Biomarker responses correlate with antibody status in mucopolysaccharidosis type I patients on long-term enzyme replacement therapy

Antibody formation can interfere with effects of enzyme replacement therapy (ERT) in lysosomal storage diseases. Biomarkers are used as surrogate marker for disease burden in MPS I, but large systematic studies evaluating the response of biomarkers to ERT are lacking. We, for the first time, investi...

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Published in:Molecular genetics and metabolism 2015-02, Vol.114 (2), p.129-137
Main Authors: Langereis, Eveline J., van Vlies, Naomi, Church, Heather J., Geskus, Ronald B., Hollak, Carla E.M., Jones, Simon A., Kulik, Wim, van Lenthe, Henk, Mercer, Jean, Schreider, Lena, Tylee, Karen L., Wagemans, Tom, Wijburg, Frits A., Bigger, Brian W.
Format: Article
Language:English
Subjects:
Adolescent
Adult
Antibody formation
Biomarker
Biomarkers - analysis
Child
Child, Preschool
Dermatan Sulfate - analysis
Disaccharides - analysis
Disaccharides - blood
Disaccharides - urine
Enzyme Replacement Therapy
Female
Follow-Up Studies
Glycosaminoglycans
Heparin Cofactor II - analysis
Heparitin Sulfate - analysis
Heparitin Sulfate - blood
Heparitin Sulfate - urine
Humans
Iduronidase - immunology
Iduronidase - therapeutic use
Immunoglobulin G - blood
Infant
Infant, Newborn
Laronidase
Male
Mucopolysaccharidosis I - blood
Mucopolysaccharidosis I - drug therapy
Mucopolysaccharidosis I - immunology
Mucopolysaccharidosis I - urine
Mucopolysaccharidosis type I
Recombinant Proteins - immunology
Recombinant Proteins - therapeutic use
Thrombin - analysis
Young Adult
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Summary:Antibody formation can interfere with effects of enzyme replacement therapy (ERT) in lysosomal storage diseases. Biomarkers are used as surrogate marker for disease burden in MPS I, but large systematic studies evaluating the response of biomarkers to ERT are lacking. We, for the first time, investigated the response of a large panel of biomarkers to long term ERT in MPS I patients and correlate these responses with antibody formation and antibody mediated cellular uptake inhibition. A total of 428 blood and urine samples were collected during long-term ERT in 24 MPS I patients and an extensive set of biomarkers was analyzed, including heparan sulfate (HS) and dermatan sulfate (DS) derived disaccharides; total urinary GAGs (DMBu); urinary DS:CS ratio and serum heparin co-factor II thrombin levels (HCII-T). IgG antibody titers and the effect of antibodies on cellular uptake of the enzyme were determined for 23 patients. Median follow-up was 2.3years. In blood, HS reached normal levels more frequently than DS (50% vs 12.5%, p=0.001), though normalization could take several years. DMBu normalized more rapidly than disaccharide levels in urine (p=0.02). Nineteen patients (83%) developed high antibody titers. Significant antibody-mediated inhibition of enzyme uptake was observed in 8 patients (35%), and this correlated strongly with a poorer biomarker response for HS and DS in blood and urine as well as for DMBu, DS:CS-ratio and HCII-T (all p
ISSN:1096-7192
1096-7206
DOI:10.1016/j.ymgme.2014.10.012