Therapeutic intervention in neuroinflammation for neovascular ocular diseases through targeting the cGAS-STING-necroptosis pathway.

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.

Dual anti-angiogenic and anti-inflammatory action of tRNA-Cys-5-0007 in ocular vascular disease.

BACKGROUND: Intravitreal injections of angiogenesis inhibitors have proved efficacious in the majority of patients with ocular angiogenesis. However, one-fourth of all treated patients fail to derive benefits from intravitreal injections. tRNA-derived small RNA (tsRNA) emerges as a crucial class of non-coding RNA molecules, orchestrating key roles in the progression of human diseases by modulating multiple targets. Through our prior sequencing analyses and bioinformatics predictions, tRNA-Cys-5-0007 has shown as a potential regulator of ocular angiogenesis. This study endeavors to elucidate the precise role of tRNA-Cys-5-0007 in the context of ocular angiogenesis. METHODS: Quantitative reverse transcription PCR (qRT-PCR) assays were employed to detect tRNA-Cys-5-0007expression. EdU assays, sprouting assays, transwell assays, and Matrigel assays were conducted to elucidate the involvement of tRNA-Cys-5-0007 in endothelial angiogenic effects. STZ-induced diabetic model, OIR model, and laser-induced CNV model were utilized to replicate the pivotal features of ocular vascular diseases and evaluate the influence of tRNA-Cys-5-0007 on ocular angiogenesis and inflammatory responses. Bioinformatics analysis, luciferase activity assays, RNA pull-down assays, and in vitro studies were employed to elucidate the anti-angiogenic mechanism of tRNA-Cys-5-0007. Exosomal formulation was employed to enhance the synergistic anti-angiogenic and anti-inflammatory efficacy of tRNA-Cys-5-0007. RESULTS: tRNA-Cys-5-0007 expression was down-regulated under angiogenic conditions. Conversely, tRNA-Cys-5-0007 overexpression exhibited anti-angiogenic effects in retinal endothelial cells, as evidenced by reduced proliferation, sprouting, migration, and tube formation abilities. In diabetic, laser-induced CNV, and OIR models, tRNA-Cys-5-0007 overexpression led to decreased ocular vessel leakage, inhibited angiogenesis, and reduced ocular inflammation. Mechanistically, these effects were attributed to the targeting of vascular endothelial growth factor A (VEGFA) and TGF-ß1 by tRNA-Cys-5-0007. The utilization of an exosomal formulation further potentiated the synergistic anti-angiogenic and anti-inflammatory efficacy of tRNA-Cys-5-0007. CONCLUSIONS: Concurrent targeting of tRNA-Cys-5-0007 for anti-angiogenic and anti-inflammatory therapy holds promise for enhancing the effectiveness of current anti-angiogenic therapy.

The landscape of angiogenesis and inflammatory factors in eyes with myopic choroidal neovascularization before and after anti-VEGF injection.

INTRODUCTION: To investigate the levels of angiogenesis and inflammatory cytokines in individuals with myopic choroidal neovascularization (mCNV) and the changes in these factors following intravitreal anti-VEGF injection. METHODS: Aqueous humor samples were gathered from eyes with mCNV, those with single macular bleeding (SMB) without mCNV in highly myopic eyes, and those with age-related cataracts. Using a multiplex bead immunoassay, we analyzed 28 angiogenesis and inflammatory factors in the aqueous humor. Furthermore, clinical data were documented for correlation analysis. RESULTS: In this study, the levels of vascular endothelial growth factor A (VEGF-A), interleukin 8 (IL-8), and fibroblast growth factors 1 (FGF-1) were significantly elevated in mCNV compared to SMB eyes (p < 0.05). Their odds ratios for mCNV occurrence were 1.05, 3.45, and 2.64, respectively. Hepatocyte growth factor (HGF) and VEGF-C were notably higher in mCNV than in cataract patients (p < 0.05), and VEGF-C correlated to the degree of myopic atrophic maculopathy (p = 0.024). Axial length exhibited a negative correlation with VEGF-A and positive correlations with VEGF-C, HGF, and MCP-1 (p < 0.01). Following anti-VEGF treatment, a reduction in VEGF-A, endothelin-1, and FGF-2 was noted in mCNV patients (p < 0.05), but MCP-1 levels increased. CONCLUSION: Our findings highlight the predominant role of angiogenesis and inflammation factors in mCNV pathogenesis. VEGF-C's correlation with axial length and atrophy suggests its involvement in the process of myopic atrophic maculopathy.

Crocetin inhibits choroidal neovascularization in both in vitro and in vivo models.

Choroidal neovascularization (CNV) is the primary pathogenic process underlying wet age-related macular degeneration, leading to severe vision loss. Despite current anti-vascular endothelial growth factor (VEGF) therapies, several limitations persist. Crocetin, a major bioactive constituent of saffron, exhibits multiple pharmacological activities, yet its role and mechanism in CNV remain unclear. Here, we investigated the potential effects of crocetin on CNV using in vitro and in vivo models. In human umbilical vein endothelial cells, crocetin demonstrated inhibition of VEGF-induced cell proliferation, migration, and tube formation in vitro, as assessed by CCK-8 and EdU assays, transwell and scratch assays, and tube formation analysis. Additionally, crocetin suppressed choroidal sprouting in ex vivo experiments. In the human retinal pigment epithelium (RPE) cell line ARPE-19, crocetin attenuated cobalt chloride-induced hypoxic cell injury, as evidenced by CCK-8 assay. As evaluated by quantitative PCR and Western blot assay, it also reduced hypoxia-induced expression of VEGF and hypoxia-inducible factor 1α (HIF-1α), while enhancing zonula occludens-1 expression. In a laser-induced CNV mouse model, intravitreal administration of crocetin significantly reduced CNV size and suppressed elevated expressions of VEGF, HIF-1α, TNFα, IL-1ß, and IL-6. Moreover, crocetin treatment attenuated the elevation of phospho-S6 in laser-induced CNV and hypoxia-induced RPE cells, suggesting its potential anti-angiogenic effects through antagonizing the mechanistic target of rapamycin complex 1 (mTORC1) signaling. Our findings indicate that crocetin may hold promise as an effective drug for the prevention and treatment of CNV.

Ocular syphilis masquerading as refractory retinal diseases.

PURPOSE: To report two cases of syphilis masquerading as chronic refractory macular diseases. CASE DESCRIPTIONS: Two patients had been diagnosed with neovascular age-related macular degeneration (neovascular AMD) and diabetic macular edema (DME), respectively. The disease worsened despite repeated intravitreal injections of anti-vascular endothelial growth factor (VEGF) and also surgical treatment (in suspected case of DME). Systemic evaluations were positive for syphilis. Intravenous penicillin was started, and the macular diseases improved. The lesions were well controlled afterward. CONCLUSIONS: The current two cases demonstrated that ocular syphilis can masquerade as refractory chronic retinal diseases such as DME and neovascular AMD. Laboratory evaluations for syphilis may be needed, not only for uveitis but also for refractory retinal diseases. Indocyanine green angiography may be helpful to reveal occult syphilis.

Novel CCR3-targeted cyclic peptides as potential therapeutic agents for age-related macular degeneration via inhibiting angiogenesis and reducing retinal photoreceptor damage.

The prolonged intravitreal administration of anti-vascular endothelial growth factor (VEGF) drugs is prone to inducing aberrant retinal vascular development and causing damage to retinal neurons. Hence, we have taken an alternative approach by designing and synthesizing a series of cyclic peptides targeting CC motif chemokine receptor 3 (CCR3). Based on the binding mode of the N-terminal region in CCR3 protein to CCL11, we used computer-aided identification of key amino acid sequence, conformational restriction through different cyclization methods, designed and synthesized a series of target cyclic peptides, and screened the preferred compound IB-2 through affinity. IB-2 exhibits excellent anti-angiogenic activity in HRECs. The apoptosis level of 661W cells demonstrated a significant decrease with the escalating concentration of IB-2. This suggests that IB-2 may have a protective effect on photoreceptor cells. In vivo experiments have shown that IB-2 significantly reduces retinal vascular leakage and choroidal neovascularization (CNV) area in a laser-induced mouse model of CNV. These findings indicate the potential of IB-2 as a safe and effective therapeutic agent for AMD, warranting further development.

Anti-vascular endothelial growth factor biosimilars for neovascular age-related macular degeneration.

RATIONALE: Neovascular age-related macular degeneration (AMD) is a progressive eye disease characterized by choroidal neovascularization (CNV) and is a leading cause of vision loss and disability worldwide. Although intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is an effective treatment option that helps to prevent vision loss or to improve visual acuity in people with neovascular AMD, treatment imposes a significant financial burden on patients and healthcare systems. A biosimilar is a biological product that has been developed to be nearly identical to a previously approved biological product. The use of biosimilars may help reduce costs and so may increase patient access to effective biologic medicines with similar levels of safety to the drugs on which they are based. OBJECTIVES: To assess the benefits and harms of anti-VEGF biosimilar agents compared with their corresponding anti-VEGF agents (i.e. the reference products) that have obtained regulatory approval for intravitreal injections in people with neovascular AMD. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, two other databases, and two trials registries together with reference checking and contact with study authors to identify studies that are included in the review. The latest search date was 2 June 2023. ELIGIBILITY CRITERIA: We included randomized controlled trials (RCTs) that compared approved anti-VEGF biosimilars with their reference products for treating the eyes of adult participants (≥ 50 years) who had an active primary or recurrent choroidal neovascularization lesion secondary to neovascular AMD. OUTCOMES: Our outcomes were: best-corrected visual acuity (BCVA), central subfield thickness (CST), vision-related quality of life, serious ocular and non-ocular adverse events (AE), treatment-emergent adverse events (TEAEs), anti-drug antibodies (ADAs), and serum concentrations of biosimilars and reference drugs. RISK OF BIAS: We assessed the risk of bias (RoB) for seven outcomes reported in a summary of findings table by using the Cochrane RoB 2 tool. SYNTHESIS METHODS: We synthesized results for each outcome using meta-analysis, where possible, by calculating risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI) for dichotomous outcomes and continuous outcomes, respectively. Where this was not possible due to the nature of the data, we summarized the results narratively. We used GRADE to assess the certainty of evidence for prespecified outcomes. INCLUDED STUDIES: We included nine parallel-group multi-center RCTs that enrolled a total of 3814 participants (3814 participating eyes), with sample sizes that ranged from 160 to 705 participants per study. The mean age of the participants in these studies ranged from 67 to 76 years, and the proportion of women ranged from 26.5% to 58.7%. Ranibizumab (Lucentis) was the reference product in seven studies, and aflibercept (Eyelea) was the reference product in two others. All the included studies had been supported by industry. The follow-up periods ranged from 12 to 52 weeks (median 48 weeks). Five studies (56%) were conducted in multi-country settings across Europe, North America and Asia, two studies in India, and one each in Japan and the Republic of Korea. We judged all the included studies to have met high methodological standards. SYNTHESIS OF RESULTS: With regard to efficacy, our meta-analyses demonstrated that anti-VEGF biosimilars for neovascular AMD resulted in little to no difference compared with the reference products for BCVA change at 8 to 12 weeks (MD -0.55 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, 95% CI -1.17 to 0.07; 8 studies, 3603 participants; high-certainty evidence) and the proportion of participants who lost fewer than 15 letters in BCVA at 24 to 48 weeks (RR 0.99, 95% CI 0.98 to 1.01; 7 studies, 2658 participants; moderate-certainty evidence). Almost all participants (96.6% in the biosimilar group and 97.0% in the reference product group) lost fewer than 15 letters in BCVA. The evidence from two studies suggested that there was no evidence of difference between biosimilars and reference products in vision-related quality of life measured by the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) summary scores at 24 to 48 weeks (MD 0.82, 95% CI -0.70 to 2.35; 2 studies, 894 participants; moderate-certainty evidence). With regard to the safety profile, meta-analyses also revealed little to no difference between anti-VEGF biosimilars and the reference products for the proportion of participants who experienced serious ocular AEs (RR 1.24, 95% CI 0.68 to 2.26; 7 studies, 3292 participants; moderate-certainty evidence), and for TEAEs leading to investigational product discontinuation or death (RR 0.96, 95% CI 0.63 to 1.46; 8 studies, 3497 participants; moderate-certainty evidence). Overall, 1.4% of participants in the biosimilar group and 1.2% in the reference product group experienced serious ocular adverse events. The most frequently documented serious ocular AEs were retinal hemorrhage and endophthalmitis. Although the evidence is of low certainty due to imprecision, meta-analysis suggested that anti-VEGF biosimilars led to no difference compared with the reference products for cumulative incidence of ADAs (RR 0.84, 95% CI 0.58 to 1.22; 8 studies, 3066 participants; low-certainty evidence) or mean maximum serum concentrations (MD 0.42 ng/mL, 95% CI -0.22 to 1.05; subgroup of 3 studies, 100 participants; low-certainty evidence). We judged the overall risk of bias to be low for all studies. AUTHORS' CONCLUSIONS: In our review, low to high certainty evidence suggests that there is little to no difference, to date, between the anti-VEGF biosimilars approved for treating neovascular AMD and their reference products in terms of benefits and harms. While anti-VEGF biosimilars may be a viable alternative to reference products, current evidence for their use is based on a limited number of studies - particularly for comparison with aflibercept - with sparse long-term safety data, and infrequent assessment of quality of life outcomes. Our effect estimates and conclusions may be modified once findings have been reported from studies that are currently ongoing, and studies of biosimilar agents that are currently in development. FUNDING: Cochrane Eyes and Vision US Project is supported by grant UG1EY020522, National Eye Institute, National Institutes of Health. Takeshi Hasegawa and Hisashi Noma were supported by Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (Grant numbers: 22H03554, 19K03092, 24K06239). REGISTRATION: Protocol available via doi.org/10.1002/14651858.CD015804.

Differences between young and elderly polypoidal choroidal vasculopathy patients with and without pachychoroid phenotypes.

PURPOSE: To investigate the distinct characteristics between young and elderly polypoidal choroidal vasculopathy (PCV) patients based on the pachy- or non-pachychoroid phenotypes. METHODS: PCV patients treated with intravitreal injections of Conbercept based on the 3 + PRN regimen from 27 centers of China PCV Research Alliance were included. Patients were categorized into the young and the elderly aged group based on the cut-off point determined using the Youden method according to the pachychoroid phenotypes. The characteristics of past medical history, lifestyle factors, fundus manifestations, and treatment response between the subgroups were analyzed. RESULTS: Three hundred eight eligible patients were included. Multivariate logistic regression showed a significant association between age and PCV subtype classification (OR = 0.921, P = 0.002). A cutoff age of 64.5 effectively distinguished between pachychoroid PCV and non-pachychoroid PCV (P < 0.001). Elderly PCV patients had a higher incidence of hypertension history (P = 0.044) but a lower incidence of diabetes history (P = 0.027). In terms of lifestyle, smoking history (P = 0.015) and staying up late (P = 0.004) were more significant in the young group of PCV patients. For clinical characteristics, the proportion of hemorrhagic PCV in the young group was significantly higher (P = 0.038), with a higher proportion of sharp-peaked PED (P = 0.049), thicker choroid (P < 0.001) but a lower portion of double-layer sign (P = 0.023) in OCT. Both groups showed significant anatomical changes compared to baseline in each follow-up period (P < 0.05), with the young group having a higher proportion of good anatomical response after the first injection (P = 0.009). CONCLUSION: PCV patients stratified by subtype exhibit distinct characteristics between the young and elderly groups.

Intravitreal anti-vascular endothelial growth factor and combined photodynamic therapy for pachychoroid neovasculopathy: long-term treatment outcomes.

PURPOSE: To examine the long-term visual outcomes after initial treatment with combined photodynamic therapy (PDT) or aflibercept treat-and-extend (TAE) monotherapy in patients with pachychoroid neovasculopathy (PNV). METHODS: Patients diagnosed with PNV, initially treated with PDT combined with anti-vascular endothelial growth factor (VEGF) or intravitreal aflibercept (IVA) monotherapy in the TAE protocol and followed up for at least 6 months, were included in the study. Medical records were retrospectively reviewed. Survival analysis was performed, in which deterioration in logMAR visual acuity by 0.1 or 0.3 is defined as "death." The annual number of treatments was also analyzed. Sub-analysis was performed on 33 patients diagnosed with PNV without polypoidal lesions. RESULTS: This study included 46 patients (23 in the initial combined PDT group and 23 in the IVA TAE group). Mean age, sex, mean baseline logMAR visual acuity, or duration of observation (3.6 ± 3.2 years vs. 3.1 ± 1.9 years) in both groups were comparable. As for visual outcome, no significant differences were found in survival analysis based on worsening of 0.1 or 0.3 logMAR (3-year survival; 26% vs. 26%, 91% vs. 90%, respectively). Meanwhile, the additional number of anti-VEGF injections per year was significantly lower in the initial combined PDT group than in the IVA TAE group (1.0 ± 1.3 vs. 4.1 ± 1.5, p < 0.0001). No significant differences were found in the number of additional PDTs per year (0.07 ± 0.20 vs. 0.02 ± 0.09, p = 0.27). Similar results were found in a sub-analysis of 33 patients without polyps. CONCLUSION: In the treatment of PNV, regardless of the presence of polyps, the long-term visual outcomes were similar between the initial combined PDT and IVA TAE monotherapy. However, the annual number of anti-VEGF injections was lower in the initial combined PDT group than in the aflibercept TAE group, whereas that of PDT was comparable.

IMAGING AND CLINICAL FEATURES OF PULSATILE POLYPOIDAL CHOROIDAL VASCULOPATHY.

PURPOSE: To investigate the imaging and clinical features of polypoidal choroidal vasculopathy (PCV) with pulsation. METHODS: The PCV eyes were classified into pulsatile and nonpulsatile PCV groups according to the pulsation on indocyanine green angiography. Imaging features including the dye filling time of the polyp and clinical features were compared. RESULTS: A total of 75 eyes were classified into the pulsatile PCV (30 eyes) and the nonpulsatile PCV (45 eyes) groups. The initial filling time and complete filling time of the polyp of the pulsatile PCV group (2.59 ± 0.93 and 8.33 ± 3.42 seconds) were shorter than those of the nonpulsatile PCV group (4.11 ± 1.87 and 10.63 ± 3.81 seconds, P < 0.001 and P = 0.010, respectively). The pigment epithelial detachment height of the pulsatile PCV group (414.90 ± 377.15 µ m) was greater than that of the nonpulsatile PCV group (247.81 ± 164.07 µ m, P = 0.030). The pulsatile PCV group showed a higher prevalence of subretinal hemorrhage (43.33%) after intravitreal injection than the nonpulsatile PCV group (13.95%, P = 0.005) during 12 months. The mean number of injections during 12 months of the pulsatile PCV group (5.48 ± 1.46) was greater than that of the nonpulsatile PCV group (4.09 ± 1.21, P < 0.001). CONCLUSION: Eyes with pulsatile PCV showed shorter filling time of the polyp, greater pigment epithelial detachment height, higher prevalence of subretinal hemorrhage, and more intravitreal injection numbers during 12 months. These might suggest that PCV has distinct imaging and clinical features according to the polyp pulsation.

Preserving visual acuity: a compelling 12-year case study of controlling neovascular age-related macular degeneration.

INTRODUCTION: In neovascular age-related macular degeneration (nAMD) trials, anti-VEGF injection frequency decreases after the first year, while outcomes remain primarily related to the number of injections. To the best of our knowledge, there are no reports of maintaining the best corrected visual acuity (BCVA) for more than 7 years in extension studies. OBJECTIVE: To report a 12-year follow-up of a real-world case of nAMD where BCVA was preserved from declining. CASE DESCRIPTION: A 67-year-old Caucasian female presented to our department in June 2010 due to decreased vision in her left eye (LE) within the preceding months. Examination showed a BCVA of 85 letters (L) in the right eye (RE) and 35 L in the LE. Fundus examination showed drusen in the macula of both eyes. Macular edema, loss of the macular lutein pigment, macular hypo/hyperpigmentation were observed in the LE. A diagnosis of Type 2 choroidal neovascular membrane (CNV) in the LE was established and within two months a Type 1 CNV developed in the RE. She undergone 9 injections of bevacizumab (six) and ranibizumab (three) within the first year of treatment in the LE and seven injections of ranibizumab within the first year in the RE. RESULTS: The LE had a mean of 5.2 injections per year, and the RE had a mean of 7.5 injections per year, from 2010 to 2022. RE's BCVA dropped by 8L (85L to 77L) and central retinal thickness (CRT) increased by 16 µm (276 µm to 292 µm) while LE's BCVA increased by 28L (35L to 63L) and CRT decreased by 369 µm (680 µm to 311 µm), at the twelfth year. CONCLUSIONS: Although the final visual outcome depends on baseline BCVA and lesion type or size, the number of injections is paramount in preserving BCVA and achieving favorable functional outcomes in nAMD, even after 12 years of treatment.

Long-term outcomes of anti-vascular endothelial growth factor therapy with and without posterior scleral reinforcement on myopic maculopathy in myopic choroidal neovascularization eyes.

BACKGROUND: Anti-vascular endothelial growth factor (anti-VEGF) therapy is used for myopic choroidal neovascularization (mCNV). Patchy chorioretinal atrophy (pCRA) enlargement has been reported in mCNV cases associated with vision loss. Our aim was to compare the long-term effectiveness of anti-VEGF therapy alone versus anti-VEGF followed by posterior scleral reinforcement (PSR) in controlling myopic maculopathy in mCNV eyes. METHODS: We performed a retrospective review of the medical records of 95 high myopia patients (refractive error ≥ 6.00 diopters, axial length ≥ 26.0 mm) with mCNV. Patients were treated with anti-VEGF alone (group A) or anti-VEGF followed by PSR (group B). The following data were collected: refractive error, best corrected visual acuity (BCVA), ophthalmic fundus examination, ocular coherence tomography and ocular biometry at 12 and 24 months pre- and postoperatively. The primary outcomes were changes in pCRA and BCVA. RESULTS: In 26 eyes of 24 patients, the mean pCRA size significantly increased from baseline (0.88 ± 1.69 mm2) to 12 months (1.57 ± 2.32 mm2, t = 3.249, P = 0.003) and 24 months (2.17 ± 2.79 mm2, t = 3.965, P = 0.001) postoperatively. The increase in perilesional pCRA in group B (n = 12) was 98.2% and 94.2% smaller than that in group A (n = 14) at 12 and 24 months (Beta 0.57 [95% CI 0.01, 191 1.13], P = 0.048). In group B, 7 eyes (58.3%) gained more than 2 lines of BCVA compared with only 4 eyes (28.6%) in group A at 24 months. CONCLUSION: Anti-VEGF therapy followed by PSR achieved better outcomes than anti-VEGF therapy alone in controlling the development of myopic maculopathy in mCNV and may constitute a better treatment option by securing a better long-term VA outcome.

Disease quiescence in endophthalmitis patients treated with anti-VEGF injections for retinal pathologies.

BACKGROUND: The most feared complication of intravitreal injections is the development of endophthalmitis, which could lead to irreversible visual loss. The aim of this study was to characterize the clinical profiles, causative pathogens, and clinical outcome of patients post-endophthalmitis. METHODS: Retrospective, single center case series study. Clinical records, causative pathogens and management of all cases of endophthalmitis post intravitreal anti-vascular endothelial growth factor (VEGF) injections recorded between January 1st, 2006 and May 30th, 2022; were retrieved. The visual and anatomic changes prior to the episode of endophthalmitis and up to 2 years post-treatment were compared. RESULTS: Eleven post-injection endophthalmitis eyes of 10 patients (n = 3 females; 30%) were recruited at mean age of 64.5 ± 20.4 years. The median last recorded BCVA, up to 3 months prior to the episode of endophthalmitis was 60 (Interquartile range (IQR) 55-75) ETDRS letters. Then, it dropped to 30 (IQR 0-57.5), 35 (IQR 0-52.5) and 35 (IQR 0-57.5) ETDRS letters at presentation, 6- and 12-months follow-up; respectively (p = 0.027, p = 0.017 and p = 0.012). However, at 24 months, the median BCVA returned to similar baseline values prior to the episode of endophthalmitis; BCVA 50 (IQR 0-60) ETDRS letters, p = 0.062. Interestingly, two eyes with neovascular age-related macular degeneration (NVAMD), 1 with myopic choroidal neovascularization (CNV) and 1 with retinal vein occlusion (RVO), experienced disease quiescence and did not require additional anti-VEGF injections up to 2 years of follow-up. CONCLUSION: This study demonstrates long-term recovery of vision loss due to endophthalmitis post anti-VEGF injections, regained up to 2 years later. It also indicates that disease quiescence post endophthalmitis may not only occur in eyes treated for NVAMD, but also with myopic CNV and RVO.

Use of Optical Coherence Tomography and Optical Coherence Tomography Angiography in the Diagnosis and Follow-Up of Endogenous Candida Endophthalmitis: A Case Report.

Background: Endogenous Candida endophthalmitis (ECE) is a rare but sight-threatening disease. Patients with ECE present with various clinical signs and symptoms, which can complicate the diagnosis. The aim of this report was to demonstrate the outcomes of treatment and to diagnose macular complications caused by intraocular inflammation. Case presentation: A 41-year-old woman with a history of acute intermittent porphyria presented with a progressive vision loss in her left eye. Left-eye OCT revealed findings consistent with a fungal etiology, which was confirmed by the culture of swabs collected from a central vein catheter. The outcomes of intravenous fluconazole treatment were not satisfactory, and the patient developed recurrent attacks of porphyria, suggesting a porphyrogenic effect of systemic antifungal therapy. Repeated intravitreal injections with amphotericin B led to a gradual regression of inflammatory lesions. However, follow-up examinations revealed active macular neovascularization (MNV) on both OCT and OCTA scans. The patient was administered intravitreal bevacizumab. At the 11th month of follow-up, OCT and OCTA scans showed significant inflammatory lesions regression with macula scarring, and no MNV activity was detected. Conclusions: This case highlights the importance of OCT and OCTA as valuable noninvasive imaging techniques for the identification of ECE, the monitoring of its clinical course, and the diagnosis of macular complications.

A case of choroidal neovascularization as a first manifestaion of systemic lupus erythematosus.

BACKGROUND: To report a rare occurrence of pigment epitheliopathy associated with choroidal neovasculization as a first manifestation of systemic lupus erythematosus. CASE PRESENTATION: A 54-year-old female, with no prior medical history, sought a second opinion due to sudden drop in vision in her right eye to 20/80. Slit lamp examination was normal. Fundus examination revealed the presence of a subretinal hemorrhage in the macular area. Fundus imaging including optical coherence tomography and fluorescein angiography showed multifocal retinal pigment epitheliopathy associated with choroidal neovascularization (CNV). The patient had received an intravitreal injection of Bevacizumab 2 weeks ago. It was decided to complete the loading dose regimen with two additional Bevacizumab injections, and the first injection was done 2 weeks after her presentation. Two weeks later, the patient reported a rash on her cheeks, painful joints, and purpura. Systemic workup revealed positive ANA, anti-cardiolipin antibodies, and decreased complement levels, with negative anti-histone antibodies. This led to the diagnosis of systemic lupus erythematosus (SLE) based on the "Systemic Lupus International Collaborating Clinics" criteria. The patient was treated with 50 mg of prednisolone which was then tapered. 1 month after the third injection, an showed a total resolution of the sub-retinal fluid with an improvement of vision to 20/20. No recurrence was observed during follow-up. CONCLUSION: Based on the findings from the fundus exam and imaging, systemic symptoms and the blood work-up, we postulate that the pigment epitheliopathy associated with choroidal neovascularization was related to the vaso-occlusive disease at the level of the choroid that can be part of SLE vasculopathy. To our knowledge, this represents the first case in which pigment epitheliopathy and CNV were the primary manifestations of SLE.

Prognostic factors for intravitreal conbercept in the treatment of choroidal neovascularization secondary to pathological myopia.

PURPOSE: 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.

[Choroidal neovascularization in central serous chorioretinopathy]. / Khorioidal'naya neovaskulyarizatsiya pri tsentral'noi seroznoi khorioretinopatii.

The literature review discusses the features of the pathogenesis, differential diagnosis and antiangiogenic therapy of choroidal neovascularization (CNV) associated with central serous chorioretinopathy (CSC), with particular attention given to the choice of antiangiogenic drug and therapy regimen to achieve optimal anatomical and functional outcomes in patients with CSC complicated by CNV.

Topical Application of Cell-Penetrating Peptide Modified Anti-VEGF Drug Alleviated Choroidal Neovascularization in Mice.

Background: Age-related macular degeneration (AMD) stands as the foremost cause of irreversible central vision impairment, marked by choroidal neovascularization (CNV). The prevailing clinical approach to AMD treatment relies on intravitreal injections of anti-vascular endothelial growth factor (VEGF) drugs. However, this method is encumbered by diverse complications, prompting exploration of non-invasive alternatives such as ocular administration via eye drops for anti-VEGF therapy. Methods: Two complexes, 5-FITC-CPP-Ranibizumab (5-FCR) and 5-FITC-CPP-Conbercept (5-FCC), were synthesized by incorporating the anti-VEGF drugs Ranibizumab (RBZ) or Conbercept (CBC) with cell-penetrating peptide (CPP). Circular dichroism spectrum (CD) facilitated complexes characterization. Eye drops was utilized to address laser-induced CNV in mice. Fluorescein fundus angiography (FFA) observe the CNV lesion, while FITC-dextran and IB4 dual fluorescent staining, along with hematoxylin-eosin (HE) staining, assessed in lesion size. Tissue immunofluorescence examined CD31 and VEGF expression in choroidal/retinal pigment epithelial (RPE) tissues. Biocompatibility and biosafety of 5-FCR and 5-FCC was evaluated through histological examination of various organs or cell experiments. Results: Both 5-FCR and 5-FCC exhibited favorable biocompatibility and safety profiles. VEGF-induced migration of Human umbilical vein endothelial cells (HUVECs) significantly decreased post-5-FCR/5-FCC treatment. Additionally, both complexes suppressed VEGF-induced tube formation in HUVECs. FFA results revealed a significant improvement in retinal exudation in mice. Histological examination unveiled the lesion areas in the 5-FCR and 5-FCC groups showed a significant reduction compared to the control group. Similar outcomes were observed in histological sections of the RPE-choroid-sclera flat mounts. Conclusion: In this study, utilizing the properties of CPP and two anti-VEGF drugs, we successfully synthesized two complexes, 5-FCR and 5-FCC, through a straightforward approach. Effectively delivering the anti-VEGF drugs to the target area in a non-invasive manner, suppressing the progression of laser-induced CNV. This offers a novel approach for the treatment of wet AMD.

Inactivation of adenosine receptor 2A suppresses endothelial-to-mesenchymal transition and inhibits subretinal fibrosis in mice.

Anti-vascular endothelial growth factor therapy has had a substantial impact on the treatment of choroidal neovascularization (CNV) in patients with neovascular age-related macular degeneration (nAMD), the leading cause of vision loss in older adults. Despite treatment, many patients with nAMD still develop severe and irreversible visual impairment because of the development of subretinal fibrosis. We recently reported the anti-inflammatory and antiangiogenic effects of inhibiting the gene encoding adenosine receptor 2A (Adora2a), which has been implicated in cardiovascular disease. Here, using two mouse models of subretinal fibrosis (mice with laser injury-induced CNV or mice with a deficiency in the very low-density lipoprotein receptor), we found that deletion of Adora2a either globally or specifically in endothelial cells reduced subretinal fibrosis independently of angiogenesis. We showed that Adora2a-dependent endothelial-to-mesenchymal transition contributed to the development of subretinal fibrosis in mice with laser injury-induced CNV. Deficiency of Adora2a in cultured mouse and human choroidal endothelial cells suppressed induction of the endothelial-to-mesenchymal transition. A metabolomics analysis of cultured human choroidal endothelial cells showed that ADORA2A knockdown with an siRNA reversed the increase in succinate because of decreased succinate dehydrogenase B expression under fibrotic conditions. Pharmacological inhibition of ADORA2A with a small-molecule KW6002 in both mouse models recapitulated the reduction in subretinal fibrosis observed in mice with genetic deletion of Adora2a. ADORA2A inhibition may be a therapeutic approach to treat subretinal fibrosis associated with nAMD.

Real-world experience of brolucizumab in nAMD.

PURPOSE: To evaluate real-world outcomes with neovascular age-related macular degeneration (nAMD) in relation to anatomical success, visual outcomes, and safety of intravitreal brolucizumab (IVBr) injection at 1.5 years. METHODS: Prospective, randomized, single-center study between December 2020 and December 2022 that included 71 eyes of 62 patients with nAMD, who received IVBr. Patients were divided into three groups, i.e., naïve choroidal neovascular membrane (CNVM), switched therapy (st) CNVM, and st polypoidal choroidal vasculopathy (stPCV). They were subdivided into dry, minimal fluid (fluid <50 microns)/pigment epithelial detachment (PED) and persistent fluid (fluid >100 microns)/PED subgroups depending upon the fluid level at the end of 1.5 years. Best-corrected visual acuity (BCVA), central macular thickness (CMT), status of fluid, and number of injections at 1.5 years were evaluated. From the beginning, patients were treated on pro re nata (PRN) basis. RESULTS: Of the 71 eyes, 27 eyes (38%) were naïve CNVM, 35 eyes (49.3%) were stCNVM, and 9 (12.7%) were stPCV cases. Significant vision improvement after 1.5 years was seen in the stCNVM category (P = 0.001), while CMT reduction was significant in all three groups (P < 0.05). The mean number of injections required in naïve CNVM and stCNVM groups was significantly less as compared to the stPCV group (P = 0.017). Further, vision improvement was significant in the "Minimal fluid" subgroup (P = 0.002), while the CMT improvement was significant in the "Minimal fluid" and "Dry" subgroups each with P < 0.0001. No ocular/systemic adverse events including intraocular inflammation (IOI) were noted. CONCLUSION: In a real-world scenario, with 203 procedures and 1.5-year follow-up, brolucizumab is found to be efficacious and safe with the need for a lesser number of injections and more interval-free period in the management of naïve CNVM, stCNVM, and stPCV patients.