Enzyme replacement therapy with macrophage-targeted human placental glucocerebrosidase in Gaucher disease

  • R. O. Brady
  • N. W. Barton


As part of the requirement for completion of his medical education, the French medical student Philippe C. E. Gaucher wrote a thesis in 1882, in which he described a patient with an enlarged spleen that he believed was a primary epithelioma of that organ (Gaucher, 1882). Descriptions of patients with similar presentations began to appear sporadically, and eventually the eponym “Gaucher disease” was applied to designate these individuals. The manifestations of Gaucher disease vary greatly, and three major clinical phenotypes are currently distinguished. The most prevalent is Type 1 Gaucher disease that comprises patients with involvement of systemic organs and the skeleton but the central nervous is spared The most frequent manifestations are splenomegaly, hepatomegaly, anemia, thrombocytopenia, and leukopenia. The abdomen is protuberant because of gross enlargement of the spleen and liver. The lungs may also be involved. Lymph nodes, pericardium, and the kidneys are less frequently affected. However, the skeleton is virtually always damaged. Acute episodes of bone pain and deformities of the femur are characteristic of the disorder. Other bones may also be involved, and fractures of the hip and vertebrae are not uncommon. Type 1 Gaucher disease is the most common hereditary lipid storage disorder, and it is the most prevalent genetic disease in persons of Ashkenazic Jewish ancestry where the carrier frequency may be as high as 1 in 10 persons.


Enzyme Replacement Therapy Fabry Disease Gauche Disease Gauche Cell Exogenous Enzyme 
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  1. Aghion H, (1934) La maladie de Gaucher dans l’enfance. Thèse, ParisGoogle Scholar
  2. Ashkenazi A, Zaizov R, Matoth Y, (1986) Effect of splenectomy on destructive bone changes in children with chronic (Type 1) Gaucher disease. Eur J Pediatr 145: 138–141PubMedCrossRefGoogle Scholar
  3. Barneveld RA, Keijzer W, Tegelaers, et al (1983) Assignment of the gene coding for human ß-glucocerebrosidase to the region q21-q23 of chromosome 1 using monoclonal antibodies. Hum Genet 64: 227–231PubMedCrossRefGoogle Scholar
  4. Barranger JA, Rapoport SI, Fredericks WR, et al (1979) Modification of the blood-brain barrier: increased concentration and fate of enzymes entering the brain. Proc Natl Acad Sci USA 76: 481–485PubMedCrossRefGoogle Scholar
  5. Barton NW, Furbish FS, Murray G J, Garfield M, Brady RO, (1990) Therapeutic response to intravenous infusions of glucocerebrosidase in a patient with Gaucher disease. Proc Nad Acad Sci USA 87: 1913–1916CrossRefGoogle Scholar
  6. Barton NW, Brady RO, Doppelt SH, et al (1990) Clinical effectiveness of enzyme replacement in Gaucher’s disease. Clin Res 38: 457AGoogle Scholar
  7. Barton NW, Brady RO, Dambrosia JM, et al (1991) Replacement therapy for inherited enyzme deficiency: effectiveness of macrophage-targeted glucocerebrosidase in Gaucher disease. N Engl J Med, in pressGoogle Scholar
  8. Brady RO, Kanfer J, Shapiro D, (1965a) The metabolism of glucocerebrosides. I. Purification and properties of a glucocerebroside-cleaving enzyme from spleen tissue. J Biol Chem 240: 39–42Google Scholar
  9. Brady RO, Kanfer JN, Shapiro D, (1965b) Metabolism of glucocerebrosides: evidence of an enzymatic deficiency in Gaucher’s disease. Biochem Biophys Res Commun 18: 221– 225Google Scholar
  10. Brady RO, Kanfer JN, Bradley RM, Shapiro D, (1966) Demonstration of a deficiency of glucocerebroside-cleaving enzyme in Gaucher’s disease. J Clin Invest 45: 1112–1115PubMedCrossRefGoogle Scholar
  11. Brady RO,: The sphingolipidoses (1966) N Engl Med 275:312–318Google Scholar
  12. Brady RO, Gal AE, Bradley RM, Martensson E, Wasrshaw AL, Laster L, (1967) Enzymatic defect in Fabry’s disease: ceramidetrihexosidase deficiency. N Engl J Med 276: 1163– 1167Google Scholar
  13. Brady RO, Johnson WG, Uhlendorf BW, (1971) Identification of heterozygous carriers of lipid storage diseases. Am J Med 51: 423–431PubMedCrossRefGoogle Scholar
  14. Brady RO. Tallman JF, Johnson WG, et al (1973) Replacement therapy for inherited enzyme deficiency: use of purified ceramidetrihexosidase in Fabry’s disease. N Engl J Med 289: 9–14PubMedCrossRefGoogle Scholar
  15. Brady RO, Pentchev PG, Gal AE, Hibbert SR, Dekaban AS, (1974) Replacement therapy for inherited enyzme deficiency: use of purified glucocerebrosidase in Gaucher’s disease. N Engl J Med 291: 989–993PubMedCrossRefGoogle Scholar
  16. Brady RO, Furbish FS, (1982) Enzyme replacement therapy: specific targeting of exogenous enzymes to storage cells. In: Martonosi AN, (ed) Membranes and Transport, Vol 2. Plenum, New York, p587Google Scholar
  17. Brady RO. Barton NW, Doppelt SH, Mankin HJ, (1990) Efficacy of enzyme replacement in Type 1 Gaucher disease. Am J Hum Genet 47: A151Google Scholar
  18. Brady RO, Barton, NW, (1991) Enzyme replacement therapy for Type 1 Gaucher disease. In: Desnick RJ, (ed) Treatment of genetic diseases, Churchill-Livingston, New York, in pressGoogle Scholar
  19. Eyal N, Wilder S, Horowitz M, (1990) Prevalent and rare mutations among Gaucher patients. Gene 96: 277–283PubMedCrossRefGoogle Scholar
  20. Filling-Katz MR, Barton NW, Katz NNK, (1990) Gaucher’s disease. In: Gold DH, Weingeist TA, eds. The Eye in Systemic Disease. Philadelphia: JB Lippincott, p 365Google Scholar
  21. Fink JK, Correll PH, Perry LK, Brady RO, Karlsson S, (1990) Correction of glucocerebrosidase deficiency following retroviral-mediated gene transfer into hematopoietic progenitor cells from patients with Gaucher disease. Proc Natl Acad Sci USA 87: 2334–2338PubMedCrossRefGoogle Scholar
  22. Furbish FS, Blair HE, Shiloach J, Pentchev PG, Brady RO, (1977) Enzyme replacement therapy in Gaucher’s disease: large-scale purification of glucocerebrosidase suitable for human administration. Proc Nad Acad Sci USA 74: 3560–3563CrossRefGoogle Scholar
  23. Furbish FS, Steer CJ, Barranger JA, Jones EA, Brady RO, (1978) The uptake of native and desialylated glucocerebrosidase by rat hepatocytes and Kupffer cells. Biochem Biophys Res Commun 149: 1047–1053CrossRefGoogle Scholar
  24. Furbish FS, Oliver KL, Zirzow GC, Brady RO, Barranger JA, (1984) Interaction of human placental glucocerebrosidase with hepatic lectins. In: Barranger JA, Brady RO, (eds) Molecular basis of lysosomal storage disorders, Academic Press, Orlando, p 219Google Scholar
  25. Gaucher PCE, (1882) De l’épithélioma primitif de la rate. Thèse de ParisGoogle Scholar
  26. Kampine JP, Brady RO, Kanfer JN, Feld M, Shapiro D, (1967) The diagnosis of Gaucher’s disease and Niemann-Pick disease using small samples of venous blood. Science 155: 86–88PubMedCrossRefGoogle Scholar
  27. Kattlove HE, Williams JC, Gaynor E, Spivack M, Bradley RM, Brady RO, (1969) Gaucher cells in chronic myelocytic leukemia: an acquired abnormality. Blood 33: 379–390PubMedGoogle Scholar
  28. Lieb, (1924) Cerebrosidespeicherung bei Splenomegalie Typus Gaucher. Ztschr Physiol Chem 140: 305–313CrossRefGoogle Scholar
  29. Murray GJ, Howard KD, Richards SM, Barton NW, Brady RO, (1991) Gaucher’s disease: lack of antibody response in 12 patients following repeated intravenous infusions of macrophage-targeted glucocerebrosidase. J Immunol Methods, in press.Google Scholar
  30. Parker RI, Barton NW, REad EJ, Brady RO, (1991) Hematologic improvement in a patient with Gaucher’s disease on long-term enzyme replacement therapy: evidence for decreased splenic sequestration and improved red blood cell survival. Am J Hematol, manuscript submittedGoogle Scholar
  31. Pentchev PG, Brady RO, Hibbert SR, Gal AE, Shapiro D, (1973) Isolation and characterization of glucocerebrosidase from human placental dissue. J Biol Chem 248: 5256–5261PubMedGoogle Scholar
  32. Pentchev PG, Brady RO, Gal AE, Hibbert SR, (1975) Replacement therapy for inherited enyzme deficiency: sustained clearance of accumulated glucocerebroside in Gaucher’s disease following infusion of purified glucocerebrosidase. J Mol Med 1: 73–78Google Scholar
  33. Rose JS, Grabowski GA, Barnett SH, Desnick RJ, (1982) Accelerated skeletal deterioration after splenectomy in Gaucher Type 1 disease. AJR [Am J Roentgenology] 139: 1202–1204Google Scholar
  34. Schneider EL, Ellis WG, Brady RO, McCulloch JR, Epstein CJ, (1972) Infantile (Type II) Gaucher’s disease: in utero diagnosis and fetal pathology. J Pediatr 81: 1134–1139PubMedCrossRefGoogle Scholar
  35. Scriver CR, Beaudet AL, Sly WS, Valle D, (1989) The metabolic basis of inherited disease, 6th edn. McGraw-Hill, New York Stahl PD, Wileman TE, Shepard VL, (1984) The mannose-recognition pathway-implications for lysosome physiology. In: Barranger JA, Brady RO, (eds) Molecular basis of lysosomal storage disorders. Academic Press, Orlando, p 209Google Scholar
  36. Steer CJ, Clarenburg R, (1979) Unique distribution of glycoprotein receptors on parenchymal and sinusoidal cells of rat liver. J Biol Chem 254: 4457–4461PubMedGoogle Scholar
  37. Svennerholm L, Håkansson G, Månsson JE, Nilsson O, (1982) Chemical differentiation of the Gaucher subtypes. In: Desnick RJ, Gatt S, Grabowski GA, (eds) Gaucher disease: a century of delineation and research, Alan R Liss, New York, p 231Google Scholar
  38. Takasaki S, Murray GJ, Furbish FS, Brady RO, Barranger JA, Kobata A, (1984) Structure of N-asparagine-linked oligosaccharide units of human placental ß-glucocerebrosidase. J Biol Chem 259: 10112–10117PubMedGoogle Scholar
  39. Trams EG, Brady RO, (1960) Cerebroside synthesis in Gaucher’s disease. J Clin Invest 39: 1546–1560PubMedCrossRefGoogle Scholar
  40. Weinreb NJ, Brady RO, Tappel AL, (1968) The lysosomal localization of sphingolipid hydrolases. Biochim Biophys Acta 159: 141–146PubMedGoogle Scholar
  41. Yu K-T, Merrick HFW, Verderese C, et al (1990) Horizontal supranuclear gaze palsy: a marker for severe systemic involvement in Type III Gaucher’s disease. Neurology 40: S357Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1991

Authors and Affiliations

  • R. O. Brady
    • 1
  • N. W. Barton
    • 1
  1. 1.Developmental and Metabolic Neurology BranchNational Institute of Neurological Disorders and Stroke National Institutes of HealthBethesdaUSA

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