| Project/Area Number |
16K10769
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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 |
Neurosurgery
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| Research Institution | Keio University |
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Principal Investigator |
Kanai Ryuichi 慶應義塾大学, 医学部(信濃町), 共同研究員 (50327532)
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| Co-Investigator(Kenkyū-buntansha) |
峯 裕 慶應義塾大学, 医学部(信濃町), 訪問研究員 (10306730)
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| Research Collaborator |
WAKIMOTO Hiroaki
SASAKI Hikaru
KURODA Toshihiko
MIYOSHI Hiroyuki
TAMURA Ryota
NAGASHIMA Hideaki
TODA Masahiro
YOSHIDA Kazunari
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | 膠芽腫 / 悪性脳腫瘍 / 腫瘍溶解ウイルス / 悪性神経膠腫 / グリオーマ幹細胞 / 抗腫瘍免疫 / 腫瘍溶解ウィルス / 神経幹細胞 / HSV / 条件複製型HSV / iPS / 脳腫瘍学 / ウイルス療法 |
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| Outline of Final Research Achievements |
We attempted to establish an effective therapy against malignant gliomas, using a combination of conditionally replicating oncolytic virus and neural stem cells. To effectively target malignant cells that diffusely invade brain parenchyma, we designed an oncolytic virus which starts lytic replication only under doxycycline (Dox). We constructed a shuttle plasmid that starts translation of ICP4 in the presence of Dox, and confirmed that d120, a replication incompetent HSV mutant, forms plaques in cells transfected by the plasmid, only in the presence of Dox. Also, in vitro, we evaluated cytotoxicity of d120 against human neural stem cells. We concluded that the strategy was feasible, as d120 was appropriately attenuated for this purpose. We confirmed that patient derived glioma stem cells readily form tumors in the brains of nude mice, and that those tumors pathologically resemble brain tumors in patients. Likewise, mouse glioma stem cells form invasive brain tumors in wildtype mice.
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| Academic Significance and Societal Importance of the Research Achievements |
膠芽腫など悪性神経膠腫は、放射線治療や化学療法に抵抗性で、脳実質へ広範に浸潤するため、既存の手法では治療効果改善は望めない。免疫療法やウイルス療法などの新規治療法に関し、現在も米国を中心に臨床試験が進行中だが、成績改善には本質的な見直しが必要だろう。本研究では、脳実質に浸潤した悪性腫瘍細胞を標的とし、薬剤誘導性に複製開始する腫瘍溶解ウイルスを神経幹細胞の性質を利用して運搬させ、浸潤した脳実質内で膠芽腫細胞を殺傷する手法を考案した。本研究分野では、治療ベクターが脳内に浸潤した腫瘍細胞へ到達できないことが課題だが、これを打開する手法となる。改善が必要だが、有望な手法であり、本分野での期待は高い。
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