Pub Date : 2024-12-01Epub Date: 2024-10-23DOI: 10.1089/jop.2024.0084
Adnan Dibas, Subrata Batabyal, Sanghoon Kim, Michael Carlson, Samarendra Mohanty, Najam A Sharif
Purpose: Leber congenital amaurosis (LCA) is a sight-threatening inherited retinal disorder (IRD) caused by numerous genetic mutations. Multi-characteristic opsin (MCO)-based optogenetic therapy allows the recruitment of residual cells of the retina in LCA for alternative vision transduction while being mutation-agnostic. Using rd12 mice, we investigated the in vivo efficacy of an adeno-associated virus2 (AAV2)-transduced ambient light-activatable MCO (MCO-010) containing a metabotropic glutamate receptor-6 bipolar cell-specific promoter/enhancer. Methods: Mice requiring > 40 s to reach and board a dimly lit hidden platform in a water-maze were selected and randomly divided into 2 cohorts. These mice were intravitreally (IVT) injected with either 1.7E9 gene copies/eye of MCO-010 or control AAV2 and re-tested in the water-maze. Spectral-domain optical coherence tomography (SD-OCT), hematoxylin and eosin staining of retinas, and electroretinographic (ERG) studies were also conducted. Results: Safety of MCO-010 in rd12 mice was confirmed by the lack of significant detrimental changes in the mouse behavior, b-wave amplitudes and in retinal thickness. rd12 control mice performed relatively poorly in the water-maze test requiring ≥ 30-60 s to find and board the platform. MCO-010-treated rd12 mice reached the platform much faster than the AAV2-treated rd12 mice, with some mice only requiring < 5 s to achieve this goal (P < 0.01-0.0024). Conclusions: IVT MCO-010 treatment was well tolerated by rd12 mice, and it prevented the decrease in retinal thickness, and preserved ERG parameters. It also significantly improved the vision in rd12 mice relative to control AAV2-injected mice. MCO-010 therefore represents a novel and efficacious optogenetic therapeutic to treat LCA and other IRDs irrespective of the genetic defect(s).
{"title":"Efficacy of Intravitreal Multi-Characteristic Opsin (MCO-010) Optogenetic Gene Therapy in a Mouse Model of Leber Congenital Amaurosis.","authors":"Adnan Dibas, Subrata Batabyal, Sanghoon Kim, Michael Carlson, Samarendra Mohanty, Najam A Sharif","doi":"10.1089/jop.2024.0084","DOIUrl":"10.1089/jop.2024.0084","url":null,"abstract":"<p><p><b><i>Purpose:</i></b> Leber congenital amaurosis (LCA) is a sight-threatening inherited retinal disorder (IRD) caused by numerous genetic mutations. Multi-characteristic opsin (MCO)-based optogenetic therapy allows the recruitment of residual cells of the retina in LCA for alternative vision transduction while being mutation-agnostic. Using <i>rd12</i> mice, we investigated the <i>in vivo</i> efficacy of an adeno-associated virus2 (AAV2)-transduced ambient light-activatable MCO (MCO-010) containing a metabotropic glutamate receptor-6 bipolar cell-specific promoter/enhancer. <b><i>Methods:</i></b> Mice requiring > 40 s to reach and board a dimly lit hidden platform in a water-maze were selected and randomly divided into 2 cohorts. These mice were intravitreally (IVT) injected with either 1.7E9 gene copies/eye of MCO-010 or control AAV2 and re-tested in the water-maze. Spectral-domain optical coherence tomography (SD-OCT), hematoxylin and eosin staining of retinas, and electroretinographic (ERG) studies were also conducted. <b><i>Results:</i></b> Safety of MCO-010 in <i>rd12</i> mice was confirmed by the lack of significant detrimental changes in the mouse behavior, b-wave amplitudes and in retinal thickness. <i>rd12</i> control mice performed relatively poorly in the water-maze test requiring ≥ 30-60 s to find and board the platform. MCO-010-treated <i>rd12</i> mice reached the platform much faster than the AAV2-treated <i>rd12</i> mice, with some mice only requiring < 5 s to achieve this goal (<i>P</i> < 0.01-0.0024). <b><i>Conclusions:</i></b> IVT MCO-010 treatment was well tolerated by <i>rd12</i> mice, and it prevented the decrease in retinal thickness, and preserved ERG parameters. It also significantly improved the vision in <i>rd12</i> mice relative to control AAV2-injected mice. MCO-010 therefore represents a novel and efficacious optogenetic therapeutic to treat LCA and other IRDs irrespective of the genetic defect(s).</p>","PeriodicalId":16689,"journal":{"name":"Journal of Ocular Pharmacology and Therapeutics","volume":" ","pages":"702-708"},"PeriodicalIF":1.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Purpose: To evaluate the efficacy of subconjunctival tranexamic acid (TXA) in reducing intraoperative bleeding, shortening surgery duration, and improving postoperative outcomes in pterygium surgery. Methods: In this double-blind, randomized controlled trial, 50 eyes of 50 patients undergoing pterygium surgery were randomly assigned to receive either subconjunctival injection of 0.25 mL of 5% TXA (TXA group, n = 25) or an equivalent volume of saline (control group, n = 25). Baseline characteristics, including age, gender, working environment, allergies, preoperative logMAR best-corrected visual acuity, and systemic anticoagulant or antiplatelet therapy, were similar between the groups. The primary outcome measures were intraoperative bleeding, surgery duration, and the number of eye spears used. Secondary outcome measures included postoperative visual acuity and pterygium recurrence rates at 3 years post-surgery. Results: No significant differences were observed between the TXA group and the control group in terms of surgery duration (445.3 ± 94.8 s vs. 423.5 ± 80.6 s, P = 0.40), the number of eye spears used (3.5 ± 2.4 vs. 3.5 ± 2.6, P = 0.97), or the weight of absorbed blood (1.94 ± 1.40 grams vs. 1.90 ± 1.25 grams, P = 0.91). Additionally, there were no significant differences in postoperative visual acuity (0.14 ± 0.13 logMAR vs. 0.20 ± 0.19 logMAR, P = 0.39) or pterygium recurrence rates at 3 years post-surgery (8.0% vs. 4.4%, P = 0.60). Subconjunctival TXA injection was safe, with no reported adverse events or complications associated with its use. Conclusion: Subconjunctival injection of TXA did not significantly reduce intraoperative bleeding, shorten surgery duration, or improve postoperative outcomes in pterygium surgery. The intervention was safe and well-tolerated, but further research is warranted to explore alternative interventions or modifications to the surgical technique that may improve outcomes in pterygium surgery.
{"title":"Duration of Bare Sclera Pterygium Surgery Combined with Mitomycin C with and Without Tranexamic Acid: A Randomized Double-Blind Controlled Trial.","authors":"Nevo Kovalis, Shmuel Graffi, Shadi Safuri, Yinon Shapira, Geulah Ben-David, Michael Mimouni","doi":"10.1089/jop.2024.0068","DOIUrl":"10.1089/jop.2024.0068","url":null,"abstract":"<p><p><b><i>Purpose:</i></b> To evaluate the efficacy of subconjunctival tranexamic acid (TXA) in reducing intraoperative bleeding, shortening surgery duration, and improving postoperative outcomes in pterygium surgery. <b><i>Methods:</i></b> In this double-blind, randomized controlled trial, 50 eyes of 50 patients undergoing pterygium surgery were randomly assigned to receive either subconjunctival injection of 0.25 mL of 5% TXA (TXA group, <i>n</i> = 25) or an equivalent volume of saline (control group, <i>n</i> = 25). Baseline characteristics, including age, gender, working environment, allergies, preoperative logMAR best-corrected visual acuity, and systemic anticoagulant or antiplatelet therapy, were similar between the groups. The primary outcome measures were intraoperative bleeding, surgery duration, and the number of eye spears used. Secondary outcome measures included postoperative visual acuity and pterygium recurrence rates at 3 years post-surgery. <b><i>Results:</i></b> No significant differences were observed between the TXA group and the control group in terms of surgery duration (445.3 ± 94.8 s vs. 423.5 ± 80.6 s, <i>P</i> = 0.40), the number of eye spears used (3.5 ± 2.4 vs. 3.5 ± 2.6, <i>P</i> = 0.97), or the weight of absorbed blood (1.94 ± 1.40 grams vs. 1.90 ± 1.25 grams, <i>P</i> = 0.91). Additionally, there were no significant differences in postoperative visual acuity (0.14 ± 0.13 logMAR vs. 0.20 ± 0.19 logMAR, P = 0.39) or pterygium recurrence rates at 3 years post-surgery (8.0% vs. 4.4%, <i>P</i> = 0.60). Subconjunctival TXA injection was safe, with no reported adverse events or complications associated with its use. <b><i>Conclusion:</i></b> Subconjunctival injection of TXA did not significantly reduce intraoperative bleeding, shorten surgery duration, or improve postoperative outcomes in pterygium surgery. The intervention was safe and well-tolerated, but further research is warranted to explore alternative interventions or modifications to the surgical technique that may improve outcomes in pterygium surgery.</p>","PeriodicalId":16689,"journal":{"name":"Journal of Ocular Pharmacology and Therapeutics","volume":" ","pages":"675-679"},"PeriodicalIF":1.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01Epub Date: 2024-10-02DOI: 10.1089/jop.2024.0111
Amritha T M Seetharaman, Caroline E Owens, Rajashekhar Gangaraju
Montelukast, a Food and Drug Administration-approved drug for asthma and allergic rhinitis modulates leukotriene (LT) receptors and serves as a critical anti-inflammatory agent. Recent research suggests that the LT signaling pathway targeted by montelukast has broader implications for diseases such as fibrosis, cardiovascular diseases, cancer, cerebrovascular disease, and immune defense. This expanded understanding highlights montelukast's potential for repurposing in conditions involving aberrant stress mechanisms, including ocular diseases marked by inflammation, oxidative stress, ER stress, and apoptosis, among several others. This review delves into montelukast's therapeutic mechanisms across various diseases, draws parallels to ocular conditions, and examines clinical trials and associated adverse effects to underscore the unmet need for cysteinyl LT receptor antagonism by montelukast as an effective therapy for visual deficits.
{"title":"Cysteinyl Leukotriene Receptor Antagonism by Montelukast to Treat Visual Deficits.","authors":"Amritha T M Seetharaman, Caroline E Owens, Rajashekhar Gangaraju","doi":"10.1089/jop.2024.0111","DOIUrl":"10.1089/jop.2024.0111","url":null,"abstract":"<p><p>Montelukast, a Food and Drug Administration-approved drug for asthma and allergic rhinitis modulates leukotriene (LT) receptors and serves as a critical anti-inflammatory agent. Recent research suggests that the LT signaling pathway targeted by montelukast has broader implications for diseases such as fibrosis, cardiovascular diseases, cancer, cerebrovascular disease, and immune defense. This expanded understanding highlights montelukast's potential for repurposing in conditions involving aberrant stress mechanisms, including ocular diseases marked by inflammation, oxidative stress, ER stress, and apoptosis, among several others. This review delves into montelukast's therapeutic mechanisms across various diseases, draws parallels to ocular conditions, and examines clinical trials and associated adverse effects to underscore the unmet need for cysteinyl LT receptor antagonism by montelukast as an effective therapy for visual deficits.</p>","PeriodicalId":16689,"journal":{"name":"Journal of Ocular Pharmacology and Therapeutics","volume":" ","pages":"617-628"},"PeriodicalIF":1.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01Epub Date: 2024-10-02DOI: 10.1089/jop.2024.0130
Matthew Hill, Cynthia Andrews-Pfannkoch, Evan Atherton, Travis Knudsen, Emma Trncic, Alan D Marmorstein
Purpose: The goal of this study was to develop a lot release assay for iPSC residuals following directed differentiation of iPSCs to retinal pigment epithelial (RPE) cells. Methods: RNA Sequencing (RNA Seq) of iPSCs and RPE derived from them was used to identify pluripotency markers downregulated in RPE cells. Quantitative real time PCR (qPCR) was then applied to assess iPSC residuals in iPSC-derived RPE. The limit of detection (LOD) of the assay was determined by performing spike-in assays with known quantities of iPSCs serially diluted into an RPE suspension. Results:ZSCAN10 and LIN28A were among 8 pluripotency markers identified by RNA Seq as downregulated in RPE. Based on copy number and expression of pseudogenes and lncRNAs ZSCAN10 and LIN28A were chosen for use in qPCR assays for residual iPSCs. Reverse transcription PCR indicated generally uniform expression of ZSCAN10 and LIN28A in 21 clones derived from 8 iPSC donors with no expression of either in RPE cells derived from 5 donor lines. Based on qPCR, ZSCAN10, and LIN28A expression in iPSCs was generally uniform. The LOD for ZSCAN10 and LIN28A in qPCR assays was determined using spike in assays of RPE derived from 2 iPSC lines. Analysis of ΔΔCt found the limit of detection to be <0.01% of cells, equivalent to <1 iPSC/10,000 RPE cells in both iPSC lines. Conclusions: qPCR for ZSCAN10 and LIN28A detects <1 in 10,000 residual iPSCs in a population of iPSC-derived RPE providing an adequate LOD of iPSC residuals for lot release testing.
{"title":"Detection of Residual iPSCs Following Differentiation of iPSC-Derived Retinal Pigment Epithelial Cells.","authors":"Matthew Hill, Cynthia Andrews-Pfannkoch, Evan Atherton, Travis Knudsen, Emma Trncic, Alan D Marmorstein","doi":"10.1089/jop.2024.0130","DOIUrl":"10.1089/jop.2024.0130","url":null,"abstract":"<p><p><b><i>Purpose:</i></b> The goal of this study was to develop a lot release assay for iPSC residuals following directed differentiation of iPSCs to retinal pigment epithelial (RPE) cells. <b><i>Methods:</i></b> RNA Sequencing (RNA Seq) of iPSCs and RPE derived from them was used to identify pluripotency markers downregulated in RPE cells. Quantitative real time PCR (qPCR) was then applied to assess iPSC residuals in iPSC-derived RPE. The limit of detection (LOD) of the assay was determined by performing spike-in assays with known quantities of iPSCs serially diluted into an RPE suspension. <b><i>Results:</i></b> <i>ZSCAN10</i> and <i>LIN28A</i> were among 8 pluripotency markers identified by RNA Seq as downregulated in RPE. Based on copy number and expression of pseudogenes and lncRNAs <i>ZSCAN10</i> and <i>LIN28A</i> were chosen for use in qPCR assays for residual iPSCs. Reverse transcription PCR indicated generally uniform expression of <i>ZSCAN10</i> and <i>LIN28A</i> in 21 clones derived from 8 iPSC donors with no expression of either in RPE cells derived from 5 donor lines. Based on qPCR, <i>ZSCAN10</i>, and <i>LIN28A</i> expression in iPSCs was generally uniform. The LOD for <i>ZSCAN10</i> and <i>LIN28A</i> in qPCR assays was determined using spike in assays of RPE derived from 2 iPSC lines. Analysis of ΔΔC<sub>t</sub> found the limit of detection to be <0.01% of cells, equivalent to <1 iPSC/10,000 RPE cells in both iPSC lines. <b><i>Conclusions:</i></b> qPCR for <i>ZSCAN10</i> and <i>LIN28A</i> detects <1 in 10,000 residual iPSCs in a population of iPSC-derived RPE providing an adequate LOD of iPSC residuals for lot release testing.</p>","PeriodicalId":16689,"journal":{"name":"Journal of Ocular Pharmacology and Therapeutics","volume":" ","pages":"680-687"},"PeriodicalIF":1.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11698679/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Purpose: To evaluate the effects of rebamipide ophthalmic suspension on optical quality and efficacy of patients with dry eye under different conditions. Methods: A comprehensive search across five databases (PubMed, Cochrane Library, Web of Science, China National Knowledge Infrastructure, and Wan Fang) was conducted for studies published through May 13, 2024, focusing on rebamipide for dry eye treatment. Results: A total of 11 studies including 334 patients with dry eye were included. Tear breakup time (TBUT) values of patients with dry eye increased significantly after 2 weeks (standardized mean difference [SMD] =1.07, 95% confidence interval [CI] = [0.05, 2.09]), 4 weeks (SMD = 1.26, 95% CI = [0.77, 1.75]), and 12 weeks (SMD = 1.04, 95% CI = [0.37, 1.71]) of rebamipide treatment. Subgroup analysis revealed that patients with dry eye wearing soft contact lens (SCL) exhibited higher TBUT values after 4 weeks of rebamipide treatment compared with those who received rebamipide alone. In addition, rebamipide significantly improved fluorescein staining score of patients with dry eye after 4 weeks of treatment (SMD = -0.34, 95% CI = [-0.63, -0.06]). However, 4 weeks of rebamipide treatment showed no significant effect on Schirmer I test values (SMD = -0.04, 95%, CI = [-0.43, 0.35]) and higher-order aberrations (SMD = -0.73, 95% CI = [-1.77, 0.30]). Conclusions: These results indicate a significant improvement in the efficacy of rebamipide treatment for patients with dry eye, particularly for those wearing SCL. The effect of rebamipide on visual quality was found to correlate with the underlying dry eye status.
目的:评估瑞巴派特眼用混悬液在不同条件下对干眼症患者光学质量和疗效的影响。方法在五个数据库(PubMed、Cochrane Library、Web of Science、中国国家知识基础设施和万方数据库)中对截至 2024 年 5 月 13 日发表的研究进行了全面检索,重点关注瑞巴派特用于干眼症治疗的研究。研究结果共纳入 11 项研究,包括 334 名干眼症患者。干眼症患者的泪液破裂时间(TBUT)值在接受瑞巴咪啶治疗 2 周(标准化平均差 [SMD] =1.07,95% 置信区间 [CI] = [0.05,2.09])、4 周(SMD =1.26,95% CI = [0.77,1.75])和 12 周(SMD =1.04,95% CI = [0.37,1.71])后显著增加。亚组分析显示,与单独接受瑞巴咪啶治疗的患者相比,佩戴软性隐形眼镜(SCL)的干眼症患者在接受 4 周瑞巴咪啶治疗后的 TBUT 值更高。此外,治疗 4 周后,干眼症患者的荧光素染色评分明显提高(SMD = -0.34,95% CI = [-0.63, -0.06])。然而,4周的雷帕米特治疗对Schirmer I测试值(SMD = -0.04,95% CI = [-0.43,0.35])和高阶像差(SMD = -0.73,95% CI = [-1.77,0.30])没有明显影响。结论:这些结果表明,对干眼症患者,尤其是佩戴 SCL 的干眼症患者而言,瑞贝美的疗效显著提高。研究发现,瑞巴派特对视觉质量的影响与干眼症的基本状况有关。
{"title":"Effects of Rebamipide for Dry Eye on Optical Quality and Efficacy: A Systematic Review and Meta-Analysis.","authors":"Yu-Ling Yan, Jing-Yao Chang, Xin-Ru Ling, Chun-Yan Xue","doi":"10.1089/jop.2024.0098","DOIUrl":"10.1089/jop.2024.0098","url":null,"abstract":"<p><p><b><i>Purpose:</i></b> To evaluate the effects of rebamipide ophthalmic suspension on optical quality and efficacy of patients with dry eye under different conditions. <b><i>Methods:</i></b> A comprehensive search across five databases (PubMed, Cochrane Library, Web of Science, China National Knowledge Infrastructure, and Wan Fang) was conducted for studies published through May 13, 2024, focusing on rebamipide for dry eye treatment. <b><i>Results:</i></b> A total of 11 studies including 334 patients with dry eye were included. Tear breakup time (TBUT) values of patients with dry eye increased significantly after 2 weeks (standardized mean difference [SMD] =1.07, 95% confidence interval [CI] = [0.05, 2.09]), 4 weeks (SMD = 1.26, 95% CI = [0.77, 1.75]), and 12 weeks (SMD = 1.04, 95% CI = [0.37, 1.71]) of rebamipide treatment. Subgroup analysis revealed that patients with dry eye wearing soft contact lens (SCL) exhibited higher TBUT values after 4 weeks of rebamipide treatment compared with those who received rebamipide alone. In addition, rebamipide significantly improved fluorescein staining score of patients with dry eye after 4 weeks of treatment (SMD = -0.34, 95% CI = [-0.63, -0.06]). However, 4 weeks of rebamipide treatment showed no significant effect on Schirmer I test values (SMD = -0.04, 95%, CI = [-0.43, 0.35]) and higher-order aberrations (SMD = -0.73, 95% CI = [-1.77, 0.30]). <b><i>Conclusions:</i></b> These results indicate a significant improvement in the efficacy of rebamipide treatment for patients with dry eye, particularly for those wearing SCL. The effect of rebamipide on visual quality was found to correlate with the underlying dry eye status.</p>","PeriodicalId":16689,"journal":{"name":"Journal of Ocular Pharmacology and Therapeutics","volume":" ","pages":"629-637"},"PeriodicalIF":1.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01Epub Date: 2024-10-02DOI: 10.1089/jop.2024.0103
Santosh Bhujbal, Ilva D Rupenthal, Philipp Steven, Priyanka Agarwal
Dry eye disease (DED) is a rapidly growing ocular surface disease with a significant socioeconomic impact that affects the patients' visual function and, thus, their quality of life. It is distinguished by a loss of tear film homeostasis, leading to tear film instability, hyperosmolarity, ocular surface inflammation, and neurosensory abnormalities, with all of these playing etiological roles in the propagation of the vicious DED circle. While current treatments primarily focus on reducing tear film instability and hyperosmolarity, increasingly more attention is being placed on tackling the underlying inflammation that propagates and potentiates these factors. As such, preclinical models are crucial to further elucidate the DED pathophysiology and develop novel therapeutic strategies. This review outlines the role of inflammation in DED, highlighting related signs and diagnostic tools before focusing on relevant preclinical animal models and potential therapeutic strategies to tackle DED-associated inflammation.
{"title":"Inflammation in Dry Eye Disease-Pathogenesis, Preclinical Animal Models, and Treatments.","authors":"Santosh Bhujbal, Ilva D Rupenthal, Philipp Steven, Priyanka Agarwal","doi":"10.1089/jop.2024.0103","DOIUrl":"10.1089/jop.2024.0103","url":null,"abstract":"<p><p>Dry eye disease (DED) is a rapidly growing ocular surface disease with a significant socioeconomic impact that affects the patients' visual function and, thus, their quality of life. It is distinguished by a loss of tear film homeostasis, leading to tear film instability, hyperosmolarity, ocular surface inflammation, and neurosensory abnormalities, with all of these playing etiological roles in the propagation of the vicious DED circle. While current treatments primarily focus on reducing tear film instability and hyperosmolarity, increasingly more attention is being placed on tackling the underlying inflammation that propagates and potentiates these factors. As such, preclinical models are crucial to further elucidate the DED pathophysiology and develop novel therapeutic strategies. This review outlines the role of inflammation in DED, highlighting related signs and diagnostic tools before focusing on relevant preclinical animal models and potential therapeutic strategies to tackle DED-associated inflammation.</p>","PeriodicalId":16689,"journal":{"name":"Journal of Ocular Pharmacology and Therapeutics","volume":" ","pages":"638-658"},"PeriodicalIF":1.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01Epub Date: 2024-10-25DOI: 10.1089/jop.2024.0064
Jin Sun Hwang, Hyun Beom Song, Geonhui Lee, Sangmoo Jeong, Dae Joong Ma
Purpose: To examine the potential protective effects of adipose-derived mesenchymal stem cell-derived extracellular vesicles (ASC-EVs) on ARPE-19 cells exposed to hydrogen peroxide (H2O2) stress and to evaluate their ability to delay retinal degeneration in Royal College of Surgeons (RCS) rats. Methods: ARPE-19 cells were pre-treated with ASC-EVs for 24 h, followed by exposure to 200 μM H2O2 for an additional 24 h. RCS rats received an intravitreal injection of phosphate-buffered saline in one eye and ASC-EVs in the other eye. Results: ASC-EV pretreatment significantly protected against H2O2 in the Cell Counting Kit-8 assay and was also effective in the lactate dehydrogenase-release assay. It notably reduced early apoptosis (Annexin V-fluorescein isothiocyanate/propidium iodide assay) and late apoptosis (Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling assay), while significantly decreasing intracellular reactive oxygen species, glutathione levels, and superoxide dismutase activity. NFE2L2, HMOX1, and NQO1 mRNA levels, along with Nrf2, HO-1, and NQO1 protein levels, were significantly elevated with ASC-EV pretreatment. Compared with ARPE-19-derived EVs, 11 miRNAs were upregulated and 34 were downregulated in ASC-EVs. In RCS rats, intravitreal injections of ASC-EVs led to significant preservation of the outer nuclear layer and photoreceptor segments, along with increased nuclear Nrf2 expression and elevated HO-1 and NQO1 levels in the inner retina. Eyes that received intravitreal injections of ASC-EVs demonstrated significantly preserved electroretinography a- and b-wave amplitudes at 1 week post-injection, though this effect faded by 2 weeks. Conclusions: ASC-EVs mitigated apoptosis and oxidative stress in ARPE-19 cells subjected to H2O2 exposure and temporarily slowed retinal degeneration in RCS rats via Nrf2 pathway activation by miRNAs.
目的:研究脂肪间充质干细胞衍生的细胞外囊泡(ASC-EVs)对暴露于过氧化氢(H2O2)应激的ARPE-19细胞的潜在保护作用,并评估其延缓皇家外科学院(RCS)大鼠视网膜变性的能力。方法:预处理 ARPE-19 细胞:一只眼睛接受磷酸盐缓冲盐水静脉注射,另一只眼睛接受ASC-EVs静脉注射。结果在细胞计数试剂盒-8测定中,ASC-EV预处理能明显抑制H2O2,在乳酸脱氢酶释放测定中也有效。它明显减少了早期细胞凋亡(Annexin V-荧光素异硫氰酸酯/碘化丙啶检测)和晚期细胞凋亡(末端脱氧核苷酸转移酶 dUTP Nick End Labeling 检测),同时显著降低了细胞内活性氧、谷胱甘肽水平和超氧化物歧化酶活性。经 ASC-EV 预处理后,NFE2L2、HMOX1 和 NQO1 mRNA 水平以及 Nrf2、HO-1 和 NQO1 蛋白水平均明显升高。与 ARPE-19 衍生的 EV 相比,ASC-EV 中有 11 个 miRNA 上调,34 个下调。在RCS大鼠中,玻璃体内注射ASC-EVs可显著保留核外层和感光节段,同时增加核Nrf2的表达,提高视网膜内层的HO-1和NQO1水平。注射ASC-EVs后1周,视网膜电图a波和b波振幅得到明显保护,但这种效果在2周后逐渐消失。结论ASC-EVs能减轻暴露于H2O2的ARPE-19细胞的凋亡和氧化应激,并通过miRNAs激活Nrf2通路暂时减缓RCS大鼠的视网膜退化。
{"title":"Extracellular Vesicles Derived from Adipose-Derived Mesenchymal Stem Cells Alleviate Apoptosis and Oxidative Stress of Retinal Pigment Epithelial Cells Through Activation of Nrf2 Signaling Pathway.","authors":"Jin Sun Hwang, Hyun Beom Song, Geonhui Lee, Sangmoo Jeong, Dae Joong Ma","doi":"10.1089/jop.2024.0064","DOIUrl":"10.1089/jop.2024.0064","url":null,"abstract":"<p><p><b><i>Purpose:</i></b> To examine the potential protective effects of adipose-derived mesenchymal stem cell-derived extracellular vesicles (ASC-EVs) on ARPE-19 cells exposed to hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) stress and to evaluate their ability to delay retinal degeneration in Royal College of Surgeons (RCS) rats. <b><i>Methods:</i></b> ARPE-19 cells were pre-treated with ASC-EVs for 24 h, followed by exposure to 200 μM H<sub>2</sub>O<sub>2</sub> for an additional 24 h. RCS rats received an intravitreal injection of phosphate-buffered saline in one eye and ASC-EVs in the other eye. <b><i>Results:</i></b> ASC-EV pretreatment significantly protected against H<sub>2</sub>O<sub>2</sub> in the Cell Counting Kit-8 assay and was also effective in the lactate dehydrogenase-release assay. It notably reduced early apoptosis (Annexin V-fluorescein isothiocyanate/propidium iodide assay) and late apoptosis (Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling assay), while significantly decreasing intracellular reactive oxygen species, glutathione levels, and superoxide dismutase activity. <i>NFE2L2</i>, <i>HMOX1</i>, and <i>NQO1</i> mRNA levels, along with Nrf2, HO-1, and NQO1 protein levels, were significantly elevated with ASC-EV pretreatment. Compared with ARPE-19-derived EVs, 11 miRNAs were upregulated and 34 were downregulated in ASC-EVs. In RCS rats, intravitreal injections of ASC-EVs led to significant preservation of the outer nuclear layer and photoreceptor segments, along with increased nuclear Nrf2 expression and elevated HO-1 and NQO1 levels in the inner retina. Eyes that received intravitreal injections of ASC-EVs demonstrated significantly preserved electroretinography a- and b-wave amplitudes at 1 week post-injection, though this effect faded by 2 weeks. <b><i>Conclusions:</i></b> ASC-EVs mitigated apoptosis and oxidative stress in ARPE-19 cells subjected to H<sub>2</sub>O<sub>2</sub> exposure and temporarily slowed retinal degeneration in RCS rats via Nrf2 pathway activation by miRNAs.</p>","PeriodicalId":16689,"journal":{"name":"Journal of Ocular Pharmacology and Therapeutics","volume":" ","pages":"688-701"},"PeriodicalIF":1.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01Epub Date: 2024-09-26DOI: 10.1089/jop.2024.0155
Gary D Novack
{"title":"Eyes on New Product Development.","authors":"Gary D Novack","doi":"10.1089/jop.2024.0155","DOIUrl":"10.1089/jop.2024.0155","url":null,"abstract":"","PeriodicalId":16689,"journal":{"name":"Journal of Ocular Pharmacology and Therapeutics","volume":" ","pages":"543-544"},"PeriodicalIF":16.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01Epub Date: 2024-08-16DOI: 10.1089/jop.2024.0029
Jason Bacharach, Eugene B McLaurin, Steven Silverstein, Mourad Amrane, Jean-Sebastien Garrigue, Dahlia Ismail, William J Flynn
Purpose: To compare intraocular pressure (IOP), ocular surface disease (OSD) parameters, and safety in patients with open-angle glaucoma (OAG)/ocular hypertension (OH) and concurrent OSD treated with preservative-free latanoprost 0.005% cationic emulsion (PF-latanoprost-E) or travoprost-Z 0.004% ophthalmical solution containing a soft preservative system. Methods: Patients with OAG/OH and OSD were randomized to treatment with PF-latanoprost-E or travoprost-Z nightly for 3 months. Outcomes included mean diurnal IOP reduction; OSD endpoints, including symptom improvement, tear break-up time (TBUT), and corneal fluorescein staining (CFS) score; and safety after 1 and 3 months. Results: A total of 105 patients were randomized, 51 to PF-latanoprost-E and 54 to travoprost-Z. IOP reductions (LS mean differences) at 3 months were numerically greater in the PF-latanoprost-E than in the travoprost-Z group at 8AM (7.2 versus 6.0 mmHg), 10AM (6.7 versus 5.9 mmHg), and 4PM (6.0 versus 5.4 mmHg). LS mean changes in IOP from baseline in both groups at 1 and 3 months, however, were comparable. Mean ± SD CFS scores on the Ora scale at month 3 showed significantly greater reductions in the PF-latanoprost-E than in the travoprost-Z group (-1.07 ± 1.863 versus -0.16 ± 2.553 P = 0.0461). The mean TBUT at month 3 showed similar improvements in both groups (1.1 versus 1.0 s, P > 0.05). OSD symptoms improved but did not differ significantly in the two groups. Overall safety was comparable in both groups. Conclusion: PF-latanoprost-E effectively and safely lowered IOP and improved OSD parameters in patients with OAG/OH. These findings provide evidence for the beneficial effects of this new formulation of latanoprost in glaucoma patients with OSD.
{"title":"Efficacy and Safety of a Preservative-Free Latanoprost Cationic Emulsion in Patients with Open-Angle Glaucoma and Concurrent Ocular Surface Disease: A Randomized Phase 2 Study.","authors":"Jason Bacharach, Eugene B McLaurin, Steven Silverstein, Mourad Amrane, Jean-Sebastien Garrigue, Dahlia Ismail, William J Flynn","doi":"10.1089/jop.2024.0029","DOIUrl":"10.1089/jop.2024.0029","url":null,"abstract":"<p><p><b><i>Purpose:</i></b> To compare intraocular pressure (IOP), ocular surface disease (OSD) parameters, and safety in patients with open-angle glaucoma (OAG)/ocular hypertension (OH) and concurrent OSD treated with preservative-free latanoprost 0.005% cationic emulsion (PF-latanoprost-E) or travoprost-Z 0.004% ophthalmical solution containing a soft preservative system. <b><i>Methods:</i></b> Patients with OAG/OH and OSD were randomized to treatment with PF-latanoprost-E or travoprost-Z nightly for 3 months. Outcomes included mean diurnal IOP reduction; OSD endpoints, including symptom improvement, tear break-up time (TBUT), and corneal fluorescein staining (CFS) score; and safety after 1 and 3 months. <b><i>Results:</i></b> A total of 105 patients were randomized, 51 to PF-latanoprost-E and 54 to travoprost-Z. IOP reductions (LS mean differences) at 3 months were numerically greater in the PF-latanoprost-E than in the travoprost-Z group at 8AM (7.2 versus 6.0 mmHg), 10AM (6.7 versus 5.9 mmHg), and 4PM (6.0 versus 5.4 mmHg). LS mean changes in IOP from baseline in both groups at 1 and 3 months, however, were comparable. Mean ± SD CFS scores on the Ora scale at month 3 showed significantly greater reductions in the PF-latanoprost-E than in the travoprost-Z group (-1.07 ± 1.863 versus -0.16 ± 2.553 <i>P</i> = 0.0461). The mean TBUT at month 3 showed similar improvements in both groups (1.1 versus 1.0 s, <i>P</i> > 0.05). OSD symptoms improved but did not differ significantly in the two groups. Overall safety was comparable in both groups. <b><i>Conclusion:</i></b> PF-latanoprost-E effectively and safely lowered IOP and improved OSD parameters in patients with OAG/OH. These findings provide evidence for the beneficial effects of this new formulation of latanoprost in glaucoma patients with OSD.</p>","PeriodicalId":16689,"journal":{"name":"Journal of Ocular Pharmacology and Therapeutics","volume":" ","pages":"553-561"},"PeriodicalIF":1.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01Epub Date: 2024-07-12DOI: 10.1089/jop.2024.0041
Shahna S Hameed, Nicole E Bodi, Ryan C Miller, Tasneem P Sharma
Purpose: Glaucoma is a leading cause of irreversible blindness. Glaucomatous intraocular pressure (IOP) triggers deleterious effects, including gliosis, optic nerve (ON) axonal retraction, neurotrophic factor deprivation, inflammation, and other pathological events, leading to retinal ganglion cell (RGC) loss. Trophic factor impairment enhances RGC apoptosis susceptibility. Neuritin 1 (NRN1), a neurotrophic protein downstream of various neurotrophins, exhibited RGC protection and regeneration in axotomy models. We evaluated human recombinant NRN1's impact on human RGCs cultured in pressurized conditions within the ex vivo translaminar autonomous system to simulate glaucoma pathogenesis. Methods: Human glaucomatous and non-glaucomatous donor eyes were obtained from eye banks according to the Declaration of Helsinki. Initially, we evaluated NRN1and RGC marker expression in glaucoma and non-glaucomatous retina to determine the NRN1 level and its association with RGC loss. Further, we evaluated NRN1's therapeutic potential by treating pressurized human eyes at normal and high IOP for seven days. Retina, ON, and conditioned medium were analyzed for RGC survival (THY1, RBPMS), gliosis (GFAP), apoptosis (CASP3, CASP7), and extracellular matrix deposition (COLIV, FN) by qRT-PCR and western blotting. Paraphenylenediamine staining assessed ON axonal degeneration, whereas ex vivo electroretinogram assessed retinal activity. Results: Glaucomatous retinas exhibited significant reductions in both NRN1 (*p = 0.007, n = 5) and RGC marker expression (*p = 0.04, n = 5). NRN1 treatment reduced gliosis, extracellular matrix deposition, ON degeneration, and increased retinal activity in pressure-perfused eyes. Conclusions: Our study confirms that NRN1 enhances human RGC survival and improves retinal function in degenerative conditions, substantiating it as a promising candidate for rescuing human RGCs from degeneration.
{"title":"Neuritin 1 Drives Therapeutic Preservation of Retinal Ganglion Cells in an <i>Ex Vivo</i> Human Glaucoma Model.","authors":"Shahna S Hameed, Nicole E Bodi, Ryan C Miller, Tasneem P Sharma","doi":"10.1089/jop.2024.0041","DOIUrl":"10.1089/jop.2024.0041","url":null,"abstract":"<p><p><b><i>Purpose:</i></b> Glaucoma is a leading cause of irreversible blindness. Glaucomatous intraocular pressure (IOP) triggers deleterious effects, including gliosis, optic nerve (ON) axonal retraction, neurotrophic factor deprivation, inflammation, and other pathological events, leading to retinal ganglion cell (RGC) loss. Trophic factor impairment enhances RGC apoptosis susceptibility. Neuritin 1 (NRN1), a neurotrophic protein downstream of various neurotrophins, exhibited RGC protection and regeneration in axotomy models. We evaluated human recombinant NRN1's impact on human RGCs cultured in pressurized conditions within the <i>ex vivo</i> translaminar autonomous system to simulate glaucoma pathogenesis. <b><i>Methods:</i></b> Human glaucomatous and non-glaucomatous donor eyes were obtained from eye banks according to the Declaration of Helsinki. Initially, we evaluated NRN1and RGC marker expression in glaucoma and non-glaucomatous retina to determine the NRN1 level and its association with RGC loss. Further, we evaluated NRN1's therapeutic potential by treating pressurized human eyes at normal and high IOP for seven days. Retina, ON, and conditioned medium were analyzed for RGC survival (<i>THY1</i>, <i>RBPMS</i>), gliosis (<i>GFAP</i>), apoptosis (<i>CASP3</i>, <i>CASP7</i>), and extracellular matrix deposition (COLIV, FN) by qRT-PCR and western blotting. Paraphenylenediamine staining assessed ON axonal degeneration, whereas ex <i>vivo</i> electroretinogram assessed retinal activity. <b><i>Results:</i></b> Glaucomatous retinas exhibited significant reductions in both NRN1 (<i>*p</i> = 0.007, <i>n</i> = 5) and RGC marker expression (<i>*p</i> = 0.04, <i>n</i> = 5). NRN1 treatment reduced gliosis, extracellular matrix deposition, ON degeneration, and increased retinal activity in pressure-perfused eyes. <b><i>Conclusions:</i></b> Our study confirms that NRN1 enhances human RGC survival and improves retinal function in degenerative conditions, substantiating it as a promising candidate for rescuing human RGCs from degeneration.</p>","PeriodicalId":16689,"journal":{"name":"Journal of Ocular Pharmacology and Therapeutics","volume":" ","pages":"596-607"},"PeriodicalIF":1.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11698685/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141600255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}