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The efficacy of intracerebroventricular idursulfase-beta enzyme replacement therapy in mucopolysaccharidosis II murine model: heparan sulfate in cerebrospinal fluid as a clinical biomarker of neuropathology

  • Young Bae Sohn
  • Ah-Ra Ko
  • Mi-ran Seong
  • Soyeon Lee
  • Mi Ra Kim
  • Sung Yoon Cho
  • Jung-Sun Kim
  • Makoto Sakaguchi
  • Takahiro Nakazawa
  • Motomichi Kosuga
  • Joo Hyun Seo
  • Torayuki Okuyama
  • Dong-Kyu Jin
Original Article

Abstract

Mucopolysaccharidosis II (MPS II) is caused by a deficiency of iduronate-2-sulfatase that results in accumulation of glycosaminoglycans (GAG), including heparan sulfate (HS), which is considered to contribute to neuropathology. We examined the efficacy of intracerebroventricular (ICV) enzyme replacement therapy (ERT) of idursulfase-beta (IDS-β) and evaluated the usefulness of HS as a biomarker for neuropathology in MPS II mice. We first examined the efficacy of three different doses (3, 10, and 30 μg) of single ICV injections of IDS-β in MPS II mice. After the single-injection study, its long-term efficacy was elucidated with 30 μg of IDS-β ICV injections repeated every 4 weeks for 24 weeks. The efficacy was assessed by the HS content in the cerebrospinal fluid (CSF) and the brain of the animals along with histologic examinations and behavioral tests. In the single-injection study, the 30 μg of IDS-β ICV injection showed significant reductions of HS content in brain and CSF that were maintained for 28 days. Furthermore, HS content in CSF was significantly correlated with HS content in brain. In the long-term repeated-injection study, the HS content in the brain and CSF was also significantly reduced and correlated. The histologic examinations showed a reduction in lysosomal storage. A significant improvement in memory/learning function was observed in open-field and fear-conditioning tests. ICV ERT with 30 μg of IDS-β produced significant improvements in biochemical, histological, and functional parameters in MPS II mice. Furthermore, we demonstrate for the first time that the HS in the CSF had significant positive correlation with brain tissue HS and GAG levels, suggesting HS in CSF as a useful clinical biomarker for neuropathology.

Notes

Acknowledgements

This study was supported by AnGes MG, Inc. (PHX0143471) and Samsung Medical Center (GFO2170061).

Compliance with ethical standards

Conflict of interest

Young Bae Sohn, Ah-Ra Ko, Mi-ran Seong, Soyeon Lee, Mi Ra Kim, Sung Yoon Cho, Jung-Sun Kim, Makoto Sakaguchi, Takahiro Nakazawa, Motomichi Kosuga, Joo Hyun Seo, Torayuki Okuyama, and Dong-Kyu Jin declared that they have no conflict of interest.

Animal rights

All institutional and national guidelines for the care and use of laboratory animals were followed.

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Copyright information

© SSIEM 2018

Authors and Affiliations

  • Young Bae Sohn
    • 1
  • Ah-Ra Ko
    • 2
    • 3
  • Mi-ran Seong
    • 2
  • Soyeon Lee
    • 2
  • Mi Ra Kim
    • 2
  • Sung Yoon Cho
    • 3
  • Jung-Sun Kim
    • 4
    • 5
  • Makoto Sakaguchi
    • 6
  • Takahiro Nakazawa
    • 6
  • Motomichi Kosuga
    • 7
  • Joo Hyun Seo
    • 7
  • Torayuki Okuyama
    • 7
  • Dong-Kyu Jin
    • 3
  1. 1.Department of Medical Genetics, Ajou University HospitalAjou University School of MedicineSuwonRepublic of Korea
  2. 2.Research Institute for Future MedicineSamsung Biomedical Research CenterSeoulRepublic of Korea
  3. 3.Department of Pediatrics, Samsung Medical CenterSungkyunkwan University School of MedicineSeoulRepublic of Korea
  4. 4.Department of Pathology and Translational Genomics, Samsung Medical CenterSungkyunkwan University School of MedicineSeoulRepublic of Korea
  5. 5.Department of Health Sciences and TechnologySungkyunkwan UniversitySeoulRepublic of Korea
  6. 6.AnGes, Inc.OsakaJapan
  7. 7.Center for Lysosomal Storage DiseasesNational Center for Child Health and DevelopmentTokyoJapan

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