Details of a Researcher - Kurihara, Toshihide

Papers - Kurihara, Toshihide

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Prediction of causative genes in inherited retinal disorder from fundus photography and autofluorescence imaging using deep learning techniques

Fujinami-Yokokawa Y, Ninomiya H, Liu X, Yang L, Pontikos N, Yoshitake K, Iwata T, Sato Y, Hashimoto T, Tsunoda K, Miyata H, Fujinami K†

Br J Ophthalmol. (BMJ) bjophthalmol-2020-318544 2021

Accepted, ISSN 00071161

<sec><title>Background/Aims</title>To investigate the utility of a data-driven deep learning approach in patients with inherited retinal disorder (IRD) and to predict the causative genes based on fundus photography and fundus autofluorescence (FAF) imaging.

</sec><sec><title>Methods</title>Clinical and genetic data from 1302 subjects from 729 genetically confirmed families with IRD registered with the Japan Eye Genetics Consortium were reviewed. Three categories of genetic diagnosis were selected, based on the high prevalence of their causative genes: Stargardt disease (<italic>ABCA4</italic>), retinitis pigmentosa (<italic>EYS</italic>) and occult macular dystrophy (<italic>RP1L1</italic>). Fundus photographs and FAF images were cropped in a standardised manner with a macro algorithm. Images for training/testing were selected using a randomised, fourfold cross-validation method. The application program interface was established to reach the learning accuracy of concordance (target: >80%) between the genetic diagnosis and the machine diagnosis (<italic>ABCA4</italic>, <italic>EYS</italic>, <italic>RP1L1</italic> and normal).

</sec><sec><title>Results</title>A total of 417 images from 156 Japanese subjects were examined, including 115 genetically confirmed patients caused by the three prevalent causative genes and 41 normal subjects. The mean overall test accuracy for fundus photographs and FAF images was 88.2% and 81.3%, respectively. The mean overall sensitivity/specificity values for fundus photographs and FAF images were 88.3%/97.4% and 81.8%/95.5%, respectively.

</sec><sec><title>Conclusion</title>A novel application of deep neural networks in the prediction of the causative IRD genes from fundus photographs and FAF, with a high prediction accuracy of over 80%, was highlighted. These achievements will extensively promote the quality of medical care by facilitating early diagnosis, especially by non-specialists, access to care, reducing the cost of referrals, and preventing unnecessary clinical and genetic testing.

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Rice Bran and Vitamin B6 Suppress Pathological Neovascularization in a Murine Model of Age-Related Macular Degeneration as Novel HIF Inhibitors

Ibuki M*, Lee D*, Shinojima A*, Miwa Y, Tsubota K†, Kurihara T†

Int J Mol Sci. (MDPI AG) 21 ( 23 ) 1 - 24 2020.12

Accepted, ISSN 16616596

Pathological neovascularization in the eye is a leading cause of blindness in all age groups from retinopathy of prematurity (ROP) in children to age-related macular degeneration (AMD) in the elderly. Inhibiting neovascularization via antivascular endothelial growth factor (VEGF) drugs has been used for the effective treatment. However, anti-VEGF therapies may cause development of chorioretinal atrophy as they affect a physiological amount of VEGF essential for retinal homeostasis. Furthermore, anti-VEGF therapies are still ineffective in some cases, especially in patients with AMD. Hypoxia-inducible factor (HIF) is a strong regulator of VEGF induction under hypoxic and other stress conditions. Our previous reports have indicated that HIF is associated with pathological retinal neovascularization in murine models of ROP and AMD, and HIF inhibition suppresses neovascularization by reducing an abnormal increase in VEGF expression. Along with this, we attempted to find novel effective HIF inhibitors from natural foods of our daily lives. Food ingredients were screened for prospective HIF inhibitors in ocular cell lines of 661W and ARPE-19, and a murine AMD model was utilized for examining suppressive effects of the ingredients on retinal neovascularization. As a result, rice bran and its component, vitamin B6 showed inhibitory effects on HIF activation and suppressed VEGF mRNA induction under a CoCl2-induced pseudo-hypoxic condition. Dietary supplement of these significantly suppressed retinal neovascularization in the AMD model. These data suggest that rice bran could have promising therapeutic values in the management of pathological ocular neovascularization.

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Relationship between nerve fiber layer defect and the presence of epiretinal membrane in a Japanese population: The JPHC-NEXT Eye Study.

Uchida A, Sasaki M†, Motomura K, Yuki K, Kurihara T, Tomita Y, Ozawa Y, Yamagishi K†, Kawasaki R, Hanyuda A, Sawada N, Tsubota K, Tsugane S, Iso H

Sci Rep. (Scientific Reports) 10 ( 1 ) 779 - 779 2020.12

Accepted

The study subjects were residents of Chikusei city, Japan, aged 40 years or older who attended annual health check-up programs and participated in the JPHC-NEXT Eye Study which performed non-mydriatic fundus photography of both eyes. The relationship of glaucomatous fundus changes such as optic disc cupping (cup to disc ratio ≥ 0.7) and retinal nerve fiber layer defect (NFLD) with the presence of epiretinal membrane (ERM) were examined cross-sectionally. A total of 1990 persons gave consent to participate in this study in 2013. The overall prevalence of ERM was 12.9%. Of these, 1755 had fundus photographs of sufficient quality and no history of intraocular surgery (mean age: 62.3 ± 10.0 years). After adjusting for age, sex and refractive error, NFLD was positively associated with the presence of ERM (odds ratio [OR]: 2.48; 95% confidence interval [CI]: 1.24, 4.96; P = 0.010), but optic disc cupping was not (OR: 1.33; CI: 0.71, 2.48; P = 0.37). The results did not necessarily suggest an association between glaucoma and ERM, but indicated an association between NFLD and ERM.

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Genetic Spectrum of EYS-associated Retinal Disease in a Large Japanese Cohort: Identification of Disease-associated Variants with Relatively High Allele Frequency.

Yang L*, Fujinami K*†, Ueno S, Kuniyoshi K, Hayashi T, Kondo M, Mizota A, Naoi N, Shinoda K, Kameya S, Fujinami-Yokokawa Y, Liu X, Arno G, Pontikos N, Kominami T, Terasaki H, Sakuramoto H, Katagiri S, Mizobuchi K, Nakamura N, Mawatari G, Kurihara T, Tsubota K, Miyake Y, Yoshitake K, Iwata T, Tsunoda K

Sci Rep. (Scientific Reports) 10 ( 1 ) 5497 - 5497 2020.12

Accepted

Biallelic variants in the EYS gene are a major cause of autosomal recessive inherited retinal disease (IRD), with a high prevalence in the Asian population. The purpose of this study was to identify pathogenic EYS variants, to determine the clinical/genetic spectrum of EYS-associated retinal disease (EYS-RD), and to discover disease-associated variants with relatively high allele frequency (1%-10%) in a nationwide Japanese cohort. Sixty-six affected subjects from 61 families with biallelic or multiple pathogenic/disease-associated EYS variants were ascertained by whole-exome sequencing. Three phenotype groups were identified in EYS-RD: retinitis pigmentosa (RP; 85.94%), cone-rod dystrophy (CORD; 10.94%), and Leber congenital amaurosis (LCA; 3.12%). Twenty-six pathogenic/disease-associated EYS variants were identified, including seven novel variants. The two most prevalent variants, p.(Gly843Glu) and p.(Thr2465Ser) were found in 26 and twelve families (42.6%, 19.7%), respectively, for which the allele frequency (AF) in the Japanese population was 2.2% and 3.0%, respectively. These results expand the phenotypic and genotypic spectrum of EYS-RD, accounting for a high proportion of EYS-RD both in autosomal recessive RP (23.4%) and autosomal recessive CORD (9.9%) in the Japanese population. The presence of EYS variants with relatively high AF highlights the importance of considering the pathogenicity of non-rare variants in relatively prevalent Mendelian disorders.

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Clinical and Genetic Characteristics of 18 Patients from 13 Japanese Families with CRX-associated retinal disorder: Identification of Genotype-phenotype Association.

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

Sci Rep. (Scientific Reports) 10 ( 1 ) 9531 - 9531 2020.12

Accepted

Inherited retinal disorder (IRD) is a leading cause of blindness, and CRX is one of a number of genes reported to harbour autosomal dominant (AD) and recessive (AR) causative variants. Eighteen patients from 13 families with CRX-associated retinal disorder (CRX-RD) were identified from 730 Japanese families with IRD. Ophthalmological examinations and phenotype subgroup classification were performed. The median age of onset/latest examination was 45.0/62.5 years (range, 15-77/25-94). The median visual acuity in the right/left eye was 0.52/0.40 (range, -0.08-2.00/-0.18-1.70) logarithm of the minimum angle of resolution (LogMAR) units. There was one family with macular dystrophy, nine with cone-rod dystrophy (CORD), and three with retinitis pigmentosa. In silico analysis of CRX variants was conducted for genotype subgroup classification based on inheritance and the presence of truncating variants. Eight pathogenic CRX variants were identified, including three novel heterozygous variants (p.R43H, p.P145Lfs*42, and p.P197Afs*22). A trend of a genotype-phenotype association was revealed between the phenotype and genotype subgroups. A considerably high proportion of CRX-RD in ADCORD was determined in the Japanese cohort (39.1%), often showing the mild phenotype (CORD) with late-onset disease (sixth decade). Frequently found heterozygous missense variants located within the homeodomain underlie this mild phenotype. This large cohort study delineates the disease spectrum of CRX-RD in the Japanese population.

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Oral Bovine Milk Lactoferrin Administration Suppressed Myopia Development through Matrix Metalloproteinase 2 in a Mouse Model

Ikeda SI*, Kurihara T†, Toda M, Jiang X, Torii H, Tsubota K†

Nutrients. (MDPI AG) 12 ( 12 ) 1 - 9 2020.12

Accepted

Recent studies have reported an association between myopia development and local ocular inflammation. Lactoferrin (LF) is an iron-binding protein present in saliva, tears, and mother’s milk. Furthermore, sequestering iron by LF can cause its antibacterial property. Moreover, LF has an anti-inflammatory effect. We aimed to determine the suppressive effect of LF against the development and progress of myopia using a murine lens-induced myopia (LIM) model. We divided male C57BL/6J mice (3 weeks old) into two groups. While the experimental group was orally administered LF (1600 mg/kg/day, from 3-weeks-old to 7-weeks-old), a similar volume of Ringer’s solution was administered to the control group. We subjected the 4-week-old mice to −30 diopter lenses and no lenses on the right and left eyes, respectively. We measured the refraction and the axial length at baseline and 3 weeks after using a refractometer and a spectral domain optical coherence tomography (SD-OCT) system in both eyes. Furthermore, we determined the matrix metalloproteinase-2 (MMP-2) activity, and the amount of interleukin-6 (IL-6), MMP-2, and collagen 1A1 in the choroid or sclera. The eyes with a minus lens showed a refractive error shift and an axial length elongation in the control group, thus indicating the successful induction of myopia. However, there were no significant differences in the aforementioned parameters in the LF group. While LIM increased IL-6 expression and MMP-2 activity, it decreased collagen 1A1 content. However, orally administered LF reversed these effects. Thus, oral administration of LF suppressed lens-induced myopia development by modifying the extracellular matrix remodeling through the IL-6–MMP-2 axis in mice.

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Efficacy of the Newly Invented Eyelid Clamper in Ultra-Widefield Fundus Imaging

Ozawa N*, Mori K*, Katada Y, Tsubota K†, Kurihara T†

Life. (Life) 10 ( 12 ) 1 - 7 2020.12

Accepted

BACKGROUND: Ultra-widefield fundus imaging is widely used for obtaining wide angle images of the retina in one single image. Although it has a potential to obtain a wide area of retinal photographs, images are often obstructed by eyelashes or eye lids. In this study, we used a newly invented eyelid clamper, which can keep an eye open without touching conjunctiva or lid margin, to assess the efficacy in clinical use by comparing with conventional tape fixation. METHODS: Ultra-widefield fundus images were captured with an ultra-widefield imaging system in 19 patients who visited to the outpatient clinic of Department of Ophthalmology, Keio University Hospital with the eyelid clamper or a conventional tape fixation. The area of imaged retinas was outlined and quantified with pixels. After obtaining images, patients answered a questionnaire. RESULTS: The average number of pixels in total areas with the eyelid clamper or with tape fixation were 4.31 ± 0.35 and 4.32 ± 0.34 mega pixels, respectively, showing no significant difference between the groups (p = 0.889). The average face pain scale of the eyelid clamper was 1.13 on a scale of 0 to 5. The number of patients who did not feel any pain was nine (47.4%). CONCLUSIONS: The eyelid clamper can be applied in clinical setting and can better support obtaining sufficiently wide fundus images compared to a conventional tape fixation.

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Axial length shortening in a myopic child with anisometropic amblyopia after wearing violet light-transmitting eyeglasses for 2 years

Ofuji Y*, Torii H*, Yotsukura E, Mori K, Kurihara T, Negishi K, Tsubota K†

Am J Ophthalmol Case Rep. (Elsevier BV) 20 101002 2020.12

Accepted, ISSN 24519936

© 2020 The Authors Purpose: To report a case in which the axial length (AL) shortened and the choroid thickened due to the use of violet light-transmitting eyeglasses. Observations: A 4-year-old boy with high myopia was referred to Keio University Hospital. He was prescribed standard eyeglasses. Six months after the first visit, his best-corrected visual acuities were 1.2 and 0.4 in the right and left eyes, respectively, with the standard eyeglasses, and he was diagnosed with anisometropic amblyopia. The right eye then was patched for 6 hours daily during the daytime. Because of the availability of violet light-transmitting eyeglasses, we changed the eyeglasses and instructed his parents to have him engage in outdoor activities for over 2 hours daily to be exposed to sufficient violet light. As a result, the violet light entered his left eye and minimal violet light entered his right eye. The changes in the ALs, choroidal thicknesses, and cycloplegic objective refractions in the right and left eyes during 2 years of wearing violet light-transmitting eyeglasses were +0.85 and −0.20 mm, +4.9 and + 115.7 μm, and −1.02 and + 1.88 D, respectively. Conclusions and importance: We successfully described a case in which the myopia improved, the AL shortened, and the choroid thickened after using violet light-transmitting eyeglasses.

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Automatic screening for diabetic retinopathy in interracial fundus images using artificial intelligence

Katada Y*, Ozawa N*, Masayoshi K, Ofuji Y, Tsubota K†, Kurihara T†

Intell Based Med. (Elsevier BV) 3-4 100024 2020.12

Accepted, ISSN 2666-5212

The development of deep learning technology and high-performance computers in recent years has enabled significant improvement in the accuracy of image recognition, and efforts are currently being made toward the development of ophthalmic artificial intelligence (AI). In this study, deep learning was applied to fundus image analysis. The fundus images were automatically classified by their severity index and the recognition accuracies for Japanese and American data were compared. We trained a deep convolutional neural network and a support vector machine using a data set consisting of 35,126 open-source American clinical fundus images, which were graded for diabetic retinopathy by licensed ophthalmologists. The grading accuracy of the trained AI model was evaluated by comparison with its performance for 200 Japanese fundus images obtained at Keio University Hospital. The trained AI model exhibited a sensitivity of 81.5% and specificity of 71.9% for the American validation data set, and a sensitivity of 90.8% and specificity of 80.0% for the Japanese data set. This indicates that the proposed AI program developed using American image data can be applied to fundus photographs of Japanese subjects and thus represents an interracial screening model. It can be used for screening tests and applied to telemedicine systems.

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A Murine Model of Ischemic Retinal Injury Induced by Transient Bilateral Common Carotid Artery Occlusion

Lee D*, Miwa Y*, Jeong H, Ikeda SI, Katada Y, Tsubota K†, KuriharaT†

J Vis Exp. (Journal of Visualized Experiments) 2020 ( 165 ) 1 - 19 2020.11

Accepted, ISSN 1940087X

© 2020 JoVE Journal of Visualized Experiments. Diverse vascular diseases such as diabetic retinopathy, occlusion of retinal veins or arteries and ocular ischemic syndrome can lead to retinal ischemia. To investigate pathological mechanisms of retinal ischemia, relevant experimental models need to be developed. Anatomically, a main retinal blood supplying vessel is the ophthalmic artery (OpA) and OpA originates from the internal carotid artery of the common carotid artery (CCA). Thus, disruption of CCA could effectively cause retinal ischemia. Here, we established a mouse model of retinal ischemia by transient bilateral common carotid artery occlusion (tBCCAO) to tie the right CCA with 6-0 silk sutures and to occlude the left CCA transiently for 2 seconds via a clamp, and showed that tBCCAO could induce acute retinal ischemia leading to retinal dysfunction. The current method reduces reliance on surgical instruments by only using surgical needles and a clamp, shortens occlusion time to minimize unexpected animal death, which is often seen in mouse models of middle cerebral artery occlusion, and maintains reproducibility of common retinal ischemic findings. The model can be utilized to investigate the pathophysiology of ischemic retinopathies in mice and further can be used for in vivo drug screening.

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PPARα Agonist Oral Therapy in Diabetic Retinopathy

Tomita Y*, Lee D*, Tsubota K†, Kurihara T†

Biomedicines. (MDPI AG) 8 ( 10 ) 1 - 18 2020.10

Accepted

Diabetic retinopathy (DR) is an eye condition that develops after chronically poorly-managed diabetes, and is presently the main cause for blindness on a global scale. Current treatments for DR such as laser photocoagulation, topical injection of corticosteroids, intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents and vitreoretinal surgery are only applicable at the late stages of DR and there are possibilities of significant adverse effects. Moreover, the forms of treatment available for DR are highly invasive to the eyes. Safer and more effective pharmacological treatments are required for DR treatment, in particular at an early stage. In this review, we cover recently investigated promising oral pharmacotherapies, the methods of which are safer, easier to use, patient-friendly and pain-free, in clinical studies. We especially focus on peroxisome proliferator-activator receptor alpha (PPARα) agonists in which experimental evidence suggests PPARα activation may be closely related to the attenuation of vascular damages, including lipid-induced toxicity, inflammation, an excess of free radical generation, endothelial dysfunction and angiogenesis. Furthermore, oral administration of selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) agonists may induce hepatic fibroblast growth factor 21 expression, indirectly resulting in retinal protection in animal studies. Our review will enable more comprehensive approaches for understanding protective roles of PPARα for the prevention of DR development.

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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 2020.10

Accepted

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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A Fairy Chemical Suppresses Retinal Angiogenesis as a HIF Inhibitor

Lee D*, Miwa Y*, Wu J, Shoda C, Jeong H, Kawagishi H, Tsubota K†, Kurihara T†

Biomolecules. (MDPI AG) 10 ( 10 ) 1 - 14 2020.10

Accepted

Neovascular retinal degeneration is a leading cause of blindness in advanced countries. Anti-vascular endothelial growth factor (VEGF) drugs have been used for neovascular retinal diseases; however, anti-VEGF drugs may cause the development of chorioretinal atrophy in chronic therapy as they affect the physiological amount of VEGF needed for retinal homeostasis. Hypoxia-inducible factor (HIF) is a transcription factor inducing VEGF expression under hypoxic and other stress conditions. Previously, we demonstrated that HIF was involved with pathological retinal angiogenesis in murine models of oxygen-induced retinopathy (OIR), and pharmacological HIF inhibition prevented retinal neovascularization by reducing an ectopic amount of VEGF. Along with this, we attempted to find novel effective HIF inhibitors. Compounds originally isolated from mushroom-forming fungi were screened for prospective HIF inhibitors utilizing cell lines of 3T3, ARPE-19 and 661W. A murine OIR model was used to examine the anti-angiogenic effects of the compounds. As a result, 2-azahypoxanthine (AHX) showed an inhibitory effect on HIF activation and suppressed Vegf mRNA upregulation under CoCl2-induced pseudo-hypoxic conditions. Oral administration of AHX significantly suppressed retinal neovascular tufts in the OIR model. These data suggest that AHX could be a promising anti-angiogenic agent in retinal neovascularization by inhibiting HIF activation.

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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) 2020.09

Last author, Corresponding author

<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

Am J Med Genet C Semin Med Genet. (Wiley) 184 ( 3 ) 675 - 693 2020.09

Accepted, 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†

Int J Mol Sci. (International Journal of Molecular Sciences) 21 ( 17 ) 1 - 17 2020.09

Accepted, 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 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†

Am J Med Genet C Semin Med Genet. (American Journal of Medical Genetics, Part C: Seminars in Medical Genetics) 184 ( 3 ) 694 - 707 2020.09

Accepted, 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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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

Am J Med Genet C Semin Med Genet. (American Journal of Medical Genetics, Part C: Seminars in Medical Genetics) 184 ( 3 ) 656 - 674 2020.09

Accepted, ISSN 15524868

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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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 2020.08

Accepted, 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 2020.08

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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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