Restoring Light Sensitivity in Blind Retinae using Third Generation Photopharmacology

Abstract

More than 300 million people worldwide are suffering from blindness or impaired vision. Although the photoreceptor cells often undergo complete degeneration, the remains of the retinal circuitry are often not affected. In order to restore light sensitivity to blind retinae, optochemical tools targeting receptors natively expressed in retinal cells provide a new photopharmacological strategy without the need of any genetic manipulation. Photochromic ligands (PCL) are chemically modified in such a way that they enable optical control of neuronal activity by acting as selective photoswitchable receptor ligands or blockers of voltage-gated ion channels (VGIC). It has previously been shown that photoswitchable potassium channel blockers, e.g. AAQ, or DENAQ (Polosukhina et al. 2012 and Tochitsky et al. 2014, respectively), are able to restore light sensitivity to a retina from genetically blind mice. However, the aforementioned molecules harbor some difficulties in the application to the retina. We now developed Red-DAD, a third-generation PCL targeting VGICs. In multi-electrode array and whole-cell patch-clamp experiments we could demonstrate that Red-DAD is able to trigger retinal ganglion cell (RGC) spiking in a light-dependent fashion in blind mice. This molecule exhibits several features making it superior to previous PCLs for the application in vision restoration. The compound is not permanently charged and also red-shifted, i.e. one can switch with blue or white light. Additionally, pharmacological approaches reveal that Red-DAD targets bipolar cells (BPs) rather than retinal RGCs, thereby utilizing the intrinsic processing circuits of the retina. Taken together, Red-DAD is a very promising next-generation molecule for restoring light sensitivity in blind retinae.