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Treatment with Polyethylene Glycol-Conjugated Fungal d-Amino Acid Oxidase Reduces Lung Inflammation in a Mouse Model of Chronic Granulomatous Disease

Research Project

Project/Area Number 16K09972
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Pediatrics
Research InstitutionUniversity of Miyazaki

Principal Investigator

Nunoi Hiroyuki  宮崎大学, 医学部, 元教授 研究生 (50218260)

Co-Investigator(Kenkyū-buntansha) 前田 浩  崇城大学, DDS研究所, 特任教授 (90004613)
松倉 誠  崇城大学, 薬学部, 教授 (70238997)
Research Collaborator Maeda Hiroshi  崇城大学, DDS研究所, 特任教授 (90004613)
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥130,000 (Direct Cost: ¥100,000、Indirect Cost: ¥30,000)
Fiscal Year 2017: ¥130,000 (Direct Cost: ¥100,000、Indirect Cost: ¥30,000)
Fiscal Year 2016: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
KeywordsPEG-DAO酵素補充療法 / CGDマウス / カンジダ死菌誘発性肺炎 / D型アミノ酸 / カンジダ死菌による肺炎実験 / PEG-DAO / D-amino acid / カンジダ死菌による肺肉芽腫症 / カンジダ死菌による肉芽腫モデル / 酵素補充療法
Outline of Final Research Achievements

Chronic granulomatous disease (CGD) is a primary immunodeficiency wherein phagocytes are unable to produce reactive oxygen species (ROS) owing to a defect in the NADPH oxidase complex. Patients with CGD experience bacterial and fungal infections and excessive inflammatory disorders. Bone marrow transplantation and gene therapy are theoretically curative, however, residual pathogenic components cause inflammation and/or organic damage in patients. In this study, the efficacy of the ROS-generating enzyme replacement therapy was tested with PEG-fDAO using three experimental strategies with the in vivo lung inflammation model of gp91phox-knockout CGD mice. The lung weight and pathological findings suggest the condition was ameliorated by administration PEG-fDAO, followed by intraperitoneal injection of d-phenylalanine or d-proline. These data reveal the targeted delivery of PEG-fDAO and show that PEG-fDAO can be used to treat inflammation in CGD in vivo.

Academic Significance and Societal Importance of the Research Achievements

慢性肉芽腫症(CGD)は活性酸素産性能の欠損により、殺菌能が低下するために、激しい感染症を繰り返す疾患である。これまで、骨髄移植や遺伝子治療が成功を収めつつあるが、患者状態の悪い場合は前処置の問題など非常なリスクを伴うことが問題であった。我々は、炎症局所で過酸化水素を産生できるPEG化したD-アミノ酸オキシダーゼ(PEG-pDAO)を用いた酵素補充療法をCGD患者好中球を用いたin vitroでの有用性を証明してきた。今回カンジダ死菌で誘発されたCGDマウス肺炎モデルを用いて新たに開発したPEG-fDAOのin vivoでの有用性を確認し、CGDの新たな酵素補充療法による治療法を提示した。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (4 results)

All 2018 2016

All Journal Article (2 results) (of which Peer Reviewed: 2 results) Presentation (2 results) (of which Int'l Joint Research: 1 results,  Invited: 1 results)

  • [Journal Article] Necrotizing Ulcer After BCG Vaccination in a Girl With Leukocyte-adhesion Deficiency Type 1.2018

    • Author(s)
      Kurosawa H, Mizukami T, Nunoi H, Kato M, Sato Y, Okuya M, Fukushima K, Katsuyama Y, Arisaka O.
    • Journal Title

      J Pediatr Hematol Oncol.

      Volume: 49(1) Issue: 1 Pages: 62-66

    • DOI

      10.1097/mph.0000000000000853

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A Hot-spot Mutation in CDC42 (p.Tyr64Cys) and Novel Phenotypes in a Third Patient with Takenouchi-Kosaki Syndrome.2018

    • Author(s)
      Motokawa M, Watanabe S, Nakatomi A, Kondoh T, Matsumoto T, Morifuji K, Sawada H, Nishimura T, Nunoi H, Yoshiura KI, Moriuchi H, Dateki S.
    • Journal Title

      J Hum Genet.

      Volume: 63 Issue: 3 Pages: 387-390

    • DOI

      10.1038/s10038-017-0396-5

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Presentation] Clinical and Genetic Profiles of Chronic Granulomatous Disease in Japan2016

    • Author(s)
      Tomoyuki Mizukami, Mayumi Iwata-Okada, Toyoki Nishimura,Hiroyuki Nunoi et al
    • Organizer
      European Society of Immuno Deficiency
    • Place of Presentation
      Barcelona, Spain
    • Year and Date
      2016-09-21
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] CGD登録事業から学んだこと2016

    • Author(s)
      布井博幸
    • Organizer
      食細胞機能異常研究会
    • Place of Presentation
      東京
    • Related Report
      2016 Research-status Report
    • Invited

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Published: 2016-04-21   Modified: 2023-01-30  

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