Anti-vascular endothelial growth factor therapy for diabetic macular edema

Boyer, David S.; Hopkins, J Jill; Sorof, Jonathan M.; Ehrlich, Jason S.

doi:10.1177/2042018813512360

Cited by 157 publications

(134 citation statements)

References 97 publications

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“…1 By producing a sustained expression of antiangiogenic molecules, the AAV vectors eliminate the risks associated with repeated intraocular pharmacotherapy and offer considerable promise for the treatment of DR and DME. Here, we show that diabetes-induced BRB pathology is reversed by the intravitreal delivery of AAV2 vectors encoding the antiangiogenic and anti-vasopermeability factors sFlt-1 and vasoinhibin, and that the AAV2 vasoinhibin vector is a safe procedure for reducing retinal microvessel abnormalities and electrophysiological dysfunction due to diabetes.…”

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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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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“…These medications bind VEGF, thereby decreasing angiogenesis and vascular permeability, causing regression of diabetic neovascularization and reduction in DME respectively [1,5]. Several recent clinical trials suggest that these therapies are more effective for DME than laser therapy [6][7][8][9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Treatment strategies for refractory diabetic macular edema: switching anti-VEGF treatments, adopting corticosteroid-based treatments, and combination therapy

Hussain

Ciulla

2016

Expert Opinion on Biological Therapy

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“…Anti-vascular endothelial growth factor (anti-VEGF) drugs are widely used in the treatment of diabetic macular edema (DME); this is supported by an extensive body of literature, demonstrating substantial improvements in visual and anatomic outcomes (4)(5)(6)(7)(8)(9)(10) . The choroid is a vascularized tissue that plays a vital role in providing metabolic support to the outer retina, including the photoreceptors and prelaminar portion of the optic nerve head (11,12) .…”

Section: Introductionmentioning

confidence: 93%

“…Choroidal thinning, increased thickness of the extracellular matrix, and decreased vessel diameter have been observed on SD-OCT imaging in the eyes of patients with diabetes (16,24,25) . Anti-VEGF treatment has demonstrated utility in improving visual and anatomical outcomes in DME (4)(5)(6)(7)(8)(9)(10) . The effects of anti-VEGF therapy on choroidal thickness in various diseases, including AMD and DM, have been reported in several previous studies (18,19) .…”

Section: Discussionmentioning

confidence: 99%

Effect of intravitreal anti-VEGF on choroidal thickness in patients with diabetic macular edema using spectral domain OCT

Kniggendorf¹,

Novais²,

Kniggendorf³

et al. 2016

Arquivos Brasileiros De Oftalmologia

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Approved by the following research ethics committee: UNIFESP (#1.093.853). ABSTRACTPurpose: To evaluate choroidal thickness (CT) using spectral domain optical coherence tomography (SD-OCT) imaging at baseline and 6 months after intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatment in patients with diabetic macular edema (DME). Methods: A retrospective chart review was performed to identify patients with DME who underwent intravitreal injection of anti-VEGF (bevacizumab or ranibizumab) in a pro re nata (PRN) regimen. Subfoveal choroidal thickness was compared between values obtained at baseline and at 6-month follow-up visits. Results: Thirty-nine eyes (15 females, 24 males) from 39 patients were enrolled (mean age, 62.43 ± 8.7 years; range, 44-79 years). Twenty-three and 16 eyes were treated with ranibizumab and bevacizumab respectively. The mean number of anti-VEGF injections was 2.28 ± 1.27 (range, 1-5). Mean nasal, subfoveal, and temporal choroidal thickness (CT) measurements at baseline were 234.10 ± 8.63 μm, 246.89 ± 8.94 μm, and 238.12 ± 8.20 μm, respectively, and those at 6 months post-treatment were 210.46 ± 8.00 μm, 215.66 ± 8.29 μm, and 212.43 ± 8.14 μm, respectively. Significant differences in CT were observed between baseline and the 6-month follow-up at all measured points (p=0.0327). Conclusions: Over a 6-month period, the use of intravitreal anti-VEGF was associated with significant thinning of the choroid in patients with DME. The clinical significance of a thinner choroid in DME is currently unknown; however, it may contribute to long-term adverse effects on choroidal and retinal function, representing an area requiring future investigation.

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Anti-vascular endothelial growth factor therapy for diabetic macular edema

Cited by 157 publications

References 97 publications

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

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

Treatment strategies for refractory diabetic macular edema: switching anti-VEGF treatments, adopting corticosteroid-based treatments, and combination therapy

Effect of intravitreal anti-VEGF on choroidal thickness in patients with diabetic macular edema using spectral domain OCT

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