Development of human biopsy-derived intestinal organoids monolayers and application for pharmaceutical research
| Project/Area Number |
20K20381
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| Project/Area Number (Other) |
18H05373 (2018-2019)
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| Research Category |
Grant-in-Aid for Challenging Research (Pioneering)
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| Allocation Type | Multi-year Fund (2020)
Single-year Grants (2018-2019) |
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| Review Section |
Medium-sized Section 47:Pharmaceutical sciences and related fields
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| Research Institution | Osaka University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
仲瀬 裕志 札幌医科大学, 医学部, 教授 (60362498)
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| Project Period (FY) |
2018-06-29 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥26,000,000 (Direct Cost: ¥20,000,000、Indirect Cost: ¥6,000,000)
Fiscal Year 2020: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000)
Fiscal Year 2019: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000)
Fiscal Year 2018: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000)
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| Keywords | ヒト小腸オルガノイド / ヒト小腸吸収上皮細胞 / 分化 / 創薬 / iPS細胞 |
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| Outline of Research at the Start |
本研究では、ヒト腸オルガノイド培養技術を用いて、生検より得たヒト小腸組織からオルガノイドを作製し、さらにヒト小腸オルガノイドから吸収上皮細胞（単層膜）への培養方法を確立し、“吸収・代謝・排泄”を同時に評価できる新規in vitro評価系の開発を進める。本評価系は、経口投与製剤の開発における創薬プロセスの刷新・効率化に直結することが期待される。
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| Outline of Final Research Achievements |
The human small intestine is the key organ for absorption, metabolism, and excretion of orally administered drugs. To preclinically predict these reactions in drug discovery research, a cell model that can precisely recapitulate the in vivo human intestinal monolayer is desired. Here, we developed a monolayer platform using human biopsy-derived duodenal organoids for application to pharmacokinetic studies. The human duodenal organoid-derived monolayer was prepared by a simple method in 3 to 8 days. It consisted of polarized absorptive cells and had tight junctions. It showed much higher cytochrome P450 (CYP) 3A4 and carboxylesterase (CES) 2 activities than the existing models (Caco-2 cells). It also showed efflux activity of P-glycoprotein (P-gp) and inducibility of CYP3A4. This monolayer assay system can be a general platform for a wide range of applications including pharmaceutical research.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究によりヒト小腸での“吸収・排泄・代謝”を同時に評価可能なin vitro評価系が開発されることで、現在までモデル＆シミュレーションでしか予測できなかった薬物の消化管での利用率予測を正確に見積もることが可能となり、ヒト投与量の正確な見積もり、並びにより精度の高い薬物吸収過程における薬物相互作用の予測がin vitro試験で可能となる。即ち、小腸アベイラビリティを評価できる初めてのin vitroモデルの基盤が構築され、創薬プロセスの飛躍的な効率化が期待できる。これらは合理的な医薬品審査へも寄与し、もって国民の健康の増進に資することが期待される。
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Report
(5 results)
Research Products
(31 results)
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[Journal Article] Monolayer platform using human biopsy-derived duodenal organoids for pharmaceutical research.2021
Author(s)
Yamashita T., Inui T., Yokota J., Kawakami K., Morinaga G., Takatani M., Hirayama D., Nomoto R., Ito K., Cui Y., Ruez S., Harada K., Kishimoto W., Nakase H., Mizuguchi H.
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Journal Title
Mol. Ther. Methods. Clin. Dev.
Volume: 22
Pages: 263-278
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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