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KAKEN_18K19622seika.pdf
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自殺遺伝子CD-UPRTゲノム編集iPS細胞を用いた遺伝子治療
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ジサツ イデンシ CD-UPRT ゲノム ヘンシュウ iPS サイボウ オ モチイタ イデンシ チリョウ
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Jisatsu idenshi CD-UPRT genomu henshū iPS saibō o mochiita idenshi chiryō
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Gene therapy using genome-edited iPS cells with CD-UPRT for malignant glioma
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戸田, 正博
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トダ, マサヒロ
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Toda, Masahiro
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慶應義塾大学・医学部 (信濃町) ・教授
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Research team head
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科研費研究者番号 : 20217508
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2021
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科学研究費補助金研究成果報告書
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2020
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悪性グリオーマは予後不良の脳腫瘍であり、腫瘍幹細胞 (BTSC) はびまん性に浸潤する性質を有する。神経幹細胞(NSC)は、脳腫瘍へ遊走する性質を持ち、治療遺伝子を搭載する運搬体として注目される。本研究では、浸潤性BTSCの根絶を目指して iPS細胞から分化誘導したNSCを用いた自殺遺伝子細胞治療の開発を行った。ゲノム編集技術を利用して、iPS細胞への治療遺伝子yCD-UPRTの挿入部位を最適化し、優れた治療用NSCへ分化誘導することに成功した。その後、BTSCへの治療効果を評価し、顕著な効果を得た。本研究は、ゲノム編集技術と遺伝子細胞療法を組み合わせた革新的治療戦略と考える。
Glioblastoma is characterized by diffuse infiltration into the normal brain. Invasive glioma stem cells (GSCs) is an underlying cause of treatment failure. Here we show that neural stem cells (NSCs) derived from CRISRP/Cas9-edited human induced pluripotent stem cell (hiPSC) expressing a suicide gene had high tumor-trophic migratory capacity, leading to marked in vivo anti-tumor effects. Time-lapse imaging of organotypic brain slice cultures first visualized the directional migration of NSCs toward GSCs and the bystander killing effect. The gene insertion to house-keeping gene locus provided higher and stable transgene expression than other common insertion sites. Our results indicate the potential benefit of NSC-based gene therapy for invasive GSCs. Furthermore, the present research concept may become a platform to promote clinical studies using hiPSC.
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研究種目 : 挑戦的研究 (萌芽)
研究期間 : 2018~2020
課題番号 : 18K19622
研究分野 : 脳神経外科学
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