Development of treatments for age-related macular degeneration targeting fibrosis suppression and neuroprotective effects

• Project/Area Number: 18K09455
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56060:Ophthalmology-related
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Hatanaka Hiroki 京都府立医科大学, 医学(系)研究科(研究院), 客員講師 (80368050)
• Co-Investigator(Kenkyū-buntansha): 外園 千恵 京都府立医科大学, 医学(系)研究科(研究院), 教授 (30216585)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 加齢黄斑変性 / 網膜色素上皮細胞 / 線維化 / 脈絡膜血管新生 / 加齢性黄斑変性症 / 加齢黄斑変性症 / 血管新生 / エピジェネティック制御 / マクロファージ / ヒストン脱アせチル化 / 加齢黄斑変性(AMD) / 脈絡血管新生(CNV) / 瘢痕組織形成 / HDAC阻害

Outline of Final Research Achievements

OBP801 showed an inhibitory effect not only on TGF-β and TNF-α but also on fibrotic changes induced by CTGF and PDGF. It was also found that the expression of the HAT genes were suppressed in the fibrotic cells, and the HAT activity of the cells was decreased. We found that recovery from the disruption of this epigenetic regulatory mechanism was the mechanism of action of the fibrosis-suppressing effect in OBP801, and these research results were summarized in a paper and accepted. It was also found that the inhibitory effect of OBP801 on fibrotic tissue formation is also effective for fibroblasts. Furthermore, the direct inhibitory effect of OBP801 on angiogenesis has been confirmed as a primitive result.

Academic Significance and Societal Importance of the Research Achievements

加齢黄斑変性(AMD)は近年著しく増加中の重篤な視力障碍を引き起こす疾患である。現在主流の治療法である抗VEGF治療はCNV抑制を目的としており、視力予後因子である網膜組織の線維化に対する治療法は未だ存在しない。本研究で行われたOBP801の複数種細胞における線維性組織形成阻害効果の検証とその作用機序の解析、および血管内皮細胞に対する管腔形成阻害効果の実証により、CNVだけでなく線維性組織形成等を標的としたAMD治療薬としての開発が大きく前進したと言える。

Research Products

• [Journal Article] Epigenetic regulation of the epithelial mesenchymal transition induced by synergistic action of TNF-α and TGF-β in retinal pigment epithelial cells (2021)
  • Author(s): Hatanaka Hiroki、Mukai Atsushi、Ito Eiko、Ueno Morio、Sotozono Chie、Kinoshita Shigeru、Hamuro Junji
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 544 Pages: 31-37
  • DOI: 10.1016/j.bbrc.2021.01.060
  • Peer Reviewed
• [Presentation] A new pluripotent epigenetic repressor of diverse genes, OBP801, remarkably prevents chorioretinal fibrosis and choroidal neovascularization (2018)
  • Author(s): Atsushi Mukai, Hiroki Hatanaka, Morio Ueno, Tetsuya Yamagishi, Kazuhito Yoneda, Yasuo Urata, Shigeru Kinoshita, Chie Sotozono, Junji Hamuro
  • Organizer: 2018 XXIII Biennial Meeting of the International Society for Eye Research
  • Int'l Joint Research
• [Presentation] Novel low molecular weight compound OBP-801 ameliorates detrimental scar formation accompaneid in glaucoma filtration surgery (2018)
  • Author(s): Yuji Yamamoto, Atsushi Mukai, Morio Ueno, Junji Hamuro, Yasuo Urata, Shigeru Kinoshita, Chie Sotozono
  • Organizer: 2018 XXIII Biennial Meeting of the International Society for Eye Research
  • Int'l Joint Research