Cytokines in neovascular age-related macular degeneration: fundamentals of targeted combination therapy

Abstract

The neovascular form of age-related macular degeneration (AMD), called wet-AMD or choroidal neovascularisation, begins with damage to the outer retinal cells and retinal pigment epithelium (RPE), which elicits a cascade of inflammatory and angiogenic responses leading to neovascularisation under the macula. Studies showed that oxidative damage, chronic inflammation of the RPE and complement misregulation work at different steps of this disease. After established neovascularisation, several pro- and antiangiogenic agents start to play an important role. Vascular endothelial growth factors (VEGFs) are the most specific and potent regulators of angiogenesis, which are inhibited by intravitreal injections of ranibizumab, bevacizumab, VEGF Trap, pegaptanib sodium and other agents under investigation. Pigment epithelium-derived factor, on the other hand, shows neuroprotective and antiangiogenic activities. Hepatocyte growth factor (HGF) has a mitogenic effect on a wide range of epithelial and endothelial cells, and it is inhibited by an anti-HGF monoclonal antibody. Platelet-derived growth factor is a potent chemoattractant and mitogen for both fibroblasts and retinal RPE cells, which has been inhibited experimentally by VEGF Trap and human anti-platelet-derived growth factor-D monoclonal antibody. Fibroblast growth factor-2 has pleiotropic effects in different cell and organ systems, and it is blocked by anti-FGF antibodies, with a greater benefit regarding antiangiogenesis when combined treatment with anti-VEGF is performed. Tumour necrosis factor alpha is expressed in the retina and the choroid, and its blockade in choroidal neovascularisation includes the use of monoclonals such as infliximab. This paper reviews the most important cytokines involved in the pathogenesis of wet-AMD, with emphasis on potential combined therapies for disease control.

PLGA Microparticles Entrapping Chitosan-Based Nanoparticles for the Ocular Delivery of Ranibizumab

“…Further, VEGF has 8 cysteine residues (32) , therefore, CNAC may introduce additive anti-angiogenic activity via VEGF binding and consequent neutralization. Indeed, NAC has been reported to have antiangiogenic activity and targets multiple pathways involved in angiogenesis including oxidation and inflammation (33,34) . Given NAC and chitosan's anti-angiogenic activity, we hypothesized that CNAC would enhance the anti-angiogenic activity of ranibizumab.…”

Comparative Analysis of Hyaluronan’s Affinity for Antivascular Endothelial Growth Factor Agents

“…VEGF and FGF-2 are representative targeted cytokines in age-related macular degeneration, while EGF is considered irrelevant to age-related macular degeneration [6]. Interestingly, VEGF and FGF-2, the most relevant angiogenic cytokines involved in choroidal neovascularization, showed a relatively low affinity to hyaluronan, which might implicate that the vitreous body excludes angiogenic effects in the cavity.…”

Comparison of Combined Bevacizumab plus Dexamethasone Vs. Ranibizumab Monotherapy as First-Line Therapy in Patients with Treatment Naive Neovascular Age-Related Macular Degeneration in Real-Life Clinical Practice: A Retrospective Case-Series Analysis

“…The combination of substances which act through different mechanisms may improve long-term efficacy, safety and outcomes. It may also lead to a reduction of needed intravitreal injections [20][21][22][23].…”

“…Combined treatment (Corticosteroids plus anti-VEGF), aiming at multiple components of the disease may be effective in controlling the disease progression and restoring the visual acuity in neovascular AMD [20][21][22][23].…”