Development of therapeutic strategy targeting EMT against intraocular fibrosis

• Project/Area Number: 17H05101
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Ophthalmology
• Research Institution: Kyushu University
• Principal Investigator: ISHIKAWA KEIJIRO 九州大学, 医学研究院, 助教 (00795304)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥21,320,000 (Direct Cost: ¥16,400,000、Indirect Cost: ¥4,920,000); Fiscal Year 2019: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2018: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000); Fiscal Year 2017: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000)
• Keywords: 線維化 / 上皮間葉転換 / 形質転換 / マトリセルラー蛋白 / 網膜 / 加齢黄斑変性 / 増殖硝子体網膜症 / 眼科学 / トランスレーショナルリサーチ / 糖尿病網膜症 / 上皮間葉移行

Outline of Final Research Achievements

To develop novel therapy against intra-ocular fibrosis, we first tested the effect of several chemical compounds and found ROCK inhibitors as promising drug that enables significant suppression of RPE (retinal pigment epithelium)-EMT (epithelial-to-mesenchymal transition). We evaluated the drug’s stability in the eye after vitreous injection. In vivo experiment using animal model of intra-ocular fibrosis revealed the drug’s efficacy inhibiting fibrosis development. We further investigate the ROCK inhibitor’s potential for successful RPE cell transplantation therapy.
To investigate periostin (PN) and tenascin-C (TNC) expression in the aqueous humor and trabeculectomy specimens of patients with neovascular glaucoma (NVG) secondary to proliferative diabetic retinopathy (PDR). The NVG group had significantly higher levels of PN and TNC compared with the PDR group. Increased PN and TNC expression suggests their possible involvement in the pathogenesis of NVG secondary to PDR.

Academic Significance and Societal Importance of the Research Achievements

ROCK阻害剤の眼内線維増殖に対する薬効、薬理学的解析がなされ、将来的に臨床応用されれば、患者の視機能維持が期待され、その社会貢献ははかり知れない。また、新規治療により硝子体手術や抗VEGF薬硝子体注射件数を減少させることができる可能性があり、患者負担の軽減だけでなく、医療財政の観点からも有益となる。

Research Products

• [Journal Article] Increased expression of periostin and tenascin-C in eyes with neovascular glaucoma secondary to PDR (2020)
  • Author(s): Ishikawa K, Kohno RI, Mori K, Murakami Y, Nakao S, Akiyama M, Yoshida S, Sonoda KH
  • Journal Title: Graefes Arch Clin Exp Ophthalmol. Volume: 258 Pages: 621-628
  • Peer Reviewed
• [Journal Article] Vitrectomy with peripapillary internal limiting membrane peeling for macular retinoschisis associated with normal-tension glaucoma (2020)
  • Author(s): Ishikawa K, Fukui T, Nakao S, Shiose S, Sonoda KH
  • Journal Title: Am J Ophthalmol Case Rep. Volume: 18 Pages: 100663-100663
  • Peer Reviewed
• [Journal Article] Decrease in the number of microaneurysms in diabetic macular edema after anti-vascular endothelial growth factor therapy: implications for indocyanine green angiography-guided detection of refractory (2020)
  • Author(s): Mori K, Yoshida S, Kobayashi Y, Ishikawa K, Nakao S, Hisatomi T, Masatoshi Haruta, Ishibashi T
  • Journal Title: Graefes Arch Clin Exp Ophthalmol. Volume: 258 Issue: 4 Pages: 735-741
  • DOI: 10.1007/s00417-020-04608-9
  • Peer Reviewed
• [Journal Article] Microaneurysm Imaging using Multiple En Face Optical Coherence Tomography Angiography Image Averaging: Morphology and Visualization (2019)
  • Author(s): Kaizu Y, Nakao S, Wada I, Arima M, Yamaguchi M, Ishikawa K, Akiyama M, Kishimoto J, Hisatomi T, Sonoda KH
  • Journal Title: Ophthalmology Retina Volume: 4 Issue: 2 Pages: 175-186
  • DOI: 10.1016/j.oret.2019.09.010
  • Peer Reviewed
• [Journal Article] Different distributions of M1 and M2 macrophages in a mouse model of laser-induced choroidal neovascularization. (2017)
  • Author(s): Zhou Y, Yoshida S, Kubo Y, Yoshimura T, Kobayashi Y, Nakama T, Yamaguchi M, Ishikawa K, Oshima Y, Ishibashi T:
  • Journal Title: Mol Med Rep Volume: 15(6) Issue: 6 Pages: 3949-3656
  • DOI: 10.3892/mmr.2017.6491
  • Peer Reviewed / Open Access
• [Journal Article] DNA Methylomes Reveal Biological Networks Involved in Human Eye Development, Functions and Associated Disorders (2017)
  • Author(s): Berdasco Maria、Yoshida Shigeo、Nakama Takahito、Ishikawa Keijiro、Ishibashi Tatsuro、Boubekeur Amina M et al.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 11762-11762
  • DOI: 10.1038/s41598-017-12084-1
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Periostin in vitreoretinal diseases (2017)
  • Author(s): Yoshida Shigeo、Nakama Takahito、Ishikawa Keijiro、Nakao Shintaro、Sonoda Koh-hei、Ishibashi Tatsuro
  • Journal Title: Cellular and Molecular Life Sciences Volume: 74 Issue: 23 Pages: 4329-4337
  • DOI: 10.1007/s00018-017-2651-5
  • Peer Reviewed
• [Presentation] An association between RPE disruption and fibrotic scar formation after aflibercept therapy for neovascular age-related macular degeneration (2019)
  • Author(s): Ishikawa K, Shiose S, Akiyama M, Kano K, Kaizu Y, Wada I, Nakao S, Oshima Y, Sonoda KH
  • Organizer: ARVO, Vancouver, Canada
• [Presentation] An association between RPE disruption and fibrotic scar formation after aflibercept therapy for neovascular age-related macular degeneration (2019)
  • Author(s): Ishikawa K. et al.
  • Organizer: 2019 ARVO Annual Meeting
  • Int'l Joint Research
• [Presentation] ROCK inhibitor Ripasudil reverses phenotype from EMT to MET in subretinal fibrosis (2019)
  • Author(s): Wada I. et al.
  • Organizer: 2019 ARVO Annual Meeting
  • Int'l Joint Research
• [Presentation] ROCK inhibitor Ripasudil (K-115) suppresses subretinal fibrosis in laser-induced CNV model (2017)
  • Author(s): Wada I, Nakao S, Yamaguchi M, Ishikawa K, Yoshida S, Kaizu Y, Isobe T, Kaneko Y, Ishibashi T, Sonoda KH
  • Organizer: ARVO, Baltimore, USA, 2017
  • Int'l Joint Research