12.5Potential Therapeutics

chelator for treatment of retinal degenerations should be absorbed in sufficient quantity through the GI tract, and transit the BBB and the blood–retinal barrier efficiently. Chelators must be uncharged, lipid soluble, and of small molecular size to facilitate passage through the BBB and blood–retinal barrier [80, 81]. In addition, the ideal chelator might selectively bind iron and not other biologically important divalent metals such as Zn2+ [82].

The clinically available iron chelators are deferoxamine, deferiprone, and deferasirox. Another potentially therapeutic iron chelator is salicylaldehyde isonicotinoyl hydrazone (SIH). The advantages and disadvantages of each of these chelators are described in Table 12.1. Previously, in vitro experiments demonstrated iron in the RPE and Bruch’s membrane is chelatable with deferoxamine. However, deferoxamine is an inefficient and cumbersome iron chelator requiring subcutaneous or intravenous administration. In addition, deferoxamine has serious systemic side effects and can be toxic to the retina. In contrast, deferiprone can be administered orally and systemic side effects can be prevented by careful monitoring. Oral deferiprone was found to be effective in decreasing retinal iron levels and oxidative stress in mice with age-dependent iron accumulation from combined ceruloplasmin and hephaestin deficiency [45]. Unlike deferoxamine, deferiprone was not found to be toxic to the mouse retina. Recently, the iron chelator salicylaldehyde isonicotinoyl hydrazone was also found to decrease levels of reactive oxygen species and protect against RPE cell death in human RPE cell lines exposed to oxidative stress induced by hydrogen

peroxide [83, 84]. In the experiments performed by Lukinova et al., the RPE cells treated with SIH were also resistant to oxidative stress induced by staurosporine, anti-Fas, and exposure to A2E plus blue light [83]. This has promising implications for the treatment of retinal diseases.

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Chapter 13

Mechanisms of Pathological VEGF Production in the Retina and Modification with VEGF-Antagonists

Alexa Klettner and Johann Roider

Abstract The production of Vascular Endothelial Growth Factor (VEGF) in the retina is important to maintain the vasculature in the choroid and has protective function on the retinal pigment epithelium and the neuroretina. The expression of VEGF is mainly regulated by the presence of oxygen, a decline of oxygen partial pressure resulting in an activation of Hypoxia Inducible Factor 1a (HIF-1a), inducing the expression of VEGF. A plethora of other factors are also involved, including oxidative stress, hyperglycemia, or inflammatory cytokines. An increase in VEGF secretion can lead to pathological vascularization in the retina, as seen in exudative age-related macular degeneration (AMD), retinopathy of prematurity or in diabetic retinopathy. In order to treat pathological neovascularizations in the retina, VEGF antagonists have been introduced into the clinic and approved for the treatment of wet AMD. Recently, VEGF-antagonists have also been approved for the treatment of diabetic macular edema. New products are developed, e.g., VEGF-Trap Eye or VEGF receptor antagonists which are currently being tested in clinical trials. VEGF siRNAs are also being tested. VEGF-antagonists neutralize secreted VEGF by inhibiting the binding of VEGF to its receptor. Additional pathways are possible, e.g., interfering with autoregulatory pathways. VEGF-receptor antagonists inhibit the signal transduction induced by VEGF binding. Anti-VEGF-siRNA intracellularly inhibits the expression of VEGF and might also exert an RNA specific, VEGF-independent effect.

A. Klettner (*) • J. Roider

Department of Ophthalmology, University of Kiel, University Medical Center, Arnold Heller-Str. 3, 24105, Kiel, Germany

e-mail: aklettner@auge.uni-kiel.de

in Applied Basic Research and Clinical Practice, DOI 10.1007/978-1-61779-606-7_13, © Springer Science+Business Media, LLC 2012