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

Autor: Langereis EJ; Department of Pediatric Metabolic Diseases, Emma Children's Hospital and Amsterdam Lysosome Center 'Sphinx', Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands., van Vlies N; Department of Pediatric Metabolic Diseases, Emma Children's Hospital and Amsterdam Lysosome Center 'Sphinx', Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Laboratory for Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands., Church HJ; Genetic Medicine, Manchester Academic Health Science Centre, Central Manchester University Hospitals, NHS Foundation Trust, St Mary's Hospital, Manchester, UK., Geskus RB; Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands., Hollak CE; Department of Internal Medicine, Division of Endocrinology and Metabolism and Amsterdam Lysosome Center 'Sphinx', Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands., Jones SA; Genetic Medicine, Manchester Academic Health Science Centre, Central Manchester University Hospitals, NHS Foundation Trust, St Mary's Hospital, Manchester, UK., Kulik W; Laboratory for Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands., van Lenthe H; Laboratory for Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands., Mercer J; Genetic Medicine, Manchester Academic Health Science Centre, Central Manchester University Hospitals, NHS Foundation Trust, St Mary's Hospital, Manchester, UK., Schreider L; Stem Cell & Neurotherapies, Centre for Genomic Medicine, University of Manchester, Manchester, UK., Tylee KL; Genetic Medicine, Manchester Academic Health Science Centre, Central Manchester University Hospitals, NHS Foundation Trust, St Mary's Hospital, Manchester, UK., Wagemans T; Department of Pediatric Metabolic Diseases, Emma Children's Hospital and Amsterdam Lysosome Center 'Sphinx', Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Laboratory for Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands., Wijburg FA; Department of Pediatric Metabolic Diseases, Emma Children's Hospital and Amsterdam Lysosome Center 'Sphinx', Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: f.a.wijburg@amc.uva.nl., Bigger BW; Stem Cell & Neurotherapies, Centre for Genomic Medicine, University of Manchester, Manchester, UK.
Jazyk: angličtina
Zdroj: Molecular genetics and metabolism [Mol Genet Metab] 2015 Feb; Vol. 114 (2), pp. 129-37. Date of Electronic Publication: 2014 Oct 29.
DOI: 10.1016/j.ymgme.2014.10.012
Abstrakt: Background: 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.
Methods: 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.
Results: Median follow-up was 2.3 years. 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<0.006).
Conclusions: This study shows that, despite a response of all studied biomarkers to initiation of ERT, some biomarkers were less responsive than others, suggesting residual disease activity. In addition, the correlation of cellular uptake inhibitory antibodies with a decreased biomarker response demonstrates a functional role of these antibodies which may have important clinical consequences.
(Copyright © 2014 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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