Makoto Aihara

Introduction This prospective, phase III, randomised, multicentre, double-masked study (jRCT2031210122) assessed the intraocular pressure (IOP)-lowering efficacy, tolerability and superiority of netarsudil 0.02% + concomitant latanoprost 0.005% to placebo + latanoprost in Japanese participants with primary open-angle glaucoma (POAG) or ocular hypertension (OHT) who have inadequate IOP reduction with latanoprost monotherapy. Methods Participants received latanoprost once daily for 6 weeks. Eligible participants (n = 246) with POAG (n = 165) or OHT (n = 81) were randomised (1:1) to netarsudil + latanoprost (n = 122) or placebo + latanoprost (n = 124) for 4 weeks. Primary endpoint was mean diurnal (MD) IOP at week 4, with superiority demonstrated if the between-group difference in least squares mean MD IOP was < 0 and p < 0.05. Secondary endpoints included MD IOP at weeks 1 and 2. Adverse events (AEs) were recorded. Results At week 4, MD IOP (standard error) was 15.29 (0.17) versus 17.65 (0.17) mmHg with netarsudil + latanoprost versus placebo + latanoprost, respectively [difference, − 2.36 (p < 0.0001)]. The differences at weeks 1 and 2 between netarsudil + latanoprost and placebo + latanoprost were − 2.47 and − 2.41 (p < 0.0001), respectively. At each visit, netarsudil + latanoprost significantly reduced MD IOP versus placebo + latanoprost (p < 0.0001). Of those receiving netarsudil + latanoprost, 64.8% reported AEs versus 21.0% receiving placebo + latanoprost. Conjunctival hyperaemia was the most reported AE in both groups (53.3% vs. 6.5%). No serious AEs were reported. Conclusion Netarsudil + latanoprost was superior to placebo + latanoprost in lowering elevated IOP in Japanese patients with POAG or OHT. No new safety signals were reported. Trial Registration Japan registry of clinical trials: jRCT2031210122.

Retinal vein occlusion (RVO) is a common vascular disease that leads to vision loss due to macular edema (ME). This study investigated the role of autotaxin (ATX), a lysophospholipase D, in the pathogenesis of RVO. In mice, RVO was induced by intravenous administration of rose bengal followed by laser irradiation of retinal veins. ATX expression in the retina was evaluated using immunohistochemistry. Intravitreal ATX was administered, and retinal changes were assessed using fluorescence angiography and optical coherence tomography (OCT). In human retinal microvascular endothelial cells (HRMECs), intercellular barrier function was evaluated using transepithelial electrical resistance (TEER). In the murine RVO model, the ATX inhibitor HA130 was administered intravitreally, and retinal thickness was measured and compared using OCT. ATX expression was increased in retinal vessels in the RVO model. Intravitreal administration of ATX induced retinal edema and serous retinal detachment (SRD). ATX significantly disrupted the barrier integrity of HRMECs and promoted the expression of vascular endothelial growth factor (VEGF), which was ameliorated by HA130. Intravitreal administration of HA130 significantly reduced retinal thickening caused by retinal edema secondary to RVO and the elevated expression of intercellular adhesion molecule (ICAM)-1 in the retina. These findings suggest that ATX plays a critical role in RVO-induced ME by disrupting endothelial barrier integrity, potentially through the upregulation of VEGF in retinal endothelial cells and subsequent ICAM-1 upregulation in the retina.

Background/Objectives: The aim of this study was to investigate the longitudinal visual field (VF) and circumpapillary retinal nerve fiber layer thickness (cpRNFLT) changes in open-angle glaucomatous (OAG) participants with unilateral peripapillary intrachoroidal cavitation (PICC) and to identify factors associated with VF progression. Methods: Sixty eyes of 30 OAG patients with unilateral PICC were included in this retrospective longitudinal observational study. Humphrey 24–2 VF testing and optical coherence tomography scanning were performed in all eyes over a period exceeding 5 years. VF progression was assessed using mean deviation (MD) and superior and inferior total deviation (TD) slopes. Structural progression was evaluated using global, superior, and inferior cpRNFLT thinning rates. Longitudinal changes were compared between PICC eyes and their contralateral non-PICC eyes. Factors associated with superior or inferior TD slopes were analyzed using linear mixed-effects models. The following variables were included as explanatory variables: age, sex, intraocular pressure, axial length, Bruch’s membrane opening (BMO) and scleral flange opening (SFO) area, SFO/BMO offset magnitude, disk tilt, disk rotation, baseline superior or inferior TD, baseline corresponding cpRNFLT, and the presence of PICC. Results: MD slope was −0.24 ± 0.35 dB/year in PICC eyes and −0.35 ± 0.53 dB/year in contralateral eyes. There was no significant difference in MD slope, superior and inferior TD slope, or the rate of cpRNFLT thinning (all p > 0.05). In multivariable analysis, the presence of PICC was associated with slower progression in the corresponding superior VF (p = 0.037), whereas greater SFO/BMO offset magnitude was associated with faster progression (p = 0.047). Conclusions: OAG eyes with PICC exhibited modest functional and structural progression over 5 years, comparable to that of contralateral non-PICC eyes. The presence of PICC was associated with slower corresponding superior VF progression, whereas greater myopia-associated structural change was related to faster progression. Our findings characterize the clinical course of eyes with pronounced myopic ONH deformation, highlighting the importance of detailed ONH structural assessment in the management of myopic glaucoma.

Although mutations in human patatin-like phospholipase PNPLA6 are associated with hereditary retinal degenerative diseases, its mechanistic action in the retina is poorly understood. Here, we uncover the molecular mechanism by which PNPLA6 dysfunction disturbs retinal homeostasis and visual function. PNPLA6, by acting as a phospholipase B, regulates choline mobilization from phosphatidylcholine and subsequent choline turnover for phosphatidylcholine regeneration in retinal pigment epithelial cells. PNPLA6-driven choline is supplied from retinal pigment epithelial cells to adjacent photoreceptor cells to support their survival. Inhibition of this pathway results in abnormal morphology, proliferation, metabolism, and functions of retinal pigment epithelial and photoreceptor cells, and mice with retina-specific PNPLA6 deletion exhibit retinitis pigmentosa-like retinal degeneration. Notably, these abnormalities are entirely rescued by choline supplementation. Thus, PNPLA6 plays an essential role in retinal homeostasis by controlling choline availability for phospholipid recycling and provide a framework for the development of an ophthalmic drug target for retinal degeneration.

This study evaluated the effects of α2-adrenergic agonist, prostaglandin F2α analog, and EP2 receptor agonist on tunicamycin-induced endoplasmic reticulum (ER) stress and fibrosis in human trabecular meshwork (TM) cells. Human TM cells were treated with tunicamycin for 24 h, followed by cotreatment with brimonidine (BRI), latanoprost (LAT), or omidenepag (OMD). Immunocytochemistry was used to assess expressions of collagen type I alpha 1 chain (COL1A1), fibronectin, F-actin, and alpha-smooth muscle actin (α-SMA). Western blotting was performed to evaluate levels of C/EBP homologous protein (CHOP), 78-kDa glucose-regulated protein (GRP78), and splicing X-box binding protein-1 (sXBP-1). Real-time qPCR was used to examine the mRNA expressions of COL1A1, connective tissue growth factor (CTGF), fibronectin, α-SMA, CHOP, GRP78, and sXBP-1. Expressions of COL1A1, CTGF, F-actin, fibronectin, α-SMA, CHOP, GRP78, and sXBP-1 significantly increased after tunicamycin treatment. BRI cotreatment significantly downregulated the mRNA and protein expressions of GRP78, and LAT or OMD cotreatment significantly reduced the CHOP and sXBP-1 expressions compared to the tunicamycin-treated group. BRI, LAT, or OMD cotreatment significantly attenuated cellular cytoskeletal changes and the increase of fibrosis markers such as COL1A1, CTGF, fibronectin, and α-SMA. In addition, COL1A1 mRNA expression was significantly lowered with LAT or OMD cotreatment compared to the BRI-cotreated group. Cotreatment with α2-adrenergic agonist, prostaglandin F2α analog, or EP2 receptor agonist alleviates tunicamycin-induced ER stress in human TM cells.

Précis: Preservative-free omidenepag isopropyl (OMDI) 0.002% ophthalmic solution and OMDI 0.002% ophthalmic solution preserved with benzalkonium chloride (BAK) were bioequivalent in lowering intraocular pressure (IOP) after 4 weeks’ treatment in patients with primary open angle glaucoma (POAG) or ocular hypertension (OHT). Objective: Preservatives in ophthalmic solutions for lowering IOP are associated with ocular surface disease. The DAISY study evaluated the bioequivalence of preservative-free OMDI 0.002% ophthalmic solution (DE-117B), with OMDI 0.002% preserved with BAK. Methods: DAISY was a phase 3, randomized, evaluator-masked, crossover study conducted in Japan. Patients with POAG or OHT were randomized 1:1 to DE-117B or OMDI 0.002% for 4 weeks (period 1) and then crossed over for 4 weeks (period 2). A 4-week washout preceded both periods. The primary efficacy endpoint was mean diurnal (MD) IOP at week 4 (combined periods 1 and 2). Bioequivalence between DE-117B and OMDI was defined as a 95% CI between −1.5 and 1.5 for least squares mean between-group difference in MD IOP. Adverse events were monitored. Results: Of 74 patients enrolled, 38 were randomized to DE-117B, then OMDI, and 36 were randomized to OMDI then DE-117B. DE-117B and OMDI demonstrated bioequivalence at week 4 [MD IOP ± SD in summary statistics: 17.76 ± 2.05 mm Hg (DE-117B) vs 17.71 ± 2.01 mm Hg (OMDI); least squares mean ± SE between-group difference in linear mixed effect model: −0.02 ± 0.18 mm Hg (95% CI: −0.38 to 0.35)]. DE-117B versus OMDI was associated with numerically lower overall ocular discomfort. Conclusions: Preservative-free DE-117B and BAK-containing OMDI were bioequivalent in lowering IOP after 4 weeks’ treatment in Japanese patients with POAG or OHT. DE-117B was well tolerated with a similar safety profile to OMDI.

Purpose: The objective of this study is to estimate the area of the Foveal Avascular Zone (FAZ) from B-scan OCT images using machine learning algorithms. Methods: We developed machine learning models to predict the FAZ area from OCT B-scan images of eyes without retinal vascular diseases. The study involved three models: Model 1 predicted the FAZ length from B-scan images; Model 2 estimated the FAZ area from the predicted length using 1, 3, or 5 horizontal measurements; and Model 3 converted the FAZ area from pixels to mm². The models’ performance was evaluated using Mean Absolute Error (MAE), Mean Squared Error (MSE), and the Coefficient of Determination (R²). The FAZ area was subsequently estimated by sequentially applying Models 1→2→3 on a new dataset. Results: Model 1 achieved a MAE of 2.86, MSE of 17.56, and R² of 0.87. Model 2’s performance improved with the number of horizontal measurements, with the best results obtained using 5 lines (MAE: 40.36, MSE: 3129.65, R²: 0.95). Model 3 achieved a MAE of 1.52e-3, MSE of 4.0e-6, and R² of 1.0. The accuracy of FAZ area estimation increased with the number of B-scan images used, with the correlation coefficient rising from 0.475 (1 line) to 0.596 (5 lines). Bland–Altman analysis showed improved agreement between predicted and actual FAZ areas with increasing B-scan images, evidenced by decreasing biases and narrower limits of agreement. Conclusions: This study successfully developed machine learning models capable of predicting FAZ area from OCT B-scan images. These findings demonstrate the potential for using OCT images to predict OCTA data, particularly in populations where OCTA imaging is challenging, such as children and the elderly. Future studies could explore the developmental mechanisms of the FAZ and macula, providing new insights into retinal health across different age groups.