ENZYME THERAPY IN GAUCHER-DISEASE TYPE-1 - EFFECT OF NEUTRALIZING ANTIBODIES TO ACID BETA-GLUCOSIDASE

Gaucher disease type 1, a non-neuronopathic lysosomal storage disease, is caused by mutations at the acid beta-glucosidase locus. Periodic i nfusions of macrophage-targeted acid beta-glucosidase reverse hepatosp lenomegaly, hematologic, and bony findings in many patients. Two patie nts receiving enzyme therapy developed neutralizing antibodies to acid beta-glucosidase that were associated with a lack of improvement or p rogressive disease. After initial improvement, case 1 had no additiona l response to 2 years of high-dose (50 U/ kg every 2 weeks) enzyme the rapy. similarly, case 2 initially showed a favorable response to enzym e therapy that plateaued after 1 year of treatment. Both patients deve loped minor allergic reactions and antibodies to acid beta-glucosidase within the first 6 months of treatment. Enzyme therapy was discontinu ed in case 1, with resultant disease progression and need for splenect omy. An immunosuppression/tolerization protocol was initiated in case 2 because of disease progression and stable neutralizing antibody tite rs. The IgG neutralizing antibodies rapidly and completely inactivated the wild-type, but not the N370S, acid beta-glucosidase in vitro. Ant ibodies to human serum albumin and chorionic gonadotropin also develop ed. The finding of neutralizing antibodies to acid beta-glucosidase du ring enzyme therapy for Gaucher disease has significant implications f or monitoring the therapeutic responses and for potential alternative future therapies for Gaucher disease. (C) 1997 by The American Society of Hematology.