This study aimed to investigate the effect and mechanism of levodopa (L-DOPA) in the treatment of age-related macular degeneration (AMD). A wet AMD cell model was created via CoCl2 treatment of ARPE-19 cells. The cytoprotective effects of L-DOPA in the model were determined using CCK-8, flow cytometry, TUNEL, qPCR, and ELISA assays. Subsequently, circRNA sequencing and bioinformatics analysis were used to screen differentially expressed circRNAs, which were overexpressed in ARPE-19 cells, to explore their role in wet AMD. The findings revealed that 200 μM CoCl2 treatment inhibited the cell viability and the production of tyrosinase, melanin, and pigment epithelium-derived growth factor but promoted apoptosis and the expression of vascular endothelial growth factor in ARPE-19 cells. Moreover, 20 μM L-DOPA exerted the best therapeutic effect on the model. qPCR showed that Hsa_circ_0018401 (circ-SGMS1) was significantly differentially expressed in each experimental group, which was consistent with the sequencing results. The overexpression of circ-SGMS1 in ARPE-19 cells reversed the effects of CoCl2. Fluorescence in situ hybridization showed that circ-SGMS1 was expressed more in the nucleus than in the cytoplasm. qPCR assays indicated that circ-SGMS1 overexpression did not have a significant effect on the expressions of VEGFA and KDR but significantly reduced the expressions of HIF-1a and THBS1. Circ-SGMS1 is of immense significance in the AMD treatment mechanism of L-DOPA. Overexpression of circ-SGMS1 may alleviate wet AMD by inhibiting HIF-1a and THBS1 expression.

Age-related macular degeneration (AMD) is the leading cause of severe loss of central vision among people over 50. The pathophysiology of the disease is multifactorial and can be attributed to genetics, aging, inflammation, environmental factors, and lifestyle factors including smoking, diet, obesity, and alcohol consumption. While there is no treatment for dry AMD, the current standard treatment for wet AMD is an intraocular injection of anti-vascular endothelial growth factor-an effective, yet expensive, therapy that requires ongoing treatment. As the aging population continues to grow, and AMD diagnoses continue to rise, new treatments should be explored to reduce vision complications and decrease treatment burdens. Many systemic conditions have progressive pathological changes that may affect AMD, particularly those affecting systemic vasculature like diabetes and cardiovascular status. Consequently, systemic drugs used to treat coexistent systemic diseases may influence some of the pathogenic mechanisms of AMD and lead its progression or delay. In this review we explore the current literature to summarize the findings of the reported effects of antihypertensives, immunosuppressants, cholesterol lowering agents, non-steroidal anti-inflammatory drugs, dopamine precursors, hypoglycemic agents, and anticoagulants on AMD.

Optic disc pit-associated maculopathy (ODP-M) is a rare presentation in children. Therefore, only a few pediatric cases successfully managed have been reported in the literature. This video shows successful management of ODP-M with human amniotic membrane graft in a pediatric case presenting with recurrence with intraoperative optical coherence tomography (OCT).

To compare clinical and imaging characteristics of extensive macular atrophy with pseudodrusen-like appearance (EMAP) versus diffuse-trickling geographic atrophy (DTGA) and non-diffuse-trickling geographic atrophy (nDTGA) phenotypes of age-related macular degeneration. Prospective, observational study performed in the Ophthalmology Department of IRCCS San Raffaele Hospital between January 2015 and January 2021. Patients examination included fundus autofluorescence (FAF) and optical coherence tomography at baseline and follow-up visits. We measured subfoveal choroidal thickness (SCT), Sattler/choroid ratio (SCR), choroidal vascularity index and ellipsoid zone disruption distance on OCT scans. We calculated progression rates and circularity of the atrophic lesions on FAF images. These variables were compared between the three groups and correlations with progression rates and visual acuity were assessed. Sixty-three eyes from 63 patients were included: 18 with EMAP, 18 with DTGA and 27 with nDTGA. Mean follow-up was 3.73 ± 2.12 years. EMAP and DTGA shared a faster progression, lower circularity and SCR, and higher EZ disruption distance than nDTGA, while SCT and CVI were similar between the three groups. Baseline circularity and SCR correlated with progression rates. EMAP and DTGA show similar OCT and FAF characteristics, which differ from nDTGA.

Neovascular age-related macular degeneration (nAMD) management is one of the largest single-disease contributors to hospital outpatient appointments. Partial automation of nAMD treatment decisions could reduce demands on clinician time. Established artificial intelligence (AI)-enabled retinal imaging analysis tools, could be applied to this use-case, but are not yet validated for it. A primary qualitative investigation of stakeholder perceptions of such an AI-enabled decision tool is also absent. This multi-methods study aims to establish the safety and efficacy of an AI-enabled decision tool for nAMD treatment decisions and understand where on the clinical pathway it could sit and what factors are likely to influence its implementation.

Long-term light exposure, especially in the spectrum of blue light, frequently causes excessive oxidative stress in dry age-related macular degeneration (AMD). Here, to gain insight into the underlying mechanism, we focused on mitochondrial dynamics alterations under long-term exposure to blue light in mouse and retinal cells. Six-month-old C57BL/6 mice were exposed to blue light (450 nm, 800 lx) for 2 weeks. The phenotypic changes in the retina were assayed using haematoxylin-eosin staining and transmission electron microscopy. Long-term blue light exposure significantly thinned each retinal layer in mice, induced retinal apoptosis and impaired retinal mitochondria. A retinal pigment epithelial cell line (ARPE-19) was used to verify the phototoxicity of blue light. Flow cytometry, immunofluorescence and MitoSox Red probe experiments confirmed that more total and mitochondria-specific ROS were generated in the blue light group than in the control group. Mito-Tracker Green probe showed fragmented mitochondrial morphology. The western blotting results indicated a significant increase in DRP1, OMA1, and BAX and a decrease in OPA1 and Bcl-2. In conclusion, long-term exposure to blue light damaged the retinas of mice, especially the ONL and RPE cells. There was destruction and dysfunction of mitochondria in RPE cells in vivo and in vitro. Mitochondrial dynamics were disrupted with characteristics of fusion-related obstruction after blue-light irradiation.

In October 2019, Novartis launched brolucizumab, a single-chain variable fragment molecule targeting vascular endothelial growth factor A, for the treatment of neovascular age-related macular degeneration. In 2020, rare cases of retinal vasculitis and/or retinal vascular occlusion (RV/RO) were reported, often during the first few months after treatment initiation, consistent with a possible immunologic pathobiology. This finding was inconsistent with preclinical studies in cynomolgus monkeys that demonstrated no drug-related intraocular inflammation, or RV/RO, despite the presence of preexisting and treatment-emergent antidrug antibodies (ADAs) in some animals. In this study, the immune response against brolucizumab in humans was assessed using samples from clinical trials and clinical practice. In the brolucizumab-naïve population, anti-brolucizumab ADA responses were detected before any treatment, which was supported by the finding that healthy donors can harbor brolucizumab-specific B cells. This suggested prior exposure of the immune system to proteins with structural similarity. Experiments on samples showed that naïve and brolucizumab-treated ADA-positive patients developed a class-switched, high-affinity immune response, with several linear epitopes being recognized by ADAs. Only patients with RV/RO showed a meaningful T cell response upon recall with brolucizumab. Further studies in cynomolgus monkeys preimmunized against brolucizumab with adjuvant followed by intravitreal brolucizumab challenge demonstrated that high ADA titers were required to generate ocular inflammation and vasculitis/vascular thrombosis, comparable to RV/RO in humans. Immunogenicity therefore seems to be a prerequisite to develop RV/RO. However, because only 2.1% of patients with ADA develop RV/RO, additional factors must play a role in the development of RV/RO.

Ocular neovascular diseases including neovascular age-related macular degeneration (nvAMD) are widespread causes of blindness. Patients' non-responsiveness to currently used biologics that target vascular endothelial growth factor (VEGF) poses an unmet need for novel therapies. Here, we identify protein arginine methyltransferase 5 (PRMT5) as a novel therapeutic target for nvAMD. PRMT5 is a well-known epigenetic enzyme. We previously showed that PRMT5 methylates and activates a proangiogenic and proinflammatory transcription factor, the nuclear factor kappa B (NF-κB), which has a master role in tumor progression, notably in pancreatic ductal adenocarcinoma and colorectal cancer. We identified a potent and specific small molecule inhibitor of PRMT5, PR5-LL-CM01, that dampens the methylation and activation of NF-κB. Here for the first time, we assessed the antiangiogenic activity of PR5-LL-CM01 in ocular cells. Immunostaining of human nvAMD sections revealed that PRMT5 is highly expressed in the retinal pigment epithelium (RPE)/choroid where neovascularization occurs, while mouse eyes with laser induced choroidal neovascularization (L-CNV) showed PRMT5 is overexpressed in the retinal ganglion cell layer and in the RPE/choroid. Importantly, inhibition of PRMT5 by PR5-LL-CM01 or shRNA knockdown of PRMT5 in human retinal endothelial cells (HRECs) and induced pluripotent stem cell (iPSC)-derived choroidal endothelial cells (iCEC2) reduced NF-κB activity and the expression of its target genes, such as tumor necrosis factor α (TNF-α) and VEGF-A. In addition to inhibiting angiogenic properties of proliferation and tube formation, PR5-LL-CM01 blocked cell cycle progression at G1/S-phase in a dose-dependent manner in these cells. Thus, we provide the first evidence that inhibition of PRMT5 impedes angiogenesis in ocular endothelial cells, suggesting PRMT5 as a potential therapeutic target to ameliorate ocular neovascularization.