Abstract: We reviewed randomized controlled trials associated with the intravitreal use of aflibercept for this article. These studies proved that aflibercept is an effective anti-vascular endothelial growth factor agent for the treatment of neovascular age-related macular degeneration (nAMD), myopic choroidal neovascularization (mCNV), diabetic macular edema (DME), and macular edema associated with retinal vein occlusion. The incidence of severe ocular or systemic complications after intravitreal administration of aflibercept was low.
Abstract: High speed and small gauge vitrectomy systems have made surgical intervention in complications of diabetic retinopathy (DR) safer. The availability of anti-vascular endothelial growth factor (anti-VEGF) compounds for use in DR has significantly improved intraoperative and postoperative outcomes. This review discusses the indications for surgical intervention in DR. The role of anti-VEGF compounds is discussed as surgical adjuvants with an emphasis on timing of treatment before surgery.
Abstract: Diabetic retinopathy (DR) is a complex multifactorial disease and one of the leading causes of visual impairment worldwide. DR pathogenesis is still not completely understood and, even if studies performed in the past focused on microvascular dysfunction as the main event, growing body of scientific evidence has demonstrated an important role of inflammation and neurodegeneration in the onset and progression of DR. This review summarizes current literature on the role of inflammation in the pathogenesis and progression of DR. In particular, it focuses on clinical inflammatory biomarkers detectable with non-invasive retinal imaging, suggestive of a local inflammatory condition. Current available treatments are applicable only at advanced stages of disease, therefore, there is the need to detect biomarkers of subclinical or early DR that can help in DR management before irreversible damage occurs. A better understanding of inflammatory pathways involved in DR may permit to implement more specific and personalized therapeutic strategies and clinical biomarkers may be a helpful tool in the everyday clinical practice to direct the patient to the most appropriate treatment option.
Abstract: Diabetic retinopathy (DR) is a leading cause of visual loss worldwide. Disease severity is graded from mild non-proliferative DR to proliferative DR. Optical coherence tomography angiography (OCTA) has become widely accepted as a useful noninvasive technique that provides detailed imaging of the ocular vessels. It is also becoming an increasingly essential tool for both qualitative and quantitative assessment of DR, especially with the advent of wider imaging capabilities. Various angiographic features of DR, such as microaneurysms, intraretinal microvascular abnormalities, neovascularization, and nonperfusion have been comprehensively studied and described using OCTA. Different quantitative OCTA metrics have been introduced, such as vessel density, foveal avascular zone (FAZ) area, and area of nonperfusion. Current research has been focusing on the application of quantitative OCTA for the diagnosis of DR and treatment monitoring. The primary purpose of this article is to review the use of OCTA, including its challenges, in the diagnosis and management of DR.
Abstract: Diabetic retinopathy (DR) is the most common microvascular complication in patients with diabetes mellitus (DM), and remains the single greatest cause of blindness in working age adults around the world. In this article, we review the evolution of pharmacotherapies for both diabetic macular edema (DME) and DR such as anti-vascular endothelial growth factor inhibitors and various steroid formulations, as well as other emerging pharmacotherapies currently in late stage clinical testing for this disease.
Background: Diabetic macular edema (DME) is a leading cause of severe visual impairments in older and the working-age population. An important target of current therapy is vascular endothelial growth factor (VEGF), which plays a role in the pathogenesis of DME by inducing angiogenesis and increasing vascular permeability. Currently available anti-VEGF agents include off-label use of Bevacizumab, which has been shown to be effective in the treatment of DME. However, many patients with DME do not respond or demonstrate only a partial response to this agent. As of November 2016, the Canadian Health authorities approved Aflibercept as an anti-VEGF agent for treatment of DME, and the patients who are non-responders to Bevacizumab are switched to this non-off label medication. We aimed to investigate the anatomical and functional visual changes associated with response to Aflibercept in a real-life Canadian population of Bevacizumab non-responders.
Methods: A retrospective review of chronic DME patients refractory to bevacizumab treatment who were switched to Aflibercept was done. Best-corrected visual acuity (BCVA), Intraocular pressure (IOP), central subfield thickness (CST), average macular thickness, and total macular volume were extracted at the visit prior to switching to Aflibercept (baseline) as well as the first, second and third follow-up visits after switching. Anatomical and functional visual changes were compared using Generalized Estimating Equations and the association between variables was tested using Pearson correlation test with significance set at P<0.05.
Results: Twenty-six eyes with mean age of 63 were included. Average CST at baseline was 421.5±116.1 μm and the number of Bevacizumab injections received prior to switching was 15.3±8.0. No significant changes were observed in terms of BCVA and IOP, from baseline to any of the follow-ups. Switching to Aflibercept significantly improved CST, average macular thickness, and total macular volume. From baseline to the first follow-up visit, CST decreased from 421.5±116.1 to 333.0±91.2 μm (P=0.001) and average macular thickness reduced from 344.6±74.9 to 322.2±60.5 μm (P=0.008). Similarly, total macular volume decreased from 12.4±2.7 to 11.6±2.2 μm3, measured at baseline and the first follow-up (P=0.007). No further improvements were observed from the first follow-up to the subsequent ones. The median CST value at baseline (378 μm) was used to classify the patients into low and high CST groups. We observed that those with higher CST at baseline (>378 μm) showed a trend for improvements in visual acuity (P=0.058). Pearson correlation test confirmed the association between higher CST at baseline and better visual outcomes in response to switching to Aflibercept (P=0.018).
Conclusions: Our data evidenced significant anatomical improvements in macula, which did not translate to immediate functional vision improvements. Bevacizumab non-responders with higher CST might also gain visual acuity and benefit functionally from switching to Aflibercept.
Background: Overexpression of inducible nitric oxide synthase (iNOS) has been reported in diabetic retinopathy (DR). The kinin B1 receptor (B1R) is also overexpressed in DR, and can stimulate iNOS via Gαi/ERK/MAPK pathway. We previously showed that the topical administration of a B1R antagonist, LF22-0542, significantly reduces leukocyte infiltration, increased vascular permeability and overexpression of several inflammatory mediators, including iNOS in DR. Thus, the aim of this study was to determine whether the pro-inflammatory effects of B1R are attributed to oxidative stress caused by the activation of iNOS pathway in order to identify new therapeutic targets for the treatment of DR. iNOS and B1R being absent in the normal retina, their inhibition is unlikely to result in undesirable side effects. The approach will be no invasive by eye application of drops.
Methods: Diabetes was induced in male Wistar rats (200–230 g) by a single intraperitoneal injection of streptozotocin (STZ, 65 mg/kg b.w). One week later, rats were randomly divided into four groups (N=5) and treated for one week as follows: Gr 1: control rats treated with the selective iNOS inhibitor (1,400 W, 0.06 μM twice a day by eye-drops ×7 days), Gr 2, STZ-diabetic rats treated with 1,400 W, Gr 3: control rats received a selective B1R agonist [Sar (D-Phe8)-des-Arg9-BK, 100 μg twice a week] by intravitreal injections (itrv) and treated with 1,400 W, Gr 4: STZ-diabetic rats + B1R agonist +1,400 W. At the end of treatment and two weeks post-STZ, three series of experiments were carried out to measure vascular permeability (by Evans blue dye method) and the expression of vasoactive and inflammatory mediators, including iNOS, VEGF-A, VEGF-R2, IL-1β, Cox-2, TNF-α, bradykinin 1 and 2 receptors and carboxypeptidase M/kininase 1 (by Western Blotting and qRT-PCR). The nitrosative stress (nitrosylation of proteins) was also assessed by Western Blotting. One-way Anova test with Bonferroni post hoc was used for statistical analysis.
Results: STZ-diabetic rats showed a significant increase in retinal vascular permeability (22.8 μg/g Evans blue dye per g of fresh retinas, P=0.016) compared with control rats and control treated rats (17.2 and 16.8 μg/g respectively). The injections of B1R agonist amplified the increase of vascular permeability which was normalized by the 1,400 W. The overexpression of inflammatory markers was also normalized by the 1,400 W in STZ-diabetic rats received or not the B1R agonist.
Conclusions: These results support a contribution of iNOS in the deleterious effects of B1R in this model of diabetic retinopathy. Hence, iNOS inhibition by ocular application of 1,400 W may represent a promising and non-invasive therapeutic approach in the treatment of diabetic retinopathy.
Background: Sight-threatening diabetic macular edema (DME) is caused by increased microvascular permeability. While few direct vascular targeting strategies are available, VEGF pathway inhibition has shown to be effective in reducing retinal vascular leakage but is associated with non-negligible side effects. Thus, more options are needed. Vascular specific Activin-like kinase receptor type I (ALK1) pathway and its circulating ligand Bone morphogenetic protein-9 (BMP9) is known for its potent quiescent and stabilizing effect on the vasculature. However, little is known about this pathway in the context of microvascular permeability associated with diabetes. We hypothesize that BMP9/ALK1 pathway is inhibited in diabetic (DB) retinas leading to vascular destabilization and leakage and that its activation could re-establish proper vascular endothelial barrier functions (EBF).
Methods: The effect of hyperglycemia (i.e., HG >10 mM of D-glucose) on Alk1 signaling was evaluated in vitro by subjecting endothelial cells (EC) to increasing concentrations of D-glucose (5, 11, 25 mM) and in vivo using DB mice (Streptozotocin-induced diabetes). The contribution of Alk1 signaling on EBF was evaluated using Evans Blue permeation in inducible endothelial specific Alk1 KO mice. To evaluate the potential protective effects of BMP9/Alk1 signaling on EBF, BMP9 overexpression was achieved using adenoviral delivery in DB mice. Statistical-One-Way ANOVA or Student’s t-test was used.
Results: Endothelial tissue from DB mice showed a significant inhibition of BMP9/ALK1-canonical Smad1,5,8 quiescence signaling (DB n=5; CTL n=4; P<0.01), which was associated with reduced expression of target genes (JAG1, Id1,3, Hey1,2 & HES). Moreover, we showed that retinal hyperpermeability associated with diabetes was exacerbated in Alk1 heterozygote mice (n=4–9/group; P<0.0001). Finally, we demonstrated that activation of Alk1 signaling in ECs prevented vascular permeability induced by HG, both in vitro (n=3; P=0.009) and in vivo (n=4–9/group; P<0.0001).
Conclusions: Consistent with our hypothesis, vascular stability and quiescence induced by BMP9-ALK1 signaling is inhibited in the DB/HG endothelium which could be an important factor in vascular leakage leading to DME. Our results show that activation of this pathway could offer a therapeutically interesting future option to slow down the onset of DME.
Abstract: The bone morphogenetic protein (BMP) family of proteins has a multitude of roles throughout the body. It plays important roles in development and in the adult vascular endothelium, by modulating the angiogenic response. The endothelial-specific receptor BMP receptor Alk1 is of particular importance in the proper remodeling of the vasculature and its ligand BMP9 has been shown to be a potent inhibitor of neovascularization. Dysregulated BMP signaling has been linked to multiple vascular diseases and can lead to the abnormal angiogenesis. We therefore investigated the role of BMP9/Alk1 signaling in retinal angiogenesis, and its therapeutic implications for vascular pathologies of the eye.
Background: To investigate the effect of sirolimus (SRL) eye drops on acute alkali-burn-induced corneal neovascularization (CNV) and explore its possible mechanism.
Methods: A total of 57 male Sprague-Dawley rats weighing 160–180 g were randomly divided into four groups including a normal control group (NC group, n=12), an untreated alkali-burned model control group (MC group, n=15), a blank eye drop treatment group (BT group, n=15), and an SRL eye drop treatment group (ST group, n=15). Corneal inflammation and CNV were observed and scored under a slit-lamp microscope 3, 7, and 14 days after alkali exposure. Three rats were randomly sacrificed in each group before modeling and 3, 7, 14 days after modeling, and the corneas of right eyes were harvested for Western blotting to compare the expression levels of VEGFR2 and caspase-3.
Results: Corneal inflammation scoring showed that the corneal edema and conjunctival congestion were severe in the MC, BT, and ST groups 1 day after alkali exposure but were alleviated at day 3. The corneal transparency was significantly higher in the ST group than in the MC and BT groups at days 7 (F=9.77, P<0.05) and 14 (F=5.81, P<0.05). At day 1, the corneal limbal vascular network was markedly filled. SNV was obvious at days 3, 7, and 14. The new blood vessels were shorter and sparser in the ST group than in the MC and BT groups, and the CNV scores showed significant differences among these groups (day 3: F=8.60, P<0.05; day 7: F=11.40, P<0.05; and day 14: F=41.59, P<0.01). Western blotting showed that the expressions of VEGFR2 and caspase-3 were low before modeling and showed no significant difference among the different groups (F=0.52, P>0.05; F=0.98, P>0.05). The corneal expression of VEGFR2 became significantly higher in the MC and BT groups than in the ST group 3, 7, and 14 days after alkali exposure, and there were significant differences in relative gray-scale values among these groups (day 3: F=32.16, P<0.01; day 7: F=85.96, P<0.01; day 14: F=57.68, P<0.01). The increase in the corneal expression of caspase-3 was significantly larger in the ST group than in the MC and BT groups at days 3, 7, and 14, and there were significant differences in relative gray-scale values among groups (day 3: F=32.16, P<0.01; day 7: F=53.02, P<0.01; day 14: F=38.67, P<0.01).
Conclusions: SRL eye drops can alleviate acute alkali-burn-induced corneal inflammation and inhibit alkali-burn-induced CNV in rat models. It can reduce VEGFR2 expression and increase caspase-3 expression in the corneal tissue, which may contribute to the inhibition of alkali-burn-induced CNV.
