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Development of immunostimulatory mRNA and lymphoid tissue-targeting carriers for cancer vaccine

Research Project

Project/Area Number 18H03529
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 90120:Biomaterials-related
Research InstitutionKyoto Prefectural University of Medicine (2020-2021)
The University of Tokyo (2018-2019)

Principal Investigator

内田 智士  京都府立医科大学, 医学(系)研究科(研究院), 准教授 (20710726)

Co-Investigator(Kenkyū-buntansha) 弓場 英司  大阪府立大学, 工学(系)研究科(研究院), 准教授 (80582296)
Project Period (FY) 2018-04-01 – 2022-03-31
Project Status Declined (Fiscal Year 2021)
Budget Amount *help
¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000)
Fiscal Year 2021: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2018: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
KeywordsmRNAワクチン / がんワクチン / 細胞性免疫 / 2本鎖RNA / 脂質性ナノ粒子 / 高分子ミセル / アジュバント / ガンワクチン / 2本鎖mRNA
Outline of Annual Research Achievements

mRNAワクチンは効果的に細胞性免疫を誘導できるため、がんワクチンへ有望である。mRNAワクチンでは、主に脂質性ナノ粒子を構成する脂質性ナノ粒子を構成する脂質に免疫賦活化アジュバントとしての活性が付与されてきたが、脂質は体内動態の制御が困難であり、我々はより動態制御が容易なmRNAにアジュバント活性を付与した。本研究では、mRNAへのアジュバント活性の導入方法と、mRNA送達システムの構築を行っている。これまでに、mRNAに2本鎖構造を搭載することで、アジュバントとしての活性を併せ持つ設計を最適化し、さらに、免疫原性の低い脂質性ナノ粒子と併用することで、優れたワクチン効果が得られることを、マウスにて実証していた。
本年度の研究では、モデル抗原を発現するがん細胞を移植したマウスモデルにおいて、前年度までに構築したmRNAワクチンシステムにより、高い抗がん活性が得られることを示した。すなわち、独自に設計したシステムのがんワクチンへの有効性が実証された。
また、より安全性の高い投与を目指し、脂質を用いないmRNA送達方法も検討している。これまでに、我々は表面がポリエチレングリコールで覆われた高分子ミセルを用いることで、安全なmRNA送達が可能であることを示してきた。一方、この高分子ミセルは、安全性が高いものの、RNA分解酵素に対する耐性が低いことが課題であった。これに対して、本年度、mRNA修飾など様々な方法論でこの課題を克服することに成功した。さらに、高分子ミセルを用いて独自の2本鎖構造を有するmRNを送達することで、マウスに対して優れた細胞性免疫誘導活性を得ることができることも実証した。
以上のように、本年度までに、独自に開発したシステムが、モデル抗原を用いた評価において、優れた効果を示すことを実証した。

Research Progress Status

翌年度、交付申請を辞退するため、記入しない。

Strategy for Future Research Activity

翌年度、交付申請を辞退するため、記入しない。

Report

(3 results)
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • 2018 Annual Research Report

Research Products

(47 results)

All 2021 2020 2019 2018 Other

All Journal Article (22 results) (of which Int'l Joint Research: 12 results,  Peer Reviewed: 22 results,  Open Access: 9 results) Presentation (20 results) (of which Int'l Joint Research: 8 results,  Invited: 8 results) Remarks (3 results) Patent(Industrial Property Rights) (2 results) (of which Overseas: 1 results)

  • [Journal Article] Co-encapsulation of Cas9 mRNA and guide RNA in polyplex micelles enables genome editing in mouse brain2021

    • Author(s)
      S. Abbasi, S. Uchida, K. Toh, T.A. Tockary, A. Dirisala, K. Hayashi, S. Fukushima, K. Kataoka
    • Journal Title

      Journal of Controlled Release

      Volume: 332 Pages: 260-268

    • DOI

      10.1016/j.jconrel.2021.02.026

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Treatment of ischemic neuronal death by introducing brain-derived neurotrophic factor mRNA using polyplex nanomicelle2021

    • Author(s)
      Y. Fukushima, S. Uchida, H. Imai, H. Nakatomi, K. Kataoka, N. Saito, K. Itaka
    • Journal Title

      Biomaterials

      Volume: 270 Pages: 120681-120681

    • DOI

      10.1016/j.biomaterials.2021.120681

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] mRNA loading into ATP-responsive polyplex micelles with optimal density of phenylboronate ester crosslinking to balance robustness in the biological milieu and intracellular translational efficiency2021

    • Author(s)
      Yoshinaga Naoto、Uchida Satoshi、Dirisala Anjaneyulu、Naito Mitsuru、Osada Kensuke、Cabral Horacio、Kataoka Kazunori
    • Journal Title

      J. Control. Release

      Volume: 330 Pages: 317-328

    • DOI

      10.1016/j.jconrel.2020.12.033

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Transient stealth coating of liver sinusoidal wall by anchoring two-armed PEG for retargeting nanomedicines2020

    • Author(s)
      Dirisala Anjaneyulu、Uchida Satoshi、Toh Kazuko、Li Junjie、Osawa Shigehito、Tockary Theofilus A.、Liu Xueying、Abbasi Saed、Hayashi Kotaro、Mochida Yuki、Fukushima Shigeto、Kinoh Hiroaki、Osada Kensuke、Kataoka Kazunori
    • Journal Title

      Science Advances_

      Volume: 6

    • DOI

      10.1126/sciadv.abb8133

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Bundling of mRNA strands inside polyion complexes improves mRNA delivery efficiency in vitro and in vivo2020

    • Author(s)
      Koji Kyoko、Yoshinaga Naoto、Mochida Yuki、Hong Taehun、Miyazaki Takuya、Kataoka Kazunori、Osada Kensuke、Cabral Horacio、Uchida Satoshi
    • Journal Title

      Biomaterials

      Volume: 261 Pages: 120332-120332

    • DOI

      10.1016/j.biomaterials.2020.120332

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Guanidine-phosphate interactions stabilize polyion complex micelles based on flexible catiomers to improve mRNA delivery2020

    • Author(s)
      T. Miyazaki, S. Uchida, H. Hatano, Y. Miyahara, A. Matsumoto, H. Cabral
    • Journal Title

      European Polymer Journal

      Volume: 140 Pages: 110028-110028

    • DOI

      10.1016/j.eurpolymj.2020.110028

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Polymeric Nanocarriers with Controlled Chain Flexibility Boost mRNA Delivery In Vivo through Enhanced Structural Fastening2020

    • Author(s)
      Miyazaki Takuya、Uchida Satoshi、Nagatoishi Satoru、Koji Kyoko、Hong Taehun、Fukushima Shigeto、Tsumoto Kouhei、Ishihara Kazuhiko、Kataoka Kazunori、Cabral Horacio
    • Journal Title

      Adv Healthc Mater

      Volume: 9 Pages: 2000538-2000538

    • DOI

      10.1002/adhm.202000538

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Nanomedicine-Based Approaches for mRNA Delivery2020

    • Author(s)
      S. Uchida, F. Perche, C. Pichon, H. Cabral
    • Journal Title

      Mol. Pharm._

      Volume: 17 Pages: 3654-3684

    • DOI

      10.1021/acs.molpharmaceut.0c00618

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] mRNA as a Tool for Gene Transfection in 3D Cell Culture for Future Regenerative Therapy2020

    • Author(s)
      S. Uchida, K. Yanagihara, A. Matsui, K. Kataoka, K. Itaka
    • Journal Title

      Micromachines

      Volume: 11 Pages: 426-426

    • DOI

      10.3390/mi11040426

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A chemically unmodified agonistic DNA with growth factor functionality for in vivo therapeutic application2020

    • Author(s)
      Ueki Ryosuke、Uchida Satoshi、Kanda Naoto、Yamada Naoki、Ueki Ayaka、Akiyama Momoko、Toh Kazuko、Cabral Horacio、Sando Shinsuke
    • Journal Title

      Science Advances_

      Volume: 6

    • DOI

      10.1126/sciadv.aay2801

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A 50-nm-Sized Micellar Assembly of Thermoresponsive Polymer-Antisense Oligonucleotide Conjugates for Enhanced Gene Knockdown in Lung Cancer by Intratracheal Administration.2020

    • Author(s)
      B. S. Kim, S. Osawa, M. Naito, S. Ogura, R. Kamegawa, H. Ishida, H. J. Kim, S. Uchida, K. Miyata
    • Journal Title

      Advanced Therapeutics

      Volume: 3 Pages: 1900123-1900123

    • DOI

      10.1002/adtp.201900123

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Single-stranded DNA-packaged polyplex micelle as adeno-associated-virus-inspired compact vector to systemically target stroma-rich pancreatic cancer.2019

    • Author(s)
      T. A. Tockary, W. Foo, A. Dirisala, Q. Chen, S. Uchida, S. Osawa, Y. Mochida, X. Liu, H. Kinoh, H. Cabral, K. Osada, K. Kataoka
    • Journal Title

      ACS Nano

      Volume: 13 Pages: 12732-12742

    • DOI

      10.1021/acsnano.9b04676

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Enhancement of motor function 1 recovery after spinal cord injury in mice by delivery of brain derived neurotrophic factor mRNA.2019

    • Author(s)
      S. T. Crowley, Y. Fukushima, S. Uchida, K. Kataoka, K. Itaka
    • Journal Title

      Mol Ther Nucleic Acids

      Volume: 17 Pages: 465-476

    • DOI

      10.1016/j.omtn.2019.06.016

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Bundling mRNA strands to prepare nano-assemblies with enhanced stability towards RNase for in vivo delivery.2019

    • Author(s)
      N. Yoshinaga, E. Cho, K. Koji, Y. Mochida, M. Naito, K. Osada, K. Kataoka, H. Cabral, S. Uchida
    • Journal Title

      Angewandte Chemie International Edition

      Volume: 58 Pages: 11360-11363

    • DOI

      10.1002/anie.201905203

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] In vivo rendezvous of small nucleic acid drugs with charge-matched block catiomers to target cancers2019

    • Author(s)
      Watanabe Sumiyo、Hayashi Kotaro、Toh Kazuko、Kim Hyun Jin、Liu Xueying、Chaya Hiroyuki、Fukushima Shigeto、Katsushima Keisuke、Kondo Yutaka、Uchida Satoshi、Ogura Satomi、Nomoto Takahiro、et al.
    • Journal Title

      Nat. Commun.

      Volume: 10 Pages: 1-13

    • DOI

      10.1038/s41467-019-09856-w

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] PEG-OligoRNA Hybridization of mRNA for Developing Sterically Stable Lipid Nanoparticles toward In Vivo Administration2019

    • Author(s)
      Kurimoto Shota、Yoshinaga Naoto、Igarashi Kazunori、Matsumoto Yu、Cabral Horacio、Uchida Satoshi
    • Journal Title

      Molecules

      Volume: 24 Pages: 1303-1303

    • DOI

      10.3390/molecules24071303

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Treatment of intervertebral disk disease by administration of messenger RNA encoding a cartilage-anabolic transcription factor.2019

    • Author(s)
      C. -Y. Lin, S. T. Crowley, S. Uchida, Y. Komaki, K. Kataoka, K. Itaka
    • Journal Title

      Molecular Therapy - Nucleic Acids

      Volume: 16 Pages: 162-171

    • DOI

      10.1016/j.omtn.2019.02.012

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Design concepts of polyplex micelles for in vivo therapeutic delivery of plasmid DNA and messenger RNA.2019

    • Author(s)
      S. Uchida, K. Kataoka
    • Journal Title

      Journal of Biomedical Materials Research Part A

      Volume: 107 Pages: 978-990

    • DOI

      10.1002/jbm.a.36614

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Precise tuning of disulfide crosslinking in mRNA polyplex micelles for optimizing extracellular and intracellular nuclease tolerability.2019

    • Author(s)
      A. Dirisala, S. Uchida, T. A. Tockary, N. Yoshinaga, J. Li, S. Osawa, L. Gorantla, S. Fukushima, K. Osada, K. Kataoka
    • Journal Title

      Journal of Drug Targeting

      Volume: 印刷中 Pages: 670-680

    • DOI

      10.1080/1061186x.2018.1550646

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Tunable non-enzymatic degradability of N-substituted polyaspartamide main chain by amine protonation and alkyl spacer length in side chains for enhanced messenger RNA transfection efficiency.2019

    • Author(s)
      M. Naito, Y. Otsu, R. Kamegawa, K. Hayashi, S. Uchida, H. -J. Kim, K. Miyata
    • Journal Title

      Sci. Technol. Adv. Mater.

      Volume: 20 Pages: 105-115

    • DOI

      10.1080/14686996.2019.1569818

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Induced packaging of mRNA into polyplex micelles by regulated hybridization with a small number of cholesteryl RNA oligonucleotides directed enhanced in vivo transfection.2019

    • Author(s)
      N. Yoshinaga, S. Uchida, M. Naito, K. Osada, H. Cabral, K. Kataoka
    • Journal Title

      Biomaterials

      Volume: 197 Pages: 255-267

    • DOI

      10.1016/j.biomaterials.2019.01.023

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Prolonged engraftment of transplanted hepatocytes in the liver by transient pro-survival factor supplementation using ex vivo mRNA transfection.2018

    • Author(s)
      A. Matsui, S. Uchida, A. Hayashi, K. Kataoka, K. Itaka
    • Journal Title

      J Control Release

      Volume: 285 Pages: 1-11

    • DOI

      10.1016/j.jconrel.2018.06.033

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] メッセンジャーRNAのCOVID-19ワクチンへの応用とその後の展望2021

    • Author(s)
      内田 智士
    • Organizer
      2020年度 医療産業イノベーションフォーラム,
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 新型コロナウイルスや未来のパンデミックに対するmRNAナノワクチンの開発2020

    • Author(s)
      内田 智士
    • Organizer
      第7回COINSシンポジウム ~小さく寄り添い大きく守る、未来の医療はすぐそこに~
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] RNAオリゴマーを用いたmRNA修飾法の開発とmRNA送達、ワクチンへの展開2020

    • Author(s)
      内田 智士
    • Organizer
      核酸医薬シンポジウム2020
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] mRNA bundling inside polyion complexes for their physical and biological stabilization2020

    • Author(s)
      S. Uchida, K. Koji, N. Yoshinaga, Y. Mochida, T. Hong, H. Cabral
    • Organizer
      8th International mRNA Health Conference
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] mRNA nanomachine for treating rare genetic disorders2020

    • Author(s)
      S. Uchida
    • Organizer
      India-Japan Webinar on "Rare Genetic Disorders"
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] RNA構造に着目したメッセンジャーRNA 医薬の機能化2020

    • Author(s)
      内田 智士
    • Organizer
      第69回 高分子討論会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] DNA、mRNAのex vivo導入による細胞治療の効果向上2020

    • Author(s)
      内田 智士
    • Organizer
      第36回日本DDS学会学術集会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Preparation of nanoassemblies from several mRNA strands for enhancing nuclease stability.2020

    • Author(s)
      S. Uchida, N. Yoshinaga, E. Cho, K. Koji, K. Kataoka, H. Cabral
    • Organizer
      International Symposium on Biomedical Materials for Drug/Gene Delivery
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Development of mRNA polyplex micelles through engineering polymers and mRNA for in vivo therapeutic applications2020

    • Author(s)
      S. Uchida
    • Organizer
      IBS CNM Seminar
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Stabilization of mRNA polyplex micelles for in vivo delivery by engineering mRNA2019

    • Author(s)
      S. Uchida, N. Yoshinaga, H. Cabral, K. Kataoka
    • Organizer
      2nd G’L’owing Polymer Symposium in KANTO
    • Related Report
      2019 Annual Research Report
  • [Presentation] 複複数のmRNA鎖を束ねることで生体内酵素分解を抑制させたmRNAナノ集合体の開発2019

    • Author(s)
      内田 智士、吉永 直人、趙 オル、小路 恭子、長田 健介、片岡 一則、Horacio Cabral
    • Organizer
      第41回バイオマテリアル学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Nanoengineering mRNA through short RNA hybridization for biomedical application2019

    • Author(s)
      S. Uchida
    • Organizer
      1st Thailand-Australia-Japan Joint Research Meeting on Nanomedicine
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 複数のmRNA鎖を束ねたナノ集合体の開発と生体内投与2019

    • Author(s)
      内田 智士、吉永 直人、趙 オル、小路 恭子、長田 健介、片岡 一則、Horacio Cabral
    • Organizer
      日本核酸医薬学会第5回年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 複数のmRNA鎖からなるナノ集合体を用いたmRNA安定化とその生体内投与2019

    • Author(s)
      内田 智士、吉永 直人、趙 オル、小路 恭子、長田 健介、片岡 一則、Horacio Cabral
    • Organizer
      第35回日本DDS学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Hybridization of mRNA with a small number of short cholesteryl RNA oligonucleotides for tight mRNA packaging to polyplex micelles.2019

    • Author(s)
      S. Uchida, N. Yoshinaga, H. Cabral, K. Kataoka
    • Organizer
      19th Smposium for gene design and delivery
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] コレステロール修飾相補鎖RNAを用いたmRNA搭載高分子ミセル安定化2018

    • Author(s)
      内田 智士、吉永 直人、長田 健介、位髙 啓史、Horacio Cabral、片岡 一則
    • Organizer
      第40回日本バイオマテリアル学会大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 免疫賦活化アジュバント機能一体型 2本鎖mRNAワクチン2018

    • Author(s)
      内田 智士、位髙 啓史、片岡 一則
    • Organizer
      日本核酸医薬学会第4回年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 高分子ミセルを用いた メッセンジャー(m)RNA医薬の送達と 疾患治療への展開2018

    • Author(s)
      内田 智士
    • Organizer
      第34回日本DDS学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Therapeutic application of mRNA delivery using polyplex micelles2018

    • Author(s)
      Satoshi Uchida, Keiji Itaka, Kazunori Kataoka
    • Organizer
      Finland-Japan Workshop: The next generation medical engineering in biomaterials
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Incorporation of Immunostimulatory Property to Messenger RNA Molecule by Hybridizing RNA to Poly A Sequence for Effective Vaccination2018

    • Author(s)
      Satoshi Uchida, Keiji Itaka, Kazunori Kataoka
    • Organizer
      21st annual meeting ASGCT
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Remarks] ホームページ

    • URL

      http://www.f.kpu-m.ac.jp/y/medchem/uchida.html

    • Related Report
      2020 Annual Research Report
  • [Remarks] ホームページ

    • URL

      http://www.bmc.t.u-tokyo.ac.jp/suchida.html

    • Related Report
      2019 Annual Research Report
  • [Remarks]

    • URL

      http://www.bmc.t.u-tokyo.ac.jp/suchida.html

    • Related Report
      2018 Annual Research Report
  • [Patent(Industrial Property Rights)] ゲノム編集用ミセル2020

    • Inventor(s)
      1.片岡 一則,内田 智士,アッバシ サエド
    • Industrial Property Rights Holder
      川崎市産業振興財団
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2020-113434
    • Filing Date
      2020
    • Related Report
      2020 Annual Research Report
  • [Patent(Industrial Property Rights)] mRNA送達用キャリアおよびこれを含む組成物2019

    • Inventor(s)
      片岡 一則,内田 智士,アンジャネユル ディリサラ
    • Industrial Property Rights Holder
      川崎市産業振興財団
    • Industrial Property Rights Type
      特許
    • Filing Date
      2019
    • Related Report
      2019 Annual Research Report
    • Overseas

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Published: 2018-04-23   Modified: 2021-12-27  

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