Enzyme replacement therapy in mucopolysaccharidosis I: Altered distribution and targeting of a-L-induronidase in immunized rats

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dc.contributor.authorTurner, C.
dc.contributor.authorHopwood, J.
dc.contributor.authorBrooks, D.
dc.date.issued2000
dc.description.abstractEnzyme replacement therapy (ERT) has been developed and trialed for the treatment of human lysosomal storage disorder patients. The viability of ERT for the treatment of these severe multiple pathology disorders has subsequently been established. However, in both animal model studies and human clinical trials, some individuals have been shown to develop an immune response to the replacement protein. This potential complication for treatment has been investigated by the infusion of recombinant human alpha-L-iduronidase (rh-alpha-L-iduronidase) into nonimmune and immunized rats to simulate mucopolysaccharidosis type I ERT in the presence of different levels of antibody. In rats with high antibody titers to rh-alpha-L-iduronidase (titer 1,024,000) there was evidence of altered organ distribution and subcellular targeting when compared to either lower titer immunized rats (titers less than 64,000) or nonimmune rats (titers 512-1024). In addition, hypersensitivity reactions were observed for high titer rats (titer 1,024,000) during rh-alpha-L-iduronidase infusion, but not for the other two treatment groups. A rat with an antibody titer of 64,000 had only minor changes in subcellular targeting and organ distribution when infused with rh-alpha-L-iduronidase. This implied that a high level of antibody was required to effect changes in alpha-L-iduronidase enzyme targeting and distribution. Notably, in the high titer rats, the antibody produced appeared to increase the tissue and subcellular level of rh-alpha-L-iduronidase specific activity. This suggested that antibody production may not always result in an adverse effect on ERT.
dc.identifier.citationMolecular Genetics and Metabolism, 2000; 69(4):277-285
dc.identifier.doi10.1006/mgme.2000.2979
dc.identifier.issn1096-7192
dc.identifier.issn1096-7206
dc.identifier.orcidBrooks, D. [0000-0001-9098-3626]
dc.identifier.urihttp://hdl.handle.net/2440/7716
dc.language.isoen
dc.publisherAcademic Press Inc Elsevier Science
dc.source.urihttps://doi.org/10.1006/mgme.2000.2979
dc.subjectLiver
dc.subjectAnimals
dc.subjectHumans
dc.subjectRats
dc.subjectMucopolysaccharidosis I
dc.subjectDrug Hypersensitivity
dc.subjectTritium
dc.subjectIduronidase
dc.subjectRecombinant Proteins
dc.subjectAntibodies
dc.subjectImmunization
dc.subjectInjections, Subcutaneous
dc.subjectBiological Transport
dc.subjectTissue Distribution
dc.subjectDose-Response Relationship, Drug
dc.titleEnzyme replacement therapy in mucopolysaccharidosis I: Altered distribution and targeting of a-L-induronidase in immunized rats
dc.typeJournal article
pubs.publication-statusPublished

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