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Mol Genet Metab. 2014 Feb;111(2):139-46. doi: 10.1016/j.ymgme.2013.09.013. Epub 2013 Sep 21.

Enzyme augmentation therapy enhances the therapeutic efficacy of bone marrow transplantation in mucopolysaccharidosis type II mice.

Author information

  • 1Department of Gene Therapy, Institute of DNA Medicine, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan; Department of Pediatrics, Kitasato University Graduate School of Medicine, Kanagawa, Japan.
  • 2Department of Gene Therapy, Institute of DNA Medicine, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan.
  • 3Division of Stem Cell Therapy, Center for Stem Cell and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
  • 4Department of Gene Therapy, Institute of DNA Medicine, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan; Department of Pediatrics, The Jikei University School of Medicine, Tokyo, Japan.
  • 5Division of Neuropathology, Department of Pathology, The Jikei University School of Medicine, Tokyo, Japan.
  • 6Advanced Clinical Research Center, Institute of Neurological Disorders, Kanagawa, Japan.
  • 7BioMarin Pharmaceutical Inc., San Diego, CA, USA.
  • 8Department of Gene Therapy, Institute of DNA Medicine, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan; Department of Pediatrics, The Jikei University School of Medicine, Tokyo, Japan. Electronic address: tohashi@jikei.ac.jp.

Abstract

Before the availability of an enzyme replacement therapy (ERT) for mucopolysaccharidosis type II (MPS II), patients were treated by bone marrow transplantation (BMT). However, the effectiveness of BMT for MPS II was equivocal, particularly at addressing the CNS manifestations. To study this further, we subjected a murine model of MPS II to BMT and evaluated the effect at correcting the biochemical and pathological aberrations in the viscera and CNS. Our results indicated that BMT reduced the accumulation of glycosaminoglycans (GAGs) in a variety of visceral organs, but not in the CNS. With the availability of an approved ERT for MPS II, we investigated and compared the relative merits of the two strategies either as a mono or combination therapy. We showed that the combination of BMT and ERT was additive at reducing tissue levels of GAGs in the heart, kidney and lung. Moreover, ERT conferred greater efficacy if the immunological response against the infused recombinant enzyme was low. Finally, we showed that pathologic GAGs might potentially represent a sensitive biomarker to monitor the therapeutic efficacy of therapies for MPS II.

© 2013.

KEYWORDS:

Bone marrow transplantation; Enzyme replacement therapy; Glycosaminoglycan; Hunter syndrome; Mucopolysaccharidosis; Pathologic glycosaminoglycan

PMID:
24100247
[PubMed - indexed for MEDLINE]
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