研究者詳細 - 栗原　俊英

論文 - 栗原　俊英

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Association between axial length and choroidal thickness in early age-related macular degeneration

Sato M., Minami S., Nagai N., Suzuki M., Kurihara T., Shinojima A., Sonobe H., Akino K., Ban N., Watanabe K., Uchida A., Shinoda H., Tsubota K., Ozawa Y.

PLoS ONE （PLoS ONE） 15 （ 10 ） e0240357 2020年10月

査読有り

© 2020 Sato et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The clinical course of age-related macular degeneration (AMD) is related to choroidal conditions, and can be determined by the evaluation of the central choroidal thickness (CCT). The aim of this study was to determine the association between the axial length (AL) and choroidal thickness in AMD by measuring these parameters in patients with and without AMD. Seventy eyes of 70 patients (34 men and 36 women; age, 64-88 years; mean age, 77.0 ± 6.5 years) who underwent cataract surgery from February 2015 to March 2020 at the Department of Ophthalmology, Keio University School of Medicine were retrospectively analyzed. The AMD group (29 patients, 29 eyes) included eyes with early AMD, whereas the control group (41 patients, 41 eyes) included those without ocular diseases other than cataract. Optical coherence tomography images were used to measure the CCT and the choroidal vessel diameter (CVD). The IOL Master was used to measure the AL. The results revealed that mean CCT was greater in the AMD group (238.3 ± 108.3 μm) compared with the age-matched control group (187.2 ± 66.8 μm) (p = 0.03). The CCT was negatively correlated with AL in the overall sample (r = -0.42, p = 0.001), the AMD group (r = -0.42, p = 0.02), and the control group (r = -0.42, p = 0.006). Note that all eyes with CCT > 350 μm were included in the AMD group. CCT and CVD were positively correlated in the overall sample (r = 0.76, p < 0.001) as well as in the individual groups (AMD: R = 0.82, p < 0.001; control: R = 0.76, p = 0.004). Given that CCT is an important parameter for predicting the prognosis of subfoveal diseases, routine evaluation of AL may be valuable for a better understanding of the pathogenesis of AMD.

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High-sensitivity vision restoration via ectopic expression of chimeric rhodopsin in mice

Katada Y, Yoshida K, Kobayashi K, Okano H, Kandori H, Tsubota K†, Kurihara T†

bioRxiv. （Cold Spring Harbor Laboratory） 2020年09月

最終著者, 責任著者

<title>Abstract</title>Photoreception requires amplification by mammalian rhodopsin through G protein activation, which requires a visual cycle. To achieve this in retinal gene therapy, we incorporated human rhodopsin cytoplasmic loops into <italic>Gloeobacter</italic> rhodopsin, thereby generating <italic>Gloeobacter</italic> and human chimeric rhodopsin (GHCR). In a murine model of inherited retinal degeneration, we induced retinal GHCR expression by intravitreal injection of a recombinant adeno-associated virus vector. Retinal explant and visual thalamus electrophysiological recordings, behavioral tests, and histological analysis showed that GHCR restored dim-environment vision and prevented the progression of retinal degeneration. Thus, GHCR may be a potent clinical tool for the treatment of retinal disorders.

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RP2-associated retinal disorder in a Japanese cohort: Report of novel variants and a literature review, identifying a genotype–phenotype association

Fujinami K., Liu X., Ueno S., Mizota A., Shinoda K., Kuniyoshi K., Fujinami-Yokokawa Y., Yang L., Arno G., Pontikos N., Kameya S., Kominami T., Terasaki H., Sakuramoto H., Nakamura N., Kurihara T., Tsubota K., Miyake Y., Yoshiake K., Iwata T., Tsunoda K.

American Journal of Medical Genetics, Part C: Seminars in Medical Genetics （American Journal of Medical Genetics, Part C: Seminars in Medical Genetics） 184 （ 3 ） 675 - 693 2020年09月

査読有り, ISSN 15524868

© 2020 The Authors. American Journal of Medical Genetics Part C: Seminars in Medical Genetics published by Wiley Periodicals LLC. The retinitis pigmentosa 2 (RP2) gene is one of the causative genes for X-linked inherited retinal disorder. We characterized the clinical/genetic features of four patients with RP2-associated retinal disorder (RP2-RD) from four Japanese families in a nationwide cohort. A systematic review of RP2-RD in the Japanese population was also performed. All four patients were clinically diagnosed with retinitis pigmentosa (RP). The mean age at examination was 36.5 (10–47) years, and the mean visual acuity in the right/left eye was 1.40 (0.52–2.0)/1.10 (0.52–1.7) in the logarithm of the minimum angle of resolution unit, respectively. Three patients showed extensive retinal atrophy with macular involvement, and one had central retinal atrophy. Four RP2 variants were identified, including two novel missense (p.Ser6Phe, p.Leu189Pro) and two previously reported truncating variants (p.Arg120Ter, p.Glu269CysfsTer3). The phenotypes of two patients with truncating variants were more severe than the phenotypes of two patients with missense variants. A systematic review revealed additional 11 variants, including three missense and eight deleterious (null) variants, and a statistically significant association between phenotype severity and genotype severity was revealed. The clinical and genetic spectrum of RP2-RD was illustrated in the Japanese population, identifying the characteristic features of a severe form of RP with early macular involvement.

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Pemafibrate protects against retinal dysfunction in a murine model of diabetic retinopathy

Tomita Y., Lee D., Miwa Y., Jiang X., Ohta M., Tsubota K., Kurihara T.

International Journal of Molecular Sciences （International Journal of Molecular Sciences） 21 （ 17 ） 1 - 17 2020年09月

査読有り, ISSN 16616596

© 2020, MDPI AG. All rights reserved. Diabetic retinopathy (DR) is one of the leading causes of blindness globally. Retinal neuronal abnormalities occur in the early stage in DR. Therefore, maintaining retinal neuronal activity in DR may prevent vision loss. Previously, pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, was suggested as a promising drug in hypertriglyceridemia. However, the role of pemafibrate remains obscure in DR. Therefore, we aimed to unravel systemic and retinal changes by pemafibrate in diabetes. Adult mice were intraperitoneally injected with streptozotocin (STZ) to induce diabetes. After STZ injection, diet supplemented with pemafibrate was given to STZ-induced diabetic mice for 12 weeks. During the experiment period, body weight and blood glucose levels were examined. Electroretinography was performed to check the retinal neural function. After sacrifice, the retina, liver, and blood samples were subjected to molecular analyses. We found pemafibrate mildly improved blood glucose level as well as lipid metabolism, boosted liver function, increased serum fibroblast growth factor21 level, restored retinal functional deficits, and increased retinal synaptophysin protein expression in STZ-induced diabetic mice. Our present data suggest a promising pemafibrate therapy for the prevention of early DR by improving systemic metabolism and protecting retinal function.

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Clinical and genetic characteristics of 10 Japanese patients with PROM1-associated retinal disorder: A report of the phenotype spectrum and a literature review in the Japanese population

Fujinami K., Oishi A., Yang L., Arno G., Pontikos N., Yoshitake K., Fujinami-Yokokawa Y., Liu X., Hayashi T., Katagiri S., Mizobuchi K., Mizota A., Shinoda K., Nakamura N., Kurihara T., Tsubota K., Miyake Y., Iwata T., Tsujikawa A., Tsunoda K.

American Journal of Medical Genetics, Part C: Seminars in Medical Genetics （American Journal of Medical Genetics, Part C: Seminars in Medical Genetics） 184 （ 3 ） 656 - 674 2020年09月

査読有り, ISSN 15524868

© 2020 The Authors. American Journal of Medical Genetics Part C: Seminars in Medical Genetics published by Wiley Periodicals LLC. Variants in the PROM1 gene are associated with cone (−rod) dystrophy, macular dystrophy, and other phenotypes. We describe the clinical and genetic characteristics of 10 patients from eight Japanese families with PROM1-associated retinal disorder (PROM1-RD) in a nationwide cohort. A literature review of PROM1-RD in the Japanese population was also performed. The median age at onset/examination of 10 patients was 31.0 (range, 10–45)/44.5 (22–73) years. All 10 patients showed atrophic macular changes. Seven patients (70.0%) had spared fovea to various degrees, approximately half of whom had maintained visual acuity. Generalized cone (−rod) dysfunction was demonstrated in all nine subjects with available electrophysiological data. Three PROM1 variants were identified in this study: one recurrent disease-causing variant (p.Arg373Cys), one novel putative disease-causing variant (p.Cys112Arg), and one novel variant of uncertain significance (VUS; p.Gly53Asp). Characteristic features of macular atrophy with generalized cone-dominated retinal dysfunction were shared among all 10 subjects with PROM1-RD, and the presence of foveal sparing was crucial in maintaining visual acuity. Together with the three previously reported variants [p.R373C, c.1551+1G'A (pathogenic), p.Asn580His (likely benign)] in the literature of Japanese patients, one prevalent missense variant (p.Arg373Cys, 6/9 families, 66.7%) detected in multiple studies was determined in the Japanese population, which was also frequently detected in the European population.

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Clinical and genetic characteristics of Stargardt disease in a large Western China cohort: Report 1

Liu X., Meng X., Yang L., Long Y., Fujinami-Yokokawa Y., Ren J., Kurihara T., Tsubota K., Tsunoda K., Fujinami K., Li S.

American Journal of Medical Genetics, Part C: Seminars in Medical Genetics （American Journal of Medical Genetics, Part C: Seminars in Medical Genetics） 184 （ 3 ） 694 - 707 2020年09月

査読有り, ISSN 15524868

© 2020 The Authors. American Journal of Medical Genetics Part C: Seminars in Medical Genetics published by Wiley Periodicals LLC. Stargardt disease 1 (STGD1) is the most prevalent retinal dystrophy caused by pathogenic biallelic ABCA4 variants. Forty-two unrelated patients mostly originating from Western China were recruited. Comprehensive ophthalmological examinations, including visual acuity measurements (subjective function), fundus autofluorescence (retinal imaging), and full-field electroretinography (objective function), were performed. Next-generation sequencing (target/whole exome) and direct sequencing were conducted. Genotype grouping was performed based on the presence of deleterious variants. The median age of onset/age was 10.0 (5–52)/29.5 (12–72) years, and the median visual acuity in the right/left eye was 1.30 (0.15–2.28)/1.30 (0.15–2.28) in the logarithm of the minimum angle of resolution unit. Ten patients (10/38, 27.0%) showed confined macular dysfunction, and 27 (27/37, 73.7%) had generalized retinal dysfunction. Fifty-eight pathogenic/likely pathogenic ABCA4 variants, including 14 novel variants, were identified. Eight patients (8/35, 22.8%) harbored multiple deleterious variants, and 17 (17/35, 48.6%) had a single deleterious variant. Significant associations were revealed between subjective functional, retinal imaging, and objective functional groups, identifying a significant genotype–phenotype association. This study illustrates a large phenotypic/genotypic spectrum in a large well-characterized STGD1 cohort. A distinct genetic background of the Chinese population from the Caucasian population was identified; meanwhile, a genotype–phenotype association was similarly represented.

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Closure of macular hole secondary to ischemic hemi-central retinal vein occlusion by retinal photocoagulation and topical anti-inflammatory treatment.

Asato T, Nagai N, Suzuki M, Uchida A, Kurihara T, Ban N, Minami S, Shinoda H, Tsubota K, Ozawa Y†

Lasers Med Sci. （Lasers in Medical Science） 36 （ 2 ） 469 - 471 2020年08月

査読有り, ISSN 02688921

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Starburst amacrine cells amplify optogenetic visual restoration through gap junctions.

Katada Y, Kunimi H, Kobayashi K, Okano H, Tanaka KF, Tsubota K†, Kurihara T†

bioRxiv. （Molecular Therapy - Methods and Clinical Development） 30 1 - 14 2020年08月

最終著者, 責任著者

Ectopic induction of optogenetic actuators, such as channelrhodopsin, is a promising approach to restoring vision in the degenerating retina. However, the cell type-specific response of ectopic photoreception has not been well understood. There are limits to obtaining efficient gene expression in a specifically targeted cell population by a transgenic approach. In the present study, we established a murine model with high efficiency of gene induction to retinal ganglion cells (RGCs) and amacrine cells using an improved tetracycline transactivator-operator bipartite system (KENGE-tet system). To investigate the cell type-specific visual restorative effect, we expressed the channelrhodopsin gene into RGCs and amacrine cells using the KENGE-tet system. As a result, enhancement in the visual restorative effect was observed to RGCs and starburst amacrine cells. In conclusion, a photoresponse from amacrine cells may enhance the maintained response of RGCs and further increase or improve the visual restorative effect.

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Hyperreflective material in optical coherence tomography images of eyes with myopic choroidal neovascularization may affect the visual outcome

Mushiga Y., Minami S., Uchida A., Nagai N., Suzuki M., Kurihara T., Sonobe H., Ban N., Watanabe K., Shinoda H., Tsubota K., Ozawa Y.

Journal of Clinical Medicine （Journal of Clinical Medicine） 9 （ 8 ） 1 - 10 2020年08月

査読有り

The visual outcome of myopic choroidal neovascularization (CNV) after anti-vascular endothelial growth factor (anti-VEGF) therapy varies among individuals. We retrospectively analyzed the data of 24 eyes (24 patients) with treatment-naïve myopic CNV who underwent anti-VEGF monotherapy following a pro-re-nata regimen at the Division of Medical Retina Clinic, Department of Ophthalmology, Keio University Hospital between May 2014 and December 2017. The mean age was 70.6 ± 2.1 years, and 16 (66.7%) patients were female. Overall, the mean best-corrected visual acuity (BCVA) improved (p = 0.034), and the mean height of the hyperreflective material (HRM), involving the CNV lesion recorded by optical coherence tomography, decreased (p < 0.01) 12 months after the initial treatment. Fifteen eyes (62.5%) achieved a BCVA of better than 0.10 in LogMAR at 12 months; they had a better BCVA (p = 0.015) and lower HRM intensity (p = 0.033) at baseline than the others. Remarkably, the BCVA improved (p < 0.05) and the HRM height (p < 0.01) decreased only in eyes with a final BCVA better than 0.10 as early as 1 month after the initial treatment, which was still present at 12 months. The HRM height and intensity, not only the BCVA, would be valuable in evaluating the prognosis of myopic CNV after anti-VEGF therapy, although further study is required.

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Retinal microglia are critical for subretinal neovascular formation

Usui-Ouchi A., Usui Y., Kurihara T., Aguilar E., Dorrell M.I., Ideguchi Y., Sakimoto S., Bravo S., Friedlander M.

JCI Insight （JCI Insight） 5 （ 12 ） 137317 2020年06月

査読有り

© 2020, American Society for Clinical Investigation. Abnormal subretinal neovascularization is a characteristic of vision-threatening retinal diseases, including macular telangiectasia (MacTel) and retinal angiomatous proliferation (RAP). Subretinal neovascular tufts and photoreceptor dysfunction are observed in very-low-density lipoprotein receptor (Vldlr–/–) mutant mice. These changes mirror those observed in patients with MacTel and RAP, but the pathogenesis is largely unknown. In this study, we show that retinal microglia were closely associated with retinal neovascular tufts in Vldlr–/– mice and retinal tissue from patients with MacTel; ablation of microglia/macrophages dramatically prevented formation of retinal neovascular tufts and improved neuronal function, as assessed by electroretinography. Vldlr–/– mice with retinal pigmented epithelium–specific (RPE-specific) Vegfa had greatly reduced subretinal infiltration of microglia/macrophages, subsequently reducing neovascular tufts. These findings highlight the contribution of microglia/macrophages to the pathogenesis of neovascularization, provide valuable clues regarding potential causative cellular mechanisms for subretinal neovascularization in patients with MacTel and RAP and suggest that targeting microglia activation may be a therapeutic option in these diseases.

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The area and number of intraretinal cystoid spaces predict the visual outcome after ranibizumab monotherapy in diabetic macular Edema

Nagai N., Suzuki M., Uchida A., Kurihara T., Ban N., Minami S., Shinoda H., Tsubota K., Ozawa Y.

Journal of Clinical Medicine （Journal of Clinical Medicine） 9 （ 5 ） E1391 2020年05月

査読有り

Visual outcomes in diabetic macular edema (DME) after anti-vascular endothelial growth factor therapy vary across individuals. We retrospectively reviewed the clinical records for 46 treatment-naive eyes of 46 patients with DME who underwent intravitreal ranibizumab (IVR) monotherapy with a pro re nata regimen for 12 months. Overall, mean best-corrected visual acuity (BCVA) improved. Multivariate analyses adjusted for age and baseline BCVA showed that the area ratio, compared with the retinal area, and the number of intraretinal cystoid spaces evaluated on OCT (optical coherence tomography) images at baseline positively correlated with LogMAR BCVA and the extents of ellipsoid zone and external limiting membrane disruption at 12 months, and negatively correlated with central retinal thickness at the time of edema resolution. Therefore, a high area ratio and large number of intraretinal cystoid spaces resulted in a disorganized outer retinal structure at 12 months, a thin and atrophic retina after edema resolution, and a worse visual outcome. The area ratio and number of intraretinal cystoid spaces on initial OCT images were predictors of the visual outcome after IVR therapy in DME irrespective of baseline age and BCVA. The factors were related to retinal neurodegenerative changes in DME and could help in obtaining proper informed consent before treatment.

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Clinical and genetic characteristics of 15 affected patients from 12 Japanese families with GUCY2D-associated retinal disorder

Liu X., Fujinami K., Kuniyoshi K., Kondo M., Ueno S., Hayashi T., Mochizuki K., Kameya S., Yang L., Fujinami-Yokokawa Y., Arno G., Pontikos N., Sakuramoto H., Kominami T., Terasaki H., Katagiri S., Mizobuchi K., Nakamura N., Yoshitake K., Miyake Y., Li S., Kurihara T., Tsubota K., Iwata T., Tsunoda K., Consortium J.E.G.

Translational Vision Science and Technology （Translational Vision Science and Technology） 9 （ 6 ） 2 - 2 2020年05月

査読有り

© 2020 The Authors. Purpose: To determine the clinical and genetic characteristics of patients with GUCY2D-associated retinal disorder (GUCY2D-RD). Methods: Fifteen patients from 12 families with inherited retinal disorder (IRD) and harboring GUCY2D variants were ascertained from 730 Japanese families with IRD. Comprehensive ophthalmological examinations, including visual acuity (VA) measure-ment, retinal imaging, and electrophysiological assessment were performed to classify patients into three phenotype subgroups; macular dystrophy (MD), cone-rod dystrophy (CORD), and Leber congenital amaurosis (LCA). In silico analysis was performed for the detected variants, and the molecularly confirmed inheritance pattern was determined (autosomal dominant/recessive [AD/AR]). Results: The median age of onset/examination was 22.0/38.0 years (ranges, 0-55 and 1-73) with a median VA of 0.80/0.70 LogMAR units (ranges, 0.00-1.52 and 0.10-1.52) in the right/left eye, respectively. Macular atrophy was identified in seven patients (46.7%), and two had diffuse fundus disturbance (13.3%), and six had an essentially normal fundus (40.0%). There were 11 patients with generalized cone-rod dysfunction (78.6%), two with entire functional loss (14.3%), and one with confined macular dysfunction (7.1%). There were nine families with ADCORD, one with ARCORD, one with ADMD, and one with ARLCA. Ten GUCY2D variants were identified, including four novel variants (p.Val56GlyfsTer262, p.Met246Ile, p.Arg761Trp, p.Glu874Lys). Conclusions: This large cohort study delineates the disease spectrum of GUCY2D-RD. Diverse clinical presentations with various severities of ADCORD and the early-onset severe phenotype of ARLCA are illustrated. A relatively lower prevalence of GUCY2D-RD for ADCORD and ARLCA in the Japanese population was revealed. Translational Relevance: The obtained data help to monitor and counsel patients, especially in East Asia, as well as to design future therapeutic approaches.

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Macular pigment optical density and photoreceptor outer segment length as predisease biomarkers for age-related macular degeneration

Nagai N., Minami S., Suzuki M., Shinoda H., Kurihara T., Sonobe H., Watanabe K., Uchida A., Ban N., Tsubota K., Ozawa Y.

Journal of Clinical Medicine （Journal of Clinical Medicine） 9 （ 5 ） E1347 2020年05月

査読有り

To explore predisease biomarkers, which may help screen for the risk of age-related macular degeneration (AMD) at very early stages, macular pigment optical density (MPOD) and photoreceptor outer segment (PROS) length were analyzed. Thirty late AMD fellow eyes, which are at high risk and represent the predisease condition of AMD, were evaluated and compared with 30 age-matched control eyes without retinal diseases; there was no early AMD involvement in the AMD fellow eyes. MPOD was measured using MPS2® (M.E. Technica Co. Ltd., Tokyo, Japan), and PROS length was measured based on optical coherence tomography images. MPOD levels and PROS length in the AMD fellow eyes were significantly lower and shorter, respectively, than in control eyes. MPOD and PROS length were positively correlated in control eyes (R = 0.386; p = 0.035) but not in AMD fellow eyes. Twenty (67%) AMD fellow eyes met the criteria of MPOD < 0.65 and/or PROS length < 35 µm, while only five (17%) control eyes did. After adjusting for age and sex, AMD fellow eyes more frequently satisfied the definition (p < 0.001; 95% confidence interval, 3.50–60.4; odds ratio, 14.6). The combination of MPOD and PROS length may be a useful biomarker for screening predisease AMD patients, although further studies are required in this regard.

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Hypoxia-inducible factor inhibitors derived from marine products suppress a murine model of neovascular retinopathy

Shoda C., Miwa Y., Nimura K., Okamoto K., Yamagami S., Tsubota K., Kurihara T.

Nutrients （Nutrients） 12 （ 4 ） 1055 2020年04月

査読有り

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Neovascular retinal degenerative diseases are the leading causes of blindness in developed countries. Anti-vascular endothelial growth factor (VEGF) therapy is commonly used to treat these diseases currently. However, recent reports indicate that long term suppression of VEGF in the eye is associated with chorioretinal atrophy. Therefore, a physiological amount of VEGF is required for retinal homeostasis. Hypoxia-inducible factor (HIF) is a transcriptional factor upstream of VEGF. We previously reported that HIF regulated pathological angiogenesis in the retina of murine models of oxygen-induced retinopathy and laser-induced choroidal neovascularization. Most of the known HIF inhibitors are anti-cancer agents which may have systemic adverse effects in for clinical use; thus, there is a need for safer and less invasive HIF inhibitors. In this study, we screened marine products, especially fish ingredients, and found that six species of fish had HIF inhibitory effects. Among them, administration of Decapterus tabl ingredients significantly suppressed retinal neovascular tufts by inhibiting HIF expression in a murine oxygen-induced retinopathy model. These results indicate that particular fish ingredients can act as anti-angiogenic agents in retinal neovascularization diseases.

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Correlation between macular pigment optical density and neural thickness and volume of the retina

Nagai N., Asato T., Minami S., Suzuki M., Shinoda H., Kurihara T., Sonobe H., Watanabe K., Uchida A., Ban N., Tsubota K., Ozawa Y.

Nutrients （Nutrients） 12 （ 4 ） 1 - 10 2020年04月

査読有り

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Macular pigment (MP), which is composed of lutein/zeaxanthin/mezo-zeaxanthin, is concentrated in the central part of the retina, the macula. It protects the macula by absorbing short-wavelength light and suppressing oxidative stress. To evaluate whether MP levels are related to retinal neural protection and resulting health, we analyzed the association between the MP optical density (MPOD), and the macular thickness and volumes. Forty-three eyes of 43 healthy adult volunteers (21 men and 22 women; age: 22–48 (average 31.4 ± 1.1) years) were analyzed. Highly myopic eyes (<-6 diopters) were excluded. MPOD was measured using MPS2®, and the neural retinal thickness and volume were measured using optical coherence tomography. The mean MPOD was 0.589 ± 0.024, and it positively correlated with the central retinal thickness (P = 0.017, R = 0.360) and retinal volume of the fovea (1-mm diameter around the fovea; P = 0.029, R = 0.332), parafovea (1–3-mm diameter; P = 0.002, R = 0.458), and macula (6-mm diameter; P = 0.003, R = 0.447). In the macular area (diameter: 6 mm), MPOD was correlated with the retinal neural volume of the ganglion cell layer (P = 0.037, R = 0.320), inner plexiform layer (P = 0.029, R = 0.333), and outer nuclear layer (P = 0.020, R = 0.353). Thus, MPOD may help in estimating neural health. Further studies should determine the impact of MP levels on neuroprotection.

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Lactoferrin Has a Therapeutic Effect via HIF Inhibition in a Murine Model of Choroidal Neovascularization

Ibuki M., Shoda C., Miwa Y., Ishida A., Tsubota K., Kurihara T.

Frontiers in Pharmacology （Frontiers in Pharmacology） 11 174 - 174 2020年02月

査読有り

© Copyright © 2020 Ibuki, Shoda, Miwa, Ishida, Tsubota and Kurihara. Background: Lactoferrin, a type of glycoprotein, is contained in exocrine fluids such as tears, breast milk, sweat, and saliva, and is known to have anti-microbial, antioxidant, and anti-cancer effects. In the ophthalmological field, topical administration of lactoferrin has been reported to have a therapeutic effect in a murine dry eye model. Hypoxia-inducible factor (HIF) regulates various gene expressions under hypoxia, including vascular endothelial growth factor (VEGF), and is considered as an alternative target for neovascular ocular diseases such as age-related macular degeneration (AMD). We previously screened natural products and identified lactoferrin as a novel HIF inhibitor. In this study, we confirmed that lactoferrin has an HIF inhibitory effect and a therapeutic effect in a murine model of neovascular AMD. Methods: HIF inhibitory effects of lactoferrin were evaluated using a luciferase assay and western blotting in vitro. The quantified volume of choroidal neovascularization (CNV) induced by laser irradiation was compared with oral lactoferrin administration or conditional tissue specific Hif1a knockout mice. Results: Lactoferrin administration showed a significant HIF inhibitory effect in the retinal neuronal cells. Oral administration of lactoferrin or conditional Hif1a gene deletion significantly reduced CNV volume compared to controls. Conclusions: Lactoferrin has a therapeutic effect in a laser CNV model by suppressing the retinal HIF activity.

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Predicting recurrences of macular edema due to branch retinal vein occlusion during anti-vascular endothelial growth factor therapy

Suzuki M., Nagai N., Minami S., Kurihara T., Kamoshita M., Sonobe H., Watanabe K., Shinoda H., Tsubota K., Ozawa Y.

Graefe's Archive for Clinical and Experimental Ophthalmology （Graefe's Archive for Clinical and Experimental Ophthalmology） 258 （ 1 ） 49 - 56 2020年01月

査読有り, ISSN 0721832X

© 2019, The Author(s). Purpose: To determine the predictive factors for recurrent macular edema due to branch retinal vein occlusion (BRVO) during intravitreal ranibizumab (IVR) monotherapy. Methods: Clinical records were retrospectively reviewed for 65 patients (mean age 66.5 years, 65 eyes) who were diagnosed with macular edema due to BRVO and treated with IVR monotherapy for 12 months at the Medical Retina Division, Department of Ophthalmology, Keio University Hospital between October 2013 and August 2017. Best-corrected visual acuity (BCVA), fundus findings, and sectional optical coherence tomography (OCT) images were analyzed. Results: Overall BCVA and central retinal thickness (CRT) improved (all p < 0.01). BCVA at 12 months was significantly worse in patients with recurrent macular edema (40 eyes [61.5%]) (p < 0.01) than in those without, while CRT decreased and was comparable in both groups at 12 months. Logistic regression analyses showed association of recurrence with disorganization of the retinal inner layer (DRIL) temporal to the fovea at baseline (odds ratio = 7.74; 95% confidence interval 1.62–37.08, p = 0.01), after adjusting for age, gender, and initial CRT. Conclusion: Recurrent macular edema due to BRVO affects visual outcome and is associated with initial DRIL temporal to the fovea, evaluated using OCT sectional images before treatments. DRIL may facilitate determination of follow-up schedules in clinical practice.

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Estimation of the minimum effective dose of dietary supplement crocetin for prevention of myopia progression in mice.

Mori K, Kurihara T†, Jiang X, Ikeda SI, Yotsukura E, Torii H, Tsubota K†

Nutrients. 12 （ 1 ） 180 2020年01月

責任著者, 査読有り

Risk of newly developing visual field defect and neurodegeneration after pars plana vitrectomy for idiopathic epiretinal membrane

Akino K., Nagai N., Watanabe K., Ban N., Kurihara T., Uchida A., Shinoda H., Tsubota K., Ozawa Y.

British Journal of Ophthalmology （British Journal of Ophthalmology） 105 （ 12 ） 1683 - 1687 2020年

査読有り, ISSN 00071161

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. Background/Aims: Pars plana vitrectomy (PPV) is widely performed in patients with idiopathic epiretinal membrane (iERM) to improve vision. Postoperative visual field defects (VFDs) have been previously reported. However, whether they occur when using the most recent PPV system, and the frequency of VFDs as measured by standard automated perimetry, remain poorly documented and were examined in this study. Methods: Data of 30 eyes (30 patients; mean age, 66.1 years; 15 men) who underwent PPV for iERM during February 2016-June 2019 and had preoperative and postoperative visual field measurements using standard automated perimetry (Humphrey visual field analyser 30-2 program) were retrospectively analysed. Eyes with diseases other than iERM, including moderate-to-severe cataract or preoperative VFDs were excluded. Results: VFD, defined by the Anderson and Patella's criteria, was found in 73.3% of the eyes 1 month after PPV. After age adjustment, internal limiting membrane (ILM) peeling was identified as a risk factor for postoperative VFD (p=0.035; 95% CI 1.173 to 92.8). Postoperative VFD was frequently observed nasally (86.4%, p=0.002), and on optical coherence tomography measurements, ganglion cell layer (GCL) thinning was found temporal to the fovea (p=0.008). Thinning of the superior and inferior retinal nerve fibre layers and of the GCL temporal to the fovea were significant in eyes after ILM peeling (all p<0.05). Conclusion: ILM peeling may cause inner retinal degeneration and lead to the development of VFDs after PPV, which should be further examined.

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Long-term follow-up of a Chinese patient with KCNV2-retinopathy

Lie H., Wang G., Liu X., Meng X., Long Y., Ren J., Yang L., Fujinami-Yokokawa Y., Kurihara T., Tsubota K., Fujinami K., Li S.

Ophthalmic Genetics （Ophthalmic Genetics） 42 （ 2 ） 144 - 149 2020年

査読有り, ISSN 13816810

© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC. Purpose: To characterize and monitor the clinical and electrophysiological features of a Chinese patient with KCNV2 retinopathy. Methods: A 17-year-old Chinese male with the diagnosis of cone dystrophy with supernormal rod response (CDSRR) was followed-up for 5 years, with full ophthalmological examinations, including decimal best corrected visual acuity (BCVA), fundus photography, fundus autofluorescence (FAF) imaging, spectral-domain optical coherence tomography (SD-OCT), and full-field electroretinogram (ERG). Genetic screening was performed to detect the sequence variations in the retinal dystrophy associated genes in the patient and his parents. Results: The patient demonstrated the characteristic full-field electroretinography (ERG) features of CDSRR, namely a profound enlargement of the dark-adapted ERG b-wave amplitude with increasing flash strength and a broadened a-wave trough; this case also had undetectable light-adapted ERGs. A BCVA of 0.15 was maintained over 5 years in both eyes; while progressive macular atrophy was identified. Molecular genetic analyses revealed two novel disease-causing KCNV2 variants in compound heterozygous state: c.1408 G > C (p.Gly470Arg) and c.1500 C > G (p.Tyr500Ter). Conclusions: This is the first long-term case study of an East Asian patient with molecularly confirmed CDSRR. The progressive atrophy with maintained VA demonstrated in this case will be valuable for increasing the understanding of the natural course of KCNV2 retinopathy and it will help in counselling patients with this disease.

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