組換えカイコ繭由来ライソゾーム病治療薬の開発  [in Japanese] Development of Enzyme Drugs Derived from Transgenic Silkworms to Treat Lysosomal Diseases  [in Japanese]

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Author(s)

    • 伊藤 孝司 Itoh Kohji
    • 徳島大学大学院薬科学教育部附属医薬創製教育研究センター創薬生命工学分野|徳島大学薬学部創薬生命工学研究室 Department of Medicinal Biotechnology, Institute for Medicinal Research, Graduate School of Pharmaceutical Sciences, Tokushima University|Department of Medicinal Biotechnology, Faculty of Pharmaceutical Sciences, Tokushima University
    • 西岡 宗一郎 Nishioka So-ichiro
    • 徳島大学大学院薬科学教育部附属医薬創製教育研究センター創薬生命工学分野 Department of Medicinal Biotechnology, Institute for Medicinal Research, Graduate School of Pharmaceutical Sciences, Tokushima University
    • 日高 朋 Hidaka Tomo
    • 徳島大学薬学部創薬生命工学研究室 Department of Medicinal Biotechnology, Faculty of Pharmaceutical Sciences, Tokushima University
    • 辻 大輔 Tsuji Daisuke
    • 徳島大学大学院薬科学教育部附属医薬創製教育研究センター創薬生命工学分野|徳島大学薬学部創薬生命工学研究室 Department of Medicinal Biotechnology, Institute for Medicinal Research, Graduate School of Pharmaceutical Sciences, Tokushima University|Department of Medicinal Biotechnology, Faculty of Pharmaceutical Sciences, Tokushima University
    • 真板 宣夫 Maita Nobuo
    • 徳島大学先端酵素学研究所疾患プロテオミクス研究部門 Division of Disease Proteomics, Institute for Advanced Medical Sciences, Tokushima University

Abstract

 Lysosomal storage diseases (LSDs) are inborn errors caused by genetic defects of lysosomal enzymes associated with the excessive accumulation of natural substrates and neurovisceral manifestations. Until now, enzyme replacement therapy (ERT) with human lysosomal enzymes produced by genetically engineered mammalian cell lines has been applied clinically to treat several LSDs. ERT is based on the incorporation of <i>N</i>-glycosylated lysosomal enzymes through binding to glycan receptors on the surface of target cells and delivery to lysosomes. However, ERT has several disadvantages, including difficulty in mass producing human enzymes, dangers of pathogen contamination, and high cost. Recently, we have succeeded in producing transgenic silkworms which overexpress human lysosomal enzymes in silk glands, and have purified active and functional enzymes from middle silk glands and cocoons. Silk gland- and cocoon-derived human enzymes carrying high-mannose and pauci-mannose <i>N</i>-glycans are endocytosed by monocytes <i>via</i> the mannose receptor pathway; these were then delivered to lysosomes. Human cathepsin A (Ctsa) precursor proteins purified from the cocoons have been found to suppress microglial activation in the brains of <i>Ctsa</i>-deficient mice; this deficiency is caused by a splicing defect, and serves as a galactosialidosis model associated with the combination of a deficiency of lysosomal neuraminidase 1 (NEU1) and the accumulation of sialyloligosaccharides. Transgenic silkworms overexpressing human lysosomal enzymes in silk glands could serve as a future bioresource to provide safe therapeutic enzymes for the treatment of LSDs. The combination of recent developments in transglycosylation technology with microbial endoglycosidases will aid in the development of therapeutic glycoproteins as bio-medicines.<br>

Journal

  • YAKUGAKU ZASSHI

    YAKUGAKU ZASSHI 138(7), 885-893, 2018

    The Pharmaceutical Society of Japan

Codes

  • NII Article ID (NAID)
    130007386663
  • NII NACSIS-CAT ID (NCID)
    AN00284903
  • Text Lang
    JPN
  • ISSN
    0031-6903
  • NDL Article ID
    029150243
  • NDL Call No.
    Z19-411
  • Data Source
    NDL  J-STAGE 
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