Aflibercept (VEGF-TRAP): the next anti-VEGF drug

The inflammatory cytokine, vascular endothelial growth factor (VEGF), plays a central role in human growth and development, and vascular maintenance. VEGF mediated angiogenesis is essential for tumor growth, as well as exudative age-related macular degeneration, proliferative diabetic retinopathy and retinopathy of prematurity, all of which are characterized by abnormal neovascularization. Ischemia and inflammation also lead to VEGF-mediated breakdown of the blood-retinal barrier, which causes vision diminishing macular edema. To combat these effects, anti-VEGF drugs (antibodies, aptamers, and tyrosine kinase inhibitors) have been developed for both systemic and local (intraocular) use. The next drug to receive regulatory approval will probably be aflibercept (VEGF-Trap), a fusion protein with high VEGF affinity attributed to binding sequences from the native receptors VEGFR1 and VEGFR2. Aflibercept monotherapy significantly reduces tumor growth and extends survival in several orthotropic animal models, and has both prevented and reduced the growth of experimental choroidal neovascularization. Ongoing phase III trials are evaluating the effectiveness of aflibercept combined with chemotherapy in patients with advanced carcinomas. The phase III VELOUR trial determined that patients receiving aflibercept with irinotecan/5-FU as second line chemotherapy for metastatic colorectal cancer experienced extended progression free survival and overall survival. Intravitreal aflibercept improved visual acuity in patients with exudative age-related macular degeneration and was non-inferior to standard therapy (ranibizumab). Ongoing phase III trials are investigating the use of aflibercept for retinal vein occlusions and diabetic macular edema. A regulatory approval application for use in exudative macular degeneration has been filed, with a decision expected by late 2011.     

Pegylated nanoceria: A versatile nanomaterial for noninvasive treatment of retinal diseases

Oxidative stress induced reactive oxygen species has been implicated as the primary molecular mechanism in the pathogenesis of debilitating retinal diseases such as diabetic retinopathy, neovascularization and age-related macular degeneration. Nanoceria (cerium oxide nanoparticles) has recently received much attention, because of its superior and regenerative radical scavenging properties. This review focuses on retinal applications of nanoceria and functionalized nanoceria. Studies in animal models showed that nanoceria possess antioxidant, anti-inflammatory, anti-angiogenic, anti-apoptotic properties and preserves retinal morphology and prevents loss of retinal functions. Nanoceria have been tested in animal models of age-related macular degeneration and neovascularization and their efficacy have been shown to persist for a long time, without any collateral effects. To date, several pharmaceutical formulations of nanoceria have been developed for their prospective clinical ophthalmic applications such as chitosan coated nanoceria, nanoceria loaded into hydrogels, nanoceria embedded in wafers and contact lens and organosilane or polyethylene glycol functionalized nanoceria. Based on their nano size range, ocular permeation could be achieved to allow topical administration of nanoceria. PEGylation of nanoceria represents the key strategy to support eye drop formulation with enhanced corneal permeation, without altering chemical physical properties. Based on their excellent antioxidant properties, nano-size, safety and tolerability, PEGylated nanoceria represent a new potential therapeutic for the treatment.     

Antineovascular agents in the treatment of eye diseases

Neovascularization is a common and potentially visually threatening complication of eye diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). An antiangiogenic therapy is aimed at inhibiting the growth of new blood vessels and should prevent onset or progression of neovascularization. Accumulated evidence indicates that growth factors, endothelial cell surface receptors, and extracellular matrix (ECM) proteins are major mediators of neovascularization and appealing targets for pharmacotherapeutical intervention. Vascular endothelial growth factor (VEGF) plays a critical role in the pathogenesis of retinal neovascularization (in linking tissue ischemia to angiogenesis), and is likely to contribute also significantly to choroidal neovascularization (CNV). Several antineovascular agents antagonize the function of VEGF, by blocking its proangiogenic activity. Indeed, VEGF targeting or disruption of VEGF signalling is the most effective strategy known so far in the pharmacological treatment of ocular neovascularization. Other compounds such as pigment epithelium-derived factor (PEDF) either aim at balancing the levels of pro-angiogenic and angiostatic molecules, target inflammation (cyclooxygenase inhibitors, steroids) or comprise modifiers of the ECM such as inhibitors of matrix metalloproteinases (MMPs) and agents that block the action of integrins. Vascular targeting agents (combretastatin) promote removal of newly formed vessels. This review provides an update on recent investigations directed at the pharmacotherapeutical management of ocular neovascular diseases, placing special emphasis on the underlying target molecules and relevant intracellular signalling pathways.     

Aldose reductase / polyol inhibitors for diabetic retinopathy

Diabetic retinopathy is the most common microvascular complication of diabetes and the most severe of diabetic ocular complications. This review describes retinal changes at different stages of diabetic retinopathy and risk factors associated with this devastating disease. Special attention is focused on aldose reductase, the first enzyme of the sorbitol pathway of glucose metabolism. The current knowledge on the enzyme localization in the retina, and the role for increased aldose reductase activity in retinal capillary cell loss and formation of acellular capillaries, capillary basement membrane thickening, increased vascular permeability and disruption of blood-retinal barrier, and increased leukocyte adhesion to endothelial cells associated with early diabetic retinopathy, as well as neovascularization associated with advanced (proliferative) diabetic retinopathy, gained through the experimental studies in animal models of diabetes and galactose feeding, is described in detail. The review also analyzes the potential mechanisms underlying aldose reductase involvement in pathogenesis of diabetic retinopathy, and discusses interactions between aldose reductase and other pathogenetic factors such as formation of advanced glycation end-products, oxidative-nitrosative stress, protein kinase C, mitogen-activated protein kinase, and poly(ADP-ribose) polymerase activations, inflammation, and growth factor imbalances. A detailed analysis of clinical diabetic retinopathy trials of aldose reductase inhibitors is also provided.     

Ocular angiogenesis: translating preclinical indications to successful clinical development

Angiogenesis-related ocular diseases such as age-related macular degeneration (AMD) or diabetic retinopathy have a high socioeconomic impact in western countries and are the leading causes of blindness. Conventional treatment modalities for AMD are of limited success. Inhibition of new vessel formation and targeting of pathological vessels seem to be the best choice in AMD. A variety of animal models mimic the relevant aspects of choroidal neovascularisation (CNV) and allow for therapy screening. Preclinical and clinical studies show that a variety of different strategies are very promising. Stategies include inhibition or blocking of vascular endothelial growth factor, a key player in angiogenesis), blocking specific receptors, application of naturally occurring angiogenesis inhibitors and gene therapy. However, the multistep pathways involved in ocular angiogenesis suggest that a cocktail approach is required for effective long-term treatment and prevention of CNV.     

Small-interfering RNAs (siRNAs) as a promising tool for ocular therapy

RNA interference (RNAi) can be used to inhibit the expression of specific genes in vitro and in vivo, thereby providing an extremely useful tool for investigating gene function. Progress in the understanding of RNAi-based mechanisms has opened up new perspectives in therapeutics for the treatment of several diseases including ocular disorders. The eye is currently considered a good target for RNAi therapy mainly because it is a confined compartment and, therefore, enables local delivery of small-interfering RNAs (siRNAs) by topical instillation or direct injection. However, delivery strategies that protect the siRNAs from degradation and are suitable for long-term treatment would be help to improve the efficacy of RNAi-based therapies for ocular pathologies. siRNAs targeting critical molecules involved in the pathogenesis of glaucoma, retinitis pigmentosa and neovascular eye diseases (age-related macular degeneration, diabetic retinopathy and corneal neovascularization) have been tested in experimental animal models, and clinical trials have been conducted with some of them. This review provides an update on the progress of RNAi in ocular therapeutics, discussing the advantages and drawbacks of RNAi-based therapeutics compared to previous treatments.     

Targeted pharmacotherapy of retinal diseases with ranibizumab

Diseases of retinal and/or choroidal blood vessels are the most prevalent causes of moderate and severe vision loss in developed countries. Vascular endothelial growth factor (VEGF)-A plays a critical role in the pathogenesis of many of these diseases. Ranibizumab is a humanized antigen-binding fragment that binds all isoforms of VEGF-A. Intraocular injections of ranibizumab cause significant visual improvement in approximately 40% of patients with choroidal neovascularization due to age-related macular degeneration (AMD). Pilot trials have indicated that intraocular injections of ranibizumab also provide benefits in patients with macular edema due to diabetic retinopathy or retinal vein occlusions. Based upon several case series, bevacizumab, a full-length humanized monoclonal antibody that binds all isoforms of VEGF-A, improves vision in patients with choroidal neovascularization due to AMD and other diseases. Case series also suggest that bevacizumab can cause regression of retinal neovascularization in patients with proliferative diabetic retinopathy. Taken together, results with ranibizumab and bevacizumab suggest that potent antagonists of VEGF will provide the foundation of treatment for a wide variety of diseases complicated by retinal or choroidal neovascularization, or by excessive vascular leakage leading to macular edema.     

Looking into anti-angiogenic gene therapies for disorders of the eye

Age-related macular degeneration (AMD) and proliferative diabetic retinopathy (DR) are the most common causes of visual impairment in the developed world. Because the key factor in AMD and DR is aberrant neovascularization in the retina (DR) or in the choroid (AMD), strategies to inhibit abnormal neovascularization represent a compelling therapeutic approach. Here we review various anti-angiogenic strategies for the treatment of ocular neovascular diseases with special emphasis on gene transfer as a way of achieving high, sustained concentrations of anti-angiogenic proteins in the back of the eye without concomitant systemic toxicity.     

PtdIns-4,5-P2 as a potential therapeutic target for pathologic angiogenesis

A variety of diseases arise, at least in part, when the events controlling the formation and stability of blood vessels are deregulated. For instance, the growth and survival of solid tumors are tightly linked to their ability to undergo vascularization. Similarly, pathologic angiogenesis of the retina or choroid underscores blinding diseases that afflict a substantial percentage of the world's population. Therefore, it is of great interest to develop antiangiogenic drugs that will relieve the burden of vascular diseases such as cancer, age-related macular degeneration and proliferative diabetic retinopathy. In this article, the authors highlight their recent discovery that PtdIns-4,5-P2)can regulate vessel stability. This finding identifies PtdIns-4,5-P2 as a novel target for angiogenesis therapies.     

Somatostatin analogues as drug therapies for retinopathies

Proliferative retinopathies account for the majority of cases of vision loss throughout the world. Currently accepted therapy for retinopathy consists of retinal ablation by panretinal laser photocoagulation or cryotherapy. This technique is not without deleterious effects to patients, including diminished night vision, reduced peripheral vision and loss of precise vision, decreasing visual acuity by one to two lines in magnitude. One promising area of research into pharmacotherapeutics for retinopathies, especially proliferative diabetic retinopathy, involves the use of synthetic analogues of somatostatin. The rationale for somatostatin as a therapeutic agent for retinal neovascularization is discussed. Somatostatin analogues such as octreotide have shown promise as a safe and effective treatment for severe proliferative diabetic retinopathy by blocking the local and systemic production of growth hormone and insulin-like growth factor type 1 associated with angiogenesis and endothelial cell proliferation. There are also observations suggesting an autocrine and paracrine effect of somatostatin, perhaps directly on retinal cells, which are known to express somatostatin receptors (SSTR). SSTR2 and SSTR3 are the most important receptor subtypes mediating growth hormone secretion and endothelial cell cycle arrest, retinal endothelial cell apoptosis and release of insulin. Thus, analogues that target these receptor subtypes may prove more useful. Long-acting somatostatin analogues are currently being tested for treatment of diabetic retinopathy and are, in fact, the only therapeutic alternative for patients who fail panretinal photocoagulation. Whether such a therapy may also prove effective for other retinal vascular proliferative diseases such as retinopathy of prematurity and age-related macular degeneration remains an open question that deserves attention, given our new understanding of the cellular and molecular mechanisms by which somatostatin may exert its antiangiogenic effects.     

A pharmacokinetic study of a combination of beta adrenoreceptor antagonists - In the isolated perfused ovine eye

The treatment of posterior eye diseases, such as diabetic retinopathy and age-related macular degeneration, is of growing interest as the number of people affected by these conditions continues to rise. This study utilises the methods of cassette dosing and the perfused ovine eye model - to reduce animal usage and therefore animal time - to show that for a series of beta adrenoreceptor antagonists, lipophilicity is a key physicochemical property that governs drug distribution within the eye. Following intravitreal injection, lipophilic beta adrenoreceptor antagonists penetrate to the posterior eye, where they bind to the choroid and reside in the retina at greater concentrations than more hydrophilic beta adrenoreceptor antagonists, which preferentially penetrate to the anterior eye.     

The non-antibiotic properties of tetracyclines: Clinical potential in ophthalmic disease

IntroductionBeyond their decades of long use as broad-spectrum antibiotics, tetracyclines and their derivatives have been shown to exhibit non-antimicrobial properties including their ability to interact with matrix metalloproteinases (MMP), tissue inhibitors of MMPs, growth factors and cytokines. As such, they are capable of affecting inflammation, immunomodulation, cell proliferation, and angiogenesis. Although they have been used to treat a variety of conditions including acne, cutaneous sarcoid, and rheumatoid arthritis, amongst others, their use in treating ophthalmologic disease is in its infancy.Materials and methodsA literature review on the role of non-antimicrobial properties of tetracyclines, semisynthetic tetracyclines, and chemically modified non-antibacterial tetracyclines (CMTs) and their clinical properties was performed. The effects of these compounds in relation to ophthalmic disease are presented.ResultsDue to their non-antimicrobial properties, tetracyclines and their derivatives are capable of influencing a wide variety of ocular diseases in animal models. By affecting expression of MMP-9 and tumor necrosis factor (TNF)-α, these compounds decrease corneal permeability, improve corneal smoothness, and reduce meibomian gland dysfunction; this improves the tear film which in turn restores the optical quality of the tear film and cornea. Sterile corneal ulceration may be inhibited via anticollagenase activity; this has been demonstrated in both animal models and case reports. CMTs suppress cataractogenesis in a diabetic rat model, possibly by affecting MMPs. With respect to retinal disease, tetracyclines can inhibit both microglial-mediated cell death and retinal cell apoptosis as well as prevent retinal capillary damage via caspase inhibition thus preventing retinal neovascularization. Experimental choroidal neovascularization is reduced by inhibition of MMP-2 and MMP-9, elevation of pigment epithelial derived growth factor (PEDF), and reduction of vascular endothelial growth factor (VEGF) expression via Fas ligand.DiscussionDue to their non-antimicrobial properties, tetracyclines and their derivatives are capable of influencing a wide variety of ocular disease in animal models. Research suggests that they are able to reduce inflammation in the eyelid meibomian glands, improve optical clarity of the cornea, retard cataract formation, and limit ocular angiogenesis. They may have a role in treating the leading causes of vision loss: cataract, age-related macular degeneration, and diabetic retinopathy, all of which are anticipated to increase in incidence due to the aging population.ConclusionsTetracyclines, semisynthetic tetracyclines, and CMTs may have a role in the treatment of several important ophthalmologic diseases; however, further research is required, including prospective multicenter clinical trials.     

Neuroprotective effects of lutein in the retina

Although a large variety of pharmaceutical therapies for treating disease have been developed in recent years, there has been little progress in disease prevention. In particular, the protection of neural tissue is essential, because it is hardly regenerated. The use of nutraceuticals for maintaining the health has been supported by several clinical studies, including cross-sectional and interventional studies for age-related macular disease. However, mechanistic evidence for their effects at the molecular level has been very limited. In this review, we focus on lutein, which is a xanthophyll type of carotenoid. Lutein is not synthesized in mammals, and must be obtained from the diet. It is delivered to the retina, and in humans, it is concentrated in the macula. Here, we describe the neuroprotective effects of lutein and their underlying molecular mechanisms in animal models of vision-threatening diseases, such as innate retinal inflammation, diabetic retinopathy, and light-induced retinal degeneration. In lutein-treated mouse ocular disease models, oxidative stress in the retina is reduced, and its downstream pathological signals are inhibited. Furthermore, degradation of the functional proteins, rhodopsin (a visual substance) and synaptophysin (a synaptic vesicle protein also influenced in other neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease), the depletion of brain-derived neurotrophic factor (BDNF), and DNA damage are prevented by lutein, which preserves visual function. We discuss the possibility of using lutein, an antioxidant, as a neuroprotective treatment for humans.     

Pegaptanib sodium for the treatment of age-related macular degeneration

Background: Pegaptanib sodium, the first aptamer therapeutic approved for use and the first antiangiogenic agent used to treat ocular neovascular disease, acts by inhibiting the 165 isoform of vascular endothelial growth factor believed primarily responsible for pathologic ocular neovascularization and vascular permeability. Objective: To briefly present the pharmacology, clinical efficacy and safety, and role of pegaptanib in treating ocular neovascular diseases. Methods: A systematic literature review and synopsis. Results/conclusion: After more than 10 years in development, clinical trials have shown pegaptanib efficacy in treating choroidal neovascularization of age-related macular degeneration. Its excellent ocular and systemic safety profiles have been confirmed in up to 3 years of experience. Early phase, well-controlled studies also suggest therapeutic benefit in diabetic retinopathy and retinal vein occlusion.     

Applications of Azo-Based Probes for Imaging Retinal Hypoxia

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The role of Raf-1 kinase in diabetic retinopathy

Many metabolic pathways, including oxidative stress, PKC and the polyol pathway have been implicated in the development of diabetic retinopathy, but despite extensive research, its pathogenesis remains unclear. Recent studies have shown the role of a low-molecular-weight GTP-binding protein (H-Ras)-mediated signaling pathway in its development. The key effector protein of Ras function is a threonine/serine kinase-Raf kinase, and this kinase is involved in a variety of functions, including the cell cycle and proliferation and apoptosis. In animal models of diabetic retinopathy, Raf kinase is activated in the retina and its microvasculature. Activated Raf kinase is associated with increased apoptosis of retinal capillary cells, the process that precedes the development of retinal histopathology, and inhibition of Raf kinase ameliorates apoptosis. In clinical settings, inhibitors of Raf kinase have shown promising results in cancer treatment, and Raf kinase antisense oligonucleotides, iCo 007, is now in Phase II trial for macular edema, a chronic ocular disease associated with retinal neovascularization. Further elucidating the role of Raf kinase in diabetic retinopathy, and advances in the generation of antisense therapy for chronic diseases, should help test Raf antisense oligonucleotides for the treatment of this blinding complication that diabetic patients fear the most.     

The role of Raf-1 kinase in diabetic retinopathy

Many metabolic pathways, including oxidative stress, PKC and the polyol pathway have been implicated in the development of diabetic retinopathy, but despite extensive research, its pathogenesis remains unclear. Recent studies have shown the role of a low-molecular-weight GTP-binding protein (H-Ras)-mediated signaling pathway in its development. The key effector protein of Ras function is a threonine/serine kinase-Raf kinase, and this kinase is involved in a variety of functions, including the cell cycle and proliferation and apoptosis. In animal models of diabetic retinopathy, Raf kinase is activated in the retina and its microvasculature. Activated Raf kinase is associated with increased apoptosis of retinal capillary cells, the process that precedes the development of retinal histopathology, and inhibition of Raf kinase ameliorates apoptosis. In clinical settings, inhibitors of Raf kinase have shown promising results in cancer treatment, and Raf kinase antisense oligonucleotides, iCo 007, is now in Phase II trial for macular edema, a chronic ocular disease associated with retinal neovascularization. Further elucidating the role of Raf kinase in diabetic retinopathy, and advances in the generation of antisense therapy for chronic diseases, should help test Raf antisense oligonucleotides for the treatment of this blinding complication that diabetic patients fear the most.     

Current and future therapies for age-related macular degeneration

Background: Age-related macular degeneration is the leading cause of blindness, with an increasing incidence as the elderly population expands. Objective: In this article we review current therapeutic strategies and discuss possible future targets. Methods: A review of the literature and ongoing clinical trials was undertaken. Results: Currently, established therapies for neovascular AMD-like photodynamic therapy and anti-VEGF therapies allow stabilization or even improvement of vision. Potential future drugs under development for advanced AMD or its prevention target the signal transduction cascade of different angiogenic molecules. These drugs intervene at different levels of the involved processes including the RNA production and specific protein expression as well as inflammatory, apoptotic, or metabolic processes. Conclusion: Combining different strategies targeting angiogenesis, inflammation and apoptosis, or interfering early in – or even prior to – the formation of choroidal neovascularization, may improve the future management of age-related macular degeneration.