Updated on 2022/03/19

写真a

 
Koji Nishiguchi
 
Organization
Graduate School of Medicine Program in Integrated Medicine Head and Neck and Sensory Organ Medicine Professor
Graduate School
Graduate School of Medicine
Undergraduate School
School of Medicine Department of Medicine
Title
Professor

Degree 1

  1. 医学博士 ( 2005.3 ) 

Research Interests 6

  1. 網膜血管新生

  2. 網膜、視細胞、網膜神経幹細胞、毛様体、未熟児網膜症、マイクログリア

  3. retinal degeneration

  4. 視覚再建・弱視

  5. gene therapy

  6. genetic diagnosis

Research Areas 1

  1. Life Science / Neuroscience-general  / retinal disease, visual function

Current Research Project and SDGs 3

  1. 網膜変性疾患の分子病態の解明

  2. ぶどう膜炎、網膜硝子体疾患、眼病理の臨床

  3. 遺伝子治療・ゲノム編集・遺伝子解析

Research History 9

  1. Nagoya University   Professor

    2020.10

  2. Tohoku University   Associate professor

    2014 - 2020.9

  3. UCL Institute of Ophthalmology

    2012.1 - 2013.12

  4. スイス・ローザンヌ大学   遺伝医学   リサーチフェロー

    2011.6 - 2011.12

  5. Nagoya University   Assistant professor of hospital

    2007.6 - 2010.5

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    Country:Japan

  6. 名古屋大学付属病院眼科医員

    2006.11 - 2007.5

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    Country:Japan

  7. 東海市民病院眼科長

    2005.10 - 2006.10

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    Country:Japan

  8. 名古屋大学付属病院眼科

    1999.4 - 2000.6

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    Country:Japan

  9. 名古屋第二赤十字病院研修医

    1997.4 - 1999.3

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    Country:Japan

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Education 2

  1. Nagoya University

    2001.4 - 2005.3

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    Country: Japan

  2. Nagoya University   Faculty of Medicine

    1991.4 - 1997.3

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    Country: Japan

 

Papers 74

  1. Defects in RGS9 or its anchor protein R9AP in patients with slow photoreceptor deactivation. Reviewed

    Nature   Vol. 427 ( 6969 ) page: 75-78   2004

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

  2. Novel mutations in the cellular retinaldehyde-binding protein gene (RLBP1) associated with retinitis punctata albescens: evidence of interfamilial genetic heterogeneity and fundus changes in heterozygotes Reviewed

    Fishman GA, Roberts MF, Derlacki DJ, Grimsby JL, Yamamoto H, Sharon D, Nishiguchi KM, Dryja TP

    Arch Ophthalmol   Vol. 122 ( 1 ) page: 70-75   2004

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    Language:English   Publishing type:Research paper (scientific journal)  

  3. Mutation screening of the phosducin gene PDC in patients with retinitis pigmentosa and allied diseases Reviewed

    Mol Vis   Vol. 10   page: 62-64   2004

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

  4. A novel mutation (I143NT) in guanylate cyclase-activating protein 1 (GCAP1) associated with autosomal dominant cone degeneration Reviewed

      Vol. 45   page: 3863-3870   2004

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

  5. Recessive NRL mutations in patients with clumped pigmentary retinal degeneration and relative preservation of blue cone function Reviewed

    Nishiguchi KM, Friedman JS, Sandberg MA, Swaroop A, Berson EL, Dryja TP

      Vol. 101   page: 17819-17824   2004

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

  6. Cone cGMP-gated channel mutations and clinical findings in patients with achromatopsia, macular degeneration, and other hereditary cone diseases Reviewed

      Vol. 25   page: 248-258   2005

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

  7. Recessive mutations in the CYP4V2 gene in East Asian and Middle Eastern patients with Bietti crystalline corneoretinal dystrophy Reviewed

    Lin J, Nishiguchi KM, Nakamura M, Dryja TP, Berson EL, Miyake Y

    J Med Genet   Vol. 42   2005

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

  8. Retinopathy mutations in the bZIP protein NRL alter phosphorylation and transcriptional activity Reviewed

    Hum Mutat   Vol. 28   page: 589-598   2007

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  9. *The role of VEGF and VEGFR2/Flk1 in proliferation of retinal progenitor cells in murine retinal degeneration Reviewed

      Vol. 48   page: 4315-4320   2007

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

  10. *Identification of photoreceptor precursors in the pars plana during ocular development and after retinal injury Reviewed

    Nishiguchi KM, Nakamura M, Kaneko H, Kachi S, Terasaki H

    Invest Ophthalmol Vis Sci   Vol. 49   page: 422-428   2008.1

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

  11. *Characteristics of Bone Marrow-Derived Microglia in the Normal and Injured Retina Reviewed

    Kaneko H, Nishiguchi KM, Nakamura M, Kachi S, Terasaki H

      Vol. 49   page: 4162-4168   2008.9

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  12. *Retardation of Photoreceptor Degeneration in the Detached Retina of rd1 Mouse Reviewed

    Kaneko H, Nishiguchi KM, Nakamura M, Kachi S, Terasaki H

    Invest Ophthalmol Vis Sci   Vol. 49   page: 781-787   2008.2

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  13. TRPM1 mutations are associated with the complete form of congenital stationary night blindness Reviewed

    Nakamura M, Sanuki R, Yasuma TR, Onishi A, Nishiguchi KM, Koike C, Kadowaki M, Kondo M, Miyake Y, Furukawa T.

    Mol Vis   Vol. 16   page: 425-437   2010

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  14. Regulation of pathologic retinal angiogenesis and inhibition of VEGF-VEGFR2 binding by soluble heparan sulfate. Reviewed

    Nishiguchi KM, Kataoka K, Kachi S, Komeima K, Terasaki H

    PLoS ONE   Vol. 5   page: e13493   2010

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

  15. The roles of vitreal macrophages and circulating leukocytes in retinal neovascularization. Reviewed

    Kataoka K, Nishiguchi KM, Kaneko H, van Rooijen N, Kachi S, Terasaki H

    Invest Ophthalmol Vis Sci   Vol. in press   2010

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    Language:English   Publishing type:Research paper (scientific journal)  

  16. Switching from aflibercept to brolucizumab for the treatment of refractory neovascular age-related macular degeneration

    Ota Hikaru, Takeuchi Jun, Nakano Yuyako, Horiguchi Etsuyo, Taki Yosuke, Ito Yasuki, Terasaki Hiroko, Nishiguchi Koji M., Kataoka Keiko

    JAPANESE JOURNAL OF OPHTHALMOLOGY     2022.3

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  17. Seasonal variation in submacular hemorrhages in retinal macroaneurysms and its disappearance in age-related macular degeneration

    Kaneko Hiroki, Takashi Noriko, Matsunaga Masaaki, Ito Yasuki, Takeuchi Jun, Terasaki Hiroko, Yatsuya Hiroshi, Nishiguchi Koji M.

    GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY   Vol. 259 ( 12 ) page: 3589 - 3596   2021.12

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    Language:Japanese   Publisher:Graefe's Archive for Clinical and Experimental Ophthalmology  

    Purpose: To investigate whether previously reported seasonal variation and winter-dominant prevalence of acute massive submacular hemorrhages (SMHs) caused by age-related macular degeneration (AMD) disappeared, and those caused by retinal microaneurysms (RMAs) emerged. Method: The medical charts of 95 patients (95 eyes) with SMH caused by AMD and 76 patients (76 eyes) with SMH caused by RMAs in 2012–2019 were retrospectively reviewed. For each subject, the month of onset, the mean ambient temperature of that month were recorded. Results: The monthly numbers of cases of SMHs caused by AMD from January to December were 6, 8, 4, 9, 7, 10, 9, 11, 7, 11, 3, and 10. No significant seasonal variation in the monthly incidence was identified (Roger’s R = 1.89, p = 0.39). The monthly numbers of SMHs caused by RMAs from January to December were 3, 11, 11, 8, 7, 8, 5, 5, 2, 4, 7, and 5. There was significant seasonal variation in the monthly incidence (Roger’s R = 7.67, p = 0.02). There was no significant correlation between the monthly incidence of SMHs caused by RMAs and mean ambient temperature. Conclusion: Our previous study conducted for cases obtained in 1998–2005 showed seasonal cyclic trend in the number of SMHs caused by AMD, with the peak in winter. However, that significant seasonal variation disappeared in 2012–2019 in the present study. Common usage of OCT devices and anti-VEGF drugs might be the reason for the lack of seasonal variation in the cases of SMH caused by AMD. [Figure not available: see fulltext.]

    DOI: 10.1007/s00417-021-05280-3

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  18. CHOP deletion and anti-neuroinflammation treatment with hesperidin synergistically attenuate NMDA retinal injury in mice

    Sato Kota, Sato Taimu, Ohno-Oishi Michiko, Ozawa Mikako, Maekawa Shigeto, Shiga Yukihiro, Yabana Takeshi, Yasuda Masayuki, Himori Noriko, Omodaka Kazuko, Fujita Kosuke, Nishiguchi Koji M., Ge Shi, Nakazawa Toru

    EXPERIMENTAL EYE RESEARCH   Vol. 213   page: 108826   2021.12

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    Language:Japanese   Publisher:Experimental Eye Research  

    Glaucoma is a leading cause of blindness worldwide and is characterized by degeneration associated with the death of retinal ganglion cells (RGCs). It is believed that glaucoma is a group of heterogeneous diseases with multifactorial pathomechanisms. Here, we investigate whether anti-inflammation treatment with an ER stress blockade can selectively promote neuroprotection against NMDA injury in the RGCs. Retinal excitotoxicity was induced with an intravitreal NMDA injection. Microglial activation and neuroinflammation were evaluated with Iba1 immunostaining and cytokine gene expression. A stable HT22 cell line transfected with an NF-kB reporter was used to assess NF-kB activity after hesperidin treatment. CHOP-deficient mice were used as a model of ER stress blockade. Retinal cell death was evaluated with a TUNEL assay. As results, in the NMDA injury group, Iba1-positive microglia increased 6 h after NMDA injection. Also at 6 h, pro-inflammatory cytokines and chemokine increased, including TNFα, IL-1b, IL-6 and MCP-1. In addition, the MCP-1 promoter-driven EGFP signal, which we previously identified as a stress signal in injured RGCs, also increased; hesperidin treatment suppressed this inflammatory response and reduced stressed RGCs. In CHOP-deficient mice that received an NMDA injection, the gene expression of pro-inflammatory cytokines, chemokines, markers of active microglia, and inflammatory regulators was greater than in WT mice. In WT mice, hesperidin treatment partially prevented retinal cell death after NMDA injury; this neuroprotective effect was enhanced in CHOP-deficient mice. These findings demonstrate that ER stress blockade is not enough by itself to prevent RGC loss due to neuroinflammation in the retina, but it has a synergistic neuroprotective effect after NMDA injury when combined with an anti-inflammatory treatment based on hesperidin.

    DOI: 10.1016/j.exer.2021.108826

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  19. 特集 網膜色素変性のアップデート 【網膜色素変性:最近の話題】 SAG遺伝子変異スペクトラムとしての小口病と網膜色素変性

    西口 康二

    臨床眼科   Vol. 75 ( 12 ) page: 1453 - 1459   2021.11

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    Publisher:株式会社医学書院  

    DOI: 10.11477/mf.1410214208

    CiNii Research

  20. Voxel topology optimization of vehicle frame structure using building cube method framework

    Wada Yuji, Shimada Tokimasa, Nishiguchi Koji, Okazawa Shigenobu, Tsubokura Makoto

    Transactions of the Japan Society for Computational Engineering and Science   Vol. 2021 ( 0 ) page: 20210019 - 20210019   2021.11

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    Language:Japanese   Publisher:JAPAN SOCIETY FOR COMPUTATIONAL ENGINEERING AND SCIENCE  

    <p>To obtain the conceptual structure of an automobile frame from a large area of metal blocks by topology optimization, a volume constraint of less than 1% and sufficient element resolution are required. By using the building cube method framework, usually a finite volume method solver using hierarchical orthogonal lattices, as a voxel finite element method solver for orthogonal lattices with connectivity, we perform iterative topology optimization in a massively parallel environment. Topology optimization of billions of elements intended for a vehicle frame is performed using tens of thousands of processors and its parallel performance is measured.</p>

    DOI: 10.11421/jsces.2021.20210019

    CiNii Research

  21. Clinical findings in eyes with BEST1-related retinopathy complicated by choroidal neovascularization

    Miyagi Mai, Takeuchi Jun, Koyanagi Yoshito, Mizobuchi Kei, Hayashi Takaaki, Ito Yasuki, Terasaki Hiroko, Nishiguchi Koji M., Ueno Shinji

    GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY   Vol. 260 ( 4 ) page: 1125 - 1137   2021.10

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    Language:Japanese   Publisher:Graefe's Archive for Clinical and Experimental Ophthalmology  

    Purpose: To determine the characteristics of eyes diagnosed with Best vitelliform macular dystrophy (BVMD) and autosomal recessive bestrophinopathy (ARB) complicated by choroidal neovascularization (CNV). Methods: This was a retrospective, multicenter observational case series. Fourteen genetically confirmed BVMD patients and 9 ARB patients who had been examined in 2 ophthalmological institutions in Japan were studied. The findings in a series of ophthalmic examinations including B-scan optical coherence tomography (OCT) and OCT angiography (OCTA) were reviewed. Results: CNV was identified in 5 eyes (17.9%) of BVMD patients and in 2 eyes (11.1%) of ARB patients. Three of 5 eyes with BVMD were classified as being at the vitelliruptive stage and 2 eyes at the atrophic stage. The CNV in 2 BVMD eyes were diagnosed as exudative because of acute visual acuity reduction, retinal hemorrhage, and intraretinal fluid, while the CNV in 3 BVMD eyes and 2 ARB eyes were diagnosed as non-exudative. The visual acuity of the two eyes with exudative CNV did not improve despite anti-VEGF treatments. None of the eyes with non-exudative CNV had a reduction of their visual acuity for at least 4 years. All of the CNV were located within hyperreflective materials which were detected in 16 eyes (57.1%) of the BVMD eyes and in 7 eyes (38.9%) of the ARB eyes. Conclusions: CNV is a relatively common complication in BEST1-related retinopathy in Asian population as well. The prognosis of eyes with exudative CNV is not always good, and OCTA can detect CNV in eyes possessing hyperreflective materials.

    DOI: 10.1007/s00417-021-05447-y

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  22. Polypoidal choroidal vasculopathy in a case of retinitis pigmentosa, successfully treated with intravitreal aflibercept. International journal

    Nana Takahashi, Hiroshi Kunikata, Masayuki Yasuda, Takehiro Hariya, Koji M Nishiguchi, Toru Nakazawa

    American journal of ophthalmology case reports   Vol. 23   page: 101123 - 101123   2021.9

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    Purpose: Polypoidal choroidal vasculopathy (PCV) is a subtype of age-related macular degeneration that is seen frequently in Asians. Nevertheless, it is rare for this condition to be combined with retinitis pigmentosa (RP). The purpose of this paper is to present findings from this rare combination in a Japanese patient, and to describe its successful treatment with intravitreal aflibercept (IVA). Observations: The patient was a 71-year-old Japanese woman with RP (diagnosed at the age of 30) and PCV. She noticed a decrease in vision in her right eye 6 months previously. Decimal best-corrected visual acuity (BCVA) was 0.05 in her right eye. Optical coherence tomography and indocyanine green angiography (IA) revealed serous retinal detachment (SRD) and PCV in her right eye. The SRD was initially resolved after 3 monthly treatments with IVA, but recurrences began 5 months later, requiring four more treatments with IVA, performed about every 4 months within the next 12 months, for successful resolution. There were no recurrences of PCV in 7 more months of follow-up, as confirmed with IA at the final appointment. Final decimal BCVA in the right eye improved to 0.15. Furthermore, macular retinal sensitivity, measured with microperimetry, increased after the treatment, and RP-related visual field narrowing, determined by Goldmann perimetry, did not progress throughout follow up of 26 months. Conclusion: More than 2 years of follow up showed that IVA may be effective for treating PCV, even in RP patients, and can increase central visual function without causing progression of RP-related visual field narrowing.

    DOI: 10.1016/j.ajoc.2021.101123

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  23. Regional differences in genes and variants causing retinitis pigmentosa in Japan.

    Yoshito Koyanagi, Masato Akiyama, Koji M Nishiguchi, Yukihide Momozawa, Yoichiro Kamatani, Sadaaki Takata, Chihiro Inai, Yusuke Iwasaki, Mikako Kumano, Yusuke Murakami, Shiori Komori, Dan Gao, Kentaro Kurata, Katsuhiro Hosono, Shinji Ueno, Yoshihiro Hotta, Akira Murakami, Hiroko Terasaki, Yuko Wada, Toru Nakazawa, Tatsuro Ishibashi, Yasuhiro Ikeda, Michiaki Kubo, Koh-Hei Sonoda

    Japanese journal of ophthalmology   Vol. 65 ( 3 ) page: 338 - 343   2021.5

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

    PURPOSE: To investigate the regional differences in the genes and variants causing retinitis pigmentosa (RP) in Japan STUDY DESIGN: Retrospective multicenter study METHODS: In total, 1204 probands of each pedigree clinically diagnosed with nonsyndromic RP were enrolled from 5 Japanese facilities. The regions were divided into the Tohoku region, the Kanto and Chubu regions, and the Kyushu region according to the location of the hospitals where the participants were enrolled. We compared the proportions of the causative genes and the distributions of the pathogenic variants among these 3 regions. RESULTS: The proportions of genetically solved cases were 29.4% in the Tohoku region (n = 500), 29.6% in the Kanto and Chubu regions (n = 196), and 29.7% in the Kyushu region (n = 508), which did not differ statistically (P = .99). No significant regional differences in the proportions of each causative gene in genetically solved patients were observed after correction by multiple testing. Among the 29 pathogenic variants detected in all 3 regions, only p.(Pro347Leu) in RHO was an autosomal dominant variant; the remaining 28 variants were found in autosomal recessive genes. Conversely, 78.6% (275/350) of the pathogenic variants were detected only in a single region, and 6 pathogenic variants (p.[Asn3062fs] in EYS, p.[Ala315fs] in EYS, p.[Arg872fs] in RP1, p.[Ala126Val] in RDH12, p.[Arg41Trp] in CRX, and p.[Gly381fs] in PRPF31) were frequently found in ≥ 4 patients in the single region. CONCLUSION: We observed region-specific pathogenic variants in the Japanese population. Further investigations of causative genes in multiple regions in Japan will contribute to the expansion of the catalog of genetic variants causing RP.

    DOI: 10.1007/s10384-021-00824-w

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  24. A hypomorphic variant in EYS detected by genome-wide association study contributes toward retinitis pigmentosa. International journal

    Koji M Nishiguchi, Fuyuki Miya, Yuka Mori, Kosuke Fujita, Masato Akiyama, Takashi Kamatani, Yoshito Koyanagi, Kota Sato, Toru Takigawa, Shinji Ueno, Misato Tsugita, Hiroshi Kunikata, Katarina Cisarova, Jo Nishino, Akira Murakami, Toshiaki Abe, Yukihide Momozawa, Hiroko Terasaki, Yuko Wada, Koh-Hei Sonoda, Carlo Rivolta, Tatsuhiko Tsunoda, Motokazu Tsujikawa, Yasuhiro Ikeda, Toru Nakazawa

    Communications biology   Vol. 4 ( 1 ) page: 140 - 140   2021.1

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

    The genetic basis of Japanese autosomal recessive retinitis pigmentosa (ARRP) remains largely unknown. Herein, we applied a 2-step genome-wide association study (GWAS) in 640 Japanese patients. Meta-GWAS identified three independent peaks at P < 5.0 × 10-8, all within the major ARRP gene EYS. Two of the three were each in linkage disequilibrium with a different low frequency variant (allele frequency < 0.05); a known founder Mendelian mutation (c.4957dupA, p.S1653Kfs*2) and a non-synonymous variant (c.2528 G > A, p.G843E) of unknown significance. mRNA harboring c.2528 G > A failed to restore rhodopsin mislocalization induced by morpholino-mediated knockdown of eys in zebrafish, consistent with the variant being pathogenic. c.2528 G > A solved an additional 7.0% of Japanese ARRP cases. The third peak was in linkage disequilibrium with a common non-synonymous variant (c.7666 A > T, p.S2556C), possibly representing an unreported disease-susceptibility signal. GWAS successfully unraveled genetic causes of a rare monogenic disorder and identified a high frequency variant potentially linked to development of local genome therapeutics.

    DOI: 10.1038/s42003-021-01662-9

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  25. RETINAL SENSITIVITY AND VESSEL DENSITY AFTER MACULAR HOLE SURGERY WITH THE SUPERIOR INVERTED INTERNAL LIMITING MEMBRANE FLAP TECHNIQUE. Reviewed International journal

    Hiroshi Kunikata, Masayuki Yasuda, Naoko Aizawa, Urara Osada, Koji M Nishiguchi, Toshiaki Abe, Toru Nakazawa

    Retina (Philadelphia, Pa.)   Vol. 41 ( 1 ) page: 45 - 53   2021.1

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    PURPOSE: To evaluate retinal vessel density and retinal sensitivity (RS) after macular hole surgery with the superior inverted internal limiting membrane flap technique. METHODS: Retrospective, observational case series. Twenty-one patients with idiopathic macular hole underwent 27-gauge vitrectomy with the superior inverted internal limiting membrane flap technique and triamcinolone acetonide. Measurements included RS, which was measured with microperimetry, as well as retinal vessel density in the superficial capillary plexus (SCP) and deep capillary plexus (DCP), which was measured with optical coherence tomography angiography. All parameters were evaluated in the superior and inferior sectors of the macula preoperatively and 1, 3, and 6 months postoperatively. RESULTS: Six months postoperatively, retinal thickness in the inferior sector was unchanged, but retinal thickness in the superior sector decreased significantly (P < 0.01). SCP vessel density in both sectors was unchanged at all postoperative time points. DCP vessel density in both sectors increased very significantly at 3 months (P < 0.01) and returned to baseline at 6 months. RS in the inferior sector increased by 47% 3 months postoperatively and by 61% 6 months postoperatively (P < 0.05 and P < 0.001, respectively), but RS in the superior sector increased only at 6 months postoperatively and only by 22% (P < 0.05). CONCLUSION: Lower recovery of RS in the superior sector suggests that internal limiting membrane peeling might affect the postoperative visual function.

    DOI: 10.1097/IAE.0000000000002839

    PubMed

  26. Ocular microcirculation changes, measured with laser speckle flowgraphy and optical coherence tomography angiography, in branch retinal vein occlusion with macular edema treated by ranibizumab. International journal

    Toshifumi Asano, Hiroshi Kunikata, Masayuki Yasuda, Koji M Nishiguchi, Toshiaki Abe, Toru Nakazawa

    International ophthalmology   Vol. 41 ( 1 ) page: 151 - 162   2021.1

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    PURPOSE: This study searched for early predictive vascular biomarkers for visual outcomes in eyes with macular edema caused by branch retinal vein occlusion (BRVOME). METHODS: Twenty-four eyes of 24 subjects with BRVOME were treated with the intravitreal injection of ranibizumab (IVR) for at least 6 months. We measured mean blur rate (MBR) in the optic nerve head (ONH) and vessel density (VD) in the macula with laser speckle flowgraphy and optical coherence tomography angiography, respectively. RESULTS: Six-month post-IVR best-corrected visual acuity (BCVA) was correlated positively with age, pre-IVR BCVA, 1-month post-IVR BCVA, 3-month post-IVR BCVA and pre-IVR systolic blood pressure (P < 0.001, P < 0.001, P < 0.001, P < 0.001 and P = 0.02, respectively) and negatively with pre-IVR overall MBR, 1-month post-IVR overall MBR, 6-month post-IVR overall MBR, 3-month post-IVR deep retinal capillary plexus (DCP) VD and 6-month post-IVR DCP VD (P = 0.03, P = 0.03, P = 0.02, P = 0.01 and P = 0.005, respectively). Furthermore, a multiple regression analysis showed that pre-IVR overall MBR (β =  - 0.67, P = 0.009) was among independent prognostic factors predicting 6-month post-IVR BCVA. Six-month post-IVR DCP VD was also correlated with overall MBR at all time points. CONCLUSION: ONH blood flow may be a pre-IVR biomarker of both visual outcomes and post-IVR deep macular microcirculation in eyes with BRVOME.

    DOI: 10.1007/s10792-020-01562-7

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  27. Companion diagnosis for retinal neuroprotective treatment by real-time imaging of calpain activation using a novel fluorescent probe. Reviewed International journal

    Toshifumi Asano, Yuri Nagayo, Satoru Tsuda, Azusa Ito, Wataru Kobayashi, Kosuke Fujita, Kota Sato, Koji M Nishiguchi, Hiroshi Kunikata, Hiroyoshi Fujioka, Mako Kamiya, Yasuteru Urano, Toru Nakazawa

    Bioconjugate chemistry   Vol. 31 ( 9 ) page: 2241 - 2251   2020.9

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    Calpain activation induces retinal ganglion cell (RGC) death, while calpain inhibition suppresses RGC death, in animal studies. However, the role of calpain in human retinal disease is unclear. This study investigated a new strategy to study the role of calpain based on real-time imaging. We synthesized a novel fluorescent probe for calpain, acetyl-L-leucyl-L-methionine-hydroxymethyl rhodamine green (Ac-LM-HMRG) and used it for real-time imaging of calpain activation. The toxicity of Ac-LM-HMRG was evaluated with a lactate dehydrogenase (LDH) cytotoxicity assay, retinal sections, and electroretinograms (ERG). Here, we performed real-time imaging of calpain activation in a rat model. First, we administered N-methyl-D-aspartate (NMDA) to induce retinal injury. Twenty minutes later, we administered an intravitreal injection of Ac-LM-HMRG. Real-time imaging was then completed with a non-invasive confocal scanning laser ophthalmoscope. The inhibitory effect of SNJ-1945 against calpain activation was also examined with the same real-time imaging method. Ac-LM-HMRG had no toxic effects. The number of Ac-LM-HMRG-positive cells in real-time imaging significantly increased after NMDA injury, and SNJ-1945 significantly lowered the number of Ac-LM-HMRG-positive cells. Real-time imaging with Ac-LM-HMRG was able to quickly quantify the NMDA-induced activation of calpain and the inhibitory effect of SNJ-1945. This technique, used as a companion diagnostic system, may aid research into the development of new neuroprotective therapies.

    DOI: 10.1021/acs.bioconjchem.0c00435

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  28. Serum anti-recoverin antibodies is found in elderly patients with retinitis pigmentosa and cancer. Reviewed International journal

    Taimu Sato, Koji M Nishiguchi, Kosuke Fujita, Fuyuki Miya, Takashi Inoue, Erika Sasaki, Toshifumi Asano, Satoru Tsuda, Yukihiro Shiga, Hiroshi Kunikata, Mitsuru Nakazawa, Toru Nakazawa

    Acta ophthalmologica   Vol. 98 ( 6 ) page: e722 - e729   2020.9

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    PURPOSE: To screen for anti-recoverin antibodies in elderly patients with retinitis pigmentosa (RP) with or without cancer and cross-sectionally characterize the seropositive patients clinically. METHODS: Serum from 75 RP patients who had been tested for mutations in a panel of 83 RP genes and 73 normal controls, all aged 50-80 years, were screened for anti-recoverin antibodies by Western blot using recombinant recoverin, retinal lysate from a marmoset and commercial anti-recoverin antibodies as a control. RESULTS: Three RP patients with typical pigmentary degeneration of the 75 (4.0%) were seropositive for anti-recoverin antibody. Pathogenic mutations were identified in two seropositive RP patients. All three patients had visual impairment since childhood and were diagnosed as RP by the age of 30. The severity of the retinopathy varied greatly among these three patients, ranging in visual acuity from light perception OU to 20/30 OU. Retinitis pigmentosa (RP) patients with a history of cancer were more likely to have anti-recoverin antibodies (3/14; 21.4%) than those without (0/61; 0%; p = 0.005, Fischer exact test). All 73 healthy controls with no history of cancer were also seronegative. CONCLUSION: Our results show that serum anti-recoverin antibodies can be detected in typical RP patients with identified pathogenic mutations and that a history of cancer may increase the risk of developing anti-recoverin antibodies.

    DOI: 10.1111/aos.14373

    PubMed

  29. Successful surgical outcomes after 23-, 25- and 27-gauge vitrectomy without scleral encircling for giant retinal tear. Reviewed

    Hiroshi Kunikata, Naoko Aizawa, Risa Sato, Koji M Nishiguchi, Toshiaki Abe, Toru Nakazawa

    Japanese journal of ophthalmology   Vol. 64 ( 5 ) page: 506 - 515   2020.9

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    PURPOSE: Retinal detachment due to giant retinal tears (GRTs), tears larger than 90°, is rare and difficult to treat. Here, we show and compare surgical results of 23-, 25- and 27-gauge (G) micro-incision vitrectomy surgery (MIVS) for GRT. STUDY DESIGN: Retrospective and interventional case series. METHODS: Retrospective review of 41 eyes of 38 patients with GRT who underwent MIVS. Surgical outcomes after MIVS, including reattachment rates and postoperative complications, were compared between instrument gauges. All patients were followed for at least 6 months postoperatively. RESULTS: MIVS with 23G, 25G and 27G instruments was performed in 7, 19 and 15 eyes, respectively. Silicone oil (SO) was used in 34 of 41 eyes (83%) with a mean removal time of 43.8 days after first surgery. Best-corrected visual acuity (BCVA) was recovered or maintained in 39 eyes (95%). Reattachment was attained after initial surgery in 38 of 41 eyes (93%) (23G: 6/7 [86%]; 25G: 17/19 [89%]; 27G: 15/15 [100%]). Final reattachment was eventually achieved in all eyes (two eyes needed support from scleral encircling). Postoperative complications occurred in 16 eyes (39%) (23G: 3/7 [43%]; 25G: 8/19 [42%]; 27G: 5/15 [33%]), including macular pucker, cystoid macular edema, macular hole, subretinal perfluorocarbon liquid, retinal folds, vitreous hemorrhage and redetachment. There were no significant differences between the three groups in rate of high myopia, GRT size, operation time, phacovitrectomy rate, SO usage rate, initial reattachment rate, final reattachment rate, preoperative BCVA, final BCVA or rate of postoperative complications. CONCLUSION: Despite occasional postoperative complications, primary MIVS, regardless of gauge size, appears to be a safe and feasible option for GRT surgery.

    DOI: 10.1007/s10384-020-00755-y

    PubMed

  30. Clinical characteristics and high resolution retinal imaging of retinitis pigmentosa caused by RP1 gene variants. Reviewed

    Shinji Ueno, Yoshito Koyanagi, Taro Kominami, Yasuki Ito, Kenichi Kawano, Koji M Nishiguchi, Carlo Rivolta, Toru Nakazawa, Koh-Hei Sonoda, Hiroko Terasaki

    Japanese journal of ophthalmology   Vol. 64 ( 5 ) page: 485 - 496   2020.9

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    PURPOSE: To report the clinical course and high resolution images of autosomal recessive retinitis pigmentosa (RP) associated with a variant of the RP1 gene (c.4052_4053ins328/p.Tyr1352Alafs*9; m1), a high frequency founder variant in Japanese RP patients. STUDY DESIGN: Retrospective case series. METHODS: Nine patients from 5 unrelated Japanese families were studied. Five patients had the m1 variant homozygously, and 4 patients had the m1 variant compound heterozygously with another frameshift variant (c.4196delG/p.Cys1399Leufs*5). Ophthalmic examinations including adaptive optics (AO) fundus imaging were performed periodically. RESULTS: The fundus photographs, fundus autofluorescence (FAF) images, and optical coherence tomographic (OCT) images indicated severe retinal degeneration in all the patients involving the macula even at a young age (20 s). The areas of surviving photoreceptors in the central macula were seen as hyper-autofluorescent regions in the FAF images and preserved outer retinal structure in the OCT images; they were identifiable in the AO fundus images in 8 eyes. The borders of the surviving photoreceptor areas were surrounded by hyporeflective clumps, presumably containing melanin, and the size of these areas decreased progressively during the 4-year follow-up period. The disappearance of the surviving photoreceptor areas was associated with complete blindness. CONCLUSION: Patients with RP associated with the m1 variant have a progressive and severe retinal degeneration that begins at an early age. Monitoring the surviving photoreceptor areas by AO fundus imaging can provide a more precise pathological record of retinal degeneration.

    DOI: 10.1007/s10384-020-00752-1

    Web of Science

    Scopus

    PubMed

  31. Association of retinal vessel density with retinal sensitivity in surgery for idiopathic epiretinal membrane. Reviewed International journal

    Urara Osada, Hiroshi Kunikata, Masayuki Yasuda, Kazuki Hashimoto, Koji M Nishiguchi, Toru Nakazawa

    Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie   Vol. 258 ( 9 ) page: 1911 - 1920   2020.9

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    PURPOSE: The success of surgical treatment for idiopathic epiretinal membrane (ERM) is measured by postoperative best-corrected visual acuity (BCVA), metamorphopsia, and foveal retinal sensitivity (RS).This study searched for predictive biomarkers of surgical success by determining the association between foveal RS and various aspects of vessel density (VD) in the fovea of patients with ERM. METHODS: The study examined 25 eyes of 25 patients with ERM who underwent 27-gauge microincision vitrectomy surgery (MIVS). RS was measured with microperimetry (MP-3; NIDEK) at four central points in the fovea with an interpoint distance of 2°. VD was measured with SD-OCT (RS 3000; NIDEK) within the 1-mm2 square defined by the 4 RS points at various depths, including the superficial and deep retinal capillary plexus (SCP and DCP, respectively). RESULTS: Though VD did not change throughout the follow-up period, BCVA and RS significantly improved 1 and 3 months after surgery, respectively (both P < 0.0017). Postoperative RS at 6 months was positively correlated with postoperative DCP VD at 1, 3, and 6 months (r = 0.62, P = 0.001; r = 0.40, P = 0.049; r = 0.53, P = 0.007, respectively), but not with SCP VD at any time point. Multiple regression analysis confirmed that postoperative RS at 6 months was associated with postoperative DCP VD at 1 month (P = 0.03). CONCLUSION: Higher postoperative DCP VD at 1 month contributed to better postoperative foveal RS at 6 months. Early postoperative VD in the fovea might be a useful predictive biomarker of late postoperative RS in the fovea in ERM patients.

    DOI: 10.1007/s00417-020-04754-0

    PubMed

  32. Effect of the chemical structure on the drug release from brinzolamide based nano eye-drops

    Yoshitaka Koseki, Yoshikazu Ikuta, Kota Sato, Shigenobu Aoyagi, Satoshi Inada, Tsunenobu Onodera, Hidetoshi Oikawa, Koji M. Nishiguchi, Toru Nakazawa, Hitoshi Kasai

    Molecular Crystals and Liquid Crystals   Vol. 706 ( 1 ) page: 122 - 128   2020.7

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    DOI: 10.1080/15421406.2020.1743447

  33. Systemic oxidative stress level in patients with central serous chorioretinopathy. Reviewed International journal

    Hiroshi Kunikata, Risa Sato, Koji M Nishiguchi, Toru Nakazawa

    Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie   Vol. 258 ( 7 ) page: 1575 - 1577   2020.7

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    DOI: 10.1007/s00417-020-04664-1

    PubMed

  34. Genetic variants associated with the onset and progression of primary open-angle glaucoma. Reviewed International journal

    Fumihiko Mabuchi, Nakako Mabuchi, Yoichi Sakurada, Seigo Yoneyama, Kenji Kashiwagi, Hiroyuki Iijima, Zentaro Yamagata, Mitsuko Takamoto, Makoto Aihara, Takeshi Iwata, Kazuki Hashimoto, Kota Sato, Yukihiro Shiga, Koji M Nishiguchi, Toru Nakazawa, Masato Akiyama, Kazuhide Kawase, Mineo Ozaki, Makoto Araie

    American journal of ophthalmology   Vol. 215   page: 135 - 140   2020.7

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    PURPOSE: To investigate the genetic variants associated with the onset and progression of primary open-angle glaucoma (POAG). DESIGN: Case-control genetic association study. METHODS: Japanese POAG patients (n=505) and control subjects (n=246) were genotyped for 22 genetic variants predisposing to POAG that can be classified into those associated with intraocular pressure (IOP) elevation (IOP-related genetic variants) and optic nerve vulnerability independent of IOP (non-IOP-related genetic variants). The total number of risk alleles of the 17 IOP-related and 5 non-IOP-related genetic variants were calculated as the genetic risk score (GRS), and the associations between the GRS and family history of glaucoma as an indicator of POAG onset and age at the diagnosis of glaucoma as an indicator of POAG progression were evaluated. RESULTS: There was a significant association (P=0.014, odds ratio: 1.26 per GRS) between the non-IOP-related GRS, but not IOP-related GRS, and a family history of glaucoma in POAG. As the non-IOP-related GRS increased, the risk of a family history of glaucoma increased. In contrast, a significant association (P=0.0014, Beta=-0.14) was found between the IOP-related GRS, but not non-IOP-related GRS, and age at the diagnosis of glaucoma. As the IOP-related GRS increased, age at the diagnosis of glaucoma decreased. CONCLUSIONS: The results indicate that non-IOP-related (optic nerve vulnerability) rather than IOP-related (IOP elevation) genetic variants may play an important role in the onset of POAG (family history of glaucoma) and that IOP-related rather than non-IOP-related genetic variants may play an important role its progression (age at the diagnosis of glaucoma).

    DOI: 10.1016/j.ajo.2020.03.014

    PubMed

  35. Association of CRX genotypes and retinal phenotypes confounded by variable expressivity and electronegative electroretinogram. Reviewed International journal

    Koji M Nishiguchi, Hiroshi Kunikata, Kosuke Fujita, Kazuki Hashimoto, Yoshito Koyanagi, Masato Akiyama, Yasuhiro Ikeda, Yukihide Momozawa, Koh-Hei Sonoda, Akira Murakami, Yuko Wada, Toru Nakazawa

    Clinical & experimental ophthalmology   Vol. 48 ( 5 ) page: 644 - 657   2020.7

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    IMPORTANCE: A framework for understanding the phenotypic features of CRX retinopathy was established. BACKGROUND: To perform a phenotype-genotype correlation analysis in two groups of patients with heterozygous mutations in distinct locations of the CRX gene, encoding the cone-rod homeobox. DESIGN: Multicentre retrospective study. PARTICIPANTS: Twenty-one Japanese patients from 14 families with a heterozygous CRX mutation. METHODS: Retrospective data analysis. MAIN OUTCOME MEASURES: Clinical records on CRX mutation, symptoms, best-corrected visual acuity (BCVA), visual field, fundus photography, fundus auto-fluorescence, optical coherence tomography and electroretinograms (ERGs). RESULTS: Six different CRX heterozygous mutations were identified in the subjects. Twelve patients from 9 families shared the p.R41W mutation and 1 patient had the p.R43C mutation, both of which affect the homeobox domain of CRX. These patients often displayed adult-onset retinal dystrophy with macular degeneration. In contrast, five patients with downstream mutations (p.S204fs, p.S213fs, p.G243X and p.L299F) displayed retinal degeneration or macular degeneration with bone-spicule pigmentation. Three asymptomatic carriers with different mutations (p.R41W, p.S213fs and p.G243X) were present in both groups. Nearly all patients and carriers had an electronegative ERG in response to a bright flash under dark adaptation. There was no cross-sectional association between patients' age and BCVA, despite progressive decline in BCVA. CONCLUSIONS AND RELEVANCE: Heterozygous mutations within or downstream of the homeobox domain in CRX relate to the difference associated retinal phenotypes, which was confounded by variable expressivity and electronegative ERGs. CRX mutations should be considered in patients with an electronegative ERG with minimal or no macular changes.

    DOI: 10.1111/ceo.13743

    PubMed

  36. A founder Alu insertion in RP1 gene in Japanese patients with retinitis pigmentosa.

    Nishiguchi KM, Fujita K, Ikeda Y, Kunikata H, Koyanagi Y, Akiyama M, Abe T, Wada Y, Sonoda KH, Nakazawa T

    Japanese journal of ophthalmology   Vol. 64 ( 4 ) page: 346 - 350   2020.7

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    DOI: 10.1007/s10384-020-00732-5

    PubMed

  37. SAG変異を病因とする小口病と網膜色素変性の臨床表現型比較

    西口 康二, 池田 康博, 細野 克博, 和田 裕子, 園田 康平, 堀田 喜裕, 村上 晶, 中澤 満, 中澤 徹, 阿部 俊明

    眼科臨床紀要   Vol. 13 ( 7 ) page: 490 - 490   2020.7

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  38. Signs of Oguchi Disease and Pigmentary Degeneration from Early in Life. Reviewed International journal

    Koji M Nishiguchi, Hiroshi Kunikata, Toru Nakazawa

    Ophthalmology   Vol. 127 ( 6 ) page: 825 - 825   2020.6

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    DOI: 10.1016/j.ophtha.2020.02.020

    PubMed

  39. 経角膜硝子体切除を併用した眼内レンズ強膜内固定術3症例の検討 Reviewed

    新田 文彦, 國方 彦志, 大友 孝昭, 西口 康二, 阿部 俊明, 中澤 徹

    臨床眼科   Vol. 74 ( 5 ) page: 582 - 588   2020.5

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    <文献概要>目的:落屑症候群ではチン小帯脆弱のため眼内レンズ強膜内固定術を要することが多いが,長期的には緑内障濾過手術も必要になりやすいため,硝子体切除術を併施する際にも結膜と強膜への侵襲は最小限にとどめたい。今回,眼内レンズ強膜内固定術の際の硝子体切除術を経角膜で行った落屑症候群3症例を報告する。対象と方法:対象は落屑症候群の3症例(男性1例,女性2例,平均年齢84歳)で,中間透光体は白内障2例,眼内レンズ亜脱臼1例であり,いずれにも水晶体振盪があった。術前の矯正視力は0.2〜0.5であった。これらに対して硝子体手術装置を用い経角膜硝子体切除を併施した強膜内固定術(ダブルニードルテクニックを用いたフランジ法)を行った。結果:白内障眼2例の硝子体切除は経角膜的に行うことができた。眼内レンズ亜脱臼の1例では術中に眼内レンズが眼底後極に落下し,後極操作の際に非接触式広角眼底観察システムに硝子体鑷子が干渉したため,経毛様体扁平部硝子体切除術に移行した。最終的に,全例で強膜内固定術を行えた。術後の矯正視力は0.6〜0.9と全例で改善した。全例で一時的に高眼圧(22〜28mmHg)となり,降圧点眼加療を要したことと,軽度の角膜浮腫とデスメ膜皺襞が生じた以外は合併症もなく順調に経過した。結論:将来的に緑内障手術を行う可能性がある落屑症候群などの症例での硝子体切除は,結膜強膜保護の観点から経角膜アプローチは利点があると思われる。現在のサイズの接触レンズや非接触式広角眼底観察システムを用いた手術では後極の操作に難があり,安全,かつスムースに行えない可能性があるため,さらなる工夫が必要と思われた。

  40. 経角膜硝子体切除を併用した眼内レンズ強膜内固定術3症例の検討

    新田 文彦, 國方 彦志, 大友 孝昭, 西口 康二, 阿部 俊明, 中澤 徹

    臨床眼科   Vol. 74 ( 5 ) page: 582 - 588   2020.5

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    Language:Japanese   Publisher:(株)医学書院  

    <文献概要>目的:落屑症候群ではチン小帯脆弱のため眼内レンズ強膜内固定術を要することが多いが,長期的には緑内障濾過手術も必要になりやすいため,硝子体切除術を併施する際にも結膜と強膜への侵襲は最小限にとどめたい。今回,眼内レンズ強膜内固定術の際の硝子体切除術を経角膜で行った落屑症候群3症例を報告する。対象と方法:対象は落屑症候群の3症例(男性1例,女性2例,平均年齢84歳)で,中間透光体は白内障2例,眼内レンズ亜脱臼1例であり,いずれにも水晶体振盪があった。術前の矯正視力は0.2〜0.5であった。これらに対して硝子体手術装置を用い経角膜硝子体切除を併施した強膜内固定術(ダブルニードルテクニックを用いたフランジ法)を行った。結果:白内障眼2例の硝子体切除は経角膜的に行うことができた。眼内レンズ亜脱臼の1例では術中に眼内レンズが眼底後極に落下し,後極操作の際に非接触式広角眼底観察システムに硝子体鑷子が干渉したため,経毛様体扁平部硝子体切除術に移行した。最終的に,全例で強膜内固定術を行えた。術後の矯正視力は0.6〜0.9と全例で改善した。全例で一時的に高眼圧(22〜28mmHg)となり,降圧点眼加療を要したことと,軽度の角膜浮腫とデスメ膜皺襞が生じた以外は合併症もなく順調に経過した。結論:将来的に緑内障手術を行う可能性がある落屑症候群などの症例での硝子体切除は,結膜強膜保護の観点から経角膜アプローチは利点があると思われる。現在のサイズの接触レンズや非接触式広角眼底観察システムを用いた手術では後極の操作に難があり,安全,かつスムースに行えない可能性があるため,さらなる工夫が必要と思われた。

    Other Link: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J01537&link_issn=&doc_id=20200525220013&doc_link_id=10.11477%2Fmf.1410213554&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1410213554&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

  41. Endogenous endophthalmitis caused by group B streptococcus; case reports and review of 35 reported cases. Reviewed International journal

    Masaaki Yoshida, Shunji Yokokura, Takashi Nishida, Kiyofumi Mochizuki, Takashi Suzuki, Kazuichi Maruyama, Takaaki Otomo, Koji M Nishiguchi, Hiroshi Kunikata, Toru Nakazawa

    BMC ophthalmology   Vol. 20 ( 1 ) page: 126 - 126   2020.3

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    BACKGROUND: Group B streptococcus (GBS), a gram-positive coccus that occasionally causes neonatal sepsis or invasive infection in the elderly, has been considered a rare cause of endogenous bacterial endophthalmitis (EBE). However, the number of invasive GBS infections is increasing, particularly in elderly patients with underlying conditions such as diabetes mellitus (DM), cardiovascular disease and cancer. We report 6 cases of EBE caused by GBS and review the literature. METHODS: Retrospective case series and literature review. RESULTS: In the current case series, 6 eyes of 6 patients developed EBE caused by GBS. The average age was 73.5 years. The focus of infection included the urinary tract, cellulitis, arthritis, peritonitis, catheter-associated infection and endocarditis. Four patients had DM. While all 6 strains were sensitive to β-lactams (penicillins and cephems), 4 strains were resistant to levofloxacin (no data for 1 isolate). Each case was treated with the systemic antibiotic to which the individual strain was sensitive. All cases showed poor visual acuity at presentation (decimal visual acuity: less than 0.03). Vitrectomy with intravitreal antibiotics injection was performed in 4 cases. Visual acuity recovered in 4 cases and did not recover in 2 cases, even after vitrectomy. The literature review of 53 eyes of 41 patients revealed that 60% of eyes finally lost all vision, and death occurred in 2 cases. Initial visual acuity of less than counting fingers was associated with a final outcome of lost vision. Of 41 patients, 13 (32%) had DM as an underlying medical condition. The most common extra-ocular infection focus was endocarditis (37%). CONCLUSIONS: DM is common in patients with EBE caused by GBS. While the 4 cases in the current report had a relatively good visual acuity outcome, despite poor initial visual acuity, the literature review indicated that EBE caused by GBS is generally a severe condition with a poor prognosis. The current study also indicates the importance of considering the possibility of endocarditis on encountering EBE caused by GBS.

    DOI: 10.1186/s12886-020-01378-0

    PubMed

  42. 広義原発開放隅角緑内障関連遺伝子領域の多型と酸化ストレスの関係

    佐藤 正隆, 橋本 和軌, 志賀 由己浩, 二宮 高洋, 檜森 紀子, 西口 康二, 中澤 徹

    日本眼科学会雑誌   Vol. 124 ( 臨増 ) page: 236 - 236   2020.3

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  43. Single AAV-mediated mutation replacement genome editing in limited number of photoreceptors restores vision in mice. Reviewed International journal

    Koji M Nishiguchi, Kosuke Fujita, Fuyuki Miya, Shota Katayama, Toru Nakazawa

    Nature communications   Vol. 11 ( 1 ) page: 482 - 482   2020.1

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    Supplementing wildtype copies of functionally defective genes with adeno-associated virus (AAV) is a strategy being explored clinically for various retinal dystrophies. However, the low cargo limit of this vector allows its use in only a fraction of patients with mutations in relatively small pathogenic genes. To overcome this issue, we developed a single AAV platform that allows local replacement of a mutated sequence with its wildtype counterpart, based on combined CRISPR-Cas9 and micro-homology-mediated end-joining (MMEJ). In blind mice, the mutation replacement rescued approximately 10% of photoreceptors, resulting in an improvement in light sensitivity and an increase in visual acuity. These effects were comparable to restoration mediated by gene supplementation, which targets a greater number of photoreceptors. This strategy may be applied for the treatment of inherited disorders caused by mutations in larger genes, for which conventional gene supplementation therapy is not currently feasible.

    DOI: 10.1038/s41467-019-14181-3

    PubMed

  44. Exploring the Novel Susceptibility Gene Variants for Primary Open-Angle Glaucoma in East Asian Cohorts: The GLAU-GENDISK Study. Reviewed

    Kim YW, Kim YJ, Cheong HS, Shiga Y, Hashimoto K, Song YJ, Kim SH, Choi HJ, Nishiguchi KM, Kawai Y, Nagasaki M, Nakazawa T, Park KH, Kim DM, Jeoung JW

    Scientific reports   Vol. 10 ( 1 ) page: 221   2020.1

  45. In vivo imaging of the light response in mouse retinal ganglion cells based on a neuronal activity-dependent promoter. Reviewed

    Fujita K, Nishiguchi KM, Sato K, Nakagawa Y, Nakazawa T

    Biochemical and biophysical research communications   Vol. 521 ( 2 ) page: 471 - 477   2020.1

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    DOI: 10.1016/j.bbrc.2019.10.155

    PubMed

  46. Progression from Classical Oguchi Disease to Retinitis Pigmentosa after 50 Years.

    Nishiguchi KM, Oguchi Y, Nakazawa T

    Ophthalmology   Vol. 127 ( 1 ) page: 51   2020.1

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    DOI: 10.1016/j.ophtha.2019.09.015

    PubMed

  47. Progression from classical Oguchi disease to retinitis pigmentosa after 50 years Reviewed

    Nishiguchi KM, Oguchi Y, Nakazawa T

    Ophthalmology   Vol. in press   2020

  48. Phenotypic Features of Oguchi Disease and Retinitis Pigmentosa in Patients with S-Antigen Mutations: A Long-Term Follow-up Study. Reviewed International journal

    Koji M Nishiguchi, Yasuhiro Ikeda, Kosuke Fujita, Hiroshi Kunikata, Makoto Akiho, Kazuki Hashimoto, Katsuhiro Hosono, Kentaro Kurata, Yoshito Koyanagi, Masato Akiyama, Takefumi Suzuki, Ryo Kawasaki, Yuko Wada, Yoshihiro Hotta, Koh-Hei Sonoda, Akira Murakami, Mitsuru Nakazawa, Toru Nakazawa, Toshiaki Abe

    Ophthalmology   Vol. 126 ( 11 ) page: 1557 - 1566   2019.11

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    PURPOSE: To present phenotypic features of 22 patients with S-antigen (SAG) mutations. DESIGN: Retrospective cohort study. PARTICIPANTS: Twenty-one Japanese patients from 16 families with a homozygous c.924delA mutation and 1 patient with a homozygous c.636delT mutation in the SAG gene. METHODS: Clinical records on symptoms; best-corrected visual acuity; and Goldmann perimetry, fundus photography, fundus autofluorescence (FAF), OCT, and electroretinography results were reviewed. MAIN OUTCOME MEASURES: Best-corrected visual acuity, Goldmann perimetry results, imaging findings, and electroretinography results. RESULTS: Ten patients had Oguchi disease and 12 had retinitis pigmentosa (RP) with mean follow-up periods of 13.8 and 10.2 years, respectively. Retinitis pigmentosa patients were older (mean age, 56.0 years) than those with Oguchi disease (mean age, 22.1 years; P < 0.001) at the initial visit. Night blindness noted in childhood was the most common initial symptom for both Oguchi disease (80.0%) and RP (91.7%) patients. Best-corrected visual acuity in the logarithm of the minimum angle of resolution (logMAR) was well preserved in Oguchi disease patients (mean, 0.02 logMAR in both eyes) but reduced in most RP patients (mean, 1.32 logMAR [right eye] and 1.35 logMAR [left eye]). Similarly, the visual field in the retinal area was preserved in Oguchi disease patients (mean, 677 mm2 right eye and 667 mm2 left eye) and reduced in RP patients (mean, 369 mm2 right eye and 294 mm2 left eye). Fundus images revealed a characteristic golden sheen with no retinal degeneration in Oguchi disease patients, excluding 2 with macular degeneration detected by FAF, OCT, or both and 1 with mild retinal degeneration confirmed by OCT and fluorescein angiography. Pigmentary retinal degeneration most evident posteriorly was observed in RP patients, accompanied by a characteristic golden sheen in 12 of 14 patients undergoing ultra-widefield fundus imaging. OCT showed disrupted macular structure, and FAF revealed variable hypofluorescence. Electroretinography identified absent rod responses in both diseases, along with relative preservation of cone responses in Oguchi disease patients. Three patients showed progressive loss of the golden sheen based on fundus images, including 1 who demonstrated RP 26 years after the initial diagnosis of Oguchi disease. CONCLUSIONS: Retinitis pigmentosa with SAG mutations often shows a characteristic golden sheen surrounding posterior pigmentary retinal degeneration. Oguchi disease can show progressive degeneration in adulthood, rarely resulting in RP.

    DOI: 10.1016/j.ophtha.2019.05.027

    PubMed

  49. Genetic characteristics of retinitis pigmentosa in 1204 Japanese patients. Reviewed

    Koyanagi Y, Akiyama M, Nishiguchi KM, Momozawa Y, Kamatani Y, Takata S, Inai C, Iwasaki Y, Kumano M, Murakami Y, Omodaka K, Abe T, Komori S, Gao D, Hirakata T, Kurata K, Hosono K, Ueno S, Hotta Y, Murakami A, Terasaki H, Wada Y, Nakazawa T, Ishibashi T, Ikeda Y, Kubo M, Sonoda KH

    Journal of medical genetics   Vol. 56 ( 10 ) page: 662 - 670   2019.10

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    <sec><title>Background</title>The genetic profile of retinitis pigmentosa (RP) in East Asian populations has not been well characterised. Therefore, we conducted a large-scale sequencing study to investigate the genes and variants causing RP in a Japanese population.

    </sec><sec><title>Methods</title>A total of 1209 Japanese patients diagnosed with typical RP were enrolled. We performed deep resequencing of 83 known causative genes of RP using next-generation sequencing. We defined pathogenic variants as those that were putatively deleterious or registered as pathogenic in the Human Gene Mutation Database or ClinVar database and had a minor allele frequency in any ethnic population of ≤0.5% for recessive genes or ≤0.01% for dominant genes as determined using population-based databases.

    </sec><sec><title>Results</title>We successfully sequenced 1204 patients with RP and determined 200 pathogenic variants in 38 genes as the cause of RP in 356 patients (29.6%). Variants in six genes (<italic>EYS</italic>, <italic>USH2A</italic>, <italic>RP1L1</italic>, <italic>RHO</italic>, <italic>RP1</italic> and <italic>RPGR</italic>) caused RP in 65.4% (233/356) of those patients. Among autosomal recessive genes, two known founder variants in <italic>EYS</italic> [p.(Ser1653fs) and p.(Tyr2935*)] and four East Asian-specific variants [p.(Gly2752Arg) in <italic>USH2A</italic>, p.(Arg658*) in <italic>RP1L1</italic>, p.(Gly2186Glu) in <italic>EYS</italic> and p.(Ile535Asn) in <italic>PDE6B</italic>] and p.(Cys934Trp) in <italic>USH2A</italic> were found in ≥10 patients. Among autosomal dominant genes, four pathogenic variants [p.(Pro347Leu) in <italic>RHO</italic>, p.(Arg872fs) in <italic>RP1</italic>, p.(Arg41Trp) in <italic>CRX</italic> and p.(Gly381fs) in <italic>PRPF31</italic>] were found in ≥4 patients, while these variants were unreported or extremely rare in both East Asian and non-East Asian population-based databases.

    </sec><sec><title>Conclusions</title>East Asian-specific variants in causative genes were the major causes of RP in the Japanese population.

    </sec>

    DOI: 10.1136/jmedgenet-2018-105691

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  50. 開放隅角緑内障1家系におけるOPTN遺伝子の新規N51T変異の同定

    前川 重人, 橋本 和軌, 志賀 由己浩, 津田 聡, 面高 宗子, 横山 悠, 西口 康二, 中澤 徹, 日本緑内障学会遺伝子研究班

    日本緑内障学会抄録集   Vol. 30回   page: 184 - 184   2019.9

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  51. A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy. Reviewed International journal

    Nikopoulos K, Cisarova K, Quinodoz M, Koskiniemi-Kuendig H, Miyake N, Farinelli P, Rehman AU, Khan MI, Prunotto A, Akiyama M, Kamatani Y, Terao C, Miya F, Ikeda Y, Ueno S, Fuse N, Murakami A, Wada Y, Terasaki H, Sonoda KH, Ishibashi T, Kubo M, Cremers FPM, Kutalik Z, Matsumoto N, Nishiguchi KM, Nakazawa T, Rivolta C

    Nature communications   Vol. 10 ( 1 ) page: 2884 - 2884   2019.6

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    Hereditary retinal degenerations (HRDs) are Mendelian diseases characterized by progressive blindness and caused by ultra-rare mutations. In a genomic screen of 331 unrelated Japanese patients, we identify a disruptive Alu insertion and a nonsense variant (p.Arg1933*) in the ciliary gene RP1, neither of which are rare alleles in Japan. p.Arg1933* is almost polymorphic (frequency = 0.6%, amongst 12,000 individuals), does not cause disease in homozygosis or heterozygosis, and yet is significantly enriched in HRD patients (frequency = 2.1%, i.e., a 3.5-fold enrichment; p-value = 9.2 × 10-5). Familial co-segregation and association analyses show that p.Arg1933* can act as a Mendelian mutation in trans with the Alu insertion, but might also associate with disease in combination with two alleles in the EYS gene in a non-Mendelian pattern of heredity. Our results suggest that rare conditions such as HRDs can be paradoxically determined by relatively common variants, following a quasi-Mendelian model linking monogenic and complex inheritance.

    DOI: 10.1038/s41467-019-10746-4

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  52. Quantitative analysis of the macula with optical coherence tomography angiography in normal Japanese subjects: The Taiwa Study. Reviewed International journal

    Risa Sato, Hiroshi Kunikata, Toshifumi Asano, Naoko Aizawa, Naoki Kiyota, Yukihiro Shiga, Koji M Nishiguchi, Keiichi Kato, Toru Nakazawa

    Scientific reports   Vol. 9 ( 1 ) page: 8875 - 8875   2019.6

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    This study evaluated age-related changes in the superficial and deep retinal capillary plexus (SCP and DCP, respectively) and in the foveal avascular zone (FAZ). SCP and DCP perfusion density (PD) were measured in optical coherence tomography angiography (OCTA) macular scans of 145 eyes of 145 healthy Japanese subjects, and findings were compared with SCP FAZ and clinical data. We found that age was negatively correlated with SCP and DCP PD (r = -0.17, P = 0.04 and r = -0.20, P = 0.02, respectively) and positively correlated with FAZ area (r = 0.18, P = 0.03). SCP and DCP PD were correlated with each other (r = 0.67, P < 0.001). FAZ area was negatively correlated with SCP PD, DCP PD and central macular thickness (CMT) (r = -0.18, P = 0.03; r = -0.25, P < 0.01; and r = -0.39, P < 0.001, respectively). FAZ was larger and CMT was lower (P = 0.01 and P < 0.001, respectively) in women than men. SCP and DCP PD were positively correlated with estimated glomerular filtration rate (r = 0.17, P = 0.03 and r = 0.24, P < 0.01, respectively). Multiple regression analysis confirmed that age independently affected DCP PD and FAZ (P = 0.02 and P < 0.01, respectively) and that CMT independently affected FAZ area (P < 0.001). Thus, normal subjects showed age-related decreases in macular PD and renal function. FAZ and CMT were related, suggesting that age-related changes in macular thickness also affect capillary vasculature.

    DOI: 10.1038/s41598-019-45336-3

    PubMed

  53. Correlation between aqueous flare and residual visual field area in retinitis pigmentosa. Reviewed International journal

    Koji M Nishiguchi, Yu Yokoyama, Hiroshi Kunikata, Toshiaki Abe, Toru Nakazawa

    The British journal of ophthalmology   Vol. 103 ( 4 ) page: 475 - 480   2019.4

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    BACKGROUND/AIMS: To investigate the relationship between aqueous flare, visual function and macular structures in retinitis pigmentosa (RP). METHODS: Clinical data from 123 patients with RP (227 eyes), 35 patients with macular dystrophy (68 eyes) and 148 controls (148 eyes) were analysed. The differences in aqueous flare between clinical entities and the correlation between aqueous flare (measured with a laser flare cell meter) versus visual acuity, visual field area (Goldmann perimetry) and macular thickness (optical coherence tomography) in patients with RP were determined. Influence of selected clinical data on flare was assessed using linear mixed-effects model. RESULTS: Aqueous flare was higher in patients with RP than patients with macular dystrophy or controls (p=7.49×E-13). Aqueous flare was correlated with visual field area (R=-0.379, p=3.72×E-9), but not with visual acuity (R=0.083, p=0.215). Macular thickness (R=0.234, p=3.74×E-4), but not foveal thickness (R=0.122, p=0.067), was positively correlated with flare. Flare was not affected by the presence of macular complications. All these associations were maintained when the right and the left eyes were assessed separately. Analysis by linear mixed-effects model revealed that age (p=8.58×E-5), visual field area (p=8.01×E-7) and average macular thickness (p=0.037) were correlated with flare. CONCLUSION: Aqueous flare and visual field area were correlated in patients with RP. Aqueous flare may reflect the degree of overall retinal degeneration more closely than the local foveal impairment.

    DOI: 10.1136/bjophthalmol-2018-312225

    PubMed

  54. Macular Dystrophy and Cone-Rod Dystrophy Caused by Mutations in the RP1 Gene: Extending the RP1 Disease Spectrum. Reviewed

    Verbakel SK, van Huet RAC, den Hollander AI, Geerlings MJ, Kersten E, Klevering BJ, Klaver CCW, Plomp AS, Wesseling NL, Bergen AAB, Nikopoulos K, Rivolta C, Ikeda Y, Sonoda KH, Wada Y, Boon CJF, Nakazawa T, Hoyng CB, Nishiguchi KM

    Investigative ophthalmology & visual science   Vol. 60 ( 4 ) page: 1192 - 1203   2019.3

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  55. Macular degeneration as a common cause of visual loss in spinocerebellar ataxia type 1 (SCA1) patients. Reviewed

    Nishiguchi KM, Aoki M, Nakazawa T, Abe T

    Ophthalmic genetics   Vol. 40 ( 1 ) page: 49 - 53   2019.2

  56. Alternative methods to detect anti-TRPM1 antibodies. Reviewed

    Nishiguchi KM, Fujita K, Inoue T, Nakazawa T

    Clinical & experimental ophthalmology   Vol. 47 ( 1 ) page: 148 - 149   2019.1

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  57. Anti-TRPM1 antibodies in patients with retinal degeneration. Reviewed

    Nishiguchi KM, Fujita K, Inoue T, Nakazawa T

    Clinical & experimental ophthalmology   Vol. 46 ( 9 ) page: 1087 - 1089   2018.12

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  58. Reliable detection of low visual acuity in mice with pattern visually evoked potentials. Reviewed

    Tokashiki N, Nishiguchi KM, Fujita K, Sato K, Nakagawa Y, Nakazawa T

    Scientific reports   Vol. 8 ( 1 ) page: 15948   2018.10

  59. Retained Plasticity and Substantial Recovery of Rod-Mediated Visual Acuity at the Visual Cortex in Blind Adult Mice with Retinal Dystrophy. Reviewed

    Nishiguchi KM, Fujita K, Tokashiki N, Komamura H, Takemoto-Kimura S, Okuno H, Bito H, Nakazawa T

    Molecular therapy : the journal of the American Society of Gene Therapy   Vol. 26 ( 10 ) page: 2397 - 2406   2018.10

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  60. Metabolomic changes in the mouse retina after optic nerve injury. Reviewed International journal

    Kota Sato, Daisuke Saigusa, Ritsumi Saito, Amane Fujioka, Yurika Nakagawa, Koji M Nishiguchi, Taiki Kokubun, Ikuko N Motoike, Kazuichi Maruyama, Kazuko Omodaka, Yukihiro Shiga, Akira Uruno, Seizo Koshiba, Masayuki Yamamoto, Toru Nakazawa

    Scientific reports   Vol. 8 ( 1 ) page: 11930 - 11930   2018.8

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    In glaucoma, although axonal injury drives retinal ganglion cell (RGC) death, little is known about the underlying pathomechanisms. To provide new mechanistic insights and identify new biomarkers, we combined latest non-targeting metabolomics analyses to profile altered metabolites in the mouse whole retina 2, 4, and 7 days after optic nerve crush (NC). Ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry and liquid chromatography Fourier transform mass spectrometry covering wide spectrum of metabolites in combination highlighted 30 metabolites that changed its concentration after NC. The analysis displayed similar changes for purine nucleotide and glutathione as reported previously in another animal model of axonal injury and detected multiple metabolites that increased after the injury. After studying the specificity of the identified metabolites to RGCs in histological sections using imaging mass spectrometry, two metabolites, i.e., L-acetylcarnitine and phosphatidylcholine were increased not only preceding the peak of RGC death in the whole retina but also at the RGC layer (2.3-fold and 1.2-fold, respectively). These phospholipids propose novel mechanisms of RGC death and may serve as early biomarkers of axonal injury. The combinatory metabolomics analyses promise to illuminate pathomechanisms, reveal biomarkers, and allow the discovery of new therapeutic targets of glaucoma.

    DOI: 10.1038/s41598-018-30464-z

    PubMed

  61. Ecel1 Knockdown With an AAV2-Mediated CRISPR/Cas9 System Promotes Optic Nerve Damage-Induced RGC Death in the Mouse Retina. Reviewed International journal

    Sato K, Shiga Y, Nakagawa Y, Fujita K, Nishiguchi KM, Tawarayama H, Murayama N, Maekawa S, Yabana T, Omodaka K, Katayama S, Feng Q, Tsuda S, Nakazawa T

    Investigative ophthalmology & visual science   Vol. 59 ( 10 ) page: 3943 - 3951   2018.8

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    Purpose: To assess the therapeutic potential of endothelin-converting enzyme-like 1 (Ecel1) in a mouse model of optic nerve crush. Methods: Ecel1 expression was evaluated with real time quantitative (qRT)-PCR, Western blotting, and immunohistochemistry in mouse retinas after optic nerve crush. Vinblastine administration to the optic nerve and the intravitreal injection of N-methyl-d-aspartate (NMDA) were used to assess Ecel1 gene expression. Ecel1 was deleted with an adeno-associated viral (AAV) clustered regulatory interspaced short palindromic repeat (CRISPR)/Cas9 system, and retinal ganglion cell (RGC) survival was investigated with retrograde labeling, qRT-PCR, and visual evoked potential. Results: Optic nerve crush induced Ecel1 expression specifically in the RGCs, peaking on day 4 after optic nerve crush. Ecel1 gene expression was induced by the vinblastine-induced inhibition of axonal flow, but not by NMDA-induced excitotoxicity, even though both are triggers of RGC death. Knockdown of Ecel1 promoted the loss of RGCs after optic nerve crush. Conclusions: Our data suggest that Ecel1 induction is part of the retinal neuroprotective response to axonal injury in mice. These findings might provide insight into novel therapeutic targets for the attenuation of RGC damage, such as occurs in traumatic optic neuropathy.

    DOI: 10.1167/iovs.18-23784

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  62. Prevalence of anti-retinal antibodies in epiretinal membranes and macular holes. Reviewed International journal

    Hiroshi Kunikata, Kosuke Fujita, Koji M Nishiguchi, Toru Nakazawa

    Clinical & experimental ophthalmology   Vol. 46 ( 5 ) page: 556 - 558   2018.7

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  63. Levels of Anti-Retinal Antibodies in Retinal Detachment and Proliferative Vitreoretinopathy. Reviewed International journal

    Reo Ichinohasama, Koji M Nishiguchi, Kosuke Fujita, Naoko Aizawa, Takashi Inoue, Erika Sasaki, Hiroshi Kunikata, Toru Nakazawa

    Current eye research   Vol. 43 ( 6 ) page: 804 - 809   2018.6

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    PURPOSE: The purpose of the study is to investigate the correlation between intraocular anti-retinal antibodies and clinical measurements in patients with rhegmatogenous retinal detachment (RRD) and proliferative vitreoretinopathy (PVR). MATERIAL AND METHODS: Aqueous humor and vitreous samples were collected from patients with RRD, PVR, and from control subjects with macular hole. The levels of total protein (TP), IgG, and anti-retinal antibodies were determined with a bicinchoninic acid assay, enzyme-linked immunosorbent assay, and dot blot, respectively. Correlations between these measurements were assessed using Pearson's correlation test. Analysis of variance followed by a post-hoc test or the Student t-test was used to compare differences between groups. RESULTS: The levels of anti-retinal antibodies and IgG were correlated with each other (P < 0.010). The IgG concentration was higher in patients with PVR than in controls in both the aqueous humor (P < 0.001) and the vitreous (P < 0.001), but not in patients with RRD. Conversely, TP levels and anti-retinal antibodies in both ocular fluids from RRD and PVR patients did not significantly differ from the controls. In a subgroup analysis, vitreal anti-retinal antibody levels were correlated with average macular thickness in the re-attached macula following surgery for macula-off RRD/PVR (P = 0.012). Furthermore, patients with post-operative cystoid macular edema had a higher level of vitreal anti-retinal antibodies than those without (P = 0.009). CONCLUSIONS: Intravitreal anti-retinal antibodies were increased in the eyes with maculopathy after surgical intervention for RRD/PVR.

    DOI: 10.1080/02713683.2018.1451544

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  64. Genome-wide association study identifies seven novel susceptibility loci for primary open-angle glaucoma Reviewed

    Yukihiro Shiga, Japan Glaucoma Society Omics Group (JGS-OG), Masato Akiyama, Koji M. Nishiguchi, Kota Sato, Nobuhiro Shimozawa, Atsushi Takahashi, Yukihide Momozawa, Makoto Hirata, Koichi Matsuda, Taiki Yamaji, Motoki Iwasaki, Shoichiro Tsugane, Isao Oze, Haruo Mikami, Mariko Naito, Kenji Wakai, Munemitsu Yoshikawa, Masahiro Miyake, Kenji Yamashiro, Kenji Kashiwagi, Takeshi Iwata, Fumihiko Mabuchi, Mitsuko Takamoto, Mineo Ozaki, Kazuhide Kawase, Makoto Aihara, Makoto Araie, Tetsuya Yamamoto, Yoshiaki Kiuchi, Makoto Nakamura, Yasuhiro Ikeda, Koh-Hei Sonoda, Tatsuro Ishibashi, Koji Nitta, Aiko Iwase, Shiroaki Shirato, Yoshitaka Oka, Mamoru Satoh, Makoto Sasaki, Nobuo Fuse, Yoichi Suzuki, Ching-Yu Cheng, Chiea Chuen Khor, Mani Baskaran, Shamira Perera, Tin Aung, Eranga N. Vithana, Jessica N. Cooke Bailey, Jae H. Kang, Louis R. Pasquale, Jonathan L. Haines, Janey L. Wiggs, Kathryn P. Burdon, Puya Gharahkhani, Alex W. Hewitt, David A. Mackey, Stuart MacGregor, Jamie E. Craig, R. Rand Allingham, Micheal Hauser, Adeyinka Ashaye, Donald L. Budenz, Stephan Akafo, Susan E.I. Williams, Yoichiro Kamatani, Toru Nakazawa, Michiaki Kubo

    Human Molecular Genetics   Vol. 27 ( 8 ) page: 1486 - 1496   2018.4

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    Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide for which 15 diseaseassociated loci had been discovered. Among them, only 5 loci have been associated with POAG in Asians. We carried out a genome-wide association study and a replication study that included a total of 7378 POAG cases and 36 385 controls from a Japanese population. After combining the genome-wide association study and the two replication sets, we identified 11 POAG-associated loci, including 4 known (CDKN2B-AS1, ABCA1, SIX6 and AFAP1) and 7 novel loci (FNDC3B, ANKRD55-MAP3K1, LMX1B, LHPP, HMGA2, MEIS2 and LOXL1) at a genome-wide significance level (P&lt
    5.0×10-8), bringing the total number of POAG-susceptibility loci to 22. The 7 novel variants were subsequently evaluated in a multiethnic population comprising non-Japanese East Asians (1008 cases, 591 controls), Europeans (5008 cases, 35 472 controls) and Africans (2341 cases, 2037 controls). The candidate genes located within the new loci were related to ocular development (LMX1B, HMGA2 and MAP3K1) and glaucoma-related phenotypes (FNDC3B, LMX1B and LOXL1). Pathway analysis suggested epidermal growth factor receptor signaling might be involved in POAG pathogenesis. Genetic correlation analysis revealed the relationships between POAG and systemic diseases, including type 2 diabetes and cardiovascular diseases. These results improve our understanding of the genetic factors that affect the risk of developing POAG and provide new insight into the genetic architecture of POAG in Asians.

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  65. Discovery of a Cynomolgus Monkey Family With Retinitis Pigmentosa. Reviewed International journal

    Yasuhiro Ikeda, Koji M Nishiguchi, Fuyuki Miya, Nobuhiro Shimozawa, Jun Funatsu, Shunji Nakatake, Kohta Fujiwara, Takashi Tachibana, Yusuke Murakami, Toshio Hisatomi, Shigeo Yoshida, Yasuhiro Yasutomi, Tatsuhiko Tsunoda, Toru Nakazawa, Tatsuro Ishibashi, Koh-Hei Sonoda

    Investigative ophthalmology & visual science   Vol. 59 ( 2 ) page: 826 - 830   2018.2

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    Purpose: To accelerate the development of new therapies, an inherited retinal degeneration model in a nonhuman primate would be useful to confirm the efficacy in preclinical studies. In this study, we describe the discovery of retinitis pigmentosa in a cynomolgus monkey (Macaca fascicularis) pedigree. Methods: First, screening with fundus photography was performed on 1443 monkeys at the Tsukuba Primate Research Center. Ophthalmic examinations, such as indirect ophthalmoscopy, ERGs using RETeval, and optic coherent tomography (OCT) measurement, were then performed to confirm diagnosis. Results: Retinal degeneration with cystoid macular edema was observed in both eyes of one 14-year-old female monkey. In her examinations, the full-field ERGs were nonrecordable and the outer layer of the retina in the parafoveal area was not visible on OCT imaging. Moreover, less frequent pigmentary retinal anomalies also were observed in her 3-year-old nephew. His full-field ERGs were almost nonrecordable and the outer layer was not visible in the peripheral retina. His father was her cousin (the son of her mother's older brother) and his mother was her younger half-sibling sister with a different father. Conclusions: The hereditary nature is highly probable (autosomal recessive inheritance suspected). However, whole-exome analysis performed identified no pathogenic mutations in these monkeys.

    DOI: 10.1167/iovs.17-22958

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  66. Quantitative MRI evaluation of glaucomatous changes in the visual pathway. Reviewed International journal

    Fukuda M, Omodaka K, Tatewaki Y, Himori N, Matsudaira I, Nishiguchi KM, Murata T, Taki Y, Nakazawa T

    PloS one   Vol. 13 ( 7 ) page: e0197027   2018

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    BACKGROUND: The aims of this study were to investigate glaucomatous morphological changes quantitatively in the visual cortex of the brain with voxel-based morphometry (VBM), a normalizing MRI technique, and to clarify the relationship between glaucomatous damage and regional changes in the visual cortex of patients with open-angle glaucoma (OAG). METHODS: Thirty-one patients with OAG (age: 55.9 ± 10.7, male: female = 9: 22) and 20 age-matched controls (age: 54.9 ± 9.8, male: female = 10: 10) were included in this study. The cross-sectional area (CSA) of the optic nerve was manually measured with T2-weighed MRI. Images of the visual cortex were acquired with T1-weighed 3D magnetization-prepared rapid acquisition with gradient echo (MPRAGE) sequencing, and the normalized regional visual cortex volume, i.e., gray matter density (GMD), in Brodmann areas (BA) 17, 18, and 19, was calculated with a normalizing technique based on statistic parametric mapping 8 (SPM8) analysis. We compared the regional GMD of the visual cortex in the control subjects and OAG patients. Spearman's rank correlation analysis was used to determine the relationship between optic nerve CSA and GMD in BA 17, 18, and 19. RESULTS: We found that the normal and OAG patients differed significantly in optic nerve CSA (p < 0.001) and visual cortex GMD in BA 17 (p = 0.030), BA 18 (p = 0.003), and BA 19 (p = 0.005). In addition, we found a significant correlation between optic nerve CSA and visual cortex GMD in BA 19 (r = 0.33, p = 0.023), but not in BA 17 (r = 0.17, p = 0.237) or BA 18 (r = 0.24, p = 0.099). CONCLUSION: Quantitative MRI parametric evaluation of GMD can detect glaucoma-associated anatomical atrophy of the visual cortex in BA 17, 18, and 19. Furthermore, GMD in BA 19 was significantly correlated to the damage level of the optic nerve, as well as the retina, in patients with OAG. This is the first demonstration of an association between the cortex of the brain responsible for higher-order visual function and glaucoma severity. Evaluation of the visual cortex with MRI is thus a very promising potential method for objective examination in OAG.

    DOI: 10.1371/journal.pone.0197027

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  67. Optic nerve head microcirculation in autosomal dominant optic atrophy and normal-tension glaucoma Reviewed

    Noriko Himori, Hiroshi Kunikata, Maki Inoue, Takayuki Takeshita, Koji M. Nishiguchi, Toru Nakazawa

    ACTA OPHTHALMOLOGICA   Vol. 95 ( 8 ) page: e799 - e800   2017.12

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  68. The neuroprotective effect of hesperidin in NMDA-induced retinal injury acts by suppressing oxidative stress and excessive calpain activation Reviewed

    Shigeto Maekawa, Kota Sato, Kosuke Fujita, Reiko Daigaku, Hiroshi Tawarayama, Namie Murayama, Satoru Moritoh, Takeshi Yabana, Yukihiro Shiga, Kazuko Omodaka, Kazuichi Maruyama, Koji M. Nishiguchi, Toru Nakazawa

    Scientific Reports   Vol. 7 ( 1 ) page: 6885   2017.7

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    We found that hesperidin, a plant-derived bioflavonoid, may be a candidate agent for neuroprotective treatment in the retina, after screening 41 materials for anti-oxidative properties in a primary retinal cell culture under oxidative stress. We found that the intravitreal injection of hesperidin in mice prevented reductions in markers of the retinal ganglion cells (RGCs) and RGC death after N-methyl-D-aspartate (NMDA)-induced excitotoxicity. Hesperidin treatment also reduced calpain activation, reactive oxygen species generation and TNF-α gene expression. Finally, hesperidin treatment improved electrophysiological function, measured with visual evoked potential, and visual function, measured with optomotry. Thus, we found that hesperidin suppressed a number of cytotoxic factors associated with NMDA-induced cell death signaling, such as oxidative stress, over-activation of calpain, and inflammation, thereby protecting the RGCs in mice. Therefore, hesperidin may have potential as a therapeutic supplement for protecting the retina against the damage associated with excitotoxic injury, such as occurs in glaucoma and diabetic retinopathy.

    DOI: 10.1038/s41598-017-06969-4

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  69. Spatially and Temporally Regulated NRF2 Gene Therapy Using Mcp-1 Promoter in Retinal Ganglion Cell Injury Reviewed

    Kosuke Fujita, Koji M. Nishiguchi, Yukihiro Shiga, Toru Nakazawa

    MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT   Vol. 5   page: 130 - 141   2017.6

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    Publishing type:Research paper (scientific journal)   Publisher:CELL PRESS  

    Retinal ganglion cell degeneration triggered by axonal injury is believed to underlie many ocular diseases, including glaucoma and optic neuritis. In these diseases, retinal ganglion cells are affected unevenly, both spatially and temporally, such that healthy and unhealthy cells coexist in different patterns at different time points. Herein, we describe a temporally and spatially regulated adeno-associated virus gene therapy aiming to reduce undesired off-target effects on healthy retinal neurons. The Mcp-1 promoter previously shown to be activated in stressed retinal ganglion cells following murine optic nerve injury was combined with the neuroprotective intracellular transcription factor Nrf2. In this model, Mcp-1 promoter driven NRF2 expression targeting only stressed retinal ganglion cells showed efficacy equivalent to non-selective cytomegalovirus promoter-driven therapy for preventing cell death. However, cytomegalovirus promoter-mediated NRF2 transcription induced cellular stress responses and death of Brn3A-positive uninjured retinal ganglion cells. Such undesired effects were reduced substantially by adopting the Mcp-1 promoter. Combining a stress-responsive promoter and intracellular therapeutic gene is a versatile approach for specifically targeting cells at risk of degeneration. This strategy may be applicable to numerous chronic ocular and non-ocular conditions.

    DOI: 10.1016/j.omtm.2017.04.003

    Web of Science

    PubMed

  70. The neuroprotective effect of latanoprost acts via klotho-mediated suppression of calpain activation after optic nerve transection Reviewed

    Kotaro Yamamoto, Kota Sato, Masayoshi Yukita, Masayuki Yasuda, Kazuko Omodaka, Morin Ryu, Kosuke Fujita, Koji M. Nishiguchi, Shigeki Machida, Toru Nakazawa

    JOURNAL OF NEUROCHEMISTRY   Vol. 140 ( 3 ) page: 495 - 508   2017.2

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    Publishing type:Research paper (scientific journal)   Publisher:WILEY  

    Latanoprost was first developed for use in glaucoma therapy as an ocular hypotensive agent targeting the prostaglandin F2 alpha (FP) receptor. Subsequently, latanoprost showed a neuroprotective effect, an additional pharmacological action. However, although it is well-known that latanoprost exerts an ocular hypotensive effect via the FP receptor, it is not known whether this is also true of its neuroprotective effect. Klotho was firstly identified as the gene linked to the suppression of aging phenotype: the defect of klotho gene in mice results aging phenotype such as hypokinesis, arteriosclerosis, and short lifespan. After that, the function of klotho was also reported to maintain calcium homeostasis and to exert a neuroprotective effect in various models of neurodegenerative disease. However, the function of klotho in eyes including retina is still poorly understood. Here, we show that klotho is a key factor underlying the neuroprotective effect of latanoprost during post-axotomy retinal ganglion cell (RGC) degeneration. Importantly, a quantitative RT-PCR gene expression analysis of klotho in sorted rat retinal cells revealed that the highest expression level of klotho in the retina was in the RGCs. Latanoprost acid, the biologically active form of latanoprost, inhibits post-traumatic calpain activation and concomitantly facilitates the expression and shedding of klotho in axotomized RGCs. This expression profile is a good match with the localization, not of the FP receptor, but of organic anion transporting polypeptide 2B1, known as a prostaglandin transporter, in the ocular tissue. Furthermore, an organic anion transporting polypeptide 2B1 inhibitor suppressed latanoprost acid-mediated klotho shedding exvivo, whereas an FP receptor antagonist did not. The klotho fragments shed from the RGCs reduced the intracellular level of reactive oxygen species, and a specific klotho inhibitor accelerated and increased RGC death after axotomy. We conclude that the shed klotho fragments might contribute to the attenuation of axonal injury-induced calpain activation and oxidative stress, thereby protecting RGCs from post-traumatic neuronal degeneration.

    DOI: 10.1111/jnc.13902

    Web of Science

    PubMed

  71. Brimonidine Enhances the Electrophysiological Response of Retinal Ganglion Cells through the Trk-MAPK/ERK and PI3K Pathways in Axotomized Eyes Reviewed

    Masayoshi Yukita, Kazuko Omodaka, Shigeki Machida, Masayuki Yasuda, Kota Sato, Kazuichi Maruyama, Koji M. Nishiguchi, Toru Nakazawa

    CURRENT EYE RESEARCH   Vol. 42 ( 1 ) page: 125 - 133   2017.1

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    Publishing type:Research paper (scientific journal)   Publisher:TAYLOR & FRANCIS INC  

    Purpose: To investigate changes in retinal ganglion cell (RGC) activity by measuring the positive scotopic threshold response (pSTR) of the electroretinogram (ERG) in axotomized eyes after brimonidine injection.Methods: In 50 adult Sprague-Dawley rats, the left eye was axotomized and injected with phosphate buffered saline (PBS) or brimonidine and the contralateral right eye was left untreated. Scotopic ERGs were recorded simultaneously from both eyes on days 1, 2, 3, 7, and 10 after the intravitreal injection, and the amplitude of the a- and b-waves and the pSTR were measured. Surviving RGCs in the flat-mounted retinas were counted 10 days after axotomy. In addition to brimonidine, K252a (an inhibitor of tyrosine kinase phosphorylation of the Trk receptors), U0126 (a MAPK/ERK kinase inhibitor), and LY294002 (phosphoinositide 3-kinases [PI3Ks]) were also injected intravitreally into the left eye, and ERGs were recorded using the same protocol.Results: The pSTR amplitude increased significantly in the axotomized eyes with brimonidine, to 122.9 5.0%, 161.8 +/- 8.3%, and 133.6 +/- 8.1% on days 1, 2, and 3 (P &lt; 0.01), respectively, compared to the axotomized eyes treated with PBS (control). The increased pSTR amplitude returned to normal (103.6 +/- 6.7%) on day 7, although there were a greater number of surviving RGCs in the treatment groups than in the controls. The intravitreal injection of K252a, U0126, or LY294002 significantly attenuated the increase in pSTR induced by intravitreal brimonidine (P &lt; 0.01).Conclusion: Intravitreal brimonidine enhanced the survival and electrophysiological activity of the RGCs in rats. The mechanism of this electrophysiological change may involve activation of the Trk-MAPK/ERK and Trk-PI3K signals.

    DOI: 10.3109/02713683.2016.1153112

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    PubMed

  72. Whole Genome Sequencing in Patients with Retinitis Pigmentosa

    Nishiguchi Koji M.

    ADVANCES IN VISION RESEARCH, VOL I: GENETIC EYE RESEARCH IN ASIA AND THE PACIFIC     page: 83 - 91   2017

  73. Genetic analysis of Japanese primary open-angle glaucoma patients and clinical characterization of risk alleles near CDKN2B-AS1, SIX6 and GAS7 Reviewed

    Yukihiro Shiga, Japan Glaucoma Society Omics Group (JGS-OG), Koji M. Nishiguchi, Yosuke Kawai, Kaname Kojima, Kota Sato, Kosuke Fujita, Mai Takahashi, Kazuko Omodaka, Makoto Araie, Kenji Kashiwagi, Makoto Aihara, Takeshi Iwata, Fumihiko Mabuchi, Mitsuko Takamoto, Mineo Ozaki, Kazuhide Kawase, Nobuo Fuse, Masayuki Yamamoto, Jun Yasuda, Masao Nagasaki, Toru Nakazawa

    PLoS ONE   Vol. 12 ( 12 ) page: e0186678   2017

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    Publishing type:Research paper (scientific journal)   Publisher:Public Library of Science  

    Purpose To test the genetic association between Japanese patients with primary open-angle glaucoma (POAG) and the previously reported POAG susceptibility loci and to perform genotype–phenotype analysis. Methods Genetic associations for 27 SNPs from 16 loci previously linked to POAG were assessed using genome-wide SNP data of the primary cohort (565 Japanese POAG patients and 1,104 controls). Reproducibility of the assessment was tested in 607 POAG cases and 455 controls (second cohort) with a targeted genotyping approach. For POAG-associated variants, a genotype–phenotype correlation study (additive, dominant, recessive model) was performed using the objective clinical data derived from 598 eyes of 598 POAG patients. Results Among 27 SNPs from 16 loci previously linked to POAG, genotypes for total of 20 SNPs in 13 loci were available for targeted association study. Among 8 SNPs in 3 loci that showed at least nominal association (P &lt
    5.00E-02) in the primary cohort, a representative SNP for each loci (rs2157719 for CDKN2B-AS1, rs33912345 for SIX6, and rs9913911 for GAS7) were selected. For these SNPs the association was found significant in both the second cohort analysis and meta-analysis. The genotype–phenotype analysis revealed significant correlations between CDKN2B-AS1 (rs2157719) and decreased intraocular pressure (? = -6.89 mmHg, P = 1.70E-04
    dominant model) after multiple corrections. In addition, nominal correlation was observed between CDKN2B-AS1 (rs2157719) and optic nerve head blood flow (? = -0.54 and -0.67 arbitrary units (AU), P = 2.00E-02 and 1.39E-02), between SIX6 (rs33912345) and decreased total peripapillary retinal nerve fiber layer thickness (? = -2.16 and -2.82 ?m, P = 4.68E-02 and 2.40E-02, additive and recessive model, respectively) and increased optic nerve head blood flow (? = 0.44 AU, P = 2.20E-02
    additive model) and between GAS7 (rs9913911) and increased cup volume (? = 0.03 mm3, P = 4.60E-02) and mean cup depth (? = 0.03 mm3, P = 4.11E-02
    additive model) and decreased pattern standard deviation (? = -0.87 dB, P = 2.44E-02
    dominant model). Conclusion The association between SNPs near GAS7 and POAG was found in Japanese patients for the first time. Clinical characterization of the risk variants is an important step toward understanding the pathology of the disease and optimizing treatment of patients with POAG.

    DOI: 10.1371/journal.pone.0186678

    Scopus

    PubMed

  74. Additive effects of genetic variants associated with intraocular pressure in primary open-angle glaucoma Reviewed

    Fumihiko Mabuchi, Nakako Mabuchi, Yoichi Sakurada, Seigo Yoneyama, Kenji Kashiwagi, Hiroyuki Iijima, Zentaro Yamagata, Mitsuko Takamoto, Makoto Aihara, Takeshi Iwata, Kazuhide Kawase, Yukihiro Shiga, Koji M. Nishiguchi, Toru Nakazawa, Mineo Ozaki, Makoto Araie

    PLOS ONE   Vol. 12 ( 8 ) page: e0183709   2017

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    Publishing type:Research paper (scientific journal)   Publisher:PUBLIC LIBRARY SCIENCE  

    To investigate the association between the additive effects of genetic variants associated with intraocular pressure (IOP) and IOP, vertical cup-to-disc ratio (VCDR), and high tension glaucoma (HTG) or normal tension glaucoma (NTG) as phenotypic features of primary open-angle glaucoma (POAG), and to evaluate the clinical usefulness of the additive effects of IOP-related genetic variants for predicting IOP elevation, Japanese patients with HTG (n = 255) and NTG (n = 261) and 246 control subjects were genotyped for nine IOP-related genetic variants near CAV2, GAS7, GLCCI1/ICA1, ABCA1, ARHGEF12, FAM125B, FNDC3B, ABO, and PTPRJ/AGBL2. The total number of risk alleles of these genetic variants was calculated for each participant as a genetic risk score (GRS), and the association between the GRS and the maximum IOP, mean VCDR, and phenotype (HTG or NTG) of POAG was evaluated. As the GRS increased, the maximum IOP (P = 0.012) and VCDR (P = 0.010) significantly increased. The GRS (9.1 +/- 1.9) in patients with HTG was significantly higher (P = 0.011) than that (8.7 +/- 1.8) in control subjects. The patients with GRS &gt;= 12 as a cut-off value had a 2.54 times higher (P = 0.0085) risk on HTG (maximum IOP &gt;= 22mmHg) compared with all patients. The IOP-related GRS approach substantiated that the IOP and VCDR were increased by the additive effects of IOP-related genetic variants in POAG. The high IOP-related GRS in patients with HTG but not NTG shows that there are differences in the genetic background between HTG and NTG and supports the notion that the phenotype (HTG or NTG) in patients with POAG depends on the additive effects of IOP-related genetic variants. The above-mentioned cut-off value of IOP-related GRS may be clinically useful for predicting the risk of IOP elevation.

    DOI: 10.1371/journal.pone.0183709

    Web of Science

    PubMed

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Books 2

  1. 眼科臨床エキスパート 小口病

    西口康二( Role: Contributor)

    医学書院 

  2. 遺伝子診断・治療 最新主要文献でみる眼科学レビュー

    西口康二( Role: Contributor)

    総合医学社 

MISC 13

  1. Ophthalmologic Genetics-Molecular Genetics and Developments in Therapeutic Strategies for Intractable Eye Diseases-

    村上晶, 高丹, 藤巻拓郎, 舟木俊成, 山口昌大, 川村雄一, 藤木慶子, 岩田文乃, 平形寿彬, 平塚義宗, 土至田宏, 小野浩一, 中谷智, 太田俊彦, 猪俣武範, 松田彰, 海老原伸行, 横山利幸, 早川むつ子, 渡邉すみ子, 岩田岳, 須賀晶子, 和田裕子, 西口康二, 小柳俊人, 小柳俊人

    日本眼科学会雑誌   Vol. 125 ( 3 )   2021

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  2. Autosomal Recessive Bestrophinopathy Complicated by Angle Closure: a Case Report

    西口康二, 国松志保, 國方彦志, 中澤徹, 中澤徹

    日本眼科学会雑誌   Vol. 124 ( 9 )   2020

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  3. Prediction of glaucomatous visual field progression by genetic variants associated with primary open-angle glaucoma

    Fumihiko Mabuchi, Yoichi Sakurada, Kenji Kashiwagi, Mitsuko Takamoto, Makoto Aihara, Takeshi Iwata, Kazuki Hashimoto, Kota Sato, Yukihiro Shiga, Koji Nishiguchi, Toru Nakazawa, Masato Akiyama, Kazuhide Kawase, Mineo Ozaki, Makoto Araie

    INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE   Vol. 60 ( 9 )   2019.7

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    Language:English   Publishing type:Research paper, summary (international conference)   Publisher:ASSOC RESEARCH VISION OPHTHALMOLOGY INC  

    0

    Web of Science

  4. 特発性黄斑前膜術後の網膜感度と術前の黄斑血管密度との関係

    長田麗, 國方彦志, 安田正幸, 橋本和軌, 相澤奈帆子, 西口康二, 阿部俊明, 中澤徹

    日本眼科学会雑誌   Vol. 123   page: 173   2019.3

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    Language:Japanese  

    J-GLOBAL

  5. 滲出性網膜剥離を発症し、診断に苦慮した網膜血管腫の一例

    橋本 清香, 國方 彦志, 油井 奈保子, 西口 康二, 阿部 俊明, 中澤 徹

    眼科臨床紀要   Vol. 12 ( 3 ) page: 253 - 253   2019.3

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    Language:Japanese   Publisher:眼科臨床紀要会  

  6. 網膜脈絡膜・視神経委縮症に関する調査研究 網膜色素変性に関する調査研究

    山本修一, 高橋政代, 村上晶, 池田康博, 平見恭彦, 岩田岳, 川崎良, 西口康二

    網膜脈絡膜・視神経萎縮症に関する調査研究 平成30年度 総括・分担研究報告書(Web)     2019

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  7. B群溶血性連鎖球菌による内因性眼内炎の6例

    吉田真彰, 横倉俊二, 西田崇, 望月清文, 鈴木崇, 丸山和一, 丸山和一, 西口康二, 國方彦志, 中澤徹

    日本眼感染症学会・日本眼炎症学会・日本コンタクトレンズ学会総会・日本涙道・涙液学会プログラム・講演抄録集   Vol. 56th-53rd-62nd-8th   2019

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  8. 新しい眼科病診連携システムの網膜疾患診療における有用性

    國方 彦志, 加藤 圭一, 齋藤 慶治, 檜森 紀子, 相澤 奈帆子, 西口 康二, 中山 雅晴, 阿部 俊明, 中澤 徹

    眼科臨床紀要   Vol. 11 ( 11 ) page: 856 - 857   2018.11

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    Language:Japanese   Publisher:眼科臨床紀要会  

  9. Pars plana vitrectomy with endolaser cyclophotocoagulation for refractory glaucoma in eleven eyes

    高橋 成奈, 横山 悠, 國方 彦志, 西口 康二, 新田 文彦, 竹下 孝之, 中澤 徹

    臨床眼科   Vol. 72 ( 10 ) page: 1451 - 1458   2018.10

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    Language:Japanese   Publisher:医学書院  

  10. 日本緑内障学会遺伝子研究班の活動報告

    中澤徹, 志賀由己浩, 西口康二, 間渕文彦, 柏木賢治, 高本光子, 相原一, 尾崎峯生, 川瀬和秀, 岩田岳, 新家眞

    日本緑内障学会抄録集   Vol. 29th   2018

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  11. OCTアンジオグラフィによる黄斑剥離裂孔原性網膜剥離眼の検討

    油井奈保子, 國方彦志, 相澤奈帆子, 新田文彦, 大友孝昭, 西口康二, 阿部俊明, 中澤徹

    日本眼循環学会講演抄録集   Vol. 35th   2018

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  12. A Case of Endophthalmitis Associated with Epidemic Keratoconjunctivitis

      Vol. 34 ( 6 ) page: 880 - 882   2017.6

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  13. 新しい眼科病診連携システムの網膜疾患診療における有用性

    國方彦志, 加藤圭一, 齋藤慶治, 檜森紀子, 相澤奈帆子, 西口康二, 中山雅晴, 阿部俊明, 中澤徹

    日本網膜硝子体学会総会プログラム・講演抄録集   Vol. 56th   page: 132   2017

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    Language:Japanese  

    J-GLOBAL

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KAKENHI (Grants-in-Aid for Scientific Research) 7

  1. 網膜色素変性症治療のための高効率なゲノム編集遺伝子治療の開発

    Grant number:21K09673  2021.4 - 2024.3

    科学研究費助成事業  基盤研究(C)

    藤田 幸輔, 西口 康二

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    Authorship:Coinvestigator(s) 

    網膜色素変性は、本邦での中途失明原因の第2位の遺伝性疾患である。本研究の目的は、ゲノム編集を用いて、網膜色素変性症の病因となる遺伝子変異をより効率的に修復できる遺伝子治療の技術を開発することである。申請者らが作製に成功したゲノム編集遺伝子治療アデノ随伴ウイルス(AAV)ベクターを用いて、全盲網膜変性マウスを対象とした遺伝子治療を行い、より効果的な治療法を決定する。本研究により、効率的なゲノム修復ができるようになった場合、治療不可能であった遺伝子変異に対する治療が可能となる。開発した遺伝子治療法は、網膜色素変性だけではなく、他の遺伝性疾患の治療にも応用できるものである。

  2. エピゲノム編集による抹消血を用いた網膜色素変性病因遺伝子の発現解析法の開発

    Grant number:20K09765  2020.4 - 2023.3

    科学研究費助成事業  基盤研究(C)

    西口 康二, 中澤 徹, 藤田 幸輔

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    Authorship:Principal investigator 

    Grant amount:\4420000 ( Direct Cost: \3400000 、 Indirect Cost:\1020000 )

    網膜色素変性(RP)患者由来の不死化リンパ球を対象に、ゲノム編集技術を用いて特定のRP病因遺伝子のプロモーターを非メチル化することにより同遺伝子の強制発現細胞株の樹立を可能にする技術を開発する。この細胞株を用いて、本来リンパ球では発現しないRP病因遺伝子のmRNA発現解析を行い、同患者のゲノム情報と照合することにより、逆算的に病因変異が同定可能か検証する。このアプローチの有用性が明らかになった場合、比較的簡便かつ安価な遺伝子診断補助検査法の開発が可能になり、遺伝性疾患の診断率の向上に寄与すると期待される。
    1.まずは、EYS遺伝子変異が同定済みの患者1名の不死化リンパ球をEBVウィルスを用いて作製した。次にEYS遺伝子変異を有する患者と正常者の末梢血由来のリンパ芽球を用いて網膜特異的な発現を示すEYSアイソフォームの発現を誘導する方法として、ゲノム編集を用いて同遺伝子のプロモーター領域を非メチル化された合成プロモーターに置換することを行った。しかし、この方法では、EYS mRNAの発現が安定しなかった。そのために、脱メチル化剤を添加したところ、これらの正常者の由来のリンパ芽球においてはEYS mRNAの発現が確認された一方で、患者由来のリンパ芽球ではEYS mRNAの発現は見られなかった。しかし、患者由来のリンパ芽球に脱メチル化剤に加えてmRNA分解抑制剤を添加したところ、EYS mRNAの発現が誘導された。
    2. 前述の方法は薬剤により遺伝子発現を誘発するため、安定的なmRNA発現解析には適さない。また、シーケンス結果もゲノム領域によってばらつきがあった。そのために、新たなEYS遺伝子発現誘導の方法として、Cas9のnucleaseを不活化した変異体であるdCas9にtranscriptional activatorを付加しものとEYSのpromotor領域にデザインしたガイドRNAを用いてEYSの発現を誘導する方法をまずはHEK293T細胞を用いて確立した。この方法では薬剤でEYS発現を誘発する必要がない。現在、EYSを恒常的に発現する細胞株を樹立するために、dCas9を用いたEYS発現システムを正常者リンパ芽球のゲノムに組み込む実験を行っている。
    当初の計画では、2020年度は①非メチル化プロモーター置換用のベクターの作製を行い、そのうえで②不死化リンパ球における mRNA発現解析の最適化に着手する予定だった。
    まず、①は完成し実際不死化リンパ球に投与したところ、EYS遺伝子発現は誘導されたが、脱メチル化剤の投与が必要であった。薬剤誘発モデルでは、安定したmRNA発現の評価が難しいため、方針を転換し、dCas9とガイドRNAを使った転写誘導を試みたところ、薬剤を使わずにEYS発現を得ることが確認された。次のステップとしてdCas9とガイドRNAを正常者リンパ芽球のゲノムに組み込む実験を行っている。
    2021年度は、EYSを恒常的に発現する患者由来EYS発現不死化リンパ球を樹立する。EYSのRT-PCRを行い、プロモーターの置換によりHEK293T細胞でisoform 4が発現していることを確認する。EYS遺伝子変異が同定済みの患者3名の不死化リンパ球を追加で作製する。同細胞株に対して上記研究項目で開発したベクターを遺伝子導入する。それらの細胞に対して、非メチルプロモーターに挿入されたタグ配列を指標に、EYS強制発現細胞株を樹立する。同細胞を用いてRNAシーケンスを行い、EYSのmRNAシーケンスと既知のゲノム変異情報を比較することにより、病因変異の逆算的同定が可能か検証する。

  3. 網膜色素変性を自然発症するカニクイザルの病態解明と繁殖に向けた準備

    Grant number:19K09971  2019.4 - 2022.3

    科学研究費助成事業  基盤研究(C)

    池田 康博, 西口 康二, 下澤 律浩

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    本研究では、以下の3つのテーマを実施する。テーマ1.RPを自然発症するカニクイザルの家系調査、テーマ2.病因遺伝子の同定と病態メカニズムの解析、テーマ3.繁殖コロニー構築に向けた準備。初年度に眼科的検査を実施し、RPを発症した新たな個体の探索を行う。RPを発症した個体については経時的に血液や前房水などのサンプルを採取する。さらに眼球を用いた病理組織学的ならびに分子生物学的解析により病態メカニズムを解明する。並行しながらテーマ2の病因遺伝子検索を実施する。病因遺伝子が同定された後、家系における遺伝子スクリーニング検査により、病因遺伝子を有する個体を同定しながら、テーマ3へと進む予定である。
    網膜色素変性(RP)は、現時点で有効な治療法の確立されていない眼科領域の難病で、我が国の中途失明原因の第2位である。本研究では、RPの治療法開発を目指し、疾患モデル動物として、よりヒトに近いカニクイザルでの繁殖コロニー構築するための準備を目的とする。これまでに我々は、常染色体劣性遺伝形式でRPを自然発症するカニクイザル2頭(個体A:2007年生雌、個体B:2013年生雄)を同定し、国立研究開発法人医薬基盤・健康・栄養研究所霊長類医科学研究センター(つくば市)にて飼育している。令和元年度は、これまでに発症の確認された個体の近親にあたる個体の眼科的検査を実施し、RPを有する発症個体を1頭(個体C:2017年生雄)、さらにヘテロの個体も新たに数頭同定できた。
    本年6月に個体Bが死亡したため、眼球を摘出し、病理標本を作製した。眼科的検査にて診断された通り、既に網膜変性が生じていることを病理組織学的に確認した。また、本年度実施予定の全ゲノムシーケンスによる新たな病因遺伝子解析は、現時点で個体数が十分ではないと判断されたため延期とした。
    病因遺伝子を保因していると考えられる個体については、近親交配を避けながら優先的に交配、または人工授精を行った。新たに数頭の新規個体が誕生した。個体の成長を観察しながら、まずは眼底写真を撮影し、疾患発症の有無についてスクリーニングする予定となっている。また、発症が疑われる個体については、網膜電図測定等の確定診断に必要な眼科的検査を実施する手順となっている。
    研究開始当初、常染色体劣性遺伝形式でRPを自然発症するカニクイザル2頭(個体A、個体B)を保有していたが、初年度に新たな疾患を有する個体C(雄)を同定した。令和2年6月に個体Bが死亡したため、眼球を摘出し、病理標本を作製した。眼科的検査にて診断された通り、既に網膜変性が生じていることを病理組織学的に確認した。
    さらに、疾患を発症している可能性のある新たに出生した個体に対する眼底検査ならびに眼科的検査は、新型コロナウイルス感染症拡大の影響で現地を訪問できなかったため、本年度の実施を断念した(テーマ1)。
    また、本年度実施予定の全ゲノムシーケンスによる新たな病因遺伝子解析は、現時点で個体数が十分ではないと判断されたため延期とした。(テーマ2)。
    テーマ3として、病因遺伝子を保因していると考えられる個体については、近親交配を避けながら優先的に交配、または人工授精を行った。また、個体Cは性成熟に達していないことが確認された。
    テーマ1として、新たに出生した個体を中心に、眼底検査を実施する。眼底検査にて異常が疑われる個体については、網膜電図を測定し診断を確定する。
    テーマ2として、全ゲノムシーケンスによる新たな病因遺伝子解析を実施する。さらに、死亡した個体Bの網膜組織よりRNAを抽出し、RNA seq解析による病因遺伝子解析も併せて実施する。有望な候補となる新規遺伝子や既知の網膜色素変性関連遺伝子にミスセンス変異が見つかった場合は、病気との関連性を証明するために遺伝子の発現解析や機能解析の実験を行う。
    テーマ3として、引き続き交配を進めるが、個体Aは繁殖から引退する予定であり、閉経前に採卵して凍結保存する。さらに、個体Aから採取した卵子を用いて人工授精を施行する。

  4. Development of a novel CRISPR-Cas9 vector for functional analysis of retinal disease-related genes

    Grant number:18K09395  2018.4 - 2021.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Fujita Kosuke

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    Based on the miniaturization of each part required for genome editing, we developed a single AAV platform that can locally replace mutant sequences with wild-type counterparts. In blind mice, the mutation replacement rescued approximately 10% of photoreceptors, resulting in increased visual acuity to approximately 60% of controls. Surprisingly, these effects were comparable to recovery mediated by photoreceptor-targeted gene supplementation. This strategy paves the way for the treatment of hereditary disorders caused by mutations in larger genes where traditional gene replacement therapies are not currently feasible.

  5. Comparison of plasticity between rod and cone visual pathways

    Grant number:16K11315  2016.4 - 2019.3

    Nishiguchi Koji

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    Authorship:Principal investigator 

    Grant amount:\4810000 ( Direct Cost: \3700000 、 Indirect Cost:\1110000 )

    Mice defective of Pde6c and Gnat1 resulting in congenital lack of cone and rod function are virtually blind from birth. In this study, we treated mice of different ages by supplementing GNAT1 gene followed by assessment of visual recovery.
    As a result, the levels of functional restoration measured at the retina and visual cortex were not significantly different between mice treated at 1M, 3M, and 9M following GNAT1 gene supplementation therapy. Moreover, visual restoration at the level of visual cortex were similar to mice with only Pde6c defect.
    The results indicate that rod visual pathway in adult mice retain substantial plasticity.

  6. In vivo imaging of retinal ganglion cell function using adeno-associated virus

    Grant number:16K15730  2016.4 - 2018.3

    Nakazawa Toru

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    Glaucoma, a leading cause of blindness worldwide, is characterized by progressive loss of the retinal ganglion cells (RGCs). To study neuronal activity in pathogenesis of RGC death, we developed in vivo imaging for quantitating activities of neuronal activity. E-SARE drives neuronal activity dependent gene expression at high levels.
    The E-SARE-driven fluorescent protein reporters was packaged into AAV. The temporal activity was monitored using confocal ophthalmoscopy. Dark-adapted animals were kept in dark for 48 hours before use. Light-adapted animals were kept under a constant light for 6 hours after dark-adaptation for 48 hours before use. E-SARE reporter expression was induced by light stimulation, and localized in RGC. Increased reporter activity occurred by 2 hours after light stimuli, and decreased at 2hours after dark-adaptation showing 44% decreases. This E-SARE reporter in vivo cellular imaging is a usuful tool to assess the RGCs function in retinal diseases.

  7. Flatmount法を用いた毛様体・網膜幹細胞からの視細胞再生についての解析

    2007

    科学研究費補助金  若手研究(B),課題番号:19791263

    西口 康二

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Teaching Experience (On-campus) 1

  1. 現代医療と生命科学

    2021

 

Social Contribution 1

  1. 日本網膜色素変性症協会オンラインセミナー

    Role(s):Lecturer

    日本網膜色素変性症協会  2021.11

Media Coverage 1

  1. コラム執筆 Newspaper, magazine

    中日新聞