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 infusions of macrophage-targeted acid beta-glucosidase reverse hepatosplenomegaly, hematologic, and bony findings in many patients. Two patients receiving enzyme therapy developed neutralizing antibodies to acid beta-glucosidase that were associated with a lack of improvement or progressive disease. After initial improvement, case 1 had no additional response to 2 years of high-dose (50 U/kg every 2 weeks) enzyme therapy. Similarly, case 2 initially showed a favorable response to enzyme therapy that plateaued after 1 year of treatment. Both patients developed minor allergic reactions and antibodies to acid beta-glucosidase within the first 6 months of treatment. Enzyme therapy was discontinued in case 1, with resultant disease progression and need for splenectomy. An immunosuppression/tolerization protocol was initiated in case 2 because of disease progression and stable neutralizing antibody titers. The IgG neutralizing antibodies rapidly and completely inactivated the wild-type, but not the N370S, acid beta-glucosidase in vitro. Antibodies to human serum albumin and chorionic gonadotropin also developed. The finding of neutralizing antibodies to acid beta-glucosidase during enzyme therapy for Gaucher disease has significant implications for monitoring the therapeutic responses and for potential alternative future therapies for Gaucher disease.
Ponce
E
E
Division of Human Genetics, Children's Hospital Research Foundation, Cincinnati, OH 45229-3039, USA.
Moskovitz
J
J
Grabowski
G
G
D000293:Adolescent; D000906:Antibodies / Q000097:blood / Q000276:immunology*; D005260:Female; D005776:Gaucher Disease / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D005962:Glucosylceramidase / Q000276:immunology / Q000627:therapeutic use*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D008297:Male
D000906:Antibodies; D007074:Immunoglobulin G; D005962:Glucosylceramidase