Anti‐VEGF Aptamer (Pegaptanib) Therapy for Ocular Vascular Diseases

Abstract

Vascular endothelial growth factor (VEGF) is a central regulator of both physiological and pathological angiogenesis. Pegaptanib, a 28-nucleotide RNA aptamer specific for the VEGF(165) isoform, binds to it in the extracellular space, leaving other isoforms unaffected, and inhibits such key VEGF actions as promotion of endothelial cell proliferation and survival, and vascular permeability. Pegaptanib already has been examined as a treatment for two diseases associated with ocular neovascularization, age-related macular degeneration (AMD) and diabetic macular edema (DME). Preclinical studies have shown that VEGF(165) alone mediates pathological ocular neovascularization and that its inactivation by pegaptanib inhibits the choroidal neovascularization observed in patients with neovascular AMD. In contrast, physiological vascularization, which is supported by the VEGF(121) isoform, is unaffected by this inactivation of VEGF(165). In addition, animal model studies have shown that intravitreous injection of pegaptanib can inhibit the breakdown of the blood-retinal barrier characteristic of diabetes and even can reverse this damage to some degree. These preclinical findings formed the basis for randomized controlled trials examining the efficacy of pegaptanib as a therapy for AMD and DME. The VEGF Inhibition Study in Ocular Neovascularization (VISION) trial comprising two replicate, pivotal phase 3 studies, demonstrated that intravitreous injection of pegaptanib resulted in significant clinical benefit, compared with sham injection, for all prespecified clinical end points, irrespective of patient demographics or angiographic subtype, and led to pegaptanib's approval as a treatment for AMD. A phase 2 trial has provided support for the efficacy of intravitreous pegaptanib in the treatment of DME.

Blood–retinal barrier disruption and ultrastructural changes in the hypoxic retina in adult rats: the beneficial effect of melatonin administration

“…VEGF may promote vascular permeability 80, 81 via synthesis or release of NO 23. Currently there is interest in the use of anti‐VEGF therapy in the treatment of the macular oedema accompanying diabetic retinopathy and other retinal vasculopathies 82, 83, and it is therefore noteworthy that VEGF production can be suppressed by melatonin administration, as shown in this study.…”

Blood–retinal barrier disruption and ultrastructural changes in the hypoxic retina in adult rats: the beneficial effect of melatonin administration

“…VEGF may promote vascular permeability 80, 81 via synthesis or release of NO 23. Currently there is interest in the use of anti‐VEGF therapy in the treatment of the macular oedema accompanying diabetic retinopathy and other retinal vasculopathies 82, 83, and it is therefore noteworthy that VEGF production can be suppressed by melatonin administration, as shown in this study.…”

Retinal changes in an experimental model of early type 2 diabetes in rats characterized by non-fasting hyperglycemia

“…Although the pathogenesis of DR is still far from being fully understood, VEGF is recognized as a major contributor to its development, and is implicated as the initiator and mediator of nonproliferative and proliferative DR (Aiello and Wong, 2000;Lutty et al, 1996). In fact, clinical trials using anti-VEGF therapies are showing promising results against advanced stages of DR (Arevalo et al, 2007;Ng and Adamis, 2006). Our results indicate that only the combined treatment induced a significant increase in retinal VEGF levels.…”

Programmable Loading of a Multivalent LRPPRC Aptamer onto a Rectangular DNA Tile Inhibits the Proliferation of Lung Adenocarcinoma Cells

“…The novelty of the article to put forward a new concept is that aptamers can play a role as not only a traditional molecular recognition tool but also directly as a treatment. Reassuringly, several aptamerbased drugs were authorized by the FDA such as pegaptanib sodium (Macugen; Eyetech Pharmaceuticals/Pfizer), 39 avacincaptad pegol intravitreal solution (Izervay; Iveric Bio), 40 and Apc001 (Aptacure Therapeutics Ltd.). 41 Fortunately, aptamers are also being studied and developed as valuable chemical tools with the potential for cancer intervention and treatment.…”

Blood–retinal barrier disruption and ultrastructural changes in the hypoxic retina in adult rats: the beneficial effect of melatonin administration

“…VEGF may promote vascular permeability 80, 81 via synthesis or release of NO 23. Currently there is interest in the use of anti‐VEGF therapy in the treatment of the macular oedema accompanying diabetic retinopathy and other retinal vasculopathies 82, 83, and it is therefore noteworthy that VEGF production can be suppressed by melatonin administration, as shown in this study.…”

Retinal changes in an experimental model of early type 2 diabetes in rats characterized by non-fasting hyperglycemia

“…Although the pathogenesis of DR is still far from being fully understood, VEGF is recognized as a major contributor to its development, and is implicated as the initiator and mediator of nonproliferative and proliferative DR (Aiello and Wong, 2000;Lutty et al, 1996). In fact, clinical trials using anti-VEGF therapies are showing promising results against advanced stages of DR (Arevalo et al, 2007;Ng and Adamis, 2006). Our results indicate that only the combined treatment induced a significant increase in retinal VEGF levels.…”

Programmable Loading of a Multivalent LRPPRC Aptamer onto a Rectangular DNA Tile Inhibits the Proliferation of Lung Adenocarcinoma Cells

“…The novelty of the article to put forward a new concept is that aptamers can play a role as not only a traditional molecular recognition tool but also directly as a treatment. Reassuringly, several aptamerbased drugs were authorized by the FDA such as pegaptanib sodium (Macugen; Eyetech Pharmaceuticals/Pfizer), 39 avacincaptad pegol intravitreal solution (Izervay; Iveric Bio), 40 and Apc001 (Aptacure Therapeutics Ltd.). 41 Fortunately, aptamers are also being studied and developed as valuable chemical tools with the potential for cancer intervention and treatment.…”

Blood–retinal barrier disruption and ultrastructural changes in the hypoxic retina in adult rats: the beneficial effect of melatonin administration

“…VEGF may promote vascular permeability 80, 81 via synthesis or release of NO 23. Currently there is interest in the use of anti‐VEGF therapy in the treatment of the macular oedema accompanying diabetic retinopathy and other retinal vasculopathies 82, 83, and it is therefore noteworthy that VEGF production can be suppressed by melatonin administration, as shown in this study.…”

Retinal changes in an experimental model of early type 2 diabetes in rats characterized by non-fasting hyperglycemia

“…Although the pathogenesis of DR is still far from being fully understood, VEGF is recognized as a major contributor to its development, and is implicated as the initiator and mediator of nonproliferative and proliferative DR (Aiello and Wong, 2000;Lutty et al, 1996). In fact, clinical trials using anti-VEGF therapies are showing promising results against advanced stages of DR (Arevalo et al, 2007;Ng and Adamis, 2006). Our results indicate that only the combined treatment induced a significant increase in retinal VEGF levels.…”

Programmable Loading of a Multivalent LRPPRC Aptamer onto a Rectangular DNA Tile Inhibits the Proliferation of Lung Adenocarcinoma Cells

“…The novelty of the article to put forward a new concept is that aptamers can play a role as not only a traditional molecular recognition tool but also directly as a treatment. Reassuringly, several aptamerbased drugs were authorized by the FDA such as pegaptanib sodium (Macugen; Eyetech Pharmaceuticals/Pfizer), 39 avacincaptad pegol intravitreal solution (Izervay; Iveric Bio), 40 and Apc001 (Aptacure Therapeutics Ltd.). 41 Fortunately, aptamers are also being studied and developed as valuable chemical tools with the potential for cancer intervention and treatment.…”