Neovascular Lesions Research Articles

Two macular holes due to choroidal neovascularization after pars plana vitrectomy with internal limiting membrane peeling

Introduction: To present a case of two macular holes (MHs) with myopic choroidal neovascularization (CNV) lesion. Case Presentation: A single case was evaluated. A 72-year-old woman presented with two small MHs in her left eye. One year ago, she had undergone vitrectomy for myopic foveal schisis, and a significant reduction of the schisis and a CNV lesion was observed after surgery. On examination, OCT (optical coherence tomography) showed the atrophic CNV and two MHs were located upper and lower close to the edge of the CNV. A PPV (pars plana vitrectomy) with two free ILM (internal limiting membrane) flaps implant was performed in her left eye. At 3 months after surgery, the two macular holes were both closed and the BCVA (best corrected visual acuity) was improved. Conclusions: Two MHs secondary to the regression of CNV after primary PPV combined with complete ILM peeling in eyes with macular schisis.

Morphometrics of polypoidal choroidal vasculopathy lesions and choroidal vascular associated with treatment response using swept-source optical coherence tomography angiography

PurposeTo evaluate quantitative metrics of neovascularization lesions and choroidal vascular using swept-source optical coherence tomography angiography (SS-OCTA) in polypoidal choroidal vasculopathy (PCV) eyes, and investigate the relationship between imaging biomarkers and treatment outcomes of intravitreal anti-vascular endothelial growth factor (VEGF). MethodsWe retrospectively recruited 56 PCV patients. Choroidal features included subfoveal choroidal thickness (SFCT) and choroidal vascularity index (CVI). Quantitative metrics of neovascularization lesions included total vessel length (TVL), average vessel length (AVL), junction density (JD), total number of endpoints (TNE), and mean lacunarity (ML). We performed multivariate logistic and linear regression models to determine the prognostic factors for functional and morphological outcomes. ResultsBy comparison, functional good-responders had poorer best corrected visual acuity, higher TNE, and lower ML at baseline. Morphological good-responders had higher central retinal thickness, higher TNE, lower TVL and AVL, lower ML, lower SFCT and CVI. High-shrinkage of vessel area subgroup had higher JD and TNE, lower TVL and AVL, lower ML, lower SFCT and CVI. Multivariate analysis showed good morphological response was correlated with lower SFCT (P < 0.01). High-shrinkage subgroup was correlated with lower AVL (P = 0.017) and higher TNE (P < 0.01). ConclusionQuantitative metrics of neovascularization lesions and choroidal characteristics using SS-OCTA had the potential to be imaging biomarkers for predicting the response to anti-VEGF treatment. PCV lesions with higher TNE and lower AVL tended to appear higher shrinkage of vessel area, and lower SFCT was correlated with good morphological response.

Imaging-Guided Classification of Neovascularization in Neovascular Age-Related Macular Degeneration: Progress to Date.

Purpose: To review the evolution of terminology describing the classification of lesions in neovascular age-related macular degeneration (nAMD) based on retinal imaging technologies. Methods: A review of the current and historical literature on imaging-guided classification of neovascularization in nAMD was performed. Results: Imaging-guided classification of neovascularization in nAMD facilitates understanding of the pathological mechanisms and disease progression. Neovascularization classification has evolved with advances in imaging technologies, from earlier classifications based on neovascularization patterns assessed by fluorescein angiography to multimodal imaging patterns, resulting in varied descriptions of lesions depending on the techniques used. Until recently, there has been a lack of consensus regarding the clinical features of choroidal neovascularization lesion types as a result of the imaging modalities initially used to define them; a recent consensus on classification has the potential to simplify and clarify descriptions of neovascularization in nAMD. The use of multimodal imaging techniques will improve lesion identification and has the potential to individualize treatment plans and improve outcomes. Conclusions: Widespread adoption of a consensus-based, image-guided classification system for neovascular lesions in nAMD and the appropriate imaging techniques used to identify them will aid clinical research and could potentially improve patient outcomes by individualizing treatment plans in the future.

α-Klotho prevents diabetic retinopathy by reversing the senescence of macrophages

BackgroundDiabetic retinopathy (DR) is a common microvascular complication of diabetes mellitus (DM) and a significant cause of acquired blindness in the working-age population worldwide. Aging is considered as an important risk factor for DR development. Macrophages in aged mice bear typical M2 marker proteins but simultaneously express a pro-inflammatory factor profile. This may explain why the level of intraocular inflammation does not decrease during proliferative diabetic retinopathy (PDR) despite the occurrence of neovascularization and fibrosis (M2 activation). α-Klotho (KL) was originally discovered as a soluble anti-aging factor, which is mainly expressed in kidney tubular epithelium, choroid plexus in the brain and secreted in the blood. However, the role of KL in DR pathophysiology has not been previously reported.MethodsType 1 (streptozotocin [STZ]-induced) and type 2 (a high-fat diet along with a low dose of STZ) diabetic mouse models were established and injected with or without KL adenovirus via the tail vein for 12 weeks. Vldlr−/− mice were injected intravitreally with or without soluble KL protein from P8 to P15. The retinal structure and function were analyzed by electroretinogram and optical coherence tomography. The neovascular lesions were analyzed by retinal flat mount and RPE flat mount. The senescence markers, macrophage morphology, and KL expression levels were detected by immunofluorescence staining. A cell model was constructed using RAW264.7 cells stimulated by 4-hydroxynonenal (4HNE) and transfected with or without KL adenovirus. The senescence-associated secretory phenotypes were detected by qRT-PCR. Senescence was detected by SA-β-Gal staining. Serum, aqueous humor, and vitreous humor KL levels of proliferative diabetic retinopathy (PDR) patients were measured by enzyme‐linked immunosorbent assay. Quantitative proteomics and bioinformatics were applied to predict the change of proteins and biological function after overexpression of KL in macrophages. The effects of KL on the HECTD1 binding to IRS1 were analyzed by bioinformatics, molecular docking, and Western Blot.ResultsSerum, aqueous humor, and vitreous humor KL levels were lower in patients with PDR than in those with cataracts. KL relieved the retinal structure damage, improved retina function, and inhibited retinal senescence in diabetic mice. KL administration attenuated the neovascular lesions in VLDLR−/− mice by decreasing the secretion of VEGFA and FGF2 from macrophages. KL also protected RAW264.7 cells from 4HNE-induced senescence. Additionally, it inhibited E3 ubiquitin ligase HECTD1 expression in both diabetic mouse peripheral blood mononuclear cells and 4HNE-treated RAW264.7 cells. KL inhibited HECTD1 binding to IRS1 and reduced the ubiquitination of IRS1.ConclusionsMacrophage aging is involved in DM-induced retinopathy. KL alleviates DM-induced retinal macrophage senescence by downregulating HECTD1 and decreasing IRS1 ubiquitination and degradation. Meanwhile, KL administration attenuated the neovascular lesions by altering the activation state of macrophages and decreasing the expression of VEGFA and FGF2.

Natural killer cells promote neutrophil extracellular traps and restrain macular degeneration in mice.

Neovascular age-related macular degeneration (nvAMD) is the leading cause of blindness in the elderly population. Although it is known that nvAMD is associated with focal inflammation, understanding of the precise immune components governing this process remains limited. Here, we identified natural killer (NK) cells as a prominent lymphocyte population infiltrating the perivascular space of choroidal neovascularization (CNV) lesions in patients with nvAMD and in mouse models. Olink proteomic analysis and single-cell RNA sequencing combined with knockout studies demonstrated the involvement of C-C chemokine receptor 5 (CCR5) in NK cell recruitment and extravasation at the CNV sites of mice. Depletion of NK cells or inhibition of activating receptor NK group 2, member D (NKG2D) inhibited the formation of neutrophil extracellular traps, increased vascular leakage, and exacerbated pathological angiogenesis, indicating that NK cells restrain pathogenesis in this mouse model. Age is the strongest risk factor for AMD, and we show that NK cells from aged human donors exhibited a less cytotoxic phenotype. NK cells from old mice exhibited compromised protective effects in the CNV mouse model. In addition, interleukin-2 complex-mediated expansion of NK cells improved CNV formation in mice. Collectively, our study highlights NK cells as a potential therapeutic target for patients with nvAMD.

Long-term functional, anatomical outcome, and qualitative analysis by OCTA, as a predictor of disease recurrences in patients with choroidal neovascularization secondary to angioid streaks

BackgroundTo report the risk of exudation recurrence and long-term outcomes in patients with choroidal neovascularization secondary to angioid streaks, according to its morphology and characteristics by optical coherence tomography angiography.MethodsRetrospective analysis of electronic medical records from three hospitals. We enrolled patients with a clinical diagnosis of angioid streaks choroidal neovascularization that had a minimum follow-up of 12 months. From each record, we extracted general demographic data, best corrected visual acuity (baseline, before and after each disease recurrence and last on file), type of treatment, time between last intravitreal injection and disease recurrence, and classification of the neovascular lesion morphology by optical coherence tomography, and optical coherence tomography angiography. Patients with myopic choroidal neovascularization were used as controls. Interobserver agreement was assessed with a Cohen-Kappa test. The Odds ratio was calculated with a chi2 test for significance. Visual acuity change through time was evaluated with an ANOVA for repeated measurements with an alpha value of 0.05 for statistical significance.ResultsWe enrolled 30 patients in the study group and 14 in the control group. In the study group, the baseline and final BCVA were 0.861 ± 0.59 and 1.095 ± 0.61 logMAR (p = 0.1) respectively. Control group: 1.045 ± 0.57 and 0.617 ± 0.53 logMAR (p < 0.05). In the study group, the predominant CNV type by OCTA was mixed (37%), and interlacing (57%) in the control group. Mixed and cog-wheel patterns at baseline had increased Odds for recurrence in the study group (p = 0.09). Patients in the study group required more intravitreal injections on each recurrence episode to achieve disease control (3.5 ± 1.5 vs.1.4 ± 0.2, p < 0.01).ConclusionsThe benefits of anti-VEGF treatment are lost over time in patients with angioid streaks and CNV. Lesion characteristics by optical coherence tomography angiography could help physicians predict the risk of recurrence.Trial registrationRetrospective registered, and IRB approved.

Factors affecting prognosis and need for anti-vascular endothelial growth factor injections in wet age-related macular degeneration.

To understand factors affecting visual prognosis and the number of intravitreal antivascular endothelial growth factor (anti-VEGF) injections needed to stabilize wet age-related macular degeneration (AMD). In this retrospective cohort, 119 treatment-naïve wet AMD patients were followed for two years. In patients with bilateral disease, the eye with worse best-corrected visual acuity (BCVA) or that received more intravitreal injections was recruited as the study eye. In all visits, BCVA was recorded, ophthalmological examination was performed including macular optical coherence tomography imaging. Twenty health status/lifestyle questions were asked to the patients via phone as potential risk factors. All patients received 3 loading doses of intravitreal bevacizumab injections and received repeat injections of aflibercept or ranibizumab when the eye had a new, active neovascular lesion. Patients who took regular micronutrition had similar visual outcome and injection numbers compared to the ones who did not. Patients with bilateral disease needed less intravitreal injections compared to unilateral AMD patients (p = 0.016) and women on hormone replacement therapy (HRT) required less injections compared to the women who were not (p = 0.024). Female patients had a mean gain of 2.7 letters while male patients lost 3.8 letters (p = 0.038). Wet AMD started at an earlier age in smokers (p = 0.002). Patients with a better education level presented earlier with better BCVA (p = 0.037). HRT and anti-VEGF injections to the fellow eye improved the prognosis of wet AMD, while male patients had slightly worse prognosis. Estrogen's protective effects and potential contribution in wet AMD needs further attention. Retrospectively registered: 2020/0622.

Long-term results of the treatment of patients with exudative age-related macular degeneration during the COVID-19 pandemic

PurposeTo quantify the long-term impact (24 months) on the visual results and activity of neovascular lesions of COVID-19 confinement in patients with nAMD in our population. MethodsA retrospective observational study of patients with nAMD who attended consultation or were treated during the 3 months before confinement was carried out. Results144 patients (168 eyes) with nAMD were included, 51 of them (35.42%) came during confinement, and at 24 months the final cohort was 118 patients (133 eyes).The previous VA of 57.99 ± 23.68 letters decreased, clinically relevant and statistically significant, by an average of 6.87 (±16.84) and 7.89 (±19.58) at 12- and 24-months follow-up. This change differs significantly from the two-year vision change observed in the national database of pretreated patients.The median number of injections and consultations is lower in our group at 12 months, compared to the pre-pandemic national database, and tends to equalize at 24 months.We did not find differences in vision when we compared patients who attended consultations during confinement or in treatment intervals greater than 8 weeks (Tq8w). ConclusionsThe VA of patients with nAMD decreased significantly after confinement, probably due to the lower number of antiangiogenic injections and consultations during the first year, and did not recover during the second year despite the increase in the number of injections and visits close to those reported before confinement.

Qualitative and quantitative comparisons of type 1 macular neovascularizations between pachychoroid neovasculopathy and neovascular age-related macular degeneration using optical coherence tomography angiography

ObjectivesTo compare qualitative and quantitative features of type 1 macular neovascularizations (MNV) in pachychoroid neovasculopathy (PNV) and neovascular age-related macular degeneration (nAMD).MethodsForty-three treatment-naive eyes of 41 PNV patients and 40 treatment-naive eyes of 38 patients with nAMD were included. The patients were classified as PNV or nAMD according to the presence of pachychoroid features and soft/reticular drusen. Presence of central trunk and maturity of the MNV were evaluated on optical coherence tomography angiography (OCTA) images. MNV area, vessel density (VD), total vessel length (VL), number of intersection points (IPs), fractal dimension (FD), and lacunarity (LAC) were calculated using ImageJ software and FracLac plugin.ResultsThe mean age was 56.8 ± 8.7 years in PNV and 70.4 ± 8.8 years in neovascular AMD groups (p < 0.001). Compared to nAMD, the presence of central trunk was less frequent in PNV (48.8% vs 77.5%, p = 0.007). Immature MNV pattern was observed more frequently in PNV eyes than nAMD (41.9% vs 20.0%, p = 0.009). PNV cases had significantly lower median MNV area [0.913(1.115) vs 2.542(3.273) mm²], total VL [14.84 (20.46) vs 36.34 (44.68) mm], number of IPs [104(140) vs 335(417.3)], and FD [1.56(0.10) vs 1.59(0.11)] comparing to nAMD cases (p < 0.001, p = 0.001, p < 0.001, p = 0.043 respectively). However, the mean VD (42.4 ± 6.8 vs 42.9 ± 9.0%) and the median LAC values [0.42 (0.09) vs 0.42 (0.09)] did not differ significantly between groups (p = 0.776, p = 0.526, respectively).ConclusionMorphological and quantitative differences exist in type 1 neovascular lesions. Type 1 MNVs in the PNV group are characterized by a smaller and less complex structure.

NONEXUDATIVE INTRARETINAL FLUID IN INTERMEDIATE AGE-RELATED MACULAR DEGENERATION.

To describe the occurrence of nonexudative intraretinal fluid (IRF) in intermediate age-related macular degeneration. A retrospective study was designed to include consecutive cases with intermediate age-related macular degeneration associated with IRF. A multimodal imaging approach was used to confirm diagnosis of IRF in intermediate age-related macular degeneration. Multimodal imaging included color fundus photograph, fundus autofluorescence, fluorescein angiography, indocyanine green angiography, optical coherence tomography, and optical coherence tomography angiography. Ten eyes of 10 patients (2 male and 8 female patients, ages 68-80 years) showing IRF in intermediate age-related macular degeneration were included in the study. The mean best-corrected visual acuity was 20/40 Snellen equivalent. Multimodal imaging including fluorescein angiography/indocyanine green angiography and optical coherence tomography demonstrated the absence of macular neovascularization in all cases; optical coherence tomography-angiography did not detect any abnormal flow signal associated with IRF. Seven of 10 patients developed IRF in correspondence of pigment epithelium detachment. Three of 10 patients presented IRF in correspondence of an area of nascent geographic atrophy. Nonexudative intraretinal fluid in intermediate age-related macular degeneration is a novel, distinctive feature that is characterized by the presence of IRF with no evidence of macular neovascular lesions. The authors described different phenotypes of IRF in intermediate age-related macular degeneration. The definite diagnosis of this condition requires further studies with thorough application of multimodal imaging.

Sulfated CXCR3 Peptide Trap Use as a Promising Therapeutic Approach for Age-Related Macular Degeneration.

Chemokines have various biological functions and potential roles in the development or progression of neuroinflammatory diseases. However, the specific pathogenic roles of chemokines in the major cause for vision loss among the elderly, the leading cause of blindness in older individuals, remain elusive. Chemokines interact with their receptors expressed in the endothelium and on leukocytes. The sulfation of tyrosine residues in chemokine receptors increases the strength of ligand-receptor interaction and modulates signaling. Therefore, in the present study, we aimed to construct a human recombinant sulfated CXCR3 peptide trap (hCXCR3-S2) and mouse recombinant sulfated CXCR3 peptide trap (mCXCR3-S2) to demonstrate in vivo effects in preventing choroidal neovascularization (CNV) and chemotaxis. We generated expression vectors for mCXCR3-S2 and hCXCR3-S2 with GST domains and their respective cDNA sequences. Following overexpression in E. coli BL21 (DE3), we purified the fusion proteins from cell lysates using affinity chromatography. First, the impact of hCXCR3-S2 was validated in vitro. Subsequently, the in vivo efficacy of mCXCR3-S2 was investigated using a laser-induced CNV mouse model, a mouse model of neovascular age-related macular degeneration (AMD). hCXCR3-S2 inhibited the migration and invasion of two human cancer cell lines. Intravitreal injection of mCXCR3-S2 attenuated CNV and macrophage recruitment in neovascular lesions of mouse models. These in vitro and in vivo effects were significantly stronger with CXCR3-S2 than with wild-type CXCR3 peptides. These findings demonstrate that the sulfated form of the CXCR3 peptide trap is a valuable tool that could be supplemented with antivascular endothelial growth factors in AMD treatment.

Intravitreal bevacizumab in choroidal neovascularisation in Vogt‐Koyanagi‐Harada disease in a child: A review of literature

Aims/Purpose: Interest of bevacizumab in children in the treatment of choroidal neoplasms in Vogt Koyanagi Harada syndrome.Methods: In this work we report the case of an extra‐foveal choroidal neovascularization in a child followed for VKH syndrome with a good response to intravitreal injections of bevacizumab.Results: We report the case of a 12‐year‐old child who initially presented to the hospital in 2020 for bilateral decreased visual acuity and headache. There was no history of systemic disease. Initial visual acuity was 1/10 in both eyes. Biomicroscopic examination revealed granulomatous retrodescemetic precipitates, 2× anterior chamber tyndall, 1× vitreous tyndall, and bilateral exudative retinal detachment associated with bilateral papilledema in both eyes. Based on these findings, a diagnosis of Vogt‐Koyanagi‐Harada syndrome was made, and treatment was initiated with intravenous, oral, and topical corticosteroids. Visual acuity improved to 6/10 OD and 7/10 OS the following month. The patient was then followed up at the university hospital regularly. After controlling the inflammation, steroids were decreased over a period of 2 years but the patient relapsed at high dose to declare cortico‐dependence. Anti‐TNF alpha was started to control the inflammation and visual acuity remained stable until July 2022. Choroidal neovascularization then developed, reducing the patient's visual acuity to 3/10 in both eyes within 1 month. Fluorescein angiography and macular OCT confirmed the diagnosis of extrafoveolar choroidal neovascularization in both eyes. After obtaining informed consent, intravitreal bevacizumab was injected 3 times at 6 week intervals in each eye. After the 6th injection, the patient's best‐corrected visual acuity improved to 8/10 in the right eye and 10/10 in the left eye. The fundus photograph illustrates the regression of the choroidal neovessels. Fluorescein angiography confirmed the reduction in leakage. Choroidal neovascular membranes can cause severe visual impairment and are a major challenge in the management of patients.Conclusions: This case illustrates that intravitreal bevacizumab has a possible role in the treatment of the disease, with regression of neovascular lesions in the eye.

Insights into myopic choroidal neovascularization based on quantitative proteomics analysis of the aqueous humor

BackgroundPrevious studies on the biomarkers of pathologic myopia choroidal neovascularization (pmCNV) development merely detected limited types of proteins and provide a meagre illustration of the underlying pathways. Hence, a landscape of protein changes in the aqueous humor (AH) of pmCNV patients is lacking. Here, to explore the potential mechanisms and biomarkers of pmCNV, we analyzed the clinical data and protein profile among atrophic (A) lesions, tractional lesions (T) and neovascular (N) lesions in myopic patients based on the ATN grading system for myopic maculopathy (MM).ResultsAfter investigating demographic data of our patients, a correlation was found between A and N lesions (R = 0.5753, P < 0.0001). Accordingly, groups were divided into patients without MM, patients with myopic atrophic maculopathy (MAM), and patients with pmCNV (N2a lesion). In proteomics analysis, the increased protein level of GFAP and complement-associated molecules in AH samples of the 3 groups also indicated that MAM and pmCNV shared similar characteristics. The GO enrichment and KEGG pathway analysis were performed, which mapped that differential expressed proteins mainly engaged in JAK-STAT pathway between the pmCNV group and two controls. Furthermore, we identified several potential biomarkers for pmCNV, including FCN3, GFAP, EGFR, SFRP3, PPP2R1A, SLIT2, and CD248.ConclusionsAtrophic lesions under pathologic myopic conditions demonstrated similarities to neovascularization development. Potential biomarkers including GFAP were associated with the pathogenesis of pmCNV. In summary, our study provides new insights for further research on pmCNV development.

Preliminary analysis of predicting the first recurrence in patients with neovascular age-related macular degeneration using deep learning

BackgroundTo predict, using deep learning, the first recurrence in patients with neovascular age-related macular degeneration (nAMD) after three monthly loading injections of intravitreal anti-vascular endothelial growth factor (anti-VEGF).MethodsOptical coherence tomography (OCT) images were obtained at baseline and after the loading phase. The first recurrence was defined as the initial appearance of a new retinal hemorrhage or intra/subretinal fluid accumulation after the initial resolution of exudative changes after three loading injections. Standard U-Net architecture was used to identify the three retinal fluid compartments, which include pigment epithelial detachment, subretinal fluid, and intraretinal fluid. To predict the first recurrence of nAMD, classification learning was conducted to determine whether the first recurrence occurred within three months after the loading phase. The recurrence classification architecture was built using ResNet50. The model with retinal regions of interest of the entire region and fluid region on OCT at baseline and after the loading phase is presented.ResultsA total of 1,444 eyes of 1,302 patients were included. The mean duration until the first recurrence after the loading phase was 8.20 ± 15.56 months. The recurrence classification system revealed that the model with the fluid region of OCT after the loading phase provided the highest classification performance, with an area under the receiver operating characteristic curve (AUC) of 0.725 ± 0.012. Heatmap analysis revealed that three pathological fluids, subsided choroidal neovascularization lesions, and hyperreflective foci were important areas for the first recurrence.ConclusionsThe deep learning algorithm allowed for the prediction of the first recurrence for three months after the loading phase with adequate feasibility. An automated prediction system may assist in establishing patient-specific treatment plans and the provision of individualized medical care for patients with nAMD.

Comparison of Neoatherosclerosis and Neovascularization of Restenosis after Drug-Eluting Stent Implantation: An Optical Coherence Tomography Study.

Neoatherosclerosis (NA) is associated with stent failure. However, systematic studies on the manifestations of NA and neovascularization (NV) at different stages after drug-eluting stent (DES) implantation are lacking. Moreover, the relationship between NA and NV in in-stent restenosis (ISR) has not been reported. This study aimed to characterize NA and NV in patients with ISR at different post-DES stages and compare the association between NA and NV in ISR lesions. A total of 227 patients with 227 lesions who underwent follow-up optical coherence tomography before percutaneous coronary intervention for DES ISR were enrolled and divided into early (E-ISR: 1 year), late (L-ISR: 1-5 years), and very-late (VL-ISR: 5 years) ISR groups. Furthermore, ISR lesions were divided into NV and non-NV groups according to the presence of NV. The prevalence of NA and NV was 52.9% and 41.0%, respectively. The prevalence of lipidic NA (E-ISR, 32.7%; L-ISR, 50.0%; VL-ISR, 58.5%) and intimal NV (E-ISR, 14.5%; L-ISR, 30.8%; VL-ISR, 38.3%) increased with time after stenting. NA was higher in ISR patients with NV lesions than in those without (p 0.001). Patients with both ISR and NV had a higher incidence of macrophage infiltration, thin-cap fibroatheroma, intimal rupture, and thrombosis (p 0.01). Progression of lipidic NA was associated with L-ISR and VL-ISR but may not be related to calcified NA. NA was more common in ISR lesions with NV; its formation may substantially promote NA progression and plaque instability.

PolySialic acid-nanoparticles inhibit macrophage mediated inflammation through Siglec agonism: a potential treatment for age related macular degeneration.

Age-related macular degeneration (AMD) is a chronic, progressive retinal disease characterized by an inflammatory response mediated by activated macrophages and microglia infiltrating the inner layer of the retina. In this study, we demonstrate that inhibition of macrophages through Siglec binding in the AMD eye can generate therapeutically useful effects. We show that Siglecs-7, -9 and -11 are upregulated in AMD associated M0 and M1 macrophages, and that these can be selectively targeted using polysialic acid (PolySia)-nanoparticles (NPs) to control dampen AMD-associated inflammation. In vitro studies showed that PolySia-NPs bind to macrophages through human Siglecs-7, -9, -11 as well as murine ortholog Siglec-E. Following treatment with PolySia-NPs, we observed that the PolySia-NPs bound and agonized the macrophage Siglecs resulting in a significant decrease in the secretion of IL-6, IL-1β, TNF-α and VEGF, and an increased secretion of IL-10. In vivo intravitreal (IVT) injection of PolySia-NPs was found to be well-tolerated and safe making it effective in preventing thinning of the retinal outer nuclear layer (ONL), inhibiting macrophage infiltration, and restoring electrophysiological retinal function in a model of bright light-induced retinal degeneration. In a clinically validated, laser-induced choroidal neovascularization (CNV) model of exudative AMD, PolySia-NPs reduced the size of neovascular lesions with associated reduction in macrophages. The PolySia-NPs described herein are therefore a promising therapeutic strategy for repolarizing pro-inflammatory macrophages to a more anti-inflammatory, non-angiogenic phenotype, which play a key role in the pathophysiology of non-exudative AMD.

Polypoidal Choroidal Vasculopathy: Evaluation Based on 3-Dimensional Reconstruction of OCT Angiography

Three-dimensional (3D) reconstruction using swept-source OCT angiography (SS-OCTA) can provide insights into the nature and structure of polypoidal choroidal vasculopathy (PCV) and its component parts, the polypoidal lesion (PL) and the branching neovascular network (BNN). This study aims to describe novel observations of PCV using 3D reconstruction of SS-OCTA, and to compare these observations with similar images of type I macular neovascularization (MNV) typical neovascular age-related macular degeneration (nAMD). Clinical case series. Patients with PCV in either eye from clinical studies conducted in a tertiary retina center. Images with prespecified SS-OCTA imaging protocol were obtained and reconstructed in 3D. Forty neovascularization lesions (30 PCV and 10 typical nAMD) based on SS-OCTA were analyzed. The following 3 specific features were evaluated: (1) the pattern of flow signal within the PLs as either homogenous or showing internal vascular architecture; (2) the configuration of the BNN as hypermature, mature, or immature; and (3) the spatial arrangement of the PLs in relation to the BNN. Comparisons were made between PCV and typical nAMD. All PLs exhibited internal vascular architecture in the form of coil-like loops and none exhibited homogenous flow. Small focal nodules were present within this internal vascular architecture in 70% of PLs. Branching neovascular networks exhibited a hypermature/mature configuration (100 vs. 50%, P < 0.01) and were associated with thicker choroid compared with typical nAMD type 1 MNV (238.7 ± 104.3 vs. 155.6 ± 49.2, P= 0.02). The BNN and PL were located at distinct anteroposterior planes in 81% of the eyes. We identified proliferating vasculature in both the PL and the BNN. Comparison of the configuration suggests that the BNN represents a more chronic and inactive lesion than the PL. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Effect of sunitinib against Echinococcus multilocularis through inhibition of VEGFA-induced angiogenesis

BackgroundAlveolar echinococcosis (AE) is a lethal zoonosis caused by the fox tapeworm Echinococcus multilocularis. The disease is difficult to treat, and an effective therapeutic drug is urgently needed. Echinococcus multilocularis-associated angiogenesis is required by the parasite for growth and metastasis; however, whether antiangiogenic therapy is effective for treating AE is unclear.MethodsThe in vivo efficacy of sunitinib malate (SU11248) was evaluated in mice by secondary infection with E. multilocularis. Enzyme-linked immunosorbent assays (ELISAs) were used to evaluate treatment effects on serum IL-4 and vascular endothelial growth factor A (VEGFA) levels after SU11248 treatment. Gross morphological observations and immunohistochemical staining were used to evaluate the impact of SU11248 on angiogenesis and the expression of pro-angiogenic factors VEGFA and VEGF receptor 2 (VEGFR2) in the metacestode tissues. Furthermore, the anthelmintic effects of SU11248 were tested on E. multilocularis metacestodes in vitro. The effect of SU11248 on the expression of VEGFA, VEGFR2, and phosphorylated VEGFR2 (p-VEGFR2) in liver cells infected with protoscoleces in vitro was detected by western blotting, reverse transcription quantitative polymerase chain reaction (RT-qPCR), and enzyme-linked immunosorbent assay (ELISA). The influence of SU11248 on endothelial progenitor cell (EPC) proliferation and migration was determined using CCK8 and transwell assays.ResultsIn vivo, SU11248 treatment markedly reduced neovascular lesion formation and substantially inhibited E. multilocularis metacestode growth in mice. Further, it exhibited high anti-hydatid activity as efficiently as albendazole (ABZ), and the treatment resulted in reduced protoscolex development. In addition, VEGFA, VEGFR2, and p-VEGFR2 expression was significantly decreased in the metacestode tissues after SU11248 treatment. However, no effect of SU11248 on serum IL-4 levels was observed. In vitro, SU11248 exhibited some anthelmintic effects and damaged the cellular structure in the germinal layer of metacestodes at concentrations below those generally considered acceptable for treatment (0.12–0.5 μM). Western blotting, RT-qPCR, and ELISA showed that in co-cultured systems, only p-VEGFR2 levels tended to decrease with increasing SU11248 concentrations. Furthermore, SU11248 was less toxic to Reuber rat hepatoma (RH) cells and metacestodes than to EPCs, and 0.1 μM SU11248 completely inhibited EPC migration to the supernatants of liver cell and protoscolex co-cultures.ConclusionsSU11248 is a potential candidate drug for the treatment of AE, which predominantly inhibits parasite-induced angiogenesis. Host-targeted anti-angiogenesis treatment strategies constitute a new avenue for the treatment of AE.Graphical

Macular Neovascularization Type Influence on Anti-VEGF Intravitreal Therapy Outcomes in Age-Related Macular Degeneration

PurposeTo evaluate the influence of macular neovascularization (MNV) lesion type on 12 months clinical outcomes in treatment-naïve eyes with age-related macular degeneration (nAMD) eyes treated with anti-vascular endothelial growth factor (VEGF) drugs nationwide. DesignMulticenter national nAMD database observational study. SubjectsOne thousand six-hundred six treatment-naïve nAMD eyes (1330 patients) undergoing Anti-VEGF therapy for 12 months nationwide. MethodsDemographics, visual acuity (VA) in logarithm of the minimum angle of resolution (logMAR) letters, number of injections and visits data was collected using a validated web-based tool. Neovascular lesion phenotype was classified as type 1 (T1, n=711), type 2 (T2, n=505), type 3 (T3, n=315) and aneurysmal type 1 (A-T1, n=75), according to the new proposed consensus classification. Main outcome measuresMean VA change at 12 months, final VA at 12 months, number of injections, time to lesion inactivation. ResultsA total of 1606 treatment-naïve nAMD eyes (1330 patients) received a median of 7 injections over 12 months. Mean (±standard deviation) baseline VA was significantly lower for T2 (49.4±23.5 letters) compared to T1 (57.8±20.8) and T3 (58.2 ±19.4)(both p<0.05) lesions. Mean VA change at 12 months was significantly greater for A-T1 (+9.5 letters) compared to T3 (+3.1 letters, p<0.05). T3 lesions had fewer active visits (24.9%) than the other lesion types (T1 30.5%, T2 32.6%, A-T1 27.5%, all p<0.05). Aflibercept was the most used drug in A-T1 lesions (70.1%) and ranibizumab in T1 (40.7%), T2 (57.7%) and T3 (47.6%) lesions. ConclusionsThis study highlights the relevance of MNV type on clinical outcomes in nAMD and reports significant differences in baseline VA, VA change and lesion activity at 12 months. This report provides data about lesion-specific clinical features, which may guide the management of nAMD cases and potentially support a personalized clinical decision making in these patients.

End binding-3 inhibitor activates regenerative program in age-related macular degeneration

Wet age-related macular degeneration (AMD), characterized by leaky neovessels emanating from the choroid, is a main cause of blindness. As current treatments for wet AMD require regular intravitreal injections of anti-vascular endothelial growth factor (VEGF) biologics, there is a need for the development of less invasive treatments. Here, we designed an allosteric inhibitor of end binding-3 (EB3) protein, termed EBIN, which reduces the effects of environmental stresses on endothelial cells by limiting pathological calcium signaling. Delivery of EBIN via eye drops in mouse and non-human primate (NHP) models of wet AMD prevents both neovascular leakage and choroidal neovascularization. EBIN reverses the epigenetic changes induced by environmental stresses, allowing an activation of a regenerative program within metabolic-active endothelial cells comprising choroidal neovascularization (CNV) lesions. These results suggest the therapeutic potential of EBIN in preventing the degenerative processes underlying wet AMD.