Development of Enzyme Drugs Derived from Transgenic Silkworms to Treat Lysosomal Diseases

  • Itoh Kohji
    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
  • Nishioka So-ichiro
    Department of Medicinal Biotechnology, Institute for Medicinal Research, Graduate School of Pharmaceutical Sciences, Tokushima University
  • Hidaka Tomo
    Department of Medicinal Biotechnology, Faculty of Pharmaceutical Sciences, Tokushima University
  • Tsuji Daisuke
    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
  • Maita Nobuo
    Division of Disease Proteomics, Institute for Advanced Medical Sciences, Tokushima University

Bibliographic Information

Other Title
  • 組換えカイコ繭由来ライソゾーム病治療薬の開発
  • Symposium Review 組換えカイコ繭由来ライソゾーム病治療薬の開発
  • Symposium Review クミカエ カイコケン ユライ ライソゾームビョウ チリョウヤク ノ カイハツ

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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 N-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 N-glycans are endocytosed by monocytes via 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 Ctsa-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, 2018-07-01

    The Pharmaceutical Society of Japan

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