Development of a neuroprotective therapy for retinitis pigmentosa based on the iPS research

• Project/Area Number: 15K10903
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Ophthalmology
• Research Institution: Keio University
• Principal Investigator: Ozawa Yoko 慶應義塾大学, 医学部(信濃町), 専任講師 (90265885)
• Research Collaborator: KAWASHIMA Hirohiko ; OSADA Hideto
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 網膜 / 神経保護 / iPS細胞 / 幹細胞 / iPS / 再生

Outline of Final Research Achievements

We have previously developed induced-pluripotent stem cell (iPSC) lines from somatic cells of a patient with retinitis pigmentosa, which is a hereditary disease caused by gene mutation. The iPS cells were differentiated into retinal cells to reveal the mechanism of the disease in vitro, and the study proposed candidate therapeutic drugs for neuroprotection. In the current study, we treated the mouse model of retinitis pigmentosa (P23H rhodopsin knock-in mice) with one of the candidate drugs to analyze the protective effects in vivo.

Research Products

• [Journal Article] Maculopapular rash after intravitreal injection of an anti-vascular endothelial growth factor, aflibercept, for treating age-related macular degeneration: A case report. (2017)
  • Author(s): Nagai N, Ibuki M, Shinoda H, Kameyama K, Tsubota K, Ozawa Y.
  • Journal Title: Medicine (Baltimore) Volume: 96 Issue: 21 Pages: e6965-e6965
  • DOI: 10.1097/md.0000000000006965
  • Peer Reviewed / Open Access
• [Journal Article] Neuroprotective effect of bilberry extract in a murine model of photo-stressed retina. (2017)
  • Author(s): Osada H, Okamoto T, Kawashima H, Toda E, Miyake S, Nagai N, Kobayashi S, Tsubota K, Ozawa Y.
  • Journal Title: PLoS One Volume: 12 Issue: 6 Pages: e0178627-e0178627
  • DOI: 10.1371/journal.pone.0178627
  • Peer Reviewed / Open Access
• [Journal Article] Absolute and estimated values of macular pigment optical density in young and aged Asian participants with or without age-related macular degeneration. (2017)
  • Author(s): Ozawa Y, Shigeno Y, Nagai N, Suzuki M, Kurihara T, Minami S, Hirano E, Shinoda H, Kobayashi S, Tsubota K.
  • Journal Title: Send to BMC Ophthalmol Volume: 17 Issue: 1 Pages: 161-166
  • DOI: 10.1186/s12886-017-0557-5
  • Peer Reviewed / Open Access
• [Journal Article] Neuroprotective role of retinal SIRT3 against acute photo-stress. (2017)
  • Author(s): Ban N, Ozawa Y, Osada H, Jonathan B. Lin, Toda E, Watanabe M, Yuki K, Kubota S, Rajendra S. Apte, Tsubota K.
  • Journal Title: NPJ Aging Mech Dis. Volume: 3 Issue: 1
  • DOI: 10.1038/s41514-017-0017-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Benefits of aflibercept treatment for age-related macular degeneration patients with good best-corrected visual acuity at baseline. (2017)
  • Author(s): Minami S, Nagai N, Suzuki M, Kurihara T, Sonobe H, Kamoshita M, Uchida A, Shinoda H, Takagi H, Sonoda S, Sakamoto T, Tsubota K, Ozawa Y
  • Journal Title: Sci Rep. Volume: 8 Issue: 1 Pages: 1-8
  • DOI: 10.1038/s41598-017-18255-4
  • Peer Reviewed / Open Access
• [Journal Article] Novel RP1L1 variants and genotype-photoreceptor microstructural phenotype associations in cohort of Japanese patients with occult macular dystrophy. (2016)
  • Author(s): Fujinami K, Kameya S, Kikuchi S, Ueno S, Kondo M, Hayashi T, Shinoda K, Machida S, Kuniyoshi K, Kawamura Y, Akahori M, Yoshitake K, Katagiri S, Nakanishi A, Sakuramoto H, Ozawa Y, Tsubota K, Yamaki K, Mizota A, Terasaki H, Miyake Y, Iwata T, Tsunoda K.
  • Journal Title: Invest Ophthalmol Vis Sci. Volume: 57 Issue: 11 Pages: 4837-4846
  • DOI: 10.1167/iovs.16-19670
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lutein acts via multiple antioxidant pathways in the photo-stressed retina. (2016)
  • Author(s): Kamoshita M, Toda E, Kobayashi S, Tsubota K, Osada H, Ozawa Y
  • Journal Title: Sci Rep. Volume: 22 Issue: 1
  • DOI: 10.1038/srep30226
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Sneddon’s syndrome with optic disc macroaneurysm and macular edema successfully treated with subtenon steroid injection. (2016)
  • Author(s): Nagai N, Ohta Y, Izumi-Nagai K, Shinoda H, Tsubota K, Ozawa Y
  • Journal Title: Acta Ophthalmol. Volume: 94 Issue: 6 Pages: 517-9
  • DOI: 10.1111/aos.12909
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Non-responsiveness to intravitreal aflibercept treatment in neovascular age-related macular degeneration: implications of serous pigment epithelial detachment. (2016)
  • Author(s): Nagai N, Suzuki M, Uchida A, Kurihara T, Kamoshita M, Minami S, Shinoda H, Tsubota K, Ozawa Y.
  • Journal Title: Sci Rep. Volume: 11 Issue: 1 Pages: 29619-29619
  • DOI: 10.1038/srep29619
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Neuroprotective effect of activated 5'-adenosine monophosphate-activated protein kinase on cone system function during retinal inflammation. (2016)
  • Author(s): Kamoshita M, Fujinami K, Toda E, Tsubota K, Ozawa Y
  • Journal Title: BMC Neurosci. Volume: 17 Issue: 1
  • DOI: 10.1186/s12868-016-0268-5
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Distinct responsiveness to intravitreal ranibizumab therapy in polypoidal choroidal vasculopathy with single or multiple polyps. (2016)
  • Author(s): Suzuki M, Nagai N, Shinoda H, Uchida A, Kurihara T, Tomita Y, Kamoshita M, Iyama C, Tsubota K, Ozawa Y
  • Journal Title: American Journal of Ophthalmology Volume: 166 Pages: 52-59
  • DOI: 10.1016/j.ajo.2016.03.024
  • Peer Reviewed / Open Access
• [Journal Article] Angiopoietin-like protein 2 is a multistep regulator of inflammatory neovascularization in a murine model of age-related macular degeneration. (2016)
  • Author(s): M. Hirasawa, K. Takubo, H. Osada, S. Miyake, E. Toda, M. Endo, K. Umezawa, K. Tsubota, Y. Oike and Y. Ozawa
  • Journal Title: J. Biol. Chem. Volume: 291 Issue: 14 Pages: 7373-7385
  • DOI: 10.1074/jbc.m115.710186
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Functional Visual Acuity in Age-Related Macular Degeneration. (2016)
  • Author(s): Tomita Y, Nagai Y, Suzuki M, Shinoda H, Uchida A, Mochimaru H, Izumi-Nagai K, Sasaki M, Tsubota K, Ozawa Y
  • Journal Title: Optometry and Vision Science Volume: 93 Issue: 1 Pages: 70-76
  • DOI: 10.1097/opx.0000000000000755
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The Neuroprotective Effect of Rapamycin as a Modulator of the mTOR-NF-κB Axis during Retinal Inflammation. (2016)
  • Author(s): Okamoto T, Ozawa Y, Kamoshita M, Osada H, Toda E, Kurihara T, Nagai N, Umezawa K, Tsubota K
  • Journal Title: PLoS One Volume: 11(1) Issue: 1 Pages: 1-14
  • DOI: 10.1371/journal.pone.0146517
  • Peer Reviewed / Open Access
• [Journal Article] Glaucomatous Visual Field Defect Severity and the Prevalence of Motor Vehicle Collisions in Japanese: a hospital/clinic-based cross-sectional study. (2015)
  • Author(s): Ono T, Yuki K, Asaoka R, Kouyama K, Abe T, Tanabe S, Fukagawa K, Uchino M, Shimoyama M, Ozawa Y, Ozeki N, Shiba D, Tsubota K.
  • Journal Title: Journal of Ophthalmology Volume: 1 Pages: 1-8
  • DOI: 10.1155/2015/497067
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Association of macular pigment optical density with serum concentration of oxidized low-density lipoprotein in healthy adults. (2015)
  • Author(s): Nagai N, Izumi-Nagai K, Suzuki M, Shinoda H, Koto T, Uchida A, Mochimaru H, Tomita Y, Miyake S, Kobayashi S, Sasaki M, Tsubota K, Ozawa Y.
  • Journal Title: Retina Volume: 35(4) Issue: 4 Pages: 820-826
  • DOI: 10.1097/iae.0000000000000382
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Bilberry extract supplementation for preventing eye fatigue in video display terminal workers. (2015)
  • Author(s): Ozawa Y, Kawashima M, Inoue S, Inagaki E, Suzuki A, Ooe E, Kobayashi S, Tsubota K.
  • Journal Title: The journal of nutrition, health & aging Volume: 19 Issue: 5 Pages: 548-54
  • DOI: 10.1007/s12603-014-0573-6
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Blue light-induced inflammatory marker expression in the retinal pigment epithelium-choroid of mice and the protective effect of a yellow intraocular lens material in vivo. (2015)
  • Author(s): Narimatsu T, Negishi K, Miyake S, Hirasawa M, Kurihara T, Tsubota K, Ozawa Y
  • Journal Title: Experimental Eye Research. Volume: 132 Pages: 48-51
  • DOI: 10.1016/j.exer.2015.01.003
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Predisposing factors for IOL dislocation treated by pars plana vitrectomy; Involvement of atopic dermatitis. (2015)
  • Author(s): 8.Yotsukura-Tsutsui E, Koto T, Tsubota K, Ozawa Y.
  • Journal Title: Journal of Cataract and Refractive Surgery. Volume: 41 Issue: 4 Pages: 892-4
  • DOI: 10.1016/j.jcrs.2014.12.047
  • Open Access / Acknowledgement Compliant
• [Journal Article] Wide-Angle Viewing System versus Conventional Indirect Ophthalmoscopy for Scleral Buckling. (2015)
  • Author(s): Tomita Y, Kurihara T, Uchida A, Nagai N, Shinoda H, Tsubota K, Ozawa Y
  • Journal Title: Scientific Reports Volume: 5:13256 Issue: 1 Pages: 1-7
  • DOI: 10.1038/srep13256
  • Peer Reviewed / Open Access
• [Journal Article] Vision loss by central retinal vein occlusion after Kaatsu training: a case report. Medicine (Baltimore). (2015)
  • Author(s): Ozawa Y, Koto T, Shinoda H, Tsubota K.
  • Journal Title: Medicine (Baltimore). Volume: 94 Issue: 36 Pages: 36-36
  • DOI: 10.1097/md.0000000000001515
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Role of Angptl2 in laser-induced CNV. (2017)
  • Author(s): Ozawa Y
  • Organizer: International Retina Summit. Dongguan
  • Int'l Joint Research / Invited
• [Presentation] Neuro-inflammation in Metabolic Syndrome. (2017)
  • Author(s): Ozawa Y
  • Organizer: 14th International Ocular Inflammation Society Meeting in conjunction with SOIE.
  • Int'l Joint Research / Invited
• [Presentation] Molecular Mechanisms of Lutein’s Effect in Preventing AMD. (2017)
  • Author(s): Ozawa Y
  • Organizer: Global Ocular Inflammation Workshops
  • Int'l Joint Research / Invited
• [Presentation] Inflammatory responses in AMD Pathogenesis. (2017)
  • Author(s): Ozawa Y
  • Organizer: 32nd Asia-Pacific Academy of Ophthalmology.
  • Int'l Joint Research / Invited
• [Presentation] Real-world clinical features of PCV in AMD. (2017)
  • Author(s): Ozawa Y
  • Organizer: Harvard Medical School Department of Ophthalmology Massachusetts Eye and Ear RETINA SERVICE CONFERENCE
  • Int'l Joint Research / Invited
• [Presentation] Bicistronic 2A-peptide-based co-expression reporter knock-in hiPSC lines revealed gene expression profiles during human photoreceptor differentiation. (2017)
  • Author(s): Homma K, Ozawa Y.
  • Organizer: Society for Neuroscience 2017
  • Int'l Joint Research
• [Presentation] Neuroprotective role of retinal SIRT3 against acute photo-stress. (2017)
  • Author(s): Ozawa Y, Ban N, Ishida S, Apte RS, Tsubota K.
  • Organizer: The 50th Retina society.
  • Int'l Joint Research
• [Presentation] Bicistronic 2A-peptide-based co-expression reporter knock-in strategy for the labeling of human induced pluripotent stem cell-derived photoreceptors. (2017)
  • Author(s): 本間耕平，小沢洋子.
  • Organizer: 第40回日本分子生物学会年会
• [Presentation] 光照射直後の網膜における酸素消費速度(OCR)の低下 (2017)
  • Author(s): 川島弘彦，岡本知大，戸田枝里子，長田秀斗，鴨下衛，永井紀博，篠田肇，坪田一男，小沢洋子.
  • Organizer: 第56回日本網膜硝子体学会
• [Presentation] 光障害に対するビルベリーエキスの網膜保護効果. (2017)
  • Author(s): 長田秀斗, 岡本知大, 川島弘彦, 戸田枝里子, 小林沙織, 坪田一男, 小沢洋子.
  • Organizer: 第17回日本抗加齢医学会総会
• [Presentation] ノックインヒトiPS細胞による3次元網膜組織の可視化への取り組み. (2017)
  • Author(s): 本間耕平，小沢洋子.
  • Organizer: 視覚科学フォーラム
• [Presentation] Predictive factors for non-response to intravitreal aflibercept treatment in neovascular age-related macular degeneration. (2016)
  • Author(s): Nagai N, Suzuki M, Uchida A, Kurihara T, Kamoshita M, Minami S, Shinoda H, Tsubota K, Ozawa Y.
  • Organizer: The Association for Research in Vision and Ophthalmology
  • Place of Presentation: シアトル（アメリカ）
  • Year and Date: 2016-05-01
  • Int'l Joint Research
• [Presentation] Treatment Responses to the Intravitreal Aflibercept in Polypoidal Choroidal Vasculopathy at year 1. (2016)
  • Author(s): Minami S, Nagai N, Suzuki M, Kurihara T, Shinoda H, Tsubota K, Ozawa Y.
  • Organizer: The Association for Research in Vision and Ophthalmology
  • Place of Presentation: シアトル（アメリカ）
  • Year and Date: 2016-05-01
  • Int'l Joint Research
• [Presentation] Aerobic exercise protects retinal function in type 2 diabetic mice. (2016)
  • Author(s): Kamoshita M, Osada H, Toda E, Sano K, Kawashima M, Nagai N, Shinoda H, Tsubota K, Ozawa Y.
  • Organizer: The Association for Research in Vision and Ophthalmology
  • Place of Presentation: シアトル（アメリカ）
  • Year and Date: 2016-05-01
  • Int'l Joint Research
• [Presentation] The neuroprotective effect of rapamycin as a modulator of the mTOR-NF-κB axis during retinal inflammation. (2016)
  • Author(s): Okamoto T, Kamoshita M, Osada H, Toda E, Nagai N, Tsubota K, Ozawa Y.
  • Organizer: The Association for Research in Vision and Ophthalmology
  • Place of Presentation: シアトル（アメリカ）
  • Year and Date: 2016-05-01
  • Int'l Joint Research
• [Presentation] AMPK activation protects photoreceptors from light-induced degeneration. (2016)
  • Author(s): Kawashima H, Osada H, Toda E, Okamoto T, Kamoshita M, Nagai N, Tsubota K, Ozawa Y.
  • Organizer: The Association for Research in Vision and Ophthalmology
  • Place of Presentation: シアトル（アメリカ）
  • Year and Date: 2016-05-01
  • Int'l Joint Research
• [Presentation] The use of induced pluripotent stem cells (iPSCs) to reveal pathogenic gene mutations and explore treatments for retinitis pigmentosa. (2016)
  • Author(s): Ozawa Y
  • Organizer: International Society for Eye Research XXII Biennial Meeting in Tokyo
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Int'l Joint Research / Invited
• [Presentation] Lutein/Zeaxanthin as a preventive approach for age-related macular degeneration. (2016)
  • Author(s): Ozawa Y
  • Organizer: The 3rd International Conference on Pharma and Food.
  • Place of Presentation: 日本平ホテル（静岡県清水市）
  • Int'l Joint Research / Invited
• [Presentation] Neurodegeneration in the diabetic retina. (2015)
  • Author(s): Ozawa Y
  • Organizer: The 2015 IOIS Congress
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2015-09-25
  • Invited
• [Presentation] Light-induced inflammation in the underlying mechanism of AMD. (2015)
  • Author(s): Ozawa Y
  • Organizer: The 2015 IOIS Congress
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2015-09-25
  • Invited
• [Presentation] 6. Ozawa Y. The use of induced pluripotent stem cells (iPSCs) to reveal pathogenic gene mutations and explore treatments for retinitis pigmentosa (2015)
  • Author(s): Ozawa Y
  • Organizer: The 9th APVRS (Asia Pacific Vitreo-retina Socoity)
  • Place of Presentation: Sydney, Australia
  • Year and Date: 2015-07-31
  • Invited
• [Presentation] Retinal photo-damage and the underlying mechanisms (2015)
  • Author(s): Ozawa Y
  • Organizer: The 2nd International Symposium of Blue Light Society
  • Place of Presentation: New York, USA
  • Year and Date: 2015-06-26
  • Invited
• [Presentation] Neuroprotective effect of rapamycin in the retina. (2015)
  • Author(s): Okamoto T, Ozawa Y
  • Organizer: ARVO annual meeting 2015 (The Association for Research in Vision and Ophthalmology)
  • Place of Presentation: Denver, Colorado, USA
  • Year and Date: 2015-05-03
  • Int'l Joint Research
• [Presentation] Light-induced retinal degeneration and AMPK. (2015)
  • Author(s): Kawashima H, Ozawa Y
  • Organizer: ARVO annual meeting 2015 (The Association for Research in Vision and Ophthalmology)
  • Place of Presentation: Denver, Colorado, USA
  • Year and Date: 2015-05-03
  • Int'l Joint Research