Five vascular endothelial growth factor receptor (VEGFR) ligands (VEGF-A, -B, –C, -D, and placental growth factor [PlGF]) constitute the VEGF family. VEGF-A binds VEGF receptors 1 and 2 (VEGFR1/2), whereas VEGF-B and PlGF only bind VEGFR1. Although much research has been conducted on VEGFR2 to elucidate its key role in retinal diseases, recent efforts have shown the importance and involvement of VEGFR1 and its family of ligands in angiogenesis, vascular permeability, and microinflammatory cascades within the retina. Expression of VEGFR1 depends on the microenvironment, is differentially regulated under hypoxic and inflammatory conditions, and it has been detected in retinal and choroidal endothelial cells, pericytes, retinal and choroidal mononuclear phagocytes (including microglia), Müller cells, photoreceptor cells, and the retinal pigment epithelium. Whilst the VEGF-A decoy function of VEGFR1 is well established, consequences of its direct signaling are less clear. VEGFR1 activation can affect vascular permeability and induce macrophage and microglia production of proinflammatory and proangiogenic mediators. However the ability of the VEGFR1 ligands (VEGF-A, PlGF, and VEGF-B) to compete against each other for receptor binding and to heterodimerize complicates our understanding of the relative contribution of VEGFR1 signaling alone toward the pathologic processes seen in diabetic retinopathy, retinal vascular occlusions, retinopathy of prematurity, and age-related macular degeneration. Clinically, anti-VEGF drugs have proven transformational in these pathologies and their impact on modulation of VEGFR1 signaling is still an opportunity-rich field for further research.
The SERC provided a diverse group of approximately 150 scientists and physicians representing industry and academia from 14 countries with a unique opportunity to explore the latest approaches to drug and gene delivery to the posterior segment of the eye. Unlike the 2009 SERC meeting, which focused on novel drug delivery platforms while elucidating the anatomic barriers to reach the posterior segment, 1 the most recent meeting explored strategies for bypassing ocular barriers using novel materials, nanoparticulate delivery systems, and gene therapy. It brought together experts in both ophthalmology and tangentially related areas to discuss the application and inherent technical challenges for translating experimental results from the laboratory bench to dependable medical therapies at the bedside and, where possible, it exemplified findings in ocular models with methods and results gleaned from disciplines outside of ophthalmology. The present review of the SERC provides investigators with tools to navigate these nascent approaches by exploring strategies from key laboratory investigations, drug development specialists, and clinical trials.The 2-day conference comprised the following six sessions: (1) barriers to drug delivery and transporter-guided drug design; (2) drug/gene delivery systems and cell therapies for the eye; (3) pharmacokinetics (PK), pharmacodynamics, and alternative routes of drug delivery; (4) nanotechnology for diagnosis and treatment of posterior eye disease; (5) translation of gene delivery for posterior eye disease; and (6) clinical trials.Rather than being a deliberate summary of each presentation, this review describes the common themes expressed during the six sessions.
In this rabbit study, the Retisert provides relatively constant levels of FA in the posterior pole, which is consistent with previous reports of its clinical utility.
PURPOSE. We characterized tear protein markers in dry eye disease (DED).METHODS. In this prospective study, based on the ocular surface disease index (OSDI) and corneal staining (CS), 95 DED patients (OSDI ‡13) with increasing CS were enrolled into 3 severity groups: DE1 (CS <4), DE2 (CS 4-7), and DE3 (CS >7), while 25 asymptomatic subjects with no CS were enrolled into the control group (OSDI <13 and CS ¼ 0). Tear fluid was collected at day 0 and day 7 visits, and concentrations of 43 protein markers were measured by multiplexed immunoassay. RESULTS.We analyzed 22 control and 80 DED subjects. Among 33 markers detectable, good inter-visit repeatability was observed with 25 markers, with intraclass correlation coefficients (ICC) ranging from 0.85-0.60; ICCs were <0.60 in the other 8. Correlation with clinical measures was found with two markers, with absolute partial correlation coefficients >0.40: Interleukin-1 receptor antagonist (IL-1Ra) and IL-8. IL-1Ra and IL-8 correlated with conjunctival staining (0.43, P < 0.001 and 0.35, P < 0.01, respectively), and with Schirmer test (À0.58 and À0.42, P < 0.001). IL-1Ra and IL-8 in DE3 were 4.4-and 2.1-fold higher than in DE1 (P ¼ 0.0001 and 0.0007), and 1.9-and 1.6-fold higher than in DE2 (P ¼ 0.022 and 0.017). IL-1Ra in DE2 was 2.3-fold higher than in DE1 (P ¼ 0.038).CONCLUSIONS. Tear levels of many immune mediators were highly repeatable between visits in DED. Among them, IL-1Ra and IL-8 were associated with clinical signs and disease severity defined by corneal staining. (Invest Ophthalmol Vis Sci. 2012; 53:4556-4564) DOI:10.1167/iovs.11-9054 D ry eye disease (DED) is a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.1 DED is a highly prevalent condition that affects 5% or more people of various ages in the United States, and the ocular discomfort, irritation, and blurred vision often experienced by dry eye patients can affect daily activity and workrelated tasks, thus leading to reduced quality of life. 1-5Symptoms of ocular discomfort or irritation felt by patients generally is the first step of diagnosis of DED and, currently, disease severity is classified by certain clinical objective measurements, such as corneal staining (CS) or tear break up time (TBUT).Significant progress has been made towards identifying and characterizing the underlying inflammation on the ocular surface in DED through clinical and preclinical research, which has led to better understanding of the key role of inflammation in DED pathogenesis. 6-12 Different methodologies have been used to collect ocular specimens from patients, and to quantify the molecular and cellular components involved in ocular surface inflammation and in other biologic or pathologic aspects of DED.7,13-18 Up-regulated cell surface expression of human leukocyte antigen (HLA)-DR, inter...
These studies, together with data from clinical trials, provide strong evidence that inhibition of VEGF(165) by pegaptanib in the eye is a safe therapy for the treatment of ocular neovascular disease.
Age-related Macular Degeneration (AMD) is the leading cause of visual impairment and blindness in the elderly in developed countries. Neovascular/exudative (wet) AMD is the aggressive form of AMD and can involve choroidal neovascularization and vascular leakage. Anti-vascular endothelial growth factor (anti-VEGF) medications have significantly improved treatment of wet-AMD. However, only approximately 40% of patients obtain full benefit from anti-VEGF therapy and the medications are given by intravitreal injection. Axitinib, a small molecule multi-receptor tyrosine kinase inhibitor used for the treatment of advanced renal cell carcinoma, is taken orally and inhibits VEGF activity by blocking VEGF receptors. Axitinib also has the advantage of blocking platelet derived growth factor (PDGF) receptors which play a role in neovascularization. Using in vitro human retinal microvascular endothelial cells (HRMVECs), human brain vascular pericytes (HBVRs), 3D co-culture vessel sprout assay, and in vivo laser induced rat choroidal neovascularization (CNV) models, the effect of axitinib on neovascularization was evaluated. Axitinib inhibited neovascularization better than anti-VEGF and/or anti-hPDGF-B mAb in the in vitro models demonstrating that combined inhibition of both VEGF and PDGF pathways may be synergistic in treating wet-AMD. Additionally, axitinib showed good efficacy at a low dose (0.875 mg/day) in laser-induced CNV model in rats. In conclusion our data shows that axitinib, an inhibitor of VEGF and PDGF-B pathways may be useful in ameliorating wet-AMD therapy.
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