Development of a new classification and therapy based on the elucidation of molecular pathophysiology of central serous choroid retinopathy

• Project/Area Number: 22K09773
• 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: Osaka Metropolitan University
• Principal Investigator: Honda Shigeru 大阪公立大学, 大学院医学研究科, 教授 (60283892)
• Project Period (FY): 2022-04-01 – 2025-03-31
• Project Status: Completed (Fiscal Year 2024)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2024: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2023: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2022: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 中心性漿液性脈絡網膜症 / 分子メカニズム / SLC7A5 / 補体H因子 / ステロイド / LAT1 / CFH / 網膜色素上皮細胞 / 遺伝子発現 / ハイドロコーチゾン / アルドステロン / フルオレセイン輸送 / 分子生物学的病態 / 新分類構築 / 治療法開発

Outline of Research at the Start

CSCは働き盛りの男性に好発する疾患であるが、その病態には不明な点が多く、様々な危険因子は報告されているものの、それらがどのように同疾患の発症に繋がるのかは推測の域を出ない。本研究では先に報告されたCSCの感受性遺伝子について、生体(網膜)内の局在と働きを明らかにすることでCSCの分子生物学的病態を解明する。本研究によってCSCの分子メカニズムを基にした病態理解を進めると共に、それらがどの様な臨床所見に繋がるかを明らかにする。それによってCSCの新たな分類と理にかなった治療選択基準を提案する。同時に病態の分子生物学的理解に基づいた、創薬を含む新たな治療法および予防法の開発を目指す。

Outline of Final Research Achievements

We conducted a study to clarify the molecular pathology of central serous chorioretinopathy (CSC). We demonstrated that LAT1, encoded by SLC7A5, a susceptibility gene for CSC, is expressed in the retinal pigment epithelium (RPE) and is regulated by hydrocortisone (HC) or aldosterone (ALD), and that both HC and ALD increase the amount of sodium fluorescein transport in the RPE, which is significantly suppressed by a selective LAT1 inhibitor. On the other hand, protein structure analysis using artificial intelligence predicted that short consensus repeat 2 of complement factor H (CFH) binds to adrenomedullin to promote vasodilation.

Academic Significance and Societal Importance of the Research Achievements

中心性漿液性脈絡網膜症(CSC)は働き盛りの男性に好発する疾患で、慢性例や再発例では網膜色素上皮の変性や萎縮および視細胞の障害が生じ、不可逆的視力低下を来すため、同疾患の予防と治療は社会的に大変重要な課題である。しかしながら、CSCの病態には不明な点が多く、様々な危険因子は報告されているものの、それらがどのように同疾患の発症に繋がるのかは推測の域を出なかった。本研究ではCSCの感受性遺伝子について、その局在と働きの一部を明らかにすることで同疾患の分子病態の解明を行った。本研究によってCSCの分子メカニズムを基にした病態理解が進み、理にかなった治療選択及び新たな治療法や予防法の開発が期待される。

Research Products

• [Journal Article] The Past, Present, and Future Perspective of Photodynamic Therapy for Age-Related Macular Degeneration (2025)
  • Author(s): Honda Shigeru
  • Journal Title: Journal of Clinical Medicine Volume: 14 Issue: 4 Pages: 1240-1240
  • DOI: 10.3390/jcm14041240
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide association and multi-omics analyses provide insights into the disease mechanisms of central serous chorioretinopathy (2025)
  • Author(s): Mori Y, van Dijk EHC, Miyake M, Hosoda Y, den Hollander AI, Yzer S, Miki A, Chen LJ, Ahn J, Takahashi A, Morino K, Nakao SY, Hoyng CB, Ng DSC, Cen LP, Chen H, Ng TK, Pang CP, Joo K, Sato T, Sakata Y, Tajima A, Tabara Y; Nagahama Study Group; Park KH, Matsuda F, Yamashiro K, Honda S, Nagasaki M, Boon CJF, Tsujikawa A
  • Journal Title: Scientific Reports Volume: 15 Issue: 1 Pages: 9158-9158
  • DOI: 10.1038/s41598-025-92210-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Efficacy and safety of brolucizumab every 6?weeks induction therapy for neovascular age-related macular degeneration (2025)
  • Author(s): Honda Shigeru、Maruyama-Inoue Maiko、Otsuji Tsuyoshi、Kyo Akika、Kobayashi Yume、Yamamoto Yuki、Gomi Fumi
  • Journal Title: Scientific Reports Volume: 15 Issue: 1 Pages: 5705-5705
  • DOI: 10.1038/s41598-025-89638-1
  • Peer Reviewed / Open Access
• [Journal Article] Japanese Clinical Guidelines for Neovascular Age-Related Macular Degeneration (2025)
  • Author(s): Tomohiro Iida、Fumi Gomi、Tsutomu Yasukawa、Kenji Yamashiro、Shigeru Honda、Ichiro Maruko、Keiko Kataoka
  • Journal Title: Japanese Journal of Ophthalmology Volume: －
  • Peer Reviewed / Open Access
• [Journal Article] The hypothetical molecular mechanism of the ethnic variations in the manifestation of age-related macular degeneration; focuses on the functions of the most significant susceptibility genes (2024)
  • Author(s): Honda Shigeru、Misawa Norihiko、Sato Yusuke、Oikawa Daisuke、Tokunaga Fuminori
  • Journal Title: Graefe's Archive for Clinical and Experimental Ophthalmology Volume: - Issue: 9 Pages: 2799-2811
  • DOI: 10.1007/s00417-024-06442-9
  • Peer Reviewed
• [Journal Article] Immunohistochemical expression of Fibrillin-1 in idiopathic epiretinal membranes (2024)
  • Author(s): Tien Luu Viet、Yamamoto Manabu、Tagami Mizuki、Misawa Norihiko、Honda Shigeru
  • Journal Title: Graefe's Archive for Clinical and Experimental Ophthalmology Volume: 263 Pages: 415-424
  • DOI: 10.1007/s00417-024-06667-8
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Switching to Intravitreal Brolucizumab after Ranibizumab or Aflibercept Using Treat and Extend Regimen for Neovascular Age-Related Macular Degeneration in Japanese Patients: 1-Year Results and Factors Associated with Treatment Responsiveness (2024)
  • Author(s): Hirayama Kumiko、Yamamoto Manabu、Honda Shigeru、Kyo Akika、Misawa Norihiko、Kohno Takeya
  • Journal Title: Journal of Clinical Medicine Volume: 13 Issue: 15 Pages: 4375-4375
  • DOI: 10.3390/jcm13154375
  • Peer Reviewed / Open Access
• [Journal Article] One-Year Outcome of Intravitreal Injection of Ranibizumab Biosimilar for Myopic Choroidal Neovascularization in Japanese Patients (2024)
  • Author(s): Tomita Mami、Yamamoto Manabu、Hirayama Kumiko、Kyo Akika、Misawa Norihiko、Kinari Gen、Kohno Takeya、Honda Shigeru
  • Journal Title: Journal of Clinical Medicine Volume: 13 Issue: 16 Pages: 4641-4641
  • DOI: 10.3390/jcm13164641
  • Peer Reviewed / Open Access
• [Journal Article] The impact of removing the epiretinal membrane and inner limiting membrane for sustained subretinal fluid by macular neovascularization refractory to anti-VEGF therapy (2024)
  • Author(s): Nihei Aki、Yamamoto Manabu、Hirayama Kumiko、Kyo Akika、Misawa Norihiko、Kohno Takeya、Honda Shigeru
  • Journal Title: American Journal of Ophthalmology Case Reports Volume: 35 Pages: 102078-102078
  • DOI: 10.1016/j.ajoc.2024.102078
  • Peer Reviewed / Open Access
• [Journal Article] Six-Year Outcomes in Subjects with Polypoidal Choroidal Vasculopathy in the EVEREST?II Study (2024)
  • Author(s): Teo Kelvin Yi Chong、Park Kyu-Hyung、Ngah Nor Fariza、Chen Shih-Jen、Ruamviboonsuk Paisan、Mori Ryusaburo、Kondo Nagako、Lee Won Ki、Rajagopalan Rajesh、Obata Ryo、Wong Ian Y. H.、Chee Caroline、Terasaki Hiroko、Sekiryu Tetsuju、Chen Shih-Chou、Yanagi Yasuo、Honda Shigeru、Lai Timothy Y. Y.、Cheung Chui Ming Gemmy
  • Journal Title: Ophthalmology and Therapy Volume: 13 Issue: 4 Pages: 935-954
  • DOI: 10.1007/s40123-024-00888-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Increased sodium fluorescein transport by corticosteroids is inhibited by a LAT-1 specific inhibitor in retinal pigment epithelial cells in vitro (2023)
  • Author(s): Misawa Norihiko、Honda Shigeru
  • Journal Title: Scientific Reports Volume: 13 Issue: 1 Pages: 22981-22981
  • DOI: 10.1038/s41598-023-50196-z
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy, durability, and safety of faricimab up to every 16 weeks in patients with neovascular age-related macular degeneration: 1-year results from the Japan subgroup of the phase 3 TENAYA trial (2023)
  • Author(s): Mori Ryusaburo、Honda Shigeru、Gomi Fumi、Tsujikawa Akitaka、Koizumi Hideki、Ochi Haruka、Ohsawa Shino、Okada Annabelle Ayame、on behalf of TENAYA and LUCERNE Investigators
  • Journal Title: Japanese Journal of Ophthalmology Volume: 67 Issue: 3 Pages: 301-310
  • DOI: 10.1007/s10384-023-00985-w
  • Peer Reviewed / Open Access
• [Journal Article] Practical treatment options for persistent central serous chorioretinopathy and early visual and anatomical outcomes (2023)
  • Author(s): Yamada-Okahara Naoko、Kyo Akika、Hirayama Kumiko、Yamamoto Manabu、Kohno Takeya、Honda Shigeru
  • Journal Title: Japanese Journal of Ophthalmology Volume: 67 Issue: 3 Pages: 295-300
  • DOI: 10.1007/s10384-023-00978-9
  • Peer Reviewed
• [Journal Article] Genome-Wide Association Study of Age-Related Macular Degeneration Reveals 2 New Loci Implying Shared Genetic Components with Central Serous Chorioretinopathy (2023)
  • Author(s): Masato Akiyama , Masahiro Miyake , Yukihide Momozawa , Satoshi Arakawa , Maiko Maruyama-Inoue , Mikiko Endo , Yusuke Iwasaki , Kazuyoshi Ishigaki , Nana Matoba , Yukinori Okada , Miho Yasuda , Yuji Oshima , Shigeo Yoshida , Shin-Ya Nakao , Kazuya Morino , Yuki Mori , Ai Kido , et al
  • Journal Title: Ophthalmology Volume: 130 Issue: 4 Pages: 361-372
  • DOI: 10.1016/j.ophtha.2022.10.034
  • Peer Reviewed
• [Journal Article] Comparative Treatment Study on Macular Edema Secondary to Branch Retinal Vein Occlusion by Intravitreal Ranibizumab with and without Selective Retina Therapy (2023)
  • Author(s): Yamamoto Manabu、Miura Yoko、Hirayama Kumiko、Kyo Akika、Kohno Takeya、Theisen-Kunde Dirk、Brinkmann Ralf、Honda Shigeru
  • Journal Title: Life Volume: 13 Issue: 3 Pages: 769-769
  • DOI: 10.3390/life13030769
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Early anatomical changes and association with photodynamic therapy induced acute exudative maculopathy in patients with macular diseases (2022)
  • Author(s): Honda Satoshi、Kohno Takeya、Yamamoto Manabu、Hirayama Kumiko、Kyo Akika、Hirabayashi Michiko、Honda Shigeru
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 9105-9105
  • DOI: 10.1038/s41598-022-13208-y
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide Survival Analysis for Macular Neovascularization Development in Central Serous Chorioretinopathy Revealed Shared Genetic Susceptibility with Polypoidal Choroidal Vasculopathy (2022)
  • Author(s): Mori Yuki、Miyake Masahiro、Hosoda Yoshikatsu、Miki Akiko、Takahashi Ayako、Muraoka Yuki、Miyata Manabu、Sato Takehiro、Tamura Hiroshi、Ooto Sotaro、Yamada Ryo、Yamashiro Kenji、Nakamura Makoto、Tajima Atsushi、Nagasaki Masao、Honda Shigeru、Tsujikawa Akitaka
  • Journal Title: Ophthalmology Volume: 129 Issue: 9 Pages: 1034-1042
  • DOI: 10.1016/j.ophtha.2022.04.018
  • Peer Reviewed
• [Presentation] Increase in the sodium fluorescein transport by corticosteroids and its inhibition by a LAT1-specific inhibitor in retinal pigment epithelial cells in vitro. (2024)
  • Author(s): Misawa N, Honda S.
  • Organizer: The Association for Research in Vision and Ophthalmology
  • Int'l Joint Research
• [Presentation] 光線力学的療法後脈絡膜静脈のうっ滞軽減に伴い軽快した中心性漿液性網脈絡膜症の1例 (2024)
  • Author(s): 長富友里、河野 剛也、三澤 宣彦、居 明香、平山 公美子、山本 学、河島卓弥、平林 倫子、本田 茂
  • Organizer: 第128回 日本眼科学会総会
• [Presentation] Pachychorid disease spectrumにおける眼底自発蛍光所見と遺伝因子の影響について (2024)
  • Author(s): 三澤 宣彦、居 明香、平山 公美子、山本 学、河野 剛也、本田 茂
  • Organizer: 第128回 日本眼科学会総会
• [Presentation] 黄斑疾患に対する光線力学療法後の急性滲出性黄斑症発症に関わる因子の検討 (2024)
  • Author(s): 居 明香、山本 学、河野 剛也、平山 公美子、三澤 宣彦、本田 茂
  • Organizer: 第128回 日本眼科学会総会
• [Presentation] The latest consensus on management of neovascular AMD in Japan. Honda S (2024)
  • Author(s): Shigeru Honda
  • Organizer: The Beijing PCV forum
  • Int'l Joint Research / Invited
• [Presentation] Comparison of fundus autofluorescence findings with a genetic predisposition in central serous chorioretinopathy. (2023)
  • Author(s): Norihiko Misawa, Akika Kyo, Kumiko Hirayama, Manabu Yamamoto, Takeya Kohno, Shigeru Honda
  • Organizer: The Association for Research in Vision and Ophthalmology
  • Int'l Joint Research
• [Presentation] 中心性漿液性脈絡網膜症における眼底自発蛍光所見と遺伝因子の関連について (2023)
  • Author(s): 三澤宣彦、居明香、平山公美子、山本学、河野剛也、本田茂
  • Organizer: 第127回 日本眼科学会総会
• [Presentation] 光線力学療法後に周辺部に及ぶ上脈絡膜液が出現した中心性漿液性脈絡網膜症の2例 (2023)
  • Author(s): 河野剛也、平山公美子、山本学、居明香、三澤宣彦、川島卓弥、平林倫子、本田茂
  • Organizer: 第39回 日本眼循環学会
• [Presentation] 光線力学的療法後脈絡膜静脈のうっ滞軽減に伴い警戒した中心性漿液性脈絡網膜症の1例 (2023)
  • Author(s): 河野剛也、平山公美子、山本学、居明香、三澤宣彦、田町知子、平林倫子、本田茂
  • Organizer: 第62回 日本網膜硝子体学会総会
• [Presentation] 光線力学的療法 (2023)
  • Author(s): 本田茂
  • Organizer: 第62回 日本網膜硝子体学会総会
  • Invited
• [Presentation] The outer blood-retinal barrier in central serous chorioretinopathy (2023)
  • Author(s): Shigeru Honda
  • Organizer: 第48回日本微小循環学会総会
  • Invited
• [Presentation] ARPE19細胞におけるステロイド負荷とSLC7A5発現量解析 (2022)
  • Author(s): 三澤宣彦、本田茂
  • Organizer: 第126回日本眼科学会総会
• [Presentation] 中心性漿液性脈絡網膜症への光線力学療法の治療効果における遺伝因子の関連について (2022)
  • Author(s): 三澤宣彦、居明香、平山公美子、山本学、河野剛也、本田茂
  • Organizer: 第76回日本臨床眼科学会