Mounting evidence suggests that immunological mechanisms play a fundamental role in the pathogenesis of diabetic retinopathy (DR) and diabetic macular edema (DME). Upregulation of cytokines and other ...proinflammatory mediators leading to persistent low-grade inflammation is believed to actively contribute to the DR-associated damage to the retinal vasculature, inducing breakdown of the blood-retinal barrier, subsequent macular edema formation, and promotion of retinal neovascularization. This review summarizes the current knowledge of the biological processes providing an inflammatory basis for DR and DME. In addition, emerging therapeutic approaches targeting inflammation are discussed, including blockade of angiopoietin 2 and other molecular targets such as interleukin (IL)-6, IL-1β, plasma kallikrein, and integrins.
Micropulse laser treatment is an alternative to the conventional continuous-wave laser for the treatment of retinal or macular diseases. In contrast to the conventional laser, the therapeutic effect ...of the subthreshold micropulse laser is not accompanied by thermal retinal damage. This fact is of particular importance when a treatment near the fovea is required. Micropulse treatment is applied in indications such as central serous chorioretinopathy (CSC), diabetic macular edema (DME), or macular edema due to retinal vein occlusion (RVO). This review outlines and discusses the published literature of subthreshold micropulse laser treatment for CSC, DME, and macular edema after RVO.
Age-related macular degeneration (AMD) is a leading cause of blindness. Genetic variants at the chromosome 1q31.3 encompassing the complement factor H (CFH, FH) and CFH related genes (CFHR1-5) are ...major determinants of AMD susceptibility, but their molecular consequences remain unclear. Here we demonstrate that FHR-4 plays a prominent role in AMD pathogenesis. We show that systemic FHR-4 levels are elevated in AMD (P-value = 7.1 × 10
), whereas no difference is seen for FH. Furthermore, FHR-4 accumulates in the choriocapillaris, Bruch's membrane and drusen, and can compete with FH/FHL-1 for C3b binding, preventing FI-mediated C3b cleavage. Critically, the protective allele of the strongest AMD-associated CFH locus variant rs10922109 has the highest association with reduced FHR-4 levels (P-value = 2.2 × 10
), independently of the AMD-protective CFHR1-3 deletion, and even in those individuals that carry the high-risk allele of rs1061170 (Y402H). Our findings identify FHR-4 as a key molecular player contributing to complement dysregulation in AMD.
To determine clinical correlations to intraocular vascular endothelial growth factor A (VEGF-A) suppression times (VSTs) on the treatment of neovascular age-related macular degeneration (nAMD) with ...ranibizumab (Lucentis) or aflibercept (Eylea).
Seven of 89 treatment-naïve nAMD eyes showed persistent choroidal neovascular membrane (CNV) activity throughout a spectral domain optical coherence tomography (SD-OCT)-driven pro re nata (PRN) regimen of intravitreal ranibizumab injections over 28±4 months. The treatment was switched to PRN aflibercept injections and patients were followed for another 15±2 months. A total of 160 aqueous humour specimens were collected before the intravitreal injections, and their VEGF-A concentrations were assayed by Luminex multiplex bead analysis (Luminex, Austin, Texas, USA). Intraocular VEGF-A concentrations were correlated to CNV activity shown by SD-OCT.
The mean duration of suppression of VEGF-A concentrations in aqueous humour below the lower limit of quantification of our assay was 34±5 (26-69) days for ranibizumab and 67±14 (49-89) days for aflibercept (p<0.001). The percentual reduction of central retinal volume (CRV) 6 weeks after injection was higher for aflibercept compared with ranibizumab (p=0.009). The time point of clinical re-activity occurred about 50% earlier than the respective VST for each ranibizumab and aflibercept.
The VST under aflibercept treatment exceeded that under ranibizumab treatment by a factor of 2. This difference correlated with differential clinical CRV reduction 6 weeks after the respective injection. For both medications, clinical activity was found at a time point as early as 50% of the individual VST.
NCT01213667, post-results.
Central serous chorioretinopathy (CSC) is a common cause of central vision loss, primarily affecting men 20–60 years of age. To date, no consensus has been reached regarding the classification of ...CSC, and a wide variety of interventions have been proposed, reflecting the controversy associated with treating this disease. The recent publication of appropriately powered randomised controlled trials such as the PLACE trial, as well as large retrospective, non-randomised treatment studies regarding the treatment of CSC suggest the feasibility of a more evidence-based approach when considering treatment options. The aim of this review is to provide a comprehensive overview of the current rationale and evidence with respect to the variety of interventions available for treating CSC, including pharmacology, laser treatment, and photodynamic therapy. In addition, we describe the complexity of CSC, the challenges associated with treating CSC, and currently ongoing studies. Many treatment strategies such as photodynamic therapy using verteporfin, oral mineralocorticoid antagonists, and micropulse laser treatment have been reported as being effective. Currently, however, the available evidence suggests that half-dose (or half-fluence) photodynamic therapy should be the treatment of choice in chronic CSC, whereas observation may be the preferred approach in acute CSC. Nevertheless, exceptions can be considered based upon patient-specific characteristics.
•The treatment of central serous chorioretinopathy (CSC) is controversial.•In chronic CSC, the most effective treatment appears to be half-dose (or half-fluence) photodynamic therapy (PDT).•In acute CSC, observation or early half-dose (or half-fluence) PDT can be considered.•Future studies will shed light on the efficacy of new treatment strategies.
We report the development of a platform of dual targeting Fab (DutaFab) molecules, which comprise two spatially separated and independent binding sites within the human antibody CDR loops: the ...so-called H-side paratope encompassing HCDR1, HCDR3 and LCDR2, and the L-side paratope encompassing LCDR1, LCDR3 and HCDR2. Both paratopes can be independently selected and combined into the desired bispecific DutaFabs in a modular manner. X-ray crystal structures illustrate that DutaFabs are able to bind two target molecules simultaneously at the same Fv region comprising a VH-VL heterodimer. In the present study, this platform is applied to generate DutaFabs specific for VEGFA and PDGF-BB, which show high affinities, physico-chemical stability and solubility, as well as superior efficacy over anti-VEGF monotherapy in vivo. These molecules exemplify the usefulness of DutaFabs as a distinct class of antibody therapeutics, which is currently being evaluated in patients.
Purpose
To investigate a possible correlation between established imaging biomarkers for age-related macular degeneration and local complement system activation, measured in aqueous humor (AH) of ...patients with early stages of age-related macular degeneration (AMD) and controls.
Methods
This analysis included prospectively acquired AH samples of 106 eyes (35 with early/intermediate AMD, 71 controls). The levels of complement protein 3 (C3), 4 (C4), 5 (C5); activation products of complement factor 3a (C3a) and Ba, C3b/iC3b; complement factors B, D, H, I (CFB, CFD, CFH, CFI); and total protein concentration were analyzed. Quantitative levels of complement factors were correlated to the presence of reticular pseudodrusen (RPD), the presence of hyperreflective foci (HRF), and total drusen volume (DV) graded on imaging by spectral-domain optical coherence tomography and using Spearman’s rank correlation test.
Results
DV correlated with C3b/iC3b (
r
= 0.285;
P
= 0.034), C3a (
r
= 0.200;
P
= 0.047), Ba (
r
= 0.262;
P
= 0.009), and C5 (
r
= 430;
P
= 0.005), and showed a tendency towards correlation with C3a (
r
= 0.198;
P
= 0.057). HRF correlated significantly with C5 (
r
= 0.388;
P
= 0.011) and RPD showed a tendency towards correlation with CFB (
r
= 0.196;
P
= 0.050).
Conclusion
In patients with early AMD, HRF and drusen parameters but not RPD show low to fair levels of correlation with local complement activation in patients’ AH. Better understanding of complement activation could provide some insights into the pathogenesis of AMD. Imaging biomarkers could be useful to identify suitable patients for future clinical trials with complement-modulating therapies.
Purpose To determine the duration of suppression of aqueous humor concentrations of vascular endothelial growth factor (VEGF) in eyes with neovascular age-related macular degeneration (AMD) treated ...with aflibercept. Design Nonrandomized prospective clinical study. Methods Twenty-seven eyes of 27 neovascular AMD patients receiving intravitreal aflibercept injections on a pro re nata regimen driven by spectral-domain optical coherence tomography (SD OCT) were included in this study. A total of 132 aqueous humor specimens were collected before intravitreal aflibercept injections and their VEGF-A concentrations assayed by multiplex bead analysis. Results Mean aqueous humor VEGF concentrations before treatment initiation were 90.6 ± 37.1 pg/mL (range 23.4–190.3 pg/mL). Intravitreal injection of aflibercept suppressed the aqueous VEGF concentrations to below the lower limit of quantification (<4 pg/mL) in all patients. The mean duration of VEGF suppression below the lower limit of quantification was >71 ± 18 days. The earliest time after injection at which the VEGF concentration recovered to above the lower limit of quantification was 55 days in 1 patient and >56 days, the recommended aflibercept treatment interval, in 20 patients. The aqueous VEGF recovery status of 6 patients was uncertain after 56 days. Conclusions On average, VEGF concentrations in the aqueous humor were suppressed below the lower limit of quantification after intravitreal aflibercept injections for about 10 weeks. This aqueous suppression time suggests durable VEGF inhibition for most patients dosed with aflibercept every 8 weeks.
Variants in the chromosomal region 10q26 are strongly associated with an increased risk for age-related macular degeneration (AMD). Two potential AMD genes are located in this region: ARMS2 and HTRA1 ...(high-temperature requirement A1). Previous studies have suggested that polymorphisms in the promotor region of HTRA1 result in overexpression of HTRA1 protein. This study investigated the role of HTRA1 overexpression in the pathogenesis of AMD. Transgenic Htra1 mice overexpressing the murine protein in the retinal pigment epithelium (RPE) layer of the retina were generated and characterized by transmission electron microscopy, immunofluorescence staining and Western Blot analysis. The elastic layer of Bruch's membrane (BM) in the Htra1 transgenic mice was fragmented and less continuous than in wild type (WT) controls. Recombinant HTRA1 lacking the N-terminal domain cleaved various extracellular matrix (ECM) proteins. Subsequent Western Blot analysis revealed an overexpression of fibronectin fragments and a reduction of fibulin 5 and tropoelastin in the RPE/choroid layer in transgenic mice compared to WT. Fibulin 5 is essential for elastogenesis by promoting elastic fiber assembly and maturation. Taken together, our data implicate that HTRA1 overexpression leads to an altered elastogenesis in BM through fibulin 5 cleavage. It highlights the importance of ECM related proteins in the development of AMD and links HTRA1 to other AMD risk genes such as fibulin 5, fibulin 6, ARMS2 and TIMP3.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To evaluate a machine learning algorithm that automatically grades age-related macular degeneration (AMD) severity stages from optical coherence tomography (OCT) scans.
A total of 3265 OCT scans from ...1016 patients with either no signs of AMD or with signs of early, intermediate, or advanced AMD were randomly selected from a large European multicenter database. A machine learning system was developed to automatically grade unseen OCT scans into different AMD severity stages without requiring retinal layer segmentation. The ability of the system to identify high-risk AMD stages and to assign the correct severity stage was determined by using receiver operator characteristic (ROC) analysis and Cohen's κ statistics (κ), respectively. The results were compared to those of two human observers. Reproducibility was assessed in an independent, publicly available data set of 384 OCT scans.
The system achieved an area under the ROC curve of 0.980 with a sensitivity of 98.2% at a specificity of 91.2%. This compares favorably with the performance of human observers who achieved sensitivities of 97.0% and 99.4% at specificities of 89.7% and 87.2%, respectively. A good level of agreement with the reference was obtained (κ = 0.713) and was in concordance with the human observers (κ = 0.775 and κ = 0.755, respectively).
A machine learning system capable of automatically grading OCT scans into AMD severity stages was developed and showed similar performance as human observers. The proposed automatic system allows for a quick and reliable grading of large quantities of OCT scans, which could increase the efficiency of large-scale AMD studies and pave the way for AMD screening using OCT.
PDF
