2018 Fiscal Year Final Research Report
Proof of concept study of a novel excess chromosome elimination therapy to ameliorate and prevent trisomy 21 associated complications
| Project/Area Number |
16K09964
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Mie University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
宮川 世志幸 日本医科大学, 医学部, 講師 (90415604)
緒方 藍歌 名古屋大学, 医学系研究科, 特任助教 (70718311)
高成 広起 徳島大学, 病院, 特任講師 (70723253)
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| Research Collaborator |
Wakita Sachiko
Kokubo Yasumasa
Okamoto Takayuki
Hara Mari
Ichishi Masako
Kawano Mitsuo
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Keywords | ダウン症候群 / トリソミー / 染色体工学 / iPS細胞 / CRISPR/Cas |
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| Outline of Final Research Achievements |
Down syndrome is a chromosomal condition caused by an excess of chromosome 21, leading to an array of lifelong complications. The elimination of extra chromosome 21 could be directly linked to a primary intervention in this context for a person with Down syndrome. The overexpression of ZSCAN4 protein, a transcription factor previously reported as an aneuploidy correction effector, showed no significant extra chromosome elimination rate compared with no-treatment control trisomy 21 iPS cells in our in vitro setting. In an effort to delete extra chromosome, we next employ CRSPR/Cas9 system for DNA double-strand breaks on a single targeted chromosome 21, and found that 7% of entire chromosome loss rate on average by FISH analysis. The strategy to induce single chromosome cleavages at a multiple site using CRISPR/Cas9 thus may contribute to both basic and clinical science for aneuploidy-associated pathological condition, including Down syndrome and other autosomal trisomies.
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| Free Research Field |
遺伝学
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| Academic Significance and Societal Importance of the Research Achievements |
細胞内にある複数の相同染色体のうち、単一の染色体をCRISPR/Cas9システムを用いてアレル特異的に切断することにより、標的染色体を細胞内から消去可能であることを示した点は、学術的意義があると判断される。オフターゲット、Cas9蛋白の抗原性、DNAの変異誘導と蓄積、デリバリー法等、臨床応用には複数の解決すべき課題が複数あるも、これまで染色体の消去が困難ないし不可能であった背景に照らし合わせれば、本原理は過剰染色体を後天的に消去する基盤技術として臨床的展開が見込める技術と判断され、人口の0.1%弱の人がDown症候群を有する事実に鑑みれば、十分に社会的意義のある成果といえる。
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