Topical Use of Kinase Inhibitors There is mounting evidence that the response to VEGF inhibitors in patients with retinal neovascularization differs from that in patients with retinal edema. Proliferative diabetic retinopathy and neovascular glaucoma are exquisitely sensitive to treatment with VEGF inhibitors. Resolution of abnormal vessels often begins 1 day after treatment, and complete regression is commonly observed. In contrast, early studies indicate that although some patients with retinal edema have a response to treatment, the response is often partial and higher doses may be required, implying that pathways other than that of VEGF are involved. Thus, the response of a patient with retinal edema to a VEGF-specific inhibitor may reflect the extent to which the VEGF pathway is involved - a contribution that may vary over time or among patients.

Recent work has implicated VEGF-independent mechanisms in certain retinal diseases. For example, erythropoietin has been implicated in diabetic neovascular disease and the carbonic anhydrase-kallikrein system in diabetic retinal edema. The inhibition of multiple targets simultaneously tends to result in a robust therapeutic effect, suggesting that targeting of more than one pathway supporting angiogenesis may increase the clinical benefit in the eye. Since the relative contributions of different pathways may vary in different patients (and possibly over time in the same patient), the optimal treatment strategy may involve multidrug therapies that are initiated serially, similar to the approach used to treat glaucoma.

The study by Scheppke et al. underscores the importance of understanding the mechanisms of VEGF action. The authors have established a role for Src and Yes kinases in VEGF-mediated retinal vascular permeability, since Src and Yes knockout mice were markedly resistant to VEGF-induced retinal vascular permeability and much less susceptible to retinal edema after laser-induced vein occlusion than were control mice (View Figure). The authors also observed that systemic or topical application of a VEGF receptor 2-Src kinase inhibitor abrogated vascular leakage induced by the intraocular injection of VEGF. Doukas et al. applied a topical, multitargeted kinase inhibitor of VEGF, platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) pathways. As in the study by Scheppke et al., Doukas et al. observed reduced vascular leakage associated with topical use of the agent. They also observed partial protection against laser-induced retinal edema and choroidal neovascularization, perhaps because multiple pathways were targeted.

The ability to provide effective topical therapies for intraocular neovascularization and retinal edema could revolutionize the current care of many diseases that lead to these conditions. The benefits would include ease of therapy, a reduced risk of complication, and ease of combining multiple therapies. The targeting of multiple pertinent pathways with a single molecule has a potential for efficacy that is greater than that of a compound directed at a single molecule.

However, this approach also has a potential risk of increased side effects. Indeed, Doukas et al. found substantial toxic effects when their compound was administered systemically but not when it was administered topically (although the animals received the drug for only 28 days). Topical delivery in these instances has the added benefit of providing less systemic exposure and thus potentially fewer side effects. The studies by Scheppke and Doukas provide evidence that multitargeted and topical therapy could become a reality for many of the most severe sight-threatening conditions of our time.

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N Engl J Med 359;9:967-969