beutler E, Grabowski G. Gaucher disease. In: Scriver CR, Beaudet AL, Sly WS, et al., editors. The metabolic basis of inherited disease. New York: McGraw-Hill Publishing Company, 1995: 2641–70
Beutler E. Gaucher’s disease in an asymptomatic 72-year old. JAMA 1977; 237: 2529
Stowens DW, Teitelbaum SL, Kahn AJ, et al. Skeletal complications of Gaucher disease. Medicine (Baltimore) 1985; 64: 310–22
Siegal A, Gutman A, Shapiro MS, et al. Renal involvement in Gaucher’s disease. Postgrad Med J 1981; 57: 398–401
Svennerholm L, Dreborg S, Erikson A, et al. Gaucher disease of the Norrbottnian type (type III): phenotypic manifestations. In: Desnick RJ, Gatt S, Grabowski GA, editors. Gaucher disease: a century of delineation and research. New York: Alan R. Liss, 1982: 67–94
Patterson MC, Horowitz M, Abel RB, et al. Isolated horizontal nuclear gaze palsy as a marker of severe systemic involvement in Gaucher’s disease. Neurology 1993; 43: 1993–7
Chabas A, Cormand B, Grinberg D, et al. Unusual expression of Gaucher’s disease: cardiovascular calcifications in three sibs homozygous for the D409H mutation. J Med Genet 1995; 32: 740–2
Abrahamov A, Elstein D, Gross-Tsur V, et al. Gaucher’s disease variant characterised by progressive calcification of the heart valves and unique genotype. Lancet 1995; 346: 1000–3
Kattlove HE, Williams JC, Gaynor E, et al. Gaucher cells in chronic myelocytic leukemia: an acquired abnormality. Blood 1969; 33: 379–90
Daniels LB, Glew RH. β-Glucosidase assays in the diagnosis of Gaucher’s disease. Clin Chem 1982; 28: 569–77
Aerts JMFG, Donker Koopman WE, Koot M, et al. Deficient activity of glucocerebrosidase in urine from patients with type 1 Gaucher disease. Clin Chim Acta 1986; 158: 155–64
Beutler E, Gelbart T. Glucocerebrosidase (Gaucher disease). Hum Mutat 1996; 8: 207–13
Beutler E, Nguyen NJ, Henneberger MW, et al. Gaucher disease: gene frequencies in the Ashkenazi Jewish population. Am J Hum Genet 1993; 52: 85–8
Beutler E. Gaucher disease. Adv Genet 1995; 32: 17–49
Sidransky E, Ginns EI. Phenotypic and genotypic heterogeneity in Gaucher disease: implications for genetic counseling. J Genet Couns 1994; 3: 13–22
Sibille A, Eng CM, Kim S-J, et al. Phenotype/genotype correlations in Gaucher disease type 1: clinical and therapeutic implications. Am J Hum Genet 1993; 52: 1094–101
Lacerda L, Amaral O, Pinto R, et al. Gaucher disease: N370S glucocerebrosidase gene frequency in the Portuguese population. Clin Genet 1994; 45: 298–300
Shiloni E, Bitran D, Rachmilewitz E, et al. The role of splenectomy in Gaucher’s disease. Arch Surg 1983; 118: 929–32
Salky B, Kreel I, Gelernt I, et al. Splenectomy for Gaucher’s disease. Ann Surg 1979; 190: 592–4
Harinck HI, Bijvoet OL, van der Meer JW, et al. Regression of bone lesions in Gaucher’s disease during treatment with aminohydroxypropylidene bisphosphonate [letter]. Lancet 1984; II: 513
Samuel R, Katz K, Papapoulos SE, et al. Aminohydroxy propylidene bisphosphonate (APD) treatment improves the clinical skeletal manifestations of Gaucher’s disease. Pediatrics 1994; 94: 385–9
Rappeport J, Barranger J, Ginns E. Bone marrow transplantation in Gaucher disease. Birth Defects 1986; 22: 101–9
Ringden D, Groth CG, Erikson A, et al. Ten years experience of bone marrow transplantation for Gaucher disease. Transplantation 1995; 59: 864–70
Ohashi T, Boggs S, Robbins P, et al. Efficient transfer and sustained high expression of the human glucocerebrosidase gene in mice and their functional macrophages following transplantation of bone marrow transduced by a retroviral vector. Proc Natl Acad Sci USA 1992; 89: 11332–6
Brady RO, Pentchev PG, Gal AE, et al. Replacement therapy for inherited enzyme deficiency: use of purified glucocerebrosidase in Gaucher’s disease. N Engl J Med 1974; 291: 989–93
Furbish F, Steer C, Barranger J, et al. The uptake of native and desialylated glucocerebrosidase by rat hepatocytes and Kuppfer cells. Biochem Biophys Res Commun 1978; 81: 1047–53
Belchetz P, Crawley JCW, Braidman IP, et al. Treatment of Gaucher’s disease with liposome entrapped glucocerebroside: beta-glucosidase. Lancet 1977; II: 116
Beutler E, Dale GL, Guinto E, et al. Enzyme replacement therapy in Gaucher’s disease: preliminary clinical trial of a new enzyme preparation. Proc Natl Acad Sci USA 1977; 74: 4620–3
Furbish F, Steer C, Krett N, et al. Uptake and distribution of placental glucocerebrosidase in rat hepatic cells and effects of sequential deglycosylation. Biochim Biophys Acta 1981; 673: 425–34
Willemsen R, Tibbe JM, Kroos MA, et al. A biochemical and immunocytochemical study on the targeting of alglucerase in murine liver. Histochem J 1995; 27: 639–46
Bijsterbosch MK, Donker W, van de Bilt H, et al. Quantitative analysis of the targeting of mannose terminal glucocerebrosidase: predominant uptake by liver endothelial cells. Eur J Biochem 1996; 237: 344–9
Sato Y, Beutler E. Binding, internalization and degradation of mannose-terminated glucocerebrosidase by macrophages. J Clin Invest 1993; 91: 1909–17
Beutler E, Kuhl W, Vaughan LM. Failure of alglucerase infused into Gaucher disease patients to localize in marrow macrophages. Mol Med 1995; 1: 320–4
Mistry P, Wraight EP, Cox TM. Therapeutic delivery of proteins to macrophages: implications for treatment of Gaucher’s disease. Lancet 1996; 348: 1555–9
Barton NW, Furbish FS, Murray GJ, et al. Therapeutic response to intravenous administration of glucocerebrosidase in a patient with Gaucher disease. Proc Natl Acad Sci USA 1990; 87: 1913–6
Barton NW, Brady RO, Dambrosia JM, et al. Replacement therapy for inherited enzyme deficiency — macrophage targeted glucocerebrosidase for Gaucher’s disease. N Engl J Med 1991; 324: 1464–70
Figueroa ML, Rosenbloom BE, Kay AC, et al. A less costly regimen of alglucerase to treat Gaucher’s disease. N Engl J Med 1992; 327: 1632–6
Zimran A, Hadas-Halpern I, Zevin S, et al. Low dose high frequency enzyme replacement therapy for very young children with Gaucher disease. Br J Haematol 1993; 85: 783–6
Pastores GM, Sibille AR, Grabowski GA. Enzyme therapy in Gaucher disease type 1: dosage efficacy and adverse events in 33 patients treated for 6 to 24 months. Blood 1993; 82(2): 408–16
Hollak CEM, Aerts JMFG, Goudsmit R, et al. Individualized low dose alglucerase therapy for type 1 Gaucher disease. Lancet 1995; 345: 1474–8
Kerem E, Elstein D, Abrahamov A, et al. Pulmonary function abnormalities in type 1 Gaucher disease. Eur Respir J 1996; 9: 340–5
Dawson A, Elias DJ, Rubenson D, et al. Pulmonary hypertension developing after alglucerase therapy in two patients with type 1 Gaucher disease complicated by the hepatopulmonary syndrome. Ann Intern Med 1996; 125: 901–4
Rosenthal D, Doppelt S, Mankin H, et al. Enzyme replacement therapy for Gaucher disease: skeletal responses to macrophage-targeted glucocerebrosidase. Pediatrics 1995; 96(4): 629–37
Belmatoug N, Billette de Villemeur T. Skeletal response to enzyme replacement therapy for type 1 Gaucher disease: a preliminary report of the French experience. Semin Hematol 1995; 32Suppl. 1: 33–8
Beutler E, Demina A, Laubscher K, et al. The clinical course of treated and untreated Gaucher disease: a study of 45 patients. Blood Cells Mol Dis 1995; 21: 86–108
Elstein D, Hadas-Halpern I, Itzchaki A, et al. Effect of low-dose enzyme replacement therapy on bones in Gaucher disease patients with severe skeletal involvement. Blood Cells Mol Dis 1996; 22: 104–11
Sidransky E, Ginns EI, Westmann JA, et al. Pathological fractures may develop in Gaucher patients receiving enzyme replacement therapy. Am J Hematol 1994; 47: 247–9
NIH Technology Assessment Panel on Gaucher Disease. Gaucher disease: current issues in diagnosis and treatment. JAMA 1996; 275: 548–53
Zimran A, Kay AC, Gelbart T, et al. The natural history of adult type Gaucher disease: clinical laboratory, radiologic and genetic features of 53 patients. Medicine 1992; 71: 337–53
Zimran A, Elstein D, Kannai R, et al. Low-dose enzyme replacement therapy for Gaucher’s disease: effects of age, sex, genotype and clinical features on response to treatment. Am J Med 1994; 97: 3–13
Beutler E. Treatment regimens in Gaucher’s disease [letter]. Lancet 1995; 346: 581–2
Barton NW. Enzyme replacement therapy: the facts and fantasies of dosing. Gauch Clin Perspect 1993; 1: 5–7
Boot RG, Hollak CEM, Verhoek M, et al. Glucocerebrosidase genotype of Gaucher patients in The Netherlands: limitations in prognostic value. Hum Mutat. In press
Barton NW, Brady RO, Dambrosia JM. Treatment of Gaucher’s disease. N Engl J Med 1993; 328: 1564–5
Zimran A, Hollak C, Abrahamov A, et al. Home treatment with intravenous enzyme replacement therapy for Gaucher disease: an international collaborative study of 33 patients. Blood 1993; 82: 1107–9
Lee RE. The pathology of Gaucher disease. In: Desnick RJ, Gatt S, Grabowski GA, editors. Gaucher disease: a century of delineation and research. New York: Alan R. Liss, 1982: 177–217
Beutler E, Kay A, Saven A, et al. Enzyme replacement therapy for Gaucher disease. Blood 1991; 78: 1183–9
Hollak CEM, Aerts JMFG, van Oers MHJ. Treatment of Gaucher’s disease. N Engl J Med 1993; 328: 1565–6
Hollak CEM, van Weely S, van Oers MHJ, et al. Marked elevation of plasma chitotriosidase activity: a novel hallmark of Gaucher disease. J Clin Invest 1994; 93: 1288–92
Richards S, Olson T, McPherson J. Antibody response in patients with Gaucher disease after repeated infusion with macrophage-targeted glucocerebrosidase. Blood 1993; 82(5): 1402–9
Sidransky E, Dietrich K, Ginns E. False-positive pregnancy tests in Gaucher’s disease [letter]. Lancet 1994; 344: 1156
Cohen Y, Elstein D, Abrahamov A, et al. HCG contamination of alglucerase: clinical implications in low-dose regimen. Am J Hematol 1994; 47: 235–6
Granovski-Grisaru S, Aboulafia Y, Diamant YZ, et al. Gynaecologic and obstetric aspects of Gaucher’s disease: a survey of 53 patients. Am J Obstet Gynecol 1995; 172: 1284–90
Elstein D, Granovski-Grisaru S, Rabinovitz R, et al. Use of enzyme replacement therapy for Gaucher disease during pregnancy. Am J Obstet Gynecol. In press
Grabowski GA, Barton NW, Pastores G, et al. Enzyme therapy in type 1 Gaucher disease: comparative efficacy of mannose-terminated glucocerebrosidase from natural and recombinant sources. Ann Intern Med 1995; 122: 33–9
Zimran A, Elstein D, Levy-Lahad E. Replacement therapy with imiglucerase for type 1 Gaucher’s disease. Lancet 1995; 345: 1479–80
Wood AJJ. The prevention and treatment of osteoporosis. N Engl J Med 1992; 327: 620–7
Verderese CL, Graham OC, Holder-McShane CA, et al. Gaucher’s disease: a pilot study of the symptomatic responses to enzyme replacement therapy. J Neurosci Nurs 1993; 25: 296–301
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hollak, C.E.M., Aerts, J.M.F.G. & van Oers, M.H.J. Alglucerase. BioDrugs 9, 11–23 (1998). https://doi.org/10.2165/00063030-199809010-00002
Published:
Issue Date:
DOI: https://doi.org/10.2165/00063030-199809010-00002