Anti-VEGF for the Management of Diabetic Macular Edema

Stefanini, Francisco Rosa; Badaró, Emmerson; Falabella, Paulo; Koss, Michael; Farah, Michel Eid; Maia, Maurício

doi:10.1155/2014/632307

Cited by 57 publications

(51 citation statements)

References 43 publications

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“…The efficacy and safety of anti-VEGF therapy have recently been proved by various clinical trials as to the normalization of abnormally permeable tumor vessels [36] or the suppression of blood-retinal barrier breakdown [37]. We demonstrated for the first time that anti-VEGF treatment prevented EBI after SAH via inhibiting the upregulation of TNC in this study.…”

Section: Discussionsupporting

confidence: 50%

Anti-Vascular Endothelial Growth Factor Treatment Suppresses Early Brain Injury After Subarachnoid Hemorrhage in Mice

et al. 2015

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The role of vascular endothelial growth factor (VEGF) in early brain injury (EBI) after subarachnoid hemorrhage (SAH) remains unclear. The aim of this study was to investigate effects of anti-VEGF therapy on EBI after SAH. C57BL/6 male mice underwent sham or filament perforation SAH modeling, and vehicle or two dosages (0.2 and 1 μg) of anti-VEGF antibody were randomly administrated by an intracerebroventricular injection. Neuroscore, brain water content, immunoglobulin G staining, and Western blotting were performed to evaluate EBI at 24-48 h. To confirm the role of VEGF, anti-VEGF receptor (VEGFR)-2 (a major receptor of VEGF) antibody was intracerebroventricularly administered and the effects on EBI were evaluated at 24 h. A higher dose, but not a lower dose, of anti-VEGF antibody significantly ameliorated post-SAH neurological impairments and brain edema at 24-48 h post-SAH. Post-SAH blood-brain barrier disruption was also inhibited by anti-VEGF antibody. The protective effects of anti-VEGF antibody were associated with the inhibition of post-SAH induction of VEGF, VEGFR-2, phosphorylated VEGFR-2, interleukin-1β and a matricellular protein tenascin-C (TNC). Anti-VEGFR-2 antibody also suppressed post-SAH neurological impairments and brain edema associated with VEGFR-2 inactivation and TNC downregulation. These findings demonstrated that VEGF causes post-SAH EBI via VEGFR-2 and TNC and that anti-VEGF therapy is effective for post-SAH EBI.

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Section: Discussionsupporting

confidence: 50%

Anti-Vascular Endothelial Growth Factor Treatment Suppresses Early Brain Injury After Subarachnoid Hemorrhage in Mice

et al. 2015

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“…However, repeated intravitreal injections of antiVEGF medications are necessary in patients with centerinvolving diabetic macular edema. The average number of injections is around 7 in the first year of treatment and 4 in the second year as indicated by recent studies [53,54] . Intravitreal antiVEGF therapy is generally safe with regard to sideeffects of medication, although the incidence of systemic thromboembolic events varies among trials [55] .…”

Section: Diabetic Macular Edemamentioning

confidence: 78%

Diabetic retinopathy - ocular complications of diabetes mellitus

Nentwich¹

2015

WJD

400

287

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In industrialized nations diabetic retinopathy is the most frequent microvascular complication of diabetes mellitus and the most common cause of blindness in the working-age population. In the next 15 years, the number of patients suffering from diabetes mellitus is expected to increase significantly. By the year 2030, about 440 million people in the age-group 20-79 years are estimated to be suffering from diabetes mellitus worldwide (prevalence 7.7%), while in 2010 there were 285 million people with diabetes mellitus (prevalence 6.4%). This accounts for an increase in patients with diabetes in industrialized nations by 20% and in developing countries by 69% until the year 2030. Due to the expected rise in diabetic patients, the need for ophthalmic care of patients (i.e., exams and treatments) will also increase and represents a challenge for eye-care providers. Development of optimized screening programs, which respect available resources of the ophthalmic infrastructure, will become even more important. Main reasons for loss of vision in patients with diabetes mellitus are diabetic macular edema and proliferative diabetic retinopathy. Incidence or progression of these potentially blinding complications can be greatly reduced by adequate control of blood glucose and blood pressure levels. Additionally, regular ophthalmic exams are mandatory for detecting ocular complications and initiating treatments such as laser photocoagulation in case of clinical significant diabetic macular edema or early proliferative diabetic retinopathy. In this way, the risk of blindness can considerably be reduced. In advanced stages of diabetic retinopathy, pars-plana vitrectomy is performed to treat vitreous hemorrhage and tractional retinal detachment. In recent years, the advent of intravitreal medication has improved therapeutic options for patients with advanced diabetic macular edema.

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“…The levels of VEGF increase in the vitreous of patients with DR and DME 24,25 and the clinical use of anti-VEGF molecules improves DME. 26,27 One such anti-VEGF agent is sFlt-1, which corresponds to the secreted extracellular domain of VEGF receptor 1 and blocks VEGF action by sequestering VEGF. 28 Vasoinhibins comprise a family of peptides that are generated by the specific proteolytic cleavage of prolactin and they exert potent antiangiogenic and anti-vasopermeability effects.…”

Section: Discussionmentioning

confidence: 99%

Diabetes enhances the efficacy of AAV2 vectors in the retina: therapeutic effect of AAV2 encoding vasoinhibin and soluble VEGF receptor 1

Díaz‐Lezama

Adán‐Castro

et al. 2016

Laboratory Investigation

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Adeno-associated virus (AAV) vector-mediated delivery of inhibitors of blood-retinal barrier breakdown (BRBB) offers promise for the treatment of diabetic macular edema. Here, we demonstrated a reversal of blood-retinal barrier pathology mediated by AAV type 2 (AAV2) vectors encoding vasoinhibin or soluble VEGF receptor 1 (sFlt-1) when administered intravitreally to diabetic rats. Efficacy and safety of the AAV2 vasoinhibin vector were tested by monitoring its effect on diabetes-induced changes in the retinal vascular bed and thickness, and in the electroretinogram (ERG). Also, the transduction of AAV2 vectors and expression of AAV2 receptors and co-receptors were compared between the diabetic and the non-diabetic rat retinas. AAV2 vasoinhibin or AAV2 sFlt-1 vectors were injected intravitreally before or after enhanced BRBB due to diabetes induced by streptozotocin. The BRBB was examined by the Evans blue method, the vascular bed by fluorescein angiography, expression of the AAV2 EGFP reporter vector by confocal microscopy, and the AAV2 genome, expression of transgenes, receptors, and co-receptors by quantitative PCR. AAV2 vasoinhibin and sFlt-1 vectors inhibited the diabetes-mediated increase in BRBB when injected after, but not before, diabetes was induced. The AAV2 vasoinhibin vector decreased retinal microvascular abnormalities and the diabetes-induced reduction of the B-wave of the ERG, but it had no effect in non-diabetic controls. Also, retinal thickness was not altered by diabetes or by the AAV2 vasoinhibin vector. The AAV2 genome, vasoinhibin and sFlt-1 transgenes, and EGFP levels were higher in the retinas from diabetic rats and were associated with an elevated expression of AAV2 receptors (syndecan, glypican, and perlecan) and co-receptors (fibroblast growth factor receptor 1, αvβ5 integrin, and hepatocyte growth factor receptor). We conclude that retinal transduction and efficacy of AAV2 vectors are enhanced in diabetes, possibly due to their elevated cell entry. AAV2 vectors encoding vasoinhibin and sFlt-1 may be desirable gene therapeutics to target diabetic retinopathy and macular edema.

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Anti-VEGF for the Management of Diabetic Macular Edema

Cited by 57 publications

References 43 publications

Anti-Vascular Endothelial Growth Factor Treatment Suppresses Early Brain Injury After Subarachnoid Hemorrhage in Mice

Anti-Vascular Endothelial Growth Factor Treatment Suppresses Early Brain Injury After Subarachnoid Hemorrhage in Mice

Diabetic retinopathy - ocular complications of diabetes mellitus

Diabetes enhances the efficacy of AAV2 vectors in the retina: therapeutic effect of AAV2 encoding vasoinhibin and soluble VEGF receptor 1

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