Generation of antigen-specific T lymphocytes using genome editing technique

• Project/Area Number: 17KK0189
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research)
• Allocation Type: Multi-year Fund
• Research Field: Tumor therapeutics
• Research Institution: Chiba University
• Principal Investigator: Ouchi Yasuo 千葉大学, 大学院医学研究院, 特任助教 (70553858)
• Project Period (FY): 2018 – 2021
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥15,600,000 (Direct Cost: ¥12,000,000、Indirect Cost: ¥3,600,000)
• Keywords: ゲノム編集技術 / 脂質ナノ粒子 / T細胞 / 免疫細胞療法 / COVID-19 / ゲノム編集 / がん免疫療法 / 免疫学 / バイオテクノロジー

Outline of Final Research Achievements

In this study, I developed non-viral genome editing tools that can be useful in the genome editing technology of T cells for successful cancer immunotherapy. As a result, we succeeded in developing mRNA lipid nanoparticles(LNPs) that enable highly efficient gene delivery into T cells, and developed genome-editing LNPs carrying CRISPR/Cas9 genome editing tools against PD-1 and TCR genes. Our genome-editing LNPs allows us to easily perform genome editing in human T cells. We have also developed LNPs carrying RNA editing tools against SARS-CoV-2 and confirmed that it showed high antiviral effects in the human lung organoid model of COVID-19.

Academic Significance and Societal Importance of the Research Achievements

近年、がん免疫細胞療法などを中心にゲノム編集技術の臨床応用が進められている。しかし、多くの問題を有しており、社会実装が困難な状況である。本研究ではT細胞を標的としたmRNA 脂質ナノ粒子を開発し、ゲノム編集技術を搭載することで簡便かつ迅速にゲノム編集T細胞を得る技術を開発した。また本技術を新型コロナウイルス感染症にも応用することで、高効率でSARS-CoV-2ウイルスを肺上皮細胞から除去できるRNA編集搭載脂質ナノ粒子を開発した。これらの研究成果は今後ゲノム編集技術を用いた治療法の社会実装を進めるうえで重要な基盤技術となると期待している。

Research Products

• [Int'l Joint Research] Salk institute for biological studies(米国) (2018)
• [Journal Article] FoxM1 delays senescence and extends lifespan (2022)
  • Author(s): Ouchi Y, Sahu S, Belmonte JCI
  • Journal Title: Nature Aging Volume: -
  • Int'l Joint Research
• [Journal Article] Deletion of Tgfβ signal in activated microglia prolongs hypoxia-induced retinal neovascularization enhancing Igf1 expression and retinal leukostasis. (2022)
  • Author(s): Usui-Ouchi A, Eade K, Giles S, Ideguchi Y, Ouchi Y, Aguilar E, Guoqin W, Marra K, Berlow R, Friedlander M
  • Journal Title: GLIA Volume: -
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Fibroblasts from different body parts exhibit distinct phenotypes in adult progeria Werner syndrome (2021)
  • Author(s): Kato H, Maezawa Y, Takayama N, Ouchi Y, Kaneko H, Kinoshita D, Takada-Watanabe A, Oshima M, Koshizaka M, Ogata H, Kubota Y, Mitsukawa N, Eto K, Iwama A, Yokote K.
  • Journal Title: Aging (Albany NY) Volume: 13 Issue: 4 Pages: 4946-4961
  • DOI: 10.18632/aging.202696
  • Peer Reviewed / Open Access
• [Journal Article] Generation of disease-specific and CRISPR/Cas9-mediated gene-corrected iPS cells from a patient with adult progeria Werner syndrome (2021)
  • Author(s): Kato Hisaya、Maezawa Yoshiro、Ouchi Yasuo、Takayama Naoya、Sone Masamitsu、Sone Kanako、Takada-Watanabe Aki、Tsujimura Kyoko、Koshizaka Masaya、Nagasawa Sayaka、Saitoh Hisako、Ohtaka Manami、Nakanishi Mahito、Tahara Hidetoshi、Shimamoto Akira、Iwama Atsushi、Eto Koji、Yokote Koutaro
  • Journal Title: Stem Cell Research Volume: 53 Pages: 102360-102360
  • DOI: 10.1016/j.scr.2021.102360
  • Peer Reviewed / Open Access
• [Journal Article] SCD2-mediated monounsaturated fatty acid metabolism regulates cGAS-STING-dependent type I IFN responses in CD4+ T cells (2021)
  • Author(s): Kanno Toshio、Nakajima Takahiro、Yokoyama Satoru、Asou Hikari K.、Sasamoto Shigemi、Kamii Yasuhiro、Hayashizaki Koji、Ouchi Yasuo、Onodera Taishi、Takahashi Yoshimasa、Ikeda Kazutaka、Hasegawa Yoshinori、Kinjo Yuki、Ohara Osamu、Nakayama Toshinori、Endo Yusuke
  • Journal Title: Communications Biology Volume: 4(1) Issue: 1 Pages: 820-820
  • DOI: 10.1038/s42003-021-02310-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] DUSP10 constrains innate IL-33-mediated cytokine production in ST2hi memory-type pathogenic Th2 cells (2018)
  • Author(s): Yamamoto, T., Endo, Y., Onodera, A., Hirahara, K., Asou, H., Nakajima, T., Kanno, T., Ouchi, Y., Uematsu, S., Nishimasu, H., Nureki, O., Tumes, D. J., Shimojo, N., and Nakayama, T.
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 4231-4231
  • DOI: 10.1038/s41467-018-06468-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effects of long-term intake of a yogurt fermented with Lactobacillus delbrueckii subsp. bulgaricus 2038 and Streptococcus thermophilus 1131 on mice (2018)
  • Author(s): Usui Yuki、Kimura Yasumasa、Satoh Takeshi、Takemura Naoki、Ouchi Yasuo、Ohmiya Hiroko、Kobayashi Kyosuke、Suzuki Hiromi、Koyama Satomi、Hagiwara Satoko、Tanaka Hirotoshi、Imoto Seiya、Eberl G?rard、Asami Yukio、Fujimoto Kosuke、Uematsu Satoshi
  • Journal Title: International Immunology Volume: 30 Issue: 7 Pages: 319-331
  • DOI: 10.1093/intimm/dxy035
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Patent(Industrial Property Rights)] 老化の評価方法 (2021)
  • Inventor(s): 大内靖夫、加藤尚也、横手幸太郎、江藤浩之、金子ひより、前澤善朗
  • Industrial Property Rights Holder: 大内靖夫、加藤尚也、横手幸太郎、江藤浩之、金子ひより、前澤善朗
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2021-097552
  • Filing Date: 2021
• [Patent(Industrial Property Rights)] アンチセンスオリゴマー (2021)
  • Inventor(s): 大内靖夫、加藤尚也、横手幸太郎、江藤浩之
  • Industrial Property Rights Holder: 大内靖夫、加藤尚也、横手幸太郎、江藤浩之
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2021-081389
  • Filing Date: 2021