論文 - 池田 康博
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Genetic Risk Stratification of Primary Open-Angle Glaucoma in Japanese Individuals. 査読あり
Akiyama M, Tamiya G, Fujiwara K, Shiga Y, Yokoyama Y, Hashimoto K, Sato M, Sato K, Narita A, Hashimoto S, Ueda E, Furuta Y, Hata J, Miyake M, Ikeda HO, Suda K, Numa S, Mori Y, Morino K, Murakami Y, Shimokawa S, Nakamura S, Yawata N, Fujisawa K, Yamana S, Mori K, Ikeda Y, Miyata K, Mori K, Ogino K, Koyanagi Y, Kamatani Y, Biobank Japan Project, Ninomiya T, Sonoda KH, Nakazawa T, Japan Glaucoma Society Omics Group, Genomic Research Committee of the Japanese Ophthalmological Society
Ophthalmology 131 ( 11 ) 1271 - 1280 2024年7月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Ophthalmology
Purpose: To assess the impact of genetic risk estimation for primary open-angle glaucoma (POAG) in Japanese individuals. Design: Cross-sectional analysis. Participants: Genetic risk scores (GRSs) were constructed based on a genome-wide association study (GWAS) of POAG in Japanese people. A total of 3625 Japanese individuals, including 1191 patients and 2434 controls (Japanese Tohoku), were used for the model selection. We also evaluated the discriminative accuracy of constructed GRSs in a dataset comprising 1034 patients and 1147 controls (the Japan Glaucoma Society Omics Group [JGS-OG] and the Genomic Research Committee of the Japanese Ophthalmological Society [GRC-JOS]) and 1900 participants from a population-based study (Hisayama Study). Methods: We evaluated 2 types of GRSs: polygenic risk scores using the pruning and thresholding procedure and a GRS using variants associated with POAG in the GWAS of the International Glaucoma Genetics Consortium (IGGC). We selected the model with the highest areas under the receiver operating characteristic curve (AUC). In the population-based study, we evaluated the correlations between GRS and ocular measurements. Main Outcome Measure: Proportion of patients with POAG after stratification according to the GRS. Results: We found that a GRS using 98 variants, which showed genome-wide significance in the IGGC, showed the best discriminative accuracy (AUC, 0.65). In the Japanese Tohoku, the proportion of patients with POAG in the top 10% individuals was significantly higher than that in the lowest 10% (odds ratio [OR], 6.15; 95% confidence interval [CI], 4.35–8.71). In the JGS-OG and GRC-JOS, we confirmed similar impact of POAG GRS (AUC, 0.64; OR [top vs. bottom decile], 5.81; 95% CI, 3.79–9.01). In the population-based study, POAG prevalence was significantly higher in the top 20% individuals of the GRS compared with the bottom 20% (9.2% vs. 5.0%). However, the discriminative accuracy was low (AUC, 0.56). The POAG GRS was correlated positively with intraocular pressure (r = 0.08: P = 4.0 × 10–4) and vertical cup-to-disc ratio (r = 0.11; P = 4.0 × 10–6). Conclusions: The GRS showed moderate discriminative accuracy for POAG in the Japanese population. However, risk stratification in the general population showed relatively weak discriminative performance. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
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Specification of variant interpretation guidelines for inherited retinal dystrophy in Japan 査読あり
Fujinami K., Nishiguchi K.M., Oishi A., Akiyama M., Ikeda Y., Hotta Y., Kondo H., Maeda A., Miyake M., Kondo M., Sakamoto T.
Japanese Journal of Ophthalmology 68 ( 4 ) 389 - 399 2024年7月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Japanese Journal of Ophthalmology
Accurate interpretation of sequence variants in inherited retinal dystrophy (IRD) is vital given the significant genetic heterogeneity observed in this disorder. To achieve consistent and accurate diagnoses, establishment of standardized guidelines for variant interpretation is essential. The American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for variant interpretation serve as the global “cross-disease” standard for classifying variants in Mendelian hereditary disorders. These guidelines propose a systematic approach for categorizing variants into 5 classes based on various types of evidence, such as population data, computational data, functional data, and segregation data. However, for clinical genetic diagnosis and to ensure standardized diagnosis and treatment criteria, additional specifications based on features associated with each disorder are necessary. In this context, we present a comprehensive framework outlining the newly specified ACMG/AMP rules tailored explicitly to IRD in the Japanese population on behalf of the Research Group on Rare and Intractable Diseases (Ministry of Health, Labour and Welfare of Japan). These guidelines consider disease frequencies, allele frequencies, and both the phenotypic and the genotypic characteristics unique to IRD in the Japanese population. Adjustments and modifications have been incorporated to reflect the specific requirements of the population. By incorporating these IRD-specific factors and refining the existing ACMG/AMP guidelines, we aim to enhance the accuracy and consistency of variant interpretation in IRD cases, particularly in the Japanese population. These guidelines serve as a valuable resource for ophthalmologists and clinical geneticists involved in the diagnosis and treatment of IRD, providing them with a standardized framework to assess and classify genetic variants.
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Relationships between causative genes and epiretinal membrane formation in Japanese patients with retinitis pigmentosa. 査読あり
Nakamura S, Fujiwara K, Fukushima M, Shimokawa S, Shimokawa S, Koyanagi Y, Hisatomi T, Takeda A, Yasuhiro I, Murakami Y, Sonoda KH
Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie 262 ( 11 ) 3553 - 3558 2024年6月
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Genetic and Clinical Features of ABCA4-Associated Retinopathy in a Japanese Nationwide Cohort. 査読あり
Mizobuchi K, Hayashi T, Tanaka K, Kuniyoshi K, Murakami Y, Nakamura N, Torii K, Mizota A, Sakai D, Maeda A, Kominami T, Ueno S, Kusaka S, Nishiguchi KM, Ikeda Y, Kondo M, Tsunoda K, Hotta Y, Nakano T
American journal of ophthalmology 264 36 - 43 2024年3月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：American Journal of Ophthalmology
Purpose: To clarify the genetic and clinical features of Japanese patients with ABCA4-associated retinopathy. Design: Retrospective, multicenter cohort study. Methods: Patients with retinal degeneration and biallelic ABCA4 variants were recruited from 13 different hospitals. Whole exome sequencing analysis was used for genetic testing. Comprehensive ophthalmic examinations were performed on matched patients. The primary outcome measure was identifying multimodal retinal imaging findings associated with disease progression. Results: This study included 63 patients: 19 with missense/missense, 23 with missense/truncation, and 21 with truncation/truncation genotypes. In total, 62 variants were identified, including 29 novel variants. Six patients had a mild phenotype characterized by foveal-sparing or preserved foveal structure, including 4 with missense/missense and 2 with missense/truncation genotypes. The p.Arg212His variant was the most frequent in patients with mild phenotypes (4/12 alleles). Clinical findings showed a disease duration-dependent worsening of the phenotypic stage. Patients with the truncation/truncation genotype exhibited rapid retinal degeneration within a few years and definite fundus autofluorescence imaging patterns, including hyper autofluorescence at the macula and few or no flecks. Conclusions: Our results indicate that missense/missense or missense/truncation genotypes, including the p.Arg212His variant, are associated with a relatively mild phenotype. In contrast, the truncation/truncation genotype causes rapid and severe retinal degeneration in Japanese patients with ABCA4-associated retinopathy. These data are vital in predicting patient prognosis, guiding genetic counseling, and stratifying patients for future clinical trials.
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Mawatari G., Hiwatashi S., Motani T., Nagatomo S., Ando E., Kuwahata T., Ishizu M., Ikeda Y.
Japanese Journal of Ophthalmology 68 ( 4 ) 321 - 326 2024年
担当区分：最終著者, 責任著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Japanese Journal of Ophthalmology
Purpose: To investigate the efficacy of our wearable night-vision aid in patients with concentric peripheral visual field loss. Study Design: Prospective, single blind, three-group, and three-period crossover clinical study. Methods: The study included patients with concentric peripheral visual field loss, a best-corrected visual acuity (decimal visual acuity) of 0.1 or higher in the better eye, and the presence of a central visual field. HOYA MW10 HiKARI® (HOYA Corporation), our original wearable night-vision aid, was used as the test device with three types of camera lenses (standard-, middle-, and wide-angle lenses). Under both bright and dark conditions, the angle of the horizontal visual field was measured using each of the three lens types for each group. The baseline angle was measured when each participant wore the night-vision aid (powered off). Results: The study included 21 participants. Under bright condition, the perceived horizontal visual field was significantly wider than the baseline setup when using the standard-angle lens (“the standard lens”); the middle-angle lens (“the middle lens”) was significantly wider than both the baseline setup and the standard lens; and the wide-angle lens (“the wide lens”) was significantly wider than the other lenses. Under dark condition, the perceived horizontal visual field was again significantly wider when using the middle lens than the baseline setup and the standard lens, and when using the wide lens, the perceived horizontal visual field was again wider than when using the other lenses. The control in the bright condition was significantly wider (p < 0.001) than when used in the dark condition, while the standard-angle lens in the dark condition was significantly wider (p = 0.05) than when used in the bright condition. In regards to the middle and wide lenses, there was no statistically significant result emerging from either of the illumination conditions. Conclusion: Our wearable night-vision aid with a middle-angle or wide-angle lens appears to provide wider visual field images in patients with concentric peripheral visual field loss, regardless of whether the illumination conditions are bright or dark.
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Funatsu J, Murakami Y, Shimokawa S, Nakatake S, Fujiwara K, Okita A, Fukushima M, Shibata K, Yoshida N, Koyanagi Y, Akiyama M, Notomi S, Nakao S, Hisatomi T, Takeda A, Paschalis EI, Vavvas DG, Ikeda Y, Sonoda KH
PNAS nexus 1 ( 1 ) 1 - 14 2022年3月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：PNAS Nexus
Retinitis pigmentosa (RP) is an intractable inherited disease that primarily affects the rods through gene mutations followed by secondary cone degeneration. This cone-related dysfunction can lead to impairment of daily life activities, and ultimately blindness in patients with RP. Paradoxically, microglial neuroinflammation contributes to both protection against and progression of RP, but it is unclear which population(s)— tissue-resident microglia and/or peripheral monocyte-derived macrophages (mϕ)— are implicated in the progression of the disease. Here, we show that circulating blood inflammatory monocytes (IMo) are key effector cells that mediate cone cell death in RP. Attenuation of IMo and peripherally engrafted mϕ by Ccl2 deficiency or immune modulation via intravenous nanoparticle treatment suppressed cone cell death in rd10 mice, an animal model of RP. In contrast, the depletion of resident microglia by a colony-stimulating factor 1 receptor inhibitor exacerbated cone cell death in the same model. In human patients with RP, IMo was increased and correlated with disease progression. These results suggest that peripheral IMo is a potential target to delay cone cell death and prevent blindness in RP.
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Murakami Y., Hisai T., Shimokawa S., Fukushima M., Fujiwara K., Hirata A., Takada A., Miyahara F., Nakashima N., Kobayakawa Y., Arima M., Mawatari G., Ishizu M., Kaida T., Miyata K., Ikeda Y., Sonoda K.H.
Japanese Journal of Ophthalmology 2025年
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Japanese Journal of Ophthalmology
Purpose: The Retinitis Pigmentosa Progression and Inflammatory Marker Registry (RP-PRIMARY) is intended as a prospective observational study aimed at establishing sensitive outcome measures to detect the efficacy of anti-inflammatory agents in future clinical trials. The following is the RP-PRIMARY study protocol. Study Design: Prospective, multicenter study. Methods: We will recruit 100 patients with typical RP (any genetic mutation) and the following characteristics: age 20–70 years; mean retinal sensitivity ≥ 10 dB at 12 central points on Humphrey 10-2 visual field tests; central foveal thickness ≤ 250 μm on optical coherence tomography (OCT); and no ocular complications unrelated to RP or serious systemic complications. Early Treatment Diabetic Retinopathy Study (ETDRS). visual acuity, Humphrey 10-2 visual field tests, OCT, and fundus autofluorescence imaging will be performed every 3 months for 2 years. Inflammatory indices such as aqueous flare values, high-sensitivity C-reactive protein (CRP), serum IL-8, and CD14/16 inflammatory monocyte proportion will be measured every year. The primary endpoint will be the progression rate of retinal sensitivity loss on the Humphrey 10-2 visual field tests. The secondary endpoints will be the rate of decline of each parameter and its association with inflammatory indices. Standard-operation-procedure documents were prepared for all study procedures, and consultations with the regulatory agency were conducted to ensure the data reliability for future use in clinical trials. Conclusions: Detailed registry data on the natural history and inflammatory profile of RP will be useful in designing study protocols for anti-inflammatory therapy for RP and as natural history data for drug applications.
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Fukuyama H., Ishikawa H., Gomi F., Yamamoto S., Baba T., Sato E., Kitahashi M., Tatsumi T., Miura G., Niizawa T., Sakamoto T., Yamakiri K., Yamashita T., Otsuka H., Sameshima S., Yoshinaga N., Sonoda S., Hirakata A., Koto T., Inoue M., Hirota K., Itoh Y., Orihara T., Emoto Y., Sano M., Takahashi H., Tokizawa R., Yamashita H., Nishitsuka K., Kaneko Y., Nishi K., Yoshida A., Ono S., Hirokawa H., Sogawa K., Omae T., Ishibazawa A., Kishi S., Akiyama H., Matsu-moto H., Mukai R., Morimoto M., Nakazawa M., Suzuki Y., Kudo T., Adachi K., Ishida S., Noda K., Kase S., Mori S., Ando R., Saito M., Suzuki T., Takahashi K., Nagai Y., Nakauchi T., Yamada H., Kusaka S., Tsujioka D., Tsujikawa A., Suzuma K., Ishibashi T., Sonoda K.H., Ikeda Y., Kohno R., Ishikawa K., Kondo M., Kozawa M., Kitaoka T., Tsuiki E., Ogura Y., Yoshida M., Morita H., Kato A., Hirano Y., Sugitani K., Terasaki H., Iwase T., Ito Y., Ueno S., Kaneko H., Nonobe N., Kominami T., Azuma N., Yokoi T., Shimada H., Nakashizuka H., Hattori T., Shinojima A., Kutagawa Y., Shiraga F., Morizane Y., Kimura S., Ikeda T., Kida T., Sato T., Fukumoto M., Emi K., Nakashima H., Ohji M.
Scientific Reports 14 ( 1 ) 2024年12月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Scientific Reports
We investigated the impact of drainage retinotomy on the outcome of pars plana vitrectomy for repair of rhegmatogenous retinal detachment (RRD). This study was a retrospective observational multicenter study. All patients were registered with the Japan-Retinal Detachment Registry. We analyzed 1887 eyes with RRD that had undergone vitrectomy and were observed for 6 months between February 2016 and March 2017. We compared the baseline characteristics and postoperative outcomes between eyes with and without drainage retinectomy. We then performed propensity score matching using preoperative findings as covariates to adjust for relevant confounders. Of 3446 eyes, 1887 met the inclusion criteria. Among them, 559 eyes underwent vitrectomy with drainage retinotomy, and 1328 eyes underwent vitrectomy without drainage retinotomy. After propensity score matching, each group comprised 544 eyes. There was no significant difference between the two groups in BCVA at 6 months after vitrectomy (0.181 vs. 0.166, P = 0.23), the primary anatomical success rate (6.3% vs. 4.4%, P = 0.22), or the rate of secondary surgery for ERM within 6 months (1.5% vs. 1.3%, P = 1.0). Drainage retinectomy does not increase the risk of decreased postoperative BCVA, surgical failure, or secondary surgery for ERM within six months outcomes.
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Fukushima M., Tao Y., Shimokawa S., Zhao H., Shimokawa S., Funatsu J., Hisai T., Okita A., Fujiwara K., Hisatomi T., Takeda A., Ikeda Y., Sonoda K.H., Murakami Y.
Ophthalmology Science 4 ( 6 ) 100582 2024年11月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Ophthalmology Science
Purpose: To compare the usefulness of microperimetry and static automated perimetry in patients with retinitis pigmentosa (RP), using macular anatomical metrics as a reference. Design: Prospective observational study. Participants: Forty-eight eyes of 48 patients with RP in Kyushu University Hospital who underwent microperimetry-3 (MP-3) and Humphrey Field Analyzer (HFA) 10-2 testing ≥3 times during ≥2 years were included. Methods: Macular anatomy (ellipsoid zone [EZ] length) was assessed by OCT, and macular function was assessed by MP-3 (mean retinal sensitivity at radii 2°, 4°, and 8°) and HFA10-2 program (mean retinal sensitivity at radii 2°, 4°, and 8°). Correlations between functional and anatomical parameters were analyzed cross sectionally at baseline and longitudinally by comparing the rate of progression. Main Outcome Measures: Correlation coefficients between anatomical and functional metrics. Results: The mean age at baseline was 50.1 ± 12.3 years, and the mean follow-up period was 2.8 ± 0.7 years. At baseline, EZ length was significantly correlated with MP-3 mean retinal sensitivity at radii 2°, 4°, and 8° (Spearman's ρ = 0.65, 0.84, 0.89; all P < 0.005) and HFA10-2 mean retinal sensitivity at radii 2°, 4°, and 8° (Spearman's ρ = 0.61, 0.73, 0.78; all P < 0.005). Longitudinal analysis showed that the slope of EZ length (−88.92 μm/year) was significantly correlated with the slope of MP-3 retinal sensitivity at 8° radius (−0.62 decibels [dB]/year; Spearman's ρ = 0.31, P=0.03) and the slope of HFA retinal sensitivity at 8° radius (−0.60 dB/year; Spearman's ρ = 0.43, P < 0.005). Conclusions: Both MP-3 and HFA values were cross sectionally well-correlated with EZ length in patients with patients; however, these associations became weaker in the longitudinal analysis. This highlights the need for researchers to explore additional or more sensitive parameters to better monitor RP progression. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
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増刊号 6年前の常識は現在の非常識!-AI時代へ向かう今日の眼科医へ Ⅷ.網膜 遺伝子治療 招待あり
池田 康博
臨床眼科 78 ( 11 ) 220 - 226 2024年10月
担当区分：筆頭著者, 責任著者 記述言語：日本語 掲載種別：論文集(書籍)内論文 出版者・発行元：株式会社医学書院
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Tachibana T., Notomi S., Funatsu J., Fujiwara K., Nakatake S., Murakami Y., Nakao S., Kanamoto T., Ikeda Y., Ishibashi T., Sonoda K.H., Hisatomi T.
Japanese Journal of Ophthalmology 68 ( 5 ) 500 - 510 2024年9月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Japanese Journal of Ophthalmology
Purpose: Extracellular Adenosine triphosphate (ATP) released by dying cells may cause a secondary cell death in neighboring cells in retinal degeneration. We investigated intraocular ATP kinetics to gain mechanical insights into the pathology in rhegmatogenous retinal detachment (RRD). Study design: Retrospective clinical study. Methods: Vitreous or subretinal fluids (SRF) were obtained from patients with RRD (n=75), macular hole (MH; n=20), and epiretinal membrane (ERM; n=35) during vitrectomy. ATP levels in those samples were measured by luciferase assay. Results: Mean ATP levels in the vitreous from RRD patients were significantly higher compared to those from MH and ERM patients (2.3 and 0.3 nM, respectively. P<0.01). Mean ATP levels in the SRF from RRD (11.7 nM) were higher than those in the vitreous from RRD (P<0.01). Mean ATP levels in the vitreous with short durations (1–8 days) of RRD were higher compared to those with long durations (>8 days) (3.2 and 1.4 nM, respectively. P<0.05). Similarly, ATP in SRF with short durations were higher than those with long durations (23.8 and 3.6 nM, respectively. P<0.05). Furthermore, the concentrations of ectonucleoside triphosphate diphosphohydrolase-1 (ENTPD1), a major ATP degradative enzyme, in the vitreous from RRD were higher than those from MH/ERM (1.2 and 0.2 ng/ml, respectively. P<0.01). ENTPD1 expression was localized in the cytoplasm of CD11b-positive infiltrating cells in the vitreous and retinal cells. Conclusion: ATP increased in the vitreous and SRF in RRD and decreased over time with an upregulation of ENTPD1. The kinetics indicate the pathological mechanism of the excessive extracellular ATP after RRD.
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Arima M., Inoue H., Misumi A., Tsukamoto S., Matsushita I., Araki S., Ohta M., Takahashi K., Imazato M., Goto T., Aoki Y., Tagawa K., Hirose M., Fujita Y., Yoshida N., Nakao S., Kondo H., Kusuhara K., Kimura K., Hasegawa S., Ikeda Y., Kodama Y., Moritake H., Ochiai M., Ohga S., Kishimoto J., Todaka K., Ieiri I., Sonoda K.H.
Japanese Journal of Ophthalmology 68 ( 5 ) 490 - 499 2024年9月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Japanese Journal of Ophthalmology
Purpose: To assess the safety and efficacy of ripasudil for retinopathy of prematurity (ROP). Study design: Phase 1/2, multicenter, open-label, single-arm, 12-week clinical trial. Methods: Infants born with gestational age (GA) of ≤ 32 weeks or weight of ≤ 1500 g with zone I or II, ≥ stage 1, ROP in both eyes were enrolled. Ripasudil eye drops were administered to patients in both eyes. Phase 1 was a dose-escalation study (once daily for 1 week, then twice daily for 2 weeks); an additional dosing up to 9 weeks was allowed if no safety issues occurred. In phase 2, ripasudil was administered twice daily for up to 12 weeks. Adverse events were assessed. The proportion of patients with type 1 ROP progression, number of days for type 1 ROP progression, and progression to the most advanced ROP stage were estimated. Results: Twenty-four infants were enrolled (phase 1, n = 3; phase 2, n = 21). Nineteen and four patients experienced systemic and ocular adverse events, respectively. Efficacy endpoints were not different between the ripasudil and historical control groups. However, in the GA ≤ 27 weeks subgroup, fewer patients progressed to type 1 ROP in the ripasudil than in the historical control group (P = 0.09). In the GA ≤ 27 weeks subgroups, the 25th percentile for the number of days for type 1 ROP progression was 22 days in the historical control group and 44 days in the ripasudil group. Conclusion: Ripasudil was safe and inhibited/delayed type 1 ROP progression, especially in infants with short GA.
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特集 第77回日本臨床眼科学会講演集[5] 原著 抗アクアポリン4抗体陽性視神経炎の視力の経過 査読あり
山添 早織, 中馬 秀樹, 池田 康博
臨床眼科 78 ( 7 ) 823 - 827 2024年7月
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Goto K, Koyanagi Y, Akiyama M, Murakami Y, Fukushima M, Fujiwara K, Iijima H, Yamaguchi M, Endo M, Hashimoto K, Ishizu M, Hirakata T, Mizobuchi K, Takayama M, Ota J, Sajiki AF, Kominami T, Ushida H, Fujita K, Kaneko H, Ueno S, Hayashi T, Terao C, Hotta Y, Murakami A, Kuniyoshi K, Kusaka S, Wada Y, Abe T, Nakazawa T, Ikeda Y, Momozawa Y, Sonoda KH, Nishiguchi KM
Journal of medical genetics 61 ( 7 ) 613 - 620 2024年6月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of Medical Genetics
Background As gene-specific therapy for inherited retinal dystrophy (IRD) advances, unified variant interpretation across institutes is becoming increasingly important. This study aims to update the genetic findings of 86 retinitis pigmentosa (RP)-related genes in a large number of Japanese patients with RP by applying the standardised variant interpretation guidelines for Japanese patients with IRD (J-IRD-VI guidelines) built upon the American College of Medical Genetics and Genomics and the Association for Molecular Pathology rules, and assess the contribution of these genes in RP-allied diseases. Methods We assessed 2325 probands with RP (n=2155, including n=1204 sequenced previously with the same sequencing panel) and allied diseases (n=170, newly analysed), including Usher syndrome, Leber congenital amaurosis and cone-rod dystrophy (CRD). Target sequencing using a panel of 86 genes was performed. The variants were interpreted according to the J-IRD-VI guidelines. Results A total of 3564 variants were detected, of which 524 variants were interpreted as pathogenic or likely pathogenic. Among these 524 variants, 280 (53.4%) had been either undetected or interpreted as variants of unknown significance or benign variants in our earlier study of 1204 patients with RP. This led to a genetic diagnostic rate in 38.6% of patients with RP, with EYS accounting for 46.7% of the genetically solved patients, showing a 9% increase in diagnostic rate from our earlier study. The genetic diagnostic rate for patients with CRD was 28.2%, with RP-related genes significantly contributing over other allied diseases. Conclusion A large-scale genetic analysis using the J-IRD-VI guidelines highlighted the population-specific genetic findings for Japanese patients with IRD; these findings serve as a foundation for the clinical application of gene-specific therapies.
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Wong T.Y., Haskova Z., Asik K., Baumal C.R., Csaky K.G., Eter N., Ives J.A., Jaffe G.J., Korobelnik J.F., Lin H., Murata T., Ruamviboonsuk P., Schlottmann P.G., Seres A.I., Silverman D., Sun X., Tang Y., Wells J.A., Yoon Y.H., Wykoff C.C., Aaberg T., Abbey A., Abdulaeva E., Abengoechea S., Abraham P., Ach T., Adams S., Adan Civera A., Adrean S., Agostini H., Alam S., Alezzandrini A., Alfaro V., Aliseda D., Almony A., Amat P., Amini P., Antoszyk A., Arias L., Asaria R., Avila M., Awh C.C., Bafalluy J., Baker C., Bandello F., Barakat M., Barraza K., Bator G., Belfort R., Bergstrom C., Bertolucci G., Bochow T., Bolz M., Borcz E., Bordon A., Boyer D., Bratko G., Brent M., Brown J., Brown D.M., Budzinskaya M., Buffet S., Burgess S., Burton B., Busquets M., Cabrera F., Cagini C., Calzada J., Campochiaro P., Carlson J., Castellarin A., Cava C., Chaikitmongkol V., Chan C., Chang E., Chang J., Chang A., Charles S., Chaudhry N., Chee C., Chen J., Chen F., Chen S.J., Cheong-Leen R., Chiang A., Chittum M., Chow D., Connolly B., Cornut P.L., Danzig C., Das A., Daskalov V., Desco C., Dessouki A., Dickinson J., Do B., Dollin M., Dugel P.
Ophthalmology 131 ( 6 ) 708 - 723 2024年6月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Ophthalmology
Purpose: To evaluate the 2-year efficacy, durability, and safety of dual angiopoietin-2 and vascular endothelial growth factor (VEGF) A pathway inhibition with intravitreal faricimab according to a personalized treat-and-extend (T&E)-based regimen with up to every-16-week dosing in the YOSEMITE and RHINE (ClinicalTrials.gov identifiers, NCT03622580 and NCT03622593, respectively) phase 3 trials of diabetic macular edema (DME). Design: Randomized, double-masked, noninferiority phase 3 trials. Participants: Adults with visual acuity loss (best-corrected visual acuity [BCVA] of 25–73 letters) due to center-involving DME. Methods: Patients were randomized 1:1:1 to faricimab 6.0 mg every 8 weeks, faricimab 6.0 mg T&E (previously referred to as personalized treatment interval), or aflibercept 2.0 mg every 8 weeks. The T&E up to every-16-week dosing regimen was based on central subfield thickness (CST) and BCVA change. Main Outcome Measures: Included changes from baseline in BCVA and CST, number of injections, durability, absence of fluid, and safety through week 100. Results: In YOSEMITE and RHINE (n = 940 and 951, respectively), noninferior year 1 visual acuity gains were maintained through year 2; mean BCVA change from baseline at 2 years (weeks 92, 96, and 100 average) with faricimab every 8 weeks (YOSEMITE and RHINE, +10.7 letters and +10.9 letters, respectively) or T&E (+10.7 letters and +10.1 letters, respectively) were comparable with aflibercept every 8 weeks (+11.4 letters and +9.4 letters, respectively). The median number of study drug injections was lower with faricimab T&E (YOSEMITE and RHINE, 10 and 11 injections, respectively) versus faricimab every 8 weeks (15 injections) and aflibercept every 8 weeks (14 injections) across both trials during the entire study. In the faricimab T&E arms, durability was improved further during year 2, with > 60% of patients receiving every-16-week dosing and approximately 80% receiving every-12-week or longer dosing at week 96. Almost 80% of patients who achieved every-16-week dosing at week 52 maintained every-16-week dosing without an interval reduction through week 96. Mean CST reductions were greater (YOSEMITE/RHINE weeks 92/96/100 average: faricimab every 8 weeks –216.0/–202.6 µm, faricimab T&E –204.5/–197.1 µm, aflibercept every 8 weeks –196.3/–185.6 µm), and more patients achieved absence of DME (CST < 325 μm; YOSEMITE/RHINE weeks 92–100: faricimab every 8 weeks 87%–92%/88%–93%, faricimab T&E 78%–86%/85%–88%, aflibercept every 8 weeks 77%–81%/80%–84%) and absence of intraretinal fluid (YOSEMITE/RHINE weeks 92–100: faricimab every 8 weeks 59%–63%/56%–62%, faricimab T&E 43%–48%/45%–52%, aflibercept every 8 weeks 33%–38%/39%–45%) with faricimab every 8 weeks or T&E versus aflibercept every 8 weeks through year 2. Overall, faricimab was well tolerated, with a safety profile comparable with that of aflibercept. Conclusions: Clinically meaningful visual acuity gains from baseline, anatomic improvements, and extended durability with intravitreal faricimab up to every 16 weeks were maintained through year 2. Faricimab given as a personalized T&E-based dosing regimen supports the role of dual angiopoietin-2 and VEGF-A inhibition to promote vascular stability and to provide durable efficacy for patients with DME. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
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Genotypes and clinical features of RHO-associated retinitis pigmentosa in a Japanese population. 査読あり
Tsutsui S, Murakami Y, Fujiwara K, Koyanagi Y, Akiyama M, Takeda A, Ikeda Y, Sonoda KH
Japanese journal of ophthalmology 68 ( 1 ) 1 - 11 2024年1月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Japanese Journal of Ophthalmology
Purpose: To report the genotypes and clinical features of RHO-associated retinitis pigmentosa (RHO-RP) in the Kyushu region of Japan. Study Design: Retrospective, single-center study. Methods: Sixteen RP patients with pathogenic RHO variants seen at Kyushu University Hospital were investigated. Clinical data including age, best-corrected visual acuity (BCVA) in logarithm of the minimum angle of resolution (logMAR) units, visual field, fundus photography, and optical coherence tomography were retrospectively obtained. Visual outcomes were compared between classical and sector phenotypes and among genetic variants. Results: The mean age at the first visit was 54.0 ± 15.7 years, with a mean follow-up of 7.6 ± 4.0 years. Fourteen patients (87.5%) showed the classical RP phenotype, of whom four were associated with p.[Pro23Leu] and two had p.[Pro347Leu] variants. In addition, two patients with the sector phenotype harbored p.[Ala164Val] variants. Among the classical RHO-RP patients, the mean BCVA decreased from 0.60 to 1.08 logMAR over the follow-up period (7.4 ± 4.1 years) whereas BCVA was preserved at 0.04 logMAR in sector RHO-RP patients (9.0 ± 3.0 years). Genotype-to-phenotype analysis demonstrated that p.[Pro347Leu] was associated with severe vision loss at an earlier age. Macular complications such as epiretinal membrane and cystoid macular edema were observed in 5 classical RHO-RP patients. Conclusion: p.[Pro23Leu], but not p.[Pro23His], was a frequent variant causing RHO-RP in the Kyushu region of Japan. As reported in previous studies, patients with the p.[Pro347Leu] variant showed a more severe phenotype, and variants causing sector RHO-RP were associated with a good prognosis.
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Hidaka T, Chuman H, Ikeda Y
Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie 262 ( 1 ) 161 - 169 2024年1月
担当区分：最終著者, 責任著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Graefe's Archive for Clinical and Experimental Ophthalmology
Purpose: To investigate the objective function of the inner retinal layer in each stage of primary open angle glaucoma (POAG) using the photopic negative response (PhNR) measured by RETeval full-field electroretinography (ERG), and to identify which PhNR parameter is the most useful. Methods: Ninety eyes of 90 patients with POAG (30 with mild POAG (mean deviation (MD) ≥ -6 dB) and 60 with moderate-to-advanced POAG (MD < -6 dB)) and 76 eyes of 76 control cases were examined. We investigated six PhNR parameters and their relationships with the results of the Humphrey 30–2 visual field test and the thickness of the circumpapillary retinal nerve fiber layer (cpRNFL) obtained from optical coherence tomography. The following PhNR parameters were assessed: base-to-trough (BT), peak-to-trough (PT), 72msPhNR, the W-ratio, P-ratio, implicit time (IT), and a-wave and b-wave amplitudes on ERG. Results: All PhNR parameters other than IT significantly differed between the all POAG (all stages) and control groups and between the moderate-to-advanced POAG and control groups. BT and 72msPhNR in the mild POAG group, significantly differed from those in the control group. Regarding the relationships between PhNR parameters and the visual field and between these parameters and cpRNFL thickness, correlations were observed between all PhNR parameters, except PT and IT, and both the visual field and cpRNFL thickness in the all and moderate-to-advanced POAG groups. 72msPhNR correlated with cpRNFL thickness in the mild POAG group. The area under the receiver operating characteristic curve was greater for BT than for the other PhNR parameters in both the mild and moderate-to-advanced POAG groups. The discriminant linear function for examining the presence or absence of POAG and the threshold for diagnosis were quantitatively obtained as follows. Regarding BT: discriminant = 0.505 × BT + 2.017; threshold = positive for POAG, negative for no POAG; correct answer rate = 80.7%. Concerning 72msPhNR: discriminant = 0.533 × 72msPhNR + 1.553; threshold = positive for POAG and negative for no POAG; correct answer rate = 77.1%. Conclusion: RETeval-measured PhNR parameters were useful for an objective evaluation of visual function in moderate-to-advanced POAG. BT appeared to be the most diagnostically useful parameter.
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視交叉内の黄斑線維走行部に限局する 接合部障害と思われた特発性視交叉炎の一例 査読あり
田村 千奈見, 長友 さおり, 中馬 秀樹, 池田 康博
神経眼科 40 ( 3 ) 248 - 253 2023年9月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：日本神経眼科学会
37歳の男性が左眼の霧視を自覚した．矯正視力は右1.2 左0.6．相対的瞳孔求心路障害（relative afferent pupillary defect: RAPD）は陰性であった．周辺視野欠損は明らかでなく，ハンフリー静的視野10-2プログラムを用いた中心視野に両耳側半盲と左眼の中心感度の低下を認めた．頭部磁気共鳴画像（MRI）にて視交叉内部後方やや左側よりに造影される病変を認めた．視交叉炎と診断し原因検索を行い，明らかな全身性炎症性疾患は認められなかった．その後自然軽快し，左矯正視力は1.0まで回復，両耳側半盲は消失し，左眼の中心感度も正常化した．頭部MRIの造影効果も消失した．本症例は，視交叉内の黄斑線維走行部に限局した接合部障害をきたした特発性視交叉炎で，組織学的研究を臨床的に証明する，まれでかつ貴重な症例であると思われた．またこのような症例は，適切な視野プログラムを選択しないと病変を見逃す可能性があり，注意を要すると思われた．
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Obata S., Sawada O., Kakinoki M., Matsumoto R., Saishin Y., Ohji M., Yamamoto S., Baba T., Sato E., Kitahashi M., Tatsumi T., Miura G., Nizawa T., Sakamoto T., Yamakiri K., Yamashita T., Otsuka H., Sameshima S., Yoshinaga N., Sonoda S., Hirakata A., Koto T., Inoue M., Hirota K., Itoh Y., Orihara T., Emoto Y., Sano M., Takahashi H., Tokizawa R., Yamashita H., Nishitsuka K., Kaneko Y., Nishi K., Yoshida A., Ono S., Hirokawa H., Sogawa K., Omae T., Ishibazawa A., Kishi S., Akiyama H., Matsumoto H., Mukai R., Morimoto M., Nakazawa M., Suzuki Y., Kudo T., Adachi K., Ishida S., Noda K., Kase S., Mori S., Ando R., Saito M., Suzuki T., Takahashi K., Nagai Y., Nakauchi T., Yamada H., Kusaka S., Tsujioka D., Tsujikawa A., Suzuma K., Ishibashi T., Sonoda K.H., Ikeda Y., Kohno R., Ishikawa K., Kondo M., Kozawa M., Kitaoka T., Tsuiki E., Ogura Y., Yoshida M., Morita H., Kato A., Hirano Y., Sugitani K., Terasaki H., Iwase T., Ito Y., Ueno S., Kaneko H., Nonobe N., Kominami T., Azuma N., Yokoi T., Shimada H., Nakashizuka H., Hattori T., Shinojima A., Kitagawa Y., Shiraga F., Morizane Y., Kimura S., Ikeda T., Kida T., Sato T., Fukumoto M.
Japanese Journal of Ophthalmology 67 ( 4 ) 417 - 423 2023年7月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Japanese Journal of Ophthalmology
Purpose: To investigate the effects of internal limiting membrane (ILM) peeling on retinal attachment after a single surgery, and on postoperative visual acuity (VA) at 6 months, in eyes with macula-off rhegmatogenous retinal detachment (RRD) complicated by proliferative vitreoretinopathy (PVR). Study design: Nationwide, multicenter retrospective cohort study. Methods: The Japan-RD Registry database was used for analysis of patients who had undergone vitrectomy for macula-off RRD complicated by PVR. Multivariate analysis was performed to detect prognostic factors for retinal attachment after a single surgery and for VA at 6 months postoperatively. Retinal attachment after a single surgery or VA at 6 months postoperatively was the objective variable; ILM peeling, preoperative VA, PVR grade, age, and intraocular pressure were explanatory variables. Results: Eighty-nine eyes met the inclusion criteria; ILM peeling was performed in 25 eyes (28%). Preoperative VA was significantly associated with retinal attachment, but ILM peeling did not (odds ratios = 2.1 and 1.3, respectively; p = 0.009 and 0.67, respectively). Poor preoperative VA and younger patient age were significantly associated with poor postoperative VA, but ILM peeling was not (β-values = 0.37, −0.008, and 0.15, respectively; p < 0.001, p = 0.02, and p = 0.15, respectively. Conclusions: Preoperative VA was a risk factor associated with retinal attachment. Preoperative VA and patient age were risk factors associated with postoperative poor VA. In eyes with macula-off RRD complicated by PVR, ILM peeling did not have a clear beneficial effect on anatomical and functional outcomes, suggesting that it may be unnecessary for eyes with this condition.
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Shimura M., Kitano S., Ogata N., Mitamura Y., Oh H., Ochi H., Ohsawa S., Hirakata A., Bolz M., Findl O., Pollreisz A., Weger M., Daskalov V., Misheva A., Petkova I., Guneva D.T., Vassileva P., Cornut P.L., Korobelnik J.F., Lebreton O., Tadayoni R., Eter N., Feltgen N., Framme C., Lorenz K., Spital G., Bator G., Seres A., Szalczer L., Toth-Molnar E., Vajas A., Varsanyi B., Goldstein M., Levy J., Morori-Katz H., Rosenblatt I., Yoreh B., Bandello F., Cagini C., Mastropasqua L., Nicolo M., Parravano M.C., Viola F., Fukutomi A., Hayashi K., Hirakata A., Honda S., Ikeda Y., Ito Y., Kawasaki T., Kimura K., Kishino G., Kitano S., Maeno T., Murakami T., Noda K., Obana A., Oh H., Sawada O., Shimouchi A., Sugimoto M., Sugita I., Takagi H., Takayama K., Tanabe T., Yasukawa T., Yoshida S., Garcia R., Rechy D.L., Canton V.M., Estudillo J.R., Barraza K., Fernandez C., Guzman M., Lujan S., Gawecki M., Herba E., Michalska-Malecka K., Muzyka-Wozniak M., Nester-Ostrowska K., Oleksy P., Wowra B., Wylęgała E., Budzinskaya M., Kulikov A., Morugova T., Hurcikova M., Kacerík M., Lipkova B., Abengoechea S., Civera A.A., Amat P., Cabrera F., Cava C., Garcia-Layana A., Ulla F.G., Moreno J.M.R.
Japanese Journal of Ophthalmology 67 ( 3 ) 264 - 279 2023年5月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Japanese Journal of Ophthalmology
Purpose: To evaluate efficacy, durability, and safety of faricimab in Japanese patients with diabetic macular edema (DME). Study design: Subgroup analysis of 2 global, multicenter, randomized, double-masked, active-comparator–controlled, phase 3 trials (YOSEMITE, NCT03622580; RHINE, NCT03622593). Methods: Patients with DME were randomized 1:1:1 to intravitreal faricimab 6.0 mg every 8 weeks (Q8W), faricimab 6.0 mg per personalized treatment interval (PTI), or aflibercept 2.0 mg Q8W through week 100. Primary endpoint was best-corrected visual acuity (BCVA) change from baseline at 1 year, averaged over weeks 48, 52, and 56. This is the first time 1-year outcomes between Japanese patients (only enrolled into YOSEMITE) and the pooled YOSEMITE/RHINE cohort (N = 1891) have been compared. Results: The YOSEMITE Japan subgroup included 60 patients randomized to faricimab Q8W (n = 21), faricimab PTI (n = 19), or aflibercept Q8W (n = 20). Consistent with global results, the adjusted mean (95.04% confidence interval) BCVA change at 1 year in the Japan subgroup was comparable with faricimab Q8W (+11.1 [7.6–14.6] letters), faricimab PTI (+8.1 [4.4–11.7] letters), and aflibercept Q8W (+6.9 [3.3–10.5] letters). At week 52, 13 (72%) patients in the faricimab PTI arm achieved ≥ Q12W dosing, including 7 (39%) patients receiving Q16W dosing. Anatomic improvements with faricimab were generally consistent between the Japan subgroup and pooled YOSEMITE/RHINE cohort. Faricimab was well tolerated; no new or unexpected safety signals were identified. Conclusion: Consistent with global results, faricimab up to Q16W offered durable vision gains and improved anatomic and disease-specific outcomes among Japanese patients with DME.
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第5土曜特集 mRNAワクチンやゲノム編集で注目が集まる遺伝子治療 遺伝子治療技術を用いた疾患治療 眼科疾患に対する遺伝子治療 招待あり
池田 康博
医学のあゆみ 285 ( 5 ) 414 - 419 2023年4月
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Drinking hydrogen water improves photoreceptor structure and function in retinal degeneration 6 mice 査読あり
Igarashi T., Ohsawa I., Kobayashi M., Miyazaki K., Igarashi T., Kameya S., Shiozawa A.L., Ikeda Y., Miyagawa Y., Sakai M., Okada T., Sakane I., Takahashi H.
Scientific Reports 12 ( 1 ) 13610 2022年12月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Scientific Reports
Retinitis pigmentosa (RP) is a genetically heterogeneous group of inherited retinal disorders involving the progressive dysfunction of photoreceptors and the retinal pigment epithelium, for which there is currently no treatment. The rd6 mouse is a natural model of autosomal recessive retinal degeneration. Given the known contributions of oxidative stress caused by reactive oxygen species (ROS) and selective inhibition of potent ROS peroxynitrite and OH·by H2 gas we have previously demonstrated, we hypothesized that ingestion of H2 water may delay the progression of photoreceptor death in rd6 mice. H2 mice showed significantly higher retinal thickness as compared to controls on optical coherence tomography. Histopathological and morphometric analyses revealed higher thickness of the outer nuclear layer for H2 mice than controls, as well as higher counts of opsin red/green-positive cells. RNA sequencing (RNA-seq) analysis of differentially expressed genes in the H2 group versus control group revealed 1996 genes with significantly different expressions. Gene and pathway ontology analysis showed substantial upregulation of genes responsible for phototransduction in H2 mice. Our results show that drinking water high in H2 (1.2–1.6 ppm) had neuroprotective effects and inhibited photoreceptor death in mice, and suggest the potential of H2 for the treatment of RP.
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Yamakiri K., Sakamoto T., Koriyama C., Kawasaki R., Baba T., Nishitsuka K., Koto T., Terasaki H., Yamamoto S., Baba T., Sato E., Kitahashi M., Tatsumi T., Miura G., Niizawa T., Yamashita T., Otsuka H., Sameshima S., Yoshinaga N., Sonoda S., Hirakata A., Koto T., Inoue M., Hirota K., Itoh Y., Orihara T., Emoto Y., Sano M., Takahashi H., Tokizawa R., Yamashita H., Kaneko Y., Nishi K., Yoshida A., Ono S., Hirokawa H., Sogawa K., Omae T., Ishibazawa A., Kishi S., Akiyama H., Matsumoto H., Mukai R., Morimoto M., Nakazawa M., Suzuki Y., Kudo T., Adachi K., Ishida S., Noda K., Kase S., Mori S., Ando R., Saito M., Suzuki T., Takahashi K., Nagai Y., Nakauchi T., Yamada H., Kusaka S., Tsujioka D., Tsujikawa A., Suzuma K., Ishibashi T., Sonoda K.H., Ikeda Y., Kohno R., Ishikawa K., Kondo M., Kozawa M., Kitaoka T., Tsuiki E., Ogura Y., Yoshida M., Morita H., Kato A., Hirano Y., Sugitani K., Terasaki H., Iwase T., Ito Y., Ueno S., Kaneko H., Nonobe N., Kominami T., Azuma N., Yokoi T., Shimada H., Nakashizuka H., Hattori T., Shinojima A., Kitagawa Y., Shiraga F., Morizane Y., Kimura S., Ikeda T., Kida T.
Scientific Reports 12 ( 1 ) 2022年12月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Scientific Reports
The purpose of this study was to investigate the effects of surgeon-related factors on the surgical outcome of pars plana vitrectomy (PPV) and scleral buckling (SB) surgery on eyes with a rhegmatogenous retinal detachment (RRD). This was a nationwide, multicenter, observational study of the data in the Japan-RD Registry. Registered cases that had undergone surgery for a RRD by 128 accredited surgeons in 26 institutions were studied. The surgeon-related factors that significantly affected surgical success and visual outcomes of simple RRD treated by PPV or SB at 6 months postoperatively were analyzed and compared. Among 3446 registered cases, 2533 cases met the inclusion criteria with 1896 in the PPV group and 637 cases in the SB group. The median total number of lifetime cases was 150 and the rate of surgeries/year was 22. Multivariate regression analyses showed that the number and rate of surgeries/year were not significantly associated with the surgical outcome in the PPV group. However, surgeons with a higher average annual number of surgeries had significantly better surgical outcomes in the SB group (P = 0.038). Analyses of a nationwide registry showed that SB but not PPV surgeries require sufficient experience and case numbers to acquire and maintain skills to treat RRDs successfully.
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Takano F, Ueda K, Godefrooij DA, Yamagami A, Ishikawa H, Chuman H, Ishikawa H, Ikeda Y, Sakamoto T, Nakamura M
Orphanet journal of rare diseases 17 ( 1 ) 319 2022年8月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Orphanet Journal of Rare Diseases
Background: Leber hereditary optic neuropathy (LHON) is an acute or subacute optic neuropathy that mainly affects young males. The first nationwide epidemiological survey of LHON was conducted in 2014 in Japan, and LHON was officially designated as a rare intractable disease by the Japanese government in 2015. We conducted a second survey of the annual incidence of LHON in 2019, and estimated the total number of patients with LHON in Japan. Results: A questionnaire was sent to 997 facilities accredited by the Japanese Ophthalmological Society and/or affiliated with the councilors of the Japanese Neuro-Ophthalmology Society. Responses were received from 791 facilities, with a response rate of 79%. Fifty-five newly diagnosed cases (49 males and 6 females) of LHON were reported from 35 institutions in 2019, with a median age of 28.5 for males and 49.5 years for females. The total number of newly diagnosed cases was calculated as 69 (62 were males and 7 were females, 95% confidence interval 55–83), and the total number of patients was estimated to be 2491 (95% confidence interval: 1996–2986), suggesting a prevalence of LHON in Japan of 1:50,000. Conclusion: The incidence of LHON in 2019 was lower than the estimate in 2014, whereas its prevalence may be similar to that reported in other countries. The accurate estimation of the incidence and prevalence of patients with LHON requires prospective registration.
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Sano Y, Koyanagi Y, Wong JH, Murakami Y, Fujiwara K, Endo M, Aoi T, Hashimoto K, Nakazawa T, Wada Y, Ueno S, Gao D, Murakami A, Hotta Y, Ikeda Y, Nishiguchi KM, Momozawa Y, Sonoda KH, Akiyama M, Fujimoto A
Journal of medical genetics 2022年6月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of Medical Genetics
Despite the successful identification of causative genes and genetic variants of retinitis pigmentosa (RP), many patients have not been molecularly diagnosed. Our recent study using targeted short-read sequencing showed that the proportion of carriers of pathogenic variants in EYS, the cause of autosomal recessive RP, was unexpectedly high in Japanese patients with unsolved RP. This result suggested that causative genetic variants, which are difficult to detect by short-read sequencing, exist in such patients. Using long-read sequencing technology (Oxford Nanopore), we analysed the whole genomes of 15 patients with RP with one heterozygous pathogenic variant in EYS detected in our previous study along with structural variants (SVs) in EYS and another 88 RP-associated genes. Two large exon-overlapping deletions involving six exons were identified in EYS in two patients with unsolved RP. An analysis of an independent patient set (n=1189) suggested that these two deletions are not founder mutations. Our results suggest that searching for SVs by long-read sequencing in genetically unsolved cases benefits the molecular diagnosis of RP.
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Kawano S., Imai T., Sakamoto T., Yamamoto S., Baba T., Sato E., Kitahashi M., Tatsumi T., Miura G., Niizawa T., Sakamoto T., Yamakiri K., Yamashita T., Otsuka H., Sameshima S., Yoshinaga N., Sonoda S., Hirakata A., Koto T., Inoue M., Hirota K., Itoh Y., Orihara T., Emoto Y., Sano M., Takahashi H., Tokizawa R., Yamashita H., Nishitsuka K., Kaneko Y., Nishi K., Yoshida A., Ono S., Hirokawa H., Sogawa K., Omae T., Ishibazawa A., Kishi S., Akiyama H., Matsumoto H., Mukai R., Morimoto M., Nakazawa M., Suzuki Y., Kudo T., Adachi K., Ishida S., Noda K., Kase S., Mori S., Ando R., Saito M., Suzuki T., Takahashi K., Nagai Y., Nakauchi T., Yamada H., Kusaka S., Tsujioka D., Tsujikawa A., Suzuma K., Ishibashi T., Sonoda K.H., Ikeda Y., Kohno R., Keijiro Ishikawa , Kondo M., Kozawa M., Kitaoka T., Tsuiki E., Ogura Y., Yoshida M., Morita H., Kato A., Hirano Y., Sugitani K., Terasaki H., Iwase T., Ito Y., Ueno S., Kaneko H., Nonobe N., Kominami T., Azuma N., Yokoi T., Shimada H., Nakashizuka H., Hattori T., Shinojima A., Kutagawa Y., Shiraga F., Morizane Y., Kimura S., Ikeda T., Kida T., Sato T., Fukumoto M., Emi K., Nakashima H., Ohji M.
Japanese Journal of Ophthalmology 66 ( 3 ) 271 - 277 2022年5月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Japanese Journal of Ophthalmology
Purpose: To investigate the characteristics of retinal detachment (RD) and compare the outcomes of surgical interventions, such as scleral buckling (SB), pars plana vitrectomy (PPV), or PPV combined with SB, conducted on holidays and on workdays to determine the optimal surgical timing for primary RD treatment in clinical practice. Study design: Retrospective cohort study. Methods: The cohort included 3178 patients with primary RD registered in the Japan Retinal Detachment Registry between February 2016 and March 2017. Surgery data were divided into holiday and workday groups. A descriptive analysis of primary RD characteristics was performed, and the outcomes for each surgical intervention were assessed. The primary outcome was anatomical failure at 6 months post-surgery classified as follows: level 1, inoperable state; level 2, anatomical recovery with silicone-oil use; and level 3, additional surgery required for RD repair. Results: The holiday group comprised 108 and the workday, 3070 cases of primary RD. Compared with those in the workday group, surgery in the holiday group took longer (PPV, P < 0.0001; SB, P = 0.047) and was performed by less experienced surgeons (P = 0.014). However, there were no statistically significant differences in surgical failure 6 months post-surgery between the workday and holiday groups. Conclusion: Although surgery conducted on holidays and workdays was not significantly different in terms of outcome, some surgery should be postponed with proper preoperative interim measures to limit RD progress until it can be conducted on workdays by a well-prepared team.
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Long-term Outcomes of Cataract Surgery in Patients with Retinitis Pigmentosa 査読あり
Nakamura S., Fujiwara K., Yoshida N., Murakami Y., Shimokawa S., Koyanagi Y., Ikeda Y., Sonoda K.H.
Ophthalmology Retina 6 ( 4 ) 268 - 272 2022年4月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Ophthalmology Retina
Purpose: To investigate the long-term outcomes of cataract surgery in patients with retinitis pigmentosa (RP). Design: Retrospective, observational study. Participants: Sixty-four patients with typical RP (22 men, 42 women; average age, 62.8 ± 10.1 years) who underwent cataract surgery at Kyushu University Hospital between May 2007 and October 2015 and were followed up for ≥3 years after the surgery. Methods: Differences between presurgery and postsurgery visual function, including best-corrected visual acuity (BCVA) and parameters in the Humphrey field analyzer (HFA) examination using the central 10-2 program, were investigated. The presurgery conditions of the foveal ellipsoid zone (EZ) were classified into 3 grades (grade 1: invisible; grade 2: abnormal; grade 3: normal) based on OCT findings. Main Outcome Measures: BCVA, the retinal sensitivity in the HFA 10-2 test. Results: Cataract surgery was performed in 96 eyes, with an average follow-up period of 5.8 ± 2.4 years. The mean presurgery BCVA was 0.64 ± 0.52 logarithm of the minimum angle of resolution (logMAR), and the final postsurgery BCVA was 0.61 ± 0.67 logMAR (P = 0.57). Significant improvement in the postsurgery BCVA was observed only in eyes with preserved foveal EZ (grade 3) (P < 0.01). In 62 eyes of 45 patients who underwent the HFA 10-2 test, the mean values of deviation, macular sensitivity, and foveal sensitivity at the final visit were significantly decreased compared with preoperative values (P < 0.01), whereas those in grade 3 eyes did not change significantly after the surgery (P = 0.13). Conclusions: In the long-term course after cataract surgery in patients with RP, many patients experienced vision loss with progression of the disease. The preoperative finding of preserved foveal EZ was associated with a better visual prognosis, suggesting that EZ evaluation is useful for predicting the long-term visual outcome of cataract surgery in patients with RP.
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Wykoff C.C., Abreu F., Adamis A.P., Basu K., Eichenbaum D.A., Haskova Z., Lin H., Loewenstein A., Mohan S., Pearce I.A., Sakamoto T., Schlottmann P.G., Silverman D., Sun J.K., Wells J.A., Willis J.R., Tadayoni R., Aaberg T., Abbey A., Abdulaeva E., Abengoechea S., Abraham P., Ach T., Adams S., Adan Civera A., Adrean S., Agostini H., Alam S., Alezzandrini A., Alfaro V., Aliseda D., Almony A., Amat P., Amini P., Antoszyk A., Arias L., Asaria R., Avila M., Awh C.C., Bafalluy J., Baker C., Bandello F., Barakat M., Barraza K., Bator G., Baumal C., Belfort R., Bergstrom C., Bertolucci G., Bochow T., Bolz M., Borcz E., Bordon A., Boyer D., Bratko G., Brent M., Brown J., Brown D.M., Budzinskaya M., Buffet S., Burgess S., Burton B., Busquets M., Cabrera F., Cagini C., Calzada J., Campochiaro P., Carlson J., Castellarin A., Cava C., Chaikitmongkol V., Chan C., Chang E., Chang J., Chang A., Charles S., Chaudhry N., Chee C., Chen J., Chen F., Chen S.J., Cheong-Leen R., Chiang A., Chittum M., Chow D., Connolly B., Cornut P.L., Csaky K., Danzig C., Das A., Daskalov V., Desco C., Dessouki A., Dickinson J., Do B., Dollin M., Dugel P., Dusova J., Eldem B.
The Lancet 399 ( 10326 ) 741 - 755 2022年2月
掲載種別：研究論文（学術雑誌） 出版者・発行元：The Lancet
Background: To reduce treatment burden and optimise patient outcomes in diabetic macular oedema, we present 1-year results from two phase 3 trials of faricimab, a novel angiopoietin-2 and vascular endothelial growth factor-A bispecific antibody. Methods: YOSEMITE and RHINE were randomised, double-masked, non-inferiority trials across 353 sites worldwide. Adults with vision loss due to centre-involving diabetic macular oedema were randomly assigned (1:1:1) to intravitreal faricimab 6·0 mg every 8 weeks, faricimab 6·0 mg per personalised treatment interval (PTI), or aflibercept 2·0 mg every 8 weeks up to week 100. PTI dosing intervals were extended, maintained, or reduced (every 4 weeks up to every 16 weeks) based on disease activity at active dosing visits. The primary endpoint was mean change in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Efficacy analyses included the intention-to-treat population (non-inferiority margin 4 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); safety analyses included patients with at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (YOSEMITE NCT03622580 and RHINE NCT03622593). Findings: 3247 patients were screened for eligibility in YOSEMITE (n=1532) and RHINE (n=1715). After exclusions, 940 patients were enrolled into YOSEMITE between Sept 5, 2018, and Sept 19, 2019, and 951 patients were enrolled into RHINE between Oct 9, 2018, and Sept 20, 2019. These 1891 patients were randomly assigned to faricimab every 8 weeks (YOSEMITE n=315, RHINE n=317), faricimab PTI (n=313, n=319), or aflibercept every 8 weeks (n=312, n=315). Non-inferiority for the primary endpoint was achieved with faricimab every 8 weeks (adjusted mean vs aflibercept every 8 weeks in YOSEMITE 10·7 ETDRS letters [97·52% CI 9·4 to 12·0] vs 10·9 ETDRS letters [9·6 to 12·2], difference −0·2 ETDRS letters [−2·0 to 1·6]; RHINE 11·8 ETDRS letters [10·6 to 13·0] vs 10·3 ETDRS letters [9·1 to 11·4] letters, difference 1·5 ETDRS letters [−0·1 to 3·2]) and faricimab PTI (YOSEMITE 11·6 ETDRS letters [10·3 to 12·9], difference 0·7 ETDRS letters [−1·1 to 2·5]; RHINE 10·8 ETDRS letters [9·6 to 11·9], difference 0·5 ETDRS letters [−1·1 to 2·1]). Incidence of ocular adverse events was comparable between faricimab every 8 weeks (YOSEMITE n=98 [31%], RHINE n=137 [43%]), faricimab PTI (n=106 [34%], n=119 [37%]), and aflibercept every 8 weeks (n=102 [33%], n=113 [36%]). Interpretation: Robust vision gains and anatomical improvements with faricimab were achieved with adjustable dosing up to every 16 weeks, demonstrating the potential for faricimab to extend the durability of treatment for patients with diabetic macular oedema. Funding: F Hoffmann-La Roche.
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特集 今知っておきたいゲノム医療と遺伝子治療-基礎から臨床まで 各論 遺伝子治療 遺伝性網膜疾患に対する遺伝子治療 査読あり
池田 康博
小児内科 54 ( 2 ) 349 - 353 2022年2月
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Shimokawa S., Murakami Y., Fujiwara K., Funatsu J., Nakatake S., Koyanagi Y., Akiyama M., Yoshida N., Takeda A., Ikeda Y., Sonoda K.H.
Retina 42 ( 1 ) 168 - 173 2022年1月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Retina
Purpose: To investigate the rate of the recurrence of cystoid macular edema (CME) secondary to retinitis pigmentosa (RP) after the initiation of topical dorzolamide and the recurrence risk factors. Methods: We retrospectively analyzed the data of RP patients at Kyushu University Hospital. We included patients who showed a treatment response to 1.0% topical dorzolamide. The day of treatment initiation was set as the baseline. Topical dorzolamide treatment was continued during the follow-up. The recurrence of CME (defined as a .20% increase in central subfield thickness compared to previous visit, or a central subfield thickness value that exceed baseline value) was evaluated at each follow-up visit. Risk factors for RP-CME recurrence were analyzed by Cox proportional hazards modeling. A Kaplan–Meier survival analysis was used to evaluate the time to recurrent RP-CME. Results: Forty RP-CME patients showed a treatment response to topical dorzolamide. During the mean 3.9-year follow-up, 14 patients exhibited recurrence; its rate was 15.6%, 34.7%, and 48.7% at 1, 3, and 5 years, respectively. A high baseline central subfield thickness was significantly associated with recurrent (hazard ratio 1.11, 95% CI: 1.05–1.18, P = 0.0004). Conclusion: The recurrence rate of RP-CME increased with time. A high baseline central subfield thickness value was a risk factor for recurrence.
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Regional and sex differences in retinal detachment surgery: Japan-retinal detachment registry report 査読あり
Funatsu R., Terasaki H., Sakamoto T., Yamamoto S., Baba T., Sato E., Kitahashi M., Tatsumi T., Miura G., Niizawa T., Yamakiri K., Yamashita T., Otsuka H., Sameshima S., Yoshinaga N., Sonoda S., Hirakata A., Koto T., Inoue M., Hirota K., Itoh Y., Orihara T., Emoto Y., Sano M., Takahashi H., Tokizawa R., Yamashita H., Nishitsuka K., Kaneko Y., Nishi K., Yoshida A., Ono S., Hirokawa H., Sogawa K., Omae T., Ishibazawa A., Kishi S., Akiyama H., Matsumoto H., Mukai R., Morimoto M., Nakazawa M., Suzuki Y., Kudo T., Adachi K., Ishida S., Noda K., Kase S., Mori S., Ando R., Saito M., Suzuki T., Takahashi K., Nagai Y., Nakauchi T., Yamada H., Kusaka S., Tsujioka D., Tsujikawa A., Suzuma K., Ishibashi T., Sonoda K.H., Ikeda Y., Kohno R., Ishikawa K., Kondo M., Kozawa M., Kitaoka T., Tsuiki E., Ogura Y., Yoshida M., Morita H., Kato A., Hirano Y., Sugitani K., Terasaki H., Iwase T., Ito Y., Ueno S., Kaneko H., Nonobe N., Kominami T., Azuma N., Yokoi T., Shimada H., Nakashizuka H., Hattori T., Shinojima A., Kitagawa Y., Shiraga F., Morizane Y., Kimura S., Ikeda T., Kida T., Sato T., Fukumoto M., Emi K., Nakashima H., Ohji M.
Scientific Reports 11 ( 1 ) 2021年12月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Scientific Reports
It is known that social factors affect the choice of treatments, and special attention has been paid to sex differences. The purpose of this study was to determine whether regional and sex differences exist in the treatment of rhegmatogenous retinal detachment (RD). We used Japan-RD Registry database of 2523 patients aged ≥ 40 years between February 2016 and March 2017 in 5 Japanese regions. Regional differences of patients’ perioperative factors were analyzed. The factors affecting the proportion of patients who underwent surgery within one week of the onset, defined as early-surgery, were examined by logistic regression. We observed regional differences in perioperative factors, especially in the use of phacovitrectomy, general anesthesia, and air-tamponade, which was higher in certain regions. (Fisher’s exact test, all P = 0.012) The proportion of early-surgery was significantly higher among men in Kyushu region (Odds ratio (OR) 1.83; 95% confidence interval (CI) 1.08–3.12; P = 0.02), and it was also significantly higher after adjusting for covariates (OR 1.89; 95% CI 1.06–3.42; P = 0.02). Regional and sex differences exist in the treatment of RD in Japan. Although there was no significant differences in the anatomical outcomes, women in certain regions of Japan are less likely to receive early surgical intervention for RD.
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Murakami Y., Koyanagi Y., Fukushima M., Yoshimura M., Fujiwara K., Akiyama M., Momozawa Y., Ueno S., Terasaki H., Oishi A., Miyata M., Ikeda H., Tsujikawa A., Mizobuchi K., Hayashi T., Fujinami K., Tsunoda K., Park J.Y., Han J., Kim M., Lee C.S., Kim S.J., Park T.K., Joo K., Woo S.J., Ikeda Y., Sonoda K.H.
Ophthalmology Retina 5 ( 12 ) 1269 - 1279 2021年12月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Ophthalmology Retina
Purpose: To investigate the genotype and long-term clinical phenotype of patients with Bietti crystalline dystrophy (BCD) in Korea and Japan. Design: Retrospective case series. Participants: We analyzed 62 patients with clinical features of BCD who harbor pathogenic biallelic CYP4V2 variants in their homozygote or compound heterozygote. Methods: Data were collected from patient charts, including age, best-corrected visual acuity (BCVA), Goldmann perimetry results, fundus photography, OCT findings, fundus autofluorescence results, and electroretinography findings. We compared the clinical course of the patients with homozygous c.802-8_810de117insGC [exon7del], the most common mutation in the East Asian population, with those of the patients with other genotypes. Main Outcome Measures: Best-corrected visual acuity, visual field (VF), and their changes during follow-up. Results: The mean age at the first visit was 55.2 years, with a mean follow-up of 7.1 years. The mean BCVAs at the first and last visits were 0.28 logarithm of the minimum angle of resolution (logMAR) and 0.89 logMAR, respectively. In genetic testing, c.802-8_810de117insGC was detected in 86 of 124 alleles of the patients, and 36 patients were homozygous for this mutation. The age, BCVA, VF area, central foveal thickness, and abnormal hypoautofluorescent area at either the first or last visit were not different between the exon7del homozygotes and the others. The mean BCVA changes per year were 0.089 logMAR in the exon7del homozygotes and 0.089 logMAR in the others. An age- and gender-adjusted linear regression analysis showed no association between the exon7del homozygote status and the rate of vision loss. Characteristic crystalline deposits in the posterior pole were generally observed in younger patients and disappeared over time along with progressive retinochoroidal atrophy. Conclusions: Patients with BCD and a homozygote for c.802-8_810de117insGC accounted for more than 50% of this cohort of Korean and Japanese patients, and the clinical effect of this deleterious variant was not severe in the spectrum of CYP4V2 retinopathy.
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Nishiguchi K.M., Miya F., Mori Y., Fujita K., Akiyama M., Kamatani T., Koyanagi Y., Sato K., Takigawa T., Ueno S., Tsugita M., Kunikata H., Cisarova K., Nishino J., Murakami A., Abe T., Momozawa Y., Terasaki H., Wada Y., Sonoda K.H., Rivolta C., Tsunoda T., Tsujikawa M., Ikeda Y., Nakazawa T.
Communications Biology 4 ( 1 ) 140 2021年12月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Communications Biology
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.
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特集 網膜色素変性のアップデート 【治療法開発研究の最前線】 網膜色素変性に対する遺伝子治療 招待あり
池田 康博
臨床眼科 75 ( 12 ) 1475 - 1482 2021年11月
担当区分：筆頭著者, 責任著者 記述言語：日本語 掲載種別：論文集(書籍)内論文 出版者・発行元：株式会社医学書院
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Genetic and phenotypic landscape of PRPH2-associated retinal dystrophy in Japan 査読あり
Oishi A., Fujinami K., Mawatari G., Naoi N., Ikeda Y., Ueno S., Kuniyoshi K., Hayashi T., Kondo H., Mizota A., Shinoda K., Kusuhara S., Nakamura M., Iwata T., Tsujikawa A., Tsunoda K.
Genes 12 ( 11 ) 2021年11月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Genes
Peripherin-2 (PRPH2) is one of the causative genes of inherited retinal dystrophy. While the gene is relatively common in Caucasians, reports from Asian ethnicities are limited. In the present study, we report 40 Japanese patients from 30 families with PRPH2-associated retinal dystrophy. We identified 17 distinct pathogenic or likely pathogenic variants using next-generation sequencing. Variants p.R142W and p.V200E were relatively common in the cohort. The age of onset was generally in the 40’s; however, some patients had earlier onset (age: 5 years). Visual acuity of the patients ranged from hand motion to 1.5 (Snellen equivalent 20/13). The patients showed variable phenotypes such as retinitis pigmentosa, cone-rod dystrophy, and macular dystrophy. Additionally, intrafamilial phenotypic variability was observed. Choroidal neovascularization was observed in three eyes of two patients with retinitis pigmentosa. The results demonstrate the genotypic and phenotypic variations of the disease in the Asian cohort.
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Regional differences in genes and variants causing retinitis pigmentosa in Japan 査読あり
Koyanagi Y., Akiyama M., Nishiguchi K.M., Momozawa Y., Kamatani Y., Takata S., Inai C., Iwasaki Y., Kumano M., Murakami Y., Komori S., Gao D., Kurata K., Hosono K., Ueno S., Hotta Y., Murakami A., Terasaki H., Wada Y., Nakazawa T., Ishibashi T., Ikeda Y., Kubo M., Sonoda K.H.
Japanese Journal of Ophthalmology 65 ( 3 ) 338 - 343 2021年5月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Japanese Journal of Ophthalmology
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.
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Gene therapy for patients with retinitis pigmentosa 査読あり
Ikeda Y.
Japanese Journal of Clinical Ophthalmology 75 ( 12 ) 1475 - 1482 2021年
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Japanese Journal of Clinical Ophthalmology
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Effect of Topical Dorzolamide on Cystoid Macular Edema in Retinitis Pigmentosa. 査読あり
Shimokawa S, Fujiwara K, Murakami Y, Funatsu J, Nakatake S, Yoshida N, Sonoda KH, Ikeda Y.
Ophthalmol Retina 4 ( 10 ) 1036 - 1039 2020年10月
記述言語：英語 掲載種別：研究論文（その他学術会議資料等） 出版者・発行元：Ophthalmology Retina
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Okita A., Murakami Y., Shimokawa S., Funatsu J., Fujiwara K., Nakatake S., Koyanagi Y., Akiyama M., Takeda A., Hisatomi T., Ikeda Y., Sonoda K.H.
Investigative ophthalmology & visual science 61 ( 11 ) 30 2020年9月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Investigative ophthalmology & visual science
Purpose: Retinal degeneration involves neuroinflammation, and pro-inflammatory cytokines/chemokines are markedly increased in the eyes of patients with retinitis pigmentosa (RP). In this study, we investigated the changes of serum cytokines/chemokines in RP, and their relationships with visual parameters. Methods: Forty-five consecutive patients with typical RP aged 20 to -39 years and 28 age-matched and gender-matched controls were included. Fifteen cytokines (interleukin [IL]-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, IL-13, 1L-15, IL-17, IL-23, interferon [IFN]-γ, and tumor necrosis factor [TNF]-α, TNF-β) and 9 chemokines (eotaxin, growth-related oncogene [GRO]-α, I-309, IL-8, IFN-γ-inducible protein [IP]-10, monocyte chemotactic protein [MCP]-1, MCP-2, regulated activation normal T-cell expressed and secreted [RANTES], and thymus and activated regulated chemokine [TARC]) in the serum were simultaneously measured by a multiplexed immunoarray (Q-Plex). Relationships between these cytokines/chemokines and indices of central vision, such as visual acuity (VA), the values of static perimetry tests (Humphrey Field analyzer, the central 10-2 program), and optical coherence tomography measures were analyzed in the patients with RP. Results: Among the 15 cytokines and 9 chemokines, serum IL-8 and RANTES levels were significantly increased in patients with RP compared with controls (IL-8: P < 0.0001; RANTES: P < 0.0001). Among the elevated cytokines/chemokines, the levels of IL-8 were negatively correlated with VA (ρ = 0.3596 and P = 0.0165), and the average retinal sensitivity of four central points (ρ = -0.3691 and P = 0.0291), and 12 central points (ρ = -0.3491 and P = 0.0398), as well as the central subfield thickness (ρ = -0.3961 and P = 0.0094), and ellipsoid zone width (ρ = -0.3841 and P = 0.0120). Conclusions: Peripheral inflammatory response may be activated and serum IL-8 levels are associated with central vision in patients with RP.
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Koyanagi Y., Ueno S., Ito Y., Kominami T., Komori S., Akiyama M., Murakami Y., Ikeda Y., Sonoda K.H., Terasaki H.
Investigative Ophthalmology and Visual Science 61 ( 10 ) 6 2020年8月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Investigative Ophthalmology and Visual Science
Copyright 2020 The Authors. PURPOSE. To determine the relationship between the macular curvature and the causative genes of retinitis pigmentosa (RP). METHODS. We examined the medical records of the right eyes of 65 cases with RP (31 men and 34 women; average age, 47.6 years). There were 31 cases with the EYS variants, 11 cases with the USH2A variants, six cases with the RPGR variants, 13 cases with the RP1 variants, and four cases with the RP1L1 variants. The mean curvature of Bruch’s membrane was calculated within 6 mm of the fovea as the mean macular curvature index (MMCI, 1/μm). We used multiple linear regression analysis to determine the independence of the causative genes contributing to the MMCIs after adjustments for age, sex, axial length, and width of the ellipsoid zone. RESULTS. The median MMCI was -31.2 × 10-5/μm for the RPGR eyes, -16.5 × 10-5/μm for the RP1L1 eyes, -13.0 × 10-5/μm for the RP1 eyes, -9.8 × 10-5/μm for the EYS eyes, and -9.0 × 10-5/μm for the USH2A eyes. Compared with the EYS gene as the reference gene, the RPGR gene was significantly related to the MMCI values after adjusting for the other parameters (P = 5.30 × 10-6). In contrast, the effects of the other genes, USH2A, RP1, and RP1L1, were not significantly different from that of the EYS gene (P = 0.26, P = 0.49, and P = 0.92, respectively). CONCLUSIONS. The RPGR gene had a stronger effect on the steep macular curvature than the other ciliopathy-related genes.
DOI： 10.1167/IOVS.61.10.6
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Nishiguchi K.M., Kunikata H., Fujita K., Hashimoto K., Koyanagi Y., Akiyama M., Ikeda Y., Momozawa Y., Sonoda K.H., Murakami A., Wada Y., Nakazawa T.
Clinical and Experimental Ophthalmology 48 ( 5 ) 644 - 657 2020年7月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Clinical and Experimental Ophthalmology
© 2020 Royal Australian and New Zealand College of Ophthalmologists 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
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A founder Alu insertion in RP1 gene in Japanese patients with retinitis pigmentosa 査読あり
Nishiguchi K.M., Fujita K., Ikeda Y., Kunikata H., Koyanagi Y., Akiyama M., Abe T., Wada Y., Sonoda K.H., Nakazawa T.
Japanese Journal of Ophthalmology 64 ( 4 ) 346 - 350 2020年7月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Japanese Journal of Ophthalmology
© 2020, Japanese Ophthalmological Society. Purpose: To screen for the 328 bp Alu insertion (c.4052_4053ins328, p.Tyr1352Alafs) in RP1 in a group of retinitis pigmentosa (RP) patients who had been previously identified with a heterozygous deleterious mutation in the gene. Study design: Prospective, clinical and experimental study. Methods: The Alu insertion in RP1 was screened with an optimized PCR-based method in 26 RP patients with a heterozygous deleterious mutation (nonsense or frameshift) in RP1 that had been identified in a preceding genetic study. The genetic location of the previously identified mutation and its inheritance pattern were assessed. Results: Out of 26 RP patients with a heterozygous deleterious mutation in RP1, 5 (19.2%) were found to carry an additional heterozygous Alu insertion, presumably resulting in a compound heterozygous state. This included 3 patients who had been previously diagnosed as autosomal dominant RP based on genetic findings. They were re-diagnosed as having an autosomal recessive disease following our new findings. In all patients identified with the Alu insertion, the other mutations found in the preceding study were outside the defined region in exon 4 (encoding amino acids 677 to 917) in which truncation mutations have been suggested to exert a dominant negative effect. Conclusion: The founder Alu insertion in RP1 is an important cause of autosomal recessive RP in Japanese patients and can be missed in standard targeted resequencing. Screening optimized for this mutation is warranted, particularly in patients with a heterozygous deleterious mutation outside the defined region in exon 4 of RP1.
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Aqueous flare and progression of visual field loss in patients with retinitis pigmentosa 査読あり
Fujiwara K., Ikeda Y., Murakami Y., Tachibana T., Funatsu J., Koyanagi Y., Nakatake S., Shimokawa S., Yoshida N., Nakao S., Hisatomi T., Ishibashi T., Sonoda K.H.
Investigative Ophthalmology and Visual Science 61 ( 8 ) 26 2020年7月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Investigative Ophthalmology and Visual Science
© 2020 The Authors. PURPOSE. To investigate the association between aqueous flare and progression of visual field loss using the Humphrey Field Analyzer in patients with retinitis pigmentosa (RP). METHODS. We examined a total of 101 eyes of 101 patients who were diagnosed with typical RP. Sixty-one percent of the patients were female, and the mean age of the total group was 47.4 years. Aqueous flare, visual field (by an Humphrey Field Analyzer, the central 10-2 SITA-Standard program), and optical coherence tomography measurements were obtained for all patients. The slope, which was derived from serial values of mean deviation, macular sensitivity, or foveal sensitivity for each eye with univariate linear regression, was used for analysis. RESULTS. Aqueous flare values were significantly correlated with the mean deviation slope (r =-0.20, P = 0.046), macular sensitivity slope (r =-0.28, P = 0.005) and foveal sensitivity slope (r =-0.20, P = 0.047). The values of the retinal sensitivity slope significantly decreased as the aqueous flare level increased (all P < 0.05). These associations remained unchanged after adjustment for age, sex, and posterior subcapsular cataract, and epiretinal membrane. CONCLUSIONS. Elevation of aqueous flare is a risk factor for the decline of central visual function in RP. Aqueous flare may be a useful marker for disease progression in RP.
DOI： 10.1167/IOVS.61.8.26
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Shimokawa S., Nakao S., Murakami Y., Ikeda Y., Sonoda K.H.
American Journal of Ophthalmology Case Reports 18 100682 2020年6月
記述言語：日本語 掲載種別：症例報告 出版者・発行元：American Journal of Ophthalmology Case Reports
Purpose: Two diabetic case reports of serous retinal detachment (SRD) accompanied by pachychoroid in hypotony maculopathy after trabeculectomy for neovascular glaucoma (NVG). Observations: Case 1: A 66-year-old female with stage 3 NVG and decreased vision acuity in the left eye. After trabeculectomy, postoperative laser suture lysis (LSL) resulted in development of hypotony maculopathy, followed by pachychoroid and SRD. Injection of C3F8 gas in the anterior chamber was unsuccessful and transconjunctival scleral re-suturing was performed. Intraocular pressure (IOP) consequently increased and SRD improved. Case 2: A 60-year-old man with stage 2 NVG and decreased vision acuity in the right eye. Trabeculectomy was uneventful, but postoperative LSL also resulted in development of hypotony maculopathy followed by pachychroid and SRD. Intravitreal bevacizumab injection had no effect and transconjunctival flap re-suturing was performed. IOP consequently increased and SRD improved. Conclusions: SRD accompanied by pachychoroid was observed in hypotony maculopathy in diabetic cases. VEGF-independent exudative change in hypotony maculopathy may be due to hydrostatic pressure elevation in choroidal blood vessels based on Starling's hypothesis with the consequent breakdown of retinal pigment epithelium barrier in diabetic patients.
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Serous retinal detachment accompanied by pachychoroid in hypotony maculopathy after trabeculectomy for diabetic neovascular glaucoma. 査読あり
Shimokawa S, Nakao S, Murakami Y, Ikeda Y, Sonoda KH.
Am J Ophthalmol Case Rep 2020年3月
記述言語：英語 掲載種別：研究論文（その他学術会議資料等）
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Sakamoto T., Kawano S., Kawasaki R., Hirakata A., Yamashita H., Yamamoto S., Ishibashi T., Sato E., Kitahashi M., Tatsumi T., Miura G., Niizawa T., Yamakiri K., Yamashita T., Otsuka H., Sameshima S., Yoshinaga N., Sonoda S., Koto T., Inoue M., Hirota K., Itoh Y., Orihara T., Emoto Y., Sano M., Takahashi H., Tokizawa R., Nishitsuka K., Kaneko Y., Nishi K., Yoshida A., Ono S., Hirokawa H., Sogawa K., Omae T., Ishibazawa A., Kishi S., Akiyama H., Matsumoto H., Mukai R., Morimoto M., Nakazawa M., Suzuki Y., Kudo T., Adachi K., Ishida S., Noda K., Kase S., Mori S., Ando R., Saito M., Suzuki T., Takahashi K., Nagai Y., Nakauchi T., Yamada H., Kusaka S., Tsujioka D., Tsujikawa A., Suzuma K., Sonoda K.H., Ikeda Y., Kohno R., Ishikawa K., Kondo M., Kozawa M., Kitaoka T., Tsuiki E., Ogura Y., Yoshida M., Morita H., Kato A., Hirano Y., Sugitani K., Terasaki H., Iwase T., Ito Y., Ueno S., Kaneko H., Nonobe N., Kominami T., Azuma N., Yokoi T., Shimada H., Nakashizuka H., Hattori T., Shinojima A., Kutagawa Y., Shiraga F., Morizane Y., Kimura S., Ikeda T., Kida T., Sato T., Fukumoto M., Emi K., Nakashima H., Ohji M., Kakinoki M.
Japanese Journal of Ophthalmology 64 ( 1 ) 1 - 12 2020年1月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Japanese Journal of Ophthalmology
Purpose: To report the demographics and clinical characteristics of patients with a primary retinal detachment (RD). Design: Prospective cohort study by a registry design. Participants: Patients with RD treated at vitreoretinal sub-specialty institutions in Japan from February 2016 to March 2017. Methods: Descriptive statistics for the primary RD, and multivariable ordered logistic regression and multiple linear regression analyses were performed. Results: 3178 eyes of 3178 cases were analyzed. The interval from onset to surgery was significantly shorter in patients in the 40-year age group than in other age groups except for the 50-year age group (P<0.05, Steel-Dwass test). The proportion of complex cases was significantly higher in the 10-year, 70-year, and 80+ year age groups than in the 40 and 50-year age groups (P<0.05, Steel-Dwass test). The size of RD was significantly associated with the male sex (odds ratio, 1.29; 95% confidence interval [CI], 1.07 to 1.56; P=0.0085) and the interval from onset to surgery (odds ratio, 1.03 95% CI, 1.01 to 1.04; P=0.0014). Low IOPs in eyes with RD were significantly associated with an older age (-0.24 mmHg/10 years, 95% CI, -0.32 to -0.16], P<0.0001) and larger RD area (-0.91 mmHg/quadrant, 95% CI, [-1.06 to -0.76], P <0.0001). Conclusion: Profile and clinical characteristics of patients with a primary RD were not exactly the same as previous reports. A preoperative low IOP was associated with several ocular factors while the area of RD was associated not only with ocular but with social factors as well.
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Direct comparison of retinal structure and function in retinitis pigmentosa by co-registering microperimetry and optical coherence tomography. 査読あり
Funatsu J, Murakami Y, Nakatake S, Akiyama M, Fujiwara K, Shimokawa S, Tachibana T, Hisatomi T, Koyanagi Y, Momozawa Y, Sonoda KH, Ikeda Y.
PLoS One. 2019年12月
記述言語：英語 掲載種別：研究論文（学術雑誌）
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Nikopoulos K., Cisarova K., Quinodoz M., Koskiniemi-Kuendig H., Miyake N., Farinelli P., Rehman A., Khan M., Prunotto A., Akiyama M., Kamatani Y., Terao C., Miya F., Ikeda Y., Ueno S., Fuse N., Murakami A., Wada Y., Terasaki H., Sonoda K., Ishibashi T., Kubo M., Cremers F., Kutalik Z., Matsumoto N., Nishiguchi K., Nakazawa T., Rivolta C.
Nature Communications 10 ( 1 ) 2019年12月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Nature Communications
© 2019, The Author(s). 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.
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Kaizu Y., Nakao S., Arima M., Hayami T., Wada I., Yamaguchi M., Sekiryu H., Ishikawa K., Ikeda Y., Sonoda K.
Scientific Reports 9 ( 1 ) 2019年12月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Scientific Reports
© 2019, The Author(s). Our study evaluated the diagnostic capability of flow density (FD) in OCT angiography (OCTA) for diabetic retinopathy (DR) detection in diabetic patients. We studied 93 eyes of 68 diabetic patients who underwent OCTA (36 and 57 eyes without and with DR, respectively). Retinal capillary FD of a 2.6 × 2.6 mm2 area and four divided areas at the superficial (SCP) and deep capillary plexus (DCP) were measured. Predictions were evaluated using the area under the receiver operating characteristic curve (AUC). The diagnostic capabilities of the FDs in discriminating between eyes without DR and eyes with total or early DR were compared. Furthermore, predictions with foveal avascular zone (FAZ) area, hemoglobin A1c (HbA1c), and DM duration were also compared with FD. Prediction using FD AUC in the temporal side in the DCP (0.83) was the highest and significantly better than all other AUCs examined (P < 0.05), including discriminating between eyes without DR and with early DR (P < 0.01). Prediction using this particular AUC was also significantly better than that by FAZ area and HbA1c (P < 0.001 and <0.001, respectively). Area-divided FD in OCTA may be valuable for diagnosing retinopathy in diabetic patients.
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Notomi S, Ishihara K, Efstathiou NE, Lee JJ, Hisatomi T, Tachibana T, Konstantinou EK, Ueta T, Murakami Y, Maidana DE, Ikeda Y, Kume S, Terasaki H, Sonoda S, Blanz J, Young L, Sakamoto T, Sonoda KH, Saftig P, Ishibashi T, Miller JW, Kroemer G, Vavvas DG.
Proc Natl Acad Sci U S A. 116 ( 47 ) 23724 - 23734 2019年11月
記述言語：英語 掲載種別：研究論文（学術雑誌）
© 2019 National Academy of Sciences. All rights reserved. The early stages of age-related macular degeneration (AMD) are characterized by the accumulation of basal laminar deposits (BLamDs). The mechanism for BLamDs accumulating between the retinal pigment epithelium (RPE) and its basal lamina remains elusive. Here we examined the role in AMD of lysosome-associated membrane protein-2 (LAMP2), a glycoprotein that plays a critical role in lysosomal biogenesis and maturation of autophagosomes/ phagosomes. LAMP2 was preferentially expressed by RPE cells, and its expression declined with age. Deletion of the Lamp2 gene in mice resulted in age-dependent autofluorescence abnormalities of the fundus, thickening of Bruch’s membrane, and the formation of BLamDs, resembling histopathological changes occurring in AMD. Moreover, LAMP2-deficient mice developed molecular signatures similar to those found in human AMD—namely, the accumulation of APOE, APOA1, clusterin, and vitronectin—adjacent to BLamDs. In contrast, collagen 4, laminin, and fibronectin, which are extracellular matrix proteins constituting RPE basal lamina and Bruch’s membrane were reduced in Lamp2 knockout (KO) mice. Mechanistically, retarded phagocytic degradation of photoreceptor outer segments compromised lysosomal degradation and increased exocytosis in LAMP2-deficient RPE cells. The accumulation of BLamDs observed in LAMP2-deficient mice was eventually followed by loss of the RPE and photoreceptors. Finally, we observed loss of LAMP2 expression along with ultramicroscopic features of abnormal phagocytosis and exocytosis in eyes from AMD patients but not from control individuals. Taken together, these results indicate an important role for LAMP2 in RPE function in health and disease, suggesting that LAMP2 reduction may contribute to the formation of BLamDs in AMD.
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Ishizu M., Murakami Y., Fujiwara K., Funatsu J., Shimokawa S., Nakatake S., Tachibana T., Hisatomi T., Koyanagi Y., Akiyama M., Momozawa Y., Ishibashi T., Sonoda K.H., Ikeda Y.
Investigative Ophthalmology and Visual Science 60 ( 13 ) 4462 - 4468 2019年10月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Investigative Ophthalmology and Visual Science
Copyright 2019 The Authors PURPOSE. To investigate the serum changes of antioxidant/oxidant markers and the relationship between these factors and visual function in patients with retinitis pigmentosa (RP). METHODS. Fifty-two RP patients <40 years old and 25 controls were included. Serum samples were analyzed for superoxide dismutase 3 (SOD3) activity, glutathione peroxidase (GPx), potential antioxidant (PAO), and hexanoyl-lysine (HEL). The relationships between these markers and visual parameters, including best-corrected visual acuity (BCVA), mean deviation (MD), and average retinal sensitivity of 4 or 12 central points on static perimetry tests (Humphrey Field Analyzer, the central 10–2 program) were examined in the RP patients. RESULTS. Although there was no significant difference in the serum SOD3 activity between RP patients and controls, serum SOD3 activity in the severe degeneration group with macular involvement (16.3 6 11.3 U/mL) was significantly lower compared with those in the mild degeneration group (those with midperipheral scotomas; 28.5 6 16.6 U/mL, P ¼ 0.0459). SOD3 was significantly related to visual acuity (r ¼ -0.3701, P ¼ 0.0069) and the average retinal sensitivity of four central points (r ¼ 0.3463, P ¼ 0.0137) in RP patients. The linear trends of these two parameters across SOD3 levels were also significant (P ¼ 0.0264 and 0.0172, respectively). There was no consistent correlation between other serum antioxidant/ oxidant markers and visual parameters. CONCLUSIONS. Lower serum SOD3 activity was associated with the severe retinal degeneration in RP patients. Our results suggest that serum SOD3 activity may be related to disease severity in RP.
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Ishizu M, Murakami Y, Fujiwara K, Funatsu J, Shimokawa S, Nakatake S, Tachibana T, Hisatomi T, Koyanagi Y, Akiyama M, Momozawa Y, Ishibashi T, Sonoda KH, Ikeda Y.
Invest Ophthalmol Vis Sci. 60 ( 13 ) 4462 - 4468 2019年9月
記述言語：英語 掲載種別：研究論文（学術雑誌）
Copyright 2019 The Authors PURPOSE. To investigate the serum changes of antioxidant/oxidant markers and the relationship between these factors and visual function in patients with retinitis pigmentosa (RP). METHODS. Fifty-two RP patients <40 years old and 25 controls were included. Serum samples were analyzed for superoxide dismutase 3 (SOD3) activity, glutathione peroxidase (GPx), potential antioxidant (PAO), and hexanoyl-lysine (HEL). The relationships between these markers and visual parameters, including best-corrected visual acuity (BCVA), mean deviation (MD), and average retinal sensitivity of 4 or 12 central points on static perimetry tests (Humphrey Field Analyzer, the central 10–2 program) were examined in the RP patients. RESULTS. Although there was no significant difference in the serum SOD3 activity between RP patients and controls, serum SOD3 activity in the severe degeneration group with macular involvement (16.3 6 11.3 U/mL) was significantly lower compared with those in the mild degeneration group (those with midperipheral scotomas; 28.5 6 16.6 U/mL, P ¼ 0.0459). SOD3 was significantly related to visual acuity (r ¼ -0.3701, P ¼ 0.0069) and the average retinal sensitivity of four central points (r ¼ 0.3463, P ¼ 0.0137) in RP patients. The linear trends of these two parameters across SOD3 levels were also significant (P ¼ 0.0264 and 0.0172, respectively). There was no consistent correlation between other serum antioxidant/ oxidant markers and visual parameters. CONCLUSIONS. Lower serum SOD3 activity was associated with the severe retinal degeneration in RP patients. Our results suggest that serum SOD3 activity may be related to disease severity in RP.
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Kaizu Y., Nakao S., Arima M., Wada I., Yamaguchi M., Sekiryu H., Hayami T., Ishikawa K., Ikeda Y., Sonoda K.
Acta Ophthalmologica 97 ( 5 ) e811 - e812 2019年8月
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Capillary Dropout is Dominant in Deep Capillary Plexus in Early Diabetic Retinopathy in Optical Coherence Tomography Angiography 査読あり
Kaizu Y, Nakao S, Arima M, Wada I, Yamaguchi M, Sekiryu H, Hayami T, Ishikawa K, Ikeda Y, Sonoda KH
Acta Ophthalmol 2019年8月
記述言語：英語 掲載種別：研究論文（学術雑誌）
DOI： 10.1111/aos.14041
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Capillary Dropout is Dominant in Deep Capillary Plexus in Early Diabetic Retinopathy in Optical Coherence Tomography Angiography. 査読あり
Kaizu Y, Nakao S, Arima M, Wada I, Yamaguchi M, Sekiryu H, Hayami T, Ishikawa K, Ikeda Y, Sonoda KH
Acta Ophthalmol 2019年8月
記述言語：英語 掲載種別：研究論文（その他学術会議資料等）
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Nakatake S., Murakami Y., Funatsu J., Koyanagi Y., Akiyama M., Momozawa Y., Ishibashi T., Sonoda K., Ikeda Y.
Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie 257 ( 6 ) 1169 - 1181 2019年6月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie
PURPOSE: The purpose of the study was to investigate the characteristics of the parafoveal cone density changes in patients with retinitis pigmentosa (RP) using adaptive optics scanning laser ophthalmoscopy (AO-SLO). METHODS: A total of 14 eyes of RP patients and 10 eyes of control subjects were examined. High-resolution images of cone photoreceptor cells were obtained with a Canon AO-SLO system in the four retinal regions of the superior, inferior, temporal, and nasal areas located 1.0 mm from the central fovea. The relationships of cone density with optical coherence tomography (OCT) findings and the visual sensitivity of the static perimetry tests were analyzed in RP patients. RESULTS: The averaged cone densities in RP patients were decreased at 1.0 mm eccentricity from the fovea (11,899 cells/mm2) compared with those in control subjects (16,647 cells/mm2; P < 0.01). The cone density was substantially decreased even in RP patients with an intact interdigitation zone at the examined area (12,865 cells/mm2; P < 0.01 vs. controls) and preserved visual sensitivity with > 35 dB (13,019 cells/mm2; P < 0.001 vs. controls). CONCLUSIONS: In RP, cone photoreceptor cell loss occurred in the parafoveal region with a preserved EZ/IZ or visual sensitivity. AO-SLO may be a useful modality to detect early changes of cone photoreceptor cells in RP patients.
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Night-vision aid using see-through display for patients with retinitis pigmentosa 査読あり
Ikeda Y., Nakatake S., Funatsu J., Fujiwara K., Tachibana T., Murakami Y., Hisatomi T., Yoshida S., Enaida H., Ishibashi T., Sonoda K.
Japanese Journal of Ophthalmology 63 ( 2 ) 181 - 185 2019年3月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Japanese Journal of Ophthalmology
© 2019, Japanese Ophthalmological Society. Purpose: From an early stage, retinitis pigmentosa (RP) patients suffer from night blindness which causes nocturnal mobility difficulties. We created a wearable visual aid that uses a high-performance see-through display, and added a high-sensitivity camera with a complementary metal-oxide-semiconductor sensor. Here, we evaluate the device’s efficacy for helping night-blindness sufferers walk in the dark. Study design: Prospective clinical study. Methods: Twenty-eight subjects underwent binocular visual acuity testing in the dark without (power off) and with (power on) the device. The test was carried out in a darkened room. We recorded the number of trial errors and the time it took each subject to arrive at the goal both with and without the aid of our device. Results: Our device effectively assists walking in RP patients with mobility problems in the dark. Conclusion: Binocular visual acuity in the dark was significantly improved with the aid of our device. In the walking test, the number of errors decreased greatly with the device, and the travel time was significantly shortened.
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Ishikawa S., Yoshinaga Y., Kantake D., Nakamura D., Yoshida N., Hisatomi T., Ikeda Y., Ishibashi T., Enaida H.
Graefe's Archive for Clinical and Experimental Ophthalmology 257 ( 3 ) 557 - 565 2019年3月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Graefe's Archive for Clinical and Experimental Ophthalmology
© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. Purpose: This study was conducted in order to develop a novel noninvasive system for measurement and imaging of the arterial oxygen density ratio (ODR) in the retinal microcirculation. Methods: We developed a system composed of two digital cameras with two different filters, which were attached to a fundus camera capable of simultaneously obtaining two images. Actual measurements were performed on healthy volunteer eyes (n = 61). A new algorithm for ODR measurement and pixel-level imaging of erythrocytes was constructed from these data. The algorithm was based on the morphological closing operation and the line convergence index filter. For system calibration, we compared and verified the ODR values in arterioles and venules that were specified in advance for 56 eyes with reproducibility. In 10 additional volunteers, ODR measurements and imaging of the arterial phase in the retinal microcirculation corresponding to changes in oxygen saturation of the peripheral arteries at normal breathing and breath holding were performed. Results: Estimation of incident light to erythrocytes and pixel-level ODR calculation were achieved using the algorithm. The mean ODR values of arterioles and venules were 0.77 ± 0.060 and 1.02 ± 0.067, respectively. It was possible to separate these regions, calibrate at the pixel level, and estimate the arterial phase. In each of the 10 volunteers, changes in the arterial phase ODR corresponding to changes in oxygen saturation of the peripheral arteries were observed before and after breath holding on ODR images. The mean ODR in 10 volunteers was increased by breath holding (p < 0.05). Conclusions: We developed a basic system for arterial phase ODR measurement and imaging of the retinal microcirculation. With further validation and development, this may provide a useful tool for evaluating retinal oxygen metabolism in the retinal microcirculation.
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Verbakel S., Van Huet R., Den Hollander A., Geerlings M., Kersten E., Klevering B., Klaver C., Plomp A., Wesseling N., Bergen A., Nikopoulos K., Rivolta C., Ikeda Y., Sonoda K., Wada Y., Boon C., Nakazawa T., Hoyng C., Nishiguchi K.
Investigative Ophthalmology and Visual Science 60 ( 4 ) 1192 - 1203 2019年3月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Investigative Ophthalmology and Visual Science
© 2019 The Authors. PURPOSE. To describe the clinical and genetic spectrum of RP1-associated retinal dystrophies. METHODS. In this multicenter case series, we included 22 patients with RP1-associated retinal dystrophies from 19 families from The Netherlands and Japan. Data on clinical characteristics, visual acuity, visual field, ERG, and retinal imaging were extracted from medical records over a mean follow-up of 8.1 years. RESULTS. Eleven patients were diagnosed with autosomal recessive macular dystrophy (arMD) or autosomal recessive cone-rod dystrophy (arCRD), five with autosomal recessive retinitis pigmentosa (arRP), and six with autosomal dominant RP (adRP). The mean age of onset was 40.3 years (range 14–56) in the patients with arMD/arCRD, 26.2 years (range 18–40) in adRP, and 8.8 years (range 5–12) in arRP patients. All patients with arMD/arCRD carried either the hypomorphic p.Arg1933* variant positioned close to the C-terminus (8 of 11 patients) or a missense variant in exon 2 (3 of 11 patients), compound heterozygous with a likely deleterious frameshift or nonsense mutation, or the p.Gln1916* variant. In contrast, all mutations identified in adRPand arRP patients were frame shift and/or nonsense variants located far fromthe C -terminus. CONCLUSIONS. Mutations in the RP1 gene are associated with a broad spectrum of progressive retinal dystrophies. In addition to adRP and arRP, our study provides further evidence that arCRD and arMD are RP1-associated phenotypes as well. The macular involvement in patients with the hypomorphic RP1 variant suggests that macular function may remain compromised if expression levels of RP1 do not reach adequate levels after gene augmentation therapy.
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Nishiguchi K., Ikeda Y., Fujita K., Kunikata H., Akiho M., Hashimoto K., Hosono K., Kurata K., Koyanagi Y., Akiyama M., Suzuki T., Kawasaki R., Wada Y., Hotta Y., Sonoda K., Murakami A., Nakazawa M., Nakazawa T., Abe T.
Ophthalmology 2019年
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Ophthalmology
© 2019 American Academy of Ophthalmology 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.
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Effect of Ocular Hypertension on D- β -Aspartic Acid-Containing Proteins in the Retinas of Rats 査読あり
Kanamoto T., Tachibana T., Kitaoka Y., Hisatomi T., Ikeda Y., Murakami Y., Tobiume K., Asaoka R., Kiuchi Y.
Journal of Ophthalmology 2019 2019年
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of Ophthalmology
© 2019 Takashi Kanamoto et al. Purpose. To investigate the effect of ocular hypertension-induced isomerization of aspartic acid in retinal proteins. Methods. Adult Wistar rats with ocular hypertension were used as an experimental model. D-β-aspartic acid-containing proteins were isolated by SDS-PAGE and western blot with an anti-D-β-aspartic acid antibody and identified by liquid chromatography-mass spectrometry analysis. The concentration of ATP was measured by ELISA. Results. D-β-aspartic acid was expressed in a protein band at around 44.5 kDa at much higher quantities in the retinas of rats with ocular hypertension than in those of normotensive rats. The 44.5 kDa protein band was mainly composed of α-enolase, S-arrestin, and ATP synthase subunits α and β, in both the ocular hypertensive and normotensive retinas. Moreover, increasing intraocular pressure was correlated with increasing ATP concentrations in the retinas of rats. Conclusion. Ocular hypertension affected the expression of proteins containing D-β-aspartic acid, including ATP synthase subunits, and up-regulation of ATP in the retinas of rats.
DOI： 10.1155/2019/2431481
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Genetic characteristics of retinitis pigmentosa in 1204 Japanese patients 査読あり
Koyanagi Y., Akiyama M., Nishiguchi K., 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 K.
Journal of Medical Genetics 1 - 9 2019年
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of Medical Genetics
© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ. Background: 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. Methods: 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. Results: 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 (EYS, USH2A, RP1L1, RHO, RP1 and RPGR) caused RP in 65.4% (233/356) of those patients. Among autosomal recessive genes, two known founder variants in EYS [p.(Ser1653fs) and p.(Tyr2935∗)] and four East Asian-specific variants [p.(Gly2752Arg) in USH2A, p.(Arg658∗) in RP1L1, p.(Gly2186Glu) in EYS and p.(Ile535Asn) in PDE6B] and p.(Cys934Trp) in USH2A were found in ≥10 patients. Among autosomal dominant genes, four pathogenic variants [p.(Pro347Leu) in RHO, p.(Arg872fs) in RP1, p.(Arg41Trp) in CRX and p.(Gly381fs) in PRPF31] were found in ≥4 patients, while these variants were unreported or extremely rare in both East Asian and non-East Asian population-based databases. Conclusions: East Asian-specific variants in causative genes were the major causes of RP in the Japanese population.
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Notomi S., Ishihara K., Efstathiou N.E., Lee J.J., Hisatomi T., Tachibana T., Konstantinou E.K., Ueta T., Murakami Y., Maidana D.E., Ikeda Y., Kume S., Terasaki H., Sonoda S., Blanz J., Young L., Sakamoto T., Sonoda K.H., Saftig P., Ishibashi T., Miller J.W., Kroemer G., Vavvas D.G.
Proceedings of the National Academy of Sciences of the United States of America 116 ( 47 ) 23724 - 23734 2019年
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Proceedings of the National Academy of Sciences of the United States of America
© 2019 National Academy of Sciences. All rights reserved. The early stages of age-related macular degeneration (AMD) are characterized by the accumulation of basal laminar deposits (BLamDs). The mechanism for BLamDs accumulating between the retinal pigment epithelium (RPE) and its basal lamina remains elusive. Here we examined the role in AMD of lysosome-associated membrane protein-2 (LAMP2), a glycoprotein that plays a critical role in lysosomal biogenesis and maturation of autophagosomes/ phagosomes. LAMP2 was preferentially expressed by RPE cells, and its expression declined with age. Deletion of the Lamp2 gene in mice resulted in age-dependent autofluorescence abnormalities of the fundus, thickening of Bruch’s membrane, and the formation of BLamDs, resembling histopathological changes occurring in AMD. Moreover, LAMP2-deficient mice developed molecular signatures similar to those found in human AMD—namely, the accumulation of APOE, APOA1, clusterin, and vitronectin—adjacent to BLamDs. In contrast, collagen 4, laminin, and fibronectin, which are extracellular matrix proteins constituting RPE basal lamina and Bruch’s membrane were reduced in Lamp2 knockout (KO) mice. Mechanistically, retarded phagocytic degradation of photoreceptor outer segments compromised lysosomal degradation and increased exocytosis in LAMP2-deficient RPE cells. The accumulation of BLamDs observed in LAMP2-deficient mice was eventually followed by loss of the RPE and photoreceptors. Finally, we observed loss of LAMP2 expression along with ultramicroscopic features of abnormal phagocytosis and exocytosis in eyes from AMD patients but not from control individuals. Taken together, these results indicate an important role for LAMP2 in RPE function in health and disease, suggesting that LAMP2 reduction may contribute to the formation of BLamDs in AMD.
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Kaizu Y., Nakao S., Sekiryu H., Wada I., Yamaguchi M., Hisatomi T., Ikeda Y., Kishimoto J., Sonoda K.
Graefe's Archive for Clinical and Experimental Ophthalmology 256 ( 12 ) 2275 - 2282 2018年12月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Graefe's Archive for Clinical and Experimental Ophthalmology
© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. Purpose: Fluorescein angiography (FA) has been conventionally used for detection of retinal nonperfused area (NPA) in diabetic retinopathy (DR) in spite of its qualitative evaluation. Optical coherence tomography angiography (OCTA) has been recently reported to be useful for the quantification of retinal vascular disorder in DR. In this study, we examined whether retinal flow density (FD) measurement in OCTA was useful for NPA detection in DR. Methods: The study included 41 eyes from 29 patients with DR who underwent FA and OCTA. Regions surrounded by arteries or veins were extracted in the OCTA image, and the FDs in each region were measured by Image J. Furthermore, each region was classified as NPA or perfused area (PA) in FA. The receiver operating characteristic (ROC) curve was prepared by logistic regression analysis of the FD. The AUC (area under the ROC curve) and cutoff value of FD were also calculated. Results: Two hundred fifty-two regions were analyzed and classified into 38 NPA regions and 214 PA regions using FA. FD of each capillary plexus in NPA was significantly smaller than in PA (p < 0.0001). The AUC of total capillary plexus layers (TCP), superficial capillary plexus layer (SCP), and deep capillary plexus layer (DCP) was 0.975, 0.974, and 0.971, respectively. All areas, where the FD was more than the cutoff value (0.07 in TCP), were diagnosed with PA. Three areas with intraretinal microvascular abnormalities (IRMA) were diagnosed as PA despite being below the cutoff value. Conclusions: FD measurement in OCTA is useful for NPA detection in DR.
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Assessment of central visual function in patients with retinitis pigmentosa 査読あり
Fujiwara K., Ikeda Y., Murakami Y., Tachibana T., Funatsu J., Koyanagi Y., Nakatake S., Yoshida N., Nakao S., Hisatomi T., Yoshida S., Yoshitomi T., Ishibashi T., Sonoda K.
Scientific Reports 8 ( 1 ) 2018年12月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Scientific Reports
© 2018 The Author(s). In order to clarify the disease progression in retinitis pigmentosa (RP) and its related factors, reliable data on the changes in central visual function in RP are needed. In this longitudinal study, we examined 118 patients who were diagnosed with typical RP. Visual acuity (VA), visual field using a Humphrey Field Analyzer with the central 10-2 SITA-Standard program, and optical coherence tomography measurements were obtained. The slopes, which were derived from serial values of mean deviation (MD), macular sensitivity (MS), or foveal sensitivity (FS) obtained for each eye by a linear mixed model, were used for analysis. MS and FS were calculated as the average retinal sensitivity of 12 and 4 central points respectively. There were statistically significant interactions of times with levels of the central subfield thickness (CST) on the slopes of MS and FS. Compared to the eyes without macular complications, the eyes with macular complications had steeper MD, MS and FS slopes, and this interaction was no significant, but marginal trend for the MS or FS slope (P = 0.10, 0.05, respectively). The central retinal sensitivity (i.e., MS and FS) slopes calculated were effective indices of the progression of central visual function in RP.
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Shiga Y., Akiyama M., Nishiguchi K., Sato K., Shimozawa N., Takahashi A., Momozawa Y., Hirata M., Matsuda K., Yamaji T., Iwasaki M., Tsugane S., Oze I., Mikami H., Naito M., Wakai K., Yoshikawa M., Miyake M., Yamashiro K., Kashiwagi K., Iwata T., Mabuchi F., Takamoto M., Ozaki M., Kawase K., Aihara M., Araie M., Yamamoto T., Kiuchi Y., Nakamura M., Ikeda Y., Sonoda K., Ishibashi T., Nitta K., Iwase A., Shirato S., Oka Y., Satoh M., Sasaki M., Fuse N., Suzuki Y., Cheng C., Khor C., Baskaran M., Perera S., Aung T., Vithana E., Cooke Bailey J., Kang J., Pasquale L., Haines J., Wiggs J., Burdon K., Gharahkhani P., Hewitt A., Mackey D., MacGregor S., Craig J., Rand Allingham R., Hauser M., Ashaye A., Budenz D., Akafo S., Williams S., Kamatani Y., Nakazawa T., Kubo M.
Human Molecular Genetics 27 ( 8 ) 1486 - 1496 2018年4月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Human Molecular Genetics
© The Author(s) 2018. Published by Oxford University Press. All rights reserved. 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<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.
DOI： 10.1093/hmg/ddy053
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Sainohira M., Yamashita T., Terasaki H., Sonoda S., Miyata K., Murakami Y., Ikeda Y., Morimoto T., Endo T., Fujikado T., Kamo J., Sakamoto T.
PLoS ONE 13 ( 4 ) 2018年4月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：PLoS ONE
© 2018 Sainohira 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 purpose of this study is to determine the factors related to anxiety and depression in patients with retinitis pigmentosa (RP). The status of anxiety and depression was determined in RP patients with the Hospital Anxiety and Depression Scale (HADS) questionnaire which consisted of subscales for HADS-anxiety (HADS-A) and HADS-depression (HADS-D). The vision-specific quality of life (VSQOL) was assessed with the National Eye Institute Visual Function Questionnaire 25 (NEI-VFQ25). The correlations between the HADS-A or HADS-D scores and vision-related clinical parameters such as the best-corrected visual acuity (BCVA), Functional Acuity Score, Functional Field Score, Functional Vision Score, the NEI- VFQ25 subscale score were determined. The socioeconomic status, such as the work status and membership in the RP society, was investigated to determine the factors related to the HADS-A and HADS-D scores. One hundred and twelve RP patients (46 men and 66 women) with mean age of 60.7±15.4 (standard deviation) years were studied. The HADS-A score was not significantly correlated with any visual functions but was significantly correlated with the general health condition (r = -0.34, P<0.001) and the role limitation (r = -0.20, P = 0.03) of the NEI-VFQ25 subscale. The HADS-D score was significantly correlated with all the visual functions (r = -0.38 to 0.29, P<0.001), the NEI-VFQ25 subscale score (r = - 0.58 to -0.33, P<0.001) by Spearman’s correlations. The HADS-A score was significantly higher in the members of the RP society than in non-members (P = 0.013). The mean HADS-D score of employed individuals was significantly lower than that of unemployed ones (P = 0.001) by the Mann-Whitney U test. The results indicate that visual function impairments and vision-related quality of life are associated with a depressive state, and the general health condition is related to anxiety in RP patients. Being employed may be strongly correlated with the degree of depression in RP patients.
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Koyanagi Y., Yoshida S., Kobayashi Y., Kubo Y., Nakama T., Ishikawa K., Nakao S., Hisatomi T., Ikeda Y., Oshima Y., Ishibashi T., Sonoda K.
Ophthalmologica 239 ( 2-3 ) 94 - 102 2018年3月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Ophthalmologica
© 2017 S. Karger AG, Basel. Objective: To examine the relationship between early response to anti-vascular endothelial growth factor (VEGF) treatment and visual prognosis. Methods: We retrospectively separated 20 patients with persistent diabetic macular edema (DME) into two responder status groups based on the reduction of central macular thickness (CMT) from baseline to month 3: a delayed responder group (DRG) (≤25% CMT reduction, n = 11) and an immediate responder group (IRG) (>25% CMT reduction, n = 14). We also separated the patients into two responder status groups based on the logarithm of the minimum angle of resolution (logMAR) best-corrected visual acuity (BCVA): a visual nonimprovement group (VNIG) (≥0 logMAR BCVA improvement, n = 11) and a vi sual improvement group (VIG) (<0 logMAR BCVA improvement, n = 14). Finally, we assessed the correlations between logMAR BCVA changes from baseline to month 3 (ΔBCVAM3) and those from baseline to month 12 (ΔBCVAM12). Results: At month 12, BCVA was significantly more improved in the VIG than the VNIG (p < 0.005), but was not significantly different between the DRG and the IRG (p = 0.75). The Pearson correlation coefficient showed a significant relationship between ΔBCVAM3 and ΔBCVAM12 (r = 0.60, p < 0.005). Conclusions: BCVA showed significantly greater improvement in the VIG than in the VNIG. ΔBCVAM3 may predict the visual outcome at month 12 in DME patients treated with anti-VEGF drugs.
DOI： 10.1159/000481711
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Hisatomi T., Tachibana T., Notomi S., Koyanagi Y., Murakami Y., Takeda A., Ikeda Y., Yoshida S., Enaida H., Murata T., Sakamoto T., Sonoda K., Ishibashi T.
Retina 38 ( 3 ) 471 - 479 2018年3月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Retina
Copyright © by Ophthalmin Communication Society, Inc. Purpose: To examine retinal changes after vitrectomy with internal limiting membrane (ILM) peeling, we used 3-dimensional optical coherence tomography (3D-OCT) in rhegmatogenous retinal detachment cases. Methods: The 68 eyes from 67 patients with rhegmatogenous retinal detachment were studied, including 35 detached macula cases (51%) and 33 attached macula cases. Internal limiting membrane peeling was performed with fine forceps after brilliant blue G staining. The 3D-OCT images were obtained with volume-rendering technologies from cross-sectional OCT images. Results: The 3D-OCT detected 45 eyes (66%) with ILM peeling-dependent retinal changes, including dissociated optic nerve fiber layer appearance, dimple sign, temporal macular thinning, ILM peeling area thinning, or forceps-related retinal thinning. The ILM peeled area was detectable in only 9 eyes with 3D-OCT, whereas it was undetectable in other 59 eyes. The dissociated optic nerve fiber layer appearance was detected in 8 of the total cases (12%), and dimple signs were observed in 14 cases (21%). Forceps-related thinning was also noted in eight cases (24%) of attached macula cases and in four cases (11%) of detached macula cases. No postoperative macular pucker was noted in the observational period. Conclusion: The 3D-OCT clearly revealed spatial and time-dependent retinal changes after ILM peeling. The changes occurred in 2 months and remained thereafter.
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C-Reactive protein and progression of vision loss in retinitis pigmentosa 査読あり
Murakami Y., Ikeda Y., Nakatake S., Fujiwara K., Tachibana T., Yoshida N., Notomi S., Hisatomi T., Yoshida S., Ishibashi T., Sonoda K.
Acta Ophthalmologica 96 ( 2 ) e174 - e179 2018年3月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Acta Ophthalmologica
© 2017 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd Purpose: Chronic inflammation is involved in retinitis pigmentosa (RP). We demonstrated previously that intraocular inflammatory levels, as measured by slit-lamp ophthalmoscopy or laser flare photometry, are inversely correlated with central visual function in patients with RP. Here, we investigated the relationship between serum high-sensitivity C-reactive protein (hs-CRP) and visual parameters in RP. Methods: We studied 58 consecutive typical patients with RP <40 years old and 29 age- and gender-matched controls. High-sensitivity C-reactive protein (hs-CRP) was detected by immunoturbidimetry. The relationships between hs-CRP and visual parameters including best-corrected visual acuity (BCVA), mean deviation (MD) of static perimetry tests (Humphrey Field Analyzer, the central 10-2 programme) and VA changes over the prior 5 years and MD changes over the prior 3 years were analysed in the patients with RP. Results: The serum hs-CRP levels of the patients with RP were significantly higher than those of the controls (0.06 ± 0.08 versus 0.03 ± 0.04 mg/dl, p = 0.0119). In the patients with RP, there was no correlation of hs-CRP with cross-sectionally assessed VA or MD, but the baseline hs-CRP was significantly correlated with the MD deterioration (r = −0.4073, p = 0.0314). Conclusion: The average serum hs-CRP was significantly increased in the patients with RP, and higher hs-CRP was associated with faster deterioration of central visual function. These results suggest that the systemic inflammatory profile is altered and may be associated with disease progression in RP.
DOI： 10.1111/aos.13502
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Koyanagi Y., Murakami Y., Funatsu J., Akiyama M., Nakatake S., Fujiwara K., Tachibana T., Nakao S., Hisatomi T., Yoshida S., Ishibashi T., Sonoda K., Ikeda Y.
Acta Ophthalmologica 96 ( 1 ) e59 - e67 2018年2月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Acta Ophthalmologica
© 2017 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd Purpose: To investigate the macular microvasculature changes by optical coherence tomography angiography (OCTA) and analyse the correlation between these changes and central visual function in patients with retinitis pigmentosa (RP). Methods: We measured the area of the foveal avascular zone (FAZ) and the foveal and parafoveal flow density (FFD and PFD, respectively) in the superficial (S) and deep (D) retinal plexus by OCTA (AngioVue) and compared these values between 73 RP patients and 36 healthy controls. We analysed the relationships between these microvasculature measurements and central visual functions such as visual acuity (VA) and the values of static perimetry tests (Humphrey Field Analyzer, the central 10–2 program) in the RP patients. Results: The FFD-S, PFD-S and PFD-D were significantly decreased in the RP patients compared to the controls (all p < 0.05), whereas there was no significant difference in the FAZ-S, FAZ-D or FFD-D (all p > 0.05). A subgroup analysis showed that the RP patients with VA <20/20 had increased FAZ-S compared to the controls and RP patients with VA ≥20/20 (p = 0.01 and p = 0.007, respectively). Spearman rank testing demonstrated that PFD-S and PFD-D were significantly correlated with all of the central visual parameters (all p < 0.01). The FAZ-S and FFD-S were significantly correlated with VA, and FAZ-D and FFD-D showed no significant correlation. Conclusion: Both the superficial and deep layers of the parafoveal microvasculature are attenuated in RP and correlated with reduced central visual function. The foveal microvasculature, especially in the deep layer, was relatively preserved until mild-to-moderately advanced stages.
DOI： 10.1111/aos.13475
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Murakami Y., Funatsu J., Nakatake S., Fujiwara K., Tachibana T., Koyanagi Y., Hisatomi T., Yoshida S., Sonoda S., Sakamoto T., Sonoda K., Ikeda Y.
Investigative Ophthalmology and Visual Science 59 ( 2 ) 1134 - 1143 2018年2月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Investigative Ophthalmology and Visual Science
© 2018 The Authors. PURPOSE. To investigate the relationships between foveal blood flow as measured by laser speckle flowgraphy (LSFG), the retinal-choroidal structure in enhanced depth imaging– optical coherence tomography (EDI-OCT), and central visual function in patients with retinitis pigmentosa (RP). METHODS. We studied 52 consecutive typical RP patients ≤50 years old and 21 age- and sex-matched controls. The mean blur rate (MBR), which represents the blood flow volume, was calculated in a 2.4-mm2 area centered on the fovea by LSFG. Subfoveal horizontal EDI-OCT images were recorded, and the choroidal area, choroidal hyporeflective area, and choroidal hyperreflective area were analyzed in the central 2.4-mm-wide region. The central foveal thickness (CFT), subfoveal choroidal thickness (SCT), and ellipsoid zone (EZ) width were also measured. Visual acuity (VA) and retinal sensitivity (Humphrey 10-2 program) were measured in the RP patients. RESULTS. The MBR, choroidal area, hyporeflective area, hyperreflective area, and SCT were significantly decreased in the RP patients (all P < 0.001, versus controls). Spearman’s rank testing demonstrated no significant correlation between the MBR and the choroidal structural parameters in the RP patients. Decreased MBR was significantly associated with reductions in VA, retinal sensitivity, CFT, and EZ width (all P < 0.05). The choroidal structural parameters did not correlate with central visual function, and the choroidal area, hyperreflective area, and SCT were inversely associated with CFT (all P < 0.05). CONCLUSIONS. These results demonstrated the divergence between the choroidal structure and blood function, and suggest that decreased choroidal flow, rather than the structural alteration, is closely associated with foveal degeneration in RP.
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Discovery of a cynomolgus monkey family with retinitis pigmentosa 査読あり
Ikeda Y., Nishiguchi K., Miya F., Shimozawa N., Funatsu J., Nakatake S., Fujiwara K., Tachibana T., Murakami Y., Hisatomi T., Yoshida S., Yasutomi Y., Tsunoda T., Nakazawa T., Ishibashi T., Sonoda K.
Investigative Ophthalmology and Visual Science 59 ( 2 ) 826 - 830 2018年2月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Investigative Ophthalmology and Visual Science
© 2018 The Authors. 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.
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Quantifying metamorphopsia with M-CHARTS in patients with idiopathic macular hole 査読あり
Wada I., Yoshida S., Kobayashi Y., Zhou Y., Ishikawa K., Nakao S., Hisatomi T., Ikeda Y., Ishibashi T., Sonoda K.
Clinical Ophthalmology 11 1719 - 1726 2017年9月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Clinical Ophthalmology
© 2017 Wada et al. Purpose: The purpose of this study was to determine the degree of metamorphopsia using M-CHARTS™ in patients with idiopathic macular hole before and after pars plana vitrectomy and internal limiting membrane (ILM) peeling. Patients and methods: The records of 22 eyes of 22 patients with a full-thickness macular hole who underwent pars plana vitrectomy and ILM peeling were reviewed. All patients underwent a complete ophthalmic examination including spectral-domain optical coherence tomography (OCT). Horizontal metamorphopsia (MH) and vertical metamorphopsia (MV) scores were determined using M-CHARTS at the same time. The time course of changes in metamorphopsia and the relationship between best-corrected visual acuity (BCVA) and OCT parameters were assessed. Results: Sealing of the macular hole was noted in all eyes after surgery. BCVA improved significantly from 1 month after surgery (P,0.001). The MV score was significantly higher than the MH score before surgery (P,0.05) and improved significantly from 1 month after surgery (P,0.03). The MH score improved significantly at 6 months after surgery (P,0.001). The postoperative MV and MH scores became closer to one another from 1 month after surgery. Moreover, the MV score was higher than the MH score at all postoperative assessments. There was a significant correlation between the MV and MH scores at all follow-up assessments. There was no significant correlation between BCVA and the MV or MH score at any follow-up assessment. Conclusion: The satisfaction of the patients with macular hole after surgery cannot be necessarily measured by BCVA alone, because M-scores were not correlated to BCVA in postoperative evaluation. Therefore, evaluation of the MV and MH scores can be an independent treatment outcome in addition to BCVA.
DOI： 10.2147/OPTH.S144981
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Yoshida S., Kobayashi Y., Nakao S., Sassa Y., Hisatomi T., Ikeda Y., Oshima Y., Kono T., Ishibashi T., Sonoda K.
Clinical Ophthalmology 11 1697 - 1705 2017年9月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Clinical Ophthalmology
© 2017 Yoshida et al. Background: Pars plana vitrectomy is the only treatment for advanced proliferative diabetic retinopathy (PDR). However, vitrectomy is not always successful despite current progress in vitreoretinal surgical techniques. The aim of our study was to investigate whether the vitreal concentrations of MCP-1, IL-6, IL-8, and VEGF are elevated after unsuccessful vitrectomy in patients with PDR and to investigate whether the altered levels of these cytokines are associated with the cause for the reoperation. Patients and methods: Vitreous samples were collected from 263 eyes of 233 patients: PDR (n=129 eyes), proliferative vitreoretinopathy (PVR; n=24 eyes) and nondiabetic controls (n=110 eyes) prior to vitrectomy. Vitreous samples were also collected from 14 eyes of 14 patients with PDR before vitrectomy and from the same 14 eyes before a second vitrectomy for reoperation. The levels of MCP-1, IL-6, IL-8, and VEGF were measured by flow cytometry using a cytometric bead array (CBA) assay. Results: The mean concentrations of vitreal MCP-1, IL-6, IL-8, and VEGF were significantly higher in patients with PDR and PVR (P,0.01). There were significantly high correlations among the concentrations of MCP-1, IL-6, and IL-8, whereas the correlation of VEGF with the other 3 cytokines was lower. Among the 14 patients who required reoperation, the mean vitreal concentrations of MCP-1, IL-6, and IL-8 were higher than that at the time of the initial vitrectomy (P,0.01). At the time of the reoperation vitrectomy, the mean vitreous level of MCP-1, IL-6, and IL-8 in eyes with fibrous proliferation was higher than in those without fibrous proliferation (P,0.05). In contrast, VEGF in eyes with neovascular glaucoma (NVG) or anterior hyaloidal fibrovascular proliferation (AHFVP) was higher than in the eyes without NVG and AHFVP (P,0.05). Conclusion: The elevated levels of MCP-1, IL-6, and IL-8 may be the cause of the postoperative fibrous proliferation. In contrast, VEGF may be the cause of the neovascularization after unsuccessful vitrectomy in the eyes of PDR patients.
DOI： 10.2147/OPTH.S141821
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Kaizu Y., Nakao S., Yoshida S., Hayami T., Arima M., Yamaguchi M., Wada I., Hisatomi T., Ikeda Y., Ishibashi T., Sonoda K.
Investigative Ophthalmology and Visual Science 58 ( 11 ) 4889 - 4897 2017年9月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Investigative Ophthalmology and Visual Science
© 2017 The Authors. PURPOSE. Our purpose is to evaluate the spatial bias of macular capillary dropout accompanying diabetic retinopathy (DR) using optical coherence tomography angiography (OCTA). METHODS. This study included 47 patients with diabetes and 29 healthy individuals who underwent OCTA. Retinal capillary flow density (FD) of 2.6 × 2.6 or 5.2 × 5.2 mm foveal area as well as the four divided areas (superior, inferior, temporal, nasal) without a foveal avascular zone (FAZ) at the superficial capillary plexus and deep capillary plexus (DCP) were measured respectively using ImageJ and NI Vision. Spatial biases of FD (orientation bias ratio and hierarchical bias ratio) and the correlation between FAZ and FD were examined. RESULTS. OCTA showed focal capillary dropout in DR patients. The orientation bias of FD was significantly higher in NPDR compared to NDR in the DCP (P = 0.03). The hierarchical bias of FD was significantly shifted to a DCP dominance with progression of DR (P < 0.01). In addition, the FD and FAZ area were significantly inversely correlated in both plexus in DR patients but not in healthy subjects (P < 0.01). CONCLUSIONS. Area-divided OCTA quantification shows the appearance of spatial biases of macular capillary dropout with the onset of DR, suggesting that DR-related macular capillary dropout occurs locally and randomly. Future studies are necessary to determine the clinical relevance of the spatial pattern of capillary dropout in DR.
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Kaizu Y., Nakao S., Wada I., Yamaguchi M., Fujiwara K., Yoshida S., Hisatomi T., Ikeda Y., Hayami T., Ishibashi T., Sonoda K.
Translational Vision Science and Technology 6 ( 5 ) 2017年9月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Translational Vision Science and Technology
© 2017, The Authors. Purpose: Retinal vascular networks are observed as a layered structure residing in a nerve fiber layer and an inner nuclear layer of the retina. This study aimed to evaluate reflectance confocal adaptive optics scanning laser ophthalmoscopy (AO-SLO) for imaging of the layered retinal vascular networks. Methods: This study included 16 eyes of 16 healthy cases. On the fovea, 2.8-and 3.0 mm2-areas were imaged using a prototype AO-SLO and optical coherence tomography angiography (OCTA), respectively. AO-SLO images focused on the nerve fiber and photoreceptor layers were recorded in the area. Two different vessel images (capillary networks in the superficial layer and in all layers) were generated to examine if the deep capillary network could be distinguished. We compared AO-SLO with OCTA in imaging of the layered retinal vascular networks. Results: Sufficient images of capillary networks for analysis could be generated when the motion contrast was enhanced with AO-SLO movies in seven cases (43.8%). The deep capillary network could be distinguished in the merged image. Vascular depiction performance in AO-SLO was significantly better than in OCTA at both 0.5-and 1.0-mm areas from the fovea (P < 0.05). Conclusions: Retinal vascular imaging using AO-SLO might be a useful adjunct to OCTA as a supportive method to evaluate the retina in healthy patients and patients with disease. Translational Relevance: In cases requiring accurate and detailed retinal vasculature observation, AO-SLO might be useful for evaluating retinal vascular lesions as a supportive imaging method of OCTA.
DOI： 10.1167/tvst.6.5.2
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INCOMPLETE REPAIR of RETINAL STRUCTURE after VITRECTOMY with INTERNAL LIMITING MEMBRANE PEELING 査読あり
Hisatomi T., Tachibana T., Notomi S., Nakatake S., Fujiwara K., Murakami Y., Ikeda Y., Yoshida S., Enaida H., Murata T., Sakamoto T., Sonoda K., Ishibashi T.
Retina 37 ( 8 ) 1523 - 1528 2017年8月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Retina
Purpose: To examine retinal changes after vitrectomy with internal limiting membrane (ILM) peeling, we used a cynomolgus monkey model and focused on surgical damages of ILM peeling for long observational period of 3 years. Methods: Vitrectomy was performed followed by ILM peeling similar to clinical settings in humans. Ultrastructural changes of the retina were investigated by light, transmission, and scanning electron microscopy at 3 months and 3 years after ILM peeling. Results: Ultrastructural study showed that the ILM peeled area was still clearly recognized after 3 years. The Müller cell processes covered most of the retina; however, the nerve fiber layer was partly uncovered and exposed to the vitreous space. The arcuate linear nerve fiber bundles were observed as comparable with dissociated optic nerve fiber layer appearance. Small round retinal surface defects were also observed around macula, resembling the dimple sign. Forceps-related retinal thinning was also found on the edge of ILM peeling, where we started peeling with fine forceps. Conclusion: The ultrastructural studies showed that most of ILM peeling area was covered with glial cells during wound healing processes. Retinal changes were found comparable with dissociated optic nerve fiber layer appearance or dimple sign, which were clinically observed with optical coherence tomography.
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Comparación de la efectividad de ranibizumab intravítreo para el tratamiento del edema macular diabético en ojos vitrectomizados y no vitrectomizados. 査読あり
Koyanagi Y, Yoshida S, Kobayashi Y, Kubo Y, Yamaguchi M, Nakama T, Nakao S, Ikeda Y, Ohshima Y, Ishibashi T, Sonoda K.
Ophthalmologica. 2017年7月
記述言語：英語 掲載種別：研究論文（学術雑誌）
DOI： 10.1159/000477513
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Risk factors for posterior subcapsular cataract in retinitis pigmentosa 査読あり
Fujiwara K., Ikeda Y., Murakami Y., Funatsu J., Nakatake S., Tachibana T., Yoshida N., Nakao S., Hisatomi T., Yoshida S., Yoshitomi T., Ishibashi T., Sonoda K.
Investigative Ophthalmology and Visual Science 58 ( 5 ) 2534 - 2537 2017年5月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Investigative Ophthalmology and Visual Science
© 2017 The Authors. PURPOSE. Posterior subcapsular cataract (PSC) is a frequent complication in patients with retinitis pigmentosa (RP). The risk factors for PSC formation in RP are largely unknown. The purpose of this study was to investigate the risk factors for PSC. METHODS. We retrospectively studied a total of 322 eyes of 173 patients who were diagnosed with typical RP. We considered the following possible risk factors for PSC: age, sex, hypertension, diabetes mellitus, high myopia, asthma, history of steroid intake, and aqueous flare. Aqueous flare values were measured consecutively in 2012 and 2013 using a laser flare cell meter. The lens including PSC was examined with a slit lamp after dilation with tropicamide 1% and phenylephrine 2.5%. RESULTS. The geometric mean values of aqueous flare and mean values of visual acuity were significantly higher for the RP patients with PSC compared to those without PSC (P = 0.0003, P = 0.0004, respectively). When the aqueous flare values were assessed continuously, each 1-log-transformed increase in flare levels was associated with an elevation of the likelihood of having PSC after multivariable adjustment (odds ratio: 1.71; 95% confidence interval: 1.05-2.77). There were no significant associations of the other possible risk factors with PSC. CONCLUSIONS. Our analysis demonstrated that elevated aqueous flare is a significant risk factor for PSC formation. This result might provide insights into the association of inflammation and the pathogenesis of PSC formation in RP.
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Nakama T., Yoshida S., Ishikawa K., Kubo Y., Kobayashi Y., Zhou Y., Nakao S., Hisatomi T., Ikeda Y., Takao K., Yoshikawa K., Matsuda A., Ono J., Ohta S., Izuhara K., Kudo A., Sonoda K., Ishibashi T.
Molecular Therapy - Nucleic Acids 6 279 - 289 2017年3月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Molecular Therapy - Nucleic Acids
© 2017 Retinal neovascularization (NV) due to retinal ischemia remains one of the principal causes of vision impairment in patients with ischemic retinal diseases. We recently reported that periostin (POSTN) may play a role in the development of preretinal fibrovascular membranes, but its role in retinal NV has not been determined. The purpose of this study was to examine the expression of POSTN in the ischemic retinas of a mouse model of oxygen-induced retinal NV. We also studied the function of POSTN on retinal NV using Postn KO mice and human retinal endothelial cells (HRECs) in culture. In addition, we used a novel RNAi agent, NK0144, which targets POSTN to determine its effect on the development of retinal NV. Our results showed that the expression of POSTN was increased in the vascular endothelial cells, pericytes, and M2 macrophages in ischemic retinas. POSTN promoted the ischemia-induced retinal NV by Akt phosphorylation through integrin αvβ3. NK0144 had a greater inhibitory effect than canonical double-stranded siRNA on preretinal pathological NV in vivo and in vitro. These findings suggest a causal relationship between POSTN and retinal NV, and indicate a potential therapeutic role of intravitreal injection of NK0144 for retinal neovascular diseases.
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Kobayashi Y., Yoshida S., Zhou Y., Nakama T., Ishikawa K., Kubo Y., Arima M., Nakao S., Hisatomi T., Ikeda Y., Matsuda A., Sonoda K., Ishibashi T.
Laboratory Investigation 96 ( 11 ) 1178 - 1188 2016年11月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Laboratory Investigation
Tenascin-C is expressed in choroidal neovascular (CNV) membranes in eyes with age-related macular degeneration (AMD). However, its role in the pathogenesis of CNV remains to be elucidated. Here we investigated the role of tenascin-C in CNV formation. In immunofluorescence analyses, tenascin-C co-stained with α-SMA, pan-cytokeratin, CD31, CD34, and integrin α V in the CNV membranes of patients with AMD and a mouse model of laser-induced CNV. A marked increase in the expression of tenascin-C mRNA and protein was observed 3 days after laser photocoagulation in the mouse CNV model. Tenascin-C was also shown to promote proliferation and inhibit adhesion of human retinal pigment epithelial (hRPE) cells in vitro. Moreover, tenascin-C promoted proliferation, adhesion, migration, and tube formation in human microvascular endothelial cells (HMVECs); these functions were, however, blocked by cilengitide, an integrin α V inhibitor. Exposure to TGF-β2 increased tenascin-C expression in hRPE cells. Conditioned media harvested from TGF-β2-treated hRPE cell cultures enhanced HMVEC proliferation and tube formation, which were inhibited by pretreatment with tenascin-C siRNA. The CNV volume was significantly reduced in tenascin-C knockout mice and tenascin-C siRNA-injected mice. These findings suggest that tenascin-C is secreted by transdifferentiated RPE cells and promotes the development of CNV via integrin α V in a paracrine manner. Therefore, tenascin-C could be a potential therapeutic target for the inhibition of CNV development associated with AMD.
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Changes in chorioretinal blood flow velocity and cerebral blood flow after carotid endarterectomy 査読あり
Enaida H., Nagata S., Takeda A., Nakao S., Ikeda Y., Ishibashi T.
Japanese Journal of Ophthalmology 60 ( 6 ) 459 - 465 2016年11月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Japanese Journal of Ophthalmology
© 2016, Japanese Ophthalmological Society. Purpose: To investigate the changes in chorioretinal blood flow velocity and cerebral blood after carotid endarterectomy (CEA). Methods: Nine patients with moderate to severe internal carotid artery stenosis underwent CEA. Chorioretinal blood flow velocity was measured by laser speckle flowgraphy (LSFG), while cerebral blood flow (CBF) was measured by single-photon emission computed tomography (SPECT), on the affected side both before and after CEA. LSFG was evaluated in five areas to determine mean blur rate, while CBF was calculated from regional CBF and cerebrovascular reactivity (CVR), at the middle cerebral artery (MCA) region of each patient. Results: Five cases showed an increase (mean 3.49 %, range −29.82 to 35.59 %) of average chorioretinal blood flow velocity using LSFG after CEA. A particularly averaged increase in chorioretinal blood flow was observed in the macular area compared with other areas. Similarly, there was an increase in CBF at rest (mean 11.46 %, range −14.51 to 74.14 %) observed using SPECT after surgery. Improvement of CVR was confirmed in four cases. All general and visual symptoms disappeared after CEA. Severe adverse effects, including hyperperfusion syndrome, were not observed in any cases. Conclusions: LSFG may be useful for the analysis of chorioretinal blood flow changes after CEA.
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Yamaguchi M., Nakao S., Kaizu Y., Kobayashi Y., Nakama T., Arima M., Yoshida S., Oshima Y., Takeda A., Ikeda Y., Mukai S., Ishibashi T., Sonoda K.
Scientific Reports 6 2016年9月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Scientific Reports
Histological studies from autopsy specimens have characterized hard exudates as a composition of lipid-laden macrophages or noncellular materials including lipid and proteinaceous substances (hyaline substances). However, the characteristics of hard exudates in living patients have not been examined due to insufficient resolution of existing equipment. In this study, we used adaptive optics scanning laser ophthalmoscopy (AO-SLO) to examine the characteristics of hard exudates in patients with retinal vascular diseases. High resolution imaging using AO-SLO enables morphological classification of retinal hard exudates into two types, which could not be distinguished either on fundus examination or by spectral domain optical coherence tomography (SD-OCT). One, termed a round type, consisted of an accumulation of spherical particles (average diameter of particles: 26.9 ± 4.4 μm). The other, termed an irregular type, comprised an irregularly shaped hyper-reflective deposition. The retinal thickness in regions with round hard exudates was significantly greater than the thickness in regions with irregular hard exudates (P = 0.01 â †'0.02). This differentiation of retinal hard exudates in patients by AO-SLO may help in understanding the pathogenesis and clinical prognosis of retinal vascular diseases.
DOI： 10.1038/srep33574
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Koyanagi Y., Yoshida S., Kobayashi Y., Kubo Y., Yamaguchi M., Nakama T., Nakao S., Ikeda Y., Ohshima Y., Ishibashi T., Sonoda K.
Ophthalmologica 236 ( 2 ) 67 - 73 2016年9月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Ophthalmologica
© 2016 S. Karger AG, Basel. Copyright: All rights reserved. Purpose: To compare the effectiveness of intravitreal ranibizumab (IVR) for diabetic macular edema (DME) between eyes with and without previous vitrectomy. Procedures: We prospectively assessed the best-corrected visual acuity (BCVA) and central macular thickness (CMT) after IVR for 6 months. Results: There were no significant differences in the baseline BCVA and CMT between both groups. In the nonvitrectomized group (n = 15), the mean changes of BCVA and CMT from baseline to month 6 were significant (p < 0.01). In the vitrectomized group (n = 10), the improvement appeared to be slower, and the mean BCVA improvement was not significant (p = 0.5), although the mean CMT decrease was significant (p < 0.05). There were no significant differences in the mean changes of BCVA and CMT between both groups at 6 months. Conclusions: The difference in the effectiveness of IVR between both groups was not significant. IVR can be a treatment option even for vitrectomized DME eyes.
DOI： 10.1159/000446992
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Association between aqueous flare and epiretinal membrane in retinitis pigmentosa 査読あり
Fujiwara K., Ikeda Y., Murakami Y., Nakatake S., Tachibana T., Yoshida N., Nakao S., Hisatomi T., Yoshida S., Yoshitomi T., Sonoda K., Ishibashi T.
Investigative Ophthalmology and Visual Science 57 ( 10 ) 4282 - 4286 2016年8月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Investigative Ophthalmology and Visual Science
© 2016, Association for Research in Vision and Ophthalmology Inc. All rights reserved. PURPOSE. Epiretinal membrane (ERM) is a frequent macular complication in patients with retinitis pigmentosa (RP). The etiology of ERM formation in RP is largely unknown. The purpose of this study was to investigate the association between aqueous flare, a surrogate index of intraocular inflammation, and ERM secondary to RP. METHODS. We retrospectively studied a total of 206 eyes of 117 patients who were diagnosed with typical RP. Aqueous flare values were measured consecutively in 2012 and 2013 using a laser flare cell meter. Spectral-domain optical coherence tomography images and fundus photographs taken on the same day of the aqueous flare measurements were analyzed for ERM detection. RESULTS. The mean values of aqueous flare, age, and frequency of male sex were significantly higher in the RP patients with ERM compared with the RP patients without ERM (P < 0.0001, P = 0.007, and P = 0.004, respectively). After adjustment for age and sex, the eyes in the highest quartile of aqueous flare had significantly higher odds of having ERM than those in the lowest quartile (odds ratio [OR], 2.68; 95% confidence interval [CI], 1.04-6.93), and the linear trend across flare levels was significant (P = 0.005). In addition, each 1-log-transformed increase in flare values was associated with an elevation of the likelihood of having ERM (OR, 2.59; 95% CI, 1.33-5.06). CONCLUSIONS. Our analysis demonstrated that elevated aqueous flare is associated with ERM secondary to RP, suggesting that inflammation may be implicated in the pathogenesis of ERM formation in RP.
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Interleukin-12 inhibits pathological neovascularization in mouse model of oxygen-induced retinopathy 査読あり
Zhou Y., Yoshida S., Kubo Y., Kobayashi Y., Nakama T., Yamaguchi M., Ishikawa K., Nakao S., Ikeda Y., Ishibashi T., Sonoda K.
Scientific Reports 6 2016年6月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Scientific Reports
Hypoxia-induced retinal neovascularization is a major pathological condition in many vision-threatening diseases. In the present study, we determined whether interleukin (IL)-12, a cytokine that regulates angiogenesis, plays a role in the neovascularization in a mouse model of oxygen-induced retinopathy (OIR). We found that the expressions of the mRNAs of both IL-12p35 and IL-12p40 were significantly reduced in the OIR retinas compared to that of the room air-raised control. The sizes of the avascular areas and neovascular tufts were larger in IL-12p40 knock-out (KO) mice than that in wild type (WT) mice. In addition, an intravitreal injection of recombinant IL-12 reduced both avascular areas and neovascular tufts. IL-12 injection enhanced the expressions of interferon-gamma (IFN-γ) and other downstream chemokines. In an in vitro system, IL-12 had no significant effect on tube formation of human retinal microvascular endothelial cells (HRECs). Moreover, a blockade of IFN-γ suppressed the inhibitory effect of IL-12 on pathological neovascularization. These results suggest that IL-12 plays important roles in inhibiting pathological retinal neovascularization.
DOI： 10.1038/srep28140
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Kobayashi Y., Yoshida S., Zhou Y., Nakama T., Ishikawa K., Arima M., Nakao S., Sassa Y., Takeda A., Hisatomi T., Ikeda Y., Matsuda A., Sonoda K., Ishibashi T.
Molecular Vision 22 436 - 445 2016年4月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Molecular Vision
© 2016 Molecular Vision. Purpose: We previously demonstrated that tenascin-C was highly expressed in the fibrovascular membranes (FVMs) of patients with proliferative diabetic retinopathy (PDR). However, its role in the pathogenesis of FVMs has not been determined. The purpose of this study was to investigate what role tenascin-C plays in the formation and angiogenesis of FVMs. Methods: The level of tenascin-C was determined by sandwich enzyme-linked immunosorbent assay in the vitreous samples collected from patients with PDR and with a macular hole as control. The locations of tenascin-C, α- smooth muscle actin (SMA), CD34, glial fibrillary acidic protein (GFAP), and integrin αV in the FVMs from PDR patients were determined by immunohistochemistry. We also measured the in vitro expression of the mRNA and protein of tenascin-C in vascular smooth muscle cells (VSMCs) stimulated by interleukin (IL)-13. The effects of tenascin-C on cell proliferation, migration, and tube formation were determined in human retinal endothelial cells (HRECs) in culture. Results: The mean vitreous levels of tenascin-C were significantly higher in patients with PDR than in patients with a macular hole (p<0.001). Double immunofluorescence analyses of FVMs from PDR patients showed that tenascin-C co-stained FVMs with α-SMA, CD34, and integrin αV but not with GFAP. In addition, IL-13 treatment increased both the expression and secretion of tenascin-C by VSMCs in a dose-dependent manner. Tenascin-C exposure promoted proliferation, migration, and tube formation in HRECs. Tenascin-C neutralizing antibody significantly blocked the tube formation by HRECs exposed to VSMC-IL-13-conditioned medium. Conclusions: Our findings suggest that tenascin-C is secreted from VSMCs and promotes angiogenesis in the FVMs associated with PDR.
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MUTYH promotes oxidative microglial activation and inherited retinal degeneration 査読あり
Nakatake S., Murakami Y., Ikeda Y., Morioka N., Tachibana T., Fujiwara K., Yoshida N., Notomi S., Hisatomi T., Yoshida S., Ishibashi T., Nakabeppu Y., Sonoda K.H.
JCI Insight 1 ( 15 ) 2016年
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：JCI Insight
© 2016 American Society for Clinical Investigation. All rights reserved. Oxidative stress is implicated in various neurodegenerative disorders, including retinitis pigmentosa (RP), an inherited disease that causes blindness. The biological and cellular mechanisms by which oxidative stress mediates neuronal cell death are largely unknown. In a mouse model of RP (rd10 mice), we show that oxidative DNA damage activates microglia through MutY homolog–mediated (MUYTH-mediated) base excision repair (BER), thereby exacerbating retinal inflammation and degeneration. In the early stage of retinal degeneration, oxidative DNA damage accumulated in the microglia and caused single-strand breaks (SSBs) and poly(ADP-ribose) polymerase activation. In contrast, Mutyh deficiency in rd10 mice prevented SSB formation in microglia, which in turn suppressed microglial activation and photoreceptor cell death. Moreover, Mutyh-deficient primary microglial cells attenuated the polarization to the inflammatory and cytotoxic phenotype under oxidative stress. Thus, MUTYH-mediated BER in oxidative microglial activation may be a novel target to dampen the disease progression in RP and other neurodegenerative disorders that are associated with oxidative stress.
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Correlation between macular blood flow and central visual sensitivity in retinitis pigmentosa 査読あり
Murakami Y., Ikeda Y., Akiyama M., Fujiwara K., Yoshida N., Nakatake S., Notomi S., Nabeshima T., Hisatomi T., Enaida H., Ishibashi T.
Acta Ophthalmologica 93 ( 8 ) e644 - e648 2015年12月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Acta Ophthalmologica
© 2015 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd. Purpose To investigate the changes in macular blood flow and the correlation between those changes and central visual function in patients with retinitis pigmentosa (RP). Methods The mean blur rate (MBR), a quantitative blurring index of the laser speckle pattern that represents retinal and choroidal blood flow, was measured by laser speckle flowgraphy. Mean blur rate values in the macular area were compared between 70 patients with RP and 28 control subjects. The relationships between MBR on the one hand and, on the other, visual acuity (VA), mean deviation (MD) and averaged macular sensitivity of static perimetry tests (Humphrey Filed Analyzer, the central 10-2 program) were analysed in patients with RP. Results Macular MBR was decreased to 75% in patients with RP compared with control subjects (p < 0.0001, Student's t-test). Spearman's rank testing showed that macular MBR was significantly correlated with VA (r = -0.261, p = 0.0299), MD values (r = 0.438, p = 0.0002) and averaged macular sensitivity at the central 4 and 12 points of static perimetry tests (r = 0.426 and 0.442, p = 0.0003 and 0.0002, respectively). Multivariable-adjusted analysis confirmed that MBR was independently associated with MD (p = 0.0002) and macular sensitivity at the central 4 and 12 points (p < 0.0001 and 0.0002, respectively). Conclusions Decreased macular blood flow was associated with reduced macular visual sensitivity in patients with RP. Although the cause-effect relationships remain to be elucidated, these findings suggest that vascular defects may be involved in the pathogenesis of RP such as central vision loss.
DOI： 10.1111/aos.12693
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Vitreous cysts in patients with retinitis pigmentosa 査読あり
Yoshida N., Ikeda Y., Murakami Y., Nakatake S., Tachibana T., Notomi S., Hisatomi T., Ishibashi T.
Japanese Journal of Ophthalmology 59 ( 6 ) 373 - 377 2015年11月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Japanese Journal of Ophthalmology
© 2015, Japanese Ophthalmological Society. Purpose: To determine the prevalence of vitreous cysts in patients with retinitis pigmentosa (RP). Methods: We retrospectively reviewed the charts of 435 consecutive patients diagnosed as having typical RP. Results: Vitreous cysts were diagnosed in 37 eyes of 28 patients with RP (13 males and 15 females; mean age 47.0 ± 19.8 years; range 15–79 years), for an overall prevalence of 6.4 %. The cysts were observed bilaterally in nine of the patients (32.1 %). Among these 28 patients, 11 (39.3 %) were younger than 40 years. In all, 81.8 % of the vitreous cysts were detected around the optic nerve head. Conclusions: We demonstrated that the prevalence of vitreous cysts was 6.4 % in patients with RP. These cysts were considered to be asymptomatic.
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Long-term surgical outcomes of epiretinal membrane in patients with retinitis pigmentosa 査読あり
Ikeda Y., Yoshida N., Murakami Y., Nakatake S., Notomi S., Hisatomi T., Enaida H., Ishibashi T.
Scientific Reports 5 2015年8月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Scientific Reports
Macular complications such as an epiretinal membrane (ERM), a cystoid macular edema and a macular hole lead to unexpected central vision impairment especially for patients with retinitis pigmentosa (RP). To evaluate the long-term surgical outcomes of pars plana vitrectomy (PPV) for ERM in patients with RP, we retrospectively reviewed the charts of a consecutive series of 10 RP patients who underwent PPV for ERM at Kyushu University Hospital. Visual acuity (VA) testing, a fundus examination, and an optical coherence tomography (OCT) analysis were conducted. The standard PPV using three sclerotomies was performed for ERM. PPV was performed in 12 eyes of 10 patients. One eye was excluded from the outcome assessment due to short period observation (18 months). There was no significantly deleterious change from the baseline to final VA between the operation eyes and the fellow eyes (P = 0.19). Moreover, morphological improvement was obtained in 9 of 11 eyes based on OCT. Our present data suggest that PPV may be tolerable in the management for ERM in RP patients over the long-term. Furthermore, the appearance of the ellipsoid zone was an important factor in the prediction of visual outcome and determination of surgical indication.
DOI： 10.1038/srep13078
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Relationship between aqueous flare and visual function in retinitis pigmentosa 査読あり
Murakami Y., Yoshida N., Ikeda Y., Nakatake S., Fujiwara K., Notomi S., Nabeshima T., Nakao S., Hisatomi T., Enaida H., Ishibashi T.
American Journal of Ophthalmology 159 ( 5 ) 958 - 963.e1 2015年5月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：American Journal of Ophthalmology
© 2015 by Elsevier Inc. All rights reserved. Purpose To investigate the correlation between aqueous flare values and central visual function in patients with retinitis pigmentosa (RP). Design Retrospective, observational case series. Methods We retrospectively studied 160 patients diagnosed with typical RP and 59 control subjects. Aqueous flare values were measured by laser flare cell meter. The relationships between aqueous flare and best-corrected visual acuity (VA) and mean deviation (MD) of static perimetry tests were analyzed in RP patients. Results The aqueous flare values were significantly higher in the RP patients compared to the control subjects (10.6 ± 7.9 vs 5.0 ± 2.1 photon counts per millisecond [pc/ms], P <.0001). In the RP patients, the aqueous flare values were negatively correlated with VA (r = 0.359, P <.0001) and MD (r = -0.330, P <.0001). Age-subgroup analysis showed a significant correlation between aqueous flare and VA in the RP patients' 40s, 50s, and 60s and between aqueous flare and MD in the 30s, 40s, 50s, and 60s. The RP patients with MD values ≥-15 decibels (dB) showed significantly higher levels of aqueous flare than those with MD values <-15 dB (12.0 ± 6.2 vs 8.7 ± 5.8, P =.0001). Conclusions Aqueous flare is increased in RP patients and negatively correlates with central visual function. These results suggest a close relationship between inflammation and central vision loss in RP.
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Factors affecting visual acuity after cataract surgery in patients with retinitis pigmentosa 査読あり
Yoshida N., Ikeda Y., Murakami Y., Nakatake S., Fujiwara K., Notomi S., Hisatomi T., Ishibashi T.
Ophthalmology 122 ( 5 ) 903 - 908 2015年5月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Ophthalmology
© 2015 American Academy of Ophthalmology. Purpose To investigate the factors affecting visual acuity after cataract surgery in patients with retinitis pigmentosa (RP). Design Retrospective, observational study. Participants We retrospectively reviewed the charts of a consecutive series of 40 patients with RP who underwent cataract surgery. Methods The changes in preoperative and postoperative best-corrected visual acuity (BCVA) were measured. We investigated the relation between preoperative mean deviation (MD) value on the Humphrey Field Analyzer (HFA: the central 10-2 program; Humphrey Instruments, Inc, San Leandro, CA) and final BCVA. We also investigated the relationship between preoperative ellipsoid zone (EZ; also called the inner/outer segment junction) conditions and final BCVA. In addition, we showed the prevalence of macular complications and capsule complications. Main Outcome Measures The BCVA, slit-lamp biomicroscopic analysis, visual field, and optical coherence tomography (OCT) were obtained. Results The mean of the BCVA significantly improved after cataract surgery from 0.76 (range, -0.08 to 2.30) to 0.45 (range, -0.18 to 2.00) (P < 0.005). However, final BCVA did not improve in 30 eyes (53.6%). The preoperative MD value and the final BCVA were significantly correlated, and the final BCVA significantly improved in the less advanced RP group (MD was >-15 decibels [dB]). The final BCVA was significantly better in the group in which preoperative OCT showed a normal EZ than in the groups in which the EZ was abnormal or not visible. Posterior capsular opacification was observed in 47 eyes (83.9%), and 23 eyes (41.1%) underwent YAG laser capsulotomy within a mean follow-up time of 3 years. Conclusions Final BCVA in approximately half of the eyes improved after cataract surgery in patients with RP. The preoperative ophthalmic examinations that may reflect macular (or foveal) function, such as HFA 10-2 program and OCT, are important parameters to assess postoperative visual outcome.
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Hisatomi T., Notomi S., Tachibana T., Oishi S., Asato R., Yamashita T., Murakami Y., Ikeda Y., Enaida H., Sakamoto T., Ishibashi T.
Retina 35 ( 2 ) 310 - 318 2015年2月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Retina
Copyright © by Ophthamic Communications Society. PURPOSE:: Brilliant Blue G is used as a surgical adjuvant for retinal surgery. Although BBG double or multiple staining was reported, the effectiveness and safety of repeated staining is still elusive. To further examine the effectiveness and safety, we examined BBG in clinical cases in vivo, primary cell culture in vitro, and surgically resected specimen ex vivo. METHODS:: A retrospective interventional case series with in vitro and ex vivo studies were performed. Vitrectomy was performed in 28 cases of epiretinal membrane with BBG single to multiple staining. The surgically resected membranes were stained by BBG with or without cellular fixation. Primary cell cultures were examined with BBG and live/death cell markers, such as Calcein AM and TUNEL. RESULTS:: Single staining provided satisfactory staining in seven cases. Double or multiple staining substantially visualized internal limiting membrane (21 cases), especially the edges of remaining internal limiting membrane (11 cases). Adverse retinal staining was not noted and the final visual acuity showed no difference with multiple staining. The live cells barely stained with BBG, while some dead cells were stained. CONCLUSION:: Brilliant Blue G multiple staining substantially enhanced the visualization of internal limiting membrane. The absence of abnormal staining supports the safety of repeated BBG staining.
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Proteomic study of retinal proteins associated with transcorneal electric stimulation in rats 査読あり
Kanamoto T., Souchelnytskyi N., Kurimoto T., Ikeda Y., Sakaue H., Munemasa Y., Kiuchi Y.
Journal of Ophthalmology 2015 2015年
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of Ophthalmology
© 2015 Takashi Kanamoto et al. Background. To investigate how transcorneal electric stimulation (TES) affects the retina, by identifying those proteins up-and downregulated by transcorneal electric stimulation (TES) in the retina of rats. Methods. Adult Wistar rats received TES on the left eyes at different electrical currents while the right eyes received no treatment and served as controls. After TES, the eye was enucleated and the retina was isolated. The retinas were analyzed by proteomics. Results. Proteomics showed that twenty-five proteins were upregulated by TES. The identified proteins included cellular signaling proteins, proteins associated with neuronal transmission, metabolic proteins, immunological factors, and structural proteins. Conclusions. TES induced changes in expression of various functional proteins in the retina.
DOI： 10.1155/2015/492050
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Ikeda Y., Suzuki E., Kuramata T., Kozaki T., Koyama T., Kato Y., Murakami Y., Enaida H., Ishibashi T.
Japanese Journal of Ophthalmology 59 ( 1 ) 43 - 47 2015年
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Japanese Journal of Ophthalmology
© 2014, Japanese Ophthalmological Society. Purpose: Patients in the early stage of retinitis pigmentosa (RP) suffer from night blindness and, therefore, have mobility problems at night. To assist such patients with walking in the dark, we developed a wearable visual aid utilizing a see-through display upon which assistive images from a high-sensitivity video camera are superimposed. We evaluated the efficacy of our new visual aid for RP patients. Methods: The device is equipped with a camera with a minimum illuminance of 0.08 lux and a view angle of 53° × 40°. The experiment was conducted in a room with dimmed light (illuminance level 0.2–1.2 lux). Eight subjects with RP were instructed to arrive at a goal 16 m away from the starting point, both with and without the device, passing through four 1.5-m-wide gates consisting of pairs of black square carpet pieces, white poles, red and white traffic cones and cardboard boxes with and without the device in a darkened room. Three gates, except for the boxes, which were nearest the goal, were randomly arranged along the x-axis at each trial. The number of trial failures and the time required to walk the course were assessed as outcomes. Results: Seven of the 8 subjects could walk with the aid of the device without any failure. With the device, the number of trial failures significantly decreased in number (p < 0.05) in all subjects. Conclusions: This device enabled the subjects to see objects that could not be recognized by the unaided eye. Our visual aid effectively assisted RP patients with night blindness.
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Saadat K., Murakami Y., Tan X., Nomura Y., Yasukawa T., Okada E., Ikeda Y., Yanagi Y.
FEBS Open Bio 4 1007 - 1014 2014年12月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：FEBS Open Bio
© 2014 The Authors. In this study, we show augmented autophagy in the retinal pigment epithelial cell line ARPE-19 when cultured in the presence of the lipofuscin pigment A2E. A2E alone does not induce RPE cell death, but cell death was induced in the presence of A2E with the autophagy inhibitor 3-methyladenine (3MA), with a concomitant increase in the generation of mitochondrial reactive oxygen species. On the other hand, the ATP production capacity of mitochondria was decreased in the presence of A2E, and pharmacological inhibition of autophagy had no additional effects. The altered mRNA expression level of mitochondrial function markers was confirmed by real-time polymerase chain reaction, which showed that the antioxidant enzymes SOD1 and SOD2 were not reduced in the presence of A2E alone, but significantly suppressed with the addition of 3MA. Furthermore, transmission electron micrography revealed autophagic vacuole formation in the presence of A2E, and inhibition of autophagy resulted in the accumulation of abnormal mitochondria with loss of cristae. Spheroid culture of human RPE cells demonstrated debris accumulation in the presence of A2E, and this accumulation was accelerated in the presence of 3MA. These results indicate that autophagy in RPE cells is a vital cytoprotective process that prevents the accumulation of damaged cellular molecules.
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Hisatomi T., Notomi S., Tachibana T., Sassa Y., Ikeda Y., Nakamura T., Ueno A., Enaida H., Murata T., Sakamoto T., Ishibashi T.
American Journal of Ophthalmology 158 ( 3 ) 2014年9月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：American Journal of Ophthalmology
Purpose To investigate long-term ultrastructural changes in the retina after internal limiting membrane (ILM) peeling through the examination of morphologic changes 3 years after vitrectomy in cynomolgus monkeys. Design Laboratory investigation. Methods Pars plana vitrectomy was performed, followed by ILM peeling, in 2 primate eyes. Ultrastructural changes were investigated using light microscopy and transmission and scanning electron microscopy 3 years after ILM peeling. Results The remaining posterior vitreous and ILM-peeled areas were clearly recognized after the long-term follow-up. The exposed Müller cell processes were partially damaged, while regenerative spindle-shaped Müller cell processes developed, covering most of the retina. Notably, the nerve fiber layer was found to be uncovered and exposed to the vitreous space owing to misdirection of glial wound healing in some parts. In these areas, glial wound healing occurred beneath the nerve fiber layer. Although the glial cells covered the damaged areas, there was no apparent ILM regeneration in the shape of a continuous flat sheet, with the exception of accumulated deposits of basement membrane materials. Conclusions Although the retinal structures were well preserved after ILM peeling, ILM peeling resulted in mild damage to the vitreoretinal interface, which was not completely restored even after 3 years. The multilinear shape of the exposed nerve fiber may explain the previously reported dissociated optic nerve fiber layer appearance. The glial cells produced basement membrane materials around their processes, although they did not restore the ILM as a flat sheet. © 2014 by Elsevier Inc. All rights reserved.
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Therapeutic efficacy of topical unoprostone isopropyl in retinitis pigmentosa 査読あり
Akiyama M., Ikeda Y., Yoshida N., Notomi S., Murakami Y., Hisatomi T., Enaida H., Ishibashi T.
Acta Ophthalmologica 92 ( 3 ) 2014年5月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Acta Ophthalmologica
Purpose To evaluate the therapeutic effect of topical unoprostone isopropyl (unoprostone) on patients with retinitis pigmentosa (RP). Methods Forty patients with typical forms of RP were included in the study. Seventeen of 40 patients were treated with 0.12% topical unoprostone twice daily in a randomly selected eye. Patients underwent follow-up examinations every 3 months after treatment. The efficacy of the treatment was monitored by visual acuity and visual field measurement testing using the Humphrey Field Analyzer (HFA: the central 10-2 programme). Moreover, 12 RP patients who were included this study and 12 normal subjects were evaluated in terms of their macular blood flow of both eyes after instillation of unoprostone using the laser speckle method. Results One year after treatment, the 'macular sensitivity', calculated by HFA as the average sensitivity of the central 12 points, was preserved in the fellow eyes as well as the unoprostone-treated eyes. On the other hand, that in the eyes of the control RP patient was significantly decreased. Moreover, there were significantly greater improvements of the 'macular sensitivity' in the unoprostone-treated eyes than the fellow eyes. The change ratios of macular blood flow obtained from both RP patients and normal subjects were significantly increased in both the treated and the fellow eyes. No severe side-effects were observed. Conclusions These results demonstrate that topical unoprostone might have a therapeutic efficacy in patients with RP as a consequence of the macular blood flow improvement as well as its direct neuroprotective effect. © 2013 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.
DOI： 10.1111/aos.12293
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Murakami Y., Matsumoto H., Roh M., Giani A., Kataoka K., Morizane Y., Kayama M., Thanos A., Nakatake S., Notomi S., Hisatomi T., Ikeda Y., Ishibashi T., Connor K., Miller J., Vavvas D.
Cell Death and Differentiation 21 ( 2 ) 270 - 277 2014年2月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Cell Death and Differentiation
There is no known treatment for the dry form of an age-related macular degeneration (AMD). Cell death and inflammation are important biological processes thought to have central role in AMD. Here we show that receptor-interacting protein (RIP) kinase mediates necrosis and enhances inflammation in a mouse model of retinal degeneration induced by dsRNA, a component of drusen in AMD. In contrast to photoreceptor-induced apoptosis, subretinal injection of the dsRNA analog poly(I: C) caused necrosis of the retinal pigment epithelium (RPE), as well as macrophage infiltration into the outer retinas. In Rip3-/-mice, both necrosis and inflammation were prevented, providing substantial protection against poly(I: C)-induced retinal degeneration. Moreover, after poly(I: C) injection, Rip3-/-mice displayed decreased levels of pro-inflammatory cytokines (such as TNF- and IL-6) in the retina, and attenuated intravitreal release of high-mobility group box-1 (HMGB1), a major damage-associated molecular pattern (DAMP). In vitro, poly(I: C)-induced necrosis were inhibited in Rip3-deficient RPE cells, which in turn suppressed HMGB1 release and dampened TNF- and IL-6 induction evoked by necrotic supernatants. On the other hand, Rip3 deficiency did not modulate directly TNF- and IL-6 production after poly(I: C) stimulation in RPE cells or macrophages. Therefore, programmed necrosis is crucial in dsRNA-induced retinal degeneration and may promote inflammation by regulating the release of intracellular DAMPs, suggesting novel therapeutic targets for diseases such as AMD. © 2014 Macmillan Publishers Limited.
DOI： 10.1038/cdd.2013.109
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Chromovitrectomy and vital dyes 査読あり
Enaida H., Hisatomi T., Nakao S., Ikeda Y., Yoshida S., Ishibashi T.
Developments in Ophthalmology 54 120 - 125 2014年
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Developments in Ophthalmology
© 2014 S. Karger AG, Basel. It is important to secure visibility during microsurgery. In vitreous surgery, staining and peeling of the internal limiting membrane with vital dyes, such as indocyanine green, have been widely performed since 2000, and surgical outcomes have improved in some vitreoretinal disorders such as macular holes and epiretinal membranes. It has been subsequently shown that triamcinolone acetonide is an adjuvant that is extremely effective for intraoperative vitreous visualization. In recent years, the term 'chromovitrectomy' has been used for performance of a vitrectomy using these surgical adjuvants for improved visibility. While there have been reports that an auxiliary chromovitrectomy with vital dyes is very effective, the question of retinal toxicity with use of these dyes remains. Therefore, a new safer vital dye, i.e. brilliant blue G, was developed and applied in clinical use. Chromovitrectomy using these adjuvants is an important technique that has low invasiveness and is very safe and very helpful in microincision vitrectomy surgery.
DOI： 10.1159/000360457
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Enaida H., Ikeda Y., Yoshida S., Nakao S., Hachisuka Y., Fujita K., Oshima Y., Kadonosono K., Matsui T., Ishibashi T.
Retina 33 ( 9 ) 1923 - 1930 2013年10月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Retina
PURPOSE:: The study was conducted to develop a new viewing system as a clinical prototype that enables visibility during surgery. METHODS:: The system was composed of several filters attached to the microscope. This nonrandomized, retrospective, observational case series study involved 33 eyes from 32 patients who presented with various diseases and underwent surgery. The authors evaluated the changes in visualization focusing on controlling intraoperative visibility under air infusion and enhancing Brilliant Blue G staining focusing a sharp-cut filter Y (SCY). Visibility was compared under various surgical conditions, including cataract surgery, both with and without this system. Quantitative analysis of changes in intraoperative reflection including halation under air infusion and Brilliant Blue G intensity was carried out using the International Commission on Illumination 1976 (L*, a*, b*) color space method. RESULTS:: A SCY reduced the reflection and halation by a maximum of 69.6%, when compared with use of no filter under air infusion (P < 0.01). The color difference between Brilliant Blue G-stained and nonstained areas was improved by 127.8% relative to values with no filter and using SCY (P < 0.01) in macular hole cases. Furthermore, in cataract surgery with corneal opacity, improvement of visibility was observed by SCY insertion. CONCLUSION:: The system improved intraoperative visibility under air infusion and the Brilliant Blue G staining intensity by use of SCY during vitrectomy. © by Ophthalmic CommunicationSociety Inc.
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Ikeda Y., Yoshida N., Notomi S., Murakami Y., Hisatomi T., Enaida H., Ishibashi T.
British Journal of Ophthalmology 97 ( 9 ) 1187 - 1191 2013年9月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：British Journal of Ophthalmology
Aim: To evaluate the therapeutic effect of continuous treatment with topical dorzolamide (a carbonic anhydrase inhibitor) for cystoid macular oedema (CME) associated with retinitis pigmentosa (RP). Methods: 18 eyes in 10 patients with CME secondary to RP were included. Baseline visual acuity, visual field and optical coherence tomography (OCT) measurements were obtained for all patients. All patients used 1% dorzolamide three times daily in each affected eye. Patients underwent follow-up examinations at 1, 3, 6, 12 and 18 months after treatment. The response to treatment was monitored by the Humphrey field analyser (HFA: the central 10-2 program); in addition, foveal thickness was measured by OCT. Evaluation of 'macular sensitivity' was calculated by HFA as the average of 12 central points. Results: The 'macular sensitivity' in 10 eyes in which CME was almost completely resolved was significantly improved (p<0.05). In eight of the nine eyes in which CME was almost completely resolved within 6 months, the therapeutic efficacy persisted through 18 months. Five eyes which were almost completely resolved or showed an initial response within 6 months experienced recurrence of CME. Conclusions: The prolonged (longer than 1 year) use of topical dorzolamide is effective for the treatment of CME in patients with RP. Therefore, we propose topical dorzolamide treatment as a first choice.
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Enaida H., Ueno A., Nakao S., Ikeda Y., Yoshida S., Kumano Y., Ishibashi T.
Retina 33 ( 6 ) 1270 - 1272 2013年6月
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Enaida H., Yoshida S., Nakao S., Ikeda Y., Hachisuka Y., Oshima Y., Kadonosono K., Ueno A., Ishibashi T.
Ophthalmologica 230 27 - 32 2013年4月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Ophthalmologica
© 2013 S. Karger AG, Basel. Purpose: We developed a new artificial image enhancement system aimed at intraoperative visibility improvement as a clinical prototype. We examined each optical characteristic and change in intraoperative visibility using brilliant blue G (BBG) staining with various sharp cut filters (SCFs). Method: This was a retrospective and observational study. The system was composed of several filters attached to the operating microscope. Six eyes from 6 patients who presented with macular hole and underwent surgery using this system were studied. As a clinical examination, the intraoperative visibility of BBG staining intensities was compared for 4 kinds of SCFs during vitrectomy. Quantitative evaluation was calculated using the International Commission on Illumination 1976 (L∗, a∗, b∗) color space (CIELAB) method. Furthermore, we evaluated each optical characteristic of 4 types of SCFs using extracted porcine eyes and a spectroradiometer as a clinical simulation. Results: Suitable filter selection was possible for this system. The observed color tone and spectral irradiance changes with SCF insertion changed dynamically. In macular hole cases, the color intensities between BBG-stained and nonstained areas were improved using SCF-455 and SCF-520, which was statistically significant (p < 0.05) by CIELAB. Conclusion: The system improved BBG staining intensity with the use of selective SCFs.
DOI： 10.1159/000353868
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Enaida H., Hachisuka Y., Yoshinaga Y., Ikeda Y., Hisatomi T., Yoshida S., Oshima Y., Kadonosono K., Ishibashi T.
Graefe's Archive for Clinical and Experimental Ophthalmology 251 ( 2 ) 441 - 451 2013年2月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Graefe's Archive for Clinical and Experimental Ophthalmology
Purpose: We developed a new artificial image enhancement system and evaluated its usefulness in controlling intraoperative reflection and enhancing of Brilliant Blue G (BBG) staining. Methods: The system was composed of three kinds of filters (a polarizing filter, a blue-enhancing filter, and a sharp-cut filter Y) and attached to the inferior surface of the operating microscope. Twenty-seven post-mortem extracted porcine eyes were used for a series of examinations. We performed surgery using the 23G-vitrectomy system with a halogen light and xenon lights and compared the reduction of intraoperative reflection under air condition and visibility and BBG contrast with and without this system. The evaluation of images was calculated in CIE 1976 (L*, a*, b*) color space (CIELAB) carried out by ImageJ software. The transmission of each filter and absorbance of BBG was measured by a spectrophotometer. We measured spectral irradiance at each wavelength about each filter from each light source with a spectroradiometer. Results: Under both light sources, intraoperative reflection was controlled using a polarizing (PL) filter or combination of filters under air condition. Evaluation of the value of L*within the cutter surface was changed by 37.8 % under the halogen light, and 61.6 % (averaged) under the xenon light with inserted filters versus no filter. The BBG intensity difference was obtained with sharp-cut Y filter under both light source and PL with blue enhancing filter under the halogen light using each L*, a*, b*parameter with statistically significant (p < 0.01, 0.05). However, there was a relative decrease in the observation illuminance when the filter inserted according to the attenuation total spectral irradiance. Conclusions: This system can reduce intraoperative reflections under the air condition and obtain an excellent BBG staining intensity induced by various light sources. © 2012 Springer-Verlag.
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Notomi S., Hisatomi T., Murakami Y., Terasaki H., Sonoda S., Asato R., Takeda A., Ikeda Y., Enaida H., Sakamoto T., Ishibashi T.
PLoS ONE 8 ( 1 ) 2013年1月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：PLoS ONE
Photoreceptor degeneration is the most critical cause of visual impairment in age-related macular degeneration (AMD). In neovascular form of AMD, severe photoreceptor loss develops with subretinal hemorrhage due to choroidal neovascularization (CNV), growth of abnormal blood vessels from choroidal circulation. However, the detailed mechanisms of this process remain elusive. Here we demonstrate that neovascular AMD with subretinal hemorrhage accompanies a significant increase in extracellular ATP, and that extracellular ATP initiates neurodegenerative processes through specific ligation of Purinergic receptor P2X, ligand-gated ion channel, 7 (P2RX7; P2X7 receptor). Increased extracellular ATP levels were found in the vitreous samples of AMD patients with subretinal hemorrhage compared to control vitreous samples. Extravascular blood induced a massive release of ATP and photoreceptor cell apoptosis in co-culture with primary retinal cells. Photoreceptor cell apoptosis accompanied mitochondrial apoptotic pathways, namely activation of caspase-9 and translocation of apoptosis-inducing factor (AIF) from mitochondria to nuclei, as well as TUNEL-detectable DNA fragmentation. These hallmarks of photoreceptor cell apoptosis were prevented by brilliant blue G (BBG), a selective P2RX7 antagonist, which is an approved adjuvant in ocular surgery. Finally, in a mouse model of subretinal hemorrhage, photoreceptor cells degenerated through BBG-inhibitable apoptosis, suggesting that ligation of P2RX7 by extracellular ATP may accelerate photoreceptor cell apoptosis in AMD with subretinal hemorrhage. Our results indicate a novel mechanism that could involve neuronal cell death not only in AMD but also in hemorrhagic disorders in the CNS and encourage the potential application of BBG as a neuroprotective therapy. © 2013 Notomi et al.
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Clinical evidence of sustained chronic inflammatory reaction in retinitis pigmentosa 査読あり
Yoshida N., Ikeda Y., Notomi S., Ishikawa K., Murakami Y., Hisatomi T., Enaida H., Ishibashi T.
Ophthalmology 120 ( 1 ) 100 - 105 2013年1月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Ophthalmology
Purpose: To study the nature of inflammatory reaction in eyes of patients with retinitis pigmentosa (RP) and its possible role in the pathogenesis of RP. Design: Retrospective, observational study. Participants and Controls: Three hundred seventy-one consecutive patients diagnosed with typical RP were included in this study. We included 165 patients without active inflammatory diseases, including 20 patients diagnosed with cataract, and 36 patients diagnosed with idiopathic epiretinal membrane as controls. Methods: Density of the inflammatory cells in the anterior vitreous cavity was measured and graded by slit-lamp biomicroscopy. A multiplex enzyme-linked immunosorbent assay (ELISA) was performed to evaluate the concentration of cytokines and chemokines in aqueous humor and vitreous fluid of patients with RP and controls. In addition, we investigated the relationship between visual function and anterior vitreous cells in these patients. Main Outcome Measures: Slit-lamp biomicroscopic analysis, best-corrected visual acuity, visual field analysis, and multiplex ELISA. Results: In 190 of 509 eyes with RP (37.3%), "1+" (5-9 cells per field) or more cells were observed in the anterior vitreous cavity. Strong inflammatory reaction with "2+" cells (10-30 cells per field) was associated with younger age. In the elderly patients with RP, significantly decreased visual function was seen in a group with "1+" or more cells (P<0.05). Moreover, the levels of a variety of proinflammatory cytokines and chemokines, including monocyte chemotactic protein-1, were increased both in the aqueous humor and vitreous fluid of RP patients compared with the levels in control patients. Conclusions: Sustained chronic inflammatory reaction may underlie the pathogenesis of RP, suggesting interventions for ocular inflammatory reaction as a potential treatment for patients with RP. Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article. © 2013 American Academy of Ophthalmology.
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Laboratory evidence of sustained chronic inflammatory reaction in retinitis pigmentosa 査読あり
Yoshida N., Ikeda Y., Notomi S., Ishikawa K., Murakami Y., Hisatomi T., Enaida H., Ishibashi T.
Ophthalmology 120 ( 1 ) 2013年1月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Ophthalmology
Purpose: To study the nature of retinal inflammatory response in rd10 mice, an animal model of retinitis pigmentosa (RP), and to investigate the effect of an antioxidant on retinal inflammation and photoreceptor apoptosis. Design: Experimental study. Participants and Controls: This study included 42 untreated rd10 mice, 30 N-acetylcysteine (NAC)-treated rd10 mice, and 20 C57BL/6 mice as controls. Methods: Real-time polymerase chain reaction (PCR) was performed to evaluate the expression levels of inflammatory factors (proinflammatory cytokines and chemokines) in rd10 mouse retinas. Rd10 mice were treated with an antioxidant NAC, and its effect on retinal inflammation and photoreceptor apoptosis were examined by immunohistochemistry. Main Outcome Measures: Real-time PCR and immunohistochemistry. Results: We demonstrated sequential events involving increased expression of proinflammatory cytokines and chemokines, activation of microglia, and photoreceptor apoptosis during retinal degeneration of rd10 mice. Furthermore, antioxidant treatment with NAC prevented the photoreceptor cell death along with suppression of inflammatory factors and microglial activation. Conclusions: Sustained chronic inflammatory reaction may contribute to the pathogenesis of retinal degeneration in rd10 mice, suggesting interventions for ocular inflammatory reaction using antioxidants as a potential treatment for patients with RP. Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article. © 2013 American Academy of Ophthalmology.
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Murakami Y., Ikeda Y., Yoshida N., Notomi S., Hisatomi T., Oka S., De Luca G., Yonemitsu Y., Bignami M., Nakabeppu Y., Ishibashi T.
American Journal of Pathology 181 ( 4 ) 1378 - 1386 2012年10月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：American Journal of Pathology
Retinitis pigmentosa (RP) is a genetically heterogenous group of inherited retinal degenerative diseases resulting from photoreceptor cell death and affecting >1 million persons globally. Although oxidative stress has been implicated in the pathogenesis of RP, the mechanisms by which oxidative stress mediates photoreceptor cell death are largely unknown. Here, we show that oxidation of nucleic acids is a key component in the initiation of death-signaling pathways in rd10 mice, a model of RP. Accumulation of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxo-dG) increased in photoreceptor cells, and especially within their nuclei, in rd10 mice as well as in Royal College of Surgeons rats, another model of RP caused by different genetic mutations. Vitreous samples from humans with RP contained higher levels of 8-oxo-dG excreted than samples from nondegenerative controls. Transgenic overexpression of human MutT homolog-1, which hydrolyzes oxidized purine nucleoside triphosphates in the nucleotide pool, significantly attenuated 8-oxo-dG accumulation in nuclear DNA and photoreceptor cell death in rd10 mice, in addition to suppressing DNA single-strand break formation, poly(ADP-ribose) polymerase activation, and nuclear translocation of apoptosis-inducing factor. These findings indicate that oxidative DNA damage is an important process for the triggering of photoreceptor cell death in rd10 mice and suggest that stimulation of DNA repair enzymes may be a novel therapeutic approach to attenuate photoreceptor cell loss in RP. © 2012 American Society for Investigative Pathology.
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Murakami Y., Matsumoto H., Roh M., Suzuki J., Hisatomi T., Ikeda Y., Miller J., Vavvas D.
Proceedings of the National Academy of Sciences of the United States of America 109 ( 36 ) 14598 - 14603 2012年9月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Proceedings of the National Academy of Sciences of the United States of America
Retinitis pigmentosa comprises a group of inherited retinal photoreceptor degenerations that lead to progressive loss of vision. Although in most cases rods, but not cones, harbor the deleterious gene mutations, cones do die in this disease, usually after the main phase of rod cell loss. Rod photoreceptor death is characterized by apoptotic features. In contrast, the mechanisms and features of subsequent nonautonomous cone cell death remain largely unknown. In this study, we show that receptor-interacting protein (RIP) kinase mediates necrotic cone cell death in rd10 mice, a mousemodel of retinitis pigmentosa caused by a mutation in a rod-specific gene. The expression of RIP3, a key regulator of programmed necrosis, was elevated in rd10 mouse retinas in the phase of cone but not rod degeneration. Although rd10 mice lacking Rip3 developed comparable rod degeneration to control rd10 mice, they displayed a significant preservation of cone cells. Ultrastructural analysis of rd10 mouse retinas revealed that a substantial fraction of dying cones exhibited necrotic morphology, which was rescued by Rip3 deficiency. Additionally, pharmacologic treatment with a RIP kinase inhibitor attenuated histological and functional deficits of cones in rd10 mice. Thus, necrotic mechanisms involving RIP kinase are crucial in cone cell death in inherited retinal degeneration, suggesting the RIP kinase pathway as a potential target to protect cone-mediated central and peripheral vision loss in patients with retinitis pigementosa.
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Ikeda Y., Hisatomi T., Yoshida N., Notomi S., Murakami Y., Enaida H., Ishibashi T.
Graefe's Archive for Clinical and Experimental Ophthalmology 250 ( 6 ) 809 - 814 2012年6月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Graefe's Archive for Clinical and Experimental Ophthalmology
Background: Cystoid macular edema (CME) is one of the common complications of retinitis pigmentosa (RP), and is responsible for patient complications such as blurred and reduced visual acuity and for subsequent atrophic changes in the fovea. The objective of this work was to evaluate the clinical efficacy of a topical dorzolamide (a carbonic anhydrase inhibitor) in CME associated with RP. Methods: Sixteen eyes of nine patients with CME secondary to typical forms of RP were included in the study. Baseline visual acuity, visual field, and optical coherence tomography (OCT) measurements were obtained for all patients. All patients used 1% dorzolamide three times daily in each eye. Patients underwent follow-up exams at 1, 3, and 6 months after treatment. The response to treatment was monitored by visual acuity and visual field measurement testing using the Humphrey Field Analyzer (HFA: the central 10-2 Program); in addition, foveal thickness was measured by OCT. Evaluation of macular sensitivity calculated by HFA as the average of 12 central points. Results: Thirteen (81.3%) of 16 eyes showed a clear decrease in retinal thickness after treatment. Evaluation of macular sensitivity, calculated by HFA as the average of 12 central points (with the exception of foveal point data, showed an improvement of more than 1.0 dB in nine (56.3%) of 16 eyes. Moreover, both the mean deviation value and macular sensitivity were significantly improved. No severe side-effects were seen in any of the patients examined. Conclusions: The results demonstrated that a topical dorzolamide is effective for the treatment of CME in patients with RP, and that the positive treatment effects last for up to 6 months. © Springer-Verlag 2011.
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The role of mislocalized phototransduction in photoreceptor cell death of retinitis pigmentosa 査読あり
Nakao T., Tsujikawa M., Notomi S., Ikeda Y., Nishida K.
PLoS ONE 7 ( 4 ) 2012年4月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：PLoS ONE
Most of inherited retinal diseases such as retinitis pigmentosa (RP) cause photoreceptor cell death resulting in blindness. RP is a large family of diseases in which the photoreceptor cell death can be caused by a number of pathways. Among them, light exposure has been reported to induce photoreceptor cell death. However, the detailed mechanism by which photoreceptor cell death is caused by light exposure is unclear. In this study, we have shown that even a mild light exposure can induce ectopic phototransduction and result in the acceleration of rod photoreceptor cell death in some vertebrate models. In ovl, a zebrafish model of outer segment deficiency, photoreceptor cell death is associated with light exposure. The ovl larvae show ectopic accumulation of rhodopsin and knockdown of ectopic rhodopsin and transducin rescue rod photoreceptor cell death. However, knockdown of phosphodiesterase, the enzyme that mediates the next step of phototransduction, does not. So, ectopic phototransduction activated by light exposure, which leads to rod photoreceptor cell death, is through the action of transducin. Furthermore, we have demonstrated that forced activation of adenylyl cyclase in the inner segment leads to rod photoreceptor cell death. For further confirmation, we have also generated a transgenic fish which possesses a human rhodopsin mutation, Q344X. This fish and rd10 model mice show photoreceptor cell death caused by adenylyl cyclase. In short, our study indicates that in some RP, adenylyl cyclase is involved in photoreceptor cell death pathway; its inhibition is potentially a logical approach for a novel RP therapy. © 2012 Nakao 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.
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Notomi S., Hisatomi T., Kanemaru T., Takeda A., Ikeda Y., Enaida H., Kroemer G., Ishibashi T.
American Journal of Pathology 179 ( 6 ) 2798 - 2809 2011年12月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：American Journal of Pathology
Stressed cells release ATP, which participates in neurodegenerative processes through the specific ligation of P2RX7 purinergic receptors. Here, we demonstrate that extracellular ATP and the more specific P2RX7 agonist, 2′- and 3′-O-(4-benzoylbenzoyl)-ATP, both induce photoreceptor cell death when added to primary retinal cell cultures or when injected into the eyes from wild-type mice, but not into the eyes from P2RX7 -/- mice. Photoreceptor cell death was accompanied by the activation of caspase-8 and -9, translocation of apoptosis-inducing factor from mitochondria to nuclei, and TUNEL-detectable chromatin fragmentation. All hallmarks of photoreceptor apoptosis were prevented by premedication or co-application of Brilliant Blue G, a selective P2RX7 antagonist that is already approved for the staining of internal limiting membranes during ocular surgery. ATP release is up-regulated by nutrient starvation in primary retinal cell cultures and seems to be an initializing event that triggers primary and/or secondary cell death via the positive feedback loop on P2RX7. Our results encourage the potential application of Brilliant Blue G as a novel neuroprotective agent in retinal diseases or similar neurodegenerative pathologies linked to excessive extracellular ATP. © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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Yoshida N., Hisatomi T., Ikeda Y., Kohno R., Murakami Y., Imaki H., Ueno A., Fujisawa K., Ishibashi T.
Graefe's Archive for Clinical and Experimental Ophthalmology 249 ( 10 ) 1547 - 1552 2011年10月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Graefe's Archive for Clinical and Experimental Ophthalmology
Background: Neovascular glaucoma (NVG) is a serious complication for patients with proliferative diabetic retinopathy (PDR). Bevacizumab is a full-length humanized monoclonal antibody that binds all isoforms of vascular endothelial growth factor (VEGF). Recently, encouraging results regarding the off-label use of intravitreal bevacizumab (IVB) for the treatment of NVG have been reported. We evaluated the histology of bevacizumab-treated trabeculectomy specimens to clarify IVB's biological effects on angle neovascularization. Methods: We retrospectively reviewed the charts of a consecutive series of 15 eyes of 13 patients who underwent trabeculectomy to treat NVG caused by PDR. In ten eyes of eight patients, 1.25 mg bevacizumab was injected intravitreally via the pars plana. Using light or electron microscopy, the surgically excised trabecular tissue was compared to that without IVB. Results: Light microscopy revealed decreased edema, fibrin deposition, inflammation and vascular congestion in the trabecular meshwork in specimens with IVB compared to those without IVB. Electron microscopy revealed endothelial cell degeneration in the bevacizumab-treated specimens. Conclusions: The biological effects on angle neovascularization after IVB may involve reduced vascular permeability, decreased inflammatory reaction, loss of vascular function, and endothelial cell degeneration. © 2011 Springer-Verlag.
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Miyazaki M., Ikeda Y., Yonemitsu Y., Goto Y., Murakami Y., Yoshida N., Tabata T., Hasegawa M., Tobimatsu S., Sueishi K., Ishibashi T.
Human Gene Therapy 22 ( 5 ) 559 - 565 2011年5月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Human Gene Therapy
Lentiviral vectors are promising tools for the treatment of chronic retinal diseases including glaucoma, as they enable stable transgene expression. We examined whether simian immunodeficiency virus (SIV)-based lentiviral vector-mediated retinal gene transfer of human pigment epithelium-derived factor (hPEDF) can rescue rat retinal ganglion cell injury. Gene transfer was achieved through subretinal injection of an SIV vector expressing human PEDF (SIV-hPEDF) into the eyes of 4-week-old Wistar rats. Two weeks after gene transfer, retinal ganglion cells were damaged by transient ocular hypertension stress (110mmHg, 60min) and N-methyl-d-aspartic acid (NMDA) intravitreal injection. One week after damage, retrograde labeling with 4′,6-diamidino-2-phenylindole (DAPI) was done to count the retinal ganglion cells that survived, and eyes were enucleated and processed for morphometric analysis. Electroretinographic (ERG) assessment was also done. The density of DAPI-positive retinal ganglion cells in retinal flat-mounts was significantly higher in SIV-hPEDF-treated rats compared with control groups, in both transient ocular hypertension and NMDA-induced models. Pattern ERG examination demonstrated higher amplitude in SIV-hPEDF-treated rats, indicating the functional rescue of retinal ganglion cells. These findings show that neuroprotective gene therapy using hPEDF can protect against retinal ganglion cell death, and support the potential feasibility of neuroprotective therapy for intractable glaucoma. © 2011 Mary Ann Liebert, Inc.
DOI： 10.1089/hum.2010.132
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Retinitis pigmentosa associated with asteroid hyalosis 査読あり
Ikeda Y., Hisatomi T., Murakami Y., Miyazaki M., Kohno R., Takahashi H., Hata Y., Ishibashi T.
Retina 30 ( 8 ) 1278 - 1281 2010年9月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Retina
Background: Asteroid hyalosis (AH) is a condition in which cream-colored or white spherical particles are suspended in the vitreous body. Asteroid hyalosis is considered not to cause decreased vision or any other visual symptoms except in rare cases. There have been a few reports of AH in patients with retinitis pigmentosa (RP). Methods: To assess the prevalence of AH in patients with RP, 320 patients with typical forms of RP were studied. One patient was offered a standard three-port vitrectomy, and the spherical particles obtained from her vitrectomy sample were analyzed using an energy-dispersive x-ray spectrometer. Results: Ten patients (two men and eight women) developed AH. Among them, four had bilateral AH and two had rapidly increasing vitreous opacity that led to decreased vision. One patient was a 48-year-old woman with progressive AH in the left eye. After treatment with a vitrectomy, her vision improved from 0.4 to 0.8. The spherical particles were composed of mainly calcium and phosphorus. Conclusion: The prevalence of AH in RP was higher than in previous reports, and we encountered two rare cases of progressive AH with decreased vision. We conclude that AH might lead to decreased vision in patients with RP. Copyright © by Ophthalmic Communications Society, Inc.
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Kohno R., Hata Y., Mochizuki Y., Arita R., Kawahara S., Kita T., Miyazaki M., Hisatomi T., Ikeda Y., Aiello L., Ishibashi T.
American Journal of Ophthalmology 150 ( 2 ) 223 - 229.e1 2010年8月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：American Journal of Ophthalmology
Purpose: To examine the histopathologic effect of a single intravitreal injection of bevacizumab on newly formed vessels in eyes with proliferative diabetic retinopathy (PDR). Design: Interventional case series and laboratory investigation. Methods: Two days after intravitreal injection of bevacizumab (1.25 mg/eye), pars plana vitrectomy or trabeculectomy was performed for the treatment of PDR or neovascular glaucoma (NVG) associated with PDR. Ten surgically removed preretinal proliferative tissues and 6 deep scleral flaps containing trabecular meshwork were fixed in 2% glutaraldehyde or 4% paraformaldehyde and were subjected to transmission electron microscopic analysis, immunohistochemical analysis, and terminal deoxyuridiine triphosphate (dUTP) nick-end labeling staining. Two surgically removed preretinal proliferative tissues and 2 deep scleral flaps from patients with PDR and NVG, but without preoperative intravitreal injection of bevacizumab (IVB), served as controls. Results: In control tissues, vascular endothelial cells possessed many fenestrations and were accompanied by pericytes. Apoptotic vascular endothelial cells frequently were observed in tissue after intravitreal injection of bevacizumab, whereas they were not observed in control tissues. Additionally, no apparent fenestration was observed in newly formed vessels from either proliferative tissue or trabecular meshwork after intravitreal injection of bevacizumab. In both PDR and NVG tissues after intravitreal injection of bevacizumab, overexpression of smooth muscle actin was observed in newly formed vessels, suggesting that the treatment may have increased pericytes on the vasculature as compared with control tissue. Conclusions: Intravitreal injection of bevacizumab may induce changes in immature, newly formed vessels of PDR or NVG tissue, leading to endothelial apoptosis with vascular regression, while inducing normalization of premature vessels by increasing pericyte coverage and reducing vessel fenestration. © 2010 Elsevier Inc. All Rights Reserved.
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Murakami Y., Ikeda Y., Yonemitsu Y., Miyazaki M., Inoue M., Hasegawa M., Sueishi K., Ishibashi T.
Human Gene Therapy 21 ( 2 ) 199 - 209 2010年2月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Human Gene Therapy
Lentiviral vectors are promising tools for the treatment of chronic retinal diseases, including age-related macular degeneration (AMD), as they enable stable transgene expression. On the other hand, Sendai virus (SeV) vectors provide the unique advantage of rapid gene transfer. Here we show that novel simian immunodeficiency viral vectors pseudotyped with SeV envelope proteins (SeV-F/HN-SIV) achieved rapid, efficient, and long-lasting gene transfer in the mouse retina. Subretinal exposure to SeV-F/HN-SIV vectors for only a few minutes resulted in high-level gene transfer to the retinal pigment epithelium, whereas several hours were required for gene transfer by standard vesicular stomatitis virus G-pseudotyped SIV vectors. Transgene expression continued over a 1-year period. SeV-F/HN-SIV vector-mediated retinal overexpression of soluble Fms-like tyrosine kinase-1 (sFlt-1) or pigment epithelium-derived factor (PEDF) significantly suppressed laser-induced choroidal neovascularization (CNV). Histologically, 6-month-long sustained overexpression of PEDF did not adversely affect the retina; however, that with sFlt-1 resulted in photoreceptor degeneration associated with choroidal circulation defects. These data demonstrate that brief subretinal administration of SeV-F/HN-SIV vectors may facilitate safe and efficient retinal gene transfer, and suggest the therapeutic potential of PEDF with a higher safety profile for treating CNV in AMD patients. © Copyright 2010, Mary Ann Liebert, Inc.
DOI： 10.1089/hum.2009.102
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Ikeda Y., Yonemitsu Y., Miyazaki M., Kohno R., Murakami Y., Murata T., Goto Y., Tabata T., Ueda Y., Ono F., Suzuki T., Ageyama N., Terao K., Hasegawa M., Sueishi K., Ishibashi T.
Human Gene Therapy 20 ( 9 ) 943 - 954 2009年9月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Human Gene Therapy
A phase 1 clinical trial evaluating the safety of gene therapy for patients with wet age-related macular degeneration (AMD) or retinoblastoma has been completed without problems. The efficacy of gene therapy for Leber's congenital amaurosis (LCA) was reported by three groups. Gene therapy may thus hold promise as a therapeutic method for the treatment of intractable ocular diseases. However, it will first be important to precisely evaluate the efficiency and safety of alternative gene transfer vectors in a preclinical study using large animals. In the present study, we evaluated the acute local (ophthalmic) and systemic toxicity of our simian immunodeficiency virus from African green monkeys (SIVagm)-based lentiviral vectors carrying human pigment epithelium-derived factor (SIV-hPEDF) for transferring genes into nonhuman primate retinas. Transient inflammation and elevation of intraocular pressure were observed in some animals, but these effects were not dose dependent. Electroretinograms (ERGs), including multifocal ERGs, revealed no remarkable change in retinal function. Histopathologically, SIV-hPEDF administration resulted in a certain degree of inflammatory reaction and no apparent structural destruction in retinal tissue. Regarding systemic toxicity, none of the animals died, and none showed any serious side effects during the experimental course. No vector leakage was detected in serum or urine samples. We thus propose that SIVagm-mediated stable gene transfer might be useful and safe for ocular gene transfer in a clinical setting. © Mary Ann Liebert, Inc. 2009.
DOI： 10.1089/hum.2009.048
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Ikeda Y., Yonemitsu Y., Miyazaki M., Kohno R., Murakami Y., Murata T., Tabata T., Ueda Y., Ono F., Suzuki T., Ageyama N., Terao K., Hasegawa M., Sueishi K., Ishibashi T.
Human Gene Therapy 20 ( 6 ) 573 - 579 2009年6月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Human Gene Therapy
Gene therapy may hold promise as a therapeutic approach for the treatment of intractable ocular diseases, including retinitis pigmentosa (RP). Gene transfer vectors that are able to show long-lasting transgene expression in vivo are highly desirable to treat RP; however, there is a dearth of information regarding long-term transgene expression in the eyes of large animals. We previously reported that the simian immunodeficiency virus from African green monkeys (SIVagm)-based lentiviral vector showed efficient, stable, and safe retinal gene transfer, resulting in significant prevention of retinal degeneration by gene transfer of a neurotrophic factor, human pigment epithelium-derived factor (hPEDF), in rodents. Before applying this strategy in a clinical setting, we here assessed the long-lasting transgene expression of our third-generation SIVagm-based lentiviral vectors in the retinal tissue of nonhuman primates. Approximately 20-50μl of SIV-EGFP (enhanced green fluorescent protein) or SIV-hPEDF was injected into the subretinal space via a glass capillary tube. To detect EGFP expression in the retina, we used a fluorescence fundus camera at various time points after gene transfer. Human PEDF expression was assessed by immunohistochemical analysis, Western blot assay, and enzyme-linked immunosorbent assay. The retinas demonstrated frequent EGFP expression that was preserved for at least 4 years without significant decline. The expression of hPEDF was stable, and occurred mainly in the retinal pigment epithelium. The secreted protein was detected in vitreous and aqueous humor. We thus propose that SIVagm-mediated stable gene transfer might be significantly useful for ocular gene transfer in a clinical setting. © Copyright 2009, Mary Ann Liebert, Inc.
DOI： 10.1089/hum.2009.009
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Ex Vivo Transfer of Nuclear Factor-κB Decoy Ameliorates Hepatic Cold Ischemia/Reperfusion Injury 査読あり
Yoshizumi T., Ikeda Y., Kaneda Y., Sueishi K.
Transplantation Proceedings 41 ( 5 ) 1504 - 1507 2009年6月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Transplantation Proceedings
Cold ischemia/reperfusion injury of the hepatic graft has been attributed to the release of various inflammatory cytokines. Specific inhibition of these cytokines may improve viability of the hepatic graft upon reperfusion. Herein we have assessed the efficacy of cis element decoy against nuclear factor-κB binding site delivery to the hepatic tissue in a rodent liver transplantation model. At 8 hours after reperfusion of the liver, significant reduction was noted in the livers treated with decoy in the release of cytosolic enzymes from the hepatocytes and in serum tumor necrosis factor α (P < .05). The neutrophilic infiltration into the hepatic grafts was significantly suppressed in the livers treated with decoy oligodeoxynucleotides (ODNs). Decoy ODNs against nuclear factor-κB binding site delivery improved the viability of the hepatic graft against cold ischemia/reperfusion injury in the rodent liver transplantation model. © 2009 Elsevier Inc. All rights reserved.
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Miyazaki M., Ikeda Y., Yonemitsu Y., Goto Y., Kohno R., Murakami Y., Inoue M., Ueda Y., Hasegawa M., Tobimatsu S., Sueishi K., Ishibashi T.
Journal of Gene Medicine 10 ( 12 ) 1273 - 1281 2008年12月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of Gene Medicine
Background: We previously demonstrated that a new lentiviral vector derived from nonpathogenic simian immunodeficiency virus (SIVagm) was efficient and safe for long-lasting retinal gene transfer, and that it provided the significant therapeutic effect of expressing human pigment epithelium-derived factor (hPEDF) in Royal College of Surgeons (RCS) rats. In the present study, to obtain a more pronounced outcome, we assessed the potential synergistic effect of the simultaneous gene transfer of hPEDF and human fibroblast growth factor-2 (hFGF-2) by improved third-generation SIV on RCS rats and retinal degeneration slow (rds) mice, because the former targets the primary neurons, including photoreceptor cells (PCs), whereas the latter is effective for targeting secondary neural cells, including Muller cells. Methods: Vector solution (SIV-hPEDF, SIV-hFGF-2, a 1:1 mixture of SIV-hPEDF and SIV-hFGF-2, or SIV-enhanced green fluorescent protein) was injected into the peripheral subretinal space of 3-week-old RCS rats or rds mice. Histopathological and electroretinographic assessments were made at several points after gene transfer. Results: Administration of SIV-hPEDF or SIV-hFGF-2 significantly delayed the histological PC degeneration and electrical deficit in RCS rats, and these delays were synergistically and significantly pronounced by SIV-hPEDF + SIV-hFGF-2 (1:1 mixture). In rds mice, functional therapeutic effects were observed even by SIV-PEDF, or SIV-FGF-2 alone and, moreover, both SIV-PEDF and SIV-FGF-2 showed higher therapeutic effects. Conclusions: These synergistic rescues of retinitis pigmentosa (RP) model animals are the 'proof concept' that the 'dual' expression of hPEDF and hFGF-2 dramatically improved therapeutic efficacy by keeping lower titers. This strategy may contribute to safer and more effective gene therapy for RP. Copyright © 2008 John Wiley & Sons, Ltd.
DOI： 10.1002/jgm.1257
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Murakami Y., Ikeda Y., Yonemitsu Y., Onimaru M., Nakagawa K., Kohno R., Miyazaki M., Hisatomi T., Nakamura M., Yabe T., Hasegawa M., Ishibashi T., Sueishi K.
American Journal of Pathology 173 ( 5 ) 1326 - 1338 2008年11月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：American Journal of Pathology
Photoreceptor apoptosis is a critical process of retinal degeneration in retinitis pigmentosa (RP), a group of retinal degenerative diseases that result from rod and cone photoreceptor cell death and represent a major cause of adult blindness. We previously demonstrated the efficient prevention of photoreceptor apoptosis by intraocular gene transfer of pigment epithelium-derived factor (PEDF) in animal models of RP; however, the underlying mechanism of the neuroprotective activity of PEDF remains elusive. In this study, we show that an apoptosis-inducing factor (AIF)-related pathway is an essential target of PEDF-mediated neuroprotection. PEDF rescued serum starvation-induced apoptosis, which is mediated by AIF but not by caspases, of R28 cells derived from the rat retina by preventing translocation of AIF into the nucleus. Nuclear translocation of AIF was also observed in the apoptotic photoreceptors of Royal College of Surgeons rats, a well-known animal model of RP that carries a mutation of the Mertk gene. Lentivirus-mediated retinal gene transfer of PEDF prevented the nuclear translocation of AIF in vivo, resulting in the inhibition of the apoptotic loss of their photoreceptors in association with up-regulated Bcl-2 expression, which mediates the mitochondrial release of AIF. These findings clearly demonstrate that AIF is an essential executioner of photoreceptor apoptosis in inherited retinal degeneration and provide a therapeutic rationale for PEDF-mediated neuroprotective gene therapy for individuals with RP. Copyright © American Society for Investigative Pathology.
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Murakami Y., Ikeda Y., Yonemitsu Y., Tanaka S., Kondo H., Okano S., Kohno R., Miyazaki M., Inoue M., Hasegawa M., Ishibashi T., Sueishi K.
Journal of Gene Medicine 10 ( 2 ) 165 - 176 2008年2月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of Gene Medicine
Background: Recombinant Sendai virus vectors (rSeV) constitute a new class of cytoplasmic RNA vectors that have shown efficient gene transfer in various organs, including retinal tissue; however, the related immune responses remain to be overcome in view of clinical applications. We recently developed a novel rSeV from which all envelope-related genes were deleted (rSeV/dFdMdHN) and, in the present study, assess host immune responses following retinal gene transfer. Methods: rSeV/dFdMdHN or conventional F-gene deleted rSeV (rSeV/dF) was injected into subretinal space of adult Wistar rats or C57BL/6 mice. The transgene expression and histopathological findings were assessed at various time points. Immunological assessments, including the expression of proinflammatory cytokines, natural killer (NK)-cell activity, as well as SeV-specific cytotoxic T lymphocytes (CTLs) and antibodies, were performed following vector injection. Results: rSeV/dFdMdHN showed high gene transfer efficiency into the retinal pigment epithelium at an equivalent level to that seen with rSeV/ dF. In the early phase, the upregulation of proinflammatory cytokines, local inflammatory cell infiltration and tissue damage that were all prominently seen in rSeV/dF injection were dramatically diminished using rSeV/dFdMdHN. NK cell activity was also decreased, indicating a reduction of the innate immune response. In the later phase, on the other hand, CTL activity and anti-SeV antibodies were similarly induced, even using rSeV/dFdMdHN, and resulted in transient transgene expression in both vector types. Conclusions: Deletion of envelope-related genes of rSeV dramatically reduces the vector-induced retinal damage and may extend the utility for ocular gene transfer; however, further studies regulating the acquired immune response are required to achieve long-term transgene expression of rSeV. Copyright © 2007 John Wiley & Sons, Ltd.
DOI： 10.1002/jgm.1142
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Interleukin-18 regulates pathological intraocular neovascularization 査読あり
Qiao H., Sonoda K., Ikeda Y., Yoshimura T., Hijioka K., Jo Y., Sassa Y., Tsutsumi-Miyahara C., Hata Y., Akira S., Ishibashi T.
Journal of Leukocyte Biology 81 ( 4 ) 1012 - 1021 2007年4月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of Leukocyte Biology
Recently, the proinflammatory cytokine IL-18 has been shown to have a role in angiogenesis. This study aimed to elucidate its role in abnormal neovascularization (NV) in an oxygen-induced retinopathy (OIR) mouse model of the retinopathy seen in human premature newborns. IL-18 was constitutively expressed in the retina in C57BL/6 mice, but expression transiently dropped on Day 17 after birth in mice exposed to 75% oxygen for 5 days between Days 7 and 12. Coincident with the IL-18 reduction in oxygen-treated mice, vascular endothelial growth factor was expressed in the retina, and OIR developed. By Day 24, NV in the retina had regressed to normal levels. By contrast, IL-18 knockout mice, exposed to elevated oxygen concentrations, developed more severe OIR on Day 17, and it is important that this persisted until Day 24. This suggested that IL-18 negatively regulated retinal NV. To investigate this further, we administrated recombinant IL-18 to C57BL/6 mice during the development of OIR but found no significant inhibition of retinopathy. However, when IL-18-binding protein was administered during the OIR recovery phase to neutralize endogenous IL-18, OIR was still apparent on Day 24. We therefore concluded that IL-18 regulates pathogenic retinal NV by promoting its regression rather than inhibiting its development. This suggests some useful, new approaches to treating retinopathy in humans. © Society for Leukocyte Biology.
DOI： 10.1189/jlb.0506342
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Rapid detection of SAG 926delA mutation using real-time polymerase chain reaction 査読あり
Yoshida S., Yamaji Y., Yoshida A., Ikeda Y., Yamamoto K., Ishibashi T.
Molecular Vision 12 1552 - 1557 2006年12月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Molecular Vision
Purpose: Mutation 926delA of the arrestin/S-antigen SAG gene is the main cause of Oguchi disease in the Japanese. The purpose of this study was to develop a rapid diagnostic assay to detect mutations in the SAG gene. Methods: Two sequence-specific primers and fluorophore-labeled probes for exon 11 of the SAG gene were designed, and the region spanning the mutations was amplified by polymerase chain reaction (PCR) using the LightCycler detection system (Roche Diagnostics, Mannheim, Germany). The mutations were then identified by melting curve analyses of the hybrid formed between the PCR product and a specific fluorescent probe. Results: We clearly distinguished each SAG genotype (homozygous and heterozygous 926delA and wild type) by the distinct melting peaks at different temperatures. One thermal cycling required approximately 54 min to process, and the results were 100% in concordance with the genotypes determined by DNA sequencing. Conclusions: We have succeeded in developing a rapid method to detect the most frequent mutation in the SAG gene. This method will help in identifying gene mutations associated with Oguchi disease with a rapid and reliable identification or the exclusion of the frequent mutations in the SAG gene. © 2006 Molecular Vision.
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Ikeda Y., Yonemitsu Y., Onimaru M., Nakano T., Miyazaki M., Kohno R., Nakagawa K., Ueno A., Sueishi K., Ishibashi T.
Experimental Eye Research 83 ( 5 ) 1031 - 1040 2006年11月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Experimental Eye Research
The vascular endothelial growth factor (VEGF) family plays an essential role in vascular development, angiogenesis and lymphangiogenesis. VEGF-A is a key regulator of endothelial cell functions and VEGF-C and VEGF-D are known to stimulate both angiogenesis and lymphangiogenesis. In a surgically removed subretinal vascular membrane of an age-related macular degeneration (AMD) patient, both VEGF-C and VEGF-D were confirmed, in addition to VEGF-A, to be markedly positive in the retinal pigment epithelium (RPE). There is no lymph vessel in ocular tissue, so it is possible that VEGF-C and VEGF-D expression in the RPE play some role in ocular angiogenesis, as well as VEGF-A. Next, we assessed the transition of VEGF-A, -C, and -D expression on several conditions, in human RPE. Hypoxia proverbially induced VEGF-A mRNA expression, meanwhile VEGF-C and VEGF-D mRNA expression was down-regulated. The Ca2+ deprivation from culture medium strongly up-regulated VEGF-A and VEGF-D mRNA expression. Culture on plastic flasks precoated with poly-2-hydroxyethyl methacrylate up-regulated VEGF-D expression. Meanwhile, no significant change of VEGF-C mRNA expression was found in the blockade of cell-cell and/or cell-matrix adhesion. These findings suggest the possibility that VEGF-C and VEGF-D expression in RPE modify the ocular angiogenesis as angiogenic stimulators. © 2006 Elsevier Ltd. All rights reserved.
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Kohno R., Ikeda Y., Yonemitsu Y., Hisatomi T., Yamaguchi M., Miyazaki M., Takeshita H., Ishibashi T., Sueishi K.
Brain Research 1093 ( 1 ) 54 - 70 2006年6月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Brain Research
It is well known that neural stem/progenitor cells of the central nervous system (CNS) can proliferate to form neurospheres (CNS-neurospheres) that are positive for nestin, an intermediate filament for neural progenitors. Retinal stem/progenitor properties were also isolated from the ciliary body (CB) of the eye where, as in the CNS, such stem/progenitors also form spheres and have been considered to expand only via expansion by their proliferation even from the single-cell level (called spheres of pigment cells from the ciliary margin: PCM-spheres). We here found a new and distinct process underlying the growth of CB cell-derived spheres (CB-spheres) that is unlike the mechanism of CNS- and PCM-sphere expansion; this new process is a cell proliferation-independent incorporation of neighbor spheres and cells cultured at high density (200 cells/μl). The majority of cells in CB-spheres consisted of nestin-negative epithelia-like cells and started to express nestin during the course of their expansion by high-density cultivation. The growth of CNS-neurospheres was sensitive to a cell-cycle inhibitor, whereas the growth of CB-spheres was not seriously affected by cell proliferation; rather, the spheres grew by incorporating other CB-spheres and nestin-negative adherent cells, the latter of which started to express nestin and lost the expression of epithelial markers after being incorporated. These results indicate that CB-spheres do not form by the accumulation of neural progenitors but rather by a reprogramming system from epithelia-like cells for neural differentiation, a clearly distinct mechanism from sphere formation by single-cell expansion of retinal stem/progenitor populations. © 2006 Elsevier B.V. All rights reserved.
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Tumor necrosis factor-α antisense transfer remarkably improves hepatic graft viability 査読あり
Yoshizumi T., Yonemitsu Y., Ikeda Y., Kaneda Y., Yanaga K., Sugimachi K., Sueishi K.
Liver International 26 ( 4 ) 451 - 456 2006年5月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Liver International
Background: Cold ischemia/reperfusion injury of the hepatic graft, an unsolved problem in liver transplantations, is attributed to the release of inflammatory cytokines, especially the tumor necrosis factor- (TNF) α, from activated Kupffer cells (KC). Therefore, the specific inhibition of TNF-α could improve the viability of the hepatic graft upon reperfusion.: We assessed the efficacy of TNF-α antisense (TNF-AS) oligodeoxynucleotides (ODNs) delivery to KC in a rodent liver transplantation model. Results: Seventy-one percent of the animals that received 6 hours preserved grafts in baths of lactated Ringer's solution (4°C) and were treated with TNF-AS survived for over 14 days. Eighty percent of the animals treated with vehicle, sense ODNs, or balanced salt saline (BSS) died. Four hours after reperfusion of the liver, a significant reduction was noted in livers treated with TNF-AS in the release of cytosolic enzymes from the hepatocytes and the serum TNF-α (P<0.05). The expressions of TNF-α on KC and of intercellular adhesion molecule-1 on sinusoidal endothelial cells were completely suppressed in TNF-AS-treated livers. Conclusions: TNF-AS delivery improves the viability of the hepatic graft, and this technique may solve hepatic graft nonfunction in a clinical setting. © 2006 Blackwell Munksgaard.
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Baba H., Yonemitsu Y., Nakano T., Onimaru M., Miyazaki M., Ikeda Y., Sumiyoshi S., Ueda Y., Hasegawa M., Yoshino I., Maehara Y., Sueishi K.
Arteriosclerosis, Thrombosis, and Vascular Biology 25 ( 9 ) 1938 - 1944 2005年9月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Arteriosclerosis, Thrombosis, and Vascular Biology
Objective - To assess the expression and distribution of a neurotrophic/antiangiogenic factor, pigment epithelium-derived factor (PEDF), related to angiogenesis that is a possibly key event during atherogenesis in human atherosclerotic plaques. Methods and Results - Twenty fresh aortic samples were used for reverse-transcription polymerase chain reaction (RT-PCR), Western blot, and immunohistochemistry (IHC). In addition, 80 stocked paraffin blocks of coronary arteries from 40 autopsy cases were also used. IHC revealed divergent staining patterns for PEDF in both the aortas and the coronary arteries tested, ie, "cytoplasmic staining" or "extracellular deposition," were observed, respectively. In the areas showing cytoplasmic staining, double PEDF was expressed in a majority of the foamy macrophages and in some smooth muscle cells, and the PEDF-positive cell frequency was positively correlated with that of microvessels in a cell-rich area in the coronary arteries (P<0.0001). Inversely, extracellular deposition of PEDF was seen in acellular areas and was negatively correlated with the number of microvessels (P=0.0003). Conclusions - These results suggest that PEDF may function as an antiangiogenic factor when it is deposited onto the extracellular matrix. Thus, PEDF may play a significant role in determining the balance of angiogenesis/antiangiogenesis during atherogenesis. © 2005 American Heart Association, Inc.
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Abnormal retinal vascular development in IL-18 knockout mice 査読あり
Qiao H., Sonoda K., Sassa Y., Hisatomi T., Yoshikawa H., Ikeda Y., Murata T., Akira S., Ishibashi T.
Laboratory Investigation 84 ( 8 ) 973 - 980 2004年8月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Laboratory Investigation
Recent studies have indicated that interleukin 18 (IL-18) might act as either an angiogenic or an angiostatic factor, but the true function of this protein in vascular development is unclear. We therefore investigated the role of IL-18 in the formation of retinal vessels. Development of the retinal vasculature was compared in IL-18 knockout (KO) and wild-type (WT) mice at several different time points. The formation of vessels was evaluated using angiography of flat-mounted retinal samples after inoculation with fluorescein dextran. Retinal samples from both groups were also evaluated through histological examinations, and the expression of angiogenic factors was examined using the reverse-transcription-polymerase chain reaction. The capillary retinal vessels in both WT and IL-18 KO mice had reached the peripheral retina by postnatal day (P) 7. However, IL-18 KO mice showed angiectasis and vascular leakage at P7, especially in the mid-peripheral retina. These symptoms were not observed in WT mice at any stage. Histopathological analysis confirmed abnormal vascular formation in IL-18 KO mice at P14. Interestingly, these abnormalities regressed over time and had disappeared by P84. Several angiogenesis-associated factors, including vascular enclothelial growth factor (VEGF), basic fibroblast-growth factor (bFGF), platelet-derived growth factor (PDGF) and pigment epithelium-derived factor (PEDF), were overexpressed in the retinas of IL-18 KO mice compared with those of WT mice at P14. Interferon-γ was detected only in WT mouse retinas at P14. These results provide new evidence for the role of IL-18 in retinal vascular development.
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Miyazaki M., Ikeda Y., Yonemitsu Y., Goto Y., Sakamoto T., Tabata T., Ueda Y., Hasegawa M., Tobimatsu S., Ishibashi T., Sueishi K.
Gene Therapy 10 ( 17 ) 1503 - 1511 2003年8月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Gene Therapy
Retinitis pigmentosa (RP) is a heterogenous group of inherited retinal diseases resulting in adult blindness caused by mutations of various genes. Although it is difficult to cure the blindness that results from these diseases, delaying the disease progression may be of great benefit, since the majority of RP diseases are seen in middle age or later. To test a gene therapy strategy for RP using a neurotrophic factor gene, we assessed the effect of simian lentivirus (SIV)-mediated subretinal gene transfer of pigment epithelium-derived factor (PEDF), a potent neurotrophic factor, during the disease progression in Royal College of Surgeons (RCS) rats, a well-accepted animal model of RP. Regional gene transfer via SIV into the peripheral subretinal space at the nasal hemisphere was performed in all animals to monitor site-specific transgene expression as well as the therapeutic effect in each retina. Gene transfer of lacZ and PEDF was observed in the regional pigment epithelium corresponding to the regional gene transfer. Histologically, PEDF gene transfer significantly protected the loss of photoreceptor cells (PCs) corresponding to the regions of the gene transfer, compared to those of control groups during the course of the experiment. The antiapoptotic effect of PEDF on PCs is likely to be a related mechanism, because a significant reduction of terminal dUTP-nicked end labeling-positive PC numbers was found in PEDF-treated eyes compared to those of the control group (P < 0.05). PEDF-treated eyes also retained a significant sensitivity to light flash during the experimental course. These findings clearly show that neuroprotective gene therapy using PEDF can protect retinal degeneration and functional defects in individuals with RP.
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Ikeda Y., Goto Y., Yonemitsu Y., Miyazaki M., Sakamoto T., Ishibashi T., Tabata T., Ueda Y., Hasegawa M., Tobimatsu S., Sueishi K.
Gene Therapy 10 ( 14 ) 1161 - 1169 2003年7月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Gene Therapy
Although lentivirus vectors hold promise for ocular gene therapy, they also have potential safety issues, particularly in the case of the current human immunodeficiency virus-based vectors. We recently developed a novel lentivirus vector derived from the nonpathogenic simian immunodeficiency virus from African green monkeys (SIVagm) to minimize these potentials. In this preclinical study, we evaluated whether SIV vector could be efficiently and safely applicable to retinal gene transfer by assessing the transgene expression, retinal function and histology over a 1-year period following subretinal injection in adult rats. The functional assessment via electroretinogram after both titers of SIV-lacZ (2.5 × 107 or 2.5 × 108 transducing units/ml) injection revealed both the dark and light adaptations to soon be impaired, in a dose-dependent manner, after a buffer injection as well, and all of them recovered to the control range by day 30. In both titers tested, the retinas demonstrated a frequent transgene expression mainly in the retinal pigment epithelium; however, the other retinal cells rarely expressed the transgene. Retinas exposed to a low titer virus showed no significant inflammatory reaction throughout the observation period, and also maintained the transgene expression over a 1-year period. In the retinas exposed to a high titer virus, however, mononuclear cell infiltration persisted in the subretinal area, and the retina that corresponded to the injected area finally underwent degeneration by around day 90. No retinal neoplastic lesions could be found in any animals over the 1-year period. We thus propose that SIV-mediated stable gene transfer might be useful for ocular gene transfer, however, more attention should be paid to avoiding complications when administering high titer lentivirus to the retina.
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Anti-monocyte chemoattractant protein-1 gene therapy attenuates pulmonary hypertension in rats 査読あり
Ikeda Y., Yonemitsu Y., Kataoka C., Kitamoto S., Yamaoka T., Nishida K., Takeshita A., Egashira K., Sueishi K.
American Journal of Physiology - Heart and Circulatory Physiology 283 ( 5 52-5 ) 2002年11月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：American Journal of Physiology - Heart and Circulatory Physiology
Monocyte/macrophage chemoattractant protein-1 (MCP-1), a potent chemoattractant chemokine and an activator for mononuclear cells, may play a role in the initiation and/or progression of pulmonary hypertension (PH). To determine whether blockade of a systemic MCP-1 signal pathway in vivo may prevent PH, we intramuscularly transduced a naked plasmid encoding a 7-NH 2 terminus-deleted dominant negative inhibitor of the MCP-1 (7ND MCP-1) gene in monocrotaline-induced PH. We also simultaneously gave a duplicate transfection at 2-wk intervals or skeletal muscle-directed in vivo electroporation (EP) to evaluate whether a longer or higher expression might be more effective. The intramuscular reporter gene expression was enhanced 10 times over that by EP than by simple injection, and a significant 7ND MCP-1 protein in plasma was detected only in the EP group. 7ND MCP-1 gene transfer significantly inhibited the progression of MCT-induced PH as evaluated by right ventricular systolic pressure, right ventricular hypertrophy, medial hypertrophy of pulumonary arterioles, and mononuclear cell infiltration into the lung. Differential effects of longer or higher transgene expression were not apparent. Although the in vivo kinetics of 7ND MCP-1 gene therapy should be studied further, these encouraging results suggest that an anti-inflammatory strategy via blockade of the MCP-1 signal pathway may be an alternative approach to treat subjects with PH.
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Ikeda Y., Yonemitsu Y., Sakamoto T., Ishibashi T., Ueno H., Kato A., Nagai Y., Fukumura M., Inomata H., Hasegawa M., Sueishi K.
Experimental Eye Research 75 ( 1 ) 39 - 48 2002年
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Experimental Eye Research
To determine the usefulness of recombinant Sendai virus (SeV) for ocular gene transfer, the authors characterized SeV-mediated gene transfer to the retinal tissue of adult rats via subretinal injection. Recombinant SeV encoding the lacZ gene achieved frequent transgene expression in the retinal pigment epithelium (RPE) (mean = 38.76%), while gene transfer to other retinal cells was rare. These findings are similar to those of previous reports using adenoviruses. Peak reporter gene expression of SeV in cultured RPE cells was similar to that of adenovirus at the same titer; however, SeV achieved high levels of expression after a brief vector-cell contact time, while adenovirus required over 3 hr for efficient gene transfer. This finding was also observed in vivo following a brief SeV filling in the subretinal space, and may therefore provide a clinical advantage in avoiding retinal damage due to prolonged detachment. The observed SeV-mediated gene expression in the rat retina was transient. The initial phase of the decrease in luciferase activity could be prevented by daily eye drops of dexamethasone, suggesting that the corticosteroid-sensitive host reaction may affect early clearance of the virus. The late decline of transgene expression (2 weeks) was inhibited by the immunosuppressant, cyclosporin A, in a dose-dependent manner, suggesting that the cytotoxic T-lymphocyte response may be important in this phase. This work represents the first report of SeV-mediated gene transfer to ocular tissue, and identifies recombinant SeV as a new tool for studies of retinal gene transfer and gene therapy. © 2002 Elsevier Science Ltd.
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Gene targeting to the retina 査読あり
Sakamoto T., Ikeda Y., Yonemitsu Y.
Advanced Drug Delivery Reviews 52 ( 1 ) 93 - 102 2001年10月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Advanced Drug Delivery Reviews