Targeting VEGF in eye neovascularization: What's new?: A comprehensive review on current therapies and oligonucleotide-based interventions under development

Roughly ten years ago the FDA approved most of the presently used anti-VEGF drugs for the treatment
of neovascular AMD and other eye pathologies characterized by ocular neoangiogenesis. However, the
recent findings on the physiologic activities of VEGF isoforms impose to reconsider the inhibitory effects
of pan-VEGF antagonists and the concept that to face pathological alterations at ocular level is possible
only through the full block of all VEGF isoforms. In fact, although pan-VEGF agents rapidly and effectively
contrast ocular neovascularization, vascular leakage, and other pathological changes, in the long-term
the inhibition of all VEGF isoforms likely may result in the loss of the physiologic effects exerted by
VEGF121 and the anti-angiogenic VEGF165b. Notably, selective inhibitors of VEGF165a, such as pegaptanib,
spare these targets. Moreover, preclinical and clinical evidence suggests that also systemic side effects,
secondary to intraocular treatment with non-selective anti-VEGF drugs, may be reinterpreted in light of
these recent findings, which may be useful to clinicians for the choice of the most appropriate anti-VEGF
agent.
Another aspect that should be considered is the involvement of VEGF-independent pathways in ocular
neovascularization, therefore a combined therapy can represent a more effective pharmacological
approach that might help also to counteract tachyphylaxis, an important issue in anti-VEGF treatment.
This complex picture and the recent findings on current anti-VEGF drugs should be therefore taken into
account to guide the development of novel agents targeting VEGF and/or other key factors involved in the
pathogenesis of neovascular ocular diseases along the signaling pathways stimulated by the various isoforms.
Accordingly, this review also reports on novel pharmacological molecules targeting VEGF at ocular
level and currently under development, with a special attention to oligonucleotide-based interventions.