2022 Fiscal Year Final Research Report

Development of novel treatment strategy for intestinal failure based on generation and transplantation of intestinal organoids capable of GLP-2 secretion in an inducible manner

Research Project

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Project/Area Number	21K19541
Research Category	Grant-in-Aid for Challenging Research (Exploratory)
Allocation Type	Multi-year Fund
Review Section	Medium-sized Section 55:Surgery of the organs maintaining homeostasis and related fields
Research Institution	Juntendo University
Principal Investigator	Nakamura Tetsuya 順天堂大学, 大学院医学研究科, 特任教授 (70265809)
Co-Investigator(Kenkyū-buntansha)	松本有加順天堂大学, 医学部, 助教 (50813672) 須田一人順天堂大学, 医学部, 准教授 (60784725)
Project Period (FY)	2021-07-09 – 2023-03-31
Keywords	短腸症候群 / 腸管不全 / 腸オルガノイド / 小腸移植 / 再生医療
Outline of Final Research Achievements	Combining genetic modification of intestinal organoids and the organoid transplantation technique into the mouse large intestine, we aimed to create a novel mouse model in which GLP-2 analogue, a potent humoral factor that is capable of accelerating intestinal epithelial proliferation, is locally secreted on demand from an engineered region of the large intestine generated by organoid transplantation. We have successfully created genetic materials necessary for gene editing and set up the conditions for gene transfer into intestinal organoids. We have also developed a reproducible technique for replacing the colonic epithelium with organoids by local application of the chelating agent EDTA to dissociate the epithelium and following infusion of cultured organoids to engraft. We believe that further progress in this research will pave the way to the development of novel treatment strategy applicable to patients with severe intestinal failure due to short bowel syndrome.
Free Research Field	消化管再生医学
Academic Significance and Societal Importance of the Research Achievements	短腸症候群は、残存腸の機能代償が不十分で腸管不全をきたす場合、患者生命の維持も脅かす事態を引き起こす。腸管上皮細胞が分泌するGLP-2は多彩な作用を示すペプチドホルモンで、そのアミノ酸置換をもつ製剤（Teduglutide）はGLP-2に比し生体内半減期が延長し、持続性に小腸粘膜増殖を惹起するため効果が期待されている。ただ経口投与が困難で、しかも頻回かつ長期にわたる注射投与が必要であるなど、新しい発想に基づく治療技術開発が望まれる。本研究は一部の大腸に、「永続的」にかつ「誘導性」にGLP-2アナログを分泌する画期的動物モデル構築を図るものであり、腸管不全治療の新技術を提示可能と考えられる。