Endostatin is a 20-kd fragment of the C-terminus of collagen XVIII inhibiting VEGF signaling by direct binding to the receptor KDR/Flk-1. This molecule effectively inhibits the migration of endothelial cells and induces endothelial cell apoptosis and cell cycle arrest. In a laser-induced CNV model of mice, reduced rates of CNV occurred after intravenous application of adenoviral vectors expressing endostatin [18].

14.4New Methods of Drug Delivery

New methods of drug delivery are being tested experimentally and clinically. The aim is to reduce the frequency of application, to increase efÞcacy, decrease side effects and increase safety. A continuous release may be achieved by viral vectors encoding speciÞc factors as described above or by biodegradable implants. An elegant solution, however, would be the Òmagic bulletÓ that Þnds its way to the target. Cationic liposomes (targeted delivery, e.g., Endo TAG-1) targeting growing vessels reßect this kind of strategy [19]. Liposomes loaded with antiangiogenic drugs could thus Þnd their way through the systemic circulation.

14.5Combined Strategies

Since distinct groups of drugs will target VEGF at different levels of the signaling cascade, a combined approach should affect both the source as well as the

Summary for the Clinician

› In recent years tremendous improvement in the treatment of neovascular ocular pathologies have been achieved. However, this is only a small step to what is expected in the future. Multiple new drugs for clinical application will emerge in the next years. The VEGF signaling cascade will be blocked at different levels by distinct classes of drugs (e.g., siRNA, tyrosine kinase inhibitors) using different strategies (e.g., viral vectors, implants). The inhibition of the signaling cascade will target central steps that regulate several complex processes. With the Þrst ophthalmic drug to treat neovascular AMD a most selective approach was chosen. Pegaptanib-sodium (Macugen¨) targets distinct VEGF-A isoforms. Ranibizumab (Lucentis¨) targets all VEGF-A isoforms, but is still more selective than drugs targeting not only VEGF-A but also the other members of the VEGF family. Inhibition of pathological processes will lead to greater efÞcacy. Inhibition of unrelated and physiologic processes, however, will mean an elevated risk proÞle (Fig. 14.5). Success in clinical practice will ultimately depend not only on the efÞcacy, but also on the safety proÞle and the methods and frequencies of required drug delivery.

effectors. It makes sense to block released VEGF (e.g., ranibizumab) to have an immediate effect in combination with a gene silencing strategy (e.g., siRNA) for a prolonged effect.

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