Targeting Robo4 pathway reduces corneal angiogenesis induced by herpes simplex virus. (VIR1P.967)

The cornea is a complex tissue that must preserve its transparency to maintain optimal vision. Eye infections such as with herpes simplex virus (HSV) can result in a chronic immuno-inflammatory syndrome and pathological neovascularization that impairs vision. Recent reports demonstrate that angiogenic sprouting shows morphological similarities to axon growth. Moreover there are several key molecules that upon binding to receptors regulate the direction of both capillary and axon guidance. In this study we show that Roundabout 4 (ROBO4) receptor plays a significant role reducing angiogenesis. Using ROBO4 -/- mice we demonstrate that these mice are hyper-susceptible to HSV induced corneal angiogenesis compared to wild type mice. Moreover, providing additional soluble ROBO4 protein by subconjunctival administration significantly diminished the extent of corneal angiogenesis in wild type animals. Finally, by administration of soluble ROBO4 protein to ROBO-/- HSV infected mice it was possible to rescue the wild type phenotype. In conclusion, the administration of soluble ROBO4 protein promotes the activation of the ROBO4 pathway. This could represent a valuable therapeutic tool to control corneal angiogenesis related to HSV induced stromal keratitis.