Replacement therapy for inherited enzyme deficiency--macrophage-targeted glucocerebrosidase for Gaucher's disease.
METHODS
Gaucher's disease, the most prevalent of the sphingolipid storage disorders, is caused by a deficiency of the enzyme glucocerebrosidase (glucosylceramidase). Enzyme replacement was proposed as a therapeutic strategy for this disorder in 1966. To assess the clinical effectiveness of this approach, we infused macrophage-targeted human placental glucocerebrosidase (60 IU per kilogram of body weight every 2 weeks for 9 to 12 months) into 12 patients with type 1 Gaucher's disease who had intact spleens. The frequency of infusions was increased to once a week in two patients (children) during part of the trial because they had clinically aggressive disease.


RESULTS
The hemoglobin concentration increased in all 12 patients, and the platelet count in 7. Serum acid phosphatase activity decreased in 10 patients during the trial, and the plasma glucocerebroside level in 9. Splenic volume decreased in all patients after six months of treatment, and hepatic volume in five. Early signs of skeletal improvements were seen in three patients. The enzyme infusions were well tolerated, and no antibody to the exogenous enzyme developed.


CONCLUSIONS
Intravenous administration of macrophage-targeted glucocerebrosidase produces objective clinical improvement in patients with type 1 Gaucher's disease. The hematologic and visceral responses to enzyme replacement develop more rapidly than the skeletal response.
Barton
N W
NW
Departmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
Brady
R O
RO
Dambrosia
J M
JM
Di Bisceglie
A M
AM
Doppelt
S H
SH
Hill
S C
SC
Mankin
H J
HJ
Murray
G J
GJ
Parker
R I
RI
Argoff
C E
CE
D000135:Acid Phosphatase / Q000097:blood; D000293:Adolescent; D000328:Adult; D001846:Bone Development / Q000187:drug effects; D002648:Child; D005260:Female; D005776:Gaucher Disease / Q000188:drug therapy*; D005962:Glucosylceramidase / Q000008:administration & dosage / Q000627:therapeutic use*; D005963:Glucosylceramides / Q000097:blood; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D008264:Macrophages / Q000187:drug effects*; D008297:Male; D009929:Organ Size; D013154:Spleen / Q000473:pathology
D005963:Glucosylceramides; D006454:Hemoglobins; C070292:alglucerase; D000135:Acid Phosphatase; D005962:Glucosylceramidase