Role of complement factor MASP-1/3 in age-related macular degeneration and therapeutic effect of novel complement inhibitors

• Project/Area Number: 17K16975
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Ophthalmology
• Research Institution: Fukushima Medical University
• Principal Investigator: Omori Tomoko 福島県立医科大学, 医学部, 助教 (50754222)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 加齢黄斑変性 / 補体 / 免疫学

Outline of Final Research Achievements

We aimed to clarify the role of complement factor MASP-1/3 of the lectin and alternative pathways in the development of neovascular age-related macular degeneration (nAMD). In patients with nAMD, the ratios of aqueous humor levels of C4a/C4 and C3a/C3 were significantly higher than in cataract patients, providing conclusive evidence for intraocular activation of the lectin and/or classical pathway in nAMD eyes. Furthermore, using mouse model of laser-induced choroidal neovascularization, which has been used extensively studies of nAMD, we found that the nAMD-like lesion was alleviated in mice deficient for MASP-1/3 compared to wild-type mice, although there was no significant difference between them. Our results strongly suggest the contribution of MASP-1/3 in the development of nAMD.

Academic Significance and Societal Importance of the Research Achievements

本研究の結果、第二経路に加え、眼内におけるレクチン経路と古典経路の一方または両方の活性化が滲出型加齢黄斑変性の病態に関与することが明らかとなった。よって、MASP-1/3を標的とする治療法が有効である可能性が強く示唆された。これらの成果は、滲出型加齢黄斑変性の病態における補体の関与への理解を深め、滲出型加齢黄斑変性の新規治療法や新規診断法の開発に繋がると期待される。

Research Products

• [Journal Article] Evidence for Activation of Lectin and Classical Pathway Complement Components in Aqueous Humor of Neovascular Age-Related Macular Degeneration. (2020)
  • Author(s): Omori T, Oguchi Y, Machida T, Kato Y, Ishida Y, Ojima A, Itagaki K, Shintake H, Tomita R, Kasai A, Sugano
  • Journal Title: Ophthalmic Res Volume: 63 Issue: 3 Pages: 252-258
  • DOI: 10.1159/000503258
  • Peer Reviewed
• [Journal Article] A novel complement inhibitor sMAP-FH targeting both the lectin and alternative complement pathways (2020)
  • Author(s): Takasumi M, Omori T, Machida T, Ishida Y, Hayashi M, Suzuki T, Homma Y, Endo Y, Takahashi M, Ohira H, Fujita T, Sekine H
  • Journal Title: FASEB J Volume: 34 Issue: 5 Pages: 6598-6612
  • DOI: 10.1096/fj.201902475r
  • Peer Reviewed
• [Journal Article] Anaphylatoxin Concentration in Aqueous and Vitreous Humor in the Eyes With Vitreoretinal Interface Abnormalities (2020)
  • Author(s): Yasuharu Oguchi , Tetsuju Sekiryu , Tomoko Omori , Yutaka Kato , Masashi Ogasawara , Yukinori Sugano , Kanako Itagaki , Akira Ojima , Takeshi Machida , Hideharu Sekine
  • Journal Title: Exp Eye Res Volume: 195 Pages: 108025-108025
  • DOI: 10.1016/j.exer.2020.108025
  • Peer Reviewed
• [Journal Article] Cutting Edge: Role of MASP-3 in the physiological activation of factor D of the alternative complement pathway (2019)
  • Author(s): Manabu Hayashi, Takeshi Machida, Yumi Ishida, Yusuke Ogata, Tomoko Omori, Mika Takasumi, Yuichi Endo, Toshiyuki Suzuki, Masayuki Sekimata, Yoshimi Homma, Masahito Ikawa, Hiromasa Ohira, Teizo Fujita, and Hideharu Sekine
  • Journal Title: The Journal of Immunology Volume: 203 Issue: 6 Pages: 1411-1416
  • DOI: 10.4049/jimmunol.1900605
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Complement activation product levels in aqueous humor of patients with age-related macular degeneration (2019)
  • Author(s): Kato Y, Sekiryu T, Oguchi Y, Omori T, Machida T, Sekine H
  • Organizer: ARVO annual meeting 2019
  • Int'l Joint Research
• [Presentation] 加齢黄斑変性におけるレクチン経路の関与の可能性 (2019)
  • Author(s): 大森智子，大口泰治, 町田豪, 石田由美, 加藤寛, 石龍鉄樹, 関根英治
  • Organizer: 第56回日本補体学会学術集会
• [Presentation] MASP-1、MASP-3はレクチン経路、第二経路の活性化に独立して寄与する (2018)
  • Author(s): 林学、石田由美、町田豪、尾形裕介、大森智子、高住美香、遠藤雄一、関亦正幸、伊川正人、大平弘正、藤田禎三、関根英治
  • Organizer: 第55回日本補体学会学術集会
• [Presentation] 滲出型加齢黄斑変成の前房水中補体分解産物の検討 (2018)
  • Author(s): 加藤寛、大口泰治、大森智子、町田豪、関根英治、石龍鉄樹
  • Organizer: 第38回日本眼薬理学会
• [Presentation] MASP-1 and MASP-3 play independent roles in activation of the lectin and alternative complement pathways (2018)
  • Author(s): Manabu Hayashi, Yumi Ishida, Takeshi Machida, Yusuke Ogata, Tomoko Omori, Mika Takasumi, Yuishi Endo, Masahiko Ikawa, Hiromasa Ohira, Teizo Fujita, Hideharu Sekine
  • Organizer: XXVII International Complement Workshop
  • Int'l Joint Research
• [Presentation] 補体レクチン経路と第二経路を標的とする新規抗補体薬sMAP-fHの開発 (2017)
  • Author(s): 高住美香、高橋実、大森智子、町田豪、石田由美、関根英治
  • Organizer: 第54回日本補体学会学術集会