Development of neuroprotective treatment for incurable ocular diseases

• Project/Area Number: 24249082
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Ophthalmology
• Research Institution: Kyoto University
• Principal Investigator: YOSHIMURA Nagahisa 京都大学, 医学(系)研究科(研究院), 教授 (70211662)
• Co-Investigator(Kenkyū-buntansha): IKEDA Ohashi Hanako 京都大学, 医学部附属病院, 准教授 (20372162) ; KAKIZUKA Akira 京都大学, 大学院生命科学研究科, 教授 (80204329) ; IMAMURA Hiromi 京都大学, 白眉センター, 特定准教授 (20422545)
• Project Period (FY): 2012-10-31 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥42,640,000 (Direct Cost: ¥32,800,000、Indirect Cost: ¥9,840,000); Fiscal Year 2014: ¥13,910,000 (Direct Cost: ¥10,700,000、Indirect Cost: ¥3,210,000); Fiscal Year 2013: ¥14,560,000 (Direct Cost: ¥11,200,000、Indirect Cost: ¥3,360,000); Fiscal Year 2012: ¥14,170,000 (Direct Cost: ¥10,900,000、Indirect Cost: ¥3,270,000)
• Keywords: 神経保護 / 眼難治疾患 / 眼細胞生物学

Outline of Final Research Achievements

We have examined neuroprotective effects of inhibitors for ATP activity of VCP on glaucoma and retinal degeneration animal models. The inhibitors suppressed decrease of the retinal ganglion cells and thinning of the retinal nerve fiber layer in NMDA-induced acute injury model, DBA2J, and GLAST knockout mice. The inhibitors suppressed decrease of photoreceptor cells and worsening of vusual function in rd10, rd12 mice and model rabbits of retinitis pigmentosa. The VCP ATPase inhibitors might protect neural cells by reducing decrease of ATP and ER stress in the cells.
The VCP ATPase inhibitors may be a new treatment for ocular diseases.

Research Products

• [Journal Article] KUS121, an ATP regulator, mitigates chorioretinal pathologies in animalmodels of age-related macular degeneration. (2018)
  • Author(s): Muraoka, Y., Yoshimura, N., et al.
  • Journal Title: Heliyon. Volume: 4
  • DOI: 10.1016/j.heliyon.2018.e00624
  • Peer Reviewed / Open Access
• [Journal Article] Modulation of valosin-containing protein by Kyoto University Substances (KUS) as a novel therapeutic strategy for ischemic neuronal diseases. (2017)
  • Author(s): Hata, M. & Ikeda, H. O.
  • Journal Title: Neural regeneration research Volume: 12 Pages: 1252-1252
  • DOI: 10.4103/1673-5374.213540
  • Peer Reviewed / Open Access
• [Journal Article] KUS121, a VCP modulator, attenuates ischemic retinal cell death viasuppressing endoplasmic reticulum stress. (2017)
  • Author(s): Hata, M., Yoshimura, N., et al.
  • Journal Title: Scientific reports Volume: - Pages: 44873-44873
  • DOI: 10.1038/srep44873
  • NAID: 120006222005
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] VCP/Cdc48 rescues the growth defect of a GPI10 mutant in yeast (2016)
  • Author(s): Ohnuma, Y., Takata, T., Kawawaki, J., Yasuda, K., Tanaka, K., Kimura, Y., and Kakizuka A.
  • Journal Title: FEBS Lett. Volume: 589 Pages: 576-580
  • DOI: 10.1016/j.febslet.2015.01.017
  • NAID: 120005531440
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Changes in morphology and visual function over time in mouse models of retinal degeneration : an SD-OCT, histology, and electroretinography study. (2016)
  • Author(s): Hasegawa, T., Yoshimura, N., et al.
  • Journal Title: Japanese journal of ophthalmology Volume: 60 Pages: 111-125
  • DOI: 10.1007/s10384-015-0422-0
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Neurprotective efficacies by KUS121, a VCP modulator, on animal models of retinal degeneration. (2016)
  • Author(s): Hasegawa, T. Yoshimura, N., et al.
  • Journal Title: Scientific reports Volume: 6 Pages: 31184-31184
  • DOI: 10.1038/srep31184
  • NAID: 120005829364
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Neuroprotective effects of VCP modulators in mouse models of glaucoma. (2016)
  • Author(s): Nakano, N., Yoshimura, N., et al.
  • Journal Title: Heliyon Volume: 2 Pages: 96-96
  • DOI: 10.1016/j.heliyon.2016.e00096
  • NAID: 120005753824
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Effects of sex and age on the normal retinal and choroidal structures on optical coherence tomography. (2015)
  • Author(s): Ooto, S., Hangai, M. & Yoshimura, N
  • Journal Title: Curr Eye Res Volume: 40 Pages: 213-225
  • DOI: 10.3109/02713683.2014.952828
  • Peer Reviewed
• [Journal Article] Alterations in the neural and connective tissue components of glaucomatous cupping after glaucoma surgery using swept-source optical coherence tomography (2014)
  • Author(s): Yoshikawa, M., Akagi, T., Hangai, M., Ohashi-Ikeda, H., Takayama, K., Morooka, S., Kimura, Y., Nakano, N. & Yoshimura, N
  • Journal Title: Invest Ophthalmol Vis Sci Volume: 55 Pages: 477-484
  • DOI: 10.1167/iovs.13-11897
  • Peer Reviewed
• [Journal Article] Asymmetry analysis of macular inner retinal layers for glaucoma diagnosis (2014)
  • Author(s): Yamada, H., Hangai, M., Nakano, N., Takayama, K., Kimura, Y., Miyake, M., Akagi, T., Ikeda, H. O., Noma, H. & Yoshimura, N.
  • Journal Title: Am J Ophthalmol Volume: 158 Pages: 1318-1329
  • DOI: 10.1016/j.ajo.2014.08.040
  • Peer Reviewed
• [Journal Article] High-resolution imaging of photoreceptors in macular microholes. (2014)
  • Author(s): Ooto, S., Hangai, M., Takayama, K., Ueda-Arakawa, N., Makiyama, Y., Hanebuchi, M. & Yoshimura, N
  • Journal Title: Invest Ophthalmol Vis Sci Volume: 55 Pages: 5932-5943
  • DOI: 10.1167/iovs.13-13792
  • Peer Reviewed
• [Journal Article] Comprehensive Molecular Diagnosis of a Large Cohort of Japanese Retinitis Pigmentosa and Usher Syndrome Patients by Next-Generation Sequencing (2014)
  • Author(s): Oishi, M., Oishi, A., Gotoh, N., Ogino, K., Higasa, K., Iida, K., Makiyama, Y., Morooka, S., Matsuda, F. & Yoshimura, N.
  • Journal Title: Investigative Ophthalmology & Visual Sciences Volume: 55 Pages: 7343-7354
  • DOI: 10.1167/iovs.14-15458
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Wide-field fundus autofluorescence abnormalities and visual function in patients with cone and cone-rod dystrophies. (2014)
  • Author(s): Oishi, M., Oishi, A., Ogino, K., Makiyama, Y., Gotoh, N., Kurimoto, M. & Yoshimura, N.
  • Journal Title: Invest Ophthalmol Vis Sci Volume: 55 Pages: 3572-3577
  • DOI: 10.1167/iovs.14-13912
  • Peer Reviewed
• [Journal Article] Association of retinal vessel attenuation with visual function in eyes with retinitis pigmentosa. (2014)
  • Author(s): Nakagawa, S., Oishi, A., Ogino, K., Makiyama, Y., Kurimoto, M. & Yoshimura, N
  • Journal Title: Clin Ophthalmol Volume: 8 Pages: 1487-1493
  • DOI: 10.2147/opth.s66326
  • Peer Reviewed
• [Journal Article] Cone abnormalities in fundus albipunctatus associated with rdh5 mutations assessed using adaptive optics scanning laser ophthalmoscopy. (2014)
  • Author(s): Muraoka, Y., Tsujikawa, A., Kumagai, K., Akagi-Makiyama, Y., Ooto, S., Hangai, M., Ogino, K., Gotoh, N., Oishi, A. & Yoshimura, N.
  • Journal Title: Am J Ophthalmol Volume: 157 Pages: 558-570
  • DOI: 10.1016/j.ajo.2013.10.021
  • Peer Reviewed
• [Journal Article] Prevalence and spatial distribution of cystoid spaces in retinitis pigmentosa: Investigation with spectral domain optical coherence tomography. (2014)
  • Author(s): Makiyama, Y., Oishi, A., Otani, A., Ogino, K., Nakagawa, S., Kurimoto, M. & Yoshimura, N.
  • Journal Title: Retina Volume: 34 Pages: 981-988
  • DOI: 10.1097/iae.0000000000000010
  • Peer Reviewed
• [Journal Article] Lamina cribrosa defects and optic disc morphology in primary open angle glaucoma with high myopia (2014)
  • Author(s): Kimura, Y., Akagi, T., Hangai, M., Takayama, K., Hasegawa, T., Suda, K., Yoshikawa, M., Yamada, H., Nakanishi, H., Unoki, N., Ikeda, H. O. & Yoshimura, N.
  • Journal Title: PLoS One Volume: 9
  • DOI: 10.1371/journal.pone.0115313
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Tomographic comparison of cone-rod and rod-cone retinal dystrophies. (2014)
  • Author(s): Inui, E., Oishi, A., Oishi, M., Ogino, K., Makiyama, Y., Gotoh, N., Kurimoto, M. & Yoshimura, N.
  • Journal Title: Graefes Arch Clin Exp Ophthalmol Volume: 252 Pages: 1065-1069
  • DOI: 10.1007/s00417-014-2570-1
  • Peer Reviewed
• [Journal Article] Novel vcp modulators mitigate major pathologies of rd10, a mouse model of retinitis pigmentosa. (2014)
  • Author(s): Ikeda, H. O., Sasaoka, N., Koike, M., Nakano, N., Muraoka, Y., Toda, Y., Fuchigami, T., Shudo, T., Iwata, A., Hori, S., Yoshimura, N. & Kakizuka, A.
  • Journal Title: Sci Rep Volume: 4 Pages: 5970-5970
  • DOI: 10.1038/srep05970
  • NAID: 120005464816
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Comparison of optic disc morphology of optic nerve atrophy between compressive optic neuropathy and glaucomatous optic neuropathy (2014)
  • Author(s): Hata, M., Miyamoto, K., Oishi, A., Makiyama, Y., Gotoh, N., Kimura, Y., Akagi, T. & Yoshimura, N.
  • Journal Title: PLoS One Volume: 9
  • DOI: 10.1371/journal.pone.0112403
  • Peer Reviewed / Open Access
• [Journal Article] Diversity in ATP concentrations in a single bacterial cell population revealed by quantitative single-cell imaging. (2014)
  • Author(s): Hideyuki Yaginuma, Shinnosuke Kawai, Kazuhito V. Tabata, Keisuke Tomiyama, Akira Kakizuka, Tamiki Komatsuzaki, Hiroyuki Noji, and Hiromi Imamura
  • Journal Title: Science Report Volume: 4 Pages: 6522-6522
  • DOI: 10.1038/srep06522
  • NAID: 120005575159
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Measurement of retinal nerve fiber layer thickness in eyes with optic disc swelling by using scanning laser polarimetry and optical coherence tomography (2014)
  • Author(s): Hata M, Miyamoto K, Oishi A, Kimura Y, Nakagawa S, Horii T, Yoshimura N.
  • Journal Title: Clin Ophthalmol Volume: 8 Pages: 105-111
  • DOI: 10.2147/opth.s46769
  • Peer Reviewed
• [Journal Article] High-Resolution Imaging of Retinal Nerve Fiber Bundles in Glaucoma Using Adaptive Optics Scanning Laser Ophthalmoscopy (2013)
  • Author(s): Takayama K, Ooto S, Hangai M, Ueda-Arakawa N, Yoshida S, Akagi T, Ikeda HO, Nonaka A, Hanebuchi M, Inoue T, Yoshimura N
  • Journal Title: Am J Ophthalmol. Volume: 155(5) Pages: 870-81
  • DOI: 10.1016/j.ajo.2012.11.016
  • Peer Reviewed
• [Journal Article] Peripapillary Scleral Deformation and Retinal Nerve Fiber Damage in High Myopia Assessed with Swept-Source Optical Coherence Tomography (2013)
  • Author(s): Akagi T, Hangai M, Kimura Y, Ikeda HO, Nonaka A, Matsumoto A, Akiba M, Yoshimura N.
  • Journal Title: Am J Ophthalmol Volume: 155 Pages: 927-936
  • DOI: 10.1016/j.ajo.2012.12.014
  • Peer Reviewed
• [Journal Article] Macular Imaging in Highly Myopic Eyes With and Without Glaucoma (2013)
  • Author(s): Nakano N, Hangai M, Noma H, Nukada M, Mori S, Morooka S, Takayama K, Kimura Y, Ikeda HO, Akagi T, Yoshimura N.
  • Journal Title: Am J Ophthalmol Volume: 155 Pages: 511-523
  • DOI: 10.1016/j.ajo.2013.04.028
  • Peer Reviewed
• [Journal Article] Three Dimensional Imaging of the Lamina Cribrosa Defects in Glaucoma Using Swept-source Optical Coherence Tomography (2013)
  • Author(s): Takayama K, Hangai M, Kimura Y, Morooka S, Nukada M, Akagi T, Ikeda HO, Matsumoto A, Yoshimura N.
  • Journal Title: Invest Ophthalmol Vis Sci Volume: 54 Pages: 4798-4807
  • DOI: 10.1167/iovs.13-11677
  • Peer Reviewed
• [Journal Article] Macular structure parameters as an automated indicator of paracentral scotoma in early glaucoma. (2013)
  • Author(s): Kimura Y, Hangai M, Matsumoto A, Akagi T, Ikeda HO, Ohkubo S, Sugiyama K, Iwase A, Araie M, Yoshimura N.
  • Journal Title: Am J Ophthalmol Volume: 156 Pages: 907-917
  • DOI: 10.1016/j.ajo.2013.06.029
  • Peer Reviewed
• [Journal Article] Image quality improvement in adaptive optics scanning laser ophthalmoscopy assisted capillary visualization using B-spline-based elastic image registration (2013)
  • Author(s): Uji A, Ooto S, Hangai M, Arichika S, Yoshimura N.
  • Journal Title: PLoS One Volume: 8
  • DOI: 10.1371/journal.pone.0080106
  • Peer Reviewed
• [Journal Article] Real-Time Imaging of Rabbit Retina with Retinal Degeneration by using Spectral-Domain Optical Coherence Tomography. (2012)
  • Author(s): Muraoka Y et al.
  • Journal Title: PLoS ONE Volume: 7
  • DOI: 10.1371/journal.pone.0036135
  • NAID: 120004108231
  • Peer Reviewed
• [Journal Article] A novel method to detect local ganglion cell loss in early glaucoma using spectral-domain optical coherence tomography (2012)
  • Author(s): Takayama K, Hangai M, Durbin M, Nakano N, Morooka S, Akagi T, Ikeda HO, Yoshimura N.
  • Journal Title: Invest Ophthalmol Vis Sci Volume: 53 Pages: 6904-13
  • DOI: 10.1167/iovs.12-10210
  • Peer Reviewed
• [Presentation] 網膜色素変性に対する 新規神経保護治療 (2014)
  • Author(s): 池田華子
  • Organizer: ６２回 医療相談会
  • Place of Presentation: 神戸勤労会館
  • Year and Date: 2014-12-07
• [Presentation] 網膜虚血再灌流ラットモデルにおけるvalosin-containing protein modifierの神経保護効果の検討 (2014)
  • Author(s): 畑匡侑、池田華子、飯田悠人、吉川宗光、長谷川智子、村岡勇貴、垣塚彰、吉村長久
  • Organizer: ５３回日本網膜硝子体学会総会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2014-11-28 – 2014-11-30
• [Presentation] 未来の神経保護治療 (2014)
  • Author(s): 池田華子
  • Organizer: ２５回 日本緑内障学会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2014-09-19
• [Presentation] VCP ATPase阻害剤による 新規神経保護治療 (2014)
  • Author(s): 池田華子
  • Organizer: ３４回日本眼薬理学会
  • Place of Presentation: 長良川国際会議場
  • Year and Date: 2014-09-13
  • Invited
• [Presentation] Neuroprotective effects of a VCP modulator on rat models of ischemia and reperfusion-induced retinal degeneration (2014)
  • Author(s): Masayuki Hata, Hanako O. Ikeda, Tomoko Hasegawa, Noriko Nakano, Yuki Muraoka, Akira Kakizuka, Nagahisa Yoshimura
  • Organizer: ARVO2014
  • Place of Presentation: Orland, Fla., USA
  • Year and Date: 2014-05-04 – 2014-05-08
• [Presentation] Neuroprotective effect of a valosin-containing-protein ATPase inhibitor on late-stage retinal degeneration in a mouse model. (2014)
  • Author(s): Tomoko Hasegawa, Hanako O. Ikeda, Yuki Muraoka1,Akira Kakizuka,Nagahisa Yoshimura.
  • Organizer: World Ophthalmology Congress
  • Place of Presentation: Japan, Tokyo
  • Year and Date: 2014-04-05
• [Presentation] VCP阻害剤による網膜神経保護効果のメカニズム (2013)
  • Author(s): 池田華子、中野紀子、村岡勇貴、長谷川智子、垣塚彰、吉村長久
  • Organizer: 日本眼科学会１１7回
  • Place of Presentation: 東京国際フォーラム
• [Presentation] VCP 阻害剤によるＣＣＲ２欠損マウスのドルーゼン抑制効果の検討 (2013)
  • Author(s): 村岡勇貴、池田華子、中野紀子、長谷川智子、垣塚彰、吉村長久
  • Organizer: 日本眼科学会１１7回
  • Place of Presentation: 東京国際フォーラム
• [Presentation] VCP阻害剤によるグラスト欠損マウスにおける 神経保護効果の検討 (2013)
  • Author(s): 中野紀子、池田華子、村岡勇貴、板谷正紀、垣塚彰、吉村長久
  • Organizer: 日本眼科学会１１7回
  • Place of Presentation: 東京国際フォーラム
• [Presentation] 網膜変性モデルマウスの光干渉断層計、網膜電図、組織所見の比較 (2013)
  • Author(s): 長谷川智子、池田華子、中野紀子、村岡勇貴、吉村長久
  • Organizer: 日本眼科学会１１7回
  • Place of Presentation: 東京国際フォーラム
• [Presentation] ＶＣＰ阻害剤による新規神経保護治療 (2013)
  • Author(s): 池田華子
  • Organizer: 日本眼科学会１１7回
  • Place of Presentation: 東京国際フォーラム
• [Presentation] Neuroprotective effect of valosin-containing protein inhibitors on mice models of glaucoma (2013)
  • Author(s): Hanako Ohashi Ikeda、Noriko Nakano,Yuki Muraoka, Masanori Hangai, Akira Kakizuka, Nagahisa Yoshimura
  • Organizer: ARVO 2013
  • Place of Presentation: Seattle
• [Presentation] A Novel Valosin-Containing Protein Inhibitor Suppresses Photoreceptor Degeneration in a Rabbit Model of Retinitis Pigmentosa (2013)
  • Author(s): Yuki Muraoka,1 Hanako Ohashi Ikeda,1 Noriko Nakano,1 Tomoko Hasegawa,1 Kondo Mineo,2 Hiroko Terasaki,3 Akira Kakizuka,4 Nagahisa Yoshimura1
  • Organizer: ARVO 2013
  • Place of Presentation: Seattle
• [Presentation] Optical coherence tomography, electroretinography, and histological analysis of mouse models for retinal degeneration (2013)
  • Author(s): Tomoko HasegawaHanako Ohashi Ikeda,1 Noriko Nakano,1 Yuki Muraoka,1 Akira Kakizuka,4 Nagahisa Yoshimura1
  • Organizer: ARVO 2013
  • Place of Presentation: Seattle
• [Remarks] 京都大学眼科学教室、網膜神経保護治療プロジェクト
  • URL: http://www.kuhp.kyoto-u.ac.jp/~ganka/html/mshp1.html
• [Patent(Industrial Property Rights)] 眼疾患処置薬 (2015)
  • Inventor(s): 吉村長久 他３名
  • Industrial Property Rights Holder: 吉村長久 他３名
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-02-26
  • Overseas
• [Patent(Industrial Property Rights)] 虚血性眼疾患の処置および/または予防用の医薬組成物 (2015)
  • Inventor(s): 垣塚彰、池田華子、吉村長久, 他1名
  • Industrial Property Rights Holder: 国立大学法人京都大学
  • Filing Date: 2015-02-26
  • Description: 特願2014-038457
  • Overseas
• [Patent(Industrial Property Rights)] 眼疾患治療薬 (2014)
  • Inventor(s): 池田華子、吉村長久他２名
  • Industrial Property Rights Holder: 池田華子、吉村長久他２名
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-02-28
• [Patent(Industrial Property Rights)] 眼疾患処置薬 (2014)
  • Inventor(s): 池田華子、吉村長久他５名
  • Industrial Property Rights Holder: 池田華子、吉村長久他５名
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-02-19
  • Overseas
• [Patent(Industrial Property Rights)] 眼疾患処置薬 (2014)
  • Inventor(s): 垣塚彰、池田華子、吉村長久, 他1名
  • Industrial Property Rights Holder: 国立大学法人京都大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-02-19
  • Acquisition Date: 2017-12-22
  • Description: 米国 : 9782120 日本特許登録 : 6261011 2017/10/10
• [Patent(Industrial Property Rights)] 眼疾患処置薬 (2011)
  • Inventor(s): 垣塚彰、堀清次、池田華子、吉村長久, 他3名
  • Industrial Property Rights Holder: 国立大学法人京都大学、他一社
  • Industrial Property Rights Type: 特許
  • Filing Date: 2011-09-30
  • Acquisition Date: 2015-10-16
  • Description: イギリス : 2623494 フランス : 2623494 米国 : 920619