Russell N Van Gelder, MD

Synopsis: Outer retinal degenerative diseases including age related macular degeneration and retinitis pigmentosa are among the leading causes of blindness world-wide. Blindness results from loss of photoreceptive cells. However, the inner retina is left largely intact. Several strate- gies have been explored for restoring vision to these eyes, including opto-electronics, stem cell replacement, and photopigment gene therapy. Photopharmacology is a newer approach utilizing photoswitch organic compounds, in which a photoisomerizable moiety such as azobenzene is covalently coupled to a pharmacologic agent. In some cases, this will confer light-activation to these agents. When coupled to blockers of voltage-gated potassium channels, such agents have the ability to confer light-dependent action potential generation to neurons. Our laboratory has studied a number of these photoswitch compounds for restoration of vision in animal models of outer retinal degeneration. First generation compounds such as AAQ demonstrated light- dependent retinal ganglion cell firing and restoration of behavioral light responses in blind ani- mals. Second generation compounds including DENAQ and BENAQ featured broader spectral sensitivity, better kinetics, and long durations of action. Finally, third generation compounds such as DAD demonstrate ‘upstream’ retinal specificity, high solubility, and very rapid kinetics. To understand the effect of pharmacologically reprogramming the retina, we have engineered an in vitro method for assessing visual function from explanted retina. In this system, high resolu- tion movie images are projected onto the retina and ganglion cell responses are recorded by multi-electrode array. Using a machine-learning paradigm, a computer program attempts to dis- criminate and predict images, permitting determination of outcomes such as visual acuity and contrast sensitivity. Using this technique, we demonstrate that pharmacologic photoswitches are capable of restoring high resolution vision to blind retinas. The implications of these findings for clinical translastion will be discussed.