2019 Fiscal Year Final Research Report
Rational design of high functional biosupra and development of therapeutic evaluation system with disease models
| Project/Area Number |
17H04102
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Applied pharmacology
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| Research Institution | The University of Tokushima |
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Principal Investigator |
ITOH Kohji 徳島大学, 大学院医歯薬学研究部(薬学域), 教授 (00184656)
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| Co-Investigator(Kenkyū-buntansha) |
辻 大輔 徳島大学, 大学院医歯薬学研究部(薬学域), 助教 (00423400)
広川 貴次 国立研究開発法人産業技術総合研究所, 生命工学領域, 研究チーム長 (20357867)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Keywords | バイオ医薬品 / 糖タンパク製剤 / リソソーム病 / ドラッグデリバリー / 糖鎖工学 |
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| Outline of Final Research Achievements |
Galactosialidosis (GS) model mice were established by introduction of recessive mutations inducing splicing defect into the murine cathepsin A (Ctsa) gene associated with both Ctsa and neuramnidase-1 (Neu1) deficiencies. The recombinant human CTSA precursor proteins carrying N-glycans with terminal mannose (Man) residues purified from the cocoons derived from the transgenic silkworms overexpressing the CTSA gene were intracerebroventricularly (icv) administered to be incorporated via Man receptors into the activated microglia to repress neuroinflammation. The human CTSA precursors carrying N-glycans with terminal mannose 6-phosphate receptors (M6P) were icv or intravenously administered to be incorporated via M6P receptors into the cells composing the brains or livers/spleens of GS mice to restore the intraparenchymal Neu1 activity to reduce the terminal sialylglycans accumulated in the organs.
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| Free Research Field |
病態生化学、分子治療学
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| Academic Significance and Societal Importance of the Research Achievements |
未だ治療法が無く、日本人に多い希少難病である、NEU1及びCTSA同時欠損症の病態解明と高機能型酵素を用いる新規治療法の開発研究から、ヒト培養細胞株でのNEU1遺伝子単独発現によるin vivo NEU1結晶の作製・単離法を確立し、世界初の分子特性や構造知見を得た。また農研機構との共同でCTSAを絹糸腺で高発現するTGカイコ繭から簡便精製でき、ヒト型様N型糖鎖が付加されたCTSA前駆体タンパク質は、GSモデルマウス脳室または静脈内投与により、各臓器内の両酵素活性の回復と蓄積シアリル糖鎖の減少（治療評価マーカー）が示され、バイオ医薬品の低コスト生産基材としてのTGカイコの有用性が期待された。
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