significantly increased in the ganglion and inner nuclear retinal cell layers compared with control rats [25]. Laser-induced RVO in rabbits [26] and monkeys [27] also led to increased VEGF-A mRNA expression, and VEGF-A protein expression has been localized to ischemic regions of the retinal layers affected by laser treatment [26]. Furthermore, VEGF-A inhibition prevented retinal neovascularization in an ischemia-induced mouse model [28] and iris neovascularization in a monkey model [29]. VEGF-A inhibition also prevented laser-induced CNV in monkeys and shortened the duration of CNV [30].

In clinical studies, increased levels of VEGF-A expression were found in the RPE [31], subfoveal fibroblasts [32], and surgically excised CNV [33] from eyes of neovascular AMD patients. VEGF-A is also over-expressed in the aqueous and vitreous fluid of patients with subretinal neovascularization, diabetic retinopathy, retinal vein occlusions, iris neovascularization, retinal detachment, and retinopathy of prematurity (ROP) [34–37] and in all retinal nuclear layers of eyes with ischemic central retinal vein occlusions [38]. The consistent association of pathologic ocular neovascularization with increased VEGF-A expression provided a strong rationale for exploring the therapeutic potential of anti-VEGF drugs in neovascular AMD.

Genetic case-controlled studies have shown that the VEGF gene may influence an individual’s tendency to develop AMD [39]. Analyses of single nucleotide polymorphisms (SNPs) in the VEGF-A promoter and gene have associated specific VEGF-A haplotypes with neovascular AMD [40]. In particular, the VEGF SNP 936C/T [when present with the complement factor H (CFH) Y402H] has been associated with an increased risk of developing wet AMD [41].

Pearl

VEGF-A is implicated as the major angiogenic growth factor in different exudative ocular diseases, including neovascular AMD. Moreover, VEGF-A is the most potent known inducer of vascular permeability, approximately 50,000 times more potent than histamine [9].

Antiangiogenic Drugs

Drugs that inhibit VEGF-A include pegaptanib sodium (MACUGEN; Eyetech, Inc.) and ranibizumab (LUCENTIS; Genentech/Roche), which are approved by the Food and Drug Administration (FDA) for the treatment of choroidal neovascularization (CNV) secondary to AMD. Of the two agents, ranibizumab offers substantial clinical benefit in the treatment of neovascular AMD. A third anti-VEGF agent, bevacizumab (AVASTIN; Genentech/Roche), is used off label for neovascular AMD and other exudative ocular diseases. These anti-VEGF agents, as well as others in clinical development, have shown great potential to treat eye diseases characterized by exudation and neovascularization.

Pegaptanib

Drug Overview

The first and only FDA-approved aptamer in ophthalmology is pegaptanib sodium. Approved in December 2004, pegaptanib is indicated for the treatment of neovascular AMD. By definition, aptamers are oligonucleotides or peptide molecules that bind a specific target molecule, acting as chemical antibodies [42]. The commercially available pegaptanib sodium for injection is a sterile, clear, preservative-free aqueous solution supplied in a single-dose, prefilled syringe containing 0.3 mg of active drug.

Pegaptanib is a selective anti-VEGF agent that acts in the extracellular space inhibiting the isoforms of VEGF that are at least 165 amino acids in length while not binding VEGF121 and the smaller proteolytic breakdown products that are biologically active [43]. The selectivity of pegaptanib derives from its interaction with cysteine-137, an amino acid that is contained within the 55 amino-acid heparin-binding domain of VEGF [43, 44], which is not present in the smaller isoforms and breakdown products [44–46]. The rationale for this selectivity is that the drug, at least in theory, will block only the VEGF165 isoform and larger isoforms, which were postulated to be the main isoforms involved