Correspondence

Bevacizumab vs Ranibizumab for Age-Related Macular Degeneration: Early Results of a Prospective Double-Masked, Randomized Clinical Trial

We investigated the anti-angiogenic properties of GNX-686, a newly identified maleimide-based small molecule. In vitro studies on HUVEC showed that GNX-686 inhibited cell growth with an ED₅₀ of 20–25 μM, while human HeLa tumor cells and non-transformed embryonic mouse fibroblasts were less sensitive for the drug. More importantly, at 4 μM, a concentration that was non-toxic to any cell in culture, GNX-686 showed a significant inhibitory effect on tube formation by HUVEC, indicating a profound anti-angiogenic activity. Angiogenesis inhibition was subsequenly tested in the chorioallantoic membrane (CAM) of the chicken embryo. A significant angiostatic activity was observed in the CAM model, and results were compared with the effect of bevacizumab, a well known and clinically used VEGF inhibitor. Under our experimental conditions, GNX-686 was found to be as effective as bevacizumab, significantly changing the morphology of the vascular network, as illustrated and quantified by the relative number of branching points and the relative mean mesh size of the vascular network. In another in vivo model of neovascularization, the mouse retinopathy of prematurity (ROP), the vascular network of GNX-686-treated mice was significantly altered, reducing the density of the retinal microvasculature, as compared to the control retinas. Immunohistochemical processing of the GNX-686 treated (4 μM) eyes showed over 50% reduction of the number of cell nuclei associated with neovasculature, as compared to the control-treated eye. Taken together these results demonstrate that GNX-686 is a promising anti-angiogenic compound that could be developed for the treatment of diseases characterized by aberrant angiogenesis such as ocular pathologies and cancer.

Inherited retinal degeneration results from many different mutations in either photoreceptor-specific or nonphotoreceptor-specific genes. However, nearly all mutations lead to a common blinding phenotype that initiates with rod cell death, followed by loss of cones. In most retinal degenerations, other retinal neuron cell types survive for long periods after blindness from photoreceptor loss. One strategy to restore light responsiveness to a retina rendered blind by photoreceptor degeneration is to express light-regulated ion channels or transporters in surviving retinal neurons. Recent experiments in rodents have restored light-sensitivity by expressing melanopsin or microbial opsins either broadly throughout the retina or selectively in the inner segments of surviving cones or in bipolar cells. Here, we present an approach whereby a genetically and chemically engineered light-gated ionotropic glutamate receptor (LiGluR) is expressed selectively in retinal ganglion cells (RGCs), the longest-surviving cells in retinal blinding diseases. When expressed in the RGCs of a well-established model of retinal degeneration, the rd1 mouse, LiGluR restores light sensitivity to the RGCs, reinstates light responsiveness to the primary visual cortex, and restores both the pupillary reflex and a natural light-avoidance behavior.