Gene therapy using genome-edited iPS cells with CD-UPRT for malignant glioma

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K19622
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 56:Surgery related to the biological and sensory functions and related fields
• Research Institution: Keio University
• Principal Investigator: Toda Masahiro 慶應義塾大学, 医学部(信濃町), 教授 (20217508)
• Project Period (FY): 2018-06-29 – 2021-03-31
• Keywords: glioblastoma / gene therapy / suicide gene / neural stem cell / CD-UPRT / migration / genome-editing / CRISPR/Cas9

Outline of Final Research Achievements

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.

Free Research Field

脳神経外科学

Academic Significance and Societal Importance of the Research Achievements

BTSCは正常脳組織へ浸潤して発育するため、既存の治療法とは異なる細胞傷害機序を有する新たな治療法の開発が望まれている。本研究の斬新性は、NSCの脳腫瘍へ集積する性質に着目し、iPS細胞から分化誘導されたNSCをBTSC治療のための遺伝子搭載細胞として利用することにある。iPS研究は再生医療への応用が急速に進められているが、脳腫瘍治療への応用はほとんどない。さらに、最新のゲノム編集技術を用いて、自殺遺伝子CD-UPRTをiPS細胞に組み込む点も意義深い。本研究手法は今後の遺伝子治療のプラットフォーム技術となる革新性を有している。