UNASSIGNED: Recruitment and activation of inflammatory cells, such as retinal microglia/macrophages, in the subretinal space contribute significantly to the pathogenesis of age-related macular degeneration (AMD). This study aims to explore the functional role of vascular endothelial growth factor (VEGF-A), placental growth factor (PlGF) and VEGF-A/PlGF heterodimer in immune homeostasis and activation during pathological laser-induced choroidal neovascularization (CNV).
UNASSIGNED: To investigate these roles, we utilized the PlGF-DE knockin (KI) mouse model, which is the full functional knockout (KO) of PlGF. In this model, mice express a variant of PlGF, named PlGF-DE, that is unable to bind and activate VEGFR-1 but can still form heterodimer with VEGF-A.
UNASSIGNED: Our findings demonstrate that, although there is no difference in healthy conditions, PlGF-DE-KI mice exhibit decreased microglia reactivity and reduced recruitment of both microglia and monocyte-macrophages, compared to wild-type mice during laser-induced CNV. This impairment is associated with a reduction in VEGF receptor 1 (VEGFR-1) phosphorylation in the retinae of PlGF-DE-KI mice compared to C57Bl6/J mice. Corroborating these data, intravitreal delivery of PlGF or VEGF-A/PlGF heterodimer in PlGF-DE-KI mice rescued the immune cell response at the early phase of CNV compared to VEGF-A delivery.
UNASSIGNED: In summary, our study suggests that targeting PlGF and the VEGF-A/PlGF heterodimer, thereby preventing VEGFR-1 activation, could represent a potential therapeutic approach for the management of inflammatory processes in diseases such as AMD.

Age-related macular degeneration (AMD) is a common cause of vision loss. The aggressive form of AMD is associated with ocular neovascularization and subretinal fibrosis, representing a responsive outcome against neovascularization mediated by epithelial-mesenchymal transition of retinal pigment epithelium (RPE) cells. A failure of the current treatment (anti-vascular endothelial growth factor therapy) has also been attributed to the progression of subretinal fibrosis. Hypoxia-inducible factors (HIFs) increase gene expressions to promote fibrosis and neovascularization. HIFs act as a central pathway in the pathogenesis of AMD. HIF inhibitors may suppress ocular neovascularization. Nonetheless, further investigation is required to unravel the aspects of subretinal fibrosis. In this study, we used RPE-specific HIFs or von Hippel-Lindau (VHL, a regulator of HIFs) conditional knockout (cKO) mice, along with pharmacological HIF inhibitors, to demonstrate the suppression of subretinal fibrosis. Fibrosis was suppressed by treatments of HIF inhibitors, and similar suppressive effects were detected in RPE-specific Hif1a/Hif2a- and Hif1a-cKO mice. Promotive effects were observed in RPE-specific Vhl-cKO mice, where fibrosis-mediated pathologic processes were evident. Marine products\' extracts and their component taurine suppressed fibrosis as HIF inhibitors. Our study shows critical roles of HIFs in the progression of fibrosis, linking them to the potential development of therapeutics for AMD.

Rationale: Current treatments for ocular angiogenesis primarily focus on blocking the activity of vascular endothelial growth factor (VEGF), but unfavorable side effects and unsatisfactory efficacy remain issues. The identification of novel targets for anti-angiogenic treatment is still needed. Methods: We investigated the role of tsRNA-1599 in ocular angiogenesis using endothelial cells, a streptozotocin (STZ)-induced diabetic model, a laser-induced choroidal neovascularization model, and an oxygen-induced retinopathy model. CCK-8 assays, EdU assays, transwell assays, and matrigel assays were performed to assess the role of tsRNA-1599 in endothelial cells. Retinal digestion assays, Isolectin B4 (IB4) staining, and choroidal sprouting assays were conducted to evaluate the role of tsRNA-1599 in ocular angiogenesis. Transcriptomic analysis, metabolic analysis, RNA pull-down assays, and mass spectrometry were utilized to elucidate the mechanism underlying angiogenic effects mediated by tsRNA-1599. Results: tsRNA-1599 expression was up-regulated in experimental ocular angiogenesis models and endothelial cells in response to angiogenic stress. Silencing of tsRNA-1599 suppressed angiogenic effects in endothelial cells in vitro and inhibited pathological ocular angiogenesis in vivo. Mechanistically, tsRNA-1599 exhibited little effect on VEGF signaling but could cause reduced glycolysis and NAD+/NADH production in endothelial cells by regulating the expression of HK2 gene through interacting with YBX1, thus affecting endothelial effects. Conclusions: Targeting glycolytic reprogramming of endothelial cells by a tRNA-derived small RNA represents an exploitable therapeutic approach for ocular neovascular diseases.

Choroidal neovascular membrane (CNVM) in Vogt-Koyanagi-Harada disease (VKH) is a known entity, observed primarily during the chronic convalescent and chronic-recurrent phases of the disease. However, the peripapillary location of CNVM is a rare finding.We describe a case of chronic VKH with bilateral peripapillary CNVM detected using multimodal imaging and the associated differential diagnoses and treatment approach.A combination of anti-vascular endothelial growth factor injections, systemic steroids and immunosuppressants is often required to manage the aggressive course of this choroidal neovascularisation.

To compare the efficacy and safety of the proposed aflibercept biosimilar SCD411 and reference aflibercept in patients with neovascular age-related macular degeneration, this randomized, double-masked, parallel-group, multicenter study was conducted in 14 countries from 13 August 2020 to 8 September 2022. Patients with neovascular age-related macular degeneration. With subfoveal, juxtafoveal, or extrafoveal choroidal neovascularization were aged 50 years or older. Intravitreal injection of SCD411 or aflibercept (2.0 mg) were administered every 4 weeks for the first three injections and every 8 weeks until week 48. The primary efficacy endpoint was the change in best-corrected visual acuity from baseline to week 8 with an adjusted equivalence margin of ± 3.0 letters. Patients were randomly assigned to receive either SCD411 (n = 288) or reference aflibercept (n = 288). A total of 566 participants (98.3%) completed week 8 of the study. The least-squares mean difference of change in best-corrected visual acuity from baseline to week 8 (SCD411-aflibercept) was - 0.4 letters (90% confidence interval =  - 1.6 to 0.9). The incidence of ocular (69 of 287 [24.0%] vs. 71 of 286 [24.8%]) and serious ocular (5 of 287 [1.7%] vs. 3 of 286 [1.0%]) treatment-emergent adverse effects were similar between the SCD411 and aflibercept groups. Immunogenicity analysis revealed a low incidence of neutralizing antibody formation in both groups. In conclusion, SCD411 has equivalent efficacy compared with reference aflibercept in patients with neovascular age-related macular degeneration and has a comparable safety profile. The results support the potential use of SCD411 for the treatment of neovascular age-related macular degeneration.

Adult-onset foveomacular vitelliform dystrophy (AOFVD) is a rare disease characterized by accumulation of yellowish deposits in the macula. Rarely, it may be complicated by choroidal neovascularization (CNV). Cases with CNV may be confused with occult CNV in age-related macular degeneration. In our case, we will present the visual and anatomical results of a patient with AOVF-related CNV, in which we administered 3 doses of intravitreal ranibizumab (IVR). A 59-year-old female patient, who attended our clinic with the complaint of decreased vision in both eyes, was diagnosed with AOVF-related CNV in both eyes and was treated with 3 doses of IVR for 3 months. Despite the improvement in visual and anatomical functions 1 month after the first dose, vision decreased, and anatomical functions regressed to the pre-injection state in continued injections. IVR therapy is not an appropriate treatment option in the treatment of AOVF-associated CNV.

BACKGROUND: Pathological angiogenesis causes significant vision loss in neovascular age-related macular degeneration and other retinopathies with neovascularization (NV). Neuronal/glial-vascular interactions influence the release of angiogenic and neurotrophic factors. We hypothesized that botulinum neurotoxin serotype A (BoNT/A) modulates pathological endothelial cell proliferation through glial cell activation and growth factor release.
METHODS: A laser-induced choroidal NV (CNV) was employed to investigate the anti-angiogenic effects of BoNT/A. Fundus fluorescence angiography, immunohistochemistry, and real-time PCR were used to assess BoNT/A efficacy in inhibiting CNV and the molecular mechanisms underlying this inhibition. Neuronal and glial suppressor of cytokine signaling 3 (SOCS3) deficient mice were used to investigate the molecular mechanisms of BoNT/A in inhibiting CNV via SOCS3.
RESULTS: In laser-induced CNV mice with intravitreal BoNT/A treatment, CNV lesions decreased > 30%; vascular leakage and retinal glial activation were suppressed; and Socs3 mRNA expression was induced while vascular endothelial growth factor A (Vegfa) mRNA expression was suppressed. The protective effects of BoNT/A on CNV development were diminished in mice lacking neuronal/glial SOCS3.
CONCLUSIONS: BoNT/A suppressed laser-induced CNV and glial cell activation, in part through SOCS3 induction in neuronal/glial cells. BoNT/A treatment led to a decrease of pro-angiogenic factors, including VEGFA, highlighting the potential of BoNT/A as a therapeutic intervention for pathological angiogenesis in retinopathies.

The microglia-mediated neuroinflammation have been shown to play a crucial role in the ocular pathological angiogenesis process, but specific immunotherapies for neovascular ocular diseases are still lacking. This study proposed that targeting GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) might be a novel immunotherapy for these angiogenesis diseases. We found a significant upregulation of CGAS and STING genes in the RNA-seq data derived from retinal tissues of the patients with proliferative diabetic retinopathy. In experimental models of ocular angiogenesis including laser-induced choroidal neovascularization (CNV) and oxygen-induced retinopathy (OIR), the cGAS-STING pathway was activated as angiogenesis progressed. Either genetic deletion or pharmacological inhibition of STING resulted in a remarkable suppression of neovascularization in both models. Furthermore, cGAS-STING signaling was specifically activated in myeloid cells, triggering the subsequent RIP1-RIP3-MLKL pathway activation and leading to necroptosis-mediated inflammation. Notably, targeted inhibition of the cGAS-STING pathway with C-176 or SN-011 could significantly suppress pathological angiogenesis in CNV and OIR. Additionally, the combination of C-176 or SN-011 with anti-VEGF therapy led to least angiogenesis, markedly enhancing the anti-angiogenic effectiveness. Together, our findings provide compelling evidence for the importance of the cGAS-STING-necroptosis axis in pathological angiogenesis, highlighting its potential as a promising immunotherapeutic target for treating neovascular ocular diseases.

UNASSIGNED: The aim of this study was to elucidate the role of Sema4D in the pathogenesis of senescence-associated choroidal neovascularization (CNV) and to explore its underlying mechanisms.
UNASSIGNED: In this study, we utilized a model of laser-induced CNV in both young (3 months old) and old (18 months old) mice, including those with or without Sema4D knockout. The expression and localization of Sema4D in CNV were assessed using PCR, Western blot, and immunostaining. Subsequently, the morphological and imaging examinations were used to evaluate the size of CNV and vascular leakage. Finally, the expression of M2 markers, senescence-related markers, and molecules involved in the RhoA/ROCK pathway was detected.
UNASSIGNED: We found that Sema4D was predominantly expressed in macrophages within CNV lesions, and both the mRNA and protein levels of Sema4D progressively increased following laser photocoagulation, a trend more pronounced in old mice. Moreover, Sema4D knockout markedly inhibited M2 polarization in senescent macrophages and reduced the size and leakage of CNV, particularly in aged mice. Mechanistically, aging was found to upregulate RhoA/ROCK signaling, and knockout of Sema4D effectively suppressed the activation of this pathway, with more significant effects observed in aged mice.
UNASSIGNED: Our findings revealed that the deletion of Sema4D markedly inhibited M2 macrophage polarization through the suppression of the RhoA/ROCK pathway, ultimately leading to the attenuation of senescence-associated CNV. These data indicate that targeting Sema4D could offer a promising approach for gene editing therapy in patients with neovascular age-related macular degeneration.

OBJECTIVE: To identify risk factors influencing visual outcomes in patients with pathological myopia-associated choroidal neovascularization (PM-CNV) following intravitreal injections of conbercept.
METHODS: A total of 86 eyes from 86 patients received intravitreal conbercept in a 1 + PRN regimen. After the initial injection, patients were followed for 12 months. They were categorized into two groups based on their 12-month visual acuity change: those who achieved greater than a one-line improvement in BCVA (improved group; n = 65) and those who experienced a one-line or lesser improvement or a decrease in BCVA (non-improved group; n = 21).
RESULTS: Over the 12-month period, the mean BCVA in the improved group significantly improved from 0.82 to 0.41 LogMAR. In the non-improved group, BCVA changed from 1.24 to 1.09 LogMAR. Similarly, the mean CRT decreased from 426.21 μm at baseline to 251.56 μm at 12 months in the improved group, and from 452.47 to 382.45 μm in the non-improved group. Multivariable logistic regression analyses revealed that older age (OR 1.287; 95% CI 1.019-1.625; P = 0.034), poorer baseline BCVA (OR 6.422; 95% CI 1.625-25.384; P = 0.008), the presence of subfoveal CNV (OR 4.817; 95% CI 1.242-18.681; P = 0.023), and organized interlacing patterns of CNV morphology (OR 5.593; 95% CI 1.397-22.392; P = 0.015) emerged as independent risk factors correlated with worsened visual prognosis following intravitreal conbercept injections.
CONCLUSIONS: Conbercept demonstrates significant efficacy and safety in treating PM-CNV. Key factors influencing visual recovery post-treatment include older age, poorer baseline BCVA, the presence of subfoveal CNV, and organized interlacing patterns of CNV morphology.