System-wide vitreous proteome dissection reveals impaired sheddase activity in diabetic retinopathy.

Rationale: Diabetic retinopathy (DR) is a major complication of diabetes mellitus causing significant vision loss. DR is a multifactorial disease involving changes in retinal microvasculature and neuronal layers, and aberrations in vascular endothelial growth factors (VEGF) and inflammatory pathways. Despite the success of anti-VEGF therapy, many DR patients do not respond well to the treatment, emphasizing the involvement of other molecular players in neuronal and vascular aberrations in DR. Methods: We employed advanced mass spectrometry-based proteome profiling to obtain a global snapshot of altered protein abundances in vitreous humor from patients with proliferative DR (PDR) in comparison to individuals with epiretinal membrane without active DR or other retinal vascular complications. Global proteome correlation map and protein-protein interaction networks were used to probe into the functional inclination of proteins and aberrated molecular networks in PDR vitreous. In addition, peptide-centric analysis of the proteome data was carried out to identify proteolytic processing, primarily ectodomain shedding events in PDR vitreous. Functional validation experiments were performed using preclinical models of ocular angiogenesis. Results: The vitreous proteome landscape revealed distinct dysregulations in several metabolic, signaling, and immune networks in PDR. Systematic analysis of altered proteins uncovered specific impairment in ectodomain shedding of several transmembrane proteins playing critical roles in neurodegeneration and angiogenesis, pointing to defects in their regulating sheddases, particularly ADAM10, which emerged as the predominant sheddase. We confirmed that ADAM10 protease activity was reduced in animal models of ocular angiogenesis and established that activation of ADAM10 can suppress endothelial cell activation and angiogenesis. Furthermore, we identified the impaired ADAM10-AXL axis as a driver of retinal angiogenesis. Conclusion: We demonstrate restoration of aberrant ectodomain shedding as an effective strategy for treating PDR and propose ADAM10 as an attractive therapeutic target. In all, our study uncovered impaired ectodomain shedding as a prominent feature of PDR, opening new possibilities for advancement in the DR therapeutic space.

Plasma Metabonomic Profiling of Diabetic Retinopathy.

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and the leading cause of visual impairment in working-age adults. Patients with diabetes often develop DR despite appropriate control of systemic risk factors, suggesting the involvement of other pathogenic factors. We hypothesize that the plasma metabolic signature of DR is distinct and resolvable from that of diabetes alone. A nested population-based case-control metabonomic study was first performed on 40 DR cases and 40 control subjects with diabetes using gas chromatography-mass spectrometry. Eleven metabolites were found to be correlated with DR, and the majority were robust when adjusted for metabolic risk factors and confounding kidney disease. The metabolite markers 2-deoxyribonic acid; 3,4-dihydroxybutyric acid; erythritol; gluconic acid; and ribose were validated in an independent sample set with 40 DR cases, 40 control subjects with diabetes, and 40 individuals without diabetes. DR cases and control subjects with diabetes were matched by HbA1c in the validation set. Activation of the pentose phosphate pathway was identified from the list of DR metabolite markers. The identification of novel metabolite markers for DR provides insights into potential new pathogenic pathways for this microvascular complication and holds translational value in DR risk stratification and the development of new therapeutic measures.

Updates of pathologic myopia.

Complications from pathologic myopia are a major cause of visual impairment and blindness, especially in east Asia. The eyes with pathologic myopia may develop loss of the best-corrected vision due to various pathologies in the macula, peripheral retina and the optic nerve. Despite its importance, the definition of pathologic myopia has been inconsistent. The refractive error or axial length alone often does not adequately reflect the 'pathologic myopia'. Posterior staphyloma, which is a hallmark lesion of pathologic myopia, can occur also in non-highly myopic eyes. Recently a revised classification system for myopic maculopathy has been proposed to standardize the definition among epidemiological studies. In this META-PM (meta analyses of pathologic myopia) study classification, pathologic myopia was defined as the eyes having chorioretinal atrophy equal to or more severe than diffuse atrophy. In addition, the advent of new imaging technologies such as optical coherence tomography (OCT) and three dimensional magnetic resonance imaging (3D MRI) has enabled the detailed observation of various pathologies specific to pathologic myopia. New therapeutic approaches including intravitreal injections of anti-vascular endothelial growth factor agents and the advance of vitreoretinal surgeries have greatly improved the prognosis of patients with pathologic myopia. The purpose of this review article is to provide an update on topics related to the field of pathologic myopia, and to outline the remaining issues which need to be solved in the future.

Refractive errors and age-related macular degeneration: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the association between refractive errors and age-related macular degeneration (AMD). MAIN OUTCOME MEASURES: A clear understanding of the relationship between refractive error and AMD provides insights into the pathophysiology of AMD. METHODS: We searched PubMed and Embase from their inception to July 2012 for population-based studies with data on refractive error and AMD assessed from retinal photographs at baseline and follow-up. We performed separate meta-analyses for cross-sectional studies and cohort studies using adjusted odds ratios (ORs) and hazard ratios (HRs) under random effects models, respectively. RESULTS: Analysis of the 6 cross-sectional studies showed that hyperopia was associated with higher odds of prevalent AMD (pooled OR hyperopia vs. emmetropia: 1.16; 95% confidence interval [CI], 1.04-1.29) and that myopia was associated with lower odds of prevalent AMD (pooled OR myopia vs. emmetropia: 0.75; 95% CI, 0.61-0.92). Analysis from the 3 cohort studies showed nonsignificant associations. Analysis of the 5 cross-sectional and 2 cohort studies showed that each diopter increase in spherical equivalent was associated with increased odds of both prevalent (pooled OR, 1.09; 95% CI, 1.06-1.12) and incident (pooled HR, 1.06; 95% CI, 1.02-1.10) AMD. In 3 cross-sectional studies with data on axial length, each millimeter increase in axial length was associated with a decreased odd of prevalent AMD (pooled OR, 0.76; 95% CI, 0.69-0.85). CONCLUSIONS: Refractive error is associated with AMD, although a temporal relationship cannot be determined on the basis of current evidence. Ophthalmologists should be aware that risk of AMD clinically seems to vary by refractive status. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Choroidal neovascularization in pathological myopia.

Myopic choroidal neovascularization (CNV) is one of the leading causes of visual impairment worldwide. The clinical and socioeconomic impact of myopic CNV in Asian countries is particularly significant due to rising trend in the prevalence and severity of pathological myopia. The exact pathogenesis of myopic CNV remains unclear and there is paucity of information with respect to incidence and risk factors for myopic CNV from prospective studies. Furthermore, there are no recognized measures that may prevent or delay the development of CNV in eyes with pathological myopia. Advances have been made in the diagnosis and characterization of myopic CNV over the years. Until recently, treatment modalities for myopic CNV were limited to thermal laser photocoagulation and photodynamic therapy with verteporfin, both these modalities primarily aim at prevention of further visual loss. In the last 5 years, inhibitors of vascular endothelial growth factor (VEGF) have been used successfully and may improve vision to some extent. Nevertheless, the long-term safety and efficacy of anti-VEGF agents remains unknown. Furthermore, the risk of developing chorioretinal atrophy remains the key factor in determining the final visual outcome. This review article summarizes the current literature on myopic CNV, highlighting new evolving diagnostic and treatment modalities, prognostic factors influencing visual outcome, and areas of future research.