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2013 Fiscal Year Final Research Report

Discovery of novel compounds regulating traffic to lysosomes and application for development of therapeutics

Research Project

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Project/Area Number 24659262
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeSingle-year Grants
Research Field Applied pharmacology
Research InstitutionThe University of Tokushima

Principal Investigator

ITOH Kohji  徳島大学, ヘルスバイオサイエンス研究部, 教授 (00184656)

Project Period (FY) 2012-04-01 – 2014-03-31
Keywordsリソソーム病 / in vivoイメージング / 酵素トラフィッキング / 疾患特異的iPS細胞 / 酵素補充療法 / GM2ガングリオシドーシス / ドラッグデリバリー / 酸性pH活性化蛍光プローブ
Research Abstract

We studied on intracellular traffic abnormality in lysosomal beta-hexosaminidase (Hex) deficiencies including Tay-Sachs disease (TSD) and Sandhoff diseases (SD) to develop novel enzyme replacement therapy based on techniques to promote delivery of recombinant Hex to lysosomes when extracellularly administrated. We developed modified Hex with high content of mannose 6-phospahte (M6P) residues, which were efficiently incorporated by disease-model cultured cells via cell surface M6P receptors. In addition, we established an iPS cell line derived from a TSD patient, and examined conditions under which neural cells including neural stem cells (NSC) and neural progenitor cells (NPC) could be induced from the TSD iPS cells. Furthermore, we developed novel fluorescent probes including Rhodol beta-GlcNAc as an artificial substrate for intracellular Hex activity and acidic pH-activatable fluorescent Rh-PM for in vivo imaging to detect lysosomal distribution of recombinant Hex.

  • Research Products

    (13 results)

All 2014 2013 2012

All Journal Article (5 results) (of which Peer Reviewed: 4 results) Presentation (6 results) (of which Invited: 1 results) Book (1 results) Patent(Industrial Property Rights) (1 results) (of which Overseas: 1 results)

  • [Journal Article] Inhibitory effects and specificity of synthetic sialyldendrimers toward recombinant human cytosolic sialidase 2 (NEU2)2013

    • Author(s)
      M.M. Rahman, S. Kitao, D. Tsuji, K. Suzuki, K. Matsuoka, F. Matsuzawa, S. Aikawa, K. Itoh.
    • Journal Title

      Glycobiol

      Volume: vol.23 Pages: pp.495-504

    • DOI

      10.1093/glycob/cws221

    • Peer Reviewed
  • [Journal Article] Chemical synthesis of biologically active monoglycosylated GM2-activator protein analog using N-sulfanylethylanilide peptide2013

    • Author(s)
      K. Sato, A. Shigenaga, K. Kitakaze, K. Sakamoto, D. Tsuji, K. Itoh, A. Otaka
    • Journal Title

      Angew. Chem. Int. Ed

      Volume: vol.52 Pages: pp.7855-7859

    • DOI

      10.1002/anie.201303390

    • Peer Reviewed
  • [Journal Article] Modeling of Human Neuraminidase-1 and Its Validation by LERE-Correlation Analysis2013

    • Author(s)
      S. Hitaoka, Y. Shibata, H. Matoba, A. Kawano, M. Harada, M.M. Rahman, D. Tsuji, T. Hirokawa, K. Itoh, T. Yoshida, H. Chuman.
    • Journal Title

      Chem-Bio Informatics Journal

      Volume: 13 Pages: 30-44

    • DOI

      10.1273/cbij.13.30

  • [Journal Article] Gene suppression via Ul small nuclear RNA interference (U1i) machinery using oligonucleotides containing 2'-modified-4'-thionucleosides2013

    • Author(s)
      Y. Kikuchi, N. Yamazaki, N. Tarashima, K. Furukawa, Y. Takiguchi, K. Itoh and N. Minakawa
    • Journal Title

      Bioorg. & Medicin. Chem

      Volume: vol.21 Pages: pp.5292-5296

    • DOI

      10.1016/j.bmc.2013.06.023

    • Peer Reviewed
  • [Journal Article] Combination with a defucosylated anti-HM1.24 monoclonal antibody plus lenalidomide induces marked ADCC against myeloma cells and their progenitors2013

    • Author(s)
      T. Harada, S. Ozaki, A. Oda, D. Tsuji, A. Ikegame, M. Iwasa, K. Udaka, S. Fujii, S. Nakamura, H. Miki, K. Kagawa, Y. Kuroda, S. Kawai, K. Itoh, H. Yamada-Okabe, T. Matsumoto, M. Abe
    • Journal Title

      PLoS One

      Volume: vol.26:8(12) Pages: e83905

    • DOI

      10.1371/journal.pone.0083905

    • Peer Reviewed
  • [Presentation] Molecular therapy and evaluation for neurodegenerative GM2 gangliosidoses2014

    • Author(s)
      K. Itoh, D. Tsuji, M. Ikuo, K. Kitakaze, D. Asanuma, M. Kamiya, Y. Urano, E. Sugiyama, M. Setou, M. Yuzaki, H. Sakuraba
    • Organizer
      International symposium "New Frontier of Molecular Neuropathology 2014"
    • Place of Presentation
      Tokyo Medical and Dental University, Tokyo(Japan) (国際・ポスター)
    • Year and Date
      20140316-17
  • [Presentation] Replacement effects of human modified lysosomal 6-hexosaminidase B on Tay-Sachs and Sandhoff disease models and imaging with Novel pH-activatable fluorescent probes imaging of endocytosed lysosomal enzymes with pH-activatable fluorescent probe and evaluation of enzyme replacement effects on lysosomal storage diseases2014

    • Author(s)
      K. Kitakaze, D. Asanuma, M. Kamiya, D. Tsuji, M. Ikuo, Y Urano, H. Sakuraba, K. Itoh
    • Organizer
      The 10^<th> Annual World Symposium 2014, The Grand Hyatt One Market Place
    • Place of Presentation
      SanDiego, CA( USA)(国際•口頭発表)
    • Year and Date
      20140214-16
  • [Presentation] Establishment of patient-derived iPS cells with neurodegenerative lysosomal storage diseases and application for evaluating lysosomal enzyme replacement effects on differentiated neural cells2014

    • Author(s)
      K. Itoh, D. Tsuji, M. Ikuo, K. Kitakaze, S. Nishioka, I. Imataki, S. Yamaguchi, Y. Chiba, H. Sakuraba, I. Kobayashi, H. Sezutsu, H. Machii
    • Organizer
      The IUBMB 10th International Symposium on Cell Surface Macromolecules, Saha ainstitute of Nuclear
    • Place of Presentation
      Kolkata( India)(国際・招待講演)
    • Year and Date
      20140120-24
    • Invited
  • [Presentation] Imaging of lysosomal enzyme replacement effects with a novel fluorescent probe and imaging mass spectrometry2014

    • Author(s)
      K. Kitakaze, M. Ikuo, E. Sugiyama, D. Asanuma, M. Kamiya, M. Setou, Y. Urano, H. Sakuraba, K. Itoh
    • Organizer
      International Symposium on Glyco-Neuroscience
    • Place of Presentation
      Awazi-yumebutai, Awaji-shima, Hyougo(Japan)(国際・ポスター)
    • Year and Date
      20140109-11
  • [Presentation] Establishment of Human Neural Cell Culture Systems Induced from iPS Cells Derived from Tay-Sachs Disease Patient for Drug Discovery2013

    • Author(s)
      K. Itoh, D. Tsuji, K. Namba, S. Yamaguchi, K. Kitakaze, I. Imataki, N. Ishimaru, H. Sakuraba
    • Organizer
      The 3^<rd> Asian Congress for Inherited Metabolic Diseases (ACIMD) /The 55^<th> Annual Meeting of The Japanese Society for Inherited Metabolic Diseases (JSIMD)
    • Place of Presentation
      Tokyo Bay Hotel club resoat, Chiba( Japan)(国際・口頭)
    • Year and Date
      20131127-29
  • [Presentation] Evaluation of enzyme replacement effect and development of purified system to obtain recombinant lysosomal enzyme with M6P-type glycan2013

    • Author(s)
      K. Kitakaze, D. Tsuji, D. Asanuma, M. Kamiya, Y. Urano, H. Sakuraba, K. Itoh
    • Organizer
      Gordon Research Conference (Lysosomal Diseases)
    • Place of Presentation
      Lucca, Barga(Italy)(国際・ポスター)
    • Year and Date
      2013-04-14
  • [Book] バイオ医薬品製造の効率化と生産基材の開発新規生産基材を利用した組換えリソソーム病治療薬の開発(第4章)2012

    • Author(s)
      伊藤 孝司
    • Total Pages
      252
    • Publisher
      株式会社シーエムシー出版監修:山口照英
  • [Patent(Industrial Property Rights)] ヘキソサミニダーゼBの基質特異性を変換し、かつ、プロテアーゼ抵抗性を付与した新規高機能型酵素2013

    • Inventor(s)
      藤孝司辻大輔桜庭均
    • Industrial Property Rights Holder
      徳島大学
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      PCT/JP2013/078179
    • Filing Date
      2013-10-17
    • Overseas

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Published: 2015-06-25  

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