Development of novel immune checkpoint inhibitor therapy by microRNAs

• Project/Area Number: 17K19590
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology and related fields
• Research Institution: Kyoto University
• Principal Investigator: ONO KOH 京都大学, 医学研究科, 准教授 (00359275)
• Research Collaborator: Izuhara Masayasu ; Rodoriguez Randolph Ruiz
• Project Period (FY): 2017-06-30 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2018: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2017: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
• Keywords: PLGAナノ粒子 / 核酸医薬 / がん免疫療法 / マイクロRNA / PD-1 / PD-L1 / CD80 / 免疫チェックポイント

Outline of Final Research Achievements

We have been focused on the functions on microRNAs mainly in cardiovascular field. This time, we have noticed that PD-1, PD-L1, and CD80 are regulated by miR-15a/ 15b/ 16/ 195/ 424/ 497/ 503 family. Therefore, we tried to develop a method to express miR-15a by the use of synthetic double strand RNAs with drug delivery system.

Academic Significance and Societal Importance of the Research Achievements

これまでの研究の中で、生体におけるmicroRNAの働きを明らかにしてきた。さらに効果的なmiRNAの標的となる分子を探索していたところ、免疫チェックポイントタンパク質のPD-1, PD-L1, CD80がmiR-15ファミリー(miR-15a/15b/16/195/424/497/503)によって制御されていることを見いだした。すなわち、miR-15ファミリーを発現させることで、PD-1およびCTLA-4経路の両方を同時に抑制できることになる。本研究においては、miR-15aファミリーをがんの局所に導入して、免疫チェックポイント抑制による新規がん治療法の開発を試みた。

Research Products

• [Journal Article] MiR-33a is a therapeutic target in SPG4-related hereditary spastic paraplegia human neurons (2019)
  • Author(s): Nakazeki F、Tsuge I、Horie T、Imamura K、Tsukita K、Hotta A、Baba O、Kuwabara Y、Nishino T、Nakao T、Nishiga M、Nishi H、Nakashima Y、Ide Y、Koyama S、Kimura M、Tsuji S、Naitoh M、Suzuki S、Izumi Y、Kawarai T、Kaji R、Kimura T、Inoue H、Ono K
  • Journal Title: Clinical Science Volume: 133 Issue: 4 Pages: 583-595
  • DOI: 10.1042/cs20180980
  • NAID: 120006937614
  • Peer Reviewed / Open Access
• [Journal Article] Hepatokine α1-Microglobulin Signaling Exacerbates Inflammation and Disturbs Fibrotic Repair in Mouse Myocardial Infarction (2018)
  • Author(s): Hakuno Daihiko、Kimura Masahiro、Ito Shinji、Satoh Junko、Nakashima Yasuhiro、Horie Takahiro、Kuwabara Yasuhide、Nishiga Masataka、Ide Yuya、Baba Osamu、Nishi Hitoo、Nakao Tetsushi、Nishino Tomohiro、Nakazeki Fumiko、Koyama Satoshi、Hanada Ritsuko、Randolph Ruiz R.、Endo Jin、Kimura Takeshi、Ono Koh
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 1-17
  • DOI: 10.1038/s41598-018-35194-w
  • NAID: 120006645320
  • Peer Reviewed / Open Access
• [Journal Article] SREBF1/MicroRNA-33b Axis Exhibits Potent Effect on Unstable Atherosclerotic Plaque Formation In Vivo (2018)
  • Author(s): Nishino T、Horie T、Baba O、Sowa N、Hanada R、Kuwabara Y、Nakao T、Nishiga M、Nishi H、Nakashima Y、Nakazeki F、Ide Y、Koyama S、Kimura M、Nagata M、Yoshida K、Takagi Y、Nakamura T、Hasegawa K、Miyamoto S、Kimura T、Ono K.
  • Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology Volume: 38 Issue: 10 Pages: 2460-2473
  • DOI: 10.1161/atvbaha.118.311409
  • Peer Reviewed / Open Access
• [Journal Article] Circulating markers of collagen types I, III, and IV in patients with dilated cardiomyopathy: relationships with myocardial collagen expression (2018)
  • Author(s): Nagao Kazuya、Inada Tsukasa、Tamura Akinori、Kajitani Kenji、Shimamura Kiyotaka、Yukawa Hiroshi、Aida Kenji、Sowa Naoya、Nishiga Masataka、Horie Takahiro、Makita Toshinori、Ono Koh、Tanaka Masaru
  • Journal Title: ESC Heart Failure Volume: 5 Issue: 6 Pages: 1044-1051
  • DOI: 10.1002/ehf2.12360
  • Peer Reviewed / Open Access
• [Journal Article] Loss of periostin ameliorates adipose tissue inflammation and fibrosis in vivo (2018)
  • Author(s): Nakazeki Fumiko、Nishiga Masataka、Horie Takahiro、Nishi Hitoo、Nakashima Yasuhiro、Baba Osamu、Kuwabara Yasuhide、Nishino Tomohiro、Nakao Tetsushi、Ide Yuya、Koyama Satoshi、Kimura Masahiro、Tsuji Shuhei、Sowa Naoya、Yoshida Shigeo、Conway Simon J.、Yanagita Motoko、Kimura Takeshi、Ono Koh
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 8553-8553
  • DOI: 10.1038/s41598-018-27009-9
  • NAID: 120006510274
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MicroRNA-33 regulates the population of peripheral inflammatory Ly6Chigh monocytes through dual pathways. (2018)
  • Author(s): Baba O, Horie T, Hakuno D, Nakashima Y, Nishi H, Kuwabara Y, Nakao T, Nishiga M, Nishino T, Ide Y, Nakazeki F, Koyama S, Kimura M, Hanada R, Kawahara M, Kimura T, and Ono K.
  • Journal Title: Mol Cell Biol. Volume: 38 Issue: 14 Pages: 1-17
  • DOI: 10.1128/mcb.00604-17
  • Peer Reviewed / Open Access
• [Journal Article] Long Non-Coding RNAs as Key Regulators of Cardiovascular Diseases (2018)
  • Author(s): Ono K, Kuwabara Y, Horie T, Kimura T.
  • Journal Title: Circulation Journal Volume: 82 Issue: 5 Pages: 1231-1236
  • DOI: 10.1253/circj.CJ-18-0169
  • NAID: 130006725985
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [Journal Article] MicroRNA-33 regulates the population of peripheral inflammatory Ly6Chigh monocytes through dual pathways. (2018)
  • Author(s): Baba O, Horie T, Nakao T, Hakuno D, Nakashima Y, Nishi H, Kuwabara Y, Nishiga M, Nishino T, Ide Y, Nakazeki F, Koyama S, Kimura M, Hanada R, Kawahara M, Kimura T, and *Ono K.
  • Journal Title: Mol Cell Biol. Volume: 印刷中
  • Peer Reviewed / Open Access
• [Journal Article] Long Non-Coding RNAs as Key Regulators of Cardiovascular Diseases. (2018)
  • Author(s): Ono K, Kuwabara Y, Horie T, Kimura T.
  • Journal Title: Circulation J. Volume: 印刷中
  • Peer Reviewed / Open Access
• [Journal Article] Genetic Ablation of MicroRNA-33 Attenuates Inflammation and Abdominal Aortic Aneurysm Formation via Several Anti-Inflammatory Pathways. (2017)
  • Author(s): Nakao T, Horie T, Baba O, Nishiga M, Nishino T, Izuhara M, Kuwabara Y, Nishi H, Usami S, Nakazeki F, Ide Y, Koyama S, Kimura M, Sowa N, Ohno S, Aoki H, Hasegawa K, Sakamoto K, Minatoya K, Kimura T, Ono K.
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 37 Issue: 11 Pages: 2161-2170
  • DOI: 10.1161/atvbaha.117.309768
  • Peer Reviewed / Open Access
• [Journal Article] Imbalanced expression of polycistronic miRNA in acute myeloid leukemia. (2017)
  • Author(s): Kotaki R, Higuchi H, Ogiya D, Katahira Y, Kurosaki N, Yukihira N, Ogata J, Yamamoto H, Mohamad Alba S, Azhim A, Kitajima T, Inoue S, Morishita K, Ono K, Koyama-Nasu R, Kotani A.
  • Journal Title: Int J Hematol. Volume: 106 Issue: 6 Pages: 811-819
  • DOI: 10.1007/s12185-017-2314-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prevention of neointimal formation using miRNA-126-containing nanoparticle-conjugated stents in a rabbit model. (2017)
  • Author(s): Izuhara M, Kuwabara Y, Saito N, Yamamoto E, Hakuno D, Nakashima Y, Horie T, Baba O, Nishiga M, Nakao T, Nishino T, Nakazeki F, Ide Y, Kimura M, Kimura T, Ono K.
  • Journal Title: PLoS One Volume: 12(3) Issue: 3 Pages: e0172798-e0172798
  • DOI: 10.1371/journal.pone.0172798
  • Peer Reviewed / Open Access
• [Journal Article] MicroRNA-33 Controls Adaptive Fibrotic Response in the Remodeling Heart by Preserving Lipid Raft Cholesterol. (2016)
  • Author(s): Nishiga M, Horie T, Kuwabara Y, Nagao K, Baba O, Nakao T, Nishino T, Hakuno D, Nakashima Y, Nishi H, Nakazeki F, Ide Y, Koyama S, Kimura M, Hanada R, Nakamura T, Inada T, Hasegawa K, Conway SJ, Kita T, Kimura T, Ono K.
  • Journal Title: Circ Res. Volume: - Issue: 5 Pages: 835-847
  • DOI: 10.1161/circresaha.116.309528
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] SREBF1/MicroRNA-33b axis exhibits potent effect on unstable atherosclerotic plaque formation in vivo (2018)
  • Author(s): Koh Ono
  • Organizer: XVIIIth International Symposium on Atherosclerosis
  • Int'l Joint Research / Invited
• [Presentation] Functions of microRNA-33a/b on inflammation and atherosclerosis (2018)
  • Author(s): Koh Ono
  • Organizer: China-Japan International Conference on Atherosclerosis 2018
  • Int'l Joint Research / Invited
• [Presentation] A Novel Long Intergenic Noncoding RNA, LincRNA-Hy5, Underlies the Heart Development and Guards the Heart from Pressure Overload (2018)
  • Author(s): 尾野 亘
  • Organizer: 第50回日本動脈硬化学会総会・学術集会
  • Invited
• [Presentation] マイクロRNAと心血管疾患、代謝性疾患 (2018)
  • Author(s): 尾野 亘
  • Organizer: 第66回日本心臓病学会
  • Invited
• [Presentation] MicroRNA-33の欠損は複数の抗炎症経路を介して大動脈瘤の形成を抑制する (2018)
  • Author(s): 尾野 亘
  • Organizer: 第59回日本脈管学会総会
  • Invited
• [Presentation] Novel Long Intergenic Noncoding RNA, Lionheart, Guards the Heart from Pressure Overload (2018)
  • Author(s): Kuwabara Y, Horie T, Baba O, Nishiga M, Nakao M, Nishino T, Nakazeki F, Koyama S, Kimura T, Ono K.
  • Organizer: 第82回日本循環器学会
• [Presentation] MicroRNA-33b promotes atherosclerotic plaque formation in Apoe-/- mice (2018)
  • Author(s): Nishino T, Horie T, Baba O, Kuwabara Y, Hakuno D, Nakashima Y, Nakao T, Nishiga M, Kimura T, Ono K.
  • Organizer: 第82回日本循環器学会
• [Presentation] Roles of microRNAs in cardiovascular diseases (2017)
  • Author(s): Koh Ono
  • Organizer: 2nd International Symposium for Noncoding RNA Neo-taxonomy In conjunction with Tokyo RNA Club 23rd meeting
  • Int'l Joint Research / Invited
• [Presentation] MicroRNA-33b promotes atherosclerotic plaque formation in Apoe-/- mice. (2017)
  • Author(s): Ono K, Nishino T, Horie T, Kuwabara Y, Nakao T, Nishiga M, Ide Y, Nakazeki F, Koyama S, Kimura M, Kimura T.
  • Organizer: 43rd Naito Conference Noncoding RNA：Biology, Chemistry, & Diseases
  • Int'l Joint Research
• [Presentation] MicroRNA-33b promotes atherosclerotic plaque formation in Apoe-/- mice. (2017)
  • Author(s): Nishino T, Horie T, Kuwabara Y, Nakao T, Nishiga M, Ide Y, Nakazeki F, Koyama S, Kimura M, Kimura T, Ono K
  • Organizer: American Heart Association Scientific Sessions 2017
  • Int'l Joint Research
• [Remarks] 京都大学循環器内科 分子循環器グループ
  • URL: http://kyoto-u-cardio.jp/kisokenkyu/metabolic/
• [Remarks] 心血管疾患分子機構解明グループ
  • URL: http://kyoto-u-cardio.jp/kisokenkyu/metabolic/
• [Patent(Industrial Property Rights)] 遺伝性痙性対麻痺(Hereditary Spastic Paraplegia; HSP)SPG4 に対するmicroRNA-33a抑制療法 (2018)
  • Inventor(s): 尾野 亘、井上治久、今村恵子、堀江貴裕、中関典子
  • Industrial Property Rights Holder: 尾野 亘、井上治久、今村恵子、堀江貴裕、中関典子
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-119251
  • Filing Date: 2018
• [Patent(Industrial Property Rights)] miR-33bノックインマウスによる非アルコール性脂肪肝炎モデル (2018)
  • Inventor(s): 尾野 亘、堀江貴裕、西野共達
  • Industrial Property Rights Holder: 尾野 亘、堀江貴裕、西野共達
  • Industrial Property Rights Type: 特許
  • Filing Date: 2018
  • Overseas