Yimin Qin, Chengcheng Lei, Tianfeng Lin, Xiaotong Han, Decai Wang
Purpose: The purpose of this study was to identify potential drug targets for myopia and explore underlying mechanisms.
Methods: Mendelian randomization (MR) was implemented to assess the effect of 2684 pharmacologically targetable genes in the blood and retina on the risk of myopia from a genomewide association study (GWAS) for age-at-onset of spectacle wearing-inferred mean spherical equivalent (MSE; discovery cohort, N = 287,448, European), which was further validated in a GWAS for autorefraction-measured MSE (replication cohort, N = 95,619, European). The reliability of the identified significant potential targets was strengthened by colocalization analysis. Additionally, enrichment analysis, protein-protein interaction network, and molecular docking were performed to explore the functional roles and the druggability of these targets.
Results: This systematic drug target identification has unveiled 6 putative genetically causal targets for myopia-CD34, CD55, Wnt3, LCAT, BTN3A1, and TSSK6-each backed by colocalization evidence in adult blood eQTL datasets. Functional analysis found that dopaminergic neuron differentiation, cell adhesion, Wnt signaling pathway, and plasma lipoprotein-associated pathways may be involved in myopia pathogenesis. Finally, drug prediction and molecular docking corroborated the pharmacological value of these targets with LCAT demonstrating the strongest binding affinity.
Conclusions: Our study not only opens new avenues for the development of therapeutic interventions for myopia but may also help to understand the underlying mechanisms of myopia.
{"title":"Identification of Potential Drug Targets for Myopia Through Mendelian Randomization.","authors":"Yimin Qin, Chengcheng Lei, Tianfeng Lin, Xiaotong Han, Decai Wang","doi":"10.1167/iovs.65.10.13","DOIUrl":"10.1167/iovs.65.10.13","url":null,"abstract":"<p><strong>Purpose: </strong>The purpose of this study was to identify potential drug targets for myopia and explore underlying mechanisms.</p><p><strong>Methods: </strong>Mendelian randomization (MR) was implemented to assess the effect of 2684 pharmacologically targetable genes in the blood and retina on the risk of myopia from a genomewide association study (GWAS) for age-at-onset of spectacle wearing-inferred mean spherical equivalent (MSE; discovery cohort, N = 287,448, European), which was further validated in a GWAS for autorefraction-measured MSE (replication cohort, N = 95,619, European). The reliability of the identified significant potential targets was strengthened by colocalization analysis. Additionally, enrichment analysis, protein-protein interaction network, and molecular docking were performed to explore the functional roles and the druggability of these targets.</p><p><strong>Results: </strong>This systematic drug target identification has unveiled 6 putative genetically causal targets for myopia-CD34, CD55, Wnt3, LCAT, BTN3A1, and TSSK6-each backed by colocalization evidence in adult blood eQTL datasets. Functional analysis found that dopaminergic neuron differentiation, cell adhesion, Wnt signaling pathway, and plasma lipoprotein-associated pathways may be involved in myopia pathogenesis. Finally, drug prediction and molecular docking corroborated the pharmacological value of these targets with LCAT demonstrating the strongest binding affinity.</p><p><strong>Conclusions: </strong>Our study not only opens new avenues for the development of therapeutic interventions for myopia but may also help to understand the underlying mechanisms of myopia.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11314700/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Virginie Chotard, Francesco Trapani, Guilhem Glaziou, Berat Semihcan Sermet, Pierre Yger, Olivier Marre, Alexandra Rebsam
Purpose: Mammals with albinism present low visual discrimination ability and different proportions of certain retinal cell subtypes. As the spatial resolution of the retina depends on the visual field sampling by retinal ganglion cells (RGCs) based on the convergence of upstream cell inputs, it could be affected in albinism and thus modify the RGC function.
Methods: We used the Tyrc/c line, a mouse model of oculocutaneous albinism type 1 (OCA1), carrying a tyrosinase mutation, and previously characterized by a total absence of pigment and severe visual deficits. To assess their retinal function, we recorded the light responses of hundreds of RGCs ex vivo using multi-electrode array (MEA). We estimated the receptive field (RF)-center diameter of Tyr+/c and Tyrc/c RGCs using a checkerboard stimulation before simultaneously stimulating the center and surround of RGC RFs with full-field flashes.
Results: Following checkerboard stimulation, the RF-center diameters of RGCs were indistinguishable between Tyrc/c and Tyr+/c retinas. Nevertheless, RGCs from Tyrc/c retinas presented more OFF responses to full-field flashes than RGCs from Tyr+/c retinas. Unlike Tyr+/c retinas, very few OFF-center RGCs switched polarity to ON or ON-OFF responses after full-field flashes in Tyrc/c retinas, suggesting a different surround suppression in these retinas.
Conclusions: The retinal output signal is affected in Tyrc/c retinas, despite intact RF-center diameters of their RGCs. Adaptive mechanisms during development are probably responsible for this change in RGC responses, related to the absence of ocular pigments.
{"title":"Altered Functional Responses of the Retina in B6 Albino Tyrc/c Mice.","authors":"Virginie Chotard, Francesco Trapani, Guilhem Glaziou, Berat Semihcan Sermet, Pierre Yger, Olivier Marre, Alexandra Rebsam","doi":"10.1167/iovs.65.10.39","DOIUrl":"10.1167/iovs.65.10.39","url":null,"abstract":"<p><strong>Purpose: </strong>Mammals with albinism present low visual discrimination ability and different proportions of certain retinal cell subtypes. As the spatial resolution of the retina depends on the visual field sampling by retinal ganglion cells (RGCs) based on the convergence of upstream cell inputs, it could be affected in albinism and thus modify the RGC function.</p><p><strong>Methods: </strong>We used the Tyrc/c line, a mouse model of oculocutaneous albinism type 1 (OCA1), carrying a tyrosinase mutation, and previously characterized by a total absence of pigment and severe visual deficits. To assess their retinal function, we recorded the light responses of hundreds of RGCs ex vivo using multi-electrode array (MEA). We estimated the receptive field (RF)-center diameter of Tyr+/c and Tyrc/c RGCs using a checkerboard stimulation before simultaneously stimulating the center and surround of RGC RFs with full-field flashes.</p><p><strong>Results: </strong>Following checkerboard stimulation, the RF-center diameters of RGCs were indistinguishable between Tyrc/c and Tyr+/c retinas. Nevertheless, RGCs from Tyrc/c retinas presented more OFF responses to full-field flashes than RGCs from Tyr+/c retinas. Unlike Tyr+/c retinas, very few OFF-center RGCs switched polarity to ON or ON-OFF responses after full-field flashes in Tyrc/c retinas, suggesting a different surround suppression in these retinas.</p><p><strong>Conclusions: </strong>The retinal output signal is affected in Tyrc/c retinas, despite intact RF-center diameters of their RGCs. Adaptive mechanisms during development are probably responsible for this change in RGC responses, related to the absence of ocular pigments.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11361382/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kelleigh Hogan, Xiangqin Cui, Annette Giangiacomo, Andrew J Feola
Purpose: Hormonal therapy (HT) has been suggested to lower the risk of developing glaucoma. Our goal was to investigate the association between HT use and the onset of glaucoma diagnosis in postmenopausal women.
Methods: This retrospective case-only study included female veterans with open-angle glaucoma from VA records between 2000 to 2019. Propensity score matching was used to match HT (n = 1926) users to untreated (n = 1026) women on multiple covariates (e.g., age of menopause, BMI, blood pressure, antihypertensive medications, and a co-morbidity index). A simple linear regression was used to evaluate the impact of HT duration on the age of glaucoma diagnosis, and multivariate linear regression analysis was used to determine which factors contributed to the age at diagnosis of glaucoma.
Results: We found a linear relationship between the age at diagnosis of glaucoma and menopause in women with (r = 0.54) and without HT (r = 0.57) use. HT users tended to have a later diagnosis of glaucoma. Our multivariate analysis found that 0-2 years, 2-5 years, and >5 years of HT use were associated with a 2.20 [confidence interval (CI), 1.64, 2.76], 3.74 [CI, 3.02, 4.46], and 4.51 [CI, 3.84, 5.18] years later diagnosis of glaucoma. An interaction (-0.009 [-0.015, -0.003]) was observed between HT duration and age of menopause diagnosis, with the impact of HT decreasing for later menopause ages.
Conclusions: Longer duration of HT use was associated with a later diagnosis of glaucoma in postmenopausal women in this case-only analysis. The impact of HT may be modulated by menopausal age, although further study is needed. The findings support a protective role of estrogen in glaucoma pathogenesis.
{"title":"Postmenopausal Hormone Therapy Was Associated With Later Age of Onset Among Glaucoma Cases.","authors":"Kelleigh Hogan, Xiangqin Cui, Annette Giangiacomo, Andrew J Feola","doi":"10.1167/iovs.65.10.31","DOIUrl":"10.1167/iovs.65.10.31","url":null,"abstract":"<p><strong>Purpose: </strong>Hormonal therapy (HT) has been suggested to lower the risk of developing glaucoma. Our goal was to investigate the association between HT use and the onset of glaucoma diagnosis in postmenopausal women.</p><p><strong>Methods: </strong>This retrospective case-only study included female veterans with open-angle glaucoma from VA records between 2000 to 2019. Propensity score matching was used to match HT (n = 1926) users to untreated (n = 1026) women on multiple covariates (e.g., age of menopause, BMI, blood pressure, antihypertensive medications, and a co-morbidity index). A simple linear regression was used to evaluate the impact of HT duration on the age of glaucoma diagnosis, and multivariate linear regression analysis was used to determine which factors contributed to the age at diagnosis of glaucoma.</p><p><strong>Results: </strong>We found a linear relationship between the age at diagnosis of glaucoma and menopause in women with (r = 0.54) and without HT (r = 0.57) use. HT users tended to have a later diagnosis of glaucoma. Our multivariate analysis found that 0-2 years, 2-5 years, and >5 years of HT use were associated with a 2.20 [confidence interval (CI), 1.64, 2.76], 3.74 [CI, 3.02, 4.46], and 4.51 [CI, 3.84, 5.18] years later diagnosis of glaucoma. An interaction (-0.009 [-0.015, -0.003]) was observed between HT duration and age of menopause diagnosis, with the impact of HT decreasing for later menopause ages.</p><p><strong>Conclusions: </strong>Longer duration of HT use was associated with a later diagnosis of glaucoma in postmenopausal women in this case-only analysis. The impact of HT may be modulated by menopausal age, although further study is needed. The findings support a protective role of estrogen in glaucoma pathogenesis.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11346078/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Benjamin J Wendel, Vimal Prabhu Pandiyan, Teng Liu, Xiaoyun Jiang, Ayoub Lassoued, Emily Slezak, Sierra Schleufer, Palash Bharadwaj, William S Tuten, Debarshi Mustafi, Jennifer R Chao, Ramkumar Sabesan
Purpose: Retinitis pigmentosa (RP), the most common inherited retinal disease, is characterized by progressive photoreceptor degeneration. It remains unknown to what extent surviving photoreceptors transduce light and support vision in RP. To address this, we correlated structure and functional measures using adaptive optics scanning laser ophthalmoscopy (AOSLO), adaptive optics microperimetry, and adaptive optics optical coherence tomography (AO-OCT)-based optoretinograms (ORGs).
Methods: Four patients with RP were imaged with AOSLO across the visual field covering the transition zone (TZ) of normal to diseased retina. Cone density was estimated in discrete regions spanning the TZ. Visual sensitivity was assessed by measuring increment thresholds for a 3-arcmin stimulus targeted via active eye tracking in AOSLO. ORGs were measured at the same locations using AO-OCT to assess the cones' functional response to a 528 ± 20-nm stimulus. Individual cone outer segment (COS) lengths were measured from AO-OCT in each subject.
Results: Cone density was significantly reduced in patients with RP. Density reduction correlated with TZ location in 3 patients with RP, while a fourth had patches of reduced density throughout the retina. ORG amplitude was reduced in regions of normal and reduced cone density in all patients with RP. ORG response and COS length were positively correlated in controls but not in patients with RP. Despite deficits in cone density and ORG, visual sensitivity remained comparable to controls in three of four patients with RP.
Conclusions: ORG-based measures of retinal dysfunction may precede deficits in cone structure and visual sensitivity. ORG is a sensitive measure of RP disease status and has significant potential to provide insight into disease progression and treatment efficacy.
目的视网膜色素变性(RP)是最常见的遗传性视网膜疾病,其特征是进行性感光细胞变性。目前仍不清楚在 RP 中存活的光感受器能在多大程度上传递光线并支持视力。为了解决这个问题,我们使用自适应光学扫描激光眼底镜(AOSLO)、自适应光学显微测距仪和基于自适应光学光学相干断层扫描(AO-OCT)的视网膜图(ORGs)对结构和功能进行了相关测量:方法:用自适应光学光学相干断层扫描(AO-OCT)对四名视网膜病变患者的正常视网膜向病变视网膜过渡区(TZ)的整个视野进行成像。在跨越 TZ 的离散区域估算锥体密度。通过在 AOSLO 中进行主动眼球跟踪,测量 3 分米刺激目标的增量阈值,从而评估视觉灵敏度。使用 AO-OCT 在相同位置测量视网膜视网膜外节(ORG),以评估锥体对 528 ± 20 纳米刺激的功能反应。通过 AO-OCT 测量每个受试者的锥体外节(COS)长度:结果:RP 患者的锥体密度明显降低。在 3 名 RP 患者中,密度降低与 TZ 位置相关,第四名患者的整个视网膜上都有密度降低的斑块。在所有 RP 患者中,视锥密度正常和降低区域的 ORG 振幅均减小。在对照组中,ORG 反应和 COS 长度呈正相关,但在 RP 患者中却不相关。尽管视锥密度和 ORG 存在缺陷,但四名 RP 患者中有三人的视觉灵敏度仍与对照组相当:结论:基于视网膜功能障碍的ORG测量可能先于视锥结构和视觉灵敏度的缺陷。ORG是衡量RP疾病状态的灵敏指标,在深入了解疾病进展和治疗效果方面具有巨大潜力。
{"title":"Multimodal High-Resolution Imaging in Retinitis Pigmentosa: A Comparison Between Optoretinography, Cone Density, and Visual Sensitivity.","authors":"Benjamin J Wendel, Vimal Prabhu Pandiyan, Teng Liu, Xiaoyun Jiang, Ayoub Lassoued, Emily Slezak, Sierra Schleufer, Palash Bharadwaj, William S Tuten, Debarshi Mustafi, Jennifer R Chao, Ramkumar Sabesan","doi":"10.1167/iovs.65.10.45","DOIUrl":"10.1167/iovs.65.10.45","url":null,"abstract":"<p><strong>Purpose: </strong>Retinitis pigmentosa (RP), the most common inherited retinal disease, is characterized by progressive photoreceptor degeneration. It remains unknown to what extent surviving photoreceptors transduce light and support vision in RP. To address this, we correlated structure and functional measures using adaptive optics scanning laser ophthalmoscopy (AOSLO), adaptive optics microperimetry, and adaptive optics optical coherence tomography (AO-OCT)-based optoretinograms (ORGs).</p><p><strong>Methods: </strong>Four patients with RP were imaged with AOSLO across the visual field covering the transition zone (TZ) of normal to diseased retina. Cone density was estimated in discrete regions spanning the TZ. Visual sensitivity was assessed by measuring increment thresholds for a 3-arcmin stimulus targeted via active eye tracking in AOSLO. ORGs were measured at the same locations using AO-OCT to assess the cones' functional response to a 528 ± 20-nm stimulus. Individual cone outer segment (COS) lengths were measured from AO-OCT in each subject.</p><p><strong>Results: </strong>Cone density was significantly reduced in patients with RP. Density reduction correlated with TZ location in 3 patients with RP, while a fourth had patches of reduced density throughout the retina. ORG amplitude was reduced in regions of normal and reduced cone density in all patients with RP. ORG response and COS length were positively correlated in controls but not in patients with RP. Despite deficits in cone density and ORG, visual sensitivity remained comparable to controls in three of four patients with RP.</p><p><strong>Conclusions: </strong>ORG-based measures of retinal dysfunction may precede deficits in cone structure and visual sensitivity. ORG is a sensitive measure of RP disease status and has significant potential to provide insight into disease progression and treatment efficacy.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11364184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142107451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jungeun Won, Hiroyuki Takahashi, Stefan B Ploner, Wenke Karbole, Omar Abu-Qamar, Antonio Yaghy, Anna Marmalidou, Stephanie Kaiser, Yunchan Hwang, Junhong Lin, Andre Witkin, Shilpa Desai, Caroline R Baumal, Andreas Maier, Christine A Curcio, Nadia K Waheed, James G Fujimoto
Purpose: A micrometer scale hyporeflective band within the retinal pigment epithelium basal lamina - Bruch's membrane complex (RPE-BL-BrM) was topographically measured in aging and age-related macular degeneration (AMD).
Methods: In a prospective cross-sectional study, 90 normal eyes from 76 subjects (range = 23-90 years) and 53 dry AMD eyes from 47 subjects (range = 62-91 years) were enrolled. Isotropic volume raster scans over 6 mm × 6 mm (500 × 500 A-scans) were acquired using a high-resolution (2.7 µm axial resolution) spectral-domain optical coherence tomography (SD-OCT) prototype instrument. Six consecutive optical coherence tomography (OCT) volumes were computationally motion-corrected and fused to improve feature visibility. A boundary regression neural network was developed to measure hyporeflective band thickness. Topographic dependence was evaluated over a 6-mm-diameter Early Treatment Diabetic Retinopathy Study (ETDRS) grid.
Results: The hyporeflective band thickness map (median of 4.3 µm and 7.8 µm in normal and AMD eyes, respectively) is thicker below and radially symmetric around the fovea. In normal eyes, age-associated differences occur within 0.7 to 2.3 mm from the foveal center (P < 0.05). In AMD eyes, the hyporeflective band is hypothesized to be basal laminar deposits (BLamDs) and is thicker within the 3-mm ETDRS circle (P < 0.0002) compared with normal eyes. The inner ring is the most sensitive location to detect age versus AMD-associated changes within the RPE-BL-BrM. AMD eyes with subretinal drusenoid deposits (SDDs) have a significantly thicker hyporeflective band (P < 0.001) than those without SDDs.
Conclusions: The hyporeflective band is a quantifiable biomarker which differentiates AMD from aging. Longitudinal studies are warranted. The hyporeflective band may be a useful biomarker for risk stratification and disease progression.
{"title":"Topographic Measurement of the Subretinal Pigment Epithelium Space in Normal Aging and Age-Related Macular Degeneration Using High-Resolution OCT.","authors":"Jungeun Won, Hiroyuki Takahashi, Stefan B Ploner, Wenke Karbole, Omar Abu-Qamar, Antonio Yaghy, Anna Marmalidou, Stephanie Kaiser, Yunchan Hwang, Junhong Lin, Andre Witkin, Shilpa Desai, Caroline R Baumal, Andreas Maier, Christine A Curcio, Nadia K Waheed, James G Fujimoto","doi":"10.1167/iovs.65.10.18","DOIUrl":"10.1167/iovs.65.10.18","url":null,"abstract":"<p><strong>Purpose: </strong>A micrometer scale hyporeflective band within the retinal pigment epithelium basal lamina - Bruch's membrane complex (RPE-BL-BrM) was topographically measured in aging and age-related macular degeneration (AMD).</p><p><strong>Methods: </strong>In a prospective cross-sectional study, 90 normal eyes from 76 subjects (range = 23-90 years) and 53 dry AMD eyes from 47 subjects (range = 62-91 years) were enrolled. Isotropic volume raster scans over 6 mm × 6 mm (500 × 500 A-scans) were acquired using a high-resolution (2.7 µm axial resolution) spectral-domain optical coherence tomography (SD-OCT) prototype instrument. Six consecutive optical coherence tomography (OCT) volumes were computationally motion-corrected and fused to improve feature visibility. A boundary regression neural network was developed to measure hyporeflective band thickness. Topographic dependence was evaluated over a 6-mm-diameter Early Treatment Diabetic Retinopathy Study (ETDRS) grid.</p><p><strong>Results: </strong>The hyporeflective band thickness map (median of 4.3 µm and 7.8 µm in normal and AMD eyes, respectively) is thicker below and radially symmetric around the fovea. In normal eyes, age-associated differences occur within 0.7 to 2.3 mm from the foveal center (P < 0.05). In AMD eyes, the hyporeflective band is hypothesized to be basal laminar deposits (BLamDs) and is thicker within the 3-mm ETDRS circle (P < 0.0002) compared with normal eyes. The inner ring is the most sensitive location to detect age versus AMD-associated changes within the RPE-BL-BrM. AMD eyes with subretinal drusenoid deposits (SDDs) have a significantly thicker hyporeflective band (P < 0.001) than those without SDDs.</p><p><strong>Conclusions: </strong>The hyporeflective band is a quantifiable biomarker which differentiates AMD from aging. Longitudinal studies are warranted. The hyporeflective band may be a useful biomarker for risk stratification and disease progression.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11318361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141906662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Purpose: The most common method of delivery of genes to the outer retina uses recombinant adeno-associated virus (AAV) injected into the subretinal space using a surgical procedure. In contrast, most drugs are delivered to the retina using an intravitreal approach in an office setting. The objective of the current study was to develop AAV vectors that can reach the outer retina via intravitreal injection.
Methods: Recently, we described a molecular chaperone (Nuc1) that enhanced the penetration of small and large molecules, including AAV, into the retina. The Nuc1 amino acid sequence or a truncated version of Nuc1 (IKV) was genetically incorporated into an exposed loop of AAV2/9 VP1 protein. These novel recombinant AAV vectors expressing green fluorescent protein (GFP) or nuclear factor erythroid 2 p45-related factor 2 (Nrf2) were injected into the vitreous of C57Bl/6J or Nrf2 knockout mice, respectively. The amount of GFP expression or oxidative stress as measured by 8-Hydroxy-2'-deoxyguanosine staining in C57Bl/6J or Nrf2 knockout mice, respectively, was quantified.
Results: Incorporation of Nuc1 into AAV2/9 did not lead to significant expression of GFP in the murine retina. However, incorporation of IKV into AAV2/9 led to robust expression of GFP in photoreceptors and retinal pigment epithelium (RPE) via the intravitreal and subretinal routes of delivery. Furthermore, expression of Nrf2 using an IKV vector led to a reduction in oxidative stress in the retina of C57Bl/6J and Nrf2 knockout mice.
Conclusions: We have developed a novel AAV vector that enables delivery of transgenes to the outer retina of mice, including photoreceptors and RPE following intravitreal injection.
{"title":"Retinal Penetrating Adeno-Associated Virus.","authors":"Binit Kumar, Manish Mishra, Siobhan Cashman, Rajendra Kumar-Singh","doi":"10.1167/iovs.65.10.30","DOIUrl":"10.1167/iovs.65.10.30","url":null,"abstract":"<p><strong>Purpose: </strong>The most common method of delivery of genes to the outer retina uses recombinant adeno-associated virus (AAV) injected into the subretinal space using a surgical procedure. In contrast, most drugs are delivered to the retina using an intravitreal approach in an office setting. The objective of the current study was to develop AAV vectors that can reach the outer retina via intravitreal injection.</p><p><strong>Methods: </strong>Recently, we described a molecular chaperone (Nuc1) that enhanced the penetration of small and large molecules, including AAV, into the retina. The Nuc1 amino acid sequence or a truncated version of Nuc1 (IKV) was genetically incorporated into an exposed loop of AAV2/9 VP1 protein. These novel recombinant AAV vectors expressing green fluorescent protein (GFP) or nuclear factor erythroid 2 p45-related factor 2 (Nrf2) were injected into the vitreous of C57Bl/6J or Nrf2 knockout mice, respectively. The amount of GFP expression or oxidative stress as measured by 8-Hydroxy-2'-deoxyguanosine staining in C57Bl/6J or Nrf2 knockout mice, respectively, was quantified.</p><p><strong>Results: </strong>Incorporation of Nuc1 into AAV2/9 did not lead to significant expression of GFP in the murine retina. However, incorporation of IKV into AAV2/9 led to robust expression of GFP in photoreceptors and retinal pigment epithelium (RPE) via the intravitreal and subretinal routes of delivery. Furthermore, expression of Nrf2 using an IKV vector led to a reduction in oxidative stress in the retina of C57Bl/6J and Nrf2 knockout mice.</p><p><strong>Conclusions: </strong>We have developed a novel AAV vector that enables delivery of transgenes to the outer retina of mice, including photoreceptors and RPE following intravitreal injection.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11346080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zhihui She, Krista M Beach, Li-Fang Hung, Lisa A Ostrin, Earl L Smith, Nimesh B Patel
Purpose: The purpose of this study was to determine the effects of axial elongation on optic nerve head morphology and macula inner retinal thickness in young rhesus monkeys.
Methods: Both eyes of 26 anisometropic, 1-year-old rhesus monkeys were imaged using optical coherence tomography (OCT). Before imaging, the animals were sedated, their eyes were dilated, and axial length was measured using an optical biometer. OCT imaging included a 20 degrees, 24-line radial scan centered on the optic nerve head (ONH) and two 20 degrees × 20 degrees raster scans, one centered on the ONH and the other on the macula. Radial scans were analyzed using programs written in MATLAB to quantify the Bruch's membrane opening (BMO) area and position, minimum rim width (MRW), anterior lamina cribrosa surface (ALCS) position, size of any scleral crescent, circumpapillary retinal nerve fiber layer (RNFL), and choroid thickness (pCh). Macula total retinal thickness (mTRT) and ganglion cell inner plexiform layer (GCIPL) thicknesses were quantified from macula scans. Linear least square regression was determined for OCT measures and axial length of the right eye, and for inter-eye differences.
Results: Animals were 341 ± 18 days old at the time of imaging. BMO area (R2 = 0.38), ALCS position (R2 = 0.45), scleral crescent area (R2 = 0.35), pCh thickness (R2 = 0.21), mTRT (R2 = 0.24), and GCIPL thickness (R2 = 0.16) were correlated with the axial length (all P < 0.05). For each of these parameters, the right-eye regression slope did not differ from the slope of the interocular difference (P > 0.57).
Conclusions: There are posterior segment morphological differences in anisometropic rhesus monkeys related to axial length. Whether these differences increase the risk of pathology remains to be investigated.
{"title":"Optic Nerve Head Morphology and Macula Ganglion Cell Inner Plexiform Layer Thickness in Axially Anisometropic Rhesus Monkeys.","authors":"Zhihui She, Krista M Beach, Li-Fang Hung, Lisa A Ostrin, Earl L Smith, Nimesh B Patel","doi":"10.1167/iovs.65.10.44","DOIUrl":"10.1167/iovs.65.10.44","url":null,"abstract":"<p><strong>Purpose: </strong>The purpose of this study was to determine the effects of axial elongation on optic nerve head morphology and macula inner retinal thickness in young rhesus monkeys.</p><p><strong>Methods: </strong>Both eyes of 26 anisometropic, 1-year-old rhesus monkeys were imaged using optical coherence tomography (OCT). Before imaging, the animals were sedated, their eyes were dilated, and axial length was measured using an optical biometer. OCT imaging included a 20 degrees, 24-line radial scan centered on the optic nerve head (ONH) and two 20 degrees × 20 degrees raster scans, one centered on the ONH and the other on the macula. Radial scans were analyzed using programs written in MATLAB to quantify the Bruch's membrane opening (BMO) area and position, minimum rim width (MRW), anterior lamina cribrosa surface (ALCS) position, size of any scleral crescent, circumpapillary retinal nerve fiber layer (RNFL), and choroid thickness (pCh). Macula total retinal thickness (mTRT) and ganglion cell inner plexiform layer (GCIPL) thicknesses were quantified from macula scans. Linear least square regression was determined for OCT measures and axial length of the right eye, and for inter-eye differences.</p><p><strong>Results: </strong>Animals were 341 ± 18 days old at the time of imaging. BMO area (R2 = 0.38), ALCS position (R2 = 0.45), scleral crescent area (R2 = 0.35), pCh thickness (R2 = 0.21), mTRT (R2 = 0.24), and GCIPL thickness (R2 = 0.16) were correlated with the axial length (all P < 0.05). For each of these parameters, the right-eye regression slope did not differ from the slope of the interocular difference (P > 0.57).</p><p><strong>Conclusions: </strong>There are posterior segment morphological differences in anisometropic rhesus monkeys related to axial length. Whether these differences increase the risk of pathology remains to be investigated.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11364186/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142107452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pam A T Heutinck, L Ingeborgh van den Born, Maikel Vermeer, Adriana I Iglesias Gonzales, Carel B Hoyng, Jan Willem R Pott, Hester Y Kroes, Mary J van Schooneveld, Camiel J F Boon, Maria M van Genderen, Astrid S Plomp, Yvonne de Jong-Hesse, Michelle B van Egmond-Ebbeling, Lies H Hoefsloot, Arthur A Bergen, Caroline C W Klaver, Magda A Meester-Smoor, Alberta A H J Thiadens, Virginie J M Verhoeven
Purpose: Gene-based therapies for inherited retinal dystrophies (IRDs) are upcoming. Treatment before substantial vision loss will optimize outcomes. It is crucial to identify common phenotypes and causative genes in children. This study investigated the frequency of these in pediatric IRD with the aim of highlighting relevant groups for future therapy.
Methods: Diagnostic, genetic, and demographic data, collected from medical charts of patients with IRD aged up to 20 years (n = 624, 63% male), registered in the Dutch RD5000 database, were analyzed to determine frequencies of phenotypes and genetic causes. Phenotypes were categorized as nonsyndromic (progressive and stationary IRD) and syndromic IRD. Genetic causes, mostly determined by whole-exome sequencing (WES), were examined. Additionally, we investigated the utility of periodic reanalysis of WES data in genetically unresolved cases.
Results: Median age at registration was 13 years (interquartile range, 9-16). Retinitis pigmentosa (RP; n = 123, 20%), Leber congenital amaurosis (LCA; n = 97, 16%), X-linked retinoschisis (n = 64, 10%), and achromatopsia (n = 63, 10%) were the most frequent phenotypes. The genetic cause was identified in 76% of the genetically examined patients (n = 473). The most frequently disease-causing genes were RS1 (n = 32, 9%), CEP290 (n = 28, 8%), CNGB3 (n = 21, 6%), and CRB1 (n = 17, 5%). Diagnostic yield after reanalysis of genetic data increased by 7%.
Conclusions: As in most countries, RP and LCA are the most prominent pediatric IRDs in the Netherlands, and variants in RS1 and CEP290 were the most prominent IRD genotypes. Our findings can guide therapy development to target the diseases and genes with the greatest needs in young patients.
{"title":"Frequency and Genetic Spectrum of Inherited Retinal Dystrophies in a Large Dutch Pediatric Cohort: The RD5000 Consortium.","authors":"Pam A T Heutinck, L Ingeborgh van den Born, Maikel Vermeer, Adriana I Iglesias Gonzales, Carel B Hoyng, Jan Willem R Pott, Hester Y Kroes, Mary J van Schooneveld, Camiel J F Boon, Maria M van Genderen, Astrid S Plomp, Yvonne de Jong-Hesse, Michelle B van Egmond-Ebbeling, Lies H Hoefsloot, Arthur A Bergen, Caroline C W Klaver, Magda A Meester-Smoor, Alberta A H J Thiadens, Virginie J M Verhoeven","doi":"10.1167/iovs.65.10.40","DOIUrl":"10.1167/iovs.65.10.40","url":null,"abstract":"<p><strong>Purpose: </strong>Gene-based therapies for inherited retinal dystrophies (IRDs) are upcoming. Treatment before substantial vision loss will optimize outcomes. It is crucial to identify common phenotypes and causative genes in children. This study investigated the frequency of these in pediatric IRD with the aim of highlighting relevant groups for future therapy.</p><p><strong>Methods: </strong>Diagnostic, genetic, and demographic data, collected from medical charts of patients with IRD aged up to 20 years (n = 624, 63% male), registered in the Dutch RD5000 database, were analyzed to determine frequencies of phenotypes and genetic causes. Phenotypes were categorized as nonsyndromic (progressive and stationary IRD) and syndromic IRD. Genetic causes, mostly determined by whole-exome sequencing (WES), were examined. Additionally, we investigated the utility of periodic reanalysis of WES data in genetically unresolved cases.</p><p><strong>Results: </strong>Median age at registration was 13 years (interquartile range, 9-16). Retinitis pigmentosa (RP; n = 123, 20%), Leber congenital amaurosis (LCA; n = 97, 16%), X-linked retinoschisis (n = 64, 10%), and achromatopsia (n = 63, 10%) were the most frequent phenotypes. The genetic cause was identified in 76% of the genetically examined patients (n = 473). The most frequently disease-causing genes were RS1 (n = 32, 9%), CEP290 (n = 28, 8%), CNGB3 (n = 21, 6%), and CRB1 (n = 17, 5%). Diagnostic yield after reanalysis of genetic data increased by 7%.</p><p><strong>Conclusions: </strong>As in most countries, RP and LCA are the most prominent pediatric IRDs in the Netherlands, and variants in RS1 and CEP290 were the most prominent IRD genotypes. Our findings can guide therapy development to target the diseases and genes with the greatest needs in young patients.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11361385/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Purpose: Keratoconus (KC), characterized by progressive corneal protrusion and thinning, is a complex disease influenced by the combination of genetic and environmental factors. The purpose of this study was to explore potential gene‒environment interaction between the calpastatin (CAST) gene and eye-rubbing in KC.
Methods: A case-only study including 930 patients (676 patients with eye-rubbing and 254 patients without eye-rubbing) from the Chinese Keratoconus (CKC) cohort study was performed in the present study. Genotyping of single nucleotide polymorphism (SNP) was conducted using the Illumina Infinium Human Asian Screening Array (ASA) Beadchip. The gene‒environment interactions between CAST gene and eye-rubbing were analyzed using PLINK version 1.90. The interactions between CAST genotypes and eye-rubbing were analyzed by logistic regression models. The SNP-SNP-environment interactions were analyzed using generalized multifactor dimensionality reduction (GMDR).
Results: Three SNPs in CAST gene, namely, rs26515, rs27991, and rs9314177, reached the significance threshold for interactions (defined as P < 2.272 × 10-3). Notably, the minor alleles of these three SNPs exhibited negative interactions with eye-rubbing in KC. The results of logistic regression models revealed that the minor allele homozygotes and heterozygotes of rs26515, rs27991, and rs9314177 also exhibited negative interactions with eye-rubbing. Furthermore, GMDR analysis revealed the significant SNP-SNP-environment interactions among rs26515, rs27991, rs9314177, and eye-rubbing in KC.
Conclusions: This study identified rs26515, rs27991, and rs9314177 in CAST gene existed gene-environment interactions with eye-rubbing in KC, which is highly important for understanding the underlying biological mechanisms of KC and guiding precision prevention and proper management.
{"title":"Gene‒Environment Interaction Between CAST Gene and Eye-Rubbing in the Chinese Keratoconus Cohort Study: A Case-Only Study.","authors":"Shanshan Yin, Liyan Xu, Kaili Yang, Qi Fan, Yuwei Gu, Chenchen Yin, Yonghao Zang, Yifan Wang, Yi Yuan, Anqi Chang, Chenjiu Pang, Shengwei Ren","doi":"10.1167/iovs.65.10.36","DOIUrl":"10.1167/iovs.65.10.36","url":null,"abstract":"<p><strong>Purpose: </strong>Keratoconus (KC), characterized by progressive corneal protrusion and thinning, is a complex disease influenced by the combination of genetic and environmental factors. The purpose of this study was to explore potential gene‒environment interaction between the calpastatin (CAST) gene and eye-rubbing in KC.</p><p><strong>Methods: </strong>A case-only study including 930 patients (676 patients with eye-rubbing and 254 patients without eye-rubbing) from the Chinese Keratoconus (CKC) cohort study was performed in the present study. Genotyping of single nucleotide polymorphism (SNP) was conducted using the Illumina Infinium Human Asian Screening Array (ASA) Beadchip. The gene‒environment interactions between CAST gene and eye-rubbing were analyzed using PLINK version 1.90. The interactions between CAST genotypes and eye-rubbing were analyzed by logistic regression models. The SNP-SNP-environment interactions were analyzed using generalized multifactor dimensionality reduction (GMDR).</p><p><strong>Results: </strong>Three SNPs in CAST gene, namely, rs26515, rs27991, and rs9314177, reached the significance threshold for interactions (defined as P < 2.272 × 10-3). Notably, the minor alleles of these three SNPs exhibited negative interactions with eye-rubbing in KC. The results of logistic regression models revealed that the minor allele homozygotes and heterozygotes of rs26515, rs27991, and rs9314177 also exhibited negative interactions with eye-rubbing. Furthermore, GMDR analysis revealed the significant SNP-SNP-environment interactions among rs26515, rs27991, rs9314177, and eye-rubbing in KC.</p><p><strong>Conclusions: </strong>This study identified rs26515, rs27991, and rs9314177 in CAST gene existed gene-environment interactions with eye-rubbing in KC, which is highly important for understanding the underlying biological mechanisms of KC and guiding precision prevention and proper management.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11361386/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Peer Review in Ophthalmology: A Collaborative Approach to Training the Next Generation of Reviewers.","authors":"Matilda F Chan","doi":"10.1167/iovs.65.10.1","DOIUrl":"10.1167/iovs.65.10.1","url":null,"abstract":"","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11305435/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141859795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}