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

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.

• Authors: Kazumasa Akiyama, Yohta Shimada, Takashi Higuchi, Makoto Ohtsu, Hiromitsu Nakauchi, Hiroshi Kobayashi, Takahiro Fukuda, Hiroyuki Ida, Yoshikatsu Eto, Brett E Crawford, Jillian R Brown, Toya Ohashi
• Journal: Molecular genetics and metabolism (Mol Genet Metab) Vol. 111 Issue 2 Pg. 139-46 (Feb 2014) ISSN: 1096-7206 [Electronic] United States
• PMID: 24100247 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013.

Chemical References

• Glycosaminoglycans
• Recombinant Proteins
• Iduronate Sulfatase
• idursulfase

Topics

• Animals
• Bone Marrow Transplantation
• Brain (drug effects, metabolism, pathology)
• Combined Modality Therapy
• Disease Models, Animal
• Enzyme Replacement Therapy
• Female
• Glycosaminoglycans (metabolism)
• Humans
• Iduronate Sulfatase (administration & dosage, metabolism)
• Kidney (drug effects, metabolism, pathology)
• Lung (drug effects, metabolism, pathology)
• Mice
• Mice, Transgenic
• Mucopolysaccharidosis II (enzymology, pathology, therapy)
• Myocardium (metabolism, pathology)
• Recombinant Proteins (administration & dosage)
• Treatment Outcome